Outcomes following allogeneic hematopoietic cell transplantation relapse in Philadelphia chromosome‐positive acute lymphoblastic leukemia
Authors: Tamer Othman, Shanpeng Li, Jianying Zhang, Hoda Pourhassan, Vaibhav Agrawal, Dat Ngo, Jason Chen, Leonardo Farol, Firoozeh Sahebi, Karamjeet Sandhu, Ricardo Spielberger, Guido Marcucci, Stephen J. Forman, Anthony S. Stein, Ryotaro Nakamura, Vinod Pullarkat, Matthew Mei, Ibrahim Aldoss, Paul Koller
Journal: American Journal of Hematology (2024)

Improved first progression-free survival following allogeneic hematopoietic cell transplantation relapse with the use of immunotherapy. Allogeneic hematopoietic cell transplantation (HCT) is potentially curative in Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).1 However, ~30%–35% eventually relapse, and outcomes in this setting have historically been poor. Recent advancements in allogeneic HCT techniques, such as improved supportive care, increasing use of reduced intensity conditioning over myeloablative regimens and alternative donors to matched siblings,2 the availability of more potent tyrosine kinase inhibitors (TKI), increasing use of TKI maintenance post-HCT, and the accessibility to novel salvage immunotherapeutics, including blinatumomab, inotuzumab ozogamicin (InO), and chimeric antigen receptor T-cell therapy, have improved outcomes in Ph+ ALL patients.1, 3 While outcomes with these newer therapies have been described in patients with Philadelphia-negative ALL who relapsed after HCT, there are no reports describing the outcomes with these therapies in patients with Ph+ ALL who relapse after HCT. Herein, we report the City of Hope (COH) experience in managing Ph+ ALL post-HCT relapse. We retrospectively analyzed Ph+ ALL adult patients who underwent their first allogeneic HCT at COH and relapsed between July 1, 2006, and January 30, 2023. We defined morphologic relapse as bone marrow (BM) blasts ≥5%, evidence of extramedullary/lymph node disease (LND), or central nervous system (CNS)-3 disease or cranial nerve involvement. Measurable residual disease (MRD) relapse was defined as either ≥0.01% blasts by multiparameter flow cytometry (MFC) or BCR::ABL1 transcripts by PCR. Progression-free survival (PFS), defined as time from post-HCT relapse to progression (i.e., documented morphologic or MRD relapse after starting first treatment line post-HCT relapse), was the primary endpoint. PFS was chosen as event-free survival often includes treatment discontinuation, which we did not believe was relevant here, and relapse-free survival has not consistently included MRD relapse in the literature.4 The complete molecular response (CMR) rate, defined as BCR::ABL1 <0.01%, and overall survival, the time from post-relapse HCT to death, were the secondary endpoints. Survival probabilities were obtained using the Kaplan–Meier estimator, starting at the time of relapse post-HCT. Cox proportional hazards model was used to calculate hazard ratios in both the univariate and multivariate analyses. Alive patients were censored at the date of last follow-up. A log-rank test was used to compare the survival probabilities between two groups. We identified 290 adult patients with Ph+ ALL who received their first allogeneic HCT at COH, of whom 53 (18.3%) relapsed. Twenty-two patients (41.5%) had BM relapse, 2 patients (3.8%) had isolated LN relapse, 10 patients (18.9%) had isolated CNS relapse, and 19 patients (35.8%) had MRD relapse. Among MRD relapse patients, 7 (36.9%) were both MRD-positive at the time of HCT and had persistent MRD-positivity on their first disease assessment post-HCT. Patient, disease, and transplant characteristics are described in Supplementary Table 1. Of note, the median follow-up for our cohort after the first post-HCT relapse was 2.2 years (range, 0.02–12.8). The median time to morphologic and MRD relapse were 15.3 (range, 4.6–191.0) and 3.2 (range, 