ISSN 1866-8836
Клеточная терапия и трансплантация

Change template to: announce

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Cellular factors of antitumor immunity in patients with chronic lympholeukemia

Natalya V. Issayeva, Galina A. Zaitseva, Tamara P. Zagoskina

Clinical and pathological characterization of the t(14;19)(q32;q13)-positive splenic marginal zone lymphoma

Hunan L. Julhakyan, Tatyana N. Obukhova, Irina B. Kaplanskaya, Rima S. Samoylova, Andrey I. Vorobiev

Expression of tumor-associated genes in multiple myeloma patients during high-dose chemotherapy and auto-SCT

Tatiana V. Gaponova, Lidia S. Mendeleeva, Andrey V. Misurin, Elena Yu. Varlamova, Elena N. Parovichnikova,
Valeriy G. Savchenko

Prognostic value of apoptosis of tumor clone bone marrow cells in patients with multiple myeloma

Zhanna V. Chubukina, Ludmila N. Bubnova, Stanislav S. Bessmeltsev

Treatment results of children with Hodgkin’s disease (HD) according to protocols DAL-HD and GPOH-HD

Margarita B. Belogurova1,2, Galina G. Radulesku1,2, Tatyana D. Viktorovich1,2, Emilia D. Chavpetsova2, Ludmila I. Shats1,2, Yulia V. Dinikina1

Salvage therapy in relapsed Hodgkin's lymphoma patients

Elena S. Belyaeva, Olga V. Morozova, Andrey I. Slugin, Alexander V. Popa, Georgy L. Mentkevich

Anemias in lymphomas: pathogenesis mechanisms

Anna S. Lyamkina, Tatiana I. Pospelova

Impact of positron emission tomography on primary staging and changing the therapeutic modality in lymphoma patients

Natalia B. Mikhaylova1, Marina S. Tlostanova2, Yulia N. Vinogradova2, Ekaterina I. Ivanova2, Anna V. Kritskaya2, Sergey E. Korolev1, Anna A. Rats1, Alexander A. Pugachev1, Nikolay V. Ilyin2, Boris V. Afanasyev1, Leonid A. Tyutin2

High-dose melphalan versus melphalan plus dexamethasone in patients with AL amyloidosis

Anna G. Smirnova1, Alexey V. Smirnov2, Axel R. Zander3, Boris V. Afanasyev1

Allogeneic stem cell transplantation in multiple myeloma: single centre experience of 112 patients

Liisa Volin, Heli Uotinen, Eeva Juvonen, Anne Nihtinen, Tapani Ruutu

The role of p53 polymorphisms in non–Hodgkin’s lymphomas’ susceptibility and prognosis

Elena N. Voropaeva, Tatiana I. Pospelova, Mikhail I. Voevoda, Olga V. Beresina

Association between HLA class I antigens and survival length in patients with multiple myeloma

Elena A. Senkina, Galina A. Zaitseva, Tamara P. Zagoskina, Konstantin A. Martynov

Bone marrow angiogenesis is a prognostic value in patients with multiple myeloma undergoing high-dose therapy and autologous stem cell transplantation

Olga S. Pokrovskaya, Lidia S. Mendeleeva, Irina B. Kaplanskaya, Elena Yu. Varlamova, Elena N. Parovichnikova, Sergey M. Kulikov, Valeriy G. Savchenko

Virus participation in renal damage in AL patients: histopathological study

Ekaterina G. Vorozheikina1, Vladimir V. Varshavski2, Ekaterina P. Golitsina2, Evgenia N. Glasko1, Irina B. Kaplanskaya1, Ljudmila S. Birjukova1, Elena N. Parovichnikova1, Valeriy G. Savchenko1

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Cellular factors of antitumor immunity in patients with chronic lympholeukemia

Download PDF version

Natalya V. Issayeva, Galina A. Zaitseva, Tamara P. Zagoskina

FSE, Kirov Research Institute of Hematology and Blood Transfusion of FMBA of Russia, Kirov, Russia

The purpose of the study was to analyze a number of cellular factors of antitumor immunity in patients with chronic lympholeukemia (CLL) at the beginning of the disease. Using the method of flow cytometry, the absolute content of the following lymphocyte subpopulations in the peripheral blood were assessed as the main antitumor factors in 59 CLL patients: NC-cells (CD3-/CD(16+56)+), NC-cells with a high cytotoxic activity (CD3-/CD8+), Т-NK-lymphocytes (CD3+/CD(16+56)+), CD3+/CD8+-lymphocytes including T-lymphocytes with cytotoxic properties. The count of lymphocytes functioning as antitumor immunity activators was also taken into account, i.e., all T-lymphocytes (CD3+/CD19-) and T-helpers (CD3+/CD4+).

An expressed spread in the values of the indices studied was revealed in the result of the investigation. A decrease in the content of cells with the markers CD3-/CD(16+56)+, CD3-/CD8+, CD3+/CD(16+56)+, and CD3+/CD8+ was seen in 10%, 10.8%, 38.3%, and 19% of patients, respectively. A combined decrease in two or three studied effectors of antitumor immunity was noted in 52% of patients. A quantitative deficiency of antitumor immunity activators – all T-lymphocytes and T-helpers – was less commonly observed.

The conclusion was that laboratory assessment of the main effectors for antitumor protection of CLL patients with the aim to reveal patients with their depression is advisable and can be taken into consideration when stratifying the patients.

Keywords

chronic lympholeukemia, antitumor immunity, T-lymphocytes, NC-cells

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Clinical and pathological characterization of the t(14;19)(q32;q13)-positive splenic marginal zone lymphoma

Download PDF version

Hunan L. Julhakyan, Tatyana N. Obukhova, Irina B. Kaplanskaya, Rima S. Samoylova, Andrey I. Vorobiev

Hematology Research Center of the Russian Academy of Medical Science, Moscow, Russia

Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm which is characterized by splenomegaly, lymphocytosis, and involvement of bone marrow and, sometimes, an M–component. The most frequent findings in SMZL involve chromosomes 1, 3, 7 (usually deleted in 7q), and 18. The t(14;19)(q32;q13) is a rare cytogenetic abnormality with a bcl-3 rearrangement that has been reported in B-cell lymphomas and leukemia.

