Phase II Study of Combination of hyperCVAD with Dasatinib in Frontline Therapy of Patients with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)
Authors: Ravandi Farhad , Thomas Deborah , Kantarjian Hagop , Faderl Stefan , Koller Charles , Dara Samuel , Garris Rebecca , Kebriaei Partow , Borthakur Gautam , Wierda William , Burger Jan , Cortes Jorge , O’Brien Susan 
Published: April 2020

Abstract
Background: Combination of cytotoxic chemotherapy with imatinib has improved the outcome for patients with Ph+ ALL with durable remissions in some patients without an allogeneic stem cell transplant. The dual Src and Abl inhibitor dasatinib has significant clinical activity in patients with imatinib-resistant lymphoid blast phase CML and Ph+ ALL.
Methods: In this phase II trial, patients with newly diagnosed Ph+ ALL receive dasatinib 50 mg po bid (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine plus methotrexate. Patients (pts) in CR continue to receive maintenance dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. Minimal residual disease (MRD) monitoring is conducted and patients may receive early and late intensifications depending on their MRD status.
Results: To date 22 pts with untreated Ph+ ALL and 6 pts with 1 prior cycle of chemotherapy (before Ph+/BCR-ABL+ status was known) have received a median of 6 cycles (range 1–8); 9 pts are receiving maintenance in CR. Median age is 52 years (range 21 – 79); 16 pts were older than 50 years. Median WBC at diagnosis was 20.5 ×109/L (range, 1.6 –275 × 109/L). 5 pts had CNS involvement at presentation. All pts are evaluable for assessment of response; 26 (93%) achieved CR after 1 cycle. Two pts died before response assessment from infections; in both pts, bone morrow exam on day 14 showed no detectable disease. Twenty one of 26 (81%) evaluable pts achieved cytogenetic (CG) CR after 1 cycle; 2 had a major CG response (5% and 15% Ph+), 2 had insufficient metaphases, and one is unknown (no CG exam on day 21 marrow); 1 pt developed a pseudodiploid clone. To date, 14 pts (50%) have achieved complete molecular remission (CMR) and 5 (18%) have achieved a major molecular response (MMR) at a median of 10 weeks from initiation of treatment (range 2 – 46 weeks). MRD assessment by flow cytometry is negative in 22 (85%) pts at a median of 3 weeks (range, 2–17 weeks). The median time to neutrophil and platelet recovery for cycle 1 is 18 and 23 days and for subsequent cycles is 15 and 20 days, respectively. Grade ≥3 toxicity has included 13 episodes of bleeding (8 GI, 2 GU, 1 soft tissue hematoma and 2 subdural hematomas), 3 episodes of pleural effusions, infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and reversible rise in creatinine unrelated to treatment. With a median follow up of 10 months (range, 2–21), 21 pts are alive and 18 are in CR; 2 died at induction, 3 pts died in CR; 1 from an unrelated cardiac event and 2 from infections. 5 pts have relapsed (response durations were 54, 48, 47, 32, and 22 weeks) and 2 of them have died. In 2 pts morphological relapse was preceded by flow and molecular relapse. Four relapsed pts developed new ABL mutations (3 T315I and 1 F359V). One patient has undergone an allogeneic stem cell transplant.
Conclusions: The combination of hyperCVAD with dasatinib is effective in achieving molecular remissions in patients with Ph+ ALL. There is a high incidence of T315I ABL mutation among the relapsed patients.