Inotuzumab ozogamicin leads to high rates of measurable residual disease negativity for patients with B-cell acute lymphoblastic leukemia in morphologic remission

Abstract

Abstract Background The eradication of measurable residual disease (MRD) is essential for sustaining long-term remission in patients (pts) with B-cell acute lymphoblastic leukemia (B-cell ALL). Inotuzumab ozogamicin (InO) is a CD22-targeting antibody that demonstrates efficacy in the frontline and relapsed/refractory setting. Here, we provide the 3-year updated results from a phase 2 study evaluating the safety and efficacy of reduced dose InO in pts with B-cell ALL in morphologic remission with detectable MRD. Methods Adult pts with B-ALL in remission with detectable MRD were eligible. For pts with Philadelphia (Ph)-negative ALL, MRD positivity was defined by least 1x10-4 by multiparameter flow cytometry (FCM) and/or any level by next-generation sequencing (NGS) for immunoglobulin/T-cell receptor gene rearrangements (IG/TR) at sensitivity of 1x10-6. For pts with Ph-positive ALL, MRD positivity was defined as a ratio of BCR::ABL1 to ABL1 by polymerase chain reaction (PCR) of ≥0.01% or detectable MRD at a level of at least 1x10-4 by FCM and/or any level by NGS for IG/TR. InO was administered at 0.6 mg/m2 on Day 1 and 0.3 mg/m2 on Day 8 of Cycle 1, and 0.3 mg/m2 on Days 1 and 8 of Cycles 2-6. All pts received ursodiol for hepatic sinusoidal obstruction syndrome (SOS) prophylaxis. Pts with Ph-positive ALL received a concomitant BCR::ABL1 tyrosine kinase inhibitor. Results Between November 201-May 2025, 37 pts with a median age of 49 years (range, 19-71 years) were enrolled. Twenty-eight pts (76%) were in first complete remission (CR1) and 9 (24%) were in CR2 and beyond. Twenty pts (54%) had Ph–positive ALL. The remaining pts (n=17, 46%) had Ph-negative ALL; 8 pts (47%) had Ph-like ALL. Twenty-four pts (65%) received prior blinatumomab, 4 pts (11%) previously received CAR T, and 5 pts (14%) had previously undergone allogeneic stem cell transplant (ASCT). Pts received a median of 3 cycles (1-6) of InO. Twenty-five pts (68%) responded and achieved MRD-negativity by either FCM, NGS, or PCR overall. For pts with Ph-negative ALL, 12 (71%) received InO for MRD-positivity by FCM; 10 of these pts (83%) became MRD-negative by FCM after a median of 0.87 months (0.7-1.4). Nine out of 11 (81%) pts with available NGS-MRD testing became NGS-MRD negative. For pts with Ph-positive ALL, 9 (45%) received InO for MRD-positivity by FCM (7 of these pts [78%] also had positive BCR::ABL1 transcripts); all of these pts (100%) became MRD-negative by FCM after a median of 0.9 months (0.7-1.7). Nine pts (45%) with negative MRD by FCM received InO for BCR::ABL1 transcript positivity; 2 of these pts (22%) became BCR::ABL1 transcript negative after a median of 0.8 months (0.7-0.9). Four out of 6 (67%) pts with available NGS-MRD testing became NGS-MRD negative. Out of all enrolled pts, 7 (19%) received InO for isolated NGS-MRD positivity; 4 (57%) became NGS-MRD negative. At last follow-up, 11 pts (32%) have relapsed (including 3 non-responders and 8 responders; 7 in CR1 and 4 in CR2+; none had received ASCT prior to relapse; 3 had become NGS-MRD negative with InO). 19 pts (51%) remain alive in CR and 7 pts (19%) died in CR (n=2 septic shock, n=1 renal failure, n=1 multiorgan failure, n=1 hospice care, n=2 unknown). Of the pts who achieved NGS-MRD negativity, (n=13), 3 (23%) relapsed (none received ASCT). Only 1 pt received ASCT post achievement of NGS-MRD negativity. After a median follow-up of 39 months (1-63), the median overall survival (OS) was 40 months, with a 3-year OS rate of 59%. The median OS for Ph-positive ALL vs. Ph-negative ALL was 61 months vs. 40 months (p=0.99), with 3-year OS rates of 67% vs. 55%, respectively. The median OS for pts treated in CR 1 vs. CR2+ was 61 months vs. 14 months (p=0.06). In responding pts who achieved MRD-negativity (either by FCM or NGS) to InO, for pts who underwent ASCT vs. no ASCT, the 3-year OS rate was 71% vs. 56%, respectively, (p=0.6), with 3-year EFS rates of 57% vs. 44%, respectively (p=0.43). Most adverse events were low grade; SOS occurred in 3 pts (8%): 1 pt with Ph-negative ALL developed SOS 2 weeks after ASCT and recovered with defibrotide; 2 pts with Ph-positive ALL developed SOS while on concomitant ponatinib. Conclusion InO results in high rates of MRD-negativity in pts with B-cell ALL and positive MRD, with clearance of MRD by FCM and NGS achieved in the majority of pts. Our data support the use of InO as an effective and safe method of MRD-eradication, especially in earlier lines of treatment.