bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment with GT1708F, an Oral Smoothened Inhibitor, in Patients with Myeloid Malignancies: A Phase I Study
Authors: Jin Jie , Qi Junyuan , Zhao Weihua , Wang Huafeng , Song Lin , Lin Yu , Tong Youzhi , Ni Xiang , Dong Min , He Xiaohan
Published: December 2023

Introduction: Activation of the Hedgehog signaling pathway has been correlated with the development and disease progression of myeloid leukemia. This Phase I clinical trial aimed to evaluate the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety and tolerability of GT1708F in patients with myeloid malignancies.

Methods: This Phase I study enrolled patients with myeloid malignancies who were refractory, resistant or intolerant to previous treatments at three centers in China. Eligible patients were enrolled at each dose cohort to evaluate DLTs during the first continuous 28-day dosing period. The dose levels were determined employing the escalation with overdose control (EWOC) method, guided by an adaptive Bayesian logical analysis model (ABLRM). The decision to escalate the dosage to the subsequent cohort was informed by the recommendations of the safety monitoring committee after each round. Pharmacokinetic blood samples were collected in the first cycle of the treatment.

Results: As of May 25, 2023, 18 patients have been enrolled in 7 dose cohorts: 15 with acute myeloid leukemia (AML) and 3 with myelodysplastic syndromes (MDS). Patients received GT1708F once daily orally at 20 mg QD (n=1), 40 mg QD (n=1), 80 mg QD (n=4), 120 mg QD (n=3), 180 mg QD (n=3), 240 mg QD (n=3), 320 mg QD (n=3). No DLT was reported across these dose cohorts and the MTD was not reached. 17(93.3%) patients experienced at least one treatment-emergent adverse event (TEAE). 13 (72.2%) patients experienced at least one treatment related AE (TRAE). 11(61%) patients experienced at least one TEAE of Grade 3 or higher in severity, 4 (22.2%) of whom had TRAE(s) including lung infection, anemia, pharyngitis, and creatine kinase increased. Eight patients experienced 13 serious adverse events (SAE), two of which were assessed by the investigator as possibly related to GT1708F, both being lung infections. 15 patients completed at least one efficacy evaluation. No patient achieved complete or partial remission while 5 AML patients achieved stable disease with one patient lasting for 6 cycles and 2 patients lasting for 3 cycles. GT1708F is rapidly absorbed in the body with a peak time of 0.5-1hr after a single oral dose. As the dose increased from 20mg QD to 320 QD, the maximum concentration of the drug in the body increased linearly, showing quasi-linear pharmacokinetic characteristics.

Conclusions: Our study indicated good safety and tolerability of GT1708F in patients with myeloid malignancies. In addition, a potential efficacy signal of GT1708F for these patients was observed, providing a rationale for further exploration in combination with other therapeutic modalities.
Establishing Standard of Care in Predicting Serious Complications for Patients Planned to Undergo Allogenic Hematopeotic Stem Cell Transplantation
Authors: Reschke Madlen , Gross Jonathan P. , Hegner Janina , Seiler Jonas , Sürücü Gülüstan , Penack Olaf , Weschke Daniel , Higgins David , Oevermann Lena
Published: December 2023

Background: There is no reliable way to predict the individual risk of suffering from relevant complications during the course of Hematopoetic Stem Cell Transplantation (HSCT), because the huge amount of multidimensional parameters influencing clinical outcome is impossible for a human to compute accurately.

Reliable prediction of complications: supports patients and physicians to make informed decisions, simplifies choosing best matched HSCT donors to avoid complications and enables superior, individualized planning of conditioning and prophylaxis. Up to now prediction is not based on evidence but rather experience, which differs amongst physicians.

MatchGraft.AI is an artificial intelligence based machine learning tool that predicts the individual risk of acute Graft versus Host Disease, recurrence of basic disease and overall risk of death, using only pre transplant data (Table 1). The model was trained and tested on retrospective data of an international, multicenter cohort.

Aim: Explore standard of care of choosing an HSCT donor and compare choice with real world data and MatchGraft.AI.

Method: We developed an electronic questionnaire with 200 short patient histories including all parameters Matchgraft.AI is using. Pediatric and adult, benign and malignant cases with different donor types (matched unrelated, matched sibling, haploidentical family donor) are represented. This real world data is derived from a retrospective cohort of pediatric and adult patients of Charité Universitätsmedizin. 50 international experts in HSCT will: 1. choose a donor 2. predict individual risk of acute Graft versus Host Disease, risk of relapse and overall death for 50 individual patients.

Cases are randomly allotted according to the physician's specialty (adult/pediatric treater, both). Questionnaires are anonymized. Answers are not traceable to the expert. Personal results compared with real world outcome and MatchGraft.AI can be provided to participants, if they wish.

Results: We compare sensitivity and specificity of MatchGraft.AI to the standard of care, which is expert opinion and real world outcome.

We examine: 1. whether the choosing of a donor is dependent on the individual physician or consistent throughout different HSCT experts. 2. how precise HSCT experts can predict the occurrence of severe complications for patients planned to undergo HSCT. 3. how well MatchGraft.AI can predict the occurrence of severe complications for patients planned to undergo HSCT in comparison.

