Haematologica

Genetics as predictive marker for consolidation therapy with high-dose cytarabine in acute myeloid leukemia

Richard F. Schlenk — Sat, 01 Jun 2024 00:00:00 +0000

Chimeric antigen receptor therapy for T-cell acute lymphoblastic leukemia: finally catching up with B-cell leukemia?

Ofrat Beyar-Katz, Jacob M. Rowe — Sat, 01 Jun 2024 00:00:00 +0000

CApSiZing T-cell acute lymphoblastic leukemia

Komal Mandleywala, Daniel Herranz — Thu, 18 Jan 2024 00:00:00 +0000

Anatomy of a crime: how IL7R and NRAS join forces to drive T-cell acute lymphoblastic leukemia

João T. Barata — Thu, 08 Feb 2024 00:00:00 +0000

SEQ-ing the genetic constellation of acute lymphoblastic leukemia

Zhenhua Li, Allen Eng Juh Yeoh — Thu, 21 Dec 2023 00:00:00 +0000

Charting a path through resistance: histone deacetylase inhibitors for TP53-mutated B-cell acute lymphoblastic leukemia

Eitan Kugler — Thu, 15 Feb 2024 00:00:00 +0000

Be aware of the X: BCOR mutations in myeloid neoplasms

Guillermo Ramil, Marta Pratcorona, Josep F. Nomdedéu — Thu, 08 Feb 2024 00:00:00 +0000

Anticoagulation and thrombocytopenia in cancer: what more can we learn from existing randomized controlled trials

Anna Falanga, Cinzia Giaccherini — Thu, 14 Dec 2023 00:00:00 +0000

Adenovirus-associated thrombosis and thrombocytopenia: an emerging anti-PF4 disorder

Andrew B. Song, Hanny Al-Samkari — Thu, 08 Feb 2024 00:00:00 +0000

Introduction. Immunotherapy for childhood malignancies: the future is now

Franco Locatelli — Fri, 10 May 2024 13:53:07 +0000

Chimeric antigen receptor T-cell therapy in childhood acute myeloid leukemia: how far are we from a clinical application?

Swati Naik, M. Paulina Velasquez, Stephen Gottschalk — Fri, 10 May 2024 13:53:27 +0000

Recurrent and/or refractory (R/R) pediatric acute myeloid leukemia (AML) remains a recalcitrant disease with poor outcomes. Cell therapy with genetically modified immune effector cells holds the promise to improve outcomes for R/R AML since it relies on cytotoxic mechanisms that are distinct from chemotherapeutic agents. While T cells expressing chimeric antigen receptors (CAR T cells) showed significant anti-AML activity in preclinical models, early phase clinical studies have demonstrated limited activity, irrespective of the targeted AML antigen. Lack of efficacy is most likely multifactorial, including: (i) a limited array of AML-specific targets and target antigen heterogeneity; (ii) the aggressive nature of R/R AML and heavy pretreatment of patients; (iii) T-cell product manufacturing, and (iv) limited expansion and persistence of the CAR T cells, which is in part driven by the immunosuppressive AML microenvironment. Here we review the results of early phase clinical studies with AML-specific CAR T cells, and avenues investigators are exploring to improve their effector function.

Bispecific T-cell engagers in childhood B-acute lymphoblastic leukemia

Kaylyn Utley Lyons, Lia Gore — Fri, 10 May 2024 13:53:49 +0000

Immunotherapy has revolutionized treatment for a wide variety of cancers yet its use has been relatively limited in childhood malignancies. With the introduction of bispecific T-cell engagers (BiTE®) and chimeric antigen T-cell receptor technologies, previously refractory patients have attained remission, including molecularly negative states of disease, thus providing the possibility of long-term cure. Blinatumomab is a widely available CD3-CD19 BiTE that has dramatically changed the landscape of therapy for some children with precursor-B acute lymphoblastic leukemias (B-ALL) and lymphoblastic lymphomas. Challenges remain with using BiTE in a broader population although the appeal of now-confirmed reduced toxicity and deeper molecular remissions suggests that this approach will be an essential part of future treatment of childhood B-ALL. Herein, we review some of the pertinent literature covering clinical trials with blinatumomab and address future approaches and combination trials including BiTE.

Chimeric antigen receptor T-cell therapy for T-cell acute lymphoblastic leukemia

Bernice L.Z. Oh, Natasha Vinanica, Desmond M.H. Wong, Dario Campana — Fri, 10 May 2024 13:54:20 +0000

Chimeric antigen receptor (CAR) T-cell therapy is a new and effective treatment for patients with hematologic malignancies. Clinical responses to CAR T cells in leukemia, lymphoma, and multiple myeloma have provided strong evidence of the antitumor activity of these cells. In patients with refractory or relapsed B-cell acute lymphoblastic leukemia (ALL), the infusion of autologous anti-CD19 CAR T cells is rapidly gaining standard-of-care status and might eventually be incorporated into frontline treatment. In T-ALL, however, leukemic cells generally lack surface molecules recognized by established CAR, such as CD19 and CD22. Such deficiency is particularly important, as outcome is dismal for patients with T-ALL that is refractory to standard chemotherapy and/or hematopoietic stem cell transplant. Recently, CAR T-cell technologies directed against T-cell malignancies have been developed and are beginning to be tested clinically. The main technical obstacles stem from the fact that malignant and normal T cells share most surface antigens. Therefore, CAR T cells directed against T-ALL targets might be susceptible to self-elimination during manufacturing and/or have suboptimal activity after infusion. Moreover, removing leukemic cells that might be present in the cell source used for CAR T-cell manufacturing might be problematic. Finally, reconstitution of T cells and natural killer cells after CAR T-cell infusion might be impaired. In this article, we discuss potential targets for CAR T-cell therapy of T-ALL with an emphasis on CD7, and review CAR configurations as well as early clinical results.

