Significant progress has been made in the treatment of adults with B cell acute lymphoblastic leukemia (ALL), largely driven by immunotherapy. Blinatumomab, a CD3/CD19 bispecific T cell engager, demonstrates improved survival in relapsed/refractory ALL and among patients with measurable residual disease (MRD) positivity 1-4. When added to hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine), consolidation with blinatumomab resulted in 3-year relapse-free survival (RFS) and overall survival (OS) of 74% and 82%, respectively, among patients with newly diagnosed (ND) Philadelphia (Ph)-negative B-ALL 5, 6. The Phase 3 ECOG-ACRIN 1910 trial assessed the impact of blinatumomab in consolidation among patients achieving an MRD-negative (< 10−4) complete remission (CR) after induction, resulting in improved OS and RFS versus consolidation chemotherapy alone 7. Of the 488 patients enrolled, only 224 achieved MRD-negative remission and underwent randomization to consolidation chemotherapy with/without blinatumomab, thereby not representing an intention-to-treat population. To assess the impact of blinatumomab for adults with ND Ph-negative B-ALL, we conducted a propensity-matched analysis comparing the outcomes of patients who received hyper-CVAD alone versus hyper-CVAD with blinatumomab. Patients 16–60 years old receiving hyper-CVAD (NCT01363128) 8 or hyper-CVAD and sequential blinatumomab with/without inotuzumab ozogamicin (NCT02877303) from November 2002 to January 2025 were included 6, 9. The treatment regimens are previously described in detail; however, in hyper-CVAD plus blinatumomab, there is a reduction from eight hyper-CVAD courses to four, and beginning with patient 39, inotuzumab was added for a total of eight doses, along with a reduction in the methotrexate and cytarabine doses. Intrathecal chemotherapy administrations were increased from 8 to 12, and maintenance was reduced from 30 cycles of POMP to 12 POMP cycles with 1 course of blinatumomab given every third course 6, 8, 9. Allogeneic stem cell transplantation (alloSCT) was performed at the physician's discretion. The study was approved by the MD Anderson Institutional Review Board and conducted in accordance with the Declaration of Helsinki. The overall response rate (ORR) included patients achieving CR or CR with incomplete platelet recovery (CRp) with transfusion independence. MRD was evaluated by multiparameter flow cytometry (MFC; 10−4) and by next-generation sequencing (NGS) for IG/TR rearrangements (10−6, clonoSEQ). OS was defined as the time from treatment initiation to death from any cause, with event-free survival (EFS) defined as the time from treatment initiation to relapse or death, whichever occurred first; both censored at last follow-up. Multiple imputation was performed for missing covariates to minimize potential bias. Multivariate Cox proportional hazards regression analyses (MVA) were conducted to evaluate the impact of clinical factors on survival. Logistic regression was used for propensity score calculation based on baseline covariates, with propensity score matching performed with the nearest neighbor matching method and a caliper of 0.200. Two hundred and forty-one patients were treated with hyper-CVAD (November 2002–April 2021; n = 161) or hyper-CVAD plus blinatumomab (November 2016–January 2025; n = 80). While some patients in hyper-CVAD plus blinatumomab also received inotuzumab (n = 49), we refer to this group as hyper-CVAD plus blinatumomab throughout the manuscript. Baseline patient characteristics prior to and after matching are described in Table 1. Propensity score matching identified 55 patients in each cohort, with no significant differences remaining between the two cohorts. The response rates before and after matching are depicted in Table S1, with high ORR in both groups and no significant differences. With a median follow-up of 153 months for hyper-CVAD and 36 months for hyper-CVAD plus blinatumomab, the survival outcomes for pre-matched patients are depicted in Figures S1–S4. Univariate and multivariate Cox regression analyses for OS and