Results of SWOG 1318: A Phase 2 Trial of Blinatumomab Followed By Pomp (Prednisone, Vincristine, Methotrexate, 6-Mercaptopurine) Maintenance in Elderly Patients with Newly Diagnosed Philadelphia Chromosome Negative B-Cell Acute Lymphoblastic Leukemia

The prognosis of elderly patients (pts) with acute lymphoblastic leukemia (ALL) remains poor, and novel therapeutic approaches are clearly needed. CD19 is expressed on the majority of precursor-B ALLs and represents an attractive therapeutic target. The anti-CD19 bi-specific engager antibody blinatumomab has demonstrated significant activity in both relapsed/refractory ALL and minimal residual disease (MRD) positive ALL. Therefore, we evaluated blinatumomab as a single agent in the upfront treatment of newly diagnosed elderly pts with Philadelphia chromosome (Ph) negative B-lineage ALL to determine response rates and overall survival (OS).

Methods: Pts were treated at National Clinical Trial Network sites from June 2015 to September 2017. The primary objective of the study was to estimate 3-year OS. An IND was approved by the FDA and the protocol was approved by a central institutional review board. Eligibility: age > 65 years, newly diagnosed Ph negative B-lineage ALL with adequate organ function and no evidence of central nervous system (CNS) disease. Pts received blinatumomab for induction at standard dosing for 1-2 cycles until attainment of complete response (CR) or CR with incomplete count recovery (CRi) (defined below). Pts then received 3 cycles of blinatumomab post-remission therapy followed by 18 months of maintenance POMP (prednisone, vincristine, 6-mercaptopurine, methotrexate). A total of 8 doses of intrathecal methotrexate were administered as CNS prophylaxis. Cytogenetic risk was ascribed by NCCN 2018 criteria and bone marrow samples were analyzed for the presence of the Ph-like signature. MRD was assessed centrally by 8 color flow cytometry pre-treatment, on Day 35 of induction cycle 1, and on Day 35 of re-induction (if applicable). Response was assessed at the completion of 1-2 cycles of blinatumomab. CR was defined as < 5% marrow blasts with no evidence of extramedullary disease and recovery of counts [absolute neutrophil count (ANC) > 1000/uL, platelets >100,000/uL]. CRi was defined the same as CR but ANC < 1000/ uL and/ or platelets ≤ 100,000/ uL. OS was measured from day of registration on trial until the date of death. Disease-free survival (DFS) was measured from the date the pt achieved CR/ CRi until relapse or death. Toxicities were graded according to NCI CTCAE version 4.0.

Results: Of 31 pts enrolled, 29 were eligible. The median age was 75 years (range 66 - 84), 22 (76%) were male, median baseline white blood count was 3.7 x 10³/uL (range 0.3 - 7,100), and median bone marrow blast count percentage was 86.5% (range 30-100). Three pts received hydroxyurea or steroids prior to treatment initiation. Cytogenetic risk at diagnosis was: poor (34% of pts; n=10), standard (55% of pts; n=16), good (3% of pts; n=1) and unknown (7% of pts, n=2). Testing for the Ph-like signature is being completed. The most common Grade 3-5 non-hematologic toxicities related to treatment during induction were hyperglycemia (14%), dyspnea (10%), febrile neutropenia (10%), hypertension (10%), and lung infection (7%). One pt developed Grade 3 cytokine release syndrome and 1 developed Grade 3 neurotoxicity. No pts died during the first 28 days of treatment. The overall response rate (CR + CRi) was 66% (all CRs). Thirteen of the 19 responders have available MRD data post-treatment. Of these, 12 pts (92%) achieved MRD negativity, all at Cycle 1 Day 35. One pt required 2 cycles of blinatumomab to achieve CR. One pt proceeded to allogeneic hematopoietic stem cell transplant. The median follow-up time is 1 year and median duration on trial is 170 days (6 pts are still on maintenance therapy). OS estimated by Kaplan Meier at 6 months is 79% (95% CI 58%-90%) and at 1 year is 65% (95% CI 43%-80%). DFS estimated at 6 months is 68% (95% CI 43%-84%) and at 1 year is 56% (95% CI 31%-75%). No baseline features including CD19 expression (by percentage or mean-fluorescent intensity) or presence of a CD19 negative subpopulation were associated with response.

Conclusions: Blinatumomab was well tolerated and effective in the treatment of newly diagnosed elderly patients with Ph negative B-lineage ALL. Further follow up will determine the durability of these responses.