ISSN 1866-8836
Клеточная терапия и трансплантация

Stroke before hematopoietic stem cell transplantation is a possible risk factor for post-transplant adverse outcomes

Alexey Yu. Polushin, Iaroslav B. Skiba, Maria D. Vladovskaya, Ivan S. Moiseev, Alexander D. Kulagin

Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Alexey Yu. Polushin, Pavlov University, 6-8, L. Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 816-75-59
E-mail: alexpolushin@yandex.ru


Citation: Polushin AY, Skiba IB, Vladovskaya MD, et al. Stroke before hematopoietic stem cell transplantation is a possible risk factor for post-transplant adverse outcomes. Cell Ther Transplant 2024; 13(1): 34-41.

doi 10.18620/ctt-1866-8836-2024-13-1-34-41
Submitted 20 January 2024
Accepted 01 March 2024

Summary

More than 50,000 hematopoietic stem cell transplants (HSCT) are performed annually in the world for blood malignancies, solid tumors, aplastic anemia, primary immunodeficiency, autoimmune and metabolic diseases. Stroke occurs in 3% of patients over post-transplant period (about 1,500 cases annually), whereas 70% of them are at risk for unfavorable outcome in the next 1.5 years. The data on effects of preceding acute cerebrovascular accident (CVA) on the outcomes of subsequent HSCT are not presented in the literature. Our aim was to evaluate the effects of stroke occurring before HSCT on the transplant outcomes in patients with hematological diseases.

Patients and methods

The stories of 899 HSCTs were reviewed at the RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation (Pavlov University) from january 2016 to january 2018. The HSCT parameters, characteristics of the donor and recipient were taken for analysis. In addition to comparing features between groups, pseudorandomization was performed using the Propensity Score Matching method. The survival analysis was carried out using the Kaplan-Meier method and the log-rank test.

Results

Of 899 HSCTs, 16 patients (1.8%) had a history of cerebrovascular events before transplantation (0.4%, ischemic stroke; 1.4%, hemorrhagic stroke or intracranial hemorrhage). In the group of patients with a history of stroke, compared with the group of patients without them, there were more patients with leukemia (p=0.02); allogeneic transplantation (vs autologous, p=0.01), donors were more likely to have partial rather than full HLA compatibility with recipients (p=0.06). These patients had lower body mass index (p=0.02) and Karnofsky/ECOG score (p=0.01). Presence of a cerebrovascular event was significantly associated with decreased overall survival among HSCT recipients (p=0.0012).

Conclusion

Oncohematological patients with stroke before HSCT are not characterized by "classical" risk factors (diabetes mellitus, venous system diseases, decreased cardiac output, massive atherosclerosis of the extracranial arteries), thus limiting ability of assessing potential efficiency of guidelines for secondary stroke prevention when treating the underlying disease. The article discusses more relevant causes of stroke in oncohematological patients. A history of stroke before HSCT, along with other factors related to the treatment method, donor and recipient characteristics may have a significant impact on the HSCT outcome. To date, stroke in the history of HSCT recipient is not a contraindication for this treatment mode. However, the selection of recipients is a very important stage when planning such an intensive (difficult) treatment, and requires an interdisciplinary balance between indications and contraindications for unrelated HSCT.

Keywords

Stroke, ischemic stroke, hemorrhage stroke, hematological diseases, leukemia, hematopoietic cells transplantation, allogeneic transplantation, neurological complications.


Introduction

Hematopoietic stem cell transplantation (HSCT) is an effective method of treating malignant diseases of the blood system (leukemia, lymphoma, chronic myeloproliferative diseases, multiple myeloma), congenital and acquired aplasia of hematopoiesis, primary immunodeficiency, autoimmune disorders.

More than 50,000 HSCTs are performed annually worldwide [1, 2]. The life-threatening diseases comprise major indication for HSCT which is routinely applied and consists of several stages: 1) myelo- and immunoablation with the use of chemotherapy of varying intensity (conditioning regimen); 2) prevention of the graft-versus-host disease (GvHD), 3) graft transfusion; 4) prevention and treatment of complications during postcytostatic aplasia of hematopoiesis and graft engraftment period [3].

The following factors are most important for the successful HSCT: 1) clinical status of the underlying disease (remission, progression, etc.); 2) the type of HSCT associated with donor selection [4]; 3) conditioning regimen and GvHD prevention; 4) comorbidity (obesity, significant dysfunction of the heart, kidneys, liver, lungs, diabetes mellitus, other tumors, autoimmune diseases, significant gastrointestinal diseases, infections, etc).

