Haematologica

Aspirin is a life-saving drug for patients with acute myocardial infarction

2024-11-01T19:45:15+00:00

The unexpected and unresolved roles of PDGFRA and PDGFRB in T-cell acute lymphoblastic leukemia

2024-11-01T09:55:58+00:00

Acute myeloid leukemia at first relapse: approaching the precipice

2024-11-01T09:55:59+00:00

HES6: an emerging player in human hematopoiesis

2024-11-01T09:56:01+00:00

The Gordian knot: ruxolitinib or transplants for high-risk myelofibrosis

2024-11-01T09:56:03+00:00

Sickle cell and autoimmune disease: a double whammy

2024-11-01T09:56:05+00:00

Donor dilemmas in hereditary hematopoietic malignancies

2024-11-01T09:56:06+00:00

Nodular lymphocyte-predominant Hodgkin lymphoma: advances in disease biology, risk stratification, and treatment

2024-11-01T09:56:07+00:00

Recent updates have detailed how patients with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) may be better risk stratified using prognostic scoring systems. Most patients with NLPHL present with early-stage disease and have an indolent disease course. To reflect these differences from classic Hodgkin lymphoma, nomenclature has been updated to recognize nodular lymphocyte-predominant B-cell lymphoma as an alternative to NLPHL. The Global NLPHL One Working Group have published their pivotal dataset in 2024 which challenges the prognostic significance of variant immunoarchitectural (IAP) patterns and proposes a new prognostic scoring system. Key identified prognostic factors include age >45 years, stage III-IV disease, hemoglobin <10.5 g/dL and splenic involvement. After multivariate analysis, variant IAP was not shown to be associated with inferior outcome. As most patients with NLPHL have excellent long-term survival, identifying patients where treatment de-escalation is appropriate will help to minimize toxicity. De-escalation strategies include observation after fully resected stage I disease, active surveillance, anti-CD20 antibody monotherapy, radiotherapy in early-stage disease, and avoiding anthracycline- or bleomycin-containing chemotherapy regimens. Evidence supporting the use of novel therapies remains limited with disappointing results from a recently published study of ibrutinib in patients with relapsed NLPHL. Hopefully, future trials will investigate novel agents such as checkpoint inhibitors, T-cell engaging antibodies and chimeric antigen receptor T-cell therapy.

Revumenib for patients with acute leukemia: a new tool for differentiation therapy

2024-11-01T09:58:29+00:00

Treatment of acute leukemia is gradually moving away from a “one-size-fits-all” approach, as scientific and clinical advances expand the arsenal of available targeted therapies. One of the recent additions is the group of menin inhibitors; oral, selective, small molecules that disrupt the interaction between the chromatin adapter menin, and an epigenetic regulator, the lysine methyltransferase 2A (KMT2A) complex. Two susceptible leukemia subtypes have been identified: (i) acute myeloid leukemia with a mutation in nucleophosmin 1 (NPM1), and (ii) any acute leukemia, myeloid or lymphoid, with a translocation resulting in the rearrangement of KMT2A. These leukemias share a distinct genetic expression, maintained by the KMT2A-menin interaction. Together they account for approximately 40% of patients with acute myeloid leukemia and 10% of patients with acute lymphoblastic leukemia. This spotlight review follows the journey of revumenib, as a representative of menin inhibitors, from bench to bedside. It focuses on the pathophysiology of leukemias sensitive to menin inhibition, delineation of how this understanding led to targeted drug development, and data from clinical trials. The important discovery of resistance mechanisms is also explored, as well as future directions in the use of menin inhibitors for treating leukemia.

Towards personalized prevention of Herpes zoster infection in patients with hematologic diseases or hematopoietic stem cell transplant recipients: a position paper from an ad hoc Italian expert panel

2024-11-01T09:58:26+00:00

The identification of patients at high risk of Herpes zoster (HZ) requiring a preventive strategy with antiviral prophylaxis and anti-HZ vaccine is a clinically relevant issue in patients with immunological impairment. The absence of trials comparing vaccination to pharmacological prophylaxis or defining their sequential use makes the optimal preventive strategy uncertain. This article presents the results of group discussion among a panel of experts convened ad hoc to review the literature regarding antiviral prophylaxis and vaccine efficacy and safety in populations with malignant and non-malignant hematologic diseases, and in subjects submitted to hematopoietic stem cell transplantation. The expert panel used consensus methodology and proposed solutions for preventive strategies, producing advice for the management of the most relevant unmet clinical needs. This comprehensive overview aims to support the practice of pharmacological and vaccination-based HZ prevention and inform the design and conduct of new studies in the field.

