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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 -
Journal of Molecular Neuroscience : MN Feb 2015Cerebral ischemic injury involves a variety of cellular and molecular events. Signal transducers and activators of transcription-1 (STAT-1) activation is associated with...
Cerebral ischemic injury involves a variety of cellular and molecular events. Signal transducers and activators of transcription-1 (STAT-1) activation is associated with neuronal cell death and contributes to ischemic injury. The effects of fludarabine, a specific inhibitor of STAT1 protein, on cerebral ischemic/reperfusion (I/R) injury were studied in a rat model. Rats subjected to I/R injury were either treated with intra-cerebroventricular injection of fludarabine (5,000 μM, 10 μl) or saline 20 min before middle cerebral artery occlusion (MCAO). MR examinations including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI) were performed after I/R period. Then rat brains were sectioned for triphenyltetrazolium chloride (TTC) stains, analyzed by Western blot and TUNEL staining of apoptosis. It was found that fludarabine treatment decreased the infarct volume of the cerebrum and the number of apoptotic neural cells in the ischemic brain. Compared to saline-treated group, the apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) in the ischemic region were greater, and the mean transit time (MTT) was shortened in the fludarabine-treated group. Moreover, fludarabine inhibited the expression level of phosphorylated STAT1 (P-STAT1) in neural cells after I/R injury, whereas the expression of phosphorylated STAT3 (P-STAT3) was increased. Therefore, we concluded that fludarabine administrated in early stage of cerebral ischemia had neuroprotective effects, and the underlying mechanism could be mediated through inhibiting STAT1 phosphorylation and activating the cross regulation between STAT1 and STAT3 in neural cells.
Topics: Animals; Apoptosis; Brain; Infarction, Middle Cerebral Artery; Male; Phosphorylation; Rats; Rats, Sprague-Dawley; STAT1 Transcription Factor; STAT3 Transcription Factor; Vidarabine
PubMed: 24825839
DOI: 10.1007/s12031-014-0320-9 -
Biology of Blood and Marrow... Dec 2014We treated 14 patients with GATA2 deficiency using a nonmyeloablative allogeneic hematopoietic stem cell transplantation regimen. Four patients received peripheral blood... (Clinical Trial)
Clinical Trial
We treated 14 patients with GATA2 deficiency using a nonmyeloablative allogeneic hematopoietic stem cell transplantation regimen. Four patients received peripheral blood stem cells from matched related donors (MRD), 4 patients received peripheral blood stem cells from matched unrelated donors (URD), 4 patients received hematopoietic stem cells from umbilical cord blood donors (UCB), and 2 patients received bone marrow cells from haploidentical related donors. MRD and URD recipients received conditioning with 3 days of fludarabine and 200 cGy total body irradiation (TBI). Haploidentical related donor recipients and UCB recipients received cyclophosphamide and 2 additional days of fludarabine along with 200 cGY TBI. MRD, URD, and UCB recipients received tacrolimus and sirolimus for post-transplantation immunosuppression, whereas haploidentical recipients received high-dose cyclophosphamide followed by tacrolimus and mycophenolate mofetil. Eight patients are alive with reconstitution of the severely deficient monocyte, B cell, and natural killer cell populations and reversal of the clinical phenotype at a median follow-up of 3.5 years. Two patients (1 URD recipient and 1 UCB recipient) rejected the donor graft and 1 MRD recipient relapsed with myelodysplastic syndrome after transplantation. We are currently using a high-dose conditioning regimen with busulfan and fludarabine in patients with GATA2 deficiency to achieve more consistent engraftment and eradication of the malignant myeloid clones.
Topics: Adolescent; Adult; Allografts; Antineoplastic Agents; Bone Marrow Transplantation; Child; Cord Blood Stem Cell Transplantation; Female; Follow-Up Studies; GATA2 Transcription Factor; Genetic Diseases, Inborn; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Tacrolimus; Transplantation Conditioning; Unrelated Donors; Vidarabine; Whole-Body Irradiation
PubMed: 25111582
DOI: 10.1016/j.bbmt.2014.08.004 -
Frontiers of Medicine Feb 2021Post-transplantation cyclophosphamide (PT-Cy) alone or in combination with other immunosuppressive drugs has emerged as a promising strategy in the setting of allogeneic...
