A Phase IB Study of Blinatumomab (blina) in Patients with B Cell Acute Lymphoblastic Leukemia (ALL) and B-Cell Non-Hodgkin Lymphoma (NHL) As Post-Allogeneic Blood or Marrow Transplant (allo-BMT) Remission Maintenance
Authors: Webster Jonathan , Ambinder Richard F. , Jones Richard J. , Wagner-Johnston Nina D. , Prince Gabrielle T. , Shedeck Audra , Blackford Amanda , Luznik Leo , Gojo Ivana 
Published: February 2020

Background: AlloBMT can be curative as consolidation for high risk B ALL and NHL. However, long term survival is limited by transplant-related toxicity and particularly by disease relapse. Post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis limits GVHD and facilitates the use of alternative allograft sources. Moreover, following PTCy, cellular immune reconstitution is favorable for the integration of strategies to augment anti-tumor immunity. Blina, a CD19/CD3 bispecific T cell engager antibody construct, is effective in the treatment of CD19+ ALL and NHL. Blina leads to T cell activation that may enhance established posttransplant tumor-specific T cell responses, leading to a more potent graft-versus-tumor effect. Thus, we have undertaken a phase Ib trial to assess the tolerability and preliminary efficacy of blina as post-alloBMT remission maintenance in B-cell ALL and NHL.
Methods: Patients ³18 years-old with high risk CD19+ B ALL or NHL who underwent alloBMT using PTCy were eligible including those with prior blina exposure. Patients had to be 60-180 days from transplant with documented count recovery and no evidence of disease progression. Patients had to be off all post-transplant immunosuppression including steroids for the treatment of GVHD for ≥4 weeks prior to treatment initiation, and without a history of grade ≥3 acute GVHD or severe chronic GVHD. Patients could receive two cycles of blina if they had evidence of disease (including MRD) at their pre- and/or post-transplant evaluations but otherwise received only one cycle. Blina was given as a continuous infusion at 9 mcg/day on C1D1-7 and 28 mcg/day on C1D8-28 and C2D1-28.
Results: As of July 23, 2019, 12 adults (10 males/2 females) have enrolled including 4 patients with B ALL and 8 patients with NHL. Among the B ALL patients, two with known TP53 mutations were transplanted in CR1, while two with relapsed disease were transplanted in CR3. Among the NHL patients, five had large cell transformation (3 from follicular and 2 from CLL); one had relapsed primary CNS lymphoma (PCNSL); one had relapsed mantle cell lymphoma (MCL); and one had diffuse large B cell lymphoma (DLBCL). The median age was 53 (range, 30-73). All patients underwent alloBMT using a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation (TBI). Eight patients received allografts from haploidentical donors, three from matched-unrelated donors, and one from a matched-related donor. Five patients received peripheral blood allografts, and seven bone marrow. Two patients were enrolled after a second alloBMT, and 3/4 ALL patients previously received blina. Baseline characteristics are presented in Figure 1. Patients started blina a median of 144 days post-transplant (range, 90-180). One patient stopped treatment on day 5 due to a grade 2 tremor, and one patient required dose reduction on day 25 due to grade 4 neutropenia. Toxicities were otherwise mild and are presented in Figure 2. There were no exacerbations of GVHD. At a median follow-up of 13.7 months after BMT (range 3.8-23 months), ten patients remain in remission, while one patient suffered a third CNS relapse of ALL at 20.6 months after his 2nd transplant and another had relapse of his transformed lymphoma. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented.
Conclusions: Post-alloBMT maintenance therapy with blina is feasible with minimal toxicity. 83% of the very high risk patients treated on study remain in CR at a median of 13.7 months post-transplant. Based on promising safety and efficacy data from the phase IB, the plan is to proceed to the phase II portion of the study.

Disclosures
Webster: Amgen: Consultancy; Genentech: Research Funding; Pfizer: Consultancy. Wagner-Johnston:Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents & Royalties: Patent holder. Gojo:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Research Funding; Jazz: Consultancy, Honoraria; Amgen Inc: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Amphivena: Research Funding.

OffLabel Disclosure:
Blinatumomab is not labeled for use as post-transplant maintenance therapy or for use in the non-Hodgkin lymphoma.