Conclusion: This study will provide important data about the standard of care in HSCT donor choosing and for the planned prospective study evaluating MatchGraft.AI.
CD10 -CD14 -hla-DR -CD45 +SSC ++ Neutrophils with G-MDSC-like Feature Relate to Progress and Poor Prognosis in Non-Hodgkins Lymphoma Patients
Authors: Zhou Ji , Li Yingwei , Liang Xue , Zhai Zhimin
Published: December 2023

Objectives: To explore CD10-CD14-CD45+HLA-DR+SSC++ neutrophils (CD10- neus) frequency in non-Hodgkins lymphoma (NHL) patients, and their immunologic characteristics and clinical significance. Methods: 90 NHL patients were involved, 47 age and gender-matched volunteers recruited as healthy controls (HC). The CD10- neus frequency in peripheral blood from the HC and NHL patients was detected. Then the CD10- and CD10+ neutrophils were isolated, and their morphologic characterization was compared. CD3+ T cells were also sorted for culture alone or co-culture with the autologous CD10+ or CD10- neutrophils for 48h, then the proliferation and viability of T cells were determined. The levels of Arg-1 and ROS in CD10+ or CD10- neutrophils were examined. Results: Little Few CD10- neus were detected in HC (1.94% ± 1.76), but the level was significantly elevated in newly diagnosed (NDP) and relapsed NHL patients (RLP), 37.90% ± 23.34 and 45.38% ± 20.89 respectively, there was a decrease in the remission patients (RMP, 26.62% ± 16.54). In NDP, CD10- neus at advanced stages was significantly higher than that at limited stages (50.16% ± 27.82 vs. 25.21±12.51, P = 0.017); similarly, the CD10- neus in patients with higher IPI score (3 to 5 points) more than that with lower IPI score (-2) group (53.94% ± 29.09 vs. 30.33 ± 17.73, P = 0.0154). According to the median value of CD10- neus, we further divided the patients into CD10- neus high or low two subgroups, the remission rate after 2 - 4 times first-line treatments in NDP with high CD10- neuts significantly lower than that in patients with low CD10- neuts (12.5% vs 88.24%, P = 0.001); the relapse free survival (RFS) in RMP with high CD10- neus significantly shorter than that with low CD10- neus (11.5 vs. 33.5 months, P = 0.001); the overall survive (OS) in RLP with high CD10- neus also shorter than that with low CD10- neus (23 vs. 39.5 months, P = 0.001). The CD10- neus from NHL mainly consisted of immature neutrophils, strong inhibited T-cell proliferation and viability, Arg-1 and ROS in CD10- neutrophils neuts vastly increased comparing to that from HC. Conclusions: CD10- neus in NHL have the two main characteristics of MDSCs cells (immature and T cell inhibition), the increased may predict disease progression and poor prognosis.
A Phase II Study of the Efficacy and Safety of the Srmt (Sintilimab, Rituximab, Methotrexate, and Temozolomide) Regimen in Newly Diagnosed Primary Central Nervous System Lymphoma
Authors: Zeng Zhiyong , Yang Apeng , Lin Yuanxiang , Chen Junmin
Published: December 2023

BACKGROUND

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of lymphoma with poor prognosis. One potential therapeutic approach could involve targeting the programmed death-1 (PD-1) immune checkpoint pathway, as these tumors often express PD-L1. However, the efficacy of this strategy using sintilimab in combination with immunochemotherapy as frontline therapy for patients with newly diagnosed PCNSL remains uncertain.

METHODS

In this phase II trial with a safety run-in, we enrolled treatment-naive PCNSL patients between the ages of 18 and 70, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. All patients were given sintilimab combined with rituximab, high-dose methotrexate and temozolomide (SRMT) regimen (six cycles every 21 days): sintilimab (200 mg, i.v., Day-0), rituximab (375 mg/m 2, i.v., Day-0), methotrexate (3.0 g/m 2, i.v., Day-1 or 1.0 g/m 2 for patients aged ≥65 years, and temozolamide (150 mg/m 2/d, p.o., Days 1-5). The primary outcome was overall response rate (ORR), with secondary outcomes including duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and potential biomarkers.

RESULTS

Between 3 April 2020 and 23 August 2022, a total of 28 patients were enrolled. No dose-limiting toxicities were observed during the safety run-in period. Among 27 evaluable patients, the primary outcome was met with an impressive ORR of 96.3% (95% CI: 81-99.9%). In detail, 25 patients (92.6%) achieved a complete response and one (3.7%) exhibited a partial response. As of 7 April 2023, the median follow-up was 20.8 months. The Medians for DOR, PFS, and OS were not reached. Remarkably, 2-year PFS and 2-year OS were 65.4% (48.1-88.8%) and 88.5% (74.1-100%), respectively. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (18.5%) and aspartate aminotransferase (14.8%). Additionally, the receiver operating characteristic analysis revealed that the baseline IL10/IL6 ratio in cerebrospinal fluid exhibited promising performance in predicting PFS, achieving an area under curve of 0.91 at 2 years.

CONCLUSIONS

The SRMT regimen as frontline treatment for PCNSL is highly efficacious and well tolerated. (Chinese Clinical Trial Registry number: ChiCTR1900027433).
API-192, an Allogeneic CD19/20 CAR-NKT Cell Product Derived from Cord Blood CD34+ HSPCs for the Treatment of B-Cell Malignancies
Authors: Gov Lanny , Yu Jiaji , Qubain Maha , Pompura Saige L , Allen Sean D , Christopher Michael A , Wiezorek Jeff
Published: December 2023

