Characteristics and outcomes of patients with relapsed Philadelphia chromosome‐positive acute lymphoblastic leukemia after failure of a frontline ponatinib‐containing therapy
Authors: Nicholas J. Short, Elias Jabbour, Lewis F. Nasr, Nitin Jain, Fadi G. Haddad, Ghayas C. Issa, Koji Sasaki, Jayastu Senapati, Partow Kebriaei, Rebecca Garris, Marina Konopleva, Farhad Ravandi, Hagop Kantarjian
Journal: American Journal of Hematology (2024)

Frontline therapy of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) consists of chemotherapy or blinatumomab in combination with a BCR::ABL1 tyrosine kinase inhibitor (TKI). Ponatinib is a potent BCR::ABL1 TKI that is active against T315I ABL1 mutations, which are the dominant mechanism of relapse with earlier-generation TKIs. Promising outcomes have been achieved with frontline ponatinib-based regimens in Ph + ALL. With hyper-CVAD plus ponatinib, a 6-year overall survival (OS) of 75% has been reported, which compares favorably to historical expectations with hyper-CVAD in combination with a first- or second-generation TKI.1 In an updated analysis from an ongoing study of the chemotherapy-free combination of ponatinib and blinatumomab, the estimated 2-year OS rate is 89%, without the need for allogeneic hematopoietic stem cell transplantation (HSCT) in first remission in the vast majority of patients (<5% transplant rate for the study population).2 Ponatinib was also recently shown to be superior to imatinib in a randomized phase III clinical trial in adults with newly diagnosed Ph + ALL.3 However, despite encouraging data reported with ponatinib-containing frontline regimens, some patients still relapse. The characteristics of patients with Ph + ALL who relapse following a frontline ponatinib-based regimen have not been systemically evaluated. In this analysis, we sought to evaluate the patterns of relapse in these patients and to describe their clinical outcomes following salvage therapy. We retrospectively evaluated the outcomes of patients with Ph + ALL following the failure of a ponatinib-based regimen. To be eligible for this analysis, patients were required to have received ponatinib as frontline therapy and subsequently experienced hematologic/morphological and/or extramedullary relapse. Patients were categorized as either ponatinib-resistant (in cases where relapse occurred while on ponatinib) or ponatinib-intolerant (in cases where relapse occurred after discontinuation of ponatinib due to toxicity). Clinical outcomes were analyzed from the time of the first relapse following the use of a frontline ponatinib-based regimen (defined as the time of "ponatinib failure" for this analysis). Relapse-free survival (RFS) was calculated from the time of second complete remission (CR) or CR with incomplete hematologic recovery (CRi) until relapse or death from any cause, censored if the patient was alive at the last follow-up. OS was calculated from the time of ponatinib failure until death from any cause, censored if the patient was alive at the last follow-up. Between March 2012 and September 2023, we identified 22 patients with Ph + ALL who experienced treatment failure after a frontline ponatinib-containing regimen (out of 201 patients with newly diagnosed Ph + ALL treated with ponatinib). The characteristics of the study population are summarized in Table S1. The median age of patients at the time of ponatinib failure was 49 years (range, 27–76 years). Sixteen patients (73%) received chemotherapy as part of frontline therapy and 6 (27%) received a frontline chemotherapy-free regimen. Four patients (18%) had received inotuzumab ozogamicin prior to relapse and 11 patients (50%) had received blinatumomab; all four patients received inotuzumab ozogamicin due to persistent or recurrent measurable residual disease (MRD). No patient had undergone prior allogeneic HSCT. Eighteen patients (82%) had achieved complete molecular response (CMR; defined as no detectable BCR::ABL1 transcripts with a sensitivity of at least 10−4) within 3 months of the start of therapy. Sixteen patients (73%) were ponatinib-resistant and 6 (27%) were ponatinib-intolerant. Among the ponatinib-resistant patients, 11 of 16 (69%) were receiving ponatinib at a dose of 15 mg daily at the time of relapse. Among the six ponatinib-intolerant patients, four were on dasatinib at the time of relapse, and one each was on imatinib and nilotinib. Reasons for ponatinib intolerance were: cardiovascular toxicity in four patients, venous thromboembolism in one patient, and liver function test abnormalities in one patient. Among the ponatinib-resistant patients, the median time from diagnosis to relapse was 24.1 months (range, 8.8–79.0 months). Among the ponatinib-intolerant patients, the median time from diagnosis to relapse was 31.4 