High-risk Myelodysplastic Syndrome Research Articles

Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine

Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.

Germline variant of CTC1 gene in a patient with pulmonary fibrosis and myelodysplastic syndrome.

Telomeropathies are associated with a wide range of diseases and less common combinations of various pulmonary and extrapulmonary disorders. In proband with high-risk myelodysplastic syndrome and interstitial pulmonary fibrosis, whole exome sequencing revealed a germline heterozygous variant of CTC1 gene (c.1360delG). This "frameshift" variant results in a premature stop codon and is classified as likely pathogenic/pathogenic. So far, this gene variant has been described in a heterozygous state in adult patients with hematological diseases such as idiopathic aplastic anemia or paroxysmal nocturnal hemoglobinuria, but also in interstitial pulmonary fibrosis. Described CTC1 gene variant affects telomere length and leads to telomeropathies. In our case report, we describe a rare case of coincidence of pulmonary fibrosis and hematological malignancy caused by a germline gene mutation in CTC1. Lung diseases and hematologic malignancies associated with short telomeres do not respond well to standard treatment.

Real-world (RW) treatment (tx) patterns of patients (pts) with higher-risk myelodysplastic syndrome (MDS) in a US RWE database (COTA).

e19077 Background: Pts with higher-risk MDS have poor outcomes. To understand current tx patterns/identify unmet needs, the COTA database, using pt-level curated electronic health record (EHR) data from centers across the US, was analyzed. Methods: This was a retrospective, descriptive analysis of deidentified secondary data from the COTA MDS RWE database. Data were abstracted from EHRs using these criteria: inclusion of adults with IPSS-R intermediate (I)/high (H)/very high-risk (vHR) MDS on/after 1/1/2012, exclusion of pts with no diagnosis date/clinician notes or pts with concurrent malignancies. Follow-up was until the last recorded event (last visit/other cancer/death; data cutoff 06/2022). Results: Data from 640 pts were included in this analysis. See Table for baseline demographic data. Most pts with IR- (225/281, 80%) and HR-MDS (162/239, 68%) were treated at community centers; pts with vHR-MDS were equally treated at academic (59/120, 49%) and community centers (61/120, 51%). Genetic/molecular data were limited; among pts with data available, the most common genetic mutation was TP53 (75/215, 35%). Of 640 pts, 108 (17%) did not receive tx and 110 (17%) received allogeneic stem cell transplant (alloSCT). Of those given systemic tx, hypomethylating agents (HMAs) were the most common first-line tx (444/532, 83%). Venetoclax was given to 35/640 pts (5%; as first line: 10/532, 2%; as second line: 20/170, 12%; as third line: 4/66, 6%). Median time to start tx from diagnosis was 2.2, 1.1, and 0.9 mo for IR-, HR-, and vHR-MDS, respectively. Of 512 pts assessed for first-line tx with duration data, tx duration was 7.4, 5.4, and 4.2 mo for IR-, HR-, and vHR-MDS, respectively. In 340 pts—including pts who underwent alloSCT—with response data, pts with IR-, HR-, and vHR-MDS had RW response rates (any response) of 73%, 72%, and 58%, respectively. Median OS (mOS) from start of tx was 29.0, 20.3, and 11.9 mo for IR-, HR-, and vHR-MDS, respectively. mOS (from tx start) according to tx: alloSCT 31.4 mo, chemotherapy 19.1 mo, HMAs 23.1 mo, investigational 22.1 mo, venetoclax 10.1 mo, and others 23.8 mo. About 20% of pts transformed into acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, or chronic lymphocytic leukemia. Conclusions: This RW study showed that available tx for pts with higher-risk MDS in the US is limited and remains a high unmet need. [Table: see text]

A phase I study of MEK inhibitor selumetinib in combination with azacitidine in patients with higher-risk chronic myeloid neoplasia.

