The Characteristics and Prognosis of Patients with Clonal Cytopenias of Undetermined Significance, Including Cancer and Therapy-Related Clonal Cytopenias

Background: Clonal cytopenias of undetermined significance (CCUS) refers to unexplained cytopenia(s) arising in the context of myeloid-associated somatic mutations (MT) and that do not meet diagnostic criteria for defined myeloid neoplasms (MN). CCUS is often preceded by clonal hematopoiesis, with an associated high probability of disease progression, along with significant morbidity, particularly cardiovascular disease (CVD). Various selection pressures create clonal composition and propagation, leading to clonal diversification, dominance, and the genomic landscape of neoplastic phenotypes. We previously described the molecular prognostic pattern on CCUS outcomes. Herein, we expanded our cohort and further assessed the outcomes in patients with a history of cancer and potential therapy-related CCUS.

Methods: In a multicenter CCUS data registry, we collected patients' clinical data, laboratory parameters, cytogenetics, molecular genetics, and disease course. We described patients' baseline characteristics, including molecular features and their outcomes. We assessed the characteristics of patients with CCUS who had a history of cancer (c-CCUS), including hematologic diseases (HD) other than MN or a solid tumor (ST), and patients who received prior cytotoxic therapies (t-CCUS), including chemotherapy, radiation therapy, autologous stem cell transplantation, chimeric antigen receptor T-cell therapy, or an immune checkpoint inhibitor for their primary cancers other than MN, and the rest of the patients (NOS-CCUS). The relationship between independent variables and outcomes was assessed using Cox proportional hazards models. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. All statistical analysis was performed using R.

Results: A total of 356 CCUS cases were identified. The mean age was 67.7(SD 12.9) years, with 128 (36%) females. The number of patients with c-CCUS and t-CCUS was 133 (37.4%) and 66 (18.5%), respectively. Among the patients with c-CCUS, 72 (46.2%) had HD, 67 (50.4%) had ST, and 17 (12.8%) had both. NOS-CCUS included 223 (62.6%) patients. The median number of comorbidities was 2 (Q1-Q3: 2-4), with CVD being the most common (115, 32.3%), followed by autoimmune diseases (44, 12.3%).

A total of 592 variants were identified in the entire cohort, with the most common MT being TET2 (141, 23.8%), followed by DNMT3A (79, 13.3%), SRSF2 (60, 10.1%), ASXL1 (49, 8.3%), and U2AF1 (27, 4.6%). The median variant allele fraction was 27.9% (IQR: 32.8%), and 316 (88.7%) patients had at least 1 MT, with 159 (44.7%) having ≥2 MTs. Eighty (22.3%) patients had abnormal cytogenetics.

There were no significant differences in age, gender, or lab parameters between patients with c-CCUS and those without. But patients with CCUS-ST and t-CCUS were older, with a mean age of 72.9 (SD:10, p<0.001) and 72 (SD: 9.9, p=0.003) years, respectively. Patients with CCUS-HD were younger, with a mean age of 64.4 (SD:15.2, p=0.016), and had lower hemoglobin (mean: 10.5, SD: 2, g/dL) and platelet counts (mean: 124, SD: 107X 10^9/L), compared to those without HD (both p=0.03). The MT patterns were similar among the groups, except CCUS-HD had a prominent DNMT3A^MT (27.9%), followed by TET2^MT (8.7%) and ASXL1^MT (6.7%). The prevalence of TP53^MT (n=1, 2%) and PPM1D^MT (n=0) was low, but cytogenetic abnormalities were more common in t-CCUS (n=22, 33.3%, p=0.03) (Table 1 andFigure 1).

The median follow-up duration for the cohort was 19.4 (IQR: 17.2) months, with 39 (10%) progression events and 52 (14.5%) deaths of any causes. Co-mutation (≥2 MTs) status had a negative impact on both PFS (HR: 4.66, CI: 2.65-9.65, p<0.0001) and OS (HR: 1.77, CI: 1.01-3.1, p=0.04) after adjusting for age. In the functional pathway analysis, MTs in splicing factors are associated with inferior PFS (HR: 4.04, CI: 2.1-7.78, p<0.0001), and cell signaling factors (HR: 2.16, CI 1.02-4.6, p=0.04) are associated with inferior OS. There were no significant differences in the PFS or OS between patients with c-CCUS and those without (both p>0.05), but patients with t-CCUS had an inferior OS compared to those without (HR: 2.13, CI: 1.16-3.84, p=0.01).

Conclusion: In this large cohort of patients with CCUS, we demonstrated that the progression risks of CCUS are driven by MT patterns (≥2 MTs and splicing factors). Both molecular data and clinical history had an impact on their mortality.

