Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence.

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 CCUS patients 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 <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 <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's 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.

Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer.

BACKGROUND: Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs). CSCs are implicated in tumor recurrence and metastasis in multiple cancers. METHODS: Protein localization assays including immunofluorescence and subcellular fractionation were used to identify CD55 at the cell surface and nucleus of cancer cells. Protein half-life determinations were used to compare cell surface and nuclear CD55 stability. CD55 deletion mutants were generated and introduced into cancer cells to identify the nuclear trafficking code, cisplatin sensitivity, and stem cell frequency that were assayed using in vitro and in vivo models. Detection of CD55 binding proteins was analyzed by immunoprecipitation followed by mass spectrometry. Target pathways activated by CD55 were identified by RNA sequencing. RESULTS: CD55 localizes to the nucleus of a subset of OC specimens, ascites from chemoresistant patients, and enriched in chemoresistant OC cells. We determined that nuclear CD55 is glycosylated and derived from the cell surface pool of CD55. Nuclear localization is driven by a trafficking code containing the serine/threonine (S/T) domain of CD55. Nuclear CD55 is necessary for cisplatin resistance, stemness, and cell proliferation in OC cells. CD55 S/T domain is necessary for nuclear entry and inducing chemoresistance to cisplatin in both in vitro and in vivo models. Deletion of the CD55 S/T domain is sufficient to sensitize chemoresistant OC cells to cisplatin. In the nucleus, CD55 binds and attenuates the epigenetic regulator and tumor suppressor ZMYND8 with a parallel increase in H3K27 trimethylation and members of the Polycomb Repressive Complex 2. CONCLUSIONS: For the first time, we show CD55 localizes to the nucleus in OC and promotes CSC and chemoresistance. Our studies identify a therapeutic mechanism for treating platinum resistant ovarian cancer by blocking CD55 nuclear entry.

Durable responses in acute lymphoblastic leukaemia with the use of FLT3 and IDH inhibitors.

Data regarding the use of FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1/2 (IDH1/2) inhibitors in acute lymphoblastic leukaemia (ALL) are lacking. We identified 14 patients with FLT3- or IDH1/2-mutated ALL. Three early T-cell precursor-ALL patients received FLT3 or IDH2 inhibitors. Patient 1 maintains a complete remission (CR) with enasidenib after intolerance to chemotherapy. Patient 2 maintained a CR for 27 months after treatment with enasidenib for relapsed disease. Patient 3 was treated with venetoclax and gilteritinib at the time of relapse and maintained a CR with gilteritinib for 8 months. These cases suggest that FLT3 and IDH inhibitors could represent a viable therapeutic option for ALL patients with these mutations.

Sequential tumor molecular profiling identifies likely germline variants.

PURPOSE: To identify likely germline DNA variants from sequential tumor profiling data from hematopoietic malignancies (HMs). METHODS: The coefficient of variance was calculated from variant allele frequency of next-generation sequencing assays. Variants' likelihood of being germline was ranked on a 1 to 5 scale. Outcomes were examined in patients with such variants. RESULTS: In a pilot set of 33 genes, 89% of grade 1, 77% of grade 2, 62% of grade 3, 52% of grade 4, and 21% of grade 5 variants were confirmed to be germline. Among those, 22% were pathogenic or likely pathogenic in genes recognized as conferring hereditary HM risk, including BRCA1/2, CHEK2, CSF3R, and DDX41. To determine if this approach identified genes with known autosomal dominant inheritance, we analyzed sequential data from 1336 genes in 1135 HM patients. Among unique variants, 16% occurred in hereditary HM genes, and 15% were deleterious. Patients with grade 1/2 alleles had decreased survival 2 years after initial molecular testing (78% versus 88%, P = .0037) and increased all-cause mortality compared with those without (hazard ratio 2.02, 95% CI 1.18-3.46, P = .019). CONCLUSION: Variant germline status may be predicted using sequential tumor profiling and patients with likely germline variants experience inferior outcomes compared with those without.