TPS7084 Background: Myelodysplastic syndrome (MDS), Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes present significant clinical challenges for patients deemed transplant ineligible, and who are relapsed or refractory to conventional therapies. RAS-pathway activating mutations in myeloid malignancies are associated with a proliferative phenotype and contribute to disease progression. Cooperation between RAS-dependent signaling and epigenetic dysregulation provides the basis for rationally designed combination studies. Selumetinib (AZD6244) is a potent, selective, orally bioavailable, and non-ATP competitive small molecule inhibitor of MEK1/2, downstream of RAS. Methods: This is an investigator-initiated, Phase I, open-label dose-escalation study of selumetinib in combination with azacitidine for patients with higher risk MDS, MDS/MPNs, and myelofibrosis. The trial will enroll patients with high-risk myeloid neoplasms that meet disease-specific criteria for MDS or MPNs and who require treatment. This phase I study follows a 3+3 dose-escalation design, with three planned dose levels across two different cohorts (A and B). The dose of azacitidine 75 mg/m2 will remain stable, with three planned selumetinib dose levels (50 mg, 75 mg, and 100mg, respectively) across the two cohorts. Azacitidine will be given on days 1-7 followed by selumetinib from days 7-21 of 28 day cycles. Cohort A includes subjects with MDS with relapsed/refractory disease requiring therapy and MDS/MPN overlap syndromes; Cohort B includes subjects with myelofibrosis refractory or intolerant to JAK inhibitor therapy or ineligible for ruxolitinib treatment given baseline cytopenias (thrombocytopenia &lt; 50,000/uL, anemia &lt; 9 g/dL, and/or red cell transfusion dependent). The trial has an enrollment goal of 18 to 24 subjects, and treatment will continue indefinitely if the patient continues to derive benefit. Dose escalation will proceed independently within both cohorts. Cohort A is nearing completion of enrollment and cohort B is actively enrolling. The primary objective is to determine the maximum tolerated dose of selumetinib in combination with azacitidine. Select secondary and exploratory objectives include describing the preliminary clinical response rates and observing relationships between the presence of RAS activating mutations, RAS pathway activation, and clinical response. Clinical trial information: NCT03326310 .

Transplant teeter-totter: How hematologists communicate the high risk, high reward nature of allogeneic hematopoietic cell transplant with patients.

e24189 Background: While allogeneic hematopoietic cell transplant (HCT) offers a chance of cure for many patients with aggressive blood cancers, it carries many risks. Little is known about how hematologists communicate this uncertainty with patients. In this secondary analysis from a telemedicine study assessing how transplant hematologists facilitate shared decision making with patients, we evaluated how physicians discuss the high risk, high reward concept of allogeneic HCT. Methods: This is a qualitative analysis of transcribed video-recorded virtual encounters of transplant hematologists with patient actors. We recruited US hematologists who routinely perform allogeneic HCT via email. Participants conducted up to an hour-long video encounter with an actor trained to portray a 67-year-old man recently diagnosed with high-risk myelodysplastic syndrome and referred for specialty hematology consultation for discussion of treatment options. Results: Transcripts from 33 hematologists (mean age 46 +/- 11 years; 61% male) were available at the time of analysis. Hematologists frequently used “teeter-totter” language that oscillated between optimistic encouragement and cautious hesitancy about allogeneic HCT: HCT represented the best and only chance for cure, but it was dangerous, required sacrifice, and did not ensure long term survival. Many hematologists used tentative hedging to describe HCT’s intent for possible (rather than certain) cure, and many detailed the effect of potential undesirable complications on survival and quality of life. They also acknowledged that given HCT’s unpredictability and complexity, prognostication for any individual patient was difficult if not impossible, especially early on. The teeter-totter language frequently occurred within the same sentence or speaker turn (e.g. it may “give[] you a cure, but it comes at a price”) and also played out more gradually throughout the encounter both in exchanges between hematologist and patient and by the hematologist. With respect to decision making, some hematologists expressed their goal for the patient to understand the teeter-totter of transplant in order to make a well-informed decision based upon the patient’s personal risk tolerance/aversion. Others proposed that they share an acceptance of the teeter-totter and together deal with complications one step at a time along the transplant journey. Many reinforced that transplant offered the best chance for long term survival despite the risks and that they would do everything they could to help the patient achieve this. Conclusions: Hematologists use “teeter-totter” language to express uncertainty, hope, and caution about the high risk, high reward nature of allogeneic HCT. This language is used to prepare patients for unpredictable and uncontrollable aspects of the transplant journey and to inform decision making.

The genetics of transformation from myelodysplastic syndrome to secondary acute myeloid leukemia.

