A Phase II Study of Dasatinib in Patients with Chronic Myeloid Leukemia (CML) in Lymphoid Blast Crisis or Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Who Are Resistant or Intolerant to Imatinib: The ‘START-L’ CA180015 Study.

Abstract

Patients with CML in lymphoid blast crisis (LBC-CML) or advanced Ph+ ALL have an unsatisfactory and only brief response to imatinib mesylate (IM). Moreover, treatment options in pts who failed IM are extremely limited. Dasatinib (BMS-354825) is a novel, oral kinase inhibitor that targets BCR-ABL and SRC kinases, and has shown promising clinical activity in a Phase I dose escalating study in patients with BCR-ABL-positive leukemias. Between January 2005 and June 2005, 77 pts (42 CML-LBC and 35 Ph+ ALL) who had failed IM-based therapy were enrolled in this multinational Phase II study investigating the safety and efficacy of dasatinib. This preliminary analysis summarizes data on the first 28 pts accrued (13 CML-LBC and 15 Ph+ ALL) who were accrued prior to March 20, 2005. Dasatinib was administered orally at 70 mg twice daily (BID) on a continuous daily dosing schedule; dose escalation to 100 mg BID or dose reduction to 50 mg and 40 mg BID were allowed for poor initial response or persistent toxicity, respectively. Complete blood counts were performed weekly and bone marrow evaluation, including cytogenetic analysis, was scheduled every month. Mutation analyses were performed in all pts. 27 pts were IM resistant and 1 was IM intolerant; 17 (61%) pts had received prior IM doses >600 mg/day, 13 (46%) pts received IM for <1 year and 12 pts (43%) previously underwent stem cell transplantation. Response on prior IM regimen included complete hematologic response (CHR) in 19 (68%) pts and major cytogenetic response (MCyR) in 11 (39%) pts. Median time from leukemia diagnosis was 16.6 months (range 4.9–101.6). Median age was 44 years (range 20–84) and 61% of pts were male. At baseline, median platelet count was 37 x 103/mm3 (range 7–360) with median peripheral blood blasts of 35% (range 0–90) and median blasts in bone marrow of 81% (1–100). Dasatinib doses were escalated in 8 (29%) pts and 3 (11%) pts required dose reduction. 13 pts had a major hematologic response (7 CHR and 6 no evidence of leukemia, [CHR without complete recovery of PMN or platelets]) and 12 pts had a cytogenetic response within 1–3 months (11 complete and 1 minor). 9/13 pts (69% of responding pts) maintained their response after a median follow-up of 14+ weeks (range 10+ - 24+). Complete clearing of extramedullary sites was documented. Analysis of molecular response is ongoing. The majority of pts had grade 3 or 4 myelosuppression, which was pre-existing in most cases (63% with grade 3–4 neutropenia and 58% with grade 3–4 thrombocytopenia had the same grade at study entry); PMN <500/mm3 in 64% of pts and platelets <25 x 103/mm3 in 71% of pts. Non-hematologic toxicities included grade 1 and 2 peripheral edema (3 pts) and grade 1 facial edema (2 pts). GI intolerance was infrequent. In conclusion, dasatinib has significant and clinically meaningful efficacy in this heavily pretreated population of LBC-CML and Ph+ ALL pts with acquired resistance to imatinib. Updated data on all 77 patients with a minimum of 6 months’ follow-up will be presented.

Novel agents to override imatinib resistance mechanisms

“…Hematological adverse effects were severe in every START study group: grade 3-4 thrombocytopenia and neutropenia were seen in about 80% of patients. Nonhematological adverse effects such as grade 1-2 diarrhea, headache, skin rash, and hydrothorax were observed in many cases and grade 3-4 severe hydrothorax was observed in 6-1% of patients, a higher rate compared with clinical studies of other tyrosine kinase inhibitors Ottmann et al, 2005;Guilhot et al, 2007;Talpaz et al, 2005]. The START-R study investigated the efficacy of 140 mg/day (70 mg  2/day) dasatinib or 800 mg/day IM in 150 patients who were resistant to 400-600 mg IM.…”

Chronic Myeloid Leukemia: Diagnosis and Treatment

“…Among patients in CP, 44% had a CCGR, whereas 46% to 66% of patients with advanced-phase CML had MCGRs. [173][174][175][176] In a dose-escalating study, dasatinib rendered 2-log or greater reductions in Bcr-Abl transcripts in 43% of patients in advanced phase, and 37% of patients in CP achieved 2-log or greater reductions, including 4 patients in each group who had an MMR. 178 Overall, dasatinib is well tolerated, with myelosuppression and gastrointesti-nal toxic effects seen in some patients.…”