Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia

Abstract

Key Points• Nilotinib plus multiagent chemotherapy was feasible and showed a comparable outcome to previous results with imatinib for Ph-pos ALL.• The achievement of deep MR with nilotinib at postremission correlated well with the clinical outcomes for Ph-pos ALL.We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios £10 23 and MR5 for ratios <10 25. Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P 5 .004) or 6.3 times (P 5 .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298. (Blood. 2015;126(6):746-756)

Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

“…49 Both dasatinib and nilotinib have been used in combination with chemotherapy for the front-line treatment of de novo Ph + ALL. 18,20,50 Prior to the advent of TKIs, combination chemotherapy regimens were not durable. Myeloablative ASCT was considered to be the only curative option and was offered to all patients with Ph + ALL in first CR who had a suitable donor.…”

Evidence-Based Guidelines for the Use of Tyrosine Kinase Inhibitors in Adults with Philadelphia Chromosome–Positive or Bcr-Abl–Positive Acute Lymphoblastic Leukemia: A Canadian Consensus

“…In the de novo study, induction with nilotinib plus chemotherapy was given to 50 patients with Ph+ all. Results demonstrated a cr rate of 90%, with an os rate of 66% at 2 years 79 . In one study in the relapsed setting, a partial response of 10% was found 31 .…”

“…Nilotinib: Three studies in a total of 70 patients examined the efficacy of nilotinib: one in de novo patients and two in relapsed patients 31,45,79 . In the de novo study, induction with nilotinib plus chemotherapy was given to 50 patients with Ph+ all.…”

“…A major hematologic response was reported in 17 of 46 patients (37%) and a cytogenetic response was reported in 11 of 41 patients (27%). 31,45,79 , and ponatinib 86 have been studied in patients who are resistant or intolerant to imatinib. Those agents have produced hematologic and cytogenetic responses in that group of patients.…”

“…Although the panel is aware of three studies using nilotinib 31,45,79 , three studies using bosutinib 50,58,75 , and one study using ponatinib 86 in patients with Ph+ or BCR-ABL+ all, very few data are available, and the duration of follow-up with the use of those agents is less than that with imatinib and dasatinib in the relapsed and refractory setting.…”