e19073 Background: Gene mutations play key role in the transformation from myelodysplastic syndrome (MDS) to secondary acute myeloid leukemia (s-AML). The aim of this study was to explore the clonal progression pattern from MDS to s-AML. Methods: A total of 663 patients diagnosed with MDS (n = 291), s-AML (n = 86), and primary AML (p-AML) (n = 286, M3 excluded) were enrolled in this study from May 2018 to December 2021, and the median age was 57 year-old (range 1~88). The diagnosis was established according to the WHO criteria. The MDS patients were divided into low-risk MDS ( n = 158) and high-risk MDS (n = 133) according to 2012 IPSS-R. Next generation sequencing was performed to detect the mutations of entire coding regions of 112 genes related with hematologic tumors in all patients. Results: It was found that mutations from 31 genes occurred in both MDS and AML, including DNA methylation ( DNMT3A, TET2, IDH1, IDH2, WT1), chromatin modification ( SETBP1, ASXL1, EZH2, PHF6), RNA splicing ( U2AF1, SF3B1, SRSF2, ZRSR2), transcription regulation ( TP53, CEBPA, RUNX1, ETV6, GATA2, BCOR, BCORL1), signal transduction pathways ( NRAS, KRAS, PTPN11, NOTCH1, FLT3, JAK2, KIT), and others ( NPM1, FAT, STAG2, DDX41). By enrichment analysis, those mutations were classified into two categories: type A mutations ( FLT3, IDH1, NPM1, NRAS, PTPN11, WT1, CEBPA) and type B mutations ( IDH2, KRAS, U2AF1, ZRSR2, SRSF2, STAG2, DNMT3A, EZH2, RUNX1, ETV6, TP53). The type A genes were significantly enriched in p-AML than in MDS, while some type B mutations, particularly RNA splicing, were significantly enriched in MDS than in p-AML. The VAFs of type A mutations were significantly lower than those of type B mutations. The longitudinal analysis of 10 patients with s-AML revealed two main models of clonal evolution, linear evolution and clone sweeping. Although the two models differed in the disease development, new sub-clones appeared in 9/10 patients. Interestingly, many of the new mutations were type A mutations (n = 7, 7/10), and 7 out of 10 patients carried type B mutations when they were at MDS state. The VAF data also showed that the preexisting mutations were generally higher than the newly emerging genetic alterations. Finally, an individual case was used to delineate the clone evolution. The patient was initially diagnosed with 5q syndrome and U2AF1 mutation (type B) was identified. After treatment, the patient experienced remission, and developed a new ETV6 mutation while the clonal size of U2AF1 decreased. When the patient relapsed, the clone size of ETV6 decreased while U2AF1 mutated clone size were amplified, a typical “clone sweeping” pattern. When the patient eventually transformed to s-AML, three type A mutations ( NRAS, KRAS and PTPN11) appeared simultaneously. Conclusions: This study revealed that the type A mutations are mainly responsible for the progression of MDS to AML, and the type B mutations are related to the clonal origin of MDS.

BOS-371, a monoclonal antibody against IL1RAP: Characterization in preclinical models of AML.

7030 Background: IL1 receptor accessory protein (IL1RAP) is a cell surface protein overexpressed on leukemia stem cells (LSC) and progenitors in AML, CML and high-risk MDS. It is an indispensable co-receptor for the IL1 superfamily, but its role reaches beyond anti-apoptotic pathways. IL1RAP directly interacts with and potentiates signaling of FLT3 and c-KIT which have significant roles in AML pathogenesis. High IL1RAP is correlated with poor prognosis and IL1 blockade attenuates expansion of LSCs. Thus, targeting IL1RAP has emerged as a promising immunotherapeutic approach for myeloid malignancies. BOS-371 is a humanized monoclonal antibody targeting IL1RAP that has been Fc-engineered to enhance its capacity to induce antibody directed cell cytotoxicity (ADCC) and deplete IL1RAP-expressing AML cells. Methods: The preclinical activity of BOS-371 was characterized using multiple assays. In vitro analysis included: binding affinity in IL1RAP-expressing cell lines; inhibition of IL1-dependent signaling as measured by IL1a -stimulated secretion of IL6 from MRC5 lung cancer cells; measurement of ADCC in co-cultures of human NK cells with either IL1RAP-expressing cell lines or primary AML cells; and cell growth by monitoring metabolic activity of primary AML cells. In vivo efficacy of BOS-371 was determined in AML models: MV4-11 and ML2 cells (CDX) implanted in NOG and NOD-SCID mice, respectively, and patient-derived (PDX) leukemia cells implanted in NOG mice. Results: BOS-371 binds with high affinity to IL1RAP-expressing cells (average EC50 337pM) leading to potent inhibition of IL1 signaling (IC50 600pM). Co-culture assays in the presence of BOS-371 showed potent induction of ADCC with an EC50 of 60-70pM (cell lines) or 4-11pM (primary cells) and 80-100% cell lysis (both cell lines and primary cells). The ability of BOS-371 to impact AML cell growth exclusively through inhibition of IL1 signaling was measured in a panel of 15 primary AML samples. Incubation with BOS-371 led to IC50s ranging from 20-700nM in responsive samples. Evaluation of BOS-371 activity in vivo showed that administration of BOS-371 resulted in significant anti-leukemic activity. In CDX studies, BOS-371 treatment led to &gt; 50% decrease in systemic disease and engraftment in bones and organs. The results observed in CDX AML models were reproduced in PDX mouse models of AML, where decreases in both peripheral ( &gt; 70%) and bone marrow ( &gt; 50%) disease burden in response to BOS-371 were observed. Conclusions: These findings demonstrate that BOS-371 binds with high affinity to IL1RAP, potently inhibits IL1 signaling and induces ADCC, leading to anti-leukemic activity in vitro and in vivo. The preclinical results support the clinical investigation of BOS-371 for the treatment of myeloid malignancies. A Phase 1 trial is currently in development.

