No standard of care for elderly patients with aggressive adult T-cell leukemia/lymphoma (ATL) has been established. We evaluated the efficacy of CHOP every 2 weeks with mogamulizumab (Moga) (Moga-CHOP-14) for untreated elderly patients with ATL. In this multicenter phase 2 trial, patients aged ≥66 years and those aged 56-65 years ineligible for transplantation received 6 cycles of Moga-CHOP-14, followed by 2 cycles of Moga monotherapy. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints were the complete response (CR) rate, overall response rate (ORR), overall survival (OS), 1-year event-free survival (EFS), and safety. We also investigated the impact of CCR4 mutation and Moga-associated cutaneous adverse events (cAEs) on PFS and OS. The study protocol was amended to allow the dosing interval to be extended to 21 days at the physician's discretion. Among 48 evaluable patients, the 1-year PFS was 36.2% (90% confidence interval [CI], 24.9-47.6), with a median follow-up of 1.6 years. One-year OS and EFS were 66.0% (95% CI, 50.6-77.6) and 29.9% (95% CI, 17.6-43.2), respectively. CR and ORR were 64.6% (95%CI, 49.5-77.8) and 91.7% (95% CI, 80.0-97.7). No unexpected toxicities were observed. Of the 47 patients who received ≥2 cycles of CHOP, 20 (42.6%) received CHOP-14, among whom 12 (25.5%) completed 6 cycles. CCR4 mutation and Moga-associated cAE were associated with better OS. This study showed that Moga-CHOP significantly improved PFS, though the optimal interval for CHOP remains undetermined. Moga-CHOP is now considered a preferable first-line treatment for these patients. Clinical Trial Identifier: jRCTs041180130.

Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell-driven malignancies marked by excessive myelopoiesis and high risk of myelofibrosis, which remains therapeutically challenging. Senescent neutrophils home daily to the bone marrow (BM) to be cleared by macrophages. This avoids their accumulation, which can increase the risk of chronic inflammation or oncogenesis. Neutrophils carrying the most common oncogenic MPN driver (JAK2V617F) are protected from apoptosis, which may prolong their lifespan and enhance their pro-inflammatory activity. On the other hand, abnormal interactions of neutrophils with megakaryocytes ("emperipolesis") have been associated with BM fibrosis in disparate hematological disorders, including MPN and grey platelet syndrome; however, the underlying pathophysiology remains unclear. We investigated neutrophil homeostasis and cellular interactions in MPN. We found that senescent neutrophils evade homeostatic clearance and accumulate in JAK2V617F MPN, but not in MPN caused by the second most prevalent mutations affecting Calreticulin (CALR) gene. This is explained by GM-CSF-JAK2-STAT5-dependent upregulation of the "don't-eat-me" signal CD24 in neutrophils. Mechanistically, JAK2V617F CD24hi neutrophils evade efferocytosis, invade megakaryocytes and increase active TGF-b. Collectively, JAK2V617F neutrophil-megakaryocyte interactions promote platelet production in a humanized bioreactor and myelofibrosis in mouse models. Notably, chronic antibody blockade or genetic loss of CD24 restores clearance of senescent neutrophils, reduces emperipolesis and active TGF-b. Consequently, CD24 blockade improves thrombocytosis and prevents myelofibrosis in MPN mice. Taken together, these findings reveals defective neutrophil clearance as a cause of pathogenic microenvironmental interactions of inflammatory neutrophils with megakaryocytes, associated with myelofibrosis in MPN. Our study postulate CD24 as a candidate innate immune checkpoint in MPN.

As evidenced by the excellent survival outcomes, chronic myeloid leukemia (CML) treatment in the era of tyrosine kinase inhibitors (TKIs) is often successful. However, when response milestones are not met or lost, treatment decision-making may be challenging. The availability for first-, second- or subsequent-line use of six different TKIs, each with definite and often non-overlapping features in terms of mechanism of action, potency, activity against resistance mutations and tolerability profile provides a reassuring opportunity to rescue an optimal response, but it must be exploited carefully to avoid hasty or inappropriate choices. When and how to sequence TKIs, and if and when to consider transplant are very important issues. 'One for all' rules cannot be formulated, since for each individual patient the decision process requires investigation and integration of a series of clinical and biological factors. After discussing how resistance is defined, we here aim to provide practical guidance to therapeutic reassessment, discussing which laboratory investigations should be performed, how they should be interpreted, which additional clinical considerations are mandatory, and how these factors should be weighed and reasonably concur to the final decision.