EFS in the pre-matched cohort demonstrated that age, smoking, BMI, ECOG, KMT2A rearrangement, Philadelphia chromosome-like (Ph-like), and receipt of blinatumomab were significant predictors for survival, with inotuzumab not arising as an independent factor on MVA (Tables 2a, S2b). Hyper-CVAD N = 161 Hyper-CVAD + blinatumomab +/− inotuzumab N = 80 Hyper-CVAD N = 55 Hyper-CVAD + blinatumomab +/− inotuzumab N = 55 With propensity score matching, after a median follow-up of 116 months for hyper-CVAD and 39 months for hyper-CVAD plus blinatumomab, median EFS was not reached (NR) for either (Figure 1a), with 3-year EFS of 69% versus 86%, respectively (p = 0.009). Median OS was NR for either (Figure 1b), with 3-year OS with hyper-CVAD versus hyper-CVAD plus blinatumomab of 69% and 90%, respectively (p = 0.006). In the adolescent and young adult (AYA; 16–39 years old) population, median EFS and OS were NR in either, with 3-year EFS of 77% versus 89% for hyper-CVAD versus hyper-CVAD plus blinatumomab, respectively (p = 0.116). Three-year OS was 77% versus 96% for hyper-CVAD versus hyper-CVAD plus blinatumomab, respectively (p = 0.042) (Figure 2a,b). In the Ph-like population, median EFS was 77 months in hyper-CVAD versus NR in hyper-CVAD plus blinatumomab, with 3-year EFS of 63% versus 83%, respectively (p = 0.271). Median OS for Ph-like was 101 months versus NR, with 3-year OS of 63% versus 100% for hyper-CVAD versus hyper-CVAD plus blinatumomab, respectively (p = 0.099) (Figure 2c,d). For patients with high-risk cytomolecular features (defined as KMT2A-r, Ph-like, complex cytogenetics, low hypodiploidy/near triploidy, or TP53mut), median EFS for hyper-CVAD versus hyper-CVAD plus blinatumomab was 53 months versus NR, with 3-year EFS of 57% versus 81%, respectively (p = 0.013). Median OS for high-risk patients was 101 months versus NR for hyper-CVAD versus hyper-CVAD plus blinatumomab, with 3-year OS of 57% and 84%, respectively (p = 0.014) (Figure 2e,f). Among matched patients, 15 (27%) patients proceeded to alloSCT in each cohort. Seven (13%) of the 55 patients in hyper-CVAD plus blinatumomab died, including 4 (7%) post-alloSCT and 3 (5%) with relapsed disease. Of the 55 patients treated with hyper-CVAD, 21 (38%) died, 6 (11%) post-alloSCT, and 11 (20%) with relapsed disease. One patient (2%) developed therapy-related MDS, two patients (4%) died in CR, and one patient (2%) died with unknown disease status. Through our propensity score analysis, the addition of blinatumomab to hyper-CVAD was associated with improved survival among patients with ND B-ALL while allowing for a reduction in the number of intensive chemotherapy and maintenance courses. The utilization of propensity score matching allowed us to balance patient characteristics between those treated with hyper-CVAD and those treated with hyper-CVAD plus blinatumomab. The E1910 trial was a landmark analysis among responders; therefore, it did not represent an intention-to-treat population, where less than half of the patients were randomized and evaluable 7. Our propensity score analysis enables evaluation among all treated patients and provides a robust assessment of blinatumomab's impact, short of a randomized controlled trial. The incorporation of blinatumomab is being evaluated in various settings to determine the optimal timing of administration and patient populations; however, few of these groups have investigated the de-intensification of chemotherapy with blinatumomab 7, 10-12. Specifically, E1910 added four blinatumomab courses to four consolidation chemotherapy courses while maintaining the same chemotherapy intensity 7. In contrast, with hyper-CVAD and sequential blinatumomab, four courses of intensive consolidation chemotherapy were replaced with four courses of blinatumomab, resulting in lower overall exposure to cytotoxic therapy. Even in the setting of less chemotherapy, our results are consistent with E1910, which reported 3-year RFS and OS of 80% and 85%, respectively, with the addition of blinatumomab among adults in an MRD-negative CR 7. Our matched analysis demonstrated