D'Sa, Shirley

7094 Background: Waldenström Macroglobulinemia (WM) remains incurable with current available therapeutic options. Treatment options for relapsed/refractory pts are limited and often continuous, underscoring the need for new agents with novel mechanisms of action and pt-centered, fixed duration therapy. Iopofosine I 131 is a novel radiopharmaceutical compound composed of a lipid raft-targeting phospholipid ether covalently bound to 131 I, a beta emitting radioisotope. Here, we report preliminary sub-group results of the CLOVER-WaM study [NCT02952508] in WM pts treated with a Bruton’s Tyrosine Kinase inhibitor (BTKi) immediately prior to iopofosine. Methods: Eligible WM pts had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m 2 on days 1 and 15 of each 57-day cycle. The primary efficacy endpoint was major response rate (MRR; partial response or better, as determined by the modified IWWM-VI). Secondary and exploratory endpoints included overall response rate (ORR), treatment-free survival (TFS), progression free survival (PFS), duration of response (DOR), and clinical benefit rate (CBR; stable disease or better). Herein, efficacy endpoints were assessed in the modified intent-to-treat (mITT) population (all pts who received ≥60 mCi total administered dose of iopofosine I 131), and whose treatment regimen prior to iopofosine included a BTKi. Safety was evaluated using CTCAE v4.03 in pts who received ≥1 dose of iopofosine. Data cut off for this analysis was Jan. 16, 2026. Results: As previously reported, 65 pts were dosed and 55 are included in the mITT population. Of those, 22 (40%) had received a BTKi containing regimen immediately prior to iopofosine; and 11 who previously received at least 2 regimens utilizing BTKis and 12 who were refractory to rituximab. In this subgroup, median age was 70.5 (range 55-88), 17 (77%) were male, and 5 (23%) were female. The median number of prior therapies was 3 (range 2-7), 15/22 (68%) were MYD88 mutated and 18/22 (82%) were TP53 wildtype. The MRR was 15/22 (68.2%), ORR was 19/22 (86.4%) and CBR was 100%, median PFS was 12 months (range 1.6 to 28.0) and median TFS was 19.1 months (range 2.5-34.4). Grade ≥ 3, related treatment emergent adverse events (TEAE) occurring in > 10% of pts included anemia (41%), leukopenia (41%), neutropenia (58%), and thrombocytopenia (86%). Conclusions: Iopofosine I 131 demonstrated significant efficacy; 100% CBR, 86.4% ORR and 68.2% MRR with a median PFS of 12 months (range: 1.6 – 28.0 months) in a pt population with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile with cytopenias as the only Grade 3 or greater TEAE. Based on the results of this pivotal trial, iopofosine I 131 could be a promising novel treatment for WM pts after BTKi therapy. Clinical trial information: NCT02952508 .

Abstract Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in patients treated with chemoimmunotherapy remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early end point, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At a median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each; P = .4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median 3.3 vs 8.8 years; hazard ratio [HR], 2.8; P = .0036) and OS (HR, 2.6; P = .036) compared with CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS, 71% vs 86%; HR, 3.1; P = .005) and higher mortality (standardized mortality ratio [SMR], 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR, 1.1). In conclusion, BR is effective irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Patients without POD24 represent a cohort with distinctly favorable outcome.

Introduction: WM is a rare subtype of lymphoma, identified by the presence of IgM paraprotein, infiltration of clonal, small lymphoplasmacytic B cells in the bone marrow, and the somatic mutation, MYD88 L265P, which is observed in over 90% of WM patients. We previously identified two rare variants at 6p25.3 (EXOC2) and 14q32.13 (TCL1) that were significantly associated with an increased risk of WM/LPL (PMID: 30305637). However, the genetic basis for WM/LPL predisposition remains largely unknown. We conducted the largest WM/LPL GWAS to discover further germline susceptibility loci for WM/LPL. Methods: Our meta-analysis discovery set included 1,707 cases and 58,328 controls of European ancestry from the InterLymph Consortium, genotyped on a high-density SNP array and imputed to TOPMed, providing over 10 million common variants for association testing. Germline genetic loci with suggestive significance (P<5x10-6) were selected for replication in four independent sets (570 cases and 771,770 controls; UK Biobank, Copenhagen Hospital Biobank, FinnGen, Mayo Clinic), giving us a total of 2,277 WM/LPL cases and 831,098 controls. Conditional and sensitivity analyses were performed considering family history and sex. A transcriptome-wide association study (TWAS) was performed using FUSION with expression quantitative trait loci (eQTL) data from GTEx and Young Finns Study in whole blood, lymphocytes, and other tissues. Functional annotations were done using FUMA, F-MAGMA, FORGE, and OpenTarget. Colocalization was measured using CoLoC with whole blood gene expression data. Results & Discussion: We identified 11 germline genetic loci associated with WM/LPL risk that replicated and reached genome-wide significance (P< 5x10-8), including the two known loci on 6p25.3 and 14q32.13 and nine novel loci in the following regions: 6p25.3 (n=2 independent loci), 2q37.1, 9p13.2, 6p21.32, 10q23.31, 16q21, 1p31.1, and 15q15.1. Four of the discovered variants showed strong associations with WM/LPL [odds ratios (ORs) >10]. Enrichment was observed for enhancer and promoter elements in B-cells (FDR q < 0.01), and gene-based and colocalization analyses identified several potential biological pathways. Colocalization analyses show the intronic PAX5 risk variant on 9p (OR=1.5, P= 2.3x10-25) associated with whole blood eQTL expression of PAX5, which plays an essential role in regulating lymphoid progenitors to the B-lymphocyte lineage, as well as RP11-297B17.3 (RNA gene, antisense to PAX5). In addition, GWAS have shown this variant is in linkage disequilibrium (LD) with GWAS loci for CD20 on IgD+ CD38- B cell that represents a specific immunophenotype that helps identify and characterize B cells involved with WM and other similar conditions. The 2q37.1 (SP140) locus (OR=1.6, P=1.2x10-33) contains variants linked to chronic lymphocytic leukemia (CLL) and autoimmune diseases, including multiple sclerosis and Crohn's disease. This locus is important in chromatin-mediated gene regulation, suggesting a significant role in the immune system. The specific variant influences exon-skipping and potentially protein expression, altering the gene's function. The variants on 10q23.31 in FAS (OR=1.3, P=4.4x10-13) and 15q15.1 (OR=1.2, P=8.5x10-11) in BCL2 modifying factor (BMF), are in strong LD with known CLL susceptibility variants. The 15q variant is also linked with multiple lymphoid leukemia GW significant SNPs. Sex-specific analyses identified one novel locus at 20q13.33 associated with the expression of ZGPAT and UCKL1 in males (OR=1.9, P=9.5x10-10). TWAS identified associations with CRHR1 and CDKN2A; overexpression of both are shown to be associated with an increased risk of WM/LPL. Expression of CDKN2A has been linked to childhood acute lymphoblastic leukemia, while CRHR1 has been associated with breast cancer risk. Conclusions: Our study, the largest GWAS of WM to date, has identified 11 susceptibility loci, including two previously known and nine novel regions. The findings underscore the genetic complexity of WM, with the PAX5 and SP140 loci implicated in both chromatin-mediated gene regulation and immune system functions. These insights not only enhance our understanding of WM predisposition but also pave the way for future research focused on functional understanding of these loci, potentially leading to new therapeutic strategies.