bluuebunny/crossref_metadata_2025 huggingface dataset:
Tucidinostat Plus Pediatric-Inspired Chemotherapy As First-Line Therapy for Newly Diagnosed ETP-ALL/Lbl: An Open-Label, Single-Arm, Phase 2 Trial
Authors: Lin Jieping , Ding Chenhao , Huang Zicong , Zihong Cai , Li Jia , Wang Zhixiang , Li Xiaofang , Zhou Xuan , He Bailin , Zhong Wenhao , Xuan Li , Liu Qifa , Xu Yang , Zhou Hongsheng
Published: December 2024

Background Early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) is a distinct subtype of T-ALL/LBL, with a dismal prognosis. The aim of this study was to investigate the effectiveness and safety of histone deacetylase inhibitor (HDACi) tucidinostat combined with pediatric-inspired chemotherapy for new diagnosed ETP-ALL/LBL.

MethodsThis phase 2 trial was conducted at Nanfang Hospital in China. Patients aged 14-55 years with newly diagnosed ETP-ALL/LBL were eligible. Patients received pediatric-inspired chemotherapy in combination with tucidinostat, which was orally administered once daily at a dosage of 10 mg from induction therapy to consolidation therapy. The primary endpoint was 3-year event-free survival (EFS). Secondary endpoints were overall survival (OS), relapse-free survival (RFS), complete remission rate and adverse events. This study is registered with ClinicalTrials.gov, number NCT03553238.

Findings From June 2018 to June 2022, 54 patients with ETP-ALL/LBL were enrolled (37 [68%] male; 17 [32%] female; 54 [100%] Asian; median age 24 years [IQR 19-31]). The composite complete remission (CRc, complete response [CR] plus complete response with incomplete blood count recovery [CRi]) rate and MRD negativity after induction therapy was 91% (49 of 54 patients) and 65% (35 of 54 patients), respectively. The MRD negativity after consolidation was achieved in 87% patients (47 of 54 patients). With a median follow-up of 39.3 months (IQR, 20.6 to 60.0), the 3-year EFS rate was 67.7% (95% CI 56.2-81.7), the 3-year OS rate was 71.5% (95% CI 60.2-84.9) and the 3-year RFS rate was 67.5% (95% CI 55.9-81.6). The most common grade 3-4 adverse events were neutropenia (94%), anemia (85%), thrombocytopenia (76%), infection (53%), and hypokalemia (21%).

InterpretationTucidinostat plus pediatric regimen is an effective and well-tolerated regimen for new diagnosed ETP-ALL/LBL, with high CRc and MRD negativity rates, as well as encouraging survival outcomes.
GATA1 Insufficiencies in Dysmegakaryopoiesis of Myelodysplastic Syndromes/Neoplasms
Authors: Li Fuhui , Zhang Yudi , Li Chengwen , Sun Qi , Liu Jinqin , Qin Tiejun , Xu Zefeng , Li Bing , Qu Shiqiang , Pan Lijuan , Gao Qingyan , Jiao Meng , Gale Robert Peter , Xiao Zhijian
Published: December 2024

Introduction: GATA1 is one of critical transcription factors for megakaryopoiesis and platelet production. Our study aimed to explore the correlations between GATA1 expression and dysmegakaryopoiesis in myelodysplastic syndromes/neoplasm (MDS).

Methods: Data of blood cell counts, cytogenetics and next-generation sequencing from 90 MDS patients at diagnosis were collected. Firstly, we assessed GATA1 expression level of megakaryocytes by performing immunohistochemical staining on bone marrow biopsy sections from the aforementioned 90 MDS patients. According to GATA1 expression level of megakaryocytes and positive megakaryocyte percentage, we assigned each patient a GATA1 score. Furthermore, we explored the correlation between GATA1 expression levels and cytogenetic abnormalities of the same megakaryocytes using the morphology antibody chromosome (MAC) technique on fresh bone marrow smears from another 6 MDS patients. To explore the significance of GATA1 expression levels in the prognosis of MDS, we included GATA1 scores in a multivariable analysis of overall survival (OS).

Results: Patients with abnormal karyotypes showed decreased GATA1 scores than those with normal karyotypes (6.0 [3.0-10.5] versus 12.0 [4.0-12.0] scores, P = 0.024). Compared with TP53-wildtype patients, GATA1 scores significantly decreased in TP53-mutated patients (3.0 [2.3-6.0] versus 12.0 [6.5-12.0] scores, P < 0.001). However, patients with mutations of other genes showed no significant differences in GATA1 scores compared with wildtype patients (P > 0.05). GATA1 expression levels were significantly downregulated in dysplastic megakaryocytes, especially micromegakaryocytes (P < 0.001). Furthermore, we found that GATA1-negative megakaryocytes had higher frequencies of cytogenetic abnormalities (87.5% versus 47.6%, P = 0.002) using MAC technique. The multivariable analysis of overall survival that lower GATA1 scores (P = 0.005) were significantly associated with inferior OS in MDS, independent of the IPSS-R higher-risk category (IPSS-R scores > 3.5 points).

Conclusion: Our results indicated that decreased GATA1 expression level of megakaryocytes was significantly associated with TP53 mutations, abnormal karyotypes and dysmegakaryopoiesis in MDS, suggesting that downregulation of GATA1 expression levels of megakaryocytes plays a critical role in the pathogenesis of MDS.
Clinical Response and Safety for Relapsed/Refractory Diffuse Large B Cell Lymphoma Treated By Glofitamab Combined with Chemo-Free Regimens
Authors: Zhao Xia , Liu Zhihe , Xu Junqing
Published: December 2024

Background:

The prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) is poor. Glofitamab, a bispecific antibody that recruits T cells to tumor cells, has shown promise. Still, real-world data on its combined use with chemo-free regimens for R/R DLBCL is limited.

