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Cytological and molecular remissions with blinatumomab treatment in second or later bone marrow relapse in pediatric acute lymphoblastic leukemia (ALL).
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Background: Pediatric B-precursor acute lymphoblastic leukemia (ALL) in second or later relapse is an aggressive malignancy that needs therapeutic approaches with new mechanisms of action. Blinatumomab, a bispecific T-cell engaging (BiTE) antibody, has shown a hematological remission rate of 69% in adult patients with relapsed/refractory ALL. In order to establish a recommended dose in pediatric patients, a phase I multicenter trial was initiated. Methods: The primary endpoint is to determine the maximum tolerable dose defined by ≤1 of 6 patients experiencing dose limiting toxicity (DLT) within the 1st course of treatment. Up to 6 different dose levels of blinatumomab are being evaluated. Eligible patients must be <18 years old and have B-precursor ALL that is refractory or in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoetic stem cell transplantation (HSCT). Blinatumomab is administered by continuous IV infusion over 28 days followed by a 14-day treatment-free interval (up to 5 cycles). To date, 3 dose levels have been explored (Table). Results: Seventeen patients have been treated thus far with a total of 32 cycles. One DLT (gastrointestinal hemorrhage) at dose level 2 (15 µg/m²/d) and two DLTs at dose level 3 (30 µg/m²/d; both cytokine release syndrome) with 1 death have been observed. One patient had generalized seizures on the 3rd day of the 2nd treatment cycle at the first dose level of 5 µg/m2/d, which was completely reversible. The patient successfully underwent an allogeneic HSCT after blinatumomab. Eight (47%) of the 17 patients reached a cytological complete remission in bone marrow and a molecular remission defined as MRD by PCR <10-4. Conclusions: A phase I trial of blinatumomab in patients with relapsed/refractory pediatric ALL has shown hematological and molecular remissions. Dose-limiting cytokine release syndrome has been noted. Alternative dosing regimens are being explored in current cohorts to refine the recommended dose of blinatumomab in this patient population. Clinical trial information: NCT01471782.
|Cohort||Dose level µg/m²/d||Patients treated
|Bone marrow CR/MR
|1||5||5||0||2 / 2|
|2||15||7||1||4 / 4|
|3||30||5||2||2 / 2|
|Total||17||3||8 / 8|