Aim

The aim of the study was to characterize the clinical and morphological changes in patients with t(14;19)(q32;q13)-positive SMZL.

Patients, methods and results

In our center between January 2005 and February 2009, 3 cases of SMZL with t(14;19)(q32;q13) were identified. All the patients (males, median age 58 years, range 51–67 years) presented with lymphoma with B-symptoms, a high level of lactate dehydrogenase (LDH), hepatosplenomegaly, and with splenic hilar lymphadenopathy only. The median hemoglobin was 110 g/l (range 92–122 g/l). All patients had a normal leukocyte count with an absolute lymphocytosis (median lymphocyte count 72.3 x 109 g/l, range
58–83 x 10
9/l) and thrombocytopenia. A morphological examination of the peripheral blood and bone marrow lymphocytes showed that all lymphocytes were atypical with a wide cytoplasm and nuclear indentation. In all cases bone marrow involvement was nodular and composed of heterogeneous mixture cells, with the majority being medium sized. The results of the immunophenotypic analysis were the expression of mature
B-cells antigens and an absence of
СD10-, CD23-, CD5-, CD43-, CyclinD1-.

In debut two patients were to receive chemotherapy (CHOP–regimen). However there was progression: enlargement of the spleen and a decrease in the thrombocyte count. All patients underwent a splenectomy. The median weight of the spleen was 2083 g (range 1800–2850 g). The splenic section generally showed massive nodular patterns (involving the white and red pulp) associated with diffuse invasion of the sinuses. In each case, high Ki-67 was discovered. Progression occurred 3–6 months after the splenectomies, and was characterized by an increase in the leukocyte count (range
45.4–101.8 x 10
9 /l), a high level of LDH, and an appearance of peripheral and visceral lymph nodes. In consideration of increasing the leukocyte count and the presence of lymphadenopathy in all patients, alkylating agents were used (in one patient chlorambucil, and in two cyclophosphamide). There was a normal peripheral blood index, LDH level , and an absence of lymphadenopathy in all cases after 4–6 months of treatment with alkylating agents. Median observation was 19+ months (range 17–22 months). All patients were alive.

Conclusion

SMZL with t(14;19)(q32;q13) is a distinct variant that is characterized by transient progression after splenectomy and high efficiency of alkylating agents.

Keywords

splenic marginal zone lymphoma, t(14;19)(q32;q13), morphology, spleen, splenectomy, alkylating agents

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Cases of secondary acute myeloid leukemia and myelodysplastic syndrome in patients with multiple myeloma

Download PDF version

Alexander S. Luchinin

Research Institute of Hematology and Blood Transfusion as a Federal State establishment under Rosmedtechnologies

Standard chemotherapy using alkylating agents both during the induction of remission and its maintenance therapy had been applied for 30 years in treatment of multiple myeloma (MM). But after a long treatment utilizing alkylating preparations the risk of secondary leukemias becomes unjustified.

We analysed 329 MM cases during the years 1994 to 2008. The males numbered 128 (39%) and the females 201 (61%). The median overall survival (OS) rate for all patients was 31 months. Secondary leukemias were diagnosed in 5 MM patients and were diagnosed as follows: AML (M2 subtype according to FAB) in 2 patients, refractory anemia with excess blasts (RAEB-1 according to WHO) in 2 patients and refractory anemia with excess blasts (RAEB-2 according to WHO) in 1 patient. The median period before a second tumor appeared was 7.3 years. The actuary risk of secondary leukemia after 5 years of MM was 1.3%. The general occurrence of secondary AML and MDS equaled 1.7%. Low occurrence of this phenomenon is due to the fact that the mean period for development of a secondary tumor is 3 times greater than the median life expectancy for MM patients. The median OS rate after the diagnosis of a second leukemia was 2 months.

Thus, secondary AML and MDS are rare complications of chemotherapy in MM patients. But if they appear and develop, it leads to a rapid reduction of life expectancy for the patients because of resistance to the therapy carried out. Patients with smoldering myeloma and a high life expectancy of 5 to 10 years die of a qualitatively new leukemia as a result of a long chemotherapy using alkylating agents. That is why the risk of a second tumor cannot be considered as justified.

Keywords

multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Expression of tumor-associated genes in multiple myeloma patients during high-dose chemotherapy and auto-SCT

Download PDF version

Tatiana V. Gaponova, Lidia S. Mendeleeva, Andrey V. Misurin, Elena Yu. Varlamova, Elena N. Parovichnikova,
Valeriy G. Savchenko

National Research Center for Hematology, Moscow, Russia

High-dose therapy enables further improvement in the outcome of multiple myeloma (MM) patients. However, it is still necessary to determine prognostic factors that may influence treatment results and provide additional criteria for the precise selection of treatment approaches. There are several tumor-associated genes (MAGE, LAGE, GAGE, PRAME) that are over-expressed in different malignancies including MM. These genes are believed to modulate cancer properties and should be taken into account during treatment. Their significance as prognostic factors is under investigation.

The aim of our study was to analyze the expression levels of PRAME, WT1, and XIAP genes in MM patients at diagnosis and during high-dose chemotherapy followed by auto-SCT and therapy of proteasome inhibitors.

Our study included 34 primary MM patients; all of them gave informed consent. The median age was 48 years (range 31–62). IgG MM was diagnosed in 28 cases, IgA MM in 2 and light chain MM in 4. Initial treatment consisted of 3 cycles of VAD. If CR or PR were not achieved, the treatment was changed to bortezomib at 1.3 mg/m2 on days 1,4,8, and 11 and dexamethasone (dex) at 40 mg daily on days 1–4 (4–6 cycles). If CR or PR was attained, stem cell mobilization was performed with cyclophosphamide 6 mg/m2+G-CSF. Melphalan at 200 mg/m2 was given before auto-SCT. Investigation was performed before therapy (n=34), after VAD (n=20), after bortezomib (n=10), and after auto-SCT (n=9). Results were normalized against the expression of the ABL gene, which was used as an internal control.

