Osman, Afaf E.G.

Summary Evidence for an association between insulin‐like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF‐I concentrations and risk of MM by combining baseline serological data among UK Biobank participants ( n = 444 187; 732 incident MM) with a two‐sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF‐I and IGF‐binding protein 3 (IGFBP‐3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF‐I level was positively associated with MM risk Hazard ratio‐HR‐per one standard deviation‐SD‐increase (HR 1‐SD = 1.11, 95% confidence interval [CI]: 1.01–1.22; p ‐value = 0.03), especially closer to diagnosis. Genetically inferred IGF‐I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05–1.54) but not with any other LNs. Genetically inferred IGFBP‐3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF‐I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR 1‐SD in obese male = 1.36, 95% CI: 1.14–1.61). Our serological and MR analyses suggest a contributing role of IGF‐I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex‐specific adiposity.

Abstract Introduction Heterozygous germline pathogenic variants (PVs) in the 5' untranslated region of ANKRD26 cause inherited thrombocytopenia and predisposition to hematologic malignancy (HM). The estimated lifetime HM risk is ~10% based on families ascertained from an inherited thrombocytopenia cohort. However, the malignancy spectrum, molecular features, precursor states, and overall clinical outcomes remain poorly defined. Methods We established an international, multicenter cohort of individuals with ANKRD26-related thrombocytopenia diagnosed after undergoing genetic evaluation due to a personal and/or family history of thrombocytopenia and/or HM. Clinical, pathologic, and molecular data were collected for 27 individuals with germline ANKRD26 PVs from 21 unrelated families treated at 11 institutions across 5 countries. Statistical analyses were performed using R (v4.4.2). Results Patients were predominantly male (18/27) and white (25/27). Thrombocytopenia was typically identified in childhood (median age 10 years, range 0-48) with a genetic diagnosis made later (median age 53 years, range 2-80). The mean (+/- SD) pre-malignancy platelet count was 45 +/- 24 K/uL (range 5-87). ANKRD26 PVs observed in each family included: c.-126T>C (n=9), c.-128G>A (n=3), c.-134G>A (n=3), c.-116C>T (n=3), c.-118C>T (n=2), and c.-118C>A (n=1). Thirteen HMs were diagnosed in 11 of 27 (41%) patients, including myelodysplastic neoplasm/syndrome (MDS, n=5), acute myeloid leukemia (AML, n=3), chronic myeloid leukemia (CML, n=2), MDS/myeloproliferative neoplasm (MPN) overlap (n=2), and Langerhans cell histiocytosis (n=1). The median age at first HM diagnosis was 63 years (range 49-80). Recurrent somatic features in myeloid malignancies included complex karyotype (4/11, 36%) and TP53 mutations (5/10, 50%). Of the 3 patients with AML, 1 achieved a partial remission (PR) with venetoclax combined with cladribine, idarubicin, and cytarabine but relapsed, 1 achieved a PR with azacitidine but relapsed <100 days after haploidentical allogeneic stem cell transplantation (alloSCT), and 1 had primary refractory disease. Among 5 patients with MDS, 1 was refractory to decitabine, 1 underwent alloSCT but relapsed 2 years post-transplant, 1 remains in remission post-alloSCT with 1 year of follow-up, 1 is undergoing alloSCT evaluation, and 1 was lost to follow-up. Both patients with CML achieved durable major molecular remissions with imatinib. To better estimate HM risk, we assumed 100% penetrance of thrombocytopenia for ANKRD26 PV carriers and included family members with chronic thrombocytopenia who had not had germline genetic testing. In this expanded series (n=62), 16 individuals developed a HM (26%). Additional diagnoses included MDS with progression to AML (n=1), AML (n=1), CML (n=1), and leukemia of unknown type (n=2). Cumulative incidence of HM was 0% by age 40 years, 17% by age 60 years, and 60% by age 80 years. Somatic sequencing of peripheral blood was performed in 5 HM-unaffected ANKRD26 PV carriers. One individual was found to have clonal hematopoiesis driven by TET2 (c.1648C>T, p.Arg550*) with a variant allele frequency (VAF) of 9% at age 55. Bone marrow biopsy showed mild megakaryocytic atypia and 4% blasts without overt evidence of malignancy. To assess the prevalence of ANKRD26-related HM, we assessed the frequency of ANKRD26 PVs in 2 large MDS/AML cohorts. In the ARUP database (9662 AML, 6397 MDS), 2 individuals (0.01%) had an ANKRD26 PV with a VAF consistent with germline origin. In the MSK-IMPACT Heme Germline MDS/AML cohort (n = 284), no ANKRD26 P/LP variants were identified. Conclusions Germline ANKRD26 PVs underlie <1% of MDS/AML diagnoses but may represent a high-risk subtype characterized by complex karyotype, TP53 mutations, and high risk of relapse. Among our series, the incidence of HM was low early in life but increased substantially with age, reaching 60% by 80 years. This exceeds prior estimates, which were derived from individuals ascertained from thrombocytopenia-based registries. Together, our findings suggest that ANKRD26-associated HM may represent a high-risk clinical entity, and that age and family history should inform surveillance strategies. More studies are needed to define genetic and environmental modifiers of HM risk as well as precursor states to enable early detection and disease interception.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and comprehensive care of patients with MDS based on a review of recent clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts is convened at least on an annual basis. During the annual meeting, the panel evaluates new and emerging data to inform their recommendations. These NCCN Guidelines Insights review the recent updates, including treatment recommendations both for lower-risk and higher-risk MDS, preference stratification of therapeutic agents, and emerging data on novel therapeutics.