The glutamate/aspartate transporter EAAT1 is crucial for T-cell acute lymphoblastic leukemia proliferation and survival

2024-11-01T09:56:10+00:00

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of pediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the tricarboxylic acid cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20⁺ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models

2024-11-01T09:56:13+00:00

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph⁺ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with ≥20% CD20⁺ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph⁺ BCP-ALL, indicating a potential widespread clinical application of rituximab in combination with TKI. Consequently, we examined the influence of TKI on the antitumor effectiveness of anti-CD20 monoclonal antibodies by evaluating levels of CD20 on the cell surface and conducting in vitro functional assays. All tested TKI were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of rituximab-mediated complement- dependent cytotoxicity. Interestingly, these TKI displayed varied effects on natural killer (NK) cell-mediated antibody- dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-monoclonal antibody-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity in patients’ blood, as determined by an ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKI for combination therapy with anti-CD20 monoclonal antibodies.

Prognostic impact of ‘multi-hit’ versus ‘single-hit’ TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases

2024-11-01T09:56:18+00:00

While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation (TP53MT) compared to a single-hit (SH) mutation in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an in-depth analysis utilizing data from ten US academic institutions to study differences in molecular characteristics and outcomes of SH (N=139) versus MH (N=243) TP53MT AML. Complex cytogenetics were more common in MH than in SH TP53MT AML (P<0.001); whereas ASXL1 (P<0.001), RAS (P<0.001), splicing factor (P=0.003), IDH1/2 (P=0.001), FLT3 ITD (P<0.001) and NPM1 (P=0.005) mutations clustered significantly with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between patients with SH or MH disease (event-free survival: 3.0 vs. 2.20 months, respectively, P=0.22; overall survival: 8.50 vs. 7.53 months, respectively, P=0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation as a time-dependent covariate were associated with superior event-free survival (hazard ratio [HR]=0.44, 95% confidence interval [95% CI]: 0.19-1.01, P=0.05 and HR=0.34, 95% CI: 0.18-0.62, P<0.001) and overall survival (HR=0.24, 95% CI: 0.08-0.71, P=0.01 and HR=0.28, 95% CI: 0.16-0.47, P<0.001). Complex cytogenetics (HR=1.56, 95% CI: 1.01-2.40, P=0.04) retained an unfavorable significance for overall survival. Our analysis suggests that MH TP53MT is less relevant in independently predicting outcomes in patients with AML than in those with MDS.

Outcomes and genetic dynamics of acute myeloid leukemia at first relapse

2024-11-01T09:56:22+00:00

Patients with relapsed acute myeloid leukemia (AML) experience dismal outcomes. We performed a comprehensive analysis of patients with relapsed AML to determine the genetic dynamics and factors predicting survival. We analyzed 875 patients with newly diagnosed AML who received intensive treatment or low-intensity treatment. Of these patients, 197 subsequently relapsed. Data were available for 164 of these patients, with a median time from complete remission/complete remission with incomplete blood count recovery to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation. At relapse, mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated intensively had a higher rate of emergence of TP53 mutations (16%), compared to patients given low-intensity treatment (1%, P=0.009). The overall response rates were 38% and 35% for patients treated with salvage intensive treatment or low-intensity treatment, respectively. Seventeen patients (10%) underwent allogeneic stem cell transplantation after salvage therapy. The median overall survival duration after relapse was 5.3 months, with a 1-year overall survival rate of 17.6%. Complex karyotype (hazard ratio [HR]=2.14, P<0.001), a KMT2A rearrangement (HR=3.52, P=0.011), time in remission <12 months (HR=1.71, P=0.011), and an elevated white blood cell count at relapse (HR=2.38, P=0.005) were independent risk factors for overall survival duration. More effective frontline and maintenance therapies are warranted to prevent relapsed AML.

