Blinatumomab and Ponatinib Versus Hyper‐ CVAD and Ponatinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome‐Positive Acute Lymphoblastic Leukemia: A Propensity Score Analysis

Outcomes in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have improved significantly with the advent of BCR::ABL1 tyrosine kinase inhibitors (TKIs) [1, 2]. Ponatinib, a third-generation TKI active against the T315I mutation, and blinatumomab, a CD3/CD19 bispecific T-cell engager, have each demonstrated high rates of deep molecular response and durable survival [3-9]. Recent studies combining blinatumomab with potent TKIs suggest that chemotherapy-free approaches may achieve outcomes comparable to intensive chemotherapy-based regimens [7, 9-11]. However, no randomized trial directly compares these strategies. We, therefore, conducted a propensity score analysis comparing the outcomes of patients with newly diagnosed Ph + ALL who received Hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate and cytarabine) with ponatinib versus blinatumomab with ponatinib. Patients ≥ 18 years with newly diagnosed Ph + ALL treated on clinical trial with Hyper-CVAD plus ponatinib (NCT01424982; 2011–2019) or blinatumomab plus ponatinib (NCT03263572; 2018–2025) were included. Details of each regimen have been previously reported [12-14]. Allogeneic stem cell transplantation (alloSCT) was offered to patients in first complete remission at the discretion of the treating physician. The protocols were approved by the MD Anderson Institutional Review Board and the study was conducted in accordance with the Declaration of Helsinki. Complete response (CR) and CR with incomplete count recovery (CRi) were defined per standard definitions. Complete molecular response (CMR) was defined as the absence of detectable BCR::ABL1 transcripts measured by polymerase chain reaction (sensitivity, 0.01%) in either bone marrow or peripheral blood. Measurable residual disease (MRD) was evaluated by multiparameter flow cytometry (MFC) (sensitivity, 1 × 10−4) and by next-generation sequencing (NGS) for IG/TR rearrangements (sensitivity, 1 × 10−6 by clonoSEQ) in patients in the blinatumomab plus ponatinib cohort. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan–Meier method. Cumulative incidence of relapse (CIR) was calculated with death and relapse as competing events. Baseline patient characteristics were compared between groups utilizing χ2 or Fisher's exact test for categorical data and Mann–Whitney U for continuous data. Multiple imputations were performed for missing variables to reduce the potential for bias. Logistic regression was utilized for propensity score calculation based on baseline covariates including age, gender, race, ethnicity, Easter Cooperative Oncology Group (ECOG) performance status, body mass index (BMI), smoking history, white blood cell (WBC) count, hemoglobin, platelet count, percentage of blasts in bone marrow, the presence of central nervous system (CNS) disease, percentage of CD19 and CD20 expression, BCR::ABL1/ABL1 ratio, and BCR::ABL1 transcript type. Propensity score matching was performed using the nearest neighbor method with a caliper of 0.2. Overall, prior to matching, 62 patients treated with blinatumomab plus ponatinib and 68 patients treated with Hyper-CVAD plus ponatinib were identified. Baseline characteristics before and after propensity matching are included in Table 1. Propensity score matching identified 40 patients in each cohort and eliminated any significant differences in baseline characteristics between the groups. The median age was 52 years (range, 18–83) in the blinatumomab plus ponatinib cohort and 53 years (23–74) in the Hyper-CVAD plus ponatinib group (p = 0.637). The response rates for both the pre-matched and matched patients are included in Table 2. After matching, all patients achieved a response with either treatment. After cycle 1, 56% of patients achieved a CMR with blinatumomab plus ponatinib versus 38% with Hyper-CVAD plus ponatinib (p = 0.115). The 3-month and anytime CMR rates were 68% and 80%, respectively, with blinatumomab plus ponatinib and 78% (p = 0.453) and 90% (p = 0.348) with Hyper-CVAD plus ponatinib. With blinatumomab plus ponatinib, MRD was also evaluated by NGS, with 15 of 34 patients (44%) achieving NGS MRD-negativity