Acute Lymphoblastic Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

Measurable residual disease in acute lymphoblastic leukemia: methods and clinical context in adult patients.

Measurable residual disease (MRD) is the most powerful independent predictor of risk of relapse and long-term survival in adults and children with acute lymphoblastic leukemia (ALL). For almost all patients with ALL there is a reliable method to evaluate MRD, which can be done using multi-color flow cytometry, quantitative polymerase chain reaction to detect specific fusion transcripts or immunoglobulin/T-cell receptor gene rearrangements, and high-throughput next-generation sequencing. While next-generation sequencing-based MRD detection has been increasingly utilized in clinical practice due to its high sensitivity, the clinical significance of very low MRD levels (<10-4) is not fully characterized. Several new immunotherapy approaches including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cell therapies have demonstrated efficacy in eradicating MRD in patients with B-ALL. However, new approaches to target MRD in patients with T-ALL remain an unmet need. As our MRD detection assays become more sensitive and expanding novel therapeutics enter clinical development, the future of ALL therapy will increasingly utilize MRD as a criterion to either intensify or modify therapy to prevent relapse or de-escalate therapy to reduce treatment-related morbidity and mortality.

A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level -1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m2 cytarabine D5-8, and 8 mg/m2 idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).

Impact of comorbidities on outcomes of elderly patients with diffuse large B-cell lymphoma.

International prognostic index (IPI) has remained the primary prognostic tool in diffuse large B cell lymphoma (DLBCL) for more than 20 years. Even though the disease is more common in older population, the impact of comorbidities, dose reductions, and treatment-related adverse events (TAEs) on the outcome in elderly DLBCL patients has not been well established. We studied 413 consecutive patients aged ≥ 60 years who were treated at the Cleveland Clinic. The median age at diagnosis was 69 years, 58% of patients had high IPI score, and 85% had low Charlson comorbidity index (CCI). Forty percent of patients required dose reductions during treatment, 78% achieved CR, and 70% experienced at least one grade II-IV TAE. High IPI score, high CCI, reduced dose chemotherapy, TAE, and hospitalization were significant predictors of death and relapse. In multivariable analysis, high IPI and CCI were independent predictors of overall and progression free survival. A simple model combining IPI and CCI could reliably distinguish three prognostically separate risk groups. Our results suggest that incorporation of CCI in current prognostic models can improve prognostication of older DLBCL patients and CCI might be a valuable tool in evaluating the eligibility of older patients for clinical trial enrollment.

Suicidal ideation among patients with Behçet's syndrome.

OBJECTIVES: To evaluate the frequency of suicidal ideation among Behçet's syndrome (BS) patients compared to healthy and diseased controls and to delineate possible factors predicting an increase in suicidal ideation. METHODS: We included consecutive BS patients attending our outpatient clinic, patients with ankylosing spondylitis (AS) and healthy hospital staff as controls. Suicidal ideation was assessed by a standard questionnaire. Linear regression was used to identify the factors associated with suicidal ideation, such as demographic and clinical features, drugs, disease activity assessed using the Behçet's disease current activity form (BDCAF) for BS patients and BASDAI for AS patients, Behçet's disease quality of life (BDQoL) and Beck depression inventory (BDI) score. RESULTS: We surveyed 303 BS patients, 52 AS patients and 106 healthy controls. Suicidal thoughts, as reflected by a positive response to the first three items of the questionnaire, were higher among BS patients with major organ involvement (42%) than those with mucocutaneous involvement (35%) and the control groups. There were significantly more BS patients with active major organ involvement who had thought to terminate their lives without plans within the last year (25.5%) compared to those with active mucocutaneous involvement (8.7%) and active AS patients (10%) (p=0.012). Patient-reported joint pain (ß=-0.155, p=0.046), BDQoL (ß=0.176, p=0.032), and BDI (ß=0.017, p<0.0001) scores, suicidal thoughts before the onset of BS (ß=-0.124, p=0.043), neurologic involvement (ß=0.119, p=0.047) and past prednisone use (ß=0.212, p=0.005) were independent predictors of suicidal thoughts. CONCLUSIONS: BS patients with major organ involvement have increased thoughts of suicide during the active stages of their disease. A number of risk factors could help physicians to identify patients with increased suicidal thoughts.

