Treatment Of Myelodysplastic Syndromes Research Articles

The Impact of BMI on Next Generation Sequencing Panels for Patients with Myelodysplastic Syndromes

Introduction:The usage of cytogenetics and next generation sequencing (NGS) has become more prominent in recent years for risk stratification of patients (pts) with myelodysplastic syndromes (MDS). Management of these patients is a multi-faceted endeavor which requires understanding of how MDS genetics interacts with a patient's lifestyle and co-morbidities. Obesity rates in the United States continue to rise; the current rate in Virginia is 30% (Centers for Disease Control and Prevention, CDC). This study analyzed whether body mass index (BMI) at diagnosis was correlated with the number or type of MDS mutations seen on initial NGS and whether obesity influenced outcomes stratified by individual mutations.Methods:Adult pts diagnosed with MDS at the University of Virginia from August 2012 to December 2019 who had cytogenetics and NGS panels done prior to initiation of MDS therapy were included. Any patient without the aforementioned initial diagnostic information was excluded. MDS disease characteristics, treatment type, comorbidities, and patient demographics were assessed including weight, height, and BMI (categories defined per CDC) at time of diagnosis. The primary aim of this analysis was to evaluate the association of BMI with the number and type of mutations on NGS panel at diagnosis. Wilcoxon-Mann-Whitney tests were used to explore the difference in BMI by presence of 13 mutations of interest: ASXL1, DNMT3A, FLT3, IDH1, IDH2, NPM1, NRAS, SETBP1, SF3B1, SRSF2, TET2, TP53, and U2AF1. The Spearman correlation coefficient was used to assess the relationship between BMI and total number of mutations. Kaplan-Meier estimates, log rank tests, and Cox proportional hazard models were used for time-to-event analyses. All analyses were performed using SAS 9.2 (SAS Institute, Cary, NC).Results:143 MDS pts met inclusion criteria with a median age at diagnosis of 69 (range 39-87) and 60.7% (n=88) were male. The median weight was 81.3 kg and the median BMI at diagnosis was 27.7 kg (range 16.04-52.66). There were 29 pts in the normal BMI class (20%), 4 pts in the underweight class (3%), 38 pts in the obese class (26%), and 72 pts in the overweight class (50%). By IPPS-R risk scoring system, 64 pts were low or very low risk (44%), 39 pts intermediate risk (27%), and 41 pts high or very high risk (29%).There was no difference in the median number of mutations across BMI groups with a spearman correlation coefficient of 0.05 (Figure 1). However, the median BMI was significantly lower in patients with the NPM1 mutation versus those without (p=0.04), diagnosed prior to the WHO re-classification of these patients to acute myeloid leukemia (AML). Presence of the NPM1 mutation in MDS is also associated with worse PFS and an increased hazard ratio of 9.4 (p=0.0003), likely behaving similarly to AML. In comparison, presence of the SF3B1 mutation was found to be protective wherein patients who lacked the mutation had an increased hazard ratio of 6.0 (p=0.0133). BMI alone did not predict for progression free survival (PFS) or overall survival (OS); this was also true regardless of patient residency based on zip code. However, obese patients exhibiting the NPM1 and SF3B1 had better PFS (Figure 2). Moreover, the landmark analysis indicates among patients who are alive and free of progression at 20 months after MDS diagnosis, overweight patients exhibit better PFS than normal/underweight or obese patients (p=0.0192) (Figure 3).Conclusion:While BMI in pts with MDS does not appear to predict the gross number of NGS mutations, NPM1 mutations occurred more often in pts with low BMIs. Overweight pts who did not progress by 20 months have a better PFS. Prospective and larger retrospective studies are needed to expand on the findings that BMI may have an unexplored potential in stratifying pts with newly diagnosed MDS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

RVU120 (SEL120) CDK8/19 Inhibitor - a Drug Candidate for the Treatment of MDS Can Induce Erythroid Differentiation