after cycle 1 and 53 of 55 patients (96%) achieving NGS MRD-negativity overall. Among the matched patients, after a median follow-up of 28 months for blinatumomab plus ponatinib and 143 months for Hyper-CVAD plus ponatinib, the 2-year PFS rates were 91% versus 70%, respectively (p = 0.039). Median PFS was not reached with blinatumomab plus ponatinib and 111 months with Hyper-CVAD plus ponatinib. The 2-year OS rates were 100% and 78% (p = 0.027), respectively, with median OS was not reached for either (Figure 1A,B). Survival analyses of the pre-matched patients are included in Figure S1. The estimated 2-year CIR rate was 9% and 13% for the blinatumomab plus ponatinib and Hyper-CVAD plus ponatinib cohorts, respectively (p = 0.48) (Figure S2A). Outcomes for patients who achieved CMR were similar to the entire cohort with a median PFS that was not reached in blinatumomab plus ponatinib and 96 months in Hyper-CVAD plus ponatinib (p = 0.08). In this subgroup, the estimated 2-year CIR rate was 10% in blinatumomab plus ponatinib versus 14% in Hyper-CVAD plus ponatinib (p = 0.52). CNS relapse was observed in 1 patient in each cohort. Subgroup survival analyses in the matched patients by age (< 60 years and ≥ 60 years), transcript type (p190 and p210), baseline WBC ≥ 30 × 109/L and WBC ≥ 70 × 109/L are depicted in Figure S3. Among matched patients, 1 (3%) proceeded to alloSCT with blinatumomab plus ponatinib versus 8 (20%) with Hyper-CVAD plus ponatinib (p = 0.029). Eighteen (23%) of the matched patients died, including 2 (5%) in blinatumomab plus ponatinib and 16 (40%) in Hyper-CVAD. The overall rate of vascular events with blinatumomab plus ponatinib was 23% (≥ Grade 3: 10%) and 33% (≥ Grade 3: 18%) with Hyper-CVAD plus ponatinib. The rate of grade ≥ 3 infection with Hyper-CVAD plus ponatinib is 89% overall, of which 47% occurs during induction [15]. Cytokine release syndrome and neurotoxicity occur in 12% and 25% of patients, respectively, with blinatumomab plus ponatinib, all grade 1–2. The rate of grade ≥ 3 fever/febrile neutropenia was only 3% [9]. The estimated 2-year NRM rate was 0% and 18% for the blinatumomab plus ponatinib and Hyper-CVAD plus ponatinib, respectively (p = 0.04) (Figure S2B). In our propensity score analysis, treatment with blinatumomab plus ponatinib was associated with significantly improved PFS and OS compared with Hyper-CVAD plus ponatinib, with fewer patients proceeding to alloSCT and markedly reduced NRM. Outside of a randomized prospective trial, these results indicate the superiority of blinatumomab over intensive chemotherapy with ponatinib for patients with newly diagnosed Ph + ALL. The improved outcomes observed with blinatumomab plus ponatinib are likely related to the high CMR rate coupled with the lower relapse rate and significantly reduced NRM. This is consistent with prior studies demonstrating significantly improved outcomes with the achievement of CMR [9, 11]. As a result of the high CMR rates in the phase 2 of blinatumomab and ponatinib, more than 70% of patients remain in continuous remission with only two patients proceeding to alloSCT [8]. These results are consistent with previous reports including the GIMEMA trial, where 12% of patients proceeded to alloSCT [11]. Furthermore, the reliance on alloSCT is less than the D-ALBA trial of blinatumomab with dasatinib, where 38% of patients proceeded to alloSCT [10]. Overall, the results in the present propensity analysis with blinatumomab plus ponatinib yielding a 2-year PFS rate of 91% and 2-year OS rate of 100% with only 1 patient who proceeded to alloSCT, in contrast to a 2-year PFS rate of 70% and 2-year OS rate of 78% achieved with Hyper-CVAD plus ponatinib with 20% of patients proceeding to alloSCT, are promising. Replacement of a traditional intensive chemotherapy backbone with blinatumomab spares patients from chemotherapy-associated morbidity and mortality. Furthermore, vascular events, particularly severe events, were fewer with blinatumomab plus ponatinib due to the reduced ponatinib dose utilized in this regimen beginning with induction. Despite no patients experiencing early 4-week mortality, 12% of patients treated with Hyper-CVAD and ponatinib on the phase 2 clinical trial experienced death in remission, which was mostly seen in those older than 60 