bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Rates of Undetectable MRD By Phased-Seq on Interim and End of Treatment Timepoints in Untreated Advanced Stage Chl Treated with Pembrolizumab + AVD
Authors: Lynch Ryan C , Alig Stefan K. , Ujjani Chaitra S. , Poh Christina , Warren Edus H. , Smith Stephen D. , Shadman Mazyar , Till Brian G. , Raghunathan Vikram , Tseng Yolanda D , Ottemiller Susan , Joy Bonnie , Fessel Melissa Mary , Du Hongyan , Vandermeer Jacquelin , Kelly Alyssa , Rasmussen Heather , Voutsinas Jenna M. , Alizadeh Ash A. , Gopal Ajay K. 
Published: December 2024

Introduction
We previously reported initial (n=30) efficacy results of a frontline study of pembrolizumab + AVD (Lynch et al Blood 2023, ASH 2023) in classic Hodgkin lymphoma (CHL). Despite finding surprisingly high rates of positive interim and EOT PET/CT compared to historical data, observed outcomes were excellent. Herein we present updated clinical data for our full 50-patient study including interim and end of treatment (EOT) MRD testing by PhasED-Seq
Methods
We examined additional long-term follow up of patients with pembrolizumab combined with concurrent AVD in previously untreated CHL as previously described (NCT03331341). Samples were analyzed for ctDNA at baseline, post cycle 1 (if available), post cycle 2, and end of treatment. ctDNA levels were quantified as haploid genome equivalents/mL plasma using PhasED-Seq (Kurtz et al. Nat Biotech 2021).
Results
50 patients were enrolled between Feb 1, 2019, and Apr 13, 2023, with a median follow up of 3.1 years; 3-year PFS and OS were 98% and 100%, respectively. Among advanced stage patients (n=38), 3-year PFS and OS were 97% and 100%, respectively.
In patients where samples were available for analysis, baseline ctDNA was detectable in 11/12 (92%) of early-stage patients, and 36/37 (97%) of advanced stage patients. 7/8 (88%) early-stage patients had undetectable MRD (uMRD) at C3D1, and all cleared ctDNA by EOT and none have relapsed to date. Among advanced stage patients, 22/29 (76%) of samples at C2D1 and 29/35 (83%) samples at C3D1 had uMRD. In contrast, the PET CR rate at C3D1 in advanced stage patients was only 58%. At EOT, 31/34 (91%) advanced stage samples had uMRD compared to a PET CR rate of 73%. The only patient in the study to relapse had a negative interim PET but did not clear ctDNA at any timepoint. Two additional patients had minute amounts of ctDNA detectable at the end of treatment after levels dropped &gt;20,000 fold when compared to baseline. Both patients have not relapsed 3 years and 14 months after completion of treatment, respectively. Some timepoints did not have plasma samples available, and no samples were drawn for sequencing during follow-up,
Conclusion
Pembrolizumab + AVD continues to demonstrate durable efficacy in previously untreated CHL. No patient who has cleared ctDNA as measured by PhasED-Seq has relapsed to date despite high rates of interim-PET and EOT PET positivity. The role of PhasED-Seq will be further examined in the upcoming Phase 2 MRD-adapted PRECISE-HL study in untreated advanced stage CHL.
Preliminary Efficacy of Orelabrutinib Targeted Therapy in Induction Therapy of Primary Central Nervous System Diffuse B-Cell Lymphoma
Authors: Zhou Sha , Rao Jun , Xiang Xixi , Zeng Yunjing , Li Jiali , Yang Hanshan , Liu Bo , Zhang Xi , Gao Li 
Published: December 2024

Objective: To evaluate the efficacy and safety of the induction regimen of targeted therapy of Orelabrutinib combined with chemotherapy in primary central nervous system diffuse B-cell lymphoma.
Methods: Patients aged 18 years and above with primary central nervous system diffuse B-cell lymphoma received ROM induction regimen (Orelabrutinib 150mg qd，rituximab 375mg/m2 day1, high-dose MTX 3.5 g/m2 day2, /28 days) for 3 courses. Patients who did not achieve partial remission (PR) or complete remission (CR) after 3 courses were excluded from the study. Patients who achieved PR or CR received consolidate treatment of autologous stem cell transplantation (ASCT), whole brain radiotherapy, or another 3 courses of ROM chemotherapy. Preliminary exploration the efficacy and safety of ROM induction therapy.