In primary MM patients, PRAME gene expression was found in 62% (n=21), WT1 in 20% (n=7) of patients, all of who were PRAME positive. Median expression levels were 0.3% (0.001–132%) for PRAME and 0.01% (0.002–2.54%) for WT1. In primary MM patients the XIAP expression was found in 100%. The meaning of XIAP/ABL*100% varied between the range of 5 to 5382% (median 28%). Of the MM patients, 41% (n=14) demonstrated XIAP hyperexpression (XIAP/ABL*100%>40%). We subdivided MM patients into two groups according to XIAP/ABL*100%, meaning that I<40%, II>40%. In the control group of healthy donors (n=9) PRAME gene expression was found in 50% (median expression 0.003%), WT1 in 12% (median 0.0017%), and XIAP in 62% (median 2%). PRAME, WT1, and XIAP expression did not correlate with tumor bulk and was independent of the levels of M–protein, beta-2M, and albumin.

In the group with primary XIAP hyperexpression (II) we observed that the decrease of XIAP expression paralled tumor reduction (from more then 40% to 5–20%). By contrast, in group I the XIAP gene expression increased right after chemotherapy initiation to extremely high levels of 2425%. However, after high-dose melphalan and auto-SCT, the XIAP level significantly decreased (22–157%) along with the attainment of CR or very good PR. The level of the XIAP gene expression changed depending on the response of the bortezomib treatment. In the MM patients who achieved CR+PR after 4–6 courses of bortesomib+dex (n=6), the expression of XIAP reduced from 11–325% (median 66%) to 1–123% (median 20%). In the MM patients with a poor response after 4–6 courses of bortesomib+dex (n=4), we observed an increased expression of XIAP from 16–127% (median 36%) to 22–528% (median 121%).

The expression of PRAME significantly decreased after 3 VAD cycles to 0.001–207% (n=10): at the moment of auto-SCT it was 0.001–6.1% (n=6) and after auto-SCT it was 0.004–4.9% (n=9). However, for WT1we observed an increase of WT1 expression after 3 VAD cycles to 0.004–0.07% (n=5); at the moment of auto-SCT it was 0.001–0.4% (n=6), and after auto-SCT it was 0.0193–2.03% (n=7). In the patients with high primary PRAME expression (>median expression) the frequency of CR+PR was significantly lower than in PRAME–negative primary patients and in patients with low (<median expression) primary PRAME expression (27% vs 69). It should be stressed that during treatment in a small number of initially negative PRAME and WT1 gene patients, we demonstrated detection by PCR. We detected the appearance of gene expression during therapy at low levels in 1 of 13 initially negative PRAME patients (6.1%) and in 8 of 26 initially negative WT1 patients (range of level 0.01–1.03%). The detection of gene expression did not correlate with disease status. All these patients achieve CR+VGPR. In one of the secondary positive patients – who acquired PRAME and WT1 – relapse occurred, with high and low expression of PRAME (104%), WT1 (0,62%), and XIAP (1264%).

Conclusion

The expression of the PRAME gene was found in 62% of primary patients, and the level of PRAME decreased with tumor reduction. A high expression level of PRAME turned out to be a factor of unfavorable prognosis. The expression of WT1 was found in 20% of MM patients – all of who were PRAME positive. WT1 expression increased during treatment in a small group of patients. Some initially negative patients acquired PRAME and WT1 expression during treatment, but clinical relevance of this is so far unclear. In the MM patients at diagnosis, the level of XIAP expression was high. The decrease of XIAP expression correlates with the chemotherapy and proteasome inhibitor treatment efficicacy. XIAP expression comes to the normal values at the time of CR and PR achievement.

Keywords

multiple myeloma, prognostic factors, tumor associated genes

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Prognostic value of apoptosis of tumor clone bone marrow cells in patients with multiple myeloma

Download PDF version

Zhanna V. Chubukina, Ludmila N. Bubnova, Stanislav S. Bessmeltsev

Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia

Purpose

To study the apoptosis of tumor cells (plasma cells, PC) in bone marrow of patients with multiple myeloma (MM) and to evaluate the possibility of using this parameter as a predictor of treatment efficacy.

Materials and Methods

The study comprised 34 patients with active stage MM. Myelogram: PC 11.4–86.4 %. Apoptosis of PC was detected by binding Annexin V-FITC with a membrane marker of early apoptosis–phosphatidylserine. The analysis was performed using the Flow Cytometer “Cytomics FC 500 Beckman Coulter”, USA. Apoptosis of PC was evaluated before and after a course of specific therapy.

Results

It was demonstrated that initially spontaneous apoptosis of PC in all MM patients was on average 25.4 ± 3.3%. But in 32% (11) of patients apoptosis was significantly lower than average (15.6 ± 2.9%),while in 68% (23) of patients PC apoptosis was significantly higher than average (35.2 ± 3.0%). After treatment there was a 2.5-fold (39.1 ± 4.1%) increase of apoptosis index in those patients with an initial decrease. This coincided with an occurrence of clinical–hematological remission in this group. In patients with a higher initial spontaneous apoptosis, its increase had not been noted in any case (34.6 ± 2.8%), and clinical therapeutic effect was also absent.

Conclusion

Initially decreased apoptosis of bone marrow PC is a predictor of a more favorable course of disease and of therapeutic efficacy. On the contrary, a higher level on initial spontaneous PC apoptosis is prognostically an unfavorable marker, because tumor cells remain refractory to chemotherapy and the induction of the apoptotic process is insufficient.

Keywords

multiple myeloma, apoptosis, plasma cells

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Treatment results of children with Hodgkin’s disease (HD) according to protocols DAL-HD and GPOH-HD

Download PDF version

Margarita B. Belogurova1,2, Galina G. Radulesku1,2, Tatyana D. Viktorovich1,2, Emilia D. Chavpetsova2, Ludmila I. Shats1,2, Yulia V. Dinikina1

1St. Petersburg State Pediatric Medical Academy, Division of Oncology with a course of radiodiagnostics and radiotherapy;
2City Clinical Hospital №31, Department of Pediatric Oncology and Hematology, St. Petersburg, Russia

Correspondence

Margarita B. Belogurova, City Clinical Hospital №31, Department of Pediatric Oncology and Hematology, St. Petersburg, 197110, Russia
E-mail: deton.hospital31@inbox.ru

According to the data of the population-based Cancer Registry 2008, the structure of oncopediatric morbidity in SPb in the age group of 10–14 years (y) is most frequently malignant lymphoma  (30.7%), both for girls and boys.

