Introduction: Cytokine receptor-like factor 2 rearrangement (CRFL2r), a Philadelphia chromosome-like (Ph-like) aberration, is a poor prognostic marker in B-cell acute lymphoblastic leukemia (B-ALL) which endows relative chemotherapeutic-resistance. Extramedullary disease (EMD), including both central nervous system (CNS) and non-CNS involvement, is another adverse factor associated with poor prognosis. However, the relationship between CRLF2r and EMD remains unknown. Based on an initial observation of patients with CRLF2r B-ALLwho had EMD, asingle-center retrospective review was conducted to evaluate the incidence of EMD in CRLF2-r B-ALL patients.

Methods: This was a single center retrospective analysis of children, adolescents, and young adults (AYA) patients with relapsed/refractory B-ALL who were evaluated for a chimeric antigen receptor (CAR) T-cell therapy between 2012-2024 (NCT01593696, NCT02315612, NCT03448393, and NCT05442515).

The primary objective of this retrospective analysis was to determine the incidence of EMD in patients with CRFL2r B-ALL. Secondary objectives included describing sites of EMD, evaluating for differences of EMD incidence between patients with CRLF2r and non-CRLF2r, and describing additional cytogenetics/molecular findings.

All subjects' EMD status were assessed from initial diagnosis through the course of evaluation and/or treatment at our institution. EMD was defined by involvement of B-ALL outside the bone marrow established by tissue biopsy, CSF sampling, or imaging (e.g., 8-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), CT, or magnetic resonance imaging (MRI)). Sites of EMD disease were categorized as CNS-EMD and/or non-CNS-EMD. Isolated extramedullary (iEMD) relapse was defined as relapse occurring in an extramedullary site without concurrent bone marrow (BM) involvement. Patients with CNS-2 and CNS-3 status were classified as CNS-EMD. Analysis was primarily descriptive. Categorical variables were compared non-parametric tests, including Fisher's exact tests, and continuous variables with Mann-Whitney in GraphPad Prism (v9.3.1). A p-value less than 0.05 was considered statistically significant.

Results: Amongst 177 patients, 95 (53.7%) had EMD at any timepoint and 21 (11.9%) had CRLF2r. Amongst the 95 with EMD, 19 (20%) had CRLF2r. Additionally, 19 of 21 (90.5%) patients with CRLF2r had EMD at some point in their treatment course. In contrast, 76 of 156 (48.7%) patients withoutCRLF2r had EMD (p=0.0003).

The median age at initial diagnosis was 18.8 years (range, 5.4-33.8 years), and the median at presentation to the NIH was 21.4 (range, 7.8-35.8 years). They were heavily pre-treated with a median of 4 prior lines of therapies (range, 2-7). At diagnosis, 8 (38.1%) patients with CRLF2r presented with EMD: 7 with CNS and 1 with non-CNS EMD, involving para-aortic lymph node. At relapse, 17 (80.9%) had EMD: 4 (19%) had CNS-EMD, 9 (42.9%) had non-CNS-EMD and 4 (19%) had both. Isolated EMD was observed in 2 (11.8%) patients at first relapse and in 3 (17.6%) patients with multiple relapses. Additional molecular aberrations detected in this population included JAK1, JAK2, NRAS, CDKN2A, CDKN2B, IDH1, STAT3, KRAS, PTPN11 and KMT2D mutations.

Notably, after blinatumomab and/or inotuzumab (administered for marrow relapse), five (23.8%) patients with CRLF2r B-ALL relapsed with EMD. Three (14.3%) had with combined BM and EMD relapse: 2 with non-CNS-and 1 with CNS-EMD, while two patients developed isolated EMD disease. Additionally, after hematopoietic cell transplant (HCT), 6 of 21 (28.6%) patients with CRLF2r B-ALL relapsed: 4 (19%) had combined medullary/EMD, and 2 (10%) had both isolated CNS- and non-CNS EMD involvement.

Conclusions: Based on our analysis, we identified that patients with CRLF2r had higher rate of EMD compared to those without CRLF2. While limited by factors inherent to retrospective analyses, our findings nonetheless suggest a potential association among CRLF2r and EMD that warrants further study. This is particularly imperative as this relationship may impact treatment approaches and guide decision making. Additionally, in raising awareness about the presence of non-CNS EMD in B-ALL patients, establishing systematic approaches to assess for non-CNS EMD in high-risk patients is warranted.

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2025
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