Autologous chimeric antigen receptor (CAR)-T cell therapies induce durable remissions and improve survival in patients with advanced B cell malignancies. However, challenges such as manufacturing variability, cost, and time to treatment highlight the need for an allogeneic, off-the-shelf approach that preserves the efficacy of autologous CAR-T. Additionally, antigen escape is one of the established mechanisms of resistance to current CAR-T therapies which target a single antigen. Classical natural killer T (NKT) cells express an invariant T cell receptor (iTCR) that is restricted to the conserved CD1d protein, making it a promising cell type for allogeneic therapies as they do not require TCR gene editing to avoid graft-vs-host (GvH) disease. Furthermore, NKT cells mediate dendritic cell cross-priming, target immunosuppressive myeloid cells/macrophages in the tumor microenvironment, and directly kill CD1d + tumor cells through the iTCR. Endogenous NKT cells are an extremely rare population in the blood (<1% of lymphocytes), posing manufacturing challenges. API-192 is a human cord blood CD34 + hematopoietic stem and progenitor cell-derived NKT cell product engineered to express dual CARs targeting CD19 and CD20 and armored with soluble IL-15 for improved expansion and persistence. The Appia Cells Utilized for Allogeneic (ACUA) platform enables the production of large numbers of product NKT cells co-expressing multiple transgenes at high purity (>90% iTCR + 19CAR + 20CAR +) with no purification step or gene editing. Phenotypically, API-192 cells are predominantly CD4 -CD8 - or CD4 -CD8 +, express major activating NK receptors, and harbor intracellular stores of cytotoxic molecules, resembling endogenous NKT cells. API-192 kills Raji and Nalm6 tumor cells in a CAR-specific and dose-dependent manner and can control multiple rounds of tumor challenge in vitro. API-192 secretes pro-inflammatory cytokines and proliferates in response to tumor antigen . In human tumor xenograft models in immunocompromised mice, API-192 robustly expands, suppresses tumor growth, and exhibits prolonged persistence, enabling control of a tumor rechallenge 70 days after initial dosing. API-192 expresses lower levels of MHC I and MHC II molecules relative to conventional CAR-T cells and elicits less IFN-γ release by NK and T cells in mixed lymphocyte reaction (MLR) assays, indicative of a more favorable immunogenic profile. Compared to conventional CAR-T cells, API-192 also secretes minimal levels of IFN-γ in response to co-culture with healthy donor peripheral blood mononuclear cells, consistent with the expression of a non-HLA restricted TCR and low GvH risk. These results demonstrate the feasibility, potency, and potential safety of API-192, warranting further development as a novel allogeneic therapy.
Genetic Variations in Multiple Myeloma with Extramedullary Disease
Authors: Kim Dajung , Jeong Seri , Song Kevin , Jo Jae-Cheol , Lee JiHyun , Jeong Jee-Yeong , Lee Ho Sup
Published: December 2023

Background

Extramedullary disease (EM) is aggressive form of MM in which clonal plasma cells exist outside the BM. EM may be found in up to 30% of MM patients and is associated with an adverse prognosis. However, the genetic pathogenesis of EM have not yet been precisely elucidated.

Patients and Methods

From 2005 to 2020, among patients diagnosed with MM with EM (EMM) confirmed by image study, a total of 12 patients for whom tumor tissue or BM specimens could be obtained were enrolled. Both bone-related EM (EM-B) and soft-tissue-related EM (EM-S) were defined as EM.

We performed whole-exome sequencing (WES) and NanoString nCounter assay to investigate the genetic alterations in EMM patients. A total of 9 formalin-fixed paraffin-embeded (FFPE) tumor tissues and 6 BM specimen from 12 EMM patients were sequenced. Paired BM and FFPE were available for analysis in 3 patients. To clarify the genetic difference between MM and EMM, 8 BM samples of 5 MM patients were analyzed as controls. In addition, 4 buccal swabs from one EMM patient were sequenced for germline control.

Results

The median age was 57 years (range 50-65). Two patients had EM-S involving meninges and Lt. psoas muscle showed adverse prognosis compared to patients with EM-B, with survivals of 1 month and 11 months after diagnosis of EM. One of them had a gain (1q21) chromosomal aberration classified as high risk cytogenetics.

WES was performed on 12 EMM cases (BM=6, FFPE=8). In WES, MAP2K3, AHNAK2, CDC27, MUC4, and NBPF1 were the five genes with the most variation in both BM and FFPE (Fig. 1). In particular, CDC27 gene was altered only in FFPE (6 out of 8 samples).

We performed RNA analysis by NanoString in 9 EMM patients (BM=6, FFPE=6) and 5 MM patients. Compared with MM, ARG1, IRF4, and CEP55 were up-regulated and CDKN1C, IL15, and CD3E were down-regulated in the BM of EMM. Comparison of BM specimens from MM and plasmacytoma from EMM showed IRF4 up-regulation in EMM. In plasmacytoma, chemokine and chemokine receptor related genes such as CXCL8, S100A9, S100A8, CCR4, CXCR2, and CXCR4 were down-regulated. Up-regulation of IRF4 was also observed in EMM when comparing normal buccal swab and EMM specimens.

Conclusions

In our study, significant genetic alterations have been identified. Especially, in WES analysis, CDC27 was mutated only in FFPE of EMM patients, and in Nanostring analysis, IRF4 was up-regulated all EMM samples. Further studies are needed to confirm the genetic alterations in more EMM patients.
Real-World Treatment Patterns and Outcomes Among Patients with Primary Hemophagocytic Lymphohistiocytosis with and without Infection at Diagnosis and Treated with Emapalumab: The Real-HLH Study
Authors: Allen Carl E , Chandrakasan Shanmuganathan , Jordan Michael B. , Leiding Jennifer W , Oladapo Abiola , Pednekar Priti , Walkovich Kelly , Yee John
Published: December 2023

Background: Primary hemophagocytic lymphohistiocytosis (pHLH), a rare, life-threatening, hyperinflammatory syndrome, characteristically shows overproduction of interferon gamma (IFNγ). Since FDA approval of emapalumab for refractory, recurrent, or progressive pHLH or intolerance with conventional therapy, there are limited real-world data on its use. The REAL-HLH study assessed real-world treatment patterns and outcomes among patients treated with emapalumab. Emapalumab treatment patterns and outcomes in the real world among patients with pHLH with or without infection at HLH diagnosis are presented.

