Concurrent Use of Blinatumomab and Donor Lymphocyte Infusion (DLI) for Treatment of Relapsed Precursor B Cell Acute Lymphoblastic Leukemia (pre B ALL) after Allogeneic Hematopoietic Cell Transplant (HCT)

Abstract

Adults with relapsed pre B ALL after allogeneic HCT historically have poor prognosis, but new therapies may improve outcomes. Blinatumomab is a bispecific engager anti-CD19/CD3 antibody that simultaneously binds cytotoxic T cells and CD19+ normal and malignant B cells. Each cycle consists of a 4-week continuous infusion. Blinatumomab engages endogenous T cells and is usually used as a bridge to HCT; however in the post-HCT setting donor T cells are engaged. DLI used for treatment of ALL relapse after transplant exerts modest effect, and we hypothesized that co-administration of blinatumomab and DLI may have synergistic anti-leukemic activity. We report 2 cases of relapsed Philadelphia chromosome (Ph) negative pre B ALL after HCT treated concurrently with blinatumomab and DLI. Case 1: A 35 year-old woman with pre B ALL received a matched related donor peripheral blood HCT in first remission using clofarabine and busulfan preparative regimen. Marrow relapse occurred 136 days after HCT with 24% donor chimerism. She received salvage chemotherapy with 2 DLI (5 x 107 CD3 cells/kg each) but had persistent disease (7% marrow blasts and 99% donor chimerism). Blinatumomab was subsequently started. After 2 cycles marrow showed complete hematologic remission, 98% donor chimerism and persistent cytogenetic abnormality. Third and fourth DLI were given on day 15 of the third and fourth cycles of blinatumomab. No adverse effects were noted during lymphocyte infusion. There was no exacerbation of the mild chronic skin GVHD present prior to the third cycle of blinatumomab. Extramedullary relapse in a CD19+ sacral mass was discovered 1 month after cycle 4 of blinatumomab, successfully treated with radiation. Patient currently has second extramedullary ALL relapse with a CD19- lung mass (16 months after HCT and 11 months after first relapse) with no ALL in the marrow and 100% donor chimerism. Case 2: A 71 year-old woman with Ph-negative pre B ALL received reduced intensity conditioning matched unrelated donor peripheral blood HCT in second remission using fludarabine, 2 Gy TBI and ATG as preparative regimen. She developed flow cytometry and cytogenetic relapse 106 days after HCT with 97% donor chimerism. Blinatumomab was started and DLI (1 x 107 CD3 cells/kg) was given on day 2 of cycle 3 of blinatumomab without adverse events. She developed grade 3 late onset acute skin and gut GVHD 15 days after completion of cycle 3 of blinatumomab which was successfully treated with corticosteroids. No further cycles of blinatumomab or DLI were given and she remains in complete remission for 6 months. Co-administration of DLI and blinatumomab appears to be safe with no acute adverse effects observed in 2 patients. Dual therapy resulted in anti-leukemia effect in both cases of pre B ALL relapsed after HCT. A larger series is needed for further investigation of the safety and efficacy of this approach.