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Myeloid and erythroid precursor vacuolation is a common dysplastic finding associated with myeloid malignancies, toxins, drug, and nutritional deficiencies. It has been described as a core morphologic feature in VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome. We sought to determine the number of cases attributable to VEXAS syndrome in bone marrow biopsies and aspirates (BAMB) reporting myeloid precursor vacuolation. We reviewed 1318 individual BAMB reports from January 2020 to July 2021 where "vacuole(s)," "vacuolation," or "vacuolated" was reported. Bone marrow biopsies with vacuolation confined to blasts or those completed as routine workup prior to stem cell transplant or post induction chemotherapy for AML (acute myeloid leukemia) were excluded. Myeloid and erythroid precursor vacuolation was noted in 219 reports representing 210 patients. The most common etiology was myelodysplastic syndrome (MDS) (38.6%), AML (16.7%), lymphoproliferative disorders and multiple myeloma (7.6%), drug or toxin exposure (5.2%) myeloproliferative neoplasm (MPN) or MPN/MDS overlap syndrome (4.3%). VEXAS syndrome was determined to be the etiology in 2.9% of patients. Two additional cases of VEXAS syndrome with bone marrow biopsies reported in the specified time frame did not explicitly report myeloid or erythroid precursor vacuolation but were identified based on clinical suspicion and repeat BAMB review. Myeloid and erythroid precursor vacuolation is a dysplastic feature attributable to VEXAS syndrome in at least 2.9% of cases. Standardized reporting of vacuolization, triaging of molecular sequencing and optimal treatment of this disorder are critical issues facing those seeing patients with suspected VEXAS syndrome. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a hematologic malignancy that most frequently develops in older adults. Overall, AML is associated with a high mortality although advancements in genetic risk stratification and new treatments are leading to improvements in outcomes for some subgroups. In this review, we discuss an individualized approach to intensive therapy with a focus on the role of recently approved novel therapies as well as the selection of post-remission therapies for patients in first remission. We discuss the management of patients with relapsed and refractory AML, including the role of targeted treatment and allogeneic stem cell transplant. Next, we review non-intensive treatment for older and unfit AML patients including the use of azacitidine and venetoclax. Finally, we discuss the integration of palliative care in the management of patients with AML. [ABSTRACT FROM AUTHOR]

Purpose of Review: An intact DNA damage response is crucial to preventing cancer development, including in myeloid and lymphoid malignancies. Deficiencies in the homologous recombination (HR) pathway can lead to defective DNA damage responses, and this can occur through inherited germline mutations in HR pathway genes, such as CHEK2 and ATM. We now understand that germline mutations can be identified frequently (~ 5–10%) in patients with myeloid and lymphoid malignancies, and among the most common of these are CHEK2 and ATM. We review the role that deleterious germline CHEK2 and ATM variants play in the development of hematopoietic malignancies, and how this influences clinical practice, including cancer screening, hematopoietic stem cell transplantation, and therapy choice. Recent Findings: In recent large cohorts of patients diagnosed with myeloid or lymphoid malignancies, deleterious germline loss of function variants in CHEK2 and ATM are among the most common identified. Germline CHEK2 variants predispose to a range of myeloid malignancies, most prominently myeloproliferative neoplasms and myelodysplastic syndromes (odds ratio range: 2.1–12.3), and chronic lymphocytic leukemia (odds ratio 14.83). Deleterious germline ATM variants have been shown to predispose to chronic lymphocytic leukemia (odds ratio range: 1.7–10.1), although additional studies are needed to demonstrate the risk they confer for myeloid malignancies. Early studies suggest there may also be associations between deleterious germline CHEK2 and ATM variants and development of clonal hematopoiesis. Summary: Identifying CHEK2 and ATM variants is crucial for the optimal management of patients and families affected by hematopoietic malignancies. Opening Clinical Case: "A 45 year-old woman presents to your clinic with a history of triple-negative breast cancer diagnosed five years ago, treated with surgery, radiation, and chemotherapy. About six months ago, she developed cervical lymphadenopathy, and a biopsy demonstrated small lymphocytic leukemia. Peripheral blood shows a small population of lymphocytes with a chronic lymphocytic leukemia immunophenotype, and FISH demonstrates a complex karyotype: gain of one to two copies of IGH and FGFR3; gain of two copies of CDKN2C at 1p32.3; gain of two copies of CKS1B at 1q21; tetrasomy for chromosome 3; trisomy and tetrasomy for chromosome 7; tetrasomy for chromosome 9; tetrasomy for chromosome 12; gain of one to two copies of ATM at 11q22.3; deletion of chromosome 13 deletion positive; gain of one to two copies of TP53 at 17p13.1). Given her history of two cancers, you arrange for germline genetic testing using DNA from cultured skin fibroblasts, which demonstrates pathogenic variants in ATM [c.1898 + 2 T > G] and CHEK2 [p.T367Metfs]. Her family history is significant for multiple cancers. (Fig. 1)." [ABSTRACT FROM AUTHOR]

