Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib

Abstract

Dasatinib, a potent inhibitor of BCR-ABL in vitro, is effective for patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib. To provide a more definitive assessment of dasatinib in chronic-phase (CP)-CML, we report extended follow-up of a phase II trial, presenting data for the entire patient cohort (N=387). Dasatinib (70 mg) twice daily was administered to patients with imatinib-resistant or -intolerant CP-CML. With median follow-up of 15.2 months (treatment duration, <1-18.4 months), a complete hematologic response was attained or maintained in 91% of patients. A major cytogenetic response (MCyR) was attained or maintained by 59% (52% imatinib resistant and 80% imatinib intolerant); this was complete in 49% of patients (40% imatinib resistant and 75% imatinib intolerant). Of 230 patients achieving an MCyR, 7 experienced disease progression. Fifteen-month progression-free survival was 90% while overall survival was 96%. Grade 3/4 thrombocytopenia and neutropenia were reported in 48 and 49% of patients, respectively. Non-hematologic toxicity (any grade) consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), dyspnea (30%) and pleural effusion (27%). Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML.

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

“…70 Dasatinib also was associated with grade 3/4 nonhematologic AEs, including pleural effusion in 6% of patients. 70 To minimize dasatinib-related toxicity while maintaining efficacy, a dose-optimization study was initiated.…”

“…70 Dasatinib also was associated with grade 3/4 nonhematologic AEs, including pleural effusion in 6% of patients. 70 To minimize dasatinib-related toxicity while maintaining efficacy, a dose-optimization study was initiated. 74 In that phase 3 trial, 670 patients with imatinib-resistant or imatinib-intolerant CML-CP were randomized to receive 1 of 4 doses of dasatinib: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily.…”

“…69 Results from phase 2 trials led to the approval of dasatinib in the United States, the European Union, and other regions for use in imatinib-resistant CML. [70][71][72][73] In SRC/ABL Tyrosine Kinase Inhibition Activity Research Trial C (or the START-C trial), dasatinib was administered at 70 mg twice daily to 387 patients who had CML-CP and resistance (n ¼ 288) or intolerance (n ¼ 99) to imatinib. 70 After a median follow-up of 15.2 months, 91% of patients achieved a CHR, 59% achieved an MCyR, and 49% achieved a CCyR.…”

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

“…112 When grouped together, the presence or absence of an Abl kinase mutation did not appear to influence the rates of CHR or MCyR in imatinib-resistant patients receiving dasatinib in the previously published START trials. 36,105 However, specific mutations appear to be differentially resistant to dasatinib both in vitro, as well as in vivo. Jabbour and colleagues also recently demonstrated equivalent response rates to second-generation TKIs when imatinib-resistant patients were grouped according to the presence or absence of a mutation.…”

“…36 The START-C trial also evaluated dasatinib in 288 imatinib-resistant patients, and demonstrated that 85% of patients had achieved a new CHR, 51% obtained a new MCyR and 40% had achieved a new CCyR, corroborating the results from the START-R trial. 105 Nilotinib has also been evaluated in several trials for patients with imatinib-resistant CP-CML. Kantarjian and colleagues 106 reported on approximately 220 imatinib-resistant CP-CML patients receiving nilotinib 400 mg twice daily, and after a median follow-up of 19 months, 56% achieved a McyR, whereas 41% obtained a CCyR.…”