bluuebunny/crossref_metadata_2025 huggingface dataset:
Aberrant 3'UTR Processing Regulates Leukemogenesis and Therapy Resistance
Authors: Wang Eric , Han Cuijuan , Calderon Alexander
Published: December 2023

A block in cellular differentiation is a hallmark of acute myeloid leukemia (AML) that promote clonal expansion and influence therapy response 1,2. It has become evidently clear that non-genetic mechanisms are critical to prevent malignant cells to resume its lineage maturation trajectory 3,4. However, there is still an incomplete understanding of gene regulatory pathways that induce differentiation arrest of leukemia cells. Here, we applied an immunophenotypic readout and positive selection CRISPR/Cas9 screens to identify suppressors of leukemia differentiation. These screens converged on ZBTB7A, a zinc finger transcription factor whose loss-of-function restricted AML maturation in the prescence of differentiation-inducing agents. Mechanstically, ZBTB7A ablation led to an elevated inflammatory state to stimulate leukemia proliferation. In addition, we found that genetic deletion of ZBTB7A and its paralog, ZBTB7B cooperatively suppresses myeloid differentiation and promotes resistance to several clinical compounds. Lastly, we identify that leukemic cells hijack multiple upstream 3'UTR processes, such as alternative polyadenylation and mRNA decay to downregulate ZBTB7A and ZBTB7B expression. Together, these data provide fundamental insight into non-genetic mechanisms that impede myeloid differentiation and mediate drug resistance.
Caebv Disease Originates from Infected Hematopoietic Stem Cells
Authors: Wang Jingshi , Wei Na , Zhang Jia , Wu Lin , Wang Xi , Wang Zhao
Published: December 2023

Background Chronic active Epstein-Barr Virus (EBV) disease (CAEBV) is lethal syndrome due to persistent EBV infection. When diagnosed as CAEBV, EBV infection was observed in multiple hematopoietic lineages, but the etiology of CAEBV is still elusive.

Methods Bone marrow and peripheral cells derived from five CAEBV patients, one EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) patient, and two healthy controls were analyzed. Multiple assays were applied to identify and characterize EBV-infected cells, including quantitative PCR (qPCR), PrimeFlow and single-cell RNA-sequencing (scRNA-seq). Based on scRNA-seq data, alterations in gene expression of particular cell types were analyzed between CAEBV patients and controls, and between infected and uninfected cells. One CAEBV patient was treated with allogeneic hematopoietic stem cell transplantation (HSCT), and the samples derived from this patient were analyzed again six month after HSCT.

Results EBV infected the full spectrum of the hematopoietic system including both lymphoid and myeloid lineages, so as hematopoietic stem cells (HSCs) in the CAEBV patients. EBV-infected HSCs exhibited a higher differentiation rate towards downstream lineages, and the EBV infection had an impact on both the innate and adaptive immunity, resulting in inflammatory symptoms. EBV infected cells were thoroughly removed from the hematopoietic system after HSCT.

Conclusions Token together,multiple lines of evidence presented in this study suggest that CAEBV disease originates from the infected hematopoietic stem cells.

Figure 1. EBV-infected HSCs were detected in CAEBV patients with multiple assays.
Mitoxantrone Hydrochloride Liposome Injection Combined with Carmustine, Etoposide, and Cytarabine As Conditioning of Autologous Hematopoietic Stem Cell Transplantation in NHL Patients：a Prospective Single-Arm Clinical Trial
Authors: Wang Xiaoning , Ren Juan , Zhu Huachao , Zhang Mei , He Pengcheng
Published: December 2023

Background：High-dose chemotherapy and autologous stem-cell transplantation (ASCT) is standard consolidation therapy for aggressive lymphoma.Choosing the most effective conditioning regimen prior to ASCT can lead to longer survival in these patients.Mitoxantrone liposome is an anthraquinone antibiotic anti-tumor drug. Previous studies have shown that mitoxantrone liposome monotherapy or combined with other drugs has achieved good efficacy for T-cell lymphoma, but there are no reports of its application in conditioning.

Objective:This is a prospective single-arm clinical study to evaluate the efficacy and safety of mitoxantrone hydrochloride liposome injection combined with carmustine, etoposide, cytarabine (modified BEAM protocol) as conditioning of autologous hematopoietic stem cell transplantation for NHL patients (NCT05681403).

Methods: Patients with non-Hodgkin lymphoma who planned to undergo ASCT were eligible to participate in the trial if they were 18 to 60 years of age.The patients received mitoxantrone hydrochloride liposome injection 24 mg/m 2,ivgtt,d-7, carmustine 300 mg/m 2,ivgtt,d-6, etoposide200 mg/m 2,ivgtt,d-5~ -2,cytarabine 200 mg/m 2 q12h,ivgtt,d-5~ -2 as conditioning regimen.The primary end point was the relapse rate within three years and the secondary end point was adverse events of modified BEAM protocol.

Results：Twenty-five NHL patients (median age 39 years old,17 males and 8 females) were enrolled,including 40% DLBCL, 12% MCL, 4% primary mediastinal B-cell lymphoma,4%B lymphoblastic lymphoma,4%Marginal zone B-cell lymphoma,12% PTCL-NOS, 8% ALK +ALCL,8% NK/T lymphoma, 8% AITL,4% ALK -ALCL and 4% Sézary syndrome. 18 cases achieved complete remission before ASCT, while 7 cases received partial remission before ASCT. The median of neutrophil recovery time was 11 days(7-15) and the median of platelet recovery was 12days (7-60).Nausea,vomit,constipation,blue skin and cough were the most frequently reported conditioning related AEs (88%,16%,12%,12% and 8% of patients,respectively), and other AE included 1 case of hypoxemia, 1 case of hypotension, 1 case of palpitation, 1 case of rash. Except one patient experienced a grade 3 vomit ,the others were grade 1-2 and improved after symptomatic treatment. Nine patients experienced febrile neutropenia and 2 cases of sepsis, 4 cases of respiratory infection, and 3 cases of oral mucositis. All partial remission patients achieved complete remission post-HSCT and one of them relapsed 7 months after ASCT.The others were all in complete remission during follow-up.

