Citations

e19078 Background: MECOM (EVI1) rearrangements in MDS/AML are rare and carry an unfavorable prognosis. Although allogeneic stem cell transplantation (allo-HSCT) may prolong survival, factors impacting outcomes are not known. We conducted a retrospective analysis of patients with MECOM (EVI1) to associate clinicopathologic variables with prognosis. Methods: This study was approved by the Mayo Clinic IRB. Patients >18 years of age with MDS or AML and MECOM EVI1 at Mayo Clinic between 01/2012 and 12/2022 were included. Response was defined by ELN criteria. Intensive chemotherapy was defined as 7+3 or high dose cytarabine. Non-intensive chemotherapy included hypomethylating agents with or without venetoclax. Median overall survival (OS) and median leukemia free survival (LFS) were estimated using the Kaplan-Meier method. Outcome differences between sub-groups and univariate analyses were assessed with Cox regression. Results: Sixty patients met criteria for inclusion. Sixty-three percent (n = 38) were male and the median age at diagnosis was 67.8 yrs (range, 56 – 75). Eighty percent had AML (n = 48) and 18% had MDS (n = 11). Sixty-seven percent of patients had secondary AML/MDS (n = 40). Inv(3)/t(3;3) was present in 65% (n = 39) and t(3;21) was present in 12% (n = 7). Thirty-eight percent (n = 23) of patients had cooccurring monosomy 7 or 7q deletion and 5% had complex karyotype (n = 3). SF3B1 was the most common cooccurring mutation in 31% (n = 10), followed by KRAS in 19% (n = 6). Thirty-eight percent of patients (n = 23) received intensive chemotherapy. Complete response (CR) rates were 36% with intensive treatment (n = 8) and 4% with non-intensive treatment (n = 1; p = 0.007). Thirty percent (n = 18) underwent SCT (78% in CR1 and 22% in CR2) and of those, myeloablative conditioning (MAC) was used in 38% while 61% received reduced intensity conditioning (RIC). The mOS in the entire cohort was 11 months (95% CI 6.2, 17). Patients who received a SCT had longer mOS compared to patients who did not (19 vs 6.2 months, HR = 0.31, 95% CI 0.16,0.64; p = 0.001). AML-MRC was a poor prognostic factor in the HCST group for OS (HR = 4.23, 95% CI 1.02, 17.5, p = 0.047). Intensive vs. non-intensive chemotherapy, response prior to transplant (CR vs. no CR), or having 2 or more mutations on NGS did not significantly impact OS or LFS. Conclusions: In line with previous reports, allo-HSCT was associated with improved survival outcomes. Our results showed a high frequency of secondary AML/MDS, but only AML-MRC was associated with decreased survival outcomes. Regardless of therapy type, outcomes were poor. Novel therapies are urgently needed for these patients.

VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 VEXAS patients for CH in their peripheral blood (PB) and correlated findings with clinical outcomes in 77. UBA1mutwere most common at hotspot p.M41 (median variant allele frequency/VAF = 75%). Typical CH mutations co-occurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mutwas the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed two major patterns: with either typical CH preceding UBA1mutselection in a clone (Pattern 1), or occurring as an UBA1mutsubclone or in independent clones (Pattern 2). VAF in PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