Will we have a match? Observations from decision making conversations between hematologists and White and Black patients considering allogeneic stem cell transplant.

12133 Background: Allogeneic stem cell transplant (alloSCT) is the only treatment associated with cure for high-risk myelodysplastic syndrome (MDS), but carries substantial risks. One routinely mentioned concern is donor source. While white patients have an 80% chance of finding an unrelated fully matched donor, Black patients have among the lowest chance at 30%. The aim of this secondary analysis, from a telemedicine study assessing how hematologists engage in shared decision making with patients considering alloSCT, is to analyze how hematologists navigate discussions about donor concerns related to the apparent race of the patient. Methods: This is a qualitative analysis of transcribed video-recorded virtual encounters. We recruited US hematologists who perform alloSCT and randomized them to meet with a patient actor of Black or white race. The hematologists conducted a new patient encounter with the actors who were trained to portray the same 67 year old man with newly diagnosed high-risk MDS referred for specialty consultation to discuss treatment options. The patient character had multiple healthy siblings and children. Results: Transcripts from a total of 33 hematologists were available at the time of analysis (61% male, 30% non-white, mean age 46 +/- 11 years). Hematologists spent varying amounts of time discussing the concept of transplant donation. While some used complex language to describe matching and HLA tissue markers, others used simplified terms of finding a donor with “an immune system that’s similar to your own,” to eradicate foreign MDS cells and avoid attack on healthy cells. The majority emphasized searching for a donor among siblings, given the highest likelihood of matching. Conversations with the white actor included reassurance of finding a fully matched donor, whether through family or the international registry. Hematologists frequently disclosed the highest chance of success for people of European ancestry. While hematologists mentioned the registry in conversations with the Black actor, they rarely disclosed the lower chance of finding a fully matched unrelated donor. Instead they reassured that with better technology haploidentical match could be an option through donation from their child, “with as favorable outcomes.” Some gave the Black actor an overestimation of finding a fully matched donor through the registry. Non-white hematologists more frequently acknowledged the concept of race in stem cell donation. Conclusions: Hematologists use multiple strategies to help patients understand the donor process. They reveal to white patients the high likelihood of finding a fully matched donor while appearing to avoid discussing the lower odds for a Black patient.

UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome

Tandem-duplication mutations of the UBTF gene (UBTF-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), FLT3-internal tandem duplications (FLT3-ITD), WT1-mutations) and inferior outcome. Due to limited knowledge on UBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF-TDs were overall rare (n = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with UBTF-TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3-ITD (50% vs. 20.8%) co-mutations, whereas UBTF-TDs were mutually exclusive with several class-defining lesions such as mutant NPM1, in-frame CEBPAbZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n = 5) retained the UBTF-TD mutation, UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of UBTF-mutant patients, UBTF-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52–3.17, p < 0.001], RFS [HR: 1.59; 95% CI 1.02–2.46, p = 0.039] and OS [HR: 1.64; 95% CI 1.08–2.49, p = 0.020]). In summary, UBTF-TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients.

CPX-351 for higher risk myelodysplastic syndrome: cytarabine and daunorubicin in disguise?

Higher-risk myelodysplastic syndrome is a heterogenous disease with a poor prognosis that occurs in older people. 1 Greenberg PL Myelodysplastic syndromes, thy name is heterogeneity. Br J Haematol. 2023; 201: 381-382 Crossref PubMed Scopus (0) Google Scholar Current treatment regimens usually result in a transient and often less than complete response. Only allogeneic haematopoietic stem-cell transplantation (HSCT) can potentially cure a select group of relatively young and fit patients. These patients usually receive remission induction therapy before allogeneic HSCT, but in the absence of well designed, prospective randomised clinical trials, its value remains uncertain. 2 de Witte T Bowen D Robin M et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017; 129: 1753-1762 Crossref PubMed Scopus (213) Google Scholar CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 studyCPX-351 appears to be active and safe in patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia, allowing bridging to allogenic HSCT in most patients. Full-Text PDF

CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 study

CPX-351, an encapsulated form of cytarabine and daunorubicin, has shown greater efficacy than the classic 3 + 7 treatment administration in secondary acute myeloid leukaemia. Given that higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia share similarities with secondary acute myeloid leukaemia, we aimed to investigate the safety and efficacy of CPX-351 in this context. This investigator-initiated two-cohort phase 2 trial was conducted by the Groupe Francophone des Myélodysplasies, with 12 participating centres in France. It comprised cohort A (reported here and completed), which included patients in first-line treatment, and cohort B, which was stopped for lack of inclusion (ie, not enough patients met the inclusion criteria), for patients with hypomethylating agent failure that is not reported here. Cohort A enrolled patients with newly diagnosed higher-risk myelodysplastic syndrome or chronic myelomonocytic leukaemia (aged 18-70 years old) with an Eastern Cooperative Oncology Group performance status of 0-1. Intravenous CPX-351 (100 mg/m2 cytarabine and 44 mg/m2 daunorubicin) was given on days 1, 3, and 5, with a second induction cycle given (same daily dose on days 1 and 3) if at least a partial response was not reached. Patients who responded could receive up to four monthly consolidation cycles (same daily dose on day 1) or allogeneic haematopoietic stem-cell transplantation (HSCT). Overall response rate after one or two induction courses according to European LeukemiaNet 2017 acute myeloid leukaemia was the primary endpoint after CPX-351 induction, whether patients received one or two induction cycles. Safety was assessed in all patients enrolled (in cohort A). This trial is registered with ClinicalTrials.gov, NCT04273802. Between April 29, 2020, and Feb 10, 2021, 21 (68%) male and ten (32%) female patients were enrolled. 27 (87%) of 31 patients responded (95% CI 70-96). 16 (52%) of the 31 patients received at least one consolidation cycle. 30 (97%) of the 31 patients included were initially considered eligible for allogeneic HSCT and 29 (94%) of the 31 patients had the procedure. Median follow-up was 16·1 months (IQR 8·3-18·1). The most common grade 3-4 adverse events were pulmonary (eight [26%] of 31 patients) and cardiovascular (six [19%] of 31 patients). There were 14 serious adverse events (mainly hospitalisation for infection [n=5] and only one was treatment-related) and no treatment-related death. CPX-351 appears to be active and safe in patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia, allowing bridging to allogenic HSCT in most patients. Jazz Pharmaceuticals.

Next-generation sequencing of baseline genetic mutations and outcomes of eltrombopag and azacitidine therapy in patients with myelodysplastic syndromes and thrombocytopenia: Data from the SUPPORT clinical trial.

Eltrombopag has been previously shown to be effective in reversing azacitidine-mediated thrombocytopenia. This was further investigated in the SUPPORT trial, a phase III study assessing the efficacy/safety of eltrombopag plus azacitidine in patients with intermediate- to high-risk myelodysplastic syndromes and thrombocytopenia. The results did not support a clinical benefit for the addition of eltrombopag to azacitidine. We investigated if the somatic mutational profiles in the patient cohort were associated with treatment outcomes. Based on the available data, we observed no imbalance in the mutational profiles between treatment arms or a clear association between identified somatic mutations and clinical outcomes.

A randomized comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: the UK NCRI AML19 trial

AbstractLiposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia (AML); to date, there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). A total of 189 patients were randomized (median age, 56 years). Per clinical criteria, 49% of patients had de novo AML, 20% had secondary AML, and 30% had high-risk MDS. MDS-related cytogenetics were present in 73% of the patients, with a complex karyotype in 49%. TP53 was the most common mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 (44%) patients. The overall response rate (CR + CRi) after course 2 was 64% and 76% for CPX-351 and FLAG-Ida, respectively. There was no difference in OS (13.3 months vs 11.4 months) or event-free survival in multivariable analysis. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months). There was no difference between the treatment arms in patients with clinically defined secondary AML or those with MDS-related cytogenetic abnormalities; however, an exploratory subgroup of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months). In conclusion, the OS of younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.

Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914 Alone or in Combination With Standard-of-Care Agents in Patients With Advanced Hematologic Malignancies

BackgroundThe Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are implicated in tumorigenesis; the pan-PIM kinase inhibitor, INCB053914, demonstrated antitumor activity in hematologic malignancy preclinical models. Patients and MethodsThis phase 1/2 study evaluated oral INCB053914 alone or combined with standard-of-care agents for advanced hematologic malignancies (NCT02587598). In Parts 1/2 (monotherapy), patients (≥18 years) had acute leukemia, high-risk myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasm, myelofibrosis (MF), multiple myeloma, or lymphoproliferative neoplasms. In Parts 3/4 (combination therapy), patients had relapsed/refractory or newly diagnosed (≥65 years, unfit for intensive chemotherapy) acute myeloid leukemia (AML) or MF with suboptimal ruxolitinib response. ResultsParts 1/2 (n = 58): 6 patients experienced dose-limiting toxicities (DLTs), most commonly aspartate aminotransferase/alanine aminotransferase-elevated (AST/ALT; each n = 4). Fifty-seven patients (98.3%) had treatment-emergent adverse events (TEAEs), most commonly ALT-elevated and fatigue (36.2% each); 48 (82.8%) had grade ≥3 TEAEs, most commonly anemia (31.0%); 8 (13.8%) had grade ≥3 ALT/AST-elevated TEAEs. Parts 3/4 (n = 39): for INCB053914 + cytarabine (AML; n = 6), 2 patients experienced DLTs (grade 3 maculopapular rash, n = 1; grade 3 ALT-elevated and grade 4 hypophosphatemia, n = 1); for INCB053914 + azacitidine (AML; n = 16), 1 patient experienced a DLT (grade 3 maculopapular rash). Two complete responses were observed (1 with incomplete count recovery). For INCB053914 + ruxolitinib (MF; n = 17), no DLTs occurred; 3 patients achieved best reduction of >25% spleen volume at week 12 or 24. ConclusionINCB053914 was generally well tolerated as monotherapy and in combinations; TEAEs were most commonly ALT/AST-elevated. Limited responses were observed with combinations. Future studies are needed to identify rational, effective combination strategies.

Autoimmune HLA Alleles and Neoepitope Presentation Predict Post-Allogenic Transplant Relapse.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can cure patients with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, many patients relapse or develop debilitating graft-versus-host disease. Transplant restores T-cell reactivity against tumor cells, implicating patient human leukocyte antigen (HLA)-dependent antigen presentation via the major histocompatibility complex as a determinant of response. We sought to identify characteristics of the HLA genotype that influence response in allo-HSCT patients. We collected HLA genotype and panel-based somatic mutation profiles for 55 patients with AML and MDS and available data treated at the University of California San Diego Moores Cancer Center between May 2012 and January 2019. We evaluated characteristics of the HLA genotype relative to relapse-free time and overall survival (OS) post-allo-HSCT using univariable and multivariable regression. In multivariable regression, the presence of an autoimmune allele was significantly associated with relapse-free time (hazard ratio [HR], 0.25; p = 0.01) and OS (HR, 0.16; p < 0.005). The better potential of the donor HLA type to present peptides harboring driver mutations trended toward better relapse-free survival (HR, 0.45; p = 0.07) and significantly correlated with longer OS (HR, 0.33; p = 0.01) though only a minority of cases had an HLA mismatch. In this single institution retrospective study of patients receiving allo-HSCT for relapsed AML/MDS, characteristics of an individual's HLA genotype (presence of an autoimmune allele and potential of the donor HLA to better present peptides representing driver mutations) were significantly associated with better outcomes. These findings suggest that HLA type may guide the optimal application of allo-HSCT and merit evaluation in larger cohorts. ClinicalTrials.gov Identifier: NCT02478931.

Abstract A14: Ex vivo immune activation with the macrophage-targeting immunotherapy, anti-Clever-1 antibody bexmarilimab, in acute myeloid leukemia and myelodysplastic syndrome

