High Molecular Remission Rate in Pediatric Patients (pts) with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (r/r ALL) Treated with Blinatumomab: Rialto an Open-Label, Multicenter, Expanded Access Study

Introduction

Despite a high cure rate for pediatric ALL, the prognosis for pts who suffer from r/r disease remains poor. Pediatric pts with r/r ALL face multiple lines of therapy, acute and long-term treatment toxicities, and have limited survival. New agents that are able to provide durable disease control and long-term survival with limited toxicity are needed. Blinatumomab (blin) is a bispecific T-cell engaging (BiTE®) antibody construct that redirects CD3+ cytotoxic T cells to lyse CD19+ B cells. We evaluated the safety and efficacy of blin in pediatric pts with B-cell precursor r/r ALL enrolled in an expanded access study initiated in 2014 (NCT02187354).

Methods

Eligible pts with r/r CD19+ ALL (≥ 2 relapses, relapse after allogeneic hematopoietic stem cell transplant [HSCT], or refractory to prior treatment) were > 28 days to < 18 years of age and had ≥ 5% blasts or < 5% blasts but with a minimal residual disease (MRD) level ≥ 10^-3. Prior treatment with blin was allowed if the pt was not blin-refractory or intolerant (study re-enrollment was not allowed). Blin was dosed by continuous infusion (4 weeks on/2 weeks off) for up to 5 cycles: 15 µg/m²/d for pts with ≤ 25% blasts; 5 µg/m²/d on days 1−7 of cycle 1, 15 µg/m²/d thereafter for pts with > 25% blasts. Subsequent therapy, including HSCT, was off protocol and per investigator preference. The primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included morphologic complete response (CR; < 5% blasts) and MRD response (< 10^-4 leukemic blasts by PCR or flow cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and HSCT rate after blin treatment.

Results

Of 98 treated pts (median age, 8.5 [range 0.4-17.0] years), 93% were enrolled in Europe, 54% had > 25% blasts at baseline, 41% had ≥ 50% blasts, and 48% had a cytogenetic abnormality. Prior treatments included HSCT (44%), radiotherapy (15%), and blin (4%); 56% of pts had ≥ 2 relapses, 41% had relapsed after HSCT, 14% were primary refractory and 20% were refractory to reinduction therapy.

At data cutoff (March 9, 2018), 37 pts were on study. The median number of completed treatment cycles was 2 (range 1-5), with 4 pts completing 5 cycles of blin.

Overall, 99% of pts experienced a TEAE, with a rate of 64% for grade ≥ 3. TRAEs were reported in 77% of pts (26% for grade ≥ 3); 21% were deemed serious. The most frequent TEAEs (any grade) included pyrexia (83%), vomiting (27%), headache (24%), and anemia (19%). Among TEAE categories of interest, rates of any grade/grade ≥ 3 were 67%/9% for infusion reactions, 44%/16% for infections, 43%/5% for neurologic events, 40%/31% for cytopenias, 18%/12% for elevated liver enzymes, 16%/2% for cytokine release syndrome, 8%/0% for decreased immunoglobulins, 4%/2% for tumor lysis syndrome, and 1%/0% for capillary leak syndrome. Dose interruption due to a TRAE was required by 19% of pts, and 4% discontinued blin due to a TRAE. There were 9 fatal AEs, all unrelated to blin.

In the first 2 cycles of treatment, 60% of all 98 pts achieved CR, 40% achieved CR with full recovery of peripheral blood counts (PBC), and 48% achieved MRD response. Of 2 pts with t(17;19), both achieved CR with full PBC recovery and MRD response; of 4 pts with Down syndrome, 3 achieved CR (2 full PBC recovery) and MRD response; of 4 pts who had received prior blin treatment, 3 achieved CR (3 full PBC recovery) with blin retreatment and 2 achieved MRD response. Among 59 pts who achieved CR within 2 cycles, 27 (46%) proceeded to HSCT; 19 relapsed and 5 died after a median follow-up 5.3 (range, 0.3-13.2) months for a median RFS of 8.5 (95% CI, 2.9-NE) months from the time of CR. Among all 98 pts, median follow-up was 12.2 (range, 0.5-14.1) months; there were 38 deaths (32 disease related), and median OS was 13.0 (95% CI, 9.3-NE) months.

Conclusions

The safety profile of single-agent blin in this expanded access study was generally consistent with profiles reported in prior controlled trials of blin in pediatric and adult pts with r/r ALL. Blin was active in this pediatric r/r ALL population. Blin induced MRD response in almost half of the pts, including pts with t(17;19) or prior blin treatment. Pts with a lower leukemia burden (< 50% blasts) had a better probability of response to blin vs pts with a higher burden. These data further support blin as a treatment option for pediatric pts with r/r ALL.

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