Background: Myelodysplastic syndromes (MDS) are a group of malignant blood disorders characterized by ineffective hematopoiesis and cytopenias and frequent evolution to acute myeloid leukemia (AML). MDS results from the expansion of genetically and epigenetically changed clones with impaired differentiation and maturation. Primary clinical goals in MDS are to achieve remissions, alleviate symptoms associated with cytopenias, and minimize the transfusion burden. While supportive red blood cell transfusions, erythropoiesis-stimulating agents and novel targeted agents may lead to clinical improvement, an allogeneic bone marrow transplant (BMT) remains the only potential curative option for patients with MDS. RVU120 (SEL120) is a specific, selective inhibitor of CDK8 and its paralog CDK19. A first-in-human Phase Ib clinical trial with RVU120 in patients with AML or high risk (HR)-MDS is currently ongoing. Preclinical studies indicated the strong antileukemic potential of RVU120 that was often associated with the multilineage commitment of CD34+ AML cells. Moreover, RVU120 could improve proliferation and induce erythroid differentiation of CD34+ cells derived from Diamond-Blackfan anemia (DBA) patients.Aims: Primary aim was to evaluate the erythroid differentiation potential of RVU120 in primary MDS and transformed cord blood CD34+ blood cells characterized with an early block in erythroid differentiation.Methods: Efficacy and mechanism of action of RVU120 and other CDK8 inhibitors were investigated in cord blood (CB) cells transduced with TLS-ERG, a fusion gene generated from t(16;21)(p11;q22). Transformed cells displayed an increased capacity for self-renewal, proliferation, and altered erythroid differentiation. Efficacy was further tested in CD34+ cells isolated from BM of MDS patients and established MDS cell lines. Cells were treated with RVU120 and global transcriptional changes and chromatin status were analyzed by RNA-seq, ATAC-seq, and ChIP-seq. Cell cycle, proliferation, and lineage-specific markers were studied by flow cytometry in liquid and semi-solid methylcellulose-based media.Results: RVU120 treatment leads to transcriptional reprogramming of transformed CD34+ CB cells. The most profound changes included decreased CDK8 occupancy followed by increased STAT5 and RNA Polymerase II loading at transcription start site and gene bodies. RVU120 treatment transcriptionally represses multiple genes associated with hematopoietic and leukemia stem cells such as CD34, FLI1, ENG and RGS18 and importantly induce the expression of genes involved in erythroid commitment, including regulators of erythroid/megakaryocytic fate, such as RGS18, KLF1, FLI1, INHBA, GATA1/2 and hemoglobin genes. Detailed analysis of transformed CB and MDS CD34+ cells by flow cytometry at early and late time points reflected sequential changes in the expression of lineage-specific surface markers, leading to erythroid differentiation.Conclusions: Presented results indicate strong erythroid differentiation potential of RVU120 in CD34+ cells that acquired genetic abnormalities leading to arrested erythroid commitment, characteristics of many MDS and AML subtypes. Observed differentiation phenotype strikingly resembles effects of RVU120 in DBA cells caused by disruption of genes encoding ribosomal proteins. Detailed transcriptomic profiling strongly links the differentiation with enrichment of genes representing regulators of erythroid commitment and hemoglobin metabolism. Further studies are warranted to investigate the efficacy of RVU120 in chronic anemias associated with bone marrow failures in AML and MDS patients. [Display omitted] DisclosuresPakulska: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Obacz: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Goller: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Combik: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Keska: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mazan: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Juszczynski: Ryvu Therapeutics: Current equity holder in publicly-traded company. Brzozka: Ardigen: Current Employment, Membership on an entity's Board of Directors or advisory committees; Selvita SA: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Dziedzic: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Angelosanto: Ryvu Therapeutics: Current Employment. Shamsili: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rzymski: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Novel Prediction Models for Myelodysplastic Syndromes Using Machine Learning

Novel Prediction Models for Myelodysplastic Syndromes Using Machine Learning

Allogeneic Hematopoietic Cell Transplantation Outcomes of Patients with R/R AML or Higher-Risk MDS Treated with the TIM-3 Inhibitor MBG453 (Sabatolimab) and Hypomethylating Agents

Allogeneic Hematopoietic Cell Transplantation Outcomes of Patients with R/R AML or Higher-Risk MDS Treated with the TIM-3 Inhibitor MBG453 (Sabatolimab) and Hypomethylating Agents

Oral Decitabine/Cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: A Longer-Term Follow-up of from the Ascertain Study

▪Background/Introduction:Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%; 90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study.Methods:We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety.Results:Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR; CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant.Conclusions:Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC; in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population.

