Immunological effects of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or philadelphia chromosome-positive acute lymphoblastic leukemia

Abstract

Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib. Lymphocyte subpopulations and their functional activities including T-cell response to mitogens, NK cytotoxic activity and thymic function, determined by quantification of the T cell receptor (TCR) excision circles (TREC) and TCR repertoire, were evaluated at several time points, including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180−270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR Vβ families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation.

Relapse Prevention with Tyrosine Kinase Inhibitors after Allogeneic Transplantation for Philadelphia Chromosome–Positive Acute Lymphoblast Leukemia: A Systematic Review

“…Varda-Bloom et al [26] (n = 12) studied the effects of nilotinib after allo-HSCT in patients with CML (n = 7) and Ph+ ALL (n = 5) ( Table 3). Nilotinib was administered in doses ranging from 200 to 300 mg twice daily.…”

“…The OS and EFS/DFS at 7.5 months to 2 years ranged from 69% to 84% and 56%to 84%, respectively. The third trial reported EFS and OS at 5 years of 60% each in patients with Ph+ ALL [26].…”

Maintenance Strategies After Hematopoietic Cell Transplantation

“…The OS of the remaining two patients was 10.2 and 32.5 months. 108 A similar study of 16 patients with CML/ALL patients reported a 2-year OS of 69% and PFS of 56%. 109 Dasatinib, also a second-generation TKI, has the most published retrospective studies of Ph+ ALL patients.…”

“…Nilotinib, a second-generation TKI, has also been prospectively studied as maintenance postallo-HCT; however, these trials include patients with CML or ALL. 108,109 A small study of 12 patients (5 ALL) reported 3/5 Ph+ patients with ALL were alive and remained in CR 5-8 years after allo-HCT. The OS of the remaining two patients was 10.2 and 32.5 months.…”

The role of early molecular predictor in transplant-eligible chronic myelogenous leukemia

“…TKI therapy after allo-SCT may affect or hinder the immune reconstitution after transplant. A recent study of a small series of patients found that nilotinib prophylaxis after allo-SCT in patients with advanced CML or Philadelphia chromosome-positive acute lymphoblastic leukemia did not jeopardize immune reconstitution or function following transplantation [8]. Further studies must evaluate the role of TKI therapy as prophylactic therapy or preemptive therapy triggered by the detection of minimal residual disease, in the posttransplantation setting in transplant-eligible CML patients.…”