months (range, 11.4–80.7 months) and the median time from ponatinib intolerance to relapse was 22.4 months (range, 6.1–69.1 months). Among 17 patients with MRD testing (PCR for BCR::ABL1) within 4 months prior to relapse, MRD recurrence or an increase in MRD levels was observed in eight patients (47%). The types of relapses observed in the cohort were: bone marrow only (n = 12, 54%), central nervous system (CNS)-only (n = 6, 27%), bone marrow with CNS, and/or non-CNS extramedullary involvement (n = 3, 14%), and non-CNS extramedullary-only (n = 1, 5%). All non-CNS extramedullary relapses occurred in the lymph nodes and were biopsy-proven. There was no difference in the number of doses of intrathecal chemotherapy for patients with CNS-only versus other types of relapses (median of 12 doses in both groups). Extramedullary-only relapses were more common in patients who received a frontline chemotherapy-free regimen than in those who received a chemotherapy-based regimen (four out of six [67%] v.s three out of 16 [19%], respectively; p = .05). ABL1 kinase domain testing was performed on 13 patients with bone marrow relapse as previously described4: five patients (38%) had no detectable ABL1 mutation, four patients (31%) had a T315I mutation, two patients (15%) had an E255K mutation, and one patient each (8%) had a E255V or F359K mutation. Among the four patients who developed a T315I mutation, three were ponatinib-intolerant and were receiving dasatinib at the time of relapse. Overall, 20 patients (91%) received at least one subsequent therapy after ponatinib failure. Among these patients, the median number of subsequent therapies was 1 (range, 1–5); 7 of the 20 patients (35%) received two or more subsequent therapies after ponatinib failure. A variety of salvage regimens were used. All patients received a TKI with first salvage. The TKIs used were: ponatinib in eight patients (40%), dasatinib in seven patients (35%), bosutinib in four patients (20%), and olverembatinib in one patient (5%). One patient who was considered ponatinib-intolerant was rechallenged with ponatinib at the time of relapse due to T315I mutation; all other patients who received ponatinib in first salvage were classified as ponatinib-resistant. No patient received TKI monotherapy as first salvage. Thirteen patients (65%) received chemotherapy as part of first salvage therapy, six (30%) received blinatumomab, four (20%) received inotuzumab ozogamicin, and seven (35%) received CD19 chimeric antigen receptor (CAR) T-cells. Overall, 16 patients (80%) received blinatumomab, inotuzumab ozogamicin or CAR T-cells with first salvage. All seven patients who relapsed in the CNS received cranial and/or spinal irradiation (six with their first salvage regimen; and one as part of HSCT conditioning). Overall, 18 patients (90%) achieved second remission following the first salvage therapy, including CR in 15 patients and CRi in three patients. All patients who received blinatumomab, inotuzumab ozogamicin, and/or CD19 CAR T-cells as part of their first salvage therapy achieved CR/CRi. Among 12 responding patients with bone marrow relapse, 10 (83%) achieved a CMR. Two patients did not respond to first salvage therapy, both of whom had bone marrow-only relapses. One patient received venetoclax plus ponatinib and the other received MOpAD (methotrexate, vincristine, pegylated-asparaginase, and dexamethasone), ofatumumab, and dasatinib as first salvage. Both patients received subsequent salvage regimens but did not respond to any of them. The patient characteristics, responses to salvage therapy, and disposition for the study cohort are shown in Figure 1A and Table S2. The median duration of follow-up of the entire study population was 18.6 months (range, 1.1–112.9 months) from the time of ponatinib failure. Among the 18 responders to first salvage therapy, six patients (33%) relapsed in the absence of HSCT, one (6%) died in remission, five (28%) proceeded to HSCT in second remission, and six (33%) are still alive in continuous ongoing remission without HSCT. The recommendation for HSCT in second remission was individualized and no formal criteria were used. The median duration of remission of the six patients who remain in remission without HSCT is 5.3 months (range, 1.0–104.8 months). Among the five patients transplanted in second remission, one died from HSCT-related complications, one died from unknown causes, and three are still alive in continuous remission. Among the nine patients who are alive and in ongoing second remission, the median duration of remission was 14.2 months (range, 1.0–104.8 months). For the entire cohort, the median RFS was 14.7 months (1-year and 2-year RFS: 55% and 37%, respectively), and the median OS was 22.6 months (1-year and 2-year OS: 68% and 