Methods: Data were extracted via a retrospective medical chart review of patients with pHLH treated with ≥1 dose of emapalumab between Nov. 20, 2018, and Oct. 31, 2021, across 33 US hospitals from time of emapalumab initiation to end of data availability, death, or study end (Dec. 31, 2021). Data are presented as summary statistics and comparisons using χ 2 tests.

Results: Forty-six of 105 enrolled patients met the pHLH classification criteria; 25/46 (54.3%) had infection at diagnosis with viral infections being most common (18/25; 72.0%). Baseline characteristics are provided in Table 1. The median (range) times from HLH diagnosis to emapalumab initiation and treatment duration with emapalumab for the 2 groups are provided in Table 2. Median (range) starting, maximum single, and cumulative administered dose of emapalumab for the 2 groups are provided in Table 2. Overall survival rates from emapalumab initiation for patients with (18/25; 72.0%) and without infection (16/21;76.2%) were comparable; p=0.747. A greater proportion of eligible patients without infection (15/19; 78.9%) received hematopoietic stem cell transplantation (HSCT) compared with those with infection (16/23; 69.6%), but the difference was not statistically significant (p=0.491).

Conclusion: This is the first study to report real-world treatment patterns with emapalumab across a diverse patient population with pHLH with or without infection at diagnosis. Over 54% of the patients with pHLH presented with infection at diagnosis. The infection status at diagnosis did not affect the overall survival rate and the proportion of patients proceeding to HSCT after emapalumab treatment.
Radiomic Features Prognosticates Treatment Response in CAR-T Cell Therapy
Authors: Balagurunathan Yoganand , Wei Zhouping , Qi Jin , Dean Erin A. , Thompson Zachary , Choi Jung , Jain Michael D. , Locke Frederick L.
Published: December 2023

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common, aggressive disease form that accounts for 30% of all lymphoma cases. Recent development in chimeric antigen receptor (CAR) T-cell therapy has shown tremendous promise in providing a cure to patients with relapsed/refractory (R/R) DLBCL. We propose to develop Radiomics (quantitative image metric) based biomarker as a surrogate to tumor burden assessment and compare its ability to prognosticate treatment response to engineered cell-based treatments.

METHODS: We identified a cohort of 58 patients with R/R DLBCL, whose largest lesions on the baseline positron emission tomography /computed tomography (PET/CT) imaging were identified along with their anatomical sites related to non-lymphatics. The lesion's co-registered PET imaging was used to converge on a regional boundary to obtain the most active part of the lesion, applying Standardized Uptake Value definition with 41% regional threshold. The lesion regions were characterized using imaging metrics (radiomics) followed by principal component (PC) analysis to reduce the dimensionality in the feature categories (Size, Shape and Texture). These Radiomics metrics along with metabolic tumor volume (MTV) were used both collectively and independently to assess prognosis to disease progression measured by overall survival. We assessed and report the correlation between the principal components and the tumor burden.

RESULTS: We find that Shape-PC (Non-Lymph) were prognostic (p < 0.0073) along with MTV (p < 0.00026) of Overall survival (1 year after treatment), using median value of the respective metrics as a cutpoint. We find these Shape-PC metrics showed moderate to weak correlation with MTV (spearman's ρ of 0.42, p < 0.01, for Shape-PC1).

CONCLUSION: We identified Non-Size based features that are prognostic to patient response to treatment. These metrics provide complementary information to MTV and may serve as a surrogate to treatment response.
Structural Basis for Activation of the Thrombopoietin Receptor (MPL) By Its Ligand (TPO)
Authors: Bratkowski Matthew , Mafi Amirhossein , Geng Jiefei , Kutskova Yuliya , Brito Alysso , Rathinaswamy Manoj K , Sridar Janani , Eaton Dan , Hao Qi , Paddock Marcia
Published: December 2023

Myeloproliferative leukemia protein (MPL), also known as thrombopoietin receptor, is a class I cytokine receptor expressed on hematopoietic progenitors that is critical for normal platelet production by promoting myeloid progenitor growth and differentiation toward the megakaryocyte lineage. The ligand for MPL, thrombopoietin (TPO), stimulates platelet production through binding MPL via two sequential sites, a high- and then a low-affinity interface that together induce MPL dimerization and result in an active conformation allowing downstream JAK2/STAT5 signaling. Despite intense interest in characterizing the molecular mechanism of the interaction between MPL and TPO over the last several decades, no experimental structural evidence has been reported. Here we present a 3.39 Å cryo-EM structure of the ectodomain of mouse MPL bound to TPO. TPO features both low and high affinity sites that each bind to one MPL monomer in agreement with previous functional studies. Our structure reveals that several patient mutations associated with congenital amegakaryocytic thrombocytopenia (CAMT) and aplastic anemia are found at MPL-TPO interaction sites. The structure further explains additional patient mutations, as well as published experimental mutations that have previously been the basis of structure-function studies. Building on this structure, we generated a molecular dynamics simulation model of the full length human MPL-TPO complex, revealing that TPO binding to full length MPL results in unexpected MPL-MPL intramolecular interactions that stabilize the dimer to allow for efficient signaling. Functional characterization of deleterious mutations predicted by our structure and modelling have revealed additional residues critical to MPL-TPO and MPL-MPL interactions, providing further validation of our proposed structure. Overall, our studies reveal new insight into a receptor-cytokine interaction critical for normal hematopoiesis and platelet production that are frequently mutated in disease, provide the structural basis underlying existing experimental findings, and provide additional insight into the nature of hematopoietic growth factor signaling which could benefit future therapeutic research.
Immunosuppressant Drug-Associated Non-Hodgkin Lymphoma: A Real-World Pharmacovigilance Database Analysis
Authors: Ananthaneni Anil , Heap David , Weis Francesca , Chowdary Sriram , Sam Riya , Al-Yafeai Zaki , Ramadas Poornima
Published: December 2023

