Long-Term Survival in ALL after Blinatumomab Treatment Linked to MRD, T-Cell Expansion

Patients with relapsed/refractory B-precursor acute lymphocytic leukemia (ALL) treated with the bispecific T-cell engager antibody construct blinatumomab experienced a median overall survival (OS) of 13 months, with about one-third of patients alive 30 months after treatment, according to a long-term follow-up analysis of an exploratory, dose-finding phase II study. Those patients with longer-term survival also all had a minimal residual disease (MRD) response, suggesting that MRD response in this disease setting may translate into clinical benefit.

“The prognosis is poor for adult patients with relapsed/refractory B-precursor ALL,” Gerhard Zugmaier, MD, and co-authors wrote in their report of the results. With traditional chemotherapy approaches, the median OS is 4.5 to 8.4 months, and five-year survival rates are just seven to 10 percent. In a previous exploratory dose-finding phase II study in adult patients with relapsed/refractory B-precursor ALL, treatment with blinatumomab resulted in 69 percent of patients achieving a complete response (CR) or CR with partial hematologic recovery (CRh), and 88 percent of these responders achieved an MRD response in the first two treatment cycles.

In the current analysis, Dr. Zugmaier, from Amgen Research in Munich, Germany, and colleagues expanded on the previous study by evaluating clinical characteristics, long-term outcomes of blinatumomab treatment, and T-cell and B-cell kinetics during treatment.

The open-label, multicenter, exploratory, single-arm, phase II study included 36 adult patients with relapsed/refractory B-precursor ALL who were treated at nine centers in Germany between October 6, 2010, and June 19, 2012. Patient follow-up is ongoing.

Patients were excluded from the study if they had undergone autologous hematopoietic cell transplantation (autoHCT) within six weeks or allogeneic HCT (alloHCT) within three months before starting blinatumomab treatment, had a history or presence of clinically relevant central nervous system (CNS) pathology, active graft-versus-host disease (GVHD) and/or had received immunosuppressive therapy for GVHD within one week of blinatumomab treatment start, or had active infections.

Each treatment cycle was six weeks, with four weeks of continuous intravenous infusion and a two-week treatment-free interval. Researchers obtained a bone marrow biopsy before the first cycle of blinatumomab and again on day 29 of each treatment cycle.

The 36 patients were randomized to three cohorts with the following dosing schedules:

  • Cohort 1 (n=7): blinatumomab 15 μg/m2/day
  • Cohort 2a (n=5): blinatumomab 5 μg/m2/day during week one, then 15 μg/m2/day
  • Cohort 2b (n=6): blinatumomab 5 μg/m2/day during week one, then 15 μg/m2/day during week two, then 30 μg/m2/day
  • Cohort 3, extension cohort (n=18): same regimen as cohort 2a

Seventeen patients (47%) achieved CR with blinatumomab treatment, defined as:

  • ≤5% blasts in the bone marrow
  • No evidence of circulating blasts or extra medullary disease
  • Platelets greater than 100,000 μL
  • Hemoglobin ≥11 g/dL
  • Absolute neutrophil count (ANC) >1500 μL

Eight patients (22%) achieved CRh as best response during treatment.

Patients who did not reach CR or CRh had partial remission (n=2) or hypocellular bone marrow (n=4), or were refractory to treatment (n=4) or unevaluable (n=1). Twenty-five patients (69%) had an MRD response (defined as <10-4 blasts), including 22 of the 25 patients who experienced CR/CRh, two patients with hypocellular bone marrow, and one patient with normocellular marrow but low peripheral counts.

After a median follow-up of 32.6 months (range = 0.8-41.9 months), median OS was 13 months (95% CI 8.5-21.9; TABLE). At 33 months, however, Dr. Zugmaier and colleagues identified a plateau in OS. Median relapse-free survival (RFS) was 8.8 months, and, again, the researchers identified a plateau in RFS at 18 months.

Ten of the 36 patients (28%) were considered long-term survivors, meaning they had an OS of 30 months or longer. Notably, none of the patients without MRD response were considered a long-term survivor.

Six of the 10 survivors remained relapse-free after blinatumomab treatment, two of whom received blinatumomab only and four who received blinatumomab followed by alloHCT. “These data suggest that the use of allogeneic SCT as consolidation for blinatumomab is a feasible treatment concept that warrants testing in larger trials,” the authors noted.

Long-term survivors also showed a higher degree of T-cell expansion during the first and second treatment cycles, compared with “only minor or even absent T-cell expansion at OS of <30 months,” the authors reported. “This is the first, albeit limited, data set to support this hypothesis, and additional studies are needed to verify the observation.”


Reference

Zugmaier G, Gokbuget N, Klinger M, et al. Long-term survival and T-cell kinetics in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia who achieved minimal residual disease response following treatment with anti-CD19 BiTE® antibody construct blinatumomab. Blood. 2015 October 19. [Epub ahead of print]

TABLE. Summary of Response, Follow-Up Treatment, and Relapse
Outcome MRD Responders MRD Non-responders
Overall survival ≥30 months Overall survival <30 months Total Overall survival <30 months
n=10 n=15 n=25 n=11
Best response
CR 7 (70%) 8 (53%) 15 (60%) 2 (18%)
CRh 2 (20%) 5 (33%) 7 (28%) 1 (9%)
Hypocellular bone marrow 1 (10%) 1 (7%) 2 (8%) 2 (18%)
Partial remission 0 (0%) 1 (7%) 1 (4%) 1 (9%)
AlloHCT after CR/CRh 5 (50%) 8 (53%) 13 (52%) 0 (0%)
AlloHCT after hypocellular bone marrow 1 (10%) 1 (7%) 2 (8%) 1 (9%)
Retreatment with blinatumomab 1 (10%) 2 (13%) 3 (12%) 2 (18%)
Relapse-free after blinatumomab 6 (60%) 0 (0%) 6 (24%) 0 (0%)
Blinatumomab treatment only 2 (20%) 0 (0%) 2 (8%) 0 (0%)
Blinatumomab and AlloHCT 4 (40%) 0 (0%) 4 (16%) 0 (0%)

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