Introduction
Over recent years, scientometric criteria have been increasingly used, in order to evaluate the effectiveness of scientific institutions, enabling us to present the fact-based characteristics of the institutions, and their impact on development of world science, if used in correct manner. To some degree, such an evaluation is important for monitoring the quality of both individual and team work, as well as efficient use of resources allocated for research.
Similarly, scientometric methods are increasingly used to answer the questions of preferential financial support for certain areas of research, and discern the priority products and technologies, as well as to resolve problems with research staff recruitment [1].
Current science management is largely focused on accountability. Therefore, quantitative evaluation of research activities sufficiently adds to qualitative assessments of research (i.e., peer reviewing of projects and articles). Hence, bibliometric evaluation with its measurements of research output and citation impact seems to be a quite important quantitative approach [2].
The Strategy for the Development of Medical Science is one of the key documents that determines the development trends of medical science in Russia. According to it, the main goal is to create high-tech innovative products ensuring the improvement of public health based on the transfer of innovative technologies to practical healthcare. To achieve this goal, it was necessary to arrange a network of leading centers for the prioritized areas [3].
To arrange such a system and provide methodological support of research projects for the leading institutions, a Decree №125 was issued by the Ministry of Healthcare of Russian Federation (March 21, 2017) entitled: "On arranging measures for establishment of network of National Research and Practical Medical Centers". Its implementation started by creating a network of National Medical Research Centers (NMRCs) on the basis of specialized research institutions subordinated to the Ministry of Healthcare of the Russian Federation that are leaders in the top areas of medical science. At the same time, the educational priorities in medical research were assigned to specialized research centers, but not to appropriate educational institutions (e.g., medical universities), being in controbersy with global trends in the basic science development. Thus, a network of 22 NMRCs was arranged [4, 5], involving the four research centers that conduct research in the field of oncology and hematology.
Hence, along with the National Research Center for Hematology, this study also included other major Russian centers active in clinical and experimental hematology, i.e., N. N. Blokhin National Medical Research Center of Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, N. N. Petrov National Medical Research Center of Oncology, and Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation which is a part the St. Petersburg I. Pavlov Medical University.
Among the scientific indices of the institutions that are widely used in the reports, there is a clear bias towards quantitative characteristics, such as total number of articles, the number of articles indexed in the Web of Science (WoS) and Scopus international databases, total impact factor of the journals in which the articles were published, etc. At the same time, the indices characterizing quality of published works (citation scores) and, indirectly, the reputation of the institution (Hirsch index of the organization) are practically not used. Nevertheless, the Hirsch index is most difficult to manipulate by researchers and management staff at the institutions, and, therefore, it can be more objective when comparing scientific reputation characteristics [6].
The aim of our work was to perform a scientometric evaluation of these organizations, relying primarily on their quality indicators and impact of the research results. Moreover, our task was to determine the position of R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation (R. Gorbacheva Institute), a large university research center which is not an autonomous legal entity, and which was not put on the list of NMRCs with special support for research activities.
Materials and methods
Our study included five major institutions active in Hematology/Oncology over last 3 years (2016-2018), i.e., N. N. Petrov National Medical Research Center of Oncology (St. Petersburg), National Medical Research Center of Hematology (Moscow), N. Blokhin National Medical Research Center of Oncology (Moscow), Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow), and Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at the I. Pavlov First St. Petersburg State Medical Unibersity.
For the convenience of this study, we concentrated precisely on the qualitative and reputation indices of the work of organizations for the period of 2016 to 2018. WoS and Scopus databases were used as a data source, which allowed filtering publications in journals that did not receive worldwide recognition. Publications marked "articles" were taken into account. This is especially important, since a Department of Hematology at the Pavlov University was also included into the study, and so without the filtering, publications by students and postgraduates occupied at the University, in general, could give a distorted characteristic of publications from the local researchers [7]. The list of publications was limited to keywords defining the field of research (Table 1), thus allowing to filter out most of the publications, first of all, by other branches of the I. Pavlov St. Petersburg Medical University that were not related to the specific area of Hematology/Oncology/Transplantation. Hence, the analysis was limited by the scientific publications from R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, and the I. Pavlov University Department of Hematology, Transfusiology and Transplantation.
To evaluate the research activities of major haematological centers in Russia, we have calculated the widely used scientometric indicators, e.g., the citation index, which can be calculated for publications and also for organizations and individual researchers or research teams.
However, these commonly used indices have a significant drawback, i.e., they vary greatly for different areas, which can lead to distortions and inaccurate data. There are various approaches to the allocation of scientific fields for calculating the weighted average indicators in each of them.
Hence, to normalize indicators in the WoS system, classification is used based on the topics of the journals included in indexing. But this approach has a number of significant drawbacks, the main one of which is the inadequate processing of publications in interdisciplinary journals and other journals with a wide coverage. Therefore, more accurate, it seems the selection of areas based on individual publications, and not on the level of entire journals [1].
To perform the statistical evaluation, we used MS Excel software for plotting the diagrams. The ScVal database concerning the specialized St. Petersburg and Moscow centers were kindly provided by Dr. Mark A. Akoev (Laboratory of Scientometry, B. Yeltsin Ural Federal University, Yekaterinburg, Russia).
Results
Common scientometry
Comparison of the characteristics of organizations was done by the number of articles and citations for the period 2016-2018, and by the Hirsch index, calculated on the basis of their publications. The results are presented in Table 2 (according to WoS data) and in Table 3 (according to Scopus data).
Table 2. Common scientometric indices of the four major NMRCs active in Hematology/Oncology, and Raisa Gorbacheva Memorial Research Institute, according to the Web of Science data
N. N. Blokhin National Medical Research Center of Oncology is a leader by the number of WoS-indexed publications (2798 papers). However, the average number of citations per publication proved to be the highest for N. N. Petrov NMRC of Oncology (7.8). For N.N. Blokhin NMRC of Oncology, this figure is almost the same as for R. Gorbacheva Memorial Research Institute, i.e. (6.98 and 6.5, respectively). At the same time, National Research Center for Hematology, ranking second in the number of publications, is significantly behind other surveyed institutions in terms of citation, with average citation number only 1.5 per an article. The same conclusions can be drawn by evaluating Hirsch index of these institutions (Table 3, Fig. 1). The N. Blokhin National Medical Research Center of Oncology (22), N. Petrov National Medical Research Center of Oncology (17) and R. Gorbacheva Memorial Research Institute (10) are in the top three for this index, and the National Research Center for Hematology has a lower Hirsch index level (5). Thus, on the basis of WoS-derived data, the N. N. Blokhin National Medical Research Center of Oncology is the leader in publishing activity in Oncology/Hematology among the studied organizations, and R. Gorbacheva Memorial Research Institute holds a middle position among the research centers working in this field.
Similar results are obtained when evaluating the publications of these institutions according to Scopus data. Here, the same three leading organizations are determined by the Hirsch index, and R. Gorbacheva Memorial Research Institute proved to be a leader in the number of publications referred in Scopus (890 publications over three years).
Table 3. Common scientometric indices of four NMRCs and R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation,according to the Scopus data
Figure 1. Hirsch Index of the four Russian NMRCs (see Table 3), and the R. Gorbacheva Institute (I. Pavlov University), as based on Scopus data
SciVal approach
A more profound study on the contribution of these organizations was done using the Elsevier SciVal online platform, which is based on the Scopus database, thus allowing monitoring and analysis of international scientific research using visualization tools and modern metrics for citations, economic and social efficiency. Each scientific topic in the Scopus database is a collection of documents united by a common research interest, grouped together in a SciVal cluster, as based on analysis of direct citations in the lists of document links (a document can have only one topic). While indexing, the newly published documents are added to the relevant topics, as based on the lists of appropriate links. Thus, the clusters reflect a narrow scientific direction, characterized by a set of keywords (e.g., in oncology/hematology), as well as the relationship between authors and cross-citations. As for 2017, 91726 clusters were allocated in SciVal [8]. The SciVal platform provides access to research results from more than 14.000 research institutions from 230 countries. Such wide service coverage allows us to evaluate and compare the research results of similar scientific organizations around the world.
The assessment was done according to the following indicators:
1. Scientific Products (Scholarly Output) – the total number of published research results. SO is an indicator that determines the productivity of scientific work. The following publications are included: journal article; chapter or article in the book; books (monographs, textbooks and reference books); software; report. Excludes: patents, dissertations.
2. The share of publications in the cluster (Publication share, %). A comparison of research results was carried out according to the metrics of the TC.307 cluster, which can be described by the following keywords: Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Transplants.
3. Field-Weighted Citation Impact is a science-normalized citation rate [9]. Calculated by SciVal, this indicator is equal to the ratio of the number of links received by researchers' publications to the average number of links received by all other similar publications indexed in the Scopus database.
The Field-Weighted Citation Impact of 1.00 indicates that publications cited on average for similar publications issued worldwide.
Field-Weighted Citation Impact higher than 1.00 indicates that publications were cited more often than might be expected based on global average for similar publications. For example, a score of 1.44 means that the results were cited 44% more often than expected.
Field-Weighted Citation Impact less than 1.00 indicates that publications were cited less than would be expected based on the world average for similar publications. For example, a rating of 0.85 means 15% less cited than the world average.
Similar publications are publications in the Scopus database that have the same year of publication, type of publication, and discipline.
Field-Weighted Citation Impact refers to citations received in the year of publication plus the next 3 years.
This indicator is useful for evaluating publications regardless of their differences in size, disciplinary profile, age and type of publication, as well as for assessing the level of citation of a researcher.
Figure. 2. Distribution of publications of R. Gorbacheva Memorial
Research Institute of Pediatric Oncology, Hematology and
Transplantation (Pavlov University) by the SciVal topic clusters (TCs)
Abscissa, number of publications; Ordinate shows the publication share which is the 5-year publication output of the given institution divided by the publication output from the institution ranked #1 worldwide within a particular competency. Publication clusters mean the groups of highly cited publications and the current publications that cite them. Area of the circles reflects the field-weighted citation impact.
The analysis of scientific publications has shown that the performance of R. Gorbacheva Memorial Research Institute in different topic clusters (TC), according to SciVal data, does not correlate with the number of the articles published in the specified TCs. The highest share among high-ranked world publications for R. Gorbacheva Memorial Research Institute corresponds to the TC. 307 (HSCT and adjacent areas), followed by TC.1326 (multilayer films, microparticles), whereas the total number of publications is highest in TC.307 followed by TC.134 (leukemia research), as seen from Table 4 and Fig. 2. On the other hand, we see a correlation between the share among world publications and field-weighted citation impact, thus suggesting that the papers from R. Gorbacheva Memorial Research Institute in TC.307 and TC.1326 are highly shared among the world publications, and also have high field-weighted citation impact. In general, the indices of scientific works from R. Gorbacheva Memorial Research Institute based on SciVal data are at comparable level with the bulk of world publications in the selected topic clusters (TCs).
Table 4. Number of publications by the R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation (Pavlov University) in different topic clusters (TC) according to SciVal data
Discussion
At the present time, there is no unified solution for a comprehensive model of science, or a list of scientific topics (and their relative value). Therefore, in order to assess the scientific significance of an institution, it is necessary to rely both on metrics obtained from various sources and on the results of expert evaluation.
The comparative assessment method we used is based on the clustering of the SCOPUS citation network. Firstly, this allows a more accurate assessment of the development within narrow range of studies for the organizations performing a wide-range research. Secondly, modern scientific trends consider interdisciplinary basis for many new achievements in research. Taking into account the fact that all clusters have a dynamic nature, it does not allow a general description of the work of a distinct organization, even in a specified field. Comparing efficiency of institutions by the metrics of only one cluster of items does not characterize the work of the organization as a whole, but only allows us to describe the degree of development of research in a single narrow area. Therefore, these results do not allow conclusions about the work of specific organizations, but the results will be useful to consider when choosing institutions developing similar scientific projects.
Conclusion
1. Over the past three years, according to Scopus and WoS, there has been an increase in the number of publications in the field of hematology in the major specialized Russian scientific institutions coordinated into a network of National Medical Research Centers (NMRCs), thus indicating advancements and growing relevance of this clinical topic.
2. The use of widespread scientometric indicators, such as numbers of publications, citation, and the Hirsch index, does not allow an unambiguous conclusion about the leadership of scientific organizations, even those conducting research in one narrow area.
3. The efficiency of research in Hematology and related fields at the Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, a part of St. Petersburg State Medical University, may not be lower, and, sometimes, even higher than in specialized research centers, as evidenced by the number of cited works in international databases.
4. A study of publication activity using the SciVal system showed that the research-funding bodies may consider R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation (at the Pavlov University) a perspective university platform for research in relevant areas of Hematology/Oncology, along with existing specialized scientific institutions.
Acknowledgement
The authors would like to thank Mark A. Akoev (Scientific Laboratory "Laboratory of Scientometry", The B. Yeltsin Ural Federal University, Yekaterinburg, Russia) for his help in selecting materials.
No conflicts of interest reported.
References
- Ruiz-Castillo J, Waltman L. Field-normalized citation impact indicators using algorithmically constructed classification systems of science. Journal of Informetrics. 2015;9(1):102-117.
- Bornmann L, Wohlrabe K. Normalisation of citation impact in economics. Scientometrics. 2019;120(2):841-884.
- Demina MA. Legal regulation of scientific and innovative activities of medical organizations. Actual Problems of Russian Law. 2018; 11 (96):116-123 (In Russian). DOI: 10.17803/1994-1471.2018.96.11.116-123.
- Decree of the Ministry of Health of Russia (March 21, 2017, N 125) "On the organization of work on the formation of a network of national scientific and practical medical centers." URL: https://rulaws.ru/acts/Prikaz-Minzdrava-Rossii-ot-11.09.2017-N-622/(In Russian).
- Decree of the Ministry of Health of Russia (September 11, 2017, N 622) "On the network of national medical research centers. URL: https://rulaws.ru/acts/Prikaz-Minzdrava-Rossii-ot-11.09.2017-N-622/ (Accessed: 19.10.2019) (In Russian).
- Pavlou C, Elkind E. Manipulating citation indices in a social context. Proc Intern Joint Conference on Autonomous Agents and Multiagent Systems (AAMAS). 2016: 32-40.
- Khrustalev MB, Tishkov AV, Maksimova AA, Turbina NY. Comparing research performance of national medical research centers and medical universities in Russia according to scientific indicators. University Management: Practice and Analysis. 2019; 23(3):108-118 (In Russian).
- Klavans R, Boyack KW. Research portfolio analysis and topic prominence. Journal of Informetrics. 2017;11(4):1158-1174.
- Akoev MA, Markusova VA, Moskaleva OV, Pislyakov VV. Guidelines for scientometry: indicators of the development of science and technology. Publishing House of the Ural University: Yekaterinburg, 2014 (In Russian).
Introduction
Over recent years, scientometric criteria have been increasingly used, in order to evaluate the effectiveness of scientific institutions, enabling us to present the fact-based characteristics of the institutions, and their impact on development of world science, if used in correct manner. To some degree, such an evaluation is important for monitoring the quality of both individual and team work, as well as efficient use of resources allocated for research.
Similarly, scientometric methods are increasingly used to answer the questions of preferential financial support for certain areas of research, and discern the priority products and technologies, as well as to resolve problems with research staff recruitment [1].
Current science management is largely focused on accountability. Therefore, quantitative evaluation of research activities sufficiently adds to qualitative assessments of research (i.e., peer reviewing of projects and articles). Hence, bibliometric evaluation with its measurements of research output and citation impact seems to be a quite important quantitative approach [2].
The Strategy for the Development of Medical Science is one of the key documents that determines the development trends of medical science in Russia. According to it, the main goal is to create high-tech innovative products ensuring the improvement of public health based on the transfer of innovative technologies to practical healthcare. To achieve this goal, it was necessary to arrange a network of leading centers for the prioritized areas [3].
To arrange such a system and provide methodological support of research projects for the leading institutions, a Decree №125 was issued by the Ministry of Healthcare of Russian Federation (March 21, 2017) entitled: "On arranging measures for establishment of network of National Research and Practical Medical Centers". Its implementation started by creating a network of National Medical Research Centers (NMRCs) on the basis of specialized research institutions subordinated to the Ministry of Healthcare of the Russian Federation that are leaders in the top areas of medical science. At the same time, the educational priorities in medical research were assigned to specialized research centers, but not to appropriate educational institutions (e.g., medical universities), being in controbersy with global trends in the basic science development. Thus, a network of 22 NMRCs was arranged [4, 5], involving the four research centers that conduct research in the field of oncology and hematology.
Hence, along with the National Research Center for Hematology, this study also included other major Russian centers active in clinical and experimental hematology, i.e., N. N. Blokhin National Medical Research Center of Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, N. N. Petrov National Medical Research Center of Oncology, and Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation which is a part the St. Petersburg I. Pavlov Medical University.
Among the scientific indices of the institutions that are widely used in the reports, there is a clear bias towards quantitative characteristics, such as total number of articles, the number of articles indexed in the Web of Science (WoS) and Scopus international databases, total impact factor of the journals in which the articles were published, etc. At the same time, the indices characterizing quality of published works (citation scores) and, indirectly, the reputation of the institution (Hirsch index of the organization) are practically not used. Nevertheless, the Hirsch index is most difficult to manipulate by researchers and management staff at the institutions, and, therefore, it can be more objective when comparing scientific reputation characteristics [6].
The aim of our work was to perform a scientometric evaluation of these organizations, relying primarily on their quality indicators and impact of the research results. Moreover, our task was to determine the position of R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation (R. Gorbacheva Institute), a large university research center which is not an autonomous legal entity, and which was not put on the list of NMRCs with special support for research activities.
Materials and methods
Our study included five major institutions active in Hematology/Oncology over last 3 years (2016-2018), i.e., N. N. Petrov National Medical Research Center of Oncology (St. Petersburg), National Medical Research Center of Hematology (Moscow), N. Blokhin National Medical Research Center of Oncology (Moscow), Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow), and Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at the I. Pavlov First St. Petersburg State Medical Unibersity.
For the convenience of this study, we concentrated precisely on the qualitative and reputation indices of the work of organizations for the period of 2016 to 2018. WoS and Scopus databases were used as a data source, which allowed filtering publications in journals that did not receive worldwide recognition. Publications marked "articles" were taken into account. This is especially important, since a Department of Hematology at the Pavlov University was also included into the study, and so without the filtering, publications by students and postgraduates occupied at the University, in general, could give a distorted characteristic of publications from the local researchers [7]. The list of publications was limited to keywords defining the field of research (Table 1), thus allowing to filter out most of the publications, first of all, by other branches of the I. Pavlov St. Petersburg Medical University that were not related to the specific area of Hematology/Oncology/Transplantation. Hence, the analysis was limited by the scientific publications from R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, and the I. Pavlov University Department of Hematology, Transfusiology and Transplantation.
To evaluate the research activities of major haematological centers in Russia, we have calculated the widely used scientometric indicators, e.g., the citation index, which can be calculated for publications and also for organizations and individual researchers or research teams.
However, these commonly used indices have a significant drawback, i.e., they vary greatly for different areas, which can lead to distortions and inaccurate data. There are various approaches to the allocation of scientific fields for calculating the weighted average indicators in each of them.
Hence, to normalize indicators in the WoS system, classification is used based on the topics of the journals included in indexing. But this approach has a number of significant drawbacks, the main one of which is the inadequate processing of publications in interdisciplinary journals and other journals with a wide coverage. Therefore, more accurate, it seems the selection of areas based on individual publications, and not on the level of entire journals [1].
To perform the statistical evaluation, we used MS Excel software for plotting the diagrams. The ScVal database concerning the specialized St. Petersburg and Moscow centers were kindly provided by Dr. Mark A. Akoev (Laboratory of Scientometry, B. Yeltsin Ural Federal University, Yekaterinburg, Russia).
Results
Common scientometry
Comparison of the characteristics of organizations was done by the number of articles and citations for the period 2016-2018, and by the Hirsch index, calculated on the basis of their publications. The results are presented in Table 2 (according to WoS data) and in Table 3 (according to Scopus data).
Table 2. Common scientometric indices of the four major NMRCs active in Hematology/Oncology, and Raisa Gorbacheva Memorial Research Institute, according to the Web of Science data
N. N. Blokhin National Medical Research Center of Oncology is a leader by the number of WoS-indexed publications (2798 papers). However, the average number of citations per publication proved to be the highest for N. N. Petrov NMRC of Oncology (7.8). For N.N. Blokhin NMRC of Oncology, this figure is almost the same as for R. Gorbacheva Memorial Research Institute, i.e. (6.98 and 6.5, respectively). At the same time, National Research Center for Hematology, ranking second in the number of publications, is significantly behind other surveyed institutions in terms of citation, with average citation number only 1.5 per an article. The same conclusions can be drawn by evaluating Hirsch index of these institutions (Table 3, Fig. 1). The N. Blokhin National Medical Research Center of Oncology (22), N. Petrov National Medical Research Center of Oncology (17) and R. Gorbacheva Memorial Research Institute (10) are in the top three for this index, and the National Research Center for Hematology has a lower Hirsch index level (5). Thus, on the basis of WoS-derived data, the N. N. Blokhin National Medical Research Center of Oncology is the leader in publishing activity in Oncology/Hematology among the studied organizations, and R. Gorbacheva Memorial Research Institute holds a middle position among the research centers working in this field.
Similar results are obtained when evaluating the publications of these institutions according to Scopus data. Here, the same three leading organizations are determined by the Hirsch index, and R. Gorbacheva Memorial Research Institute proved to be a leader in the number of publications referred in Scopus (890 publications over three years).
Table 3. Common scientometric indices of four NMRCs and R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation,according to the Scopus data
Figure 1. Hirsch Index of the four Russian NMRCs (see Table 3), and the R. Gorbacheva Institute (I. Pavlov University), as based on Scopus data
SciVal approach
A more profound study on the contribution of these organizations was done using the Elsevier SciVal online platform, which is based on the Scopus database, thus allowing monitoring and analysis of international scientific research using visualization tools and modern metrics for citations, economic and social efficiency. Each scientific topic in the Scopus database is a collection of documents united by a common research interest, grouped together in a SciVal cluster, as based on analysis of direct citations in the lists of document links (a document can have only one topic). While indexing, the newly published documents are added to the relevant topics, as based on the lists of appropriate links. Thus, the clusters reflect a narrow scientific direction, characterized by a set of keywords (e.g., in oncology/hematology), as well as the relationship between authors and cross-citations. As for 2017, 91726 clusters were allocated in SciVal [8]. The SciVal platform provides access to research results from more than 14.000 research institutions from 230 countries. Such wide service coverage allows us to evaluate and compare the research results of similar scientific organizations around the world.
The assessment was done according to the following indicators:
1. Scientific Products (Scholarly Output) – the total number of published research results. SO is an indicator that determines the productivity of scientific work. The following publications are included: journal article; chapter or article in the book; books (monographs, textbooks and reference books); software; report. Excludes: patents, dissertations.
2. The share of publications in the cluster (Publication share, %). A comparison of research results was carried out according to the metrics of the TC.307 cluster, which can be described by the following keywords: Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Transplants.
3. Field-Weighted Citation Impact is a science-normalized citation rate [9]. Calculated by SciVal, this indicator is equal to the ratio of the number of links received by researchers' publications to the average number of links received by all other similar publications indexed in the Scopus database.
The Field-Weighted Citation Impact of 1.00 indicates that publications cited on average for similar publications issued worldwide.
Field-Weighted Citation Impact higher than 1.00 indicates that publications were cited more often than might be expected based on global average for similar publications. For example, a score of 1.44 means that the results were cited 44% more often than expected.
Field-Weighted Citation Impact less than 1.00 indicates that publications were cited less than would be expected based on the world average for similar publications. For example, a rating of 0.85 means 15% less cited than the world average.
Similar publications are publications in the Scopus database that have the same year of publication, type of publication, and discipline.
Field-Weighted Citation Impact refers to citations received in the year of publication plus the next 3 years.
This indicator is useful for evaluating publications regardless of their differences in size, disciplinary profile, age and type of publication, as well as for assessing the level of citation of a researcher.
Figure. 2. Distribution of publications of R. Gorbacheva Memorial
Research Institute of Pediatric Oncology, Hematology and
Transplantation (Pavlov University) by the SciVal topic clusters (TCs)
Abscissa, number of publications; Ordinate shows the publication share which is the 5-year publication output of the given institution divided by the publication output from the institution ranked #1 worldwide within a particular competency. Publication clusters mean the groups of highly cited publications and the current publications that cite them. Area of the circles reflects the field-weighted citation impact.
The analysis of scientific publications has shown that the performance of R. Gorbacheva Memorial Research Institute in different topic clusters (TC), according to SciVal data, does not correlate with the number of the articles published in the specified TCs. The highest share among high-ranked world publications for R. Gorbacheva Memorial Research Institute corresponds to the TC. 307 (HSCT and adjacent areas), followed by TC.1326 (multilayer films, microparticles), whereas the total number of publications is highest in TC.307 followed by TC.134 (leukemia research), as seen from Table 4 and Fig. 2. On the other hand, we see a correlation between the share among world publications and field-weighted citation impact, thus suggesting that the papers from R. Gorbacheva Memorial Research Institute in TC.307 and TC.1326 are highly shared among the world publications, and also have high field-weighted citation impact. In general, the indices of scientific works from R. Gorbacheva Memorial Research Institute based on SciVal data are at comparable level with the bulk of world publications in the selected topic clusters (TCs).
Table 4. Number of publications by the R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation (Pavlov University) in different topic clusters (TC) according to SciVal data
Discussion
At the present time, there is no unified solution for a comprehensive model of science, or a list of scientific topics (and their relative value). Therefore, in order to assess the scientific significance of an institution, it is necessary to rely both on metrics obtained from various sources and on the results of expert evaluation.
The comparative assessment method we used is based on the clustering of the SCOPUS citation network. Firstly, this allows a more accurate assessment of the development within narrow range of studies for the organizations performing a wide-range research. Secondly, modern scientific trends consider interdisciplinary basis for many new achievements in research. Taking into account the fact that all clusters have a dynamic nature, it does not allow a general description of the work of a distinct organization, even in a specified field. Comparing efficiency of institutions by the metrics of only one cluster of items does not characterize the work of the organization as a whole, but only allows us to describe the degree of development of research in a single narrow area. Therefore, these results do not allow conclusions about the work of specific organizations, but the results will be useful to consider when choosing institutions developing similar scientific projects.
Conclusion
1. Over the past three years, according to Scopus and WoS, there has been an increase in the number of publications in the field of hematology in the major specialized Russian scientific institutions coordinated into a network of National Medical Research Centers (NMRCs), thus indicating advancements and growing relevance of this clinical topic.
2. The use of widespread scientometric indicators, such as numbers of publications, citation, and the Hirsch index, does not allow an unambiguous conclusion about the leadership of scientific organizations, even those conducting research in one narrow area.
3. The efficiency of research in Hematology and related fields at the Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, a part of St. Petersburg State Medical University, may not be lower, and, sometimes, even higher than in specialized research centers, as evidenced by the number of cited works in international databases.
4. A study of publication activity using the SciVal system showed that the research-funding bodies may consider R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation (at the Pavlov University) a perspective university platform for research in relevant areas of Hematology/Oncology, along with existing specialized scientific institutions.
Acknowledgement
The authors would like to thank Mark A. Akoev (Scientific Laboratory "Laboratory of Scientometry", The B. Yeltsin Ural Federal University, Yekaterinburg, Russia) for his help in selecting materials.
No conflicts of interest reported.
References
- Ruiz-Castillo J, Waltman L. Field-normalized citation impact indicators using algorithmically constructed classification systems of science. Journal of Informetrics. 2015;9(1):102-117.
- Bornmann L, Wohlrabe K. Normalisation of citation impact in economics. Scientometrics. 2019;120(2):841-884.
- Demina MA. Legal regulation of scientific and innovative activities of medical organizations. Actual Problems of Russian Law. 2018; 11 (96):116-123 (In Russian). DOI: 10.17803/1994-1471.2018.96.11.116-123.
- Decree of the Ministry of Health of Russia (March 21, 2017, N 125) "On the organization of work on the formation of a network of national scientific and practical medical centers." URL: https://rulaws.ru/acts/Prikaz-Minzdrava-Rossii-ot-11.09.2017-N-622/(In Russian).
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Максим Б. Хрусталев, Артем В. Тишков, Наталья Ю. Турбина, Анна А. Максимова
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24365" ["VALUE"]=> array(2) { ["TEXT"]=> string(4452) "<p style="text-align: justify;">Цель работы – дать наукометрическую характеристику основных российских организаций, проводящих исследования в области онкологии и гематологии, опираясь, прежде всего, на показатели качества и влияния результатов научных исследований, оценить их позиции в тематических научных кластерах по данным международных баз цитирования.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">Проведено сравнение наукометрических показателей (количество публикаций, цитируемость, индекс Хирша организации) пяти организаций, проводящих исследования в области онкологии и гематологии: четыре НМИЦ и НИИ детской онкологии, гематологии и трансплантологии им. Р. Горбачевой (НИИДОГиТ) в составе Первого Санкт-Петербургского государственного медицинского университета им. И. Павлова. Оценена также продуктивность научной работы НИИДОГиТ, количество публикаций в соответствующих научных тематических кластерах (ТК), средневзвешенное цитирование по данным SciVal и доля среди мировых публикаций. Перечень публикаций был ограничен ключевыми словами, определяющими область исследований этих организаций.</p> <h3>Результаты</h3> <p style="text-align: justify;">Анализ научных публикаций выявил, что показатели научной работы НИИДОГиТ, не входящего в сеть национальных медицинских исследовательских центров, находятся на лидирующих позициях, лишь немного уступая показателям центров онкологии имени Н. Н. Петрова и им. Н. Н. Блохина. Показатели научной работы НИИДОГиТ на основании данных SciVal находятся на уровне по сравнению с показателями мировых публикаций в выбранных ТК.</p> <h3>Выводы</h3> <p style="text-align: justify;">Результативность научных исследований, которая косвенно отражается в количестве высокоцитируемых публикаций в образовательном учреждении оказывается на уровне не ниже, а иногда и выше, чем в специализированных научных учреждениях. Изучение публикационной активности с помощью системы SciVal показало, что спонсирующие организации могут рассматривать НИИДОГиТ им. Р. М. Горбачевой, как перспективную площадку для проведения исследований в соответствующих областях наравне с существующими специализированными научными учреждениями.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Гематология, онкология, национальные медицинские исследовательские центры, медицинский университет, наукометрические показатели, анализ цитирования, библиометрия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4294) "Цель работы – дать наукометрическую характеристику основных российских организаций, проводящих исследования в области онкологии и гематологии, опираясь, прежде всего, на показатели качества и влияния результатов научных исследований, оценить их позиции в тематических научных кластерах по данным международных баз цитирования.
Материалы и методы
Проведено сравнение наукометрических показателей (количество публикаций, цитируемость, индекс Хирша организации) пяти организаций, проводящих исследования в области онкологии и гематологии: четыре НМИЦ и НИИ детской онкологии, гематологии и трансплантологии им. Р. Горбачевой (НИИДОГиТ) в составе Первого Санкт-Петербургского государственного медицинского университета им. И. Павлова. Оценена также продуктивность научной работы НИИДОГиТ, количество публикаций в соответствующих научных тематических кластерах (ТК), средневзвешенное цитирование по данным SciVal и доля среди мировых публикаций. Перечень публикаций был ограничен ключевыми словами, определяющими область исследований этих организаций.
Результаты
Анализ научных публикаций выявил, что показатели научной работы НИИДОГиТ, не входящего в сеть национальных медицинских исследовательских центров, находятся на лидирующих позициях, лишь немного уступая показателям центров онкологии имени Н. Н. Петрова и им. Н. Н. Блохина. Показатели научной работы НИИДОГиТ на основании данных SciVal находятся на уровне по сравнению с показателями мировых публикаций в выбранных ТК.
Выводы
Результативность научных исследований, которая косвенно отражается в количестве высокоцитируемых публикаций в образовательном учреждении оказывается на уровне не ниже, а иногда и выше, чем в специализированных научных учреждениях. Изучение публикационной активности с помощью системы SciVal показало, что спонсирующие организации могут рассматривать НИИДОГиТ им. Р. М. Горбачевой, как перспективную площадку для проведения исследований в соответствующих областях наравне с существующими специализированными научными учреждениями.
Ключевые слова
Гематология, онкология, национальные медицинские исследовательские центры, медицинский университет, наукометрические показатели, анализ цитирования, библиометрия.
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Gorbacheva Institute) which is a part of I. Pavlov St. Petersburg State Medical University, using the following scientometric indices: citation, collective Hirsch index, as well as the productivity of research determined as relative share of publications in the scientific TC, as well as Field-weighted Citation Impact, using the SciVal platform. The list of publications was limited to keywords defining the field of research of these organizations.</p> <h3>Results</h3> <p style="text-align: justify;">Comparative evaluation of research publication activity in oncohematology has shown the leading position of R. Gorbacheva Institute, as a part of I. Pavlov St. Petersburg State Medical University, which was not included into the NMRCs network. Its rating was only slightly lower than the indices of N. Petrov National Medical Research Center of Oncology and N. Blokhin National Medical Research Center of Oncology. The overall indices of the citation impact based on SciVal analytic platform assessed for R. Gorbacheva Institute are at a level compared to the figures for world publications in the selected topic clusters.</p> <h3>Conclusion</h3> <p style="text-align: justify;">Efficiency of clinical research at an educational institution, evaluated as the number of highly cited publications proved to be not lower, but sometimes even higher than in specialized research institutions working in the field. Appropriate publishing activity evaluated by the SciVal system showed that the funding authorities providing research financiation should recognize R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at the Pavlov University as a perspective university-based platform for research in relevant areas, along with existing specialized scientific institutions.</p> <h2>Keywords</h2> <p style="text-align: justify;">Hematology, oncology, national medical research centers, medical university, scientometric indexes, bibliometry, citation analysis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2753) "The aim of this survey was to perform scientometric evaluation of the major Russian institutions conducting research in the field of oncology and hematology, relying primarily on the common quality indicators and impact of the research results, to аssess their position in the scientific topic clusters (TC) according to international citation databases.
Materials and methods
A comparison was made between five organizations conducting research in the field of oncology and hematology, i.e., four National Medical Research Centers (NMRCs), and Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation (R. Gorbacheva Institute) which is a part of I. Pavlov St. Petersburg State Medical University, using the following scientometric indices: citation, collective Hirsch index, as well as the productivity of research determined as relative share of publications in the scientific TC, as well as Field-weighted Citation Impact, using the SciVal platform. The list of publications was limited to keywords defining the field of research of these organizations.
Results
Comparative evaluation of research publication activity in oncohematology has shown the leading position of R. Gorbacheva Institute, as a part of I. Pavlov St. Petersburg State Medical University, which was not included into the NMRCs network. Its rating was only slightly lower than the indices of N. Petrov National Medical Research Center of Oncology and N. Blokhin National Medical Research Center of Oncology. The overall indices of the citation impact based on SciVal analytic platform assessed for R. Gorbacheva Institute are at a level compared to the figures for world publications in the selected topic clusters.
Conclusion
Efficiency of clinical research at an educational institution, evaluated as the number of highly cited publications proved to be not lower, but sometimes even higher than in specialized research institutions working in the field. Appropriate publishing activity evaluated by the SciVal system showed that the funding authorities providing research financiation should recognize R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at the Pavlov University as a perspective university-based platform for research in relevant areas, along with existing specialized scientific institutions.