Background: The association between immunosuppressant drugs and lymphoma has been reported frequently; however, the precise relationship remains uncertain. Non-Hodgkin lymphoma (NHL) is among the most common cancers associated with long-term immunosuppressant drug use. The FDA Adverse Event Reporting System (FAERS) is a publicly available tool that collects reports of adverse events from healthcare professionals, manufacturers and consumers.

Methods: Nine immunosuppressant drugs belonging to different classes were shortlisted . The FAERS database was searched for all types of NHL as an adverse event reported between 2013 and 2022. Reporting odds ratio (ROR) was used to measure disproportionality in reporting of adverse events for these drugs.

Results: When NHL was analyzed as a percentage of all cancers reported for a particular drug,azathioprine had the highest percentage (22.14%) followed by methotrexate (18.94%), mycophenolate (14.04%), infliximab/biosimilars (11.22%), cyclosporine (10.71%), etanercept (10.44%), tacrolimus (10.13%), adalimumab/biosimilars (8.80%) and sirolimus (8.51%). Drugs with highest ROR for NHL included azathioprine (2.09, 95% CI 1.94-2.24) followed by methotrexate (1.90, 95% CI 1.82-1.98) and azathioprine (1.17, 95% CI 1.10-1.25). Drugs with lowest ROR for NHL included adalimumab/biosimilars (0.62, 95% CI 0.59-0.65) followed by sirolimus (0.66, 95% CI 0.54-0.80) and tacrolimus (0.78, 95% CI 0.73-0.84).

Conclusions: Although all immunosuppressive drugs have been associated with an increased risk of developing NHL, it is advisable to exercise caution with prescribing azathioprine, methotrexate and mycophenolate in patients with preexisting risk. While the use of adalimumab is an independent risk factor for the development of lymphoma, it had the lowest odds of NHL compared to other immunosuppressant drugs in the study. Prospective studies are needed to better understand the true incidence of NHL associated with immunosuppressant drugs.
Patterns of Disease, Risk Factors and Treatment in Chronic Lymphocytic Leukemia (CLL). a retrospective Report of Real World Patient Cohort from United Arab Emirates
Authors: Alam Arif , Al Qawasmeh Khaled , Alam Nida , McCarthy Philip L.
Published: December 2023

Introduction:

Chronic Lymphocytic Leukemia (CLL) is an indolent B cell Malignancy. It is the most common type of leukemia in Western Hemisphere (35% of all leukemia (American Cancer Society. Cancer Facts & Figures 2023) but is rare in East Asia. Data about CLL in Middle Eastern countries is scarce. Here we report a retrospective analysis of the patients with CLL seen in a real world setting at the largest cancer center in UAE.

Methods:

This is a retrospective analysis of patients diagnosed with CLL between January 2018 to September 2022. Data was collected from Electronic Medical Records (EMR) regarding patient demographics, risk profile (genetics) and treatment patterns.

Results:

Thirty-seven patients with CLL were seen in the study period. They accounted for approximately 3 % of all leukemia patients (Al-Shamsi HO. The State of Cancer Care in the United Arab Emirates in 2022. Clin Pract. 2022 Nov 23;12(6):955-985). The median age was 59 years (range 30 to 88 years.) Sixteen percent of the patients were under the age of 50 years. The majority of the patients were male (5:1). The median WBC at presentation was 30000/μl, Hemoglobin was 112 grams/liter and platelet count was 140000/μl.

Approximately one third of the patients (35%, 13 out of 37) have not required any therapy due to early-stage disease and/or comorbidities. Twenty-four patients (65 %) had advanced stage disease and required therapy at the time of diagnosis.

FISH results are available for 19/24 patients on therapy. The most common was deletion 13q (8/24) followed by Trisomy 12 (7/24). 17p/TP 53 deletion was seen in3/24 and 1/24 had ATM gene deletion. IGHV mutational analysis is not available for most patients

Treatment patterns showed chemoimmunotherapy (CIT) in 10/24 patients (Bendamustine rituximab N=8 and FCR N= 2), BTK inhibitors as single agent 9/24 while 5/24 patients receive Venetoclax R in combination with Anti CD 20 antibody.

Conclusion:

This is the first report on CLL seen in a large tertiary care center in UAE over a period of 5 years. The number of patients is significantly less (3%) as compared to incidence in western hemisphere (35%) of all leukemia cases. Median age (59 years) is at least a decade earlier than western hemisphere with a preponderance in males.

