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1935 Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
Leukemia, ALL, Diseases, Non-Biological, Therapies, chemotherapy, Lymphoid Malignancies
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Philip C. Amrein, MD1, Karen K. Ballen, MD2, Kristen E. Stevenson, MS3*, Traci M. Blonquist, MS4*, Andrew M. Brunner5*, Gabriela S. Hobbs, MD6, Hanno R. Hock, MD, PhD7*, Steven L. McAfee, MD8*, Jenna A. Moran, NP6*, Meghan Bergeron, NP6*, Julia E. Foster, NP6*, Christina Bertoli, NP6*, Kristin McGregor6*, Molly Macrae6*, Meghan Burke6*, Tanya T. Behnan, BS6*, Tina T. Som, RN6*, Aura Y. Ramos, RN6*, Megan K. Vartanian, RN6*, Jennifer Lombardi Story6*, Christine Connolly6*, Timothy A. Graubert, MD9, Donna S. Neuberg, ScD3 and Amir T. Fathi10

1Leukemia Center/MGH Cancer Center, Massachusetts General Hospital, Belmont, MA
2Division of Hematology/Oncology, University of Virginia Health Center, Charlottesville, VA
3Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
4Data Science, Dana-Farber Cancer Institute, Boston, MA
5Center for Leukemia, Massachusetts General Hospital, Boston, MA
6Leukemia Center, Massachusetts General Hospital, Boston, MA
7Leukemia Center, Massachusetts General Hospital / Harvard Medical School, Boston, MA
8Massachusetts General Hospital, Blood and Marrow Transplant Program, Boston, MA
9Leukemia Center, Massachussets General Hospital, Charlestown, MA
10Leukemia Center, Massachusetts General Hospital, Center for Leukemia, Cambridge, MA

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL.

Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt’s) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1.

A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial.

After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table.

Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT’s: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%].

Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission.

Disclosures: Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs: Incyte: Research Funding; Bayer: Research Funding; Merck: Research Funding; Constellation: Honoraria, Research Funding; Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Neuberg: Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi: Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Agios: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Kite: Consultancy; Celgene / BMS: Consultancy, Research Funding; Novartis: Consultancy; Boston Biomedical: Consultancy; PTC Therapeutics: Consultancy; Trovagene: Consultancy; Takeda: Consultancy, Research Funding; Genentech: Consultancy; Blueprint: Consultancy; Pfizer: Consultancy; NewLink Genetics: Consultancy; Forty Seven: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy.

OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

*signifies non-member of ASH