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Abstract: Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Mutations in UBA1, which are disease-defining for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet polymerase chain reaction profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established World Health Organization (WHO) disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n = 2027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n = 12) and of unknown significance (n = 15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO 2016 criteria as MDS with multilineage dysplasia or MDS with single-lineage dysplasia. Patients had a median of 1 additional myeloid gene mutation, often in TET2 (n = 12), DNMT3A (n = 10), ASXL1 (n = 3), or SF3B1 (n = 3). Retrospective clinical review, where possible, showed that 82% (28/34) UBA1-mutant cases had VEXAS syndrome-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1 mutations in patients with MDS argues for systematic screening for UBA1 in the management of MDS., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

BACKGROUND: Risk stratification and therapeutic decision-making for myelodysplastic syndromes (MDS) are based on the International Prognostic Scoring System–Revised (IPSS-R), which considers hematologic parameters and cytogenetic abnormalities. Somatic gene mutations are not yet used in the risk stratification of patients with MDS. METHODS: To develop a clinical-molecular prognostic model (IPSS-Molecular [IPSS-M]), pretreatment diagnostic or peridiagnostic samples from 2957 patients with MDS were profiled for mutations in 152 genes. Clinical and molecular variables were evaluated for associations with leukemia-free survival, leukemic transformation, and overall survival. Feature selection was applied to determine the set of independent IPSS-M prognostic variables. The relative weights of the selected variables were estimated using a robust Cox multivariable model adjusted for confounders. The IPSS-M was validated in an external cohort of 754 Japanese patients with MDS. RESULTS: We mapped at least one oncogenic genomic alteration in 94% of patients with MDS. Multivariable analysis identified TP53multihit, FLT3 mutations, and MLLPTD as top genetic predictors of adverse outcomes. Conversely, SF3B1 mutations were associated with favorable outcomes, but this was modulated by patterns of comutation. Using hematologic parameters, cytogenetic abnormalities, and somatic mutations of 31 genes, the IPSS-M resulted in a unique risk score for individual patients. We further derived six IPSS-M risk categories with prognostic differences. Compared with the IPSS-R, the IPSS-M improved prognostic discrimination across all clinical end points and restratified 46% of patients. The IPSS-M was applicable in primary and secondary/therapy-related MDS. To simplify clinical use of the IPSS-M, we developed an open-access Web calculator that accounts for missing values. CONCLUSIONS: Combining genomic profiling with hematologic and cytogenetic parameters, the IPSS-M improves the risk stratification of patients with MDS and represents a valuable tool for clinical decision-making. (Funded by Celgene Corporation through the MDS Foundation, the Josie Robertson Investigators Program, the Edward P. Evans Foundation, the Projects of National Relevance of the Italian Ministry of University and Research, Associazione Italiana per la Ricerca sul Cancro, the Japan Agency for Medical Research and Development, Cancer Research UK, the Austrian Science Fund, the MEXT [Japanese Ministry of Education, Culture, Sports, Science and Technology] Program for Promoting Research on the Supercomputer Fugaku, the Japan Society for the Promotion of Science, the Taiwan Department of Health, and Celgene Corporation through the MDS Foundation.)

Background: Advance care planning, the process through which patient values and goals are explored and documented, is a core quality indicator in cancer care. However, patient values are predominantly elicited at the end of life; patient values earlier in serious illness are not clearly delineated. The objective of this analysis is to assess the content of patient-verified summaries of health-related values among newly diagnosed cancer outpatients in order to develop a theoretical framework to guide future values discussions and optimize person-centered oncologic care., Methods: Values summaries among patients with gastrointestinal (GI) cancers or myelodysplastic syndrome (MDS) were extracted from the medical record. Modified grounded theory analysis included interdisciplinary team coding of values summaries to identify key domains; code categorization; and identification of thematic constructs during successive consensus meetings. A final round of coding stratified themes by disease type., Results: Analysis of 128 patient values summary documents from 67 patients (gastrointestinal [GI] cancers, n = 49; myelodysplastic syndrome [MDS], n = 18) generated 115 codes across 12 categories. Resultant themes demonstrated patients' focus on retaining agency, personhood and interpersonal connection amidst practical and existential disruption caused by cancer. Themes coalesced into a theoretical framework with 5 sequenced constructs beginning with the cancer diagnosis, leading to 3 nesting constructs of individual identity (character), interpersonal (communication) preferences and needs, and social identity (connection), signifying sources of meaning and fulfillment. Values differences between GI cancer and MDS patients-including greater focus on normalcy, prognosis, and maintaining professional life among GI patients-reflected the distinct therapeutic options and prognoses across these disease groups., Conclusions: Patient values reflect goals of meaning-making and fulfillment through individual agency and interpersonal supports in the setting of a newly diagnosed cancer. Early, nurse-led values discussions provide important and patient-specific data that are informative and likely actionable by clinicians in the delivery of person-centered care. Values can also facilitate discussions between patients and families and clarify patient preferences., (© 2022. The Author(s).)