Selective Targeting of Splicing Factor Mutant Hematopoietic Stem and Progenitor Cells Via STAT3 Inhibition

Myelodysplastic syndrome (MDS) is a bone marrow failure disorder driven by dysfunction of hematopoietic stem and progenitor cells (HSPCs). Patient sequencing studies over the last decade have revealed that mutations in splicing machinery predominate in MDS, thus selective targeting of these cells is therapeutically attractive. STAT3 inhibition has been explored previously as a means to eradicate HSPCs in MDS. While efficacy was demonstrated in a subset of samples, the underlying mechanism for this selectivity remains unknown. We examined RNAseq of MDS CD34+ HSPCs with splicing factor mutations versus wildtype, finding alternative splicing and differential expression of STAT3 pathway components. Functionally, we explored if STAT3 signaling represents a novel vulnerability in SF3B1 mutant HSPCs using a multi-model approach of in vivo zebrafish and mouse systems, and in vitro assays of CRISPR-engineered human leukemia K562 cells and primary MDS samples. Utilizing the small molecule STAT3 inhibitor STATTIC, we found that human cells carrying MDS-associated SF3B1 point mutations had heightened sensitivity to STAT3 inhibition compared to wildtype controls. To evaluate the activity of STAT3 inhibition in vivo, we utilized an Mx1-cre conditional knock-in mouse model of mutant SF3B1 (Sf3b1+/K700E). We demonstrated that in vivo STATTIC treatment selectively depleted Sf3b1 mutant cells over wildtype in vivo. RNAseq of sf3b1 homozygous mutantzebrafish cells revealed conserved dysregulation of STAT3 pathway splicing and target expression. Diminishing Stat3 (via morpholino knockdown, stable mutants, or STATTIC treatment) decreased HSPCs in sf3b1 heterozygotes but not wildtype embryos, demonstrating synthetic lethality between Sf3b1 and Stat3. Our data indicate that SF3B1 heterozygosity, regardless of the type of mutation, confers a heightened sensitivity to STAT3 inhibition in zebrafish, mouse, and human HSPCs. Critically, our data indicate that SF3B1-mutant cells can be selectively killed in vivo while sparing wildtype cells. We sought to rescue HSPCs in sf3b1 homozygous mutant zebrafish, however overexpression of ligands Osm and Il6 or wildtype Stat3 was insufficient. Instead, overexpression of constitutively-active Stat3 partially restored HSPCs, indicating that functional Stat3 signaling downstream of Sf3b1 is critical for HSPC formation. To investigate the specificity of the synthetic lethality for SF3B1, we assessed the STAT3 synthetic lethal interaction with other mutated splicing factors in MDS. Similar to SF3B1, we demonstrated STAT3 synthetic lethality with U2AF1 and SRSF2 heterozygosity in zebrafish and human cells. RNA-sequencing analysis of STATTIC-treated K562 cells revealed an exacerbation of splicing alterations upon STAT3 inhibition that was more pronounced in SF3B1+/K666N cells compared to wildtype. Even more strikingly, we demonstrated that constitutive activation of STAT3 could partially reverse defective splicing in zebrafish sf3b1 homozygous mutant cells. Mechanistically, these data strongly support coordinated splicing dysfunction as the underlying cause for STAT3-SF3B1 synthetic lethality. Together, we demonstrated a conserved and selective synthetic lethal interaction between STAT3 function and splicing factor defects that represents a novel liability for mutant HSPCs with important implications for MDS treatment. DisclosuresShastri: Guidepoint: Consultancy; Kymera Therapeutics: Research Funding; Onclive: Honoraria; GLC: Consultancy. Verma: Curis: Research Funding; BMS: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Eli Lilly: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; GSK: Research Funding; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company.

