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Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common., (© 2024 Wiley Periodicals LLC.)

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is associated with a poor response to standard chemotherapy. However, outcomes with novel antibody and cellular therapies in relapsed/refractory (r/r) Ph-like ALL are largely unknown. We conducted a single-center retrospective analysis of adult patients (n = 96) with r/r B-ALL and fusions associated with Ph-like who received novel salvage therapies. Patients were treated with 149 individual novel regimens (blinatumomab = 83, inotuzumab ozogamicin [InO] = 36, and CD19CAR T cells = 30). The median age at first novel salvage therapy was 36 years (range; 18-71). Ph-like fusions were IGH::CRLF2 (n = 48), P2RY8::CRLF2 (n = 26), JAK2 (n = 9), ABL-class (n = 8), EPOR::IGH (n = 4) and ETV6::NTRK2 (n = 1). CD19CAR T cells were administered later in the course of therapy compared to blinatumomab and InO (p < .001) and more frequently in recipients who relapsed after allogeneic hematopoietic cell transplantation (alloHCT) (p = .002). Blinatumomab was administered at an older age compared to InO and CAR T-cells (p = .004). The complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates were 63%, 72%, and 90% following blinatumomab, InO and CD19CAR, respectively, among which 50%, 50%, and 44% of responders underwent consolidation with alloHCT, respectively. In multivariable analysis, the type of novel therapy (p = .044) and pretreatment marrow blasts (p = .006) predicted the CR/CRi rate, while the Ph-like fusion subtype (p = .016), pretreatment marrow blasts (p = .022) and post-response consolidation with alloHCT (p < .001) influenced event-free survival. In conclusion, novel therapies are effective in inducing high remission rates in patients with r/r Ph-like ALL and successfully transitioning the responders to alloHCT., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for acute lymphoblastic leukemia (ALL), yet large amounts of data describing alloHCT outcomes in Philadelphia (Ph)-like ALL are lacking. We retrospectively analyzed archived DNA samples from consecutive adults with B-cell Ph-negative ALL who underwent alloHCT in complete remission (CR) (n = 127) at our center between 2006 and 2020. Identification of fusions associated with Ph-like ALL was performed using cumulative results from RNA-seq, conventional cytogenetics, fluorescence in situ hybridization, and whole genome array studies. Fusions associated with Ph-like ALL were detected in 56 (44%) patients, of whom 38 were carrying CRLF2r. Compared with other non-Ph-like ALL (n = 71), patients with fusions associated with Ph-like ALL were more frequently Hispanic (P = .008), were less likely to carry high-risk cytogenetics (P < .001), and were more likely to receive blinatumomab prior to HCT (P = .019). With the median followup of 3.5 years, patients with Ph-like ALL fusions had comparable posttransplant outcomes compared with other B-cell ALL: 3-year relapse-free survival (RFS) (41% vs 44%; P = .36), overall survival (OS) (51% vs 50%; P = .59), and relapse (37% vs 31%; P = .47). In multivariable analysis, age (P = .023), disease status at the time of transplant (P < .001), and donor type (P = .015) influenced OS. RFS (primary endpoint) was significantly influenced by disease status (P < .001) and conditioning regimen intensity (P = .014). In conclusion, our data suggest that alloHCT consolidation results in similarly favorable survival outcomes in adult patients with Ph-like fusions and other high-risk B-cell ALL., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease-positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19- disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood., Methods: This study retrospectively reviewed the outcomes of adult patients with B-cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013-2021) and analyzed factors associated with treatment response and EMD failure., Results: The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P = .049) and no history of previous EMD (P = .019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P = .005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P = .012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD., Conclusions: A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure., Lay Summary: Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. Most extramedullary failure cases retain CD19 expression., (© 2021 American Cancer Society.)