Allogeneic chimeric antigen receptor T cells for children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia

Franco Locatelli, Francesca del Bufalo, Concetta Quintarelli — Fri, 10 May 2024 00:00:00 +0000

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a breakthrough cancer therapy over the past decade. Remarkable outcomes in B-cell lymphoproliferative disorders and multiple myeloma have been reported in both pivotal trials and real-word studies. Traditionally, the use of a patient’s own (autologous) T cells to manufacture CAR products has been the standard practice. Nevertheless, this approach has some drawbacks, including manufacturing delays, dependence on the functional fitness of the patient’s T cells, which can be compromised by both the disease and prior therapies, and contamination of the product with blasts. A promising alternative is offered by the development of allogeneic CAR-cell products. This approach has the potential to yield more efficient drug products and enables the use of effector cells with negligible alloreactive potential and a significant CAR-independent antitumor activity through their innate receptors (i.e., natural killer cells, γδ T cells and cytokine induced killer cells). In addition, recent advances in genome editing tools offer the potential to overcome the primary challenges associated with allogeneic CAR T-cell products, namely graft-versus-host disease and host allo-rejection, generating universal, off-the-shelf products. In this review, we summarize the current pre-clinical and clinical approaches based on allogeneic CAR T cells, as well as on alternative effector cells, which represent exciting opportunities for multivalent approaches and optimized antitumor activity.

Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia

Erica Brivio, Francisco Bautista, C. Michel Zwaan — Fri, 10 May 2024 13:55:08 +0000

The treatment of childhood acute lymphoblastic leukemia (ALL) has reached overall survival rates exceeding 90%. The present and future challenges are to cure the remainder of patients still dying from disease, and to reduce morbidity and mortality in those who can be cured with standard-of-care chemotherapy by replacing toxic chemotherapy elements while retaining cure rates. With the novel therapeutic options introduced in the last years, including immunotherapies and targeted antibodies, the treatment of ALL is undergoing major changes. For B-cell precursor ALL, blinatumomab, an anti-CD19 bispecific antibody, has established its role in the consolidation treatment for both high- and standard-risk first relapse of ALL, in the presence of bone marrow involvement, and may also have an impact on the outcome of high-risk subsets such as infant ALL and Philadelphia chromosome-positive ALL. Inotuzumab ozogamicin, an anti-CD22 drug conjugated antibody, has demonstrated high efficacy in inducing complete remission in relapsed ALL, even in the presence of high tumor burden, but randomized phase III trials are still ongoing. For T-ALL the role of CD38-directed treatment, such as daratumumab, is gaining interest, but randomized data are needed to assess its specific benefit. These antibodies are currently being tested in patients with newly diagnosed ALL and may lead to major changes in the present paradigm of treatment of pediatric ALL. Unlike the past, lessons may be learned from innovations in adult ALL, in which more drastic changes are piloted that may need to be translated to pediatrics.

CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia

Thu, 07 Dec 2023 00:00:00 +0000

CASZ1 is a conserved transcription factor involved in neural development, blood vessel assembly and heart morphogenesis. CASZ1 has been implicated in cancer, either suppressing or promoting tumor development depending on the tissue. However, the impact of CASZ1 on hematological tumors remains unknown. Here, we show that the T-cell oncogenic transcription factor TAL1 is a direct positive regulator of CASZ1, that T-cell acute lymphoblastic leukemia (T-ALL) samples at diagnosis overexpress CASZ1b isoform, and that CASZ1b expression in patient samples correlates with PI3K-AKT-mTOR signaling pathway activation. In agreement, overexpression of CASZ1b in both Ba/F3 and T-ALL cells leads to the activation of PI3K signaling pathway, which is required for CASZ1b-mediated transformation of Ba/F3 cells in vitro and malignant expansion in vivo. We further demonstrate that CASZ1b cooperates with activated NOTCH1 to promote T-ALL development in zebrafish, and that CASZ1b protects human T-ALL cells from serum deprivation and treatment with chemotherapeutic drugs. Taken together, our studies indicate that CASZ1b is a TAL1-regulated gene that promotes T-ALL development and resistance to chemotherapy.

Mechanism of co-operation of mutant IL-7Rα and mutant NRAS in acute lymphoblastic leukemia: role of MYC

Thu, 30 Nov 2023 00:00:00 +0000

Acute lymphoblastic leukemia (ALL) is an aggressive leukemia which can be derived from either T-cell or B-cell precursors. With current treatments, the survival rate is high, but the treatments are highly toxic with severe side effects. Individual mutations in IL7Ra and RAS pathways have been previously shown to be prevalent in ALL, and especially in relapsed patients. The relationship of IL-7Ra and RAS was investigated by transducing immature mouse thymocytes with the combination of these mutants. The resultant ALL cells were analyzed to identify the regulators and the oncoproteins that are up-regulated or down-regulated by the combination of IL7Ra with NRAS. Leukemia cells showed a significant increase in IL7Ra-mediated BCL2 expression, and an increase in MYC protein levels was mainly induced by NRAS signaling. MYC was both necessary and sufficient to replace mutant NRAS, and drugs targeting the MYC pathway showed a therapeutic benefit in IL-7Ra/NRAS T-ALL. We suggest that MYC protein stability can be regulated by PLK-1 kinase, which was increased mainly by the NRAS signal. These studies identify novel pathways of oncogenesis and new targets for intervention that could lead to better therapeutic development.

