PROLONGED LEUKEMIA FREE SURVIVAL FOLLOWING BLINATUMOMAB (ANTI-CD19 BITE®) TREATMENT OF PATIENTS WITH MINIMAL RESIDUAL DISEASE (MRD) OF B PRECURSOR ALL: UPDATED RESULTS OF A PHASE II STUDY
AuthorBargou, C, Department of Internal Medicine II, Division of Hematology and Medical Oncology,, Wuerzburg, Germany(P)
KeywordsB cell acute lymphoblastic leukemia, CD19, MRD, Phase II
Background: In B-lineage acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) is an independent poor prognostic factor and new treatments are needed. CD19 is the most frequently expressed B-cell differentiation antigen. It can be targeted by blinatumomab, a member of a novel class of T-cell engaging bispecific single-chain antibodies (BiTE antibodies). A Phase 2 study was conducted in collaboration with the German Multicenter Study Group on Adult Lymphoblastic Leukemia (GMALL) in order to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.
Methods: Between May 2008 and November 2009, 21 patients with MRD persistence or relapse (MRD-level = 10-4) after induction and consolidation therapy were treated with blinatumomab as a four-week continuous intravenous infusion at a dose of 15 µg/m²/d followed by a 2-week treatment-free period (1 cycle). Sixteen patients with Ph-negative (2 patients with MLL-AF4) and 5 patients with Ph-positive ALL were enrolled. MRD was assessed by quantitative reverse transcriptase-polymerase chain reaction for either rearrangements of immunoglobulin or T-cell-receptor genes, or specific genetic aberrations.
Results: Sixteen out of 20 evaluable patients (13 out of 15 patients with Ph-negative and 3 out of 5 patients with Ph-positive ALL) became MRD-negative (MRD-level <10-4) after one cycle of blinatumomab regardless of the MRD level prior to study treatment. Nine patients were enrolled with high MRD load (> 10-2) prior to study treatment. All of these 9 patients became MRD-negative. Thirteen out of 16 patients with persistent MRD prior to study treatment and 3 out of 4 patients with MRD-relapse became MRD-negative.
Nineteen patients are evaluable for duration of hematological relapse-free survival (median follow up 11 months, range from 3 to 20 months). One patient withdrew consent for follow-up.
Fifteen patients remain in continuous hematological remission. Four non-transplanted patients experienced hematological relapse (3 responders and 1 non-responder).
Ten responders are not transplanted after treatment with blinatumomab.
Six out of these 10 non-transplanted responders are still MRD-negative without additional treatment.
Six out of 7 non-transplanted responders with Ph-negative ALL are still MRD-negative without additional treatment.
Eight patients (6 responders, 2 non-responders) underwent allogeneic HSCT after at least one cycle of blinatumomab (median 2 cycles) and all remain alive without hematologic relapse.
Transient pyrexia (100%), chills (42.9%), headache (42.9%) were the most common clinical adverse events (AEs), which all resolved to baseline during treatment. Target-mediated Grade 3 or 4 lymphopenia (33.3%) and hypogammaglobulinemia (14.3%) were also observed, but without increased incidence of opportunistic infections. Grade 3 seizure, which was fully reversible within 1 day after drug discontinuation, was observed in 1 patient.
There were no blinatumomab related deaths.
Conclusion: Blinatumomab induces complete molecular remissions in patients with persistent and relapsed MRD independent from the extend of MRD-positivity and prolong leukemia-free survival with a favorable safety and tolerability profile. These molecular remissions might be durable without additional conventional maintenance chemotherapy. |