The comorbidity index of HSCT patient [5, 6] as recommended by the European Society for Blood and Marrow Transplantation (EBMT), involves 17 parameters, each of which is assessed in 1 to 3 points. The total zero score determines a low risk of death (4%) up to 100 days after HSCT. The values of 1 to 3 points represent intermediate risk (16%); >3 points are associated with high risk of death (29%). Hence, the recipient is assessed at 3 points in case of severe liver, or lung dysfunction. A history of acute cerebrovascular accident (CVA) may add only 1 point, thus implying a possible negative contribution of previous acute CVA of <3%.

Thus, we discuss a clinical category that may impact the survival of HSCT recipient, however, considered in the context of other, more affecting factors. Precise role of the past acute stroke as a risk factor for HSCT outcomes is difficult within a single-center study. However, evaluation of this factor seems to be important for the problem statement.

Brain stroke is known to be a common complication in the cancer patients [7-9]. Some oncological diseases, especially with primary damage to the nervous system, as well as leukemias (due to high risk of blast cell-induced damage), may be strongly associated with development of ischemic and hemorrhagic strokes [10-12]. Some data indicate a higher risk of hemorrhagic and ischemic stroke in the first 6 months after the oncological diagnosis, while the development of a cerebrovascular event worsens the patient's prognosis in the future [13-15]. The stroke is known to occur in 3% of patients over the post-transplant period (potentially 1,500 per year). Of them, 70% are at risk of unfavorable outcome in the next 1.5 years [9]. The data on effects of preceding stroke on the outcome of subsequent HSCT are not presented in the literature. Our aim was to evaluate the effects of pre-transplant cerebrovascular accidents (CVA) on the outcomes of HSCT in patients with oncohematological diseases.

Materials and methods

Within single-center retrospective cohort study, medical documents of 899 HSCT patients were analyzed at the RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology (Pavlov University, St. Petersburg) from January 2016 to January 2018. Different HSCT parameters, characteristics of the donor and recipient, as well as performance status and clinical data at the last visit to neurologist were registered for all patients (Table 1). The protocol of the recipient examination before HSCT included a survey by a neurologist and results of imaging studies (depending on the age and type of HSCT). The endpoint of the study was the recording of lethal outcomes.

Two groups of patients were under study: 1) subjects with a history of stroke (till 2 years) before HSCT (n=16), 2) patients without a history of stroke before HSCT (n=883). The intergroup characteristics were compared using Fisher test (for categorical features) and Mann-Whitney-Wilcoxon test (for quantitative parameters). The obtained p values were compared at a threshold level of 0.05. To ensure the balance of clinically significant signs between the compared groups, pseudo-randomization was performed using the Propensity Score Matching method (group ratio 1:15). Such parameters as allogeneic HSCT, underlying disease (leukemia), complete HLA compatibility of the donor-recipient pairs were coded as "1". Autologous type of HSCT, primary disease other than leukemia, partial matching of donor and recipient were coded as "0". Survival analysis was performed using the Kaplan-Meier method and log-rank test. Statistical data processing was carried out using the R application package (version 4.1.2).

Table 1. Clinical characteristics of HSCT recipients over the period of 2016 to 2018 depending on the presence/absence of stroke in anamnesis

Polushin-tab01.jpg

Note: F, females, M, males; MPD, myeloproliferative disease; MDS, myelodysplastic syndrome; CR – conditioning regimen; CVD, cardiovascular disease.

Results

Among the recipients of HSCT for the period 2016-2018, cerebrovascular events (within a period of no more than 2 years before the procedure) were noted in 1.8% of cases (n=16) including 4 patients (0.4%) with a history of ischemic stroke, and 12 patients (1.4%), with hemorrhagic stroke or intracranial hemorrhage. Among the patients with a history of CVA, when compared with CVA-free cases, the leukemia patients were more common (68.8% vs 64.0%; p=0.01). Partial HLA-compatibility in recipient-donor pairs was more often (60.0% versus 35.7%; p=0.06). The patients with cerebrovascular events also had a lower body mass index (1.23±0.5 vs 1.55±0.5; p=0.02) and lower Karnofsky/Lansky index among patients <14 years of age (73.75±20.9 vs 85.14±15.0, р=0.01), as shown in Table 1.

Due to the revealed heterogeneity of groups for a number of clinically significant parameters and small number of patients with CVA, pseudo-randomization was carried out, and a sample of patients without CVA was established according to a ratio of 1:15 (Fig. 1).

Polushin-fig01.jpg

Figure 1. Balance of covariates during pseudorandomization of patients with a stroke observed before HSCT

Following the pseudorandomization, occurence of CVA proved to be significantly associated with decrease in overall survival post-transplant (mean observation period was 24 months) (Fig. 2).

