High-risk Myelodysplastic Syndrome Research Articles

Abstract CT060: Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS)

Abstract Background:Evorpacept (EVO) is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of other anti-neoplastic therapies with minimal additional toxicity. Here, we present final phase 1 results from the ASPEN-02 study. Methods:ASPEN-02 is an open-label, multicenter phase 1/2 study designed to evaluate the safety and activity of EVO in combination with azacitidine (AZA) in subjects with newly diagnosed (ND) higher-risk (HR) or relapsed/refractory (R/R) MDS. Adult subjects with ND HR (IPSS-R > 3.5) or R/R MDS were enrolled into phase 1 cohorts receiving escalating doses of EVO (20 mg/kg Q2W, 30 mg/kg Q2W, and 60 mg/kg Q4W) combined with AZA (75 mg/m2 IV/SC x 7d) in a 28-day treatment cycle. A phase 1 dose expansion portion enrolled adults with ND HR MDS into two dosing cohorts determined to be safe at EVO 40 mg/kg Q4W and 60 mg/kg Q4W. This clinical trial is registered at clinicaltrials.gov: NCT04417517. Results: As of June 2, 2023, 65 subjects were treated in the phase 1 portion, including 13 subjects with R/R MDS [EVO doses of 20 mg/kg Q2W (n=1) or 60 mg/kg Q4W (n=12)], and 52 subjects with ND HR MDS [EVO doses of 40 mg/kg Q4W (n=23) and 60 mg/kg Q4W (n=29)]. Of 52 ND HRMDS subjects, 9 (17.3%) had therapy-related MDS. Multi-hit TP53 mutations were present at baseline in 2/13 (15.4%) R/R MDS and 3/52 (5.8%) ND HR MDS patients. 13/13 (100%) R/R MDS patients had received prior hypomethylating agents or cytotoxic chemotherapy. Median age was 70 (range 24 - 88) years, and baseline ECOG scores were 0 (n=27, 41.5%), 1 (n=31, 47.7%), or 2 (n=7, 10.8%). No dose-limiting toxicity was observed, and a maximum tolerated dose (MTD) was not reached. Treatment-emergent AEs and treatment-related AEs for EVO were reported in 65/65 (100%) and 35/65 (53.8%) subjects respectively; discontinuation, however, was infrequent. Seven (10.8%) subjects experienced a serious adverse event related to EVO. There were no EVO-related deaths on study. Preliminary PK indicated dose-proportional pharmacokinetics consistent with prior studies. Objective response [complete remission (CR), partial remission (PR), marrow CR (mCR), hematologic improvement (HI)], per modified International Working Group 2006 criteria, was observed in 19/52 (36.5%) ND HR [CR=8, mCR=9, HI=2] and 2/13 (15.4%) R/R [mCR=2] MDS subjects. Conclusion:The myeloid checkpoint inhibitor EVO was well tolerated in combination with AZA with an initial safety and activity profile comparable to that of historical AZA monotherapy. Additional updated data will be provided at the time of presentation. Citation Format: Guillermo Garcia-Manero, Bart L. Scott, Ashwin Kishtagari, Srinivasa R. Sanikommu, Aref Al-Kali, Je-Hwan Lee, Juan M. Bergua Burgues, Maria Diez-Campelo, Harry P. Erba, Carmen Garcia-Hernandez, Guillermo Sanz Santillana, Casey O'Connell, Jun-Ho Jang, Dong-Yeop Shin, Hamid Sayar, Mayank Rao, Richard S. Schwartz, Grace An, Feng Jin, Alison J. Forgie, Athanasios C. Tsiatis, Jessica K. Altman. Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT060.

Abstract CT115: A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in a hematologic malignancies cohort

