Implementation of and Systems-Level Barriers to Guideline-Driven Germline Genetic Evaluation in the Care of Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia.

PURPOSE: Knowledge of an inherited predisposition to myelodysplastic syndrome (MDS) and AML has important clinical implications for treatment decisions, surveillance, and care of at-risk relatives. National Comprehensive Cancer Network (NCCN) guidelines recently incorporated recommendations for germline genetic evaluation of patients with MDS/AML on the basis of personal and family history features, but the practicality of implementing these recommendations has not been studied. METHODS: A hereditary hematology quality improvement (QI) committee was formed to implement these guidelines in a prospective cohort of patients diagnosed with MDS/AML. Referral for germline genetic testing was recommended for patients meeting NCCN guideline criteria. Referral patterns and genetic evaluation outcomes were compared with a historical cohort of patients with MDS/AML. Barriers to evaluation were identified. RESULTS: Of the 90 patients with MDS/AML evaluated by the QI committee, 59 (66%) met criteria for germline evaluation. Implementation of the QI committee led to more referrals for germline evaluation in accordance with NCCN guidelines (31% v 14%, P = .03). However, the majority of those meeting criteria were never referred due to high medical acuity or being deceased or in hospice at the time of QI committee recommendations. Despite this, two (17%) of the 12 patients undergoing genetic testing were diagnosed with a hereditary myeloid malignancy syndrome. CONCLUSION: Current NCCN guidelines resulted in two thirds of patients with MDS/AML meeting criteria for germline evaluation. A hereditary hematology-focused QI committee aided initial implementation and modestly improved NCCN guideline adherence. However, the high morbidity and mortality and prolonged inpatient stays associated with MDS/AML challenged traditional outpatient genetic counseling models. Further improvements in guideline adherence require innovating new models of genetic counseling and testing for this patient population.

Venous Thromboembolism in Peritoneal Mesothelioma: Uncovering the Hidden Risk.

INTRODUCTION: Venous thromboembolism (VTE) is a common complication in patients with abdominal malignancies. Despite known associations between pleural mesothelioma and increased VTE risk, the characteristics of VTE in patients with peritoneal mesothelioma (PeM) remain undescribed. METHODS: Patients treated for PeM were retrospectively identified from our institutional database. The frequency of VTE was assessed and logistic regression modeling was employed to assess VTE risk factors. The association between VTE and overall survival was also ascertained. Recommended thromboprophylaxis for patients who underwent surgery at our institution comprised a single preoperative dose of prophylactic anticoagulation, followed by daily dosing for four weeks postoperatively. RESULTS: Among 120 PeM patients, 26 (21.7%) experienced VTE, including 19/91 (20.9%) surgical patients, 4/23 (17.4%) patients who received systemic therapy, and 3/6 (50%) patients who underwent observation (p = 0.21). Most events were symptomatic (n = 16, 62%) and were attributable to pulmonary emboli (n = 16, 62%). The 90-day postoperative VTE rate was 4.4% (4/91), including 1 of 60 patients who underwent index surgical intervention at our institution and 3 patients with surgery elsewhere. A low serum albumin concentration was associated with VTE in non-surgical patients (odds ratio 0.12, confidence interval [CI] 0.02-0.72; p = 0.03). No significant difference in overall survival was observed between patients with and without VTE (median 46.0 months [CI 24.9-67.0] vs. 55.0 months [CI 27.5-82.5]; hazard ratio 0.98 [CI 0.54-1.81], p = 0.98). CONCLUSIONS: A high risk of VTE was observed in PeM patients, warranting suspicion throughout the disease trajectory. Postoperative VTE rates were within acceptable limits with 4-week thromboprophylaxis.

Implementation of a prospective screening strategy to identify adults with a telomere biology disorder among those undergoing lung transplant evaluation for interstitial lung disease.