Keywords
Hematology, oncology, national medical research centers, medical university, scientometric indexes, bibliometry, citation analysis.
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" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24369" ["VALUE"]=> array(2) { ["TEXT"]=> string(2911) "<p style="text-align: justify;">The aim of this survey was to perform scientometric evaluation of the major Russian institutions conducting research in the field of oncology and hematology, relying primarily on the common quality indicators and impact of the research results, to аssess their position in the scientific topic clusters (TC) according to international citation databases.</p> <h3>Materials and methods</h3> <p style="text-align: justify;">A comparison was made between five organizations conducting research in the field of oncology and hematology, i.e., four National Medical Research Centers (NMRCs), and Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation (R. Gorbacheva Institute) which is a part of I. Pavlov St. Petersburg State Medical University, using the following scientometric indices: citation, collective Hirsch index, as well as the productivity of research determined as relative share of publications in the scientific TC, as well as Field-weighted Citation Impact, using the SciVal platform. The list of publications was limited to keywords defining the field of research of these organizations.</p> <h3>Results</h3> <p style="text-align: justify;">Comparative evaluation of research publication activity in oncohematology has shown the leading position of R. Gorbacheva Institute, as a part of I. Pavlov St. Petersburg State Medical University, which was not included into the NMRCs network. Its rating was only slightly lower than the indices of N. Petrov National Medical Research Center of Oncology and N. Blokhin National Medical Research Center of Oncology. The overall indices of the citation impact based on SciVal analytic platform assessed for R. Gorbacheva Institute are at a level compared to the figures for world publications in the selected topic clusters.</p> <h3>Conclusion</h3> <p style="text-align: justify;">Efficiency of clinical research at an educational institution, evaluated as the number of highly cited publications proved to be not lower, but sometimes even higher than in specialized research institutions working in the field. Appropriate publishing activity evaluated by the SciVal system showed that the funding authorities providing research financiation should recognize R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at the Pavlov University as a perspective university-based platform for research in relevant areas, along with existing specialized scientific institutions.</p> <h2>Keywords</h2> <p style="text-align: justify;">Hematology, oncology, national medical research centers, medical university, scientometric indexes, bibliometry, citation analysis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2753) "The aim of this survey was to perform scientometric evaluation of the major Russian institutions conducting research in the field of oncology and hematology, relying primarily on the common quality indicators and impact of the research results, to аssess their position in the scientific topic clusters (TC) according to international citation databases.
Materials and methods
A comparison was made between five organizations conducting research in the field of oncology and hematology, i.e., four National Medical Research Centers (NMRCs), and Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation (R. Gorbacheva Institute) which is a part of I. Pavlov St. Petersburg State Medical University, using the following scientometric indices: citation, collective Hirsch index, as well as the productivity of research determined as relative share of publications in the scientific TC, as well as Field-weighted Citation Impact, using the SciVal platform. The list of publications was limited to keywords defining the field of research of these organizations.
Results
Comparative evaluation of research publication activity in oncohematology has shown the leading position of R. Gorbacheva Institute, as a part of I. Pavlov St. Petersburg State Medical University, which was not included into the NMRCs network. Its rating was only slightly lower than the indices of N. Petrov National Medical Research Center of Oncology and N. Blokhin National Medical Research Center of Oncology. The overall indices of the citation impact based on SciVal analytic platform assessed for R. Gorbacheva Institute are at a level compared to the figures for world publications in the selected topic clusters.
Conclusion
Efficiency of clinical research at an educational institution, evaluated as the number of highly cited publications proved to be not lower, but sometimes even higher than in specialized research institutions working in the field. Appropriate publishing activity evaluated by the SciVal system showed that the funding authorities providing research financiation should recognize R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at the Pavlov University as a perspective university-based platform for research in relevant areas, along with existing specialized scientific institutions.
Keywords
Hematology, oncology, national medical research centers, medical university, scientometric indexes, bibliometry, citation analysis.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2753) "The aim of this survey was to perform scientometric evaluation of the major Russian institutions conducting research in the field of oncology and hematology, relying primarily on the common quality indicators and impact of the research results, to аssess their position in the scientific topic clusters (TC) according to international citation databases.
Materials and methods
A comparison was made between five organizations conducting research in the field of oncology and hematology, i.e., four National Medical Research Centers (NMRCs), and Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation (R. Gorbacheva Institute) which is a part of I. Pavlov St. Petersburg State Medical University, using the following scientometric indices: citation, collective Hirsch index, as well as the productivity of research determined as relative share of publications in the scientific TC, as well as Field-weighted Citation Impact, using the SciVal platform. The list of publications was limited to keywords defining the field of research of these organizations.
Results
Comparative evaluation of research publication activity in oncohematology has shown the leading position of R. Gorbacheva Institute, as a part of I. Pavlov St. Petersburg State Medical University, which was not included into the NMRCs network. Its rating was only slightly lower than the indices of N. Petrov National Medical Research Center of Oncology and N. Blokhin National Medical Research Center of Oncology. The overall indices of the citation impact based on SciVal analytic platform assessed for R. Gorbacheva Institute are at a level compared to the figures for world publications in the selected topic clusters.
Conclusion
Efficiency of clinical research at an educational institution, evaluated as the number of highly cited publications proved to be not lower, but sometimes even higher than in specialized research institutions working in the field. Appropriate publishing activity evaluated by the SciVal system showed that the funding authorities providing research financiation should recognize R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at the Pavlov University as a perspective university-based platform for research in relevant areas, along with existing specialized scientific institutions.
Keywords
Hematology, oncology, national medical research centers, medical university, scientometric indexes, bibliometry, citation analysis.
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Khrustalev" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24365" ["VALUE"]=> array(2) { ["TEXT"]=> string(4452) "<p style="text-align: justify;">Цель работы – дать наукометрическую характеристику основных российских организаций, проводящих исследования в области онкологии и гематологии, опираясь, прежде всего, на показатели качества и влияния результатов научных исследований, оценить их позиции в тематических научных кластерах по данным международных баз цитирования.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">Проведено сравнение наукометрических показателей (количество публикаций, цитируемость, индекс Хирша организации) пяти организаций, проводящих исследования в области онкологии и гематологии: четыре НМИЦ и НИИ детской онкологии, гематологии и трансплантологии им. Р. Горбачевой (НИИДОГиТ) в составе Первого Санкт-Петербургского государственного медицинского университета им. И. Павлова. Оценена также продуктивность научной работы НИИДОГиТ, количество публикаций в соответствующих научных тематических кластерах (ТК), средневзвешенное цитирование по данным SciVal и доля среди мировых публикаций. Перечень публикаций был ограничен ключевыми словами, определяющими область исследований этих организаций.</p> <h3>Результаты</h3> <p style="text-align: justify;">Анализ научных публикаций выявил, что показатели научной работы НИИДОГиТ, не входящего в сеть национальных медицинских исследовательских центров, находятся на лидирующих позициях, лишь немного уступая показателям центров онкологии имени Н. Н. Петрова и им. Н. Н. Блохина. Показатели научной работы НИИДОГиТ на основании данных SciVal находятся на уровне по сравнению с показателями мировых публикаций в выбранных ТК.</p> <h3>Выводы</h3> <p style="text-align: justify;">Результативность научных исследований, которая косвенно отражается в количестве высокоцитируемых публикаций в образовательном учреждении оказывается на уровне не ниже, а иногда и выше, чем в специализированных научных учреждениях. Изучение публикационной активности с помощью системы SciVal показало, что спонсирующие организации могут рассматривать НИИДОГиТ им. Р. М. Горбачевой, как перспективную площадку для проведения исследований в соответствующих областях наравне с существующими специализированными научными учреждениями.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Гематология, онкология, национальные медицинские исследовательские центры, медицинский университет, наукометрические показатели, анализ цитирования, библиометрия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4294) "Цель работы – дать наукометрическую характеристику основных российских организаций, проводящих исследования в области онкологии и гематологии, опираясь, прежде всего, на показатели качества и влияния результатов научных исследований, оценить их позиции в тематических научных кластерах по данным международных баз цитирования.
Материалы и методы
Проведено сравнение наукометрических показателей (количество публикаций, цитируемость, индекс Хирша организации) пяти организаций, проводящих исследования в области онкологии и гематологии: четыре НМИЦ и НИИ детской онкологии, гематологии и трансплантологии им. Р. Горбачевой (НИИДОГиТ) в составе Первого Санкт-Петербургского государственного медицинского университета им. И. Павлова. Оценена также продуктивность научной работы НИИДОГиТ, количество публикаций в соответствующих научных тематических кластерах (ТК), средневзвешенное цитирование по данным SciVal и доля среди мировых публикаций. Перечень публикаций был ограничен ключевыми словами, определяющими область исследований этих организаций.
Результаты
Анализ научных публикаций выявил, что показатели научной работы НИИДОГиТ, не входящего в сеть национальных медицинских исследовательских центров, находятся на лидирующих позициях, лишь немного уступая показателям центров онкологии имени Н. Н. Петрова и им. Н. Н. Блохина. Показатели научной работы НИИДОГиТ на основании данных SciVal находятся на уровне по сравнению с показателями мировых публикаций в выбранных ТК.
Выводы
Результативность научных исследований, которая косвенно отражается в количестве высокоцитируемых публикаций в образовательном учреждении оказывается на уровне не ниже, а иногда и выше, чем в специализированных научных учреждениях. Изучение публикационной активности с помощью системы SciVal показало, что спонсирующие организации могут рассматривать НИИДОГиТ им. Р. М. Горбачевой, как перспективную площадку для проведения исследований в соответствующих областях наравне с существующими специализированными научными учреждениями.
Ключевые слова
Гематология, онкология, национальные медицинские исследовательские центры, медицинский университет, наукометрические показатели, анализ цитирования, библиометрия.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(4294) "Цель работы – дать наукометрическую характеристику основных российских организаций, проводящих исследования в области онкологии и гематологии, опираясь, прежде всего, на показатели качества и влияния результатов научных исследований, оценить их позиции в тематических научных кластерах по данным международных баз цитирования.
Материалы и методы
Проведено сравнение наукометрических показателей (количество публикаций, цитируемость, индекс Хирша организации) пяти организаций, проводящих исследования в области онкологии и гематологии: четыре НМИЦ и НИИ детской онкологии, гематологии и трансплантологии им. Р. Горбачевой (НИИДОГиТ) в составе Первого Санкт-Петербургского государственного медицинского университета им. И. Павлова. Оценена также продуктивность научной работы НИИДОГиТ, количество публикаций в соответствующих научных тематических кластерах (ТК), средневзвешенное цитирование по данным SciVal и доля среди мировых публикаций. Перечень публикаций был ограничен ключевыми словами, определяющими область исследований этих организаций.
Результаты
Анализ научных публикаций выявил, что показатели научной работы НИИДОГиТ, не входящего в сеть национальных медицинских исследовательских центров, находятся на лидирующих позициях, лишь немного уступая показателям центров онкологии имени Н. Н. Петрова и им. Н. Н. Блохина. Показатели научной работы НИИДОГиТ на основании данных SciVal находятся на уровне по сравнению с показателями мировых публикаций в выбранных ТК.
Выводы
Результативность научных исследований, которая косвенно отражается в количестве высокоцитируемых публикаций в образовательном учреждении оказывается на уровне не ниже, а иногда и выше, чем в специализированных научных учреждениях. Изучение публикационной активности с помощью системы SciVal показало, что спонсирующие организации могут рассматривать НИИДОГиТ им. Р. М. Горбачевой, как перспективную площадку для проведения исследований в соответствующих областях наравне с существующими специализированными научными учреждениями.
Ключевые слова
Гематология, онкология, национальные медицинские исследовательские центры, медицинский университет, наукометрические показатели, анализ цитирования, библиометрия.
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Alexander Friedenstein is considered the founder of the mesenchymal stem cell concept. He described fibroblasts like clonogenic cells, forming colonies, named by him CFU-F. The MSCs are multi-potential, and differentiate into osteoblasts, chondrocytes and adipocytes [1] and support hematopoiesis. Alexander Friedenstein himself refers to Alexander Maximov, who first described stromal-hematopoietic interrelationship, hypothesizing that committed hematopoietic precursors descend from the hematopoietic stem cells, due to local impacts generated by marrow stroma, leading to hematopoietic differentiation [2, 3]. These fibroblast like clonogenic cells have been named by Caplan mesenchymal stem cells [4]. These CFU-F have been shown to be negative for the markers CD34, CD45, CD14, MHCII and positive for the markers CD90, CD105, MHCI an CD73. These cells can be induced and differentiated to adipocytes, documented by staining of lipid vacuols with sudan red, into osteoblasts, which can be documented by staining of calcium deposits with silver nitrate and into chondroblasts, documented by staining of proteoglycanes with alcian blue. These precursors can be propagated millionfold in liquid culture [5, 6, 7].
MSCs are immunoprivileged cells and possess immunomodulatory properties, modulating all populations of the innate and adaptive immune system [8]. MSC decrease proliferation cytotoxicity and interferon-γ production by NK cells, diminish proliferation of B cells and their differentiation to plasma cells. They decrease proliferation and CTL formation as well as interferon gamma production of T-Cells, increase regulatory T-Cells and decrease differentiation, maturation and activation of dendritic cells [8]. MHC suppress T-cell proliferation and TH1 specific cytokine secretion [9].
There has been an immense interest in clinical application of MSCs for several reasons:
1. There is no need for complicated donor search. MSC can be given beyond the MHC barrier. That leads to easy availability.
2. One donation provides cells for many treatments, which makes this approach inexpensive.
3. No major side effects have been reported from MSC infusion. MSC treatment is considered to be safe.
The mechanism of action of MSC has been explored in several preclinical systems, like acute kidney injury, where MSC therapy augments expression of anti-apoptotic BCL-2 and inhibits that of pro-inflammatory genes, like eNOS. It inhibits expression of pro-inflammatory genes (IL1-beta, TNF-alpha, IFN-gamma) and it increases the expression of anti-inflammatory IL-10 [10, 11, 12]. MSC therapy has been further explored in models for radiation injury, where it rescued mice after supralethal irradiation [13]. In this model MSC treatment leads to an increased expression of genes related to detoxification, cell metabolism, cell motility, anti- inflammation and anti-apoptosis, as well as a decreased expression of genes associated with toxification, inflammation and apoptosis [13]. Based on several studies in kidney, heart, radioprotection and graft-versus-host disease, it could be shown that MSCs are anti-inflammatory, anti-apoptotic, angiogenic and mitogenic [14, 15, 16].
The first area of MSC therapy was acute graft-versus-host disease, where Katharina Le Blanc could show effectiveness in steroid resistant acute graft-versus-host disease in a proof of concept study [17], followed by a multi-center European study including 55 patients, leading to complete response in 30 patients and to some improvement in 9, which lead to lower transplant related mortality in responding patients [18]. The company Osiris Therapeutics carried out a phase 3 trial in adults and children with GvHD, in which only the subset of children showed a significant response to MSCs [19, 20]. Osiris did not obtain licenses for MSC treatment of GvHD in the United States and Europe, following the study. Health Canada gave a notice of compliance with conditions (hightened post-market surveillance), but so far no approval. In Japan, MSCs can be marketed (Tem-cell) for acute graft-versus-host disease [21]. In Europe a new attempt in steroide resistant GvHD treatment with standardized MSC from several donors, is carried out in a multi-center study. The preliminary reports appear very promising [22].
210 studies are listed as completed under clinicaltrials.gov. Major entities include are as follows: rheumatic arthritis/osteoarthrtis (n=12); amyotrophic lateral sclerosis (n=9); graft-versus-host disease (n=8); multiple sclerosis (n=7); diabetes (n=7); Crohn’s disease (n=6); myocardial infarction (n=5); spinal cord injury (n=4).
The general overview of all these studies, reveals some activity, but not enough for licensing in all countries, in steroid resistant GvHD, some activity in Crohn’s disease, where several randomized studies could show that a reduction of steroid dose is possible, following MSC treatment [23, 24]. Encouraging findings in spinal cord injury, where improved sensory and bladder function were noted, but no improvement in motor function and the treatment was proven to be safe [25]. In Amyotrophic-Lateral-Sklerosis (ALS), a disease with very few treatment options, several studies showed slower progression of disease in the treated group, but larger studies are needed [26, 27].
There are several encouraging studies in MS, a large randomized study has been initiated by Andrea Uccelli and several European groups [28].
In Lupus several studies showed improved disease activity, but a large-scale validation is needed [29, 30]. The results of the studies in Diabetes mellitus are less encouraging, even though there has been some improvement in DMT1 [31, 32]. Results in arthritis show inconsistent results and in heart disease large randomized studies showed no long-term benefit [33-37].
The field of MSC is under attack from two directions. Several studies have shown that the phenotype of MSC in vitro does not reflect cell identity and function. Stromal cells from bone marrow, muscle, peritoneum and cord blood have been isolated and the gene expression profiles clearly separated by origin of cells and MSCs from different sources have radically different, differentiation properties [38], leading to the editorial "Clear up the Stem Cell mess", by Sipp Douglas et al. [39]. He states that the confusion about mesenchyme stem cells is making it easier for people to sell unproven treatments. The problem lies in the name mesenchymal stem cell. Caplan, who coined the term mesenchymal stem cell, recommended the more correct term of "Medicinal Signaling Cells". Other investigators use the term Mesenchymal Stroma Cell, which might suffice to get these cells out of the hyped stem cell theater.
The excellent sales argument for MSC – no complicated donor search, one donation for many treatments and the safety of the infusion, led to an explosion of unapproved stem cell treatments in USA, Australia and Japan, with direct to consumer marketing. In 2016 there were 351 US companies selling putative stem cell treatments, mostly MSCs, directly to the consumer [39].To dispel the MSC myth one should stop bunching multiple cell types, under one catch-all phrase. Clinical trial registries, as well as editors and reviewers should be more critical. One should watch for well designed and well described clinical studies in regenerative medicine. Regulators should stop commercial clinics from selling unproven treatments whenever possible. Physicians should discourage their patients from receiving unproven stem cell therapies. Overall one should keep in mind, not to pour out the baby with the bath water: it will take more time to firmly establish MSC treatment in Regenerative Medicine.
Acknowledgement
Thanks to Andrea Zander for her assistance in the preparation of the manuscript.
Conflict of interest
None reported.
References
- Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. (). Stromal cells responsible for trabsferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation. 1974; 17:331-340.
- Maximov AA. Über experimentelle Erzeugung von Knochenmarksgewebe. Anat Anz. 1906; 28: 24-38.
- Afanasyev BV, Elstner E, Zander AR. A. Friedenstein, founder of the mesenchymal stem cell concept. Cell Ther Transplant. 2009; 1(3): 35-38.
- Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991; 9:641-650.
- Porcellini A. Regenerative medicine: a review. Rev Bras Hematol Hemoter. 2009;31 (Suppl. 2). 31:63-66. DOI:10.1590/S1516-84842009000800017.
- Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C. Adipose-derived stem cells: Isolation, expansion and differentiation. Methods. Methods in Stem Cell Res. 2008; 45(2):115-120.
- Lange C, Schroeder J, Stute N, Lioznov MV, Zander AR. High-potential human mesenchymal stem cells. Stem Cells Dev. 2005;14(1):70-80.
- Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499-3506.
- Fang L, Lange C, Engel M, Zander A, Fehse B. Sensitive balance of suppressing and activating effects of mesenchymal stem cells on T-cell proliferation. Transplantation. 2006;82(10):1370-1373.
- Tögel F, Westenfelder C. Treatment of acute kidney injury with allogeneic mesenchymal stem cells: preclinical and initial clinical data. In: Regenerative Nephrology (Ed. M. Goligorsky), Elsevier, 2011. pp. 315-339.
- Tögel F, Westenfelder C. Mesenchymal stem cells: a new therapeutic tool for AKI. Nat Rev Nephrol. 2010; 6(3):179-183, DOI: 10.1038/nrneph.2009.229.
- Tögel F, Westenfelder C. The role of multipotent marrow stromal cells (MSCs) in tissue regeneration. Organogenesis.2011; 7(2):96-100, DOI: 10.4161/org.7.2.15781.
- Lange C, Brunswig-Spickenheie B, Cappallo-Obermann H, Eggert K, Gehling UM, Rudolph C, Schlegelberger B, Cornils K, Zustin J, Spiess AN, Zander AR. PLos One. 2011;6(1):e14486. Doi: 10.1089/scd.2009.0494.
- Krause K, Fehse B, Jaquet K, Lange C, Kyriazis K, Boczor S, Zander A, Kuck K. Analysis of progenitor cell mobilization and erythropoietin plasma levels in patients with acute myocardial infarction. Exp Clin Cardiol. 2005;10(2):104-107.
- Wang S, Qu X, Zhao RS. Clinical applications of mesenchymal stem cells. J Hematol Oncol. 2012. 5:19. DOI:10.1186/1756-8722-5-19.
- Zander AR, Lange C, Westenfelder C. Mesenchymal stromal cells: main factor or helper in regenerative medicine? Kidney Int. 2011; 1(3 Suppl):74-76.
- Le Blanc K, Rasmussen I, Sundberg B, Gotherstorm C, Hassan M, Uzunel M et al. Treatment of severe acute graft-versus-host-disease with third-party haploidentical mesenchymal stem cells. Lancet. 200;363:1439-1441.
- Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler M, Bacigalupo A, Fibbe W, Ringden O et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008; 371,1579-1586.
- Martin PJ, Uberti JP, Soiffer RJ, Klingermann H, Waller EK, Daly AS, Herrmann RP, Kebriaei P. Prochymal improves response rates in patients with steroid-refractory, acute GvHD: results of a randomized, placebo-controlled, multicenter Phase III trial in GvHD. Biol Blood Marrow Transplant. 2010;16: S169-S170.
- Kurtzberg J, Prasad V, Grimley M, Horn B, Carpenter P, Jacobsohn D, Prochop S. Allogeneic human mesenchymal stem cell therapy (Prochymal®) as a rescue agent for severe treatment resistant GVHD in pediatric patients. Biol. Blood Marrow Transplant. 2010; 16: S169.
- Hara A, Sato D, Sahara Y. New governmental regulatory system for stem cell-based therapies in Japan. Ther Innov Regul Sci. 2014; 48:681-688.
- Bader P. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplant. 2018; 53:852-862.
- Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M , Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Leselbaum A ,Danese S; ADMIRE CD Study Group Collaborators. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomized, double-blind controlled trial. Lancet 2016; 388:1281-1290.
- Panes J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Diez MC, Tagarro I, Leselbaum A, Danese S;ADMIRE CD Study Group Collaborators. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2018; 154: 1334-1342 e4.
- Cofano F, Boido M, Monticelli M, Zenga F, Ducati A, Vercelli A, Garbossa D. Mesenchymal stem cells for spinal cord injury: current options. Int J Mol Sci. 2019; 20(11). pii: E2698.
- Gugliandolo A, Bramanti P, Mazzon E. Mesenchymal stem cells: a potential therapeutic approach for amyotriphic lateral sclerosis. Stem Cells Int. 2019; 2019:3675627.
- Oh KW, Noh MY, Kwon MS, Kim HY, Oh SI, Park J, Kim HJ, Ki CS, Kim SH. Repeated intrathecal mesenchymal stem cells for amyotrophic lateral sclerosis. Ann Neurol. 2018;84(3):361-373.
- Uccelli A, Laroni A, Brundin L, Clanet M, Fernandez O, Nabavi SM, Muraro PA, Oliveri RS, Radue EW, Sellner J, Soelberg Sorensen P, Sormani MP, Wuerfel JT, Battaglia MA, Freedman MS; MESEMS study group. Mesenchymal stem cells for multiple sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for therapy of multiple sclerosis“. Trials. 2019, May 9; 20(1):263. DOI 10.1186/s13063-019-3346-z.
- Deng D, Zhang P, Guo Y, Lim TO. A randomized double-blind placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis“. Ann Rheum Dis. 2017;76(8):1436-1439.
- Cras A. Update on mesenchymal stem cell-based therapy in lupus and scleroderma. Arthritis Res Ther. 2015 Nov. 3; 17:301.
- Zang L, Hao H, Liu J, Li Y, Han W, Mu Y. Mesenchymal stem cell therapy in type 2 diabetes mellitus. Diabetol Metab Syndr. 2017 May 15;9:36.
- Moreira A, Kahlenberg S, Hornsby P. Therapeutic potential of mesenchymal stem cells for diabetes. J Mol Endocrinol. 2017; 59(3):R109-R120.
- Liu L, Wong CW, Han M, Farhoodi HP, Liu G, Liu Y, Liao W, Zhao W. Meta-analysis of preclinical studies of mesenchymal stromal cells to treat rheumatoid arthritis. EBioMedicine. 2019 Sep; 47: 563-577. DOI: 10.1016/j.ebiom.2019.08.073.
- Fan Yang, Yang Li. Effects of mesenchymal stem cells in autoimmune arthritis. Eur Med J. 2018 ;3 (4):130-137.
- Steinhoff G, Nesteruk J, Wolfien M, Große J, Ruch U, Vasudevan P, Müller P. Stem cells and heart disease – Brake or accelerator? Adv Drug Deliv Rev. 2017;120:2-24. DOI: 10.1016/j.addr.2017.10.007.
- Lalu MM, Mazzarello S, Zlepnig J, Dong YY, Montroy J, McIntyre L, Devereaux PJ, Stewart DJ. Safety and efficacy of adult stem cell therapy for acute myocardial infarction and ischemic heart failure (SafeCell Heart): a systematic review and meta-analysis. Stem Cells Transl Med; 7(12): 857-866.
- Blau HM, Daley GQ. Stem cells in the treatment of disease. New Engl J Med. 2019; 308:1748-1760. DOI: 10.1056/NEJMra1716145.
- Sacchetti B, Funari A, Remoli C, Giannicola G, Kogler G, Liedtke S, Cossu G, Serafini M, Sampaolesi M, Tagliafico E, Tenedini E, Saggio I, Robey PG, Riminucci M, Bianco P. No identical mesenchymal stem cells at different times and sites: human committed progenitors of distinct origin and differentiation potential are incorporated as adventitial cells in microvessels. Stem Cell Rep. 2016; 6(6): 897-913.
- Sipp D, Robey PG, Turner L. Clear up this stem-cell mess. Nature. 2018; 561(7724): 455-457.
Introduction
Alexander Friedenstein is considered the founder of the mesenchymal stem cell concept. He described fibroblasts like clonogenic cells, forming colonies, named by him CFU-F. The MSCs are multi-potential, and differentiate into osteoblasts, chondrocytes and adipocytes [1] and support hematopoiesis. Alexander Friedenstein himself refers to Alexander Maximov, who first described stromal-hematopoietic interrelationship, hypothesizing that committed hematopoietic precursors descend from the hematopoietic stem cells, due to local impacts generated by marrow stroma, leading to hematopoietic differentiation [2, 3]. These fibroblast like clonogenic cells have been named by Caplan mesenchymal stem cells [4]. These CFU-F have been shown to be negative for the markers CD34, CD45, CD14, MHCII and positive for the markers CD90, CD105, MHCI an CD73. These cells can be induced and differentiated to adipocytes, documented by staining of lipid vacuols with sudan red, into osteoblasts, which can be documented by staining of calcium deposits with silver nitrate and into chondroblasts, documented by staining of proteoglycanes with alcian blue. These precursors can be propagated millionfold in liquid culture [5, 6, 7].
MSCs are immunoprivileged cells and possess immunomodulatory properties, modulating all populations of the innate and adaptive immune system [8]. MSC decrease proliferation cytotoxicity and interferon-γ production by NK cells, diminish proliferation of B cells and their differentiation to plasma cells. They decrease proliferation and CTL formation as well as interferon gamma production of T-Cells, increase regulatory T-Cells and decrease differentiation, maturation and activation of dendritic cells [8]. MHC suppress T-cell proliferation and TH1 specific cytokine secretion [9].
There has been an immense interest in clinical application of MSCs for several reasons:
1. There is no need for complicated donor search. MSC can be given beyond the MHC barrier. That leads to easy availability.
2. One donation provides cells for many treatments, which makes this approach inexpensive.
3. No major side effects have been reported from MSC infusion. MSC treatment is considered to be safe.
The mechanism of action of MSC has been explored in several preclinical systems, like acute kidney injury, where MSC therapy augments expression of anti-apoptotic BCL-2 and inhibits that of pro-inflammatory genes, like eNOS. It inhibits expression of pro-inflammatory genes (IL1-beta, TNF-alpha, IFN-gamma) and it increases the expression of anti-inflammatory IL-10 [10, 11, 12]. MSC therapy has been further explored in models for radiation injury, where it rescued mice after supralethal irradiation [13]. In this model MSC treatment leads to an increased expression of genes related to detoxification, cell metabolism, cell motility, anti- inflammation and anti-apoptosis, as well as a decreased expression of genes associated with toxification, inflammation and apoptosis [13]. Based on several studies in kidney, heart, radioprotection and graft-versus-host disease, it could be shown that MSCs are anti-inflammatory, anti-apoptotic, angiogenic and mitogenic [14, 15, 16].
The first area of MSC therapy was acute graft-versus-host disease, where Katharina Le Blanc could show effectiveness in steroid resistant acute graft-versus-host disease in a proof of concept study [17], followed by a multi-center European study including 55 patients, leading to complete response in 30 patients and to some improvement in 9, which lead to lower transplant related mortality in responding patients [18]. The company Osiris Therapeutics carried out a phase 3 trial in adults and children with GvHD, in which only the subset of children showed a significant response to MSCs [19, 20]. Osiris did not obtain licenses for MSC treatment of GvHD in the United States and Europe, following the study. Health Canada gave a notice of compliance with conditions (hightened post-market surveillance), but so far no approval. In Japan, MSCs can be marketed (Tem-cell) for acute graft-versus-host disease [21]. In Europe a new attempt in steroide resistant GvHD treatment with standardized MSC from several donors, is carried out in a multi-center study. The preliminary reports appear very promising [22].
210 studies are listed as completed under clinicaltrials.gov. Major entities include are as follows: rheumatic arthritis/osteoarthrtis (n=12); amyotrophic lateral sclerosis (n=9); graft-versus-host disease (n=8); multiple sclerosis (n=7); diabetes (n=7); Crohn’s disease (n=6); myocardial infarction (n=5); spinal cord injury (n=4).
The general overview of all these studies, reveals some activity, but not enough for licensing in all countries, in steroid resistant GvHD, some activity in Crohn’s disease, where several randomized studies could show that a reduction of steroid dose is possible, following MSC treatment [23, 24]. Encouraging findings in spinal cord injury, where improved sensory and bladder function were noted, but no improvement in motor function and the treatment was proven to be safe [25]. In Amyotrophic-Lateral-Sklerosis (ALS), a disease with very few treatment options, several studies showed slower progression of disease in the treated group, but larger studies are needed [26, 27].
There are several encouraging studies in MS, a large randomized study has been initiated by Andrea Uccelli and several European groups [28].
In Lupus several studies showed improved disease activity, but a large-scale validation is needed [29, 30]. The results of the studies in Diabetes mellitus are less encouraging, even though there has been some improvement in DMT1 [31, 32]. Results in arthritis show inconsistent results and in heart disease large randomized studies showed no long-term benefit [33-37].
The field of MSC is under attack from two directions. Several studies have shown that the phenotype of MSC in vitro does not reflect cell identity and function. Stromal cells from bone marrow, muscle, peritoneum and cord blood have been isolated and the gene expression profiles clearly separated by origin of cells and MSCs from different sources have radically different, differentiation properties [38], leading to the editorial "Clear up the Stem Cell mess", by Sipp Douglas et al. [39]. He states that the confusion about mesenchyme stem cells is making it easier for people to sell unproven treatments. The problem lies in the name mesenchymal stem cell. Caplan, who coined the term mesenchymal stem cell, recommended the more correct term of "Medicinal Signaling Cells". Other investigators use the term Mesenchymal Stroma Cell, which might suffice to get these cells out of the hyped stem cell theater.
The excellent sales argument for MSC – no complicated donor search, one donation for many treatments and the safety of the infusion, led to an explosion of unapproved stem cell treatments in USA, Australia and Japan, with direct to consumer marketing. In 2016 there were 351 US companies selling putative stem cell treatments, mostly MSCs, directly to the consumer [39].To dispel the MSC myth one should stop bunching multiple cell types, under one catch-all phrase. Clinical trial registries, as well as editors and reviewers should be more critical. One should watch for well designed and well described clinical studies in regenerative medicine. Regulators should stop commercial clinics from selling unproven treatments whenever possible. Physicians should discourage their patients from receiving unproven stem cell therapies. Overall one should keep in mind, not to pour out the baby with the bath water: it will take more time to firmly establish MSC treatment in Regenerative Medicine.
Acknowledgement
Thanks to Andrea Zander for her assistance in the preparation of the manuscript.
Conflict of interest
None reported.
References
- Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. (). Stromal cells responsible for trabsferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation. 1974; 17:331-340.
- Maximov AA. Über experimentelle Erzeugung von Knochenmarksgewebe. Anat Anz. 1906; 28: 24-38.
- Afanasyev BV, Elstner E, Zander AR. A. Friedenstein, founder of the mesenchymal stem cell concept. Cell Ther Transplant. 2009; 1(3): 35-38.
- Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991; 9:641-650.
- Porcellini A. Regenerative medicine: a review. Rev Bras Hematol Hemoter. 2009;31 (Suppl. 2). 31:63-66. DOI:10.1590/S1516-84842009000800017.
- Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C. Adipose-derived stem cells: Isolation, expansion and differentiation. Methods. Methods in Stem Cell Res. 2008; 45(2):115-120.
- Lange C, Schroeder J, Stute N, Lioznov MV, Zander AR. High-potential human mesenchymal stem cells. Stem Cells Dev. 2005;14(1):70-80.
- Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499-3506.
- Fang L, Lange C, Engel M, Zander A, Fehse B. Sensitive balance of suppressing and activating effects of mesenchymal stem cells on T-cell proliferation. Transplantation. 2006;82(10):1370-1373.
- Tögel F, Westenfelder C. Treatment of acute kidney injury with allogeneic mesenchymal stem cells: preclinical and initial clinical data. In: Regenerative Nephrology (Ed. M. Goligorsky), Elsevier, 2011. pp. 315-339.
- Tögel F, Westenfelder C. Mesenchymal stem cells: a new therapeutic tool for AKI. Nat Rev Nephrol. 2010; 6(3):179-183, DOI: 10.1038/nrneph.2009.229.
- Tögel F, Westenfelder C. The role of multipotent marrow stromal cells (MSCs) in tissue regeneration. Organogenesis.2011; 7(2):96-100, DOI: 10.4161/org.7.2.15781.
- Lange C, Brunswig-Spickenheie B, Cappallo-Obermann H, Eggert K, Gehling UM, Rudolph C, Schlegelberger B, Cornils K, Zustin J, Spiess AN, Zander AR. PLos One. 2011;6(1):e14486. Doi: 10.1089/scd.2009.0494.
- Krause K, Fehse B, Jaquet K, Lange C, Kyriazis K, Boczor S, Zander A, Kuck K. Analysis of progenitor cell mobilization and erythropoietin plasma levels in patients with acute myocardial infarction. Exp Clin Cardiol. 2005;10(2):104-107.
- Wang S, Qu X, Zhao RS. Clinical applications of mesenchymal stem cells. J Hematol Oncol. 2012. 5:19. DOI:10.1186/1756-8722-5-19.