Komrokji:AbbVie: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Acceleron Pharma: Consultancy; Geron: Consultancy; PharmaEssentia, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma, Innovent: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Patel:Celgene/BMS: Research Funding; Pfizer: Research Funding; Servier/Agios: Research Funding; Kronos Bio: Research Funding; AbbVie: Consultancy. Zeidan:Novartis, Cardiff Oncology, Pfizer: Other: Travel Support; Celgene/BMS, Novartis, AbbVie, Gilead, Kura, Loxo Oncology, Geron: Other: Clinical Trial Committee; Celgene/BMS, Novartis, Cardiff Oncology, AbbVie: Consultancy, Honoraria, Other: Advisory Board; Celgene/BMS, Novartis, Cardiff Oncology, AbbVie, Pfizer, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Amgen, Aprea, Astex, Pfizer, Medimmune/AstraZeneca, ADC Therapeutics: Research Funding; Gilead, Kura, Loxo Oncology: Consultancy, Honoraria, Other: Clinical Trial Committee; Pfizer, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Amgen, Aprea, Gilead, Kura, Loxo Oncology, Otsuka, Jazz, Agios, Acceleron, Astellas, Daiichi-Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Ionis, Epizyme, Janssen, Syndax, Genentec: Consultancy, Honoraria, Other: Advisory Boards; Astex, Medimmune, Astrazeneca, ADC Therapeutics: Research Funding; Celgene/BMS, AbbVie, Pfizer, Boeringer-Ingelheim, Trovagene, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, Amgen, Otsuka: Consultancy, Honoraria, Research Funding; Jazz, Agios, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, Beyondspring, Gilead, Kura, Tyme, Janssen, Syndax, Geron, Ionis, Epizyme: Consultancy, Honoraria. Kishtagari:CTI Biopharm: Speakers Bureau. Zeidner:AbbVie: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Immunogen: Honoraria; Servier: Consultancy, Honoraria; Shattuck Labs: Honoraria; Arog: Research Funding; Astex: Research Funding; Jazz: Research Funding; Merck: Research Funding; Stemline: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Syndax: Research Funding; Takeda: Research Funding; Genentech: Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Coombs:Beigene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria; TG Therapeutics: Honoraria; MEI Pharma: Honoraria; Loxo/Lilly: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; CTI Biopharma: Current equity holder in publicly-traded company. Madanat:BluePrint Medicines, GERON, OncLiv: Consultancy, Honoraria; Sierra Oncology, Stemline Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees. Foran:AbbVie, Actinium, Aptose, Astex, H3Biosciences, Kura Oncology, Trillium, Xencor: Research Funding; Novartis, Servier, Pfizer, BMS, Taiho: Other: Formal Advisory Activities. Desai:Takeda, Bristol Myers Squibb, Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Research: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Research Funding; Celldex Therapeutics: Research Funding; CTI Biopharma: 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; Medicom Worldwide: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Physician Educational Resource: Honoraria; Picnic Health: Honoraria; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AAMDSIF: Honoraria. Al Malki:Hasna Biopharma: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; CareDx: Consultancy, Research Funding; NexImmune: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Lai:Astellas, Jazz: Speakers Bureau; AbbVie, Agios/Servier, Daiichi-Sankyo, Jazz, Macrogenics, PDS, Pfizer, Genentech, Taiho, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Osman:Syros Pharmaceuticals: Research Funding; Karyopharm Therapeutics: Research Funding. Abaza:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; ALX Oncology: Research Funding. Taylor:Karyopharm, Inc: Honoraria. Brunner:Janssen: Research Funding; Celgene/BMS: Consultancy, Research Funding; Agios: Honoraria; AstraZeneca: Research Funding; Acceleron: Honoraria; GSK: Research Funding; Keros Therapeutics: Consultancy; Novartis: Consultancy, Research Funding; Taiho: Consultancy; Takeda: Consultancy, Research Funding; Aprea: Research Funding. Carraway:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: DSMB; Takeda: Other: DSMB; Syndax: Other: DSMB; Stemline: Speakers Bureau; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Speakers Bureau. Padron:Syntrix Pharmaceuticals: Research Funding; Blueprint: Honoraria; Kura: Research Funding; BMS: Research Funding; Taiho: Honoraria; Incyte: Research Funding; Stemline: Honoraria. Patnaik:Kura Oncology, Stemline Therapeutics: Research Funding. Savona:AbbVie: Consultancy, Other: travel expenses; Forma: Consultancy; Astex Pharmaceuticals: Research Funding; Ryvu Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Taiho Pharmaceutical: Consultancy; Karyopharm Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Research Funding; Novartis: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy, Other: Travel expenses, Research Funding; Geron: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; ALX Oncology: Research Funding; Sierra Oncology: Consultancy, Other: travel expenses. Al-Kali:Astex: Other: research support to institution.