Relapse of Myelodysplastic Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation as Blood Bank Sees It: a Case Report

Abstract Introduction/Objective Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for patients with myelodysplastic syndrome (MDS). Nonetheless, a large proportion of patients with MDS experience disease relapse. Declining donor chimerism and detection of recurrent gene mutations have been used as indicators of graft failure and recurrent disease. Blood Bank serologic findings have rarely been described as first indicators of disease relapse in this setting and could potentialy add to engraftment and relapse surveillance testing. Methods/Case Report A 72-year-old, ABO group O, RhD positive male with history of anti-Fyb alloimmunization underwent allo-HSCT from an ABO group B, RhD negative, Fyb positive donor as part of the treatment for MDS. Successful engraftment was achieved, and the patient’s red blood cell phenotype transitioned to ABO group B, RhD negative, Fyb positive. Two years following allo-HSCT, the patient received chemotherapy for recurrent cholangiocarcinoma. Supportive blood component transfusions were provided, all of which typed as RhD negative. However, new antibody with anti-D specificity was detected in serum while the patient still typed as ABO group B, RhD negative, preceding anti-D and later recurrent anti-Fyb detection in eluate, and prompting further chimerism testing. Declining donor chimerism was noted (72% donor, compared to >98% donor on prior chimerism testing). Chemotherapy and donor-lymphocyte infusion were initiated. Results (if a Case Study enter NA) NA Conclusion The early detection of de novowlvw anti-D was most consistent with resurgence of patient’s erythroids within the bone marrow in the presence of donor’s immune system. This was followed by sufficient peripheralization of patient’s red blood cells and detection of anti-D in the eluate. Lastly, the switch to recipient’s immune system is evidenced by recurrent detection of anti-Fyb in the eluate. This case, therefore, emphasizes the utility of Blood Bank serology in raising suspicion for disease relapse and guiding further allo-HSCT patient management. More systematic use of Blood Bank serology may serve as a time- and cost-effective adjunct to the current strategies employed for detection of disease recurrence in allo-HSCT recipients.

Lymphocytic Infiltrate and p53 Protein Expression as Predictive Markers of Response and Outcome in Myelodysplastic Syndromes Treated with Azacitidine.

High-risk Myelodysplastic syndromes (MDS) represent therapeutical challenges and are usually managed with hypomethylating agents such as azacitidine. Given the lack of data in the literature concerning azacitidine effects on bone marrow, we retrospectively analyzed 57 high-risk MDS cases in order to identify any changes induced by azacitidine therapy or relevant correlations between therapy response and pre- or post-treatment features. Azacitidine treatment had no significant impact on bone marrow cellularity or morphological dysplastic features. On the contrary, although not statistically significant, we observed a slight decrease in CD34+ and CD117+ blasts and p53+ precursors after treatment. Moreover, pre-treatment IPSS-R cytogenetic score (p = 0.004), lymphocytic infiltrate (p = 0.017) and p53+ elements (p = 0.001) correlated with AML progression; pre-treatment lymphocytic infiltrate was also linked to better response to therapy (p = 0.004), suggesting an anti-tumoral role of bone marrow microenvironment. Post-treatment blast count impacted negatively on overall survival (p = 0.035) and risk of leukemic progression (p = 0.04), while both post-treatment lymphocytic infiltrate and p53+ elements showed significant correlation with treatment response (p = 0.004 and p = 0.003 respectively). Higher post-treatment p53+ elements correlated also with risk of leukemic progression (p = 0.013). Our results suggest the possible role of lymphocytic infiltrate and p53+ elements as predictive markers in MDS treated with azacitidine, disclosing new chapters in the understanding of MDS evolution and treatment.

Integrated traditional Chinese and conventional medicine in the treatment of anemia due to lower-risk myelodysplastic syndrome: study protocol for a randomized placebo-controlled trial

BackgroundErythropoiesis and iron homeostasis are closely related; anemia due to lower-risk myelodysplastic syndromes (MDS) remains difficult to treat. In the last decade, we have been committed to improving the regulation of iron metabolism using traditional Chinese medicine (TCM). Previous studies have found that the TCM Yi Gong San (YGS) can reduce the expression of transferrin by inhibiting hepcidin overexpression caused by inflammation, promote the outward transfer of intracellular iron, and improve the symptoms of anemia. Here, our study aimed to compare the efficacy of a conventional drug with YGS with that of conventional medicine with placebo to provide a scientific basis for making clinical decisions.MethodsA prospective, multicenter, double-blinded, randomized controlled clinical trial will be conducted to evaluate the therapeutic efficacy of conventional medicine combined with YGS with that of conventional medicine alone in the treatment of MDS. A total of 60 patients would be enrolled in this study, with each treatment group (conventional medicine + YGS and conventional medicine + placebo) comprising 30 patients. Oral medication would be administered twice daily for 3 months. All patients would be followed up throughout the 3-month period. The primary outcome was measured by assessing blood hemoglobin level. The secondary outcome was measured by assessing TCM symptom score, iron metabolism, hepcidin levels, and inflammatory factors.DiscussionThis trial would aim to demonstrate the effectiveness and feasibility of YGS in the treatment of lower-risk MDS anemia, as well as its impact on inflammatory factors and iron metabolism in patients with lower-risk MDS.Trial registrationChinese Clinical Trials Registry (http://www.chictr.org.cn/) ChiCTR1900026774. Registered on October 21, 2019.