Conclusion:Mitoxantrone hydrochloride liposome injection combined with carmustine, etoposide, cytarabine (modified BEAM protocol) was a well-tolerated and effective conditioning regimen for NHL and the study is ongoing and updated results will be presented in the future.
One Case of Heavy Chain Deposition Disease Treated with Dara+KD Regimen and Literature Review
Authors: Chen Meilan , Li Juan
Published: December 2023

Background: Heavy chain deposition disease (HCDD) is a systemic disease caused by the deposition of monoclonal immunoglobulin heavy chains in tissues.It is a rare monoclonal immunoglobulin deposition disease. The mechanism of HCDD is still unclear, which may be related to the deletion of heavy chain constant region 1 and the activation of the Complement system by monoclonal heavy chains. Renal biopsy remains the gold standard for diagnosing HCDD at present. There are significant individual differences in the formation of abnormal heavy chains in HCDD patients, and FLC, M protein, and complement detection have certain reference significance for the evaluation of diagnosis and treatment processes. The chemotherapy scheme represented by Bortezomib has a certain effect. HDM/ASCT and kidney transplantation can be used as second-line treatment for some patients. At present, there is no report on the use of CD38 monoclonal antibody combined with KD regimen.

Objective: To explore the efficacy and toxicity of CD38 monoclonal antibody combined with KD regimen in the treatment of heavy chain deposition disease.

Methods: The diagnosis, treatment and efficacy of HCDD who hospitalized in the Hematology Department of the First Affiliated Hospital of Sun Yat-sen University was analyzed, and the value of CD38 monoclonal antibody combined with KD regimen in the treatment of HCDD was discussed. The patient was male, 44 years old, due to “depressed edema of both lower limbs and eyelid edema for more than two months”.

Results: Heavy chain deposition disease is a rare malignant Plasma cell disease. CD38 monoclonal antibody combined with KD regimen can rapidly alleviate the disease,.This patient got CR and obvious improvement of clinical symptoms after 1 cycle chemotherapy, and has no obvious side effects.We be expected to do 4 cycle chemothetaphy and would do ASCT.until now,this patient has got 3 cycles.

Conclusion: Heavy chain deposition disease is a rare malignant Plasma cell disease. CD38 monoclonal antibody combined with KD regimen can rapidly alleviate the disease, with fast onset time, high CR rate, obvious improvement of clinical symptoms, and no obvious side effects.
Demethylation Strategies for the Treatment of Acute Myeloid Leukemia: Targeting Protacs That Degrade DNA Methyltransferase
Authors: Zhang Nan , Xin Lilan , Wang Qian , Chen Guopeng , Ma Linlu , Liang Yuxing , Zhou Fuling
Published: December 2023

Background

DNA methylation is crucial in the pathogenesis of acute myeloid leukemia (AML), characterized by abnormal proliferation of myeloid cells and disrupted DNA methylation patterns. These aberrant patterns contribute to the dysregulation of key genes involved in AML development and progression. Therefore, targeting DNA methyltransferases (DNMTs) to restore proper DNA methylation patterns has emerged as a promising therapeutic strategy. However, traditional demethylation therapies (e.g. azacytidine, decitabine) face challenges in effectively and selectively targeting DNMTs.

Methods

In this study, we investigated the potential of a novel approach utilizing proteolysis targeting chimeras (PROTACs) for selective degradation of DNMTs in AML cells. A series of PROTAC molecules was designed and synthesized, with GSK3685032 serving as the ligand for DNMTs. The E3 ligase CRBN was employed to mediate the proteasomal degradation process.

Results

The designed PROTACs efficiently degraded DNMTs in AML cell lines, as demonstrated by immunoblotting and immunofluorescence assays. Genome-wide DNA methylation analysis revealed a significant reduction in global DNA methylation levels following PROTAC-mediated DNMT degradation.In AML PDX models, the PROTACs effectively decreased DNMT protein levels, resulting in substantial reduction of global DNA methylation and significant inhibition of tumor growth. Furthermore, combination studies revealed synergistic effects when the PROTAC-mediated DNMT degradation was combined with standard clinical therapeutic agents.The combination approach showed enhanced therapeutic efficacy compared to either treatment alone, suggesting a potential strategy for improved AML treatment outcomes.

Conclusions

The study highlights the potential of PROTAC-mediated DNMT degradation as a promising targeted demethylation strategy for AML. This approach holds promise for improving treatment outcomes, particularly in AML patients with DNMT mutations. Further research is warranted to fully evaluate the efficacy of this approach in clinical settings.

Keywords: Acute myeloid leukemia, DNA methylation, PROTACs
Fluid-Overload Associated Large B-Cell Lymphoma Clinicopathologic Features and Determinants of Outcomes: Analysis of a Pooled Database
Authors: Graham Christopher , Gupta Supriya , Haddad Philip A
Published: December 2023

Background:

Fluid overload-associated large B-cell lymphoma (FOLBCL) is a new WHO lymphoma entity previously known as PEL-like lymphoma or HHV8-unrelated PEL-like lymphoma. It is a rare lymphoma that arises within fluid-filled body cavities without a solid component. FOLBCL occurs in the absence of immunodeficiency and is commonly associated with conditions associated with fluid overload. It expresses mature B-cell phenotype and occasional EBV infection markers. We conducted this study to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect outcomes in this rare and newly-defined lymphoma subtype.

