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Leukemia Nov 2023Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, the prognosis of which varies according to the cytogenetic group. We characterized a rare chromosomal...
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, the prognosis of which varies according to the cytogenetic group. We characterized a rare chromosomal abnormality (del(8p), deletion of the short arm of chromosome 8) in the context of CLL. By comparing the largest cohort of del(8p) CLL to date (n = 57) with a non-del(8p) cohort (n = 155), del(8p) was significantly associated with a poor prognosis, a shorter time to first treatment, worse overall survival (OS), and a higher risk of Richter transformation. For patients treated with fludarabine-based regimens, the next-treatment-free survival and the OS were shorter in del(8p) cases (including those with mutated IGHV). One copy of the TNFRSF10B gene (coding a pro-apoptotic receptor activated by TRAIL) was lost in 91% of del(8p) CLL. TNFRSF10B was haploinsufficient in del(8p) CLL, and was involved in the modulation of fludarabine-induced cell death - as confirmed by our experiments in primary cells and in CRISPR-edited TNFRSF10B knock-out CLL cell lines. Lastly, del(8p) abrogated the synergy between fludarabine and TRAIL-induced apoptosis. Our results highlight del(8p)'s value as a prognostic marker and suggest that fit CLL patients (i.e. with mutated IGHV and no TP53 disruption) should be screened for del(8p) before the initiation of fludarabine-based treatment.
Topics: Humans; Chromosome Aberrations; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Prognosis; Receptors, TNF-Related Apoptosis-Inducing Ligand; Vidarabine
PubMed: 37752286
DOI: 10.1038/s41375-023-02035-3 -
Heliyon Nov 2023Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, which is distinguished by the loss of dopaminergic (DA) neurons in the...
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, which is distinguished by the loss of dopaminergic (DA) neurons in the substantia nigra and the formation of intraneuronal. Numerous studies showed that the damage and dysfunction of mitochondria may play key roles in DA neuronal loss. Thus, it is necessary to seek therapeutic measures for PD targeting mitochondrial function and biogenesis. In this study, through screening the purchased compound library, we found that marine derived vidarabine had significant neuroprotective effects against rotenone (ROT) induced SH-SY5Y cell injury. Further studies indicated that vidarabine pretreatment significantly protected ROT-treated SH-SY5Y cells from toxicity by preserving mitochondrial morphology, improving mitochondrial function, and reducing cell apoptosis. Vidarabine also reduced the oxidative stress and increased the expression levels of PGC-1α, NRF1, and TFAM proteins, which was accompanied by the increased mitochondrial biogenesis. However, the neuroprotective effects of vidarabine were counteracted in the presence of SIRT1-specific inhibitor Ex-527. Besides, vidarabine treatment attenuated the weight loss, alleviated the motor deficits and inhibited the neuronal injury in the MPTP induced mouse model. Thus, vidarabine may exert neuroprotective effects via a mechanism involving specific connections between the SIRT1-dependent mitochondrial biogenesis and its antioxidant capacity, suggesting that vidarabine has potential to be developed into a novel therapeutic agent for PD.
PubMed: 38027872
DOI: 10.1016/j.heliyon.2023.e21695 -
Nature Cancer Jun 2024In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR...
In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 10 T cells per m after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 10 CAR T cells per m after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1-2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3-4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044 .
Topics: Humans; Sarcoma; Middle Aged; Female; Male; Receptor, ErbB-2; Adult; Immunotherapy, Adoptive; Aged; Receptors, Chimeric Antigen; T-Lymphocytes; Lymphocyte Depletion; Prospective Studies; Vidarabine; Cyclophosphamide; Treatment Outcome
PubMed: 38658775
DOI: 10.1038/s43018-024-00749-6 -
Bone Marrow Transplantation Sep 2023
Treosulfan, thiotepa and fludarabine conditioning regimen prior to first allogeneic stem cell transplantation in acute myeloid leukemia and high-risk myelodysplastic syndromes: a single center experience.
