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Multicenter Study
. 2024 Nov 7;144(19):2033-2044.
doi: 10.1182/blood.2024024756.

Risk prediction for clonal cytopenia: multicenter real-world evidence

Zhuoer Xie  1   2 , Rami Komrokji  1 , Najla Al Ali  1 , Alexandra Regelson  3 , Susan Geyer  3 , Anand Patel  4 , Caner Saygin  4 , Amer M Zeidan  5 , Jan Philipp Bewersdorf  6 , Lourdes Mendez  5 , Ashwin Kishtagari  7 , Joshua F Zeidner  8 , Catherine C Coombs  8 , Yazan F Madanat  9 , Stephen Chung  9 , Talha Badar  10 , James Foran  10 , Pinkal Desai  11 , Charlton Tsai  11 , Elizabeth A Griffiths  12 , Monzr M Al Malki  13 , Idoroenyi Amanam  13 , Catherine Lai  14 , H Joachim Deeg  15 , Lionel Ades  16 , Cecilia Arana Yi  17 , Afaf E G Osman  18 , Shira Dinner  19 , Yasmin Abaza  19 , Justin Taylor  20 , Namrata Chandhok  20 , Deborah Soong  20 , Andrew M Brunner  21 , Hetty E Carraway  22 , Abhay Singh  22 , Chiara Elena  23 , Jacqueline Ferrari  23   24 , Anna Gallì  23 , Sara Pozzi  24 , Eric Padron  1 , Mrinal M Patnaik  2 , Luca Malcovati  23   24 , Michael R Savona  7 , Aref Al-Kali  2
Affiliations
Multicenter Study

Risk prediction for clonal cytopenia: multicenter real-world evidence

Zhuoer Xie et al. Blood. .

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.

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Conflict of interest statement