No appreciable decrease in fertility in Behçet's syndrome.

OBJECTIVES: Behçet's syndrome (BS) follows an active course during the childbearing years in both men and women. We formally surveyed the infertility rate and the effect of drugs and types of organ involvement on fertility in BS. METHODS: We compared fertility among BS patients with and without major organ involvement with those with FMF, AS and healthy controls. A structured interview was performed and the medical records of the patients were reviewed to confirm the sites of involvement and drugs they used during their entire follow-up. RESULTS: The number of female patients who were not able to ever conceive, who were not able to conceive before or after disease onset or who were able to conceive late or only with assisted reproductive technology was not increased among the BS group. The same was true for the male patients to successfully achieve a conception and/or father a child. The average number of children, miscarriages, terminations and ectopic pregnancies were similar among the groups. Infertility was more common in BS patients with major organ involvement who used cyclophosphamide (CYC) compared with those who did not (P = 0.009). CONCLUSION: Infertility is not appreciably increased among BS patients attending a dedicated outpatient clinic. Major organ involvement does not increase the risk of infertility and CYC is the only drug that seems to compromise fertility in BS.

Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T-ALL.

T lymphocyte acute lymphoblastic leukemia (T-ALL) is frequently associated with increased expression of the E protein transcription factor inhibitors TAL1 and LYL1. In mouse models, ectopic expression of TAL1 or LYL1 in T cell progenitors, or inactivation of E2A, is sufficient to predispose mice to develop T-ALL. How E2A suppresses thymocyte transformation is currently unknown. Here, we show that early deletion of E2a, prior to the DN3 stage, was required for robust leukemogenesis and was associated with alterations in thymus cellularity, T cell differentiation, and gene expression in immature CD4+CD8+ thymocytes. Introduction of wild-type thymocytes into mice with early deletion of E2a prevented leukemogenesis, or delayed disease onset, and impacted the expression of multiple genes associated with transformation and genome instability. Our data indicate that E2A suppresses leukemogenesis by promoting T cell development and enforcing inter-thymocyte competition, a mechanism that is emerging as a safeguard against thymocyte transformation. These studies have implications for understanding how multiple essential regulators of T cell development suppress T-ALL and support the hypothesis that thymocyte competition suppresses leukemogenesis.

Socioeconomic determinants of the biology and outcomes of acute lymphoblastic leukemia in adults.

ABSTRACT: Various socioeconomic and biologic factors affect cancer health disparities and differences in health outcomes. To better characterize the socioeconomic vs biologic determinants of acute lymphoblastic leukemia (ALL) outcomes, we conducted a single-institution, retrospective analysis of adult patients with ALL treated at the University of Chicago (UChicago) from 2010 to 2022 and compared our outcomes with the US national data (the Surveillance, Epidemiology, and End Results [SEER] database). Among 221 adult patients with ALL treated at UChicago, BCR::ABL1 was more frequent in patients with higher body mass index (BMI; odds ratio [OR], 7.64; 95% confidence interval [CI], 1.17-49.9) and non-Hispanic Black (NHB) ancestry (59% vs 24% in non-Hispanic White (NHW) and 20% in Hispanic patients; P = .001). In a multivariable analysis, age (hazard ratio [HR], 6.93; 95% CI, 2.27-21.1) and higher BMI at diagnosis (HR, 10.3; 95% CI, 2.56-41.5) were independent predictors of poor overall survival (OS). In contrast, race or income were not predictors of OS in the UChicago cohort. Analysis of the national SEER database (2010-2020) demonstrated worse survival outcomes in Hispanic and NHB patients than in NHW patients among adolescent and young adults (AYAs) but not in older adults (aged >40 years). Both AYA and older adult patients with higher median household income had better OS than those with lower income. Therefore, multidisciplinary medical care coupled with essential supportive care services offered at centers experienced in ALL care may alleviate the socioeconomic disparities in ALL outcomes in the United States.