Topics: Humans; Thiotepa; Busulfan; Hematopoietic Stem Cell Transplantation; Vidarabine; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37355712
DOI: 10.1038/s41409-023-02023-2 -
Bone Marrow Transplantation Jan 2024Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This... (Randomized Controlled Trial)
Randomized Controlled Trial
Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This prospective, randomized, phase 2 trial compared safety and efficacy of busulfan with treosulfan based preparative regimens. Children with non-malignant diseases received fludarabine and either intravenous (IV) busulfan (4.8 to 3.2 mg/kg/day) or IV treosulfan (10, 12, or 14 g/m/day). Thiotepa administration (2 × 5 mg/kg) was at the investigator's discretion. Primary endpoint was freedom from transplantation (treatment)-related mortality (freedom from TRM), defined as death between Days -7 and +100. Overall, 101 patients (busulfan 50, treosulfan 51) with at least 12 months follow-up were analyzed. Freedom from TRM was 90.0% (95% CI: 78.2%, 96.7%) after busulfan and 100.0% (95% CI: 93.0%, 100.0%) after treosulfan. Secondary outcomes (transplantation-related mortality [12.0% versus 3.9%]) and overall survival (88.0% versus 96.1%) favored treosulfan. Graft failure was more common after treosulfan (n = 11), than after busulfan (n = 2) while all patients were rescued by second procedures except one busulfan patient. CTCAE Grade III adverse events were similar in both groups. This study confirmed treosulfan to be an excellent alternative to busulfan and can be safely used for conditioning treatment in children with non-malignant disease.
Topics: Child; Humans; Busulfan; Prospective Studies; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation; Vidarabine; Graft vs Host Disease
PubMed: 37925531
DOI: 10.1038/s41409-023-02135-9 -
American Journal of Hematology Feb 2024Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood...
Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry-based study aimed to analyze the impact of five fludarabine-containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100-140 mg/m ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3-year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2-2.2); FB4M, 2.1 (95% CI, 1.6-2.8); FB4T, 2.7 (95% CI, 2.0-3.7); and FB2T, 2.2 (95% CI, 1.6-3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non-relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan-based conditioning, FM140T may be the preferred regimen.
Topics: Adult; Humans; Middle Aged; Busulfan; Melphalan; Retrospective Studies; Cord Blood Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Vidarabine; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Recurrence; Graft vs Host Disease; Transplantation Conditioning
PubMed: 38165068
DOI: 10.1002/ajh.27172 -
Blood Advances Feb 2024We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed...
We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2-year ibrutinib maintenance (I-M) in treatment-naïve chronic lymphocytic leukemia (CLL). Here, we report updated data from this phase 2 study with a median follow-up of 63 months. Of 85 patients enrolled, including 5 (6%) with deletion 17p or TP53 mutation, 91% completed iFCR and 2-year I-M. Five-year progression-free survival (PFS) and overall survival were 94% (95% confidence interval [CI], 89%-100%) and 99% (95% CI, 96%-100%), respectively. No additional deaths have occurred with this extended follow-up. No difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of I-M. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year I-M, and 44% at 4.5 years from treatment initiation). Thirteen patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. None had Bruton tyrosine kinase (BTK) mutations. One patient had PLCG2 mutation. Six of these patients underwent ibrutinib retreatment per protocol. Median time on ibrutinib retreatment was 34 months. The cumulative incidence of atrial fibrillation was 8%. Second malignancy or nonmalignant hematologic disease occurred in 13%, mostly nonmelanoma skin cancer. Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. This trial is registered at www.clinicaltrials.gov as #NCT02251548.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Follow-Up Studies; Treatment Outcome; Cyclophosphamide; Adenine; Piperidines; Vidarabine
PubMed: 38163317
DOI: 10.1182/bloodadvances.2023011574 -
The Lancet. Oncology Jun 2024In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.