Abstract Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Abstract VEXAS (vacuoles, E1-ubiquitin-like modifier activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described autoinflammatory disorder caused by acquired UBA1 mutations in hematopoietic precursor cells. The prevalence, clinical significance, and genomic landscape of UBA1variants in patients with hematologic malignancies (HM) remains unexplored. We analyzed the genomic profiles of 86 patients carrying 17 different UBA1variants amongst an unbiased cohort of 8,976 HM patients. Specific genetic and clinical features seen more frequently in patients with UBA1 pathogenic variants (PV) versus those with variants of uncertain significance (VUS) included: marked male predominance (98% versus 80%, P=0.002), macrocytic anemia (MCV 105 ± 1.4 fl versus 96 ± 1.4 fl, p=0.01), frequent dominant clones without concurrent somatic variants (53% versus 15%, p=0.004), and association with molecularly distinct low-risk myelodysplastic syndrome (MDS; 13%) with superior overall survival (OS). Interestingly, while the genetic profiles of UBA1 PV patients resemble patients with clonal cytopenia of unknown significance (CCUS), rapid UBA1 clonal expansion predispose patients to convert to low-grade MDS with a notably hastened progression compared to UBA1 wild-type CCUS. This “clone surge to clinical stability” (CS) is a mechanism that emphasizes the unique pathobiology of UBA1mutations in VEXAS and supports it as a distinct entity.

Abstract Background: Clonal cytopenia of undetermined significance (CCUS) is defined as persistent unexplained cytopenia with evidence of clonality [myeloid-associated somatic mutations (MTs) or cytogenetic [CG] abnormalities] but without definitive evidence of myeloid neoplasms (MN). The outcomes in CCUS patients (pts) are not well understood. Methods: The CCUS International Study database includes pts from 17 institutions who meet the criteria of CCUS and do not have other causes of cytopenia. Pts with MDS defining CG abnormalities were excluded. We collected baseline clinical data, laboratory parameters, CGs, molecular genetics, treatment, and disease course. Diverse gene panels from different institutions were collated to include a total of 70 myeloid-related somatic genes (30 genes in common). 2018 IWG MDS response criteria were used to determine response rate (RR). Disease progression (DP) is defined by progression to MN. The relationship between independent variables and DP and death was assessed using Cox proportional hazards models. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. All statistical analysis was performed using SAS. Results: A total of 258 pts were captured by July 2021. The median age was 71 (IQR 63-77) years, and 66% were male. Among 73 (28%) pts with known malignancy history, 27 (37%) pts received previous chemo- or radiation therapy. 27 (10%) pts had non-malignant hematology comorbidities. 91 (35%) had cardiovascular disease, and 33 (13%) had inflammatory disease. (Table 1) The red blood cell and platelet transfusion-dependent rates were 7.3% and 2.3%, respectively. The median number of MTs was 2 (IQR 1-3), with 221 (86%) pts had ≥1 MT, of which 116 (53%) had ≥ 2 MTs. The most common 5 MTs were TET2 (n=78, 30%), SRSF2 (n=50, 19%), DNMT3A (n=47, 18%), ASXL1 (n=40, 16%), and U2AF1 (n=22, 9%) (Figure 1). The median VAF (mVAF) was 28% (IQR: 9.2%, 43%) with VAF < 10% in 47 (18%) and VAF ≥40% in 78 (30.2%) of the MTs. mVAF of the all genes are shown in Figure 2. Among pts with CG abnormalities (n=62, 24%), trisomy 8 and -Y are the most common karyotypes (n=15 for each, 24%) (Table 2). Eighty one (31%) patients received various treatments for CCUS with modest RR, including growth factors (n=47, 18.2%, RR: 25.5%), supportive care (n=23, 9%, RR: 26%), immunoglobulin/immunosuppressive therapy (n=15, 6%, RR: 40%), and DNMTi (n=8, 3%, RR=13%). The median length of follow-up was 15.6 (IQR 6.9-30.6) months. 