Safety and Efficacy of Blinatumomab Used in Children with B-Precursor Acute Lymphoblastic Leukemia (ALL) Treated in French Hematological Centers
Authors: Derache Anne-Flore , Rialland Fanny , Michel Gerard , Perel Yves , Gandemer Virginie , Blouin Pascale , Minckes Odile , Petit Arnaud , Baruchel Andre , Brethon Benoit 
Published: October 2019

Blinatumomab is a monoclonal bispecific antibody, combining two binding sites: a CD3 site for T cells and a CD19site for the target B cells. Blinatumomab has demonstrated efficacy and safety in adult relapsed/refractory B-precursor ALL (R/R ALL) populations, but also in the pediatric R/R ALL population as shown by interim results from the Phase 1b/2 study MT103-205 (Gore L et al, ASH 2014).

Patients and methods: this retrospective study aims to evaluate safety and efficacy of Blinatumomab in 17 pediatric pts with B-precursor ALL treated in 4 french hematological centers between April 2013 and December 2015 within a compassionate use frame. These 17 pts represent the whole population of French children treated with Blinatumomab outside a clinical trial but under a Temporary Authorization for Use (ATU) given by the French Regulatory Agency (ANSM) within this period. Median age was 6.6 years (8 months - 16.6 years).

Results: 1)7 pts (41%) received Blinatumomab at a dose of 15 mcg/m2/day for 28 days/cycle in first or second complete remission for minimal residual disease (MRD) persistence. Six of those 7 pts had a molecular remission (MRD <10-4) after 1 or 2 cycles of Blinatumomab. Those 6 responders could be led to allo-HSCT. One of these died of invasive aspergillosis 131 days after allo-HSCT, without bone marrow relapse. Three pts had no relapse with a median follow-up time of 147 days (142 - 240 days). Time to relapse for the 2 remaining pts was respectively 75 and 86 days after allo-HSCT. One non responder pt was not led to allo-HSCT and died of ALL progression. 2) Ten pts (59%) with R/R ALL received Blinatumomab at a dose of 5-15 mcg/m2/day for 28 days during the first cycle then at a dose of 15 mcg/m2/day for all subsequent cycles; 2 of them being in marrow relapse after allo-HSCT. Four of those 10 pts achieved a molecular remission after 1 or 2 cycles and could receive an allo-HSCT. Two of those 4 pts had a bone marrow relapse respectively 89 and 135 days after allo-HSCT. One patient had an isolated meningeal relapse 141 days after allo-HSCT. Of note no marrow relapse has been observed in this patient with a follow-up of 2.7 years after allo-HSCT. One patient was free of disease with a short follow-up (69 days after allo-HSCT). The 6 pts who did not achieve molecular remission after one or two cycles of Blinatumomab died from ALL progression.3) In total, 10 of 17 pts have achieved a molecular remission after 1 or 2 cycles of Blinatumomab. Four of those 10 pts are alive without any further relapse, with a median follow-up time of 144 days after allo-HSCT (69 - 240 days). The 7 pts who were not in molecular remission after 1 or 2 cycles of Blinatumomab all died of ALL progression.4) Safety: regarding treatment-related adverse events of grade ≥2, 5 of 17 pts (29%) had a cytokine release syndrome of grade ≥ 2 (grade 2= 3, grade 4= 2). Five pts (29%) had an infection: 2 pts had a grade 3 viral infection (HSV oral recurrence, n=1 and herpes zoster, n=1). Two pts had grade 3 sepsis (<i>Enterococcus faecalis<i/>, n=1 and <i>Staphylococcus haemolyticus<i/>, n=1). One patient had a grade 3 soft tissue mucormycosis. Three pts (18%) had hepatic toxicity (≥ grade 3 increased ALAT, n=2). One patient had a grade 4 pericarditis without documented infection. No neurological event was observed.

Conclusion: Although our numbers are small 1) Blinatumomab is an effective bridge to HSCT for pts with persisting high MRD after intensive chemotherapy. 2) A 40% MRD response rate has been found for R/R pts but with a dismal final outcome. 3) Toxicity is manageable with a low neurological event rate (none in this study). Blinatumomab should be developed in less advanced B lineage ALL in children.

Disclosures

Baruchel: Amgen: Consultancy. Brethon:Amgen: Consultancy.