Management of complications of chimeric antigen receptor T-cell therapy: a report by the European Society of Blood and Marrow Transplantation

2024-11-01T09:56:26+00:00

Chimeric antigen receptor (CAR) T cells are in standard clinical use to treat relapsed or refractory hematologic malignancies, such as non-Hodgkin lymphoma, multiple myeloma and acute lymphoblastic leukemia. Owing to the rapidly progressing field of CAR T-cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between European centers in prevention, diagnosis and management of short- and long-term complications. To capture the current CAR T-cell management among European Society for Blood and Marrow Transplantation (EBMT) centers and to determine the medical need and specific areas for future clinical research the EBMT Transplant Complications Working Party performed a survey among 227 EBMT CAR T-cell centers. We received complete servey answers from 106 centers (47%) addressing questions in the areas of product selection, CAR T-cell logistics, management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome as well as management in later phases including prolonged cytopenias. We identified common patterns in complication management, but also significant variety in clinical management of the centers in important aspects. Our results demonstrate a high medical need for treatment harmonization and future clinical research in the following areas: treatment of steroid-refractory and very severe cytokine release syndrome/neurotoxicity, treatment of cytopenia, early discharge and outpatient management, as well as immunoglobulin substitution.

Anti-CD19 chimeric antigen receptor T-cell therapy has less efficacy in Richter transformation than in de novo large B-cell lymphoma and transformed low-grade B-cell lymphoma

2024-11-01T09:56:30+00:00

The activity of anti-CD19 chimerci antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) with Richter’s transformation (RT) to aggressive large B-cell lymphoma (LBCL) is largely unknown. In a multicenter retrospective study, we report the safety and efficacy of CAR T-cell therapy in patients with RT (N=30) compared to patients with aggressive B-cell lymphoma (N=283) and patients with transformed indolent non-Hodgkin lymphoma (iNHL) (N=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 inhibitors. Toxicities of CAR T-cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow-up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated lactate dehydrogenase, and more prior lines of therapy. CAR T-cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL.

HES6 knockdown in human hematopoietic precursor cells reduces their in vivo engraftment potential and their capacity to differentiate into erythroid cells, B cells, T cells and plasmacytoid dendritic cells

2024-11-01T09:56:36+00:00

Hematopoiesis is driven by molecular mechanisms that induce differentiation and proliferation of hematopoietic stem cells and their progeny. This involves the activity of various transcription factors, such as members of the Hairy/Enhancer of Split (HES) family, and important roles for both HES1 and HES4 have been shown in normal and malignant hematopoiesis. Here, we investigated the role of HES6 in human hematopoiesis using in vitro and in vivo models. Using bulk and single-cell RNA-sequencing data, we show that HES6 is expressed during erythroid/megakaryocyte and plasmacytoid dendritic cell development, as well as in multipotent precursors and at specific stages of T- and B-cell development following pre-B-cell receptor and pre-T-cell receptor signaling, respectively. Consistently, knockdown of HES6 in cord blood-derived hematopoietic precursors in well-defined in vitro differentiation assays resulted in reduced differentiation of human hematopoietic precursors towards megakaryocytes, erythrocytes, plasmacytoid dendritic cells, B cells and T cells. In addition, HES6 knockdown hematopoietic stem and progenitor cells displayed reduced colony-forming unit capacity in vitro and impaired potential to reconstitute hematopoiesis in vivo in a competitive transplantation assay. We demonstrate that loss of HES6 expression has an impact on cell cycle progression during erythroid differentiation and provide evidence for potential downstream target genes that affect these perturbations. Thus, our study provides new insights into the role of HES6 in human hematopoiesis.

Decision analysis for transplant candidates with primary myelofibrosis in the ruxolitinib era