Methods

Sixty-four primary patients (pts) with HD were treated from 1992 to 2002 according to the following protocols: DAL-HD-90, GPOH-HD-95 (60 pts) and GPOH-HD-2002 (4 pts). The median age was 14 y. Distribution according to stages was as follows: Stages I–II were diagnosed in 46 pts (72%), 18 pts (28%) had advanced HD. The ratio of boys to girls in the group up to 11 y was 3.5:1; after 11 y both sexes were affected equally. Diagnosis was confirmed by histology (100%) and immunohistochemistry (52%). In our pts nodular sclerosis was predominant (81%). In children under 7 y a mixed cellularity variant was more frequent. In GPOH-HD-2002 protocol procarbazine was replaced by dacarbazine to decrease the adverse effects on the male reproductive system.

Results

The CR was achieved in 61 pts (95.3%).  In terms of medical observation from 8 to 210 months OS - 94.8% ± 2.89 and did not change after 29 months. RFS and EFS were 96.5% ± 2.37 and 92.1 ± 3.39 respectively. All events were registered within a period of 11 months.

During chemotherapy early toxic effects were minimal: mucositis, duodenal ulcer, and neuropathy. Late complications of radiotherapy – muscle atrophy in area of irradiation (2 cases) and tumors of thyroid gland (2 cases) – were revealed in terms of 2 to 8 years.

Conclusions

Hodgkin’s disease in children can be considered as a practically curable disease with moderate intensive treatment and low toxicity.

Keywords

Hodgkin’s disease, children, chemotherapy, fertility

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Salvage therapy in relapsed Hodgkin's lymphoma patients

Download PDF version

Elena S. Belyaeva, Olga V. Morozova, Andrey I. Slugin, Alexander V. Popa, Georgy L. Mentkevich

N. N. Blokhin RCRC RAMS, Pediatric Oncology and Hematology Research Institute, Moscow, Russia

The treatment of children with refractory or early relapsed Hodgkin's lymphoma remains one of the most important problems in pediatric oncology. In order to improve the outcome of this group of patients we used the ViGePP regimen. We present the results of the ViGePP regimen for children with relapsed/refractory LH.

Method

Between 2008 and 2009, 9 pts with relapsed/refractory LHwere enrolled in this study. Of the 9, 4 pts had refractory LH. The median age was 15.1 y. CR (from 6–48 mo) lasted for a median of 21 mo in 5 pts.

Induction therapy consisted with 2–5 cycles of ViGePP (gemcitabine – 1000 mg/m2/d 1,8,15 d., vinorelbine – 30 mg/m2/d 1,8 d, procarbazine 100 mg/m2/d 1–7 d., prednisolone 30 mg/m2/d 1–15 d).

Results

The response rate was assessed after 2 cycles of ViGePP: CR – 3, PR – 6. After the end of treatment the status was CR – 7, PR – 1. One pt continues treatment. Two pts have been in CRII for 15 and 12 mo. One has been in CRIII for 2 mo. Two pts had a fourth relapse 7 and 9 mo after the end of treatment. Two pts in CR have been allocated for consolidation SCT. One pt died from sepsis after ASCT.

Hematological toxicity: leukopenia grade 3 (n=4), grade 4 (n=3), thrombocytopenia grade 4 (n=2), grade 3 (n=5), anemia grade 3 (n=4).

Non–hematological toxicity: mucositis grade 2 (n=2), grade 1 (n=2), gastrointestinal grade 3  (n=1), grade 2 (n=1). Liver toxicity (ALT, AST) grade 3 (n=4), grade 2 (n=3). Heart and kidney toxicity > grade 1 were not observed.

Conclusion

The ViGePP regimen was effective in 6/9 LH pts. Toxicity was acceptable. Future studies are warranted to evaluate larger cohorts of pts with relapsed and refractory LH.

Keywords

Hodgkin’s lymphoma, children, relapse, therapy, ViGePP

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Supporting therapy of natural zeolites at patients with lymphoproliferative diseases

Download PDF version

Anna S. Chernyshova, Lev E. Panin

Institute of Biochemistry, Siberian Division, Russian Academy of Medical Science, Novosibirsk, Russia

The aim of this study was to investigate liver functionin patients with lymphoproliferative diseases who had received zeolites along with polychemotherapy.

Materials and methods

Research consisted of 68 patients with T- and B-cells non–Hodgkin’s lymphomas. All patients received a polychemotherapy course of cytostatic drugs with hepatotoxic, nephrotoxic, and cardiotoxic side effects. The investigative group (IG) of 28 patients received natural zeolites between chemotherapy courses as supporting therapy. The comparison group (CG) – consisting of 40 patients of identical sex, age, and IPI– received treatment according to standard protocol.

Results

After the polychemotherapy course 6 patients (8.8%) were found to have cytolysis syndrome confirmed by an increase in alanine aminotransferase (ALT) activity. Also, the median of ALT activity in IG patients was 28.3 ed/l (21.3; 47.8), and 29.7 ed/l (22.3; 44.4) in CG patients. It was noticed later that ALT activity decreased by 18.5 ed/l (11.1;25.3) (р=0.021) during the zeolite course, in contrast with ALT activity of 29.95 ed/l (21.2;41.8) (р=0.0004) in the CG. After the introduction of cytostatic medication the mean value of the whole protein content in the IG and the CG was 71.38±1.09 and 71.95±1.42 g/l respectively. After the zeolite treatment the concentration of serum protein in the IG increased up to 73.88±0.82 g/l (р=0.026), which was higher than in the CG (71.00±0.96 g/l, р=0.033).
The fibrinogen content – after the zeolites course – in the IG increased up to 3.6 g/l (р=0.048), which is lower than that in the CG (р=0.008) by 0.84 g/l.