Polushin-fig02.jpg

Figure 2. Survival after HSCT in patients with a history of stroke

In the group of patients with a history of CVA before HSCT, the proportion of acute leukemias was higher (68.8% vs 40.4%, p=0.02) compared to the non-leukemic cases. Of 11 patients with acute leukemia and stroke, 3 had acute lymphoblastic leukemia (ALL). These ALL patients were under 13 years, with long clinical history (from 1 to 9 years) and recurrent disease with extramedullary lesions (2 cases, CNS; 1, testicular affection), severe pretreatment (repeated chemotherapy, 3; immunotherapy, 2; history of 1st HSCT, 1). The disease status at the start of conditioning therapy was as follows: 3rd remission in 2 patients, and first relapse in one case.

In the CVA group, 8 recipients of HSCT (children, 2; adults, 6 cases) had the primary diagnosis of acute myeloid leukemia. At the time of HSCT, 3 patients were in remission, whereas 5 cases showed the disease progression. There were no previous episodes of specific CNS damage. In three cases, repeated HSCT was performed. In 7 patients, HSCT was carried out within first 6 months from the diagnosis; in one case, within 1 year, and in 1 patient – after 6 years.

One patient at the age of 7 years had mature cell T-lymphoma, being rare in childhood, with brain damage and development of subacute subdural hematoma (6,5 months prior to HSCT). This patient underwent autologous HSCT and 2 allogeneic HSCTs from a haploidentical donor (now it is remission).

In one patient aged 22 years with acquired aplastic anemia, a spontaneous subarachnoid hemorrhage occurred 5 months prior to unrelated HSCT. Currently, the patient is in remission with stable donor hematopoiesis.

Two patients with congenital diseases (Fanconi anemia and osteopetrosis, 2 and 6 years, respectively) had a history of subdural hematomas 3 and 6 months before allogeneic HSCT. A patient with Fanconi anemia died from infectious complications due to insufficient graft function. The patient with osteopetrosis is alive, the graft is functioning properly.

Discussion

A significantly increased choice of pharmacological drugs over recent years has an impact on therapeutic strategies for this category of patients, and, consequently, on the range of complications connected with their use. Damage to the central nervous system, not associated with the underlying disease and infectious complications, may develop both due to direct toxic effects of certain drugs, and by indirect pathways. Complications of HSCT result from a large number of factors, e.g., high intensity of conditioning regimen, comorbidity and transplant-associated mechanisms. In most CNS events, the etiology of the process is not obvious, with similar clinical manifestations or significantly erased symptoms. The diagnostic options are limited to neuroimaging, functional, cytological, microbiological studies. Any in vivo morphological and immunological diagnostics are extremely difficult.

Among other approaches, targeted therapy may be performed as a "bridge-therapy" prior to HSCT. The target treatment may be accompanied by the development of neurological complications. Their occurrence has not been studied enough in oncohematological patients. The frequency of complications of allogeneic HSCT according to the literature data varies at a large scale: 3 to 70% [16-20]. Long-term (sequel) neurological complications make a negative contribution to survival after allogeneic HSCT, doubling mortality rates (p=0.007) [21]. CVA as a complication of HSCT, could be simply diagnosed, being a risk factor for poor outcome in patients undergoing HSCT (p=0.001) [22, 23]. To our knowledge, there are no data on the effect of stroke before HSCT on its outcome in the group of oncohematological patients.

The data analysis of the clinical register of HSCT recipients at the RM Gorbacheva Research Institute (EBMT CIC 725) for the period 2016-2018 has shown that, among 899 patients, the incidence of stroke before HSCT is 1.8% (n=16; 1.4%, hemorrhagic stroke; 0.4%, ischemic).

The relationship between stroke and leukemia revealed in our study does not contradict the data of Del Prete C. et al. [24] who reported that the risk of stroke increases 50-fold in the AML group, and their mortality is 5.5% times higher than among stroke patients without oncohematological disease [24]. Other factors logically fit into the previously proposed "red flags" for pre-transplant evaluation of oncohematological patients [4-6] including some risk factors, e.g., allogeneic HSCT, low Karnofsky/Lansky index (ECOG).

It should be noted that among the studied patients with stroke, there were no cases with definite risk factors for CVA, such as diabetes mellitus, venous disorders, radiation therapy before HSCT, and reduced cardiac output. One should also note that there were no signs of cardiovascular pathology before HSCT in 13 out of 16 patients with stroke, thus, probably, indicating a discrepancy between the risk factors of patients in the study group versus patients without oncohematological diagnosis. Therefore, it may be incorrect to apply current recommendations for secondary prevention of stroke at the stage of treatment of the main oncological diseases to the patients from our study group [25, 26]. Moreover, stroke in the oncohematological group of patients may result from other causes.