24 pts progressed to MN, 14 (58.3%) of which were MDS, 8 (33.3%) CMML, and 2 (8.3%) AML. The 2-year PFS was 86.1% (95% CI: 80-93%) with a median PFS of 16.3 (IQR: 3.7, 21) months. In the multivariable model, positive MT of KRAS (HR: 8.4, 95% CI: 1.9-36.9, p=0.005) and CBL (HR: 16.5, 95% CI: 3.7-73.8, p=0.003) were significantly associated with DP. In the functional pathway analysis, having at least 1 splicing factor MT was significantly associated with DP (HR: 2.6, 95% CI:1.2-5.9, p=0.02). TP53 was not significantly associated with DP (HR: 1.2, 95% CI: 0.2-8.7, p=0.88). Having >1 MT (HR: 3.57, 95% CI: 1.19-10.7, p=0.02) compared to a single MT was significantly associated with DP (Figure 3). Over the follow-up period, 35 pts died. The 2-year OS was 81% (95% CI: 74.9-87.9%). In the multivariable model, MT of KRAS (HR: 6.1, 95% CI: 1.8-20, p=0.003), CBL (HR: 7.3, 95% CI: 1.7-31, p=0.007), and FLT3 (HR: 19.9, 95% CI: 2.5-155, p=0.004) were significantly associated with inferior survival. In the functional pathway analysis, MTs in activated signaling pathway were significantly associated with death (HR: 4.1, 95% CI: 1.8-9, p<0.001). None of the pts with TP53 MT died. Having >1 MT was not statistically significantly associated with higher risk of death (HR: 1.5, 95% CI: 0.7-3.0, p=0.28) (Figure 4). After adjustment for co-MT status and comorbidities, baseline Hb<10 g/dL (HR: 3.7, 95% CI: 1.8-7.9, p<0.001) was significantly associated with greater mortality. Conclusion: This large retrospective study summarizes the CCUS pts' characteristics, with different MT patterns and VAF. We confirmed the impact of having >1 MT on DP, but not OS. Genes involved in activated signaling had a significant impact on both DP and OS. TP53 MT was not associated with worse outcome. Findings may be due to limited cases in the particular genes and different gene panels from multiple institutions. A longer follow-up is planned to further describe the predictors for outcome in this ongoing study. Figure 1 Figure 1. Disclosures Komrokji: Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy. Zeidan: BioCryst: Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Geron: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Janssen: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; AstraZeneca: Consultancy; Agios: Consultancy; BeyondSpring: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Astex: Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; Pfizer: Other: Travel support, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; Jasper: Consultancy; Astellas: Consultancy; ADC Therapeutics: Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Madanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda Oncology: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Novartis: Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Consultancy, Honoraria. Lai: Astellas: Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Foran: trillium: Research Funding; actinium: Research Funding; kura: Research Funding; boehringer ingelheim: Research Funding; takeda: Research Funding; abbvie: Research Funding; aptose: Research Funding; pfizer: Honoraria; novartis: Honoraria; servier: Honoraria; bms: Honoraria; revolution medicine: Honoraria; OncLive: Honoraria; gamida: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; taiho: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Desai: Astex: Research Funding; Janssen R&D: Research Funding; Kura Oncology: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy. Ades: ABBVIE: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; TAKEDA: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Brunner: Novartis, Celgene, Takeda, AstraZeneca: Research Funding; Celgene, Forty Seven Inc, Jazz: Other: Advisory Board. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Prebet: BMS: Research Funding; BMS, Curios, Daichi: Consultancy. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Savona: Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.