Methods:

To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 115 cases that fit the diagnostic criteria for FOLBCL. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).

Results:

A total of 115 patients with confirmed FOLBCL were identified. The median age was 74, with a peak incidence between 72 and 82 years. There was a male preponderance with M:F of 2. The pleural, pericardial, and peritoneal cavities were involved in 75%, 34%, and 27%, respectively. The median duration of symptoms before diagnosis was 1 month. Patients presented with constitutional symptoms and hepatosplenomegaly in 13% and 1%, respectively-no patients presented with lymph node and bone marrow involvement. The median OS of the whole group was 16 months. Patients younger than 70 had better median OS than 70 and older (24 vs. 10 months, p=0.008). The presence of any malignant peritoneal effusion was associated with worse OS when compared to effusion limited to the thoracic cavity (7 vs. 24 months, p=0.005). LDH≥500 was also associated with worse OS (p=0.02). Sex, the presence of fluid overload-causing conditions, and serum IL2R levels did not seem to impact OS. Compared to no treatment, chemotherapy had a numerically superior OS but did not reach statistical significance (19 vs. 10 months, p=0.11). However, patients that attained CR as their best response had a superior median OS (p<0.0001).

Conclusions:

This study presents updated clinicopathologic data from a pooled cohort of patients with FOLBCL. It identifies the age, the primary location of cavitary disease, LDH, active therapy, and quality of response to treatment as key determinants of OS.
Malignant Histiocytic Neoplasms' Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database
Authors: Haddad Philip A , Keerty Dinesh
Published: December 2023

Background:

Malignant histiocytosis, also known as the M-group per the Histiocyte Society classification, represents a rare, aggressive malignant group of histiocytic neoplasms. It includes histiocytic neoplasms that occur de novo (pMHN) and those that develop in association with other malignant diseases (aMHN). However, little is known about factors that impact MHN clinical outcomes. We conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in this rare histiocytic group.

Methods:

To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 270 cases of MHN. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).

Results:

A total of 270 patients with confirmed MHN were identified, with 77% pMHN and 23% aMHN. The median age was 45, with bimodal peaks between 13-26 and 52-65. There was a male preponderance with M:F of 1.6. The most common primary sites of involvement were liver (15%), CNS and spleen (13% each), thoracic, GI, and soft tissues (12% each), bones (11%), skin (10%), and H&N (8%). Lymphadenopathy and bone marrow (BM) were involved in 28% and 18%, respectively. Constitutional symptoms occurred in 12% and hemophagocytic syndrome (HPS) in 6%. The median time of MHN onset in aMHN was 12 months. The median OS of the whole group was 12 months. BM involvement had a worse median OS (p = 0.003). Stage 1 disease had better median OS than higher stages (p = 0.01). Furthermore, unifocal had better median OS than multifocal/multicentric disease (p = 0.0005). The presence of inflammatory background positively impacted OS (p = 0.01). The occurrence of HPS adversely affected OS (p < 0.0001). Compared to no treatment, localized therapies such as surgery (S) and/or radiation therapy (RT) and systemic combination chemotherapy (CT) were statistically superior, with a median OS of 3, 24, and 18 months, respectively (p = 0.02). When MHN was not amenable to complete resection, CT and CT+/-S+/-RT were superior to RT+S (p = 0.03). Having CNS or splenic-lymphatic primary involvement tended to have a numerical but non-significant worse median OS than soft tissue or visceral disease. While female sex, size<10cm, and pMHN seemed to have numerically better OS, they did not reach statistical significance. There was no difference in median OS for age.

Conclusions:

This study presents updated clinicopathologic data from a pooled cohort of patients with MHN. It identifies BM involvement, stage, extent of the disease, the inflammatory background status, occurrence of HPS, and treatment approach as critical determinants of OS.
A Retrospective Analysis of the Trends in Mantle Cell Lymphomas in the United States
Authors: Desai Krishna , Iqbal Sabah , Choi Eugene , Thar Yu Yu , Rather Manzoor , Thirumaran Rajesh
Published: December 2023

Introduction:

Mantle Cell Lymphoma (MCL) refers to the malignant B lymphocytes arising from the outer (mantle) zone of the lymphoid follicle. This rare and aggressive subtype of Non-Hodgkin Lymphoma, which accounts for ~5 percent of all NHL cases. It is associated with t(11:14) that leads to over-expression of cyclin D1, resulting in tumor cell proliferation via cell cycle dys-regulation, chromosomal instability, and epigenetic regulation. The aim of this study is to understand the epidemiology and survival predictors of MCL.

Methods:

The data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2022 Sub (2000-2020). We extracted Mantle Cell Lymphoma cases diagnosed after 20 years of age, with Lymphoid neoplasm recode 2(a)2.1.3. The analysis was stratified based on age, sex, racial incidence rates, & survival curves based were compared, using the Log-rank test (GraphPad Prism).

