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PDF file 338K, Phospho-flow data

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PDF file 7489K, CT scans

PDF file 348K, Digital PCR validation graphs

The post-transplant scoring system (PTSS), developed by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, is based on three independent post-transplant risk factors: grade of acute graft-versus-host disease, lack of platelet recovery before day 100, and relapse before day 100; discriminating low- (0), intermediate- (1–3), and high-risk (4–8) patients. We investigated the prognostic value of the PTSS in a cohort of patients with MDS who underwent myeloablative CD34-selected TCD transplants. From 2008 to 2018, 109 patients underwent a first TCD-HCT for MDS at our center. We used Cox proportional hazards models and different landmark analyses to evaluate the association of categorized PTSS score risk groups with overall survival (OS). Patients with an intermediate/ high risk PTSS score had decreased OS at day 180 (univariate HR 3.25 [95% CI 1.60, 6.60], p = 0.001) and at day 365 (univariate HR 5.42 [95% CI 2.21, 13.3], p

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.

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7–22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6–33, P, Patients with solid cancers have high rates of clonal haematopoiesis associated with increased risk of secondary leukemias. Here, by using peripheral blood sequencing data from patients with solid non-hematologic cancer, the authors profile the landscape of mosaic chromosomal alterations and gene mutations, defining patients at high risk of leukemia progression.

Summary 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.

Despite a detailed understanding of the genes mutated in myelodysplastic syndromes (MDS), diagnostic and treatment decisions for patients with MDS rely primarily on clinical and cytogenetic variables as considered by the Revised International Prognostic Scoring System (IPSS-R). Here we describe the recently developed Molecular IPSS (IPSS-M), a clinico-genomic risk stratification system that considers clinical, cytogenetic and genetic parameters; the implementation of a web portal to facilitate its adoption, a strategy to handle missing variables, and the worldwide utilization of the web calculator as a clinical support tool. The IPSS-M was trained on 2,957 clinically annotated diagnostic MDS samples profiled for mutations in 156 driver genes. To maximize the clinical applicability of the IPSS-M and account for missing genetic data (i.e genes missing from a sequencing panel), we implemented a strategy to calculate a risk score under three scenarios: best, worst and average. Last, we developed an online calculator as a standalone single-page web application using VueJs, and D3Js for the interactive visualizations, deployed through a CI/CD pipeline on AWS, where collection of anonymous usage analytics allows to track adoption and usability of the new proposed model. The model incorporates clinical, morphological, genetic variables informed by cytogenetics and constructed from the presence of oncogenic mutations in 31 genes. It delivers a unique risk score for each individual patient, as well as an assignment to one of six IPSS-M risk strata. Compared to the IPSS-R the IPSS-M re-stratified 46% of MDS patients. The model was validated in an external dataset of 754 MDS patients. We released an open-access IPSS-M web calculator available at https://mds-risk-model.com. By specifying the patient clinical and molecular profiles, the tool returns the patient-specific IPSS-M risk score and category, and the probability estimates over time for three clinical endpoints, i.e. leukemia free survival (LFS), overall survival, and incidence of leukemic transformation. Since its launch in June 2022, the calculator has been used by >6000 users in >75 countries, reaching a daily average of 100 users per day. Risks have been calculated for >45,000 patient profiles. 99.28% of the sessions initiated reach an IPSS-M score, suggesting that the calculator is intuitive and easy to use. We trained and validated the IPSS-M on 3,711 patients, a patient tailored risk stratification tool for patients with MDS that considers clinical, morphological and genetic variables inclusive of cytogenetics and mutations in one of 31 genes. The development of a web based tool was instrumental to the global dissemination of the model, enabling non-expert users to leverage the power of molecular biomarkers in risk stratification for patients with MDS. Citation Format: Elsa Bernard, Juan E. Arango Ossa, Heinz Tuechler, Peter L. Greenberg, Robert P. Hasserjian, Yasuhito Nannya, Sean M. Devlin, Maria Creignou, Philippe Pinel, Lily Monier, Juan S. Medina-Martinez, Dylan Domenico, Martin Jädersten, Ulrich Germing, Guillermo Sanz, Arjan A. van de Loosdrecht, Olivier Kosmider, Matilde Y. Follo, Felicitas Thol, Lurdes Zamora, Ronald F. Pinheiro, Andrea Pellagatti, Detlef Haase, Pierre Fenaux, Monika Belickova, Michael R. Savona, Virginia M. Klimek, Fabio P. Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Solé, Uwe Platzbecker, Michael Heuser, Peter Valent, Kazuma Ohyashiki, Carlo Finelli, Maria Teresa Voso, Lee-Yung Shih, Michaela Fontenay, Joop H. Jansen, José Cervera, Norbert Gattermann, Benjamin L. Ebert, Rafael Bejar, Luca Malcovati, Mario Cazzola, Seishi Ogawa, Eva Hellström-Lindberg, Elli Papaemmanuil. Implementation and adoption of a web tool to support precision diagnostic and treatment decisions for patient with myelodysplastic syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6168.