MD-ALL: an integrative platform for molecular diagnosis of B-acute lymphoblastic leukemia

Zunsong Hu, Zhilian Jia, Jiangyue Liu, Allen Mao, Helen Han, Zhaohui Gu — Thu, 16 Nov 2023 00:00:00 +0000

B-acute lymphoblastic leukemia (B-ALL) consists of dozens of subtypes defined by distinct gene expression profiles (GEP) and various genetic lesions. With the application of transcriptome sequencing (RNA sequencing [RNA-seq]), multiple novel subtypes have been identified, which lead to an advanced B-ALL classification and risk-stratification system. However, the complexity of analyzing RNA-seq data for B-ALL classification hinders the implementation of the new B-ALL taxonomy. Here, we introduce Molecular Diagnosis of Acute Lymphoblastic Leukemia (MD-ALL), an integrative platform featuring sensitive and accurate B-ALL classification based on GEP and sentinel genetic alterations from RNA-seq data. In this study, we systematically analyzed 2,955 B-ALL RNA-seq samples and generated a reference dataset representing all the reported B-ALL subtypes. Using multiple machine learning algorithms, we identified the feature genes and then established highly sensitive and accurate models for B-ALL classification using either bulk or single-cell RNA-seq data. Importantly, this platform integrates multiple aspects of key genetic lesions acquired from RNA-seq data, which include sequence mutations, large-scale copy number variations, and gene rearrangements, to perform comprehensive and definitive B-ALL classification. Through validation in a hold-out cohort of 974 samples, our models demonstrated superior performance for B-ALL classification compared with alternative tools. Moreover, to ensure accessibility and user-friendly navigation even for users with limited or no programming background, we developed an interactive graphical user interface for this MD-ALL platform, using the R Shiny package. In summary, MD-ALL is a user-friendly B-ALL classification platform designed to enable integrative, accurate, and comprehensive B-ALL subtype classification. MD-ALL is available from https://github.com/gu-lab20/MD-ALL.

Histone deacetylase inhibition sensitizes p53-deficient B-cell precursor acute lymphoblastic leukemia to chemotherapy

Thu, 21 Dec 2023 00:00:00 +0000

In pediatric acute lymphoblastic leukemia (ALL), mutations/deletions affecting the TP53 gene are rare at diagnosis. However, at relapse about 12% of patients show TP53 aberrations, which are predictive of a very poor outcome. Since p53-mediated apoptosis is an endpoint for many cytotoxic drugs, loss of p53 function frequently leads to therapy failure. In this study we show that CRISPR/Cas9-induced loss of TP53 drives resistance to a large majority of drugs used to treat relapsed ALL, including novel agents such as inotuzumab ozogamicin. Using a high-throughput drug screen, we identified the histone deacetylase inhibitor romidepsin as a potent sensitizer of drug responsiveness, improving sensitivity to all chemotherapies tested. In addition, romidepsin improved the response to cytarabine in TP53-deleted ALL cells in vivo. Together, these results indicate that the histone deacetylase inhibitor romidepsin can improve the efficacy of salvage therapies for relapsed TP53-mutated leukemia. Since romidepsin has been approved for clinical use in some adult malignancies, these findings may be rapidly translated to clinical practice.

Multi-gene measurable residual disease assessed by digital polymerase chain reaction has clinical and biological utility in acute myeloid leukemia patients receiving venetoclax/azacitidine

Thu, 14 Dec 2023 00:00:00 +0000

Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms

Thu, 01 Feb 2024 00:00:00 +0000

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

Granulocyte transfusions in severe aplastic anemia

Thu, 07 Dec 2023 00:00:00 +0000

Patients with severe aplastic anemia (SAA) are at high risk of morbidity and mortality due to severe infections. We aimed to characterize the role of granulocyte transfusions (GT) in SAA. Primary outcomes were survival after the first GT, including overall survival (OS) at last follow up, survival to discharge, and receipt of a hematopoietic stem cell transplant (HSCT) Secondary outcomes included evaluation of clinical response at 7 and 30 days after initiation of GT, using a clinical scoring system incorporating microbiological and radiographic response. Twenty-eight SAA patients underwent 30 GT courses with a per-dose median of 1.28x109 granulocytes/kilogram (range, 0.45-4.52x109). OS from initial GT to median last follow up (551 days) was 50%, with 39% (11/28) alive at last follow up. Sixty-four percent (18/28) of all patients survived to hospital discharge. Patients with a complete or partial response, or stable infection, at 30 days had significantly better OS compared to non-responders (P=0.0004). Eighty-six percent (18/21) of patients awaiting HSCT during GT underwent a transplant and 62% (13/21) survived to post-HSCT discharge. Sex, type of infection, and percentage of days with absolute neutrophil count >0.2x109/L during the course of GT were not predictive of survival (P=0.52, P=0.7 and P=0.28, respectively). Nine of 28 (32%) patients developed new or increased human leukocyte antigen alloimmunization during their GT course. GT in SAA may have an impact on survival in those patients with improvement or stabilization of their underlying infection. Alloimmunization can occur and OS in this population remains poor, but GT may be a useful tool to bridge patients to curative treatment with HSCT.