- Zander AR, Lange C, Westenfelder C. Mesenchymal stromal cells: main factor or helper in regenerative medicine? Kidney Int. 2011; 1(3 Suppl):74-76.
- Le Blanc K, Rasmussen I, Sundberg B, Gotherstorm C, Hassan M, Uzunel M et al. Treatment of severe acute graft-versus-host-disease with third-party haploidentical mesenchymal stem cells. Lancet. 200;363:1439-1441.
- Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler M, Bacigalupo A, Fibbe W, Ringden O et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008; 371,1579-1586.
- Martin PJ, Uberti JP, Soiffer RJ, Klingermann H, Waller EK, Daly AS, Herrmann RP, Kebriaei P. Prochymal improves response rates in patients with steroid-refractory, acute GvHD: results of a randomized, placebo-controlled, multicenter Phase III trial in GvHD. Biol Blood Marrow Transplant. 2010;16: S169-S170.
- Kurtzberg J, Prasad V, Grimley M, Horn B, Carpenter P, Jacobsohn D, Prochop S. Allogeneic human mesenchymal stem cell therapy (Prochymal®) as a rescue agent for severe treatment resistant GVHD in pediatric patients. Biol. Blood Marrow Transplant. 2010; 16: S169.
- Hara A, Sato D, Sahara Y. New governmental regulatory system for stem cell-based therapies in Japan. Ther Innov Regul Sci. 2014; 48:681-688.
- Bader P. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplant. 2018; 53:852-862.
- Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M , Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Leselbaum A ,Danese S; ADMIRE CD Study Group Collaborators. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomized, double-blind controlled trial. Lancet 2016; 388:1281-1290.
- Panes J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Diez MC, Tagarro I, Leselbaum A, Danese S;ADMIRE CD Study Group Collaborators. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2018; 154: 1334-1342 e4.
- Cofano F, Boido M, Monticelli M, Zenga F, Ducati A, Vercelli A, Garbossa D. Mesenchymal stem cells for spinal cord injury: current options. Int J Mol Sci. 2019; 20(11). pii: E2698.
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Аксель Р. Цандер
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Ключевые слова
Мезенхимные стромальные клетки, иммунные эффекты, медицинское применение.
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Uncritical, direct to consumer sales of unapproved stem cell treatments by private entrepreneurs cloud the field of MSC research and jeopardize the establishment of MSC treatment in the armamentarium of Medicine. Several more years are necessary for a full evaluation of this new treatment modality in several indications.
Keywords
Mesenchymal stromal cells, immune effects, medical applications.
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Uncritical, direct to consumer sales of unapproved stem cell treatments by private entrepreneurs cloud the field of MSC research and jeopardize the establishment of MSC treatment in the armamentarium of Medicine. Several more years are necessary for a full evaluation of this new treatment modality in several indications.
Keywords
Mesenchymal stromal cells, immune effects, medical applications.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1030) "Mesenchymal stroma cells (MSCs) have anti-inflammatory, anti-apoptotic and immunomodulating properties, and they have, therefore, been explored in the treatment of autoimmune and chronic inflammatory diseases during the last two decades. MSCs have reached regulatory approval in several countries for the treatment of Acute Graft-versus-Host Disease and for Crohn’s disease. Results in several other diseases like Lupus, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Spinal cord injury look promising.
Uncritical, direct to consumer sales of unapproved stem cell treatments by private entrepreneurs cloud the field of MSC research and jeopardize the establishment of MSC treatment in the armamentarium of Medicine. Several more years are necessary for a full evaluation of this new treatment modality in several indications.
Keywords
Mesenchymal stromal cells, immune effects, medical applications.
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Поэтому их исследовали на предмет лечения аутоиммунных и хронических воспалительных заболеваний на протяжении последних двух десятилетий. МСК получили одобрение надзорных органов в нескольких странах на лечение ими острой реакции «трансплантат против хозяина» и болезни Крона. Обещающие результаты получены при их применении для лечения некоторых других болезней, таких, как системная красная волчанка, множественный склероз, амиотрофический боковой склероз и при травмах спинного мозга. При некритичном подходе прямая продажа частными предпринимателями неразрешенных стволовых клеток для лечения вносит беспорядок в область исследований МСК и угрожают внедрению МСК в арсенал медицинских методов. Необходимы еще несколько лет для полной оценки этого нового подхода к лечению по нескольким показаниям.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Мезенхимные стромальные клетки, иммунные эффекты, медицинское применение.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1968) "Мезенхимные стромальные клетки (МСК) проявляют противовоспалительные, анти-апоптотические и иммуномодулирующие свойства. Поэтому их исследовали на предмет лечения аутоиммунных и хронических воспалительных заболеваний на протяжении последних двух десятилетий. МСК получили одобрение надзорных органов в нескольких странах на лечение ими острой реакции «трансплантат против хозяина» и болезни Крона. Обещающие результаты получены при их применении для лечения некоторых других болезней, таких, как системная красная волчанка, множественный склероз, амиотрофический боковой склероз и при травмах спинного мозга. При некритичном подходе прямая продажа частными предпринимателями неразрешенных стволовых клеток для лечения вносит беспорядок в область исследований МСК и угрожают внедрению МСК в арсенал медицинских методов. Необходимы еще несколько лет для полной оценки этого нового подхода к лечению по нескольким показаниям.
Ключевые слова
Мезенхимные стромальные клетки, иммунные эффекты, медицинское применение.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1968) "Мезенхимные стромальные клетки (МСК) проявляют противовоспалительные, анти-апоптотические и иммуномодулирующие свойства. Поэтому их исследовали на предмет лечения аутоиммунных и хронических воспалительных заболеваний на протяжении последних двух десятилетий. МСК получили одобрение надзорных органов в нескольких странах на лечение ими острой реакции «трансплантат против хозяина» и болезни Крона. Обещающие результаты получены при их применении для лечения некоторых других болезней, таких, как системная красная волчанка, множественный склероз, амиотрофический боковой склероз и при травмах спинного мозга. При некритичном подходе прямая продажа частными предпринимателями неразрешенных стволовых клеток для лечения вносит беспорядок в область исследований МСК и угрожают внедрению МСК в арсенал медицинских методов. Необходимы еще несколько лет для полной оценки этого нового подхода к лечению по нескольким показаниям.
Ключевые слова
Мезенхимные стромальные клетки, иммунные эффекты, медицинское применение.
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Treatment of cancer via adoptive transfer of CAR T cells, being proposed over 20 years ago, remained essentially unknown to the broad medical community, largely due to its very limited efficacy observed in clinical trials. CAR T cell-based therapy came into spotlight when complete responses, many of which were long-lasting, had been reported for 50-90% patients with refractory/relapsed acute lymphoblastic leukemia (r/rALL) and B-cell lymphomas [1-7]. This success stemmed from the relatively easy access of CAR T cells to cancer cells, as well as from the broad choice of targetable surface markers present on the surface of malignant B cells. In the case of ALL, these markers include pan-B cell antigens such as CD19, CD20, CD22, etc. Accordingly, normal B cells expressing the same surface markers may also be destroyed by CAR T cells [2, 3, 5]. However, this so-called "on-target off-tumor" activity is well tolerated and can be compensated by immunoglobulin replacement therapy [8]. This may not be the case, however, for most other malignancies, since cancer cells often express surface markers that are shared with normal tissues vital to the patient. Thus, the availability of a specific surface marker is central for any successful anti-cancer CAR T cell therapy, including that for prostate cancer (PCa).
Selecting a CAR target
An ideal target for CAR-based PCa therapy should display the following features: i) strong and homogeneous expression on metastatic PCa cells and limited or absent expression on non-malignant cells, ii) it should be indispensable for the growth of PCa cells, and/or iii) be enriched on the PCa stem cell population. Comprehensive and unbiased profiling of metastatic PCa-specific surfaceome is therefore warranted as this information would be instrumental for the design of highly selective and potent CARs for the therapy of PCa.
Below we summarize the data on the surface antigens having limited expression outside the prostate and PCa lesions. These targets were used for the preclinical and/or clinical development of CAR T cell-based approaches for PCa or are expected to become CAR T cell targets in the nearest future.
PSCA is a small highly glycosylated GPI-anchored protein with apparent molecular weight of ~24 kDa and predicted molecular weight of only ~10 kDa. First described in 1998, this protein has immediately attracted attention as a potential target for anticancer therapy: it was shown to be highly expressed in primary tumors and metastases of over 80% PCa patients [9-11], as well as in up to 60% pancreatic [12, 13] and bladder [14] cancer samples. It should be noted however, that PSCA expression is not restricted to the malignant prostate cells. By profiling human tissues using a PSCA-specific monoclonal antibody 1G8, various levels of PSCA expression were found for normal epithelial (basal, secretory, and neuroendocrine) cells of the prostate, transitional epithelium of the bladder, neuroendocrine cells of the stomach and the colon, as well as for collecting ducts of the kidney [10]. A number of PSCA-specific monoclonal antibodies and humanized variants thereof have been extensively characterized pre-clinically [15, 16], however they never proceeded to advanced clinical stages as monotherapy agents. Notably, 1G8-based PSCA-specific CAR T cells were shown to significantly inhibit growth of PSCA-positive non-small cell lung cancer patient-derived xenografts in mice, which provided the rationale for moving towards a clinical trial of CAR T cells in lung cancer patients (NCT03198052). Furthermore, a "switchable" PSCA-specific GoCAR T cell product (BPX-601, Bellicum Pharmaceuticals) is currently in a Phase1/2 clinical trial for patients with PSCA-positive gastric, pancreatic, and prostate tumors (NCT02744287). Whereas the data for prostate cancer patients are pending, recent analysis of several small cohorts of heavily pre-treated pancreatic patients indicates that BPX-601 infusion combined with a single injection of the small-molecule "switch" has resulted in disease stabilization, which was accompanied by generally moderate and reversible toxicities [17].
Prostate-Specific Membrane Antigen (PSMA) is a type II 100 kDa transmembrane glycoprotein frequently found in both PCa tumors in addition to a limited number of normal human tissues such as prostate epithelium, proximal renal tubules, duodenal, and rectal mucosa [18, 19]. Interestingly, in the LNCaP cell line widely used for PCa research, PSMA expression is partially modulated by steroid hormones [18]. This recapitulates the in vivo situation, as PSMA expression has been reported to be up-regulated in primary PCa tumors and metastases following androgen-deprivation therapy [20]. Nonetheless, different research groups reported the percentage of PSMA-positive prostate tumors to vary from 66 to 100% [19, 21, 22], which is likely attributable to the choice of the PSMA-specific antibody. Interestingly, PSMA is known to mark the neovasculature of various non-prostatic cancers [19, 23]. Several small-molecule inhibitors with high affinity to PSMA and PSMA-specific antibody-drug conjugates have been characterized and are now actively tested for imaging purposes (reviewed in [24]) or as therapeutic agents in Phase 2/3 clinical trials (NCT03042312; NCT02615067; NCT03511664). Excellent safety profile of such PSMA-targeted molecules establishes PSMA as a strong target for CAR T cells in the context of both metastatic PCa lesions and neovasculature of cancers other than PCa (NCT00664196, NCT01140373, NCT03089203).
ErbB2 (Her2/Neu) is a transmembrane protein known as a prominent marker of breast and gastric carcinomas. Low-level ErbB2 overexpression was found in ~20% of PCa tumors, with stronger expression correlating with rapid cancer cell proliferation and tumor recurrence [25]. Multiple ErbB2 ligands currently approved as therapeutics (such as trastuzumab and pertuzumab) make this protein a convenient target for adoptive cellular immunotherapy of PCa. Although infusion of a ErbB2-specific CAR T cell product has been implicated in a death of a clinical trial participant [26], the reason behind such outcome was likely unrelated to "on-target off-tumor" activity which would be consistent with the broad low-level expression of ErbB2 on normal epithelial cells [27], as this was not observed in a later study where a distinct anti-ErbB2 CAR and significantly lower CAR T cell dose were used [28, 29].
EpCAM (CD326) is frequently found on the surface of carcinomas of various origin, including the prostate, where this antigen was reported to be expressed in up to 87% of tumors [30]. This protein is also considered to be a cancer stem cell marker [31], which strengthens the idea of its use as a therapeutic target. Yet, EpCAM is also expressed at the basolateral cell membrane of simple, pseudo-stratified, and transitional epithelia, which raises reasonable safety concerns for EpCAM-specific CAR T cell therapy. Presently, EpCAM-specific CAR T cells are in Phase 1/2 clinical trials for several solid cancers (NCT02729493, NCT02725125, NCT03563326, NCT02915445) including PCa (NCT03013712).
CD133 (Prominin-1) is one of the several controversial markers of cancer stem cells known to be also expressed by normal stem cells and terminally differentiated epithelial cells [32]. In fact, in the context of PCa, CD133 labels only a subset of cancer stem cells [33,34], which may limit the clinical relevance of this protein as a sole CAR target. It must be noted that a recent clinical trial of CD133-specific CAR T cells for the therapy of patients with hepatocellular, pancreatic, and colorectal carcinomas suggested their overall safety and evidence of limited efficacy [35]. This was consistent with a modest pre-clinical in vitro and in vivo activity of these CAR T cells. Not a single complete response was observed among the 23 treated patients most of whom had very bulky lesions and could not be pre-conditioned. Importantly, CD133+ cells were depleted from the tumor bioptates post-treatment and a CD133- tumor escape was observed in one patient. This finding indicates that a two-pronged approach of simultaneously attacking the cancer stem cell population and the tumor cell mass should translate into stronger responses. Therefore, CAR T cells designed to target both CD133 and the surface markers of more differentiated cancer cell types, such as CD133+CEACAM5 or CD133+EGFR, should be more actively explored both pre-clinically and in the clinical setting [36]. So far, no studies of CD133-specific CAR T cells for the therapy of PCa patients have been reported.
Yet another marker of both cancer and hematopoietic stem cells, CD44, is known to be expressed by PCa stem cells [37]. Interestingly, a variant splice form of CD44 known as CD44v6 is not expressed by hematopoietic progenitor cells, and is considered as a favorable target for CAR T cell therapy [38]. CD44v6-retargeted CAR T cells have shown impressive pre-clinical activity in several hematological cancer models [38, 39], but none have so far been specifically evaluated in the context of PCa.
PCTA-1 (Galectin 8) was described as the protein expressed on PCa cells back in 1996 [40], however later it received very little attention as a therapeutic target. Likely this was due to the fact that it was and still is unclear how this protein devoid of the signal sequence is trafficked outside the cell and ultimately reaches the cell surface [41-43] and whether its surface expression is truly restricted to cancer cells (reviewed in [44, 45]). It has recently been demonstrated that patients with metastatic castration-resistant prostate cancer who received Sipuleucel-T produced significantly higher titers of PCTA-1 specific antibodies compared to the control group of patients [46]. This and other observations [47] highlight PCTA-1 as an emerging therapeutic target in PCa.
STEAP1 has been identified as a membrane protein that is overexpressed in metastatic PCa lesions compared to benign prostatic hyperplasia [48]. It was shown to be also expressed, albeit at much lower levels, by normal prostate and urinary bladder cells, however current expression profiling data are indicative of a much broader normal tissue expression of STEAP1 which includes the brain and the lungs [49]. Whether this inconsistency is associated with the specific choice of antibodies used remains to be explored. Nonetheless, recent clinical trial of MSTP2109A, a conjugate of a humanized anti-STEAP1 antibody and MMAE, has provided evidence of its moderate efficacy in the therapy of patients with metastatic castration-resistant prostate cancer (mCRPC), which was accompanied with a significant percentage of treatment-related serious adverse events [50]. Therefore, considering STEAP-1 as a possible target for CAR T cells may not be regarded as straightforward.
Survivin is broadly known as an intracellular anti-apoptotic protein involved in the control of cell proliferation [51]. It is up-regulated in multiple human cancers including PCa [52]. Intriguingly, this protein has recently been shown to be present on the surface of cancer cells [53], thereby lending itself as a prime candidate for Survivin-specific CARs.
MUC1 is expressed by tumors of a fraction of PCa patients. Across different studies, the percentage of MUC1-positive tumors ranges from 17% [54] to 58% [55]. Notably, MUC1 is also expressed by various types of epithelial cells, as well as by hematopoietic cells and activated T cells [56]. This broad expression pattern across multiple normal cell types sets MUC1 as an antigen that appears suboptimal for the target therapy of PCa. Nonetheless, recent efforts from two companies, Minerva Biotechnologies and Poseida Therapeutics, to identify binders that can reliably discriminate between cancer-specific MUC1 species (known as MUC1* or MUC1C) and the full-length MUC1 present on normal cells, have translated into the design of CAR T cells [57] showing robust anti-tumor activity in mouse xenotransplant models [58-60], with a Phase I clinical trial of MUC1*-specific CAR T cells announced for breast cancer patients (NCT04020575).
At the same time, Tn Muc1/sTn Muc1 species predominantly, although not exclusively expressed on the surface of cancerous, rather than normal tissues serve as attractive alternatives to MUC1 for CAR T cell-based therapy [61, 62], with a recently opened early phase clinical trial of TnMuc1-specific CAR T cells in advanced (non-PCa) solid cancer and multiple myeloma patients (NCT04025216). Except for one report [63], expression of these glycopeptide antigens has been extensively explored using a number of mAbs [64-66] (reviewed in [67]) in cancers other than PCa [61, 68]) and warrants further investigation, as the data have been somewhat difficult to reconcile [69].
TAG-72 epitope, established to be a sialyl-Tn O-glycan carbohydrate hapten, has been found in the vast majority of human carcinomas, including PCa. Given its rather restricted expression pattern in normal tissues [70, 71] and favorable safety profile of anti-TAG72 mAbs [72, 73], first-generation TAG-72-specific CAR T cells have been extensively evaluated both pre-clinically [74] and in two early clinical trials [75] for metastatic colorectal cancer, where they proved to be safe and inefficient largely due to the poor persistence afforded by the CAR design and rapid anti-idiotype elimination. Recent study using local delivery of optimized second-generation TAG-72-CART cells in a xenotransplanted ovarian cancer model [76] provides a strong rationale for testing TAG-72 as a promising target for CAR T cells in epithelial carcinomas including PCa.
Integrin αvβ3 is another marker frequently found on PCa cells, as well as on endothelial cells of the tumor vasculature. Expression of this protein is associated with higher risk of metastatic bone lesions [77-79]. Monoclonal αvβ3-specific antibody LM609 and a humanized derivative of LM609 have been characterized in phase I clinical trials which confirmed their safety [80], however no reports of therapeutic activity in the completed phase II clinical trial (NCT00072930) have been posted since 2008, consistent with the complex biology of αvβ3 in cancer [81]. Intriguingly, a recent study reported on the activity of hLM609-derived αvβ3-specific CAR T cells both in vitro and in vivo, in the setting of xenotransplanted human melanoma [82].
CEACAM5 and CEACAM6 are two related proteins expressed at comparable levels on both PCa and normal prostate cells [83]. Variable levels of expression of these proteins have also been reported for normal cells of the lung, pancreas, and intestine. Safety of the cell therapy targeting CEACAM5 was analyzed in several studies and the results were somewhat conflicting. Use of CEACAM5-specific recTCR-T cells was accompanied with serious colitis in all three patients who received the cell products [84]. This was unlike the situation reported for CEACAM5-specific CAR T cells based on the MFE23 scFv, where acute respiratory toxicity was observed [85]. Notably, infusion of CEACAM5-specific CAR T cells based on the alternative antigen recognition modules was not accompanied with critical adverse effects in two more clinical studies [86,87]. So far, CEACAM5-specific CAR T cells have not been tested in PCa patients. As for, CEACAM6-specific CAR T cells, the studies have not yet progressed beyond mouse xenotranplant models, and safety of such CAR T cells in humans is presently unknown [88].
TROP-2 (TACSTD2) is expressed on both benign and malignant prostate lesions [89, 90], yet it is also detectable on the normal epithelial cells of various origin [91]. No clinical trials of TROP-2-specific CAR T cells have so far been approved, however TROP-2-specific antibody-drug conjugates have been tested in patients and numerous adverse effects have been reported [92]. Hence, the safety of TROP-2-targeted CAR T cell therapy is presently questionable.
Finally, two B7-CD28 family members, B7-H3 (CD276) and B7x (VTCN1/B7-H4) have been reported to be overexpressed in a variety of cancers including PCa [93,94] (reviewed in [95, 96]), and are currently the focus of pre-clinical CAR T cell evaluation programs using AML [97], lung [98], breast [99], bile duct [100], bone and brain [101-103] cancer cells as the targets. Importantly, the findings of Phase I/IIa clinical trials of B7-H3-specific monoclonal antibody MGA271 (enoblituzumab) support its favorable safety profile [104], although surface expression of B7-H3 has been demonstrated for several normal cell types such as dendritic cells, as well as in vitro activated T-, NK- and B cells [105]. Accordingly, B7-H3-specific CARs did not display appreciable off-tumor activity in pre-clinical tests, but they may still require structural/affinity optimization to robustly discriminate between different expression levels of this antigen on normal and malignant cells upon transition to human trials. Interestingly, delayed lethal off-tumor toxicity has recently been observed for B7x-specific CAR T cells [106].
Conclusion
None of the abovementioned markers are absolutely specific for PCa or found across PCa lesions in all patients. Furthermore, a fraction of PCa tumors may be expected to be negative for all such markers, and, hence, the feasibility of delivering a targeted CAR therapy would be very low in such cases. Thus, systematic discovery of novel PCa surface markers is highly warranted. Only a handful of studies in this direction have been published to date. For instance, using a combination of proteomic and transcriptomic profiling, Lee and colleagues have identified a number of surface markers enriched in PCa subtypes [107]. Whereas the identification of known PCa markers such as CEACAM5, PSMA, STEAP1, MUC1, and TROP-2 clearly validates this approach, the rest of the high-ranking proteins reported appear to be strongly and broadly expressed in essential tissues, which makes unlikely their potential use as CAR targets.
Analysis of antibodies present in the sera of convalescent cancer patients following immunotherapy who have developed an anticancer immune response may represent an interesting resource of antigen-recognition modules in CAR design. In line with this idea, GuhaThakurta and colleagues have profiled the specificity of antibodies from 25 mCRPC patients who received a dendritic cell-based vaccine sipuleucel-T [46]. Moderate, yet significant increase in antibody titers to PCTA-1 and Galectin-3 among others was observed. The former protein has already been known as a PCa marker, whereas the latter is predominantly secreted, and is a poor candidate for CAR targeting. Nonetheless, in our opinion this approach appears highly promising. In the context of other types of cancer, antibody profiling has identified a number of putative cancer markers including Galectin-1 [108], MYPT1, PSMC5, etc [109]. Importantly, despite the fact that the above proteins lack protein domains that would anchor them at the cell surface, this approach may still be fruitful once substantially more patient samples are analyzed. Of special interest is the recent advance in the technology of single-cell profiling of repertoires of B- and T- cell receptors [110], which may help identify target-receptor pairs, once combined with the proteomics data. Using the above approaches, analysis of samples from more PCa patients may be required to capture novel or subtype-specific PCa markers, or to confidently conclude that no such targets beyond the described ones exist, and that combinations of the known targets should be exploited for CAR design.
Acknowledgements
This work was supported by the Russian Ministry of Education and Science (Agreement # 075-15-2019-1246, unique project identifier RFMEFI60417X0169).
The authors report no conflicts of interests.
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Introduction
Treatment of cancer via adoptive transfer of CAR T cells, being proposed over 20 years ago, remained essentially unknown to the broad medical community, largely due to its very limited efficacy observed in clinical trials. CAR T cell-based therapy came into spotlight when complete responses, many of which were long-lasting, had been reported for 50-90% patients with refractory/relapsed acute lymphoblastic leukemia (r/rALL) and B-cell lymphomas [1-7]. This success stemmed from the relatively easy access of CAR T cells to cancer cells, as well as from the broad choice of targetable surface markers present on the surface of malignant B cells. In the case of ALL, these markers include pan-B cell antigens such as CD19, CD20, CD22, etc. Accordingly, normal B cells expressing the same surface markers may also be destroyed by CAR T cells [2, 3, 5]. However, this so-called "on-target off-tumor" activity is well tolerated and can be compensated by immunoglobulin replacement therapy [8]. This may not be the case, however, for most other malignancies, since cancer cells often express surface markers that are shared with normal tissues vital to the patient. Thus, the availability of a specific surface marker is central for any successful anti-cancer CAR T cell therapy, including that for prostate cancer (PCa).
Selecting a CAR target
An ideal target for CAR-based PCa therapy should display the following features: i) strong and homogeneous expression on metastatic PCa cells and limited or absent expression on non-malignant cells, ii) it should be indispensable for the growth of PCa cells, and/or iii) be enriched on the PCa stem cell population. Comprehensive and unbiased profiling of metastatic PCa-specific surfaceome is therefore warranted as this information would be instrumental for the design of highly selective and potent CARs for the therapy of PCa.
Below we summarize the data on the surface antigens having limited expression outside the prostate and PCa lesions. These targets were used for the preclinical and/or clinical development of CAR T cell-based approaches for PCa or are expected to become CAR T cell targets in the nearest future.
PSCA is a small highly glycosylated GPI-anchored protein with apparent molecular weight of ~24 kDa and predicted molecular weight of only ~10 kDa. First described in 1998, this protein has immediately attracted attention as a potential target for anticancer therapy: it was shown to be highly expressed in primary tumors and metastases of over 80% PCa patients [9-11], as well as in up to 60% pancreatic [12, 13] and bladder [14] cancer samples. It should be noted however, that PSCA expression is not restricted to the malignant prostate cells. By profiling human tissues using a PSCA-specific monoclonal antibody 1G8, various levels of PSCA expression were found for normal epithelial (basal, secretory, and neuroendocrine) cells of the prostate, transitional epithelium of the bladder, neuroendocrine cells of the stomach and the colon, as well as for collecting ducts of the kidney [10]. A number of PSCA-specific monoclonal antibodies and humanized variants thereof have been extensively characterized pre-clinically [15, 16], however they never proceeded to advanced clinical stages as monotherapy agents. Notably, 1G8-based PSCA-specific CAR T cells were shown to significantly inhibit growth of PSCA-positive non-small cell lung cancer patient-derived xenografts in mice, which provided the rationale for moving towards a clinical trial of CAR T cells in lung cancer patients (NCT03198052). Furthermore, a "switchable" PSCA-specific GoCAR T cell product (BPX-601, Bellicum Pharmaceuticals) is currently in a Phase1/2 clinical trial for patients with PSCA-positive gastric, pancreatic, and prostate tumors (NCT02744287). Whereas the data for prostate cancer patients are pending, recent analysis of several small cohorts of heavily pre-treated pancreatic patients indicates that BPX-601 infusion combined with a single injection of the small-molecule "switch" has resulted in disease stabilization, which was accompanied by generally moderate and reversible toxicities [17].
Prostate-Specific Membrane Antigen (PSMA) is a type II 100 kDa transmembrane glycoprotein frequently found in both PCa tumors in addition to a limited number of normal human tissues such as prostate epithelium, proximal renal tubules, duodenal, and rectal mucosa [18, 19]. Interestingly, in the LNCaP cell line widely used for PCa research, PSMA expression is partially modulated by steroid hormones [18]. This recapitulates the in vivo situation, as PSMA expression has been reported to be up-regulated in primary PCa tumors and metastases following androgen-deprivation therapy [20]. Nonetheless, different research groups reported the percentage of PSMA-positive prostate tumors to vary from 66 to 100% [19, 21, 22], which is likely attributable to the choice of the PSMA-specific antibody. Interestingly, PSMA is known to mark the neovasculature of various non-prostatic cancers [19, 23]. Several small-molecule inhibitors with high affinity to PSMA and PSMA-specific antibody-drug conjugates have been characterized and are now actively tested for imaging purposes (reviewed in [24]) or as therapeutic agents in Phase 2/3 clinical trials (NCT03042312; NCT02615067; NCT03511664). Excellent safety profile of such PSMA-targeted molecules establishes PSMA as a strong target for CAR T cells in the context of both metastatic PCa lesions and neovasculature of cancers other than PCa (NCT00664196, NCT01140373, NCT03089203).
ErbB2 (Her2/Neu) is a transmembrane protein known as a prominent marker of breast and gastric carcinomas. Low-level ErbB2 overexpression was found in ~20% of PCa tumors, with stronger expression correlating with rapid cancer cell proliferation and tumor recurrence [25]. Multiple ErbB2 ligands currently approved as therapeutics (such as trastuzumab and pertuzumab) make this protein a convenient target for adoptive cellular immunotherapy of PCa. Although infusion of a ErbB2-specific CAR T cell product has been implicated in a death of a clinical trial participant [26], the reason behind such outcome was likely unrelated to "on-target off-tumor" activity which would be consistent with the broad low-level expression of ErbB2 on normal epithelial cells [27], as this was not observed in a later study where a distinct anti-ErbB2 CAR and significantly lower CAR T cell dose were used [28, 29].
EpCAM (CD326) is frequently found on the surface of carcinomas of various origin, including the prostate, where this antigen was reported to be expressed in up to 87% of tumors [30]. This protein is also considered to be a cancer stem cell marker [31], which strengthens the idea of its use as a therapeutic target. Yet, EpCAM is also expressed at the basolateral cell membrane of simple, pseudo-stratified, and transitional epithelia, which raises reasonable safety concerns for EpCAM-specific CAR T cell therapy. Presently, EpCAM-specific CAR T cells are in Phase 1/2 clinical trials for several solid cancers (NCT02729493, NCT02725125, NCT03563326, NCT02915445) including PCa (NCT03013712).
CD133 (Prominin-1) is one of the several controversial markers of cancer stem cells known to be also expressed by normal stem cells and terminally differentiated epithelial cells [32]. In fact, in the context of PCa, CD133 labels only a subset of cancer stem cells [33,34], which may limit the clinical relevance of this protein as a sole CAR target. It must be noted that a recent clinical trial of CD133-specific CAR T cells for the therapy of patients with hepatocellular, pancreatic, and colorectal carcinomas suggested their overall safety and evidence of limited efficacy [35]. This was consistent with a modest pre-clinical in vitro and in vivo activity of these CAR T cells. Not a single complete response was observed among the 23 treated patients most of whom had very bulky lesions and could not be pre-conditioned. Importantly, CD133+ cells were depleted from the tumor bioptates post-treatment and a CD133- tumor escape was observed in one patient. This finding indicates that a two-pronged approach of simultaneously attacking the cancer stem cell population and the tumor cell mass should translate into stronger responses. Therefore, CAR T cells designed to target both CD133 and the surface markers of more differentiated cancer cell types, such as CD133+CEACAM5 or CD133+EGFR, should be more actively explored both pre-clinically and in the clinical setting [36]. So far, no studies of CD133-specific CAR T cells for the therapy of PCa patients have been reported.
Yet another marker of both cancer and hematopoietic stem cells, CD44, is known to be expressed by PCa stem cells [37]. Interestingly, a variant splice form of CD44 known as CD44v6 is not expressed by hematopoietic progenitor cells, and is considered as a favorable target for CAR T cell therapy [38]. CD44v6-retargeted CAR T cells have shown impressive pre-clinical activity in several hematological cancer models [38, 39], but none have so far been specifically evaluated in the context of PCa.
PCTA-1 (Galectin 8) was described as the protein expressed on PCa cells back in 1996 [40], however later it received very little attention as a therapeutic target. Likely this was due to the fact that it was and still is unclear how this protein devoid of the signal sequence is trafficked outside the cell and ultimately reaches the cell surface [41-43] and whether its surface expression is truly restricted to cancer cells (reviewed in [44, 45]). It has recently been demonstrated that patients with metastatic castration-resistant prostate cancer who received Sipuleucel-T produced significantly higher titers of PCTA-1 specific antibodies compared to the control group of patients [46]. This and other observations [47] highlight PCTA-1 as an emerging therapeutic target in PCa.
STEAP1 has been identified as a membrane protein that is overexpressed in metastatic PCa lesions compared to benign prostatic hyperplasia [48]. It was shown to be also expressed, albeit at much lower levels, by normal prostate and urinary bladder cells, however current expression profiling data are indicative of a much broader normal tissue expression of STEAP1 which includes the brain and the lungs [49]. Whether this inconsistency is associated with the specific choice of antibodies used remains to be explored. Nonetheless, recent clinical trial of MSTP2109A, a conjugate of a humanized anti-STEAP1 antibody and MMAE, has provided evidence of its moderate efficacy in the therapy of patients with metastatic castration-resistant prostate cancer (mCRPC), which was accompanied with a significant percentage of treatment-related serious adverse events [50]. Therefore, considering STEAP-1 as a possible target for CAR T cells may not be regarded as straightforward.
Survivin is broadly known as an intracellular anti-apoptotic protein involved in the control of cell proliferation [51]. It is up-regulated in multiple human cancers including PCa [52]. Intriguingly, this protein has recently been shown to be present on the surface of cancer cells [53], thereby lending itself as a prime candidate for Survivin-specific CARs.
MUC1 is expressed by tumors of a fraction of PCa patients. Across different studies, the percentage of MUC1-positive tumors ranges from 17% [54] to 58% [55]. Notably, MUC1 is also expressed by various types of epithelial cells, as well as by hematopoietic cells and activated T cells [56]. This broad expression pattern across multiple normal cell types sets MUC1 as an antigen that appears suboptimal for the target therapy of PCa. Nonetheless, recent efforts from two companies, Minerva Biotechnologies and Poseida Therapeutics, to identify binders that can reliably discriminate between cancer-specific MUC1 species (known as MUC1* or MUC1C) and the full-length MUC1 present on normal cells, have translated into the design of CAR T cells [57] showing robust anti-tumor activity in mouse xenotransplant models [58-60], with a Phase I clinical trial of MUC1*-specific CAR T cells announced for breast cancer patients (NCT04020575).
At the same time, Tn Muc1/sTn Muc1 species predominantly, although not exclusively expressed on the surface of cancerous, rather than normal tissues serve as attractive alternatives to MUC1 for CAR T cell-based therapy [61, 62], with a recently opened early phase clinical trial of TnMuc1-specific CAR T cells in advanced (non-PCa) solid cancer and multiple myeloma patients (NCT04025216). Except for one report [63], expression of these glycopeptide antigens has been extensively explored using a number of mAbs [64-66] (reviewed in [67]) in cancers other than PCa [61, 68]) and warrants further investigation, as the data have been somewhat difficult to reconcile [69].
TAG-72 epitope, established to be a sialyl-Tn O-glycan carbohydrate hapten, has been found in the vast majority of human carcinomas, including PCa. Given its rather restricted expression pattern in normal tissues [70, 71] and favorable safety profile of anti-TAG72 mAbs [72, 73], first-generation TAG-72-specific CAR T cells have been extensively evaluated both pre-clinically [74] and in two early clinical trials [75] for metastatic colorectal cancer, where they proved to be safe and inefficient largely due to the poor persistence afforded by the CAR design and rapid anti-idiotype elimination. Recent study using local delivery of optimized second-generation TAG-72-CART cells in a xenotransplanted ovarian cancer model [76] provides a strong rationale for testing TAG-72 as a promising target for CAR T cells in epithelial carcinomas including PCa.
