Concomitant Use of Blinatumomab and Donor Lymphocyte Infusion for Post-Transplant Relapsed CD19 Positive Acute Lymphoblastic Leukemia: Systematic Review
Authors: Durer Ceren , Durer Seren , Shafqat Madeeha , Shah Zunairah , Sadiq Maryam , Fraz Muhammad Asad , Ahmad Malik Qistas , Fazeel Hafiz Muhammad , Samuel Sharoon , Malik Mustafa Nadeem , Lakhani Midhat , Sohail Chaudhry Saad , Qureshi Anum , Anwer Faiz 
Published: October 2019

Abstract
Background: Treatment for post-transplant relapsed/refractory acute lymphoblastic leukemia (R/R-ALL) is not well defined. A majority of ALL relapses occur within two years after allogeneic stem cell transplantation (allo-SCT). Blinatumomab, an anti-CD19/CD3 bispecific antibody, exerts cytotoxic activity leading to apoptosis of CD19 positive B cells. Blinatumomab and DLI combination therapy is a promising new concept in cancer treatment, whereby blinatumomab might achieve an initial reduction in ALL tumor burden using T-cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission.
Methods: Literature search was performed using PubMed, EMBASE, Cochrane and Web of Science databases up to 3 July 2018. MeSH terms and keywords of blinatumomab, DLI and ALL were used.
Results: Comprehensive search retrieved over 150 articles. After exclusion criteria were applied, three studies (n=15 patients) met our inclusion criteria. We summarized data on 15 patients (table 1). Outcomes were not reported homogeneously. Two studies (Ueda, M. et al. 2016; Paul, S. et al. 2017) reported CR in months and one study (Bondarenko, SN. et al. 2017) reported the response rate (RR). Before starting blinatumomab therapy, 12 patients had post-transplant bone marrow relapse, 1 patient had an extramedullary relapse and 2 patients had a minimal residual disease (MRD) without marrow relapse. Total cycles of blinatumomab ranged from 2 to 4. Total cycles of DLI ranged from 1 to 2 given after at least one cycle of blinatumomab. DLI was mostly given with blinatumomab during cycle 3 (ranged from cycle 2 to cycle 4). Blinatumomab doses were not uniformly reported. DLI doses varied between 1x107 and 5x107. Complete remission (CR) with MRD negative status was achieved after 2 cycles of blinatumomab in 3 patients, 2 of them remained in CR for 7 and 13 months. One patient achieved CR and negative MRD status 7 months after initiation of blinatumomab (total cycles of combination therapy=2). Ten patients who had median number of 2 cycles of blinatumomab showed RR of 70%. Grade I acute skin GVHD was reported in one patient during the cycle 3 of blinatumomab before the first combination therapy. One patient developed grade II aGVHD after the combination therapy (cycles were not reported). One patient developed GVHD involving mouth and skin during the second cycle of combination therapy (cycle 3). Grade 3 late-onset acute skin and gut GVHD were reported in one patient after the first dual therapy (cycle 3). No fatalities were observed with combination therapy. Therapy was stopped in one patient who had isolated central nervous system (CNS) relapse detected in the cerebral spinal fluid and orbit following allo-SCT; the patient was treated with intrathecal chemotherapy and radiation. One patient died of extramedullary and hematologic relapses seen at 6 and 11 months after initiating blinatumomab, respectively. This patient previously had a marrow relapse before starting therapy. One patient having an extramedullary disease progressed despite blinatumomab and DLI.
Conclusion: Blinatumomab and DLI combination therapy appears to be safe and effective, specially for patients with MRD positive status after stem cell transplantation. Large prospective studies are required to completely understand the efficacy and safety of this combination therapy.

Disclosures
No relevant conflicts of interest to declare.