Abstract The potential of immunotherapies in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains still under investigation. Clever-1 (also known as Stabilin-1) is a multifunctional scavenger and adhesion receptor expressed by monocytes and immunosuppressive macrophages. Bexmarilimab, a Clever-1 targeting antibody, demonstrates many immunomodulatory effects1 along with promising anti-tumor activity against solid tumors in patients with multiple lines of previous treatment2. In AML, high STAB1 (mRNA) levels associate with poor survival and resistance to therapy3. The aim of this study was to profile Clever-1 expression in AML and MDS and test in preclinical models the growth inhibitory and immunomodulatory potential of bexmarilimab, as a single agent and in combination with azaciditine and venetoclax. AML cell lines (n=11) and frozen mononuclear cells, extracted from AML (n=42) and very high risk MDS (n=4) patient bone marrow (BM) aspirates provided by the Finnish Hematology Registry and Biobank, were used. Samples were treated for 48h with bexmarilimab alone, or in combination with azacytidine and/or venetoclax. Flow cytometry was used to detect different myeloid and TBNK cell populations along with Clever-1, HLA-DR, PD-(L)1 and additional T cell activation markers. Our results confirmed Clever-1 protein expression in AML cell lines and bexmarilimab treatment induced metabolic and growth inhibition of KG1 blasts (Clever-1high). In patients with AML, FAB M4/M5 subtypes exhibited highest Clever-1 levels, along with FAB M2 patients with consequent rapid relapse. Clever-1 expression correlated negatively with monocyte MHC class II molecule, HLA-DR, expression, and BM T-cell frequency, in line with the immunosuppressed state associated with high Clever-1. Ex vivo treatment of the primary AML BM cells with bexmarilimab resulted in a notable, 5-10x fold increase in monocyte HLA-DR in samples with low basal HLA-DR and high Clever-1. The combination of azacitidine with bexmarilimab augmented HLA-DR induction by 20-110% (mean 44%). FAB M1/M2 AML showed increase in activation markers, such as Ki67, CXCR3 and Granzyme B after ex vivo bexmarilimab treatment in CD8+ T-cells. Furthermore, bexmarilimab reduced PD-1 expression in NK- and CD8+CXCR3+ T-cell populations of FAB M0-M2 AML and MDS-EB2. This project is the first comprehensive investigation of Clever-1 expression in AML and MDS patient BM blasts and monocytes. Ex vivo treatment with bexmarilimab, alone or in combination with azacytidine or venetoclax, indicate enhanced antigen presentation capability and immunological activation. These results validate the therapeutic potential of bexmarilimab in myeloid malignancies. The safety, tolerability and preliminary efficacy of bexmarilimab is now further investigated in combination with venetoclax and/or azacytidine in a phase I/II clinical trial BEXMAB (NCT05428969).1Viitala et al., Clin Cancer Res 2019;25:3289-303; 2 Bono et al., Annals of Oncology; 2021. p 32, 5: S1283-S346; 3 Lin et al., Mol Ther Nucleic Acids 2019;18:476-84 Citation Format: Arno Ylitalo, Sofia Aakko, Heikki Kuusanmäki, Mari Björkman, Juho Jalkanen, Marie-Louise Fjällskog, Caroline Heckman, Maija Hollmén, Mika Kontro. Ex vivo immune activation with the macrophage-targeting immunotherapy, anti-Clever-1 antibody bexmarilimab, in acute myeloid leukemia and myelodysplastic syndrome [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A14.

Sex Disparities in Myelodysplastic Syndromes: Genotype, Phenotype, and Outcomes.

Introduction/Background The impact of biological sex on the clinical phenotype, genotype, and outcomes among patients with MDS is not well characterized. Materials and Methods We retrospectively reviewed the clinical and genomic data from male and female patients included in our institutional MDS database at Moffitt Cancer Center. Results Among 4580 patients with MDS, 2922 (66%) were men and 1658 (34%) were women. Women were younger (mean age 66.5 vs. 69 years for men, P < .001) at diagnosis. There were more Hispanic/black women than men (9% vs. 5%, P =<.001). Women had lower hemoglobin and higher platelet counts than men. More women had del 5q/monosomy 5 abnormalities compared to men (P =<.001). Therapy related MDS were more common in women than men (25% vs.17%, P=<.001). On assessment of molecular profile, SRSF2, U2AF1, ASXL1, and RUNX1 mutations were more frequent in men. The median overall survival (mOS) was 37.5 months (mo) for females compared to 35 monthsfor males, (P=.002). The mOS was significantly prolonged for women in lower-risk MDS, but not in higher-risk MDS. Women were more likely to respond to immunosuppression with ATG/CSA than men (38% vs. 19%, P= 0.04).Conclusion Ongoing research is needed for understanding the impact of sex on phenotype, genotype, and outcomes in patients diagnosed with MDS.

Abstract IA09: Epigenomic landscapes of MDS

Abstract While significant progress has been made to understand the genetic landscape of MDS, less is known about the epigenetic makeup of this disease and how this may impact biology and response to azacitidine (AZA). To address this, we performed genomic, epigenomic and transcriptomic analysis on CD34+ cells from a multicenter cohort of 94 intermediate or higher risk MDS patients treated with AZA who had documented responses. DNA methylation (DNAme) by ERRBS, gene expression (GE) by RNA-seq, mutational profiling, and detailed clinical, cytogenetic and laboratory data were documented. Supervised and unsupervised analyses revealed that aberrant DNAme in MDS is not distributed randomly but rather is highly correlated with disease phenotypes, capturing clinically relevant heterogeneity, beyond what is identified by methodologies used in the past that focused solely on promoter regions. Moreover, this epigenetic information can be harnessed for the development of robust biomarkers predictive of AZA response and integrative approaches combining GE and DNAme data can further improve the predictive performance of these biomarkers, with an AUC score=0.92. Citation Format: Maria E. Figueroa. Epigenomic landscapes of MDS [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr IA09.

