AUTHORS
Sinan Cetin, MD, Omer Jamy, MD2, Razan Mohty, MD3, Matthew P Connor, MD4, Ibrahim Aldoss, MD5, Karamjeet Singh Sandhu, MD6, Chenyu Lin, MD7, Georgia Lill, MD8, Yannis K. Valtis I, MD9, Rawan Faramand, MD10, Noam Kopmar, MD11, Kaitlyn Cecilia Dykes, MD12, Jozal Moore, MD13, George Yaghmour, MD14, Jae H Park, MD15, Caspian Oliai, MD16, Ryan D. Cassaday, MD17, Kristen O'Dwyer, MD18, Bijal Shah, MD, MS19, Lori Muffly, MD20, Noelle Frey, MD, MSCE21, Gregory W Roloff, MD22
AFFILIATIONS
1 The University of Chicago, Chicago, Illinois, United States
2 University of Alabama at Birmingham, Birmingham, Alabama, United States
3 University of Alabama at Birmingham, Birmingham, Alabama, United States
4 Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States
5 City of Hope, Duarte, California, United States
6 City of Hope, Duarte, California, United States
7 Duke University, Durham, North Carolina, United States
8 University of California Los Angeles, Los Angeles, California, United States
9 Memorial Sloan Kettering Cancer Center, New York, New York, United States
10 Moffitt Cancer Center, Tampa, Florida, United States
11 University of Washington, Seattle, Washington, United States
12 University of California San Diego, La Jolla, California, United States
13 University of Rochester, Rochester, New York, United States
14 University of Southern California, Los Angeles, California, United States
15 Memorial Sloan Kettering Cancer Center, New York, New York, United States
16 University of California Los Angeles, Los Angeles, California, United States
17 University of Washington, Seattle, Washington, United States
18 University of Rochester, Rochester, New York, United States
19 Moffitt Cancer Center, Tampa, Florida, United States
20 Stanford University, Stanford, California, United States
21 Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States
22 The University of Chicago, Chicago, Illinois, United States
ABSTRACT
Background: Chronic myeloid leukemia (CML) in lymphoid blast phase (CML-LBP) is phenotypically indistinguishable from de novo Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL) but arises from a multipotent leukemic stem cell typically harboring the BCR::ABL1 p210 fusion. CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is approved for relapsed/refractory B-ALL, yet outcomes in CML-LBP patients (pts) with FDA-approved constructs remain undescribed.
Methods: We searched multicenter databases within the Real-world Outcomes Collaborative for CAR T in ALL (ROCCA) consortium to identify pts with CML-LP. Data captured related to CML-LBP included: BCR::ABL1 isoform, prior CML history, TKI exposure pattern, and MRD discordance. Additional data included demographics, pre-CAR treatment sequencing, disease status at infusion, post-CAR response, MRD methodology, and survival outcomes.
Results: Among 445 pts who received brexu-cel and 169 pts who received obe-cel, n=9 and n=3 were determined to have CML-LBP, respectively, comprising 12 total CML-LBP pts. The median age at infusion was 38 years (range 23–73); 8 were male. Eleven of 12 pts harbored the p210 isoform and 10 of 12 pts received ponatinib or asciminib as the final TKI preceding CAR-T. Half (6 of 12) pts received blinatumomab pre-CAR-T and 4 of 12 pts had relapsed after prior allogeneic SCT. At CAR-T infusion, 6 of 12 (50%) had overt morphological disease (>5% marrow lymphoblasts; median blast count 40%, range 14–60%), while 2 and 4 were in MRD+ and MRD− CR, respectively. Eleven of 12 pts were evaluable for response; one brexu-cel pt died at day +12 from infection and neurotoxicity before response evaluation. Among the 11 evaluable pts, 10 (91%) achieved CR/CRi: 7 of 8 (88%) brexu-cel and 3 of 3 (100%) obe-cel; 8 of the 10 responders achieved MRD negativity, assessed by flow cytometry, BCR::ABL1 PCR, and/or ClonoSeq NGS across sites. Post-CAR TKI maintenance was initiated in 5 of 9 brexu-cel and 1 of 3 obe-cel pts. One patient received consolidative SCT in MRD− remission post-brexu-cel. At time of last follow-up, 5 patients experienced post-CAR disease recurrence (3 brexu-cel; 2 obe-cel); 2 relapses were CD19-negative and 1 had myeloid transformation. One additional brexu-cel patient demonstrated BCR::ABL1-positive/ClonoSeq-negative molecular re-emergence at day +88, responding to TKI adjustment alone without evidence of B-ALL, consistent with underlying CML clone reactivation rather than CAR-T failure. Among the brexu-cel pts who achieved CR/CRi, 4 remain alive in remission 31–52 months after CAR-T without consolidative transplant, 3 of whom received post-CAR TKI maintenance (ponatinib n=2, ponatinib+asciminib n=1), while 1 remains in sustained CR MRD− without any post-CAR therapy. Four pts died (3 progressive disease; 1 transplant-related toxicity). Among the 3 obe-cel patients who achieved CR/CRi, all are alive at last follow-up at a median of 6.4 months (range 1.6–11.6) after CAR-T. MRD assessment was heterogeneous across sites and included BCR::ABL1 PCR, flow cytometry, and NGS (ClonoSeq).
Conclusions: This is the first multicenter experience reporting outcomes after commercial CAR-T (brexu-cel or obe-cel) in adults with CML-LBP. CD19-directed CAR-T is safe and effective in this patient population, with a CR rate of 91% that is durable for some patients. Similar to de novo B-ALL, CD19-negative antigen escape and myeloid transformation represent important mechanisms of resistance. Compared to de novo Ph+ B-ALL, patients with CML-LBP require BCR::ABL1 PCR alongside ALL-directed MRD assays for comprehensive response monitoring and TKI maintenance strategies informed by underlying CML biology.
DISCLOSURES
Sinan Cetin, MD: No relevant conflicts of interest to declare.