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS., (© 2021. The Author(s).)

Lay Summary: People who have advanced myelodysplastic syndromes (MDS) may live longer if they get a bone marrow transplant (BMT) instead of other therapies. However, only 15% of people with MDS actually get BMT. Experts say community physicians and transplant physicians should team up with insurance companies and patient advocacy groups to 1) spread this news about lifesaving advances in BMT, 2) ensure that everyone can afford health care, 3) provide emotional support for patients and families, 4) help patients and families get transportation and housing if they need to travel for transplant, and 5) improve care for people of under-represented racial and ethnic backgrounds., (© 2021 American Cancer Society.)

Mutations of TP53 are observed in 5-10% of patients in myelodysplastic syndrome (MDS) and are associated with adverse outcomes. Previous studies indicate that the TP53 allelic state and variant allele frequency of TP53 mutation impact patient outcomes, but there is significant heterogeneity within this MDS subgroup. We performed retrospective review of clinicopathologic and genomic information of 107 patients with TP53 -mutated MDS. We assessed each mutation according to the phenotypic annotation of TP53 mutations (PHANTM) and analyzed the associations between predicted TP53 mutant function, represented by the PHANTM combined phenotype score, and overall survival (OS) using the log rank test and Cox regression. Our results indicated that patients with PHANTM combined phenotype score above the median (>1) had significantly shorter OS compared to those with scores below the median (median OS: 10.59 and 16.51 months, respectively, p = 0.025). This relationship remained significant in multivariable analysis (HR (95%CI): 1.62 (1.01-2.58), p = 0.044) and identified to have an independent prognostic influence, accounting for known risk such as IPSS-R and other standard risk variables. Our results suggest that the functional information of TP53 mutations, represented by PHANTM combined phenotype score, are associated with the clinical outcome of patients with TP53 -mutated MDS.

Objectives: Evidence-based guidelines call for integration of palliative care within oncology from diagnosis. Misperceptions about palliative care have impeded implementation. Prior research has not examined perceptions about 'palliative care' versus 'supportive care' among patients and caregivers to whom this care is introduced routinely as part of comprehensive cancer care. We conducted a qualitative study of patients with myelodysplastic syndromes (MDS) and their informal caregivers to elicit perceptions of 'palliative care' and 'supportive care' before and after they received integrated primary/specialist palliative care from diagnosis., Methods: Patients with newly diagnosed MDS and caregivers were interviewed about their understanding of 'palliative care' and 'supportive care' at diagnosis and follow-up. Interviews were audio-recorded, transcribed, and analysed by an interdisciplinary team., Results: Forty-eight interviews were conducted in total, including with 21 patients and 13 caregivers at diagnosis, and 10 patients and 4 caregivers at follow-up. Initially, 28/34 participants (82%) associated 'palliative care' with death or fear/alarm. At follow-up, 11/14 participants (79%) recognised that 'palliative care' is not only for terminally ill patients, yet 13/14 participants (93%) still felt apprehensive about the term. Initially, 24/34 participants (71%) felt 'supportive care' sounded 'positive' and 12/14 participants (86%) reported this at follow-up. No participant associated 'supportive care' with death or fear/alarm at either time point. Among participants who had a preference, 'supportive care' was the preferred term initially and at follow-up., Conclusions: Patients with MDS and caregivers receiving integrated primary/specialist palliative care from diagnosis responded more favourably to and felt less apprehensive about 'supportive care', initially and at follow-up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer 1,2 . In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease 3,4 , rapid transformation to acute myeloid leukemia (AML) 5 , resistance to conventional therapies 6-8 and dismal outcomes 9 . Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations 10 . However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R) 11 . Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.