Results:

A total of 14166 cases of MCL were found between 2000 to 2020. Out of these, ~70.73% cases were males, and ~29.27% were females. The median age at the time of diagnosis was 69 years. Of the affected population, ~80.60% were Caucasians, ~3.92% were African-Americans, ~4.10% were Asians/Pacific Islanders, only ~0.50% were American Indians/Alaskan Natives, and ~10.32% were Hispanics. The incidence per 1,000,000, as of 2020, was 10.83 for the general population, 13.00 for Caucasians, 5.01 for African-Americans, 13.71 for American Indians/Alaskan Natives, 3.28 for Asians/Pacific Islanders, and 9.43 for Hispanics. Survival curves were not significant when compared based on the race of the patients. However, survival curves showed statistical significance when compared based on gender, with median of survival (mOS) for males was 50 months, and for females mOS was 56 months (p-value 0.0.008, Hazard Ratio 1.084 [Confidence Interval 1.035 to 1.136], using Log-rank test.

Conclusions:

Mantle Cell Lymphoma has a strong predilection for males. It is more commonly diagnosed in the late 60s, median age being 69. Unequal racial distribution was noted, with caucasians (~80%) comprising most of the patient population, and the least commonly encountered were American Indians/Alaskan Natives(~0.50%). However, when incidence rates were calculated per 1,000,000 population in 2020, it was found that the incidence in American Indians/Alaskan Natives (13.71), is drastically higher than the general population(10.83) vs. incidence in Asians/Pacific Islanders(3.28) is significantly lower than the other races. Although race played no role in prognosis, females had better survival rates than males. This retrospective study was done to aid in better understanding of this curable malignancy, despite its rarity, aggressivity and the complexity in treatment.
Clonal Expansion and Differentiation of Stem-like Memory T Cells to Tissue-Resident Memory T Cells Perpetuates Pathogenesis of Chronic Graft-Versus-Host Disease
Authors: Kong Xiaohui , Wang Bixin , Wu Xiwei , Cho Hyejin , Zheng Moqian , Zhang Yuankun , Tang Shanshan , Li Qinjian , Nasri Ubaydah , Wu Alyssa , Qin Hanjun , Pillai Raju , Nakamura Ryotaro , Martin Paul J. , Chen Yuanzhong , Zeng Defu
Published: December 2023

We and others have shown that tissue-resident memory CD4 + T cells play a critical role in maintaining chronic GVHD pathogenesis. However, the cellular and molecular mechanisms remain largely unknown. Ly108 and (TCF1) expression have been shown to reflect the stemness of memory CD8 + T cells. In the current studies, using the markers Ly108 (TCF1) and CD69, we identified four subsets of memory CD4 + T (Tm) cells in the GVHD target tissues, including Ly108 + CD69 - and Ly108 +CD69 + stem-like Tm cells, as well as Ly108 - CD69 - and Ly108 - CD69 + differentiatedTm cells. Compared to other Tm subsets, the Ly108 - CD69 + subset expressed the highest levels of IFN-γ and GM-CSF without upregulating anergy/exhaustion markers, indicating that they represent a terminally differentiated, tissue resident, pathogenic CD4 + memory T (Trm) subset. The Ly108 + Tm subsets showed self-renewal capacity and differentiation into Ly108 - Tm subsets, as demonstrated by adoptive transfer experiments. Using single-cell RNA sequencing (scRNA-seq) in conjunction with scTCR-seq analysis, we observed that Ly108 +CD69 - Tm subset was clonally related to the expanded Ly108 - CD69 - and Ly108 - CD69 + Tm subsets, suggesting a clonal expansion and differentiation of Ly108 + CD69 - stem-like memory T (Tsm) cells. In addition, we found that IFN-γ primed donor-type antigen-presenting cells (APCs) play an essential role in optimizing the transition from CD4 + Tsm cells to CD4 + Trm cells in STAT3- and BCL6-dependent manner, as indicated by ATAC-Seq analysis. Our results have elucidated a novel pathway of clonal expansion and differentiation of Tsm cells to Trm cells in the GVHD target tissues. These observations provide cellular and molecular mechanisms that explain how chronic GVHD is perpetuated by memory T cells in local tissues.

XK and BW contributed equally.
A Single Center Retrospective Analysis Comparing the Outcomes of Induction Therapy between 7+3 and FLAG-IDA/Venetoclax in Newly Diagnosed Patients with Acute Myeloid Leukemia
Authors: Abdelmessieh Peter , Varshavsky-Yanovsky Asya , Shestovska Yuliya , Khanal Rashmi , Styler Michael , Ballas Brittany , Ridgway Forrest , Sorrentino Michele , Ojala Anne , Fung Henry C.
Published: December 2023

Introduction

Induction chemotherapy (IC) in acute myeloid leukemia (AML) in younger and fit patients has historically combined an anthracycline (ie, daunorubicin or idarubicin) with the antimetabolite cytarabine, which has been termed the 7 + 3 regimen. Response rates with this current standard approach show complete response rates of 70-80%, however 30-40% still eventually relapse. Recently, the MD-Anderson group published a phase II study in which the drug venetoclax was added to the standard anthracycline/cytarabine induction regimen of FLAG-IDA. Results from this study showed an impressive 96% response rate for newly diagnosed (ND) AML patients. Based on these results we began to adopt this approach for our patients. We have induced 21 patients with this approach at our institution and have had comparable results.

No study has compared outcomes between this approach and that of standard 7 +3 in regards to response rates. Based on our improved outcomes we compared outcomes between these two approaches in our patient population by doing a retrospective chart based review on all patients that received cytotoxic induction treatment for ND-AML between 2000-2023.

Methods

Patients between 2020-2023 that were treated with induction cytotoxic chemotherapy for AML, based on WHO 2016 criteria, were retrospectively reviewed. Patients either received 7+3 or 7+3 plus midostaurin if they were FLT3+ in one arm or FLAG-IDA/Venetoclax. Patients received FLAG-IDA/Venetoclax regardless of FLT3+ status or risk of disease. Patients with extra medullary disease were excluded from this review as well as patients that received an IDH1 or 2 inhibitors in combination with 7 +3.

