Treatment With Blinatumomab Eradicates MRD in Patients with ALL

More than three-quarters of patients with acute lymphocytic leukemia (ALL) who were in complete remission (CR) following chemotherapy but still had evidence of minimal residual disease (MRD) achieved complete MRD response following treatment with blinatumomab, according to a phase II study published in Blood. Nicola Gökbuget, MD, of Goethe University Hospital in Frankfurt, Germany, and co-authors also determined that these deeper responses were associated with improved overall survival (OS).

“MRD persistence or recurrence [after induction/consolidation chemotherapy] is the most important risk factor for hematologic relapse in T- and B-cell ALL,” the authors explained. “Targeted agents with alternative mechanisms of action may reduce MRD and delay or prevent hematologic relapse.” Blinatumomab is a bispecific T-cell engager antibody construct that directs T cells to CD19-positive cells, an antigen that is expressed on blast cells in more than 95 percent of B-cell precursor ALL cases, they added.

In this international, multicenter, open-label, single-arm study, investigators enrolled 116 patients (median age = 45 years; range = 18-76 years) from 46 centers in Europe and Russia between November 2010 and February 2014. Patients with B-cell precursor ALL in first or later hematologic CR with persistent or recurrent MRD ≥10-3 after a minimum of three cycles of intensive chemotherapy were included.

At baseline, 54 patients (47%) had MRD ≥10-2, and 41 (35%) were in second or later hematologic CR. “This patient group was selected based on very poor prognosis due to a high relapse rate with continued chemotherapy, indicating resistance,” the authors wrote.

All patients received daily blinatumomab 15 µg/m2 via continuous intravenous infusion for up to four cycles (each cycle comprised 4 weeks of infusion followed by a 2-week treatment-free period). Participants were permitted to receive hematopoietic cell transplantation (HCT) any time after treatment cycle, and 76 patients did so after one (n=27), two (n=36), or three to four (n=13) cycles.

As of August 5, 2015 (data cutoff), among the 113 evaluable patients, 78 percent (n=88) achieved a complete MRD response after one cycle of blinatumomab (primary endpoint; defined as no detectable MRD at <10-4). Two additional patients achieved complete MRD response after two cycles.

Among the 103 patients with hematologic CR and MRD >10-3 at baseline, 87 percent (n=96) achieved any MRD response, including 80 percent (n=82; 95% CI 71-87) with a complete MRD response after cycle one. “Complete MRD responses were high,” the authors reported, “and no demographic/clinical characteristics were associated with MRD response after one cycle.”

Forty-five patients required treatment interruptions during cycle one, 37 of whom (82%) achieved a complete MRD response.

During a median follow-up of 29.9 months (range not provided), the rate of 18-month relapse-free survival (RFS; secondary endpoint) was 54 percent (95% CI 33-70), “exceeding the prespecified boundary of 28 percent,” the authors noted. Secondary efficacy endpoints were:

  • median RFS: 18.9 months (range = 12.3-35.2 months)
  • median duration of hematologic remission: not reached
  • median OS: 36.5 months (range = 19.8 months to not estimable)

At last follow-up, 48 of 110 patients remained in CR (36 after subsequent HCT), 38 relapsed, and 24 died in CR (20 after subsequent HCT).

The investigators also conducted a landmark analysis (with MRD assessed within 45 days of blinatumomab treatment) that confirmed that achieving a complete MRD response was associated with prolonged OS and RFS, compared with MRD non-responders (38.9 months vs. 12.5 months [p=0.002] and 23.6 months vs. 5.7 months [p=0.002], respectively). The findings “demonstrate a direct patient benefit for the immunotherapeutic conversion of MRD-positive to -negative disease,” they wrote.

All 116 patients who started cycle one experienced at least one adverse event (AE), the most common of which were pyrexia (n=103; 89%), headache (n=44; 38%), and neutropenia (n=18; 16%). The incidence of AEs was greatest during cycle one and decreased over subsequent cycles, they noted.

Neurologic AEs occurred in 61 patients (53%), the most common of which were tremors (n=35; 30%), aphasia (n=15; 13%), and dizziness (n=9; 8%). Grade 3 and 4 AEs were reported by 38 (33%) and 31 (27%) patients, respectively; they were deemed treatment-related in 29 and 22 percent of patients, respectively. Two AEs were fatal and both occurred in cycle one: atypical pneumonitis with H1N1 influenza (considered treatment-related) and subdural hemorrhage (considered unrelated to treatment).

“For those patients with AEs leading to treatment interruptions, most events resolved rapidly after stopping blinatumomab, which has a serum half-life of about two hours,” the authors added. Most patients who had grade 3/4 neurologic events resumed blinatumomab treatment after the event resolved.

“The high response rates in MRD-positive patients support the hypothesis that targeted single-drug immunotherapy has impressive anti-leukemic activity,” the authors concluded, “and that lower leukemia burden is a favorable prerequisite for this treatment principle.”

The study’s findings are limited by its open-label design, lack of a comparator arm, and potential variations between local and central MRD assessments.

Amgen Research designed the study.

The authors report financial relationships with Amgen, the manufacturer of blinatumomab. Amgen also provided editorial support.


Reference

Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-precursor acute lymphoblastic leukemia. Blood. 2018 January 22. [Epub ahead of print]

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