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Leukemia Mar 2022Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have... (Clinical Trial)
Clinical Trial
Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results in treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naive and central memory CD4 T cells and naive CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs, and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity.
Topics: Antineoplastic Combined Chemotherapy Protocols; Autoimmunity; Cyclophosphamide; Cytokines; Humans; Inflammation; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Activation; Middle Aged; Phosphoinositide-3 Kinase Inhibitors; Purines; Rituximab; T-Lymphocytes; Vidarabine
PubMed: 34743191
DOI: 10.1038/s41375-021-01441-9 -
Bone Marrow Transplantation Feb 2022We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4...
We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4 days), fludarabine (Flu, 120 [n = 23] or 250 [n = 17] mg/m) and thymoglobulin (THY). Compared to 95 patients conditioned with Bu/Cyclophosphamide (Cy) without THY, BuFluTHY-conditioned patients had lower rates of chronic graft-vs.-host disease (GVHD). Adjusted hazard ratios (HR) for BuFlu(120)THY and BuFlu(250)THY-conditioned patients were 1.60 (95% confidence interval (CI) 0.66-3.86) and 1.87 (0.68-5.11), respectively, for relapse; 0.77 (0.30-1.99) and 1.32 (0.54-3.23) for non-relapse mortality; 0.81 (0.42-1.57) and 1.38 (0.72-2.57) for overall mortality; and 0.78 (0.30-2.05) and 1.62 (0.63-4.41) for relapse or death (failure for relapse-free survival). At one year, 45% of BuFlu(120 or 250)THY-conditioned patients had mixed CD3+ chimerism compared to 0% with BuCy (p < 0.0001). None of 7 patients with long-term mixed chimerism had chronic GVHD; two relapsed, five remained stable mixed chimeras. THY is effective in reducing chronic GVHD, and long-term mixed T-cell chimerism can be compatible with relapse-free survival. However, Thy may also be associated with an increased risk of relapse and, dose-dependent, with non-relapse mortality.
Topics: Antilymphocyte Serum; Busulfan; Chimerism; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Neoplasm Recurrence, Local; Transplantation Conditioning; Vidarabine
PubMed: 34741096
DOI: 10.1038/s41409-021-01518-0 -
Molecules (Basel, Switzerland) Oct 2021In continuation of our previous effort, different selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before....
In continuation of our previous effort, different selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against preferred compounds , , , , , , , , , , , , and . The docking studies picked , , , , and . While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds and . Finally, a density-functional theory (DFT) study suggested vidarabine () to be the most relevant SARS-Cov-2 nsp10 inhibitor.
Topics: Antiviral Agents; Binding Sites; Biological Products; COVID-19; Density Functional Theory; Humans; Ligands; Molecular Docking Simulation; S-Adenosylmethionine; SARS-CoV-2; Small Molecule Libraries; Vidarabine; Viral Regulatory and Accessory Proteins; COVID-19 Drug Treatment
PubMed: 34684735
DOI: 10.3390/molecules26206151 -
Journal of Cancer Research and Clinical... Oct 2022Treosulfan and fludarabine (Treo/Flu) were successfully introduced into toxicity-reduced conditioning for SCT. However, the risk of post-SCT relapse remains a matter of...
PURPOSE
Treosulfan and fludarabine (Treo/Flu) were successfully introduced into toxicity-reduced conditioning for SCT. However, the risk of post-SCT relapse remains a matter of concern. We report the results of a novel individual treatment approach with Treo/Flu and cytarabine (Treo/Flu/AraC) conditioning prior to allogeneic SCT in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasms (MPN).
METHODS
Seventy-seven patients (median age 54 years) at high risk of disease relapse due to unfavorable cytogenetics or failure to achieve complete remission prior to SCT were included. Median follow-up was 3.2 years.