The wider perspective: twenty years of clinical trials inmyelodysplastic syndromes.

Most patients with myelodysplastic syndromes (MDS) require therapeutic intervention. However, there are few approved treatments for MDS. To explore reasons, we searched clinicaltrials.gov and clinicaltrialsregister.eu for MDS trials from 2000 to 2020. We assessed which agents were under investigation and analysed clinical trial characteristics and continuation rates from phase I to II to III to approval. As such, we identified 384 unique agents in 426 phase I, 430 phase II and 48 phase III trials. Success rates for phase III trials and agents were low, and MDS trials took markedly longer to complete than the average clinical trial. Although success rates were higher when MDS-specific phase I trials were conducted, 52% of the agents had not been evaluated in a phase I trial for MDS. MDS trials often failed to include quality of life, an especially important outcome for older MDS patients. Our work identifies factors potentially contributing to the paucity of available agents for MDS. We suggest a framework to improve clinical research in MDS that might ultimately augment the number of available agents.

P300 suppresses the transition of myelodysplastic syndromes to acute myeloid leukemia.

Myelodysplastic syndromes (MDS) are hematopoietic stem and progenitor cell (HSPC) malignancies characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Epigenetic regulators are recurrently mutated in MDS, directly implicating epigenetic dysregulation in MDS pathogenesis. Here, we identified a tumor suppressor role of the acetyltransferase p300 in clinically relevant MDS models driven by mutations in the epigenetic regulators TET2, ASXL1, and SRSF2. The loss of p300 enhanced the proliferation and self-renewal capacity of Tet2-deficient HSPCs, resulting in an increased HSPC pool and leukemogenicity in primary and transplantation mouse models. Mechanistically, the loss of p300 in Tet2-deficient HSPCs altered enhancer accessibility and the expression of genes associated with differentiation, proliferation, and leukemia development. Particularly, p300 loss led to an increased expression of Myb, and the depletion of Myb attenuated the proliferation of HSPCs and improved the survival of leukemia-bearing mice. Additionally, we show that chemical inhibition of p300 acetyltransferase activity phenocopied Ep300 deletion in Tet2-deficient HSPCs, whereas activation of p300 activity with a small molecule impaired the self-renewal and leukemogenicity of Tet2-deficient cells. This suggests a potential therapeutic application of p300 activators in the treatment of MDS with TET2 inactivating mutations.

