Dismal outcomes of patients with relapsed/refractory Philadelphia chromosome‐negative B‐cell acute lymphoblastic leukemia after failure of both inotuzumab ozogamicin and blinatumomab
Authors: Nicholas J. Short, Walid Macaron, Marina Konopleva, Farhad Ravandi, Nitin Jain, Ghayas C. Issa, Tapan Kadia, Koji Sasaki, Partow Kebriaei, Musa Yilmaz, Philip A. Thompson, Koichi Takahashi, Hussein A. Abbas, William G. Wierda, Rebecca Garris, Hagop M. Kantarjian, Elias Jabbour
Journal: American Journal of Hematology (2022)

To the Editor: Both inotuzumab ozogamicin (INO) and blinatumomab result in superior response rates and overall survival (OS) in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), as compared with conventional cytotoxic chemotherapy.1, 2 Several studies have also combined these agents with chemotherapy—and with each other—in the relapsed/refractory setting, with some promising results reported. For example, the use of low-intensity chemotherapy with mini-hyper-CVD plus INO, with or without blinatumomab, resulted in an overall response rate of 88% and a 3-year OS rate of 42% in patients with B-cell ALL treated in first salvage.3 These agents are also increasingly being incorporated into frontline regimens, both in clinical trials and with the standard of care use of blinatumomab for persistent or recurrent measurable residual disease.4 Although the use of INO and blinatumomab earlier in the treatment algorithm may be improving outcomes in B-cell ALL, many patients still relapse. Outside of clinical trials, effective treatment options for these patients are limited, and the expected outcomes of patients following failure of both INO and blinatumomab are not well established. Such information would help to gauge the success (or failure) of novel investigational agents and combinations that are being studied in ongoing clinical trials. We retrospectively evaluated the outcomes of patients with Philadelphia chromosome-negative B-cell ALL following treatment failure of both INO and blinatumomab. To be eligible for this analysis, patients were required to have received both INO and blinatumomab over the course of their ALL treatment; these agents could have been given in any sequence and could have been given either as monotherapy, in combination with other agents, or in combination with each other, as long as at least one of them was given in the salvage setting. While patients who received either INO or blinatumomab in the frontline setting could be included, they must have received the other agent subsequently for relapsed/refractory disease. Patients who received both INO and blinatumomab in the frontline setting were excluded. Clinical outcomes were analyzed from the time of the first relapse or instance of disease refractoriness that occurred following receipt of both INO and blinatumomab. Remission duration was calculated from the time of first complete remission (CR) or CR with incomplete hematologic recovery (CRi) following INO and blinatumomab failure until relapse, censored for death in remission or if the patient was alive at last follow-up. Relapse-free survival (RFS) was calculated from the time of first CR/CRi following INO and blinatumomab failure until relapse or death from any cause, censored if the patient was alive at last follow-up. OS was calculated from the time of INO and blinatumomab failure until death from any cause, censored if the patient was alive at last follow-up. Between 2/2012 and 10/2021, we identified 65 patients with Philadelphia chromosome-negative B-cell ALL who experienced treatment failure after receiving both INO and blinatumomab. The baseline characteristics of the study population are shown in Table S1. The median age of patients at the time of INO and blinatumomab failure was 39 years (range, 18–82 years). Fifty patients (77%) received both INO and blinatumomab for relapsed/refractory disease; the other 23% of patients received one of these agents in the frontline setting or as MRD-directed therapy. Patients had received a median of 3 lines of therapies (range, 2–6) at the time of INO and blinatumomab failure. Twenty-four patients (37%) had undergone hematopoietic stem cell transplantation (HSCT) prior to INO and blinatumomab failure, and 3 patients (5%) had received prior chimeric antigen receptor (CAR) T-cell therapy. At the time of INO and blinatumomab failure, 40% of patients had a detectable TP53 mutation. Flow cytometry for CD19 and CD22 expression was available prior to receipt of either INO or blinatumomab and also at the time of INO and blinatumomab failure in 29 patients. Four patients (14%) lost CD19 expression at the time of INO and blinatumomab failure, and 3 patients (10%) lost CD22 expression. Overall, 54 patients (83%) received at least one subsequent therapy after INO and blinatumomab failure. Among these patients, the median number of subsequent therapies was 2 (range, 1–6). One patient was lost to follow-up following salvage therapy, and therefore, 53 patients were evaluable for response to salvage therapy. Sixteen patients (30%) achieved CR/CRi to the first salvage therapy received after INO and blinatumomab failure, with a CR rate of 9% and a CRi rate of 21%. Best response to any salvage therapy is shown in Table S2. Overall, 22 patients (42%) achieved CR/CRi with at least one subsequent salvage therapy. CR and CRi were achieved in 17% and 25% of patients, respectively. Age at the time of INO and blinatumomab failure did not impact response rates to subsequent therapy. The CR/CRi rate was higher for those with first remission duration ≥1 year as compared with those who were refractory to induction therapy or had first remission duration <1 year (59% vs. 29%, respectively; p = 0.02). Among responders, 73% also achieved flow MRD negativity at a sensitivity of 0.01%. Nine responses (41%) were achieved with an investigational trial drug or regimen, and 13 (59%) were achieved with commercial agent(s). Among the 9 responses to investigational therapies, 4 were achieved with a venetoclax-based regimen, 3 with a CAR T-cell product, and 2 with a chemotherapy and monoclonal antibody combination. Nine patients (41% of responders) were bridged to allogeneic HSCT; among all patients with INO