PELI2 regulates early B-cell progenitor differentiation and related leukemia via the IL-7R expression

Thu, 07 Dec 2023 00:00:00 +0000

Little is known about the transition mechanisms that govern early lymphoid lineage progenitors from common lymphoid progenitors (CLP). Pellino2 (PELI2) is a newly discovered E3 ubiquitin ligase, which plays important roles in inflammation and the immune system. However, the physiological and molecular roles of PELI2 in the differentiation of immune cells are largely unknown. Here, by using a conditional knockout mouse model, we demonstrated that PELI2 is required for early B-cell development and stressed hematopoiesis. PELI2 interacted with and stabilized PU.1 via K63-polyubiquitination to regulate IL-7R expression. The defects of B-cell development induced by PELI2 deletion were restored by overexpression of PU.1. Similarly, PELI2 promoted TCF3 protein stability via K63-polyubiquitination to regulate IL-7R expression, which is required for the proliferation of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. These results underscore the significance of PELI2 in both normal B lymphopoiesis and malignant B-cell acute lymphoblastic leukemia via the regulation of IL-7R expression, providing a potential therapeutic approach for BCP-ALL.

Massive parallel sequencing unveils homologous recombination deficiency in follicular dendritic cell sarcoma

Thu, 23 Nov 2023 00:00:00 +0000

Standardized treatment options are lacking for patients with unresectable or multifocal follicular dendritic cell sarcoma (FDCS) and disease-related mortality is as high as 20%. Applying whole-genome sequencing (WGS) in one case and whole-exome sequencing (WES) in additional twelve cases, this study adds information on the molecular landscape of FDCS, expanding knowledge on pathobiological mechanisms and identifying novel markers of potential theragnostic significance. Massive parallel sequencing showed high frequency of mutations on oncosuppressor genes, particularly in RB1, CARS and BRCA2 and unveiled alterations on homologous recombination DNA damage repair-related genes in 70% (9/13) of cases. This indicates that patients with high-stage FDCS may be eligible for poly ADP ribose polymerase inhibition protocols. Low tumor mutational burden was confirmed in this study despite common PDL1 expression in FDCS arguing on the efficacy of immune checkpoint inhibitors. CDKN2A deletion, detected by WGS and confirmed by fluorescence in situ hybridization in 41% of cases (9/22) indicates that impairment of cell cycle regulation may sustain oncogenesis in FDCS. Absence of mutations in the RAS/RAF/MAPK pathway and lack of clonal hematopoiesis-related mutations in FDCS sanction its differences from dendritic cell-derived neoplasms of hematopoietic derivation. WGS and WES in FDCS provides additional information on the molecular landscape of this rare tumor, proposing novel candidate genes for innovative therapeutical approaches to improve survival of patients with multifocal disease.

STAT5B mutations in myeloid neoplasms differ by disease subtypes but characterize a subset of chronic myeloid neoplasms with eosinophilia and/or basophilia

Thu, 16 Nov 2023 00:00:00 +0000

STAT5B has been reported as a recurrent mutation in myeloid neoplasms with eosinophilia, but its overall frequency and importance across a spectrum of myeloid neoplasms are largely unknown. We conducted a multicenter study on a series of 82 myeloid neoplasms with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutations in myeloid neoplasms was low, <0.5%, but mutations were detected in all categories of such neoplasms, including myelodysplastic syndrome (MDS, 28%), acute myeloid leukemia (AML, 26%), myelodysplastic/myeloproliferative neoplasm (MDS/MPN, 18%), Philadelphia chromosome-negative classic MPN (12%), systemic mastocytosis (1%), and, with a notably high frequency, chronic eosinophilic leukemia, not otherwise specified (CEL-NOS, 15%). STAT5B mutations occurred preferentially in the SH2 domain (95%), involved 12 different codons, with the N642H hotspot being the most common (78%). Co-mutations were present in all cases and clonal hierarchy analysis showed that STAT5B mutations tended to be subclonal in AML, MPN, and MDS, but frequently dominant/co-dominant in CEL-NOS (83%), followed by MDS/MPN (40%). Across the group, eosinophilia and/or basophilia were common (41%), frequently observed in cases in which STAT5B mutations were detected at initial diagnosis (P<0.0001), with a high variant allele frequency (median 42.5%, P=0.0001), as a dominant/ co-dominant clone (P<0.0001), involving the canonical N642H (P=0.0607), and associated with fewer co-mutations (P=0.0009). Our data show that the characteristics and importance of a STAT5B mutation differ among myeloid neoplasms, but if present as a dominant mutation and detected at initial diagnosis, it appears to be a driver mutation in a subgroup of chronic myeloid neoplasms, preferentially promoting a proliferation of eosinophils and basophils.

Differences in venous clot structures between hemophilic mice treated with emicizumab versus factor VIII or factor VIIIFc

Thu, 07 Dec 2023 00:00:00 +0000

Recombinant factor VIII (rFVIII), rFVIIIFc and emicizumab are established treatment options in the management of hemophilia A. Each has its unique mode of action, which can influence thrombin generation kinetics and therefore also the kinetics of thrombin substrates. Such differences may potentially result in clots with different structural and physical properties. A starting observation of incomplete wound closure in a patient on emicizumab prophylaxis led us to employ a relevant mouse model in which we noticed that emicizumab-induced clots appeared less stable compared to FVIII-induced clots. We therefore analyzed fibrin formation in vitro and in vivo. In vitro fibrin formation was faster and more abundant in the presence of emicizumab than in the presence of rFVIII/rFVIIIFc. Furthermore, the time-interval between the initiation of fibrin formation and factor XIII activation was twice as long for emicizumab than as for rFVIII/rFVIIIFc. Scanning electron microscopy and immunofluorescent spinning-disk confocal microscopy of in vivo-generated clots confirmed increased fibrin formation in the presence of emicizumab. Unexpectedly, we also detected a different morphology between rFVIII/rFVIIIFcand emicizumab-induced clots. Contrary to the regular fibrin mesh obtained with rFVIII/rFVIIIFc, fibrin fibers appeared to be fused into large patches upon emicizumab treatment. Moreover, fewer red blood cells were detected in regions in which these fibrin patches were present. The presence of highly dense fibrin structures associated with a diffuse fiber structure in emicizumab-induced clots was also observed when using super-resolution imaging. We hypothesize that the modified kinetics of thrombin, fibrin and factor XIIIa generation contribute to differences in structural and physical properties between clots formed in the presence of FVIII or emicizumab.