2.4–102.2) months, respectively. Management of each type of relapse is summarized in Supplementary Figure 1. Supplementary Table 2 provides a breakdown of treatment choice by three different eras: 2006–2009, 2010–2014, and 2015–2022. CMR rates to first salvage therapy are listed in Supplementary Table 3A. Of the patients with morphologic BM relapse, 15 (68.2%) achieved CR after one salvage therapy, with 13 (92.9%) responders achieving CMR. Seven patients with morphologic BM relapse developed a T315I mutation. Their responses are summarized in Supplementary Table 3B. The 2-year PFS and OS for patients with systemic relapse (BM and/or isolated LND) were 24.9% (95% confidence interval [CI], 11.4–54.4) and 43% (95% CI, 26–71), respectively (Figure 1A,B). Of the 10 isolated CNS relapses, 8 (80.0%) achieved CNS-1 and 2 were completely refractory to all therapies, and their 2-year PFS and OS were 40.0% (95% CI, 18.7–85.5) and 70.0% (95% CI, 46.7–100), respectively. Nine patients with bone marrow or isolated LN relapse underwent a second allogeneic HCT, and an additional three received donor lymphocyte infusion (DLI). Of these 12 patients, 9 (75.0%) died; 4 due to ALL, 3 due to infection, 1 due to sinusoidal obstructive syndrome (SOS), and 1 due to an unknown cause. Three patients remained alive post-second transplant/DLI after a median follow-up of 5.2 years after the first HCT relapse. Of 19 patients with MRD relapse or persistent MRD post-HCT, 16 (84.2%) were detected by PCR only, 2 (10.5%) by both MFC and PCR, and 1 by MFC alone. Eighteen patients (94.7%) achieved CMR with a TKI alone (17 received imatinib or a second-generation TKI, while 1 received ponatinib). One patient did not receive a TKI due to graft failure after their first transplant and received two subsequent transplants but died of infection before achieving CMR. The 2-year PFS and OS of MRD relapse only patients were 68.4% (95% CI, 50.4–92.9) and 83.6% (95% CI, 68.2–100), respectively (Figure 1A,B). Novel immunotherapies were only used in patients with morphologic relapse. Notably, PFS in patients with systemic relapse receiving immunotherapies as first salvage after HCT relapse was superior compared with those who did not receive immunotherapy after initial relapse post-HCT, but there was no difference in OS, possibly due to the use of these agents in subsequent relapses (Supplementary Figure 2). Univariate and multivariate analyses are shown in Supplementary Table 4. Briefly, MRD relapse only and post-HCT relapse year 2015 or after were associated with a significant improvement in PFS in the multivariate analysis, p = .02 and p = .049, respectively. Of the 53 patients who relapsed, there were 26 (49.1%) deaths. Causes of death include ALL (n = 12, 46.2%), infection while in remission (n = 8, 30.8%), SOS while in remission after receiving three doses of InO each 1 week apart followed by a second HCT 83 days after the last dose of InO (n = 1, 3.8%), therapy-related acute myeloid leukemia (n = 1, 3.8%), and unknown cause (n = 4, 15.4%). Here, we described a comprehensive analysis for managing relapsed Ph+ ALL after allogeneic HCT in the contemporary era. A prior European Society for Blood and Marrow Transplant (EBMT) report demonstrated that OS post-HCT relapse in Ph+ ALL has improved over time, with patients receiving treatment from 2015 onwards having the best survival.1 However, details on treatments in this setting were not available in this report. The improvement in outcomes in the more recent years is likely due to the use of novel immunotherapeutic agents and second- and third-generation BCR::ABL TKIs. Indeed, most post-HCT relapses in Ph+ ALL occur due to ABL kinase domain mutations,1 and ponatinib has striking efficacy in the most resistant mutations, such as T315I.5 Although our univariate and multivariate analyses did not show the superiority of ponatinib versus older generation TKIs when used as the first TKI post-HCT