Conclusion

The use of natural zeolites noticeably reduces the hepatotoxicity of chemotherapeutic drugs used for the treatment of lymphoproliferative diseases, allowing the utilization of zeolites as hepatoprotectors.

Keywords

non-Hodgkin’s lymphoma, supporting therapy, liver, natural zeolites, polychemotherapy

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Anemias in lymphomas: pathogenesis mechanisms

Download PDF version

Anna S. Lyamkina, Tatiana I. Pospelova

The State Medical University, City Hematological Center, Novosibirsk, Russia

Aims

To spot the value of blood serum cytokines (IL-1β, IL-6, TNF-α, IF-γ) in the development of an anemic syndrome in patients with lymphoproliferative diseases.

Methods

We inspected 88 patients with lymphoproliferative diseases: T and B–cellular non–Hodgkin’s lymphomas and multiple myeloma. The level of serum interleukins (IL-1β, IL-6, TNF-α, IF-γ) was identified.

Results

Patients with lymphoproliferative diseases and an anemia had average levels of IL-1β, TNF-α, IF-γ in their blood serum that were 3.4, 2.8, and 14.4 times higher respectively than in patients with lymphomas without an anemia (p<0.05). The return correlation between levels of IL-1β, TNF-α, IF-γ and the level of erythropoietin serum (r=–0.79) confirms the importance of
IL-1β, TNF-α, IF-γ in an anemia pathogenesis at hemoblastoses. For 8.3% of patients with lymphomas and an anemia,  myelodysplasia tags, recorded levels of IL-1β and TNF-α were twice as high as patients with normal erythron. This indicates a probable role of the researched cytokines in the development of secondary myelodysplasia in patients with lymphomas.

The return correlation between IL-6 and erythron of bone marrow was available in patients with multiple myeloma (r=–0.96). IL-6 raises a proliferation of myeloma cells, which, in turn, displace and depress a proliferation of remaining sprouts of myelopoiesis, including erythroid.

Conclusions

The cited data bears the importance of cytokines IL-1β, IL-6, TNF-α, and
IF-γ in a pathogenesis of an anemic syndrome for patients with lymphoproliferative diseases.

Keywords

cytokines, lymphoproliferative diseases, anemia, non-Hodgkin’s lymphoma, multiple myeloma

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Impact of positron emission tomography on primary staging and changing the therapeutic modality in lymphoma patients

Download PDF version

Natalia B. Mikhaylova1, Marina S. Tlostanova2, Yulia N. Vinogradova2, Ekaterina I. Ivanova2, Anna V. Kritskaya2, Sergey E. Korolev1, Anna A. Rats1, Alexander A. Pugachev1, Nikolay V. Ilyin2, Boris V. Afanasyev1, Leonid A. Tyutin2

1Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia; 2Russian Research Centre for Radiology and Surgical Technologies, St. Petersburg, Russia

Objectives

We investigated the usefulness of FDG-PET in initial staging and its contribution in changing the therapeutic plan in lymphoma patients.

Methods

More than 200 PET scans were performed in 95 lymphoma patients (42-HL, 53-NHL) between 2004 and 2009. In 54 cases PET was performed at diagnosis and after completion of first-line therapy. In 41 patients the first PET study was done after first-line therapy or at the relapse of the disease. Patients with metabolic activity in nodes after first-line therapy received salvage therapy consisting either of conventional chemotherapy (CT) with PET positive node irradiation or high-dose CT with HSCT.

Results

In 20% of NHL patients PET was the only method that revealed at least one pathological lesion not confirmed by computer tomography at diagnosis. In 71.2% of patients full metabolic response was achieved after first-line therapy; 27.8% of patients remained PET positive. Additional cycles of conventional CT and radiation converted PET-positivity to PET-negativity in 19.5% of cases, compared with 16% after ASCT. Early relapse was observed in 30% of patients with metabolic activity after first-line therapy compared with 20% in PET negative patients. Seventy-one percent of patients with PET-negative status did not relapse during the time of observation, whereas only 35% of patients with metabolic activity after first-line treatment remained in remission. The death rate was 23% in the PET-positive group, while no deaths were recorded in  the PET-negative group. The overall survival rate was calculated in 41 patients and is represented in Fig. 1.

Figure 1.

2009-5-en-Mikhayliva-et-al-Figure-1.JPG

Conclusion

FDG-PET is useful at primary diagnosis. Approximately 20% of lymphoma patients could benefit from therapy changing initiated by PET status.

Keywords

lymphomas, prognosis, positron emission tomography

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

High-dose melphalan versus melphalan plus dexamethasone in patients with AL amyloidosis

Download PDF version

Anna G. Smirnova1, Alexey V. Smirnov2, Axel R. Zander3, Boris V. Afanasyev1

1Chair of Hematology, Transfusiology, and Transplantology, Raisa Gorbacheva Memorial Institute of Children Hematology and Transplantation; 2Chair of Internal Medicine, Pavlov State Medical University, St. Petersburg, Russia; 3Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Correspondence
Anna G. Smirnova, Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: dr.annasmirnova@gmail.com

Purpose

AL amyloidosis is a clonal plasma cell dyscrasia related to multiple myeloma, in which monoclonal light chains transform to amyloid deposit in various tissues and lead to progressive organ dysfunction. The prognosis is poor and median survival is about 1 year in untreated patients. This study assessed whether high-dose melphalan followed by autologous hematopoietic stem-cell transplantation (AHSCT) improves the outcome of these patients.

Patients and methods

Between June 2002 and February 2009, 36 patients with AL amyloidosis were included: 20 males, 16 females. The median age was 57 y.o. The number of involved organs ranged from 1 to 5, 17 (47%) patients had more than 2 organs involved and 26 (72%) had cardiac involvement. All patients younger than 70 y.o. with a performance status of 0–2 by ECOG were aimed to AHSCT. Patients ineligible for ASCT received melphalan and dexamethasone. 

Seventeen patients received AHSCT (conditioning regimen was melphalan 100–200 mg/m2), 11 chemotherapy (melphalan+dexamethasone), and 8 died before treatment.