Safety and efficacy of allogeneic hematopoietic stem cell transplantation (alloHCT) consolidation after blinatumomab is largely undetermined. To address this issue, we assembled multi-center data of relapsed refractory (RR) acute lymphocytic leukemia (ALL) patients who received alloHCT after blinatumomab. From December 2014 to May 2019, 223 patients who received blinatumomab for RR ALL outside clinical trials were identified. Among them, 106 (47%) patients transplanted post blinatumomab were evaluated for response and toxicity. Ninety-two (87%) patients received alloHCT after achieving CR, while remaining received subsequent salvage prior to undergoing alloHCT. Progression free survival (PFS) and overall survival (OS) at 2 years post alloHCT was 48% (95% CI: 36-59%) and 58% (95% CI: 45-69%), respectively. The cumulative incidence of GIII-IV aGVHD at 3 months was 9.9% (95% CI: 5.0-16.6%). Similarly, cumulative incidence of moderate to severe cGVHD at 2 years was 34.4% (95% CI: 23.7-45.3%). The overall survival at 2 years was not significantly different in patient who achieved CR with MRD negative (68.4% [95% CI: 28.5-89.1%]) compared to CR with MRD positive (63.4% [95% CI: 47.8-75.4%]) prior to alloHCT (p = 0.8). Our real-world analysis suggests that alloHCT is feasible and effective post blinatumomab in patients with RR ALL., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Opinion Statement: Acute lymphoblastic leukemia (ALL) in adults is associated with poor outcomes as compared to children when treated with chemotherapy, leading to a considerably inferior cure rate. Historically, consolidation with allogeneic hematopoietic cell transplant (alloHCT) was routinely recommended for eligible adults with ALL in first complete remission (CR1) if a donor was available, since randomized studies showed superiority over continuing chemotherapy. With the increasing use of pediatric-inspired frontline regimens in young adults with ALL and the availability of novel salvage agents for relapsed/refractory B-cell ALL that have high potential in inducing a second CR, the role of early alloHCT in the treatment paradigm for ALL needs to be reevaluated, and the decision should be individualized for each patient. Simultaneously, alloHCT has evolved considerably lately, and historical randomized studies that have proven the benefit of alloHCT in adults with ALL in CR1 did not included the increasing use of reduced intensity conditioning and haploidentical transplants, and therefore, data may not entirely apply. Nowadays, detectable minimal residual disease (MRD) is the most prognostic determinant of ALL outcome and should be a major consideration in the decision to perform alloHcT in CR1. Nonetheless, other biological and clinical factors remain relevant and can support the complex decision-making. Such factors include high-risk leukemia genetics, the type of administered chemotherapy regimen and the ability of the patient to tolerate all key components of the regimen, and the availability of effective salvage therapies that allow alloHCT to be performed in CR2 in case of relapse after chemotherapy.

Background: The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity., Methods: In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared., Results: Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P = .73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety-two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P = .09)., Conclusions: Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL., (© 2020 American Cancer Society.)

Introduction of novel salvage therapies and expansion of the donor pool within the past decade have allowed more patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) to receive allogeneic hematopoietic cell transplantation (alloHCT). The impact of each salvage therapy on transplant outcomes have not been compared. Our primary objective was to determine post-HCT relapse-free survival (RFS) in adult patients with r/r Philadelphia-chromosome negative (Ph neg ) B-ALL. We retrospectively studied alloHCT outcomes in 108 adult patients with r/r Ph neg B-ALL transplanted in morphological remission achieved by salvage therapy. Salvage therapies were chemotherapy-based combination (n = 45, 42%), blinatumomab (n=43, 40%), inotuzumab (n = 14, 13%), or CAR T cells (n = 6, 6%). The 2-year RFS and overall survival (OS) were 44% and 50%, respectively. In multivariable analysis, conditioning with reduced-intensity or non-myeloablative regimens (hazard ratio [HR] = 2.23, 95% confidence interval [CI], 1.31-3.80; P = .003), having received ≥3 lines of therapies