Risk prediction for clonal cytopenia: multicenter real-world evidence

Zhuoer Xie; Rami Komrokji; Najla Al Ali; Alexandra Regelson; Susan Geyer; Anand Patel; Caner Saygin; Amer M. Zeidan; Jan Philipp Bewersdorf; Lourdes Mendez; Ashwin Kishtagari; Joshua F. Zeidner; Catherine C. Coombs; Yazan F. Madanat; Stephen Chung; Talha Badar; James Foran; Pinkal Desai; Charlton Tsai; Elizabeth A. Griffiths; Monzr M. Al Malki; Idoroenyi Amanam; Catherine Lai; H. Joachim Deeg; Lionel Ades; Cecilia Arana Yi; Afaf E.G. Osman; Shira Dinner; Yasmin Abaza; Justin Taylor; Namrata Chandhok; Deborah Soong; Andrew M. Brunner; Hetty E. Carraway; Abhay Singh; Chiara Elena; Jacqueline Ferrari; Anna Gallì; Sara Pozzi; Eric Padron; Mrinal M. Patnaik; Luca Malcovati; Michael R. Savona; Aref Al-Kali

doi:10.1182/blood.2024024756

Risk prediction for clonal cytopenia: multicenter real-world evidence

Zhuoer Xie^*, Rami Komrokji, Najla Al Ali, Alexandra Regelson, Susan Geyer, Anand Patel, Caner Saygin, Amer M. Zeidan, Jan Philipp Bewersdorf, Lourdes Mendez, Ashwin Kishtagari, Joshua F. Zeidner, Catherine C. Coombs, Yazan F. Madanat, Stephen Chung, Talha Badar, James Foran, Pinkal Desai, Charlton Tsai, Elizabeth A. GriffithsMonzr M. Al Malki, Idoroenyi Amanam, Catherine Lai, H. Joachim Deeg, Lionel Ades, Cecilia Arana Yi, Afaf E.G. Osman, Shira Dinner, Yasmin Abaza, Justin Taylor, Namrata Chandhok, Deborah Soong, Andrew M. Brunner, Hetty E. Carraway, Abhay Singh, Chiara Elena, Jacqueline Ferrari, Anna Gallì, Sara Pozzi, Eric Padron, Mrinal M. Patnaik, Luca Malcovati, Michael R. Savona, Aref Al-Kali^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2033-2044
Number of pages	12
Journal	Blood
Volume	144
Issue number	19
DOIs	https://doi.org/10.1182/blood.2024024756
State	Published - Nov 7 2024

Funding

The authors thank all the centers for providing the data and collaboration. Editorial assistance was provided by the Moffitt Cancer Center's Office of Scientific Publishing by Daley White and Gerard Hebert; no compensation was given beyond their regular salaries. This study was supported by the Small Grant Fellowship Award from the Mayo Clinic (Mayo Center for Clinical and Translational Science [CCaTS] grant number UL1TR000135). L.M. was supported by the Cancer Research UK (CRUK), United Kingdom, Associazione Italiana per la Ricerca sul Cancro (AIRC), Italy, and Fundacion Cient\u00EDfica-Asociacion Espanola Contra el Cancer (FC-AECC), Spain, under the International Accelerator Award Program (project numbers C355/A26819 and 22796). Collection of data at the Fred Hutchinson Cancer Center (H.J.D) was supported by the Seattle Translational Tumor Research (STTR) program at Fred Hutchinson Cancer Center. Contribution: Z.X. and A.A.-K. designed the study, contributed cases, and wrote the manuscript; Z.X. A.R. and S.G. performed the statistical analysis; C.E. J.F. A.G. S.P. and L.M. provided the independent external cohort to validate our study model; and all other authors contributed to the data collection, reviewed, and provided edits to subsequent versions of the manuscript. This study was supported by the \u201CSmall Grant Fellowship Award\u201D from the Mayo Clinic (Mayo CCaTS grant number UL1TR000135 ). L.M. was supported by the Associazione Italiana per la Ricerca sul Cancro ( AIRC ), Milan, Italy (investigator grant #20125; AIRC 5 \u00D7 1000 project #21267); and the Cancer Research UK , FC AECC and AIRC under the International Accelerator Award Program (project #C355/A26819 and #22796).

