SOHO State of the Art Updates and Next Questions: An Update on Higher Risk Myelodysplastic Syndromes.

Higher-risk myelodysplastic syndromes (HR-MDS) are clonal myeloid neoplasms that cause life-limiting complications from severe cytopenias and leukemic transformation. Efforts to better classify, prognosticate, and assess therapeutic responses in HR-MDS have resulted in publication of new clinical tools in the last several years. Given limited current treatment options and suboptimal outcomes, HR-MDS stands to benefit from the study of investigational agents.Higher-risk myelodysplastic syndromes (HR-MDS) are a heterogenous group of clonal myeloid-lineage malignancies often characterized by high-risk genetic lesions, increased blood transfusion needs, constitutional symptoms, elevated risk of progression to acute myeloid leukemia (AML), and therapeutic need for allogeneic bone marrow transplantation. Use of blast percentage and other morphologic features to define myelodysplastic neoplasm subtypes is rapidly shifting to incorporate genetics, resulting in a subset of former HR-MDS patients now being considered as AML in presence of leukemia-defining genetic alterations. A proliferation of prognostic tools has further focused use of genetic features to drive decision making in clinical management. Recently, criteria to assess response of HR-MDS to therapy were revised to incorporate more clinically meaningful endpoints and better match AML response criteria. Basic science investigations have resulted in improved understanding of the relationship between MDS genetic lesions, bone marrow stromal changes, germline predispositions, and disease phenotype. However, therapeutic advances have been more limited. There has been import of the IDH1 inhibitor ivosidenib, initially approved for AML; the Bcl-2 inhibitor venetoclax and liposomal daunorubicin/cytarabine (CPX-351) are under active investigation as well. Unfortunately, effective treatment of TP53-mutated disease remains elusive, though preliminary evidence suggests improved outcomes with oral decitabine/cedazuridine over parenteral hypomethylating agent monotherapy. Investigational agents with novel mechanisms of action may help expand the repertoire of treatment options for HR-MDS and trials continue to offer a hopeful therapeutic avenue for suitable patients.

The Times, They Are A-Changing: The Impact of Next-Generation Sequencing on Diagnosis, Classification, and Prognostication of Myeloid Malignancies With Focus on Myelodysplastic Syndrome, AML, and Germline Predisposition.

Myeloid malignancies are a manifestation of clonal expansion of hematopoietic cells driven by somatic genetic alterations that may arise in a potential background of deleterious germline variants. As next-generation sequencing technology has become more accessible, real-world experience has allowed integration of molecular genomic data with morphology, immunophenotype, and conventional cytogenetics to refine our understanding of myeloid malignancies. This has prompted revisions in the classification and the prognostication schema of myeloid malignancies and germline predisposition to hematologic malignancies. This review provides an overview of significant changes in the recently published classifications of AML and myelodysplastic syndrome, emerging prognostic scoring, and the role of germline deleterious variants in predisposing to MDS and AML.

Chronic myeloid leukemia (CML) evolves from Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) with unexpected frequency.

Myeloproliferative neoplasms (MPN) are chronic clonal disorders characterized by overproduction of myeloid-lineage blood cells and potential risk of evolution to acute myeloid leukemia (AML). Chronic myeloid leukemia (CML) is distinct from other MPNs in that its pathophysiology stems from the BCR-ABL fusion protein of the Philadelphia chromosome (Ph +). Though there are known cases of Ph- and Ph + MPNs coexisting in a single patient, overall prevalence has never been quantified in a prospective cohort. Here, we review our center's MPN registry, which shows 0.6% of Ph- MPN patients later developed CML. This development occurred no less than 10 and up to 36 years after Ph- MPN diagnosis. This rate of chronic transformation exceeds what is expected, as the incidence of CML in the United States is 2 per 100,000 people-years. The probability of this CML case rate in an average-risk population is less than 0.001%, suggesting there are shared risk factors between Ph- and Ph + MPNs. We speculate that these risk factors may include exposures, genetic predispositions, or be inherent to disease biology. Abrupt-onset leukocytosis heralded post-MPN CML in all cases here and suggests this salient clinical feature should trigger hematologists to consider this diagnosis and perform appropriate testing.