Objectives: Acute myeloid leukaemia (AML) is a disease of older adults, who are vulnerable to socio‐economic factors. We determined AML incidence in older adults and the impact of socio‐economic factors on outcomes. Methods: We included 3024 AML patients (1996–2016) identified from a population‐based registry. Results: AML incidence in patients ≥60 years increased from 11.01 (2001–2005) to 12.76 (2011–2016) per 100 000 population. Among 879 patients ≥60 years in recent eras (2010–2016), rural residents (<100 000 population) were less likely to be assessed by a leukaemia specialist (39% rural, 47% urban, p =.032); no difference was seen for lower (43%, quintile 1–3) vs. higher (47%, quintile 4–5) incomes (p =.235). Similar numbers received induction chemotherapy between residence (16% rural, 18% urban, p =.578) and incomes (17% lower, 17% high, p = 1.0). Differences between incomes were seen for hypomethylating agent treatment (14% low, 20% high, p =.041); this was not seen for residence (13% rural, 18% urban, p =.092). Among non‐adverse karyotype patients ≥70 years, 2‐year overall survival was worse for rural (5% rural, 12% urban, p =.006) and lower income (6% low, 15% high, p =.017) patients. Conclusions: AML incidence in older adults is increasing, and outcomes are worse for older rural and low‐income residents; these patients face treatment barriers. [ABSTRACT FROM AUTHOR]

Features for consideration of VEXAS syndrome in patients with autoinflammatory symptoms include dermatologic manifestations, myelodysplastic syndrome or monoclonal gammopathy, and vacuolation of myeloid and erythroid precursors in bone marrow. Through genomic sequencing, some patients with previously undiagnosed autoinflammatory diseases are now understood to have a new syndrome called vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. [Extracted from the article]

Blocked cellular differentiation is a central pathologic feature of the myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Treatment regimens promoting differentiation have resulted in incredible cure rates in certain AML subtypes, such as acute promyelocytic leukemia. Over the past several years, we have seen many new therapies for MDS/AML enter clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, fms-like kinase 3 (FLT3) inhibitors, and lenalidomide for deletion 5q (del5q) MDS. Despite not being developed with the intent of manipulating differentiation, induction of differentiation is a major mechanism by which several of these novel agents function. In this review, we examine the new therapeutic landscape for these diseases, focusing on the role of hematopoietic differentiation and the impact of inflammation and aging. We review how current therapies in MDS/AML promote differentiation as a part of their therapeutic effect, and the cellular mechanisms by which this occurs. We then outline potential novel avenues to achieve differentiation in the myeloid malignancies for therapeutic purposes. This emerging body of knowledge about the importance of relieving differentiation blockade with anti-neoplastic therapies is important to understand how current novel agents function and may open avenues to developing new treatments that explicitly target cellular differentiation. Moving beyond cytotoxic agents has the potential to open new and unexpected avenues in the treatment of myeloid malignancies, hopefully providing more efficacy with reduced toxicity. [ABSTRACT FROM AUTHOR]

