Long-term outcomes of a chemotherapy-free regimen of concomitant blinatumomab and inotuzumab ozogamicin in older patients with Philadelphia negative B-cell acute lymphoblastic leukemia Free

Background Older adults with B-cell acute lymphoblastic leukemia (B-ALL) represent a high-risk population with poor outcomes. Efforts to improve outcomes focus on de-intensifying chemotherapy regimens, but the optimal degree of reduction remains unclear, particularly for patients (pts) >70 years or unfit for intensive therapy. Here, we present more than 2-year updated results from a phase 2 study of blinatumomab (blina) and inotuzumab ozogamicin (InO) in newly diagnosed older pts with Philadelphia chromosome–negative (Ph-negative) B-ALL.

Methods This phase 2 study included pts>70 years old or unfit pts 60-70 years with Ph-negative B-ALL who had an ECOG performance status<3. Pts received the following treatment during cycle 1: dexamethasone 20 mg intravenously (IV) days 1-4, vincristine 1 mg IV day 4, fractionated InO 0.6 IV mg/m² day 1 and 0.3 IV mg/m² day 8 followed by blina IV days 15-28 (9 ug/day x 2 days followed by 28 ug/daily) followed by 2-week rest. Cycles 2-5 were blina 28 ug daily days 1-28, InO 0.3 mg/m² on days 1 and 8 (InO only during cycles 2-4; max total dose 2.7 mg/m²). Maintenance (cycles 5-8) was blina 28 ug/day days 1-28. Pts were recycled every 42 days. Pts with CD20 positive ALL could receive rituximab 375 mg/m² IV on days 2 and 9 during cycles 1-4. Pts received 12 doses of intrathecal chemotherapy and ursodiol.

Results Between April 2021-Apil 2025, 16 pts were enrolled; median age 76 years (range, 65-83); 15 (94%) were >70 years. Seven pts (44%) were female. Eight pts (50%) had a TP53^mut(median VAF 43% [range, 4-89%], median number of TP53^mut 1 [range, 1-2]), 6 pts (38%) had high risk cytogenetics (defined as KMT2Ar, complex karyotype, low hypodiploidy or near triploidy cytogenetics). One pt had Philadelphia-like disease with CRLF2 rearrangement.

Fifteen of 16 pts (94%) achieved complete remission/complete remission with incomplete count recovery (CR/CRi), with 14/15 (93%) achieving CR. Out of 15 responding pts, 13 (87%) achieved measurable residual disease (MRD)-negativity by flow cytometry (FC) at any time, with 10 pts (67%) achieving MRD-negativity after induction. Out of the 14 pts who had MRD by next generation sequencing (NGS) performed, 10 (71%) achieved NGS-negativity at any time (with 5 [36%] achieving NGS-negativity after induction), 2 (14%) had MRD detected below the limit of detection, and 2 (14%) were NGS-positive. One pt with NGS below LOD died in CR and the other continues on study in remission. On Day 14 evaluation prior to the administration of blina, of the 11 evaluable pts, 9 (82%) had achieved CR, with 3/9 (33%) achieving MRD-negativity by FC.

After a median follow-up of 27 months, the 2-year OS and EFS rates are 50% and 50%, respectively. There were no early deaths. Two pts (13%) have relapsed, of which 1 pt relapsed with extramedullary disease (1 pt had baseline KMT2Ar, 1 pt had baseline low hypodiploidy/near triploidy, both pts had concomitant baseline TP53^mut,); both relapsed pts have died. Five pts (31%) died in CR (median age 78 years [66-81], 3/5 with high-risk baseline cytomolecular features; causes of death: 1 myocardial infarction, 1 lung infection, 1 non-infectious respiratory failure, 1 after proceeding with hospice, 1 from multiorgan failure/transplant-related complications). Two pts proceeded to allogeneic stem cell transplantation (ASCT) in CR1; 1 pt is still alive in remission at last-follow up 41 months post-SCT and the other pt died on day +60 from ASCT-related complications. At last follow-up, 5 pts have completed therapy, and 3 pts remain on treatment.

The most common any grade adverse events (AE) were thrombocytopenia (n=31), leukopenia (n=26), neutropenia (n=15), altered mental status (n=12), increased ALT (n=11). The most common grade >3 AE were neutropenia (n=13), thrombocytopenia (n=9), leukopenia (n=10), anemia (n=3), altered mental status (n=2; blina was held and resumed upon resolution of AE). One pt had grade 2 cytokine release syndrome that did not require blina to be held. There were no episodes of veno-occlusive disease.

Conclusion A largely chemotherapy-free regimen of blina in combination with InO for older or unfit pts was tolerated and resulted in high rates of MRD-negative remission with 2-year survival rates of 50%. Most deaths are attributable to non-relapse mortality, suggesting that continued optimization of treatment regimens are needed for older pts with B-cell ALL.