Background: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents., Methods: We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT02228525., Findings: Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1-12·2). Two patients did not meet the full eligibility criteria after baseline assessment; therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10-48) in six patients with marrow complete remission, with an additional 12 patients (52%, 95% CI 31-73) achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths., Interpretation: Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment., Funding: Karyopharm Therapeutics., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Luminal gastrointestinal tract cancers (LGC) are common malignancies, and many patients can achieve long-term responses with surgery, cytotoxic and/or targeted therapies, and radiation. The long-term follow-up for patients with durable disease control has not been fully characterized, including subsequent malignancies. Such cases have not been comprehensively described., Patients and Methods: We identified patients evaluated for myeloid malignancies (MyM) who had a prior LGC at our institution over a 35-year period. Patient, disease, and treatment information was collected for analysis. Cytogenetic risk profiles were designated according to the Revised International Prognostic Scoring System for MDS and the European LeukemiaNet Guidelines for AML., Results: 66 patients were included in our cohort with 71 prior LGC diagnoses, including three patients with multiple LGCs. 31 cases were treated with surgery alone, and 37 patients received chemotherapy. The median age at diagnosis of MyM was 71.8 years (range, 36.2-90.5), with median duration between initiation of treatment of LGC and diagnosis MyM of 7.9 years (range 0.005-38.8). Intermediate or adverse (AML)/poor-very poor (MDS) cytogenetic risk was common, occurring in 43% of MDS patients and 100% of AML patients; deletion 5q was the most common cytogenetic abnormality overall. DNMT3A mutations were the most common molecular alteration (6 patients with 7 mutations)., Conclusions: Among patients with MyM following LGC, a high proportion harbored cytogenetic changes, many of which were adverse or poor-risk. Deletion 5q and mutated DNMT3A were the most common abnormalities identified., (Copyright © 2019. Published by Elsevier Ltd.)

Older patients with acute myelogenous leukemia (AML) are at increased risk for mortality and morbidity. While allogeneic stem cell transplantation may provide cure in some patients, many still relapse after transplant and are then left with limited therapeutic options and poor survival. Moreover, the quality of the end-of-life care for these patients has not been previously reported. We describe here the end-of-life experience of a cohort of 72 older patients with AML who relapsed after first allogeneic stem cell transplant at our dedicated cancer center. Despite a median overall survival of only 4 months, we find a high level of primary palliative care delivered by transplant/leukemia physicians through goals of care discussions and/or advanced care planning and provide evidence for high-quality end-of-life care outcomes, often with concurrent disease-directed therapy. Our results compare favorably with end-of-life care outcomes reported for older AML patients, including those who did not undergo transplant. Given the poor prognosis and unique underlying vulnerabilities in this high-risk patient population, incorporating timely advanced care planning and palliative care delivery while exploring available salvage options may further improve end-of-life care outcomes.

Background: Prior work to integrate early palliative care in oncology has focused on patients with advanced cancer and primarily on palliative care consultation. We developed this outpatient clinic initiative for newly diagnosed patients at any stage, emphasizing primary (nonspecialist) palliative care by oncology teams, with enhanced access to palliative care specialists., Methods: We piloted the project in two medical oncology specialty clinics (for patients with myelodysplastic syndrome and GI cancer, respectively) to establish feasibility. On a visit-based schedule, patients systematically reported symptoms, information/decision-making preferences, and illness understanding. They also participated in discussions of their core values with their oncology nurse. Oncology teams were first responders to palliative care needs, whereas specialists were available for clinician support and direct patient consultation., Results: All 58 eligible patients were enrolled. In both clinics, patient self-reports documented a heavy symptom burden. Information/decision-making preferences and illness understanding levels varied across patients. Patients prepared new advance directives. Oncology nurses documented discussions of core values. Requests for palliative care consultation decreased over time as oncology teams embraced their primary palliative care role with coaching from the specialists. Clinic workflow and patient volume were maintained., Conclusion: Our pilot experience suggests that in outpatient oncology clinics, a structured, scheduled, and systematic approach is feasible to deliver palliative care to newly diagnosed patients with cancer at any stage and throughout their illness trajectory. This novel approach identified important, actionable palliative care needs, relying primarily on oncology teams to respond to these needs, while enhancing access to palliative care specialist input. Expansion to additional clinics will allow evaluation of scalability and generalizability, along with measurement of a broader range of important outcomes.