Impact of mild thrombocytopenia on bleeding and recurrent thrombosis in cancer

Thu, 19 Oct 2023 00:00:00 +0000

Thrombocytopenia occurs frequently in patients with cancer-associated thrombosis (CAT), however prospective evaluation of clinical outcomes following randomization to anticoagulants is limited. The HOKUSAI VTE Cancer study was a randomized, open-label, non-inferiority, phase III trial comparing dalteparin with edoxaban in CAT patients. This post hoc analysis of Hokusai VTE Cancer Study was performed to compare outcomes in patients with platelet count ≤100x109/L at one or more specified time points (baseline, 1-month, or 3-month) versus those without thrombocytopenia. Cumulative incidences at 180 days were calculated with death as a competing risk. The primary outcome was major bleeding; secondary outcomes were clinically relevant non-major bleeding (CRNMB), recurrent thrombosis, and survival. The analysis included 1,045 patients with primarily solid tumor malignancies (89%), median age 65 years, and 52% male. The thrombocytopenia group comprised 9.6% (N=101) of the cohort and relative to the non-thrombocytopenia cohort (N=944), experienced significantly higher major bleeding (9.0% vs. 4.0%, sub-distribution hazard ratio [SHR] =2.4; P=0.02) and CRNMB (17.9% vs. 9.6%, SHR=2.0; P=0.01). Thrombocytopenia did not impact recurrent venous thromboembolic event (VTE) (9.8% vs. 7.4%, SHR=1.3; P=0.37) nor overall mortality (21.8% vs. 26.0%, HR=0.9; P=0.48). Major bleeding was higher in patients with thrombocytopenia and gastrointestinal malignancies receiving edoxaban versus dalteparin (16.8% vs. 0; P<0.01) but similar for patients with other malignancies (P=0.30). In patients with hematologic malignances and thrombocytopenia major bleeding was higher for patients receiving dalteparin compared to edoxaban (19.0% vs. 0; P<0.01). Mild thrombocytopenia was associated with a doubling in risk of major hemorrhage in patients receiving anticoagulation for CAT. Bleeding risk for edoxaban and dalteparin varied in gastrointestinal and hematologic malignances in patients with thrombocytopenia (clinicaltrails gov. Identifier: NCT02073682).

Long-term analysis of the RiBVD phase II trial reveals the unfavorable impact of TP53 mutations and hypoalbuminemia in older adults with mantle cell lymphoma; for the LYSA group

Thu, 30 Nov 2023 00:00:00 +0000

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (rituximab, bendamustine, velcade and dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients over the age of 65. We have now re-examined the classic prognostic factors, adding an assessment of TP53 mutation status. Patients (N=74; median age 73 years) were treated with the RiBVD combination. Median progression-free survival (mPFS) was 79 months and median overall survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level (Alb) 3.6 g/dL were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, P=0.014) was obtained for TP53mt versus TP53 wild-type (wt), and 3.6 (1.39-9.5, P=0.009) for Alb <3.6 g/dL versus Alb ≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PF: TP53mt (HR: 5.9 [1.77-19.5, P=0.004]), Alb <3.6 g/dL (HR: 5.2 [1.46- 18.5, P=0.011]), and ECOG=2 (HR: 3.7 [1.31-10.6, P=0.014]). Finally, a score combining TP53 status and Alb distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months, and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL.

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison

Thu, 30 Nov 2023 00:00:00 +0000

Venetoclax is a standard treatment for patients with chronic lymphocytic leukemia (CLL) following covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi-pretreated CLL. Data from patients with CLL who were venetoclax-naïve and pretreated with cBTKi received pirtobrutinib (N=146) in the phase I/II BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (N=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events. Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% confidence interval [CI]: 0.58-1.73, P=0.98 and OS: 0.64, 95% CI: 0.25-1.67, P=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs. 64.8%, P=0.01). Grade ≥3 treatment-emergent adverse events were lower in weighted analyses for pirtobrutinib versus venetoclax (all P<0.01), except for pneumonia, which was similar. These results suggest that pirtobrutinib may also be considered as an effective and well-tolerated treatment for patients with relapsed CLL following cBTKi.

t(11;14) status is stable between diagnosis and relapse and concordant between detection methodologies based on fluorescence in situ hybridization and next-generation sequencing in patients with multiple myeloma

Thu, 23 Nov 2023 00:00:00 +0000

Multiple myeloma (MM) is associated with a wide variety of recurrent genomic alterations. The most common translocation in MM is t(11;14). In this retrospective, single-center, non-interventional study, patients’ bone marrow samples were examined at diagnosis and at relapse(s) following treatment with anti-myeloma regimens to determine whether t(11;14) status was stable over time. This stability cohort consisted of 272 patients, of whom 118 were t(11;14)-positive at diagnosis and 154 were negative. All patients in the stability cohort retained the same t(11;14) status at relapse that they had at diagnosis of MM. Sixteen patients who had t(11;14)-positive MM at diagnosis had multiple longitudinal assessments by fluorescence in situ hybridization (FISH) at relapse events and remained t(11;14)-positive across all timepoints. Patients who had t(11;14)-positive disease at diagnosis of monoclonal gammopathy of unknown significance or smoldering MM also retained t(11;14) positivity through MM diagnosis and relapse. The t(11;14) fusion patterns also remained constant for 90% of patients. For detection of t(11;14), results from FISH and next-generation sequencing (NGS) were compared to determine the rate of concordance between these two methods. This concordance cohort contained 130 patients, of whom 66 had t(11;14)-positive disease and 64 were t(11;14)-negative. In this sample set, the concordance between FISH- and NGS-based detection of t(11;14) was 100%. These results strongly suggest that the t(11;14) rearrangement remains stable during the full disease course in patients with MM and can be detected by FISH- and NGS-based methodologies.

