Nilotinib Combined with Multi-Agent Chemotherapy for Adult Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Interim Results of Korean Adult ALL Working Party Phase 2 Study

Incorporation of imatinib into classical cytotoxic chemotherapy has improved the response and survival of patients with Philadelphia chromosome-positive (Ph+) adult acute lymphoblastic leukemia (ALL). Nilotinib (Tasigna, Novartis Pharma, Basel, Switzerland), a second-generation tyrosine kinase inhibitor with enhanced in-vitro inhibition of BCR-ABL kinase, showed faster and deeper responses than imatinib among patients with chronic myeloid leukemia. Moreover, less serious gastrointestinal adverse effects of nilotinib may be beneficial to combination with intensive chemotherapy in Ph+ ALL when compared with imatinib. Herein, we report interim results of a prospective single-arm multicenter phase-2 study evaluating the safety and efficacy of nilotinib-combined multi-agent chemotherapy in Ph+ ALL.

Patients aged over 18 years old were eligible if they had newly diagnosed Ph+ ALL, and adequate hepatic/renal/cardiac function. Diagnosis of Ph+ ALL was dependent upon confirmation of t(9;22) with cytogenetics by conventional GTL-band technique, and/or positive molecular analysis with nested RT PCR for detection of BCR-ABL fusion transcripts. Written informed consent was obtained from all patients. All patients received induction treatment consisting of vincristine, daunorubicin, oral prednisolone, and nilotinib. After achieving complete remission (CR), patients received either 5 courses of consolidation followed by 2-year maintenance with 6-mercaptopurine plus methotrexate, or allogeneic hematopoietic cell transplantation (alloHCT) according to the donor availability and his/her general condition. Nilotinib was administered twice a day with a single dose of 400mg (800mg per day) from day8 of induction until the initiation of alloHCT or the end of maintenance therapy. Quantitative RT-PCR assays were performed at the central lab with Light-Cycler Technology at the time of diagnosis, at CR, and every 3 months thereafter. BCR-ABL quantification was expressed relative to the amount of glucose-6-phosphate dehydrogenase (G6PDH) mRNA. The molecular response was defined as complete (MCR) if the BCR-ABL/G6PDH ratio was less than 1×10⁻⁶. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). For interim analysis, outcome was updated as of July 1, 2011.

A total of 50 consecutive patients (male: female = 22: 28) were enrolled onto the study between January 2009 and December 2010. The median age was 44.5 (range 18–71) years old. Type of BCR breakpoint was minor (e1a2) in 66% of patients. The median BCR-ABL/G6PDH ratio was 6.09 (bone marrow) and 3.08 (peripheral blood) at the diagnosis. Except five patients who died in aplasia during induction, 45 (90%) patients achieved hematologic remission (HCR), and MCR rate was 54% at the time of HCR. During the whole treatment periods, administration of nilotinib was interrupted 50 times among 30 patients, and dose was reduced among 6 ones. Of 45 patients who achieved HCR, median dose intensity (DI) of nilotinib between day8 and day of confirmation of HCR was 769.2mg (range 160–800), and MCR rates were not different among two subgroups when dichotomized using the median dose intensity (60.9% vs. 59.1%). During the induction, 20% of patients experienced ≥grade 3 jaundice, which were all reversible, and 2% experienced pancreatitis. Thirty three patients underwent alloHCT, 19 with myeloablative and 14 with non-myeloablative conditioning. Incidences of ≥grade 3 acute graft-versus-host disease (GVHD) and extensive chronic GVHD were 9% and 3%, respectively. With a median follow-up of 17.4 months (range, 6.9–29.1), estimated relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) at 2 years were 71.1%, 49.4%, and 66.2%, respectively. Of 33 patients who underwent alloHCT, 2-year RFS, EFS, and OS rate were 70.5%, 60.0%, and 83.2%, respectively. Achievement of MCR and DI of nilotinib were not associated with outcome.

Nilotinib was tolerable in combination with intensive chemotherapy for adult patients with Ph+ ALL, and the outcomes were comparable to previous results based on imatinib combination. Patient recruitment is ongoing currently based on this interim analysis, and the final results are expected in 2014.

Off Label Use: Nilotinib is used as 'off-label drug' for Philadelphia chromosome-positive acute lymphoblastic leukemia in this trial. We have achieved the permission for the use of this drug in this clinical trial from the Korean FDA.