Clonal Hematopoiesis Is Associated with Increased Risk of Progression of Asymptomatic Waldenström Macroglobulinemia

Introduction Clonal hematopoiesis (CH) is associated with adverse outcomes in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma undergoing autologous stem cell transplantation. Still, its implications for patients with indolent NHL have not been well studied. Here, we report the prevalence of CH in patients with Waldenström Macroglobulinemia (WM) and its association with clinical outcomes. Methods We retrospectively reviewed clinical data of 602 patients with IgM monoclonal gammopathy of undetermined significance (MGUS), smoldering WM (SWM), and WM who had clinical next-generation sequencing (NGS) performed on bone marrow aspirates or peripheral blood obtained between October 2014 and February 2020 at the Dana-Farber Cancer Institute. An Illumina Truseq amplicon-based NGS assay of 95 genes recurrently mutated in myeloid and lymphoid neoplasms was utilized. Each specimen yielded ~2 million reads and ~1500X average coverage, with 90% of amplicons having >200X coverage. Pathogenic driver variants were identified based on mutation type, position, and frequency in published reports and public databases. To unambiguously differentiate CH mutations from those in the WM clone, CH was defined by the presence of somatic mutations in DNMT3A, TET2, or ASXL1 (DTA). Results The cohort included 147 patients with MGUS or asymptomatic WM and 453 patients with symptomatic WM, with a median age of 66 years (range = 40-89) and 68 years (range = 33-93), respectively, at the time of first NGS assay. The prevalence of CH-DTA was 14% in symptomatic WM patients and did not differ significantly in MGUS (13%) or SWM (14%). Among precursor patients, there was an increased risk of progression to symptomatic WM for those with CH-DTA [7/20 patients with vs. 11/116 without CH-DTA progressed over a median of 54 months (P = 0.002)]. In symptomatic WM patients, CH-DTA was positively associated with older age (P < 0.001) at the time of NGS, with a median age of 72 vs. 67 years for patients with versus those without CH-DTA. CH-DTA was not associated with inferior overall survival (OS) with a relatively short median follow-up from diagnosis and NGS assay. OS was 6.7 years (95% CI = 6.1-7.6) for patients with CH-DTA and 2.5 years for patients without DH-DTA (95% CI = 2.2-2.8). The most common cause of death was disease progression, with no significant difference between those with or without CH-DTA. Patients with CH-DTA had an increased risk of cardiovascular disease (30% vs. 18%, P = 0.036). Conclusions We demonstrate that CH is common in WM patients and is associated with an increased risk of progression from precursor states but not with inferior survival. Further work is needed to determine how the presence of CH might promote progression to WM and whether it can be incorporated into future risk stratification models. Importantly, our data do not support changes in clinical management or alterations in therapy for patients with WM and coexistent CH and reinforce the need to interpret NGS results within their specific clinical context. Disclosures Steensma: Novartis: Current Employment. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Treon: X4: Research Funding; Dana Farber Cancer Institute: Current Employment; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Sperling: Adaptive: Consultancy.

Orthopedic Toxicities Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Adolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely heavily on corticosteroids and asparaginase and are known to increase the risk of osteonecrosis (ON) and fractures in children, particularly adolescents. Orthopedic toxicity among young adults treated on pediatric-inspired regimens is not well described. Here, we report the symptomatic orthopedic toxicities of patients aged 15-50 years treated on sequential Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Among 367 patients with a median age of 23 years (range 15-50, 68% < 30 years), 60 patients were diagnosed with ON (5-year cumulative incidence (CI) 17%; [95% confidence interval 13-22]) and 40 patients experienced fracture (5-year CI 12% [95% CI 8-15]). Patients < 30 years were significantly more likely to be diagnosed with ON (5-year CI 21% vs. 8%, p=0.004). Patients treated more recently on pegaspargase-based protocols were significantly more likely to be diagnosed with ON compared to those treated on earlier trials with native E.coli asparaginase (5-year CI 24% vs 5%, p<0.001). Of the 54 ON events for which adequate information was available, surgery was performed in 25 (46%). Patients with ON had superior overall survival (OS) compared to those without (multivariable OS HR 0.15 [95% CI: 0.05-0.46], p=0.001; ON included as a time-varying exposure). Increased rates of orthopedic toxicity in late generation protocols may be driven by the pharmacokinetic drug interaction between pegaspargase and dexamethasone, leading to higher dexamethasone exposure.

Gastrointestinal Cancers: 2021 ASCO Annual Meeting Highlights for the Advanced Practitioner

Nina N. Grenon, DNP, AGCNP-BC, AOCN®, of Dana-Farber Cancer Institute, evaluates data on single and dual immunotherapy for advanced esophageal squamous cell carcinoma; maintenance therapy for metastatic colorectal cancer; a HER2-targeted therapy for colorectal cancer; adjuvant therapy for resected esophageal cancer and gastroesophageal junction cancer; and standard of care for patients with advanced biliary tract cancer.

