Allogeneic hematopoietic stem cell transplantation for relapsed and refractory chronic lymphocytic leukemia: single-center experience
Olga B. Kalashnikova, Maria O. Ivanova, Daniil I. Shmidt, Kirill V. Lepik, Eugeniya S. Borzenkova, Vadim N. Nemykin, Elena V. Kondakova, Natalya B. Mikhaylova, Elena I. Darskaya, Boris V. Afanasyev
Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
Contact: Dr. Daniil I. Shmidt
Chronic lymphocytic leukemia (CLL) is one of the most common types of lymphoma. While the development of novel agents shifted the paradigm of CLL management, allogeneic stem cell transplantation (allo-HSCT) is the only treatment that offers the possibility of a cure for relapsed/refractory (r/r) cases. Allo-HSCT is also possesses the risk of severe complications and mortality, therefore the optimization of allo-HSCT patient selection, timing, and preparative regimens is an actual problem. This report presents an analysis of Pavlov University experience in allo-HSCT for r/r CLL.
Patients and methods
Retrospective analysis included 23 patients (pts) diagnosed with CLL who underwent allo-HSCT at the First Pavlov Saint Petersburg State Medical University between 2006 and 2019. The male-to-female ratio was 20:3. Median age at HSCT was 48 years (33-66). In 30% of pts (7 pts) TP53 disruption was detected prior to HSCT, 22% (5 pts) had del11q, 48% (11 pts) had aberrant karyotypes. There was no cytogenetic data in one case. Mutation status was properly defined in 4 pts (all had unmutated IGHV). Among 9 patients with assessed CD38 expression, 6 was CD38+. One patient had Richter syndrome. One patient developed fludarabine-induced bone marrow aplasia prior to HSCT. Median number of therapy lines prior HSCT was 3 (1-8). Disease status prior to transplant was CR in 4 pts, PR in 10 pts, SD in 2 pts and PD in 7 pts. Novel agents were used as bridge therapy to allo-HSCT in 7 pts (6 received ibrutinib, 1 received venetoclax). Prior to transplant, 11 pts had resistance to chemoimmunotherapy and 2 pts were resistant to ibrutinib. Median EBMT score was 5 (1-7). The median time to transplant was 46 months (2 to 132).
Eight pts (35%) had fully matched related donor HSCT, while 15 pts (65%) had unrelated donor HSCT (10 fully matched, 4 mismatches, 1 unknown). Most pts had fludarabine- and bendamustine-based conditioning regimen (65%, n=15): 7 pts had FBR (fludarabine, bendamustine, rituximab) regimen, 8 pts had Flu+Benda only. In 13 transplanted patients, cyclophosphamide was used as acute graft-versus-host disease (aGVHD) prevention strategy. aGVHD developed in 17 pts (74%). Of these, 12 pts (52%) developed grade 1-2 and 5 pts (22%) had grade 3-4 aGVHD. Median follow-up was 21 months. Median follow-up of surviving pts was 112 months. Two-year overall survival (OS) rate was 62%. Two-year progression-free survival (PFS) was 53%. Non-relapse mortality was 22% (5 pts). The factors that significantly influenced OS in univariate analysis were as follows: best response to HSCT (p<0.001), stage 3-4 aGVHD (p=0.0002), disease status at the time of HSCT (p=0.0008), fludarabine and bendamustine-containing regimen along with post-transplant cyclophosphamide (p=0.0059), сyclophosphamide-based GVHD prophylaxis (p=0.05), resistance to chemoimmunotherapy prior to HSCT (p=0.05), and del13q (p=0.0144).
Allo-HSCT is a feasible treatment method for patients with r/r CLL. Patients who respond to treatment tend to do better on HSCT. Disease status prior to transplant is an important modifiable prognostic factor. Fludarabine and bendamustine along with cyclophosphamide-based GVHD prophylaxis regimen improve survival. NRM is of major concern in this setting.
Allogeneic hematopoietic stem cell transplantation, chronic lymphocytic leukemia.