AUTHORS
Hannah Goulart, MD, Tamer Othman, MD2, Marlise Rachael Luskin, MD, MSCE3, Jayastu Senapati, MBBS, MD, DM4, Marina Konopleva, MD, PhD5, John Wei, MD6, Lourdes Mendez, MD7, Dajaina Martin, MD8, Himachandana Atluri, MD9, Madina Sukhanova10, Hanno Hock11, Hamed Youshanlouei, MD12, Nicholas Short, MD13, Ashwin Kishtagari, MBBS, MSCI14, Ramzi Abboud, MD15, Bijal Shah, MD, MS16, Jae H Park, MD17, Michaela Liedtke, MD18, Lori Muffly, MD19, Ryan D. Cassaday, MD20, Caner Saygin, MD21, Ibrahim Aldoss, MD22, Elias Jabbour, MD23, Nitin Jain, MD24
AFFILIATIONS
1 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
2 City of Hope, Irvine, California, United States
3 Dana Farber Cancer Institute, Boston, Massachusetts, United States
4 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
5 Montefiore, New York, New York, United States
6 Montefiore, New York, New York, United States
7 Yale School of Medicine, New Haven, Connecticut, United States
8 Yale School of Medicine, New Haven, Connecticut, United States
9 Northwestern University, Chicago, Illinois, United States
10 Northwestern University, Chicago, Illinois, United States
11 Massachusetts General Hospital, Boston, Massachusetts, United States
12 University of Chicago, Chicago, Illinois, United States
13 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
14 Vanderbilt, Nashville, Tennessee, United States
15 Washington University, St. Louis, Missouri, United States
16 Moffitt, Tampa, Florida, United States
17 Memorial Sloan Kettering Cancer Center, New York, New York, United States
18 Stanford, Stanford, California, United States
19 Stanford, Stanford, California, United States
20 University of Washington, Seattle, Washington, United States
21 University of Chicago, Chicago, Illinois, United States
22 City of Hope, Irvine, California, United States
23 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
24 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
ABSTRACT
Background: Cytokine receptor-like factor 2 (CRLF2) alterations occur in approximately half of adult patients (pts) with Philadelphia-chromosome like (Ph-like) B-cell acute lymphoblastic leukemia (B-ALL) and have historically been associated with poor outcomes in the context of chemotherapy. Contemporary data describing the clinical characteristics and outcomes for this subgroup remain sparse. Therefore, we conducted a multicenter, retrospective analysis evaluating the characteristics and clinical outcomes of adults with newly diagnosed CRLF2-rearranged (CRLF2r) B-ALL.
Methods: Pts ≥18 years (yrs) old with newly diagnosed CRLF2r B-ALL treated at >10 US-based institutions between 2010-2025 were identified. CRLF2r B-ALL was defined as: CRLF2 overexpression by multiparameter flow cytometry (MFC), or CRLF2r by cytogenetics/FISH/NGS/fusion testing, or CRLF2 overexpression on low density array or other RNA sequencing methods. Baseline demographic, clinical, response including measurable residual disease (MRD), allogeneic stem cell transplant (allo-SCT), and survival data were collected using a standardized data sheet. MRD was assessed by MFC and/or next generation sequencing (NGS, clonoSEQ) when available. Endpoints included complete remission (CR) rates, MRD-negativity, event-free survival (EFS, from the start of therapy to MRD or clinical relapse, failure to achieve CR/CRi, death) and overall survival (OS).
Results: A total of 249 pts were included; median (med) age at diagnosis was 35 yrs (range, 18-87); 41 (16%) were ≥60 yrs and 172 (69%) were male. Most (80%) were of Hispanic or Latino ethnicity. CRLF2 alterations were identified as rearrangements in 198 (80%, of which 143 [72%] were IGH::CRLF2, 54 [27%] were P2YR8::CRLF2 and 1 was unknown) vs. overexpression by either MFC, FISH, or RNAseq in 51 (21%). JAK2mut was found in 37% (82/219) of pts. Karyotype was diploid (129/235, 55%), complex (14, 11%), high hyperdiploid (6, 3%), low hypodiploid (3, 1%); 1 had KMT2Ar.
Frontline induction was HCVAD/mini-CVD (112, 45%), pediatric (98, 39%), BFM (18, 7%), E1910 (6, 2%), low-dose chemo +/- blinatumomab (blina) (7, 3%), chemo-free inotuzumab (InO)/blina (4, 2%) and other (2, 1%). Blina was administered during induction in 26 pts (10%) and in consolidation in 135 (54%). InO was administered during induction 34 pts (14%) and in consolidation in 69 (28%).
Post induction (cycle 1) CR/CRi was achieved in 206 pts (83%); 97/194 (50%) achieved post-induction MRD-negativity by MFC, and 14/84 (17%) achieved MRD-negativity by NGS. A best response of CR/CRi was achieved in 233 pts (94%); 212/232 (91%) achieved MFC MRD-negativity after a med of 2 months (mos) (0.3-15), and 100/117 (86%) achieved NGS MRD-negativity after a med of 3 mos (0.5-29). 111 pts (45%) proceeded to CR1 allo-SCT after a med time 6 mos.
The med follow-up for the entire cohort is 37 mos (95% CI 33-43). The med EFS and OS were 31 (26-49) and 79 (45-not reached) mos, respectively. The estimated 3-yr EFS and OS rates were 47% and 64%, respectively. The med EFS and OS for pts ≥60 yrs vs. <60 yrs were 10 mos vs. 43 mos, p<.0001, and 23 mos vs. 101 mos, p=.0002.
For JAK2mut vs. JAK2wt, the med EFS and OS were 29 mos vs. 47 mos (p=.28), and 78 mos vs. 101 mos (p=.45). For JAK2mut, the med EFS with CR1 blina vs. no blina was 33 mos vs. 15 mos (p=.069), with med OS of 78 mos vs. 20 mos (p=.0008), respectively. There was no significant difference in EFS (p=.59) or OS (p=.45) in IGH::CRLF2 vs. P2RY8::CRLF2. For pts who achieved MFC MRD-negative CR/CRi, the med EFS was 46 mos vs. 9 mos in those who did not (p=.0007), with a med OS of 102 mos vs. 18 mos (p<.0001), respectively. For pts who received CR1 blina, the med EFS was 78 mos vs. 21 mos in those who did not (p=.002), with a med OS of 101 mos vs. 41 mos (p=.004). respectively. A landmark analysis at 6 mos demonstrated a med EFS of 95 mos in those who underwent allo-SCT vs. 24 mos in those who did not (p=.0059), with a med OS of 95 mos vs. 72 mos (p=.21), respectively.
Conclusions: This multicenter study represents the largest contemporary analysis of adults with newly diagnosed CRLF2r B-ALL. MFC MRD-negativity and CR1 blina were associated with superior outcomes, and while CR1 allo-SCT significantly improved EFS, there was no OS benefit likely due to effective salvage therapy. Further analyses with additional pts and incorporation of NGS MRD are ongoing and will be presented at the ASH meeting.
DISCLOSURES
Hannah Goulart, MD: No relevant conflicts of interest to declare.