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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Xie, Z., Komrokji, R., Al Ali, N., Regelson, A., Geyer, S., Patel, A., Saygin, C., Zeidan, A. M., Bewersdorf, J. P., Mendez, L., Kishtagari, A., Zeidner, J. F., Coombs, C. C., Madanat, Y. F., Chung, S., Badar, T., Foran, J., Desai, P., Tsai, C., ... Al-Kali, A. (2024). Risk prediction for clonal cytopenia: multicenter real-world evidence. Blood, 144(19), 2033-2044. https://doi.org/10.1182/blood.2024024756

@article{85bb842edf0548459d2a5f01f24dadb6,

title = "Risk prediction for clonal cytopenia: multicenter real-world evidence",

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.",

author = "Zhuoer Xie and Rami Komrokji and {Al Ali}, Najla and Alexandra Regelson and Susan Geyer and Anand Patel and Caner Saygin and Zeidan, {Amer M.} and Bewersdorf, {Jan Philipp} and Lourdes Mendez and Ashwin Kishtagari and Zeidner, {Joshua F.} and Coombs, {Catherine C.} and Madanat, {Yazan F.} and Stephen Chung and Talha Badar and James Foran and Pinkal Desai and Charlton Tsai and Griffiths, {Elizabeth A.} and {Al Malki}, {Monzr M.} and Idoroenyi Amanam and Catherine Lai and Deeg, {H. Joachim} and Lionel Ades and {Arana Yi}, Cecilia and Osman, {Afaf E.G.} and Shira Dinner and Yasmin Abaza and Justin Taylor and Namrata Chandhok and Deborah Soong and Brunner, {Andrew M.} and Carraway, {Hetty E.} and Abhay Singh and Chiara Elena and Jacqueline Ferrari and Anna Gall{\`i} and Sara Pozzi and Eric Padron and Patnaik, {Mrinal M.} and Luca Malcovati and Savona, {Michael R.} and Aref Al-Kali",

note = "Publisher Copyright: {\textcopyright} 2024 American Society of Hematology",

year = "2024",

month = nov,

day = "7",

doi = "10.1182/blood.2024024756",

language = "English (US)",

volume = "144",

pages = "2033--2044",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "19",

}

Xie, Z, Komrokji, R, Al Ali, N, Regelson, A, Geyer, S, Patel, A, Saygin, C, Zeidan, AM, Bewersdorf, JP, Mendez, L, Kishtagari, A, Zeidner, JF, Coombs, CC, Madanat, YF, Chung, S, Badar, T, Foran, J, Desai, P, Tsai, C, Griffiths, EA, Al Malki, MM, Amanam, I, Lai, C, Deeg, HJ, Ades, L, Arana Yi, C, Osman, AEG, Dinner, S , Abaza, Y, Taylor, J, Chandhok, N, Soong, D, Brunner, AM, Carraway, HE, Singh, A, Elena, C, Ferrari, J, Gallì, A, Pozzi, S, Padron, E, Patnaik, MM, Malcovati, L, Savona, MR & Al-Kali, A 2024, 'Risk prediction for clonal cytopenia: multicenter real-world evidence', Blood, vol. 144, no. 19, pp. 2033-2044. https://doi.org/10.1182/blood.2024024756

TY - JOUR

T1 - Risk prediction for clonal cytopenia

T2 - multicenter real-world evidence

AU - Xie, Zhuoer

AU - Komrokji, Rami

AU - Al Ali, Najla

AU - Regelson, Alexandra

AU - Geyer, Susan

AU - Patel, Anand

AU - Saygin, Caner

AU - Zeidan, Amer M.

AU - Bewersdorf, Jan Philipp

AU - Mendez, Lourdes

AU - Kishtagari, Ashwin

AU - Zeidner, Joshua F.

AU - Coombs, Catherine C.

AU - Madanat, Yazan F.

AU - Chung, Stephen

AU - Badar, Talha

AU - Foran, James

AU - Desai, Pinkal

AU - Tsai, Charlton

AU - Griffiths, Elizabeth A.

AU - Al Malki, Monzr M.

AU - Amanam, Idoroenyi

AU - Lai, Catherine

AU - Deeg, H. Joachim

AU - Ades, Lionel

AU - Arana Yi, Cecilia

AU - Osman, Afaf E.G.

AU - Dinner, Shira

AU - Abaza, Yasmin

AU - Taylor, Justin

AU - Chandhok, Namrata

AU - Soong, Deborah

AU - Brunner, Andrew M.

AU - Carraway, Hetty E.

AU - Singh, Abhay

AU - Elena, Chiara

AU - Ferrari, Jacqueline

AU - Gallì, Anna

AU - Pozzi, Sara

AU - Padron, Eric

AU - Patnaik, Mrinal M.

AU - Malcovati, Luca

AU - Savona, Michael R.

AU - Al-Kali, Aref

PY - 2024/11/7

Y1 - 2024/11/7

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85201583529&partnerID=8YFLogxK

U2 - 10.1182/blood.2024024756

DO - 10.1182/blood.2024024756

M3 - Article

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AN - SCOPUS:85201583529

SN - 0006-4971

VL - 144

SP - 2033

EP - 2044

JO - Blood

JF - Blood

IS - 19

ER -

Risk prediction for clonal cytopenia: multicenter real-world evidence

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