Key Points Adult patients with ETP-ALL/LBL have poor long-term outcomes. Novel therapies are urgently needed for adult patients with ETP-ALL/LBL.

The combination of cytotoxic chemotherapy and imatinib has improved the outcome for patients with Philadelphia chromosome-positive (Ph ؉ ) acute lymphoblastic leukemia (ALL). Dasatinib has significant clinical activity in patients with imatinib resistance. We examined the efficacy and safety of combining chemotherapy with dasatinib for patients with Ph ؉ ALL. Newly diagnosed patients received dasatinib 50 mg by mouth twice per day (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyper-CVAD, and high-dose cytarabine and methotrexate. Patients in complete remission received maintenance daily dasatinib and monthly vincristine and prednisone for 2 years, followed by dasatinib indefinitely. Thirty-five patients with untreated Ph ؉ ALL with a median age of 53 years (range, 21-79 years) were treated; 33 patients (94%) achieved complete remission. Two patients died of infections before response assessment. Grade 3 and 4 adverse events included hemorrhage and pleural and pericardial effusions. With a median follow-up of 14 months (range, 4-37 months), the median disease-free survival and median overall survival have not been reached, with an estimated 2-year survival of 64%. The combination of chemotherapy with dasatinib is effective in achieving long-term remissions in patients with newly diagnosed Ph ؉ ALL. This study was registered at www.ClinicalTrials.gov as

Background The long-term efficacy of combination of chemotherapy with dasatinib in patients with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is not well-established. Methods Patients received dasatinib with 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in complete remission (CR) continued maintenance dasatinib, vincristine and prednisone for 2 years followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplant (SCT) received it in first CR. Results 72 patients with a median age of 55 years (range 21 – 80) were treated; 69 (96%) achieved CR. Among them, 57 (83%) achieved cytogenetic (CG) CR after 1 cycle and 64 (93%) achieved a major molecular response (MMR) at a median of 4 weeks (range, 2 – 38 weeks). Minimal residual disease by flow cytometry was negative in 65 (94 %) patients at a median of 3 weeks (range, 2–37). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. With a median follow-up of 67 months (range, 33–97), 33 patients (46%) are alive and 30 (43%) are in CR; 12 underwent an allogeneic SCT. Thirty nine patients have died (3 at induction, 19 after relapse, 7 post SCT performed in CR1, and 10 in CR). The median disease free and overall survival are 31 months (range, 0.3 to 97) and 47 months (range, 0.2 to 97). Seven relapsed patients had ABL mutations including 4 T315I. Conclusion Combination of chemotherapy with dasatinib is effective in achieving long-term remissions in patients with newly diagnosed Ph+ ALL.

A B S T R A C T PurposeRelapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated highdose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and MethodsSixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m 2 , without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). ResultsThe CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single-and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). ConclusionHigh-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.