Dasatinib Proves Effective in Resistant CML

February 1, 2006

First results of four phase II studies of the investigational oral, multitargeted kinase inhibitor dasatinib (BMS-354825) showed significant efficacy in imatinib (Gleevec) resistant and intolerant patients with chronic, accelerated, and blast phase (myeloid and lymphoid) chronic myeloid leukemia (CML).

ATLANTA-First results of four phase II studies of the investigational oral, multitargeted kinase inhibitor dasatinib (BMS-354825) showed significant efficacy in imatinib (Gleevec) resistant and intolerant patients with chronic, accelerated, and blast phase (myeloid and lymphoid) chronic myeloid leukemia (CML). The studies were presented at the 47th Annual Meeting of the American Society of Hematology (ASH).

Dasatinib is several hundred times more active than imatinib and is non-cross-resistant with imatinib, said Francois Guilhot, MD, CHU La Miletrie, Poitiers, France, of the START Trial Study Group. The agent is active against 18 of 19 imatinib-resistant BCR-ABL mutants in vivo, and overcomes resistance conferred by SRC family kinase activation.

The START-A study, reported by Dr. Guilhot (abstract 39), evaluated complete and overall hematologic response rates in 107 Ph+ or BCR-ABL+ patients who progressed to accelerated phase CML on imatinib or who had to discontinue imatinib due to nonhematologic toxicity; 59% had been receiving 600 mg/d or more of ima-tinib. The open-label study was carried out at 39 international centers. Imatinib resistance was found in 93% of patients and mutations in 52%.

The intended dose of dasatinib was 70 mg twice daily, with dose escalations up to 100 mg twice daily allowed for less than optimal response. A complete hematologic response (CHR) was seen in 33% of patients, and no evidence of leukemia (NEL) in 26%, for a major hematologic response rate of 59%. At 2 to 10 months, all responders but one are still on study. A complete cytogenetic response (CCyR) was reported in 21% and a partial cytogenetic response (PCyR) in 9%, for a major cytogenetic response rate of 31%. No patients with the T315I mutation responded.

Grade 3-4 thrombocytopenia occurred in 79% of patients, and grade 3-4 neutropenia in 69%. Higher-grade nonhemato-logic toxicities were infrequent, with diarrhea most common among all grade toxicities (46%).

Dr. Guilhot concluded, "Dasatinib demonstrated significant efficacy in imatinib resistant and intolerant accelerated phase CML patients." He noted further that in patients with compromised bone marrow reserve, hematologic toxicities were "substantial but manageable."

START-B and START-L Trials

The phase II START-B study (abstract 40) enrolled imatinib resistant or intolerant CML patients in myeloid blast crisis, while START-L (abstract 42) included CML patients in lymphoid blast crisis.

Moshe Talpaz, MD, of M.D. Anderson Cancer Center, who reported on START-B, said that prior studies have shown that 95% of patients in blast crisis are resistant to imatinib at 4-year follow-up. While the disease responds to imatinib initially, hematologic responses are short-lived. Furthermore, imatinib resistance may be associated with BCR-ABL point mutations, BCR-ABL gene amplification or overexpression, or BCR-ABL-independent pathways (eg, SRC family kinase activation). Also, a subset of patients are imatinib intolerant.

START-B, an open-label, single-arm, multinational, 37-center trial, included 124 myeloid blast crisis CML patients given dasatinib 70 mg twice daily with escalation to 100 mg twice daily or reduction to 50 or 40 mg twice daily permitted. In initial reporting of data on 74 patients, imatinib resistance was found in 92% and imatinib intolerance in 8%. Forty-nine percent received more than 600 mg as their highest imatinib dose.

The mean daily dasatinib dose was 136.5 mg and median therapy duration was 6.4 months. Toxicity-driven dose reductions were reported in 30% of patients, and toxicity-driven dose interruptions, mainly to manage myelosuppression, in 53%. Discontinuations due to toxicity, however, occurred in only 7% of patients; 41% had dose escalations.