Abstract Background: Mutations in genes encoding RNA splicing factors such as SF3B1, SRSF2, U2AF1, and ZRSR2, are common genetic aberrations in many forms of myeloid neoplasms. CTX-712 is a first-in-class, orally available, highly potent, and selective small molecule inhibitor of CDC2-like kinase (CLK), a key regulator of RNA splicing. Preclinical data show that CTX-712 demonstrated anti-proliferative activity in in-vitro and in-vivo models derived from hematologic malignancies. A phase I study of CTX-712 was conducted to evaluate the safety and the preliminary efficacy of CTX-712 in patients with relapsed or refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS). Methods: The objectives of this cohort were to evaluate the dose-limiting toxicity (DLT), safety, pharmacokinetic (PK)/pharmacodynamic (PD) profiles, and preliminary efficacy of CTX-712 in patients with hematologic malignancies. A 3+3 design was used in two dose levels (70 mg and 105 mg twice a week (TW)) based on the safety data from the previous dose escalation cohort in patients with solid tumors. Results: As of data cutoff on November 20, 2023, a total of 14 patients (12 AML and 2 MDS) were enrolled in 70 mg TW (n=8) and 105 mg TW dose levels (n=6). DLT of Grade 4 pneumonia was observed in 1 of 3 DLT-evaluable patients in the 105 mg TW group. In the 70 mg TW group, no DLT was observed in 6 DLT-evaluable patients. Among the safety analysis population (n=14), median treatment duration was 76 days (Range 15-974 days). At data cutoff, treatment was ongoing in 1 patient and discontinued in 13 patients. The common any-grade adverse events (AEs) (≥30%) were diarrhea (57.1%) and nausea (42.9%). The most common Grade 3 or higher AE were white blood cell count decreased and tumor lysis syndrome (14.3%). In AML patients (n=12), complete remission (CR) was observed in 3 patients (25.0%), and CR with incomplete hematologic recovery (CRi) was observed in 1 patient (8.3%). The median time to remission was 67 days (Range 29-113 days), and the median duration of response was 281 days (Range 56-924 days). In MDS patients (n=2), CR was observed in 1 patient (50.0%). PK/PD profiles of the hematologic malignancies dose escalation cohort were comparable with those of the solid tumor cohort at the same dosage. Conclusions: CTX-712 demonstrated a manageable and tolerable safety profile and showed anti-tumor efficacy in patients with hematologic malignancies. Currently, a Phase I/II Study of CTX-712 in relapsed/refractory AML and higher risk MDS is ongoing using a new tablet formulation in the United States. Clinical trial information: jRCT2080224127 Citation Format: Hisayuki Yokoyama, Noriko Fukuhara, Koji Ando, Hiroatsu Iida, Takahiro Yamauchi, Suguru Fukuhara, Koji Izutsu, Yasushi Tanoue, Maki Yamamoto, Hirokazu Tozaki, Eiji Takahara, Shingo Shoji, Akio Mizutani, Daisuke Morishita, Robert W. Oda, Hiroshi Miyake, Noboru Yamamoto. A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in a hematologic malignancies cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT115.

Abstract 6744: Activating anti-MDS immunity with polarized dendritic cell vaccines

Abstract Less than 50% of patients with higher-risk myelodysplastic syndromes (MDS) show clinical response to standard-of-care hypomethylating (HMA) therapy. Significant enthusiasm existed for immunotherapy/HMA combinations for these patients, but studies have failed to deliver on the initial promise. We have demonstrated that patients with MDS have a deficiency in antigen-presenting cells, called CD141Hi dendritic cells (DC). DC-deficient MDS patients have reduced response to HMAs, worse overall survival, and show less response to cancer vaccination. We hypothesized that restoration of this population using a novel DC vaccination approach - alpha-type-1 polarized dendritic cells (αDC1) - might compensate for this deficiency and restore immunity. To generate αDC1s, we collected monocytes from MDS patients and healthy donors (HD) and cultured them for 6 days in vitro in the presence of recombinant human GM-CSF and IL-4 followed by an additional 18-24 hours in the presence of αDC1 maturation factors (poly-I:C/IFNα/IFNγ/TNFα/IL-1β). Overall, we attempted to generate αDC1s from 15 MDS samples; 13/15 exhibited intermediate to very high-risk disease and 10/15 are currently receiving HMA therapy. We successfully cultured cells from 8/15 samples (53%). Of the 8 MDS samples, 5 were collected from patients receiving HMA therapy (62.5%). We were unable to successfully culture αDC1s from the other 5 patients receiving HMA therapy, and thus the effect of HMA therapy on aDC1 generation remains unclear. To test the function of MDS αDC1s, we focused on two signals necessary to activate immune responses: 1) the expression of co-stimulatory molecules and 2) the production of IL-12p70. Flow cytometric analysis on αDC1s and immature DCs from MDS samples revealed intra-patient variation in the fold-change surface expression of CD40/80/83/86 and HLA-DR proteins. Additionally, there was a trend towards decreased up-regulation of CD80 and CD86 in MDS specimens compared to HD. To assess production of IL-12p70, we stimulated immature DCs and αDC1s with CD40L and performed ELISA analysis on the media supernatant. We found that 3 out of 4 samples could produce IL-12p70 (range 27 - 5,480 pg/ml). To date, our results suggest that generation of MDS patient-derived αDC1 cells is feasible and additional work is being performed to fully characterize their ability to activate anti-MDS immune responses. Since αDC1s have an established safety profile in patients with solid tumors, we anticipate that we will be able to rapidly translate our results to the clinic. Citation Format: Daniel Alvarado, Jennifer Peresie, Adam Brinkman, Cheryl Allen, Weijian Jiang, Pawel Kalinski, Tiffany Tanaka, Elizabeth Griffiths, Michael Nemeth. Activating anti-MDS immunity with polarized dendritic cell vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6744.