Integrin αvβ3 is another marker frequently found on PCa cells, as well as on endothelial cells of the tumor vasculature. Expression of this protein is associated with higher risk of metastatic bone lesions [77-79]. Monoclonal αvβ3-specific antibody LM609 and a humanized derivative of LM609 have been characterized in phase I clinical trials which confirmed their safety [80], however no reports of therapeutic activity in the completed phase II clinical trial (NCT00072930) have been posted since 2008, consistent with the complex biology of αvβ3 in cancer [81]. Intriguingly, a recent study reported on the activity of hLM609-derived αvβ3-specific CAR T cells both in vitro and in vivo, in the setting of xenotransplanted human melanoma [82].
CEACAM5 and CEACAM6 are two related proteins expressed at comparable levels on both PCa and normal prostate cells [83]. Variable levels of expression of these proteins have also been reported for normal cells of the lung, pancreas, and intestine. Safety of the cell therapy targeting CEACAM5 was analyzed in several studies and the results were somewhat conflicting. Use of CEACAM5-specific recTCR-T cells was accompanied with serious colitis in all three patients who received the cell products [84]. This was unlike the situation reported for CEACAM5-specific CAR T cells based on the MFE23 scFv, where acute respiratory toxicity was observed [85]. Notably, infusion of CEACAM5-specific CAR T cells based on the alternative antigen recognition modules was not accompanied with critical adverse effects in two more clinical studies [86,87]. So far, CEACAM5-specific CAR T cells have not been tested in PCa patients. As for, CEACAM6-specific CAR T cells, the studies have not yet progressed beyond mouse xenotranplant models, and safety of such CAR T cells in humans is presently unknown [88].
TROP-2 (TACSTD2) is expressed on both benign and malignant prostate lesions [89, 90], yet it is also detectable on the normal epithelial cells of various origin [91]. No clinical trials of TROP-2-specific CAR T cells have so far been approved, however TROP-2-specific antibody-drug conjugates have been tested in patients and numerous adverse effects have been reported [92]. Hence, the safety of TROP-2-targeted CAR T cell therapy is presently questionable.
Finally, two B7-CD28 family members, B7-H3 (CD276) and B7x (VTCN1/B7-H4) have been reported to be overexpressed in a variety of cancers including PCa [93,94] (reviewed in [95, 96]), and are currently the focus of pre-clinical CAR T cell evaluation programs using AML [97], lung [98], breast [99], bile duct [100], bone and brain [101-103] cancer cells as the targets. Importantly, the findings of Phase I/IIa clinical trials of B7-H3-specific monoclonal antibody MGA271 (enoblituzumab) support its favorable safety profile [104], although surface expression of B7-H3 has been demonstrated for several normal cell types such as dendritic cells, as well as in vitro activated T-, NK- and B cells [105]. Accordingly, B7-H3-specific CARs did not display appreciable off-tumor activity in pre-clinical tests, but they may still require structural/affinity optimization to robustly discriminate between different expression levels of this antigen on normal and malignant cells upon transition to human trials. Interestingly, delayed lethal off-tumor toxicity has recently been observed for B7x-specific CAR T cells [106].
Conclusion
None of the abovementioned markers are absolutely specific for PCa or found across PCa lesions in all patients. Furthermore, a fraction of PCa tumors may be expected to be negative for all such markers, and, hence, the feasibility of delivering a targeted CAR therapy would be very low in such cases. Thus, systematic discovery of novel PCa surface markers is highly warranted. Only a handful of studies in this direction have been published to date. For instance, using a combination of proteomic and transcriptomic profiling, Lee and colleagues have identified a number of surface markers enriched in PCa subtypes [107]. Whereas the identification of known PCa markers such as CEACAM5, PSMA, STEAP1, MUC1, and TROP-2 clearly validates this approach, the rest of the high-ranking proteins reported appear to be strongly and broadly expressed in essential tissues, which makes unlikely their potential use as CAR targets.
Analysis of antibodies present in the sera of convalescent cancer patients following immunotherapy who have developed an anticancer immune response may represent an interesting resource of antigen-recognition modules in CAR design. In line with this idea, GuhaThakurta and colleagues have profiled the specificity of antibodies from 25 mCRPC patients who received a dendritic cell-based vaccine sipuleucel-T [46]. Moderate, yet significant increase in antibody titers to PCTA-1 and Galectin-3 among others was observed. The former protein has already been known as a PCa marker, whereas the latter is predominantly secreted, and is a poor candidate for CAR targeting. Nonetheless, in our opinion this approach appears highly promising. In the context of other types of cancer, antibody profiling has identified a number of putative cancer markers including Galectin-1 [108], MYPT1, PSMC5, etc [109]. Importantly, despite the fact that the above proteins lack protein domains that would anchor them at the cell surface, this approach may still be fruitful once substantially more patient samples are analyzed. Of special interest is the recent advance in the technology of single-cell profiling of repertoires of B- and T- cell receptors [110], which may help identify target-receptor pairs, once combined with the proteomics data. Using the above approaches, analysis of samples from more PCa patients may be required to capture novel or subtype-specific PCa markers, or to confidently conclude that no such targets beyond the described ones exist, and that combinations of the known targets should be exploited for CAR design.
Acknowledgements
This work was supported by the Russian Ministry of Education and Science (Agreement # 075-15-2019-1246, unique project identifier RFMEFI60417X0169).
The authors report no conflicts of interests.
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Сергей В. Кулемзин1, Андрей А. Горчаков1,2, Александр В. Таранин1,2
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2 Новосибирский государственный университет, Новосибирск, Россия
Несмотря на значительный прогресс в области таргетной, химио- и радиотерапии, количество вариантов для пациентов с метастатическим кастрационно-резистентным раком предстательной железы остается невысоким. Большие надежды возлагались на дендритно-клеточные вакцины, в частности на sipuleucel-T, однако не все пациенты отвечают на этот тип терапии. Учитывая впечатляющий успех CAR T-клеток для лечения онкогематологических заболеваний, многие исследовательские группы начали разработку подходов CAR T-клеточной терапии кастрационно-резистентного рака предстательной железы. Из-за этого особенно актуальным стал вопрос об уникальных белках-мишенях рака простаты для CAR Т-клеточной терапии. В идеале такие белки должны отсутствовать на поверхности нормальных клеток, экспрессироваться на всех раковых клетках у всех пациентов и быть незаменимыми для выживания раковой клетки. На практике, однако, ни один из описанных к настоящему моменту поверхностных белков-маркеров рака простаты не отвечает всем указанным требованиям. В настоящем обзоре рассмотрены основные белки-мишени для CAR T-клеточной терапии рака простаты, обсуждается их безопасность и потенциальная эффективность.
Ключевые слова
Метастатический рак предстательной железы, иммунотерапия, химерные антигенные рецепторы, CAR T-клетки.
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2 Novosibirsk State University, Novosibirsk, Russia
Despite the progress achieved in target, chemo-, and radiotherapy, treatment options for patients with late-stage metastatic castration-resistant prostate cancer are presently very limited. Use of dendritic cell-based vaccines exemplified by sipuleucel-T appears is rarely curative and is effective in only a fraction of such patients. Given the success of CAR T cell therapy in the field of B cell malignancies, significant efforts have been made to adapt this powerful technology to the problem of metastatic prostate cancer. Availability of unique prostate cancer surface targets for CAR T cells has thereby become a pressing issue in the field of CAR design. Ideally, such targets should be absent from normal cells or tissues, be present on all prostate cancer cells across all patients, and be indispensable for the survival of cancer cells. In reality, however, none of the prostate cancer-associated surface markers described to date are matching such description. Here, we catalogue the list of tested as well as prospective surface antigens to be used as targets for CAR T cell therapy, and discuss the aspects of their safety and potential efficacy.
Keywords
Metastatic prostate cancer, immunotherapy, chimeric antigen receptor, CAR T cells.
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" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24481" ["VALUE"]=> array(2) { ["TEXT"]=> string(1392) "<p style="text-align: justify;">Despite the progress achieved in target, chemo-, and radiotherapy, treatment options for patients with late-stage metastatic castration-resistant prostate cancer are presently very limited. Use of dendritic cell-based vaccines exemplified by sipuleucel-T appears is rarely curative and is effective in only a fraction of such patients. Given the success of CAR T cell therapy in the field of B cell malignancies, significant efforts have been made to adapt this powerful technology to the problem of metastatic prostate cancer. Availability of unique prostate cancer surface targets for CAR T cells has thereby become a pressing issue in the field of CAR design. Ideally, such targets should be absent from normal cells or tissues, be present on all prostate cancer cells across all patients, and be indispensable for the survival of cancer cells. In reality, however, none of the prostate cancer-associated surface markers described to date are matching such description. Here, we catalogue the list of tested as well as prospective surface antigens to be used as targets for CAR T cell therapy, and discuss the aspects of their safety and potential efficacy.</p> <h2>Keywords</h2> <p style="text-align: justify;">Metastatic prostate cancer, immunotherapy, chimeric antigen receptor, CAR T cells.</p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1336) "Despite the progress achieved in target, chemo-, and radiotherapy, treatment options for patients with late-stage metastatic castration-resistant prostate cancer are presently very limited. Use of dendritic cell-based vaccines exemplified by sipuleucel-T appears is rarely curative and is effective in only a fraction of such patients. Given the success of CAR T cell therapy in the field of B cell malignancies, significant efforts have been made to adapt this powerful technology to the problem of metastatic prostate cancer. Availability of unique prostate cancer surface targets for CAR T cells has thereby become a pressing issue in the field of CAR design. Ideally, such targets should be absent from normal cells or tissues, be present on all prostate cancer cells across all patients, and be indispensable for the survival of cancer cells. In reality, however, none of the prostate cancer-associated surface markers described to date are matching such description. Here, we catalogue the list of tested as well as prospective surface antigens to be used as targets for CAR T cell therapy, and discuss the aspects of their safety and potential efficacy.
Keywords
Metastatic prostate cancer, immunotherapy, chimeric antigen receptor, CAR T cells.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1336) "Despite the progress achieved in target, chemo-, and radiotherapy, treatment options for patients with late-stage metastatic castration-resistant prostate cancer are presently very limited. Use of dendritic cell-based vaccines exemplified by sipuleucel-T appears is rarely curative and is effective in only a fraction of such patients. Given the success of CAR T cell therapy in the field of B cell malignancies, significant efforts have been made to adapt this powerful technology to the problem of metastatic prostate cancer. Availability of unique prostate cancer surface targets for CAR T cells has thereby become a pressing issue in the field of CAR design. Ideally, such targets should be absent from normal cells or tissues, be present on all prostate cancer cells across all patients, and be indispensable for the survival of cancer cells. In reality, however, none of the prostate cancer-associated surface markers described to date are matching such description. Here, we catalogue the list of tested as well as prospective surface antigens to be used as targets for CAR T cell therapy, and discuss the aspects of their safety and potential efficacy.
Keywords
Metastatic prostate cancer, immunotherapy, chimeric antigen receptor, CAR T cells.
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2 Novosibirsk State University, Novosibirsk, Russia
1 Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
2 Novosibirsk State University, Novosibirsk, Russia
Сергей В. Кулемзин1, Андрей А. Горчаков1,2, Александр В. Таранин1,2
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Kulemzin" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24477" ["VALUE"]=> array(2) { ["TEXT"]=> string(2513) "<p style="text-align: justify;">Несмотря на значительный прогресс в области таргетной, химио- и радиотерапии, количество вариантов для пациентов с метастатическим кастрационно-резистентным раком предстательной железы остается невысоким. Большие надежды возлагались на дендритно-клеточные вакцины, в частности на sipuleucel-T, однако не все пациенты отвечают на этот тип терапии. Учитывая впечатляющий успех CAR T-клеток для лечения онкогематологических заболеваний, многие исследовательские группы начали разработку подходов CAR T-клеточной терапии кастрационно-резистентного рака предстательной железы. Из-за этого особенно актуальным стал вопрос об уникальных белках-мишенях рака простаты для CAR Т-клеточной терапии. В идеале такие белки должны отсутствовать на поверхности нормальных клеток, экспрессироваться на всех раковых клетках у всех пациентов и быть незаменимыми для выживания раковой клетки. На практике, однако, ни один из описанных к настоящему моменту поверхностных белков-маркеров рака простаты не отвечает всем указанным требованиям. В настоящем обзоре рассмотрены основные белки-мишени для CAR T-клеточной терапии рака простаты, обсуждается их безопасность и потенциальная эффективность.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Метастатический рак предстательной железы, иммунотерапия, химерные антигенные рецепторы, CAR T-клетки. </p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2457) "Несмотря на значительный прогресс в области таргетной, химио- и радиотерапии, количество вариантов для пациентов с метастатическим кастрационно-резистентным раком предстательной железы остается невысоким. Большие надежды возлагались на дендритно-клеточные вакцины, в частности на sipuleucel-T, однако не все пациенты отвечают на этот тип терапии. Учитывая впечатляющий успех CAR T-клеток для лечения онкогематологических заболеваний, многие исследовательские группы начали разработку подходов CAR T-клеточной терапии кастрационно-резистентного рака предстательной железы. Из-за этого особенно актуальным стал вопрос об уникальных белках-мишенях рака простаты для CAR Т-клеточной терапии. В идеале такие белки должны отсутствовать на поверхности нормальных клеток, экспрессироваться на всех раковых клетках у всех пациентов и быть незаменимыми для выживания раковой клетки. На практике, однако, ни один из описанных к настоящему моменту поверхностных белков-маркеров рака простаты не отвечает всем указанным требованиям. В настоящем обзоре рассмотрены основные белки-мишени для CAR T-клеточной терапии рака простаты, обсуждается их безопасность и потенциальная эффективность.
Ключевые слова
Метастатический рак предстательной железы, иммунотерапия, химерные антигенные рецепторы, CAR T-клетки.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2457) "Несмотря на значительный прогресс в области таргетной, химио- и радиотерапии, количество вариантов для пациентов с метастатическим кастрационно-резистентным раком предстательной железы остается невысоким. Большие надежды возлагались на дендритно-клеточные вакцины, в частности на sipuleucel-T, однако не все пациенты отвечают на этот тип терапии. Учитывая впечатляющий успех CAR T-клеток для лечения онкогематологических заболеваний, многие исследовательские группы начали разработку подходов CAR T-клеточной терапии кастрационно-резистентного рака предстательной железы. Из-за этого особенно актуальным стал вопрос об уникальных белках-мишенях рака простаты для CAR Т-клеточной терапии. В идеале такие белки должны отсутствовать на поверхности нормальных клеток, экспрессироваться на всех раковых клетках у всех пациентов и быть незаменимыми для выживания раковой клетки. На практике, однако, ни один из описанных к настоящему моменту поверхностных белков-маркеров рака простаты не отвечает всем указанным требованиям. В настоящем обзоре рассмотрены основные белки-мишени для CAR T-клеточной терапии рака простаты, обсуждается их безопасность и потенциальная эффективность.
Ключевые слова
Метастатический рак предстательной железы, иммунотерапия, химерные антигенные рецепторы, CAR T-клетки.
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2 Новосибирский государственный университет, Новосибирск, Россия
1 Институт молекулярной и клеточной биологии СО РАН, Новосибирск, Россия
2 Новосибирский государственный университет, Новосибирск, Россия
Introduction
Discovery and clinical success of ICIs entered a new era in oncology. The 2018 Nobel Prize in Medicine was awarded to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". The principal role of immune system in tumor control was understood long ago. Earlier researchers mostly explored the opportunities to activate the immune system by stimulation of effector cells ("pressing gas pedal"). James P. Allison and Tasuku Honjo demonstrated that inhibition of checkpoints ("releasing the brake pedal") may effectively upregulate the immune system.
The ICIs demonstrate substantial efficiency in cHL. Pembrolizumab was approved for the treatment of children with cHL, but the role of other ICIs in pediatrics should only to be elucidated. Despite impressive progress in oncology, the children with refractory or resistant (R-R) cHL still demonstrate suboptimal prognosis if ≥3 lines of therapies have to be used [1]. This group of R-R cHL patients needs new approaches in management, and ICIs are among the most promising candidate drugs. The discovery of CIs introduced principally novel approach to cancer cure. This may convert cancer to one of chronic diseases [2].
The principal feature of immunity is the ability to differ between autoantigens and alloantigens. But the immune system is not ideal and regularly makes mistakes. These errors are often mild and non-significant but sometimes may lead to serious consequences such as oncological, autoimmune or infectious diseases. Studying molecular mechanisms of antigen procession, presentation, co-stimulation and inhibition is crucial for the treatment of patients with tumors.
PD-1 (programmed cell death-1) gene was discovered during the research of cell apoptosis [3]. It took a long journey to understand the function of PD-1 [2]. In terms of physiological role (immune inhibition) the definition of PD-1 is relatively correct, due to fundamental position of apoptosis in tolerance. But, in general, the term PD-1 does not precisely reflect the function of the protein.
Structurally PD-1 is a transmembrane protein and its interaction with ligands (PD-L1 or PD-L2) results in activation of PD-1/PD-L pathway [4, 5]. This effect leads to downregulation of autoreactive T cells and upregulation of T regulatory cells [6]. Development of autoimmune disorders in the model of PD-1 knockout mice proved significance of the pathway for adequate immune regulation [7]. Excessive PD-1 expression due to continuous antigen stimulation results in T-cell exhaustion and tolerance [8]. This mechanism may be realized in tumors.
PD-1 and ligands are expressed constitutive or inducibly on many tissues. PD-1 is expressed on immune cells (T-helpers, cytotoxic T-lymphocytes, natural killers, B cells, monocytes and dendritic cells) [9]. PD-L1 has extensive distribution throughout the body while PD-L2 is only present on macrophages and dendritic cells. PD-L1 can be expressed on non-hematological structures, such as endothelial cells, fibroblasts, mucous, pancreatic islet cells, astrocytes, neurons, trophoblasts, retina, heart, placenta, skeletal muscle, lung and kidney [10, 11]. Presence of PD-1 on endothelial cells may play an important role in the prevention of T cell migration into tissues and establishment of blood-organ immunological barriers [12]. Both PD-1 and PD-L1 are present on T cells, В-cells, macrophages and dendritic cells. These cells possess bimodal opportunity to regulate and to be regulated by the pathway. Some tumors also have PD-L1 on its surface, and it allows them to be "invisible" to immune system [13]. The expression of PD-1 and ligands is controlled by cytokines. For example, interferon 1 and tumor necrosis factor-α stimulate PD-L1 expression. Theoretically, combining these drugs with inducers of PD-1/PD-L1 may improve the efficiency of ICIs.
Nivo and pembro are PD-1 blocking antibodies that have been approved by the U.S. Food and Drug Administration for the treatment of сHL and some solid tumors. They were also registered in Russian Federation for the management of adult patients (nivo and pembro) and children with сHL (pembro). In the majority of сHL patients, ICIs induce durable clinical response. Complete or partial recovery of tumor immune control results in significant attenuation of disease progression. Amplification of 9p24.1 and subsequent overexpression of PD-L1 seems to be the characteristic feature of HL-specific Reed-Sternberg cells [14]. It explains high efficiency of ICIs in cHL. However, most HL patients relapse after treatment with ICIs. Therefore, it is important to improve the results by shifting to combination therapy, incorporation of ICIs earlier in treatment and consolidation with HSCT [15]. We are only in the beginning of CIs era, and appropriate schemes and schedules are only to be discovered. For example, lower dosage of nivolumab could be comparable to standard dosage of 3 mg/kg biweekly [16].
The aim of our work was to assess safety and effectiveness of nivo in childhood R-R cHL.
Patients and methods
Twenty-one children and adolescents with R-R Hodgkin's lymphoma (HL) received nivo-based therapy in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Pavlov First St. Petersburg State Medical University (see Table 1 for patient´s characteristics). Median age was 16 years (9 to 18). Histological forms of HL were as follows: nodular sclerosis was diagnosed in 15 patients (71%); mixed cellularity cHL, 4 cases (19%), lymphocyte-rich cHL, 1 (5%) and nodular lymphocyte predominant Hodgkin's lymphoma, 1 (5%). At the onset of the disease, the early-stage favorable status was diagnosed in 4 patients (19%); early-stage unfavorable or advanced disease was diagnosed in 17 cases (81%). B-symptoms were documented in 12 patients (67%). Bulky disease (>7 cm) and extranodal lesions were registered in 12 (57%) and 14 (67%) children, respectively. The disease was refractory in 9 cases (43%), whereas resistant or multiple relapses occurred in 12 patients (57%).
Table 1. Patient´s characteristics (n=21)
Abbreviations: NSCHL (nodular sclerosis classical Hodgkin lymphoma), MCCHL (mixed cellularity classical Hodgkin lymphoma), NLPHL (nodular lymphocyte predominant Hodgkin's lymphoma), LRCHL (lymphocyte-rich classical Hodgkin lymphoma), OEPA/COPDAC (vincristine, etoposide, prednisolone, doxorubicin/cyclophosphamide, vincristine, prednisolone, dacarbazine), RT (radiotherapy), BEACOPP (bleomycin, etoposide, cytarabine, cyclophosphamide, vincristine, prednisolone, procarbazine), GDP (gemcitabine, dexamethasone, cisplatin), ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), DHAP (dexamethasone, cisplatin, cytarabine), ChVPP (chlorbutine, vinblastine, prednisolone, procarbazine), IEP/ABVD (ifosfamide, etoposide, prednisolone/doxorubicin, bleomycin, vinblastine, dacarbazine), VIGEPP (vinorelbine, gemcitabine, procarbazine, prednisolone), auto-HSCT (autologous hematopoietic stem cell transplantation), GemOx (gemcitabine, oxaliplatin), ICE (ifosfamide, carboplatin, etoposide), OPPA/COPP (vincristine, prednisolone, procarbazine, doxorubicin/cyclophosphamide, vincristine, prednisolone, procarbazine), IEP (ifosfamide, etoposide, prednisolone), IGEV (ifosfamide, gemcitabine, vinorelbine), COPP (cyclophosphamide, vincristine, prednisolone, procarbazine), CEMP (cyclophosphamide, etoposide, mitoxantron, prednisolone), COPP/ABV (cyclophosphamide, vincristine, prednisolone, procarbazine/doxorubicin, bleomycin, vinblastine), BV (brentuximab vedotin), rel (relapse), ref (refractory), mr (multiple relapses), mono/comb (monotherapy/combination therapy), R/R (relapsed/refractory), CR (complete response), PR (partial response), IR (indeterminate response), N/A – not applicable.
Median number of previous therapy lines was 4 (2-7) with radiation therapy in 14 patients (67%), and autologous HSCT in 6 cases (29%). Prior to nivo therapy, 16 children (76%) had progression; 3 (14%), stabilization, and 2 (10%), partial remission according to Lugano criteria [17]. All the patients received nivo in an outpatient setting. Monotherapy was used in 13 (62%) and combination with other drugs in 8 (38%). In 5 children, combination therapy was indicated, based on opinion of attended physician. In 3 cases, other drugs were added after slow clinical response to the first nivo infusions, aiming to achieve faster clinical improvement. Treatment schedule consisted of 3 mg/kg of nivo biweekly in 11 (52%) or 40 mg of nivo biweekly in 10 (48%). Combinations of nivo with following drugs were used: brentuximab vedotin 1.8 mg/kg triweekly (n=4) with median of 5 cycles (4-7), bendamustine 180 mg/m2 triweekly (n=3) with median of 5 cycles (5-7) and gemcitabine 1000 mg/m2 №5 weekly (n=1). Median number of nivo cycles was 9 (2-28). Response to treatment was evaluated by the LYRIC criteria [18]. They represent modified Lugano recommendations, with the addition of indeterminate response (IR). This category describes possible pseudo-progression and allows to continue ICIs hoping for further best response without discontinuation of treatment in the patients with progressive disease according to previous criterial algorithms. After nivo-based treatment, 8 patients (38%) received auto- or allogeneic hematopoietic stem cell transplantation (HSCT). Conditioning regimen in autologous HSCT (n=4) was BeEAM (bendamustine, etoposide, cytarabine and melphalan). Haploidentical donors were employed in two allo-HSCTs, and two matched related siblings were used in two other cases. The conditioning regimen in allogeneic HSCT consisted of bendamustine 360 mg/m2 and Fludarabine 150 mg/m2. Graft-versus-host disease prophylaxis was based on posttransplant cyclophosphamide and calcineurin inhibitors. Radiation therapy was applied to consolidate the effect of nivo in 2 cases (10%). Eleven patients (52%) did not receive any consolidation treatment.
Results
Clinical response to nivo-based therapy was assessed in 21 patients (100%). Efficiency of treatment is shown in Table 2. Overall response (ORR) was registered in 18 children (86%); CR, in 12 cases (57%); PR, in 6 patients (29%) and IR, in 3 cases (14%). Among the patients with IR, two children relapsed, and one patient is now in remission with the follow-up of 355 days. Monotherapy resulted in ORR of 92% (12 patients); CR, in 62% (8), and PR, in 30% of cases (4). Combination therapy demonstrated similar effectiveness, i.e., ORR, 6 (75%); CR, 4; (50%); PR, 2 (25%).
Table 2. Efficiency of Nivolumab-based therapy
The three-year OS rates comprised 95%. PFS rates at 1, 2 and 3 years were 69%, 58% and 29%, respectively (Fig. 1A and 1B). Median OS was not reached. With median follow-up of 391 days (47-1137), twenty patients (95%) were alive, and 14 (67%) remained in remission state. Median PFS was 24 months. Consolidation with HSCT (auto- or allo-) resulted in 3-year PFS of 75% (Fig. 2). Only 1 patient died in early posttransplant period due to infectious complications.
The general scheme of nivo-based therapy (mono- vs combined treatment), cHL stage (early vs advanced), tumor size (bulky+ vs bulky-), B symptoms, extranodal lesions, number of prior chemotherapy lines, preceding autoHSCT, number of nivo infusions (10 vs >10, see Fig. 3), and complications of therapy did not affect OS and PFS (p>0.1).
In the monotherapy group, complications of nivo were revealed in one adolescent (7.7%). This patient developed autoimmune thyroiditis which required hormone replacement therapy. It didn't lead to discontinuation of the drug. In combination therapy group, 2 patients (25%) developed transient cytopenias that could not be attributed solely to nivo and were probably associated with cytostatics.
Figure 1. Overall survival (A) and progression-free survival (B) of the patients treated with nivolumab (n=21)
Figure 2. Progression-free survival curves with HSCT vs without following HSCT in the patients treated with nivolumab
Figure 3. Progression-free survival curves among the patients treated with nivolumab (≤10 vs >10 infusions).
Discussion
ICIs have demonstrated high efficiency and acceptable safety profile both in adults and children in large cohorts of patients (Tables 3 and 4). Administration of ICIs in adult R-R HL results in overall response (ORR) of 64-82%, with 2-year PFS of approximately 30%-58.5% [1, 19]. The largest pediatric trial with pembro included 125 children. This study clearly demonstrated safety of ICIs in children. Only 7 (6%) had clinically significant adverse effects (grade 3-5). One patient (0.8%) with renal carcinoma experienced pembro-associated pulmonary edema and died.
Table 3. Efficiency of immune checkpoint inhibitors in adult cHL
Abbreviations: ORR, overall response rate; CR, complete response; PR, partial response; HSCT, hematopoietic stem cell transplantation; PFS, progression-free survival; N/A, not applicable
Table 4. Efficiency of immune checkpoint inhibitors in pediatric cohorts
Abbreviations: HL, Hodgkin's lymphoma; NHL, non- Hodgkin's lymphoma; ORR, overall response rate; CR, complete response; PR, partial response
No major interferences on the developing immune system were observed [20]. Another important trial included children with R-R cHL treated with combination of nivo and brentuximab vedotin. Drug-related complications were registered in 32% (grade 3-4) with neutropenia among the most common. Immune-mediated adverse effects were only grade 1-2 and included rash, hypersensitivity, infusion-related reactions and did not result in discontinuation of therapy [21].
In general, the results of the present study concerning nivo-based therapy in pediatric R-R cHL are in concordance with previously published data in adults and children [22]. Higher rates of CR in children and adolescents (57%) compared to adults (15-36%) may be associated with the differences of response evaluation in these studies, may represent a unique feature of pediatric sensitivity to IСIs or may be explained by limited patient number in the study [23, 24]. Despite similar ORR in mono- and combined therapy arms, the data from other investigators strongly support the opinion that additional drugs improve the effects of nivo [25, 26].
Suboptimal 3-year PFS of 29% in this heavily pretreated group (median number of prior lines – 4) replicates earlier data of CIs administration in adults and children [1, 20]. It is important to note that PFS rates at 1 and 2 years in our study are similar or higher than in above mentioned works and steadily decrease with time. It seems that PFS after nivo does not tend to reach plateau with time.
High ORR (86%) after nivo in R-R cHL solves a challenge of remission induction and bridging to HSCT that is now possible in the majority of children. There is an opinion of principal opportunity of ICIs to cure cHL but declining PFS curve argues it, and longer follow-up is needed to draw firm conclusion. Dissociation between high 3-year OS and low PFS marks a very characteristic feature of ICIs therapy in cHL that repairs immune tumor control and improves somatic status of a patient even in active disease. Slow subclinical progression probably is driven by other non-immune mechanisms of tumor escape. Median PFS in children and adolescents in our study is 24 months and well correlates with data in other publications [20]. Longer median PFS may be explained by combination of nivo with other drugs in 38%. The positive effects of nivo significantly prolong life expectancy with good quality of life. Consolidation of nivo-induced remission with HSCT (auto or allo) results in 3-year PFS of 75%. HSCT is a potential option to improve cure rates after ICIs.
There is no established consensus opinion when to proceed with HSCT after ICIs, and what type of HSCT should be chosen. Allogeneic HSCT may be preferable, due to presumed sensitivity of the patients to immunotherapy. But autologous HSCT still may be effective in chemorefractory cases, since a recovery of chemosensitivity after ICIs treatment is hypothesized [27]. There are investigators that use both allo-HSCT and auto-HSCT to consolidate the ICIs effect [22, 24]. At the same time, an impressively high 3-year OS rate (95%) after nivo in our study, even in patients with progression, questions the need for transplantation at all [28]. Extensive follow-up is required to understand how long this clinical stabilization of cHL will continue in the majority of patients. In other words, can cHL be "cured" with morphologically and visibly obvious tumor, and if these patients may have a near-normal life expectancy similar to heathy people? This proposal seems more fantastic than real, and a longer follow-up is needed to see whether such observations will appear. Despite theoretical importance, the classical prognostic factors did not affect OS and PFS in our study. It may be explained by the domination of chemoresistance in our patients that minimizes the role of all other factors. Higher number of nivo cycles also did not improve outcome in our study. It emphasizes the challenging unsolved problem of optimal nivo treatment duration. Hypothetically, earlier consolidation with HSCT can minimize nivo-associated complications without loss of efficiency.
Only one clinically significant AE of nivo therapy was registered in the study, i.e., autoimmune thyroiditis which is a typical complication of the drug. Other characteristic autoimmune AEs were not encountered, probably due to limited patient number. All children and adolescents received nivo in outpatient setting, thus reflecting high tolerability and technical simplicity of treatment.
Conclusion
Nivo-based therapy is effective in the majority of children and adolescents with R-R cHL. In heavily pretreated patients, long-term PFS remains suboptimal, despite excellent OS levels. Consolidation with HSCT after nivo results in 75% PFS at 3 years and should be considered in the majority of patients. Nivo-based therapy is relatively safe with only one clinically significant adverse effect (autoimmune thyroiditis) observed in our study. Nivo is technically simple and well tolerable treatment that is administered in an outpatient setting.
Conflict of interest
None declared.
References
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Introduction
Discovery and clinical success of ICIs entered a new era in oncology. The 2018 Nobel Prize in Medicine was awarded to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". The principal role of immune system in tumor control was understood long ago. Earlier researchers mostly explored the opportunities to activate the immune system by stimulation of effector cells ("pressing gas pedal"). James P. Allison and Tasuku Honjo demonstrated that inhibition of checkpoints ("releasing the brake pedal") may effectively upregulate the immune system.
The ICIs demonstrate substantial efficiency in cHL. Pembrolizumab was approved for the treatment of children with cHL, but the role of other ICIs in pediatrics should only to be elucidated. Despite impressive progress in oncology, the children with refractory or resistant (R-R) cHL still demonstrate suboptimal prognosis if ≥3 lines of therapies have to be used [1]. This group of R-R cHL patients needs new approaches in management, and ICIs are among the most promising candidate drugs. The discovery of CIs introduced principally novel approach to cancer cure. This may convert cancer to one of chronic diseases [2].
The principal feature of immunity is the ability to differ between autoantigens and alloantigens. But the immune system is not ideal and regularly makes mistakes. These errors are often mild and non-significant but sometimes may lead to serious consequences such as oncological, autoimmune or infectious diseases. Studying molecular mechanisms of antigen procession, presentation, co-stimulation and inhibition is crucial for the treatment of patients with tumors.
PD-1 (programmed cell death-1) gene was discovered during the research of cell apoptosis [3]. It took a long journey to understand the function of PD-1 [2]. In terms of physiological role (immune inhibition) the definition of PD-1 is relatively correct, due to fundamental position of apoptosis in tolerance. But, in general, the term PD-1 does not precisely reflect the function of the protein.
Structurally PD-1 is a transmembrane protein and its interaction with ligands (PD-L1 or PD-L2) results in activation of PD-1/PD-L pathway [4, 5]. This effect leads to downregulation of autoreactive T cells and upregulation of T regulatory cells [6]. Development of autoimmune disorders in the model of PD-1 knockout mice proved significance of the pathway for adequate immune regulation [7]. Excessive PD-1 expression due to continuous antigen stimulation results in T-cell exhaustion and tolerance [8]. This mechanism may be realized in tumors.
PD-1 and ligands are expressed constitutive or inducibly on many tissues. PD-1 is expressed on immune cells (T-helpers, cytotoxic T-lymphocytes, natural killers, B cells, monocytes and dendritic cells) [9]. PD-L1 has extensive distribution throughout the body while PD-L2 is only present on macrophages and dendritic cells. PD-L1 can be expressed on non-hematological structures, such as endothelial cells, fibroblasts, mucous, pancreatic islet cells, astrocytes, neurons, trophoblasts, retina, heart, placenta, skeletal muscle, lung and kidney [10, 11]. Presence of PD-1 on endothelial cells may play an important role in the prevention of T cell migration into tissues and establishment of blood-organ immunological barriers [12]. Both PD-1 and PD-L1 are present on T cells, В-cells, macrophages and dendritic cells. These cells possess bimodal opportunity to regulate and to be regulated by the pathway. Some tumors also have PD-L1 on its surface, and it allows them to be "invisible" to immune system [13]. The expression of PD-1 and ligands is controlled by cytokines. For example, interferon 1 and tumor necrosis factor-α stimulate PD-L1 expression. Theoretically, combining these drugs with inducers of PD-1/PD-L1 may improve the efficiency of ICIs.
Nivo and pembro are PD-1 blocking antibodies that have been approved by the U.S. Food and Drug Administration for the treatment of сHL and some solid tumors. They were also registered in Russian Federation for the management of adult patients (nivo and pembro) and children with сHL (pembro). In the majority of сHL patients, ICIs induce durable clinical response. Complete or partial recovery of tumor immune control results in significant attenuation of disease progression. Amplification of 9p24.1 and subsequent overexpression of PD-L1 seems to be the characteristic feature of HL-specific Reed-Sternberg cells [14]. It explains high efficiency of ICIs in cHL. However, most HL patients relapse after treatment with ICIs. Therefore, it is important to improve the results by shifting to combination therapy, incorporation of ICIs earlier in treatment and consolidation with HSCT [15]. We are only in the beginning of CIs era, and appropriate schemes and schedules are only to be discovered. For example, lower dosage of nivolumab could be comparable to standard dosage of 3 mg/kg biweekly [16].
