HyperCVAD Plus Dasatinib Effective in Patients with Ph+ ALL or CML-LB
SAN DIEGO, CA—Combining the hyperCVAD regimen with dasatinib, a dual Scr and BCR-ABL kinase inhibitor, is effective in patients with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myeloid leukemia in the lymphoid blast phase (CML-LB), according to investigators at the 53rd American Society of Hematology Annual Meeting and Exposition.
Since the introduction of tyrosine kinase inhibitors (TKIs), the prognosis for patients with Ph+ ALL has improved significantly. The TKI dasatinib is approximately 325 times more potent than imatinib against BCR-ABL kinase and has shown activity in patients with resistance or intolerance to imatinib, both in those with Ph+ ALL and CML.
In this study, Theresa Liu-Dumlao, MD, University of Texas MD Anderson Cancer Center, Houston, and colleagues sought to evaluate the efficacy and safety of dasatinib when used in combination with the hyperCVAD regimen in prolonging disease-free survival and overall survival in patients with relapsed Ph+ ALL or CML-LB.
Beginning in September 2006, investigators enrolled patients ≥18 years with relapsed Ph+ ALL or CML-LB, no prior dasatinib exposure, no documented significant effusions, and ECOG performance status ≤2. Patients received dasatinib 100mg orally daily Days 1–14 for eight cycles in combination with alternating cycles of standard hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) or high-dose cytarabine with methotrexate. Concomitant rituximab was administered on Days 1 and 11 of Cycles 1–4. On August 2009, the dosing regimen for dasatinib was modified to dasatinib 100mg Days 1–14 of Cycle 1, followed by dasatinib 70mg daily for all subsequent cycles. Once in complete remission (CR), patients received 24 months of maintenance treatment of dasatinib 100mg/day (modified to 70mg/day after August 200) with vincristine 2mg/month and prednisone 200mg orally Days 1–5 every month. As soon as it was feasible, patients proceeded to an allogeneic stem cell transplant.
To date, 32 patients with relapsed Ph+ ALL (n=18) or CML-LB (n=14) have received a median of three cycles (range 1–8) of treatment, 23 on the initial regimen and nine on the modified version. Median age is 50 years (range 21–77). Median number of prior treatment regimens was one (range 1–2), which included hyperCVAD + imatinib in 10 patients (three had transplant in first CR), other combination chemotherapy in 12, monotherapy with TKI other than dasatinib in eight, and investigational agents in two patients. Pre-treatment ABL mutations were documented in nine patients and included: T315 (n=4), Y253F (n=4), Y253H (n=4), F359V (n=1), E459K (n=1), E255K (n=1), F317L (n=3), M351T (n=1).
At treatment initiation, median white blood cell count was 9.8x109/L (range 0.3–295.5). Median bone marrow blast percentage was 72% (range 0–97; one patient had solitary CNS relapse). Eight patients (25%) had CNS involvement. Pretreatment ABL mutations noted in nine patients included: T315I (n=4), Y253F (n=1), Y253H (n=4), F359V (n=1), E459K (n=1), E255K (n=1), F317L (n=3), M351T (n=1).
Overall response rate was 94%; 23 patients (72%) achieved CR and 7 (22%) had a CR with incomplete platelet recovery (CRp). One patient died during induction and one patient had progressive disease. Twenty-five patients (83%) achieved complete cytogenetic remission after one cycle of therapy. Overall, 13 patients (43%) achieved complete molecular response, and 10 (33%) major molecular response (ie, BCR-ABL/ABL <0.1%). Nine patients proceeded to allogeneic transplantation, two with Ph+ ALL and seven with CML-LB; one patient with Ph+ ALL who had previously been transplanted received donor lymphocyte infusion. Complete overall minimum residual disease response by BCR-ABL was observed in 47% and 38% of patients with Ph+ ALL and CML-LB, respectively.
Grade 3/4 toxicities were gastrointestinal and genitourinary bleeding, and subdural hematomas; pleural and pericardial effusions; infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and hyperbilirubinemia. Nine deaths have occurred following disease relapse after transplant, during induction, or due to inadequate response of infectious complications.
Median follow-up for patients is 27 months (range 6–52). Fourteen patients are currently alive with 10 patients in CR/CRp. Three-year overall survival (OS) is 76% (median not reached); 82% of patients remain in CR at three years (median CR duration not reached). For patients with Ph+ ALL, median follow-up was 139 weeks (range 74–175). In this group, three-year OS is 33% (median, 42 weeks); 30% remain in CR at three years (median CR duration, 38 weeks). Outcomes were the same for patients with CML-LB whether or not they received a transplant; three-year OS was 83% for both cohorts. Among patients with ALL, outcome was better for those who underwent transplant (two of two alive at three years vs four of 16 without transplant).
Study investigators concluded that the combination of hyperCVAD with dasatinib is effective in patients with relapsed Ph+ALL and CML-LB.