Complete Molecular and Hematologic Response in Adult Patients with Relapsed/Refractory (R/R) Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia (ALL) Following Treatment with Blinatumomab: Results from a Phase 2 Single-Arm, Multicenter Study (ALCANTARA)

Introduction. Prognosis of patients (pts) with R/R Philadelphia chromosome-positive (Ph+) ALL is dismal despite the introduction of tyrosine kinase inhibitors (TKI) which may be used as single agents or in combination regimens.  Blinatumomab is a bispecific T-cell engaging (BiTE^®) antibody construct that has shown antileukemic activity.  Among adults with R/R Ph-negative ALL receiving blinatumomab, 43% achieved complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles (Topp MS et al. Lancet Oncol 2015;16:57).  We evaluated the efficacy and tolerability of blinatumomab in pts with R/R Ph+ ALL who progressed after or were intolerant to a 2^nd or later (2+) generation TKI.

Methods. Eligible adult pts (≥ 18 years) had Ph+ B-precursor ALL and had relapsed after or were refractory to at least one 2+ generation TKI; or were intolerant to 2+ generation TKI and intolerant or refractory to imatinib.  All pts had to have >5% blasts in the bone marrow and Eastern Cooperative Oncology Group performance status ≤ 2.  Blinatumomab was dosed by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles (9 μg/d on days 1-7 in cycle 1, and 28 μg/d thereafter).  The primary endpoint was CR or CRh during the first two cycles; minimal residual disease (MRD) response based on RT-PCR amplification of BCR-ABL per central laboratory, relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) rate were key secondary endpoints.  Complete MRD response was defined as no RT-PCR amplification of BCR-ABL at a sensitivity of 10^‑5.

Results. Of 45 treated pts, 44 were resistant to 2+ generation TKI; one patient was resistant to imatinib and never exposed to 2+ generation TKI (protocol deviation).  53% of pts were men.  Median (range) age was 55 (23–78) years (≥ 65 years, 27%).  Ten pts (22%) had a BCR-ABL gene with T315I mutation.  All pts had received prior TKI (dasatinib, 87%; ponatinib, 51%; imatinib, 56%; nilotinib, 36%; bosutinib, 2%), with 60% having received ≥ 2 prior 2+ generation TKI; most pts (96%) had received prior chemotherapy.  38% of pts had ≥ 2 prior relapses and 44% had prior alloHSCT.  Efficacy outcomes for key endpoints are shown in the table.  16 pts achieved CR/CRh during the first two cycles for a response rate of 36% (95% CI: 22%, 51%); of those, 14 pts achieved CR, most of them (10/14, 71%) in cycle 1.  The patient who never received 2+ generation TKI did not respond to treatment.  12 of the 14 pts (86%) with CR and two of the two pts with CRh achieved a complete MRD response.  Among the 10 pts with T315I mutation, four achieved CR/CRh; all four also achieved a complete MRD response.  Eight CR/CRh responders (50%) relapsed, three during treatment (including two with CR who did not achieve complete MRD response).  One patient died in CR post alloHSCT.  Median (95% CI) RFS was 6.7 (4.4, not estimable) months (median follow-up, 9.0 months); median OS was 7.1 (5.6, not estimable) months (median follow-up, 8.8 months).  Patient incidence of grade ≥ 3 treatment-emergent adverse events (AEs) was 82%, most commonly febrile neutropenia (27%), thrombocytopenia (22%), anemia (16%), and pyrexia (11%).  Five pts had fatal AEs; one (septic shock) was considered treatment-related by the investigator.  Three pts discontinued because of AEs.  Cytokine release syndrome (CRS) occurred in three pts (all grade 1 or 2).  21 pts (47%) had neurologic events (paraesthesia, 13%; confusional state, 11%; dizziness, 9%; tremor, 9%); three pts had grade 3 neurologic events (aphasia, hemiplegia; and depressed level of consciousness and nervous system disorder), one of which (aphasia) required treatment interruption.

Conclusion. In this population of pts with R/R Ph+ ALL who have very poor prognosis after failure of 2+ generation TKI therapy, treatment with CD19-targeted immunotherapy blinatumomab as single agent showed antileukemic activity.  AEs were consistent with those previously reported for pts with R/R Ph-negative ALL treated with blinatumomab.