ISSN 1866-8836
Клеточная терапия и трансплантация

Impact of additional chromosomal abnormalities on survival after allo-HSCT in CML patients

Ksenia S. Afanaseva, Elena V. Morozova, Julia J. Vlasova, Maria V. Barabanshikova, Nikolai Y. Tcvetkov, Tatiana L. Gindina, Ildar M. Barkhatov, Sergey N. Bondarenko, Ivan S. Moiseev, Elena I. Darskaya, Boris V. Afanasyev

Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia


Contact: Dr. Ksenia S. Afanaseva
E-mail: afanasevaksenya11@gmail.com

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Cellular Therapy and Transplantation (CTT)
Volume 8, number 3
Contents 

Summary

Widespread use of targeted therapy with 2nd and 3rd generation tyrosine kinase inhibitors (TKIs) and appropriate revision of indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT) allowed to achieve optimal therapeutic responses in the majority of chronic myelogenous leukemia (CML) patients. Nevertheless, inadequate therapeutic response and relapses, which are in most cases associated with additional chromosomal aberrations (ACAs) and mutations in BCR-ABL kinase domain (BCR-ABL KD), still remain a problem leading to decreased overall survival (OS) in patients. Moreover, there is still no comprehensive concept delineating ACAs role and prognostic value on therapy responses. There are scarce data on the role of ACAs in allo-HSCT outcomes. The aim of our study was to evaluate the ACAs impact upon long-term OS in allo-HSCT recipients.

Patients and methods

This study included retrospective data on the cohort of 101 CML patients with median age of 38 years (range, 19-61) undergoing allo-HSCT from HLA-matched sibling (n=26), haploidentical donor (n=14), or unrelated donor (n=61) in the R. M. Gorbacheva Memorial Institute between 2010 and 2019. By the time of allo-HSCT, 11 of these patients (11%) were in chronic phase 1 (CP1); 58 (57%), in CP>1; 23, in acceleration phase (AP, 23%), and 9 (9%) were in blast crisis (BC). All the patients received 1st, 2nd or 3rd generation TKIs prior to allo-HSCT. 39 patients (39% of the total) had BCR-ABL KD mutations, whereas T315I mutation was found in 15 of them (15%). All the patients were divided into prognostic groups, depending on ACAs, according to revision of ACAs prognostic value on therapy results. 34 patients (34%) had any ACAs in Ph+ cells at any given moment starting from diagnosis, 22 (22%) of these patients had high risk group ACAs (single i(17)(q10), -7/del7q or 3q26.2 or as a component of complex ACAs and complex ACAs without these three chromosomal abnormalities). Sixteen patients (16%) had both BCR-ABL KD mutations and ACAs. A cytogenetic study of bone marrow was carried out according to standard cytogenetic procedure, mutation analysis was performed by Sanger sequencing. OS were estimated by Kaplan-Meier (long-rank test).

Results

Monosomy 7 (50%), del7q (14%), and i(17) (9%) were most frequent findings among the patients with high-risk group ACAs. Other complex karyotypes were found in 27% of patients. None of the patients in our study had 3q26.2 abberation. Post allo-HSCT OS in patients with any ACAs was lower compared to patients without additional aberrations, 33.5% vs 46.7%, accordingly. There was also a trend to lower OS in patients of high risk compared to low risk group, 24.6% vs 47.7%, accordingly. The long-term OS after allo-HSCT in patients who had both high-risk ACAs and BCR/ABL KD mutations was significantly lower compared to low-risk group patients: 18.2% vs 44.8%, accordingly (p=0.048). The 10-year OS was not reached in group 3. OS in group 3 was 15% lower compared to patients from high-risk group with ACAs.

Conclusion

The detection of ACAs in CML patients is considered an unfavorable prognostic factor in terms to response to TKIs therapy. However, the influence of ACAs on results of allo-HSCT has not been comprehensively characterized. In our study, we have not obtained statistically significant differences between recipients from high- and low-risk ACA groups, but were able to demonstrate that BCR/ABL KD mutations in high-risk group ACAs patients are an additional adverse prognostic factor and lead to lower OS rates in allo-HSCT recipients.

Keywords

Chronic myelogenous leukemia, Ph chromosome, additional chromosomal abnormalities, BCR-ABL, allo-HSCT.


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