Shah, Meera

Abstract Clonal cytopenia of undetermined significance (CCUS) is defined by a myeloid driver mutation in the context of otherwise unexplained cytopenia. CCUS has an inherent risk of progressing to myeloid neoplasm. However, it is unknown how exposure to previous cytotoxic therapy may impact the risk of progression and survival. We stratified patients with CCUS by prior exposure to DNA-damaging therapy. Of 151 patients, 46 (30%) had received cytotoxic therapy and were classified as therapy-related CCUS (t-CCUS), whereas 105 (70%) had de novo CCUS. A lower proportion of t-CCUS had hypercellular marrows (17.8% vs 44.8%, P = .002) but had higher median bone marrow blast percentages. After a median follow-up of 2.2 years, t-CCUS had significantly shorter progression-free survival (PFS, 1.8 vs 6.3 years; hazard ratio [HR], 2.1; P = .007) and median overall survival (OS; 3.6 years vs not reached; HR, 2.3; P = .007) compared with CCUS. Univariable and multivariable time-to-event analyses showed that exposure to cytotoxic therapy independently accounted for inferior PFS and OS. Despite the similarities in clinical presentation between CCUS and t-CCUS, we show that exposure to prior cytotoxic therapies was an independent risk factor for inferior outcomes. This suggests that t-CCUS represents a unique clinical entity that needs more stringent monitoring or earlier intervention strategies.

Abstract Introduction TP53-mutated (TP53mut) myeloid neoplasms (MN) are a distinct entity of myeloid neoplasms with no effective therapies and poor survival (Grob et al, Blood 2022). The TP53-deficient state facilitates the downstream dysfunction of the spindle assembly checkpoint (SAC), predisposing to genomic instability. Recently, a SAC protein, threonine tyrosine kinase (TTK), has emerged as an attractive therapeutic target. Upregulation of TTK has been described in various solid tumors. It is stipulated that targeting SAC proteins might result in extreme level of genomic instability that even cancer cells could not tolerate. We hypothesized that inhibition of TTK with a small molecular inhibitor—TTKi may offer a promising therapeutic strategy for TP53mut MN. Method We evaluated relative TTK mRNA expression and its association with TP53mut and complex karyotypes (CK) in the BEAT AML cohort (Tyner et al., 2018). We used myeloid cell lines, OCI-AML-3, THP-1, and U937 cell lines that harbor-near diploid, moderately aneuploid, and highly aneuploid karyotype, respectively. The efficacy of TTKi CFI-402257 (AbMole) was tested using cell viability, apoptosis, and colony-forming unit (CFU) assays using the standard protocol. Finally, we tested the efficacy of CFI-402257 using the diagnostic bone marrow mononuclear cell (BMMC) cells from TP53mut MN patients. Results Among 591 AML patients in the BEAT AML cohort (41.6% diploid, 35.9% non-CK, 22.7% CK), TTK mRNA expression was progressively higher with increasing chromosomal abnormality burden. TTK expression was 1.96-fold higher in TP53mut AML compared to TP53wt AML (P=0.0008). Further stratified by TP53mut VAF, there was a trend towards higher expression of TTK in TP53mut VAF≥50 compared to the cases with VAF<50 (P=0.06). Next, the treatment with TTKi (CFI-402257) led to a dose-dependent reduction in cell viability across all cell lines, with TP53mut cells (U937 and THP-1) being more sensitive than TP53-wildtype (TP53wt) OCI_AML-3 cells. Similarly, TTKi inhibited the CFU potential of THP-1, U937, and OCI-AML-3 cells. Finally, TTKi induced dose-dependent apoptosis in TP53mut MN patient BMMC but not in healthy donors, resulting in a significant reduction in colony-forming potential. Conclusion Overexpression of TTK was strongly associated with TP53mut and CK in AML. Inhibition of TTK-induced dose-dependent apoptosis in all myeloid cell lines tested with TP53mut highly aneuploid cell line (U937)—traditionally the most chemorefractory phenotype—being the most sensitive. TTKi induced preferential and dose-dependent inhibition of viability and cell proliferation potential in TP53mut MN compared to healthy donor cells, implying a therapeutic window. Further pre-clinical and clinical studies are indicated to evaluate SAC inhibition as a therapeutic strategy for TP53mut MN. Citation Format: Arini Arsana, Huixing Huang, Arief Al-Kali, Mithun Shah. Spindle assembly checkpoint as a therapeutic target for TP53-mutated myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3179.

Abstract High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.

AbstractMalignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage–dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH‐H), 9 interdigitating dendritic cell sarcoma (MH‐IDC), and 8 Langerhans cell sarcoma (MH‐LC). The median age at diagnosis was 61 years (range, 3–83). Thirty‐three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8–50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first‐line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

This case-control study examines the incidence and risks of myeloid neoplasms in adults treated for B-cell lymphoproliferative disorders or multiple myeloma.

SummaryAmong 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non‐ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A‐mutated cases less likely (p < 0.01) to be affected. Treatment‐emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.