prior to transplant (HR = 2.66, 95% CI, 1.56-4.54; P < .001), and inotuzumab (HR = 2.42, 95% CI, 1.14-5.12; Wald P value = .021) were independently associated with lower RFS. Blinatumomab (HR = 1.10, 95% CI, 0.62-1.96) had comparable RFS to chemotherapy. Incidence of hepatic sinusoidal syndrome was highest with inotuzumab (P < .001); however, 30-day mortality and intensive care unit admissions were not different per salvage therapy. The alloHCT in r/r Ph neg B-ALL after remission induction with blinatumomab or chemotherapy led to encouraging outcomes if morphologic CR was achieved. In contrast, pretransplantation inotuzumab therapy was associated with inferior RFS. Larger studies are warranted to confirm our observations. Early transplantation after relapse and the utilization of myeloablative conditioning, when feasible, were key factors associated with improved outcomes after alloHCT in these patients., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Inotuzumab ozogamicin (InO) is an anti-CD22 monoclonal antibody-drug (calicheamicin) conjugate that has shown superior efficacy compared to conventional chemotherapy in relapsed/refractory (RR) B-cell acute lymphocytic leukemia (ALL) patients. We sought to find the safety and efficacy of InO in a real-world setting., Patients and Methods: A multicenter cohort analysis on 84 RR ALL patients who received InO outside of clinical trials was conducted to evaluate response and toxicity., Results: The median (range) age of patients at InO initiation was 50 (20-87) years. Forty patients (48%) had ≥ 3 therapies and 23 patients (27%) underwent allogeneic hematopoietic stem-cell transplantation (allo-HCT) before InO. The median (range) number of cycles of InO provided was 2 (1-6), and cumulative dose was 3.3 (1.8-9.3) mg/m 2 . Overall response rate (complete remission/complete remission with incomplete count recovery) was 63%; 44% had complete remission with minimal residual disease negativity. Twenty-three patients (27%) with response received allo-HCT. The median duration of response was 11.5 months and when censored at allo-HCT was not reached (51% in remission at 2 years). The median overall survival after InO was 11.6 months and when censored at time of allo-HCT was 13.6 months. The most common grade 3 or higher adverse events observed were transaminitis (16%), hyperbilirubinemia (5%), bleeding (4%), veno-occlusive disease (2%), and hyperglycemia (2%). In multivariate analysis, allo-HCT after InO did not retain favorable significance for duration of response (hazard ratio = 1.27; 95% confidence interval, 0.89-1.61; P = .2) or overall survival (hazard ratio = 1.10; 95% confidence interval, 0.37-3.25; P = .85)., Conclusion: InO was well tolerated and had significant efficacy in RR B-cell ALL patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The availability and use of blinatumomab symbolizes a paradigm shift in the management of B-cell acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter cohort analysis of 239 ALL patients (227 relapsed refractory [RR], n = 227; minimal residual disease [MRD], n = 12) who received blinatumomab outside of clinical trials to evaluate safety and efficacy in the "real-world" setting. The median age of patients at blinatumomab initiation was 48 years (range, 18-85). Sixty-one (26%) patients had ≥3 prior therapies and 46 (19%) had allogeneic hematopoietic cell transplantation before blinatumomab. The response rate (complete remission/complete remission with incomplete count recovery) in patients with RR disease was 65% (47% MRD-). Among 12 patients who received blinatumomab for MRD, 9 (75%) patients achieved MRD negativity. In patients with RR disease, median relapse-free survival and overall survival (OS) after blinatumomab was 32 months and 12.7 months, respectively. Among patients who received blinatumomab for MRD, median relapse-free survival was not reached (54% MRD- at 2 years) and OS was 34.7 months. Grade ≥3 cytokine release syndrome, neurotoxicity, and hepatotoxicity were observed in 3%, 7%, and 10% of patients, respectively. Among patients who achieved complete remission/complete remission with incomplete count recovery, consolidation therapy with allogeneic hematopoietic cell transplantation retained favorable prognostic significance for OS (hazard ratio, 0.54; 95% confidence interval, 0.30-0.97; P = .04). In this largest "real-world" experience published to date, blinatumomab demonstrated responses comparable to those reported in clinical trials. The optimal sequencing of newer therapies in ALL requires further study., (© 2020 by The American Society of Hematology.)