A Pilot Study of the Combination of Nilotinib and Hyper-CVAD for Philadelphia Chromosome Positive Acute Lymphocytic Leukemia and Lymphoid Blast Crisis Chronic Myelogenous Leukemia

Nilotinib is a second generation bcr-abl tyrosine kinase inhibitor (TKI) that has at least 30 times the potency of Imatinib (IM). Nilotinib has been approved by the FDA for the treatment of adults with chronic myeloid leukemia (CML) in chronic phase (CP) in the frontline, and for CP or accelerated phase (AP) who are either resistant or intolerant to prior therapies, including IM. Philadelphia chromosome positive (Ph+) acute lymphocytic leukemia (ALL) and lymphoid blast crisis of CML (Ly-BC) is aggressive and rapidly fatal. Complete remissions rates are low and have short durability. Relapse is inevitable unless patients (pts) receive an allogeneic stem cell transplant (SCT). The use of TKIs against Ph+ ALL or Ly-BC has shown limited durability of response as single agents. The transient nature of response to TKI is because only some of the blasts are still sensitive to bcr-abl inhibition, while the rest of the clones are not and require the addition of chemotherapy. Hyper-CVAD combined with the first generation TKI, IM is one such chemotherapy regimen that has been used in the management of adults with Ph+ ALL or Ly-BC (Thomas D, et al. Blood, 2004). Despite achieving >90% complete remission (CR) during induction phase, some pts have resistant disease or relapse shortly after attaining remission. We hypothesized that combining nilotinib with hyper-CVAD would achieve greater rates of sustained CR which ultimately translate into lower relapse rates, superior disease free survival, long term survival, and potential cure post SCT. The goal of our pilot case series was to study the feasibility of combining the more potent TKI, nilotinib to hyper-CVAD in pts with Ph+ ALL or Ly-BC, so as to improve the efficacy.

Our case series involves 5 pts at our institution diagnosed with either Ph+ ALL or Ly-BC treated with a combination of hyper-CVAD and nilotinib given orally 400mg twice daily (initiated the day after completion of chemotherapy until the start of next cycle). After completion of eight cycles of chemotherapy, pts received either SCT or maintenance POMP in combination with nilotinib. Supportive care included prophylactic antibiotics, granulocyte colony stimulating factor, and transfusions as needed. None of them had central nervous system (CNS) involvement, but received intrathecal prophylaxis. Clinical characteristics at baseline, safety assessments, and efficacy evaluations including morphologic, cytogenetic, and molecular responses were analyzed.

All 5 pts (p190 Ph+ ALL-4, p210 Ly-BC-1; all males; Hispanic-2, Caucasian-3) received the combination for a median of 5 months. The median age was 29 (range 22–72) and the median follow-up period was 14 months. The Ly-BC pt was treated upfront with IM during CP and achieved major molecular remission (MMR) for 39 months, however due to noncompliance, relapsed with progression. All 5 patients achieved complete remission (CR), 60% after the first course. All of them achieved complete cytogenetic remission (CCyR) while 4 achieved MMR. Of the 2 Ph+ ALL pts who completed eight cycles, 1 received SCT and is in MMR for 20 months, while the other pt remains in MMR on POMP-nilotinib maintenance for over 19 months. Another pt is in MMR for 5 months. Two patients relapsed and died: the Ly-BC pt who achieved CR (without MMR) for 3 weeks and another pt that was in CCyR and MMR for 11 months. Most common adverse events included pancytopenia, fever, and infections (with no treatment related life threatening events).

Our pilot study is the first to demonstrate the feasibility of combining nilotinib with hyper-CVAD. The results thus far are encouraging and will be expanded into a larger investigator initiated phase II study that can potentially prevent the emergence of resistant clones and improve survival in patients with Ph+ ALL or Ly-BC.

Off Label Use: Pilot study of Nilotinib and hyper-CVAD in Ph+ ALL.