Dasatinib effective in imatinib resistant/intolerant CML

February 1, 2008

Study results presented at ASH 2007 showed efficacy of the novel tyrosine kinase inhibitor dasatinib (Sprycel) in imatinib (Gleevec) resistant or intolerant chronic myelogenous leukemia patients in chronic, accelerated, and blast phase

ATLANTA—Study results presented at ASH 2007 showed efficacy of the novel tyrosine kinase inhibitor dasatinib (Sprycel) in imatinib (Gleevec) resistant or intolerant chronic myelogenous leukemia patients in chronic, accelerated, and blast phase.

Richard M. Stone, MD, of the Dana-Farber Cancer Institute, presented 2-year follow-up data of the international phase II START-C trial (abstract 734). The study involved 387 patients with CP-CML who had imatinib resistance (n = 288) or intolerance (n = 99). Treatment consisted of dasatinib 75 mg twice daily.

With a median follow-up of 24 months, a complete cytogenetic response (CCyR) was achieved in 53% of patients and a major cytogenetic response (MCyR) in 62%. Nearly half of the patients (47%) experienced a major molecular response.

Overall survival at 24 months for the entire population was 94%, and for the imatinib-resistant and imatinib-intolerant populations, 92% and 100%, respectively. Progression-free survival rates for these three groups were 80%, 75%, and 94%, respectively.

"The drug appears to be active in a variety of patient subgroups examined," Dr. Stone said. Responses occurred across 42 different Bcr-Abl baseline mutations (but not T3151) and were achieved in patients with P-loop mutations and those with no prior cytogenetic response to imatinib.

Responses to dasatinib were durable, especially in patients with imatinib intolerance; 97% of those with MCyR sustained this response for more than 2 years.

At 24 months, severe (grade 3-4) hematologic toxicities consisted of leukopenia (27%), neutropenia (50%), and thrombocytopenia (49%).

No cross-toxicities

"Patients who were tolerant to imatinib do not exhibit cross-toxicities to dasatinib," Dr. Stone emphasized. Thus, patients who developed a rash on imatinib did not do so on dasatinib.

Dasatinib appears to be active in patients with imatinib resistant/intolerant CP-CML, with durable responses and high overall survival at 2 years, Dr. Stone concluded.

Ongoing phase III studies are also evaluating dasatinib as frontline treatment for CP-CML. Gautam Borthakur, MD, of M.D. Anderson Cancer Center, presented results of a small study (abstract 30) showing that dasatinib produced CCyRs in most previously untreated patients in early chronic phase and produced them faster than standard-dose imatinib (historical controls).

The study also showed that a divided dasatinib dose of 50 mg twice daily did not produce fewer side effects than a dose of 100 mg daily.

The 40 study patients with Ph+ CML in early chronic phase had received no prior therapy or less than a month of prior therapy. They were randomized to dasatinib 100 mg once daily or 50 mg twice daily.

Among 39 evaluable patients, all had a cytogenetic response: 87% CCyR, 3% partial CyR, 3% minor CyR, and 7% early CyR. Within 3 months, 72% had achieved CCyR; within 6 months, 88%; and within 12 months, 100%.

These rates were higher than those of historical controls receiving standard-dose imatinib. At 12 months, 65% of imatinib controls receiving 400 mg and 86% on 800 mg had achieved CCyR. These figures rose to 68% and 90% at 18 months vs 100% with dasatinib.

In an interview with ONI about this study, Dr. Stone said "Our data [from START-C] show that dasatinib works in the resistance setting. But why wait until a relapse? If you're a patient, you would rather try to increase your chances of a cure by using the better drug early."

Accelerated phase results

The long-term efficacy of dasatinib in imatinib resistant or intolerant patients with accelerated-phase CML was confirmed by 2-year data from START-A (abstract 470). Efficacy was demonstrated in patients with all but one (T3151) of 29 different mutations identified at baseline, said Francois Guilhot, MD, of the Centre Hospitalier de l'Universite de Poitiers.

START-A included 174 patients with AP-CML receiving dasatinib 70 mg twice daily. Reporting best responses, Dr. Guilhot said that 64% had a major hematologic response (MHR), with complete hematologic response in 50%. About one-third had CCyR (38% imatinib intolerant and 33% imatinib resistant). MHR and major CyR were sustained through 24 months in 60% and 61% of patients, respectively.

Overall survival at 24 months was 72%, with median survival not yet reached. Overall survival was similar at 24 months for those who achieved MHR at 12 weeks or less or after 12 weeks (83% and 84%, respectively). Overall survival at 24 months for those who failed to achieve MHR, however, was 37%.

Cytopenias were of some concern, Dr. Guilhot said. At 24 months, rates of grade 3-4 cytopenias were leukopenia 59%, neutropenia 76%, thrombocytopenia 82%, and anemia 70%—nearly identical to the 12-month rates.

Dr. Guilhot commented in an interview, "Accelerated phase patients have more aggressive disease, and usually these patients need higher-dose treatment. Side effects with cytopenias are usual because of a high bone marrow tumor burden with fewer normal stem cells. Currently, the optimum treatment is dasatinib 70 mg twice daily. No trials are planned for 140 mg once daily."

Blast phase CML

Two-year data confirm the efficacy of dasatinib monotherapy in blast phase CML patients for whom imatinib has failed, Carlo Gambacorti, MD, of McGill University, reported (abstract 472).

The phase II START-B/START-L trial included 157 patients who had progressed on imatinib (109 myeloid blast and 48 lymphoid blast). They received dasatinib 70 mg twice daily. Mutation data, available in 148 patients, showed the nonresponsive T3151 mutation in 14 patients. Responses are shown in the Table.

In the myeloid blast population, Bcr-Abl mutation status did not affect response rates overall. In the lymphoid blast group without mutations, however, there was a trend toward greater response.

Duration of MHR was about fourfold longer in the myeloid blast group (22.4 months vs 4.9 months for lymphoid blast). Similarly, median progression-free survival was longer in the myeloid blast group (5.6 months vs 3.1 months), with about 20% progression free at 24 months in that subset.

Median overall survival was 11.8 months and 5.3 months for the myeloid and lymphoid blast groups, respectively, with 38% alive in the myeloid group and 26% in the lymphoid group.

"This population has quite limited residual hematopoiesis, so high rates of hematological side effects are not surprising," Dr. Gambacorti noted. About one-third of patients needed dose reductions and about 60% required temporary dose interruptions because of toxicities.

"In this phase of CML, the best use of this treatment is to provide the patient with a safe and minimally toxic bridge toward bone marrow transplant when age and donor availability allow transplant to be performed," he commented.