Sepsis is characterized by a systemic inflammation and microvascular thrombosis induced by infection. NLRP6 possesses both pro- and anti-inflammatory effects with cell-type- or tissue-specific functions. However, the role of cell-type-specific NLRP6 in sepsis remains poorly understood. In the present study, we detected NLRP6 expression in platelets. By using platelet-specific NLRP6 knockout mice and the cecal ligation and puncture model of sepsis, we demonstrated that deletion of platelet NLRP6 increased the mortality, enhanced microvascular thrombosis in the lung and liver, and promoted platelet activation, platelet-neutrophil interactions as well as the neutrophil extracellular traps (NETs) formation following sepsis. Platelet function analysis in vitro showed that deletion of NLRP6 enhanced platelet aggregation, activation, and granules release. In addition, NLRP6 deletion promoted platelet NF-κB signaling via sustaining TAB1 expression independent of the inflammasome. Moreover, inhibition of NF-κB signaling abolished the aggravated effects of the absence of platelet NLRP6 on the intravascular microthrombosis and NETs formation in sepsis and increased the overall survival. Mechanistically, NLRP6 facilitated the interaction between TRIM21 and TAB1 in activated platelets, resulting in K48-linked polyubiquitination of TAB1 and subsequent degradation. Finally, sepsis plasma triggered TAB1 degradation mediated by NLRP6/TRIM21 in normal healthy platelets through TLR4/MyD88. Our study identifies a novel protective role of platelet NLRP6 in the microvascular thrombosis during sepsis, implying it as a novel target for the treatment of sepsis.

While the majority of patients with follicular lymphoma (FL) follow an indolent disease course, some patients experience a critical inflection point when FL transforms into an aggressive lymphoma. Historically, FL transformation (tFL) is marked by poor outcomes, particularly for patients with prior FL-directed treatment. Compared to FL, tFL is marked by numerous additional genetic changes, upregulates novel signaling pathways and arises from an ancestral FL clone with shared FL-initiating mutations. Prediction of tFL risk remains a high-priority area of disease research, with recent work highlighting memory-like B cell phenotypes associated with transformation risk and implicating critical tumor-immune interactions at transformation emergence. Mechanistic studies provide insight into the role of genetic drivers in determining malignant B cell phenotypes or reducing microenvironmental dependencies. In parallel, a shifting therapeutic landscape marked by novel immune-based therapeutics is improving outcomes for patients, yet further clinical outcome data in tFL are greatly needed. This review summarizes recent scientific and clinical studies in tFL and provides an updated understanding of the biological basis, diagnosis and clinical management of tFL. We conclude with a proposed plan of future research aimed at the goal of increasing tFL biologic knowledge and improving outcomes for patients with tFL.

VEXAS (Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic) syndrome is a severe monogenic disorder caused by somatic UBA1 mutations, characterized by inflammation, cytopenias and frequent association with myelodysplastic neoplasms (MDS). Steroid dependence is common, and targeted therapies have demonstrated limited efficacy. Azacitidine (AZA), a hypomethylating agent used in MDS, has shown potential in VEXAS but data remain limited. This multicenter retrospective study assessed AZA efficacy and safety in 88 genetically confirmed VEXAS patients from the FRENVEX (French VEXAS) group, 80% meeting WHO 2022 MDS criteria. Inflammatory response rates were 41% at 6 months and 54% at 12 months, regardless of MDS status. A total of 50 (61%) patients achieved inflammatory response, with 70% occurring at 6 months, suggesting a delayed median response. Among responders, relapse-free survival on AZA was 90% at 1 year and 85% at 5 years. Of the 12 responders who discontinued AZA, 9 relapsed after a median of 3.1 years (range: 0.4-5.6), with effective re-exposure in 4 of 5 patients. Hematological responses included red blood cell transfusion independence in 65% and platelet improvement in 77% of patients. Molecular response, defined as a ≥25% reduction in UBA1 variant allele frequency (VAF), was observed in 65% of patients, all of whom achieved inflammatory and hematological responses; and VAF dropped below 2% in 43% of cases. Infections (34%) and cytopenias (36%) were common, particularly during the first three cycles. This study establishes AZA as an effective therapy for VEXAS, improving inflammation, cytopenias, and UBA1 clonal burden, warranting larger prospective trials.

Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome arising in many contexts. Its underlying mechanisms are often unclear, but defective granule-mediated cytotoxicity (familial HLH) and excess IL-18 (Macrophage Activation Syndrome, MAS) provide clues. Mounting evidence suggests the causes of HLH converge on cytotoxic T lymphocyte (CTL) hyperactivation and overproduction of IFNγ. We refined an in vitro system to simultaneously quantify multiple parameters of the murine CTL immune synapse (IS). Even in haploinsufficiency, perforin deficiency prolonged IS duration and increased IFNγ/TNF production. Similarly, both target cell immortalization and inhibition of apoptotic caspases impaired IS termination and increased cytokine production. Strong CTL activation, through T-cell receptor or IL-18 signaling, also increased IFNγ secretion but accelerated target cell death. Impaired IS termination synergized with strong CTL activation in driving IFNγ production. Visually, both typical and Prf1-/- CTL-IS terminated with apoptotic contraction. We serendipitously observed many IL-18 exposed CTL-IS terminated by target cell ballooning. Both IL-18-activated CTL and IFNγ pretreatment caused up to half of target cells to die by RIPK1-dependent necroptosis. In vivo, RIPK1 inhibition ameliorated virus-triggered HLH in Il18tg more than Prf1-/- mice. By quantifying CTL-IS duration, cytokine production, and mode of cell death, we modeled multiple HLH contributors and their interactions, and identified three HLH mechanistic categories: impaired IS termination, intense CTL cytokine production, and inflammatory target cell death. Integrating the inputs and outcomes of a hyperinflammatory CTL-IS may provide a useful framework for understanding, predicting, or treating HLH in its many forms.

Despite the success of BCMA-targeting CAR-Ts in multiple myeloma, patients with high-risk cytogenetic features still relapse most quickly and are in urgent need of additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target in other cancers, as a specifically upregulated cell surface antigen in high-risk myeloma tumors. We use a structure-guided design to define a CD27-based anti-CD70 CAR-T design that outperforms all tested scFv-based CARs, leading to >80-fold improved CAR-T expansion in vivo. Epigenetic analysis via machine learning predicts key transcription factors and transcriptional networks driving CD70 upregulation in high-risk myeloma. Dual-targeting CAR-Ts against either CD70 or BCMA demonstrate a potential strategy to avoid antigen escape-mediated resistance. Together, these findings support the promise of targeting CD70 with optimized CAR-Ts in myeloma as well as future clinical translation of this approach.

Immunotherapy has become standard of care in the treatment of diffuse large B-cell lymphoma (DLBCL). Changes in immunophenotypes observed at first diagnosis predict therapy outcome but little is known about the resolution of these alterations in remission. Comprehensive characterization of immune changes from fresh, peripheral whole blood revealed a functionally relevant increase of myeloid-derived suppressor cells, reduced naïve T-cells, and an increase of activated and terminally differentiated T-cells before treatment which aggravated after therapy. Suggesting causal relation, injection of lymphoma in mice induced similar changes in the murine T cells. Distinct immune imprints were found in breast cancer and AML survivors. Identified alterations persisted beyond five years of ongoing complete remission and in DLBCL correlated with increased pro-inflammatory markers such as IL-6, B2M, or sCD14. The chronic inflammation was associated with functionally blunted T-cell immunity against SARS-CoV-2-specific peptides and reduced responses correlated with reduced Tn-cells. Persisting inflammation was confirmed by deep sequencing and by cytokine profiles, together pointing towards a compensatory activation of innate immunity. The persisting, lymphoma-induced immune alterations in remission may explain long-term complications, have implications for vaccine strategies, and are likely relevant for immunotherapies.