Results

Overall 39 patients were included in this study, 20 patients in the FLAG-IDA/Venetoclax arm and 19 patients in the 7/3 arm. In patients which response was able to be evaluated patients in the FLAG-IDA/Venetoclax cohort had a 100% overall response rate with a 95% (N = 19/20) complete response rate. Patients in the 7/3 cohort the complete remission rates were 66% (N = 12/16) with 3 of the patients achieving a complete remission with re-induction. Sixty-day morality rate was 5% (N = 1/20) in patients receiving FLAG-IDA/Venetoclax compared to 16% (N = 3/19). In terms of neutrophil recovery and toxicity results were comparable in both arms, with the average day to cell recovery being the similar in both groups.

Conclusions

FLAG-IDA/Venetoclax compared to standard 7/3 +/- FLT3 directed therapy in our patient population resulted in improved response rates and decreased 60-day mortality. Our results are similar to previously published reports in patents with ND-AML. Toxicity profiles were similar with the clear benefit of decreased early morality are increased response rates.
A Phase 1b Trial of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Myelofibrosis and Anemia
Authors: Gangat Naseema , Foran James M. , Halpern Anna B. , Rampal Raajit K. , Novikov Natasha , Buch Akshay , Pelletier Olivia , Savage William , Tefferi Ayalew
Published: December 2023

Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic elevations in hepcidin contribute to the onset and severity of anemia. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Preclinical studies have shown that DISC-0974 suppresses hepcidin and increases serum iron. A healthy volunteer study has demonstrated dose-dependent reductions in serum hepcidin, increases in serum iron with doses up to 56 mg administered subcutaneously, and increasing trends in reticulocyte count, reticulocyte hemoglobin, mean corpuscular hemoglobin, total hemoglobin (Hgb), and red blood cell count.

In this Phase 1b/2a, open-label, multiple-ascending dose study (NCT05320198), we are assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DISC-0974 in patients with MF and anemia.

Eligible participants include patients over 18 years of age with intermediate-2 or higher-risk MF and anemia. MF is required to be confirmed using the World Health Organization 2016 criteria. Anemia is defined per protocol as Hgb < 10 g/dL or transfusion dependence, as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). A stable dose of hydroxyurea and/or Janus kinase (JAK) inhibitor is allowed on trial. Major exclusion criteria include: liver iron concentration ≥ 7 mg/g dry weight; splenectomy; nutritional, genetic, infectious, or autoimmune causes of anemia. Dose escalation is based on a Bayesian optimal interval design with accelerated titration. Safety Review Committee assessments gate escalation decisions. Dosing occurs monthly for a total of 6 doses.

Primary endpoints include safety and tolerability assessments of adverse events (AEs), clinical laboratory assessments, vital signs, physical examinations, and electrocardiograms. Secondary endpoints include anemia response as defined by the IWG-MRT, transfusion response as defined by a decrease of 50% in transfusion requirement over any 8-week period, standard PK parameters and PD metrics including serum hepcidin-25, iron, transferrin saturation, ferritin, and hematology biomarkers. All data are summarized using descriptive statistics.

Initial data show a dose-related increase in pharmacokinetic parameters. DISC-0974 treatment led to dose-dependent reductions in serum hepcidin-25 and increases in serum iron levels. There have been no serious AEs or AEs leading to study withdrawal. Most AEs were mild, transient, and unrelated to DISC-0974.

As of August 1, 2023, enrollment and dose escalation are ongoing. Safety, PK, and PD data from at least the first two cohorts will be presented.
Characterization of JNJ-79635322, a Novel BCMAxGPRC5DxCD3 T-Cell Redirecting Trispecific Antibody, for the Treatment of Multiple Myeloma
Authors: Pillarisetti Ram , Yang Danlin , Yao Jianhong , Smith Melissa , Luistro Leopoldo , Vulfson Peter , Testa James , Packman Kathryn , Brodeur Scott , Attar Ricardo M. , Elsayed Yusri , Philippar Ulrike
Published: December 2023

Background: Multiple myeloma (MM) is a genetically complex and heterogenous malignancy with a poor survival rate and accounts for approximately 10% to 15% of all hematologic cancers. Despite advances in myeloma therapy, MM remains incurable. Deep and durable clinical responses have been observed when targeting the tumor associated antigens BCMA and GPRC5D with immunotherapies. Additionally, data presented at ASCO this year demonstrated a further improvement in ORR when BCMA and GPRC5D bispecifics were given in combination to relapsed or refractory MM patients. These data suggest that broader antigen coverage by redirecting T cells to two tumor surface antigens is an effective means to harness the immune system to deplete cancer cells. Targeting two tumor antigens may also reduce the likelihood of antigen escape as a primary reason for relapse. Here, we describe JNJ-79635322, a trispecific antibody targeting B-cell maturation antigen (BCMA) and G-Protein-coupled receptor class 5 member D (GPRC5D), which are both highly expressed on plasmablasts and plasma cells in myeloma patient samples. Dual antigen recognition on plasma cells with a trispecific T-cell engaging antibody engineered with a CD3 arm has the potential to enhance tumor binding through avidity that could result in efficient depletion of malignant clonal populations and prevent tumor antigen loss mediated resistance.

Methods: JNJ-79635322 is a trispecific antibody composed of an anti-CD3 binding domain an anti-BCMA binding domain, and an anti-GPRC5D binding domain. It was selected based on biophysical assessment and showed activity in multiple myeloma models.