Intracerebral haemorrhage in patients with brain metastases receiving therapeutic anticoagulation

BackgroundVenous thromboembolism is common in patients with solid malignancies and brain metastases. Whether to anticoagulate such patients is controversial given the possibility of intracerebral haemorrhage (ICH). We evaluated the added risk of ICH in patients with brain metastases receiving therapeutic anticoagulation.MethodsWe performed a matched, retrospective cohort study of 291 patients (100 receiving therapeutic anticoagulation vs 191 controls) with brain metastases managed at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between 1998 and 2015. For each patient, all MRI studies of the brain were reviewed to identify ICH. Propensity score matching and multivariable Cox regression were used to mitigate confounding.ResultsThe risk of ICH was comparable in patients receiving anticoagulation versus controls preanticoagulation. Postanticoagulation, we observed significant or borderline-significant associations between anticoagulation and development of any ICH (HR 1.31, 95% CI 0.96 to 1.79, p=0.09), ICH as identified by gradient echo/susceptibility-weighted imaging (HR 1.46, 95% CI 1.06 to 2.01, p=0.02), symptomatic ICH (HR 1.80, 95% CI 1.01 to 3.22, p=0.05), extralesional ICH (HR 5.82, 95% CI 1.56 to 21.7, p=0.009) and fatal ICH (HR 5.68, 95% CI 0.60 to 54.2, p=0.13). Anticoagulation was associated with differentially higher ICH risk in patients with prior ICH versus no prior ICH (HR 2.20 vs 0.68, respectively, p interaction <0.001) and symptomatic ICH risk in melanoma versus other primary malignancies (HR 6.46 vs 1.36, respectively, p interaction=0.02).ConclusionsAnticoagulation is associated with clinically significant ICH in patients with brain metastases, especially those with melanoma or prior ICH. The indication for anticoagulation and risk of intracerebral bleeding should be considered on an individual basis among such patients.

Genomic landscape of variant urinary tumor histologies.

467 Background: The genetics of urothelial carcinoma (UC), the most common histology of urinary tract (UT) tumors, is well characterized; much less is known about the genomic features of rare histologic variants of UT tumors. We aim to compare the genomic alterations (GA) of UT tumors with adenocarcinoma (AD), small cell (SC), squamous cell (SQ), or plasmacytoid (PC) histologies, to UC tumors. Methods: We identified patients with pure variant (AD, SC, SQ, PC) or UC histology with genetic characterization through the GENIE registry. Patient tumor genomic data were captured by Memorial Sloan Kettering Cancer Center (MSK)-IMPACT and Dana-Farber Cancer Institute (DFCI)-Oncopanel NGS initiatives. Tumors with mixed histology were excluded. We limited our analysis to genes tested >1000 times (N=211). Mutation frequencies and copy number variants (CNVs), collectively called GAs, were determined for AD, SC, SQ, PC, and UC, and were compared using the Fisher’s Exact test and Kruskall Wallis test. Nominal p values were obtained, and FDR correction was employed (q < 0.1). Results: We identified 1199 patients with available genomic data who met the inclusion criteria. Histologic distribution was: 32 AD, 13 SC, 15 SQ, 11 PC, and 1128 UC tumors. The median age was 68 years and 77% of patients were male. Statistically significant differences in genetic alterations by subtype are shown in the table below. ARID1A and KDM6A GAs were higher in UC; PC and SC; CDH1 GAs higher in PC; RB1 and TP53 GAs higher in SC; SMAD4 GAs higher in AD; and NFE2L2 GAs higher in SQ. Conclusions: Variant UT histologies exhibit a distinct pattern of alterations compared to UC, consistent with their divergent clinical behavior. This suggests different biological origins for these variant histologies and possibly different therapeutic vulnerabilities. Exploring the GAs of these UT tumors in larger datasets is warranted. [Table: see text]

Dana-Farber Cancer Institute/Mass General Brigham Fellowship Response to the COVID-19 Pandemic

The coronavirus disease (COVID)-19 pandemic has affected graduate medical education training programs, including hematology-oncology fellowship programs, both across the United States and abroad. Within the Dana-Farber Cancer Institute/Mass General Brigham hematology-oncology fellowship program, fellowship leadership had to quickly reorganize the program's clinical, educational, and research structure to minimize the risk of COVID-19 spread to our patients and staff, allow fellows to assist in the care of patients with COVID-19, maintain formal didactics despite physical distancing, and ensure the mental and physical well-being of fellows. Following the first wave of patients with COVID-19, we anonymously surveyed the Dana-Farber Cancer Institute/Mass General Brigham first-year fellows to explore their perceptions regarding what the program did well and what could have been improved in the COVID-19 response. In this article, we present the feedback from our fellows and the lessons we learned as a program from this feedback. To our knowledge, this represents the first effort in the hematology-oncology literature to directly assess a hematology-oncology program's overall response to COVID-19 through direct feedback from fellows.

Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free ALL Regimen

Background: venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL), especially in patients treated with asparaginase (ASNase)-including regiments. However, VTE risk in adult Philadelphia-positive ALL (Ph+ve ALL) patients treated with non-hyperCVAD chemotherapy is unclear. In this study, we examined VTE incidence in adult Ph+ve ALL patients treated with imatinib plus a pediatric-inspired asparaginase (ASNase)-free regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol. Methods: a single centre retrospective review of Ph+ve ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008–2019 with imatinib plus modified DFCI protocol was conducted. Results: of the 123 patients included, 30 (24.3%) had at least 1 radiology confirmed VTE event from diagnosis to the end of maintenance therapy. 86.7% (26/30) of the VTE events occurred during active treatment. Of all VTE events, the majority (53.3%) were DVT and/or PE while another significant portion were catheter-related (40.0%). Major bleeding was observed in 1 patient on VTE treatment with low molecular weight heparin (LMWH). Conclusion: a high VTE incidence (24.3%) was observed in adults Ph+ve ALL patients treated with imatinib plus an ASNase-free modified DFCI pediatric ALL protocol, suggesting prophylactic anticoagulation should be considered for all adult Ph+ve ALL patients including those treated with ASNase-free regimens.