Experience with Blinatumomab in Pediatric Patients in Argentina. Multi-Center Study

Introduction. Very high-risk and relapsed pediatric acute lymphoblastic leukemia (ALL) require high-dose chemotherapy and hematopoietic stem cell transplant (HSCT) as consolidation of treatment. Patients with positive minimal residual disease (MRD) previous to HSCT have lower survival rates. Immunotherapy is thus useful for management of MRD previous to HSCT with less chemotherapy-associated morbidity. Blinatumomab (Blina) is a bi specific monoclonal antibody against CD19 and CD3ε.

Objectives. To report the experience with Blina in children with B-ALL in Argentina and assess its toxicity, effectiveness and overall survival (OS).

Patients and methods. Retrospective analytical study. The main Argentinian pediatric hospitals participated. Patients younger than 17 years old with B-ALL in 1 ^st, 2 ^nd or 3 ^rd CR who had received 1 or 2 cycles of Blina were included. Those with negative MRD and those who didn´t complete a cycle were excluded. Toxicity was evaluated according to CTC 4.0 and effectiveness according to pre and post-infusion MRD. OS was calculated using Kaplan Meier with GraphPad Prism V5.0.

Results.

Patients. Thirty patients received Blina and 6 were excluded: 3 due to negative MRD, 2 didn´t complete 1 cycle and 1 for both reasons.Eligible: 24 patients. The median age was 5.5 (range 0.8-17) years. Patients under 1 year: 3. Distribution by sex F/M= 1/1.8.

Patients with High Risk ALL represented 42% (n=10) and relapsed ALL 58% (n=14), 10 in 1 ^st relapse and 4 in 2 ^nd relapse. Sixteen patients received 1 cycle and 8 received 2.

Median MRD previous to Blina was 0.71 (range 0.023-49)%. Thirteen patients received it in CR (MRD <1%): 7 in 1 ^st CR, 4 in 2 ^nd CR, and 2 in 3 ^rd CR. MRD was 1-5% in 6 patients and >5% in 5.

Toxicity. During the 1 ^st and 2 ^nd weeks, 25% (n=6) and 16% (n=4) presented GII-III neurological toxicity respectively. Blina infusion was temporarily withdrawn for 3 hours to 12 days in 6 patients but all completed the cycle. During the 1 ^st week, 41.5% (n=10) presented fever. During the entire 1 ^st cycle 25% (n=6) presented GIII-IV hematological toxicity, 2 patients presented GIV and 1 GIII infectious toxicity. Regarding the 8 patients who received a 2 ^nd cycle, 1 patient presented febrile neutropenia and 2 presented GIII infectious toxicity without evidence of neurological toxicity. Systemic inflammatory response syndrome was not evidenced. There were no fatal events related to Blina administration.

Efficacy. After the 1 ^st cycle of Blina 58% became MRD negative (n=14), 17% remained in CR (n=4) and 25% didn´t show any response. All patients who received a 2 ^nd cycle were in CR; however, 5 of them became MRD negative and 3 relapsed later.

Ten of the 13 patients who received Blina in CR with MRD+ became negative and 3 relapsed. Of the 5 with MRD 1-5%, 4 became negative, 1 achieved CR with MRD+ and 1 progressed. Of the 5 patients with MRD>5%, 2 achieved CR but none became MRD negative. Fifty percent of the patients received HSCT (n=12): 6 haploidentical, 2 related allogeneic and 4 unrelated.

With a median follow-up of 3.5 (1.7-56.9) months, OS at 36 months was 20.3%.

Nine patients are alive and in CR (37.5%), 6 post-HSCT and 3 post-Blina still receiving treatment. Five died in CR (4 due to HSCT complications) and 10 died due to disease relapse/progression (3 post HSCT and 7 post-Blina).

Conclusions. Blina infusion was safe with the previously described toxicities. The highest response rate was evidenced in patients in CR or with MRD 1-5% pre-Blina. The low survival rate in this cohort may be due to the high rate of relapse/progression and toxicity associated with HSCT, although HSCT is essential to consolidate Blina´s response. Blina therapy is effective in patients with very high risk or relapsed ALL with +MRD. The strategy should focus on the precise indication of patients with MRD+ as a bridge to HSCT.