Results

After a median follow-up of 36 months, the 3-year overall survival (OS) was 70% and 30% in the AHSCT and chemotherapy groups, respectively (p=0.00) (Fig. 1). Progression-free survival (PFS) of 1.5 was also better in the AHSCT group: 40% and 10%, respectively (p=0.007). The main factors that decreased OS were cardiac involvement and a performance status of more than 2 by ECOG at the time of diagnosis. Age, number of involved organs, and melphalan dose did not have an impact on OS and PFS in our study.

Figure 1.

2009-5-en-Smirnova-et-al-Figure-1.JPG

Conclusion

AL amyloidosis is usually associated with poor health status, rapid disease progression, and involvement of multiple organs. Survival depends on:
•    cardiac involvement
•    the general health of the patient
•    the intensity of the treatment

Keywords

AL amyloidosis, treatment, melphalan, hematopoietic stem-cell transplantation

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Allogeneic stem cell transplantation in multiple myeloma: single centre experience of 112 patients

Liisa Volin, Heli Uotinen, Eeva Juvonen, Anne Nihtinen, Tapani Ruutu

Department of Medicine, Division of Hematology, Helsinki University Central Hospital, Helsinki, Finland

At Helsinki University Central Hospital 112 patients with multiple myeloma (MM) have been treated with allogeneic stem cell transplantation (SCT) since 1995. The conditioning was at first myeloablative (MA), but reduced intensity conditioning (RIC) after autologous SCT has mostly been used since 1999. However, MA conditioning has been considered in young patients with aggressive disease. Of the patients 54 were male and 58 female. The median age at SCT was 50 (27–64) years. The median number of chemotherapy lines was 2 (range 1–7) before allogeneic SCT. In addition, prior autologous SCT had been performed in 71 patients. The median time from diagnosis to allogeneic SCT was 12 (4­–170) months, and the time between autologous and allogeneic SCT, 6 (2–142) months. At the time of allogeneic SCT 13 patients were in CR, 84 in PR, 4 had SD, and 11 were in progression. Eighty-six patients had a sibling donor and 26 patients had an HLA-matched unrelated donor. The conditioning was MA in 49 and RIC in 63 patients. Thirty patients received a BM graft and 82 patients a PB graft. The median follow-up time from allogeneic SCT was 43 (1–166) months. The OS was 50% at 95 months post-SCT and there were no deaths after 96 months (11 patients at risk). One hundred-day transplant-related mortality was 3.6% and that of the whole follow-up time was 10.8%. Thirty-eight patients have died. The cause of death was MM in 25 patients, GVHD in 7, and infection in 4. The present results show that with appropriate patient selection, allogeneic transplantation can be carried out in myeloma with low transplant-related mortality and encouraging survival rates. 

Keywords

myeloma, allogeneic stem cell transplantation, myeloablative and reduced intensity conditioning

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

The role of p53 polymorphisms in non–Hodgkin’s lymphomas’ susceptibility and prognosis

Download PDF version

Elena N. Voropaeva, Tatiana I. Pospelova, Mikhail I. Voevoda, Olga V. Beresina

State Medical University, Scientific Research Institute of Therapy, The Russian Academy of Medical Sciences, Novosibirsk, Russia

Purpose

The purpose of our research was to estimate genotype distribution of p53 polymorphisms in NHL patients as well as the association of them with
non-Hodgkin’s lymphoma (NHL) risk and prognosis.

Patients and methods

Ninety-nine unrelated patients from the Novosibirsk City Hematological Center with different histological NHL entities were investigated. Genotyping was carried out with use of PCR and PCR-PLRF. The genotype and alleles distribution of Arg72Pro ex4, dup16bp in3 and G/C in6 gene p53 in patients were compared with the distribution in healthy, white Russian subjects from Novosibirsk and the Novosibirsk region.

Results

Statistically significant (P < 0.05) heterogeneity was observed between the patients with indolent and aggressive variants and different histological NHL entities.  In addition, our data suggests that Pro-carrying genotypes of the p53 codon 72 (OR, 3.67; CI, 1.00–13.44; P < 0.05) and m-allele of the p53 in3 (OR, 5.56; CI, 2.25–13.7; P < 0.05) increased the risk of B non-small lymphocytic lymphoma, compared with population controls. At the same time, the patients with G-allele in6 gene p53 showed a significantly increased odds ratio (OR, 2.9; CI, 1.01–8.31; P < 0.05) of having B small lymphocytic lymphoma, compared with normal controls without G-allele. We further investigated the association of p53 polymorphisms with prognosis, according to the International Prognostic Index in NHL patients. Patients with an association of minor alleles in3, in6, and ex4 gene p53 tended to have poorer prognosis than those with normal homozygous genotype in these loci.

Conclusion

Our data suggested that Arg72Pro ex4, dup16bp in3, and G/C in6 gene p53 polymorphisms may play a role in NHL susceptibility and prognosis.

Keywords

polymorphism, p53, non-Hodgkin’s lymphoma, susceptibility

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Effects of targeted therapy of multiple myeloma according to the City Hematological Center of Novosibirsk

Download PDF version

Natalia V. Skvortsova, Tatiana I. Pospelova, Sofia J. Kovalchuk

State Medical University, City Hematological Center Novosibirsk, Russia

Aim

The aim of this research was to estimate the efficiency and toxicity of bortezomib in the treatment of patients with multiple myeloma (MM) as first-line and second-line therapies.

Methods

Fifty-five patients with MM were treated; the patients’ median age was 66.3 years with a range of 38 to 87 years. Bortezomib was used as a second-line therapy in 41 patients with MM, who had earlier received at least 4 courses of therapy. All patients were tolerant to the last scheme of therapy. Bortezomib was applied in the form of monotherapy in a dose of 1.3 mg/m2 in 21 patients (41.2%) and was also applied in combination to dexamethasone in a dose of 20 mg p.o. in 20 patients (39.2%). As a first-line therapy bortezomib has been appointed in combination with МР 10 (19.6%) by the patient. The response to bortezomib was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT). Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0.