BACKGROUND
In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available.
METHODS
GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m, days 1-3) and intravenous cyclophosphamide (250 mg/m, days 1-3). Intravenous rituximab (375 mg/m, day 1 of cycle 1; 500 mg/m, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m, day 1 of cycle 1; 500 mg/m, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment.
FINDINGS
Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy).
INTERPRETATION
With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination.
FUNDING
AbbVie, Janssen, and F Hoffmann-La Roche.
Topics: Humans; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Female; Aged; Middle Aged; Follow-Up Studies; Piperidines; Vidarabine; Rituximab; Adenine; Antibodies, Monoclonal, Humanized; Progression-Free Survival; Cyclophosphamide; Pyrazoles; Pyrimidines; Immunotherapy; Adult
PubMed: 38821083
DOI: 10.1016/S1470-2045(24)00196-7 -
Bone Marrow Transplantation May 2024A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen... (Comparative Study)
Comparative Study Randomized Controlled Trial
A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.
Topics: Humans; Busulfan; Vidarabine; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Cyclophosphamide; Aged; Middle Aged; Transplantation Conditioning; Female; Male; Registries; Melphalan; Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation
PubMed: 38383713
DOI: 10.1038/s41409-024-02241-2 -
Radiation Research Mar 2024The objective of this study is to investigate the impact of fludarabine, a signal transducer and activator of transcription-1 (STAT1) inhibitor, on the radiosensitivity...
The objective of this study is to investigate the impact of fludarabine, a signal transducer and activator of transcription-1 (STAT1) inhibitor, on the radiosensitivity of B-cell lymphoma (BCL) and to explore the underlying mechanisms. Radiotherapy is one of the primary treatments for BCL, and STAT1 plays a critical role in the transcription of cell proliferation-related genes, which are associated with radiotherapy and ferroptosis. This study aims to determine whether fludarabine can enhance the radiosensitivity of BCL and to elucidate the molecular pathways involved. Various in vitro methodologies, including CCK-8 assays, clonogenic formation assays, immunohistochemistry, immunofluorescence, flow cytometry, qRT-PCR, and Western blot analyses, were employed in B-cell lymphoma cell models to thoroughly investigate the effects of fludarabine on radiosensitivity. Subsequently, the obtained results were further validated through in vivo animal models and by examining human diffuse large B-cell lymphoma (DLBCL) cancer samples. Our findings demonstrate that the combination of fludarabine and irradiation synergistically inhibits cell viability and colony formation, while inducing apoptosis and ferroptosis in B-cell lymphoma cell lines Raji and Su-DHL-10. Moreover, fludarabine was found to enhance the ferroptosis induced by radiation, thereby synergistically impeding the growth of BCL. In vivo experiments confirmed these findings, revealing that the intraperitoneal injection of fludarabine significantly enhanced the inhibitory effects of radiation on Raji cell xenograft models, leading to an increased percentage of ferroptosis compared to models without fludarabine. Additionally, the administration of liproxstatin-1, a ferroptosis inhibitor, attenuated the inhibition of xenograft growth caused by the combination of fludarabine and irradiation. Furthermore, our analysis of clinical data revealed that increased co-expression of STAT1 and GPX4 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. These results highlight the potential of fludarabine to enhance radiosensitivity and ferroptosis induction as a promising therapeutic strategy for BCL. Our results demonstrated that fludarabine promoted radiation-induced BCL death through the ferroptosis pathway. We have identified a previously unrecognized mechanism in the fludarabine and radiation combination, indicating that it is necessary to conduct prospective clinical trials to verify this new treatment regimen in BCL.
Topics: Animals; Humans; Ferroptosis; Prospective Studies; Cell Line, Tumor; Radiation Tolerance; Apoptosis; Lymphoma, Large B-Cell, Diffuse; Vidarabine
PubMed: 38235545
DOI: 10.1667/RADE-23-00018.1