INTRODUCTION: Patients with interstitial lung disease (ILD) secondary to telomere biology disorders (TBD) experience increased morbidity after lung transplantation. Identifying patients with TBD may allow for personalized management to facilitate better outcomes. However, establishing a TBD diagnosis in adults is challenging. METHODS: A TBD screening questionnaire was introduced prospectively into the lung transplant evaluation. Patients with ILD screening positive were referred for comprehensive TBD phenotyping and concurrent telomere length measurement and germline genetic testing. RESULTS: Of 98 patients, 32 (33%) screened positive. Eight patients (8% of total; 25% of patients with a positive screen) met strict TBD diagnostic criteria, requiring either critically short lymphocyte telomeres (<1st percentile) (n = 4), a pathogenic variant in a TBD-associated gene (n = 1), or both (n = 3) along with a TBD clinical phenotype. Additional patients not meeting strict diagnostic criteria had histories consistent with TBD along with telomere lengths <10th percentile and/or rare variants in TBD-associated genes, highlighting a critical need to refine TBD diagnostic criteria for this patient population. CONCLUSION: A TBD phenotype screening questionnaire in patients with ILD undergoing lung transplant evaluation has a diagnostic yield of 25%. Additional gene discovery, rare variant functional testing, and refined TBD diagnostic criteria are needed to realize the maximum benefit of testing for TBD in patients undergoing lung transplantation.

Classification, risk stratification and response assessment in myelodysplastic syndromes/neoplasms (MDS): A state-of-the-art report on behalf of the International Consortium for MDS (icMDS).

The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes.

Germline Variants Incidentally Detected via Tumor-Only Genomic Profiling of Patients With Mesothelioma.

Importance: Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS. Objective: To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma. Design, Setting, and Participants: A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023. Main Outcomes and Measures: The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS. Results: Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127. Conclusions and Relevance: In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.

Uptake of Genetic Research Results and Patient-Reported Outcomes With Return of Results Incorporating Web-Based Predisclosure Education.

PURPOSE: We developed a web-based education intervention as an alternative to predisclosure education with a genetic counselor (GC) to reduce participant burden and provider costs with return of genetic research results. METHODS: Women at three sites who participated in 11 gene discovery research studies were contacted to consider receiving cancer genetic research results. Participants could complete predisclosure education through web education or with a GC. Outcomes included uptake of research results, factors associated with uptake, and patient-reported outcomes. RESULTS: Of 819 participants, 178 actively (21.7%) and 167 passively (20.4%) declined return of results; 474 (57.9%) were enrolled. Most (60.3%) received results although this was lower than the 70% uptake we hypothesized. Passive and active decliners were more likely to be Black, to have less education, and to have not received phone follow-up after the invitation letter. Most participants selected web education (88.5%) as an alternative to speaking with a GC, but some did not complete or receive results. Knowledge increased significantly from baseline to other time points with no significant differences between those who received web versus GC education. There were no significant increases in distress between web and GC education. CONCLUSION: Interest in web-based predisclosure education for return of genetic research results was high although it did not increase uptake of results. We found no negative patient-reported outcomes with web education, suggesting that it is a viable alternative delivery model for reducing burdens and costs of returning genetic research results. Attention to attrition and lower uptake of results among Black participants and those with less formal education are important areas for future research.

Needle in a haystack or elephant in the room? Identifying germline predisposition syndromes in the setting of a new myeloid malignancy diagnosis.

Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the proposed 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors: (1) neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction, (2) neoplasms with germline predisposition and pre-existing platelet disorder, or (3) neoplasms with germline predisposition and potential organ dysfunction. Recognizing these entities is critical because patients and affected family members benefit from interfacing with hematologists who specialize in these disorders and can facilitate tailored treatment strategies. However, identification of these syndromes in routine pathology practice is often challenging, as characteristic findings associated with these diagnoses at baseline are frequently absent, nonspecific, or impossible to evaluate in the setting of a myeloid malignancy. Here we review the formally classified germline predisposition syndromes associated with myeloid malignancies and summarize practical recommendations for pathologists evaluating a new myeloid malignancy diagnosis. Our intent is to empower clinicians to better screen for germline disorders in this common clinical setting. Recognizing when to suspect a germline predisposition syndrome, pursue additional ancillary testing, and ultimately recommend referral to a cancer predisposition clinic or hematology specialist, will ensure optimal patient care and expedite research to improve outcomes for these individuals.