Results

The overall response rate to bortezomib as a second-line therapy was 76.5%: 15 patients (29.4%) had a complete response and near complete response (CR/nCR); 21 patients (41.2%), partial response (PR); and 3 patients (5.9%), minimal response  (МR). The overall clinical response to bortezomib in firstline therapy was 80% (6 CR and 2 nCR). The most common adverse effects were neuropathy (58%), fever (25%), and asthenic syndrome (45%). Other frequent effects were: herpes Zoster (33% of cases), thrombocytopenia (45%), and anorexia (40%). All other adverse effects – such as a diarrhea and skin rashes – were documented in less than 10% of cases. The settlement median of the general survival rate was not reached, and the 5-year-old survival rate was 90%.

Conclusion

Bortezomib is a highly effective medical drug and plays an important role in the treatment of MM as a first and second-line therapy.

Keywords

multiple myeloma, bortezomib, adverse effects, chemotherapy

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Association between HLA class I antigens and survival length in patients with multiple myeloma

Download PDF version

Elena A. Senkina, Galina A. Zaitseva, Tamara P. Zagoskina, Konstantin A. Martynov

FSE Kirov Research Institute of Hematology and Blood Transfusion of FMBA of Russia, Kirov, Russia

Aim

The aim of the investigation was to determine the association between human leukocyte antigens (HLA) class I phenotype and the length of survival in patients with multiple myeloma.

Methods

HLA class I (loci A and B) antigens were tested using the standard lymphocytotoxicity test with reagents produced by “Gisans”, St. Petersburg. The HLA phenotype was identified in 120 patients with multiple myeloma. There were 53 (41.2%) males and 67 (55.8%) females among them. The median age at diagnosis was 60 years. The diagnosis of multiple myeloma was established according to standard criteria. Patients received the following chemotherapy programs: MP, M2, VAD, and PAD. Survival was calculated from the date of diagnosis using curves Kaplan-Meier (“Statistica 6.0”). Survival lengths of patient groups were compared using the log-rank method (“Biostat”).

Results

A statistically significant difference was obtained in the comparison of survival curves of patients with HLA-B5 and without (p<0.05). Patients who had HLA-B5 in their HLA phenotype, had a higher risk of death than others, with a median survival length of 29 months compared to 79 months.

Conclusion

Poor prognosis and low survival length in patients with multiple myeloma are associated with HLA-B5.

Keywords

multiple myeloma, HLA, survival

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Genetic polymorphisms of CYP1A1, GSTM1, GSTT1, and GSTP1 genes in В-cellular chronic lymphocytic leukemia (B-CLL)

Download PDF version

Vanik A. Ovsepyan, Vitaliy A. Rosin

Federal State Institution, Kirov Hematology and Blood Transfusion Research Institute under Federal Medicobiological Agency, Kirov, Russia

Aim

The aim of this study was to examine the relationship between genetic polymorphisms in GSTM1, GSTT1, GSTP1, and CYP1A1 genes and their susceptibility to B–CLL.

Methods

The DNA for our research was isolated from the leukocytes of venous peripheral blood taken from 146 patients with B-cell CLL and 221 healthy individuals, using a standard phenol-chloroform extraction method. GSTM1 and GSTT1 genotypes were determined by a multiplex PCR technique that detects homozygous deletions of the mentioned genes and the β-globin housekeeping gene as an internal control. CYP1A1 mutation A4889G (Ile462Val) and GSTP1 polymorphisms A1578G (Ile105Val) and T2293C (Аla114Val) were identified by the PCR-RFLP approach.

Results

For the first time it was shown that the mutant genotype (GSTP1-105IleVal+GSTP1-105ValVal) occurs significantly more often in B-CLL patients than that of healthy individuals (65.1% ps. 53.4%, χ2 = 4.92, p<0.05; OR=1.63, 95% CI=1.06÷2.50), whereas the "wild" genotype GSTP1-105IleIle was significantly underrepresented in patients with CLL compared with those of healthy individuals (34.9% ps. 46.6%, χ2 = 4.92, p<0.05; OR=0.62, 95% CI=0.40÷0.95).

At the same time the difference in distribution of homozygous deletion of the GSTM1 and GSTT1 genes and also of the CYP1A1-Ile462Val and GSTP1-Ala114Val genotypes between B-CLL patients and healthy individuals was statistically not significant (p>0.05).

Conclusions

The results of the current study suggested that the GSTP1 polymorphism may influence the risk of B-CLL developing.

Keywords

B-CLL, genetic susceptibility, CYP1A1 polymorphism, GSTM1 polymorphism, GSTT1 polymorphism, GSTP1 polymorphism

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Unusual B-cell lymphoproliferative disorders and the new WHO classification

Download PDF version

Margarita Palutke

Wayne State University School of Medicine, Detroit, Michigan USA

There is a group of chronic B-cell lymphoproliferative disorders that at this time are difficult to classify, many of which are thought to originate in the spleen. The terms B-cell lymphoma with villous lymphocytes, hairy cell leukemia variant, and splenic diffuse red pulp small lymphocytic lymphoma have been used. The WHO puts some of these entities into the splenic B-cell lymphoma/leukemia unclassifiable category.

We have studied a group of such disorders-which have come to us for consultation – with a variety of diagnoses, including: hairy cell leukemia, hairy cell leukemia variant, splenic marginal zone leukemia, prolymphocytic leukemia, and atypical chronic lymphocytic leukemia. In addition to morphological evaluations and flow cytometric immunophenotyping, immunohistochemical and cytogenetic studies were performed in an attempt to achieve a clinically useful diagnosis.

Keywords

chronic lymphoproliferative disorders, splenic lymphomas

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Bone marrow angiogenesis is a prognostic value in patients with multiple myeloma undergoing high-dose therapy and autologous stem cell transplantation

Download PDF version

Olga S. Pokrovskaya, Lidia S. Mendeleeva, Irina B. Kaplanskaya, Elena Yu. Varlamova, Elena N. Parovichnikova, Sergey M. Kulikov, Valeriy G. Savchenko

Research Center of Hematology, Moscow, Russia

Background

Angiogenesis plays an important role in hematological malignancies. An increase of angiogenesis – measured as bone marrow (BM) microvessel density (MVD) and as an increase in angiogenic factors – has been detected in patients with acute and chronic leukemia, myelodysplastic syndromes, and multiple myeloma (MM). Angiogenesis is a constant hallmark of multiple myeloma (MM) progression. It has also been reported that bone marrow angiogenesis is a predictive factor of poor survival in newly-diagnosed myeloma. The goal of our study was to investigate the dynamics of BM MVD in patients undergoing high-dose therapy (HDT) and autologous stem cell transplantation (ASCT).

