S62 EXABS-161-ALL Updates on Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Fadi G Haddad MD1, Jayastu Senapati MBBS, MD1, Nicholas J Short MD1, Hagop Kantarjian MD1, and Elias Jabbour MD1,* 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030. USA *Corresponding author: ejabbour@mdanderson.org Keywords Tyrosine kinase inhibitor, measurable residual disease, next-generation sequencing, asciminib, olverembatinib Introduction Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) was historically associated with poor outcomes when treated with chemotherapy followed by allogeneic stem cell transplantation (ASCT).1 Four different BCR::ABL1 tyrosine kinase inhibitors (TKIs) have been combined with chemotherapy in patients with Ph-positive ALL, leading to improved outcomes: imatinib, dasatinib, nilotinib, and ponatinib. Using more potent TKIs has increased the rates of complete molecular remission (CMR; undetectable BCR::ABL1 transcripts by reverse transcription polymerase chain reaction [RT-PCR]), which translated into improved long-term overall survival (OS) from approximately 40% with imatinib to 75% with ponatinib, with less reliance on ASCT.2 More recently, the combination of blinatumomab and TKIs in patients with newly diagnosed Phpositive ALL demonstrated encouraging results with long-term OS of 80–90%.3,4 Herein, we discuss updates in the management of Ph-positive ALL, the role of ASCT, and the approach to measurable residual disease (MRD) monitoring. Moving from ASCT to Chemotherapy-Free Regimens: A Less Toxic and Potentially Curable Approach ASCT has been always considered standard of care therapy in patients with Ph-positive ALL. However, novel therapies are re-defining the role of ASCT in patients with Ph-positive ALL in first remission. In a study of 85 patients with newly diagnosed Ph-positive ALL treated with Hyper-CVAD plus TKIs and who did not undergo ASCT, those who achieved CMR by approximately 3 months had improved survival compared to those who achieved a lesser response.5 The 4-year OS rate for these patients was 66%, and by multivariate analysis, 3-month CMR was the only variable prognostic for OS (hazard ratio [HR], 0.42; P=0.01). In a followup study of 84 patients treated with frontline Hyper-CVAD plus TKIs and who achieved CMR at 3 months, the 5-year progressionfree survival and OS rates were 68% and 72%, respectively.6 By multivariate analysis, ponatinib therapy was a favorable factor that independently predicted for relapse (HR, 0.39; P=0.03) and OS (HR, 0.38; P=0.04). Implementing ASCT in first remission was not prognostic for survival. A retrospective multicenter study compared the outcome of 230 patients with Ph-positive ALL who were treated with a TKI-based regimen, achieved CMR within 3 months, and underwent (n=98) or not (n=132) ASCT.7 By multivariate analysis, ASCT was not associated with improved OS (HR, 1.05; P=0.86) or relapse-free survival (HR, 0.86; P=0.53). To adjust for imbalances in baseline risk factors and TKI use between both groups, a propensity score matching analysis was performed. The results confirmed the findings from the multivariate analysis by showing similar 5-year rates of OS (68% versus 61%; P=0.63) and relapse-free survival (63% versus 52%; P=0.42) between patients who did and did not undergo ASCT.7 These findings suggest that patients with Ph-positive ALL treated with first-line chemotherapy plus TKIs, and who achieve early CMR, have an excellent survival and can safely avoid ASCT. More recently, the combination of blinatumomab and ponatinib showed promising results and may mitigate the need of transplant.4 Among 54 patients with newly diagnosed Ph-positive ALL treated with this regimen, the CMR was 71% after Cycle 1 and 90% overall. Additionally, 34 (89%) of 38 patients became MRDnegative by a next-generation sequencing (NGS) assay with a sensitivity of 1×10–6. Only one patient underwent ASCT due to persistently detectable BCR::ABL1 transcripts of 0.01–0.05%. After a median follow-up of 16 months, the estimated 2-year event-free survival was 80% and 2-year OS was 90%. No leukemia-related deaths have occurred. Thus, this chemotherapy-free regimen may mitigate the reliance on ASCT in the frontline setting. Treatment-Free Remission in Ph‑Positive ALL Most experts recommend 1-2 years of maintenance TKI following ASCT in patients with Ph-positive ALL.8 However, limited data are available regarding TKI discontinuation in patients who forego ASCT. One retrospective analysis reported the outcome of nine patients who achieved remission but did not undergo ASCT and eventually discontinued TKI (due to adverse events or physician’s choice). At the time of discontinuation, BCR::ABL1 transcripts were undetectable in six patients, <0.01% in two patients, and 0.01% in another patient.9 After a median followup of 49 months from treatment discontinuation, three patients had a molecular relapse within a median of 6 months, of whom
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