years [15]. This is in contrast to the mortality rates for blinatumomab with dasatinib and blinatumomab with ponatinib, which are 3% and 5%, respectively [8, 10]. We too observed decreased rates of NRM in our analysis among patients receiving blinatumomab plus ponatinib compared to Hyper-CVAD plus ponatinib. This is likely due to a reduction in both chemotherapy-related and alloSCT-related mortality as a result of less reliance on the latter. The omission of intensive chemotherapy raises concern for CNS relapse; however this risk may be mitigated with intensified CNS prophylaxis, including increased intrathecal chemotherapy and selective use of systemic CNS-directed therapy, including chimeric antigen receptor (CAR) T-cell therapy [16, 17]. Longer follow-up is needed to validate the optimal strategy to prevent CNS relapse. This study is limited by its retrospective, single-center design, differences in follow-up between cohorts, and lack of NGS MRD comparison given the treatment timeframe of the Hyper-CVAD cohort. Additionally, while outcomes among patients with IKZFplus could not be evaluated due to differences in methodology with defining this subgroup over time, an analysis of the blinatumomab plus ponatinib phase 2 results did not find a significant association between the IKZFplus genotype and relapse [8], whereas inferior OS has been reported among these patients treated with Hyper-CVAD plus ponatinib compared to patients without IKZFplus [18]. Overall, we demonstrate that blinatumomab plus ponatinib is associated with improved survival, reduced toxicity, and less reliance on alloSCT compared with Hyper-CVAD plus ponatinib and represents a promising chemotherapy-free approach for patients with newly diagnosed Ph + ALL. Prospective randomized trials are warranted to confirm these findings. The study was performed in accordance with the Declaration of Helsinki and in compliance with good clinical practice guidelines and applicable laws. The protocol was approved by the institutional review board at MD Anderson Cancer Center. Written informed consent was obtained before study entry from each patient or from the patient's legally authorized representative if the patient was unable to provide consent. K.S.: Honoraria: Otsuka, Amgen, Chugai Pharma. Consulting or Advisory Role: Novartis, Pfizer, Takeda. Research Funding: Novartis, Enliven Therapeutics (Inst). Travel, Accommodations, Expenses: Otsuka, Amgen. H.K.: Honoraria: AbbVie, Amgen, Pfizer, Ascentage Pharma Group, Ipsen, KAHR Medical, Novartis, Shenzhen Target Rx, Daiichih-Sankyo (Inst), Immunogen (Inst)Consulting or Advisory Role: AbbVie. Research Funding: Amgen (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), AbbVie (Inst), Immunogen (Inst), Jazz Pharmaceuticals (Inst), Ascentage Pharma (Inst), Daiichi Sankyo/Lilly (Inst). C.R.R.: Advisory board: Johnson and Johnson; N.J.: Honoraria: Amgen. Consulting or Advisory Role: AstraZeneca, NGM Biopharmaceuticals, Pfizer, Takeda, Novartis, Amgen. Research Funding: Takeda, Astellas Pharma, Stemline Therapeutics. WGW: Consultancy: Acerta Pharma, Abbvie, Janssen, Cyclacel Pharmaceuticals, Eli Lilly, Wiley China, Intellisphere, BeiGene, Astrazeneca, Research Funding: Acerta Pharma, Abbvie, Oncternal Therapeutics, Genentech, GSK, Janssen, Eli Lilly, Accutar Biotechnology, Novartis, Kite, NIH/NCI, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, BMS, Juno Therapeutics, F. Hoffmann-La Roche Ltd., Nurix Therapeutics, BeiGene, Gilead Sciences, Honoraria: PeerView, Global Learning Collaborative, MJH Life Sciences, PSL Group Services. T.M.K.: Honoraria: CURE. Consulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Pfizer, AbbVie/Genentech, Agios, Daiichi Sankyo/UCB Japan, Liberum, Sanofi, Servier, Pinot Bio, Sellas Life Sciences, Bristol Myers Squibb/Celgene. Research Funding: Bristol Myers Squibb, Celgene, Amgen, BiolineRx, Incyte, Genentech/AbbVie, Pfizer, Jazz Pharmaceuticals, AstraZeneca, Astellas Pharma, Ascentage Pharma, Genfleet Therapeutics, Cyclacel, Pulmotech, cellenkos, Glycomimetics, Astex Pharmaceuticals, Iterion Therapeutics, Delta-Fly Pharma, Regeneron (Inst), Sellas Life Sciences, Abcuro, DAAN Biotherapeutics. G.B.: Consulting or Advisory Role: Argenx, PTC Therapeutics, BiolineRx, BioTheryX, Nkarta, Treadwell Therapeutics, Novartis, Catamaran