Prognostic impact of secondary versus de novo ontogeny in acute myeloid leukemia is accounted for by the European LeukemiaNet 2022 risk classification.

Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prior AHD, but whether abnormal ABCs are associated with worse outcomes is unclear. Secondary-type mutations have recently been incorporated into the European LeukemiaNet (ELN) 2022 guidelines as adverse-risk features, raising the question of whether clinical descriptors of ontogeny (i.e., de novo or secondary) are prognostically significant when accounting for genetic risk by ELN 2022. In a large multicenter cohort of patients (n = 734), we found that abnormal ABCs are not independently prognostic after adjusting for genetic characteristics in dnAML patients. Furthermore, history of AHD and tAML do not confer increased risk of death compared to dnAML on multivariate analysis, suggesting the prognostic impact of ontogeny is accounted for by disease genetics as stratified by ELN 2022 risk and TP53 mutation status. These findings emphasize the importance that disease genetics should play in risk stratification and clinical trial eligibility in AML.

Myelodysplastic syndrome and autoimmune disorders: two sides of the same coin?

Systemic inflammatory and autoimmune diseases and myelodysplastic syndromes have been linked in individual patients and in larger case series for at least 25 years. These associations frequently include thyroid disease, neutrophilic dermatoses, polyarthritis, connective tissue diseases, vasculitis, and autoimmune cytopenias. Studies have found that autoimmune disease (or its therapy) is a risk factor for the development of myelodysplastic syndromes, but such syndromes might also be an instigator of autoimmune disease. Epidemiological studies examining disease risk in myelodysplastic syndromes with and without comorbid autoimmune illness have reached mixed conclusions. The pathophysiology of myelodysplastic syndromes is tightly linked to excessive inflammatory activity in the bone marrow microenvironment, which could promote systemic inflammatory and autoimmune diseases directly or by stimulation of the adaptive immune response. Alternatively, autoimmune diseases could promote clonal evolution and disordered bone marrow growth, promoting the development of myeloid malignancy. Additionally, therapy-related myeloid neoplasms-including myelodysplastic syndromes-have been diagnosed after treatment of autoimmune diseases with immunosuppressant therapies. These associations raise the following question: are myelodysplastic syndromes and systemic inflammatory and autoimmune diseases two sides of the same coin-that is, do they share an underlying disease state that can manifest as a myeloid neoplasm, an autoinflammatory illness, or both? VEXAS syndrome, which was first reported in 2020, is caused by a mutation that affects myeloid-restricted cells and manifests with both myelodysplasia and autoinflammation, and could give insight into this biological possibility. We note that systemic inflammatory and autoimmune diseases are often steroid-dependent; however, studies have also evaluated the roles of other immunomodulating therapies. In this Viewpoint, we critically appraise and review the literature on the epidemiology, pathophysiology, and management of systemic inflammatory and autoimmune diseases that are associated with myelodysplastic syndromes and related diseases.

Examining disease boundaries: Genetics of myelodysplastic/myeloproliferative neoplasms.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal myeloid malignancies that are characterized by dysplasia resulting in cytopenias as well as proliferative features such as thrombocytosis or splenomegaly. Recent studies have better defined the genetics underlying this diverse group of disorders. Trisomy 8, monosomy 7, and loss of Y chromosome are the most common cytogenetic abnormalities seen. Chronic myelomonocytic leukemia (CMML) likely develops from early clones with TET2 mutations that drive granulomonocytic differentiation. Mutations in SRSF2 are common and those in the RAS-MAPK pathway are typically implicated in disease with a proliferative phenotype. Several prognostic systems have incorporated genetic features, with ASXL1 most consistently demonstrating worse prognosis. Atypical chronic myeloid leukemia (aCML) is most known for granulocytosis with marked dysplasia and often harbors ASXL1 mutations, but SETBP1 and ETNK1 are more specific to this disease. MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) most commonly involves spliceosome mutations (namely SF3B1) and mutations in the JAK-STAT pathway. Finally, MDS/MPN-unclassifiable (MDS/MPN-U) is least characterized but a significant fraction carries mutations in TP53. The remaining patients have clinical and/or genetic features similar to the other MDS/MPNs, suggesting there is room to better characterize this entity. Evolution from age-related clonal hematopoiesis to MDS/MPN likely depends on the order of mutation acquisition and interactions between various biologic factors. Genetics will continue to play a critical role in our understanding of these illnesses and advancing patient care.

