Background: Measurable residual disease (MRD) is the strongest predictor for relapse and survival in patients (pts) with B-cell acute lymphoblastic leukemia (ALL). We previously reported an MRD response rate of 73% among pts with MRD-positivity at a threshold of >10-4. Here we report the updated results of a prospective phase 2 study of blinatumomab for patients with B-cell ALL and MRD-positivity at a threshold of 10-4 or higher (NCT02458014).

Methods: Pts with B-cell ALL in morphologic remission with detectable MRD (>10-4) after >3 months of prior therapy (those in first morphologic remission, CR1) or >1 month of prior therapy (those in second morphologic remission or later, CR2+) were eligible. Detectable MRD was defined as >10-4 by multiparameter flow cytometry (MFC) for pts with Philadelphia chromosome-negative (Ph-) ALL and a BCR::ABL1 to ABL1 ratio of >0.01% by polymerase chain reaction for pts with Ph-positive (Ph+) ALL. Blinatumomab 28 mcg/day continuous intravenous infusion was administered daily for 28 days followed by 2 weeks off. Each cycle was 6 weeks long and pts could receive up to 5 cycles followed by maintenance with blinatumomab every 3 months for up to 4 cycles. Pts with Ph+ ALL received concomitant TKIs.

Results: A total of 37 pts, median age of 43 yrs (range, 22-84 yrs) were treated. Twelve pts (32%) were Hispanic/Latino. Eighteen pts (49%) had Ph+ ALL, including 15 with prior ponatinib therapy. Five pts (14%) had CRLF2 overexpression. Twenty-seven pts (73%) were treated in CR1 and 10 (27%) in CR2+. Fourteen pts (38%) had MRD <10-3 at enrollment. After 1 cycle, 24 pts (65%) achieved MRD-negativity. Two additional pts achieved MRD-negativity after Cycle 2 and 1 after Cycle 4 for an overall MRD response rate of 73%. Three of 5 pts evaluated for MRD by next generation sequencing (NGS) at a threshold of 10-6 achieved NGS MRD-negativity. A median of 3 cycles (range, 1-9) were administered. Sixteen (84%) Ph- pts responded after a median of 41 days (range, 12-92). Among the 18 Ph+ pts, 11 (61%) achieved CMR and 4 (22%) achieved MMR. Median time to CMR was 41 days (range, 29-171). No difference in response rate was observed based upon MRD level or remission status. Nine responders (33%) proceeded to allogeneic stem cell transplantation (ASCT).

After a median follow up of 74 months, 7 (26%) of the 27 responders have relapsed in the bone marrow (n=4), CNS (n=1), bone marrow and CNS (n=1), or with extramedullary disease (n=1). Seventeen pts, 12 responders and 5 non-responders, have died. Among the 12 responders, 5 died post ASCT, 5 post relapse, and 1 died in CR. At the last follow up, 11 responders are alive in continuous MRD-negative CR. Among the 18 pts who did not proceed to SCT, 6 relapsed and 8 are alive in CR without further treatment.

Median relapse-free survival (RFS) was 42 months, and median overall survival (OS) has not been reached. The estimated 5-year OS rate was 60% (95%CI: 42%-73%) and 5-year RFS rate was 49% (95%CI: 32%-64%). Among responders, the estimated 5-year OS and RFS rates were 63% (95%CI: 42%-78%) and 52% (95%CI: 32%-69%), respectively. The 5-year OS rate was 63% (42%-78%) for pts treated in CR1 and 50% (95%CI: 19%-75%) for those in CR2+. The 5-year RFS rate was 56% (35%-72%) for CR1 pts and 30% (7%-58%) for pts in CR2+. Pts treated with MRD <10-3 had significantly improved median OS (NR versus 38.1 months, p=0.028) and RFS (NR versus 24.5 months, p=0.042) compared to those treated with MRD >10-3. Among those with MRD <10-3, the estimated 5-year OS and RFS rates were 79% (95%CI: 47%-93%) and 64% (95%CI: 34%-83%), respectively, compared to 48% (95%CI: 27%-66%) and 39% (95%CI: 20%-58%) for those with MRD >10-3. The 3 pts who achieved NGS MRD-negativity remain alive in continuous MRD-negative remission without further treatment.

Among pts in CR1, median time to ASCT was 2 months (range, 0.6-6.9). By a 2-month landmark analysis of pts in CR1, the 5-yr OS rate was 67% for those who proceeded to ASCT versus 57% for those who did not.

No new long term adverse events or deaths related to adverse events have been observed.

Conclusion: Blinatumomab induced a high level of MRD-negativity, translating into prolonged OS and RFS. Patients treated at a lower MRD threshold of <10-3 achieved improved outcomes, indicating the utility of blinatumomab in patients with low-level MRD-negativity. No difference in outcomes was observed among pts treated in CR1 who proceeded to ASCT versus those who did not.

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2025
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