The aim of our work was to assess safety and effectiveness of nivo in childhood R-R cHL.
Patients and methods
Twenty-one children and adolescents with R-R Hodgkin's lymphoma (HL) received nivo-based therapy in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Pavlov First St. Petersburg State Medical University (see Table 1 for patient´s characteristics). Median age was 16 years (9 to 18). Histological forms of HL were as follows: nodular sclerosis was diagnosed in 15 patients (71%); mixed cellularity cHL, 4 cases (19%), lymphocyte-rich cHL, 1 (5%) and nodular lymphocyte predominant Hodgkin's lymphoma, 1 (5%). At the onset of the disease, the early-stage favorable status was diagnosed in 4 patients (19%); early-stage unfavorable or advanced disease was diagnosed in 17 cases (81%). B-symptoms were documented in 12 patients (67%). Bulky disease (>7 cm) and extranodal lesions were registered in 12 (57%) and 14 (67%) children, respectively. The disease was refractory in 9 cases (43%), whereas resistant or multiple relapses occurred in 12 patients (57%).
Table 1. Patient´s characteristics (n=21)
Abbreviations: NSCHL (nodular sclerosis classical Hodgkin lymphoma), MCCHL (mixed cellularity classical Hodgkin lymphoma), NLPHL (nodular lymphocyte predominant Hodgkin's lymphoma), LRCHL (lymphocyte-rich classical Hodgkin lymphoma), OEPA/COPDAC (vincristine, etoposide, prednisolone, doxorubicin/cyclophosphamide, vincristine, prednisolone, dacarbazine), RT (radiotherapy), BEACOPP (bleomycin, etoposide, cytarabine, cyclophosphamide, vincristine, prednisolone, procarbazine), GDP (gemcitabine, dexamethasone, cisplatin), ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), DHAP (dexamethasone, cisplatin, cytarabine), ChVPP (chlorbutine, vinblastine, prednisolone, procarbazine), IEP/ABVD (ifosfamide, etoposide, prednisolone/doxorubicin, bleomycin, vinblastine, dacarbazine), VIGEPP (vinorelbine, gemcitabine, procarbazine, prednisolone), auto-HSCT (autologous hematopoietic stem cell transplantation), GemOx (gemcitabine, oxaliplatin), ICE (ifosfamide, carboplatin, etoposide), OPPA/COPP (vincristine, prednisolone, procarbazine, doxorubicin/cyclophosphamide, vincristine, prednisolone, procarbazine), IEP (ifosfamide, etoposide, prednisolone), IGEV (ifosfamide, gemcitabine, vinorelbine), COPP (cyclophosphamide, vincristine, prednisolone, procarbazine), CEMP (cyclophosphamide, etoposide, mitoxantron, prednisolone), COPP/ABV (cyclophosphamide, vincristine, prednisolone, procarbazine/doxorubicin, bleomycin, vinblastine), BV (brentuximab vedotin), rel (relapse), ref (refractory), mr (multiple relapses), mono/comb (monotherapy/combination therapy), R/R (relapsed/refractory), CR (complete response), PR (partial response), IR (indeterminate response), N/A – not applicable.
Median number of previous therapy lines was 4 (2-7) with radiation therapy in 14 patients (67%), and autologous HSCT in 6 cases (29%). Prior to nivo therapy, 16 children (76%) had progression; 3 (14%), stabilization, and 2 (10%), partial remission according to Lugano criteria [17]. All the patients received nivo in an outpatient setting. Monotherapy was used in 13 (62%) and combination with other drugs in 8 (38%). In 5 children, combination therapy was indicated, based on opinion of attended physician. In 3 cases, other drugs were added after slow clinical response to the first nivo infusions, aiming to achieve faster clinical improvement. Treatment schedule consisted of 3 mg/kg of nivo biweekly in 11 (52%) or 40 mg of nivo biweekly in 10 (48%). Combinations of nivo with following drugs were used: brentuximab vedotin 1.8 mg/kg triweekly (n=4) with median of 5 cycles (4-7), bendamustine 180 mg/m2 triweekly (n=3) with median of 5 cycles (5-7) and gemcitabine 1000 mg/m2 №5 weekly (n=1). Median number of nivo cycles was 9 (2-28). Response to treatment was evaluated by the LYRIC criteria [18]. They represent modified Lugano recommendations, with the addition of indeterminate response (IR). This category describes possible pseudo-progression and allows to continue ICIs hoping for further best response without discontinuation of treatment in the patients with progressive disease according to previous criterial algorithms. After nivo-based treatment, 8 patients (38%) received auto- or allogeneic hematopoietic stem cell transplantation (HSCT). Conditioning regimen in autologous HSCT (n=4) was BeEAM (bendamustine, etoposide, cytarabine and melphalan). Haploidentical donors were employed in two allo-HSCTs, and two matched related siblings were used in two other cases. The conditioning regimen in allogeneic HSCT consisted of bendamustine 360 mg/m2 and Fludarabine 150 mg/m2. Graft-versus-host disease prophylaxis was based on posttransplant cyclophosphamide and calcineurin inhibitors. Radiation therapy was applied to consolidate the effect of nivo in 2 cases (10%). Eleven patients (52%) did not receive any consolidation treatment.
Results
Clinical response to nivo-based therapy was assessed in 21 patients (100%). Efficiency of treatment is shown in Table 2. Overall response (ORR) was registered in 18 children (86%); CR, in 12 cases (57%); PR, in 6 patients (29%) and IR, in 3 cases (14%). Among the patients with IR, two children relapsed, and one patient is now in remission with the follow-up of 355 days. Monotherapy resulted in ORR of 92% (12 patients); CR, in 62% (8), and PR, in 30% of cases (4). Combination therapy demonstrated similar effectiveness, i.e., ORR, 6 (75%); CR, 4; (50%); PR, 2 (25%).
Table 2. Efficiency of Nivolumab-based therapy
The three-year OS rates comprised 95%. PFS rates at 1, 2 and 3 years were 69%, 58% and 29%, respectively (Fig. 1A and 1B). Median OS was not reached. With median follow-up of 391 days (47-1137), twenty patients (95%) were alive, and 14 (67%) remained in remission state. Median PFS was 24 months. Consolidation with HSCT (auto- or allo-) resulted in 3-year PFS of 75% (Fig. 2). Only 1 patient died in early posttransplant period due to infectious complications.
The general scheme of nivo-based therapy (mono- vs combined treatment), cHL stage (early vs advanced), tumor size (bulky+ vs bulky-), B symptoms, extranodal lesions, number of prior chemotherapy lines, preceding autoHSCT, number of nivo infusions (10 vs >10, see Fig. 3), and complications of therapy did not affect OS and PFS (p>0.1).
In the monotherapy group, complications of nivo were revealed in one adolescent (7.7%). This patient developed autoimmune thyroiditis which required hormone replacement therapy. It didn't lead to discontinuation of the drug. In combination therapy group, 2 patients (25%) developed transient cytopenias that could not be attributed solely to nivo and were probably associated with cytostatics.
Figure 1. Overall survival (A) and progression-free survival (B) of the patients treated with nivolumab (n=21)
Figure 2. Progression-free survival curves with HSCT vs without following HSCT in the patients treated with nivolumab
Figure 3. Progression-free survival curves among the patients treated with nivolumab (≤10 vs >10 infusions).
Discussion
ICIs have demonstrated high efficiency and acceptable safety profile both in adults and children in large cohorts of patients (Tables 3 and 4). Administration of ICIs in adult R-R HL results in overall response (ORR) of 64-82%, with 2-year PFS of approximately 30%-58.5% [1, 19]. The largest pediatric trial with pembro included 125 children. This study clearly demonstrated safety of ICIs in children. Only 7 (6%) had clinically significant adverse effects (grade 3-5). One patient (0.8%) with renal carcinoma experienced pembro-associated pulmonary edema and died.
Table 3. Efficiency of immune checkpoint inhibitors in adult cHL
Abbreviations: ORR, overall response rate; CR, complete response; PR, partial response; HSCT, hematopoietic stem cell transplantation; PFS, progression-free survival; N/A, not applicable
Table 4. Efficiency of immune checkpoint inhibitors in pediatric cohorts
Abbreviations: HL, Hodgkin's lymphoma; NHL, non- Hodgkin's lymphoma; ORR, overall response rate; CR, complete response; PR, partial response
No major interferences on the developing immune system were observed [20]. Another important trial included children with R-R cHL treated with combination of nivo and brentuximab vedotin. Drug-related complications were registered in 32% (grade 3-4) with neutropenia among the most common. Immune-mediated adverse effects were only grade 1-2 and included rash, hypersensitivity, infusion-related reactions and did not result in discontinuation of therapy [21].
In general, the results of the present study concerning nivo-based therapy in pediatric R-R cHL are in concordance with previously published data in adults and children [22]. Higher rates of CR in children and adolescents (57%) compared to adults (15-36%) may be associated with the differences of response evaluation in these studies, may represent a unique feature of pediatric sensitivity to IСIs or may be explained by limited patient number in the study [23, 24]. Despite similar ORR in mono- and combined therapy arms, the data from other investigators strongly support the opinion that additional drugs improve the effects of nivo [25, 26].
Suboptimal 3-year PFS of 29% in this heavily pretreated group (median number of prior lines – 4) replicates earlier data of CIs administration in adults and children [1, 20]. It is important to note that PFS rates at 1 and 2 years in our study are similar or higher than in above mentioned works and steadily decrease with time. It seems that PFS after nivo does not tend to reach plateau with time.
High ORR (86%) after nivo in R-R cHL solves a challenge of remission induction and bridging to HSCT that is now possible in the majority of children. There is an opinion of principal opportunity of ICIs to cure cHL but declining PFS curve argues it, and longer follow-up is needed to draw firm conclusion. Dissociation between high 3-year OS and low PFS marks a very characteristic feature of ICIs therapy in cHL that repairs immune tumor control and improves somatic status of a patient even in active disease. Slow subclinical progression probably is driven by other non-immune mechanisms of tumor escape. Median PFS in children and adolescents in our study is 24 months and well correlates with data in other publications [20]. Longer median PFS may be explained by combination of nivo with other drugs in 38%. The positive effects of nivo significantly prolong life expectancy with good quality of life. Consolidation of nivo-induced remission with HSCT (auto or allo) results in 3-year PFS of 75%. HSCT is a potential option to improve cure rates after ICIs.
There is no established consensus opinion when to proceed with HSCT after ICIs, and what type of HSCT should be chosen. Allogeneic HSCT may be preferable, due to presumed sensitivity of the patients to immunotherapy. But autologous HSCT still may be effective in chemorefractory cases, since a recovery of chemosensitivity after ICIs treatment is hypothesized [27]. There are investigators that use both allo-HSCT and auto-HSCT to consolidate the ICIs effect [22, 24]. At the same time, an impressively high 3-year OS rate (95%) after nivo in our study, even in patients with progression, questions the need for transplantation at all [28]. Extensive follow-up is required to understand how long this clinical stabilization of cHL will continue in the majority of patients. In other words, can cHL be "cured" with morphologically and visibly obvious tumor, and if these patients may have a near-normal life expectancy similar to heathy people? This proposal seems more fantastic than real, and a longer follow-up is needed to see whether such observations will appear. Despite theoretical importance, the classical prognostic factors did not affect OS and PFS in our study. It may be explained by the domination of chemoresistance in our patients that minimizes the role of all other factors. Higher number of nivo cycles also did not improve outcome in our study. It emphasizes the challenging unsolved problem of optimal nivo treatment duration. Hypothetically, earlier consolidation with HSCT can minimize nivo-associated complications without loss of efficiency.
Only one clinically significant AE of nivo therapy was registered in the study, i.e., autoimmune thyroiditis which is a typical complication of the drug. Other characteristic autoimmune AEs were not encountered, probably due to limited patient number. All children and adolescents received nivo in outpatient setting, thus reflecting high tolerability and technical simplicity of treatment.
Conclusion
Nivo-based therapy is effective in the majority of children and adolescents with R-R cHL. In heavily pretreated patients, long-term PFS remains suboptimal, despite excellent OS levels. Consolidation with HSCT after nivo results in 75% PFS at 3 years and should be considered in the majority of patients. Nivo-based therapy is relatively safe with only one clinically significant adverse effect (autoimmune thyroiditis) observed in our study. Nivo is technically simple and well tolerable treatment that is administered in an outpatient setting.
Conflict of interest
None declared.
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Андрей В. Козлов, Илья В. Казанцев, Татьяна В. Юхта, Полина С. Толкунова, Дарья А. Звягинцева, Асмик Г. Геворгян, Антон В. Малородов, Кирилл В. Лепик, Юрий Р. Залялов, Александр Н. Швецов, Анна В. Ботина, Вадим В. Байков, Елена В. Морозова, Юрий А. Пунанов, Наталья Б. Михайлова, Людмила С. Зубаровская, Борис В. Афанасьев
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24864" ["VALUE"]=> array(2) { ["TEXT"]=> string(1931) "<p style="text-align: justify;">Ингибиторы контрольных точек показали высокую эффективность в лечении классической лимфомы Ходжкина (кЛХ). Пембролизумаб одобрен для применения у детей. Назначение данного препарата приводит к высокой частоте ответа на терапию и является относительно безопасным. Роль ниволумаба у детей с кЛХ еще только предстоит определить. Целями представленной работы были оценка эффективности и оценка побочных эффектов у детей с рецидивирующим и рефрактерным течением кЛХ. Терапия на основе ниволумаба была проведена у 21-го предлеченного пациента (9-18 лет) с кЛХ. Общий ответ отмечался у 86 % (полный ответ – 57% и частичный ответ – 29%). Трехлетняя общая выживаемость и выживаемость без прогрессирования составили 95% и 29%, соответственно. Отмечалось только одно клинически значимое осложнение ниволумаба (аутоиммунный тиреоидит). Не было зарегистрировано тяжелых побочных явлений проводимой терапии.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Лимфома Ходжкина, рецидивирующая, рефрактерное течение, дети, ниволумаб.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1875) "Ингибиторы контрольных точек показали высокую эффективность в лечении классической лимфомы Ходжкина (кЛХ). Пембролизумаб одобрен для применения у детей. Назначение данного препарата приводит к высокой частоте ответа на терапию и является относительно безопасным. Роль ниволумаба у детей с кЛХ еще только предстоит определить. Целями представленной работы были оценка эффективности и оценка побочных эффектов у детей с рецидивирующим и рефрактерным течением кЛХ. Терапия на основе ниволумаба была проведена у 21-го предлеченного пациента (9-18 лет) с кЛХ. Общий ответ отмечался у 86 % (полный ответ – 57% и частичный ответ – 29%). Трехлетняя общая выживаемость и выживаемость без прогрессирования составили 95% и 29%, соответственно. Отмечалось только одно клинически значимое осложнение ниволумаба (аутоиммунный тиреоидит). Не было зарегистрировано тяжелых побочных явлений проводимой терапии.
Ключевые слова
Лимфома Ходжкина, рецидивирующая, рефрактерное течение, дети, ниволумаб.
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24885" ["VALUE"]=> array(2) { ["TEXT"]=> string(1078) "<p style="text-align: justify;">Immune checkpoint inhibitors (ICIs) are rather efficient in classical Hodgkin's lymphoma (cHL). Pembrolizumab (pembro) is approved in children and demonstrates high response rates with acceptable toxicity. The role of nivolumab (nivo) in pediatric cHL is only to be elucidated. The aim of the presented study was to assess safety and efficiency of nivo in this age group with relapsed or refractory (R-R) cHL. Twenty-one pediatric heavily pre-treated patients 9-18 years old received nivo-based therapy. Overall response was registered in 86% (complete response – 57% and partial response – 29%). Three-year overall survival (OS) and progression free survival (PFS) were 95% and 29%, respectively. Only 1 clinically significant adverse effect (AE) of nivo was registered in the study (autoimmune thyroiditis). We did not observe any unacceptable toxicity of nivo.</p> <h2>Keywords</h2> <p style="text-align: justify;">Children, Hodgkin's lymphoma, relapsed, refractory, nivolumab.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1022) "Immune checkpoint inhibitors (ICIs) are rather efficient in classical Hodgkin's lymphoma (cHL). Pembrolizumab (pembro) is approved in children and demonstrates high response rates with acceptable toxicity. The role of nivolumab (nivo) in pediatric cHL is only to be elucidated. The aim of the presented study was to assess safety and efficiency of nivo in this age group with relapsed or refractory (R-R) cHL. Twenty-one pediatric heavily pre-treated patients 9-18 years old received nivo-based therapy. Overall response was registered in 86% (complete response – 57% and partial response – 29%). Three-year overall survival (OS) and progression free survival (PFS) were 95% and 29%, respectively. Only 1 clinically significant adverse effect (AE) of nivo was registered in the study (autoimmune thyroiditis). We did not observe any unacceptable toxicity of nivo.
Keywords
Children, Hodgkin's lymphoma, relapsed, refractory, nivolumab.
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Keywords
Children, Hodgkin's lymphoma, relapsed, refractory, nivolumab.
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Keywords
Children, Hodgkin's lymphoma, relapsed, refractory, nivolumab.
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Kozlov" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24864" ["VALUE"]=> array(2) { ["TEXT"]=> string(1931) "<p style="text-align: justify;">Ингибиторы контрольных точек показали высокую эффективность в лечении классической лимфомы Ходжкина (кЛХ). Пембролизумаб одобрен для применения у детей. Назначение данного препарата приводит к высокой частоте ответа на терапию и является относительно безопасным. Роль ниволумаба у детей с кЛХ еще только предстоит определить. Целями представленной работы были оценка эффективности и оценка побочных эффектов у детей с рецидивирующим и рефрактерным течением кЛХ. Терапия на основе ниволумаба была проведена у 21-го предлеченного пациента (9-18 лет) с кЛХ. Общий ответ отмечался у 86 % (полный ответ – 57% и частичный ответ – 29%). Трехлетняя общая выживаемость и выживаемость без прогрессирования составили 95% и 29%, соответственно. Отмечалось только одно клинически значимое осложнение ниволумаба (аутоиммунный тиреоидит). Не было зарегистрировано тяжелых побочных явлений проводимой терапии.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Лимфома Ходжкина, рецидивирующая, рефрактерное течение, дети, ниволумаб.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1875) "Ингибиторы контрольных точек показали высокую эффективность в лечении классической лимфомы Ходжкина (кЛХ). Пембролизумаб одобрен для применения у детей. Назначение данного препарата приводит к высокой частоте ответа на терапию и является относительно безопасным. Роль ниволумаба у детей с кЛХ еще только предстоит определить. Целями представленной работы были оценка эффективности и оценка побочных эффектов у детей с рецидивирующим и рефрактерным течением кЛХ. Терапия на основе ниволумаба была проведена у 21-го предлеченного пациента (9-18 лет) с кЛХ. Общий ответ отмечался у 86 % (полный ответ – 57% и частичный ответ – 29%). Трехлетняя общая выживаемость и выживаемость без прогрессирования составили 95% и 29%, соответственно. Отмечалось только одно клинически значимое осложнение ниволумаба (аутоиммунный тиреоидит). Не было зарегистрировано тяжелых побочных явлений проводимой терапии.
Ключевые слова
Лимфома Ходжкина, рецидивирующая, рефрактерное течение, дети, ниволумаб.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1875) "Ингибиторы контрольных точек показали высокую эффективность в лечении классической лимфомы Ходжкина (кЛХ). Пембролизумаб одобрен для применения у детей. Назначение данного препарата приводит к высокой частоте ответа на терапию и является относительно безопасным. Роль ниволумаба у детей с кЛХ еще только предстоит определить. Целями представленной работы были оценка эффективности и оценка побочных эффектов у детей с рецидивирующим и рефрактерным течением кЛХ. Терапия на основе ниволумаба была проведена у 21-го предлеченного пациента (9-18 лет) с кЛХ. Общий ответ отмечался у 86 % (полный ответ – 57% и частичный ответ – 29%). Трехлетняя общая выживаемость и выживаемость без прогрессирования составили 95% и 29%, соответственно. Отмечалось только одно клинически значимое осложнение ниволумаба (аутоиммунный тиреоидит). Не было зарегистрировано тяжелых побочных явлений проводимой терапии.
Ключевые слова
Лимфома Ходжкина, рецидивирующая, рефрактерное течение, дети, ниволумаб.
" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24863" ["VALUE"]=> array(2) { ["TEXT"]=> string(368) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(356) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(356) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
" } } } [4]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(3) "136" ["~IBLOCK_SECTION_ID"]=> string(3) "136" ["ID"]=> string(4) "1780" ["~ID"]=> string(4) "1780" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(203) "Эффективность повторной аллогенной ТГСК у детей с острыми лейкозами при рецидиве после первой трансплантации" ["~NAME"]=> string(203) "Эффективность повторной аллогенной ТГСК у детей с острыми лейкозами при рецидиве после первой трансплантации" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(22) "01/23/2020 12:46:09 pm" ["~TIMESTAMP_X"]=> string(22) "01/23/2020 12:46:09 pm" ["DETAIL_PAGE_URL"]=> string(147) "/en/archive/tom-8-nomer-4/klinicheskie-raboty/effektivnost-povtornoy-allogennoy-tgsk-u-detey-s-ostrymi-leykozami-pri-retsidive-posle-pervoy-transp/" ["~DETAIL_PAGE_URL"]=> string(147) "/en/archive/tom-8-nomer-4/klinicheskie-raboty/effektivnost-povtornoy-allogennoy-tgsk-u-detey-s-ostrymi-leykozami-pri-retsidive-posle-pervoy-transp/" ["LIST_PAGE_URL"]=> string(12) "/en/archive/" ["~LIST_PAGE_URL"]=> string(12) "/en/archive/" ["DETAIL_TEXT"]=> string(28172) "Introduction
Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) is among superior advances in treatment of children with hematological and inherited disorders [1]. Improvement of treatment protocols based on the balanced intensification of chemotherapy (ChT) provides an increase in long-term survival of the children with acute myeloid leukemia (AML) to 70%, and acute lymphoblastic leukemia (ALL) in 90% of the cases. Chemotherapy followed by allogeneic HSCT is one of the most effective treatment methods remaining an integral part of programmed therapy for high-risk pediatric AML and ALL [2]. Relapse of acute leukemia remains a main indication for allo-HSCT, due to sufficient worsening of prognosis [17].
Along with high-risk acute leukemia in children, allo-HSCT is the only method of treatment in myelodysplastic syndrome (MDS), including juvenile myelo-monocytic leukemia (JMML) (14). Chronic myeloid leukemia (CML) deserves special indications, i.e., in cases of lost therapeutic response, intolerance to tirosine kinase inhibitors (TKI), or mutations associated with TKI resistance permit us to consider allo-HSCT a therapeutic option, due to high efficiency and individual indication strategy.
Allo-HSCT performance is accompanied by some serious complications associated with conditioning regimens, non-engraftment or graft hypofunction, and especially with relapses. Post-transplant relapse remains the most serious issue, being the main cause of mortality in these patients [1, 2, 9, 12]. Frequency of leukemia relapses after allo-HSCT is from 10 to 70% [1, 3, 4]. Prognosis for relapsing patients posttransplant is dismal, and the patients are planned for salvage therapy requiring personalized treatment approach [2]. Among possible therapies applicable after allo-HSCT, one may consider re-transplantation, the use of target and immunotherapy drugs. However, their efficiency of these options has not proven in randomized trials. Nevertheless, the reported experience of different centers is of sufficient interest for taking strategic clinical decisions. The range of problems associated with re-transplantation due to relapse is as follows – to date, the optimal timing for 2nd HSCT are not yet determined; there is no clear opinion on the graft source (bone marrow or peripheral stem cells), and donor characteristics (HLA matching, gender, age), as well as conditioning regimens, GVHD prophylaxis, subsequent therapies.
A retrospective analysis was performed at the R. M. Gorbacheva Memorial Research Institute for Children Oncology, Hematology and Transplantation concerning 50 pediatric patients with different malignant hematological diseases who were subjected to repeated allo-HSCT due to relapse or progression, primary or secondary non-engraftment. The aim of our study was to evaluate efficiency of 2nd allo-HSCT in the patients with acute leukemias, MDS, JMML, and CML in cases of evolving clinical relapse, or associated complications occurring after the 1st allo-HSCT.
Materials and methods
Table 1. Clinical characteristics of pediatric patients considered for 2nd allo-HSCT
Abbreviations: BU, Busulfan; Treo, Treosulfan; Flu, Fludarabine; Cy, Cyclophosphamide; GIAC, Bu, Ara-C, CCNU, Cy; MAC, myeloablative conditioning, RIC, reduced-intensity conditioning.
The study included 50 children with a median age of 18 years (1 to 18 y.o.) subjected to 2nd allo-HSCT at our BMT clinic from 2007 to 2018. Their primary diagnoses were as follows: ALL, 24 patients; AML, 15 cases; mixed-phenotype AML, 2 patients; JMML, 6 patients; CML, 1 patient. Relapse of the primary disease was the most common indication for 2nd allo-HSCT was diagnosed in 36 cases (72%). Other indications for 2nd HSCT were as follows: primary non-engraftment in 11 patients (22%); secondary non-engraftment in 2 patients (4%); graft hypofunction in one case (2%) in presence of resistant/refractory clinical course. The disease characteristics and parameters of the 1st HSCT are presented in Table 1.
For 40% of the patients (n=20), unrelated HLA-matched donors were chosen for allo-HSCT; matched related donor was used in 15 cases (30%); haploidentical graft was used in 14 cases (28%); autologous HSCT was carried out in 1 patient (2%). At the time of 1st HSCT, myeloablative busulfan-containing regimen (MAC) was applied in 34 patients (68%). Dependent on the stage of disease, 16 patients (32%) achieved 1st complete hematological remission (CR); 2nd or 3rd CR was registered in 18 cases (36%). Sixteen patients (32%) were in resistant relapse state, or showed primary resistance.
Median duration of remission after the 1st allo-HSCT was 148 days (31 to 1084 days). Donor lymphocyte infusions (DLI) were performed in 20 patients after 1st allo-HSCT, for relapse prophylaxis. Of them, 17 children (85%) received the therapy due to minimal residual disease (MRD) or clinical relapse, and 3 patients (15%), due to graft hypofunction. The DLI proved to be ineffective in all these patients, thus being indicative for 2nd allo-HSCT.
The patients with progression or relapse after 1st HSCT (n=38), have received cytoreductive therapy before 2nd allo-HSCT by the following schedules:
• chemotherapy (ChT) in 24 patients using FLAG protocol, or ALL-REZ BFM 2002, and AML-BFM 2004 chemotherapy blocks;
• targeted drugs (hypomethylating agents or monoclonal antibodies), in 7 patients;
• combined application of ChT and targeted drugs (hypomethylating or monoclonal antibodies) in 7 cases.
In 10 patients of 38 who underwent ChT or targeted treatment, a remission of the disease was achieved; in 12 cases, cytoreduction was observed (marrow blast count reduction to 20%). In 16 patients, stabilization or progression of the disease was registered.
Ten patients with aplasia of hematopoiesis due to primary non-engraftment, 2 patients with secondary rejection, and 1 patient with severe graft hypofunction did not receive additional therapy. Clinical characteristics of the patients subjected to 2nd allo-HSCT are shown in Table 2.
Table 2. Clinical characteristics of the patients who underwent 2nd HSCT
Abbreviations: BU, Busulfan; Treo, Treosulfan; Flu, Fludarabine; Cy, Cyclophosphamide; GIAC: Bu, Ara-C, CCNU, Cy; MAC, myeloablative conditioning, RIC, reduced-intensity conditioning; HSCs, hematopoietic stem cells; PBSC, peripheral blood stem cells.
The median time-lag between 1st and 2nd HSCT was 7.5 months. In majority of patients (n=41), the donors were changed to haploidentical HSCs donor. In 9 recipients, allo-HSCT was performed from the same donors, i.e., haploidentical transplants in 3 cases; unrelated grafts in 4 patients, and related matched donors were used in 2 cases. For 2nd allo-HSCT, the reduced-intensity conditioning regimens (RIC) were chosen for 40 patients, due to heavy pre-treatment and severe condition of the patients. Myeloablative conditioning was performed in 10 cases, because of high blast cell counts in bone marrow. Combined prophylaxis of acute graft-versus-host disease (GvHD) after 2nd allo-HSCT was based on the following immune suppression therapy, i.e., tacrolimus-based prophylaxis was administered to 38 patients; mTOR inhibitors were used in 31 cases; cyclosporine-A-based was applied in 7 patients. In 31 cases, GvHD prophylaxis was performed with cyclophosphamide (50 mg/kg) on D+3 and D+4 posttransplant. Antithymocyte globulin (ATG) was used for GVHD prophylaxis in 11 cases. Monotherapy with calcineurin inhibitors was applied in 7 children.
The Kaplan-Meier estimates were used to assess probability of OS (overall survival) and RFS (relapse-free survival). OS was defined as number of months from the date of 2nd allo-HSCT to the date of death. RFS defined as number of months from the date of 2nd allo-HSCT to the date of first documented relapse or progression. Cumulative incidence was used to estimate the probability of transplant-related mortality (TRM) and relapse. For TRM, the relapse was considered a competing event. These estimates are provided with 95% confidence intervals (CI). We didn’t perform any multivariate analysis, because of relatively small number of patients.
Results
Clinical engraftment after 2nd HSCT was registered in 44 patients (88% of total), with a median of neutrophil recovery of >500/mcL on D+21 (12 to 41), and documented clinical hematological remission. Primary non-engraftment was registered in 6 patients, including 4 cases with progression of the disease. The median observation term was 3 years 7 months (9 months to 10 years). Overall survival (OS) rate in the total group was 48% (Fig. 1), with relapse-free survival (RFS) of 60% (Fig. 3). OS among ALL patients was 46.2%; among the children with AML, 53.3%; for the group with myeloproliferative disorders (MDS, CML, JMML), 44.4%, as seen from Fig. 1.
OS among the patients with remission or cytoreduction achieved before 2nd allo-HSCT proved to be, respectively, 73.6% и 50%. Meanwhile, OS values in the patients who did not respond to the therapy, on in absence of remission (active disease) comprised only 17.6% (р=0.006), as shown in Fig. 2.
We could not demonstrate any significant difference in OS between the cases with remission of <5 months, and >5 months after 1st HSCT (respectively, 41.2% and 42.9%, p=0.7), based on median duration of the remission. Similarly, change of donor at the 2nd HSCT did not result into significant OS changes (50% versus 47%, p=0.4). Moreover, no statistically significant difference was obtained for the groups who received RIC or MAC conditioning (47% versus 50%, p=0.6).
Figure 1. Five-year OS after 2nd allo-HSCT in the entire cohort (A); in patients with ALL (B); in patients with AML (C); in MPD cases (D) after 2nd allo-HSCT
Abscissa, months after allo-HSCT, ordinate, cumulative survival.
Figure 2. Overall survival in the patients with different status prior to 2nd allo-HSCT (red graph, remission; green, cytoreduction; blue curve, no response)
Abscissa, terms after 2nd HSCT, months; ordinate cumulative survival.
Figure 3. Relapse-free survival in the entire group of patients after 2nd allo-HSCT
Abscissa, terms after 2nd HSCT, months; ordinate cumulative survival.
The study also concerned possible effects of acute or chronic GvHD upon OS levels. The 5-year OS in the patients (remission – 18 pts, cytoreduction – 12 pts, progression – 11 pts) who developed acute GVHD grade II-III was 63.6% (n=33), as compared to 9.1% (n=11) among GvHD-free cases (р=0.001). Meanwhile, the 5-year OS rate among patients with mild or moderate chronic GvHD reached 72.4% (n=29) when compared to the cases without chronic GvHD 14.3%, (n=7), p<0.0001).
From patients with high risk of relapse after 2nd allo-HSCT, 9 patients without acute or chronic GvHD were subjected to immunoadoptive therapy, i.e., infusion of donor lymphocytes (DLI), aiming to prevent potential relapse. Maintenance therapy was performed in 13 patients using 6-MP (mercaptopurine), hypomethylating agents (HMa) (5-azacytidine, dacogen), tyrosine kinase inhibitors (TKI). In summary, for the group of patients (n=13) who did not receive any prophylaxis (DLI) or supporting therapy (6-MP, HMa or TKI) after 2nd all-HSCT, due to acute or chronic GvHD OS 84.6%, (p=0.089).
Overall survival was 55.6% among the patients treated with DLI only. In the patients on maintenance therapy, the OS values proved to be 46.2%. In 9 cases of molecular recurrence (MRD, molecular or cytogenetic relapse) combined therapy was performed, i.e., chemotherapy, HMa (5-azacytidine, dacogen) and DLI, with OS of 22.2% (p=0.089).
We have analyzed the frequency of complications during early posttransplant period (D+100). The following toxic conditions were observed: severe mucositis (grade 3-4) was documented in 54% of cases (n=26); thrombotic microangiopathy, 22% (n=11); veno-occlusive disease, 16% (n=8); neurotoxicity, 16% (n=8). Among infectious complications, we observed cytomegalovirus reactivation (52%, n=26); SIRS syndrome, including sepsis, 44% (n=22); invasive mycoses, 18% (n=9).
Figure 4. Effects of 2 competing events upon general mortality after 2nd HSCT, i.e., (1) cumulative relapse rate (34%; 95%CI, 21.6%-48%), and (2) TRM rate (18%; 95%CI, 8.8-29.8%)
Relapse or progression of disease remained the main cause of mortality after 2nd allo-HSCT (65%, n=17). The median time of the relapse development in these patients comprises 58 days.
Transplant-related mortality in this group was 18%, (95%CI, 8.8-29.8%) and the relapse rate (a competing event) was 34% (95%CI, 21.6% to 48%), as shown in Fig. 4.
Discussion
Hematopoietic stem cell transplantation is the only possible treatment method in the most high-risk malignancies in children (AML, ALL etc.) [2]. Despite significant advances in the area, the posttransplant relapses remain the quite serious and common issue, being the main cause of lethal outcomes posttransplant [1, 2, 9, 12, 15]. The relapse frequency in this cohort may vary from 10 to 70% [3, 4, 15]. Clinical prognosis for post-HSCT relapsing patients remains extremely unfavorable, and these patients were intended for the salvage therapy [2]. So far, there are no clear clinical recommendations for treatment of such patients, and the issue of therapeutic options still remains open for this group [10, 15].
A significant therapeutic effect in allogeneic HSCT is achieved due to immune-mediated reactions, e.g., transplant versus leukemia effect, the main factor able to overcome the resistance of malignant cells [4, 10]. However, subsequent administration of mono- or combined therapy is the most common strategy for treatment of the posttransplant relapses, i.e., reinduction polychemotherapy, immunoadoptive cell therapy (donor lymphocyte infusion), usage of targeted drugs including monoclonal antibodies (MAb) [12]. Intensive chemotherapy results into the disease stabilization with remission achieved in 40 to 60% [4], however, without long-lasting effect in most cases, with 2-year OS of <10% [4].
Therapeutic potential of bispecific anti-CD19 monoclonal antibodies in the patients with ALL relapse was evaluated in a multicenter study of the patients who relapsed after HSCT, with a median observation term of 7.5 months. The one-year overall survival in these patients was 25% following treatment with blinatumomab [7].