a benefit with blinatumomab across multiple subsets, including AYA, those with Ph-like genotype, and other high-risk features. These findings are consistent with E1910 and other analyses demonstrating the benefit of blinatumomab in younger and molecularly unfavorable populations 7, 13, 14. Our Ph-like subgroup was small, however, and thus should be interpreted with significant caution. In our study, receipt of alloSCT was dependent upon the treating physician. We observed a similar number of patients, 27% in each of the matched cohorts, who proceeded to alloSCT. Our analysis did not demonstrate a reduced reliance on alloSCT with blinatumomab, likely due to the high-risk patients included in the matched cohort. While 87% of patients achieved MRD negativity by FCM, NGS was only more recently adopted, and with more long-term data, it is possible that we may be able to abrogate the need for alloSCT in the frontline setting for many patients with the incorporation of blinatumomab. Several limitations warrant consideration. Although propensity score matching reduces the imbalance in measured covariates, this technique only affects known variables, and there may be differences between the cohorts that were not accounted for. In addition, there is also an imbalance in follow-up time between the two cohorts that could not be fully addressed by propensity score matching; however, the validity of our findings is supported within the time frame of the median follow-up for this group, during which the majority of events occurred. An additional limitation is that a significant number of patients in hyper-CVAD plus blinatumomab also received inotuzumab; however, its use was not significant for survival on MVA and therefore was not independently contributing to the improved survival seen here. Overall, the incorporation of blinatumomab into hyper-CVAD was associated with improved OS and EFS compared with hyper-CVAD alone, with this benefit observed across multiple relevant subsets. While E1910 demonstrated a benefit for blinatumomab in consolidation among those with MRD negativity, our analysis included an intent-to-treat population and demonstrates that efficacy can be achieved while reducing overall exposure to intensive therapy. Longer follow-up and randomized trials are needed to validate these findings. This research is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA016672. This research complied with all internationally accepted standards for research practice and is in compliance with the Helsinki Declaration and received approval from the local Institutional Review Board. This retrospective study does not require informed consent due to minimal risk to participants and the use of de-identified data. E.J. has been a consultant for AbbVie, Adaptive Biotechnologies, Amgen, Bristol-Myers Squibb, Novartis, Pfizer Canada Inc., and Takeda Onc. H.G.: none. K.S. reports fees for professional activities from Amgen, Chugai Pharmaceutical, Daiichi Sankyo Company, Novartis, Otsuka Pharmaceutical Co. Ltd., and Pfizer. C.R.R. none. N.J. Research Funding: Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, Pfizer, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Fate Therapeutics, Kite/Gilead, Mingsight, Takeda, Medisix, Loxo Oncology, Novalgen, Dialectic Therapeutics, Newave, Novartis, Carna Biosciences, Sana Biotechnology, and Kisoji Biotechnology; Advisory Board/Honoraria: Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, BMS, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, Beigene, Cellectis, MEI Pharma, Ipsen, CareDX, MingSight, Autolus, and Novalgen. T.K. has been a consultant for AbbVie, Agios, BMS, Genentech, Jazz Pharmaceuticals, Novartis, Servier, and PinotBio; has received research funding from AbbVie, BMS, Genentech, Jazz Pharmaceuticals, Pfizer, Cellenkos, Ascentage Pharma, GenFleet Therapeutics, Astellas Pharma, AstraZeneca, Amgen, Cyclacel Pharmaceuticals, Delta-Fly Pharma, Iterion Therapeutics, GlycoMimetics, and Regeneron Pharmaceuticals; and has received honoraria from Astex Pharmaceuticals. C.D.: has been a board of directors