The overall hematologic response rate, 51%, was similar between imatinib resistant and intolerant patients (52% and 50%, respectively). Major hematologic responses (CHR 25%, NEL 8%) were found in 32% of patients. Complete cytogenetic responses were seen in 27%, and partial in 3%. "This is blast crisis," Dr. Talpaz underscored, "so don’t take these results lightly."

Again, responses were similar in imatinib resistant and intolerant patients. Furthermore, responses were seen equally in nonmutated and mutated cases. As expected, those with T315I mutations were resistant to therapy. The fact that some patients with other mutations also failed therapy suggests, Dr. Talpaz said, that at this phase of CML, additional factors contribute to resistance. About half of patients have not progressed so far.

Myelosuppression (nadir grade 4) occurred in a high proportion of patients (WBC 33%, ANC 63%, platelets 66%, and Hb 26%), but was present in many at baseline, Dr. Talpaz pointed out. As in START-A, grade 3-4 nonhematologic toxicities were few, with diarrhea (34%), subcutaneous edema (24%), and pleural effusion (18%) most common among overall toxicities. Dr. Talpaz said that myelosuppression, while common, was manageable with treatment interruptions.

Dr. Talpaz concluded, "In this very advanced stage of disease, dasatinib induced hematologic and cytogenetic responses in a substantial proportion of patients who were resistant to, or intolerant of, imatinib. . . . These results support the future study of dasatinib in previously untreated patients with myeloid blast crisis CML."

START-L, which included 42 CML patients in lymphoid blast crisis and 36 Ph+ ALL patients (71 imatinib resistant and 7 imatinib intolerant), showed high major hematologic response rates for dasatinib, 70 mg twice daily, and potent activity against most BCR/ABL mutations, reported Oliver G. Ottmann, MD, Goethe University, Frankfurt, Germany.

Dr. Ottmann reported major hematologic responses (sustained 4 weeks or longer) in 42% of Ph+ ALL patients and 31% of CML patients: CHR (31% and 21%, respectively) plus NEL (11% and 7%). Complete cytogenetic responses were found in 58% of Ph+ ALL patients and 43% of CML patients. Major hematologic responses were lost within approximately 2 to 4 months in 3 of the 15 Ph+ ALL responders and in 6 of the 13 CML responders.

START-C

Andreas Hochhaus, MD, III Medi-zinische Klinik Mannheim, University of Heidelberg, Germany, reported on the START-C trial (abstract 41), a nonran-dom-ized, open-label study conducted in 20 countries and 75 centers that enrolled 394 patients with Ph+ CML in chronic phase, with resistance (68%) or intolerance (32%) to imatinib. The patients received an initial dasatinib dose of 70 mg twice daily. Doses were reduced in 52% of patients, interrupted in 78%, and raised in 5%. This first analysis included 186 patients (median follow-up, 5.7 months.)

Dr. Hochhaus said that 90% of patients had a complete hematologic response (HR) to dasatinib therapy (87% of imatinib-resistant patients and 97% of imatinib-intolerant patients). A major cytogenetic response (MCR) was achieved in 45% overall (73% of intolerant patients and 31% of resistant patients). Among the MCRs, 33% were CCyRs (56% and 22% intolerant and resistant, respectively). BCR-ABL mutations were detected in 51% of resistant patients and 9% of intolerant patients. HRs were achieved in 88% of patients with mutations, with MCRs in 37%. None of the three patients with the T315I mutation responded. Dr. Hochhaus noted that responses are durable and that none of the patients achieving MCRs have progressed. Progression-free survival at 6 months was 95% (100% in the intolerant group). Myelosuppression grade 3-4 occurred in 46% of patients. Most cytopenias appeared in the second month of treatment. Nonhematologic toxicities included diarrhea, headache, rash, superficial edema, pleural effusion, GI hemorrhage, and increased liver enzymes, but the incidence of grade 3-4 side effects was no higher than 2% for any of these. Overall, there was no cross-intolerance between imatinib nonhematologic side effects and dasatinib side effects.