A Phase II Study of CLAG Regimen in Combination with Imatinib Mesylate in relapsed or Refractory Acute Myeloid Leukemia

There is no standard salvage chemotherapy regimen for relapsed or refractory (RR) AML. Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (IM) and are frequently expressed on AML blasts and marrow stromal cells and are therefore capable of activating survival pathways in these leukemic cells. Preclinical data suggested synergy in vitro between cytarabine and IM on AML cell growth inhibition. A phase I study demonstrated that the combination of IM with CLAG regimen was safe and feasible (Walker, et al, Leukemia Research 2008, 32(12)). We now report the results of a phase 2 clinical study of CLAG in combination with imatinib mesylate in patients with RR-AML.

This was a single-institution two-stage phase 2 study. The study was approved by scientific review committee and IRB. Eligibility criteria included RR-AML, or CML blast crisis. Key exclusion criteria were: ECOG performance status > 2, inadequate kidney or liver function tests, history of chronic liver disease, hepatitis, or HIV infection, prior therapy with CLAG regimen, or active systemic infection. Relapse was defined as evidence of disease following documented CR (complete response) or CRi (incomplete count recovery) to the most recent prior regimen (divided into early ≤ 12 months and late >12 months). Refractory disease was defined as failure to achieve CR after 2 cycles of induction chemotherapy, persistent disease (less than 50% reduction) in bone marrow blasts after one cycle, or persistent disease following the most recent salvage regimen. The CLAG regimen consisted of: Cladribine, 5mg/m² administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2gm/m² administered through a 4 hour IV starting 2 hours after Cladribine for 5 days starting on day 2; G-CSF: 300mcg SC for 6 days starting 12–24 hours (Day 1) before the first dose of Cladribine. IM 400mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if patient had partial response (PR). The primary endpoint was remission rate measured by standard AML response criteria; secondary endpoints included overall survival (OS) and progression free survival (PFS). Correlative studies included examinination for exon 8 and 17 c-kit mutations, phosphorylation status of c-kit receptor after IM exposure, and ex-vivo cell viability assays.

Between August 2009 and April 2011, 40 patients were consented at Moffitt Cancer Center and 38 patients were treated and evaluable. The median age was 62 years (range 26–79), 22 (58%) were male, and the majority 33 (87%) were Caucasian. Seven patients (18%) had refractory AML, 19 (50%) had early relapse, and 12 (32%) had late relapse. Eight patients (21%) had prior MDS. At original diagnosis, only 2 patients had favorable risk, 18 had intermediate risk, 16 had poor risk and 2 had missing karyotype. The median duration of follow up was 9.4 months. The overall response rate (CR + CRi) for all 38 evaluable patients was 37% (CR=26%,11% CRi). Early death (within 30 days) occurred in only 2 of 38 (5.3%) patients. The CR/CRi rate in early relapse/refractory AML was 8/26 (30.8%) (95%CI 14.3–51.8) and 6/12 (50%) (95%CI 21.1–78.9%) in late relapse.

The median OS was 11.1 month (95%CI 4.8–13.4), the median PFS was 4.9 month (95% CI 1.6–11.7). Among responders, 8/14 patients proceeded to allogeneic hematopoietic cell transplant.

The regimen was generally well tolerated. Commonly observed non-hematologic toxicities included: edema (81%), nausea (71%), diarrhea (66%), febrile neutropenia (58%), vomiting (50%), pneumonia (40%), anorexia (32%), sepsis (29%) and rash (29%). The most common grade 3 or higher adverse events (>5% of patients) included febrile neutropenia (58%), pneumonia (34%), sepsis (29%), hypokalemia (24%)., diarrhea (11%), and rash (5%). The two early deaths were attributed to hemorrhage and hepatic failure.

CLAG plus IM was well tolerated, with encouraging signs of activity in patients with poor-risk AML. Future directions for the development of this class of tyrosine kinase inhibitors (TKI) in AML include incorporation of next-generation TKIs, utilization of these agents as maintenance strategy, and identification of molecular signatures which may predict response. Updated survival and molecular correlative data will be presented.

Komrokji:Novartis: Research Funding, Speakers Bureau. Off Label Use: Imatinib use in AML. Pinilla-Ibarz:Novartis: Research Funding, Speakers Bureau.