Abstract 1484: 5-Aza-4'-thio-2'-deoxycytidine induces C to G transversions in a specific trinucleotide context and leads to acute lymphoid leukemia

Abstract Myelodysplastic syndromes (MDS) are a diverse group of blood cancers characterized by peripheral blood cytopenias and dysplastic blood cell morphology. Up to 40% of patients with high risk MDS will transform to acute myeloid leukemia (AML), an aggressive blood cancer with significant morbidity and an overall 5-year survival of less than 35%. Both MDS and AML have been linked to hypermethylation of cytosine residues. Hypermethylation in the 5’ regulatory region can result in epigenetic downregulation of gene expression, and it has been speculated that hypermethylation of tumor suppressor genes can contribute to malignant transformation. DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that are used clinically to decrease 5’-cytosine methylation, with the aim of inducing the re-expression of tumor suppressor genes resulting in a halt of tumor progression. 5-Aza-4’-thio-2’-deoxycytidine (Aza-TdCyd or ATC) is a cytidine analog that incorporates an aza modification (nitrogen in place of carbon) of the cytosine base and a thioether modification of the deoxyribose sugar. ATC is a promising new DNMT1i that has demonstrated efficacy in preclinical studies of solid tumors. Based on these prior studies, we sought to characterize the potential therapeutic effect of ATC in MDS.Mice that express a NUP98::HOXD13 (NHD13) transgene develop an MDS that closely recapitulates all of the key features of human MDS, including pancytopenia, dysplastic morphology, and transformation to AML. We transplanted NHD13 and wild-type (WT) hematopoietic stem and progenitor cells into WT recipients, and used this model of MDS to investigate the therapeutic potential of ATC. We found that ATC treatment led to both T and B lineage lymphoid leukemia (ALL) originating from the NHD13 cells. Surprisingly, ATC treatment also led to T and B lineage ALL in the WT cells, and further experiments demonstrated that non-transplanted, healthy WT mice developed T and B cell ALL after treatment with ATC. In sum, all mice that received at least 8 cycles of ATC therapy at the 1.0 mg/kg dose developed leukemia. Whole exome sequencing of tumors revealed thousands of acquired mutations, almost all of which were C>G transversions in a previously unrecognized, specific 5’-NCG-3’ context. These mutations involved a number of genes well-known to be involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Treatment of the human U937 and CEM cell lines in vitro showed thousands of acquired C>G transversions in a similar context. Taken together, these findings demonstrate that ATC can be a potent mutagen in human and mouse cells, both in vitro and in vivo. Citation Format: Ryan Matthew Bertoli, Yang Jo Chung, Michael Difilippantonio, Anthony Wokasch, Madison R. Marasco, Haley Klimaszewski, Susannah Garber, Yuelin Jack Zhu, Robert L. Walker, Dengchao Cao, James Doroshow, Paul Meltzer, Peter D. Aplan. 5-Aza-4'-thio-2'-deoxycytidine induces C to G transversions in a specific trinucleotide context and leads to acute lymphoid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1484.