Bio, Takeda, AbbVie; Research Funding: Incyte (Inst), GlaxoSmithKline (Inst), Cyclacel (Inst), BiolineRx (Inst), MedImmune (Inst), Lilly (Inst), Oncoceutics (Inst), Ryvu Therapeutics (Inst), Janssen Scientific Affairs (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Novartis (Inst), AstraZeneca (Inst), Mundipharma Research (Inst), PTC Therapeutics (Inst), BioTheryX (Inst), XBiotech (Inst), Arvinas (Inst), Astex Pharmaceuticals (Inst), TCR2 Therapeutics (Inst), Nkarta (Inst), Nkarta (Inst), Treadwell Therapeutics (Inst), Cellestia Biotech (Inst). G.C.I.: Consulting or Advisory Role: Novartis, Kura Oncology, Syndax, NuProbe, AbbVie, Sanofi. Research Funding: Novartis (Inst), Syndax (Inst), Kura Oncology (Inst), Merck, Cullinan Oncology, Astex Pharmaceuticals (Inst), NuProbe (Inst). YA: Honoraria: Astellas Pharma, Novartis. Consulting or Advisory Role: MEI Pharma. Research Funding: Jazz Pharmaceuticals (Inst), FibroGen (Inst), Sun Pharma (Inst), BerGenBio (Inst), Daiichi Sankyo/Lilly (Inst), Astex Pharmaceuticals (Inst). N.P.: Consulting or Advisory Role: Blueprint Medicines, Pacylex, Immunogen, Bristol Myers Squibb, Clearview Healthcare Partners, Astellas Pharma, CTI BioPharma Corp, AbbVie, Aptitude Health, Aplastic Anemia and MDS International Foundation, CancerNet, CareDx, Celgene, Cimeio Therapeutics, Curio Science, Dava Oncology, EUSA Pharma, Harborside Press, Imedex, Intellisphere, Intellisphere, Magdalen Medical Publishing, Medscape, Menarini Group, Neopharm, Novartis, OncLive, Patient Power, Peerview, Pharmaessentia, Physicans' Education Resource. Research Funding: US DOD (Inst). F.R.: Honoraria: Amgen, Pfizer, Astellas Pharma, Celgene, Agios, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb, Takeda, Jazz Pharmaceuticals, Novartis, Syros Pharmaceuticals, Taiho Pharmaceutical, Syndax. Consulting or Advisory Role: Amgen, Astellas Pharma, Celgene, Jazz Pharmaceuticals, Agios, AbbVie/Genentech, Bristol Myers Squibb, AstraZeneca, Taiho Oncology, Syros Pharmaceuticals, Certara Inc. Research Funding: Bristol Myers Squibb, Amgen, Macrogenics, Xencor, Selvita, Cellerant, Astex Pharmaceuticals, Taiho Oncology, Syros Pharmaceuticals, Prelude Therapeutics, Biomea Fusion, Astellas Pharma (Inst). G.G.M.: Honoraria: Curis, Bristol Myers Squibb/Celgene, Taiho Oncology, Ascentage Pharma, Servier, Keros Therapeutics. Consulting or Advisory Role: Bristol Myers Squibb, Taiho Oncology, Curis, Ascentage Pharma, Servier, Keros Therapeutics. Research Funding: Novartis, AbbVie, Bristol Myers Squibb, Genentech, Curis, Rigel, Taiho Oncology, Stemline Therapeutics, Zentalis, Chordia Therapeutics, Jazz Pharmaceuticals N.J.S.: Honoraria: Amgen. Consulting or Advisory Role: AstraZeneca, NGM Biopharmaceuticals, Pfizer, Takeda, Novartis, Amgen. Research Funding: Takeda, Astellas Pharma, Stemline Therapeutics. E.J.: Consulting or Advisory Role: Pfizer, Takeda, Amgen, AbbVie, Bristol Myers Squibb, Adaptive Biotechnologies, Genentech, Autolus, Ascentage Pharma, Taiho Pharmaceutical, Novartis, TargetRX, Terns Pharmaceuticals. Research Funding: Pfizer, Adaptive Biotechnologies, Ascentage Pharma Group, AbbVie, Takeda, Johnson & Johnson/Janssen, Jazz Pharmaceuticals, Terns Pharmaceuticals, Taiho Pharmaceutical, Novartis, Amgen, TGRX. Travel, Accommodations, Expenses: Pfizer, Aptitude Health, Autolus, Nucleus Global, ONVIV, MD Education, HMP Education, Daiichi Sankyo Nordics. X.H., M.H., R.G., H.G.: no relevant conflicts to disclose. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Figure S1: Progression-free survival of all patients before matching (A), overall survival of all patients before matching (B). Figure S2: Cumulative incidence of relapse in the matched cohort (A) and cumulative incidence of non-relapse mortality in the matched cohort (B). Figure S3: Progression-free survival (PFS) and overall survival (OS) of subgroups of interest of matched patients including PFS and OS of patients with the p190 transcript (A, B), PFS and OS of patients <60 years of age (C, D), PFS and OS of patients >60 years of age (E, F), PFS and OS of patients with the p210 transcript (G, H), PFS and OS of patients with baseline WBC > 30 × 109/L (I, J), and PFS and OS of patients with baseline WBC > 70 × 109/L (K, L). 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.