Routine clinical parameters and laboratory testing predict therapy-related myeloid neoplasms after treatment for breast cancer.

We aim to identify predictors of therapy-related myeloid neoplasms (t-MN) in patients with breast cancer (BC) and cytopenias to determine the timing of bone marrow biopsy (BMBx). Patients with BC and cytopenias who were referred for BMBx between 2002-2018 were identified using the Memorial Sloan Kettering Cancer Center institutional database. Characteristics associated with the risk of t-MN were evaluated by multivariable logistic regression and included in a predictive model. The average area under the receiver operating characteristic curve (AUC) was estimated by 5-fold cross-validation. Of the 206 BC patients who underwent BMBx included in our study, 107 had t-MN. By multivariable analysis, white blood cell count 4-11 K/mcL, absolute neutrophil count (ANC) ≥1.5 K/mcL, hemoglobin ≥12.2 g/dL, red cell distribution width 11.5-14.5%, the presence of bone metastasis and a time from BC diagnosis to BMBx <15 months significantly decreased the likelihood of t-MN. The average AUC was 0.88. We stratified our cohort by bone metastasis and by findings on peripheral smear. In both the subset without bone metastasis (n=159) and in the cohort with no blasts or dysplastic cells on peripheral smear (n=96) our variables had similar effects on the risk of t-MN. Among the 47 patients with bone metastasis, an ANC ≥1.5 K/mcL was the only variable associated with a decreased risk of t-MN. Our findings show that in patients with BC and unexplained cytopenias, clinical and laboratory parameters can predict t-MN and assist clinicians in determining the timing of a BMBx.

Advances in the Treatment of Hairy Cell Leukemia Variant.

OPINION STATEMENT: Hairy cell leukemia variant (HCL-V) is a rare B cell lymphoproliferative disorder with a clinical-pathological distinction from the classic form of hairy cell leukemia (HCL-C). HCL-V is more aggressive in nature, has a higher tendency to be refractory to conventional purine analog pharmacotherapies, and leads to a poorer prognosis. Hence, these differing features bring paramount importance to the diagnosis and management of HCL-V. While there is no genetic mutation diagnostic of HCL-V, genetic profiling efforts have identified potential therapeutic targets (i.e., MAP2K1, KDM6A, CREBBP, ARID1A, CCND3, U2AF1, KMT2C) and yielded prognostic markers (i.e., IGHV4-34 rearrangements). To date, combination chemoimmunotherapies, such as cladribine and rituximab, have shown the best results in HCL-V. Future directions include targeted therapies such as moxetumomab pasudotox, ibrutinib, trametinib, and binimetinib and potentially anti-CD22 chimeric antigen receptor T cell therapy. The purpose of this review is to provide an outline of the diagnostic approach and an update on the therapeutic advancements in HCL-V.

Evaluating the Patient with Neurotoxicity after Chimeric Antigen Receptor T-cell Therapy.

OPINION STATEMENT: Chimeric antigen receptor (CAR) T-cells are now a well-established treatment for hematologic malignancies. Their use in clinical practice has expanded quite rapidly and hospitals have developed CAR T-cell protocols to evaluate patients for associated toxicities, and particularly for neurotoxicity. There are many variables that influence the risk for developing this complication, many of which are not fully understood. The severity can be related to a particular product. Clinical vigilance is critical to facilitate early recognition of neurotoxicity, hence the importance of pre-CAR T-cell neurological evaluation of each patient. While details of such an evaluation may slightly differ between institutions, generally a comprehensive neurological evaluation including assessment of cognitive abilities along with magnetic resonance imaging (MRI) of the brain is a gold standard. Management of neurotoxicity requires a well-orchestrated team approach with specialists from oncology, neurology, oftentimes neurosurgery and neuro-intensive care. Diagnostic work-up frequently includes detailed neurologic evaluation with comparison to the baseline assessment, imaging of the brain, electroencephalogram, and lumbar puncture. While steroids are uniformly used for treatment, many patients also receive tocilizumab for an underlying and frequently concomitant cytokine release syndrome (CRS) in addition to symptom-driven supportive care. Novel CAR T-cell constructs and other agents allowing for potentially lower risk of toxicity are being explored. While neurotoxicity is predominantly an early, and reversible, event, a growing body of literature suggests that late neurotoxicity with variable clinical presentation can also occur.

Quality of life in non-melanoma skin cancer.

Basal cell carcinoma and squamous cell carcinoma are the most common malignancies and are classified under the umbrella of non-melanoma skin cancer (NMSC). NMSC exerts a small but appreciable decrement in quality of life (QOL). The impact posed may arise from the tumour itself or as a result of treatment, and through symptoms, functional limitations, cosmetic burden and auxiliary considerations such as cost and disturbance to the activities of daily living. Researchers have evaluated this burden using a variety of outcome measures including generic, dermatology-specific and disease-specific instruments. The skin cancer index represents a promising disease-specific patient-reported outcome measure in this setting. To overcome some of the constraints inherent to disease-specific instruments, and to allow comparisons with other diseases, utility weightings have been developed. Utility weightings represent a cardinal measure for a specific health status and are established through methods such as the standard gamble, willingness-to-pay and time trade-off, and have also been employed to generate utility weightings for NMSC. Utilities are becoming increasingly important as a means of comparing health states across medicine and are of particular importance from a health-care policy perspective as they are used for resource allocation. The small but definite impact on the individual's QOL posed by NMSC should be a clinical consideration for physicians and it should be recognised by researchers as a potential outcome measure.

Molecular Pathways in Clonal Hematopoiesis: From the Acquisition of Somatic Mutations to Transformation into Hematologic Neoplasm.

Hematopoietic stem cell aging, through the acquisition of somatic mutations, gives rise to clonal hematopoiesis (CH). While a high prevalence of CH has been described in otherwise healthy older adults, CH confers an increased risk of both hematologic and non-hematologic diseases. Classification of CH into clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) further describes this neoplastic myeloid precursor state and stratifies individuals at risk of developing clinically significant complications. The sequential acquisition of driver mutations, such as DNMT3A, TET2, and ASXL1, provide a selective advantage and lead to clonal expansion. Inflammation, microbiome signatures, and external selective pressures also contribute to clonal evolution. Despite significant progress in recent years, the precise molecular mechanisms driving CH transformation to hematologic neoplasms are not well defined. Further understanding of these complex mechanisms may improve risk stratification and introduce therapeutic interventions in CH. Here we discuss the genetic drivers underpinning CH, mechanisms for clonal evolution, and transformation to hematologic neoplasm.