Efficacy of Combination Blinatumomab and Ponatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) and Chronic Myeloid Leukemia in Lymphoid Blast Phase (CMLBP) in a Real World Setting
Authors: Tobon Katherine , Consalvo Kylie , Kareem Syeda Saba , Lancet Jeffrey E , Komrokji Rami S. , Pinilla-Ibarz Javier , Sallman David , Eatrides Jennifer , Walker Alison R. , Chavez Julio C. , Isenalumhe Leidy Lismeris , Shah Bijal D 
Published: December 2024

Background
Combination therapy with blinatumomab and ponatinib (BP) has been shown to be efficacious in Ph+ ALL. Here we characterize the efficacy of this regimen in Ph+ ALL and CMLBP patients (pts) at a single institution with real-world inclusion and exclusion criteria.
Methods
This retrospective study includes adult pts with newly diagnosed Ph+ ALL, relapsed or refractory Ph+ ALL, or CMLBP who received BP from January 1, 2017 to December 1, 2023. Patients with history of CNS disease, cardiovascular disease (CVD) and multiple comorbidities were included. Frontline pts could receive up to 2 cycles of debulking therapy prior to BP. Allogeneic transplant (alloSCT) or maintenance ponatinib (mP) were recommended for responding pts. Median time to progression (TTP) and median overall survival (OS) are calculated from initiation of BP using Kaplan-Meier method.
Results
62 pts were treated: 31 frontline (1L), 12 second line (2L), and 19 in later lines (3L+).
Among 1L pts, 1 had CMLBP, and 1 concurrent myeloma. Median age 51y (24-82), ECOG &gt;2 in 23%, CNS+ in 6%, and CVD in 52%. TKD mutations were seen in 2/19 (T315I and T315I/L+E255K) and restricted to those who did not receive ponatinib (P) with debulking prior to BP. IKZF1 mutation was common (8/20), but IKZF1+ was only seen in 1. Median number of blinatumomab (B) cycles was 5 (1-5), with 65% receiving at least 4. One non-responder had E255K+T315I/L. Five developed asymptomatic low-level CSF+ by flow (all &lt;1%) during BP, including 1 who was CNS+ pre-BP. All cleared with additional IT chemotherapy without later CNS/systemic relapse. Among 30 responders, 8 had alloSCT, 21 had mP, and 1 stopped therapy. Two pts relapsed during mP, 1 with IKZF1+ and 1 with MYCr. Median TTP is not reached (est. 89% with 25mo median follow-up). Four pts have died, 1 from alloSCT, and 3 from infection after later therapy (n=2) or nonadherence (n=1). Median OS is not reached (est. 86% with 25mo median follow-up).
Among 2L, 1 had CMLBP with concurrent ALL and AML. Median age 48y (25-76y), ECOG &gt;2 in 8%, CNS+ in 17%, and CVD in 17%. TKD mutations were seen in 5/8 (T315I (n=2), V299L, E292Q, and T315I+E255K); all but E292Q were associated with exposure to dasatinib. IKZF1+ seen 1/8, and IKZF1 mutation in 4/8. Median B cycles was 2 (1-5), with 2 pts receiving at least 4. Two non-responders had TKD mutations (E292Q and T315I+E255K). Among 10 responders, 4 had alloSCT, 5 had mP, and 1 progressed with AML. 1 relapsed in the CNS during mP in the absence of IT prophylaxis during/after BP. Median TTP is not reached (est.71% w/ 25 mo follow-up. Four pts have died, either from disease (2), alloSCT (1), or AML (1). Median OS is not reached (est. 62% with 35mo follow-up).
Among 3L+, 3 had CMLBP, and 1 had concurrent Ph-like ALL with CRLF2r. Median age 58y, ECOG &gt;2 in 21%, CNS+ in 42%, and CVD in 58%. Median prior lines of therapy was 3 (3-10). All pts had been treated with TKI's other than P, with TKD mutations seen in 15/18 (including compound mutations in 4). IKZF1 mutations were seen in 2, with none showing IKZF1+. Median B cycles was 2 (1-9), with 21% receiving at least 4. There were 8 non-responders, including all 4 with compound mutations, and 1 with CMLBP. Among 11 responders, 4 had alloSCT, 2 moved to other therapy for symptomatic vascular disease (CAR, Bosutinib), and 5 proceed to mP; 3 relapsed on mP, all in the CNS. Median TTP is 8mo, with 28mo median follow-up. Eleven pts have died; either due to disease (9), infection after later therapy (1), and alloSCT (1). Median OS is 28mo, with 30mo median follow-up.
No difference in OS was observed among those transplanted in remission by line of therapy or in the total population. Six pts in sustained molecular remission without alloSCT have stopped mP after a median of 34mo (25-60) from the start of BP, with no relapses observed to date. Further evaluation of outcome by molecular response kinetics using NGS and/or qPCR for BCRABL are ongoing, with results anticipated before the annual congress.
Conclusion
BP is an active combination, particularly when used in earlier lines of therapy. Use of BP in pts with advanced comorbidity appears feasible with close monitoring. TKD mutations, which were enriched in those receiving other TKI's prior to P, were associated with relapse and reduced survival. AlloSCT consolidation in responding patients did not appear to confer any OS benefit relative to mP. Finally, among those with sustained molecular remission of at least 2y, discontinuation of TKI may be feasible.