US Intergroup Study of Chemotherapy Plus Dasatinib and Allogeneic Stem Cell Transplant in Philadelphia Chromosome Positive ALL

Abstract

This multicenter trial was conducted to determine whether the addition of dasatinib to chemotherapy followed by an allogeneic hematopoietic cell transplant (HCT) in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was feasible. Patients ≥ 18 and ≤ 60 years of age with newly diagnosed Ph+ ALL received up to 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate with dasatinib. Patients with an available matched sibling or unrelated donor underwent an allogeneic HCT in first complete remission (CR1) followed by daily dasatinib starting from day 100. Others received maintenance therapy with vincristine and prednisone for 2 years and dasatinib indefinitely. 97 patients (94 evaluable) with median age of 44 years (range, 20 - 60) and median WBC at presentation of 10 × 109/L (range, 1 - 410 × 109/L) were accrued. 83 (88%) patients achieved CR or CR with incomplete count recovery (CRi) and 41 underwent ASCT in CR1. Median follow-up is 36 months (range, 9 - 63). For the overall population, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) at 3 years were 69%, 55%, and 62%, respectively. The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 175 days from the time of CR/CRi (longest time to HCT), showed statistically superior advantages for RFS and OS (p=0.038 and 0.037, respectively) for the transplanted patients. Addition of dasatinib to chemotherapy and HCT for younger patients with Ph+ ALL is feasible and warrants further testing.

Conflict of interest statement

CONFLICT OF INTEREST DISCLOSURES No COI information to disclose: Partow Kebriaei, Laura Kinsbury, Richard Little, Janis Racevskis, Naoko Takebe, Honoraria: Uma Borate, self, Alexion, Novartis, Amgen; Elisabeth Paietta, self, Amgen; Susan O’Brien, self, Gilead, Pharmacyclics, Janssen; Jerald Radich, self, Novartis, BMS, Ariad; Farhad Ravandi, self, BMS, Ariad; Martin Tall, self, St. Vincent’s Hospital, Hartford Hospital, Lundbeck Canada; Jeffrey Wong, self, Accuray, Inc. Consulting or Advisory Role: Fred Appelbaum, self, Igenica, Amgen, Pfizer, Neumedicine, Celator; Uma Borate, self, Alexion, Novartis, Suneisis; Harry Erba, self, Novartis, Incyte, Celgene, Amgen, Ariad, Seattle Genetics, Sunesis, Pfizer, Janssen, Daiichi Sankyo; Megan Othus, self, Glycomemetics, Celgene (DSMB both); Elisabeth Paietta, self, Amgen; Susan O’Brien, self, Amgen, Celgene, CLL Global Research Foundation, GSK; Jerald Radich, self, Novartis, BMS, Ariad; Farhad Ravandi, self, Ariad; Martin Tallman, self, Bioline, Biosight, Agios; Travel, Accommodations, Expenses: Uma Borate, self, Novartis, Alexion, Amgen and Jazz (as part of speakers’ bureau); Elisabeth Paietta, self, Amgen; Susan O’Brien, self (company pending); Mary Horowitz, self, Novartis; Jerald Radich, self, Novartis, BMS; Jeffrey Wong, self, Accuray, Inc. Research Funding: Harry Erba, institution, Celator, Millennium/Takeda, Seattle Genetics, Astellas, Amgen, Agio, Juno, Janssen; Mary Horowitz, self, Sobi Pharmaceuticals; Hagop Kantarjian, institution, Ariad, BMS, Pfizer, Amgen, Novartis; Jerald Radich, self, Novartis; Susan O’Brien, self/institution, Acerta, TG Therapeutics, Regeneron, Gilead, Pharmacyclics, ProNAi; Farhad Ravandi, self/institution, BMS; Martin Tallman, self, Bioline, Epizyme, Arog; Jeffrey Wong, institution, Accuray, Inc. Speakers’ Bureau: Uma Borate, self, Novartis, Alexion, Amgen and Jazz; Harry Erba, self, Novartis, Incyte, Celgene; Stock or Other Ownership: Fred Appelbaum, self, Adaptive Biotechnology; Patents, Royalties, Other Intellectual Property: Chul Ha, self, has patents but no royalty arrangements (patents held by Dr. Chul and his institution) Other Relationship: Harry Erba, self, Gyclomemetics Inc., (DSMB Chair)

Figures

Graphical abstract

Figure 1.

Treatment regimen. (A) Original regimen. Dasatinib was administered at 100 mg daily for the first 14 days of each of the consolidation cycles. (B) Modified regimen after amendment. The dasatinib dose was modified to 70 mg orally daily continuously from course 2 onward during the consolidation cycles. MTX, methotrexate.

Figure 2.

Patient disposition and response. SCT, stem cell transplant.

Figure 3.

Survival outcomes. (A) Event-free survival for the whole cohort. (B) Relapse-free survival for the whole cohort. (C) Overall survival for the whole cohort. (D) Relapse-free survival in patients with no protocol transplant in first remission. (E) Overall survival in patients with no protocol transplant in first remission.

Figure 4.

Outcomes with protocol-specified HCT. (A) Relapse-free survival after protocol-specified HCT. (B) Overall survival after protocol-specified HCT. (C) Relapse free survival; landmark analysis HCT versus no HCT, in favor of HCT; hazard ratio (HR) 0.42, 95% CI (0.18-0.97). (D) Overall survival; landmark analysis HCT versus no HCT, in favor of HCT; HR 0.35, 95% CI (0.12-0.97).

Figure 5.

Toxicity. (A) Grades 3 and 4 adverse events during induction/consolidation cycles. (B) Adverse events during maintenance cycles. GI, gastrointestinal; LFT, liver function tests; NV, nausea and vomiting.