Results: JNJ-79635322 induced potent cytotoxicity in various myeloma cell lines in vitro with concomitant T-cell activation. Importantly, JNJ-79635322 was able to deplete both dual (BCMA and GPRC5D) and single (BCMA or GPRC5D) target expressing cells efficiently. In addition, dose dependent depletion of H929 myeloma cells was observed in a more physiological healthy fresh whole blood co-culture assay. In vivo, JNJ-79635322 exhibited potent antitumor activity compared to vehicle and antibody controls in a murine MM xenograft prevention model (single target expressing clonal H929 cells) and two tumor regression models (RPMI 8226 and MM.1S cells).

Conclusion: JNJ-79635322 is a potential first-in-class trispecific antibody targeting BCMA and GPRC5D with the ability to deplete dual and single target expressing MM clones in preclinical studies vitro and in vivo. A Phase 1 dose-escalating study of JNJ-79635322 in myeloma patients is ongoing (NCT05652335).
Secondary Hemophagocytic Lymphohistiocytosis in Adults: A Single Institution Case Series
Authors: Singh Rishabh , Nain Priyanshu , Chatterjee Tulika , Kandula Manasa
Published: December 2023

Introduction:

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome caused by the abnormal activation of macrophages and T cells. The primary form, resulting from lymphocyte-related mutations, is more common in children, while the secondary (acquired) form known as sHLH prevails in adults. sHLH is often triggered by infections or malignancies (Mal-HLH) but can also be induced by autoinflammatory disorders called macrophage activation syndrome (MAS; or MAS-HLH). We present a retrospective case series of adults treated for sHLH at a single institution from 2012 to 2023.

Methods:

Retrospective data was collected using the EDW database, and 36 patients were identified using ICD 9/10 codes 288.4 and D76.1 for HLH. Subsequently, a manual review of electronic medical records was conducted; criteria for inclusion were age >18 years at the time of diagnosis and meeting HLH-2004 criteria ( Panel-1).

Results:

Out of the 36 patients reviewed, 11 met the criteria and were included in the analysis. These cases occurred between 2015 and 2023. The median age at diagnosis was 52 (range 18 to 81). The female-to-male ratio in our study was 4:7. Most patients (73%) were white. Additionally, 45% of the patients were immunocompromised.

91% of the patients presented with fever, while only 45% had splenomegaly. Trilineage cytopenias were observed in all patients. In our study, 5/11 had hypofibrinogenemia, and 6/11 had hypertriglyceridemia. Hemophagocytosis was evident in 91% of the patients. Natural Killer (NK) cell activity was measured in 4 patients, and all exhibited low or no NK cell activity. In 10 out of 10 patients, soluble IL-2 receptors were elevated.

None of the patients in the study had hepatomegaly, but all had transaminitis and hyperbilirubinemia, and 82% had elevated alkaline phosphatase levels. Elevated lactate levels were observed in 78% of patients, and 27% had a rash. Neurological features were observed in 6 out of 10 patients. Lactate dehydrogenase was elevated in all patients with a median value of 1551 U/L (range 354 - 3689)

Presumed etiologies for sHLH included malignancy (4), infection (3), autoimmune disease (3), and unknown cause (1). Treatment was highly individualized based on the underlying trigger and was guided by the HLH-94 protocol ( Panel-2). All patients received high-dose steroids, 6/11 received etoposide, and 2 received intrathecal therapy for neurological involvement.

Conclusion:

At a median follow-up period of 16 days, five patients had died. The survival rates at 30 days and 1 year were 45% and 27%, respectively. The overall mortality rate was 55%. While mortality rates were 75% in the Mal-HLH arm and 67% in the infectious arm, all patients with MAS-HLH survived while performing the study indicating a better prognosis for patients with this type of HLH.
Provisional Prognostic Score for Blastic Plasmacytoid Dendritic Cell Neoplasm
Authors: Haddad Philip A , Gaddam Shiva Jashwanth
Published: December 2023

Background

BPDCN is an aggressive hematologic malignancy which often involves the skin. This disorder has gone through many iterations over the years, being classified initially as a blastic NK-cell lymphoma, then a subset of AML, and finally recognized as a unique myeloid neoplasm. While BPDCN often follows an aggressive course, its outcomes vary considerably. We conducted this study to develop a provisional BPDCN prognostic score (BPS) for this rare disease.

Methods

We used our constructed BPDCN database, which contains retrospective data on 273 cases. Such data included demographics such as sex, age, and race. It also included disease presentation symptoms, duration of symptoms before diagnosis, site(s) of the disease, blood counts, coexisting comorbidities, disease immunohistochemical and molecular phenotype, types of treatment, and survival outcomes. Of the 273 cases, only 218 had complete survival and outcomes data, the sample chosen for this study. Cox proportional-hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on overall survival (OS). We included factors that statistically impacted OS and scored them by the impact of their hazard ratios.

Results

The median OS of the cohort was 16 months. The following dichotomous variables were identified as impactful prognostic factors in this cohort: Age>60 (10 vs. 30 months), lymphadenopathy (14 vs. 42 months), bone marrow involvement (14 vs. NR months), splenomegaly (10 vs. 16 months), and disseminated skin disease (13 vs. NR months). A prognostic model was devised using these variables to identify different levels of risk. Each variable was assigned a score of 1 when present, except for age>60, splenomegaly, and disseminated skin disease, that were assigned 2 points each as they had the highest hazard ratios of all the other variables. In this exploratory cohort, low risk was assigned a score of 0-2, intermediate risk a score of 3-4, and high risk a score of 5-8. This prognostic score system led to our cohort's most optimal risk discriminatory model, where low, intermediate, and high risk had a median OS of NR, 24, and 10 months, respectively (p<0.0001).