AZACITIDINE-INDUCED SWEET SYNDROME: A UNIQUE PRESENTATION

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Sweet's Syndrome (SS) or febrile neutrophilic dermatosis, was first described in 1964 by Robert Sweet and has a female predilection with a female to male ratio of 4:1, with the typical age of onset between 30 and 60 years of age [1]. SS can either be idiopathic, pregnancy, or drug-induced, associated with infections or with malignancies [2]. We describe a unique presentation of SS in an elderly male with myelodysplastic syndrome (MDS) receiving Azacytidine (AZA). CASE PRESENTATION: A 76-year-old Caucasian male with medical history pertinent for MDS reported a new rash and fever which started immediately after completing his second 7-day cycle of AZA. Vitals were significant for hypotension and tachycardia. Physical exam was remarkable for nodules and erythematous plaques diffusely spread across the trunk, back, upper and, lower extremities. CBC showed pancytopenia and elevated inflammatory markers. The patient was adequately resuscitated, however, required low dose pressors, transfused two units of packed red blood cells, and started on broad-spectrum antibiotics. He was admitted for sepsis and neutropenic fever. Histopathology from a punch biopsy of the right calf plaque showed mild spongiosis, acanthosis, and papillary dermal edema. The dermis contained patchy perivascular inflammation, which was lymphoplasmacytic and neutrophilic. Stains for infectious agents were negative. Tissue cultures were negative for any bacterial or fungal growth. A diagnosis of SS, secondary to AZA was made. The patient was started on systemic steroids with a slow taper and made a full recovery ten days after. DISCUSSION: All five diagnostic criteria for drug-induced Sweet's syndrome proposed by Walker and Cohen were met [3]. Including an abrupt onset of painful erythematous plaques or nodules, histopathological evidence, temperature > 38°C, a temporal relationship between administration of AZA and development of the syndrome, and the resolution of symptoms when corticosteroids were given and AZA was withheld [4]. AZA is an antineoplastic agent used in the treatment of MDS. Recently, there has been an uptick in reports on AZA-associated SS [5]. The average time to resolution of clinical symptoms in drug-induced SS is reported to be around 8 days, consistent with the patient presentation [6]. CONCLUSIONS: Our case is unique in that the patient developed diffuse lesions, differing from current literature, which supports skin manifestations at the sites of injections. Prognosis is poor in patients with MDS who have SS [7]. Hence, a timely diagnosis of this condition is critical. REFERENCE #1: Vashisht P, Bansal P, Goyal A, Hearth Holmes MP. Sweet Syndrome. 2020 Sep 14. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 28613704. DISCLOSURES: No relevant relationships by Rabia Anees, source=Web Response No relevant relationships by Rosa Arancibia, source=Web Response No relevant relationships by Andrew Doodnauth, source=Web Response No relevant relationships by Khawaja Omar, source=Web Response

TIM-3 in Leukemia; Immune Response and Beyond.

T cell immunoglobulin and mucin domain 3 (TIM-3) expression on malignant cells has been reported in some leukemias. In myelodysplastic syndrome (MDS), increased TIM-3 expression on TH1 cells, regulatory T cells, CD8+ T cells, and hematopoietic stem cells (HSCs), which play a role in the proliferation of blasts and induction of immune escape, has been reported. In AML, several studies have reported overexpression of TIM-3 on leukemia stem cells (LSCs) but not on healthy HSCs. Overexpression of TIM-3 on exhausted CD4+ and CD8+ T cells and leukemic cells in CML, ALL, and CLL patients could be a prognostic risk factor for poor therapeutic response and relapse in patients. Currently, several TIM-3 inhibitors are used in clinical trials for leukemias, and some have shown encouraging response rates for MDS and AML treatment. For AML immunotherapy, blockade TIM-3 may have dual effects: directly inhibiting AML cell proliferation and restoring T cell function. However, blockade of PD-1 and TIM-3 fails to restore the function of exhausted CD8+ T cells in the early clinical stages of CLL, indicating that the effects of TIM-3 blockade may be different in AML and other leukemias. Thus, further studies are required to evaluate the efficacy of TIM-3 inhibitors in different types and stages of leukemia. In this review, we summarize the biological functions of TIM-3 and its contribution as it relates to leukemias. We also discuss the effects of TIM-3 blockade in hematological malignancies and clinical trials of TIM-3 for leukemia therapy.

Advances in myelodysplastic syndrome.

In this review, the focus is on the most recent improvements in diagnosis, prognostication and therapy of myelodysplastic syndromes (MDS) and on their relevance for clinical management. Analytical methods to refine cytogenetic and molecular assessment of MDS have been proposed, improving prognostic stratification obtained from integration of clinical and genomic data. Novel agents with very different mode of action, as single drugs or added to HMA backbone, show promising clinical results in LR-MDS and HR-MDS. Luspatercept has obtained approval given the fact that in transfusion-dependent erythropoietic-stimulating agent resistant/relapsed LR-MDS induced nearly 50% of transfusion independence. Another investigational agent showing efficacy and possibly disease modifying activity in the same setting is the telomerase inhibitor imetelstat. Results from phase II study with azacytidine and pevonedistat indicate the concrete possibility to enhance durable responses compared with azacitidine single drug. In the same direction are the preliminary results of other agents with different mode of action: magrolimab, venetoclax, sabatolimab, as well as the targeted therapy with enasidenib and ivosidenib. New posttransplant maintenance strategies may concur to prolong response. Better diagnosis and prognostic stratification may allow a more precise and personalized treatment of MDS with novel agent combinations leading to improved therapeutic algorithms.