CVA of the hemorrhagic type in patients with osteopetrosis can develop with the slightest injury, which is most likely associated with damage to the developing brain caused by abnormally changed size of the skull (hyperostosis). As a result, the structures of the brain lose their "compensatory" spaces, in addition, "tension" of the choroid plexuses can form. Also, in oncological patients, the development of stroke of the hemorrhagic type can be facilitated by emetic syndrome during therapy with chemotherapy drugs, antibiotics, etc. and high infusion load. In some types of AML, bleeding is especially common, being, associated with the properties of the tumor clone and thrombocytopenia. In AML treatment, aplasia and thrombocytopenia develop at each stage of chemotherapy. Toxic effects of chemotherapy drugs include damage of vascular walls.

Hemorrhagic stroke in patients with oncohematological profile is usually associated with thrombocytopenia, acute renal failure, high fibrinogen levels, and cytokine reactions in response to a bacterial infection [27]. Cytokine responses may also result from an immune donor/recipient aberrant response. Pathological significance of these factors is enhanced after HSCT.

Moreover, ischemic stroke in this cohort of patients may be associated with hyperleukocytosis, hypernatremia, and disseminated intravascular coagulation [28]. So, for example, stroke in acute myeloid leukemia at the onset of the disease is associated with severely altered hematopoiesis and its replacement with a non-functional malignant cells. Our experience indicates that oncohematological patients do not have atherosclerotic manifestations at the intra- and extracerebral vascular level, so the probability of an athero-thrombotic subtype of stroke is minimal.

Infiltration of the ischemic brain with immune cells marks an essential step in post-ischemic inflammation. It has been demonstrated that CD38+ cell deficiency impairs lymphocyte activation, modulates the production of cytokines by lymphocytes [29], affects migration and activation of immune cells necessary for the development of a postischemic inflammatory response that contributes to secondary brain damage and an increase in the area of focal ischemia [30]. However, to date, there is no complete understanding of the behavior of cells (monocytes, macrophages) of both the recipient and the donor in the area of the brain ischemic/hemorrhagic zone before HSCT, especially under conditions of pancytopenia.

Conclusion

A history of stroke before HSCT can probably negatively affect the course of the post-transplant period. However, the high risk of death in such a complex category of patients cannot be explained by the only history of stroke, since CVA (stroke) is not an independent and absolutely fatal factor. It is associated with the most important criteria that have proven their influence on the outcome of HSCT, i.e., the status of malignant disease at the time of HSCT, comorbidity and constitutional features of the patient, degree of the donor-recipient HLA-compatibility, and the choice of conditioning regimen based on clinical characteristics and stage of the malignancy [4-6].

To date, a pre-transplant stroke in the history of HSCT recipient is not a contraindication for this treatment option. However, in view of their condition, assessed by ECOG, Karnofsky, Lansky scales, not every patient is eligible for this treatment method. All indices assess the patient's ability to self-service, respectively, potential recipients who, after stroke, did not reach the required level, may be not fit for HSCT. Thus, the selection of HSCT recipients is a very important point of the preparatory stage when planning such a complex procedure.

Possible reasons affecting outcomes in the study group of patients may be as follows: inability to comply with recommendations for secondary prevention of stroke at the stage of conditioning and during post-transplant period, as well as limitation of motor activity (low Karnofsky index), which hypothetically may be associated with an increased risk of venous thrombosis, hypodynamic muscle atrophy, thus delaying restoration of hematopoiesis.

Despite the fact that patients with a history of stroke had a lower survival rate after HSCT, a quarter of patients were able to tolerate the treatment. This finding indicates that a history of stroke cannot be an exclusion criterion for the potentially life-saving procedure in case of oncohematological disorder. Therefore, an interdisciplinary search for a balance between indications and contraindications for allogeneic HSCT is needed.

The limitations of our study are due to its design (single-center, retrospective), a relatively small sample of patients with a documented acute cerebrovascular accident before HSCT (limitation of certain types of statistical analysis, including assessment of the impact of the timing from the onset of stroke to the start of the procedure HSCT) and factors associated with the use of pseudorandomization [31]. Further studies are needed to identify and classify the factors associated with poor outcomes in patients with oncohematological diseases and a history of stroke.

Conflict of interest

The study had no sponsorship. Authors declare no conflict of interest. The authors are fully responsible for submitting the final version of the manuscript. All the authors took part in the development of the concept of the article and the writing of the manuscript. The final version of the manuscript was approved by all authors.

Compliance with ethical principles

The authors confirm that they respect the rights of the people participated in the study, including obtaining the required informed consent.

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Volume 13, Number 1
03/31/2024

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doi 10.18620/ctt-1866-8836-2024-13-1-34-41
Submitted 20 January 2024
Accepted 01 March 2024

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