Disease status at initiation of blinatumomab and depth of response after cycle 1 are associated with survival in Philadelphia chromosome positive B cell acute lymphoblastic leukemia patients treated with blinatumomab and tyrosine kinase inhibitors

Abstract

Abstract Introduction: Philadelphia chromosome positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) was historically classified as a very high-risk acute lymphoblastic leukemia. The development of tyrosine kinase inhibitors (TKIs) significantly improved outcomes for Ph+ B-ALL patients. Recently, clinical studies have shown outstanding response and survival outcomes using a chemotherapy free regimen of TKIs and the CD19-CD3 bi-specific T cell engager, blinatumomab (blina). We report the association of disease status at initiation of blina and early response rates with survival outcomes in newly diagnosed (ND) or relapsed/refractory (R/R) ph+ B-ALL patients treated with blina + TKIs in an off-trial setting. Methods: We retrospectively reviewed the medical records of patients with Ph+ B-ALL treated with blina-TKI for ND or R/R disease in five medical centers. The corresponding local institutional review boards approved this study. Complete molecular response (CMR) was defined as a complete remission (CR) with undetectable BCR-ABL transcripts using standardized real-time PCR. Results: We included 25 Ph+ B-ALL patients (17 ND, 8 R/R). Median age was 60 years [IQR 49.5-69.5], 52% were male, and functional status was ECOG 0-2, with 84% being ECOG 0-1. The median charlson comorbidity index (CCI) was 3 [IQR 2-5.75]. The median WBC count at diagnosis was 36.5 x109/L [IQR 8.9-95.5], and the median bone marrow blast count was 80% [55-90]. One (4%) patient initiated treatment with imatinib, 15 (60%) with dasatinib, and 9 (36%) with ponatinib. Steroids were added to TKIs in 76% of patients for a median of 42 days [IQR 30-48]. The first cycle of blina occurred after a median of 98 days [IQR 2-142] from initiating TKI. At initiation of blina cycle 1, 8 patients had active disease, and of 17 patients in complete remission (CR), 6 were in complete molecular response (CMR). Patients received a median of 3 [IQR 2-5] blina cycles, and 10 [IQR 7-12] intrathecal chemotherapy treatments. Nine (36%) patients underwent an allogeneic hematopoietic stem cell transplant (allo-HSCT). Of 23 patients who completed blina treatment, 22 (96%) continued maintenance TKIs. Ten (40%) patients required a switch to a different type of TKI at some point, 6 due to intolerance, 1 due to progression, 1 due to a T315I mutation, and 2 for other reasons. All 24 patients assessed for disease status were in CR after blina cycle 1, 70% were in CMR. After blina cycle 2, 85% were in CMR. The median follow up for all patients was 25.3 months. The Kaplan Meyer analysis showed an estimated two year OS and RFS of 85% and 77%, respectively. Five patients relapsed, 4 subsequently received salvage treatment, and only 1 patient achieved a continuous additional remission. Disease status at initiation of blina cycle 1 (active disease vs. CR vs. CMR) was associated with OS (24 month OS 30% vs 100% vs 100% respectively, p=0.001) and RFS (24 month RFS 53% vs 79% vs 100%, respectively, p=0.047). Depth of response after blina cycle 1 (CMR vs. CR with detectable BCR-ABL) was significantly associated with RFS (24 month RFS 87% vs 42%, respectively, p=0.025). A trend for association of depth of response after blina cycle 1 and OS was observed (24 month OS 100% vs. 60%, respectively, p=0.062). Noting that a low event rate and small size cohort limit this analysis, neither the presence of over 80,000 WBC at presentation, R/R status, age, BMI or undergoing a HSCT were significantly associated with survival outcomes. Conclusions: Chemotherapy free treatment with blina + TKIs in adult Ph+ B-ALL patients achieves outstanding response and survival outcomes at first or advanced lines of treatment in a real world setting. Disease status at initiation of blina and response after cycle 1 of blina are both associated with survival outcomes. A low event rate limits the ability to identify additional significant associations in this cohort.