Background Patients with congenital haptoglobin deficiency can develop anti-haptoglobin antibodies after exposure to blood products, and they can suffer from life-threatening anaphylactic transfusion reactions. Here, we present a case of a 57-year-old Chinese male with myelodysplastic syndrome who manifested an anaphylactic transfusion reaction during the transfusion of platelets. The only abnormality detected during his reaction laboratory workup was an undetectable haptoglobin level in the absence of evidence of hemolysis. Study design and methods Surface plasmon resonance (SPR) was explored as a method to be able to detect the presence of anti-haptoglobin antibodies in serum. First, haptoglobin was immobilized to the surface of an SPR sensor chip. The patient's serum sample was injected, and the binding response was monitored in real time. Serum samples from five healthy volunteers were used as negative controls. Binding specificity was assessed in competition experiments using soluble haptoglobin. Anti-IgG, -IgA, -IgM, -IgD and -IgE antibodies were used to identify the antibody isotype. Results An IgG anti-haptoglobin antibody was detected in the patient's serum with SPR. Conclusion SPR provided a rapid, readily available method for the detection of an IgG anti-haptoglobin antibody in an anhaptoglobinemic individual. This confirmed the underlying etiology of the anaphylactic nonhemolytic transfusion reaction and justified the necessity of stringently washed cellular products for all future transfusions and strong caution for future use of plasma-containing products.

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.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.

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.

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.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. 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. Clinical sequencing across a large prospective cohort of patients with myelodysplasic syndrome uncovers distinct associations between the mono- and biallelic states of TP53 and clinical presentation

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. Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.

Summary 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.

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 (&gt, 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.

N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-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 m6A coupled with ribosome profiling reveals that m6A 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.

Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rγnull background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34+ cells (n = 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n = 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n = 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34+ cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34+ cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n = 4 patients, n = 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders.

Background: Mixed phenotype acute leukemia is a rare disease characterized by an expanded blast population exhibiting multiple lineage features. It is a diagnosis of exclusion, and we and others have observed that AML-MRC or therapy-related AML cases may also exhibit similar features. We therefore sought to determine whether multi-lineage expression is present in de-novo and therapy-related MDS and whether it has an impact on clinical outcomes. Methods: We reviewed pathology, flow cytometry, cytogenetic, and molecular reports from patients seen at Memorial Sloan Kettering Cancer Center between 1996 and 2020 and identified 472 patients diagnosed with MDS using a combination of custom natural language processing tools and manual review. Cox proportional hazards modeling was performed to assess the contribution of patient characteristics, pathology, flow cytometric, cytogenetic, and molecular characteristics to overall survival (OS). Fisher's exact testing was used to assess the association of individual features. Results: We found that an abnormal myeloid lineage signature was associated with poorer OS after adjusting for age, cytogenetics, and molecular features (HR=2.3, p Conclusion: Routine flow cytometric and molecular assessment of diagnostic bone marrows can provide added prognostic value in MDS. Identification of an abnormal myeloid lineage is associated with higher risk disease, while identification of abnormal plasma cell features is associated with lower risk disease. SRSF2 mutation is also associated with abnormal plasma cell features, but does not contribute independently to OS. Abnormal T-cell features may also provide prognostic value, although assessment in a larger cohort will be necessary. We confirm previous findings indicating that TP53 mutation is associated with higher risk disease while SF3B1 mutation is associated with better outcomes characteristic of MDS-RARS. In addition, our data suggests that IDH1 and EZH2 are associated with poorer outcomes and that IDH2 is associated with lower risk disease. Figure 1 Disclosures Tallman: Bioline rx: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Abbvie: Research Funding; Cellerant: Research Funding; Orsenix: Research Funding; ADC Therapeutics: Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Research Funding; Rafael: Research Funding; Oncolyze: Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees. Levine:Morphosys: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Lilly: Consultancy, Honoraria; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Gilead: Honoraria; Novartis: Consultancy; Amgen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Xiao:Stemline Therapeutics: Research Funding. Glass:Gerson Lehman Group: Consultancy.