Abstract 3129: BYON4413, an in vivo active CD123-targeting antibody-drug conjugate, combines effectively with azacitidine and venetoclax in acute myeloid leukemia cell lines

Abstract Background: CD123, the alpha chain of the interleukin-3 receptor (IL-3Rα), is overexpressed in multiple hematologic malignancies and found particularly highly expressed on the surface of acute myeloid leukemia (AML) cells. Furthermore, increased CD123 expression on leukemic stem cells relative to non-neoplastic hematopoietic stem cells makes CD123 an attractive tumor-associated target for an antibody-drug conjugate (ADC). BYON4413 is an ADC that consists of a novel humanized IgG1 anti-CD123 antibody site-specifically conjugated with Byondis' proprietary duocarmazine linker-drug technology, ByonZine® and ByonShieLD®. The efficacy of BYON4413 is studied as monotherapy and in combination with azacitidine and venetoclax (AZA/VEN), since the AZA/VEN regimen is the standard of care (SOC) for AML patients who are ineligible for intensive chemotherapy. Method: A panel of CD123+ and CD123- hematological cell lines and AML patient-derived bone marrow mononuclear cells (BMMCs)/peripheral blood mononuclear cells (PBMCs) were utilized in in vitro studies to determine the cytotoxic effects of BYON4413. The induction of apoptosis and cell killing by BYON4413 in a triple combination with AZA/VEN was studied in vitro using the CD123+ AML cell lines MOLM-13 and MV4-11. AML patient and cell line-derived xenograft models were used to investigate the in vivo efficacy of BYON4413. Results: In vitro studies with human AML cell lines show that BYON4413 is highly effective in eradicating CD123+ cells while having little impact on CD123- cells. These results were confirmed ex vivo with AML patient-derived BMMCs/PBMCs. BYON4413 effectively killed AML patient-derived blasts while largely sparing healthy hematopoietic cells. The triple combination of BYON4413 with AZA/VEN enhanced both apoptosis and cell killing of AML cell lines compared to the singular BYON4413 treatment. In vivo studies demonstrate that BYON4413 is remarkably efficient at reducing the tumor burden in AML patient- and cell line-derived xenograft models. Conclusions: Preclinical studies show that BYON4413 has potential to be an effective targeted therapy against CD123+ hematological malignancies such as AML. The enhanced efficacy of BYON4413 together with AZA/VEN suggests that a clinical benefit from the triple combination may be achievable and is worth further exploration. A first-in-human dose-escalation and expansion trial with BYON4413, designed to enroll R/R AML and high-risk MDS patients, is scheduled to start in Q2 2024. Citation Format: Miranda M.C. van der Lee, Tanja van Achterberg, Kaylee Hersmus, Annet Brouwers-Vos, Monique van der Vleuten, Maurien Pruis, Wendy Kappers, Gijs Verheijden, Gerwin Huls, Glenn van Wigcheren, Ruud Ubink, Aloys Sesink, Alyson MacInnes, Jan Jacob Schuringa, Wim Dokter. BYON4413, an in vivo active CD123-targeting antibody-drug conjugate, combines effectively with azacitidine and venetoclax in acute myeloid leukemia cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3129.

Prognostic Value of Pretreatment Fetal Hemoglobin Levels in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia Treated with Azacitidine: A Single-center Retrospective Study.

Objective Azacitidine (AZA) has been the standard of care for elderly patients with high-risk myelodysplastic syndromes (MDS). However, reliable clinical predictors of outcome have yet to be identified. The prognostic value of fetal hemoglobin (HbF) levels has been reported for decitabine therapy. We evaluated pretreatment HbF levels in AZA monotherapy as a prognostic marker in MDS/acute myeloid leukemia (AML). Methods This study included chemotherapy-naïve patients who had received seven-day treatment schedules of AZA and whose HbF levels were measured at the onset of treatment between March 2011 and July 2020. Patients were grouped into HbF-normal (<1.0%) or HbF-elevated (≥1.0%) groups. Responses were classified according to the International Working Group 2006 criteria. Patients Twenty-nine patients were included and classified as having either MDS (n=21), chronic myelomonocytic leukemia (n=5), myelodysplastic/myeloproliferative neoplasm unclassifiable (n=1), or AML with <30% marrow blasts (n=2) based on the World Health Organization 2016 diagnostic criteria. According to the revised International Prognostic Scoring System classification, 20/29 patients were at intermediate, high, or very high risk. Pretreatment HbF levels were elevated in 13/29 patients. Results The median follow-up duration was 13.0 (range 1.5-93.5) months. The HbF-elevated group was associated with a significantly higher hematologic improvement rate (76.9% vs. 25%, p=0.009) and better overall survival (median, 21.0 vs. 13.0 months, p=0.048) than the HbF-normal group. Conclusion These results suggest that elevated pretreatment HbF levels can predict better outcomes in patients with MDS/AML treated with AZA.