and blinatumomab failure who received subsequent therapy, the rate of HSCT realization was 17%. Overall, 12 patients received CAR T-cells as at least one salvage therapy after INO and blinatumomab failure (2 with tisagenlecleucel and 10 with investigational products), with 6 of them (50%) achieving CR/CRi. The median duration of follow-up of the entire study population was 22.3 months. Among the 22 responders to subsequent salvage therapy, 10 patients (45%) relapsed, 2 patients (9%) died in remission, 9 patients (41%) proceeded to HSCT, and 1 patient (5%) is still alive in continuous ongoing remission. Among the 9 transplanted patients, 6 patients relapsed post HSCT, 1 patient died from HSCT-related complications, and 2 patients are still alive in continuous remission. For the entire cohort, the median OS was 3.8 months, and the 1-year OS rate was 22% (Figure 1A). Among the 54 patients who underwent subsequent therapy, the median duration of response was 5.0 months (1-year continuous remission rate: 17%), the median RFS was 3.5 months (1-year RFS rate: 12%), and the median OS was 4.7 months (1-year OS rate: 25%) (Figure 1B–C). OS in patients who underwent subsequent therapy was superior for those with first remission duration ≥1 year as compared with those who were primary refractory to induction therapy or had first remission duration <1 year (median OS: 9.8 months versus 3.4 months; p = 0.05; Figure 1D). Outcomes were expectedly dismal in patients who did not undergo subsequent therapy, with a median OS of 1.4 months. There was no difference in outcomes based on patient age (stratified by <60 years vs. ≥60 years), irrespective of whether they received subsequent therapy. The median post-HSCT OS for the 9 transplanted patients was 13.4 months, with a 1-year OS rate of 59% (Figure S1). The median post-CAR T-cell OS for the 12 patients who received CAR T-cell therapy was 3.9 months, with a 1-year OS rate of 36% (Figure S2). We also analyzed the outcomes of the 50 patients who received both INO and blinatumomab for relapsed/refractory ALL, excluding any patients who receive one of these agents in the frontline or MRD setting. Their baseline characteristics are shown in Table S3. Thirty-nine of these patients (78%) received at least one salvage therapy after INO and blinatumomab failure, 38 of whom were evaluable for response. Fifteen patients (39%) achieved CR/CRi with subsequent salvage therapy, with a CR rate of 13% and a CRi rate of 26%. The median OS for the 50 patients who received both INO and blinatumomab in the relapsed/refractory ALL was 2.6 months. (Figure S3A). Among these patients who underwent subsequent therapy, the median RFS was 5.9 months, and the median OS was 3.9 months (Figure S3B–C). Overall, our study shows the very poor outcomes of patients with B-cell ALL after failure of both INO and blinatumomab (median OS 3.8 months in the entire cohort). It should be noted that all of these patients were treated at a tertiary care academic institution with wide access to clinical trials, and therefore, in settings where the availability of investigational salvage therapies is less, it is possible that outcomes could be inferior. It is also notable that this study was conducted prior to the FDA approval of brexucabtagene autoleucel (previously known as KTE-X19), which resulted in a CR/CRi rate of 71% and a median OS of 18.2 months in patients with relapsed/refractory CD19-positive B-cell ALL.5 While this CAR T-cell product is a very promising therapy for patients with B-cell ALL, only 45% of treated patients had received prior blinatumomab, and only 22% had received prior INO in this phase 2 study; thus, the clinical activity of this agent in patients with INO and blinatumomab failure—the population presented in our analysis—has not yet been established. Even among those who received subsequent therapy (82% in our cohort), the median OS was only 4.7 months, highlighting the lack of effective therapies that can induce durable remissions in patients after INO and blinatumomab failure. While only 9 patients were able to be bridged to HSCT in our study, the 1-year OS of 59% in the transplanted population is encouraging and suggests that a consolidative approach with HSCT may be reasonable for these patients. Given the promising data for brexucabtagene autoleucel in patients with relapsed/refractory B-cell ALL—albeit studied in a relatively different population than our cohort—CAR T-cell therapy is also promising for these patients and may spare some of the potential morbidity and mortality of HSCT. This study serves as an important benchmark for the development of novel therapeutics and regimens for patients with relapsed/refractory B-cell ALL, as it provides a historical reference for expected response rates and survival in this setting. As INO and blinatumomab are being moved earlier into treatment algorithms and may soon be routinely used in the frontline setting, it is increasingly imperative to develop novel, effective therapies for patients who relapse or are refractory to these agents. Nicholas J. Short has served as consultant for Takeda Oncology, Amgen, AstraZeneca, Novartis, Jazz Pharmaceutics, and Pfizer and reports receiving research grants from Takeda Oncology, Astellas Pharma, Stemline Therapeutics, and Xencor. Elias Jabbour has received research funding and consulting fees from Amgen and Pfizer. The other authors have no relevant conflicts of interest to disclose. Nicholas J. Short and Walid Macaron designed the study, analyzed the data, and wrote the manuscript. Nitin Jain, Marina Konopleva, Farhad Ravandi, Ghayas C. Issa, Tapan Kadia, Koji Sasaki, Partow Kebriaei, Musa Yilmaz, Philip A. Thompson, Koichi Takahashi, Hussein Abbas, William G. Wierda, and Hagop M. Kantarjian treated patients. Rebecca Garris collected and analyzed the data. Elias Jabbour designed the study and treated patients. All authors critically reviewed and approved the manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request. K12 Paul Calabresi Clinical Oncology Scholar Award and the American Society of Hematology; MD Anderson Cancer Center, Grant/Award Number: CA016672 Data S1. Supporting Information. 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.