Background Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. The relationship between acquired gene mutations and mCAs in CH and their joint roles in leukemia development have not been systematically investigated. Methods We developed a method to reliably map mCAs at low cell fractions from deep targeted sequencing data. We applied this method in a cohort of 32,442 solid tumor patients who have undergone prospective clinical sequencing (MSK-IMPACT). We characterized gene mutations in our patient cohort using an established variant calling procedure from our previous studies. Results We jointly characterized 383 mCA events (median aberrant cell fraction 32%, range 10%-90%) and 14,789 mutations across 457 genes. mCA was significantly associated with age (OR=1.8, P20% VAF, compared to 1% of the general cohort. We identify co-mutational patterns characteristic of diverse mechanisms of clonal selection. We observe that mutations in DNMT3A, TET2, JAK2, MPL, EZH2, TP53 and ATM form recurrent double-hits with deletions or CNLOHs, resulting in either oncogene mutant dosage adjustment or inactivation of tumor suppressors. Notably, certain mCA events were highly directed events acting on previously acquired gene mutations in the corresponding loci. Of six events of 7qCNLOH, all six co-localized with an EZH2 (7q36.1) mutation (q During patient follow-up, the 3-year cumulative incidence of leukemias was significantly higher in patients with composite CH genotypes (14.6%, CI: 7-22%) as compared to patients with either mCA, gene mutation alone or no CH, of which all had a 3-year cumulative incidence of Conclusions Our joint characterization of gene mutations and mCAs in a large prospective sequencing cohort reveals a previously unrecognized layer of complexity in the evolutionary dynamics of clonal hematopoiesis that converges towards characteristic genotypes associated with distinct leukemia subtypes. This puts mCAs in the context of the continuous evolutionary process of oncogenesis that can often span years and sheds new lights on its patterns of acquisition and progression. We demonstrate that the integration of chromosomal aberrations provides additional resolution to risk stratification as well as interpretation of clinical phenotypes and that mCAs should be screened in conjunction with gene mutations to improve existing CH surveillance programs in cancer patients. Disclosures Bolton: GRAIL: Research Funding. Medina:Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Mantha:MJH Associates: Honoraria; Physicians Education Resource: Honoraria. Solit:Pfizer: Honoraria; Loxo Oncology: Honoraria; Lilly Oncology: Honoraria; Illumina: Honoraria; Vivideon Therapeutics: Honoraria. Diaz:Neophore: Consultancy, Current equity holder in private company; Merck: Consultancy; Johns Hopkins University: Patents & Royalties; Jounce Therapeutics: Current equity holder in private company; Thrive Earlier Detection: Current equity holder in private company; Personal Genome Diagnostics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Berger:Illumina: Research Funding; Roche: Consultancy; Grail: Research Funding. Levine:Lilly: Consultancy, Honoraria; Janssen: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Prelude Therapeutics: Research Funding; Gilead: Honoraria; Amgen: Honoraria; Morphosys: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Zehir:Memorial Sloan Kettering Cancer Center: Current Employment; Illumina: Honoraria. Papaemmanuil:Celgene: Consultancy, Honoraria, Research Funding; Prime Oncology: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Illumina: Consultancy, Honoraria; Kyowa Hakko Kirin: Consultancy, Honoraria; Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; MSKCC: Patents & Royalties.