RESULTS
The 1-, 2- and 3-year RFS rates were 49.4%, 41.7%, and 37.6% and OS rates were 59.3%, 49.3%, and 45.4%, respectively. Cumulative incidence of NRM was 10% at 100 days, 18.8% at 1 year and 20.1% at 2 years. The cumulative incidence of relapse increased from 31% at 1 year to 38.5% after 3 years. The cumulative incidences of engraftment, chimerism, graft-versus-host disease (GvHD) and toxicities were acceptable and comparable with similar patients conditioned with Treo/Flu or FLAMSA-RIC.
CONCLUSION
In conclusion, Treo/Flu/AraC provides tolerable, feasible, and effective conditioning for patients with AML, MDS or MPN, even in advanced disease states. The incidence of NRM and relapse is acceptable in this heavily pre-treated population with high-risk disease. Future research will aim to confirm these initial findings and include a larger number of participants in a prospective trial.
Topics: Busulfan; Cytarabine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Myeloproliferative Disorders; Recurrence; Retrospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 34674031
DOI: 10.1007/s00432-021-03836-8 -
Blood Advances Dec 2021Adding the selective BCL-2 inhibitor venetoclax to reduced-intensity conditioning chemotherapy (fludarabine and busulfan [FluBu2]) may enhance antileukemic cytotoxicity... (Clinical Trial)
Clinical Trial
Adding the selective BCL-2 inhibitor venetoclax to reduced-intensity conditioning chemotherapy (fludarabine and busulfan [FluBu2]) may enhance antileukemic cytotoxicity and thereby reduce the risk of posttransplant relapse. This phase 1 study investigated the recommended phase 2 dose (RP2D) of venetoclax, a BCL-2 selective inhibitor, when added to FluBu2 in adult patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and MDS/myeloproliferative neoplasms (MPN) undergoing transplant. Patients received dose-escalated venetoclax (200-400 mg daily starting day -8 for 6-7 doses) in combination with fludarabine 30 mg/m2 per day for 4 doses and busulfan 0.8 mg/kg twice daily for 8 doses on day -5 to day -2 (FluBu2). Transplant related-toxicity was evaluated from the first venetoclax dose on day -8 to day 28. Twenty-two patients were treated. At study entry, 5 patients with MDS and MDS/MPN had 5% to 10% marrow blasts, and 18 (82%) of 22 had a persistent detectable mutation. Grade 3 adverse events included mucositis, diarrhea, and liver transaminitis (n = 3 each). Neutrophil/platelet recovery and acute/chronic graft-versus-host-disease rates were similar to those of standard FluBu2. No dose-limiting toxicities were observed. The RP2D of venetoclax was 400 mg daily for 7 doses. With a median follow-up of 14.7 months (range, 8.6-24.8 months), median overall survival was not reached, and progression-free survival was 12.2 months (95% confidence interval, 6.0-not estimable). In patients with high-risk AML, MDS, and MDS/MPN, adding venetoclax to FluBu2 was feasible and safe. To further address relapse risk, assessment of maintenance therapy after venetoclax plus FluBu2 transplant is ongoing. This study was registered at clinicaltrials.gov as #NCT03613532.
Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Sulfonamides; Transplantation, Homologous; Vidarabine
PubMed: 34614506
DOI: 10.1182/bloodadvances.2021005566 -
Journal of Cancer Research and Clinical... Sep 2022Curative intended treatment is challenging in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and associated with a dismal prognosis for long-term...
PURPOSE
Curative intended treatment is challenging in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and associated with a dismal prognosis for long-term survival. Despite novel treatment options, the majority of patients are treated with chemotherapy-based regimens. Although widely used, little data exist on the combination of fludarabine, cytarabine, granulocyte colony stimulating factor (FLAG) and mitoxantrone as salvage strategy for r/r AML.
MATERIALS AND METHODS
Sixty-six patients receiving Mito-FLAG for r/r AML treated at a German tertiary care center between 2009 and 2019 were analyzed with regard to response rates, survival and safety profile.
RESULTS
Overall response rate was 75.8% with 56.1% of patients achieving complete remission (CR) and 19.7% partial remission (PR). After a median follow-up of 54 months, median overall survival (OS) was 13 months. Patients transitioned to allogeneic hematopoietic stem cell transplantation (alloHSCT) (75.8%) showed a significant improvement in OS with a median OS of 17 (95% CI 8.5-25.4) months vs 3 (95% CI 1.7-4.3) months (p < 0.001). 30- and 60-day mortality rates for all patients after the initial cycle of Mito-FLAG were 4.5% and 7.6%, respectively.