Patients and methods

Our study included 36 patients (pts) with newly-diagnosed MM (22 in stage II and 14 in stage III according to Salmon and Durie) – 21 males and 15 females, median age – 51 ys (range 31–67). IgG MM was diagnosed in 18 cases, IgA MM in 6 cases, IgD MM in 1 case, light chain MM in 9 cases, and nonsecretory MM in 2 cases. All patients underwent HDT that included 3–4 cycles of induction therapy (VAD), stem cell mobilization with cyclophosphamide 6 g/m2 and G-CSF 5 mcg/kg, EDAP, and 1 or 2 ASCT with melphalan 200 mg/m2. The bone marrow biopsies for histological and immunohistochemical analysis were performed at the time of diagnosis, after the induction, after stem cell mobilization, before the 1st ASCT and after the end of therapy (5 times during the treatment). The control group was constituted by the healthy donors of BM, (7 male and 3 female, median age 29, age range 17–59). In healthy donors BM biopsy was performed during BM harvesting for allo-BMT. Blood vessels were highlighted by immunostaining of endothelial cells with a monoclonal antibody to CD34 (Novocastra Lab Ltd). The MVD was calculated in 10 fields of view using a 40x objective and 16x ocular lens.

Results

At diagnosis in all MM pts MVD was extremely high compared to healthy donors (152±8 vs 74±4). A significant decrease of BM MVD under each phase of therapy was registered: after the induction therapy MVD was 124±6, before the 1st ASCT – 109±5, and at the end of treatment – 97±3. There was a statistically significant increase of MVD after stem cell mobilization due to G-CSF (143±4). Despite the evident decrease of BM MVD in pts with CR or VGPR, it stayed, nevertheless, significantly higher compared with the control group (p<0,001).

The analysis of probability of CR or VGPR duration after ASCT – according to MVD at different phases of therapy – showed that MVD at diagnosis and before the 1st ASCT are important prognostic factors. The probability of duration of CR or VGPR was 63% in the group with low MVD before the 1st ASCT compared with 15% in the group with high MVD (p<0.02). MVD was revealed to be a more powerful prognostic factor for progression free survival (PFS) than CR or VGPR achievement.

We found a good relationship between BM MVD and  the MM stage (p<0.05). The correlation between BM angiogenesis and albumin levels – as with β2-microglobulin levels – was not significant. There was no correlation between BM MVD before chemotherapy and plasma cell infiltration in these patients.

Conclusion

BM angiogenesis highly increased in patients with MM. Our data demonstrates a highly significant decrease in BM MVD in patients who achieved remission after HDT. But even after the end of HDT and ASCT, MVD is higher than in the control group. There is a statistically significant increase of MVD after stem cell mobilization with cyclophosphamide and G-CSF. MVD at the time of diagnosis and before the 1st ASCT are important prognostic factors for overall survival and PFS after ASCT. MVD before the 1st ASCT seems to be a more powerful prognostic factor for PFS than remission rate.

Our results reveal the decrease of MVD to be a powerful prognostic parameter for PFS in pts with MM, and they underscore the importance of angiogenesis in this disease.

Keywords

angiogenesis, multiple myeloma, autologous stem cell transplantation, microvessel density

F. Lymphoproliferated diseases (Lymphoma, Myeloma)

Virus participation in renal damage in AL patients: histopathological study

Download PDF version

Ekaterina G. Vorozheikina1, Vladimir V. Varshavski2, Ekaterina P. Golitsina2, Evgenia N. Glasko1, Irina B. Kaplanskaya1, Ljudmila S. Birjukova1, Elena N. Parovichnikova1, Valeriy G. Savchenko1

1National Research Center of Hematology, Moscow, Russia; 2I.M. Sechenov’s Moscow Medical Academy, Russia

Correspondence
National Research Center of Hematology, Novozykovski Pr 4., 125167 Moscow, Russia
Phone: +7 (495) 612 4592, Fax: +7 (495) 6124252 
E-mail: vekgen@mail.ru

Aim

To investigate the morphology and electron microscope characteristics of kidney damage in patients (pts) with AL.

Patients and Methods

Forty-one patients with AL from 2003 to 2008 were observed. RB was performed in 11 pts with functional renal insufficiency (3-ALL, 8-AML); the median age was 38 years (19–67). Autopsy data were studied in 30 pts with renal insufficiency and acute renal failure. Light microscopy, immunohistochemistry, and electron microscopy was used.

Results

In 30 kidney autopsies, tubular interstitial changes with sclerosis prevalence were found. In 2 pts mesangioproliferative glomerulonephritis was revealed. Other changes included  the low proliferation of mesangiocytes, arteriolosclerosis of vessels (18pts), and the presence of leukemic infiltration (7pts). Tubular-interstitial changes were found in all patients who underwent RB; in 3 cases glomerulonephritis was found and leukemic infiltration in 2. An immunohistochemical study showed that in all cases tubular epithelium cells and interstice-infiltrating lymphocytes were EBV and HSV ½ positive. CMV was found in 1 case and herpes infection also in 1 case. Increased antiviral IgD levels were found in 10 patients, DNA probes were negative. Renal structural changes analyzed by electron microscopy were difficult to interpret, but in all cases viruses were found in different cell types. We can suppose that renal structural damage was to some extent associated with the presence of viruses.

Conclusions

Kidney damage in acute leukemia is characterized mostly by tubular interstitial changes. We also proved – using electron miscopy and an immunohistochemical study – the massive viral invasion of renal tissue.

Keywords

acute leukemia, AL, kidney, renal biopsy, RB, autopsy, viruses