Analyzing Blood Cells of High-Risk Myelodysplastic Syndrome Patients Using Interferometric Phase Microscopy and Fluorescent Flow Cytometry.

Myelodysplastic syndromes (MDSs) are a group of potentially deadly diseases that affect the morphology and function of neutrophils. Rapid diagnosis of MDS is crucial for the initiation of treatment that can vastly improve disease outcome. In this work, we present a new approach for detecting morphological differences between neutrophils isolated from blood samples of high-risk MDS patients and blood bank donors (BBDs). Using fluorescent flow cytometry, neutrophils were stained with 2',7'-dichlorofluorescin diacetate (DCF), which reacts with reactive oxygen species (ROS), and Hoechst, which binds to DNA. We observed that BBDs possessed two cell clusters (designated H and L), whereas MDS patients possessed a single cluster (L). Later, we used FACS to sort the H and the L cells and used interferometric phase microscopy (IPM) to image the cells without utilizing cell staining. IPM images showed that H cells are characterized by low optical path delay (OPD) in the nucleus relative to the cytoplasm, especially in cell vesicles containing ROS, whereas L cells are characterized by low OPD in the cytoplasm relative to the nucleus and no ROS-containing vesicles. Moreover, L cells present a higher average OPD and dry mass compared to H cells. When examining neutrophils from MDS patients and BBDs by IPM during flow, we identified ~20% of cells as H cells in BBDs in contrast to ~4% in MDS patients. These results indicate that IPM can be utilized for the diagnosis of complex hematological pathologies such as MDS.

Abstract P26: Altered RNA Export Sensitizes to Nuclear Export Inhibition in SF3B1 Mutant MDS

Abstract SF3B1 mutations, the most frequent spliceosomal alterations across cancers, occur in 25% of myelodysplastic syndromes (MDS) patients yet lack effective therapies. Two phase 2 clinical trials with the XPO1 inhibitors in high-risk MDS revealed increased activity in patients with SF3B1 mutations. XPO1 (Exportin-1) plays a role in the transport of multiple RNA species, including small nuclear RNAs (snRNAs) out of the nucleus. Given the role of XPO1 in exporting snRNAs, which form the catalytic portion of the spliceosome, we hypothesized that XPO1 inhibition may preferentially affect SF3B1-mutant cells and that SF3B1-mutant high-risk MDS patients would have a better response to rational targeted drug combinations with XPO1 inhibitors. To evaluate the mechanism underlying the preferential sensitivity of SF3B1-mutant cells to XPO1 inhibition, we conducted subcellular RNA sequencing before and after XPO1 inhibition in SF3B1 wildtype and mutant cells. Transcriptomic analysis revealed increased global retention of RNA transcripts and elevated snRNAs in the nucleus after XPO1 inhibition in the SF3B1 mutant cell line. Global RNA expression and splicing analysis revealed increased alternative splicing in SF3B1 mutant cells after XPO1 inhibition. These results suggest that the preferential sensitivity of SF3B1 mutant cells to nuclear export inhibition arises through increased nuclear retention of spliceosomal snRNAs and select mRNAs that results in perturbation of apoptotic pathways. Despite the promising efficacy of XPO1 inhibition in SF3B1-mutated MDS, dose escalation is limited by toxicity. In order to identify novel drug combination targets with lower XPO1 inhibitor doses, we employed whole genome CRISPR screens in two acute myeloid leukemia (AML) cell lines treated with XPO1 inhibitor. We identified two drug targets that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and A1331852 (a BCL-XL inhibitor). In addition, BH3 profiling demonstrated increased priming of the BCL2 and BCL-XL in SF3B1 mutant cells. We further validated these combinations in vivo using competitive transplant assays in Sf3b1 K700E conditional knock-in mice. The combination of eltanexor with venetoclax and eltanexor with A1331852 showed a significant decrease in the Sf3b1-mutant burden in the peripheral blood and bone marrow progenitor compartments, suggesting a preferential sensitivity of the combinations for SF3B1 mutant cells. Although A1331852 exhibited similar results to venetoclax, there was increased weight loss and decrease in hemoglobin associated with BCLXL inhibition. In conclusion, our study provides insight on the mechanisms underlying the heightened sensitivity of XPO1 inhibition in SF3B1-mutant MDS/AML. The identification of BCL2 and BCL-XL as synergistic targets with XPO1 inhibitors, validated by in vivo testing, BH3 profiling, and RNA sequencing, highlights the potential for therapeutic combinations. Specifically, the combination of eltanexor and venetoclax could be a promising SF3B1-specific therapy. Citation Format: Sana Chaudhry, Felipe Beckedorff, Shaista Shabbir Jasdanwala, Tulasigeri M Totiger, Maurizio Affer, Nidhi Hariramani, Olivia Tonini, Stephan Noudali, Alexandra Chirino, Alyssa Cornista, Skye Montoya, Daniel Bilbao, Jumana Afaghani, Jose Antonio Rodríguez, Shruti Bhatt, Eric Wang, Justin Taylor. Altered RNA Export Sensitizes to Nuclear Export Inhibition in SF3B1 Mutant MDS [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P26.