2024-11-01T09:56:40+00:00

The recent progress with ruxolitinib treatment might improve quality of life as well as overall survival in patients with primary myelofibrosis. Therefore, the optimal timing of allogeneic hematopoietic cell transplantation (HCT) in the ruxolitinib era remains to be elucidated. We constructed a Markov model to simulate the 5-year clinical course of transplant candidates with primary myelofibrosis and compared outcomes between those who underwent immediate HCT and those whose HCT was delayed until after ruxolitinib failure. Since older age was associated with an increased risk of mortality, we analyzed patients aged <60 and ≥60 years separately in subgroup analyses. Life expectancy was consistently longer in the groups undergoing delayed HCT after ruxolitinib failure regardless of the patients’ age. Regarding quality-adjusted life years, a baseline analysis showed that immediate HCT was inferior to delayed HCT after ruxolitinib failure (2.19 vs. 2.26). In patients aged <60 years, immediate HCT was equivalent to delayed HCT after ruxolitinib failure (2.31 vs. 2.31). On the other hand, in patients aged ≥60 years, immediate HCT was inferior to delayed HCT after ruxolitinib failure (1.98 vs. 2.21). A one-way sensitivity analysis showed that the utility of being alive without chronic graft-versus-host disease after immediate HCT was the most influential parameter for quality-adjusted life years, and that a value higher than 0.836 could reverse the superiority of delayed HCT after ruxolitinib failure. As a result, delayed HCT after ruxolitinib failure is expected to be superior to immediate HCT, especially in patients aged ≥60 years, and is also a promising strategy even in those aged <60 years.

A first-in-class Wiskott-Aldrich syndrome protein activator with antitumor activity in hematologic cancers

2024-11-01T09:56:43+00:00

Hematologic cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the autoinhibited form of WASp. EG-011 possesses in vitro and in vivo antitumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding were demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs inducing actin polymerization.

Epstein-Barr virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments

2024-11-01T09:56:49+00:00

Non-Hodgkin lymphomas (NHL) commonly occur in immunodeficient patients, both those infected by human immunodeficiency virus (HIV) and those who have been transplanted, and are often driven by Epstein-Barr virus (EBV) with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 immunodeficient (34 post-transplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were large B-cell lymphoma and 25% were primary central nervous system lymphoma, while 40% were EBV+. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden, tumor landscape and tumor microenvironment and prediction of tumor neoepitopes. Both tumor mutational burden (2.2 vs. 3.4/Mb, P=0.001) and numbers of neoepitopes (40 vs. 200, P=0.00019) were lower in EBV+ than in EBV– NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations observed exclusively in EBV+ and immunodeficient NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV– cases but in only half of the EBV+ ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The tumor microenvironment analysis showed higher CD8 T-cell infiltrates in EBV+ versus EBV– NHL, together with a more tolerogenic profile composed of regulatory T cells, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T-cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV– patients, offering potential opportunities for future T-cell-based immune therapies.

Event-free survival at 36 months is a suitable endpoint for diffuse large B-cell lymphoma patients treated with immunochemotherapy: real-world evidence from the North Japan Hematology Study Group

2024-11-01T09:56:56+00:00

Information regarding follow-up duration after treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL) is important. However, a clear endpoint has yet to be established. We enrolled a total of 2,182 patients newly diagnosed with DLBCL between 2008 and 2018. The median age of the patients was 71 years. All patients were treated with rituximab- and anthracycline-based chemotherapies. Each overall survival (OS) was compared with the age- and sex-matched Japanese general population (GP) data. At a median follow-up of 3.4 years, 985 patients experienced an event and 657 patients died. Patients who achieved an event-free survival (EFS) at 36 months (EFS36) had an OS equivalent to that of the matched GP (standard mortality ratio [SMR], 1.17; P=0.1324), whereas those who achieved an EFS24 did not have an OS comparable to that of the matched GP (SMR, 1.26; P=0.0095). Subgroup analysis revealed that relatively old patients (>60 years), male patients, those with limited-stage disease, those with a good performance status, and those with low levels of soluble interleukin 2 receptor already had a comparable life expectancy to the matched GP at an EFS24. In contrast, relatively young patients had a shorter life expectancy than matched GP, even with an EFS36. In conclusion, an EFS36 was shown to be a more suitable endpoint for newly diagnosed DLBCL patients than an EFS24. Of note, younger patients require a longer EFS period than older patients in order to obtain an equivalent life expectancy to the matched GP.