Surgical phenotype of patients with peritoneal mesothelioma and a germline mutation.

BACKGROUND: This study aimed to investigate if peritoneal mesothelioma (PM) patients with germline mutations (GM) have distinct surgical characteristics when compared to those without GM. METHODS: PM patients were selected from an ongoing prospective study that conducts germline testing of 82 susceptibility genes. Germline status was correlated with surgical data obtained from a prospectively collected database using univariate, multivariate, and receiver operating characteristic (ROC) analyses. RESULTS: Out of 88 PM patients enrolled between 2009 and 2019, 18 GMs (20.5%) were identified in BRCA1-associated protein 1 (BAP1) (n = 11, 12.5% of all patients), SDHA (n = 2) and WT1, CDKN2A, CHEK2, ATM, and BRCA2 (n = 1 patient each). Surgical procedures were performed in 71 patients, the most common of which were cytoreductive surgeries with hyperthermic intraperitoneal chemotherapy (n = 61). Patients with GM presented with a higher prevalence of other prior cancers (61.1% vs. 31.4%, p = .02) and lower platelet count (251 [160-413] vs. 367 [196-780] K/µL, p = .005) compared to those without GM (n = 70). Survival outcomes did not differ significantly between the groups. Patients with BAP1 GMs were more likely to develop bicavitary disease and to present with lower platelet count and mitotic count score, and higher peritoneal cancer index (PCI, all p ≤ .04) compared with those without GM. On ROC analysis, the combination of PCI, platelet count and mitotic score yielded an area under the curve of 0.96 (95% CI, 0.91-1.0) for BAP1 GM detection among operated PM patients. CONCLUSION: Higher intraoperative tumor burden and lower platelet count and mitotic score are suggestive of BAP1 GMs in surgical PM patients and should prompt germline testing.

Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS).

Biological events that contribute to the pathogenesis of myelodysplastic syndromes/neoplasms (MDS) are becoming increasingly characterized and are being translated into rationally designed therapeutic strategies. Herein, we provide updates from the first International Workshop on MDS (iwMDS) of the International Consortium for MDS (icMDS) detailing recent advances in understanding the genetic landscape of MDS, including germline predisposition, epigenetic and immune dysregulation, the complexities of clonal hematopoiesis progression to MDS, as well as novel animal models of the disease. Connected to this progress is the development of novel therapies targeting specific molecular alterations, the innate immune system, and immune checkpoint inhibitors. While some of these agents have entered clinical trials (e.g., splicing modulators, IRAK1/4 inhibitors, anti-CD47 and anti-TIM3 antibodies, and cellular therapies), none have been approved for MDS. Additional preclinical and clinical work is needed to develop a truly individualized approach to the care of MDS patients.

68Ga-DOTATATE Avid Metastatic Vertebral Renal Cell Carcinoma in the Setting of von Hippel-Lindau Syndrome.

Although rare, a metastatic renal cell carcinoma could present with 68Ga-DOTATATE avidity. A 66-year-old man with von Hippel-Lindau syndrome (VHL) presented with 68Ga-DOTATATE uptake in the pancreatic head, splenic hilar region, and multiple osseous sites, including the right lateral portion of the T9 vertebrae. Biopsy of the T9 lesion confirmed metastatic renal cell carcinoma. Various VHL-associated cancers may display 68Ga-DOTATATE avidity, which can change and guide clinical decisions for the patient.

A Case of Isolated Myeloid Sarcoma Associated With Germline EGFR T790M Variant: The Importance of Recognizing Potential Germline Variants on Somatic Tumor Sequencing Panels.