Real-world multiple myeloma risk factors and outcomes by non-Hispanic Black/African American and non- Hispanic White race/ethnicity in the United States

Thu, 30 Nov 2023 00:00:00 +0000

Examination of the impact of race and ethnicity on multiple myeloma (MM) outcomes has yielded inconsistent results. This retrospective, real-world (RW) study describes patient, disease, and treatment characteristics (and associations with survival outcomes) among newly diagnosed MM patients of non-Hispanic (NH) Black/African American (AA) and NH White race/ethnicity in the US. We included patients from the nationwide Flatiron Health electronic health record-derived de-identified database who initiated first line of therapy (LOT) for MM between January 1, 2016 and March 31, 2022. Of 4,614 patients in our study cohort, 23.3% were NH Black/AA. Non-Hispanic Black/AA patients were younger than NH White patients at diagnosis (median 68 vs. 71 years) and more likely to be female (53.4% vs. 43.5%). Rates of high-risk cytogenetics and 1q21+ were similar between races/ethnicities. The most common primary regimen used was lenalidomide-bortezomib-dexamethasone (50.1% of NH Black/AA and 48.1% of NH White patients). Receipt of stem cell transplantation during first LOT was less common among NH Black/AA (16.5%) than NH White (21.9%) patients. Unadjusted RW progression-free survival (rwPFS) and overall survival (rwOS) were similar between races/ethnicities. After multivariable adjustment, NH Black/AA race/ethnicity was associated with slightly inferior rwPFS (hazard ratio [HR]=1.13; 95% confidence interval [CI]: 1.01-1.27). The difference in rwOS (HR=1.12; 95% CI: 0.98-1.28) was not statistically significant. In general, associations between risk factors for rwPFS and rwOS were consistent between races/ethnicities. Findings from this analysis help to inform clinicians about the impact of race/ethnicity on MM treatment paradigms and outcomes in the US.

Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma

Thu, 21 Dec 2023 00:00:00 +0000

REIIBP is a lysine methyltransferase aberrantly expressed through alternative promoter usage of NSD2 locus in t(4;14)-translocated multiple myeloma (MM). Clinically, t(4;14) translocation is an adverse prognostic factor found in approximately 15% of MM patients. The contribution of REIIBP relative to other NSD2 isoforms as a dependency gene in t(4;14)-translocated MM remains to be evaluated. Here, we demonstrated that despite homology with NSD2, REIIBP displayed distinct substrate specificity by preferentially catalyzing H3K4me3 and H3K27me3, with little activity on H3K36me2. Furthermore, REIIBP was regulated through microRNA by EZH2 in a Dicer-dependent manner, exemplifying a role of REIIBP in SET-mediated H3K27me3. Chromatin immunoprecipitation sequencing revealed chromatin remodeling characterized by changes in genome-wide and loci-specific occupancy of these opposing histone marks, allowing a bidirectional regulation of its target genes. Transcriptomics indicated that REIIBP induced a pro-inflammatory gene signature through upregulation of TLR7, which in turn led to B-cell receptor-independent activation of BTK and driving NFkB-mediated production of cytokines such as IL-6. Activation of this pathway is targetable using Ibrutinib and partially mitigated bortezomib resistance in a REIIBP xenograft model. Mechanistically, REIIBP upregulated TLR7 through eIF3E, and this relied on eIF3E RNA-binding function instead of its canonical protein synthesis activity, as demonstrated by direct binding to the 3’UTR of TLR7 mRNA. Altogether, we provided a rationale that co-existence of different NSD2 isoforms induced diversified oncogenic programs that should be considered in the strategies for t(4;14)-targeted therapy.

Recovery of uninvolved heavy/light chain pair immunoparesis in newly diagnosed transplant-eligible myeloma patients complements the prognostic value of minimal residual disease detection

Thu, 30 Nov 2023 00:00:00 +0000

Immunoparesis (IP) in multiple myeloma (MM) patients can be measured by classic assessment of immunoglobulin (Ig) levels or by analysis of the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC) by the Hevylite® assay. In this study we evaluate the prognostic value of recovery from IP measured by classic total Ig and uHLC assessment in newly diagnosed MM transplant-eligible (NDMM-TE) patients with intensive treatment and its association with minimal residual disease (MRD). Patients were enrolled and treated in the PETHEMA/GEM2012MENOS65 trial and continued in the PETHEMA /GEM2014MAIN trial. Total Ig (IgG, IgA and IgM) and uHLC were analyzed in a central laboratory at diagnosis, after consolidation treatment and after the first year of maintenance. MRD was analyzed by next-generation flow cytometry after consolidation (sensitivity level 2x10-6). We found no differences in progression-free survival (PFS) between patients who recovered and patients who didn’t recover from IP after consolidation when examining classic total Ig and uHLC. However, after the first year of maintenance, in contrast to patients with classic IP, patients with recovery from uHLC IP had longer PFS than patients without recovery, with hazard ratio of 0.42 (95% confidence interval [CI]: 0.21-0.81; P=0.008). Multivariate analysis with Cox proportional-hazards regression models confirmed recovery from uHLC IP after the first year of maintenance as an independent prognostic factor for PFS, with an increase in C-statistic of 0.05 (95% CI: -0.04 to 0.14; P<0.001) when adding uHLC IP recovery. Moreover, we observed that MRD status and uHLC IP recovery affords complementary information for risk stratification. In conclusion, recovery from uHLC IP after 1 year of maintenance is an independent prognostic factor for PFS in NDMM-TE patients who receive intensive treatment. Immune reconstitution, measured as recovery from uHLC IP, provides complementary prognostic information to MRD assessment (clinicaltrials gov. Identifiers: NCT01916252 and NCT02406144).

