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.

SOHO State of the Art Updates and Next Questions: Diagnosis and Management of Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma.

Monoclonal proteins are common, with a prevalence in the United States around 5% and the incidence increases with age. Although most patients are asymptomatic, the vast majority of cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma (MM). In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma. In this review, we summarize the current diagnosis treatment guidelines for MGUS and SMM and highlight recent advances that underscore a shifting paradigm in the evaluation and management of plasma cell precursor conditions.

Linking GATA2 to myeloid dysplasia and complex cytogenetics in adult myelodysplastic neoplasm and acute myeloid leukemia.

ABSTRACT: GATA binding protein 2 (GATA2) is a conserved zinc finger transcription factor that regulates the emergence and maintenance of complex genetic programs driving development and function of hematopoietic stem and progenitor cells (HSPCs). Patients born with monoallelic GATA2 mutations develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML), whereas acquired GATA2 mutations are reported in 3% to 5% of sporadic AML cases. The mechanisms by which aberrant GATA2 activity promotes MDS and AML are incompletely understood. Efforts to understand GATA2 in basic biology and disease will be facilitated by the development of broadly efficacious antibodies recognizing physiologic levels of GATA2 in diverse tissue types and assays. Here, we purified a polyclonal anti-GATA2 antibody and generated multiple highly specific anti-GATA2 monoclonal antibodies, optimized them for immunohistochemistry on patient bone marrow bioosy samples, and analyzed GATA2 expression in adults with healthy bone marrow, MDS, and acute leukemia. In healthy bone marrow, GATA2 was detected in mast cells, subsets of CD34+ HSPCs, E-cadherin-positive erythroid progenitors, and megakaryocytes. In MDS, GATA2 expression correlates with bone marrow blast percentage, positively correlates with myeloid dysplasia and complex cytogenetics, and is a nonindependent negative predictor of overall survival. In acute leukemia, the percent of GATA2+ blasts closely associates with myeloid lineage, whereas a subset of lymphoblastic and undifferentiated leukemias with myeloid features also express GATA2. However, the percent of GATA2+ blasts in AML is highly variable. Elevated GATA2 expression in AML blasts correlates with peripheral neutropenia and complex AML cytogenetics but, unlike in MDS, does not predict survival.

Update on the current and future use of CAR-T to treat multiple myeloma.

Chimeric antigen receptor T-cell (CAR-T) therapy has become an important intervention in the management of relapsed and relapsed/refractory multiple myeloma (MM). Currently, B-cell maturation antigen (BCMA) is the most targeted surface protein due to its ubiquitous expression on plasma cells, with increasing expression of this essential transmembrane protein on malignant plasma cells as patients develop more advanced disease. This review will explore the earliest CAR-T trials in myeloma, discuss important issues involved in CAR-T manufacturing and processing, as well as review current clinical trials that led to the approval of the two commercially available CAR-T products, Idecabtagene vicleucel and ciltacabtagene autoleucel. The most recent data from trials investigating the use of CAR-T as an earlier line of therapy will be presented. Finally, the problem of relapses after CAR-T will be presented, including several theories as to why CAR-T therapies fail and possible clinical caveats. The next generation of MM-specific CAR-T will likely include new targets such as G-protein-coupled receptor class C, Group 5, member D (GPRC5D) and signaling lymphocyte activation molecular Family 7 (SLAMF7). The role of CAR-T in the treatment of MM will undoubtedly increase exponentially in the next decade.

The Management of Relapsed and Refractory Multiple Myeloma.

The treatment of patients with relapsed and refractory multiple myeloma has become increasingly complex due to the rising number of available therapies. Patients are also increasingly exposed to, and refractory to, multiple classes of therapy at the time of progression. Patients who are at an early point in their myeloma disease course are likely to have several effective options, but choices and prognosis are limited for relapsing patients who are more heavily pretreated, particularly if they are at least triple-class refractory. When selecting the next line of therapy, it remains essential to consider patient comorbidities and frailty as well as treatment history and disease risk. Fortunately, the myeloma treatment landscape continues to evolve with the development of therapies directed toward new biologic targets, such as B-cell maturation antigen. These new agents, including bispecific T-cell engagers and chimeric antigen receptor T-cell therapy, have shown unprecedented efficacy in late-line myeloma and will be increasingly used at earlier time points. Novel combinations of currently approved treatments, including quadruplets and salvage transplantation, also remain important options for consideration.

ABO phenotype and clinical correlates of COVID-19 severity in hospitalized patients.

AIM: This study investigates the association between ABO blood phenotype and COVID-19 severity, measured by intensive care unit admission, need for intubation, hospitalization length and death. It further explores clinical predictors of COVID-19 severity within a primarily Hispanic demographic in San Diego County. MATERIALS & METHODS: We retrospectively reviewed 942 total patients, 473 with available blood type, hospitalized at five Scripps Health hospitals with COVID-19. RESULTS: No significant association was found between ABO phenotype and COVID-19 severity on multivariate analysis, while a diagnosis of anemia and male sex was associated with all severity outcomes on exploratory analysis. CONCLUSION: Our results provide relevant clinical correlates of COVID-19 severity and help better elucidate the association between ABO phenotype and COVID-19.

Dedifferentiated Liposarcoma: Systemic Therapy Options.

OPINION STATEMENT: Over the last several years, the systemic treatment landscape for dedifferentiated liposarcoma (DDLPS) has notably expanded. Historically, systemic therapy options have been limited to cytotoxic chemotherapy agents, including doxorubicin, ifosfamide, gemcitabine, and docetaxel, that were shown to have efficacy in unselected populations of patients with soft tissue sarcomas. More recently, however, there have been phase II and III trials establishing clinical benefit of the cytotoxic agents trabectedin and eribulin along with the tyrosine kinase inhibitor pazopanib in patients with advanced liposarcoma and DDLPS. Additionally, there are several investigational targeted therapies that have incorporated advances in the understanding of DDLPS disease biology, exploiting the fact that nearly all such tumors include highly amplified expression of MDM2 and CDK4. Recent clinical trials have supported the benefit of the CDK4 inhibitor abemaciclib and the nuclear export inhibitor selinexor and support continued development of anti-MDM2 therapies, with particular attention to the bone marrow toxicity and resultant thrombocytopenia that has thus far limited their use. In contrast, the checkpoint inhibitors pembrolizumab and nivolumab remain of questionable benefit, although these immunotherapy drugs may have a role when combined with other therapeutic agents. Ongoing phase III trials will clarify the role of these novel agents. Future directions include directly comparing current standard-of-care options and newer therapies, developing synergistic combinations of novel agents, and evaluating their role in patients with localized DDLPS.

Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy.

The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T0) was 50.1 months. The median overall survival (OS) from T0 for the entire cohort was 8.6 [95% C.I. 7.5-9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for "penta-refractory" patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T0 in 249 (90%) patients. Overall response rate to first regimen after T0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.

Cramér-Rao bound analysis of echo time selection for (1)H-MR spectroscopy.

The choice of echo time (TE) is a complicated and controversial issue in proton MR spectroscopy, and represents a balancing act between signal-to-noise ratio and signal complexity. The TE values used in previous literature were selected either heuristically or based on limited empirical studies. In this work, we reconsider this problem from an estimation theoretic perspective. Specifically, we analyze the Crame r-Rao lower bound on estimated spectral parameters as a function of TE, which serves as a metric to quantify the reliability of the estimation procedure. This analysis reveals that a good choice of TE often depends on the particular metabolite of interest, and is a function of both the coupling properties of the metabolites and the general complexity of the spectrum.