According to the study by Markova et al. [11] that included 41 children with posttransplant relapse of ALL, the response to blinatumomab was observed in 24 patients (59%); the two-year OS comprised 37%, 2-year relapse-free survival rate was 71%, with a median observation terms of 222 days (25 to 730 days).
Donor lymphocyte infusion is an effective treatment approach in such conditions [12]. On the ground of a retrospective study which included 171 cases, Shmid et al. have shown efficiency of donor lymphocytes when treating posttransplant relapses in AML patients. The 2-year OS among the patients achieving remission after DLI was 56%, as compared with OS of 21% in the patients that did not reach the remission state (>35% blasts in bone marrow). Meanwhile, the 2-year OS remained at 9% for the patients who did not receive DLI [6].
EBMT Acute Leukemia Working Party (M. A. Kharfan-Dabaja et al, 2018) has published a retrospective study in order to compare efficiency of repeated allo-HSCT and DLI, including 418 adult patients with AML relapse after 1st allo-HSCT. Repeated allo-HSCT was performed in 137 patients, and DLI, in 281 patients. Two-year survival following repeated allo-HSCT proved to be 26%, 5-year OS comprised 19%. Two-year OS among the DLI-treated patients was 25%, and 5-year OS, 15% [16]. In our study, the 5-year OS was 48% after repeated HSCT in general group.
Similarly, several larger studies have shown that repeated HSCT is a probable therapeutic approach [2]. In 2015, Ruutu et al. have summarized the results of 2632 repeated allo-HSCTs. Their results showed the 1-year OS rates of 40%, 5-year OS of 20% [5]. Another study from USA (Swati Naik et al., 2015) demonstrated results of repeated allo-HSCT in 43 children with relapses of different oncohematological disorders, with overall survival at 1, 5 and 10 years of, respectively, 48%, 24%, and 20% [3].
The results of multicenter retrospective study (EBMT-PDWP) were reported in 2018 [8]. Repeated allo-HSCT was performed in 373 cases; the 2- and 5-year OS values were 38% and 29%, respectively. The relapse-free survival was 30% at 2 years, and 30% at 5 years of observation. The median observation time in ALL group was 36.4 months, being 50.2 months for AML patients [8].
Despite current achievements in the posttransplant relapse treatment following allo-HSCT, using repeated allo-HSCT, the optimal timing of its performance is not yet determined, as well as preferable HSC source, change of donor (his/her gender and age), conditioning regimen, GvHD prophylaxis, posttransplant treatment, thus requiring additional multicenter studies, e.g. under participation of European teams active in oncohematology [18].
Conclusion
1. We have performed retrospective study concerning 50 pediatric patients with different blood malignancies that were subjected to repeated allogeneic HSCT due to different reasons, i.e. relapse/progression, primary or secondary non-engraftment.
2. According to our results, the repeated allo-HSCT in this cohort proved to be an effective treatment approach to the therapy of relapses in pediatric malignancies following failure of first allo-HSCT. The 2nd allo-HSCT may be effectively performed in stable somatic status, without active infections and toxic complications, upon development of remission or when achieving response to cytoreductive therapy before conditioning.
3. The option of repeated HSCT depends on clinical situation and presence of toxic complications in distinct cases. However, taking into account previous severe treatment, one should prefer reduced-intensity or reduced-toxicity conditioning regimens, despite absence of statistical difference between results from MAC and RIC cases. There is no difference upon donor change and allo-HSCT type, however, haploidentical donor seems to be preferred in this setting, due to availability, motivation and sooner performance of this HSCT mode.
4. With respect to soon development of relapses after repeated allo-HSCT (a median of 58 days), a decision on withdrawal of immune suppressive therapy and commencing posttransplant immunoadoptive treatment should be taken within D+30 to D+60 in absence of clinically significant GvHD. Administration of other therapies (DLI, hypomethylating and targeted drugs) causes a sufficient improvement of OS rates in the patients following repeated SC.
5. With development of novel monoclonal antibodies, as well as future CAR-T cell technologies, we need further studies of these therapeutic options in the posttransplant period for this cohort of patients.
Conflict of interest
Non declared.
References
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Introduction
Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) is among superior advances in treatment of children with hematological and inherited disorders [1]. Improvement of treatment protocols based on the balanced intensification of chemotherapy (ChT) provides an increase in long-term survival of the children with acute myeloid leukemia (AML) to 70%, and acute lymphoblastic leukemia (ALL) in 90% of the cases. Chemotherapy followed by allogeneic HSCT is one of the most effective treatment methods remaining an integral part of programmed therapy for high-risk pediatric AML and ALL [2]. Relapse of acute leukemia remains a main indication for allo-HSCT, due to sufficient worsening of prognosis [17].
Along with high-risk acute leukemia in children, allo-HSCT is the only method of treatment in myelodysplastic syndrome (MDS), including juvenile myelo-monocytic leukemia (JMML) (14). Chronic myeloid leukemia (CML) deserves special indications, i.e., in cases of lost therapeutic response, intolerance to tirosine kinase inhibitors (TKI), or mutations associated with TKI resistance permit us to consider allo-HSCT a therapeutic option, due to high efficiency and individual indication strategy.
Allo-HSCT performance is accompanied by some serious complications associated with conditioning regimens, non-engraftment or graft hypofunction, and especially with relapses. Post-transplant relapse remains the most serious issue, being the main cause of mortality in these patients [1, 2, 9, 12]. Frequency of leukemia relapses after allo-HSCT is from 10 to 70% [1, 3, 4]. Prognosis for relapsing patients posttransplant is dismal, and the patients are planned for salvage therapy requiring personalized treatment approach [2]. Among possible therapies applicable after allo-HSCT, one may consider re-transplantation, the use of target and immunotherapy drugs. However, their efficiency of these options has not proven in randomized trials. Nevertheless, the reported experience of different centers is of sufficient interest for taking strategic clinical decisions. The range of problems associated with re-transplantation due to relapse is as follows – to date, the optimal timing for 2nd HSCT are not yet determined; there is no clear opinion on the graft source (bone marrow or peripheral stem cells), and donor characteristics (HLA matching, gender, age), as well as conditioning regimens, GVHD prophylaxis, subsequent therapies.
A retrospective analysis was performed at the R. M. Gorbacheva Memorial Research Institute for Children Oncology, Hematology and Transplantation concerning 50 pediatric patients with different malignant hematological diseases who were subjected to repeated allo-HSCT due to relapse or progression, primary or secondary non-engraftment. The aim of our study was to evaluate efficiency of 2nd allo-HSCT in the patients with acute leukemias, MDS, JMML, and CML in cases of evolving clinical relapse, or associated complications occurring after the 1st allo-HSCT.
Materials and methods
Table 1. Clinical characteristics of pediatric patients considered for 2nd allo-HSCT
Abbreviations: BU, Busulfan; Treo, Treosulfan; Flu, Fludarabine; Cy, Cyclophosphamide; GIAC, Bu, Ara-C, CCNU, Cy; MAC, myeloablative conditioning, RIC, reduced-intensity conditioning.
The study included 50 children with a median age of 18 years (1 to 18 y.o.) subjected to 2nd allo-HSCT at our BMT clinic from 2007 to 2018. Their primary diagnoses were as follows: ALL, 24 patients; AML, 15 cases; mixed-phenotype AML, 2 patients; JMML, 6 patients; CML, 1 patient. Relapse of the primary disease was the most common indication for 2nd allo-HSCT was diagnosed in 36 cases (72%). Other indications for 2nd HSCT were as follows: primary non-engraftment in 11 patients (22%); secondary non-engraftment in 2 patients (4%); graft hypofunction in one case (2%) in presence of resistant/refractory clinical course. The disease characteristics and parameters of the 1st HSCT are presented in Table 1.
For 40% of the patients (n=20), unrelated HLA-matched donors were chosen for allo-HSCT; matched related donor was used in 15 cases (30%); haploidentical graft was used in 14 cases (28%); autologous HSCT was carried out in 1 patient (2%). At the time of 1st HSCT, myeloablative busulfan-containing regimen (MAC) was applied in 34 patients (68%). Dependent on the stage of disease, 16 patients (32%) achieved 1st complete hematological remission (CR); 2nd or 3rd CR was registered in 18 cases (36%). Sixteen patients (32%) were in resistant relapse state, or showed primary resistance.
Median duration of remission after the 1st allo-HSCT was 148 days (31 to 1084 days). Donor lymphocyte infusions (DLI) were performed in 20 patients after 1st allo-HSCT, for relapse prophylaxis. Of them, 17 children (85%) received the therapy due to minimal residual disease (MRD) or clinical relapse, and 3 patients (15%), due to graft hypofunction. The DLI proved to be ineffective in all these patients, thus being indicative for 2nd allo-HSCT.
The patients with progression or relapse after 1st HSCT (n=38), have received cytoreductive therapy before 2nd allo-HSCT by the following schedules:
• chemotherapy (ChT) in 24 patients using FLAG protocol, or ALL-REZ BFM 2002, and AML-BFM 2004 chemotherapy blocks;
• targeted drugs (hypomethylating agents or monoclonal antibodies), in 7 patients;
• combined application of ChT and targeted drugs (hypomethylating or monoclonal antibodies) in 7 cases.
In 10 patients of 38 who underwent ChT or targeted treatment, a remission of the disease was achieved; in 12 cases, cytoreduction was observed (marrow blast count reduction to 20%). In 16 patients, stabilization or progression of the disease was registered.
Ten patients with aplasia of hematopoiesis due to primary non-engraftment, 2 patients with secondary rejection, and 1 patient with severe graft hypofunction did not receive additional therapy. Clinical characteristics of the patients subjected to 2nd allo-HSCT are shown in Table 2.
Table 2. Clinical characteristics of the patients who underwent 2nd HSCT
Abbreviations: BU, Busulfan; Treo, Treosulfan; Flu, Fludarabine; Cy, Cyclophosphamide; GIAC: Bu, Ara-C, CCNU, Cy; MAC, myeloablative conditioning, RIC, reduced-intensity conditioning; HSCs, hematopoietic stem cells; PBSC, peripheral blood stem cells.
The median time-lag between 1st and 2nd HSCT was 7.5 months. In majority of patients (n=41), the donors were changed to haploidentical HSCs donor. In 9 recipients, allo-HSCT was performed from the same donors, i.e., haploidentical transplants in 3 cases; unrelated grafts in 4 patients, and related matched donors were used in 2 cases. For 2nd allo-HSCT, the reduced-intensity conditioning regimens (RIC) were chosen for 40 patients, due to heavy pre-treatment and severe condition of the patients. Myeloablative conditioning was performed in 10 cases, because of high blast cell counts in bone marrow. Combined prophylaxis of acute graft-versus-host disease (GvHD) after 2nd allo-HSCT was based on the following immune suppression therapy, i.e., tacrolimus-based prophylaxis was administered to 38 patients; mTOR inhibitors were used in 31 cases; cyclosporine-A-based was applied in 7 patients. In 31 cases, GvHD prophylaxis was performed with cyclophosphamide (50 mg/kg) on D+3 and D+4 posttransplant. Antithymocyte globulin (ATG) was used for GVHD prophylaxis in 11 cases. Monotherapy with calcineurin inhibitors was applied in 7 children.
The Kaplan-Meier estimates were used to assess probability of OS (overall survival) and RFS (relapse-free survival). OS was defined as number of months from the date of 2nd allo-HSCT to the date of death. RFS defined as number of months from the date of 2nd allo-HSCT to the date of first documented relapse or progression. Cumulative incidence was used to estimate the probability of transplant-related mortality (TRM) and relapse. For TRM, the relapse was considered a competing event. These estimates are provided with 95% confidence intervals (CI). We didn’t perform any multivariate analysis, because of relatively small number of patients.
Results
Clinical engraftment after 2nd HSCT was registered in 44 patients (88% of total), with a median of neutrophil recovery of >500/mcL on D+21 (12 to 41), and documented clinical hematological remission. Primary non-engraftment was registered in 6 patients, including 4 cases with progression of the disease. The median observation term was 3 years 7 months (9 months to 10 years). Overall survival (OS) rate in the total group was 48% (Fig. 1), with relapse-free survival (RFS) of 60% (Fig. 3). OS among ALL patients was 46.2%; among the children with AML, 53.3%; for the group with myeloproliferative disorders (MDS, CML, JMML), 44.4%, as seen from Fig. 1.
OS among the patients with remission or cytoreduction achieved before 2nd allo-HSCT proved to be, respectively, 73.6% и 50%. Meanwhile, OS values in the patients who did not respond to the therapy, on in absence of remission (active disease) comprised only 17.6% (р=0.006), as shown in Fig. 2.
We could not demonstrate any significant difference in OS between the cases with remission of <5 months, and >5 months after 1st HSCT (respectively, 41.2% and 42.9%, p=0.7), based on median duration of the remission. Similarly, change of donor at the 2nd HSCT did not result into significant OS changes (50% versus 47%, p=0.4). Moreover, no statistically significant difference was obtained for the groups who received RIC or MAC conditioning (47% versus 50%, p=0.6).
Figure 1. Five-year OS after 2nd allo-HSCT in the entire cohort (A); in patients with ALL (B); in patients with AML (C); in MPD cases (D) after 2nd allo-HSCT
Abscissa, months after allo-HSCT, ordinate, cumulative survival.
Figure 2. Overall survival in the patients with different status prior to 2nd allo-HSCT (red graph, remission; green, cytoreduction; blue curve, no response)
Abscissa, terms after 2nd HSCT, months; ordinate cumulative survival.
Figure 3. Relapse-free survival in the entire group of patients after 2nd allo-HSCT
Abscissa, terms after 2nd HSCT, months; ordinate cumulative survival.
The study also concerned possible effects of acute or chronic GvHD upon OS levels. The 5-year OS in the patients (remission – 18 pts, cytoreduction – 12 pts, progression – 11 pts) who developed acute GVHD grade II-III was 63.6% (n=33), as compared to 9.1% (n=11) among GvHD-free cases (р=0.001). Meanwhile, the 5-year OS rate among patients with mild or moderate chronic GvHD reached 72.4% (n=29) when compared to the cases without chronic GvHD 14.3%, (n=7), p<0.0001).
From patients with high risk of relapse after 2nd allo-HSCT, 9 patients without acute or chronic GvHD were subjected to immunoadoptive therapy, i.e., infusion of donor lymphocytes (DLI), aiming to prevent potential relapse. Maintenance therapy was performed in 13 patients using 6-MP (mercaptopurine), hypomethylating agents (HMa) (5-azacytidine, dacogen), tyrosine kinase inhibitors (TKI). In summary, for the group of patients (n=13) who did not receive any prophylaxis (DLI) or supporting therapy (6-MP, HMa or TKI) after 2nd all-HSCT, due to acute or chronic GvHD OS 84.6%, (p=0.089).
Overall survival was 55.6% among the patients treated with DLI only. In the patients on maintenance therapy, the OS values proved to be 46.2%. In 9 cases of molecular recurrence (MRD, molecular or cytogenetic relapse) combined therapy was performed, i.e., chemotherapy, HMa (5-azacytidine, dacogen) and DLI, with OS of 22.2% (p=0.089).
We have analyzed the frequency of complications during early posttransplant period (D+100). The following toxic conditions were observed: severe mucositis (grade 3-4) was documented in 54% of cases (n=26); thrombotic microangiopathy, 22% (n=11); veno-occlusive disease, 16% (n=8); neurotoxicity, 16% (n=8). Among infectious complications, we observed cytomegalovirus reactivation (52%, n=26); SIRS syndrome, including sepsis, 44% (n=22); invasive mycoses, 18% (n=9).
Figure 4. Effects of 2 competing events upon general mortality after 2nd HSCT, i.e., (1) cumulative relapse rate (34%; 95%CI, 21.6%-48%), and (2) TRM rate (18%; 95%CI, 8.8-29.8%)
Relapse or progression of disease remained the main cause of mortality after 2nd allo-HSCT (65%, n=17). The median time of the relapse development in these patients comprises 58 days.
Transplant-related mortality in this group was 18%, (95%CI, 8.8-29.8%) and the relapse rate (a competing event) was 34% (95%CI, 21.6% to 48%), as shown in Fig. 4.
Discussion
Hematopoietic stem cell transplantation is the only possible treatment method in the most high-risk malignancies in children (AML, ALL etc.) [2]. Despite significant advances in the area, the posttransplant relapses remain the quite serious and common issue, being the main cause of lethal outcomes posttransplant [1, 2, 9, 12, 15]. The relapse frequency in this cohort may vary from 10 to 70% [3, 4, 15]. Clinical prognosis for post-HSCT relapsing patients remains extremely unfavorable, and these patients were intended for the salvage therapy [2]. So far, there are no clear clinical recommendations for treatment of such patients, and the issue of therapeutic options still remains open for this group [10, 15].
A significant therapeutic effect in allogeneic HSCT is achieved due to immune-mediated reactions, e.g., transplant versus leukemia effect, the main factor able to overcome the resistance of malignant cells [4, 10]. However, subsequent administration of mono- or combined therapy is the most common strategy for treatment of the posttransplant relapses, i.e., reinduction polychemotherapy, immunoadoptive cell therapy (donor lymphocyte infusion), usage of targeted drugs including monoclonal antibodies (MAb) [12]. Intensive chemotherapy results into the disease stabilization with remission achieved in 40 to 60% [4], however, without long-lasting effect in most cases, with 2-year OS of <10% [4].
Therapeutic potential of bispecific anti-CD19 monoclonal antibodies in the patients with ALL relapse was evaluated in a multicenter study of the patients who relapsed after HSCT, with a median observation term of 7.5 months. The one-year overall survival in these patients was 25% following treatment with blinatumomab [7].
According to the study by Markova et al. [11] that included 41 children with posttransplant relapse of ALL, the response to blinatumomab was observed in 24 patients (59%); the two-year OS comprised 37%, 2-year relapse-free survival rate was 71%, with a median observation terms of 222 days (25 to 730 days).
Donor lymphocyte infusion is an effective treatment approach in such conditions [12]. On the ground of a retrospective study which included 171 cases, Shmid et al. have shown efficiency of donor lymphocytes when treating posttransplant relapses in AML patients. The 2-year OS among the patients achieving remission after DLI was 56%, as compared with OS of 21% in the patients that did not reach the remission state (>35% blasts in bone marrow). Meanwhile, the 2-year OS remained at 9% for the patients who did not receive DLI [6].
EBMT Acute Leukemia Working Party (M. A. Kharfan-Dabaja et al, 2018) has published a retrospective study in order to compare efficiency of repeated allo-HSCT and DLI, including 418 adult patients with AML relapse after 1st allo-HSCT. Repeated allo-HSCT was performed in 137 patients, and DLI, in 281 patients. Two-year survival following repeated allo-HSCT proved to be 26%, 5-year OS comprised 19%. Two-year OS among the DLI-treated patients was 25%, and 5-year OS, 15% [16]. In our study, the 5-year OS was 48% after repeated HSCT in general group.
Similarly, several larger studies have shown that repeated HSCT is a probable therapeutic approach [2]. In 2015, Ruutu et al. have summarized the results of 2632 repeated allo-HSCTs. Their results showed the 1-year OS rates of 40%, 5-year OS of 20% [5]. Another study from USA (Swati Naik et al., 2015) demonstrated results of repeated allo-HSCT in 43 children with relapses of different oncohematological disorders, with overall survival at 1, 5 and 10 years of, respectively, 48%, 24%, and 20% [3].
The results of multicenter retrospective study (EBMT-PDWP) were reported in 2018 [8]. Repeated allo-HSCT was performed in 373 cases; the 2- and 5-year OS values were 38% and 29%, respectively. The relapse-free survival was 30% at 2 years, and 30% at 5 years of observation. The median observation time in ALL group was 36.4 months, being 50.2 months for AML patients [8].
Despite current achievements in the posttransplant relapse treatment following allo-HSCT, using repeated allo-HSCT, the optimal timing of its performance is not yet determined, as well as preferable HSC source, change of donor (his/her gender and age), conditioning regimen, GvHD prophylaxis, posttransplant treatment, thus requiring additional multicenter studies, e.g. under participation of European teams active in oncohematology [18].
Conclusion
1. We have performed retrospective study concerning 50 pediatric patients with different blood malignancies that were subjected to repeated allogeneic HSCT due to different reasons, i.e. relapse/progression, primary or secondary non-engraftment.
2. According to our results, the repeated allo-HSCT in this cohort proved to be an effective treatment approach to the therapy of relapses in pediatric malignancies following failure of first allo-HSCT. The 2nd allo-HSCT may be effectively performed in stable somatic status, without active infections and toxic complications, upon development of remission or when achieving response to cytoreductive therapy before conditioning.
3. The option of repeated HSCT depends on clinical situation and presence of toxic complications in distinct cases. However, taking into account previous severe treatment, one should prefer reduced-intensity or reduced-toxicity conditioning regimens, despite absence of statistical difference between results from MAC and RIC cases. There is no difference upon donor change and allo-HSCT type, however, haploidentical donor seems to be preferred in this setting, due to availability, motivation and sooner performance of this HSCT mode.
4. With respect to soon development of relapses after repeated allo-HSCT (a median of 58 days), a decision on withdrawal of immune suppressive therapy and commencing posttransplant immunoadoptive treatment should be taken within D+30 to D+60 in absence of clinically significant GvHD. Administration of other therapies (DLI, hypomethylating and targeted drugs) causes a sufficient improvement of OS rates in the patients following repeated SC.
5. With development of novel monoclonal antibodies, as well as future CAR-T cell technologies, we need further studies of these therapeutic options in the posttransplant period for this cohort of patients.
Conflict of interest
Non declared.
References
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Полина В. Кожокарь1, Олеся В. Паина1, Анастасия С. Фролова1, Джемал З. Рахманова1, Анастасия C. Боровкова1, Елена В. Семенова1, Анна А. Осипова1, Кирилл А. Екушов1, Ольга А. Слесарчук1, Варвара Н. Овечкина1, Елена В. Бабенко1, Алина А. Витрищак1, Борис И. Смирнов2, Людмила С. Зубаровская1, Борис В. Афанасьев1
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2 Санкт-Петербургский государственный электротехнический университет, Санкт-Петербург, Россия
Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является стандартом терапии в группе высокого риска онкогематологических заболеваний. Несмотря на это, уровень рецидивов варьирует от 10 до 70%. До сих пор отсутствует оптимальный подход к терапии рецидива после алло-ТГСК. Возможные терапевтические опции включают в себя реиндукцию, иммуноадоптивную терапию, таргетную терапию, иммунотерапию (CAR T-клеточную терапию), повторную трансплантацию. В данной публикации представлено ретроспективное исследование пациентов с рефрактерным течением онкогематологических заболеваний, а также отторжением трансплантата в группе высокого риска, в связи с чем выполнялась повторная алло-ТГСК. Целью нашей работы был анализ результатов повторной алло-ТГСК у 50 детей с различными онкогематологическими заболеваниями: ОЛЛ – 24, ОМЛ – 15, МДС и ХМПЗ – 11 пациентов. Общая выживаемость (ОВ) по методу Каплан-Майер во всей группе составила 48%, безрецидивная выживаемость (БРВ) – 60%. Медиана наблюдения составила 3 года 7 мес. Пятилетняя ОВ в группе ОЛЛ была 46,2%, в группе ОМЛ – 53,3%, в группе МДС и МПЗ – 44,4%. Причины летальности: рецидив/прогрессия в 17 случаях (65%).Трансплантационная летальность составила 18% (95% ДИ, 8,8%-29,8%). Кумулятивная частота рецидива составила 34% (95% ДИ, 21,6%-48%).
Заключение
Повторная алло-ТГСК – эффективный метод терапии у пациентов с рецидивом заболевания после первой ТГСК. Пациенты, достигшие ремиссии или циторедукции перед алло-ТГСК, имеют статистически достоверный лучший прогноз. Развитие хронической РТПХ легкой и средней степени статистически улучшает ОВ. Не получено достоверной разницы между РИК и МАК. Посттрансплантационная терапия может улучшить результаты повторной алло-ТГСК.
Ключевые слова
Рецидив острого лейкоза, повторная алло-ТГСК, посттрансплантационная терапия, дети.
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St. Petersburg, Russia
2 Saint Petersburg State Electrotechnical University, St. Petersburg, Russia
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective treatment in high risk hematological malignancies. Nevertheless, the relapse rates after allo-HSCT range from 10% to 70%.There is no optimal strategy of the relapse therapy after allo-HSCT. Possible therapeutic options include re-induction chemotherapy, immunoadoptive therapy (DLI), target drugs, immunotherapy (CAR-T) and second allo-HSCT. The presented study is a retrospective single-institution experience of second allo-HSCT in the patients (pts) with acute leukemia relapses or graft failure in high-risk cases. The aim of our study was to analyze the outcomes after second allo-HSCT in 50 children with hematological malignancies, i.e., ALL (n=24), AML (n=15), MPDs/MDS (n=11).
Results
Forty-four patients achieved engraftment, with median neutrophil engraftment time of 21 days (12 to 41). Remission was achieved in 44 pts (88%). Median follow-up period was 3 years 7 months. Overall survival (OS), according to Kaplan-Meier method, was 48% in the whole group. Relapse-free survival (RFS) was 60%. The five-year OS in ALL group was 46.2%; in AML group, 53.3%; in MPDs/MDS, 44.4%. Causes of death were as follows: relapse/progression in 65% (n=17), transplant-related mortality (TRM), in 18% (n=9; 95%CI, 8.8%-29.8%); cumulative relapse rate was 34% (95% CI, 21.6%-48%).
Conclusion
Second allo-HSCT is an effective treatment option in cases of relapse after 1st allo-HSCT. The patients that achieved remission or even blast cytoreduction prior to 2nd allo-HSCT had better outcome. Clinical manifestations of acute and chronic GVHD can significantly improve the OS. Results of 2nd allo-HSCT were comparable when using RIC or MAC conditioning regimens. Posttransplant therapy is required to improve results after 2nd HSCT.
Keywords
Leukemia relapse, second allogeneic HSCT, posttransplant therapy, children.
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Kozhokar<sup>1</sup>, Olesya V. Paina<sup>1</sup>, Anastasia S. Frolova<sup>1</sup>, Zhemal Z. Rakhmanova<sup>1</sup>, Anastasia S. Borovkova<sup>1</sup>, Elena V. Semenova<sup>1</sup>, Anna A. Osipova<sup>1</sup>, Kirill A. Ekushov<sup>1</sup>, Olga A. Slesarchuk<sup>1</sup>, Varvara N. Ovechkina<sup>1</sup>, Elena V. Babenko<sup>1</sup>, Alina A. Vitrishchak<sup>1</sup>, Boris I. Smirnov<sup>2</sup>, Ludmila S. Zubarovskaya<sup>1</sup>, Boris V. Afanasyev<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(490) "Polina V. Kozhokar1, Olesya V. Paina1, Anastasia S. Frolova1, Zhemal Z. Rakhmanova1, Anastasia S. Borovkova1, Elena V. Semenova1, Anna A. Osipova1, Kirill A. Ekushov1, Olga A. Slesarchuk1, Varvara N. Ovechkina1, Elena V. Babenko1, Alina A. Vitrishchak1, Boris I. Smirnov2, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(490) "Polina V. Kozhokar1, Olesya V. Paina1, Anastasia S. Frolova1, Zhemal Z. Rakhmanova1, Anastasia S. Borovkova1, Elena V. Semenova1, Anna A. Osipova1, Kirill A. Ekushov1, Olga A. Slesarchuk1, Varvara N. Ovechkina1, Elena V. Babenko1, Alina A. Vitrishchak1, Boris I. Smirnov2, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24598" ["VALUE"]=> array(2) { ["TEXT"]=> string(2286) "<p style="text-align: justify;">Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective treatment in high risk hematological malignancies. Nevertheless, the relapse rates after allo-HSCT range from 10% to 70%.There is no optimal strategy of the relapse therapy after allo-HSCT. Possible therapeutic options include re-induction chemotherapy, immunoadoptive therapy (DLI), target drugs, immunotherapy (CAR-T) and second allo-HSCT. The presented study is a retrospective single-institution experience of second allo-HSCT in the patients (pts) with acute leukemia relapses or graft failure in high-risk cases. The aim of our study was to analyze the outcomes after second allo-HSCT in 50 children with hematological malignancies, i.e., ALL (n=24), AML (n=15), MPDs/MDS (n=11). </p> <h3>Results</h3> <p style="text-align: justify;">Forty-four patients achieved engraftment, with median neutrophil engraftment time of 21 days (12 to 41). Remission was achieved in 44 pts (88%). Median follow-up period was 3 years 7 months. Overall survival (OS), according to Kaplan-Meier method, was 48% in the whole group. Relapse-free survival (RFS) was 60%. The five-year OS in ALL group was 46.2%; in AML group, 53.3%; in MPDs/MDS, 44.4%. Causes of death were as follows: relapse/progression in 65% (n=17), transplant-related mortality (TRM), in 18% (n=9; 95%CI, 8.8%-29.8%); cumulative relapse rate was 34% (95% CI, 21.6%-48%). </p> <h3>Conclusion</h3> <p style="text-align: justify;">Second allo-HSCT is an effective treatment option in cases of relapse after 1<sup>st</sup> allo-HSCT. The patients that achieved remission or even blast cytoreduction prior to 2<sup>nd</sup> allo-HSCT had better outcome. Clinical manifestations of acute and chronic GVHD can significantly improve the OS. Results of 2<sup>nd</sup> allo-HSCT were comparable when using RIC or MAC conditioning regimens. Posttransplant therapy is required to improve results after 2<sup>nd</sup> HSCT.</p> <h2>Keywords</h2> <p style="text-align: justify;">Leukemia relapse, second allogeneic HSCT, posttransplant therapy, children.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2114) "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective treatment in high risk hematological malignancies. Nevertheless, the relapse rates after allo-HSCT range from 10% to 70%.There is no optimal strategy of the relapse therapy after allo-HSCT. Possible therapeutic options include re-induction chemotherapy, immunoadoptive therapy (DLI), target drugs, immunotherapy (CAR-T) and second allo-HSCT. The presented study is a retrospective single-institution experience of second allo-HSCT in the patients (pts) with acute leukemia relapses or graft failure in high-risk cases. The aim of our study was to analyze the outcomes after second allo-HSCT in 50 children with hematological malignancies, i.e., ALL (n=24), AML (n=15), MPDs/MDS (n=11).
Results
Forty-four patients achieved engraftment, with median neutrophil engraftment time of 21 days (12 to 41). Remission was achieved in 44 pts (88%). Median follow-up period was 3 years 7 months. Overall survival (OS), according to Kaplan-Meier method, was 48% in the whole group. Relapse-free survival (RFS) was 60%. The five-year OS in ALL group was 46.2%; in AML group, 53.3%; in MPDs/MDS, 44.4%. Causes of death were as follows: relapse/progression in 65% (n=17), transplant-related mortality (TRM), in 18% (n=9; 95%CI, 8.8%-29.8%); cumulative relapse rate was 34% (95% CI, 21.6%-48%).
Conclusion
Second allo-HSCT is an effective treatment option in cases of relapse after 1st allo-HSCT. The patients that achieved remission or even blast cytoreduction prior to 2nd allo-HSCT had better outcome. Clinical manifestations of acute and chronic GVHD can significantly improve the OS. Results of 2nd allo-HSCT were comparable when using RIC or MAC conditioning regimens. Posttransplant therapy is required to improve results after 2nd HSCT.
Keywords
Leukemia relapse, second allogeneic HSCT, posttransplant therapy, children.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2114) "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective treatment in high risk hematological malignancies. Nevertheless, the relapse rates after allo-HSCT range from 10% to 70%.There is no optimal strategy of the relapse therapy after allo-HSCT. Possible therapeutic options include re-induction chemotherapy, immunoadoptive therapy (DLI), target drugs, immunotherapy (CAR-T) and second allo-HSCT. The presented study is a retrospective single-institution experience of second allo-HSCT in the patients (pts) with acute leukemia relapses or graft failure in high-risk cases. The aim of our study was to analyze the outcomes after second allo-HSCT in 50 children with hematological malignancies, i.e., ALL (n=24), AML (n=15), MPDs/MDS (n=11).
Results
Forty-four patients achieved engraftment, with median neutrophil engraftment time of 21 days (12 to 41). Remission was achieved in 44 pts (88%). Median follow-up period was 3 years 7 months. Overall survival (OS), according to Kaplan-Meier method, was 48% in the whole group. Relapse-free survival (RFS) was 60%. The five-year OS in ALL group was 46.2%; in AML group, 53.3%; in MPDs/MDS, 44.4%. Causes of death were as follows: relapse/progression in 65% (n=17), transplant-related mortality (TRM), in 18% (n=9; 95%CI, 8.8%-29.8%); cumulative relapse rate was 34% (95% CI, 21.6%-48%).
Conclusion
Second allo-HSCT is an effective treatment option in cases of relapse after 1st allo-HSCT. The patients that achieved remission or even blast cytoreduction prior to 2nd allo-HSCT had better outcome. Clinical manifestations of acute and chronic GVHD can significantly improve the OS. Results of 2nd allo-HSCT were comparable when using RIC or MAC conditioning regimens. Posttransplant therapy is required to improve results after 2nd HSCT.
Keywords
Leukemia relapse, second allogeneic HSCT, posttransplant therapy, children.
