Exploring the Efficacy and Feasibility of Outpatient Blinatumomab Short Cycles in Pediatric Patients with Relapsed/Refractory B-ALL in LMIC: Preliminary Results

Abstract

CONCLUSIONS In low- and middle-income countries (LMIC) like Mexico, the treatment of patients with refractory or relapsed acute lymphoblastic leukemia (r/r ALL) represents a significant challenge due to limited access to immunotherapy and hematopoietic stem cell transplantation (HSCT). As a result, the one-year survival rate is reported to be less than 20%. The use of intensive chemotherapy has not improved survival in this group due to its high toxicity. Blinatumomab uses the patient's own cytotoxic T-cells to induce lysis of the leukemia cells expressing CD19 and has been established as a bridge therapy for transplant in patients with r/r B-ALL. The usual pattern of administration is a dose scaled up to complete a total of 28 days of infusion. According to various studies, it is considered appropriate to use repeated cycles of this antibody to achieve the desired response. However, there are also reports of patients achieving complete responses within the first 15 days of the cycle. The high costs of Blinatumomab's administration present a significant barrier to its use in LMIC. As a consequence, the application of prolonged or multiple cycles of the drug becomes unaffordable for a substantial portion of the global population. Demonstrate the safety and efficacy of utilizing short cycles of Blinatumomab (21 days) as a bridge therapy to HSCT in pediatric patients with r/r ALL to explore the potential cost-reduction benefits and increased access to this therapy in resource-limited settings. A pilot clinical trial was conducted. Pediatric patients (<16 y) diagnosed with r/r B- ALL between the years 2020-2022 were included. The usual Blinatumomab dosing regimen was adopted, but the total duration of the cycle was reduced. Continuous infusion was initiated at a dose of 5 mcg/m2/day for the first 7 days, followed by an increase to 15 mcg/m2/day for 14 days (21-day total treatment duration). To mitigate cytokine release syndrome (CRS) a single dose of dexamethasone was administered at the start of the infusion and after the dose escalation. The entire regimen was administered on an outpatient basis, with an infusion pump at home. Caregivers were instructed on the operation of the pump and detection of any signs of toxicity, with 24/7 contact with the medical team and the option to hospitalize if necessary. A total of 7 patients were included, and all of them received Blinatumomab in a single 21-day cycle. The median age was 5 years (15 mo- 13 y). The majority of patients were stratified as high-risk at the time of diagnosis (85.7%). Among the patients, 4 had relapsed ALL, while 3 had refractory disease. The median time from the initial diagnosis to the use of Blinatumomab was 16 months (ranging 7-29 mo), and the median number of treatment lines before Blinatumomab administration was 3 (ranging 2-4). The highest level of minimal residual disease (MRD) detected before the Blinatumomab treatment was 4.2% (by flow cytometry). Remarkably, all patients (100%, n=7) achieved a complete response, with MRD being negative for flow cytometry after the 21-day cycle of Blinatumomab. In 5 out of 7 patients, the administration of the drug was completely ambulatory. Only 2 patients experienced grade I CRS which was successfully managed with steroids. No adverse effects greater than grade 2 were reported, and no patient required support with transfusion therapy during or after the infusion. There were no reports of profound neutropenia, and no treatment-related deaths occurred. HSCT was conducted in all patients to consolidate the response, with 6 patients undergoing haploidentical and 1 patient undergoing identical allogeneic HSCT. At present, 5 out of 7 patients are alive and in complete remission. One patient died on day +51 post-HSCT due to pulmonary thromboembolism, and the second patient experienced relapse on day +395 post-HSCT and subsequently died on day +640 due to disease progression. The median overall survival at 3 years was 66.7%, with a median follow-up period of 21 months (4 -30mo). An alternative outpatient, low-toxicity and cost-effective treatment approach was implemented. The findings from this study could shed light on a promising strategy to improve the outcomes for patients with ALL patients with limited therapeutic options, particularly in the context of resource-constrained settings.