Use of Oral Hypomethylating Agents for the Treatment of Myelodysplastic Syndromes

Introduction Myelodysplastic syndromes (MDS) are genomically complex clonal hematopoietic stem cell neoplasms leading to myelodysplasia and ineffective hematopoiesis.1,2 MDS is a disease of older age, clinically manifesting as symptomatic cytopenias with an added propensity for transformation to acute myeloid leukemia (AML).3 The treatment of MDS is based on a risk-adapted approach per the International Prognostic Scoring System (IPSS)4 or the modified IPSS-R.5 Allogeneic stem cell transplantation (ASCT) is the only curative strategy, but most patients are not eligible due to their age or other comorbidities.6 In these patients, hypomethylating agents (HMA, either decitabine or azacitidine) are the mainstay of therapy to either alleviate cytopenias or impede disease progression. 7 Decitabine (DEC) and azacitidine (AZA) are approved to treat patients with MDS, including previously treated and untreated, de novo, and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk IPSS groups.7

Treatment of Higher-Risk MDS

Introduction Myelodysplastic syndromes (MDS) comprise a spectrum of myeloid neoplasms resulting in ineffective clonal hematopoiesis; patients are at risk of life-threatening infections or bleeding complications and progression to acute myeloid leukemia (AML). Disease risk is based on a number of factors, including depth and type of cytopenias, bone marrow blasts, cytogenetics, and, increasingly, molecular alterations. MDS at diagnosis is generally divided into lower-risk and higher-risk disease; in higher-risk MDS, survival is poor, and treatment is meant to reduce MDS-specific complications and improve quality and quantity of life. The general approach in patients with higher-risk MDS involves consideration of allogeneic transplant, the use of hypomethylating agents, as well as the role of emerging therapies and clinical trials.

Expanding the immune armoury against myelodysplastic syndrome.

Expanding the immune armoury against myelodysplastic syndrome.

The impact of CD33/CD34 ratio in the prognosis of myelodysplastic syndrome treated with azacitidine for first-line therapy

PurposeAzacitidine (AZA), a hypomethylating agent, is the standard treatment for patients with myelodysplastic syndromes (MDS). However, responses are generally transient in approximately 50% of patients. Cytomorphology and immunophenotyping are widely used in the treatment of MDS. Therefore, the present study investigated the relationship between immunophenotyping and the outcomes of MDS patients administered AZA as first-line therapy.MethodsWe retrospectively examined the relationship between immunophenotyping and the outcomes of 118 MDS patients administered AZA as first-line therapy.ResultsThe response to AZA was poorer in patients with a CD33/CD34 ratio > 1 than in those with a CD33/CD34 ratio < 1. Univariate and multivariate analyses identified higher serum LDH levels, higher risk IPSS-R, and a CD33/CD34 ratio > 1 as independent adverse prognostic factors for overall survival. A Kaplan–Meier analysis showed that a CD33/CD34 ratio > 1 was associated with poor survival.ConclusionIn the present study, a CD33/CD34 ratio > 1 in blast cells was associated with poor survival in MDS patients administered AZA as first-line therapy.

Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations.

Nonsense-mediated RNA decay (NMD) is recognized as an RNA surveillance pathway that targets aberrant mRNAs with premature translation termination codons (PTC) for degradation, however, its molecular mechanisms and roles in health and disease remain incompletely understood. In this study, we developed a novel reporter system to accurately measure NMD activity in individual cells. A genome-wide CRISPR-Cas9 knockout screen using this reporter system identified novel NMD-promoting factors, including multiple components of the SF3B complex and other U2 spliceosome factors. Interestingly, cells with mutations in the spliceosome genes SF3B1 and U2AF1, which are commonly found in myelodysplastic syndrome (MDS) and cancers, have overall attenuated NMD activity. Compared with wild-type (WT) cells, SF3B1- and U2AF1-mutant cells were more sensitive to NMD inhibition, a phenotype that is accompanied by elevated DNA replication obstruction, DNA damage, and chromosomal instability. Remarkably, the sensitivity of spliceosome mutant cells to NMD inhibition was rescued by overexpression of RNase H1, which removes R-loops in the genome. Together, these findings shed new light on the functional interplay between NMD and RNA splicing and suggest a novel synthetic lethal strategy for the treatment of MDS and cancers with spliceosome mutations. SIGNIFICANCE: This study has developed a novel NMD reporter system and identified a potential therapeutic approach of targeting the NMD pathway to treat cancer with spliceosome gene mutations.