Tripartite prehabilitation of patients with acute myeloid leukaemia and high-risk myelodysplastic syndromes during intensive chemotherapy before allogeneic haematopoietic stem cell transplantation (COHABILIT): protocol for an innovating prospective multicentre study

ObjectivesAcute myeloid leukaemia (AML) and high-risk myelodysplastic syndromes (MDS) are often treated with intensive chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT). The pretransplant treatment results in a general...

Prospective performance of the International Working Group 2023 and the International Prognostic Scoring System - Molecular in a phase II trial of guadecitabine in higher-risk myelodysplastic syndrome or chronic myelomonocytic leukemia

Guadecitabine (SGI-110) is a dinucleotide form of decitabine that has been studied in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Here we present the results of a single center phase II trial of this agent for patients with higher-risk MDS or CMML. Guadecitabine was administered at a dose of 60 mg/kg subcutaneously for five days. Of 100 enrolled patients, 82% had MDS. Median age was 69 years, International Prognostic Scoring System (IPSS) was intermediate-2 in 78% and high in 14%. Thirty-eight percent had complex cytogenetics and 32% had TP53mut. By IWG-2006 criteria, 25% achieved complete remission (CR), 30% marrow CR, and 33% no response (NR). Common grade 3 events were febrile neutropenia (32%) and infection (25%). Mortality rate at 4 and 8 weeks was 0% and 4%, respectively. Median overall survival (mOS) was 16.8 months. Transplanted patients (21%) had a mOS of 46.6 months. We then reanalyzed this dataset using IPSS-Molecular and International Working Group (IWG) 2023 response criteria. By IPSS-M, 60% of patients were classified as very high risk and 27% as high. By IWG-2023, overall response rate (ORR) was 52%, 30% CR, 14% CR with limited count recovery (CRL), with 42% no response (NR). IPSS-M provided adequate risk stratification at enrollment. Patients classified as mCR had widely different outcomes when reclassified by IWG-2023. In conclusion, SGI-110 was active in high risk MDS but survival is unlikely to be superior to current hypomethylating agents. The study is registered as NCT02131597.

Impact of Skeletal Muscle Depletion on Patients with Myelodysplastic Syndrome Treated with Azacitidine.

Azacitidine (AZA) is the standard treatment for patients with high-risk myelodysplastic syndromes (MDS). The impact of skeletal muscle depletion (SMD), which is associated with outcomes of hematological malignancies, on the clinical course of MDS patients treated with AZA was investigated. This retrospective, observational study included 50 MDS patients treated with AZA. Muscle mass was evaluated using the skeletal muscle index (SMI), which is the area of muscle mass at the third lumbar vertebra on CT images divided by the square of the height. Of the enrolled patients, 39 were males, and their median age was 69.5 years. Twenty-seven (20 male and 7 female) patients showed SMD. The median survival was 13.4 months in the SMD group and 15.2 months in the non-SMD group, with no significant difference and no significant association between the response rate or severe non-hematological toxicities and the presence of SMD. By contrast, grade 3-4 anemia and thrombocytopenia were significantly more frequent in the SMD group than in the non-SMD group. SMD was associated with severe anemia and thrombocytopenia in MDS patients treated with AZA. Reduced skeletal muscle mass may predict severe hematological toxicity in MDS patients treated with AZA.