Conclusion

This BPS is a promising new tool for risk-stratifying patients with BPDCN. However, it still requires prospective validation.
The Change of Complement Deposition after Complement Inhibitor Treatment in Paroxysmal Nocturnal Hemoglobinuria Patients
Authors: Zhang Menglu , Wang Xuan , Yang Chen , Chen Miao , Zhuang Junling , Han Bing
Published: December 2023

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disease in which abnormal complement activation results in hemolysis and thromboembolic events (TEE). Complement inhibitors (CI) have been proved to be able to suppress intravascular hemolysis (IVH) and reduce the risk of TEE. Few studies were available on the changes of complement deposition after CI and their relationship with efficacy.

Methods: PNH patients treated with full dose eculizumab, crovalimab or iptacopan at Peking Union Medical Colleague Hospital from Oct 2021 to Jul 2023 were enrolled.Patients' clinical information and blood samples were collected after 0, 1, 3, 6, 9 and 12 months of treatment. The deposition of C5b-9, C3, C4b and factor B (FB) on peripheral red blood cells (RBC), white blood cells (WBC) and platelets (PLT) was detected by double-color staining flow cytometric assay. The efficacy of each CI was correlated with complement deposition levels on three blood lineages.

Results: 23 PNH patients were enrolled. Among them, 13 patients were treated with C5 inhibitors (4 with eculizumab and 9 with crovalimab), 10 were treated with iptacopan (FB inhibitor). For patients treated with eculizumab, C5b-9+/RBC and C5b-9+/WBC significantly decreased after 3, 6 and 12 months of treatment(P<0.05); however, C3+/WBC and C3+/PLT significantly increased after 12 months (P<0.05). For covalimab-treated patients, C5b-9+/RBC significantly decreased after 6 and 12 months (P<0.05), while C3+/RBC, C3+/WBC, C4b+/RBC and C4b+/WBC increased (P<0.05) after 6 months. For those treated with iptacopan, after 1, 3, 6, 9 and 12 months, the deposition of C5b-9 on all three blood lineages significantly decreased (P<0.05), meanwhile, C3 and FB on all three lineages decreased (P<0.05); moreover, C4b+/WBC and C4b+/PLT decreased after 3, 6, 9 and 12 months (P<0.05). C5b-9+/RBC and C5b-9+/WBC were significantly associated with hemoglobin improvement after eculizumab treatment (P=0.004 and 0.018, respectively). C5b-9+/RBC was positively correlated with bilirubin (P=0.023) and C3+/RBC was positively correlated with absolute reticulocyte counts (Ret, P=0.001) after crovalimab treatment. After iptacopan treatment, C3+/RBC was positively correlated with Ret (P=0.010), C4b+/RBC was positively correlated with Ret (P=0.032) and lactose dehydrogenase (LDH, P=0.003), and FB+/RBC was positively correlated with LDH.

Conclusion: Complement inhibitors could effectively reduce C5b-9 deposition. Unlike C5 inhibitors, iptacopan also reduced the deposition of C3, C4b, and FB. C5b-9+/RBC may be correlated with the efficacy of inhibiting intravascular hemolysis. Upstream complement deposition is probably associated with breakthrough hemolysis or extravascular hemolysis.

【Key words】Paroxysmal nocturnal hemoglobinuria, complement inhibitor, complement deposition, flow cytometric assay, hemolysis
Role of Pegylated Liposomal Doxorubicin in Heavily Pretreated Relapsed Refractory Hodgkin Lymphoma Eligible for Autologous or Allogeneic Transplantation
Authors: Casadei Beatrice , Pellegrini Cinzia , Sutto Emanuele , Cantelli Martina , Argnani Lisa , Zoli Sabrina , Coppola Paolo Elia , Gentilini Marianna , Morigi Alice , Carella Matteo , Gugliotta Gabriele , Bagnato Gianmarco , Nanni Laura , Broccoli Alessandro , Stefoni Vittorio , Zinzani Pier Luigi
Published: December 2023

In the context of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), various conventional single agents and salvage chemotherapy regimens have been explored, including bendamustine, brentuximab vedotin, nivolumab, and pembrolizumab. However, there is another drug, pegylated liposomal doxorubicin (PLD), which has shown interesting results but is comparatively less recognized and mostly used in combination.

For heavily pretreated R/R cHL patients this drug, presenting a reduced cardiac toxicity compared to non-liposomal doxorubicin, may be considered as bridging therapy (BT) to transplantation (both autologous [ASCT] and allogeneic [alloSCT]).

The present retrospective study aims to determine the role of PLD monotherapy in terms of safety and effectiveness in heavily pretreated R/R cHL patients as BT to ASCT or alloSCT.

Our case series comprises 22 R/R cHL patients who were potentially eligible for transplantation and underwent PLD treatment successfully. These patients had a median of five previous treatments (range, 3-9), including ASCT in 50% of the cases and radiotherapy in 7 out of 22 cases. Of the total, 77% were primary refractory, and 63.6% remained refractory to the last previous therapy before PLD. Additionally, eight patients had advanced stage disease at the time of PLD treatment.

PLD was administered at a fixed dose of 60 mg every 21 days with a median of 4 cycles (range, 1-8). No dose reduction was needed. Few toxicities occurred. In detail, four hematological adverse events (AE) were reported in 3 patients (all grade ≥3, drug related but rapidly resolved without sequalae). Only one grade 3 extra-hematological occurred (deep vein thrombosis). Final overall response rate (ORR) was 31.8%, with 4 complete and 3 partial responses (CR, PR). Best ORR of 54.5% was reached at the third cycle (5 CR and 7 PR). Five patients subsequently proceeded to ASCT and 2 to alloSCT with 5 final CR (two patients converted from a PR and 1 from a stable disease). At a median follow-up of 6 years, median overall survival was reached at 4 years.