Treatment patterns are being rapidly revised with the availability of BTK inhibitors, Venetoclax R and anti-CD 20 monoclonal antibodies to conform with current guidelines. More epidemiologic investigation is needed to understand the low numbers of patients with CLL reported in this UAE cancer center.
Development and Validation of an Individualized and Weighted Prognostic Model in Patients with Newly Diagnosed Multiple Myeloma
Authors: Yan Wenqiang , Mao Xuehan , Mery David E. , Xu Yan , Sui Weiwei , Deng Shuhui , Zou Dehui , Shaughnessy, Jr John D , Anderson Kenneth C. , Zhan Fenghuang , Qiu Lugui , An Gang
Published: December 2023

Introduction

Multiple myeloma (MM) is a malignancy of terminally differentiated antibody-secreting plasma cells in the bone marrow with highly variable survival outcomes. Precise risk stratification not only plays a vital role in predicting patient prognoses, but critically can be used to develop risk-adapted treatment regimens. However, current risk stratification models do not adequately account for the heterogeneity of patients with new-diagnosed multiple myeloma (NDMM).

Methods

In this retrospective, multicohort study, we collected clinical data from 1792 NDMM patients and formulated a weighted Myeloma Prognostic Score System (MPSS) risk model to predict overall survival (OS). Construction of the MPSS model was carried out based on the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199) cohort, external validation cohort was created using TT2, TT3a, and TT3b cohorts from a series of randomized prospective studies from the University of Arkansas for Medical Sciences (UAMS).

Results

Each risk factor was defined as its weighted value respectively according to their hazard ratio for OS (thrombocytopenia 2, elevated LDH 1, ISS III 2, one high-risk cytogenetic aberration [HRA] 1, and ≥2 HRA 2 points). In the training cohort, patients were furtherly stratified into four risk groups: MPSS I (22.5%, 0 points), II (17.6%, 1 points), III (38.6%, 2-3 points), and IV (21.3%, 4-7 points). MPSS risk stratification showed optimal discrimination, as well as calibration, of four risk groups with median OS of 91.0, 69.8, 45.0, and 28.0 months, for patients in MPSS I to IV groups (P< 0.001), respectively. Importantly, the MPSS model retained its prognostic value in the internal validation cohort and an independent external validation cohort, and exhibited significant risk distribution compared with conventional prognostic models (R-ISS, R2-ISS, and MASS).

Conclusions

In conclusion, we formulated and validated the MPSS risk model to predict the prognosis of patients with MM using readily available standard clinical and genetic test data. The established MPSS profile shows a better performance in risk discrimination than the current R-ISS, R2-ISS, and MASS. A score-based risk stratification is derived, and identifies patients with high and ultra-high risk of death after diagnosis and may therefore aid the development of more personalized treatment strategies, especially for patients for whom current therapies are likely to fail.
Deletion 1p at Time of Diagnosis of Multiple Myeloma Portends Inferior Outcomes
Authors: Vaishnav Arti , Khan Abdullah , Zhao Qiuhong , Bumma Naresh , Cottini Francesca , Umyarova Elvira , Sharma Nidhi , Rosko Ashley E , Benson Don , Devarakonda Srinivas
Published: December 2023

Background: Multiple myeloma (MM) is associated with several cytogenetic abnormalities (CA) that influence the disease course, response to treatment and survival. Trisomies and immunoglobulin H chain translocations are primary CA while del(17p), gain(1q), del(1p) and others are secondary CA. Gain (3 copies) and amplification (>3 copies) 1q have been recognized as adverse prognostic markers and incorporated into the second revision of the International Staging System (R2-ISS). However, the role of del(1p) is less well defined, especially in the era of modern myeloma therapeutics. We aimed to analyze the outcomes of newly diagnosed MM (NDMM) patients (pts) with chromosome 1 abnormalities, mainly del 1p, treated with autologous hematopoietic cell transplant (AHCT) consolidation at The Ohio State University.

Methods: We identified and reviewed the medical records of all NDMM pts who were treated with AHCT from 1/1/2015-2/13/2019 (n=511). High-risk cytogenetics (HRC) was defined by the presence of del(17p), t(4;14), or t(14;16) similar to R-ISS; standard-risk cytogenetics (SRC) were defined as the absence of HRC. Modified HR cytogenetics (mHRC) included gain/amp 1q and/or t(14;20) in addition to HRC, while ultra high-risk (uHRC) included 2 or more mHRC risk factors.

Results: The baseline pt characteristics are presented in Table 1. Of 511 pts transplanted, 453 had cytogenetic data from diagnosis. SRC were seen in 353 pts (77.9%), while 100 (22.1%) had HRC, 156 (34.4%) had mHRC, and 43 (9.5%) had uHRC. Thirty-two (7.1%) pts had del(1p) while 105 (23.2%) had gain 1q and 30 (6.6%) had amp 1q. As expected, compared to SRC pts, pts with HRC, mHRC and uHRC had higher risk of relapse or death. Patients with gain and amp 1q had inferior outcomes in terms of PFS (HR 1.35; 95% CI 1.06-1.73, p=0.016), TTNT (HR 1.84; 95% CI 1.40-2.42, p<0.001) and OS (HR 1.47; 95% CI 1.06-2.02, p=0.02), consistent with published literature. The median PFS, TTNT and OS from AHCT in pts with gain/amp 1q was 3.17 years (y), 3.95y and 7.13y, respectively, compared to 4.01y, 7.60y and 8.21y in pts without gain/amp 1q. Pts with del(1p) had inferior PFS (median 2.43y versus 3.98y; HR 1.75; 95% CI 1.16-2.64, p=0.008), TTNT (median 2.72y versus 6.17y; HR 1.96; 95% CI 1.22-3.14, p=0.005) and OS (median 4.11y versus 8.38y; HR 2.19; 95% CI 1.34-3.58, p=0.002) from AHCT compared to those without del(1p). (Figure 1).

Conclusions: In this cohort of NDMM pts that underwent AHCT, del(1p) at diagnosis was an independent predictor of shorter PFS, TTNT and OS. Despite advances in induction regimens, AHCT consolidation and maintenance therapy, del(1p) continues to portend inferior outcomes. Larger analyses are needed to validate the prognostic value of del(1p) and investigate its role in predicting outcomes in MM.
The Efficacy of Obinutuzumab Combined with Pomalidomide and Covalent Btki for the Treatment of TP53 Mutated Mantle Cell Lymphoma (MCL): A Prospective, Open-Label, Single-Arm Study
Authors: Yang Ping , Liu Shuozi , Zhang Weilong , Wang Jing , Chen Yingtong , Jing Hongmei
Published: December 2023

Background

TP53 mutated MCL lacks effective treatment options and has a poor prognosis, posing challenges in management. The guidelines recommend clinical trials as the first choice, pomalidomide as a new generation of immunomodulators (IMiDs), which have immunomodulatory effects and modulates the tumor microenvironment. Individual cases have been reported about pomalidomide be used for relapsed and refractory MCL. In this study, we investigated the application of Pomalidomide combined with Obinutuzumab and covalent BTKi (Ibrutinib and Zanubrutinib) for the treatment of TP53 mutated MCL to provide a new treatment evidence for clinical practice.

Methods

This was a prospective, single-center, clinical study. The key inclusion criteria include: confirmed diagnosis of MCL, age≥18 years, appropriate organ function, etc, both previously untreated and relapsed patients are eligible for inclusion. All patients receive Obinutuzumab (1000 mg d1) combined with Pomalidomide (4 mg d1-21) and covalent BTKi (Ibrutinib 560mg qd or Zanubrutinib 160mg bid)for 4 cycles, every 28 days as a cycle; If the treatment is effective, patients receive Obinutuzumab (1000 mg d1, every 3 months/time) combined with Pomalidomide (4 mg d1-14/28 days) and covalent BTKi triplet combination maintenance therapy until disease progression. The primary endpoint was overall response (Lugano 2004 criteria). Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. Minimal residual disease was assessed by NGS in peripheral blood.

Results

The study included 14 patients with relapsed or refractory mantle-cell lymphoma (12 patients) or previously untreated mantle-cell lymphoma (2 patient). Patients median age 59(44 to 74) with a male-to-female ratio of 6:1, and the lines of previous treatments ranged from none to three. 85.7%（12/14）of patients had mutation of TP53, 28.6%(4/14) had mutation of CCND1, 21.4%(3/14)had mutation of SMARCA4/SAMHD1. 64.3% had a higher Ki-67≥30% and 50% had a high-risk prognostic score of MIPI-c. The complete response rate at 4 course was 64.3% and the overall response rate was 85.7%. 9 patients underwent MRD testing after 4 cycles of treatment, and MRD negative was confirmed in 100% of the patients by NGS. The most common grade 3-4 adverse events were neutropenia (in 5 [35.7%] of 14 patients), thrombocytopenia (in 3 [21.4%] of 14 patients), infections (in 2[14.3%] patients), severe Covid-19 infection was in 2[14.3%] patients.

Conclusions

Our results provide preliminary evidence that the triplet combination of Obinutuzumab, pomalidomide, and covalent BTKi is an active regimen in MCL patients with the mutation of TP53, and should be evaluated in a prospective randomized controlled trial.
Risk Factors for Severe Infection and Unfavorable Outcomes in Hematologic Malignancy Patients with COVID-19 Inflection during the Omicron Era: A Chinese Single-Center Retrospective Study
Authors: Ye Li , Yang Ye , Zhang Xuewu , Wang Lu , Zhu Li , Li Xia , Zhou Yile , Zheng Xiaolong , Zhou Xinping , Ren Yanling , Ma Liya , Xu Gaixiang , Yang Chunmei , Wang Huafeng , Zhou De , Yang Min , Ye Xingnong , Wei Juying , Yu Wen-Juan , Qian Jiejing , Lou Yinjun , Xie Wanzhuo , Huang Jian , Meng Haitao , Jin Jie , Tong Hongyan
Published: December 2023

Purpose: The objective of this study was to evaluate the potential risk factors associated with severe infection and unfavorable outcomes among individuals with hematologic malignancies who contracted the coronavirus infectious disease (COVID-19) during the Omicron era.

Methods: This retrospective analysis included adult patients with hematologic malignancies who were diagnosed with COVID-19 during the period from November 2022 to February 2023. A comparison was made between the clinical characteristics of patients who experienced persistent COVID-19 infection or succumbed to death within 30 days and those of the remaining patients.

Results: A total of 134 patients were included in the analysis, with 23.9% (n=32) presenting as asymptomatic/mild and 29.1% (n=39) classified as severe cases. Among the patients, 54.4% (n=73) had received at least two doses of vaccines. In the subgroup of asymptomatic/mild patients, 50% had received at least three doses of vaccines, while among the severe patients, 56.4% remained unvaccinated. The multivariate analysis examining risk factors for severe infection in COVID-19 and hematologic malignancy patients identified the number of vaccine doses as an independent prognostic factor. Less than two doses of vaccines were found to be associated with severe COVID-19 infection (odds ratio [OR]: 4.213, 95% confidence interval [CI] 1.433-12.392; p=0.009). In this study, patients with persistent COVID-19 infection or succumbed to death within 30 days were categorized as the unfavorable group (n=57), while the remaining patients were classified as the favorable group (n=77). A significant difference was observed between the two groups in terms of median age (p=0.015), malignancy status (p=0.001), number of vaccine doses received (p=0.001), neutrophil count (p=0.011), immunoglobulin G levels (p=0.038), and interleukin-6 levels (p=0.025). In the multivariable analysis of risk factors for unfavorable outcomes in patients with both COVID-19 and hematologic malignancies, it was found that the number of vaccine doses and the level of immunoglobulin G were independent prognostic factors. Specifically, receiving less than two doses of vaccines (OR: 233, 95%CI 0.068-0.798; p=0.020) and having an immunoglobulin G level below 1000 (OR: 220, 95%CI 0.066-0.753; p=0.014) were associated with unfavorable outcomes.