Results: From March 2021 to April 2024, a total of 30 patients with primary central nervous system diffuse B-cell lymphoma in our hospital received ROM induction regimen. The median age was 56 years (34-72), with 15 males and 15 females. Two patients experienced disease progression and died after two courses of treatment. After three courses of ROM induction therapy, 14 patients achieved CR, 11 patients achieved PR, and 3 patients had stable disease. The overall response rate (ORR) for all patients was 83.3%. The median onset time for PR is 1 course, and the median onset time for CR is 2 courses. After induction therapy, 9 patients received ASCT consolidation, 6 patients received whole brain radiotherapy consolidation, and 15 patients continued consolidation chemotherapy. After a median follow-up of 10 (2-37) months, the estimated 1-year OS was 84.6% and PFS was 76.0%. No grade III-IV hematological or non-hematological adverse events were observed in all patients.
Conclusion: The ROM regimen is an effective and safe induction therapy for primary central nervous system diffuse B-cell lymphoma, with a total response rate of 83.3% and a median onset time of 1 course for PR and 2 courses for CR. It is a promising induction therapy for primary central nervous system diffuse B-cell lymphoma.
The Effectiveness of Levofloxacin in Prevention of Febrile Episodes in Non-Hodgkin Lymphoma Patients Receiving Rituximab, Cyclophosphamide, Vincristine, Doxorubicin and Prednisolone (R-CHOP)
Authors: Surakijboworn Mutita , Uaprasert Noppachan , Rojnuckarin Ponlapat 
Published: December 2024

Background: Febrile neutropenia poses significant risks for morbidity and mortality in non-Hodgkin lymphoma (NHL) patients undergoing R-CHOP chemotherapy. Prophylactic antibacterial use after R-CHOP is controversial, especially when patients receive primary G-CSF prophylaxis, with no established standard recommendation. This study aims to evaluate the effectiveness of levofloxacin in preventing febrile episodes in NHL patients receiving R-CHOP and G-CSF prophylaxis.
Method: A randomized, single-blind, placebo-controlled trial was conducted at King Chulalongkorn Memorial Hospital, enrolling non-Hodgkin lymphoma patients undergoing R-CHOP chemotherapy from January 1, 2023, to June 30, 2024. Patients were randomly assigned to receive either levofloxacin 500 mg once daily or a matching placebo for 7 days, beginning one day after chemotherapy. All patients received primary G-CSF prophylaxis. The primary outcome was the occurrence of febrile episodes within 120 days. Secondary outcomes included rates of septic shock, septic death, all-cause mortality, chemotherapy dose reduction, and the onset of the first febrile episode and composite outcome.
Results: Eighty participants were randomly assigned to two groups, with 40 individuals in each group. Their mean age was 61 years. In the intention-to-treat analysis, febrile episodes occurred in 7.5% and 30% of participants in the levofloxacin and placebo groups, respectively (P = 0.010). Levofloxacin prophylaxis significantly reduced febrile neutropenia (2.5% vs. 20%, P = 0.013), chemotherapy dose reduction (0% vs. 12.5%, P = 0.021), and composite outcome (10% vs. 30%, P = 0.025). The hazard ratio for febrile-free survival with levofloxacin vs. placebo was 0.23 (95% CI 0.06 to 0.8; P = 0.012). No significant differences in infection-related mortality or all-cause mortality were observed between the two groups. Furthermore, no serious adverse effects were documented in either group.
Conclusions: The use of levofloxacin prophylaxis is an effective and well-tolerated strategy in reducing the incidence of febrile episodes, febrile neutropenia, and the need for chemotherapy dose reduction among NHL patients undergoing R-CHOP chemotherapy despite primary G-CSF prophylaxis. Long-term antibiotic resistance monitoring is needed.
Venetoclax Plus Idarubicin and Cytarabine Chemotherapy As First-Line Treatment for Adults with Acute Myeloid Leukaemia
Authors: Zang Shaolei , Ji Min , Zhang Jingru , Lu Fei , Zhang Chunqing , Ye Jingjing , Ji Chunyan 
Published: December 2024

Background
3+7(idarubicin/daunorubicin plus cytarabine,IA/DA) has been a standard regimen for first line induction treatment of acute myeloid leukaemia (AML) for half a century. About 60-80% of patients with acute myeloid leukaemia reach complete remission[1], and improved induction regimens are needed. It is in extensive exploration to combine venetocloax with standard cytotoxic drugs for fit AML patients to enhance clinical response. It is proved that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner [2].So in this study we aims to observe the efficacy and safety of lA plus venetoclax (IAV) regimen in newly diagnosed AML patients.
Methods
We enrolled 32 patients aged 18-60 years with previously untreated de-novo acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Patients had induction treatment with intravenous Idarubicin (12 mg/m² on days 1-3), intravenous cytarabine (100 mg/m² on days 1-7), and oral venetoclax (100 mg on day 4, 200 mg on day 5, and 400 mg on days 6-11; IAV regimen). For induction therapy, the length of the treatment was 28-35 days per cycle and the number of treatment cycles was one or two. The primary endpoint was the composite complete remission rate (complete remission plus complete remission with incomplete blood cell count recovery) after one cycle of induction treatment. Secondary endpoints were bone marrow measurable residual disease by flow cytometry, event-free survival, overall survival, and adverse events
Findings:
Between October6, 2021 andDecember 31, 2023, 32 patients were enrolled (aged16-60 years; median 46.5years), of which 11/32(34.4%) cases were in favorable risk group, 15/32(46.9%) cases were in intermediate risk group, and 6/32(18.8%) cases were in adverse risk group. 11 (38%) patients were men and 21 (62%) were women, and all were Asian.
(1). Efficacy observation: After one cycle of the lAV regimen, 87.5%(28/32) patients reached cCR, among them 90.6% patients reached MRD negative. With a median follow-up of 9 months, 24/32(75%) patints remain in CR, the median EFS and OS is not reached. The Estimated 12-months EFS is 73.3%(57.7%-93%), and 12-months OS is 86%(73.9%-100%).
(2).Safety observation: During the treatment, some patients experienced adverse reactions and complications including hematologic toxicities, liver and renal dysfunctions, febrile neutropenia. The adverse reactions was tolerated or controlled except one patient died from severe pneumonia after induction chemotherapy. Overall, the regimen was well tolerated in patients with AML at the initial diagnosis.
Conclusion
As an emerging treatment, lAV regimen is effective and safe in newly diagnosed AML patients.
Valoctocogene Roxaparvovec Estimated Long-Term Durability of Treatment Effect: An Extrapolation of the Most Recent Clinical Data
Authors: Santos Sandra , Robinson Tara M. , Trueman David 
Published: December 2024

Background: Valoctocogene roxaparvovec is a single administration AAV5-mediated gene therapy that enables endogenous FVIII production to prevent bleeding in people with severe hemophilia A (PwSHA). In the phase 3 GENEr8-1 study, valoctocogene roxaparvovec demonstrated higher probability of being bleed free, improvements in annualized bleeding rates (ABR) and in health-related quality of life (HRQOL) 4 years after infusion when compared to outcomes while on FVIII prophylaxis during the baseline period.
Aims: Estimate the long-term durability of valoctocogene roxaparvovec treatment effect by extrapolating the most recent trial data (GENEr8-1 4-5-year and 270-201 7-year data).
Methods: Durability was analyzed within a time-to-event analysis framework, which is commonly used to extrapolate observed data. The quantity of interest was the rate at which patients experienced loss of response. In alignment with the WFH guidelines and label recommendations, and to reflect the benefit of the treatment as a whole, loss of response was defined in the primary analysis as a clinical overview of an objectively measurable biomarker (FVIII levels &lt;5%), clinical endpoints (≥2 treated bleeds in 6 months) and the return to continuous prophylaxis. The primary analysis used GENEr8-1 data only. Scenario analyses were explored, where other definitions of loss of response were considered, as well as 270-201 7-year data used.
Results: In the primary analysis, the median durability of treatment effect is estimated to range from 11.0-17.0 years. In the scenario where 270-201 data were also used for the extrapolation, median estimated durability is estimated to range from 13.2-20.4 years.
Conclusions: This analysis demonstrates that the observed therapeutic benefit is expected to be sustained beyond the 7 years of follow-up in existing clinical trials, illustrating the full treatment benefit that valoctocogene roxaparvovec can bring to PwSHA.