Epeleuton, a novel synthetic ω-3 fatty acid, reduces hypoxia/ reperfusion stress in a mouse model of sickle cell disease

Thu, 14 Dec 2023 00:00:00 +0000

Inflammatory vasculopathy is critical in sickle cell disease (SCD)-associated organ damage. An imbalance between pro-inflammatory and pro-resolving mechanisms in response to different triggers such as hypoxia/reoxygenation or infections has been proposed to contribute to the progression of SCD. Administration of specialized pro-resolving lipid mediators may provide an effective therapeutic strategy to target inflammatory vasculopathy and to modulate inflammatory response. Epeleuton (15 hydroxy eicosapentaenoic acid ethyl ester) is a novel, orally administered, second-generation ω-3 fatty acid with a favorable clinical safety profile. In this study we show that epeleuton re-programs the lipidomic pattern of target organs for SCD towards a pro-resolving pattern. This protects against systemic and local inflammatory responses and improves red cell features, resulting in reduced hemolysis and sickling compared with that in vehicle-treated SCD mice. In addition, epeleuton prevents hypoxia/reoxygenation-induced activation of nuclear factor-κB with downregulation of the NLRP3 inflammasome in lung, kidney, and liver. This was associated with downregulation of markers of vascular activation in epeleuton-treated SCD mice when compared to vehicle-treated animals. Collectively our data support the potential therapeutic utility of epeleuton and provide the rationale for the design of clinical trials to evaluate the efficacy of epeleuton in patients with SCD.

An extensive database analysis demonstrates significant increase in platelet quantity in unselected hospitalized patients following treatment with oseltamivir

Thu, 22 Feb 2024 00:00:00 +0000

A retrospective analysis of gene fusions and treatment outcomes in pediatric acute megakaryoblastic leukemia without Down syndrome

Thu, 01 Feb 2024 00:00:00 +0000

Hepatosplenic T-cell lymphoma displays an original oyster-shell cytological pattern and a genomic profile distinct from that of γδ T-cell large granular lymphocytic leukemia

Thu, 25 Jan 2024 00:00:00 +0000

Safety and efficacy of anakinra in hemophagocytic lymphohistiocytosis associated with acute leukemia

Thu, 01 Feb 2024 00:00:00 +0000

Postnatal origin of the chromosomal gains in older patients with high hyperdiploid acute lymphoblastic leukemia

Thu, 15 Feb 2024 00:00:00 +0000

Update and European consensus on a patient-centered core outcome set for multiple myeloma in clinical practice and research

Thu, 01 Feb 2024 00:00:00 +0000

Longitudinal dynamics and clinically available predictors of poor response to COVID-19 vaccination in multiple myeloma

Thu, 25 Jan 2024 00:00:00 +0000

TENT5C/FAM46C modulation in vivo reveals a trade-off between antibody secretion and tumor growth in multiple myeloma

Thu, 22 Feb 2024 00:00:00 +0000

Randomized phase III GnG study on two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and double-blinded intensive postremission therapy with or without glasdegib in patients with newly diagnosed acute myeloid leukemia

Thu, 22 Feb 2024 00:00:00 +0000

A randomized, double-blind study of zinpentraxin alfa in patients with myelofibrosis who were previously treated with or ineligible for ruxolitinib: stage 2 of a phase II trial

Thu, 25 Jan 2024 00:00:00 +0000

Targeting CCR4 with mogamulizumab in refractory CD3^-CD4⁺ lymphocytic-variant hypereosinophilic syndrome

Thu, 08 Feb 2024 00:00:00 +0000

Role of red cell mass evaluation in myeloproliferative neoplasms with splanchnic vein thrombosis and normal hemoglobin value: a study of the France Intergroupe des Syndromes myeloprolifératifs

Thu, 08 Feb 2024 00:00:00 +0000

A phase II randomized, placebo-controlled, multicenter trial to evaluate the efficacy of cytomegalovirus PepVax vaccine in preventing cytomegalovirus reactivation and disease after allogeneic hematopoietic stem cell transplant

Thu, 08 Feb 2024 00:00:00 +0000

The outcome of allogeneic hematopoietic stem cell transplantation among elderly patients with severe aplastic anemia and a predictive model from the Chinese Blood and Marrow Transplant Registry group

Thu, 01 Feb 2024 00:00:00 +0000

Lenalidomide, rituximab, and methotrexate are effective in newly diagnosed primary central nervous system lymphoma

Thu, 15 Feb 2024 00:00:00 +0000

Cerebral venous sinus thrombosis and thrombocytopenia due to heparin-independent anti-PF4 antibodies after adenovirus infection

Thu, 26 Oct 2023 00:00:00 +0000

The aggravating fury rituximab obliterated

Himil Mahadevia, Ammar Al-Obaidi, Furha Cossor — Thu, 25 Jan 2024 00:00:00 +0000

Treatment of immune-mediated thrombotic thrombocytopenic purpura without plasma exchange

Thu, 22 Feb 2024 00:00:00 +0000

Haematologica

Genetics as predictive marker for consolidation therapy with high-dose cytarabine in acute myeloid leukemia

Chimeric antigen receptor therapy for T-cell acute lymphoblastic leukemia: finally catching up with B-cell leukemia?

