Daratumumab in Combination with Vincristine or Nelarabine As Effective Salvage Therapy for Patients with Acute Lymphoblastic Leukemia at High Risk of Relapse
Authors: Ofran Yishai , Ganzel Chezi , Harlev Shimrit , Slouzkey Ilana , Beyar Katz Ofrat , Hayun Michal , Kharit Mira , Rowe Jacob M. , Frisch Avraham 
Published: October 2019

Abstract
Acute lymphoblastic leukemia (ALL) relapsing after allogeneic stem cell transplantation (allo-SCT) is usually associated with poor outcome. T-ALL patients relapsing early post-allo-SCT or relapsed B-ALL patients who have failed currently available targeted and immunotherapies need an effective salvage therapy.
We herein describe 3 cases where minimal residual disease (MRD) negative remission was achieved in very high-risk relapsing ALL patients with the use of daratumumab with or without nelarabine.
Patient 1: A 24-year-old male diagnosed in May 2016 with T lymphoblastic lymphoma. Following ECOG 2993-based induction, his PET became negative. Additional 3 high-dose methotrexate and 3 consolidation cycles were prescribed followed by maintenance therapy. In August 2017, he relapsed in the bone marrow (BM) and central nervous system, and a second remission (CR2) was achieved after therapy with mitoxantrone + cytarabine. He underwent allo-SCT from his matched brother in CR2. Three and a half months after the transplant he experienced a third relapse. Two cycles of nelarabine were administrated followed by daratumumab 16mg/kg in a "myeloma like" protocol. BM at the end of 2 nelarabine cycles demonstrated remission but with 0.09% residual disease cells on flow cytometry. After the first 2 months of daratumumab, BM confirmed MRD eradication. One dose of 5x105/kg donor lymphocyte infusion (DLI) was also prescribed.
Patient 2: A 43-year-old female diagnosed with T-ALL in February 2017. Her disease was refractory to ECOG 2993-based induction and remission was achieved only after a second-line therapy with mitoxantrone + cytarabine. She was referred to allo-SCT from her matched sister, engrafted well and developed grade 2-3 acute graft-versus-host disease which responded well to steroids. Five months post-transplant an extra-medullary relapse was diagnosed in her eye and skin, while MRD was identified in her BM. The same regimen of 2 cycles of nelarabine followed by daratumumab 16mg/kg was prescribed. Extra-medullary disease was eliminated and so was the residual BM disease. One dose of 5x105/kg DLI was also prescribed.
The case of patient 3 has just been published (Ganzel C, et al. Haematologica, June 2018). In brief, this is a 21-year-old man diagnosed 7 years ago with Ph+ B-ALL. Daratumumab was prescribed to treat his 7th relapse after he had been treated with multiple TKIs, including ponatinib, underwent two allo-SCTs and received immunotherapy with 2 different anti CD19 and anti CD22 CAR-T cell agents. In parallel to daratumumab, vincristine was administered every 4 weeks as well as daily ponatinib. Molecular remission following daratumumab was confirmed by PCR for BCR/ABL.
Kinetics of response and duration of follow-up: For the patient with Ph+ ALL, daratumumab was prescribed while overt disease was present in the BM but peripheral counts were low (WBC=2,000, ANC=1,000, PLT=95,000). Hematologic remission was confirmed after 1 month and molecular remission after 4 months. Unfortunately, 6 months after the first infusion of daratumumab he relapsed again and now (one year post-daratumumab administration) he is alive and treated with bortezomib and gemtuzumab ozogamicin.
Both T-ALL patients achieved morphologic remission with nelarabine and received one DLI. MRD was identified in BM examination following nelarabine cycles and its elimination was confirmed in the BM at the end of the first 2 months of daratumumab (a total of 8 weekly infusions). Currently, these patients are 20 and 22 weeks following relapse and are alive and in molecular remission. In all 3 patients we noticed no significant side effects that could be related to daratumumab infusion. Peripheral WBC and PLT count dynamics are shown in figure 1.
Treatment of ALL patients who relapse with high-risk features is a great challenge. Herein we report three consecutive patients who achieved MRD negativity with daratumumab. Daratumumab can be combined with other effective agents in a simple and safe protocol that may be delivered even to heavily pre-treated patients. Although larger studies with longer follow-up are required, this novel approach may offer new hope for patients with a devastating disease such as relapsed ALL.

Disclosures
Ofran: Novartis: Other: Served on a Novartis advisory board.