2021 BSH guidelines for the management of adult myelodysplastic syndromes: a practical approach to a challenging disease.

Myelodysplastic syndromes (MDS) are a group of haematological malignancies with extremely variable biologic, genetic and clinical characteristics.1 The outcome of MDS patients is very heterogeneous, some having a near-normal life expectancy while others die within a few months of their diagnosis. The median age of patients at diagnosis is advanced, ranging between 70 and 75 years, thus further complicating the management of these complex syndromes, since non-haematological comorbidities frequently coexist in the elderly and tolerability of treatments is limited.2 Given the heterogeneity of the disease pathobiology and the highly variable disease course, prognostic risk stratification is of crucial importance in clinical decision-making.3 To drive appropriate counselling and individualisation of treatment decisions, several prognostic scoring systems based on clinical and haematological parameters have been developed. Principal scoring systems currently used in Europe are the International Prognostic Scoring System (IPSS), and the revised IPSS (R-IPSS), which are based on the evaluation of peripheral blood cytopenias, bone marrow blast count and cytogenetic features.4 In daily practice, reliability of these scores is limited by the variability of morphological evaluation and, less frequently, by non-informative cytogenetic findings in a proportion of patients. Moreover, other factors including the clonal mutational status have been reported to influence the prognosis of MDS patients, and to affect the clinical outcome.5, 6 In any case, diagnostic procedures and evaluation of prognosis are not covered by these guidelines as they will be published in a separate British Society for Haematology (BSH) document. Unlike the previous edition, the 2021 BSH guidelines also do not include recommendations for CMML, for which dedicated guidelines will follow. The 2021 updated BSH guidelines for the Management of Adult Myelodysplastic Syndromes provide clear, simple and practical recommendations to approach patients with such a challenging diagnosis.7 Given the heterogeneity of the disease, the importance of establishing an individual risk-adapted treatment strategy is crucial; nonetheless, transfusion requirements and infectious complications are common to almost all patients, sooner or later. The guidelines first exhaustively describe the supportive measures that should be adopted with most patients; in particular, recommendations are reported the for prevention of fungal infection, a common complication in neutropenic patients, and for transfusion thresholds and policies to be adopted to improve patient quality of life (QoL) on the one hand, saving blood products on the other. Then, individual planning of therapeutic options is described extensively, also by means of simplified algorithms. Although standard care for MDS is constantly changing, recommendations for the initial treatment choice are still based on IPSS and R-IPSS risk evaluation, and, importantly, on patient’s preference. Therapeutic measures for most lower risk patients aim to decrease the transfusion burden and improve QoL, whereas recommendations for higher risk patients aim to prolong their life. This distinction is clearly represented in these guidelines; for each group updated treatment strategies are reported, some reflecting the 2014 BSH document. Still relevant is the recommendation that the initial MDS diagnosis should be discussed by a multidisciplinary team, including a transplantation expert, as allogeneic transplantation remains the only potentially curative option. Worthy of note, in this setting recommendations for cytoreduction in advanced MDS with hypomethylating agents (HMA) or chemotherapy before transplant are still debated, although inferior survival outcomes for patients with excess BM blasts (> 5%) at the time of transplant have been reported. Moreover, it is important that clinicians review MDS cases regularly in multidisciplinary meetings to determine if a patient can become a possible transplant candidate and/or can possibly take part in a clinical trial. Patients’ details should also be made available to national and international dedicated registries, ‘to maximize information about the patient’s history and treatment of MDS in order to benefit future patients’. In general, the guidelines are proposed to improve the quality of care of patients as well as to help physicians in their daily practice. The BSH guidelines for the management of MDS represent a timely update and make a valid contribution for the diagnosis and treatment of this heterogeneous group of blood disorders.