Impact of genetic alterations on central nervous system progression of primary vitreoretinal lymphoma

2024-11-01T09:57:01+00:00

Primary vitreoretinal lymphoma (PVRL) is a rare malignant lymphoma subtype with an unfavorable prognosis due to frequent central nervous system (CNS) progression. Thus, identifying factors associated with CNS progression is essential for improving the prognosis of PVRL patients. Accordingly, we conducted a comprehensive genetic analysis using archived vitreous humor samples of 36 PVRL patients diagnosed and treated at our institution and retrospectively examined the relationship between genetic alterations and CNS progression. Whole-exome sequencing (N=2) and amplicon sequencing using a custom panel of 107 lymphomagenesis-related genes (N=34) were performed to assess mutations and copy number alterations. The median number of pathogenic genetic alterations per case was 12 (range, 0-22). Pathogenic genetic alterations of CDKN2A, MYD88, CDKN2B, PRDM1, PIM1, ETV6, CD79B, and IGLL5, as well as aberrant somatic hypermutations, were frequently detected. The frequency of ETV6 loss and PRDM1 alteration (mutation and loss) was 23% and 49%, respectively. Multivariate analysis revealed ETV6 loss (hazard ratio [HR]=3.26, 95% confidence interval [CI]: 1.08–9.85) and PRDM1 alteration (HR=2.52, 95% CI: 1.03–6.16) as candidate risk factors associated with CNS progression of PVRL. Moreover, these two genetic factors defined slow-, intermediate-, and rapid-progression groups (0, 1, and 2 factors, respectively), and the median period to CNS progression differed significantly among them (52 vs. 33 vs. 20 months, respectively). Our findings suggest that genetic factors predict the CNS progression of PVRL effectively, and the genetics-based CNS progression model might lead to stratification of treatment.

LILRB4 represents a promising target for immunotherapy by dual targeting tumor cells and myeloid-derived suppressive cells in multiple myeloma

2024-11-01T09:57:05+00:00

Multiple myeloma (MM) remains an incurable hematologic malignancy. Despite tremendous advances in the treatment of this disease, about 10% of patients still have very poor outcomes with a median overall survival of less than 24 months. Our study aimed to underscore the critical mechanisms pertaining to rapid disease progression and provide novel therapeutic choices for these ultrahigh-risk patients. We utilized single-cell transcriptomic sequencing to dissect the characteristic bone marrow niche of patients who survived less than 2 years (EM24). Notably, enrichment of a LILRB4high pre-mature plasma-cell cluster was observed in EM24 patients compared to patients with durable remission. This cluster exhibited aggressive proliferation and a drug-resistance phenotype. High levels of LILRB4 promoted MM clonogenicity and progression. Clinically, high expression of LILRB4 was correlated with poor prognosis in both newly diagnosed MM patients and relapsed/ refractory MM patients. ATAC-sequencing analysis identified that pronounced chromosomal accessibility caused the elevation of LILRB4 on MM cells. CRISPR-Cas9 deletion of LILRB4 alleviated the growth of MM cells, inhibited the immunosuppressive function of myeloid-derived suppressive cells (MDSC), and further rescued T-cell dysfunction in the MM microenvironment. Greater infiltration of MDSC was observed in EM24 patients. We therefore generated an innovative T-cell receptor-based chimeric antigen receptor T cell, LILRB4-STAR-T. Cytotoxicity experiments demonstrated that LILRB4-STAR-T cells efficaciously eliminated tumor cells and impeded MDSC function. In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T-cell immunotherapy is promising against both tumor cells and the immunosuppressive tumor microenvironment in MM.

Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma

2024-11-01T09:57:12+00:00

Belantamab mafodotin (belantamab) is a first-in-class anti-B-cell maturation antigen (BCMA) antibody-drug conjugate approved for the treatment of triple-class refractory multiple myeloma. It provides a unique therapeutic option for patients ineligible for chimeric antigen receptor (CAR) T and bispecific antibody therapy, and/or patients progressing on anti-CD38 treatment where CAR T and bispecifics might be kept in reserve. Wider use of the drug can be challenged by its distinct ocular side effect profile, including corneal microcysts and keratopathy. While dose reduction has been the most effective way to reduce these toxicities, the underlying mechanism of this BCMA off-target effect remains to be characterized. In this study, we provide the first evidence for soluble BCMA (sBCMA) in lacrimal fluid and report on its correlation with tumor burden in myeloma patients. We confirm that corneal cells do not express BCMA, and show that sBCMA-belantamab complexes may rather be internalized by corneal epithelial cells through receptor-ligand independent pinocytosis. Using an hTcEpi corneal cell-line model, we show that the pinocytosis inhibitor EIPA significantly reduces belantamab-specific cell killing. As a proof of concept, we provide detailed patient profiles demonstrating that, after belantamab-induced cell killing, sBCMA is released into circulation, followed by a delayed increase of sBCMA in the tear fluid and subsequent onset of keratopathy. Based on the proposed mechanism, pinocytosis-induced keratopathy can be prevented by lowering the entry of sBCMA into the lacrimal fluid. Future therapeutic concepts may therefore consist of belantamab-free debulking therapy prior to belantamab consolidation and/or concomitant use of γ-secretase inhibition as currently evaluated for belantamab and nirogacestat in ongoing studies.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: results of the multicenter KMMWP2201 study