or advisory committee member for Genmab, GSK, Kura Oncology, and Notable Labs; has received honoraria from Kura, Astellas Pharma, Bluebird Bio, Bristol-Myers Squibb, Foghorn Therapeutics, Immune-Onc Therapeutics, Novartis, Takeda Oncology, Gilead Sciences, and Jazz Pharmaceuticals; is a current holder of stock options for Notable Labs; has been a consultant for AbbVie and Servier; and has received research funding from Servier, Bristol-Myers Squibb, Foghorn, Immune-Onc Therapeutics, Loxo Oncology, Astex Pharmaceuticals, Cleave, and Forma. N.D. has received research funding from Astellas Pharma, AbbVie, Genentech, Daiichi Sankyo, Gilead Sciences, ImmunoGen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi Pharm, Fate Therapeutics, Amgen, Kite Pharma, Novartis, Astex Pharmaceuticals, KAHR, Shattuck, Sobi, GlycoMimetics, and Trillium; has been an advisor for Astellas Pharma, AbbVie, Genentech, Daiichi Sankyo, Novartis, Jazz Pharmaceuticals, Amgen, Servier, Karyopharm Therapeutics, Trovagene, Trillium, Syndax, Gilead Sciences, Pfizer, Bristol Myers Squibb, Kite Pharma, Actinium Pharmaceuticals, Arog Pharmaceuticals, ImmunoGen, Arcellx, and Shattuck; has been a data monitoring committee member for Kartos Therapeutics and Jazz Pharmaceuticals; has been a consultant or board of directors or advisory committee member for Agios, Celgene, Sobi, and STAR Therapeutics; and has received research funding from Karyopham Therapeutics and Newave Pharmaceutical. N.P. reports grants/contracts from the US Department of Defense; personal/consulting fees from AbbVie, Bristol Myers Squibb Company, GSK Consulting, Immunogen, Incyte Corporation, Johnson and support for other professional activities from CTI BioPharma, Dan's House of Hope, Menarini Group, and Payclex outside the submitted work. F.R. has received research funding from Amgen, Astex Pharmaceuticals/Taiho Oncology, BMS/Celgene, Syos, AbbVie, Prelude, Xencor, Astellas Pharma, and Biomea Fusion as well as honoraria from Amgen, BMS/Celgene, Syos, AbbVie, and Astellas Pharma; has been a board of directors or advisory committee member for Astex Pharmaceuticals/Taiho Oncology; and has been a consultant for BMS/Celgene, Syos, Novartis, AbbVie, AstraZeneca, and Astellas Pharma. G.M.-B. none. G.G.-M. has received research funding from Astex Pharmaceuticals, Novartis, AbbVie, BMS, Genentech, Aprea Therapeutics, Curis, and Gilead Sciences; has been a consultant for Astex Pharmaceuticals, Acceleron Pharma, and BMS; and has received honoraria from Astex Pharmaceuticals, Acceleron Pharma, AbbVie, Novartis, Gilead Sciences, Curis, Genentech, and BMS. D.H. none. M.S.: none. M.H. none. R.K.: none. M.O. none. R.G. none. N.J.S. has been a consultant for Takeda Oncology, AstraZeneca, Amgen, Novartis, and Pfizer and received research funding from Takeda Oncology, Astellas, and Stemline Therapeutics as well as honoraria from Amgen. H.M.K. has received research funding from AbbVie, Amgen, Ascentage Pharma, BMS, Daiichi Sankyo, ImmunoGen, Jazz Pharmaceuticals, and Novartis as well as honoraria from AbbVie, Amgen, Amphista Therapeutics, Ascentage Pharma, Astellas Pharma, Biologix, Curis, Ipsen, KAHR, Novartis, Pfizer, Precision Biosciences, Shenzhen TargetRx, and Takeda Oncology. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Response before and after matching. Table S2a. Univariate and multivariate analysis for overall survival in the pre-matched groups (a p-value cutoff of 0.100 from univariate to multivariate). Table S2b. Univariate and multivariate analysis for event-free survival in the pre-matched groups (a p-value cutoff of 0.100 from univariate to multivariate). Figure S1a. All pre-matched patients’ EFS. Figure S1b. All Pre-Matched Patients OS. Figure S2a. AYA pre-matched patients’ EFS. Figure S2b. AYA pre-matched patients’ OS. Figure S3a. Ph-like pre-matched patients’ EFS. Figure S3b. Ph-like pre-matched patients’ OS. Figure S4a. High-risk pre-matched patients’ EFS. Figure S4b. High-risk pre-matched patients’ OS. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Jabbour et al. (Sat,) studied this question.