Physicochemical stability of pevonedistat at 50, 100 and 200 µg/mL diluted in 0.9% sodium chloride and at 10 mg/mL in partially used vials

ObjectivesPevonedistat is a new cytotoxic used in association with azacitidine for the treatment of acute myeloid leukaemia and high-risk myelodysplastic syndromes. The manufacturer indicates an 18-hour stability after dilution in...

Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes.

Chromosomal instability is a prominent biological feature of myelodysplastic syndromes (MDS), with over 50% of patients with MDS harboring chromosomal abnormalities or a complex karyotype (CK). Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified ectopic expression of the transcription factor ONECUT3, which is associated with CKs and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of chromosome passenger complex (CPC) accumulation, besides the cell equator and midbody, during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8 and transcriptionally activated these 2 genes. We identified a lead compound, C5484617, that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK.

[Efficacy and safety analysis of venetoclax combined with hypomethylating agents for the treatment of higher-risk myelodysplastic syndromes in the real world].

Objective: To investigate the efficacy and safety of combining venetoclax (VEN) with hypomethylated drugs (HMA) in the treatment of higher-risk (IPSS-R score >3.5) myelodysplastic syndromes (MDS) . Methods: From March 2021 to December 2022, forty-five MDS patients with intermediate and high risk were treated with VEN in combination with HMAs. Clinical data were collected and analyzed retrospectively, including gender, age, MDS subtype, IPSS-R score, treatment regimen, and efficacy, etc. Kaplan-Meier method and Cox regression model were used to analyze univariate and multivariate of survival prognosis. Results: ①Forty-five patients with MDS, including ninety-one percent were classified as high or very high risk. According to the 2023 consensus proposal for revised International Working Group response criteria for higher-risk MDS, the overall response rate (ORR) was 62.2% (28/45), with the complete response rate (CR) was 33.3% (15/45). For twenty-five naïve MDS, the ORR was 68% (17/25) and the CR rate was 32% (8/25). In nonfirst-line patients, the ORR and CR were 55% (11/20) and 35% (7/20) respectively. The median cycle to best response was 1 (1-4). ②With a median followup of 189 days, the median overall survival (OS) time was 499 (95% confidence interval, 287-711) days, and most patients died from disease progression. Responders had a significantly better median OS time than nonresponders (499 days vs 228 days, P<0.001). Multifactor analysis revealed that IPSS-R score and response to treatment were independent prognostic factors for OS; the presence of SETBP1 gene mutations was associated with a longer hospital stay (51.5 days vs 27 days, P=0.017) . Conclusions: There is clinical benefit of venetoclax in combination with hypomethylated agents in patients with higher-risk MDS, but adverse events such as severe hypocytopenia during treatment should be avoided.

Glasdegib with intensive/nonintensive chemotherapy in Japanese patients with untreated acute myeloid leukemia or high-risk myelodysplastic syndromes.

Glasdegib is a potent, selective, oral inhibitor of the hedgehog signaling pathway. In this phase I study, previously untreated Japanese patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes were treated with glasdegib (100 mg once daily) combinations: low-dose cytarabine (20 mg twice daily; cohort 1, n = 6; expansion cohort, n = 15); daunorubicin and cytarabine (60 mg/m2 i.v.; cohort 2, n = 6); or azacitidine (100 mg/m2 i.v.; cohort 3, n = 6). Patients, except cohort 2, were ineligible for intensive chemotherapy. The primary end-point was dose-limiting toxicity in cohorts 1-3 and disease-modifying response in the expansion cohort. Disease-modifying response rate was tested with the null hypothesis of 6.8%, which was set based on the results from the phase II BRIGHT AML 1003 study (NCT01546038). No dose-limiting toxicities were observed in cohorts 1 or 3; one patient in cohort 2 experienced a dose-limiting toxicity of grade 3 erythroderma. The most common grade ≥3 treatment-related adverse events were neutropenia and thrombocytopenia (66.7% each) in cohort 1 and thrombocytopenia (60.0%) in the expansion cohort. In the expansion cohort, the disease-modifying response rate was 46.7% (90% confidence interval, 24.4-70.0; p < 0.0001), with all patients achieving either a complete response or complete response with incomplete blood count recovery. Median overall survival was 13.9 months. In this study, the primary disease-modifying response end-point with glasdegib plus low-dose cytarabine was met. The study confirms the safety and efficacy of glasdegib plus low-dose cytarabine in Japanese patients with AML ineligible for intensive chemotherapy.