2024-11-01T09:57:17+00:00

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed to investigate this regimen’s efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age, 63 years). The overall response rate was 90% in response-evaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, high-risk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2-3 months prior to start of KRd treatment significantly decreased PFS and OS in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e., delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AE) were observed in 56% of the patients, and non-fatal or fatal AE that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large, real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

The role of PALLD-STAT3 interaction in megakaryocyte differentiation and thrombocytopenia treatment

2024-11-01T09:57:23+00:00

Impaired differentiation of megakaryocytes constitutes the principal etiology of thrombocytopenia. The signal transducer and activator of transcription 3 (STAT3) is a crucial transcription factor in regulating megakaryocyte differentiation, however the precise mechanism of its activation remains unclear. PALLD, an actin-associated protein, has been increasingly recognized for its essential functions in multiple biological processes. This study revealed that megakaryocyte/platelet-specific knockout of Palld in mice exhibited thrombocytopenia due to diminished platelet biogenesis. In megakaryocytes, PALLD deficiency led to impaired proplatelet formation and polyploidization, ultimately weakening their differentiation for platelet production. Mechanistic studies demonstrated that PALLD bound to STAT3 and interacted with its DNA-binding domain and Src homology 2 domain via immunoglobulin domain 3. Moreover, the absence of PALLD attenuated STAT3 Y705 phosphorylation and impeded STAT3 nuclear translocation. Based on the PALLD-STAT3 binding sequence, we designed a peptide C-P3, which can facilitate megakaryocyte differentiation and accelerate platelet production in vivo. In conclusion, this study highlights the pivotal role of PALLD in megakaryocyte differentiation and proposes a novel approach for treating thrombocytopenia by targeting the PALLD-STAT3 interaction.

Stem cell factor and erythropoietin-independent production of cultured reticulocytes

2024-11-01T09:57:27+00:00

Cultured reticulocytes can supplement transfusion needs and offer promise for drug delivery and immune tolerization. They can be produced from induced pluripotent stem cells (iPSC), but the 45-day culture time and cytokine costs make largescale production prohibitive. To overcome these limitations, we have generated iPSC that express constitutive stem cell factor (SCF) receptor and jak2 adaptor alleles. We show that iPSC lines carrying these alleles can differentiate into self-renewing erythroblasts that can proliferate for up to 70 cell-doubling in a cost-effective, chemically-defined, albumin- and cytokine-free medium. These kitjak2 self-renewing erythroblasts retain the ability to enucleate at a high rate up to senescence. Kitjak2-derived cultured reticulocytes should be safe for transfusion because they can be irradiated to eliminate residual nucleated cells. The kitjak2 cells express blood group 0 and test negative for RhD and other clinically significant red blood cell antigens and have sufficient proliferation capacity to meet global red blood cell needs.