Inhibition of Glycine Transporter 1 Reduces Phototoxicity in a Mouse Model of Erythropoietic Protoporphyria (EPP)
Authors: Xiang Yi , Wu Min , Chen Yue , Reisman Scott A , Venkatraman Srikanth , Yang Hua , MacDonald Brian 
Published: December 2024

Erythropoietic protoporphyria (EPP) is a genetic disorder typically caused by reduced activity of ferrochelatase (FECH), the enzyme that catalyzes the final step in heme biosynthesis. EPP phototoxicity occurs when the photosensitive metal-free protoporphyrin IX (PPIX) in erythrocytes and skin is exposed to irradiation from sunlight, absorbs photons, and produces reactive oxygen species (ROS) that damage the skin and subdermal layers. Patients with EPP suffer from acute and severe phototoxicity after sun exposure, significantly impacting their quality of life.
Fech m1Pas /Fech m1Pas homozygous mice (EPP mice) retain approximately 5% residual FECH activity due to a severe homozygous loss-of-function mutation. EPP mice develop protoporphyria characterized by elevated PPIX levels in red blood cells (RBCs) and liver, which leads to liver fibrosis and cutaneous phototoxicity that manifests as skin lesions when these mice are exposed to light within the excitation wavelength of PPIX (395 to 410 nM) (Wang, 2019).
Glycine transporter 1 (GlyT1) mediates the import of glycine, a precursor for heme synthesis, to erythroid cells. The GlyT1 inhibitor bitopertin has been shown to decrease whole-blood PPIX levels in patients with EPP in Phase 2 clinical studies (Dickey, 2024; Ross, 2024) and in animal models (Wu, 2022).
This study evaluated whether GlyT1 inhibition can ameliorate phototoxicity via downregulating PPIX levels in Fechm1Pas/Fechm1Pas EPP mice. EPP mice were administered vehicle or a selective small molecule inhibitor of GlyT1, DISC-C, at 15 mg/kg by oral gavage twice daily for 18 days. GlyT1 inhibition decreased PPIX levels in RBCs by 43% and 37% on Day 14 and Day 18, respectively. On Day 14 of treatment, hair was shaved from the backs of EPP mice, and all mice were exposed to light at a wavelength of 395 nM (588±10% lumens/m2) for 30 minutes. Mice administered vehicle developed progressively worsening skin lesions with histopathological characterization of sterile abscesses, hyperkeratosis, and dermal lymphocyte infiltration. The skin lesions worsened over the observation period from Day 14 to Day 18, with 51.2% exposed skin area developing skin lesions at 4 days after light exposure (Day 18). In contrast, mice administered DISC-C developed skin lesions in 9.2% of exposed skin area, suggesting GlyT1 inhibition reduced phototoxicity in EPP mice. Additionally, a lower percentage of the area with skin lesions correlated with lower PPIX levels in RBCs.
Collectively, this study demonstrated that oral GlyT1 inhibitor administration decreased PPIX levels in RBCs, resulting in diminished phototoxicity upon light exposure in the EPP mouse model. Overall, these data support the rationale for treating patients with EPP with GlyT1 inhibitors.
mRNA-Laden Lipid-Nanoparticles-Enabled CD19 CAR-T Cells Engineering for the Eradication of Leukemic Cells
Authors: Chen Zhaozhao , Ren Anqi , Shu Jinhui , Li Yingying , Huang Hekuan , Hu Yu , Mei Heng 
Published: December 2024

Objective: With the continuous approval and commercialization of chimeric antigen receptor T cell (CAR-T) products worldwide, CAR-T therapy has emerged as a promising approach for treating malignant tumors. However, these viral-vectors-based CAR-T cells are of close-to-prohibitive manufacturing costs, and the risks of insertional mutagenesis and secondary tumor formation. Messenger RNA (mRNA) delivery through lipid nanoparticles (LNPs) presents a novel strategy to engineer CAR-T cells, potentially reducing production costs and improving treatment-related safety, while maintaining anti-tumor activity. In this study, we developed an innovative approach for engineering CD19 CAR-T cells using mRNA-LNPs, and the anti-leukemic cells effects of CAR-T cells were validated in both in vitro and in vivo settings.