CApSiZing T-cell acute lymphoblastic leukemia

Anatomy of a crime: how IL7R and NRAS join forces to drive T-cell acute lymphoblastic leukemia

SEQ-ing the genetic constellation of acute lymphoblastic leukemia

Charting a path through resistance: histone deacetylase inhibitors for TP53-mutated B-cell acute lymphoblastic leukemia

Be aware of the X: BCOR mutations in myeloid neoplasms

Anticoagulation and thrombocytopenia in cancer: what more can we learn from existing randomized controlled trials

Adenovirus-associated thrombosis and thrombocytopenia: an emerging anti-PF4 disorder

Introduction. Immunotherapy for childhood malignancies: the future is now

Chimeric antigen receptor T-cell therapy in childhood acute myeloid leukemia: how far are we from a clinical application?

Bispecific T-cell engagers in childhood B-acute lymphoblastic leukemia

Chimeric antigen receptor T-cell therapy for T-cell acute lymphoblastic leukemia

Allogeneic chimeric antigen receptor T cells for children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia

Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia

CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia

Mechanism of co-operation of mutant IL-7Rα and mutant NRAS in acute lymphoblastic leukemia: role of MYC

MD-ALL: an integrative platform for molecular diagnosis of B-acute lymphoblastic leukemia

Histone deacetylase inhibition sensitizes p53-deficient B-cell precursor acute lymphoblastic leukemia to chemotherapy

Multi-gene measurable residual disease assessed by digital polymerase chain reaction has clinical and biological utility in acute myeloid leukemia patients receiving venetoclax/azacitidine

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms

Granulocyte transfusions in severe aplastic anemia

PELI2 regulates early B-cell progenitor differentiation and related leukemia via the IL-7R expression

Massive parallel sequencing unveils homologous recombination deficiency in follicular dendritic cell sarcoma

STAT5B mutations in myeloid neoplasms differ by disease subtypes but characterize a subset of chronic myeloid neoplasms with eosinophilia and/or basophilia

Differences in venous clot structures between hemophilic mice treated with emicizumab versus factor VIII or factor VIIIFc

Impact of mild thrombocytopenia on bleeding and recurrent thrombosis in cancer

Long-term analysis of the RiBVD phase II trial reveals the unfavorable impact of TP53 mutations and hypoalbuminemia in older adults with mantle cell lymphoma; for the LYSA group

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison

t(11;14) status is stable between diagnosis and relapse and concordant between detection methodologies based on fluorescence in situ hybridization and next-generation sequencing in patients with multiple myeloma

Real-world multiple myeloma risk factors and outcomes by non-Hispanic Black/African American and non- Hispanic White race/ethnicity in the United States

Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma

Recovery of uninvolved heavy/light chain pair immunoparesis in newly diagnosed transplant-eligible myeloma patients complements the prognostic value of minimal residual disease detection

Epeleuton, a novel synthetic ω-3 fatty acid, reduces hypoxia/ reperfusion stress in a mouse model of sickle cell disease

An extensive database analysis demonstrates significant increase in platelet quantity in unselected hospitalized patients following treatment with oseltamivir

A retrospective analysis of gene fusions and treatment outcomes in pediatric acute megakaryoblastic leukemia without Down syndrome

Hepatosplenic T-cell lymphoma displays an original oyster-shell cytological pattern and a genomic profile distinct from that of γδ T-cell large granular lymphocytic leukemia

Safety and efficacy of anakinra in hemophagocytic lymphohistiocytosis associated with acute leukemia

Postnatal origin of the chromosomal gains in older patients with high hyperdiploid acute lymphoblastic leukemia

Update and European consensus on a patient-centered core outcome set for multiple myeloma in clinical practice and research

Longitudinal dynamics and clinically available predictors of poor response to COVID-19 vaccination in multiple myeloma

TENT5C/FAM46C modulation in vivo reveals a trade-off between antibody secretion and tumor growth in multiple myeloma

Randomized phase III GnG study on two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and double-blinded intensive postremission therapy with or without glasdegib in patients with newly diagnosed acute myeloid leukemia

A randomized, double-blind study of zinpentraxin alfa in patients with myelofibrosis who were previously treated with or ineligible for ruxolitinib: stage 2 of a phase II trial

Targeting CCR4 with mogamulizumab in refractory CD3-CD4+ lymphocytic-variant hypereosinophilic syndrome

Role of red cell mass evaluation in myeloproliferative neoplasms with splanchnic vein thrombosis and normal hemoglobin value: a study of the France Intergroupe des Syndromes myeloprolifératifs

A phase II randomized, placebo-controlled, multicenter trial to evaluate the efficacy of cytomegalovirus PepVax vaccine in preventing cytomegalovirus reactivation and disease after allogeneic hematopoietic stem cell transplant

The outcome of allogeneic hematopoietic stem cell transplantation among elderly patients with severe aplastic anemia and a predictive model from the Chinese Blood and Marrow Transplant Registry group

Lenalidomide, rituximab, and methotrexate are effective in newly diagnosed primary central nervous system lymphoma

Cerebral venous sinus thrombosis and thrombocytopenia due to heparin-independent anti-PF4 antibodies after adenovirus infection

The aggravating fury rituximab obliterated

Treatment of immune-mediated thrombotic thrombocytopenic purpura without plasma exchange

Targeting CCR4 with mogamulizumab in refractory CD3^-CD4⁺ lymphocytic-variant hypereosinophilic syndrome