Clonal hematopoiesis (CH) is frequent in cancer patients and associated with increased risk of therapy related myeloid neoplasms (tMN). To define the relationship between CH, oncologic therapy, and tMN progression, we studied 24,439 cancer patients. We show that previously treated patients have increased rates of CH, with enrichment of mutations in DNA Damage Response (DDR) genes (TP53, PPM1D, CHEK2). Exposure to radiation, platinum and topoisomerase II inhibitors have the strongest association with CH with evidence of dose-dependence and gene-treatment interactions. We validate these associations in serial sampling from 525 patients and show that exposure to cytotoxic and radiation therapy imparts a selective advantage specifically in hematopoietic cells with DDR mutations. In patients who progressed to tMN, the clone at CH demarcated the dominant clone at tMN diagnosis. CH mutational features predict risk of therapy-related myeloid neoplasm in solid tumor patients with clinical implications for early detection and treatment decisions.

In the version of this article initially published, the affiliation provided for author Matteo Giovanni Della Porta (37Cancer Center, Humanitas Research Hospital & Humanitas University, Milan, Italy) was incorrect, and a second affiliation was missing. The correct affiliations are as follows (with subsequent affiliations renumbered accordingly): 37Humanitas Clinical and Research Center–IRCCS, Humanitas Cancer Center, Milan, Italy. 38Department of Biomedical Sciences, Humanitas University, Milan, Italy. The errors have been corrected in the HTML and PDF versions of the article.

ObjectivesEvidence-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.MethodsPatients 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.ResultsForty-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.ConclusionsPatients 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.

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.

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.

Recent studies among healthy individuals show evidence of somatic mutations in leukemia-associated genes, referred to as clonal hematopoiesis (CH). To determine the relationship between CH and oncologic therapy we collected sequential blood samples from 525 cancer patients (median sampling interval time = 23 months, range: 6-53 months) of whom 61% received cytotoxic therapy or external beam radiation therapy and 39% received either targeted/immunotherapy or were untreated. Samples were sequenced using deep targeted capture-based platforms. To determine whether CH mutational features were associated with tMN risk, we performed Cox proportional hazards regression on 9,549 cancer patients exposed to oncologic therapy of whom 75 cases developed tMN (median time to transformation=26 months). To further compare the genetic and clonal relationships between tMN and the proceeding CH, we analyzed 35 cases for which paired samples were available. We compared the growth rate of the variant allele fraction (VAF) of CH clones across treatment modalities and in untreated patients. A significant increase in the growth rate of CH mutations was seen in DDR genes among those receiving cytotoxic (p=0.03) or radiation therapy (p=0.02) during the follow-up period compared to patients who did not receive therapy. Similar growth rates among treated and untreated patients were seen for non-DDR CH genes such as DNMT3A. Increasing cumulative exposure to cytotoxic therapy (p=0.01) and external beam radiation therapy (2x10-8) resulted in higher growth rates for DDR CH mutations. Among 34 subjects with at least two CH mutations in which one mutation was in a DDR gene and one in a non-DDR gene, we studied competing clonal dynamics for multiple gene mutations within the same patient. The risk of tMN was positively associated with CH in a known myeloid neoplasm driver mutation (HR=6.9, p Citation Format: Kelly L. Bolton, Ryan N. Ptashkin, Teng Gao, Lior Braunstein, Sean M. Devlin, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine Coombs, Nicole M. Caltabellotta, Mike Walsh, Ken Offit, Zsofia Stadler, Choonsik Lee, Paul Pharoah, Konrad H. Stopsack, Barbara Spitzer, Simon Mantha, James Fagin, Laura Boucai, Christopher J. Gibson, Benjamin Ebert, Andrew L. Young, Todd Druley, Koichi Takahashi, Nancy Gillis, Markus Ball, Eric Padron, David Hyman, Jose Baselga, Larry Norton, Stuart Gardos, Virginia Klimek, Howard Scher, Dean Bajorin, Eder Paraiso, Ryma Benayed, Maria Arcilla, Marc Ladanyi, David Solit, Michael Berger, Martin Tallman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Luis Diaz, Ross Levine, Lindsay Morton, Ahmet Zehir, Elli Papaemmanuil. Oncologic therapy shapes the fitness landscape of clonal hematopoiesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5703.