The findings from this retrospective analysis suggest that PLD monotherapy may be effective in treating a subset of patients with multi-relapsed or refractory cHL. PLD could be considered as a strategic and relatively low-toxicity bridging therapy option for patients undergoing transplantation.
Low Disease Relapse and High Survival in Non-Myeloablative Two-Step Haploidentical Transplant, Results of a Prospective Trial
Authors: Bi Xia , Grosso Dolores A. , Wagner John L. , Filicko-O'Hara Joanne , O'Hara William , Flomenberg Neal , Gergis Usama
Published: December 2023

Introduction

We previously developed a two-step approach that separates the lymphoid and myeloid portions of the graft, allowing a consistent T cell dosing and sparing the stem cells from the effect of cyclophosphamide. The two-step approach demonstrated safety and efficacy in patients treated with a myeloablative conditioning protocol. Here, we extended our 2-step platform to older and less fit patients and explored the effects of using a high dose of T cells on disease relapse and transplant outcomes.

Methods

Patients received fludarabine 30mg/m 2 IV daily for 3 days, from day -10 to day -8. Two hundred cGy total body irradiation (TBI) was given on day -7. This was increased to 400 cGy TBI in 2 doses after 13 patients had been treated. A fixed dose of 2 x 10 8/kg CD3+ T cells was given on day -6, followed 2 days later by cyclophosphamide 60mg/kg IV daily on day -3 and day -2. Tacrolimus and mycophenolic acid were started on day -1, followed by infusion of CD34-selected stem cells on day 0.

Results

Thirty-three patients with hematologic malignancies were treated (Table 1). Majority were haploidentical transplants (91%), and the rest were matched related donors. Median age was 68 (range, 33-76) years, with 64% patients >65 years old. Median follow-up was 31 months (range, 0-76 months). Median HCT-comorbidity score was 4 (range, 0-9). Forty-seven percent had high or very high-risk disease risk index. Twenty-seven percent had prior autologous transplant.

Overall survival was 75% at 1 year and 50% at 3 years. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were 22% and 31% at 3 years. However, the CI of relapse was much lower for patients treated with 400 cGy TBI versus those treated with 200 cGy TBI (6% vs 54%, p = 0.017) (Figure 1), while NRM was similar (25% vs 15%, p = 0.348). This contributed to a very high survival of 69% in patients who received the higher dose of TBI at 3 years, with median OS not reached.

The median time to neutrophil and platelet recovery was 11 and 17 days, respectively. The median donor CD3+ T cell chimerism at day +28 was 100% (range, 71% to 100%). The CI of grade II acute graft-versus-host-disease (GVHD) was 23% and 27% at 100 days and 6 months, respectively. The CI of chronic GVHD was 8% at 3 years. There were no grade III or IV acute GVHD, no severe chronic GVHD and no deaths attributable to acute or chronic GVHD. There were 13 deaths in the study, of which 7 died from disease relapse, 3 died from toxicity related to treatment regimen, and 2 died from infection.

Conclusions

The NMA two-step approach allo-SCT showed a low disease relapse rate and high survival in patients treated with 400 cGy TBI, despite a generally older and more medically compromised patient population.
Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio for an Early Detection of Venous Thromboembolism in COVID-19 Patients
Authors: Gharib Hussein Khalil , Szpunar Susanna , Bhargava Ashsih , Kafri Zyad
Published: December 2023

Background: Venous Thromboembolism (VTE) is an umbrella term that includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). COVID-19 infection has emerged as a risk factor for VTE; however, traditional methods of testing (D-dimer and Well's score) have been less than optimal. The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte Ratio (PLR) have a role in diagnosing DVT in non-COVID19 patients. These two inexpensive values are readily available from the complete blood count (CBC).

Objective: To determine the association of NLR and PLR on admission and imaging day with the incidence of VTE in COVID-19 patients.

Methods: This was a historical cohort study of all patients admitted with COVID-19 from 2020-2021, who underwent duplex ultrasound (US) and/or computed tomography angiography (CTA) of the chest, and serial complete blood counts (CBC) with differential measurements during hospitalization. Patients who had risk factors for VTE (active malignancy, history of thrombophilia disorders and any anticoagulation therapy) were excluded. The NLR and PLR were calculated on admission and upon imaging for eligible patients. Data were analyzed using Student's t-test, analysis of variance, the x2 test and logistic regression.

Results: We included 234 patients, 51.3% (120/234) female, 57.3% Black (134/234) with mean age 59.2 ± 15.9 years. The mean NLR on admission for all admitted patients was higher in the VTE group vs non-VTE group, 11.24 ±11.33 vs 7.66 ±5.16 respectively, (p=0.002). The mean NLR on admission for non-ICU patients was higher in the VTE group vs non-VTE group, 9.06 ± 5.72 vs 7.04 ± 4.53 respectively, (p=0.02). For ICU patients, the mean NLR on admission was higher in the VTE group vs non-VTE group, 14.49 ±16.01 vs 8.6±4.53 respectively, (p=0.02).. There was no association between PLR on admission, NLR and PLR on imaging and incidence of VTE. After controlling for sex, every unit increase in NLR at admission increased the risk of VTE by 6.8% (OR=1.068, p=0.005).

Conclusion: NLR on admission may be a useful, readily available and inexpensive method of screening for VTE in patients with COVID-19 infection.