Systematic improvements in lentiviral transduction of primary human natural killer cells undergoing ex vivo expansion.

Transduction of primary human natural killer (NK) cells with lentiviral vectors has historically been challenging. We sought to evaluate multiple parameters to optimize lentiviral transduction of human peripheral blood NK cells being expanded to large numbers using a good manufacturing practice (GMP)-compliant protocol that utilizes irradiated lymphoblastoid (LCL) feeder cells. Although prestimulation of NK cells with interleukin (IL)-2 for 2 or more days facilitated transduction with vesicular stomatitis virus glycoprotein (VSVG)-pseudotyped lentivirus, there was a subsequent impairment in the capacity of transduced NK cells to proliferate when stimulated with LCL feeder cells. In contrast, incubation of human NK cells with LCL feeder cells plus IL-2 before transduction in the presence of the TBK1 inhibitor BX795 resulted in efficient lentiviral integration (mean of 23% transgene+ NK cells) and successful subsequent proliferation of the transduced cells. Investigation of multiple internal promoter sequences within the same lentiviral vector revealed differences in percentage and level of transgene expression per NK cell. Bicistronic lentiviral vectors encoding both GFP and proteins suitable for the isolation of transduced cells with magnetic beads led to efficient transgene expression in NK cells. The optimized approaches described herein provide a template for protocols that generate large numbers of fully functional and highly purified lentivirus-transduced NK cells for clinical trials.

Comparing the Palliative Care Needs of Patients With Hematologic and Solid Malignancies.

CONTEXT: Hematologic cancer patients use palliative care services less frequently than their solid tumor counterparts. Prior work suggests that these patients have a sizable symptom burden, but comparisons between hematologic and solid tumor patients near the end of life are limited. OBJECTIVES: To compare unmet symptom needs in a cohort of hematologic and solid tumor patients referred to specialty palliative care services. METHODS: Using a novel data registry of initial palliative care encounters, we performed a cross-sectional analysis of cancer patients receiving care across 17 sites within the Global Palliative Care Quality Alliance. We compared clinically-significant symptoms (rated as four or greater in severity) between hematologic and solid tumor patients and performed multivariate logistic regression analyses examining the relationship between symptom burden and tumor type. RESULTS: We identified 1235 cancer patients, 108 of which had hematologic malignancies. Pain, dyspnea, nausea, and anorexia burden were as high among patients with hematologic as those with solid malignancies. Blood cancer patients had higher rates of clinically-significant tiredness (51% vs. 42%; P = 0.03) than solid tumor patients. Finally, blood cancer patients had greater odds of being tired (odds ratio 2.19; CI 1.22-3.91) and drowsy (odds ratio 1.81; CI 1.07-3.07) than solid tumor patients independent of age, gender, race, and performance status. CONCLUSIONS: Hematologic and solid tumor patients have significant symptom burden at time of referral to palliative care services. Blood cancer patients may have unique concerns warranting targeted attention, including substantial drowsiness and tiredness. Our findings suggest a need to optimize palliative care usage in the hematologic cancer population.

Comparing Unmet Needs to Optimize Quality: Characterizing Inpatient and Outpatient Palliative Care Populations.

