Abstract
Introduction: Outcomes for adult patients (pts) with Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL) have markedly improved in the era of post-remission consolidation with blinatumomab (blina), a bispecific CD19xCD3 T-cell engager (Foa, NEJM 2020; Jabbour, Lancet Haem 2023). Recent evidence suggests pre-blina MRD status is prognostic of post-blina outcomes in Ph- B-ALL (Bassan, Blood 2025). Here, we explored the prognostic significance of pre-blina MRD status for adult Ph+ B-ALL patients in MRD negative remission following blina consolidation.
Methods: We retrospectively reviewed pts with Ph+ B-ALL or chronic myeloid leukemia in lymphoid blast crisis (CML-LBC) age ≥18 years who were MRD-negative after receiving ≥1 cycles of blina consolidation during first complete remission (CR1) at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC) between 2012 and 2024. MRD was defined as ≥0.01% leukemia cells in the bone marrow as detected by clinical flow cytometry at the treating institution. IKZF1+ genotype was defined as concurrent IKZF1 aberration (deletion or mutation) with CDKN2A/B and/or PAX5 aberrations. All progression free (PFS) and overall survival (OS) analyses were performed from time of post-blina MRD assessment. A multivariable cox proportional hazard model was constructed from variables selected based on clinical relevance to assess effects of IKZF1+ genotype, extramedullary (EM) disease and/or central nervous system (CNS) disease at diagnosis, pre-blina MRD status, number of cycles of blina (1 vs 2+), and subsequent consolidative HCT (salvage HCT excluded; treated as a time-varying covariate) on PFS and OS.
Results: A total of 67 pts met eligibility criteria, including 43 (64.2%) pre-blina MRD-negative pts (MRD-) and 24 (35.8%) pre-blina MRD-positive pts (MRD+). Median time from treatment initiation to pre-blina MRD assessment was 62.5 days (IQR 31.2-87.7 days). The MRD- and MRD+ pts did not differ by age (median 58.1 vs. 53.3 years, respectively; p = 0.69), sex (51.7% vs. 44.4% female; p = 0.77), CML-LBC (7.0% vs. 16.7%; p = 0.24), presence of IKZF1+ genotype (14.0% vs. 4.2%; p = 0.41), EM and/or CNS disease at diagnosis (13.9% vs 20.0%; p = 0.71), or receipt of chemotherapy with induction (30.2% vs 20.8%; p = 0.57). During induction, MRD- and MRD+ pts had similar exposure rates to dasatinib (81.4% vs 91.7%, respectively; p = 0.31), ponatinib (14.0% vs. 33.3%; p = 0.11), and other TKIs (11.6% vs. 8.3%; p > 0.99). MRD- pts trended towards a greater number of blina cycles (median 2, range 1-7) than MRD+ pts (median 2, range 1-5; p = 0.06), but the proportion of pts receiving 2+ cycles of blina was similar between MRD- (72.1%) and MRD+ (58.3%) pts (p = 0.29). The frequency of consolidative HCT after blina was similar between MRD- patients (44.2%) and MRD+ patients (66.7%; p = 0.13).
With a median follow-up of 2.4 years from post-blina MRD assessment (range 0.20-7.5 years), the median PFS and OS were not reached for MRD- pts versus 3.8 years (p = 0.054) and 5.7 years (p = 0.013), respectively, for MRD+ pts. In the multivariable setting, MRD- status was associated with improved PFS (HR 0.20, 95% CI 0.04-0.88; p = 0.033) and OS (HR 0.04, 95% CI 0.002-0.54; p = 0.016) compared with MRD+ status. No other variables were significantly associated with PFS or OS on multivariable analysis.
Overall, receiving consolidative HCT post-blina was not associated with improved PFS (HR 1.27, 95% CI 0.26-6.16; p = 0.76) or OS (HR 0.71, 95% CI 0.09-5.45; p = 0.74). MRD- pts who did (n = 19) versus did not (n = 24) proceed to consolidative HCT had similar PFS (p = 0.74) and OS (p > 0.99). MRD+ pts who did (n = 16) versus did not (n = 8) proceed to HCT also had similar PFS (p = 0.44) but trended towards improved OS (no deaths versus estimated 83.3% [90% CI 38.8-96.6%] OS at 2-years, respectively; p = 0.12).
Summary: In a two-institution cohort of adult Ph+ B-ALL pts who were MRD- after blina consolidation in CR1, MRD- status pre-blina was associated with improved survival, irrespective of analyzed covariables. Post-blina HCT was not associated with improved survival, though this may be limited by sample size and follow-up duration. These data suggest pre-blina MRD status is prognostically important even in post-blina MRD- patients. Future studies to assess the role of consolidative HCT in pre-blina MRD+ and MRD- subgroups are encouraged.