Isolated myeloid sarcoma is an uncommon subtype of acute myeloid leukemia associated with variable prognosis. We present the case of a previously healthy 30-year-old man presenting with chest pain and weight loss who was found to have a large mediastinal mass. Biopsy of the mass was consistent with isolated myeloid sarcoma. A somatic tumor sequencing panel revealed an EGFR T790M variant, which was later confirmed to be of germline origin. Germline EGFR T790M variants are associated with a hereditary predisposition to lung cancer, though myeloid malignancies have not yet been described. To our knowledge, this is the first reported case of myeloid sarcoma in a patient with an underlying germline EGFR T790M mutation. As somatic tumor sequencing panels become more commonplace, it is important to recognize potential germline variants in order to facilitate appropriate referral for genetic counseling, perform confirmatory genetic testing, and to develop a personalized treatment and surveillance plan for patients and their families.

Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations.

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.

Feasibility and limitations of cultured skin fibroblasts for germline genetic testing in hematologic disorders.

To avoid acquired variants found in the blood, cultured skin fibroblasts are a recommended DNA source for germline genetic testing in patients with hematologic disorders, but data are lacking regarding practicality and limitations. We conducted a retrospective cohort study of 350 subjects with hematologic disorders who underwent skin fibroblast culture for germline genetic testing. We analyzed next-generation sequencing data from the targeted capture of 144 inherited cancer and bonemarrow failure genes to identify variants at heterozygous and subclonal variant allele frequencies. Sixteen (5%) biopsies failed to culture. Culture failure was more likely in samples with delays in culture initiation (OR = 4.3; p < 0.01) or a pathogenic variant in a telomere gene (OR = 42.6; p < 0.01). Median culture time was 28 days (IQR 22-29 days). Culture time was longer for subjects with prior allogeneic stem cell transplantation (+10.7%; p = 0.02) and shorter in subjects with a heterozygous pathogenic variant (-11.9%; p < 0.01), larger biopsy size (-10.6%; p < 0.01), or lymphoid malignancy (-8.4%; p < 0.01). Subclonal variants were identified in 10 (4%) and confirmed in five (56%) of eight with alternate samples available. Subclonal and discordant variants illustrate that germline testing from cultured skin fibroblasts requires phenotypic correlation and, in rare cases, follow-up studies for optimal interpretation.

Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges.

Over the last decade, the field of hereditary haematological malignancy syndromes (HHMSs) has gained increasing recognition among clinicians and scientists worldwide. Germline mutations now account for almost 10% of adult and paediatric myelodysplasia/acute myeloid leukaemia (MDS/AML). As our ability to diagnose HHMSs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients with MDS/AML and how to optimise management and surveillance of patients and asymptomatic carriers. Discoveries of novel syndromes combined with clinical, genetic and epigenetic profiling of tumour samples, have highlighted unique patterns of disease evolution across HHMSs. Despite these advances, causative lesions are detected in less than half of familial cases and evidence-based guidelines are often lacking, suggesting there is much still to learn. Future research efforts are needed to sustain current momentum within the field, led not only by advancing genetic technology but essential collaboration between clinical and academic communities.

Approach to the diagnosis of aplastic anemia.

Establishing a diagnosis of aplastic anemia (AA) can be challenging, but it is absolutely critical to appropriate management, especially differentiating between acquired and inherited forms of the disease. The hematology field requires updated diagnostic guidelines to ensure that appropriate clinical pathways are pursued for patients and their safety. There are increasing clinical options for patients with immunosuppressive therapy and transplant once the diagnosis is made. In a case-based format, this review emphasizes the newer data on molecular (somatic and germline) findings in AA and how they are (or are not) helpful during diagnosis. There are key details on somatic mutation profiles and stated evidence where available for prognostic and treatment indications. Germline details of newer syndromes are also outlined, which make this review modern and reflect areas of uncertainty for clinicians.

Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations.

Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.