This study analyzed the genetics of classical Hodgkin lymphoma (cHL) by using circulating tumor DNA (ctDNA). Two genetic subtypes were identified, differing in genetic instability mechanisms: one subtype (64% of cases) showed a higher mutation load and a higher fraction of mutations associated with activation-induced cytidine deaminase and microsatellite instability signatures, while the other subtype (36% of cases) exhibited chromosomal instability with more somatic copy number alterations. Whole-genome duplication was more common in cHL compared to other B-cell tumors and emerged as a prognostic biomarker for patients undergoing ABVD-based therapy. Non-coding regulatory mutations, similar to those in diffuse large B-cell lymphoma, were highly prevalent in 86% of cHL. A recurrent somatic expression quantitative trait locus (seQTL) involving the BCL6 gene was found in 30% of cases. The seQTL of BCL6 aligned with accessible chromatin and increased H3K27 acetylation in cHL, disrupted PRDM1 binding, and co-occurred with BCL6 expression in cHL cells. Weak to strong expression of BCL6 was observed in 68% of cases and BCL6 expression associated with gene repression similarly in cHL and germinal center B cells. After BCL6 degradation, the core set of genes directly bound and regulated by BCL6 was derepressed in cHL and proliferation was impaired. The number and clonality of neoantigens was associated with tumor microenvironment type and response to checkpoint blockade. Finally, ctDNA analysis was suggested as a tool to distinguish ambiguous PET/CT-positive lesions post-treatment.

Coagulation factor V (FV) is a key protein in maintaining the hemostatic balance, with abnormal plasma levels associated with both thrombotic and hemorrhagic conditions. We propose a comprehensive bioinformatic analysis integrating large scale proteogenomics and transcriptomic data from original and public datasets. We identify a biological fingerprint of 26 new proteins and loci involved in the regulation of plasma FV levels. Furthermore, the mRNA expression levels of 10 of these components show strong correlation in liver. In addition, we provide experimental evidence for the involvement of one of the newly identified players (CLEC4M) in the clearance of FV. This work opens new avenues for a better understanding of the physiological processes involved in thrombotic and bleeding disorders.

Rare thrombotic events associated with ChAdOx1 nCoV-19 (ChAdOx1) vaccination have raised concerns; however, the underlying mechanisms remain elusive. Here we report a novel biophysical mechanism by which ChAdOx1 directly interacts with platelets under arterial shear conditions, potentially contributing to post-vaccination arterial thrombosis. Using microfluidic post assays, we demonstrate that ChAdOx1 induces shear-dependent platelet aggregation, distinct from conventional von Willebrand factor-mediated adhesion. This interaction is mediated by platelet integrin αIIbβ3 and requires biomechanical activation, explaining the absence of significant binding under static conditions. Molecular dynamics simulations and docking studies reveal preferential binding of ChAdOx1's penton RGD motif to the activated conformation of αIIbβ3. Inhibiting integrin αIIbβ3 completely abolishes ChAdOx1-induced platelet aggregation, whereas blocking GPIb has minimal effect, confirming a mechanism that bypasses the conventional GPIb-dependent platelet adhesion pathway. Mutagenesis of the RGD motif to AAA eliminates platelet binding, verifying the specificity of this interaction. These findings provide a potential explanation for the association between ChAdOx1 vaccination and arterial thrombotic events, distinct from vaccine-induced immune thrombotic thrombocytopenia (VITT). Our results highlight the importance of considering biomechanical factors in vaccine-related thrombotic complications and suggest that shear-dependent integrin activation may be another determinant in the pathogenesis of these rare adverse events.

Insufficient eradication of cancer cells and survival of drug tolerant clones are major relapse driving forces. Underlying molecular mechanisms comprise activated pro-survival and anti-apoptotic signaling leading to insufficient apoptosis and drug resistance. The identification of programmed cell death pathways alternative to apoptosis opens up for possibilities to antagonize apoptosis escape routes. We have earlier shown that acute lymphoblastic leukemia (ALL) harbours a distinct propensity to undergo cell death by RIPK1-dependent necroptosis, activated by small molecule second mitochondria-derived activators of caspase (SMAC) mimetics. Despite demonstrated safety and tolerability of SMAC mimetics in clinical trials, their efficacy as single agent appears still limited, highlighting the need for combinatorial treatments. Here, we investigate so far unexplored regulatory mechanisms of necroptosis and identify targets for interference to augment the necroptotic anti-leukemia response. Ex vivo drug response profiling in a model of the bone marrow microenvironment reveals powerful synergy of necroptosis induction with histone deacetylase inhibition. Subsequent transcriptome analysis and functional in vivo CRISPR screening identify gene regulatory circuitries through the master transcription regulators SP1, p300 and HDAC2 to drive necroptosis. While deletion of SP1 or p300 confers resistance to necroptosis, loss of HDAC2 sensitizes to RIPK1-dependent cell death by SMAC mimetics. Consequently, our data inform strong in vivo anti-leukemic activity of combinatorial necroptosis induction and HDAC inhibition in patient-derived human leukemia models. Thus, transcriptional dependency of necroptosis activation is a key regulatory mechanism that identifies novel targets for interference, pointing out a strategy to exploit alternative non-apoptotic cell death pathways to eradicate resistant disease.

Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic phase chronic myeloid leukemia (CP-CML) has dramatically decreased. Imatinib was the 1st TKI introduced into the clinical arena, predominantly utilized in the 1st line setting. In cases of insufficient response, resistance, or intolerance, CML patients can subsequently be treated with a 2nd, 3rdor 4th generation TKI. However, despite the approval of 1st, 2nd, 3rd, 4th generation TKI allo-HSCT still remains indicated for a minority of CML patients. Here, we discuss the indications in the era of TKI through different cases representing the clinical situations for which allo-HSCT remains the best option. We also propose our transplant strategy to decrease transplant-related morbidity, particularly graft-versus-host disease (GvHD), and mortality in the particular context of CML, a disease that is one of the most sensitive to immune cellular therapy, allowing the use of a combination of donor lymphocyte infusion (DLI) and TKI for post-transplant molecular progression.

In 2013, we published a perspective entitled, "The myth of the second remission of acute leukemia," which underscored the dismal outcomes of relapsed acute leukemia in adults. We emphasized that only a minority of patients achieved second complete remission (CR2) after relapse and were subsequently eligible to receive a potentially curative allogeneic hematopoietic stem cell transplantation (HSCT). Hence, we urged the leukemia community not to delay HSCT in first complete remission (CR1) if indicated to avoid dire outcomes. Historically, poor outcomes resulted from suboptimal frontline therapy, inadequate risk stratification, and lack of effective agents to achieve CR2. In the past decade, remarkable progress has been made in the treatment paradigm of acute leukemia, most evidently in B-cell acute lymphoblastic leukemia. Key advancements include refinement of frontline treatment, incorporation of early immunotherapy, improved disease risk stratification based on molecular profiling and assessment of measurable residual disease, and discovery of highly effective salvage immunotherapies. These innovations have led to a high rate of cure by frontline therapy, precise selection for HSCT in CR1 for high-risk patients, and the reality of HSCT for patients in CR2. Here, we reexamine the myth of CR2 given the progress in the field.

Graft-versus-Host disease (GvHD) ensues as the most common non-relapse complication after allogeneic hematopoietic cell transplantation (allo-HCT). A pivotal goal in GvHD management revolves around quelling inflammation. Phagocytic clearance of inflammatory cells contributes substantially to termination of inflammatory processes. Nevertheless, the precise functions of phagocytosis in GvHD remain largely unclear. In this study, we identified the "don't eat me"-signal CD47 as a promising target for therapeutic interventions aimed at eradicating alloreactive T-cells subsequent to allo-HCT. Analysis of global data sets revealed a remarkable upregulation of CD47 expression on T-cells residing in the ileum of patients with inflamed intestine. Building on this finding, we examined CD47 levels in the gastrointestinal tract (GIT) following allo-HCT. Our work not only confirmed upregulated CD47 expression in the GIT of GvHD patients, but also identified CD47 on T-cells in the ileum of GvHD mice after allo-HCT. Additionally, we found that activated donor T-cells suppress antibody-dependent cellular phagocytosis (ADCP) via CD47 signaling in vitro. Application of anti-CD47 antibodies significantly invigorated the impaired ADCP of activated T-cells. Administering anti-CD47 antibodies to mice elevated phagocytosis of T-cells in the GIT, induced immunosuppressive responses and improved survival. Finally, transplantation of CD47 deficient donor T-cells significantly improved clinical GvHD score with improved survival after allo-HCT. Collectively, our findings illuminate CD47 upregulation as pivotal mechanism in GvHD patients, leading to impaired phagocytic clearance of alloreactive T-cells. This study proposes that anti-CD47 treatment could rectify the compromised phagocytosis of alloreactive T-cells, thereby aiding in the resolution of inflammation after allo-HCT.