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.

Measurable residual disease is associated with inferior outcomes in patients with acute myeloid leukemia (AML). Measurable residual disease monitoring enhances risk stratification and may guide therapeutic intervention. The European LeukemiaNet working party recently came to a consensus recommendation incorporating leukemia associated immunophenotype-based different from normal approach by multi-color flow cytometry for measurable residual disease evaluation. However, the analytical approach is highly expertise-dependent and difficult to standardize. Here we demonstrate that loss of plasmacytoid dendritic cell differentiation after 7+3 induction in AML is highly specific for measurable residual disease positivity (specificity 97.4%) in a uniformly treated patient cohort. Moreover, loss of plasmacytoid dendritic cell differentiation as determined by a blast-to-plasmacytoid dendritic cell ratio >10 was strongly associated with inferior overall and relapse-free survival (RFS) [Hazard ratio 2.79, 95% confidence interval (95%CI): 0.98-7.97; P=0.077) and 3.83 (95%CI: 1.51-9.74; P=0.007), respectively), which is similar in magnitude to measurable residual disease positivity. Importantly, measurable residual disease positive patients who reconstituted plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio

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.

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., Several studies have recently demonstrated the role of the MSI2 RNA binding protein in normal and malignant haematopoietc stem cells. In this study, the authors show that MSI2 is required for maintaining myelodysplastic syndrome stem cells in mice and that MSI2 expression predicts poor prognosis in patients affected by this disease.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). Donor T cells are critical for the graft-versus-tumor effect but carry the risk of graft-versus-host disease (GVHD). CD34 selection with immunomagnetic beads has been an effective method of depleting alloreactive donor T cells from the peripheral blood graft and has been shown to result in significant reduction in acute and chronic GVHD. We analyzed the outcomes of 102 adults (median age, 57.6 years) with advanced MDS who received a CD34-selected allo-HSCT between January 1997 and April 2012 at Memorial Sloan Kettering Cancer Center. The cumulative incidences of grades II to IV acute GVHD were 9.8% at day 100 (95% confidence interval [CI], 5.0% to 16.5%) and 15.7% at day 180 (95% CI, 9.4% to 23.4%). The cumulative incidence of chronic GVHD at 1 year was 3.9% (95% CI, 1.3% to 9.0%). The cumulative incidences of relapse were 11.8% at 1 year (95% CI, 6.4% to 18.9%) and 15.7% at 2 years (95% CI, 9.4% to 23.4%). Forty-eight patients were alive with a median follow-up of 71.7 months. Rates of overall survival (OS) were 56.9% at 2 years (95% CI, 48% to 67.3%) and 49.3% at 5 years (95% CI, 40.4% to 60.2%). Rates of relapse-free survival (RFS) were 52.0% at 2 years (95% CI, 41.9% to 61.1%) and 47.6% at 5 years (95% CI, 37.5% to 56.9%). The cumulative incidences of nonrelapse mortality were 7.8% at day 100 (95% CI, 3.7% to 14.1%), 22.5% at 1 year (95% CI, 15.0% to 31.1%), and 33.4% at 5 years (95% CI, 24.2% to 42.6%) post-transplant. The incidence of chronic GVHD/RFS overlapped with RFS. These findings demonstrate that ex vivo T cell–depleted allo-HSCT by CD34 selection offers long-term OS and RFS with low incidences of acute and chronic GVHD and without an increased risk of relapse.

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

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.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care.

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Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor–encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function(1–6). Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function(7–11), but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.

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 Escherichiacoli, 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.