Methods: With microfluidic technology, the mRNA encoding the full humanized anti-CD19 CAR was encapsulated into mRNA-lipid nanoparticles (mRNA-LNPs) and subsequently characterized. We optimized the LNP-based transfection protocol to efficiently deliver mRNA encoding CAR constructs into T cells. The engineered CAR-T cells were then evaluated for their ability to eradicate tumor cells in vitro and in vivo. We evaluated cytokine secretion and cytotoxic activity through co-culture with target cells (Raji cells) in vitro. Furthermore, we introduced mRNA-LNP-engineered CD19 CAR-T cells into NOD-scid-IL2Rγnull (NSG) mice engrafted with Raji-luc cells, and dynamically monitored changes in tumor burden using in vivo bioluminescence imaging.
Results: Our results demonstrate that the size of the mRNA-LNPs is approximately 100 nm, and possess a negative charge, and maintain stability in PBS for 7 days. mRNA-LNPs efficiently transfect T cells, leading to high expression levels of CAR molecules (&gt;70%), and the expression was maintained in vitro for 16 days. Moreover, CAR-T cells engineered using mRNA-LNPs exhibit potent cytotoxicity against tumor cells in vitro, as evidenced by increased tumor cell killing compared to traditional CAR-T cells. Furthermore, in a xenograft mouse model of Raji cells, administration of mRNA-LNP-enabled CAR-T cells resulted in significant tumor regression and prolonged survival period to more than 60 days of treated animals.
Conclusion: This study highlights the potential of mRNA-LNP transfection for CAR-T cell therapy in eradicating tumor cells. The innovative approach described here offers a promising strategy for improving the clinical outcomes of CAR-T cell therapy and advancing the field of cancer immunotherapy.
Outcomes of Acute Promyelocytic Leukemia (APL) during Pregnancy: A Systematic Review of Outcomes
Authors: Bahar Furkan , Ibis Betul , Bozkir Haktan Ovul , Khaddour Karam 
Published: December 2024

Background: Acute promyelocytic leukemia (APL) accounts for 10-15% of all acute myeloid leukemia (AML) cases. It typically presents at a relatively early age when compared to other AML types, around the 40s.The treatment of APL) during pregnancy presents significant challenges, particularly during the first trimester due to the teratogenic effect of all-trans retinoic acid (ATRA). Standard therapy involves a combination of ATRA and arsenic trioxide (ATO), which have shown high efficacy in non-high-risk APL patients. High-risk patients typically receive induction treatment with ATRA and idarubicin (AIDA), followed by consolidation with ATRA and idarubicin/cytarabine or mitoxantrone. This systematic review aims to update the literature on the management outcomes of APL during pregnancy.
Methods: We conducted a comprehensive literature search of the PubMed database, focusing on titles and abstracts. We included case reports, case series, and retrospective cohort studies, while excluding the review articles. We identified 113 patients from 76 studies. We extracted and analyzed data on patient demographics, treatment regimens, and outcomes.
Results: The median age of the patients was 28 years (range 16-41), with a mean gestational age of 25 weeks (range 3-42). 17 patients were in the first trimester, 54 in the second trimester, and 41 in the third trimester, with one case where the trimester was not specified. Regarding induction therapy, 34 patients received ATRA only, with 27 achieving complete remission (CR) (79.41%, CI 95% : 65.83-92.99); 43 received ATRA plus chemotherapy, with 40 achieving CR (93.02%, CI 95% : 85.42-100); 20 received chemotherapy alone, with 16 achieving CR (80%, CI 95% : 62.48-97.52); and 12 received ATO with or without ATRA and/or chemotherapy, with 11 achieving CR (91.67%, CI 95% : 76.01-100). Among the 113 patients, there were 34 abortions: 15 in the first trimester, 16 in the second trimester, 2 in the third trimester, and 1 with an unspecified timing. Seventy-nine patients had deliveries, comprising 45 cesarean sections, 32 vaginal deliveries, and 2 with unspecified methods. Among patients who achieved CR, unintentional abortions occurred in 2 of 16 patients treated with chemotherapy alone, 2 of 27 treated with ATRA alone, 6 of 40 treated with ATRA plus chemotherapy, and 1 of 11 treated with ATO with or without ATRA and/or chemotherapy.
Conclusion: Managing APL during pregnancy, particularly with the advent of ATO, has shown promising outcomes, though first-trimester treatment remains complex due to teratogenic risks. Our systematic review provides updated insight into the efficacy and safety of various treatment regimens, underscoring the necessity for careful monitoring and individualized therapeutic approaches to optimize outcomes for both the mother and fetus. Further research is needed to establish standardized guidelines and improve the management of APL in pregnant patients, ensuring both maternal and fetal safety.