Phase 1/2 study of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia

Abstract

BACKGROUND: Allogeneic stem cell transplantation (SCT) remains the standard treatment for advanced chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph 1 ALL). Relapsed disease is the major cause of treatment failure, especially when SCT is given in the setting of advanced disease. Tyrosine kinase inhibitors can be given after transplantation prophylactically or after the detection of minimal residual disease (MRD) to reduce the relapse risk. METHODS: Posttransplant nilotinib was started after the achievement of sustained engraftment and the resolution of transplant-related toxicities. Nilotinib was continued until progression or unacceptable toxicity. RESULTS: Twenty-two patients with advanced CML (n 5 15) or Ph 1 ALL (n 5 7) underwent SCT with human leukocyte antigen-matched siblings (n 5 11), unrelated donors (n 5 7), or alternative donors (n 5 4). Sixteen patients were given prophylactic nilotinib maintenance, which was started at a median of 38 days after transplantation. Six patients stopped the treatment because of toxicities (mostly gastrointestinal and hepatic). After nilotinib maintenance, 11 patients achieved (n 5 9) or maintained (n 5 2) a complete molecular response (CMR), and only 1 of them later relapsed. Four of the 5 patients not achieving CMR relapsed. At a median follow-up of 46 months, 9 patients were alive, and 13 had died. The 2-year overall and progression-free survival rates were 55% (95% confidence interval [CI], 34%-75%) and 45% (95% CI, 25%-66%), respectively. Among the 16 nilotinib recipients, the rates were 69% (95% CI, 46%-92%) and 56% (95% CI, 32%-81%), respectively. The 2-year nonrelapse mortality and relapse rates for all patients were 32% (95% CI, 17%-58%) and 23% (95% CI, 11%-49%), respectively. CONCLUSIONS: Nilotinib is relatively safe and effective prophylactic therapy for the prevention of relapse after SCT. It may control MRD and convert patients to CMR, which is associated with prolonged survival. These observations merit further study in larger scale studies. Cancer 2015;121:863-71.

Chronic myeloid leukemia: reminiscences and dreams

“…In this regard, it is of interest that the National Comprehensive Cancer Network (NCCN) recommends considering 12 months of standard dose imatinib following allo-SCT. 160,161 Finally, it is also reasonable to consider an allo-SCT for patients in the advanced phases of CML, in particular for those who show an initial response to TKI with or without conventional chemotherapy. 162,163 In general, responses to TKIs for such patients tend to be short term and the probability of relapse to blast crisis high.…”

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

“…We have recently demonstrated the feasibility, safety, and efficacy of nilotinib, a second-generation TKI, as maintenance therapy after allogeneic SCT in patients with advanced CML and Ph+ ALL [23]. In the current study, we show that nilotinb administration up to one year following allogeneic SCT does not jeopardize immune reconstitution and function in the recipients.…”

“…The complete eligibility criteria and the clinical characteristics of the cohorts were previously described by Shimoni et al [23]. Of the original 16 patients who participated in the clinical study, full immunological evaluation was available on 12 patients receiving nilotinib for at least 90 days following allo-SCT (Table 3).…”

“…Second generation TKIs, including nilotinib, may be more efficient in preventing and treating relapse of advanced CML and Ph+ ALL [7, 21]. However, data on their use in the post allo-SCT setting are limited [7, 22, 23]. …”

“…Nilotininb was safe and partially effective for the prevention of relapse after allo-SCT [23]. In the current study, we further explored nilotinib effect on immune reconstitution post allo-SCT.…”