Objectives: To compare the effectiveness and tolerability of micafungin versus posaconazole during chemotherapy-induced neutropenia in acute leukemia (AL) and myelodysplastic syndrome (MDS)., Methods: Patients with AL or MDS undergoing chemotherapy were randomized to open-label micafungin 100 mg intravenously daily or posaconazole suspension 400 mg orally twice daily until neutrophil recovery, up to 28 days. Patients were followed for 12 weeks. The primary endpoint was prophylaxis failure (premature discontinuation due to infection, intolerance, adverse event, or death). Time to failure and survival were calculated by Kaplan-Meier analysis., Results: From March 2011 to May 2016, 113 patients who received at least 2 doses of prophylaxis were analyzed (58 patients randomized to micafungin and 55 to posaconazole). Prophylaxis failure occurred in 34.5% and 52.7% of patients on micafungin and posaconazole, respectively (P = 0.0118). The median number of days on prophylaxis was 16 [interquartile range (IQR) 12-20] for micafungin and 13 [IQR 6-16] for posaconazole (P = 0.01). Micafungin failures were largely due to antifungal treatment; posaconazole failures were mostly due to gastrointestinal intolerance or adverse effects. IFI incidence and survival were similar between study arms., Conclusions: Our data support micafungin as alternative antifungal prophylaxis in patients with AL and MDS., (Copyright © 2018 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

N 6 -methyladenosine (m 6 A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m 6 A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m 6 A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m 6 A coupled with ribosome profiling reveals that m 6 A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.

Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) are initiated and sustained by self-renewing malignant stem cells; thus, eradication of AML and MDS stem cells is required for cure. We identified CD99 as a cell surface protein frequently overexpressed on AML and MDS stem cells. Expression of CD99 allows for prospective separation of leukemic stem cells (LSCs) from functionally normal hematopoietic stem cells in AML, and high CD99 expression on AML blasts enriches for functional LSCs as demonstrated by limiting dilution xenotransplant studies. Monoclonal antibodies (mAbs) targeting CD99 induce the death of AML and MDS cells in a SARC family kinase-dependent manner in the absence of immune effector cells or complement, and anti-CD99 mAbs exhibit antileukemic activity in AML xenografts. These data establish CD99 as a marker of AML and MDS stem cells, as well as a promising therapeutic target in these disorders., (Copyright © 2017, American Association for the Advancement of Science.)

The myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid disorders with a highly variable disease course. Diagnostic criteria to better stratify patients with MDS continue to evolve, based on morphology, cytogenetics, and the presence of cytopenias. More accurate classification of patients will allow for better treatment guidance. Treatment encompasses supportive care, treatment of anemia, low-intensity therapy, and high-intensity therapy. This portion of the guidelines focuses on diagnostic classification, molecular abnormalities, therapeutic options, and recommended treatment approaches., (Copyright © 2017 by the National Comprehensive Cancer Network.)

Purpose of Review: Therapy-related myeloid neoplasms (tMN) are increasingly recognized and studied diseases which have traditionally been defined clinically. With advances in methods used to study the genetics of aging and myeloid disease biology, novel insights are emerging which are expected to improve our understanding of the genetics and pathogenesis of tMN., Recent Findings: Clinical outcomes in tMN and de novo MDS/AML appear to be largely determined by genetics, and data are emerging to show how DNA mutations may enhance tMN risk stratification. The discovery of skewed hematopoieses and mutations in healthy older adults suggests an alternate predisposition mechanism for the genesis of tMN. Patients with tMN do respond to standard therapy and can benefit from allogeneic transplant in a manner similar to their genetically matched de novo counterpart., Summary: De novo MDS/AML and tMN have shared genetic features, and tMN clinical outcomes may depend more on the genetics at presentation than the clinical history of an antecedent malignancy. Acquired somatic mutations in genes such as TP53 and myeloid skewing with associated mutations in cancer-free older adults may predispose such individuals to tMN under the influence of myelosuppressive therapy, and this may be a route to the development of a subset of tMN.