41%, respectively) (Figure 1B,C). Among patients who relapsed in the bone marrow (with or without concomitant extramedullary relapse) the median OS was 15.7 months, and the 2-year OS was 31%; in contrast, for patients with extramedullary-only relapses, the median OS was not reached, and the 2-year OS was 86% (Figure 1D). At last follow-up, four patients were alive and in ongoing second remission for at least 2 years after ponatinib failure. Three of these patients underwent HSCT following first salvage therapy; the other patient received blinatumomab plus dasatinib as first salvage and remains in remission 9 years after relapse without HSCT. Here, we describe the largest cohort of patients with Ph + ALL relapsing after ponatinib-based frontline therapy. Among the 22 patients in our study, seven (32%) experienced extramedullary-only relapse (six of which were CNS-only), with higher rates of extramedullary-only relapses observed in patients who received a frontline chemotherapy-free regimen. This finding is consistent with reports from prospective studies of blinatumomab plus TKI regimens and highlights the need for measures to prevent CNS relapses in these patients.2, 5 In the current blinatumomab plus ponatinib clinical trial, the number of doses of prophylactic intrathecal chemotherapy has been increased from 12 to 15 and serial monitoring of the cerebrospinal fluid during maintenance is now being instituted. The use of systemic chemotherapy in patients at high risk for CNS relapse is also being considered. For patients relapsing in the bone marrow, the mechanism of resistance to ponatinib-based regimens remains poorly understood. Three of the 13 tested patients had E255K or E255V mutation which may confer resistance to ponatinib. However, in most other cases, no causative ABL1 mutation could be identified, suggesting that many relapses after ponatinib therapy may be driven by BCR::ABL1-independent mechanisms. We observed a relatively high response rate to salvage therapy (90%), and the 2-year OS of 41% observed in our cohort suggests that some patients can have long-term survival even after ponatinib failure. Impressively, these outcomes appear superior to a previous report of patients with relapsed Ph + ALL, where second remission was achieved in 84% of patients and the 2-year OS was 20%.6 The better outcomes in our cohort may be due to the frequent utilization of immunotherapy-based salvage regimens at the time of relapse. It is notable that survival in patients who experienced bone marrow relapse appeared inferior to those with extramedullary-only relapse (2-year OS 31% versus 86%, respectively). While CNS relapses remain a particular concern with chemotherapy-free regimens, these findings suggest that durable remissions can be achieved with appropriate CNS-directed therapy, including intrathecal chemotherapy, craniospinal irradiation, CAR T-cells, and/or HSCT. The appropriate consolidation for most patients with Ph + ALL who achieve second remission following ponatinib failure remains uncertain. In our study, only 28% of patients who achieved second remission underwent allogeneic HSCT. Unfortunately, the number of patients was too small to assess the relative benefit of consolidative HSCT in second remission. Three of four patients with long-term (i.e., >2 years) durable remissions after ponatinib failure underwent subsequent HSCT, which suggests that HSCT may be beneficial for some patients. However, longer-term follow-up of patients receiving novel approaches such as CAR T-cell therapy are needed to better assess the optimal consolidative strategy for patients with Ph + ALL who relapse following a ponatinib-based regimen. N.J.S. designed the study, collected and analyzed the data, treated patients, and wrote the first draft of the manuscript. E.J. and H.K. designed the study and treated patients. N.J., F.G.H., G.C.I., K.S., J.S., P.K., M.K., and F.R. treated patients. L.F.N. and R.G. collected and analyzed the data. All authors critically reviewed and approved the manuscript. This research was funded in part by the NIH/NCI Cancer Center Support Grant P30 CA016672. N.J.S. has served as a consultant for Pfizer Inc., GSK, NKARTA, Autolus, and Sanofi; has received research grants from Takeda Oncology, Astellas Pharma Inc., Stemline Therapeutics, Xencor, and NextCure; and has received honoraria from Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer Inc., Astellas Pharma Inc., Sanofi, and BeiGene. P.K. has served as a consultant for Pfizer Inc. The other authors have no relevant conflicts of interest to disclose. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Table S1. Baseline characteristics of the study population. Table S2. Treatments and outcomes of the study population. 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