Decitabine-containing conditioning improved outcomes for children with higher-risk myelodysplastic syndrome undergoing allogeneic hematopoietic stem cell transplantation.

Myelodysplastic syndrome (MDS) is a rare clonal hematopoietic disorder in children. The risk stratification system and treatment strategy for adults are unfit for children. The role of hypomethylating agents (HMAs) in higher-risk childhood MDS has not been identified. This study aimed to investigate the outcomes of hematopoietic stem cell transplantation (HSCT) in children with higher-risk MDS at one single center. A retrospective study was conducted in children with higher-risk MDS undergoing HSCT between September 2019 and March 2023 at Blood Diseases Hospital CAMS. The clinical characteristics and transplantation information were reviewed and analyzed. A total of 27 patients were analyzed, including 11 with MDS with excess blasts (MDS-EB), 14 with MDS-EB in transformation (MDS-EBt) or acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 2 with therapy-related MDS/AML (t-MDS/AML). Eight patients harbored monosomy 7. Before transplantation, induction therapy was administered to 25 patients, and 19 of them achieved bone marrow blasts <5% before HSCT. The stem cell source was unmanipulated-related bone marrow or peripheral blood stem cells for nineteen patients and unrelated cord blood for eight. All patients received decitabine-containing and Bu/Cy-based myeloablative conditioning; 26 patients achieved initial engraftment. The cumulative incidences of grade II-IV and grade III-IV acute graft-versus-host disease (GvHD) at 100 days were 65.4% and 42.3%, respectively. The incidence of cGvHD was 38.5%. The median follow-up was 26 (range 4-49) months after transplantation. By the end of follow-up, two patients died of complications and two died of disease progression. The probability of 3-year overall survival (OS) was 84.8% (95%CI, 71.1 to 98.5%). In summary, decitabine-containing myeloablative conditioning resulted in excellent outcomes for children with higher-risk MDS undergoing allogeneic HSCT.

Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study

Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia. We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1-5 and venetoclax (variable doses of 100-400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with ClinicalTrials.gov, NCT04655755, and is currently enrolling participants. Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27-94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3-4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6-16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation. This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data. MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech/AbbVie, and Astex Pharmaceuticals.

Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax.

Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood. We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes. A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes. Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.

Azacitidine Post-transplant Maintenance Improves Disease Progression in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

BackgroundMaintenance after allogeneic hematopoietic cell transplantation (alloHCT) with hypomethylating agents has yielded conflicting results. Materials and MethodsWe conducted a single center retrospective matched-control analysis with the study group (5-azacitidine [AZA] group) including adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received post-transplant AZA maintenance off clinical trial (n = 93). A matched control group was comprised of contemporaneous AML/MDS patients who did not receive any maintenance (n = 357). Primary endpoint was disease progression. ResultsThe AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years, P = .01) and lower hematopoietic comorbidity index (median: 2 vs. 3, P = .04) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33% (P = .09). The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, P = .004 and HR = 0.4, 95% CI = 0.2-0.9, P = .04). ConclusionAZA maintenance was associated with a lower progression rate in patients with high-risk FLT3-negative AML or MDS, and AZA maintenance should be considered for post-alloHCT maintenance in this subset.

Addition of Myeloablative Doses of Total Marrow Irradiation (TMI) to Myeloablative Fludarabine/Busulfan Conditioning for Allogeneic HSCT in Patients with High-Risk AML, CML, or Myelodysplastic Syndrome: A Phase II Clinical Trial

Addition of Myeloablative Doses of Total Marrow Irradiation (TMI) to Myeloablative Fludarabine/Busulfan Conditioning for Allogeneic HSCT in Patients with High-Risk AML, CML, or Myelodysplastic Syndrome: A Phase II Clinical Trial