Myelodysplastic syndromes (MDS) are driven by complex genetic and epigenetic alterations. The MSI2 RNA-binding protein has been demonstrated to have a role in acute myeloid leukaemia and stem cell function, but its role in MDS is unknown. Here, we demonstrate that elevated MSI2 expression correlates with poor survival in MDS. Conditional deletion of Msi2 in a mouse model of MDS results in a rapid loss of MDS haematopoietic stem and progenitor cells (HSPCs) and reverses the clinical features of MDS. Inversely, inducible overexpression of MSI2 drives myeloid disease progression. The MDS HSPCs remain dependent on MSI2 expression after disease initiation. Furthermore, MSI2 expression expands and maintains a more activated (G1) MDS HSPC. Gene expression profiling of HSPCs from the MSI2 MDS mice identifies a signature that correlates with poor survival in MDS patients. Overall, we identify a role for MSI2 in MDS representing a therapeutic target in this disease.

Background: Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia., Methods: This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801., Findings: Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%])., Interpretation: Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia., Funding: Sunesis Pharmaceuticals., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Chromosomal deletions associated with human diseases, such as cancer, are common, but synteny issues complicate modeling of these deletions in mice. We use cellular reprogramming and genome engineering to functionally dissect the loss of chromosome 7q (del(7q)), a somatic cytogenetic abnormality present in myelodysplastic syndromes (MDS). We derive del(7q)- and isogenic karyotypically normal induced pluripotent stem cells (iPSCs) from hematopoietic cells of MDS patients and show that the del(7q) iPSCs recapitulate disease-associated phenotypes, including impaired hematopoietic differentiation. These disease phenotypes are rescued by spontaneous dosage correction and can be reproduced in karyotypically normal cells by engineering hemizygosity of defined chr7q segments in a 20-Mb region. We use a phenotype-rescue screen to identify candidate haploinsufficient genes that might mediate the del(7q)- hematopoietic defect. Our approach highlights the utility of human iPSCs both for functional mapping of disease-associated large-scale chromosomal deletions and for discovery of haploinsufficient genes.

Background: Myelodysplastic syndromes (MDS) are characterized by ineffective erythropoiesis with dysplastic bone marrow leading to peripheral cytopenia, risk of infection, and progression to acute myelogenous leukemia. Maitake mushroom beta-glucan, a dietary supplement, stimulates hematopoietic progenitor cell differentiation, granulocyte colony-stimulating factor production, and recovery of peripheral blood leukocytes after bone marrow injury. This phase II trial examined the effects of Maitake on innate immune function in MDS., Methods: Myelodysplastic syndromes patients with International Prognostic Scoring System Low- and Intermediate-1-risk disease received oral Maitake extract at 3 mg/kg twice daily for 12 weeks. Primary endpoints included neutrophil count and function tested as endogenous or stimulated neutrophil production of reactive oxygen species (ROS) by flow cytometry compared with age-matched healthy controls (HC). ROS activators were Escherichia coli, phorbol ester, and the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Complete blood counts, chemistry panels, iron studies, and monocyte function were evaluated., Results: Of 21 patients enrolled, 18 completed the study and were evaluable. Maitake increased endogenous (basal) neutrophil (p = 0.005) and monocyte function (p = 0.021). Pre-treatment monocyte response to E. coli was reduced in MDS patients compared with HC (p = 0.002) and increased (p = 0.0004) after treatment. fMLP-stimulated ROS production response also increased (p = 0.03). Asymptomatic eosinophilia occurred in 4 patients (p = 0.014). Other changes in albumin, hemoglobin, and total protein were not clinically relevant., Conclusions: Maitake was well tolerated. Enhanced in vitro neutrophil and monocyte function following treatment demonstrate that Maitake has beneficial immunomodulatory potential in MDS. Further study is warranted.

Vemurafenib, a RAF inhibitor, extends survival in patients with BRAF(V600)-mutant melanoma but activates extracellular signal-regulated kinase (ERK) signaling in RAS-mutant cells. In a patient with a BRAF(V600K)-mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MAP-ERK kinase (MEK) inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia, and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma, and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Antimelanoma and antileukemia responses have been maintained for nearly 20 months, as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma.