An obituary on DAV-132—authors’ viewpoint on the current limits of pivotal trials in clinical microbiome research

There is an urgent need for novel approaches to reduce the spread and clinical impact of infections with MDR bacteria. Da Volterra (Paris, France) is a biopharmaceutical company specializing in the development of microbiota-protective therapies. In 2010, they introduced DAV-132, an active charcoal preparation designed to protect the gut microbiota from antibiotic selection pressure, without affecting antibiotic pharmacokinetics, at the Superbugs and Superdrugs Conference in London, UK.1 In 2016, Da Volterra joined the EU Innovative Medicines Initiative (IMI) to further develop this promising product in close cooperation with academic partners. Phase I and II trials were completed successfully, confirming the protective effect of DAV-132 on the human gut microbiota.2,3 Consequently, a Phase III trial—MICROCARE—was planned and initiated. On 2 December 2022, however, the company Da Volterra was declared bankrupt. Given the significant clinical potential of DAV-132, this turn of events can be considered tragic. Could it have been avoided? The authors of this letter were closely involved in the design and conduct of the Phase III trial necessary for registration of DAV-132, which was classified as a medical device by the competent authorities. Many hurdles had to be overcome to design and implement a trial that would be feasible to execute. To meet EMA and FDA registration criteria, it was necessary to show that DAV-132 could confer a health benefit. Protecting the microbiota is a very useful property, but is not considered a health benefit per se and is not recognized as a surrogate endpoint. Therefore, an alternative clinical endpoint had to be identified. The evidence on potential health benefits associated with a balanced human microbiota seems to be growing exponentially.4 At the same time, very little of that evidence is quantifiable and directly relatable to endpoints recognized by regulators. For the Phase III trial, we needed patients with considerable antibiotic exposure. These would have to experience a measurable clinical outcome associated with their antibiotic exposure. In addition, the frequency of this outcome to occur would need to be high enough to result in a feasible sample size. The only indication that seemed to fit these criteria was the prevention of Clostridioides difficile infections (CDI). Even though CDI is considered the most frequent healthcare-associated infectious cause of diarrhoea, its overall incidence is declining. Predicting which individual patient might develop CDI remains a major challenge, despite the identification of age and intense antibiotic exposure as key risk factors for CDI.5,6 In patients undergoing induction chemotherapy for AML or high-risk myelodysplastic syndrome the frequent co-occurrence of the latter risk factors results in a relatively high cumulative incidence of CDI, ranging from 9.4% to 23.8% within the first 120 days after initiation of induction chemotherapy.7–10 Even in this selected population, a sample size of 900 was deemed necessary to show the prophylactic efficacy of DAV-132, while assuming a clinical efficacy of DAV-132 of 50% reduction in CDI cases. At the same time, selecting such a seriously ill patient population involves risks. Chemotherapy-associated side effects can significantly impair patient compliance with trial protocols, and an increased number of serious adverse events is to be expected in this population. However, given that the sample sizes calculated for all other populations were not within a realistic range, we were left with the choice of no trial versus a trial with a considerable risk of failure.

Improving the diagnosis of myelodysplastic syndrome by red blood cell parameters.

To investigate the value of red blood cell parameters in Myelodysplastic syndrome (MDS) diagnosis and their relations to MDS subtypes and risk groups. The red blood cell parameter [mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red cell distribution width (RDW)] levels [203 MDS, 99 aplastic anemia (AA), 145 megaloblastic anemia (MA)] were collected from a single-center retrospective cohort. The cut-off values, area under the receiver operating characteristic curve (ROC) curve (AUC), sensitivity and specificity of the four parameters were calculated from the ROC. Furthermore, Kruskal-Wallis test and Dunn's Test were performed to determine erythrocyte parameters in different subtypes and prognostic risks MDS. There are significant statistic differences in RDW (P < 0.001), MCH (P = 0.036) and MCHC (P < 0.001) (MDS vs AA); RDW (P = 0.009), MCV (P < 0.001), MCH (P < 0.001) and MCHC (P = 0.001) (MDS vs MA); MCV (P = 0.011) and MCH (P = 0.008) (higher-risk MDS vs lower-risk MDS). Between MDS and MA, the area under the receiver operating characteristic curve (ROC) curve (AUC) values of MCV, MCH, MCHC, RDW were 0.846, 0.855, 0.617, and 0.593. Between MDS and AA, the AUC values of MCH, MCHC, RDW were 0.609, 0.671, and 0.662, respectively. The red blood cell parameters contribute to the differential diagnosis of MDS, AA and MA and are related to MDS subtypes and risk groups.