TY - JOUR
T1 - Bone Marrow Surveillance of Pediatric Cancer Survivors Identifies Clones that Predict Therapy-Related Leukemia
AU - Spitzer, Barbara
AU - Rutherford, Kayleigh D.
AU - Gundem, Gunes
AU - McGovern, Erin M.
AU - Millard, Nathan E.
AU - Arango, Juan E.Ossa
AU - Cheung, Irene Y.
AU - Gao, Teng
AU - Levine, Max F.
AU - Zhang, Yanming
AU - Medina-Martínez, Juan S.
AU - Feng, Yi
AU - Ptashkin, Ryan N.
AU - Bolton, Kelly L.
AU - Farnoud, Noushin
AU - Zhou, Yangyu
AU - Patel, Minal A.
AU - Asimomitis, Georgios
AU - Cobbs, Cassidy C.
AU - Mohibullah, Neeman
AU - Huberman, Kety H.
AU - Arcilla, Maria E.
AU - Kushner, Brian H.
AU - Modak, Shakeel
AU - Kung, Andrew L.
AU - Zehir, Ahmet
AU - Levine, Ross L.
AU - Armstron, Scott A.
AU - Cheung, Nai Kong V.
AU - Papaemmanuil, Elli
N1 - Funding Information:
The authors acknowledge the use of the Integrated Genomics Operation Core, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle
Funding Information:
G. Gundem reports personal fees from Isabel Inc. outside the submitted work. J.S. Medina-Martínez reports other support from Isabel Inc. outside the submitted work. K.L. Bolton reports grants from Bristol Myers Squib outside the submitted work. M.E. Arcilla reports personal fees from Invivoscribe, Biocartis, AstraZeneca, Bristol Myers Squibb, Clinical Care Options, Janssen Global Services, LLC, Physicians’ Education Resource, LLC, and Roche outside the submitted work. S. Modak reports personal fees from YMAbs Therapeutics and Illumina RP outside the submitted work. A.L. Kung reports other support from Isabel Technologies, personal fees and other support from Imago Biosciences and Emendo Biotherapeutics, and personal fees from DarwinHealth outside the submitted work. R.L. Levine reports being on the supervisory board of QIAGEN and is a scientific advisor to Imago, Mission Bio, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics, and Isoplexis; receiving research support from and consulting for Celgene and Roche and has consulted for Incyte, Janssen, Astellas, Morphosys, and Novartis; and receiving honoraria from AstraZeneca, Roche, Lilly, and Amgen for invited lectures and from Gilead for grant reviews. S.A. Armstrong reports personal fees and nonfinancial support from Neomorph, Imago Biosciences, Cyteir Therapeutics, Accent Therapeutics, Mana Therapeutics, and C4 Therapeutics, as well as grants from Novartis, Syndax, and Janssen outside the submitted work. N.K.V. Cheung reports personal fees from YMAbs Therapeutics, Abpro Lab, Eureka Therapeutics, and Biotec Pharmacon, as well as other support from YMAbs Therapeutics outside the submitted work. E. Papaemmanuil reports other support from Isabel Inc. outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
Research funding for this work included awards from Geoffrey Beene Cancer Research Center (E. Papaemmanuil and N.K.V. Cheung), Gabrielle’s Angel Foundation (E. Papaemmanuil), V Foundation (E. Papaemmanuil), and the Damon Runyon Cancer Research Foundation (Damon Runyon-Rachleff Innovation Award, E. Papaemmanuil).
Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.
PY - 2022/4/15
Y1 - 2022/4/15
N2 - Purpose: Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of nonrelapse mortality among pediatric cancer survivors. Although the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children. Experimental Design: We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric patients with solid tumor. Results: We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10 and DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13 of 17 patients at a median of 15 months before t-MDS/AL diagnosis (range, 1.3-32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14 and 1/21, respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared with transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Last, only 1% of pediatric patients with solid tumor evaluated had CH involving myeloid genes. Conclusions: These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients.
AB - Purpose: Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of nonrelapse mortality among pediatric cancer survivors. Although the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children. Experimental Design: We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric patients with solid tumor. Results: We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10 and DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13 of 17 patients at a median of 15 months before t-MDS/AL diagnosis (range, 1.3-32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14 and 1/21, respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared with transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Last, only 1% of pediatric patients with solid tumor evaluated had CH involving myeloid genes. Conclusions: These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients.
UR - http://www.scopus.com/inward/record.url?scp=85128306240&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-2451
DO - 10.1158/1078-0432.CCR-21-2451
M3 - Article
C2 - 35078859
AN - SCOPUS:85128306240
SN - 1078-0432
VL - 28
SP - 1614
EP - 1627
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -