bluuebunny/crossref_metadata_2025 huggingface dataset:
A Prospective, Open-Label, Multicenter, Randomized Controlled Study Comparing the Efficacy and Safety of Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone Combined with Orelabrutinib/Chidamide/Venetoclax/Lenalidomide/Penpulimab (Pola-RCHP-X) Versus RCHOP-X and Pola-Rchp in Previously Untreated Patients with Diffuse Large B-Cell Lymphoma
Authors: Liang Jinhua , Wang Li , Shen Haorui , Yin Hua , Wu Jiazhu , Li Yue , Pan Bihui , Zhang Xinyu , Kong Yilin , Li Jianyong , Wei Xu
Published: December 2024

Background and Significance

In recent years, most phase III clinical trials exploring first-line treatments for diffuse large B-cell lymphoma (DLBCL) have ended in failure, with the notable exception of the POLARIX study. This may be primarily due to the heterogeneity of DLBCL. Currently, the Pola-R-CHP regimen has emerged as one of the new standard first-line treatments for DLBCL. Given the heterogeneity of DLBCL, combining different therapeutic agents tailored to specific genetic subtypes may be a strategy to further improve first-line treatment efficacy. Therefore, we are planning to conduct a prospective, multicenter, randomized controlled trial to comparing the efficacy and safety of Pola-RCHP-X versus R-CHOP-X or Pola-R-CHP (NCT06516978).

Study Design and Methods:

This study aims to enroll 528 patients aged 18-80 years with an International Prognostic Index (IPI) score of 2-5, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, diagnosed with CD20+ DLBCL, and who have not received prior systemic treatment. Eligible patients will be randomly assigned in a 1:1:1 ratio to one of the following three arms: Pola-RCHP-X, R-CHOP-X, or Pola-R-CHP.

Patients in the Pola-RCHP-X and R-CHOP-X arms will first receive one cycle of Pola-R-CHP or R-CHOP while undergoing genetic subtyping. From cycles 2 to 6, patients with MCD, BN2, or N1 subtypes will receive Pola-RCHP-orelabrutinib/ R-CHOP-orelabrutinib; those with the EZB-MYC+ subtype will receive Pola-RCHP-venetoclax/ R-CHOP-venetoclax; those with the EZB-MYC− subtype will receive Pola-RCHP-chidamide/R-CHOP-chidamide; those with TP53 mutations will receive Pola-RCHP-penpulimab/R-CHOP-penpulimab; and those with the ST2 subtype or NOS will receive Pola-RCHP-lenalidomide/R-CHOP-lenalidomide. This will be followed by two cycles of Rituximab monotherapy. Patients in the Pola-R-CHP arm will receive the standard 6 cycles of Pola-R-CHP followed by 2 cycles of Rituximab.

The primary endpoint of the study is progression-free survival at 24 months (PFS24) as assessed by the investigators. Secondary endpoints include investigator-assessed complete response (CR) rate, overall response rate (ORR), event-free survival (EFS), overall survival (OS), and safety.
POD 12 As a Robust Prognostic Index in Patients with Angioimmunoblastic T-Cell Lymphoma: A Single-Center Study
Authors: Li Suxiao , Feng Xiaoyan , Zhang Jieming , Song Yunfei , Fan Mengke , Chen Qingjiang , Zhang Mingzhi , Wu Xiaolong , Dong Meng , Han Lijuan , Zhang Xudong
Published: December 2024

Objective:To analyze a set of prognostic factors for angioimmunoblastic T-cell lymphoma (AITL) and determine whether early progression of disease (POD) is associated with poor prognosis in patients with AITL. Methods: In this study, we enrolled 231 AITL patients from the First Affiliated Hospital of Zhengzhou University and established a clinical risk model specifically for POD 12 by analyzing the effects of clinical variables and POD 12 on prognosis. Results: The median age was 63 years, and 88.3% of the patients were diagnosed at an advanced stage (III/IV). The median follow-up time was 42 months, and the 5-year progression-free survival (PFS) and overall survival (OS) estimates were 11.9% and 26.6%, respectively. POD 12 occurred in 65.4% patients, with 5-year OS estimates of 10.7%.According to the multivariate analysis of POD 12, elevated LDH, ECOG score ≥2, PD-1 negativity and the longest diameter of the involved lymph node > 2 cm were associated with the development of POD 12. We established a new prognostic score (PIP model) combining these factors to define low-, intermediate-, and high-risk subgroups with POD 12 risk rates of 41.5%, 61.5% and 82.5%, respectively, and 5-year OS rates of 36.3%, 21.0% and 18.8%, respectively. Conclusion: POD 12 is a powerful prognostic factor for AITL, and patients with POD 12 have particularly poor outcomes. The new PIP model can prospectively predict the occurrence of POD 12 and the overall prognosis of patients with AITL.
Combination of All-Trans Retinoic Acid Resumes the Sustained Response of TPO-RA in ITP
Authors: Fan Wenxuan , Ye Jieyu
Published: December 2024

Sustain response off treatment (SROT) is the therapeutic goal for idiopathic thrombocytopenic purpura (ITP) patients treating by thrombopoietin receptor agonist (TPO-RA). Although the majority patients have therapeutic response during TPO-RA treatment, platelet counts may fluctuate in some cases. Researches showed that sustained and stable platelet response is one of the important conditions to achieve SROT.

All-trans retinoic acid (ATRA) has shown significant effects in treating ITP. Our study found that platelet fluctuation by TPO-RA treatment can be resumed by short term combined use of ATRA. In order to investigate whether Combination of all-trans retinoic acid resumes the sustained response of TPO-RA in ITP.

We enrolled 17 ITP patients from January 2023 to July 2024 in Nanfang hospital. Two of them were excluded because of insufficient treatment duration due to severe headache. Therefore, data from 15 patients were finally included. We defined platelet fluctuation as platelet numerical difference more than 100×109/L within one month. Oral dose of ATRA was 20mg once daily. Adverse events were monitored and assessed according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE5.0).

At baseline, the ratio of male vs. female was 2:13. The median age was 38 (range=22-64). The types of TPO-RAs used were: Eltrombopag 46.67% (7/15), Avatrombopag 26.67% (4/15), Hetrombopag 26.67% (4/15). The median time of ATRA treatment was 94 days (range=49-153). The efficiency rate of ATRA in resuming platelet response was 86.67% (13/15). Side-effects of ATRA in 15 patients were tolerable. The rate of dry and cracked lips was 13.33% (2/15). The rate of headache was 6.67% (1/15). The rate of hair loss was 13.33% (2/15). The rate of rash was 6.67% (1/15).

Our data shows that short-term treatment of ATRA in ITP during platelet fluctuation by TPO-RA may be effective and safe.
Fc Receptor-like 5 (FCRL5)-Directed CAR-T Cells Exhibit Antitumor Activity Against Multiple Myeloma
Authors: Yu Zhengyu , Tong Aipin , Niu Ting
Published: December 2024

Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse; therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment.
Bcl-Xl Is Important for the Antiapoptotic Activity of Gfi1 and Is Upregulated By Gfi1 through Hemgn
Authors: G C Binod , Dong Fan
Published: December 2024

Gfi1 is a transcriptional repressor that is critically involved in hematopoiesis. Gfi1 represses its target genes primarily through interacting with the histone demethylase LSD1 via its SNAG domain. A major function of Gfi1 in the hematopoietic system is to inhibit stress-induced apoptosis. Gfi1 has been shown to participate in post-translational modifications of the p53 protein leading to suppression of p53 activity and in PRMT1-dependent methylation of MRE11 and 53BP1, which is essential for their roles in DNA repair. We show here that Gfi1 inhibited apoptosis induced not only by DNA damage, but also by growth factor withdrawal, inhibitory cytokine TGFβ and Myc activation in a manner that was independent of p53. Interestingly, induction of DNA damage with doxorubicin (Doxo) resulted in a gradual decrease in the protein level of the pro-survival Bcl-2 family member Bcl-xL in murine pro-B Ba/F3 and human p53-deficient Burkitt lymphoma Ramos cells transduced with the doxycycline (Dox)-inducible Gfi1 (BaF/Gfi1 and Ramos/Gfi1). DNA damage-induced downregulation of Bcl-xL protein was attenuated upon induction of Gfi1 expression with Dox, concomitant with upregulation of Bcl-xL mRNA. In contrast, the levels of Bcl-xL mRNA and protein were reduced upon knockdown of Gfi1 in human p53-deficient leukemic HL-60 and U937 cells, and in lineage negative (Lin-) bone marrow (BM) cells from Gfi1-/- mice. We further show that Bcl-xL overexpression partially rescued the hypersensitivity to DNA damage of Gfi1-knocked down HL-60 and U937 cells, and of Gfi1-/- BM cells whereas Bcl-xL knockdown partially abolished the protective effect of Gfi1 on DNA damage-induced apoptosis. Notably, interaction with LSD1 was required and sufficient for Gfi1-mediaed upregulation of Bcl-xL, suggesting that Gfi1 may augment Bcl-xL expression by an indirect mechanism. We recently showed that Gfi1, via repressing PU.1, upregulated the expression of Hemgn, a nuclear protein that has been shown to augment Bcl-xL expression. Interestingly, knockdown of Hemgn in BaF/Gfi1 and Ramos/Gfi1 cells abolished Bcl-xL upregulation by Gfi1. Furthermore, Gfi1 failed to upregulate Bcl-xL in PU.1-deficient cells. Examination of the time courses of Gfi1-mediated upregulation of Hemgn and Bcl-xL revealed that Hemgn upregulation preceded and correlated well with Bcl-xL upregulation. Together, these results indicate that Bcl-xL has an important role in mediating the antiapoptotic activity of Gfi1 and that Gfi1 upregulates Bcl-xL through Hemgn, which is dependent on PU.1 repression by Gfi1.
Daratumumab for Treatment of Epstein-Barr Virus-Associated Post -Transplant Lymphocyte Proliferative Disease after Rituximab Treatment Failure
Authors: Li Gang , Yang Donglin , Feng Sizhou , Jiang Erlie , Liu Xin , Liang Chen , He Yi
Published: December 2024

Aims: To explore a new method for treating failure of rituximab plus immunosuppressant dose reduction in EB virus-related post-transplant lymphoproliferative disorders (PTLD).

Methods: This study retrospectively analyzed the clinical data of 60 patients diagnosed with PTLD at the Institute of Hematology & Blood Diseases Hospital and Chinese Academy of Medical Sciences from May 2017 to June 2024, including confirmed and clinically diagnosed cases. Among them, 22 patients underwent lymph node biopsy, and except for 3 patients whose biopsy specimens were not marked with CD38, the remaining 19 patients had positive CD38, of whom 10/19 were strongly positive. We treated 4 patients with failed rituximab plus immunosuppressant dose reduction therapy (1 case of acute T-cell leukemia, 1 case of acute myeloid leukemia, 1 case of acute B-cell leukemia, and 1 case of Ph+ mixed cell leukemia) with daratumumab.

Results: Of the 4 patients, 3 had obvious disease progression after receiving rituximab 375mg/m2/w twice (EBV-DNA progressively increased to more than 100 times the baseline level or lymph nodes progressively enlarged), and 1 had an initial EBV-DNA level of 107,310 copies/ml, which increased to 354,787 copies/ml after receiving rituximab. All 4 patients received daratumumab 16mg/kg qw 2-4 times, and all patients achieved complete remission (CR). They were followed up for 2.5 to 22.5 months, and all patients were alive and in complete remission from PTLD. 2/4 patients experienced a clear viral infection after receiving the CD38 monoclonal antibody, including one case of widespread adenovirus infection and one case of herpes simplex virus infection in the mouth, nose, and eyes, which improved after treatment.

Conclusion: This study is the first to reveal high expression of CD38 in PTLD and successfully treated 4 patients who failed to reduce their treatment with rituximab and immunosuppressants. Daratumumab may become a new option for the treatment of PTLD patients.
Early Detection of Immune-Dysregulation Predicts a Better Response to Immunosuppressive Treatment in Chronic Immune Thrombocytopenia
Authors: Palmisani Elena , Dell'Orso Gianluca , Del Bò Erica , Giarratana Mariacarla , Arcuri Luca , Guardo Daniela , Bagnasco Francesca , Grossi Alice , Lanciotti Marina , Terranova Paola , Dufour Carlo , Fioredda Francesca , Miano Maurizio
Published: December 2024

Introduction: chronicimmune thrombocytopenia (ITP) is a highly heterogeneous condition in terms of clinical course and response to treatment and it could represent the epiphenomenon of a complex immune-dysregulation process. Not all patients respond with equal effectiveness to different therapeutic approaches. However, specific indicators to predict therapeuthic response to the most suitable second-line therapy (mycophenolate mofetile, sirolimus and TPO agonists) in the acute phase have not yet been identified.

Aims: to describe the clinical and immunological features and the treatment response in order to identify a group of clinical and immunological variables predictive of a response to a specific second-line therapy.

Methods: 72 paediatric patients with persistent or chronic ITP followed at Haematology Unit, Gaslini Children Hospital have been reviewed retrospectively. Our patients present a baseline assessment with extended analysis of lymphocyte subpopulations (immunophenotype), and a follow up of at least 6 months. In this cohort, 51 patients also have an assessment of response to a second-line therapy.

Results: signs of immune-dysregulation in the aute phase, such as an increased in double T negative lymphocytes (DNT), defined according to ALPS NIH 2009 criteria (>1,5%), a reduced in T-CD4 cells and NK cells compared to age reference values (rispectively p=0.05, 0<0.05 and p<0.05) and the simultaneous presence of ¾ positive parameter of the ALPS panel (DNT, T lymphocytes B220, memory B lymphocytes CD27 and CD3+CD25+/HLADR+ ratio) (p<0.05) predict a better response to immunomodulatory therapy than TPO agonists.

Conclusion: an early immonophenotypic characterisation at diagnosis represent an excellent tool to identify the best second-line therapy (immunomodulators or TPO-agonists); it is also crucial to guide an early indication to perform genetic studies in order to orientate the use of a possible target therapies.
FAS Ablation Confers Resistance to Allogeneic CAR-T Rejection By T Cells in Absence of NK Cell Sensitization
Authors: Menegatti Silvia , Lopez-Cobo Sheila , Sutra Del Galy Aurelien , Fuentealba Jaime , Silva Lisseth , Perrin Laeticia , Heurtebise-Chrétien Sandrine , Pottez-Jouatte Valentine , Darbois Aurélie , Burgdorf Nina , Simon Albane , Laprie-Santenac Marguerite , Saitakis Michael , Wick Bruce , Webber Beau R , Moriarity Branden S , Lantz Olivier , Amigorena Sebastian , Menger Laurie
Published: December 2024

Allogeneic chimeric antigen receptor T cells (allo-CAR-T) derived from healthy donors hold potential to overcome limitations associated with autologous cancer therapies, providing immediate access to standardized, affordable batches of CAR-T with improved efficacy. Concomitant to immune reconstitution, however, allogeneic CAR-T are rejected by the host's immune system, resulting in reduced therapeutic efficacy and early relapses. To systematically identify targets overcoming allo-CAR-T rejection, we developed in vivo genome-wide CRISPR KO screens based on allogeneic T cell positive selection (screening for KO genes that promote resistance in fully mismatched immunocompetent mice). We show that Fas or B2m deletion increases the survival of allogeneic T cells in vitro and in vivo. Consequently, FAS or B2M silencing in anti-CD19 allo-CAR-T enhances their anti-leukemic activity and promotes mice survival. Nevertheless, while B2M KO allo-CAR-T become highly sensitive to NK cell-mediated rejection, FAS KO CAR-T, like control CAR-T, express normal levels of HLA-I and remain resistant to NK cell killing. We validated the results in a clinically relevant context using base-editing for multiplexing gene-KO in human CAR-T cells. CD3-FAS KO outperforms CD3-B2M KO CAR-T in the control of leukemia growth under allogeneic pressure by both T and NK cells. We conclude that CD3-FAS double-KO allogeneic CAR-T are partially protected from both T and NK cell-mediated allo-rejection, an approach with the potential to improve the efficacy of allogeneic cellular therapies in patients with B-cells neoplasms and more generally in cancer patients.
The Prognostic Value of Dynamic Minimal Residual Disease after Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma in Novel-Agent Era: Long-Term Follow-up
Authors: Yang Guangzhong , Gao Wen , Chen Wenming
Published: December 2024

ABSTRACT

Objective: To investigate the clinical prognostic value of dynamic minimal residual disease (MRD) after autologous hematopoietic stem cell transplantation (AHSCT) in patients with multiple myeloma (MM).

Methods: Patients with MM who underwent AHSCT in Beijing Chao-Yang Hospital from February 2016 to December 2019 were enrolled in this study. All the patients in the study had complete baseline data at the diagnosis. AHSCT was performed after induction chemotherapy. Response evaluation was performed after induction therapy. All the patients were assessed at approximately 100 days after AHSCT. Bone marrow MRD by NGF was performed every three months and dynamically monitored for at least 12 months. All the patients were divided into different groups according to cytogenetics and MRD status. Survivals in different groups were analyzed by IBM SPSS 22.0 statistical software.

Results: A total of 150 patients with MM were enrolled in this study at last, including 66 patients in the cytogenetic standard risk group and 84 patients in the cytogenetic high-risk group. The median age was 54 years (range 30-68 years) and 87 male patients (58.0%) was in the study.

The median follow-up was 52 months. Patients in the standard-risk group had better clinical prognosis than those in the high-risk group [median PFS in the standard-risk group was not achieved, and median PFS in the high-risk group was 45 months (P<0.001); the estimated 5-year OS rate of the standard-risk group and the high-risk group was 90.3% and 66.7%, respectively (P=0.001)].

According to MRD status of patients, patients in each group were divided into three subgroups: persistent positive (Ppos), transient negative (Tneg) and persistent negative (Pneg). The median OS and median PFS of all subgroups in the standard-risk group was not reached (P=0.118 and P=0.229). In high-risk group, the median OS of MRD Pneg subgroup was not reached, and the estimated 3-year OS rate was 100%; The median OS of MRD Ppos subgroup was 78 months, and MRD Tneg subgroup only 34 months (P<0.001) (Figure 1a); the median PFS of MRD Pneg group was not reached, and the estimated 6-year PFS rate was 69.0%; median PFS of MRD Ppos subgroup was 28 months, and MRD Tneg subgroup only 10 months (P<0.001) (Figure 1b).

Conclusions: MRD Pneg might overcome the adverse prognosis of MM patients with high-risk cytogenetics.

Figure 1a: Overall survival of pts with HRMM in different subgroups

Figure 1b: progression-free survival of pts with HRMM in different subgroups
Pharmacokinetic and Dose Response Relationships Observed in the Study “a Phase 1, Open- Label Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PTX-100 in Patients with Advanced and Relapsed/Refractory T Cell Lymphoma”
Authors: Chew Terrence , Mansour Mariam , Fernando MALAVER ORTEGA Luis , Bahadure Upaly , Yannakou Costas K. , Yatomi-Clarke Steven Lee , Prince H. Miles
Published: December 2024

PTX-100 is a small molecule inhibitor of GGT-1 that disrupts the oncogenic activity of RAS pathways by inhibiting post-translational modification of RHO, RAL, and RAC. The objective of this trial (NCT03900442) is to evaluate the safety, PK and PD of PTX-100 administered as monotherapy in patients with advanced malignancies, with an expansion cohort in T-cell lymphomas. PTX-100 was given by IV infusion in escalating doses of 500 to 2000 mg/m2 over days 1 to 5 in a 14-day cycle.

In order, to determine the optimal efficacious dose for PTX-100 and to further evaluate the clinical safety margin when administrated in multiple dose regime, a non-compartmental analysis (NCA) for PK and PD was performed, evaluating PTX-100 plasma pharmacokinetic parameters.

PTX-100 Tmax occurred in all patients within 1.3hr in each dose group. At Day1 and Day 5 of Cycle1, Plasma PTX-100 Cmax and AUC increased with increasing dose and appeared to be dose proportional over the range of 500 to 2000 mg/m2. Complete clearance of PTX-100 between doses/days has been found, with half-life of about 9hr.

To further evaluate and optimize PTX-100 dose regimens for Phase 2 efficacy, an exploration of efficacy correlation was investigated using a dose proportionality, modeling and simulation by Phoenix WinNonLin /NLME.

No PTX-100 accumulation was observed after five consecutive days of daily dosing. Simulation analysis revealed no correlation between total dose and time of response and neither between Cmax and time of response. Increase in total dose of PTX-100 dose levels beyond 2000mg/m2 correlates with decrease in overall response rate (ORR) and increasing PTX-100 dose does not reduce time to achieve ORR. However, it appears that 1500mg/m2 (i.e. total dose of 2500mg) is predicted to be the optimal dose achieving the optimum distribution of PTX-100 response.

In conclusion, PK and dose response analysis of Phase 1 study revealed that drug exposure is correlated with response to PTX-100. In contrast, no correlation is noted with dose or exposure, using hematology, RBC, WBC, Neutrophils, and Platelets. This evaluation provides information regarding the selection of the doses used in the clinic.
The Role of TET2 Mutation in Patients with Myeloproliferative Neoplasms and Thrombosis in Unusual Sites (Splanchnic Thrombosis and Cerebral Thrombosis)
Authors: Morsia Erika , Ranalli Paola , Baldoni Stefano , Lame Dorela , More' Sonia , La Barba Gaetano , Saladino Fabiola , Poloni Antonella , Olivieri Attilio , Rupoli Serena , Di Ianni Mauro , Kordasti Shahram
Published: December 2024

Introduction:

Myeloproliferative neoplasms (MPNs) associated with unusual site thrombosis (UST) exhibit a distinct clinical profile, particularly in cases of splanchnic vein thrombosis (SVT) and cerebral vein thrombosis (CVT), requiring meticulous interdisciplinary collaboration. This study aims to characterize the molecular features of MPN-UST using next-generation sequencing (NGS), with a particular emphasis on the TET2 mutation.

Methods:

We reviewed clinical and morphological data and analyzed mutational profiles via NGS in 44 consecutive MPN patients (PV [n = 11], ET [n = 12], PMF [n = 14], and MPN-U [n = 7]) admitted to the Hematology Units at AOU delle Marche and Pescara between July 1992 and November 2020, who developed SVT or CVT either at diagnosis or during follow-up.

Results:

A total of 44 patients were included in the study, with CVT accounting for 13.6% of all thromboses (n = 6) and SVT representing 86.4% (n = 38). Half of the patients presented with thrombosis at the time of MPN diagnosis. A higher proportion of patients with MPN-U was observed among those with SVT, aligning with literature findings. Molecularly, 86.4% of patients had the JAK2 V617F mutation as the driver mutation, with a median JAK2 V617F VAF of 16.7% (range, 1.89-91.0). JAK2 was the sole mutation detected by NGS in 51.35% of cases. Conversely, in JAK2 non-mutated patients, the driver mutation was the only genetic lesion found in 16.67% of cases. The primary findings in NGS included mutations in TET2 (22.7%), followed by KIT (18.2%), ASXL1 (9.1%), SETBP1 (9.1%), RUNX1 (6.8%), and GATA2 (6.8%). In 34.1% of cases, three or more mutations were present.

No differences were observed between MPN-SVT and MPN-CVT patients in terms of sex, type of MPN, or symptoms. However, a higher percentage of MPN-CVT patients had a TET2 mutation (66.6% vs. 15.7%; p = 0.0057).

With a median follow-up of 8.7 years, 9 patients died. In our cohort, age at diagnosis (HR 1.03, 95% CI 1.02-1.05, p = 0.00813) and the presence of a TET2 mutation (HR 1.25, 95% CI 1.18-1.52, p = 0.0458) were associated with poorer survival in multivariable analysis.

Discussion:

This study highlights the significant role of TET2 mutations in patients with MPN associated with UST. Our findings indicate that TET2 mutations are notably more prevalent in patients with CVT compared to those with SVT. Moreover, the presence of a TET2 mutation is associated with poorer survival, underscoring its potential as a prognostic marker. These insights emphasize the importance of molecular profiling in MPN-UST patients for better risk stratification and tailored therapeutic approaches.
Efficacy and Prognosis of Blinatumomab As a Bridge Therapy for Hematopoietic Stem Cell Transplantation for B-ALL
Authors: Lin Ting , Li Nainong
Published: December 2024

Objective:

Patients with B-ALL were included in the study. MRD of the target genes was quantified using a multiparameter Flow cytometry, and the bridged Hematopoietic stem cell transplantation was performed after 7 days of 28 UG of Blinatumoma treatment, it uses dexamethasone to prevent CRS, Levetiracetam to prevent ICAN, and trimetazidine to nourish the myocardium.

Methods:

Forty-four patients (22 female, 22 male) , with a median age of 36.5(13-60 years) . In 19 patients with Ph positive, MRD remained negative before and after transplantation in 14 patients and MRD clearance was achieved in 5 patients, while in 25 patients with Ph negative, MRD remained negative before and after transplantation in 21 patients and MRD clearance was achieved in 4 patients. During treatment with Emil Adolf von Behring, 16 patients (36.4%) developed grade 1 CRS, 1 patient developed Grade 2 CRS, and 1 patient developed grade 3 CRS. Two patients developed ICAN and one patient developed severe arrhythmia, so Emil Adolf von Behring was discontinued. All the 41 patients achieved deep remission after treatment with belintoin. On Blinatumomab, allogeneic Hematopoietic stem cell transplants were performed after a median interval of 0 days (0-40 days) , with 17 patients receiving single cord blood transplants, fifteen patients were treated with HID-HSCT in combination with cord blood transplantation, and 9 patients were treated with MSD-HSCT in combination with cord blood transplantation. With a median follow-up of 11 months, 41 patients had 1-year OS and PFS of 77.9% and 76.9% , respectively, and 10 MRD positive patients had 1-year OS and PFS of 66.4% and 65.6% , respectively, the 1-year OS and PFS of 31 MRD negative patients were 82.4% and 82% , respectively. Nine patients died after transplantation, including 9 from severe infection, 2 from GVHD and 3 from relapse.

Result:

Bridging transplantation after 7 days of continuous use of Blinatumoma has been shown to improve remission rates and long-term survival in patients with B-ALL, particularly in MRD-negative patients.
Quantitative Detection of the Expressions of BCL-2, BCL-Xl and MCL-1 in Bone Marrow Tissues with Immunofluorescence Might Predict the Efficacy of Venetoclax-Based Therapies in Acute Myeloid Leukemia
Authors: Nie Xiaqi , Yin Zhao , Yao Zurong , Chen Dandan , Liu Qifa , Yu Guopan
Published: December 2024

The expressions of anti-apoptotic proteins might be associated with the response of venetoclax (VEN)-based therapies in acute myeloid leukemia (AML). Yet, there is not a fast, easy and accurate method to quantitatively detect the expressions of different anti-apoptotic proteins. In this study we combined immunohistochemical staining with immunofluorescence technique to develop a new method of immunofluorescence, and quantitatively detected the expressions of BCL-2, BCL-xL and MCL-1 in bone marrow tissues, and then analyzed the co-relationship between the efficacy of VEN-based therapies and the expressions of the three anti-apoptotic proteins in AML. Bone marrow tissues were obtained from 21 patients with relapsed/refractory (RR)-AML and 16 with newly diagnosed (ND)-AML at diagnosis, remission and relapse, who were treated with VEN-based regimens. First, we confirmed the accuracy and the repeatability of the immunofluorescence method by comparing the consistency of the results being detected by the immunofluorescence and western blotting method, and multi vision detection of the immunofluorescence, respectively. After being confirmed, the detection showed that the median expressions of the three anti-apoptotic proteins in the patients with RR-AML were all higher than that in the ND-AML patients, and the difference in MCL-1 was significant (P=0.004). Also, the median expressions of the three proteins were all higher in the patients without acquiring complete remission (CR) (n=15) compared to those with CR (n=22), and the difference in MCL-1 tended to be significant (P=0.051). In the patients with RR-AML, those with high expressions of BCL-2 had significantly lower CR rate than those with low expressions (P=0.030). Meanwhile, high expressions of MCL-1 tended to be associated with lower CR rate in the patients with either ND-AML (P=0.067) or RR-AML (P=0.063). Furthermore, patients with high expressions of ≥2 anti-apoptotic proteins experienced lower CR rate than those with ≤1 high expression of anti-apoptotic protein. Based on the same patients, the expressions of the three proteins increased if leukemia relapsed or did not acquire response, while they significantly decreased if patients acquired CR. In the patients with ND-AML, the expression of the three proteins presented not obviously impact on the survival, while in the patients with RR-AML, those with high expressions of the three proteins tended to have poorer survival than those with lower expressions. In conclusion, quantitative detection of the expressions of BCL-2, BCL-xL and MCL-1 in bone marrow tissues with the immunofluorescence might predict the efficacy of venetoclax-based therapies in AML.

Key words immunofluorescence, anti-apoptotic protein, venetoclax, acute myeloid leukemia, efficacy
Enhancing Compliance to Massive Hemorrhage Protocol through Clinical Decision Support Tool for Thromboelastography Interpretation
Authors: Imhoff Santiago , Bag Angila , Janosky Maxwell D. , Kaufman Margit , De St Paer Brendt
Published: December 2024

Background

Englewood Health (EH) has adopted innovative approaches to Patient Blood Management (PBM) over the past 25 years, prioritizing Patient Blood Management techniques to enhance patient outcomes [1]. Implementing a massive hemorrhage protocol (MHP) based on thromboelastography (TEG) to tailor treatment of coagulopathy allows goal-directed blood product transfusion. TEG-assisted transfusion, widely used in liver transplantation, cardiac surgery, and trauma, has demonstrated a reduction in blood product use by up to 50% [2]. However, its application outside the operating room (OR) has been limited. Challenges in hospital guideline compliance due to unfamiliarity and difficulty with TEG interpretation have led to underutilization of viscoelastic tests. Simplifying viscoelastic interpretation through a decision support tool can aid physicians in treatment strategies. Tools like AvoMD, a clinical decision support (CDS) tool, help enhance compliance by providing structured guidance on TEG interpretation.

Methods

In 2023, EH decided to expand TEG for institution-wide viscoelastic testing. EH collaborated with AvoMD to integrate its customized MHP into a TEG interpretation interface, allowing clinicians to input key metrics and receive real-time treatment recommendations. Retrospective analysis compared the annual number of rotational thromboelastometry (ROTEM), previously used at EH prior to AvoMD implementation, with the number of TEG tests ordered after.

Results

Since implementation of AvoMD, the number of viscoelastic tests ordered surged by 168%. From 2020 to 2022, an average of 83 tests were ordered annually, increasing to 223 tests per year from 2023 to 2024 following AvoMD integration.

Conclusion

Recommendations for treatment of ongoing bleeding are to provide goal-directed therapy to treat the underlying issue. TEG allows physicians to assess coagulation in real time and tailor blood product administration, decreasing costs and improving patient outcomes [3,4,5]; however, viscoelastic testing use outside the cardiac OR was minimal due to clinician unfamiliarity and infrequent use.

CDS systems integrate patient information with a knowledge base to improve guideline adherence and ultimately, patient safety [6, 9]. AvoMD is a platform designed to streamline clinical decision-making by simplifying evidence-based guidelines. The TEG interpretation interface not only increased the number of viscoelastic tests ordered but also empowered physicians by providing evidence-based recommendations at point of care.

The integration of EH's PBM protocols into workflow through the AvoMD platform represents a significant advancement in the quality of patient care. This project highlights the potential of emerging technology, such as the integration of CDS platforms into electronic medical records, to enhance protocol compliance and improve patient safety [7,8].
Dose-Adjusted EPOCH-R Is Superior to R-CHOP in Frontline Treatment of Mediastinal Large B-Cell Lymphoma
Authors: Ma'koseh Mohammad , Yaseen Abeer , Abu Abed Nebras , Shahin Omar Ahmad , Abufara Alaa , Halahleh Khalid , Al-Rwashdeh Mohammad , Abdel Rahman Zaid , Al-Rabi Kamal , Abdel-Razeq Hikmat
Published: December 2024

Introduction : Primary mediastinal large B-cell lymphoma (PMLBCL) is a rare, aggressive B-cell non-Hodgkin lymphoma. Dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R), and rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone (RCHOP), are used as front-line treatments. Our study aims to compare the efficacy of these two regimens in newly diagnosed PMLBCL.

Methods: We retrospectively reviewed the medical records of adults (≥18 years) diagnosed with PMLBCL and treated in our center from 2010 to 2023. Baseline characteristics were compared using chi- square and Mann-Whitney U tests, as appropriate. Survival outcomes, including overall survival (OS), progression free survival (PFS) and relapse free survival (RFS) were plotted using the Kaplan-Meier method and compared using the log-rank test. OS and PFS were calculated from the date of initiation of chemotherapy to death and/or disease progression, respectively. Relapse free survival (RFS) was calculated from the date of documentation of complete response (CR) to relapse or death.

Results: Eighty-seven patients were included in the study, with a median age of 30 years (range: 18-55). The majority (86.5%) presented with bulky mediastinal disease (>7.5 cm) and 29 (32.6%) had an advanced-stage disease (stage III or IV). An International Prognostic Index (IPI) of >1 was observed in 28 (31.5%). Of the 87 patients, 48 (55.2%) were given R-CHOP, and 39 (44.8%) were given DA-EPOCH-R. Baseline characteristics were comparable between the 2 groups. The median number of chemotherapy cycles was 6 in both groups. Radiotherapy was more frequently administered to the R-CHOP group (66.7% vs 15.4%, P<0.001).

Following completion of first-line therapy (chemotherapy with or without radiotherapy), the complete response (CR) rate was significantly higher in patients treated with DA-EPOCH-R (92.3% vs 66.7%, P=0.004). After a median follow-up of 46.7 months (58.2 months for R-CHOP group and 26.8 months for DA-EPOCH-R), patients treated with DA-EPOCH-R had superior OS with 2-year OS rates of 94.4% compared to 72.1% for RCHOP (P=0.014), as well as PFS rates of 86.5% vs 62.2% (P=0.017). However, relapse-free survival (RFS) was similar in both treatment groups (2-year RFS 93.5% vs 93.3%, respectively, P=0.93). No therapy-related deaths occurred in either group.

Conclusions: In PMLBCL, front-line treatment with DA-EPOCH-R is associated with higher CR rates and superior PFS and OS than R-CHOP. However, RFS was similar between groups. Longer follow-up is required to evaluate long-term toxicities and potential late effects.
A Phase 1, Multicenter, Open-Label Study of UB-VV111 in Combination with Rapamycin in Relapsed/Refractory CD19+ B-Cell Malignancies
Authors: Garcia Jacob , Dehner Christine , Teoh Jeffrey , Wallis Wayne
Published: December 2024

Background and Significance:

Autologous, ex vivo-manufactured chimeric antigen receptor (CAR) T cells directed against CD19 have demonstrated clinical activity. These products have gained approvals in the relapsed/ refractory (R/R) setting in multiple B-cell malignancies (BCMs), including large B-cell lymphoma (LBCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, challenges in product availability due to limited manufacturing capacity, the need for apheresis and lymphodepletion, failure to prior ex vivo CAR T therapy, and the level of patient fitness needed to wait for and receive ex vivo autologous CAR T therapy all pose significant challenges to the field, presenting significant unmet clinical need.

UB-VV111 is a third-generation, self-inactivating, replication-incompetent lentiviral vector (LVV) investigational drug product comprising an envelope with cocal virus fusion glycoprotein (cocal) and surface engineered with a membrane-bound multidomain fusion (MDF) protein. The MDF protein contains CD58, CD80, and anti-CD3 single-chain variable fragment (scFv) components that provide both T-cell tropism and activation signals thought to be critical for effective CAR T-cell generation. UB-VV111 is designed to generate CD19-directed CAR T cells in a patient, thus addressing the delivery limitations that exist for currently available autologous CD19-directed CAR T cell therapies. UB-VV111 is to be administered by either the intranodal (IN) or intravenous (IV) route of administration (ROA). Administration of UB-VV111 by either the IN or IV ROA is expected to transduce T cells to generate CAR T cells designed to bind to CD19 antigen to mediate cell killing and express the rapamycin-activated cytokine receptor (RACR) system which, in the presence of rapamycin, is designed to enhance specific expansion of transduced cells.

Study Design and Methods:

Study UB-VV111-01 (INVICTA-1, NCT06528301) is a first-in-human, global, multicenter, dose-finding study of UB-VV111 administered IN or IV +/- rapamycin in CAR-naïve and CAR-exposed subjects with R/R LBCL and CLL/SLL. Dose escalation will proceed independently for each ROA using a Bayesian optimal interval (BOIN) design. Confirmation of CD19 expression will be required for all subjects with prior CD19-directed therapy. Major eligibility criteria include adults with R/R LBCL/CLL/SLL following at least 2 lines of prior therapy who have standard organ function, measurable disease according to Lugano 2014 (LBCL) or iwCLL 2018 (CLL/SLL), ECOG 0 or 1, and no prior allogeneic transplant. Primary objectives include determining the safety profile, maximum tolerated/administered dose, and recommended Phase 2 dose of UB-VV111 +/- rapamycin. Secondary/exploratory objectives include measuring preliminary antitumor activity (magnitude and durability), as well as translational correlates of safety/efficacy.
The Impact of the after-Hours Carechart Program in Assessing and Triaging after-Hours Patients with Malignancies Inquiries and an Analysis of the Changes to Service Access over the Course of the Covid-19 Pandemic
Authors: Bansal Saumya , Ali Amer Al Maqrashi Zainab , Youssef Cynthia , Ellis Peter
Published: December 2024

Background

Oncology patients with hematological or solid organ malignancies have limited access to their clinical team after hours, leading to increased use of emergency services and avoidable hospitalizations. A pilot project, CAREchart, employing a nurse-led after-hours telephone service, reduced emergency department (ED) visits and was subsequently implemented across Ontario, including at the Juravinski Cancer Centre (JCC) in Hamilton, Canada.

Methods

In this retrospective cohort study, data were abstracted from electronic records, including patient and disease characteristics, reason for calling, and outcomes of the call between Oct 2019 and April 2021. Patients included were aged 18 or older receiving systematic/radiation therapy at JCC. The primary outcome was the proportion of patients accessing CAREChart who were referred to the ED and admitted to the hospital. Secondary outcomes covered the impact of the COVID-19 pandemic wave 1 and 2 on the primary outcome.