Aims:

This study aimed to evaluate the clinical efficacy and safety of glofitamab combined with chemo-free regimens for treating R/R DLBCL.

Methods:

We enrolled patients with R/R DLBCL who had received at least two prior lines of therapy. Patients were pretreated with obinutuzumab to mitigate cytokine release syndrome, followed by fixed-duration glofitamab monotherapy (12 cycles). R/R double-expressor lymphoma patients received glofitamab combined with acalabrutinib (100 mg twice daily) or zanubrutinib (160 mg twice daily); R/R primary mediastinal large B-cell lymphoma patients received glofitamab combined with sintilimab (200 mg per cycle); the remaining R/R patients received glofitamab combined with polatuzumab vedotin (1.8 mg/kg) or lenalidomide (20 mg/day, days 1-14). Clinical information, overall response rates, and adverse events were collected for all patients.

Results:

Fifteen R/R DLBCL patients, with a median age of 66 years (range 29-79 years), were enrolled. The male-to-female ratio was 12:3. Based on the Ann Arbor staging system, 93.3% of patients were classified as stage III/IV, and 66.7% had an International Prognostic Index (IPI) score of ≥3. 66.7% of patients had at least two extranodal lesions. According to the Hans algorithm, 93.3% of patients were in the non-GCB group, and the median Ki-67 value was 90% (range 70%-90%). Three patients were CD5 positive, and 60.0% were diagnosed with double-expressor lymphoma. Among the cohort, three patients had P53 protein expression less than 5%, while eight patients exhibited expression greater than 50%. The median number of treatment lines was four (range 3-5). Six patients had primary refractory disease, and six experienced early relapsed. In this study, nine patients received glofitamab combined with BTK inhibitors; one received glofitamab combined with sintilimab; three received glofitamab combined with lenalidomide; and two received glofitamab combined with polatuzumab vedotin. All patients completed at least three cycles, and the overall response rate was 73.3%, with a complete response rate of 33.3% at the end of the second cycle. Adverse events were generally mild, with grade 1 or 2 cytokine release syndrome and tumor flare reaction being the most common.

Conclusion:

Glofitamab combined with chemo-free regimens demonstrated high response rates and good tolerability in R/R DLBCL patients receiving at least two-line treatments.
Interim Analysis and Feasibility of the Effects of Virtual Reality on Pain and Anxiety in Cancer Patients Undergoing Bone Marrow Biopsy
Authors: Wolfson Hannah C , Mohacsi Savannah , Pai Jonathan , Xiong Shigang , Nelson Viva , Konganige Shiran , Ghani Umair , Pinski Jacek K
Published: December 2024

Introduction/Purpose

We developed a protocol to test the hypothesis that the utility of Virtual Reality (VR) as a companion to bone marrow biopsy (BMBx) procedures will lessen patient experiences of pain and anxiety as indicated by patient-reported pain scores and anxiety surveys. The purpose of the present study was to examine the feasibility of this protocol.

Methods

We conducted a prospective, randomized study of 14 patients (of a planned total enrollment of 30 patients) undergoing BMBx. Patients were randomized 1:1 to the experimental arm (VR) or the control arm (standard of care). Pain surveys and the State Trait Anxiety Inventory (STAI) were completed before and after the BMBx procedure. Pain was rated on a scale from 0-10. The STAI scores were calculated as two sub-scores: State Anxiety Inventory (SAI) score and Trait Anxiety Inventory (TAI) score. Changes in pain and anxiety were calculated as the difference between recorded pain scores (∆Pain) and STAI sub-scores (∆SAI, ∆TAI) pre- minus post-BMBx. In R version 4.3.2, two sample t tests and Mann-Whitney U tests were used to compare changes in pain ratings and STAI sub-scores by experimental group. This was an interim analysis of 14 patients out of a planned 30 planned subjects to examine feasibility of the protocol.

Results

One patient did not complete any pain or STAI surveys and was excluded from analysis. Overall means (SD) for ∆Pain, ∆SAI, and ∆TAI were -0.92 (2.63), 2.46 (9.40), and 2.31 (3.82). Mean ∆Pain in the experimental group (n=8) and the control group (n=5) were -0.75 vs. -1.2, t test p=0.78, respectively. Mean ∆SAI in the experimental group and the control group were 2.875 vs. 1.8, t test p=0.84, respectively. Mean ∆TAI in the experimental group and the control group were 2.875 vs. 1.4, Mann Whitney U test p=0.46, respectively.

Conclusion

Differences were noted in pre- minus post- BMBx scores for pain and STAI sub-scores between the experimental group and the observational group. Although the differences in the means did not reach statistical significance due to the small number of subjects in the study, the results do support the feasibility of the protocol used in this pilot study to be expanded to a larger patient population and to a more diverse set of acutely painful procedures.
PRUNE1-IGF2BP3 Forms a Positive Feedback Loop By Stabilizing SOX4 mRNA in an m6A-Denpendent Manner to Promote Multiple Myeloma with 1q21 Gain
Authors: Wang Yawen , Liu Peng , Xu Jiadai , Li Panpan
Published: December 2024

Multiple myeloma (MM) with chromosome 1q21 Gain is a group of fatal malignancies characterized by high heterogeneity. Our previous findings have indicated that PRUNE1 (located on chromosome 1q21.3) promotes MM by enhancing the connections between purine and mitochondrion. In this study we have discovered that insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) acts downstream of PRUNE1 and is highly expressed in MM with 1q21 Gain, showing a clinical correlation with distant overall survival. To investigate the impact of IGF2BP3 on cellular proliferation, migration, and apoptosis, we conducted CCK-8 assays, transwell assays, and flow cytometry assays, respectively. Mechanistically, IGF2BP3 enhances the stability of SOX4, a transcription factor of PRUNE1, in an m6A dependent manner. This creates a positive feedback loop that promotes MM cell proliferation and invasion through enhanced glycolysis. These findings shed light into the regulatory network of SOX4/PRUNE1/IGF2BP3 among MM with 1q21 Gain and provide rationale for targeting the m6A machinery in the treatment.
Late Effects of Childhood Cancer Among Survivors in Saudi Arabia: A Multicenter Cross-Sectional Study
Authors: Alabbas Fahad , Alharbi Ibrahim , Ahmad Naveed , Alnajashi Khalid , Ballourah Walid , Alsultan Abdulrahman
Published: December 2024

Abstract

Background: With the advancement of childhood cancer therapy, long-term survivors are on therise. Reports of late effects of childhood cancer are limited. This study aims to assess the spectrum and burden of late effectsamong survivors of childhood cancer in Saudi Arabia.

Methods: This observational cross-sectional retrospective study was conducted at multiple cancer centers in Saudi Arabia. Survivors were enrolled consecutively, provided they completed at least 5 years after cancer therapy that was diagnosed before 14 years of age. Details of primary cancer diagnosis, treatment received, and current health status of the last 2 visits were assessed from electronic health records. The primary outcome was to estimate the prevalence of chronic health conditions (CHC) among survivors, while the secondary outcome included the impact of the primary diagnosis and various cancer therapies on the occurrence of CHC.

Results: 305 survivors met the inclusion criteria, with a minimum of 5 years of follow-up after completing cancer therapy as of July 2022. Female participants constituted 46% of the cohort. The median follow-up duration was 8.5 (range 5-21) years,with median ages at diagnosis and evaluation of 4 (range 0.16-14) and 14 (range 5-28) years, respectively. Hematological malignancies comprised 65.9%, with leukemia being the most prevalent (49.2%), followed by lymphoma (16.7%), and solid tumors (15.7%). Chemotherapy was administered to 287 survivors (94.1%), while radiotherapy and surgery were used in 29.2% and 22.3%, respectively. Nine patients (3%) required hematopoietic stem cell transplant. Cancer relapse and secondary malignancy were reported in 5.2% and 0.7%, respectively.Approximately 78% of the cohort experienced at least one CHC, with 31.1% and 14.2% having 2 and 3 CHC, respectively. A multivariate logistic regression analysis identified a statistically significant association between CHC and solid tumors compared to hematological malignancies (OR 2.2; 95% CI: 1.1-4.3; p=.023).Growth impairment was the most common CHC, followed by endocrine dysfunction. History of radiotherapy was significantly associated with short stature (95% CI: 1.2-3.6; p=.008).Among the subgroup analysis of 77 survivors, 39 (67.2%) had grade I (mild) disability,19% had grade II (moderate) disability, and 13.8% had grade III (severe) disability.

Conclusion: The estimation oflate effects of childhood cancer among survivors has revealed a prevalent concern. However, the majority of CHC were mild in severity. To optimize health outcomes for survivors, it is essential to minimize cancer therapy without compromising survival rates, implement well-structured and long-term follow-up tailored to individual risk profiles, utilize cost-effective screening methods, and promote prospective clinical research and establishment of a registry.
The LSD1 Inhibitor RN1 Rescues Congenital Dyserythropoietic Anemia Type II
Authors: Yu Lei , Wang Yu , King Richard , Myers Greggory , McGee Beth , Friedman Ann , Balbin-Cuesta Ginette , Lin Zesen , Drysdale Claire , Liu Xiaofang , Kerpet Claire , Deng Kaiwen , Robida Aaron , Engel James , Khoriaty Rami
Published: December 2024

Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease resulting from loss-of-function mutations in SEC23B, which encodes a component of coat complex protein II (COPII) vesicles. Mammals express two paralogous genes for SEC23, SEC23A and SEC23B, which encode proteins with ~85% amino acid sequence identity. We have previously shown that the SEC23 paralogs have identical interactomes and that SEC23A overlaps in function with SEC23B. Since the SEC23B/SEC23A expression ratio is disproportionately high in human erythroid cells, we reasoned that the endogenous SEC23A expression level is not sufficiently elevated to compensate for loss of SEC23B in CDAII erythroid cells. Indeed, we demonstrated that increasing SEC23A expression, using CRISPR activation or cDNA expression, completely rescues the SEC23B-null erythroid defect.

In this study, we generated a human erythroid cell line that expresses eGFP from the endogenous genomic locus of SEC23A and performed a small molecule screen to identify compounds that increase the SEC23A-eGFP level. The top compound passing all filters was an LSD1 inhibitor. We validated that LSD1 inhibition dramatically increased SEC23A mRNA and protein levels in primary erythroid cells derived from CD34+ human hematopoietic stem and progenitor cells (HSPCs), at doses that do not impair erythroid cell growth or differentiation. We also showed that LSD1 inhibition rescues the erythroid differentiation defect resulting from SEC23B deletion in primary human erythroid cells.

We validated LSD1 as the target of RN1 by showing that genetic downregulation of LSD1 also led to a profound induction of SEC23A mRNA levels in HPSC-derived erythroid cells. Subsequently, we validated our findings in vivo. We first demonstrated that deletion of Lsd1 in mouse erythroid cells results in increased Sec23a expression. Subsequently, we generated CDAII mice, with inducible deletion of both Sec23b alleles and haploinsufficiency for Sec23a. We showed that RN1 treatment of CDAII mice rescues the erythroid defect observed in these mice. Finally, using CUT&RUN, we found that LSD1 occupies a sequence in the SEC23A promoter, which when mutated, results in increased SEC23A expression and rescue of CDAII.

Taken together, these finding suggest that LSD1 occupies the SEC23A promoter, repressing SEC23A transcription and that in the setting of LSD1 inhibition, SEC23A expression is de-repressed, resulting in CDAII rescue. Therefore, using an unbiased screen, we have identified and validated a novel promising therapeutic strategy for CDAII, using a compound that inhibit LSD1 or a genetic approach based on deleting the SEC23A promoter sequence that is occupied by LSD1.
Cohort Comparison of Therapy-Related Myeloid Neoplasms after CAR T-Cell Therapy, Autologous Stem Cell Transplant, and Standard Cancer Therapies
Authors: Roman Diaz Jaime , Dahiya Saurabh , Sillito Francesca Emily , O'Reilly Maeve , Rejeski Kai , Buecklein Veit L. , Subklewe Marion , Iacoboni Gloria , Barba Pere , Roddie Claire , Locke Frederick , Spiegel Jay Y. , Al Ali Najla H. , Thompson Zachary , Kim Jongphil , Komrokji Rami S. , Jain Michael D.
Published: December 2024

BACKGROUND

Myeloid neoplasms (TMNs), such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), are an important cause of non-relapse mortality after CAR T-cell therapy. It is not known whether the characteristics and outcomes of TMNs after CAR T-cell therapy differ from those of TMNs occurring after other types of treatment.

METHODS

We collected a multicenter, international cohort of 51 patients diagnosed with MDS (n=36) or AML (n=15) after CAR T-cell therapy for lymphoma or myeloma. Data was gathered on baseline characteristics, disease type, exposure to chemotherapy, radiation exposure, survival, disease risk, and molecular profiles. The characteristics and mutational profiles of this cohort (CAR T) were compared to historical single-institution cohorts of TMN occurring after autologous stem cell transplant (AUTO, n=96) or other standard anti-cancer therapies (STD=244) such as chemotherapy and/or radiation.

RESULTS

The baseline characteristics for the three cohorts of TMN (post-CAR T, post-AUTO, and post-STD) were similar in terms of age, sex, and ethnicity. The time to onset of TMN was significantly shorter post-CAR T than the other cohorts (CAR T 20 months, AUTO 63.6 months, STD 62.1 months, p<0.001). No significant differences between cohorts were noted in terms of baseline IPSS-R risk categories or the frequency of any specific somatic myeloid mutation. TP53 mutations were the most common somatic mutation in all three cohorts (CAR T 47%, AUTO 47%, STD 39%) but were not more frequent in the CAR T cell cohort. Overall survival from the time of TMN diagnosis was significantly shorter in the post-CAR T cell therapy cohort (median OS months for CAR T=9.2, AUTO=24.4, STD=19.2; log-rank p=0.005).

CONCLUSIONS

The time to onset of TMNs is shorter post-CAR T cell therapy compared to post-AUTO or post-other STD cancer therapies. TMNs occurring after CAR T have a similar cytogenetic risk and mutational profile compared to other TMNs, but shorter overall survival from the time of TMN diagnosis. Additional work is needed to understand risk factors, the shorter time of onset, and the particularly poor prognosis of patients experiencing TMN after CAR T cell therapies.
Discovery of BTC-86, a Novel Second-Generation Menin-MLL Inhibitor to Overcome the Acquired Resistance in MEN1 for R/R Acute Leukemia
Authors: Liu Suxing , Hu Weimin , Yang Dexiao , Han Liang , Tong Minghui , Yan Yuna , Chan Shek Ling , Xi Zhiguo , Shi Xuan , Hu Qiyue
Published: December 2024

The menin-MLL1 interaction is essential for acute leukemias driven by MLL rearrangements (MLLr) or mutations in the nucleophosmin 1 gene (NPM1c). Menin-MLL inhibitor SNDX-5613 (revumenib) has demonstrated robust clinical responses in the clinical trial. However, somatic MEN1 mutations were found at residues M327, G331 or T349 at the revumenib-menin interface in the patients with acquired resistance to menin inhibition and post a major challenge to the management of acute leukemias driven by MLLr or NPM1c. Therefore, developing second-generation inhibitors that block MLL1 binding while having activity against those MEN1 mutations becomes an important strategy to combat acquired resistance to the first -generation menin-MLL inhibitors.

The MMPT (Matched Molecular Pair Transformation) process is used to develop menin-MLL inhibitors. Fluorescence polarization assay is used to assess the impact of BTC-86 on the binding of MLL to wild-type (WT) or mutated menin proteins. Using the MMPT process, we have discovered a novel second-generation menin-MLL inhibitor BTC-86 that has similar binding activity against wild-type menin protein and MEN1 resistance mutations. SNDX-5613 shows notable steric hinderance in the binding pocket of M327I mutant versus that of wild-type menin. Based on the modeling study, BTC-86 can adopt a novel binding mode, which shows little change in its bound position to M327I mutant compared to that of wild-type menin. BTC-86 is the most potent one in inhibition of menin-MLL1 binding against all the MEN1 acquired mutations among all five clinical molecules, including SNDX-5613, JnJ-75276617, and KO-539.

Furthermore, BTC-86 is a potent and highly selective menin-MLL inhibitor in cell viability of multiple leukemia cell lines. BTC-86 shows anti-tumor efficacies in multiple tumor mouse models carrying MLLr or NPM1c, which are correlated with in vivo on-target activity (inhibition of MEIS1 gene expression) and excellent pharmacokinetic properties.

BTC-86 has lower risk in QTc prolongation (IC50 of hERG greater than 30 µM), and has better human metabolic stability than the first-generation menin-MLL inhibitor. Moreover, it is well tolerated in an exploratory rat toxicology study.

In conclusion,BTC-86 is a potent second-generation menin-MLL inhibitor that blocks MLL1 binding while having similar activity against wild-type and mutant MEN1 proteins. IND-enabling study of BTC-86 is in progress. Further studies in clinical setting are warranted to confirm BTC-86 as a second-generation menin-MLL inhibitor for overcoming acquired resistance in MEN1.
Epidemiology and Prognostic Factors of Angioimmunoblastic T-Cell Lymphoma
Authors: Ali Hassan , Desai Krishna , Bajwa Shammas , Bajwa Umair , Faisal Muhammad Salman , Thirumaran Rajesh
Published: December 2024

Background:

Peripheral T cell lymphomas (PTCL) constitute only 10-15% of non-Hodgkins lymphoma, and is a heterogenous group of lymphomas. Angioimmunoblastic T-cell (AIB-T) lymphoma is a subset of peripheral T cell lymphomas. It is a highly aggressive malignancy originating from follicular subset of mature CD4+ helper T cell, with a high risk of relapse. AIB-T lymphoma commonly present with generalized lymphadenopathy, hepatosplenomegaly or systemic B symptoms. Diagnosed upon biopsy, AIB-T lymphoma is characterized by polymorphic infiltration of lymph nodes and manifest significant proliferation of follicular dendritic cells and high endothelial venules. Treatment options include chemotherapy (often CHOP with or without etoposide) and autologous hematopoietic stem cell transplant.

Method:

Data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2022 Sub (2000-2020). AIB-T lymphoma cases diagnosed including and after the age of 20 years were extracted from the data base using the ICD Code 9705/3. The data was stratified based on age, sex, race, primary site labelled and chemotherapy, and survival curves were compared using the Log-Rank test (GraphPad Prism).

Results:

Total 2536 cases of angioimmunoblastic T-cell lymphoma were identified, of which ~54.85% were males. The neoplasm was most commonly seen in White (66.68%) patients followed by Hispanic (14.08%), Asians/Pacific Islander (10.92%), Black (7.89%) and Alaskans/Native American (0.28%) patients. The median age of diagnosis was 69 years. The incidence rate (per million population) for the general population is around 0.05 per year. When comparing the survival curves, the data was statistically significant for age, with survival progressively tailing off with increasing age (p value <0.0001). The median of survival (mOS) for males was 17 months and females was 25 months (CI:0.619-0.746, HR: 1.159, p 0.0021). Survival analysis based on race and primary site labelled showed no statistical difference. The mOS calculated for chemotherapy was significant for 28 months (with chemo) vs 4 months (without chemo) (p value <0.0001).

Conclusions:

Angioimmunoblastic T-cell lymphoma is a rarely seen malignancy with only 2536 cases reported in the last two decades in SEER database. It has predilection for males, and majority of the cases were reported in Caucasians. Overall superior survival was observed with younger age groups, female gender and treatment with chemotherapy. Race and primary site of origin showed no association with the median of survival. Given its extremely low incidence, more research and analysis is warranted to understand this lesser known malignancy.
Persistent Thrombocytosis, an Interesting Finding in β-Thalassemia Patients Post-Splenectomy in a Tertiary Referral Center in Jordan
Authors: Aburumman Saif , Alesufi Aisheh , Abu Nasrieh Dima , Banihani Haneen , Al Nawaiseh Maram , Abu Lehyah Naser Aldain , Shersheer Qasem
Published: December 2024

Background

β-thalassemia is a common hematological disorder with defective β-globin production. Splenectomy is one of the common modalities of management in its severe forms where blood transfusion requirements are high. However, various post-splenectomy complications, such as thrombocytosis, warrant further exploration.

Methods

This was a retrospective cohort study conducted on 22 patients with β-thalassemia major who had undergone splenectomy at Al-Bashir Hospital, a tertiary referral center in Jordan, from 2019 to 2021. We analyzed demographic data, clinical outcomes (e.g., blood transfusion requirements and intervals), and laboratory values (e.g., hemoglobin and platelets counts) pre- and post-splenectomy. p-values < .05 were considered significant.

Results

All patients with a mean age of 24.71 ± 8.44 years had persistent thrombocytosis post-splenectomy. The average count of platelets peaked at 965.36 ± 413.50 cells/mm³ immediately post-surgery and fell slightly to 843.23 ± 320.08 cells/mm³ one-year post-splenectomy. Transfusion requirements reduced significantly by 42.49% from an average of 295.95 ± 68.24 ml/kg/y to 170.21 ± 54.65 ml/kg/y (p <.001). The average time interval between transfusions has increased by 60.15% from 17.14 ± 4.49 days to 27.45 ± 10.5 days (p <.001). The hemoglobin level showed a significant increase post-splenectomy, with means of 8.47 ± 1.43 g/dL pre-surgery and 9.65 ± 1.49 g/dL post-surgery. Aspirin was recommended to all patients and hydroxyurea was recommended to those with persistent thrombocytosis over 1 million (n=12) but some refused it (n=5).

Conclusions

This study further underscores the persistent thrombocytosis and reduced transfusion needs in β-thalassemia patients following splenectomy. The results of such findings, therefore, indicate that while splenectomy brings very effective control in transfusion requirements, monitoring thrombocytosis and thrombotic events should always be on the lookout. Generally, it brings out the relevance of adopting tailored management strategies to optimize patient outcomes in β-thalassemia care. Future prospective studies involving larger cohorts with a more prolonged duration of follow-up would be required to confirm these observations and define other late complications following splenectomy.
Venetoclax Plus Chidamide/Azacitidine Dual Epigenetic Target Regimen in High-Risk Acute Lymphoblastic Leukemia: Preclinical and Case Series Studies
Authors: Zheng Boyue , JIyi FU , Yijing Wang , Yu Wang , Huan Wang , Haiqing Yang , XI Yang , Zheng Hong , Hui Li
Published: December 2024

Adult T-ALL has a poor prognosis, with traditional chemotherapy showing low remission rates, high relapse rates, and poor tolerance. There is an urgent need for new treatment regimens to improve the prognosis of T-ALL patients. We propose a dual epigenetic target regimen combining venetoclax with chidamide/azacitidine. Through preclinical studies, we explored whether the combination of these three drugs has a synergistic inhibitory effect on the proliferation of Jurkat cells and retrospectively analyzed the clinical data of four T-ALL patients to preliminarily explore the efficacy and safety of this regimen. The vitro experiments demonstrated that the combination of venetoclax, chidamide, and azacitidine had a synergistic inhibitory effect on the proliferation of Jurkat cells. The study included four male patients with a median age of 40.5 years (25.3, 57.3), all with high-risk factors. One patient had refractory T-ALL (R T-ALL) that failed induction with the VDCP regimen, and three patients had newly diagnosed T-ALL (ND T-ALL). Bone marrow immunophenotyping indicated one case of Pro-T, one case of Pre-T, one case of ETP-ALL, and one case of MPAL (T/My). One patient had chromosomal abnormalities, three had gene mutations, one had a mediastinal mass, three had lymphadenopathy, and none had central nervous system involvement. Three patients achieved CR/CRi after one cycle of the regimen, and one patient achieved CR after the second cycle. Three patients achieved deep remission and MRD negativity after two cycles. Two patients underwent hematopoietic stem cell transplantation after achieving CR and are currently in sustained remission, being dynamically followed up in the outpatient clinic. The most common adverse reaction during treatment was myelosuppression. Both preclinical study conclusions and clinical research data support the venetoclax plus chidamide/azacitidine dual epigenetic target regimen as a preferred treatment option for high-risk T-ALL patients.
Inconsistent Reporting and Definition of Time-to-Event Endpoints in CAR T Clinical Trials: A Review of the Literature and a Call for Harmonization
Authors: Grady Connor B , Li Yimei , Maude Shannon L. , Hexner Elizabeth O. , Frey Noelle , Porter David L. , Hwang Wei-Ting
Published: December 2024

Introduction: Clinical trials evaluating chimeric antigen receptor T-cell therapy (CAR T) commonly report time-to-event (TTE) endpoints. However, definitions are not necessarily comparable across studies and variability can lead to misinterpretation of results or inappropriate comparisons across products and studies. Amid the rapidly increasing number of published CAR T trials-many of which were used for regulatory approval-this study aims to summarize the variation in the use and reporting of TTE endpoints in CAR T trials.

Methods: We include CAR T trials published January 2008-January 2023 on PubMed that reported at least one of these TTE endpoints: overall survival (OS), progression-free survival (PFS), duration of response/remission (DOR), disease-free survival, event-free survival (EFS), relapse-free survival (RFS), time to relapse, time to progression, or time to treatment failure. We abstracted and summarized endpoint definitions, including the time origin, events, competing events, and censoring. We assessed the completeness of endpoint reporting, overall and by subgroups such as study phase, publication year, and the journal's impact factor.

Results: We included 116 publications in the analysis. The most frequently reported TTEs were OS (83%,), PFS (56%), DOR (55%), and EFS (23%). Complete reporting of endpoints was poor overall: 32%, 24%, 25%, and 56% for OS, PFS, DOR, and EFS respectively. Complete reporting was lower in articles published before 2018, in lower impact factor journals, and in phase I trials. There was also a large variability in TTE definitions among those reported. For example, among 64 studies reporting DOR, 48% used the date of response as the time origin while 20% used the date of infusion, and 31% did not report a time origin.

Conclusion: There is substantial heterogeneity and incompleteness of TTE endpoint definitions in CAR T trials reported in the existing literature that could impact the interpretation of the study results. Improving and harmonizing reporting is required to ensure valid assessment of clinical benefit and cross-trial comparison. Complete reporting should include all the following components: time origin, event(s) of interest, competing event(s) if any, and censoring. Recommended definitions for the common TTEs and the rationales will be presented at the meeting.
Rondaptivon Pegol (BT200) to Correct Thrombocytopenia in a Peri-Interventional Setting in Type 2B Von Willebrand Disease (VWD)
Authors: Moser Miriam , Ay Cihan , Schoergenhofer Christian , Gilbert James C , Zhu Shuhao , Jilma Bernd
Published: December 2024

Introduction

Type 2B von Willebrand disease (VWD) is a qualitative VWF defect with increased binding of VWF to platelets, increased platelet clearance, potential thrombocytopenia and a substantial risk of bleeding. Rondaptivon pegol (BT200) is an aptamer binding to the A1 domain of von Willebrand Factor (VWF), which increases VWF antigen, GpIbM, collagen binding activity, multimers and platelet counts in type 2B VWD.

Methods, intervention and outcome

Two thrombocytopenic patients with type 2B VWD received BT200 peri-interventionally. Patient #1 had a suspect lesion in the lung and required bronchoscopy. As she had received BT200 in a previous phase 2 trial, she now received a loading dose of 10 mg BT200 prior to the procedure, which increased platelet counts from 46 to 108 x10E9/L after one week. Subsequent doses of BT200 normalized her platelet counts. Two months later, she received a loading dose of 12mg, 7.5 and 7.5mg BT200 at weekly intervals before an enteroscopy with thermocoagulation because of frequent bleedings due to jejunal angiodysplasia. Her platelet counts reached 160 before and 153 x10E9/L after the intervention. In both cases BT200 made it possible to conduct those diagnostic procedures, for which threshold platelet counts above the patient's baseline are required. No bleeding complications occurred.

The second patient had a femoral neck fracture that required hip surgery under prophylactic substitution wirh Haemate P, which increased VWF activity to 101%. Nevertheless, platelet counts continued to fall to 14 x10E9/L, and the patient not only showed extensive local hematomas, but also developed bleedings at distant sites (buccal, extremities). This strongly indicates that those bleedings resulted from severe thrombocytopenia, because VWF activity was normal under substitution therapy. BT200 (4.5mg) was injected four days after surgery which increased platelet counts from 25 to 49 x10E9/L after one week. A second dose of 7.5 mg increased platelet counts to 278 x10E9/L after another week.

Conclusion

BT200 corrected platelet counts facilitating two successful interventions without bleeding complications in one patient and a cessation of bleeding in a second patient, which indicates the utility of BT200 in the peri-interventional setting.

Literature

Ay C, et al. The VWF binding aptamer rondoraptivon pegol increases platelet counts and VWF/FVIII in type 2B von Willebrand disease. Blood Advances. 2022;27;6(18):5467-5476.

Cihon A, et al. Aptamer BT200 blocks interaction of K1405-1408 in the VWF-A1 domain with macrophage LRP1. Blood. 2024 Jul 12:blood.2024024055
Characterization of Bleeding in Thrombotic Thrombocytopenic Purpura Treated without Caplacizumab
Authors: Mahmoud Amir , Shah Purva , Eltaher Basant , Mostafa Mariam A , Abdelhay Ali , Abou-Ismail Mouhamed Yazan , Chaturvedi Shruti
Published: December 2024

Introduction: The addition of caplacizumab to immune thrombotic thrombocytopenia (iTTP) treatment options has led to a renewed interest in characterizing the epidemiology and risk factors for bleeding in iTTP. Limited data exist on the bleeding risk in iTTP due to systemic underreporting in earlier cohorts.

Methods: To describe the incidence, patterns, and predictors of bleeding in hospitalized iTTP patients, independent of caplacizumab (pre-caplacoizumab era), we retrospectively analyzed the National Inpatient Sample database (2012-2019) and identified all patients aged ≥18 years with a diagnosis of iTTP. Bleeding was identified using ICD-9/10 codes and characterized as major bleeding or non-major bleeding. Factors associated with bleeding were determined by multivariable logistic regression analysis.

Results: We identified 3103 iTTP hospitalizations between 2012-2019. Median age was 49 years (range 18 - 90) and 65.9% were female. Bleeding occurred in 594 (19.1%) episodes and 157 (5.1%) were characterized by major bleeding. Mucocutaneous bleeding (7.6%) was the most frequent type of bleeding and included heavy menstrual bleeding (2.6%), gingival (2.3%), epistaxis (1.4%), and skin/procedure-related bleeding (1.3%). This was followed closely by gastrointestinal bleeding (5.6%). Among patients with major bleeding (table S1), CNS bleeding was the most common at 67 (42.7%), followed by hemothorax/hemopericardium in 55 (35.0%), and hemoperitoneum in 25 (15.9%). Only 37 (1.2%) hospitalizations with bleeding required percutaneous, endoscopic, or surgical intervention for bleeding. More patients in the bleeding group (table 1) received blood transfusions (48.8% vs 33.6%; P<0.001) and platelet transfusions (21.2% vs 12.2%; P<0.001). Major bleeding was independently associated with mortality (OR, 2.62; 95% CI 1.65-4.16).

In multivariable analysis, Asian/Pacific Islander/Native American race (OR, 2.04; 95% CI 1.04-4.01), coronary artery disease (OR, 1.70; 95% CI 1.06-2.74), autoimmune disease (OR, 2.61; 95% CI 1.58-4.30), Charlson comorbidity index ≥ 3 (OR, 2.08; 95% CI 1.25-3.46), and delay ≥ 2 days in plasma exchange initiation (OR, 1.63; 95% CI 1.13-2.34), were significantly associated with major bleeding.

Conclusion: In conclusion, bleeding is a relatively common issue in acute iTTP that has not been adequately addressed in existing literature. Bleeding is mostly mild, with mucocutaneous bleeding being the most common phenotype. However, major bleeding occurs in over 5% and is associated with mortality. Further studies are needed to establish risk factors for bleeding in iTTP, especially given the increasing use of caplacizumab in the treatment of iTTP.
Rituximab, Chidamide, and Zanubrutinib±CHOP Could be a Promising Regimen for Newly Diagnosed Double-Expressor DLBCL (DE DLBCL)
Authors: Li Zhiming , Sun Peng , Zhang Lu , Fu Xiangjun , Jiang Yirong , Guo Zhi , LIU Panpan , Wang Yu , Yang Hang , Huang Kangming
Published: December 2024

Background: DLBCL patients with co-expression of MYC (≥40%) and BCL2(≥50%) by immunohistochemistry are considered as double expressor lymphomas (DE DLBCL). The prognosis of DE DLBCL is usually worse than non-DE DLBCL. The Smart Start trial had explored the feasibility of chemotherapy-free targeted therapy before frontline chemotherapy. The BTK inhibitor Zanubrutinib (Z) or epigenetic drug Chidamide (C) with R-CHOP regimen has a potential synergistic effect in the treatment of DE DLBCL. Under the inspiration of Smart Start, this trial aim to explore the feasibility of RCZ±CHOP regimen in newly diagnosed DE DLBCL.

Methods: This is a multicenter, open-label, single-arm phase II study (NCT05527912) conducted in China. If patients achieve complete response (CR) after cycle-2 (C2), RCZ will be continued for up to 8 cycles. Otherwise, RCZ-CHOP will be given for another 6 cycles. The primary endpoint is CR rate at the end of treatment (CRR-EOT); secondary endpoints included ORR (overall response rate) ,2y-PFS, and 2y-OS. Plasma samples were collected at baseline, after C2 and the EOT. In evaluable samples, circulating tumor DNA (ctDNA) assays were performed.