relapse, it should be highlighted that older TKIs were more commonly used for MRD relapse only patients, and that many patients received ponatinib for subsequent relapses after the initial HCT relapse, which affected our analysis. Moreover, although utilization of novel immunotherapies was limited, encouraging response and MRD-negativity rates were noted as previously documented in Philadelphia-negative ALL post-HCT relapse,3 while the use of immunotherapy for management of the first relapse post-HCT led to superior PFS. Past studies have shown some success with a second allogeneic HCT and/or DLI with TKIs; however, these have been largely limited to case reports and series.6 In our experience, high rates of relapse and treatment-related mortality were observed with second allogeneic HCT and DLI, and only 25.0% (3 out of 12 patients) were long-term survivors. Importantly, all but one patient with only MRD relapse was able to achieve CMR, and long-term PFS and OS for the group overall were favorable with a TKI alone approach, despite over a third of patients having persistent MRD-positivity pre- and post-HCT. Thus, it appears that TKI alone is effective in inducing durable remissions in MRD only relapse post-HCT. While this study does have limitations, including the analysis being limited to one center, the relatively small sample size, the lack of controls, and the fact that the utilization of novel agents in our cohort was limited, we can conclude that morphologic relapse in Ph+ ALL post-HCT remains challenging to manage but has improved in recent years, likely owing to increased use of novel therapies including new immunotherapies and more potent TKIs. Moreover, early detection with frequent MRD testing and early intervention with TKIs appears to improve survival. Research reported in this publication included work performed in the Biostatistics Shared Resource supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Tamer Othman, Shanpeng Li, Jianying Zhang, Hoda Pourhassan, Vaibhav Agrawal, Dat Ngo, Jason Chen, Leonardo Farol, Firoozeh Sahebi, Ricardo Spielberger, and Stephen J Forman have no conflicts to disclose. Karamjeet Sandhu: Autolus Therapeutics—Consultancy. Anthony S Stein: Sanofi—Current Employment and Current holder of stock options in a privately-held company. Guido Marcucci: Ostentus Therapeutics—Current equity holder in a private company and research funding. Ryotaro Nakamura: Napajen—Consultancy; Blue Bird—Consultancy; Sanofi—Consultancy; Omeros—Consultancy; Jazz Pharmaceuticals—Consultancy and other: research collaboration; Miyarisan—Research funding; NCCN—Other: guideline panel for HCT; Leukemia & Lymphoma Society—Other: grant reviewer; BMT CTN Steering Committee—Membership on an entity's Board of Directors or advisory committees; NCTN Lymphoma Steering Committee—Membership on an entity's Board of Directors or advisory committees; Mt. Sinai—Other: Acute GVHD; International Consortium—Other: consortium chair. Vinod Pullarkat: AbbVie—Consultancy and Speakers Bureau; Genentech—Consultancy and Speakers Bureau; Pfizer—Consultancy and Speakers Bureau; Jazz Pharmaceuticals—Consultancy and Speakers Bureau; Novartis—Consultancy and Speakers Bureau; Servier—Consultancy and Speakers Bureau; Amgen—Consultancy and Speakers Bureau. Matthew Mei: Consulting—Novartis, SeaGen, CTI, Janssen, EUSA, ADC, AstraZeneca; Speakers' Bureau—SeaGen, Incyte; Research funding—BMS, Beigene, Morphosys, Incyte. Ibrahim Aldoss: Takeda—Consultancy; Amgen—Consultancy and Honoraria; Pfizer—Consultancy; Jazz—Consultancy; Sobi—Consultancy; KiTE—Consultancy. Paul Koller—Advisory board fees from Novartis, Takeda, Daiichi Sankyo, BMS, and Ascentage, the speaker's bureau of Takeda and Novartis, reports participating in the data safety monitoring board with Treadwell Therapeutics. Consent was not required for this retrospective study. Data S1. 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