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St. Petersburg, Russia
2 Saint Petersburg State Electrotechnical University, St. Petersburg, Russia
1 Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia
2 Saint Petersburg State Electrotechnical University, St. Petersburg, Russia
Полина В. Кожокарь1, Олеся В. Паина1, Анастасия С. Фролова1, Джемал З. Рахманова1, Анастасия C. Боровкова1, Елена В. Семенова1, Анна А. Осипова1, Кирилл А. Екушов1, Ольга А. Слесарчук1, Варвара Н. Овечкина1, Елена В. Бабенко1, Алина А. Витрищак1, Борис И. Смирнов2, Людмила С. Зубаровская1, Борис В. Афанасьев1
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Kozhokar" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24579" ["VALUE"]=> array(2) { ["TEXT"]=> string(3538) "<p style="text-align: justify;">Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является стандартом терапии в группе высокого риска онкогематологических заболеваний. Несмотря на это, уровень рецидивов варьирует от 10 до 70%. До сих пор отсутствует оптимальный подход к терапии рецидива после алло-ТГСК. Возможные терапевтические опции включают в себя реиндукцию, иммуноадоптивную терапию, таргетную терапию, иммунотерапию (CAR T-клеточную терапию), повторную трансплантацию. В данной публикации представлено ретроспективное исследование пациентов с рефрактерным течением онкогематологических заболеваний, а также отторжением трансплантата в группе высокого риска, в связи с чем выполнялась повторная алло-ТГСК. Целью нашей работы был анализ результатов повторной алло-ТГСК у 50 детей с различными онкогематологическими заболеваниями: ОЛЛ – 24, ОМЛ – 15, МДС и ХМПЗ – 11 пациентов. Общая выживаемость (ОВ) по методу Каплан-Майер во всей группе составила 48%, безрецидивная выживаемость (БРВ) – 60%. Медиана наблюдения составила 3 года 7 мес. Пятилетняя ОВ в группе ОЛЛ была 46,2%, в группе ОМЛ – 53,3%, в группе МДС и МПЗ – 44,4%. Причины летальности: рецидив/прогрессия в 17 случаях (65%).Трансплантационная летальность составила 18% (95% ДИ, 8,8%-29,8%). Кумулятивная частота рецидива составила 34% (95% ДИ, 21,6%-48%).</p> <h3>Заключение</h3> <p style="text-align: justify;">Повторная алло-ТГСК – эффективный метод терапии у пациентов с рецидивом заболевания после первой ТГСК. Пациенты, достигшие ремиссии или циторедукции перед алло-ТГСК, имеют статистически достоверный лучший прогноз. Развитие хронической РТПХ легкой и средней степени статистически улучшает ОВ. Не получено достоверной разницы между РИК и МАК. Посттрансплантационная терапия может улучшить результаты повторной алло-ТГСК.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Рецидив острого лейкоза, повторная алло-ТГСК, посттрансплантационная терапия, дети. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3448) "Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является стандартом терапии в группе высокого риска онкогематологических заболеваний. Несмотря на это, уровень рецидивов варьирует от 10 до 70%. До сих пор отсутствует оптимальный подход к терапии рецидива после алло-ТГСК. Возможные терапевтические опции включают в себя реиндукцию, иммуноадоптивную терапию, таргетную терапию, иммунотерапию (CAR T-клеточную терапию), повторную трансплантацию. В данной публикации представлено ретроспективное исследование пациентов с рефрактерным течением онкогематологических заболеваний, а также отторжением трансплантата в группе высокого риска, в связи с чем выполнялась повторная алло-ТГСК. Целью нашей работы был анализ результатов повторной алло-ТГСК у 50 детей с различными онкогематологическими заболеваниями: ОЛЛ – 24, ОМЛ – 15, МДС и ХМПЗ – 11 пациентов. Общая выживаемость (ОВ) по методу Каплан-Майер во всей группе составила 48%, безрецидивная выживаемость (БРВ) – 60%. Медиана наблюдения составила 3 года 7 мес. Пятилетняя ОВ в группе ОЛЛ была 46,2%, в группе ОМЛ – 53,3%, в группе МДС и МПЗ – 44,4%. Причины летальности: рецидив/прогрессия в 17 случаях (65%).Трансплантационная летальность составила 18% (95% ДИ, 8,8%-29,8%). Кумулятивная частота рецидива составила 34% (95% ДИ, 21,6%-48%).
Заключение
Повторная алло-ТГСК – эффективный метод терапии у пациентов с рецидивом заболевания после первой ТГСК. Пациенты, достигшие ремиссии или циторедукции перед алло-ТГСК, имеют статистически достоверный лучший прогноз. Развитие хронической РТПХ легкой и средней степени статистически улучшает ОВ. Не получено достоверной разницы между РИК и МАК. Посттрансплантационная терапия может улучшить результаты повторной алло-ТГСК.
Ключевые слова
Рецидив острого лейкоза, повторная алло-ТГСК, посттрансплантационная терапия, дети.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3448) "Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является стандартом терапии в группе высокого риска онкогематологических заболеваний. Несмотря на это, уровень рецидивов варьирует от 10 до 70%. До сих пор отсутствует оптимальный подход к терапии рецидива после алло-ТГСК. Возможные терапевтические опции включают в себя реиндукцию, иммуноадоптивную терапию, таргетную терапию, иммунотерапию (CAR T-клеточную терапию), повторную трансплантацию. В данной публикации представлено ретроспективное исследование пациентов с рефрактерным течением онкогематологических заболеваний, а также отторжением трансплантата в группе высокого риска, в связи с чем выполнялась повторная алло-ТГСК. Целью нашей работы был анализ результатов повторной алло-ТГСК у 50 детей с различными онкогематологическими заболеваниями: ОЛЛ – 24, ОМЛ – 15, МДС и ХМПЗ – 11 пациентов. Общая выживаемость (ОВ) по методу Каплан-Майер во всей группе составила 48%, безрецидивная выживаемость (БРВ) – 60%. Медиана наблюдения составила 3 года 7 мес. Пятилетняя ОВ в группе ОЛЛ была 46,2%, в группе ОМЛ – 53,3%, в группе МДС и МПЗ – 44,4%. Причины летальности: рецидив/прогрессия в 17 случаях (65%).Трансплантационная летальность составила 18% (95% ДИ, 8,8%-29,8%). Кумулятивная частота рецидива составила 34% (95% ДИ, 21,6%-48%).
Заключение
Повторная алло-ТГСК – эффективный метод терапии у пациентов с рецидивом заболевания после первой ТГСК. Пациенты, достигшие ремиссии или циторедукции перед алло-ТГСК, имеют статистически достоверный лучший прогноз. Развитие хронической РТПХ легкой и средней степени статистически улучшает ОВ. Не получено достоверной разницы между РИК и МАК. Посттрансплантационная терапия может улучшить результаты повторной алло-ТГСК.
Ключевые слова
Рецидив острого лейкоза, повторная алло-ТГСК, посттрансплантационная терапия, дети.
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2 Санкт-Петербургский государственный электротехнический университет, Санкт-Петербург, Россия
1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
2 Санкт-Петербургский государственный электротехнический университет, Санкт-Петербург, Россия
Introduction
Dementia is an incurable loss of mental abilities. Dementia in elderly persons is a frequent condition and presents a large public health problem worldwide [1]. It has many different causes, among them primary genetic factors or the sequelae of other diseases such as vascular disorders. The pathogenesis of these forms of dementia is in general poorly understood, which is the major reason for the helpless attempts at developing therapies. Dementia in children – in contrast – is a rare phenomenon. Its causes are frequently well defined genetically, and its pathogenesis is sometimes well understood, which offers chances to develop a rational therapeutic approach.
The most frequent cause of dementia in young persons is a group of diseases called the Neuronal Ceroid-Lipofuscinoses (NCL). This group comprises more than a dozen diseases that are caused by mutations in different genes. All NCL have characteristic features in common: a variable clinical syndrome of dementia, epilepsy and retinopathy, as well as intracellular storage of an abnormal wax-like material called ceroid lipofuscin. The storage process causes degeneration and death of neuronal and retinal cells. NCL are presently classified according to the responsible mutated genes (CLN1, CLN2 etc.). Some of the gene mutations cause deficiencies of soluble lysosomal enzymes, others lead to dysfunction of lysosomal membrane proteins [2].
CLN2 disease, also called classical late-infantile NCL or Janský-Bielschowsky disease, typically strikes healthy-looking and normally developed 3-year-old toddlers. At this age, the disease manifests itself either strikingly with severe epilepsy, or more gradually with a slowing of further development. This is followed by dramatic loss of all mental and motor abilities and paralleled by severe brain atrophy. At the age of about 6 years, the patients are completely helpless and blind. Death usually occurs at the age of 10 to 15 years. Several cases with later manifestation and slower course of the disease have been described [3].
The disease is caused by a profound deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) in the brain. TPP1 is a protease, targeted to lysosomes via a mannose 6-phosphate receptor.
It cleaves tripeptides and is activated by clipping of a prosegment. The natural substrate and function of the enzyme are unknown, but it is clear that the deficiency of the enzyme causes storage of material and neurodegeneration.
Replacing a deficient brain protein
Replacing the missing enzyme in the brain of CLN2 patients became an attractive concept, as many enzymes can now be fabricated, and because free lysosomal enzymes are frequently taken up easily by cells [4]. Human recombinant TPP1 was made by BioMarin. However, as the protein does not cross the blood-brain barrier, injection into the CSF space was used in pre-clinical experiments (Fig. 1). In TPP1-deficient mice this led to attenuation of the disease and extended survival. Important studies were done with a natural dog model of CLN2 disease. These TPP1-deficient dogs received the enzyme by infusion into the lumbar CSF space. Their functional improvement and prolonged survival were impressive compared with untreated dogs, which persuaded us to use the treatment for patients. Studies in monkeys demonstrated that the enzyme, when injected into CSF, reached wide areas of brain.
In a clinical trial, we used the method illustrated in Fig. 2 for the application of TPP1. The enzyme (300 mg of the recombinant human TPP1, cerliponase A, Brineura©) is infused every 2 weeks through the skin into an implanted port, from where it is passed on over a thin tube to a lateral brain ventricle.
Figure 1. Preclinical studies with intrathecal application of TPP1 in various animal species and conclusions from results
Figure 2. Method used to apply TPP1 in patients
Figure 3. Results of clinical scoring of CLN2 patients from 0 to 12 years of age
Note: The score used here is a combined score for the ability of a child to walk and talk. Normal walking and talking abilities result in 3 points for each ability (6 points on this scale). Loss of abilities is scored with 2 points for a minor disturbance, 1 point for a major disturbance, and 0 points for total loss of the respective function. There is a dramatic loss of abilities between 3 and 6 years of age. The course of the disease is very uniform. (Redrawn from [5]).
Measuring efficacy of a new treatment in a rare degenerative brain disease poses the serious problem of control patients. Placebo controls were unacceptable because of the aggressiveness of the procedure and the rarity of the condition. Our solution was to use a clinical scoring system we had specifically developed for CLN2 disease. Scoring of a large number of CLN2 patients over many years had resulted in a rather precise quantitative description of the disease course and its variability [5]. Fig. 3 shows that the clinical course of CLN2 disease is characterized (1) by a dramatic loss of motor and language abilities between the ages of three and six years and (2) by great uniformity in the majority of patients. On this basis it was decided that historical untreated patients could be used as controls.
Clinical trial
A clinical trial with intrathecal TPP1 replacement therapy was performed with international cooperation and Angela Schulz as principal investigator as shown in Fig. 4. This was an open-label phase I/II dose escalation study performed 2013-2016. An extension study is presently ongoing.
Enrolled were twenty-four patients. Of them, 23 completed the study. Efficacy was measured against matched historical controls. Adverse events were relatively minor: We had some infections that could be managed easily, and there were some failures of the intraventricular device. None of the adverse events led to discontinuation of treatment [6].
Results of the trial are illustrated by Fig. 5, which shows the striking capacity of the treatment to halt the expected dramatic loss of motor and language abilities.
Figure 4. Investigators and participant institutions at the clinical trial with enzyme replacement therapy for CLN2 disease
Figure 5. Risk of losing motor and language abilities in 23 children with CLN2 disease treated with intraventricular TPP1 (cerliponase A, Brineura©) over a three-year period (blue line), compared to matched untreated historical controls (red line). Probabilities of no functional decline were calculated on the basis of motor-language scoring (see figure 3). From [6]
Summary and conclusions
Effective treatment of CLN2 disease, a rare childhood dementia, has become possible through a combination of favorable factors:
(1) The pathogenetic mechanism was known (lack of a lysosomal enzyme in brain).
(2) The deficient protein could be synthesized.
(3) For preclinical studies, a large experimental animal (natural dog model) was available.
(4) The blood-brain barrier was overcome by intra-ventricular infusion.
(5) The clinical course of the disease and its variability were sufficiently known. Historical controls could therefore be used and placebo controls avoided.
Many questions remain. We have no long-term results of this treatment. Will life-long treatment be necessary? What will be the further development of the treated patients? Are we creating a chronic disease from a dramatically cruel, relatively acute condition? An additional therapeutic approach to the retinopathy will have to be developed. Will new treatments, such as gene therapy, be safe and more effective than enzyme replacement [7]? At any rate, the results of this trial with replacement of a deficient brain protein has pushed open a door. Some principles underlying this study of a rare childhood disease may be applicable to other, much more frequent forms of dementia.
Conflict of interests
None declared.
References
- World Health Organization. Dementia: a public health priority. 2012, Geneva: Publications of the World Health Organization.
- Nita DA, Mole SE, Minassian BA. Neuronal ceroid lipofuscinoses. Epileptic Disord, 2016; 18(S2): 73-88.
- Kohlschütter A, Schulz A. CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis). Pediatric Endocrinology (Diabetes, Nutrition, Metabolism) Reviews, 2016; 13(Suppl 1): 682-688.
- Neufeld EF. Enzyme replacement therapy – a brief history, in Fabry Disease: Perspectives from 5 Years of FOS, A. Mehta, M. Beck, and G. Sunder-Plassmann, Editors. 2006: Oxford.
- Nickel M., Simonati A, Jacoby D, Lezius S, Kilian D, Van de Graaf B, Pagovich OE, Kosofsky B, Yohay K, Downs M, Slasor P, Ajayi T, Crystal RG, Kohlschutter A, Sondhi D, Schulz A. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc Health, 2018; 2(8): 582-590.
- Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschutter A, and CLN Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med, 2018; 378(20): 898-1907.
- Kohlschütter A, Schulz A, Bartsch U, Storch S. Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses. CNS Drugs, 2019; 33(4): 315-325.
Introduction
Dementia is an incurable loss of mental abilities. Dementia in elderly persons is a frequent condition and presents a large public health problem worldwide [1]. It has many different causes, among them primary genetic factors or the sequelae of other diseases such as vascular disorders. The pathogenesis of these forms of dementia is in general poorly understood, which is the major reason for the helpless attempts at developing therapies. Dementia in children – in contrast – is a rare phenomenon. Its causes are frequently well defined genetically, and its pathogenesis is sometimes well understood, which offers chances to develop a rational therapeutic approach.
The most frequent cause of dementia in young persons is a group of diseases called the Neuronal Ceroid-Lipofuscinoses (NCL). This group comprises more than a dozen diseases that are caused by mutations in different genes. All NCL have characteristic features in common: a variable clinical syndrome of dementia, epilepsy and retinopathy, as well as intracellular storage of an abnormal wax-like material called ceroid lipofuscin. The storage process causes degeneration and death of neuronal and retinal cells. NCL are presently classified according to the responsible mutated genes (CLN1, CLN2 etc.). Some of the gene mutations cause deficiencies of soluble lysosomal enzymes, others lead to dysfunction of lysosomal membrane proteins [2].
CLN2 disease, also called classical late-infantile NCL or Janský-Bielschowsky disease, typically strikes healthy-looking and normally developed 3-year-old toddlers. At this age, the disease manifests itself either strikingly with severe epilepsy, or more gradually with a slowing of further development. This is followed by dramatic loss of all mental and motor abilities and paralleled by severe brain atrophy. At the age of about 6 years, the patients are completely helpless and blind. Death usually occurs at the age of 10 to 15 years. Several cases with later manifestation and slower course of the disease have been described [3].
The disease is caused by a profound deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) in the brain. TPP1 is a protease, targeted to lysosomes via a mannose 6-phosphate receptor.
It cleaves tripeptides and is activated by clipping of a prosegment. The natural substrate and function of the enzyme are unknown, but it is clear that the deficiency of the enzyme causes storage of material and neurodegeneration.
Replacing a deficient brain protein
Replacing the missing enzyme in the brain of CLN2 patients became an attractive concept, as many enzymes can now be fabricated, and because free lysosomal enzymes are frequently taken up easily by cells [4]. Human recombinant TPP1 was made by BioMarin. However, as the protein does not cross the blood-brain barrier, injection into the CSF space was used in pre-clinical experiments (Fig. 1). In TPP1-deficient mice this led to attenuation of the disease and extended survival. Important studies were done with a natural dog model of CLN2 disease. These TPP1-deficient dogs received the enzyme by infusion into the lumbar CSF space. Their functional improvement and prolonged survival were impressive compared with untreated dogs, which persuaded us to use the treatment for patients. Studies in monkeys demonstrated that the enzyme, when injected into CSF, reached wide areas of brain.
In a clinical trial, we used the method illustrated in Fig. 2 for the application of TPP1. The enzyme (300 mg of the recombinant human TPP1, cerliponase A, Brineura©) is infused every 2 weeks through the skin into an implanted port, from where it is passed on over a thin tube to a lateral brain ventricle.
Figure 1. Preclinical studies with intrathecal application of TPP1 in various animal species and conclusions from results
Figure 2. Method used to apply TPP1 in patients
Figure 3. Results of clinical scoring of CLN2 patients from 0 to 12 years of age
Note: The score used here is a combined score for the ability of a child to walk and talk. Normal walking and talking abilities result in 3 points for each ability (6 points on this scale). Loss of abilities is scored with 2 points for a minor disturbance, 1 point for a major disturbance, and 0 points for total loss of the respective function. There is a dramatic loss of abilities between 3 and 6 years of age. The course of the disease is very uniform. (Redrawn from [5]).
Measuring efficacy of a new treatment in a rare degenerative brain disease poses the serious problem of control patients. Placebo controls were unacceptable because of the aggressiveness of the procedure and the rarity of the condition. Our solution was to use a clinical scoring system we had specifically developed for CLN2 disease. Scoring of a large number of CLN2 patients over many years had resulted in a rather precise quantitative description of the disease course and its variability [5]. Fig. 3 shows that the clinical course of CLN2 disease is characterized (1) by a dramatic loss of motor and language abilities between the ages of three and six years and (2) by great uniformity in the majority of patients. On this basis it was decided that historical untreated patients could be used as controls.
Clinical trial
A clinical trial with intrathecal TPP1 replacement therapy was performed with international cooperation and Angela Schulz as principal investigator as shown in Fig. 4. This was an open-label phase I/II dose escalation study performed 2013-2016. An extension study is presently ongoing.
Enrolled were twenty-four patients. Of them, 23 completed the study. Efficacy was measured against matched historical controls. Adverse events were relatively minor: We had some infections that could be managed easily, and there were some failures of the intraventricular device. None of the adverse events led to discontinuation of treatment [6].
Results of the trial are illustrated by Fig. 5, which shows the striking capacity of the treatment to halt the expected dramatic loss of motor and language abilities.
Figure 4. Investigators and participant institutions at the clinical trial with enzyme replacement therapy for CLN2 disease
Figure 5. Risk of losing motor and language abilities in 23 children with CLN2 disease treated with intraventricular TPP1 (cerliponase A, Brineura©) over a three-year period (blue line), compared to matched untreated historical controls (red line). Probabilities of no functional decline were calculated on the basis of motor-language scoring (see figure 3). From [6]
Summary and conclusions
Effective treatment of CLN2 disease, a rare childhood dementia, has become possible through a combination of favorable factors:
(1) The pathogenetic mechanism was known (lack of a lysosomal enzyme in brain).
(2) The deficient protein could be synthesized.
(3) For preclinical studies, a large experimental animal (natural dog model) was available.
(4) The blood-brain barrier was overcome by intra-ventricular infusion.
(5) The clinical course of the disease and its variability were sufficiently known. Historical controls could therefore be used and placebo controls avoided.
Many questions remain. We have no long-term results of this treatment. Will life-long treatment be necessary? What will be the further development of the treated patients? Are we creating a chronic disease from a dramatically cruel, relatively acute condition? An additional therapeutic approach to the retinopathy will have to be developed. Will new treatments, such as gene therapy, be safe and more effective than enzyme replacement [7]? At any rate, the results of this trial with replacement of a deficient brain protein has pushed open a door. Some principles underlying this study of a rare childhood disease may be applicable to other, much more frequent forms of dementia.
Conflict of interests
None declared.
References
- World Health Organization. Dementia: a public health priority. 2012, Geneva: Publications of the World Health Organization.
- Nita DA, Mole SE, Minassian BA. Neuronal ceroid lipofuscinoses. Epileptic Disord, 2016; 18(S2): 73-88.
- Kohlschütter A, Schulz A. CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis). Pediatric Endocrinology (Diabetes, Nutrition, Metabolism) Reviews, 2016; 13(Suppl 1): 682-688.
- Neufeld EF. Enzyme replacement therapy – a brief history, in Fabry Disease: Perspectives from 5 Years of FOS, A. Mehta, M. Beck, and G. Sunder-Plassmann, Editors. 2006: Oxford.
- Nickel M., Simonati A, Jacoby D, Lezius S, Kilian D, Van de Graaf B, Pagovich OE, Kosofsky B, Yohay K, Downs M, Slasor P, Ajayi T, Crystal RG, Kohlschutter A, Sondhi D, Schulz A. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc Health, 2018; 2(8): 582-590.
- Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschutter A, and CLN Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med, 2018; 378(20): 898-1907.
- Kohlschütter A, Schulz A, Bartsch U, Storch S. Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses. CNS Drugs, 2019; 33(4): 315-325.
Альфред Кольшюттер
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Ключевые слова
Нейрональный цероидный липофусциноз 2, трипептидил-пептидаза 1, дефицит, деменция, рекомбинантный энзим, локальная инфузия, клинический эффект.
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24505" ["VALUE"]=> array(2) { ["TEXT"]=> string(80) "<p>University Medical Center Hamburg-Eppendorf, Hamburg, Germany</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(68) "University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Keywords
Neuronal сeroid-lipofuscinosis 2, tripeptidyl peptidase 1, deficiency, dementia, recombinant enzyme, local infusion, clinical effect.
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" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24506" ["VALUE"]=> array(2) { ["TEXT"]=> string(783) "<p style="text-align: justify;">Neuronal сeroid-lipofuscinosis 2 (CLN2) is a genetic, rapidly progressive brain disorder of young humans. It leads to dementia, dramatic loss of all abilities and early death. It is caused by the deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) in the nervous system. This article is an overview of the development of replacing the deficient enzyme by repeated infusion of recombinant TPP1 in a brain ventricle, shown to be effective in halting the rapid progression of the disease.</p> <h2>Keywords</h2> <p style="text-align: justify;">Neuronal сeroid-lipofuscinosis 2, tripeptidyl peptidase 1, deficiency, dementia, recombinant enzyme, local infusion, clinical effect.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(727) "Neuronal сeroid-lipofuscinosis 2 (CLN2) is a genetic, rapidly progressive brain disorder of young humans. It leads to dementia, dramatic loss of all abilities and early death. It is caused by the deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) in the nervous system. This article is an overview of the development of replacing the deficient enzyme by repeated infusion of recombinant TPP1 in a brain ventricle, shown to be effective in halting the rapid progression of the disease.
Keywords
Neuronal сeroid-lipofuscinosis 2, tripeptidyl peptidase 1, deficiency, dementia, recombinant enzyme, local infusion, clinical effect.
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Keywords
Neuronal сeroid-lipofuscinosis 2, tripeptidyl peptidase 1, deficiency, dementia, recombinant enzyme, local infusion, clinical effect.
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(CLN2) является наследственным, быстро прогрессирующим заболеванием раннего возраста, ведущим к деменции, резкой утрате всех навыков и ранней гибели пациента. Оно вызывается дефицитом лизосомного фермента трипептидил-пептидазы 1 (ТРР1) в нервной системе. Настоящая статья является обзором разработок по замещению дефектного энзима посредством повторных инфузий рекомбинантного ТРР1 в желудочки головного мозга. Показана эффективность метода в плане сдерживания быстрой прогрессии заболевания.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Нейрональный цероидный липофусциноз 2, трипептидил-пептидаза 1, дефицит, деменция, рекомбинантный энзим, локальная инфузия, клинический эффект.</p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1357) "Нейрональный цероидный липофусциноз (CLN2) является наследственным, быстро прогрессирующим заболеванием раннего возраста, ведущим к деменции, резкой утрате всех навыков и ранней гибели пациента. Оно вызывается дефицитом лизосомного фермента трипептидил-пептидазы 1 (ТРР1) в нервной системе. Настоящая статья является обзором разработок по замещению дефектного энзима посредством повторных инфузий рекомбинантного ТРР1 в желудочки головного мозга. Показана эффективность метода в плане сдерживания быстрой прогрессии заболевания.
Ключевые слова
Нейрональный цероидный липофусциноз 2, трипептидил-пептидаза 1, дефицит, деменция, рекомбинантный энзим, локальная инфузия, клинический эффект.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1357) "Нейрональный цероидный липофусциноз (CLN2) является наследственным, быстро прогрессирующим заболеванием раннего возраста, ведущим к деменции, резкой утрате всех навыков и ранней гибели пациента. Оно вызывается дефицитом лизосомного фермента трипептидил-пептидазы 1 (ТРР1) в нервной системе. Настоящая статья является обзором разработок по замещению дефектного энзима посредством повторных инфузий рекомбинантного ТРР1 в желудочки головного мозга. Показана эффективность метода в плане сдерживания быстрой прогрессии заболевания.
Ключевые слова
Нейрональный цероидный липофусциноз 2, трипептидил-пептидаза 1, дефицит, деменция, рекомбинантный энзим, локальная инфузия, клинический эффект.
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Normal microbiota colonizing mucosal surfaces is usually identified at clinical laboratories by means of aerobic cultures in standard agar cultures. It comprises, mostly, saprophytic and oppor-tunistic bacteria. In particular, the microflora of normal oral mucosa is well known, and the most common bacterial species are identified [1, 2]. Members of normal oral microbiota exist as com-mensal flora in a symbiotic state within host tissue, thus suppressing colonization with more path-ogenic bacterial species as presented in excellent review by Hull, Chow [1]. The most common aerobic species isolated in clinical cultures from oral cavity and oropharynx mucosa include Gram-positive Streptococci (e.c., S.viridans), Staphylococcus epidermidis, Corynebacterium spp., Neisseria spp., etc. Moreover, oral cavity, and, especially, ginvival mucosa contain multiple an-aerobic flora which is represented by hundreds species, most of which could be detected only by DNA-based diagnostic techniques [3].
Intensive chemotherapy of cancer and, especially, hematopoietic stem cell transplantation (HSCT) are followed by severe immunosuppression. I.e., pronounced neutro-and lymphopenia develops within 1-2 weeks after HSCT, accomplished by reactivation of endogenous viruses, as well as opportunistic bacteria and nosocomial pathogens which may colonize different mucosal surfaces and replace conventional microflora, thus leading to local dysbacteriosis [4]. Local infections are a common consequence of severe leukopenia. E.g., a previous study of 143 HSCT patients [5] has shown nosocomial bacterial infections in ca. 25% of cases, especially, septicemia (43%), and respiratory infections. Some pathogenetic links between infections and oral mucositis were suggested by Laheji et al. [6].
In most oncohematological clinics, the bacterial cultures from local biomaterials are performed by clinical indications, e.g., due to febrile neutropenia or local inflammatory loci. Surveillance microbial diagnostics is also sometimes implemented, however, without any clinical benefits [7]. Majority of these studies concern reactivation/reinfection with different viruses, in particular, herpesviruses, parvoviruses etc. Studies in bacterial infections mainly deal with isolation of aerobically cultivated pathogenic strains, their toxins and antibiotic resistance, mainly, Pseudomonas spp., Klebsiella pneumoniae, Clostridium difficile or enteropathogenic E.coli infections.
To our knowledge, there were only few studies of microbial landscape in oral mucosa at different periods after HSCT [7]. In most cases, these studies are epidemiologically oriented, and provide relative frequencies of local pathogenic microorganisms in HSCT patients, and their potential correlations with clinically significant infections [8].
Only few works concern time dynamics of the microbial landscape in the patients after HSCT, however, lacking sufficient data on possible relations between the shifts of oral microbiota and common HSCT complications, i.e., local infections, oral mucositis, or acute graft-versus-host disease (aGVHD).
The aim of the present study was to estimate the frequency of cultivable aerobic microflora obtained from oral mucosa smears taken before HSCT and during 4 months posttransplant. We have evaluated time course for the most common microorganisms, as well as probable interactions between the frequency of their detection rates and occurrence of characteristic complications after HSCT, including mucositis, febrile neutropenia, acute GVHD, and clinically significant infectious complications.
Patients and methods
In the present study, we have evaluated results of clinical bacterial cultures from 630 smears of the oropharynx and tongue taken from 202 patients at the age of 1 to 69 (108 males and 94 females) subjected to allogeneic HSCT at the R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation from January 2016 to December 2017. Allogeneic HSCT was performed for acute myeloblastic leukemia (AML, n-63), chronic myeloid leukemia (CML, n=28), acute lymphoblastic leukemia (ALL, n=34), severe aplastic anemia (SAA, n=22), refractory anemia (RA, n=6), plasma cell dysplasia (7 cases), primary myelofibrosis (PMF, n=10). Inborn genetic disorders were treated in 9 children, Hodgkin lymphoma, in 6 patients, non-Hodgkin’s lymphomas, in 4 cases, juvenile myelomonocytic leukemia, in 3 patients; polycythemia vera, in 2 patients, essential thrombocytopenia, etc. Myeloablative conditioning regimens were performed in for 122 patients, and non-myeloablative protocols were applied in 80 cases. Bone marrow was used as a source of stem cells in 97 cases, and peripheral stem cells, in 105 patients. HSCT was carried out from related HLA-compatible donors (n=35), related haploidentical donors (33 patients), or unrelated HLA-matched donors (112 cases). Patients or their close relatives signed appropriate informed consent for their participation in the research program, and usage of their personal medical data for the scientific evaluation. The smears for bacteriological studies were taken from oropharynx or tongue. Subsequent sampling was made before HSCT and within 120 days (4 months posttransplant), according to clinical indications from the attained physicians. The biomaterials were conserved, stored and processed at the Department of Clinical Microbiology, being seeded on agar plates and cultured on the conventional nutrient media under aerobic conditions.
Statistical analysis included the patients with at least 1 result before HSCT, and 2 results within 4 months posttransplant. All the data on clinical characteristics of the patients, HSCT parameters, conditioning therapy, posttransplant complications, and bacterial cultures were taken from the hospital reports of R. Gorbacheva Memorial Institute, and laboratory database at the 1st St. Petersburg State I. Pavlov Medical University. Statistical evaluation was performed by means of the STATISTIСA 5.0 software, by means of non-parametric single-factor analysis using Hi-square criterion and Pearson correlation quotients to evaluate significance of differences between the samples. In some series, parametric methods were used using Student t-test.
Results
Common bacteria detectable in oral cavity
Total sample included 630 cultures from oral smears, with positive results for 389 specimens (61.8%). One microbial species was detected in 250 cases; 2 species, в 117 cultures, and 3 microbial species, in 22 cultures. The most common microorganisms were as follows: S.viridans 245/630 (38.9%); K.pneumoniae 42/630 (6.7%); S.epidermidis 120/630 (19.1%); Neisseria spp., 66/630 (10.5%); Corynebacterium spp., 78/630 (12.4%). Other bacteria were detected in <1% of the cultures (S. saprophyticus., Pseudomonas spp., S.faecalis, S.faecium). For statistical reasons, only 5 most common bacterial species were included into further analysis, i.e., S.viridans , K.pneumoniae, S.epidermidis, Neisseria spp., Corynebacterum spp.
Age factor
Frequency of the five common bacterial species in the oral cavity smears is shown in Table 1. For the age groups of 0-5, 6-14, 15-21 y.o., and adult persons (>22 y.o.), some significant age dependencies were revealed. I.e., S.viridans detection was maximal in smaller children (0 to 5 years old), as compared to the groups of 6-14 and 15-21 (p<0.02), then showing an increase in adult patients. Similar tendency was seen for Klebsiella pneumoniae, with higher detection rates in small children and adult patients.
Table 1. Detection of the common bacterial species in the specimens from oral cavity in children and adults at the whole observation period (-60 to +120 days post-HSCT)
Time dependence of microbial detection
Frequency of positive cultures was time-dependent, and varied for different microorganisms (Table 2). However, a significant drop was evident for all the detectable microbial species during 1st month posttransplant, most obviously, due to intensive antibacterial prophylaxis started before HSCT. The early suppression was most pronounced for S.viridans, and S.epidermidis, a normal component of oral microflora. Interestingly, an initial marginal decrease of K.pneumoniae detection was followed by its sharp increase at 2-4 months (Fig. 1).
Table 2. Time dependence for the detection frequency of common aerobic microorganisms cultured from the oral cavity of HSCT patients
Note: The difference levels (p values) were determined by the non-parametric Hi-square test. This time dynamics for 3 distinct bacterial species is also shown in Fig. 1.
Figure 1. Prevalence of S.viridans (A), S.epidermidis (B), and K.pneumoniae (C) in bacterial cultures within 1-4 months after HSCT
Abscissa, terms posttransplant (months). Ordinate, frequency of positive results. Points at the graph show M+m values.
HSCT parameters
As seen from Table 3, we have not found any significant associations between the frequency of positive cultures of common oral microbes, and source of stem cells (bone marrow vs peripheral stem cells), or type of HSCT (related vs unrelated vs haploidentical HSCT). Meanwhile, decreased detection rates of S.epidermidis proved to be significantly associated with more intensive (myeloablative) therapy, as compared to reduced-intensity regimens (Table 3). As expected, K.pneumoniae was associated with clinically significant infectious complications of either location.
Table 3. Detection rates for some common oral microorganisms in HSCT recipients over 120 days post-HSCT: dependence on transplant characteristics and posttransplant complications
Mucositis, febrile neutropenia and clinical infections
In more than 50% of patients, oral mucositis was observed within early terms after HSCT. Our data have confirmed higher frequency of oral mucositis after myeloablative conditioning treat-ment (181/330, 54.9%) against 33.1% (80/242) following reduced-intensity conditioning (р=2×10-7). Moreover, higher occurrence of febrile neutropenia was found in the group of patients with mucositis (50.3%) against 30.7% in mucositis-free cases (р=4×10-8), as seen from Table 3. Taking into account similar terms of mucositis and dysbacteriosis (1st month posttransplant), one could suggest infectious component for the oral inflammation. However, we did not reveal any significant correlations between mucositis rates, and frequency of positive cultures of the common microorganisms from oral mucosa (Table 3), thus suggesting a minimal role of these bacteria in genesis of the posttransplant oral inflammation. In addition, we have not revealed any significant correlations between presence of the major species of oral microflora, and acute skin GVHD (Table 3). Absence of correlations between bacterial landscape and main clinical complications may be connected with active antibacterial therapy over the period of post-transplant leukopenia (1-2 months post-HSCT).
Further, we have performed some comparisons between the frequencies of bacterial associations, rates of febrile neutropenia and clinically significant infections posttransplant. This survey has shown that the more frequent associations of >3 microbial species tends to correlate with higher FUO prevalence (Table 4). Increased incidence of FUO was also found after myeloablative conditioning (р=0.001), as well as in the group with oral mucositis (p=4×10-8), as well as in cases of skin aGvHD (p=0.002), thus reflecting evident inflammatory component in the both types of skin and mucosal damage, however, without any association with. Hence, early neutropenic fever is more likely associated with cytostatic chemotherapy and allogeneic HSCT, rather than with local clinically significant infections posttransplant.
Interestingly, the numbers of transplanted hematopoietic stem cells (CD34+ cells) have shown a distinct direct correlation with occurrence of early mucositis (r=0.20; p=8×107) thus again suggesting a clear relation between oral mucositis and potential immune effects of allogeneic hematopoietic cells posttransplant.
Table 4. Frequency of FUO and microbial associations: effects of different HSCT parameters and posttransplant complications
Microbial resistance
Klebsiella is the mostly discussed bacterial pathogen with high prevalence of antibiotic-resistant strains. We have tested in vitro the resistance of K.pneumoniae isolates seeded from oral cavity of 11 HSCT patients in 2017 (Table 5). Majority of the isolates showed resistance for most antibiotics commonly used in septic HSCT patients. However, most of the K.pneumoniae isolates proved to be sensitive to amikacin, gentamycin and meropenem.
Table 5. Differential in vitro antibiotic sensitivity of K.pneumoniae isolates obtained from oral cavity after hematopoietic stem cell transplantation
Note: R, resistance; S, sensitivity of the microorganism; I, intermediate values
Of note, in the patient F.Z., the initial sensitive phenotype was 1 month later changed to polyresistance, except of amikacin and meropenem, thus, probably, reflecting its replacement by a resistant bacterial strain.
