First-Line Dasatinib Plus Conventional Chemotherapy in Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): Interim Analysis of the Korean Prospective Phase II Study

Front-line combination of imatinib with conventional chemotherapy has demonstrated an improved complete remission (CR) rate, an increased transplantation proceeding rate with CR, and a better survival in adults with Ph+ ALL. However, in the light of disease aggressiveness and recurrence, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant mutations, an improved strategy to induce more effective leukemic cell clearance is clearly needed. Dasatinib, a potent dual BCR-ABL/SRC family kinase inhibitor, has been shown to be effective in patients with imatinib-resistant chronic myeloid leukemia and Ph+ ALL.

We present the first interim results of the Korean prospective phase II study protocol designed to evaluate the clinical efficacy of first-line dasatinib plus conventional chemotherapy for adults with newly diagnosed Ph+ ALL. This study is registered at www.ClinicalTrials.gov as NCT01004497. The protocol is designed for 51 patients, and recruitment started in March, 2010. The protocol enrolls patients (15–65 years) who receive dasatinib (100 mg once daily for 4 weeks) as an alternative schedule after each conventional chemotherapy course (alternating modified hyper-CVAD and high-dose cytarabine/mitoxantrone). Patients in CR who have a suitable related/unrelated donor undergo allogeneic transplantation as early as possible (depending on the speed of coordination process). Patients without a donor continue to receive dasatinib plus conventional chemotherapy (up to 4 courses; depending on the patient's tolerability) followed by dasatinib maintenance therapy (100 mg once daily for up to 2 years). Minimal residual disease monitoring for BCR-ABL transcript is centrally evaluated by real-time quantitative PCR (4.5 log sensitivity) through handling of bone marrow samples from all patients (Research Institute of Molecular Genetics, The Catholic University of Korea, Seoul, Korea).

A total of 36 patients have been enrolled to date. Of these, 3 patients are receiving the first dasatinib cycle (too early); 3 patients died before starting the first dasatinib cycle from infections. Thus, 30 patients are evaluable for assessment of response to dasatinib plus conventional chemotherapy. Median age was 47 years (range, 19 to 64 years). Karyotype analysis revealed additional chromosomal changes in 18 (60%) of the 30 patients. Twenty patients (67%) had m-BCR transcript. All patients (100%) have achieved CR with a decrease in the minimal residual disease by the first dasatinib cycle, and of these, 13 patients (43%) have achieved major molecular response [MMR; including 5 complete molecular response (CMR^4.5)]. By the second dasatinib cycle, 25 patients (83%) have achieved MMR (including 11 CMR^4.5). So far, no dasatinib-related serious adverse events (≥grade 3 toxicity) have been observed. Twenty-four (80%) of the 30 patients have undergone allogeneic transplantation in CR; 6 patients are receiving continuous dasatinib plus conventional chemotherapy in CR. With a median follow-up duration of 10 months (range, 5 to 17 months), 25 patients are at present alive in continuous CR, and 4 patients have died (2 infections during consolidation chemotherapy, 2 transplant-related complications). Only 1 patient who failed to achieve MMR has relapsed at 11 months from diagnosis (at 5 months after allogeneic transplantation). The estimated probabilities of disease-free survival and overall survival at 1 year were 76% and 83%, respectively.

Our interim analysis indicates that first-line combination of dasatinib with conventional chemotherapy appears to be effective in achieving a good quality of molecular response (MMR/CMR^4.5) in adults with Ph+ ALL. Whether this would translate to an improved long-term survival remains to be investigated.

Lee:Bristol Myers Squibb: Honoraria, Research Funding. Kim:Bristol Myers Squibb: Honoraria, Research Funding.