Abstract Introduction: Clonal hematopoiesis (CH) is defined by acquisition of somatic mutations in hematopoietic stem cells with potential for expansion over time. CH is influenced by exposures to chemotherapy/radiation & has been associated with therapy related myeloid neoplasms (tMN). Peptide receptor radionuclide therapy (PRRT) is a radionuclide therapy and is FDA approved for neuroendocrine tumors (NET). PRRT has been associated with a 2-10% risk of tMN, especially with prior exposure to alkylating agents. A prior study of 13 NET patients found CH prevalence of 64%. We carried out a prospective assessment of CH in NET patients prior to PRRT. Methods: We evaluated pre-PRRT blood samples in 37 NET patients. Genomic DNA from mononuclear cells was analyzed for CH using a custom panel targeting 229 genes to a targeted depth of >1000X. Results: After approval by Mayo Clinic IRB, 45 patients with Stage IV NET were enrolled & CH data was available for 37. Fifty-one percent of patients were female, with a median age of 68yrs (range, 34-84yrs). Types of NET included small bowel (51%), pancreatic (29%), carcinoid (8%), paraganglioma (5%), & other (5%). The median number of therapies prior to PRRT was 1 (range, 0-4) & included somatostatin analogues (SSA)-81%, alkylating agents-30%, & prior radiation-13%. Thirty-six of 37 patients had variants identified, 5 of which were presumed germline (DDX41, CDKN2B, CHEK2, POT1, ERBB2), & 17 (45.9%) had pathogenic variants meeting the operational definition of CH (DNMT3A, TET2, PPM1D, TP53, SF3B1, ASXL1). The median number of pathogenic variants per patient was 1 (range, 0-2), & 6 patients had >1. In patients >60yrs old, 46% had pathogenic variants & 3 patients with pathogenic variants (TET2, TP53, DNMT3A) were <60 years old. The most common pathogenic variants were in epigenetic regulators, DNMT3A (37.5%) & TET2 (16.7%) with a median VAF of 2.8% (range, 0.70-50%). Eight patients (47%) with pathogenic CH had grade 1 cytopenias at baseline, compared to 10 patients (50%) without pathogenic CH. One patient had grade 3/4 cytopenia at baseline & had a missense variant in TP53 (VAF 50%) & history of exposure to anthracyclines, alkylating agents, platinum & radiation. The patient developed MDS before receiving PRRT. Pathogenic CH variants were more common in patients with previous exposure to radiation (p=0.008) or SSA (p=0.005). Two patients had PPM1D variants, both with a history of prior radiation, one with a history of prior alkylating treatment. Conclusion: To our knowledge this is the largest prospective evaluation of CH in NET. We identified CH to be present in 46% of patients & DNMT3A mutations were most common. This establishes the clonal landscape with mutations involving epigenetic regulators, DNA damage repair, transcription & splicing factors. Prospective longitudinal evaluation will evaluate the association between CH, cytopenias and tMN. Citation Format: Yael Kusne, Terra Lasho, Zaid Elsabbagh, Abhishek Mangaonkar, Rachel Eiring, Timothy Hobday, Jason Starr, Tanios Bekaii-Saab, Thorvardur Halfdanarson, Mrinal Patnaik, Mohamad Sonbol. Prevalence of clonal hematopoiesis in neuroendocrine tumor patients prior to lutetium 177 dotatate therapy (Lu177): A prospective trial of 36 patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5928.

AbstractBackgroundThere is a knowledge gap regarding lobar versus sublobar resection for atypical carcinoid (AC) of the lung. As such, the authors sought to understand and analyze the outcomes of sublobar resection versus lobectomy in this patient population.MethodsA retrospective analysis using the National Cancer Database was performed to compare overall survival (OS) between patients treated with lobectomy and patients treated with sublobar resection for AC of the lung between the years 2004 and 2016. Patient characteristics were compared with χ2 tests. The Kaplan–Meier method was used to estimate OS distributions, and the log‐rank test was used to compare distributions by treatment strategy. A multivariable Cox regression model was used to assess associations between the treatment strategy and OS. A propensity score matching method was also implemented to further eliminate treatment selection bias in the study sample.ResultsThe database identified 669 patients with T1–T4 and N0–N3 lung ACs that were surgically resected. Unadjusted Kaplan–Meier survival curves did not demonstrate an OS difference between lobectomy and sublobar resection (p = .094). After propensity score matching, curves demonstrated a numerical improvement in OS with lobectomy; however, it was not statistically significant (p = .5). In a subgroup analysis, lobectomy and node‐negative disease were associated with the best OS, whereas sublobar resection and node‐positive disease were associated with the worst OS (p < .0001). Nodal involvement was associated with worse survival, regardless of surgical treatment (p < .0001).ConclusionsIn patients with T1–T4 and N0–N3 ACs of the lung, lobectomy was not associated with an improvement in OS in comparison with sublobar resection.

Abstract Minimal residual disease (MRD) assays allow response assessment in patients with multiple myeloma (MM), and negativity is associated with improved survival outcomes. The role of highly sensitive next generation sequencing (NGS) MRD in combination with functional imaging remains to be validated. We performed a retrospective analysis on MM patients who underwent frontline autologous stem cell transplant (ASCT). Patients were evaluated at day 100 post-ASCT with NGS MRD and positron emission tomography (PET-CT). Patients with ≥ 2 MRD measurements were included in a secondary analysis for sequential measurements. 186 patients were included in the analysis. At day 100, 45 (24.2%) patients achieved MRD negativity at a sensitivity threshold of 10− 6. MRD negativity was the most predictive factor for longer time to next treatment (TTNT). Negativity rates did not differ according to MM subtype, R-ISS Stage nor cytogenetic risk. PET-CT and MRD positivity had poor agreement. Patients with sustained MRD negativity had longer TTNT, regardless of baseline risk characteristics. Our results show that the “real world” ability to measure deeper and sustainable responses distinguishes a subpopulation of patients with better outcomes. Achieving MRD negativity was the strongest prognostic marker and could help guide therapy-related decisions and serve as a response marker for clinical trials.