Therapy-related myelodysplastic syndromes and acute myelogenous leukemia comprise a poor-risk subset of myelodysplastic syndromes and acute myelogenous leukemia. Large-scale mutation profiling efforts in de novo myelodysplastic syndromes have identified mutations that correlate with clinical features, but such mutations have not been investigated in therapy-related myelodysplastic syndromes and acute myelogenous leukemia. Genomic DNA from 38 patient samples were subjected to high throughput polymerase chain reaction and sequenced for TP53, TET2, DNMT3A, ASXL1, IDH1, IDH2, EZH2, EED, SUZ12, RBBP4, SRSF2, U2AF35, and SF3B1. We identified somatic mutations in 16 of 38 (42%) patients. TP53 mutations were the most common lesion, detected in 8 of 38 (21%) patients, followed by TET2 in 4 of 38 (10.5%). Cases with a TP53 mutation or loss of the TP53 locus had a worse overall survival compared to those with wild-type TP53 (8.8 vs. 37.4 months; P=0.0035).

Purpose of Review: Therapy-related myelodysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) comprise an increasingly common, poor-risk disease cohort without standard treatment options. This review describes available treatments and recent advances that may influence the clinical management of t-MDS/AML., Recent Findings: Multiple retrospective studies have identified poor-risk cytogenetics, chemotherapy resistance, comorbidities from prior cancer and therapy, and persistence of the primary malignancy as factors that contribute to poor clinical outcomes of t-MDS/AML. Recent analyses show that t-MDS/AML can respond to standard therapy, but responses are less durable. In most cases, cure is made more likely with allogeneic stem cell transplantation. These findings suggest that improved survival may result from earlier, low-intensity nontransplant therapy, and aggressive pursuit of reduced-intensity transplant approaches in eligible individuals coupled with posttransplant relapse prevention strategies. Molecular characterization of t-MDS/AML may aid future clinical management decisions and identify targets for therapy., Summary: Data emerging from recent t-MDS/AML studies are shedding light on factors that contribute to disease biology and poor clinical outcomes. These findings can be used to develop strategies to improve the treatment and survival of patients with t-MDS/AML.

Translocation t(11;17) is a well-recognized variant of acute promyelocytic leukemia (APL) and has also been identified in patients with mixed-lineage leukemia (MLL) non-APL acute myeloid leukemia. Here, we describe two patients bearing translocation t(11;17) presenting with a clinical diagnosis of de novo myelodysplastic syndrome (MDS): the first with sole karyotypic abnormality 46,XY,t(11;17)(p11.2; p13) and the second where it represented one of the two karyotypic abnormalities 46,XX,del(5)(q13q33)46,XX,del(5)(q13q33),t(11;17)(q24;q23). Molecular characterization of both cases failed to identify fusion transcripts involving MLL or PLZF-RARA and no collaborating somatic mutations commonly found among MDS patients were seen in either case, suggesting the presence of an as yet unidentified oncogenic fusion protein., (Copyright © 2012 S. Karger AG, Basel.)

Vemurafenib, a selective RAF inhibitor, extends survival among patients with BRAF V600E-mutant melanoma. Vemurafenib inhibits ERK signaling in BRAF V600E-mutant cells but activates ERK signaling in BRAF wild-type cells. This paradoxical activation of ERK signaling is the mechanistic basis for the development of RAS-mutant squamous-cell skin cancers in patients treated with RAF inhibitors. We report the accelerated growth of a previously unsuspected RAS-mutant leukemia in a patient with melanoma who was receiving vemurafenib. Exposure to vemurafenib induced hyperactivation of ERK signaling and proliferation of the leukemic cell population, an effect that was reversed on drug withdrawal.