Conflict-of-interest disclosure: R.K. reports receiving grant support from Bristol Myers Squibb (BMS); speaker bureau fees from AbbVie, Cell Therapeutics, Inc (CTI) BioPharma, Jazz Pharmaceuticals, Pharma Essentia, and Servio; and advisory board fees from AbbVie, BMS, CTI BioPharma, Geron, Jazz Pharmaceuticals, Novartis, Taiho, and Rigel Pharmaceuticals. A.P. received research funding from Pfizer and Kronos Bio; and received honoraria from BMS and AbbVie. E.A.G. has received honoraria for advisory board membership from AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI, BioPharma, Genentech, Novartis, PicnicHealth, Takeda Oncology, and Taiho Oncology; has received research funding from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, and Genentech Inc; and received honoraria for Continuing Medical Education activities from Physicians’ Educational Resource, MediCom Worldwide, American Society of Hematology, and Aplastic Anemia and Myelodysplasia Syndrome (AAMDS) International Foundation. H.E.C. has received honoraria for advisory board memberships from AbbVie, Celgene/BMS, Genentech, Jazz Pharmaceuticals, Novartis, and Daiichi Sankyo; has received research funding from Celgene; has served on speakers bureau for BMS, Jazz Pharmaceuticals, Novartis, and Stemline Therapeutics; and has served on data safety monitoring boards for Astex, AbbVie, Takeda, and Syndax. A.M.B. received consulting or advisory board honoraria from Novartis, Acceleron, Agios, AbbVie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, and Gilead; and has research support from the National Institutes of Health Specialized Programs of Research Excellence (SPORE) in Myeloid Malignancies and the Edward P. Evans Foundation. A.M.Z. received research funding (institutional) from Celgene/BMS, AbbVie, Astex, Pfizer, MedImmune/AstraZeneca, Boehringer Ingelheim, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, and Antibody Drug Conjugates (ADC) Therapeutics; participated in advisory boards, and/or had a consultancy with, and received honoraria, from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz Pharmaceuticals, Incyte, Agios, Boehringer Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme; and served on clinical trial committees for Novartis, AbbVie, Gilead, BioCryst, ALX Oncology, Geron, and Celgene/BMS. E.P. received honoraria from Stemline Therapeutics, Taiho, and Blueprint; and research funding from BMS, Incyte, Kura, and Syntrix Pharmaceuticals. Y.F.M. received honoraria/consulting fees from Blueprint Medicines, Geron, OncLive, and MD Education; participated in advisory boards and received honoraria from Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, MorphoSys, Taiho Oncology, Rigel Pharmaceuticals, and Novartis; and received travel reimbursement from Blueprint Medicines, MD Education, and MorphoSys. J.F.Z. received honoraria from advisory boards from AbbVie, BMS, Daiichi Sankyo, Genentech, Gilead, Immunogen, Servier, and Shattuck Labs; reports consultancy for AbbVie, Foghorn, Gilead, Sellas, and Servier; and received research funding from AbbVie, Arog, Astex, Gilead, Jazz, Loxo, Merck, Newave, Shattuck Labs, Stemline Therapeutics, Sumitomo Dainippon Pharma, and Takeda. A.S. received research funding from, and serves on the advisory board for Rigel Pharmaceuticals. C.C.C. received consulting or advisory board honoraria from AbbVie, AstraZeneca, BeiGene, Genentech, MEI Pharma, TG Therapeutics, Janssen, Novartis, MingSight, Octapharma, and Lilly/Loxo; serves on an independent review committee for Octapharma; serves on steering committees for AbbVie and Lilly/Loxo; has equity in CTI Biopharma and bluebird bio; serves on speakers bureaus for AbbVie, Genentech, BeiGene, and AstraZeneca; and has received research support (to institution) from AbbVie and Lilly/Loxo. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Mutational spectrum for patients with clonal cytopenia.
Figure 2.
Figure 2.
LFS. LFS (of N = 357) is stratified by (A) CCMUS; (B) PLT <100 × 109/L vs ≥100 × 109/L; (C) having <2 vs ≥2 mutations; (D) having a splicing pathway mutation; (E) Multivariable analysis including the variables of PLT <100 × 109/L vs ≥100 × 109/L and <2 vs ≥2 mutations (solid lines indicate having ≥2 mutations, dotted lines indicate mutation number <2, blue indicates PLTs of ≥100 × 109/L, and red indicates PLTs of <100 × 109/L); and (F) multivariable analysis including the variables of PLT count, having ≥2 mutations, and having a splicing pathway mutation (dotted lines indicate not having splicing mutations, solid lines indicate having splicing mutation, blue indicate PLTs of <100 × 109/L and MT <2, green indicate PLTs of <100 × 109/L and MT of ≥2, yellow indicate PLTs of ≥100 × 109/L and MT <2, and red indicate PLTs of ≥100 × 109/L and MT ≥2).
Figure 2.
Figure 2.
LFS. LFS (of N = 357) is stratified by (A) CCMUS; (B) PLT <100 × 109/L vs ≥100 × 109/L; (C) having <2 vs ≥2 mutations; (D) having a splicing pathway mutation; (E) Multivariable analysis including the variables of PLT <100 × 109/L vs ≥100 × 109/L and <2 vs ≥2 mutations (solid lines indicate having ≥2 mutations, dotted lines indicate mutation number <2, blue indicates PLTs of ≥100 × 109/L, and red indicates PLTs of <100 × 109/L); and (F) multivariable analysis including the variables of PLT count, having ≥2 mutations, and having a splicing pathway mutation (dotted lines indicate not having splicing mutations, solid lines indicate having splicing mutation, blue indicate PLTs of <100 × 109/L and MT <2, green indicate PLTs of <100 × 109/L and MT of ≥2, yellow indicate PLTs of ≥100 × 109/L and MT <2, and red indicate PLTs of ≥100 × 109/L and MT ≥2).
Figure 3.
Figure 3.
OS. OS (of N = 357) is stratified by (A) CCMUS; (B) Hb <10 vs ≥10 g/dL; (C) having ≥2 mutations; (D) having a signaling pathway mutation; (E) multivariable analysis including the variables of Hb <10 g/dL and having a signaling pathway mutation (solid lines indicate having a signaling pathway mutation, dotted lines indicate not having a signaling pathway mutation, blue indicates Hb ≥10 g/dL, and red indicates Hb <10 g/dL); and (F) multivariable analysis including the variables of Hb <10 g/dL and ≥2 mutations (solid lines indicate having ≥2 mutations, dotted lines indicate having <2 mutations, blue indicates Hb ≥10 g/dL, and red indicates Hb <10 g/dL).
Figure 4.
Figure 4.
VAF. VAF cutoff 22% predicts (A) LFS but not (B) OS.
Figure 5.
Figure 5.
CCRS. Prognostic models for (A) multivariate analysis parameters and assigned score for LFS; (B) The 2-year cumulative incidence of MN progression based on CCRS: 6.4% (95% CI, 3-11.4) for low-risk, 14.1% (95% CI, 7.9-22.2) for intermediate-risk, and 37.2% (95% CI, 19.8-54.7) for high-risk groups by the Gray test (P < .0001). (C) The number of patients within each category, cumulative MN events, and 2-year cumulative incidence.
Figure 6.
Figure 6.
Validation. The CCRS model significantly stratified LFS in the Pavia cohort (P = .005). Using low-risk group as a reference group, the HR for intermediate vs low risk (HR, 1.6; 95% CI, 0.55-4.62; P = .39) and high vs low risk (HR, 3.57; 95% CI, 1.56-8.18; P = .003).
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