Bacterial pathogens at the sites of dental infections
In 10 cases, tooth extraction was performed during 1st month after HSCT, due to acute pulpitis and local septic process. Bacterial isolates from the post-extraction wounds were obtained in 10 cases, and the following bacteria were detected: Pseudomonas aeruginosa in 3 samples, S.viridans in 2 cases, Neisseria spp., S.faecalis, S.epidermidis were found in other specimens. Of them, only P.aeruginosa is a well-known pathogenic agent to cause purulent local inflammation.
Discussion
Overall rates of positive microbial cultures from oral cavity were rather high (61.8%). Cytotoxic damage to oral epithelium due to previous chemotherapy, as well as deep leukopenia after conditioning treatment and HSCT are the key pre-requisites for oral bacterial colonization [9]. However, conventional culturing of oral samples taken at different terms post HSCT (D-60 to D+120) have shown a sufficient decrease in cultivable oral microflora within 1st month posttransplant. Such suppression of microflora could be readily explained by anti-microbial treatment administered during intensive cytostatic therapy of cancer [10, 11]. In our study, a deep suppression was shown for S.viridans, S.epidermidis, and K. pneumoniae. The latter is the known Gram-negative pathogen causing infectious complications at later terms (2-4 months posttransplant), with a tendency for polyresistance for antibiotics, as confirmed in our study.
Microbial associations of 3 or more bacteria could be found in some samples. Of note, posttransplant clinically significant infections proved to be much more often in cases with >3 microorganisms found in the oral samples, thus suggesting the microbial associations to be a marker of suppressed antimicrobial immunity post-HSCT.
Like as other common posttransplant complications, clinical infectious conditions did not show any direct correlations with either positive oral bacterial cultures, or early post-transplant mucositis (Table 3 and 4). Rather, fever of unknown origin (FUO), an early inflammatory condition without clear infectious reason, had a distinct relationship with myeloablative treatment, oral mucositis, and skin GvHD. Oral mucositis may be, at least, in part, dependent on common herpesvirus activation post-HSCT [12].
Among common bacterial species found in oral cavity of the patients, Klebsiella pneumoniae is known to produce a number of polyresistant strains, as confirmed in our study (Table 5). This feature of K.pneumoniae is typical to nosocomial infections. Decreased rates of Klebsiella detection at early terms (1st month) following HSCT could be explained by relative sensitivity of most endogenous bacterial populations to routine decontaminating therapy. At later terms (2nd and 3rd months) the sensitivity-adapted antibiotic treatment in the patients with prolonged infectious complications under the ICU conditions, may cause selection of Klebsiella strains with extended resistance spectrum as, it was revealed in our F.Z. patient at 5-6 months after HSCT.
Therefore, phenotypic and molecular monitoring of standard lactamase genes in clinical isolates before and after HSCT may further elucidate the mechanisms of resistance selection among Klebsiella and other Gram-negative bacteia, aiming for development of combined treatment schedules [13].
In this respect, the role of oral bacterial infection in development of mucositis and GvHD still remains unclear. Meanwhile, over last decades, a crucial role of gut microbiome and altered intestinal mucosa due to broad-spectrum antibacterial therapy becomes more clear and clinically confirmed, both for infectious complications and acute GvHD [14, 15, 16].
Conclusion
Cytotoxic damage of oral mucosa during intensive chemotherapy may create sufficient prerequisites for bacterial colonization. Moreover, antibacterial prophylaxis in HSCT patients causes deep suppression of oral microflora during 1st month post-HSCT, despite severe leukopenia in the patients. Known antibacterial pathogens, e.g., K.pneumoniae, or P.aerugunosa are revealed in oral cavity within 1-3 months posttransplant.
The consequences of combined anticancer and antibacterial treatment in HSCT patients deserve further studies, in particular, its correlation with mucositis, acute GvHD which may be still underlied by mixed microbial and viral infections. Bacterial imbalance post-HSCT may be a pre-requisite for additional anti-infectious therapy in complex clinical conditions involving infectious/cytotoxic/autoaggressive pathogenetic components. Significant shifts in common bacterial landscape caused by immunotoxic treatment and antibacterial therapy enable growth of other bacterial and fungal pathogens that should be studied in details by means of NGS techniques which should reveal, e.g., anaerobic pathogenic bacteria in posttransplant conditions.
References
- Hull MW, Chow AW. Indigenous microflora and innate immunity of the head and neck. Infect Dis Clin N Am 2007; 21: 265-282.
- Hegde MC, Kumar A, Bhat G, Sreedharan S. Oral microflora: a comparative study in HIV and normal patients. Indian J Otolaryngol Head Neck Surg. 2014; 66(Suppl 1): S126-S132.
- Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J. Clin. Microbiol. 2005; 43(11): 5721-5732.
- Chukhlovin AB, Pankratova OS. Opportunistic microflora at unusual sites: marker pathogens in severe posttransplant immune deficiency. Cell Ther Transplant. 2017; 6(4): 28-41.
- Marena C, Zecca M, Carenini ML, Bruschi A, Bassi ML, Olivieri P, Azzaretti S, Locatelli F. Incidence of, and risk factors for, nosocomial infections among hematopoietic stem cell transplantation recipients, with impact on procedure-related mortality. Infect Control Hosp Epidemiol. 2001;22(8):510-517.
- Lahei AMGA, de Soet JJ, von dem Borne PA, Kuijper EJ, Kraneveld EA, van Loveren C, Raber-Durlacher JE. Oral bacteria and yeasts in relationship to oral ulcerations in hematopoietic stem cell transplant recipients. Support Care Cancer. 2012; 20:3231-3240.
- Czirók E, Prinz GY, Dénes R, Reményi P, Herendi A. Value of surveillance cultures in a bone marrow transplantation unit. J Med Microbiol. 1997;46(9):785-791.
- Vavilov VN, Averianova MY, Bondarenko SN, Stancheva NV, Zubarovskaya LS, Afanasyev BV. Bacterial infections within early period after allogeneic bone marrow transplantation. Ter Arkhiv, 2015; 87(7): 88-93 (In Russian).
- Grigoriants AP, Rabinowitch IM, Chukhlovin AB. Stomatological problems and infectious complications after hematopoietic stem cell transplantation. Cell Ther Transplant 2017; 7(2):10-19.
- Bergmann OJ. Alterations in oral microflora and pathogenesis of acute oral infections during remission-induction therapy in patients with acute myeloid leukaemia. Scand J Infect Dis. 1991;23(3):355-66.
- Jones LR, Toth BB, Keene HJ. Effects of total body irradiation on salivary gland function and caries-associated oral microflora in bone marrow transplant patients. Oral Surg Oral Med Oral Pathol. 1992;73(6):670-676.
- Pankratova OS, Chukhlovin AB, Shiryaev SN, Eismont YA, Vavilov VN, Zubarovskaya LS, Afanasyev BV. Herpesviruses and oral ulcerations in hematopoietic SCT recipients. Bone Marrow Transplantation. 2013; 48:1364-1365.
- Fritzenwanker M, Imirzalioglu C, Herold S, Wagenlehner FM, Zimmer KP, Chakraborty T. Treatment Options for Carbapenem- Resistant Gram-Negative Infections. Dtsch Arztebl Int. 2018 ;115(20-21):345-352.
- Blijlevens NMA, Donnelly JP, De Pauw BE. Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplantation (2000) 25, 1269-1278.
- Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A, Koestler J, Dettmer K, Weber M, Wolff D, Hahn J, Pamer EG, Herr W, Gessner A, Oefner PJ, van den Brink MRM, Holler E. Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017; 23(5):845-852.
- Goloshchapov OV, Kucher MA, Chukhlovin AB. Gut microbiome in hematopoietic stem cell transplantation: patient- and treatment-related factors. Cell Ther Transplant. 2018; 7(4):16-28.
Introduction
Normal microbiota colonizing mucosal surfaces is usually identified at clinical laboratories by means of aerobic cultures in standard agar cultures. It comprises, mostly, saprophytic and oppor-tunistic bacteria. In particular, the microflora of normal oral mucosa is well known, and the most common bacterial species are identified [1, 2]. Members of normal oral microbiota exist as com-mensal flora in a symbiotic state within host tissue, thus suppressing colonization with more path-ogenic bacterial species as presented in excellent review by Hull, Chow [1]. The most common aerobic species isolated in clinical cultures from oral cavity and oropharynx mucosa include Gram-positive Streptococci (e.c., S.viridans), Staphylococcus epidermidis, Corynebacterium spp., Neisseria spp., etc. Moreover, oral cavity, and, especially, ginvival mucosa contain multiple an-aerobic flora which is represented by hundreds species, most of which could be detected only by DNA-based diagnostic techniques [3].
Intensive chemotherapy of cancer and, especially, hematopoietic stem cell transplantation (HSCT) are followed by severe immunosuppression. I.e., pronounced neutro-and lymphopenia develops within 1-2 weeks after HSCT, accomplished by reactivation of endogenous viruses, as well as opportunistic bacteria and nosocomial pathogens which may colonize different mucosal surfaces and replace conventional microflora, thus leading to local dysbacteriosis [4]. Local infections are a common consequence of severe leukopenia. E.g., a previous study of 143 HSCT patients [5] has shown nosocomial bacterial infections in ca. 25% of cases, especially, septicemia (43%), and respiratory infections. Some pathogenetic links between infections and oral mucositis were suggested by Laheji et al. [6].
In most oncohematological clinics, the bacterial cultures from local biomaterials are performed by clinical indications, e.g., due to febrile neutropenia or local inflammatory loci. Surveillance microbial diagnostics is also sometimes implemented, however, without any clinical benefits [7]. Majority of these studies concern reactivation/reinfection with different viruses, in particular, herpesviruses, parvoviruses etc. Studies in bacterial infections mainly deal with isolation of aerobically cultivated pathogenic strains, their toxins and antibiotic resistance, mainly, Pseudomonas spp., Klebsiella pneumoniae, Clostridium difficile or enteropathogenic E.coli infections.
To our knowledge, there were only few studies of microbial landscape in oral mucosa at different periods after HSCT [7]. In most cases, these studies are epidemiologically oriented, and provide relative frequencies of local pathogenic microorganisms in HSCT patients, and their potential correlations with clinically significant infections [8].
Only few works concern time dynamics of the microbial landscape in the patients after HSCT, however, lacking sufficient data on possible relations between the shifts of oral microbiota and common HSCT complications, i.e., local infections, oral mucositis, or acute graft-versus-host disease (aGVHD).
The aim of the present study was to estimate the frequency of cultivable aerobic microflora obtained from oral mucosa smears taken before HSCT and during 4 months posttransplant. We have evaluated time course for the most common microorganisms, as well as probable interactions between the frequency of their detection rates and occurrence of characteristic complications after HSCT, including mucositis, febrile neutropenia, acute GVHD, and clinically significant infectious complications.
Patients and methods
In the present study, we have evaluated results of clinical bacterial cultures from 630 smears of the oropharynx and tongue taken from 202 patients at the age of 1 to 69 (108 males and 94 females) subjected to allogeneic HSCT at the R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation from January 2016 to December 2017. Allogeneic HSCT was performed for acute myeloblastic leukemia (AML, n-63), chronic myeloid leukemia (CML, n=28), acute lymphoblastic leukemia (ALL, n=34), severe aplastic anemia (SAA, n=22), refractory anemia (RA, n=6), plasma cell dysplasia (7 cases), primary myelofibrosis (PMF, n=10). Inborn genetic disorders were treated in 9 children, Hodgkin lymphoma, in 6 patients, non-Hodgkin’s lymphomas, in 4 cases, juvenile myelomonocytic leukemia, in 3 patients; polycythemia vera, in 2 patients, essential thrombocytopenia, etc. Myeloablative conditioning regimens were performed in for 122 patients, and non-myeloablative protocols were applied in 80 cases. Bone marrow was used as a source of stem cells in 97 cases, and peripheral stem cells, in 105 patients. HSCT was carried out from related HLA-compatible donors (n=35), related haploidentical donors (33 patients), or unrelated HLA-matched donors (112 cases). Patients or their close relatives signed appropriate informed consent for their participation in the research program, and usage of their personal medical data for the scientific evaluation. The smears for bacteriological studies were taken from oropharynx or tongue. Subsequent sampling was made before HSCT and within 120 days (4 months posttransplant), according to clinical indications from the attained physicians. The biomaterials were conserved, stored and processed at the Department of Clinical Microbiology, being seeded on agar plates and cultured on the conventional nutrient media under aerobic conditions.
Statistical analysis included the patients with at least 1 result before HSCT, and 2 results within 4 months posttransplant. All the data on clinical characteristics of the patients, HSCT parameters, conditioning therapy, posttransplant complications, and bacterial cultures were taken from the hospital reports of R. Gorbacheva Memorial Institute, and laboratory database at the 1st St. Petersburg State I. Pavlov Medical University. Statistical evaluation was performed by means of the STATISTIСA 5.0 software, by means of non-parametric single-factor analysis using Hi-square criterion and Pearson correlation quotients to evaluate significance of differences between the samples. In some series, parametric methods were used using Student t-test.
Results
Common bacteria detectable in oral cavity
Total sample included 630 cultures from oral smears, with positive results for 389 specimens (61.8%). One microbial species was detected in 250 cases; 2 species, в 117 cultures, and 3 microbial species, in 22 cultures. The most common microorganisms were as follows: S.viridans 245/630 (38.9%); K.pneumoniae 42/630 (6.7%); S.epidermidis 120/630 (19.1%); Neisseria spp., 66/630 (10.5%); Corynebacterium spp., 78/630 (12.4%). Other bacteria were detected in <1% of the cultures (S. saprophyticus., Pseudomonas spp., S.faecalis, S.faecium). For statistical reasons, only 5 most common bacterial species were included into further analysis, i.e., S.viridans , K.pneumoniae, S.epidermidis, Neisseria spp., Corynebacterum spp.
Age factor
Frequency of the five common bacterial species in the oral cavity smears is shown in Table 1. For the age groups of 0-5, 6-14, 15-21 y.o., and adult persons (>22 y.o.), some significant age dependencies were revealed. I.e., S.viridans detection was maximal in smaller children (0 to 5 years old), as compared to the groups of 6-14 and 15-21 (p<0.02), then showing an increase in adult patients. Similar tendency was seen for Klebsiella pneumoniae, with higher detection rates in small children and adult patients.
Table 1. Detection of the common bacterial species in the specimens from oral cavity in children and adults at the whole observation period (-60 to +120 days post-HSCT)
Time dependence of microbial detection
Frequency of positive cultures was time-dependent, and varied for different microorganisms (Table 2). However, a significant drop was evident for all the detectable microbial species during 1st month posttransplant, most obviously, due to intensive antibacterial prophylaxis started before HSCT. The early suppression was most pronounced for S.viridans, and S.epidermidis, a normal component of oral microflora. Interestingly, an initial marginal decrease of K.pneumoniae detection was followed by its sharp increase at 2-4 months (Fig. 1).
Table 2. Time dependence for the detection frequency of common aerobic microorganisms cultured from the oral cavity of HSCT patients
Note: The difference levels (p values) were determined by the non-parametric Hi-square test. This time dynamics for 3 distinct bacterial species is also shown in Fig. 1.
Figure 1. Prevalence of S.viridans (A), S.epidermidis (B), and K.pneumoniae (C) in bacterial cultures within 1-4 months after HSCT
Abscissa, terms posttransplant (months). Ordinate, frequency of positive results. Points at the graph show M+m values.
HSCT parameters
As seen from Table 3, we have not found any significant associations between the frequency of positive cultures of common oral microbes, and source of stem cells (bone marrow vs peripheral stem cells), or type of HSCT (related vs unrelated vs haploidentical HSCT). Meanwhile, decreased detection rates of S.epidermidis proved to be significantly associated with more intensive (myeloablative) therapy, as compared to reduced-intensity regimens (Table 3). As expected, K.pneumoniae was associated with clinically significant infectious complications of either location.
Table 3. Detection rates for some common oral microorganisms in HSCT recipients over 120 days post-HSCT: dependence on transplant characteristics and posttransplant complications
Mucositis, febrile neutropenia and clinical infections
In more than 50% of patients, oral mucositis was observed within early terms after HSCT. Our data have confirmed higher frequency of oral mucositis after myeloablative conditioning treat-ment (181/330, 54.9%) against 33.1% (80/242) following reduced-intensity conditioning (р=2×10-7). Moreover, higher occurrence of febrile neutropenia was found in the group of patients with mucositis (50.3%) against 30.7% in mucositis-free cases (р=4×10-8), as seen from Table 3. Taking into account similar terms of mucositis and dysbacteriosis (1st month posttransplant), one could suggest infectious component for the oral inflammation. However, we did not reveal any significant correlations between mucositis rates, and frequency of positive cultures of the common microorganisms from oral mucosa (Table 3), thus suggesting a minimal role of these bacteria in genesis of the posttransplant oral inflammation. In addition, we have not revealed any significant correlations between presence of the major species of oral microflora, and acute skin GVHD (Table 3). Absence of correlations between bacterial landscape and main clinical complications may be connected with active antibacterial therapy over the period of post-transplant leukopenia (1-2 months post-HSCT).
Further, we have performed some comparisons between the frequencies of bacterial associations, rates of febrile neutropenia and clinically significant infections posttransplant. This survey has shown that the more frequent associations of >3 microbial species tends to correlate with higher FUO prevalence (Table 4). Increased incidence of FUO was also found after myeloablative conditioning (р=0.001), as well as in the group with oral mucositis (p=4×10-8), as well as in cases of skin aGvHD (p=0.002), thus reflecting evident inflammatory component in the both types of skin and mucosal damage, however, without any association with. Hence, early neutropenic fever is more likely associated with cytostatic chemotherapy and allogeneic HSCT, rather than with local clinically significant infections posttransplant.
Interestingly, the numbers of transplanted hematopoietic stem cells (CD34+ cells) have shown a distinct direct correlation with occurrence of early mucositis (r=0.20; p=8×107) thus again suggesting a clear relation between oral mucositis and potential immune effects of allogeneic hematopoietic cells posttransplant.
Table 4. Frequency of FUO and microbial associations: effects of different HSCT parameters and posttransplant complications
Microbial resistance
Klebsiella is the mostly discussed bacterial pathogen with high prevalence of antibiotic-resistant strains. We have tested in vitro the resistance of K.pneumoniae isolates seeded from oral cavity of 11 HSCT patients in 2017 (Table 5). Majority of the isolates showed resistance for most antibiotics commonly used in septic HSCT patients. However, most of the K.pneumoniae isolates proved to be sensitive to amikacin, gentamycin and meropenem.
Table 5. Differential in vitro antibiotic sensitivity of K.pneumoniae isolates obtained from oral cavity after hematopoietic stem cell transplantation
Note: R, resistance; S, sensitivity of the microorganism; I, intermediate values
Of note, in the patient F.Z., the initial sensitive phenotype was 1 month later changed to polyresistance, except of amikacin and meropenem, thus, probably, reflecting its replacement by a resistant bacterial strain.
Bacterial pathogens at the sites of dental infections
In 10 cases, tooth extraction was performed during 1st month after HSCT, due to acute pulpitis and local septic process. Bacterial isolates from the post-extraction wounds were obtained in 10 cases, and the following bacteria were detected: Pseudomonas aeruginosa in 3 samples, S.viridans in 2 cases, Neisseria spp., S.faecalis, S.epidermidis were found in other specimens. Of them, only P.aeruginosa is a well-known pathogenic agent to cause purulent local inflammation.
Discussion
Overall rates of positive microbial cultures from oral cavity were rather high (61.8%). Cytotoxic damage to oral epithelium due to previous chemotherapy, as well as deep leukopenia after conditioning treatment and HSCT are the key pre-requisites for oral bacterial colonization [9]. However, conventional culturing of oral samples taken at different terms post HSCT (D-60 to D+120) have shown a sufficient decrease in cultivable oral microflora within 1st month posttransplant. Such suppression of microflora could be readily explained by anti-microbial treatment administered during intensive cytostatic therapy of cancer [10, 11]. In our study, a deep suppression was shown for S.viridans, S.epidermidis, and K. pneumoniae. The latter is the known Gram-negative pathogen causing infectious complications at later terms (2-4 months posttransplant), with a tendency for polyresistance for antibiotics, as confirmed in our study.
Microbial associations of 3 or more bacteria could be found in some samples. Of note, posttransplant clinically significant infections proved to be much more often in cases with >3 microorganisms found in the oral samples, thus suggesting the microbial associations to be a marker of suppressed antimicrobial immunity post-HSCT.
Like as other common posttransplant complications, clinical infectious conditions did not show any direct correlations with either positive oral bacterial cultures, or early post-transplant mucositis (Table 3 and 4). Rather, fever of unknown origin (FUO), an early inflammatory condition without clear infectious reason, had a distinct relationship with myeloablative treatment, oral mucositis, and skin GvHD. Oral mucositis may be, at least, in part, dependent on common herpesvirus activation post-HSCT [12].
Among common bacterial species found in oral cavity of the patients, Klebsiella pneumoniae is known to produce a number of polyresistant strains, as confirmed in our study (Table 5). This feature of K.pneumoniae is typical to nosocomial infections. Decreased rates of Klebsiella detection at early terms (1st month) following HSCT could be explained by relative sensitivity of most endogenous bacterial populations to routine decontaminating therapy. At later terms (2nd and 3rd months) the sensitivity-adapted antibiotic treatment in the patients with prolonged infectious complications under the ICU conditions, may cause selection of Klebsiella strains with extended resistance spectrum as, it was revealed in our F.Z. patient at 5-6 months after HSCT.
Therefore, phenotypic and molecular monitoring of standard lactamase genes in clinical isolates before and after HSCT may further elucidate the mechanisms of resistance selection among Klebsiella and other Gram-negative bacteia, aiming for development of combined treatment schedules [13].
In this respect, the role of oral bacterial infection in development of mucositis and GvHD still remains unclear. Meanwhile, over last decades, a crucial role of gut microbiome and altered intestinal mucosa due to broad-spectrum antibacterial therapy becomes more clear and clinically confirmed, both for infectious complications and acute GvHD [14, 15, 16].
Conclusion
Cytotoxic damage of oral mucosa during intensive chemotherapy may create sufficient prerequisites for bacterial colonization. Moreover, antibacterial prophylaxis in HSCT patients causes deep suppression of oral microflora during 1st month post-HSCT, despite severe leukopenia in the patients. Known antibacterial pathogens, e.g., K.pneumoniae, or P.aerugunosa are revealed in oral cavity within 1-3 months posttransplant.
The consequences of combined anticancer and antibacterial treatment in HSCT patients deserve further studies, in particular, its correlation with mucositis, acute GvHD which may be still underlied by mixed microbial and viral infections. Bacterial imbalance post-HSCT may be a pre-requisite for additional anti-infectious therapy in complex clinical conditions involving infectious/cytotoxic/autoaggressive pathogenetic components. Significant shifts in common bacterial landscape caused by immunotoxic treatment and antibacterial therapy enable growth of other bacterial and fungal pathogens that should be studied in details by means of NGS techniques which should reveal, e.g., anaerobic pathogenic bacteria in posttransplant conditions.
References
- Hull MW, Chow AW. Indigenous microflora and innate immunity of the head and neck. Infect Dis Clin N Am 2007; 21: 265-282.
- Hegde MC, Kumar A, Bhat G, Sreedharan S. Oral microflora: a comparative study in HIV and normal patients. Indian J Otolaryngol Head Neck Surg. 2014; 66(Suppl 1): S126-S132.
- Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J. Clin. Microbiol. 2005; 43(11): 5721-5732.
- Chukhlovin AB, Pankratova OS. Opportunistic microflora at unusual sites: marker pathogens in severe posttransplant immune deficiency. Cell Ther Transplant. 2017; 6(4): 28-41.
- Marena C, Zecca M, Carenini ML, Bruschi A, Bassi ML, Olivieri P, Azzaretti S, Locatelli F. Incidence of, and risk factors for, nosocomial infections among hematopoietic stem cell transplantation recipients, with impact on procedure-related mortality. Infect Control Hosp Epidemiol. 2001;22(8):510-517.
- Lahei AMGA, de Soet JJ, von dem Borne PA, Kuijper EJ, Kraneveld EA, van Loveren C, Raber-Durlacher JE. Oral bacteria and yeasts in relationship to oral ulcerations in hematopoietic stem cell transplant recipients. Support Care Cancer. 2012; 20:3231-3240.
- Czirók E, Prinz GY, Dénes R, Reményi P, Herendi A. Value of surveillance cultures in a bone marrow transplantation unit. J Med Microbiol. 1997;46(9):785-791.
- Vavilov VN, Averianova MY, Bondarenko SN, Stancheva NV, Zubarovskaya LS, Afanasyev BV. Bacterial infections within early period after allogeneic bone marrow transplantation. Ter Arkhiv, 2015; 87(7): 88-93 (In Russian).
- Grigoriants AP, Rabinowitch IM, Chukhlovin AB. Stomatological problems and infectious complications after hematopoietic stem cell transplantation. Cell Ther Transplant 2017; 7(2):10-19.
- Bergmann OJ. Alterations in oral microflora and pathogenesis of acute oral infections during remission-induction therapy in patients with acute myeloid leukaemia. Scand J Infect Dis. 1991;23(3):355-66.
- Jones LR, Toth BB, Keene HJ. Effects of total body irradiation on salivary gland function and caries-associated oral microflora in bone marrow transplant patients. Oral Surg Oral Med Oral Pathol. 1992;73(6):670-676.
- Pankratova OS, Chukhlovin AB, Shiryaev SN, Eismont YA, Vavilov VN, Zubarovskaya LS, Afanasyev BV. Herpesviruses and oral ulcerations in hematopoietic SCT recipients. Bone Marrow Transplantation. 2013; 48:1364-1365.
- Fritzenwanker M, Imirzalioglu C, Herold S, Wagenlehner FM, Zimmer KP, Chakraborty T. Treatment Options for Carbapenem- Resistant Gram-Negative Infections. Dtsch Arztebl Int. 2018 ;115(20-21):345-352.
- Blijlevens NMA, Donnelly JP, De Pauw BE. Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplantation (2000) 25, 1269-1278.
- Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A, Koestler J, Dettmer K, Weber M, Wolff D, Hahn J, Pamer EG, Herr W, Gessner A, Oefner PJ, van den Brink MRM, Holler E. Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017; 23(5):845-852.
- Goloshchapov OV, Kucher MA, Chukhlovin AB. Gut microbiome in hematopoietic stem cell transplantation: patient- and treatment-related factors. Cell Ther Transplant. 2018; 7(4):16-28.
Алексей Б. Чухловин1, Анна А. Спиридонова2, Ирина Б. Баранова3, Артур П. Григорьянц3, Мария Д. Владовская1, Людмила С. Зубаровская1, Борис В. Афанасьев1
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2 Отделение клинической микробиологии, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Кафедра челюстно-лицевой хирургии, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
Нормальная аэробная и факультативно-анаэробная микробиота, колонизирующая слизистую оболочку рта, часто выявляется в клинических лабораториях. Ее состав может быть важным показателем иммунокомпромиссных состояний. Данные параметры мало изучены у пациентов после трансплантации гемопоэтических клеток (ТГСК). Целью настоящей работы была оценка выявляемости обычной аэробной и факультативно-анаэробной микробиоты, культивированной из биоматериала полости рта до ТГСК и, по клиническим показаниям, в течение 4 мес. после этого лечения.
Пациенты и методы
Мы оценили результаты посевов образцов, взятых из ротовой полости у 202 больных с онкогематологическими и врожденными заболеваниями в возрасте от 1 до 69 лет, которым была проведена аллогенная ТГСК. Анализ проводился для 3 возрастных групп: 1-5, 6-14, 15-21 и >22 лет.
Результаты
После 630 проведенных бактериологических исследований, позитивные результаты культивирования получены в 61.8% образцов. Наиболее частыми микроорганизмами были следующие: S.viridans 245/630 (38.9%); K.pneumoniae 42/630 (6.7%); S.epidermidis 120/630 (19.1%); Neisseria spp. 66/630 (10.5%); Corynebacterium spp. 78/630 (12.4%). Частота выявления микроорганизмов зависела от времени после ТГСК, а именно отмечено снижение высеваемости S.epidermidis, Corynebacterium spp. и Klebsiella spp. в течение 1-го месяца после ТГСК, что можно объяснить эффективной ранней антибактериальной деконтаминацией пациентов, начиная с момента кондиционирования. Нами показано, что частота высеваемости S.viridans и K.pneumoniae в этих образцах была различной для отдельных возрастных групп, будучи существенно повышенной у детей самого младшего возраста (до 5 лет) и у взрослых пациентов (>22 лет), по сравнению со старшими детьми и подростками. Высеваемость K.pneumoniae в образцах из полости рта оказалась существенно повышенной через 2-3 месяца после ТГСК, что сопровождалось тяжелыми инфекционными осложнениями и наличием резистентности клинических изолятов Klebsiella к большинству антибиотиков. По клиническим показаниям проведена экстракция зубов в 10 случаях в течение 1-го мес. после ТГСК. Посевы раневого отделяемого из десен показали наличие Pseudomonas aeruginosa в 3 образцах, S.viridans – в 2 случаях.
Выводы
Иммунотоксические эффекты цитостатической терапии и анализ микробиоты после ТГСК заслуживают дальнейших исследований, в том числе – анализ биологического разнообразия микробиоты полости рта посредством секвенирования гена 16S rRNA. Эти результаты могут стать основой для рациональной антибактериальной терапии при ТГСК.
Ключевые слова
Онкогематология, дети, химиотерапия, трансплантация гемопоэтических стволовых клеток, бактериальные культуры, факторы риска.
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2 Department of Clinical Microbiology, Pavlov University, St. Petersburg, Russia
3 Department of Orofacial Surgery, Pavlov University, St. Petersburg, Russia
Normal aerobic and facultative anaerobic microbiota colonizing oral mucosa is usually identified at clinical laboratories. Its composition may be important index of immunocompromised conditions. These parameters are scarcely studied in patients undergoing hematopoietic stem cell transplantation (HSCT). The aim of this work was to evaluate incidence of common aerobic and facultative anaerobic microbiota cultured from oral samples taken before HSCT and, by clinical indications, within 4 months after the treatment.
Patients and methods
We evaluated results of bacterial cultures from oral smears taken in 202 patients with oncohematological and inborn diseases at the age ranging from 1 to 69 years subjected to allogeneic HSCT. The analysis was performed for 3 age groups: 1-5, 6-14, 15-21, and >22 years old.
Results
In total observation group of 630 oral samples, the bacterial cultures proved to be positive in 61.8% of specimens. The most common microorganisms were as follows: S.viridans 245/630 (38.9%); K.pneumoniae 42/630 (6.7%); S.epidermidis 120/630 (19.1%); Neisseria spp. 66/630 (10.5%); Corynebacterium spp. 78/630 (12.4%). The incidence of microbial detection was time-dependent, with significant decrease in S.epidermidis, Corynebacterium spp. and Klebsiella spp. during 1st month posttransplant which could be explained by early effective antibacterial decontamination since the time of conditioning in early posttransplant period. We have shown that the frequency of positive tests for S.viridans and K.pneumoniae in these samples were different for distinct age groups, i.e., the positivity rates were significantly higher in youngest children (up to 5 years old) and in adult patients (>22 years old), as compared with elder children and adolesсents. Incidence of K.pneumoniae in oral samples was found to be sufficiently increased 2-3 months after HSCT, being associated with severe infectious complications, with broad antibiotic resistance in most culturable Klebsiella isolates from the patients. For clinical indications, teeth extraction was made in 10 cases during 1st month after HSCT, with Pseudomonas aeruginosa in 3 samples, S.viridans in 2 cases isolated from the local gum wounds. In conclusion, the immunotoxic effects of cytostatic therapy and microbiota analysis post-HSCT deserve further studies, including biodiversity analysis of oral microbiota by means of 16S rRNA gene sequencing. These results may represent a basis for rational antibacterial therapy in HSCT.
Keywords
Oncohematology, children, chemotherapy, hematopoietic stem cell transplantation, bacterial cultures, risk factors.
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Chukhlovin<sup>1</sup>, Anna A. Spiridonova<sup>2</sup>, Irina B. Baranova<sup>3</sup>, Artur P. Grigoriants<sup>3</sup>, Maria D. Vladovskaya<sup>1</sup>, Ludmila S. Zubarovskaya<sup>1</sup>, Boris V. Afanasyev<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(240) "Alexei B. Chukhlovin1, Anna A. Spiridonova2, Irina B. Baranova3, Artur P. Grigoriants3, Maria D. Vladovskaya1, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(240) "Alexei B. Chukhlovin1, Anna A. Spiridonova2, Irina B. Baranova3, Artur P. Grigoriants3, Maria D. Vladovskaya1, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> NULL ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "25098" ["VALUE"]=> array(2) { ["TEXT"]=> string(3211) "<p style="text-align: justify;">Normal aerobic and facultative anaerobic microbiota colonizing oral mucosa is usually identified at clinical laboratories. Its composition may be important index of immunocompromised conditions. These parameters are scarcely studied in patients undergoing hematopoietic stem cell transplantation (HSCT). The aim of this work was to evaluate incidence of common aerobic and facultative anaerobic microbiota cultured from oral samples taken before HSCT and, by clinical indications, within 4 months after the treatment.</p> <h3>Patients and methods</h3> <p style="text-align: justify;">We evaluated results of bacterial cultures from oral smears taken in 202 patients with oncohematological and inborn diseases at the age ranging from 1 to 69 years subjected to allogeneic HSCT. The analysis was performed for 3 age groups: 1-5, 6-14, 15-21, and >22 years old. </p> <h3>Results</h3> <p style="text-align: justify;">In total observation group of 630 oral samples, the bacterial cultures proved to be positive in 61.8% of specimens. The most common microorganisms were as follows: <i>S.viridans</i> 245/630 (38.9%); <i>K.pneumoniae</i> 42/630 (6.7%); <i>S.epidermidis</i> 120/630 (19.1%); <i>Neisseria spp.</i> 66/630 (10.5%); <i>Corynebacterium spp.</i> 78/630 (12.4%). The incidence of microbial detection was time-dependent, with significant decrease in <i>S.epidermidis, Corynebacterium spp.</i> and <i>Klebsiella spp.</i> during 1st month posttransplant which could be explained by early effective antibacterial decontamination since the time of conditioning in early posttransplant period. We have shown that the frequency of positive tests for <i>S.viridans</i> and <i>K.pneumoniae</i> in these samples were different for distinct age groups, i.e., the positivity rates were significantly higher in youngest children (up to 5 years old) and in adult patients (>22 years old), as compared with elder children and adolesсents. Incidence of <i>K.pneumoniae</i> in oral samples was found to be sufficiently increased 2-3 months after HSCT, being associated with severe infectious complications, with broad antibiotic resistance in most culturable <i>Klebsiella</i> isolates from the patients. For clinical indications, teeth extraction was made in 10 cases during 1<sup>st</sup> month after HSCT, with <i>Pseudomonas aeruginosa</i> in 3 samples, <i>S.viridans</i> in 2 cases isolated from the local gum wounds. In conclusion, the immunotoxic effects of cytostatic therapy and microbiota analysis post-HSCT deserve further studies, including biodiversity analysis of oral microbiota by means of 16S rRNA gene sequencing. These results may represent a basis for rational antibacterial therapy in HSCT. </p> <h2>Keywords</h2> <p style="text-align: justify;">Oncohematology, children, chemotherapy, hematopoietic stem cell transplantation, bacterial cultures, risk factors. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SOR