Conclusions: Receiving multiple doses of vaccines and having higher levels of immunoglobulin G were found to improve the clinical outcome of COVID-19 in patients with hematologic malignancies.
VLA-4 Agonist Enhances the Capacity of HSC Engraftment and Immune Reconstitution
Authors: Song Xianmin , He Qiaomei , Sun Xi , Zhang Fang , Wang Pengran , Zhang Yan
Published: December 2023

Poor donor cell implantation and delayed hematopoietic reconstitution are important factors affecting the prognosis of patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). However, our understanding of the critical endogenous signals that reconstitute hematopoiesis in transplant patients remains limited，which is essential for achieving targeted interventions and preventing donor-recipient chimeric states after transplantation. Here, we revealed the reconstitution dynamics of human allogeneic hematopoietic stem and progenitor cells (HSPCs) and immune cell subpopulations in the post-transplantation mixed donor chimerism (MDC) to fully donor chimerism (FDC) state at single-cell resolution. The hematopoietic stem cell (HSC) implantation process involves extensive interactions with immune cells mainly through surface Kcnq5, Itga4 (encoding a subunit of VLA-4), Tfrc, CD44 receptor, and ligands for Rps19, B2m, etc. Further identification of VLA-4(integrin α4β1) as a potential regulatory target for HSC implantation by single-cell sequencing of a stable allogeneic bone marrow transplantation (Allo-BMT) MDC-FDC mouse model. Grafts Itgα4 and Itgβ1 deletion impair donor implantation and further diminish the efficacy of donor lymphocyte infusion (DLI) following Allo-BMT, rather than directly affecting DLI. Critically, we identified a VLA-4 agonist that promotes donor implantation in the mixed chimeric mouse model of Allo-BMT in a time-dependent manner, with the most pronounced promotion of early T cell implantation in particular. Moreover, it was found to enhance the self-renewal capacity of HSC and lymphoid reconstitution in competitive transplantation and human umbilical cord blood transplantation xenograft experiments. Fortunately, VLA-4 agonist does not exacerbate the acute graft-versus-host disease(aGVHD) process while maintaining the graft-versus-leukemia (GVL) effect. VLA-4 agonist not only upregulates of both Itgα4 and Itgβ1 expression, but also promotes the ERK/2 phosphorylation pathway, which affects HSC biological functions, and this process can be inhibited by ERK kinase inhibitors. These results provide insights into the regenerative process of transplanted HSPCs in human patients，and demonstrate a previously unknown positive regulation of HSC engraftment and immune reconstitution by VLA-4, and allow for a new and simple translational strategy to enhance HSC transplantation.
Adolescents and Young Adults with Multiple Myeloma, Kuwait Experience
Authors: Alhuraiji Ahmad , Ghonema Rasha Galal , Hasaneen Mahmoud , Ram Mohan , Alshemmari Salem , Khadadah Fatima , Hamadah Abdulaziz , Kunhikrishnan Anitha , Shah Abdul Rashid , Pandita Ramesh
Published: December 2023

Background

Multiple myeloma MM is an incurable plasma cell malignancy with a median age of 65 years at diagnosis worldwide, a small number of publications were focused on young adult Multiple myeloma MM with special characteristics and clinical outcomes.

Objectives

To evaluate the incidence of MM among adolescent and young adults (AYA) in Kuwait aged 40 and below. Also, to describe the clinical characteristics, high risk features and treatment outcomes at the Kuwait Cancer Control Centre (KCCC).

Materials & Methods

We collected data retrospectively from the hematological malignancy registry at KCCC and looked at AYA patients (pts) with a confirmed diagnosis of Multiple myeloma at our center from 2015 till 2022, we looked at age of onset, gender, nationality, year of myeloma diagnosis, presence of extramedullary disease, International Staging System score (ISS score), cytogenetic aberrations, induction therapy, receipts of auto-transplant and maintenance therapy.

Results

From 2015 till 2022, 340 patients were diagnosed with MM in Kuwait, eleven patients were found 40 years old or younger, only one was female patients, the median age was 35 years old, around a third were Kuwaiti, 73% were non-Kuwaiti of middle eastern background, 4 patients were found to have extramedullary disease at diagnosis, with advanced stage ISS III found in 3/9 pts. One patient was found with 1Q gain and the rest of the 10 patients were with negative del17p, t (4,14), t(14,16), gain1q and t(11,14). Of note, interphase FISH cytogenetic is not done with CD138 selection. Six patients were treated with RVD induction (Lenalidomide, Bortizomib, Dexamethasone), two patients treated by CTD (Cyclophosphamide, Thalidomide, Dexamethasone), one pt treated by VCD (Bortizomib,Cyclophosphamide,Dexamethasone), one patient treated by Daratumumab RVD, and one patient treated by VTD. Overall response rate (ORR) was 90.9%, (10/11) responded patients proceeded to HDCT/ASCT and all these patients went on maintenance post-transplant, two patients were lost to follow up while 9 patients still under follow up, median follow up 33 months, one pt had a relapse after transplant.

Conclusion

MM is an uncommon disease among AYA in Kuwait (3.2%) of all myeloma patients, with favorable durable responses in this group of patients.