Results: From February 2023 till now, 43 newly diagnosed DE DLBCL patients were enrolled, with 38 patients evaluable. The median age was 55y (range: 22-68), 51.2% were male, 67.4% were Non-GCB. 18 patients who achieved CR by C2 were continued with RCZ chemo-free therapy, and CHOP were added to the 16 PR and 2 SD patients. In the 38 evaluable patients, ORR after C2 of RCZ was 89.5%(CR 47.4%, PR 42.1%, SD 5.3%, PD 5.3%). Up to now, 11 patients have completed RCZ chemo-free therapy 8 cycles (C8) and all of them have achieved CR, both ORR and CR are 100% (11/11). 17 patients have completed RCZ chemo-free therapy 2 cycles and RCZ-CHOP therapy 6 cycles, with a remarkable CR rate of 82.4% and 2 patients withdrew due to PD. For safety information in the trial, the majority of G-3/4 AEs is hematological events, including leukopenia(46.9%), neutropenia(21.9%) and thrombocytopenia(50%), mostly occurred in RCZ-CHOP period. The CR rate at C2 was 66.7% in patients with negative baseline plasma test results (n=32). The patients with BCL6 fusion of ctDNA at baseline were more prone to PD. C2 plasma ctDNA levels decreased significantly from baseline. 29 patients were evaluable for ctDNA after C2, 100%(12/12) of C2-CR patients and 58.8%(10/17) of non-C2-CR patients were negative, P=0.023. The number of detected mutations and the average VAF in plasma were also decreased in Non-C2-CR patients.

Conclusions: This trial demonstrates the RCZ±CHOP therapy could be a promising regimen with an active antitumor effect and acceptable toxicity in newly diagnosed DE DLBCL patients.
Real-World Efficacy and Safety of Letermovir Prophylaxis in Adolescent Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation: A Single Center Observational Study
Authors: Xu Ziwei , Wang Huafang
Published: December 2024

Letermovir, an inhibitor of the cytomegalovirus (CMV) terminase complex, has demonstrated remarkable efficacy in the prevention of CMV infections in adult patients through randomized controlled trials. Nevertheless, its application in adolescent patients has been relatively limited. This observational study, conducted at a single center, sought to assess and compare the efficacy and safety of letermovir (n=20) and valganciclovir (n=32) for CMV prophylaxis in adolescent patients (aged 14-18 years) undergoing allogenic hematopoietic stem cell transplantation (aHCT).

The incidence of CMV DNAemia following aHCT was 45.0% in the letermovir group and 59.4% in the control group receiving valganciclovir. Notably, 20.0% of patients receiving letermovir required preemptive therapy (PET), in contrast to 40.6% of those receiving valganciclovir. Furthermore, 10 patients in the letermovir group and 15 in the valganciclovir group developed grades Ⅱ-Ⅳ acute graft-versus-host disease (aGVHD). Among patients with grades Ⅱ-Ⅳ aGVHD, the proportion of adolescents requiring PET was significantly lower in the letermovir group compared to the valganciclovir group (10% vs 53.3%, p=0.04). The 1-year overall survival rates were 87.4% and 85% in the letermovir and valganciclovir groups, respectively (p=0.928). Importantly, no patients succumbed to CMV infection in both groups . The most common adverse events observed in the letermovir group were aGVHD (60.0%), diarrhea (25.0%), and nausea (15.0%). Leukopenia was reported in only one patient, and did not necessitate an adjustment of letermovir dosage. In this single-center real-world study, letermovir exhibited a superior efficacy and safety profile for CMV prophylaxis in adolescent patients undergoing aHCT, as compared to valganciclovir. In particular, for patients with grades Ⅱ-Ⅳ aGVHD, the administration of letermovir prophylaxis can significantly decrease the likelihood of PET. However, further prospective multi-center studies are warranted to validate the efficacy and safety of letermovir for CMV prevention in adolescent patients.
Efficient Generation of CAR-T By the First Coacervate-Based Gene Delivery System
Authors: Zhu Peipei , Gao Xiaofei , Yuan Yang , Lu Manman , Zhang Qing , Ding Menghao , Jiang Lihong , Huang Yaohuang , Lee Hsiang-Ying
Published: December 2024

Chimeric antigen receptor (CAR) T cells have achieved remarkable success in treating certain hematological malignancies. However, the effective engineering of primary cells remains a significant challenge. Coacervates are condensed droplets containing proteins or nucleic acids formed via liquid-liquid phase separation (LLPS). Here, we have identified a mammalian endogenous protein capable of forming coacervates with various nucleic acids (PCT/CN2024/099339). Our analysis revealed that these coacervates can encapsulate RNA molecules at a 1000-fold higher capacity compared to lipid nanoparticles (LNPs). Remarkably, these coacervates can enter various cell types, including human primary cells, and efficiently release nucleic acids within the cytoplasm. Based on this discovery, we have developed a non-viral, electroporation- and antibody-conjugated LNP-free, coacervate-based gene delivery system named PhaseX. We demonstrated that PhaseX can deliver mRNA encoding GFP protein into human primary T lymphocytes with over 90% efficiency and 95% viability. At day 12 post-treatment, 64% of cells still exhibited sustained GFP expression with high fluorescence intensity, indicating prolonged expression. Furthermore, we generated mRNA-based anti-CD19 CAR T cells using PhaseX. These CAR-T cells effectively eliminated tumor growth in NSG mice xenografted with CD19+ Raji cells after a single dose (5 x 106 CAR-T cells). To enhance CAR-T function, we simultaneously introduced Cas9 mRNA with sgRNAs into these CAR-T cells. This resulted in the successful knockout of multiple genes including PDCD1, and showed enhanced anti-tumor activity in vivo. For potential clinical applications, we have successfully scaled up the system to deliver mRNA into over 109 primary human T cells with over 90% efficiency. Future studies will focus on integrating genetic elements into the genome using this system. In summary, we have developed the first coacervate-based delivery system for primary cell engineering, including human primary T lymphocytes. This methodology will greatly benefit CAR-T applications, and the reagent is currently available for free testing upon request.