CONTEXT: Palliative care (PC) consultation services are available in most hospitals; outpatient services are rapidly growing to meet the needs of patients at earlier stages of the disease trajectory. OBJECTIVES: We aimed to compare the unmet needs of PC patients by location of care to better characterize these populations. METHODS: This cross-sectional secondary analysis examined patients receiving hospital and outpatient-based PC across 10 community and academic organizations in the Global Palliative Care Quality Alliance. We identified unmet symptom, advance care planning, and functional needs within our database from October 23, 2012 to January 22, 2015. Kruskal-Wallis, chi-square, and Fisher exact tests were performed. RESULTS: We evaluated 633 unique patients. Inpatients (n = 216) were older than outpatients (n = 417; 73 vs. 64 years, P < 0.0001). Seventy-six inpatients (38%) had a Palliative Performance Scale score ≤30%; no outpatients did (P < 0.0001). More inpatients rated their quality of life as poor compared with outpatients (39% vs. 21%, P = 0.0001). We found that outpatients presented with more unresolved pain than inpatients (58.5% vs. 4.1%, P < 0.0001). Conversely, more inpatients presented with unresolved anorexia (52.3% vs. 35.8%, P = 0.002) and dysphagia (28.1% vs. 5.4%, P < 0.0001) than outpatients. We found that inpatient setting was independently associated with lower performance status (odds ratio = 0.068, 95% confidence interval = 0.038-0.120, P < 0.0001). CONCLUSION: Compared with inpatients, outpatients are more burdened by pain at first PC encounter yet experience higher quality of life and better performance status. These findings suggest different clinician skillsets, and assessments are needed depending on the setting of PC consultation.

Performance of Consultative Palliative Care Model in Achieving Quality Metrics in the ICU.

CONTEXT: Quality metrics for intensive care unit (ICU)-based palliative care have been proposed, but it is unknown how consultative palliative care can contribute to performance on these measures. OBJECTIVES: Assess adherence to proposed quality metrics of ICU-based palliative care by palliative care specialists. METHODS: Surrogates for 9/14 patient-level quality metrics were assessed in all patients who received an initial palliative care specialist consult while in an ICU from 10/26/2012 to 1/16/2015 in the Global Palliative Care Quality Alliance, a nationwide palliative care quality registry. RESULTS: Two hundred fifty-four patients received an initial palliative care consultation in an ICU setting. Mean (SD) age was 67.5 (17.3) years, 52% were female. The most common reasons for consultation were symptom management (33%) and end-of-life transition (24%). Adherence to ICU quality metrics for palliative care was variable: clinicians documented presence or absence of advance directives in 36% of encounters, assessed pain in 52.0%, dyspnea in 50.8%, spiritual support in 62%, and reported an intervention for pain in 100% of patients with documented moderate to severe intensity pain. CONCLUSION: Palliative care consultations in an ICU setting are characterized by variable adherence to candidate ICU palliative care quality metrics. Although symptom management was the most common reason for palliative care consultation, consultants infrequently documented symptom assessments. Palliative care consultants performed better in offering spiritual support and managing documented symptoms. These results highlight specific competencies of consultative palliative care that should be complimented by ICU teams to ensure high-quality comprehensive care for the critically ill.

Anticholinergic Drug Burden in Noncancer Versus Cancer Patients Near the End of Life.

CONTEXT: Anticholinergic drugs can cause several side effects, impairing cognition and quality of life (QOL). Cancer patients are often exposed to increasing cumulative anticholinergic load (ACL) as they approach death, but this burden has not been examined in patients with nonmalignant diseases. OBJECTIVES: To determine ACL and its impact in noncancer versus cancer palliative care patients. METHODS: We performed a secondary analysis of 244 subjects enrolled in a randomized controlled trial. ACL was quantified with the Anticholinergic Drug Scale. We used multivariable regression to calculate the effect of ACL on key outcomes, including drowsiness, fatigue, and QOL. Patients were stratified by diagnosis, and drugs were grouped as symptom management (SM) or disease management (DM). RESULTS: Overall, ACL in cancer and noncancer patients was not significantly different (2.6 vs. 2.4; P = 0.23). SM drugs caused greater anticholinergic exposure than DM drugs in both cancer and noncancer patients (2.3 vs. 0.5, and 1.5 vs. 1.3, respectively; both P < 0.05); however, DM drugs exposed noncancer patients to relatively more ACL than cancer patients (1.2 vs. 0.6, P < 0.0001). ACL was associated with worse fatigue (odds ratio, 1.08; CI, 1.002-1.17) and worse QOL (odds ratio, 0.89; CI, 0.80-0.98). CONCLUSIONS: ACL is associated with worse fatigue and QOL and may not differ significantly between cancer and noncancer patients nearing end of life. SM drugs are more responsible for ACL in cancer and noncancer patients, although DM drugs contribute significantly to ACL in the latter group. We recommend more attention to reducing anticholinergic use in all patients with life-limiting illness.