A novel role of AURKA kinase in erythroblast enucleation

2024-11-01T09:57:29+00:00

Generation of mammalian red blood cells requires the expulsion of polarized nuclei late in terminal erythroid differentiation. However, the mechanisms by which spherical erythroblasts determine the direction of nuclear polarization and maintain asymmetry during nuclear expulsion are poorly understood. Given the analogy of erythroblast enucleation to asymmetric cell division and the key role of Aurora kinases in mitosis, we sought to investigate the function of Aurora kinases in erythroblast enucleation. We found that AURKA (Aurora kinase A) is abundantly expressed in orthochromatic erythroblasts. Intriguingly, high-resolution confocal microscopy analyses revealed that AURKA co-localized with the centrosome on the side of the nucleus opposite its membrane contact point during polarization and subsequently translocated to the anterior end of the protrusive nucleus upon nuclear exit. Mechanistically, AURKA regulated centrosome maturation and localization via interaction with γ-tubulin to provide polarization orientation for the nucleus. Furthermore, we identified ECT2 (epithelial cell transforming 2), a guanine nucleotide exchange factor, as a new interacting protein and ubiquitination substrate of AURKA. After forming the nuclear protrusion, AURKA translocated to the anterior end of the protrusive nucleus to directly degrade ECT2, which is partly dependent on kinase activity of AURKA. Moreover, knockdown of ECT2 rescued impaired enucleation caused by AURKA inhibition. Our findings have uncovered a previously unrecognized role of Aurora kinases in the establishment of nuclear polarization and eventual nuclear extrusion and provide new mechanistic insights into erythroblast enucleation.

Prevalence of autoimmune diseases in patients with sickle cell disease: a single center retrospective analysis

2024-11-01T09:57:32+00:00

Expedited evaluation of hereditary hematopoietic malignancies in the setting of stem cell transplantation

2024-11-01T09:57:34+00:00

Brexucabtagene autoleucel in relapsed or refractory mantle cell lymphoma, intention-to-treat use in the DESCAR-T registry

2024-11-01T09:57:36+00:00

Reference interval of free light chains ratio in patients with end-stage renal disease on chronic hemodialysis

2024-11-01T09:57:39+00:00

Co-transfection of murine NXPE2 and murine glycophorin A confers reactivity with Ter-119

2024-11-01T09:57:41+00:00

Response to DA-EPOCH-R is associated with activation of ‘fitter’ cytotoxic T cells in patients with newly diagnosed double and triple hit high-grade B-cell lymphoma

2024-11-01T09:57:43+00:00

No clear benefit of preventive cranial radiotherapy in childhood Philadelphia-positive acute lymphoblastic leukemia: a retrospective analysis of the EsPhALL2010 study

2024-11-01T09:57:46+00:00

A targeted gene signature stratifying mediastinal gray zone lymphoma into classical Hodgkin lymphoma-like or primary mediastinal B-cell lymphoma-like subtypes

2024-11-01T09:57:49+00:00

Long-term outcomes of newly diagnosed POEMS syndrome patients who received first-line lenalidomide-based therapy

2024-11-01T10:09:57+00:00

Histamine dihydrochloride and low-dose interleukin-2 has anti-leukemic efficacy in NPM1-mutated and myelomonocytic/monocytic acute myeloid leukemia

2024-11-01T09:57:55+00:00

FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): the Mayo Clinic experience

2024-11-01T10:12:16+00:00

Excellent outcome of children/adolescents with primary mediastinal large B-cell lymphoma treated with a FAB/ LMB-based chemotherapy regimen with rituximab

2024-11-01T09:58:00+00:00

Multiple myeloma in the young: insights on prognosis, clinical features and treatment outcome derived from nationwide German registry data and a nested multicenter sample

2024-11-01T09:58:04+00:00

Microbiota signature of oral chronic graft-versus-host disease 6+ years after transplantation

2024-11-01T09:58:08+00:00

Extending duration of letermovir prophylaxis in haploidentical stem cell transplantation

2024-11-01T09:58:11+00:00

Late-onset NPM1 mutation in a MYC-amplified relapsed/refractory acute myeloid leukemia patient treated with gemtuzumab ozogamicin and glasdegib

2024-11-01T09:58:15+00:00

Myeloid neoplasm with histiocytosis and spleen tyrosine kinase fusion responds to fostamatinib

2024-11-01T09:58:17+00:00

Clonal evolution from B-cell acute lymphoblastic leukemia with BCR::ABL1 multilineage involvement to acute myeloid leukemia after multiple anti-CD19 chimeric antigen receptor T-cell therapy

2024-11-01T09:58:20+00:00

Integration of genotypic data into clinical trial design and reporting in hereditary hemorrhagic telangiectasia could help personalize treatment

2024-11-01T09:58:13+00:00

Erratum to: Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma

2024-11-01T19:45:16+00:00

Erratum to: Stem cell factor and erythropoietin-independent production of cultured reticulocytes

2024-11-01T19:45:17+00:00