We retrospectively assessed morphologic and cytogenetic responses to 5-azacytidine and decitabine in a cohort of 42 adult therapy-related myelodysplastic syndromes (tMDS) patients treated at Memorial Sloan-Kettering Cancer Center and in 2 industry-sponsored decitabine trials (D0007 and DACO-020). The overall response rate (complete remission+marrow CR+hematologic improvement) was 38%, including 6 patients with complete remission (14%), 6 with marrow CR with or without hematologic improvement (14%), and 4 with hematologic improvement alone (10%). We conclude that DNA methyltransferase inhibitors showed activity in tMDS that is roughly comparable to that seen in de novo MDS., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Sodium salicylate is an inexpensive, readily available anti-inflammatory agent which inhibits NF-κB in in vitro models. We examined whether it was possible to safely achieve and maintain salicylate levels known to inhibit NF-κB in vitro in 11 patients with MDS or AML taking sodium salicylate. Most patients achieved the target blood salicylate level (20-30mg/dL) with acceptable toxicity, including reversible grade 1/2 elevations of hepatic transaminases (n=4) and ototoxicity (n=4). One patient had grade 3/4 elevations in AST/ALT. This study suggests that sodium salicylate may be safely combined with conventional chemotherapy regimens which are not associated with significant ototoxicity or hepatotoxicity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The treatment of monoclonal Ig deposition disease (MIDD) is controversial and not standardized. We report our experience with high dose melphalan and auto-SCT (HDM/auto-SCT) in seven patients with MIDD associated with underlying Durie-Salmon stage IB multiple myeloma, including five with light chain deposition disease, one with light and heavy chain deposition disease and one with light chain crystal deposition disease. The median age of these patients was 50 years; six of them were male subjects. A monoclonal kappa-light chain was detected by Serum Free Light Chain Assay in all seven. The patients received melphalan 140 mg/m(2) followed by auto-SCT. All patients are alive and six remain in hematologic CR with a median follow up of 23.6 months (7.9-69.8 months). Renal function has improved compared to pre-HDSM/auto-SCT in five patients--two of whom had a renal transplant and became dialysis independent--remained stable in one and worsened in one leading to hemodialysis despite hematologic CR. Our results corroborate previous experience with HDM/auto-SCT in MIDD and argue in favor of kidney transplantation in patients who achieve hematologic CR after HDM/auto-SCT. Although this approach appears effective, multi-center studies are needed to define the optimal treatment for patients with MIDD.

Purpose: Epigenetic modulation of gene expression plays an important role in cancer, including leukemia. Furthermore, histone deacetylase inhibitors may induce the reexpression or repression of genes critical for normal hematopoiesis. The purpose of this study was to evaluate the toxicity, pharmacokinetic profile, and selected pharmacodynamic properties of the histone deacetylase inhibitor depsipeptide in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML)., Experimental Design: Depsipeptide was administered to MDS or AML patients at a (solid tumor) phase I dose of 18 mg/m(2) i.v. on days 1 and 5 every 3 weeks. Toxicities and clinical activity were monitored and pharmacokinetic and pharmacodynamic studies were done., Results: Twelve patients (nine with AML, three with MDS) received one to five cycles of depsipeptide. The most common grade 3/4 toxicities were febrile neutropenia/infection (five patients), neutropenia/thrombocytopenia (nine patients), nausea (nine patients), and asymptomatic hypophosphatemia (three patients). No clinically significant cardiac toxicity was observed. The best response of 11 assessed patients was one complete remission in a patient with AML, stable disease in six patients, and progression of disease in four patients. Exploratory laboratory studies showed modest but rapid increases in apoptosis and changes in myeloid maturation marker expression. Histone H3 and H4 acetylation levels were evaluated in five patients; no consistent changes were observed., Conclusion: Depsipeptide therapy can be administered with acceptable short-term toxicity. However, gastrointestinal symptoms and fatigue seem to be treatment-limiting after multiple cycles. Depsipeptide monotherapy has limited clinical activity in unselected AML/MDS patients.

Lenalidomide is approved for red blood cell (RBC) transfusion-dependent anemia due to low or intermediate-1 (int-1) risk myelodysplastic syndromes (MDSs) associated with a chromosome 5q deletion with or without additional cytogenetic abnormalities. We report results of a multicenter, phase 2 trial evaluating lenalidomide therapy for transfusion-dependent patients with low- or int-1-risk MDS without deletion 5q. Eligible patients had 50,000/mm(3) or more platelets and required 2 U or more RBCs within the previous 8 weeks; 214 patients received 10 mg oral lenalidomide daily or 10 mg on days 1 to 21 of a 28-day cycle. The most common grade 3/4 adverse events were neutropenia (30%) and thrombocytopenia (25%). Using an intention-to-treat analysis, 56 (26%) patients achieved transfusion independence (TI) after a median of 4.8 weeks of treatment with a median duration of TI of 41.0 weeks. In patients who achieved TI, the median rise in hemoglobin was 32 g/L (3.2 g/dL; range, 10-98 g/L [1.0-9.8 g/dL]) from baseline. A 50% or greater reduction in transfusion requirement occurred in 37 additional patients, yielding a 43% overall rate of hematologic improvement (TI response + ||>or= 50% reduction in transfusion requirement). Lenalidomide has clinically meaningful activity in transfusion-dependent patients with low- or int-1-risk MDS who lack the deletion 5q karyotypic abnormality.