We carried out a single-cell (sc) multiomic analysis on a series of MYD88 mutated Waldenström macroglobulinemia (WM) cases and identified two distinct subtypes of disease, memory B-cell-like (MBC-like) and plasma cell-like (PC-like), based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully towards a plasma cell (PC) and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the memory B-cell (MBC) stage, upregulates key MBC genes, and is characterized by upregulated BCR and AKT/mTOR signaling. In contrast, the PC-like subtype can partially differentiate towards a PC, upregulates key PC genes, has enhanced NF-kB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined scRNA-sequencing and scATAC-sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the two disease subtypes were validated further using hierarchical clustering of bulk RNA-seq data from a secondary set of cases. The biological significance of the subtypes was further established using whole genome sequencing, where it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as two disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features with potential implications for WM treatment strategies.

We sought to develop a survival model in chronic myelomonocytic leukemia (CMML) that is primarily based on clinical variables and examine additional impact from mutations and karyotype. 457 molecularly-annotated patients were considered. Multivariable analysis identified circulating Blasts ≥2% (1 point), Leukocytes ≥13 x 109/L (1 point), and severe (2 points) or moderate (1 point) Anemia as preferred risk variables in developing a clinical risk Stratification Tool for overall survival (OS), acronymized to "BLAST": low-risk (0 points; median 63 months); intermediate-risk (1 point; median 28 months; HR 2.2, 95% CI 1.6-3.0), and high-risk (2-4 points; median 13 months; 5.4, 4.1-7.3); the corresponding 3/5 year OS rates were 68%/53%, 43%/18%, and 12%/1%. BLAST model performance (AUC 0.77/0.85 at 3/5-years) was shown to be comparable to that of the molecular CMML-specific prognostic scoring system (CMML-mol; AUC 0.73/0.75) and the international prognostic scoring system-molecular (IPSS-M; AUC 0.73/0.74). Multivariable analysis of mutations and karyotype identified PHF6MUT and TET2MUT as being "favorable" and DNMT3AMUT, U2AF1MUT, BCORMUT, SETBP1MUT, ASXL1MUT, NRASMUT, PTPN11MUT, RUNX1MUT, TP53MUT, and adverse karyotype, "unfavorable". Molecular information was subsequently encoded in a combined clinical-molecular risk model (BLAST-mol; AUC 0.80/0.86 at 3/5-years) that included the aforementioned BLAST clinical risk variables and a 3-tiered molecular risk score. BLAST and BLAST-mol were subsequently validated by two separate external cohorts. Independent risk factors for blast transformation included DNMT3AMUT, ASXL1MUT, PHF6WT, leukocytes ≥13 x 109/L, and ≥2% circulating or ≥10% bone marrow blasts. The current study proposes an easy to implement, globally applicable, and molecularly adaptive risk model for CMML.

The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary endpoints were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR+CRh), and safety and tolerability. Secondary endpoints included overall response rate (ORR) and duration of response. As of September 18, 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 prior lines of therapy, 35.9%; prior venetoclax, 75.0%). The CR+CRh rate was 23.4% (1-sided P=.0014); the ORR was 46.9%. Median duration of CR+CRh was 4.7 months. Five of 30 responders (16.7%) proceeded to hematopoietic stem cell transplant (HSCT); 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as NCT04065399.

Small molecules that inhibit LSD1 (lysine-specific demethylase 1, KDM1A) have been shown to induce abundant fetal hemoglobin (HbF) levels in red blood cells both in vitro and in vivo, therefore potentially serving as potent and cost-effective therapeutics to treat the β-globinopathies, sickle cell disease (SCD) and β-thalassaemia major (TM). However, most LSD1 inhibitors (LSD1i) that induce HbF in vivo are covalent and irreversible, which leads to adverse effects. In this study, we utilized structure-aided drug design to develop potent new reversible LSD1i's leading to robust γ-globin expression in vitro. Moreover, in a mouse model of SCD, oral administration of these novel inhibitors lead to significant HbF elevation and alleviation of multiple features of disease pathology that are the usual consequences of SCD. In addition, we discovered that combined treatment of an LSD1i with a BRD4 degrader (BD-9136) represses the induction of RUNX1 and PU.1, thereby rescuing the erythroid to myeloid lineage conversion that accompanies LSD1i in hematopoiesis. The data indicate that this new generation of LSD1i can effectively induce HbF levels, reduce SCD pathologies, and are well-tolerated by oral administration in SCD mice. We anticipate that the combination of these or related binary compounds offer exciting new therapeutic possibilities for treating SCD and TM.