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis.

Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies. SIGNIFICANCE: CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.

Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.

Novel use of propranolol for management of pain in children with vertebral hemangioma: report of two cases.

INTRODUCTION: Vertebral hemangioma (VH) is an exceedingly rare neoplasm in pediatric population with less than 10 cases reported in the literature. It is usually asymptomatic in adults and diagnosed incidentally at radiographic investigations of other medical conditions. In this report, we describe two children who presented to our institution with severe back pain and were diagnosed with VH. CASE REPORTS: Case 1 was an 8-year-old male with a pain score of 10 out of 10 at presentation. Clinical investigations eliminated the possibility of a neoplasm or infectious process and MRI findings were highly suggestive of an aggressive vertebral hemangioma. Case 2 was a 17-year-old female who presented with back pain radiating to shoulders. Her pain score was 4 out of 10 and she was diagnosed with vertebral hemangioma due to the specific findings on MRI studies. DISCUSSION: Both patients received propranolol with a dose of 20 and 40 mg per day, respectively. They were free of pain at 2 months follow-up. There are different invasive treatment modalities for the management of VH, including vertebroplasty, kyphoplasty, radiotherapy, alcohol injection, embolization, and surgery. These methods have been used in adult patients for several years, but each of them has potential risks which make these options unsuitable for children. CONCLUSION: Propranolol is a beta blocker which is safely used in the management of infantile hemangiomas. This is the first report demonstrating its efficacy in symptomatic treatment of childhood VH. The lesions did not show any regression, but the pain relief obtained was very significant under propranolol therapy.

Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T lymphocyte acute lymphoblastic leukemia.

T lymphocyte acute lymphoblastic leukemia (T-ALL) is frequently associated with increased expression of the E protein transcription factor inhibitors TAL1 and LYL1. In mouse models, ectopic expression of Tal1 or Lyl1 in T cell progenitors or inactivation of E2a, is sufficient to predispose mice to develop T-ALL. How E2a suppresses thymocyte transformation is currently unknown. Here, we show that early deletion of E2a , prior to the DN3 stage, was required for robust leukemogenesis and was associated with alterations in thymus cellularity, T cell differentiation, and gene expression in immature CD4+CD8+ thymocytes. Introduction of wild-type thymocytes into mice with early deletion of E2a prevented leukemogenesis, or delayed disease onset, and impacted the expression of multiple genes associated with transformation and genome instability. Our data indicate that E2a suppresses leukemogenesis by promoting T cell development and enforcing inter-thymocyte competition, a mechanism that is emerging as a safeguard against thymocyte transformation. These studies have implications for understanding how multiple essential regulators of T cell development suppress T-ALL and support the hypothesis that thymus cellularity is a determinant of leukemogenesis.

Paired bone marrow and peripheral blood samples demonstrate lack of widespread dissemination of some CH clones.

Clonal hematopoiesis (CH) represents clonal expansion of mutated hematopoietic stem cells detectable in the peripheral blood or bone marrow through next generation sequencing. The current prevailing model posits that CH mutations detected in the peripheral blood mirror bone marrow mutations with clones widely disseminated across hematopoietic compartments. We sought to test the hypothesis that all clones are disseminated throughout hematopoietic tissues by comparing CH in hip vs peripheral blood specimens collected at the time of hip replacement surgery. Here, we show that patients with osteoarthritis have a high prevalence of CH, which involve genes encoding epigenetic modifiers and DNA damage repair pathway proteins. Importantly, we illustrate that CH, including clones with variant allele frequencies >10%, can be confined to specific bone marrow spaces and may be eliminated through surgical excision. Future work will define whether clones with somatic mutations in particular genes or clonal fractions of certain sizes are either more likely to be localized or are slower to disseminate into the peripheral blood and other bony sites.