Blinatumomab and Venetoclax for Minimal Residual Disease Relapse in Acute Lymphoblastic Leukemia

Introduction: The 5-year relative survival in patients aged 15-24 years old is around 57% (Blood 2019; 134: 407-410), with a median survival after relapse of 10 months. No uniform consensus about rescue treatment is available, but those who achieve a complete remission can undergo to an allogeneic transplant if feasible. The use of intense rescue chemotherapy is associated with systemic toxicities and risk of serious infections that can delay an allogeneic transplant.

Objective: We describe the combination of two ALL targeted therapies, combining bispecific T-cell engager (BiTE) against CD 19 (Blinatumomab) and selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, an antiapoptotic protein (Venetoclax). This combination was developed based in their mechanism of action that offers synergetic effects against ALL cells and the reports of ongoing clinical trials using Venetoclax combinations for ALL, but no with Blinatumomab.

Patients and methods: Patients with B cell precursors ALL in minimal residual disease relapse by flow cytometry. Rescue treatment with Blinatumomab and Venetoclax before allogeneic transplant.

Results: Two patients treated with LAFAMI-LLA-2002 Protocol (Blood 2009; 114: 4104 and Hematologia 2016; 17: 5137), adapted to young adults with high dose methotrexate at 5 gr/m2 every four months in the maintenance phase, had MDR positivity by FC in the surveillance phase, with normal CBC. One male with 22 years old at the time of relapse, after 60 months of surveillance with 1.9 % of malignant lymphoblasts. One female with 21 years old at the time of relapse, after 25 months of surveillance with 0.2 % of malignant lymphoblasts. Both relapses were confirmed with an additional MRD one week after. Extension studies were performed, including PET-CT, to determinate other affected sites and were negative. Treatment administrated was Blinatumomab at 9 mcg/day continuous IV infusion on days 1-7 and 28 mcg/day on days 8-14 with Venetoclax in a ramp-up phase for 5 weeks. Both patients were in negative MRD after the complete Blinatumomab and continue with Venetoclax while a donor was available. No side effects were observed during and after the treatment. Both patients had a compatible sibling and underwent for allogeneic transplant. At the moment of this report the patients have 11 months and 18 months after transplant with EMR negative and complete donor cells from the bone marrow, with no secondary effects.

Conclusion: This is a novel combination with no reports of its use before our communication. Targeted therapies in low leukemic burden is a feasible treatment with no side effects and rapid control of the relapse, allowing the patients to reach an allogeneic transplant as soon as possible avoiding substantial toxicity and risk of infections. No infusion related reaction or cytokine release syndrome were observed due low leukemic burden. More patients need to be included to this combination to demonstrate reproducibility, optimizing time and costs.