Among the drug combinations designed for the initial treatment of multiple myeloma, none has been unequivocally shown to be superior. However, a regimen leading to a high response rate and a low incidence of adverse events is highly desirable. We report the results of a phase II clinical trial involving 45 patients with Durie-Salmon stage II and III multiple myeloma. Doxorubicin and dexamethasone were given for 2 or 3 months followed by thalidomide and dexamethasone for 2 months (AD-TD regimen) with prophylactic antibiotics and daily aspirin (81 mg/d). Among the 42 patients whose response could be assessed, 38 responded to therapy (90.5%). The intent-to-treat response rate was 84.4% with seven complete responses (CR 15.5%), nine near complete responses (nCR 20.0%), and 22 partial responses (PR 48.9%). Two patients had stable disease (4.4%), and two progression of disease (4.4%). Normalization of the free light chain ratio after one or two cycles of treatment was highly predictive of achievement of CR or nCR. Patients tolerated the treatment well although five patients developed thromboembolic complications (11%). AD-TD administered with low dose aspirin for deep vein thrombosis prophylaxis was well tolerated and yielded a high response rate with minimal treatment-related morbidity.

Melanoma-inhibiting activity (MIA) is a 107 amino-acid protein secreted from melanoma cells and frequently detectable at high concentration in the serum of patients with advanced melanoma. Early studies suggested that MIA may be a useful serum tumor-marker for detection of recurrent or progressive disease. We evaluated the sensitivity of serum MIA levels in predicting the risk of relapse in patients with American Joint Committee on Cancer (AJCC) Stage II, III, and IV melanoma. MIA was measured by ELISA in serum from 39 patients with AJCC Stage II, III and IV disease at a single time-point 1 month to 5 years after they were rendered free of disease. Twenty-three of the 39 patients recurred, with a median follow-up of 4.5 months. Only four of the 23 patients who recurred had shown elevated MIA values (17% sensitivity). Of the 16 patients who remain free of disease (median follow-up 3.5 years, range 11 months to 6.3 years), one patient had an elevated MIA. There was no significant difference in the proportion of patients with elevated serum MIA between the patients who recurred and those who remained free of disease. In this series, serum MIA was not a sensitive marker for relapse in patients who were clinically free of disease after treatment.

We conducted a randomized trial in HLA*A0201+ patientswith American Joint Committee on Cancer stage III or IV melanoma immunized with tyrosinase 368-376(370D) peptide and gp100 209-217(210M) peptide to compare the potency of three different adjuvants. Patients received 3 monthly immunizations with 500 microg of each peptide either with incomplete Freund's adjuvant (IFA), QS-21, or granulocyte macrophage colony-stimulating factor (GM-CSF). The primary end point was induction of IFN-gamma release by CD8+ T cells against tyrosinase and gp100 peptides measured by enzyme-linked immunospot assays without in vitro prestimulation measured pretreatment, 2 and 8 weeks after the third vaccination. Four of 9 and 4 of 8 patients immunized using QS-21 and GM-CSF, respectively, developed increased frequencies of CD8+ T cells against tyrosinase 370D peptide compared with 0 of 9 patients immunized using IFA (P = 0.045). T-cell responses against a gp100-related peptide showed similar results, but their relevance to T-cell reactivity against native gp100 209-217 is uncertain. These results show that: (a) QS-21 and GM-CSF are superior to IFA as immunological adjuvants for vaccination against tyrosinase 370D peptide; and (b) with appropriate adjuvants, increased frequencies of peptide-specific T cells after vaccination can be detected by enzyme-linked immunospot without prolonged prestimulation in vitro.

The main use of systemic chemotherapy in metastatic melanoma remains palliative. Dacarbazine (dimethyl-1-triazeno imidazole-4-carboxamide [DTIC]) is the standard chemotherapy agent for advanced disease. The combination chemotherapy and biochemotherapy regimens have achieved higher response rates, but have not led to durable remission or improved survival. The field of systemic therapy remains in need of a more effective and less toxic treatment strategy.

Treatment of metastatic melanoma with biochemotherapy results in the rapid onset of anemia, requiring blood transfusion in 9 of 13 (69%) patients. Prophylactic use of weekly subcutaneous recombinant epoetin alfa eliminated the need for transfusion in all but 1 of 21 (5%) patients.