There has been an explosion of knowledge about the role of metabolism and the mitochondria in acute myeloid leukemia (AML). We have also recently seen several waves of novel therapies change the treatment landscape for AML, such as the selective B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. In this new context, we review the rapidly advancing literature on the role of metabolism and the mitochondria in AML pathogenesis, and how these are interwoven with the mechanisms of action for novel therapeutics in AML. We also review the role of oxidative phosphorylation (OxPhos) in maintaining leukemia stem cells (LSCs), how recurrent genomic alterations in AML alter downstream metabolism, and focus on how the BCL-2 pathway and the mitochondria are inextricably linked in AML. Thus, we provide an overview of the mitochondria and metabolism in the context of our new therapeutic world for AML and outline how targeting these vulnerabilities may produce novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Classic Hodgkin lymphoma (CHL) is the rarest post-transplant lymphoproliferative disorder (PTLD) subtype. Few cases of patients with metachronous discordant PTLD episodes including CHL-PTLD have been reported, but the incidence of and risk factors for this phenomenon are unknown. Patients with CHL-PTLD were identified from an institutional PTLD database. Of 13 patients identified with CHL-PTLD six (46%) had antecedent non-CHL-PTLD: three had polymorphic PTLD, two monomorphic PTLD, and one nondestructive PTLD. Patients with prior metachronous non-CHL-PTLD were younger at transplant and had a longer latency time to CHL-PTLD post-transplant. The prevalence of EBV seronegativity at transplant was high in both groups, but prolonged high-level EBV DNAemia only occurred in some with metachronous non-CHL-PTLD. In conclusion, patients with CHL-PTLD have metachronous non-CHL-PTLD diagnoses with discordant histology more commonly than previously recognized. Primary EBV infection with chronically elevated EBV viral loads may represent unique risk factors for CHL-PTLD following an initial non-CHL-PTLD event. [ABSTRACT FROM AUTHOR]

Summary: Post‐transplant lymphoproliferative disorder (PTLD) may arise after solid organ transplantation, and the most common subtype resembles diffuse large B cell lymphoma (DLBCL). In DLBCL‐type PTLD, the anti‐CD20 antibody rituximab (R) may be combined with chemotherapy (R‐CHOP) or use a strategy (R‐primary; similar to the PTLD‐1 clinical trial) consisting of induction with four weekly doses of R‐alone, without any chemotherapy or sequential R‐CHOP follow‐up. Here we report on a multicentre retrospective cohort of solid organ transplant patients with DLBCL‐type PTLD that were treated with R. In 168 adults, two‐year overall survival (OS) was 63·7% [95% CI (confidence interval) 56·6–71·7%]. No difference in OS was observed, whether patients were treated with R‐CHOP versus the R‐primary strategy. In the 109 patients treated with R‐primary, multivariate analysis found that baseline IPI score and the response to R‐induction predicted OS. Patients who responded to R‐induction had durable remissions without the addition of chemotherapy. Conversely, of the 46 patients who had stable or progressive disease after R‐induction (R‐failure), those who received R‐CHOP had an only marginally improved outcome, with a two‐year OS of 45% (23·1–65·3%) vs. no R‐CHOP at 32% (14·7–49·8%). In real‐world patients, R‐failure and high IPI scores predict a poor outcome in DLBCL‐type PTLD. [ABSTRACT FROM AUTHOR]

Introduction: Epstein‐Barr virus (EBV) associated smooth muscle tumors (EBV‐SMT) are a rare complication of solid organ transplantation (SOT). Incidence data related to this EBV‐SMT are limited. EBV DNA is universally present in these tumors. How these cells get infected with EBV, whether this is a result of primary EBV infection vs reactivation, and how persistent active EBV infection post‐transplant influences EBV‐SMT pathogenesis remains unknown. Methods: Among 5006 SOT recipients (474 pediatric, 4532 adult) receiving SOT at our center between Jan 1984 and Dec 2015, three cases of post‐transplant EBV‐SMT were identified. Results: All cases were pediatric heart transplants who were EBV seronegative prior to transplant, and experienced primary EBV infection with persistently elevated EBV viral loads, despite antiviral therapy. Two are deceased at 3.2 and 0.9 years post‐diagnosis, while one remains alive 6.2 years post diagnosis. The overall local incidence of post‐transplant EBV‐SMT at our institution was 0.7 (95% CI, 0.2‐1.7) per 1000 patient years, and 2.6 (95% CI, 0.6‐6.7) per 1000 patient years in pediatric heart transplants. A literature review identified 36 pediatric and 51 adult cases of post‐transplant EBV‐SMT. Conclusions: We hypothesize that pre‐transplant EBV seronegativity, followed by primary EBV infection and persistently high EBV viral loads, represents a unique risk factor for post‐transplant EBV‐SMT. Pediatric heart transplant recipients were found to be disproportionately affected by post‐transplant EBV‐SMT at our institution. [ABSTRACT FROM AUTHOR]