Identification and management of clonal hematopoiesis of indeterminate potential (CHIP) in cancer survivors: The Cleveland Clinic experience.
Authors: Kuzmanovic Teodora , Horvath Donna , Slaughter Maurice , Karasik Natalya , Bosler David , Moore Halle C. F. , Abraham Jame , Geiger Jessica Lyn , Funchain Pauline , Gerds Aaron Thomas , Advani Anjali S. , Mukherjee Sudipto , Molina John Carlos , Balderman Sophia Rebecca , Sekeres Mikkael A. , Maciejewski Jaroslaw P. , Bolwell Brian James , Carraway Hetty E , Patel Bhumika J , Singh Abhay 
Published: June 2023

7010 Background: Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is found in healthy populations as well as cancer patients (pts) and is associated with (w/) cardiovascular disease (CVD), risk of hematologic neoplasms (HN), and all-cause mortality. Germline variants (var) predispose to CHIP. However, described var are nonspecific to solid tumor pts. Identifying CHIP risk factors and mitigation strategies is paramount for improving outcomes. Methods: Pts in breast (BC) and head & neck cancer (HNC) survivorship (2020-2023) following curative treatment (tx) were eligible for our 10 year (yr) prospective study of annual next generation sequencing (NGS) and complete blood count (CBC) to identify CHIP. Mutations (mt) were classified as clinically significant (CS) or var of unknown significance (VUS), and as CH (med. VAF 4.7%) or potentially germline (PG; med. VAF 50%). Pts w/ CHIP were managed in both CHIP Clinic (CC) and Preventive Cardiology (PC) for monitoring and CVD reduction. Fisher’s exact and ANOVA tests were used for analyses. Results: Of 168 pts enrolled (117 BC, 51 HNC), 158 had NGS: 73 yr 1, 85 through yr 2 or 3; 22 pts received chemotherapy (CT), 49 radiation therapy (RT), 72 CT & RT (CRT). Sixty-eight pts (43%) had a mt; 21 (13%) had CHIP (6 w/ PG VUS). CHIP was found to be associated w/ older age (69 vs. 58, p= 0.0002). The most common CHIP mt were DNMT3A (n = 11), PPM1D (6), TET2 (6), JAK2 a nd TP53 (2). Two pts without yr 1 mt developed CHIP in yr 2. For PPM1D, 2 PG VUS were point mt from DNA transitions while 6 CHIP were truncating from transversions and deletions. All pts w/ PPM1D had RT (7/8 CRT), suggesting a molecular signature which varies from transition-driven aging. Six pts had thrombocytopenia (TP), 3 w/ PPM1D CHIP. TP was more common in CHIP (OR 11, p= 0.0356) and PPM1D (OR 29, p= 0.0016). In this cohort, anemia was not seen in pts w/ CHIP ( p= 0.048). Normal CBC was 6x less common in pts w/ CRT ( p= 2.3x10-7). Seven CHIP pts were seen by PC; 4 had yr 2 NGS following PC visit. All pts had addition of new/dose escalation of current CVD medication. Two CHIP pts had stable NGS; 2 CHIP & PG VUS pts had clonal changes including mt disappearance and acquisition. Of note, the PG VUS’s were assessed for institutional incidence in 3,918 HN pts w/ NGS data and in Mastermind (MM) for frequency of occurrence in published literature. Sixteen PG VUS (40%) occurred at our institution (13 found in MM, 7 classified as rare (avg gnomAD MAF 6x10-4)) and associated w/ HN, notably TET2 (n = 3). Conclusions: This ongoing prospective study is one of the largest to report characteristics and outcomes of CHIP pts in CC/PC and is expected to accrue more in expansion. We anticipate highlighting risk factors for CHIP progression and report novel PG VUS, which may portend health risks based on their prevalence in HN. Furthermore, it appears that a strategy for CVD prevention may promote clonal stability in survivorship pts.