Results

A total of 636 calls were made to the CAREChart program from October 2019 to April 2021. Among these, 199 (31.3 %) of calls were directed to ED, 154 (24.4%) visited ED, out of which 93 (14.6%) required admission. This finding was consistent across different time periods: pre-COVID-19, COVID-19 Wave 1, and COVID-19 Wave 2, with 30.8%, 30.8%, and 31.7% of patients directed to the ED, respectively. Similarly, 10.8%, 15.4%, and 15.6% of patients required admission during the pre-COVID-19 period, COVID-19 Wave 1, and COVID-19 Wave 2, respectively. Forty patients (6.3%) visited the ED, and 27 required admission (4.2%) when they were not initially advised to go to the ED through CAREChart.

Conclusions

The CAREChart program provides a unique avenue for JCC cancer patients to access care after hours. The program was successful in avoiding >65% of potential ED visits thus reducing hospitalizations in these patients.
Epidemiological Analysis and Overall Survival of Leukemia in Adults in a Developing Middle Eastern Country over 18 Years
Authors: Abdulelah Ahmed A , Abdulelah Zaid A , Saadeh Aseel , Al Ta'ani Omar , AlQirem Lina , Alhajahjeh Abdulrahman , Abdel-Razeq Hikmat , Haddadin Michael
Published: December 2024

Introduction: Leukemia in adults imposes significant global health burden not only due to the presenting clinical characteristics, but also due to the resultant morbidity and mortality. Therefore, the identification of the epidemiological features, including the overall survival and crude incidence, in developing middle eastern countries such as Jordan is of paramount importance and significance in the risk stratification and introduction of effective measures.

Methods: Thorough data on a cohort of 4146 adult individuals of different nationalities residing in Jordan who were diagnosed with leukemia during the period of 2000-2018 was retrieved from the Jordan Cancer Registry, the formal cancer epidemiology reporting entity in Jordan. Statistical analysis was performed to establish the epidemiological characteristics of leukemia in adults in Jordan over a period of 18 years.

Results: A total of 4146 adult patients with a mean age of 49.5 ± 18 years old and a male predominance of 59.5% were included in the analysis. A considerable portion, 50.5%, of the study population were non-smokers at the time of diagnosis. Acute myeloid leukemia was the most commonly encountered leukemia as it accounted for 35.2% of all cases, followed by chronic myeloid leukemia in 20.8% of the patients, and subsequently followed by chronic lymphocytic leukemia and acute lymphocytic leukemia that were reported in 17.2% and 15.7% of the patients, respectively. Hairy cell leukemia was identified in 102 (2.5%) of the patients. A statistically significant decline in the crude incidence of adult leukemia over 18 years was evident with a crude incidence estimated effect of -0.048. The overall survival was 88.0%, 84.7%, 84.1%, 83.8%, and 83.4% at 1-year, 2-year, 3-year, 4-year, and 5-year interval, respectively.

Conclusion: Over a span of 18 years, adult leukemia in Jordan demonstrated a relatively young average age at diagnosis and thus mandates thorough vigilance. Interestingly however, Jordan demonstrates a higher 5-year survival rate than the witnessed overall survival rates internationally.
Evaluating Recent Drug Approvals for Hematologic Malignancies Utilizing the New European Society of Medical Oncology Magnitude of Clinical Benefit Scale for Hematology (ESMO-MCBS:H)
Authors: Hirsh Ryan , Moyers Justin , Benjamin David , Pourhassan Hoda
Published: December 2024

Introduction:

Over the last decade, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have steadily leaned towards granting regulatory approval based on earlier phase trials and surrogate endpoints. Despite obtaining regulatory approval, many countries hold additional standards to assess the value of a new drug approval. The ESMO-MCBS is a tool created to evaluate the values and reduce bias or hype of drug approvals using various metrics: efficacy, quality of life, and duration of response. In 2023, the ESMO-MCBS:H was created for hematological malignancies. We aimed to evaluate recent drug approvals using the new ESMO-MCBS:H criteria for hematologic malignancies.

Methods:

We included all drugs approved for a hematologic malignancy between 2019 and 2024. Drugs were assessed using ESMO-MCBS:H forms 2a, 2b, 2c, or 3 depending on the trial type and primary endpoints leading to drug approval. Approvals were independently scored by two reviewers with a third reviewer to adjudicate scoring differences.

Results:

66 drugs were approved by either FDA or EMA during this time. 88% (n=58) were approved by both EMA and FDA, 12% (n=8) by FDA alone. No drugs were approved by the EMA alone without preceding or subsequent FDA approval. 4 drug approvals were for pediatric indications. 36 approvals (n=35/66, 53 %) were based on early phase 1 and/or 2 trial data. Approvals were for leukemias (n=16; 24%), lymphomas (n=25, 38%), myeloma (n=18, 27%), or CLL/SLL (n=6; 9%). 13% of approvals (n=9/66) were for drugs with a biomarker matched indication.

Substantial benefit criteria were met by 17 of 66 approvals (26%). Substantial benefit criteria were met by 0% (N=0/8) of drug indication by approved by FDA alone versus 29% of drugs approved by both the FDA and EMA (n=17/58), however was not statistically significant (p=0.08).

Approvals based on early phase (phase 1 and/or 2) trials met criteria in 17% (n=6/35) of trials and 36% of later phase (phase 3) trials met criteria (n=11/31) without statistical significance (p=0.09).

No significant difference in approvals meeting substantial benefit were seen for biomarker matched therapies (33%; n=3/9) versus unmatched therapies (25%; n=14/57) (p=0.58).

No therapies approved for a pediatric indication met criteria for substantial benefit (n=0/4).

Conclusion:

Few drugs approved by both agencies met the rigorous ESMO-MCBS:H criteria for substantial benefit. Recent approvals meeting substantial benefit criteria were not statistically correlated with approval agency, phase of trial utilized for approval, or biomarker selection of therapies. Drug approvals must balance proven benefit to access to innovative and new therapies.