CONCLUSION
The Mito-FLAG salvage protocol represents an effective and feasible treatment regimen for r/r AML. Importantly, a high rate of transition to successful alloHSCT with the aim of long-term disease-free survival has been shown.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Mitoxantrone; Prognosis; Remission Induction; Salvage Therapy; Treatment Outcome; Vidarabine
PubMed: 34609595
DOI: 10.1007/s00432-021-03821-1 -
British Journal of Haematology Nov 2021Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma...
Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel-related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 10 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.
Topics: Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal, Humanized; Biological Products; Biomarkers; Cyclophosphamide; Cytokine Release Syndrome; Drug Therapy, Combination; Female; Humans; Immunotherapy, Adoptive; Leukapheresis; Levetiracetam; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Nervous System Diseases; Neutropenia; Propensity Score; Vidarabine; Young Adult
PubMed: 34590303
DOI: 10.1111/bjh.17673 -
PloS One 2021Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly...
Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; DNA Mutational Analysis; Female; Gene Expression Regulation, Leukemic; Genomics; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; RNA Splicing; Rituximab; Vidarabine
PubMed: 34506616
DOI: 10.1371/journal.pone.0257353 -
Blood Feb 2022The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important...
The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Myelopoiesis; Myeloproliferative Disorders; Neoplasms, Second Primary; Sulfonamides; Vidarabine; bcl-2-Associated X Protein
PubMed: 34469514
DOI: 10.1182/blood.2021012775 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Jul 2021To investigate the efficacy of fludarabine and cyclophosphamide combined with rituximab (FCR) in previously untreated patients with chronic lymphocytic leukemia (CLL) ....
To investigate the efficacy of fludarabine and cyclophosphamide combined with rituximab (FCR) in previously untreated patients with chronic lymphocytic leukemia (CLL) . The clinical data of 43 enrolled patients from May 2004 to December 2017 were analyzed the efficacy and survival results. A total of 43 patients with 31 males and 12 females, and the median age was 58 years old (range 36 to72) before treatment. There were 8 patients with symptom B. The median number of peripheral blood lymphocyte was 26 (3-550) ×10(9)/L. IGHV unmutated was detected in 62.1% (18/29) patients, P53 deletion in 14% (6/43) patients, RB1 deletion in 18.6% (8/43) patients, Trisomy 12 in 25.6% (11/33) patients, ATM deletion in 16.7% (7/42) patients, respectively. The median number of treatment courses administered was 4 (range 2-6) . Twenty patients obtained CR (46.5%) , 18 patients obtained PR, 4 patients were SD, 1 patient was PD. The overall response rate (ORR) was 88.37%. Seven patients obtained MRD negative. After the median follow-up time of 51 (6-167) months, median PFS was 67 (29-105) months, median OS was not reach, 5-year PFS was (62.1±8.6) %, 10-year PFS was (31±14.3) %, 5-year OS was (70.5±8.3) %, and 10-year OS was (51.3±13.8) %. Less than 4 courses predicted adverse OS (<0.05) . P53 deletion and less than 4 courses were associated with poor PFS (<0.001) , and the prognostic value still remained after multivariate analysis[=7.65 (95% 1.74-33.60) , =0.007; =3.75 (95% 1.19-11.80) , =0.025]. Eighteen patients (41.9%) appeared grade 2-3 infection after chemotherapy, and 19 patients (44.2%) appeared grade 3-4 hematological adverse reactions. One patient (2.3%) was developed tumor lysis syndrome. All adverse reactions were controlled or recovered spontaneously. Previously untreated CLL patients treated with FCR had a high response rate and good survival rate, which is an important treatment choice for fit patients.
Topics: Adult; Cyclophosphamide; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Rituximab; Vidarabine
PubMed: 34455740
DOI: 10.3760/cma.j.issn.0253-2727.2021.07.003