Fludarabine and intravenous busulfan conditioning with post-transplantation cyclophosphamide for allogeneic peripheral stem cell transplantation for adult patients with lymphoid malignancies: a prospective single-arm phase II study.
Post-transplantation cyclophosphamide (PT-Cy) alone or in combination with other immunosuppressive drugs has emerged as a promising strategy in the setting of allogeneic hematopoietic stem cell transplantation. Improved survival rate was reported in lymphoid malignancies following PT-Cy strategy compared with myeloid disease in non-myeloablative bone marrow transplant setting. Thus, we aimed to evaluate the safety and efficacy of PT-Cy combined with cyclosporine as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and T cell-replete peripheral stem cell transplantation in lymphoid malignancies. This single-arm phase II clinical trial (NCT01435447) involving 31 adult patients was conducted from January 2013 to June 2018. The donor-type neutrophil engraftment rate was 100%, and the overall incidence of grade II to IV and grade III to IV acute GVHD was 39% and 24%, respectively. The cumulative incidence rates of chronic GVHD (35%), including moderate to severe forms (10%), were reduced compared with those of the historical group (P = 0.03 and P = 0.04, respectively). With a median follow-up of 18 months, the estimated 2-year overall and event-free survival was 64.8% (95% confidence interval: 47.8%-86.7%) and 58.4% (95% CI: 41.9%-81.7%), respectively. The 2-year cumulative incidence rate of relapse was 19.5% (95% CI: 9.0%-35.8%), whereas the non-relapse mortality rate was 21.8% (95% CI: 11.3%-38.1%). These results demonstrated the feasibility of PT-Cy as GVHD prophylaxis in this clinical setting. This strategy could significantly reduce the incidence of chronic GVHD and its moderate to severe forms but not of acute GVHD and results in similar survival outcomes compared with the historical group. A prospective study with additional patients is warranted to confirm the role of PT-Cy in lymphoid malignancy.
Topics: Adult; Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Neoplasms; Peripheral Blood Stem Cell Transplantation; Pharmaceutical Preparations; Prospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 32524356
DOI: 10.1007/s11684-019-0730-8 -
Toxicology and Applied Pharmacology Oct 2018The complex genetic diversity of chronic lymphocytic leukemia (CLL) makes it difficult to determine the effective and durable therapy beneficial to patients. During the...
The complex genetic diversity of chronic lymphocytic leukemia (CLL) makes it difficult to determine the effective and durable therapy beneficial to patients. During the several past years' significant insights in the biology of the disease and its treatment have been made, allowing for the identification of promising novel therapeutic agents. The investigation of signaling pathways to understand the biological character of CLL together with the development of molecular profiling is key in personalized approach in therapy for this disease. As it was already proven, maltotriose (M3) modified fourth generation poly(propylene imine) dendrimers (PPI-G4) modulate BCR, TRAIL and WNT signaling pathway gene expression in CLL cells and strongly influence their survival by inducing apoptosis and inhibiting proliferation. The aim of this study was to evaluate the influence of PPI-G4-M3 dendrimers on NFκB pathway gene expression in CLL (MEC-1) cells with 60 K microarray, as it is one of the major factors in the pathogenesis of B-cell neoplasms. The findings were compared with those obtained with Fludarabine (FA) and the results indicate that PPI-G4-M3 dendrimers affect the expression of the examined genes and exert comparable effect on the CLL cells to FA. Dendrimers are one of the most potent groups of nanometer-sized macromolecules for closing the gap between the present ineffective treatment and the future effective personalized therapy due to their potential versatile biological properties.
Topics: Cell Line, Tumor; Dendrimers; Gene Expression Regulation; Humans; Leukemia, Lymphoid; NF-kappa B; Nanoparticles; Protein Array Analysis; Signal Transduction; Transcriptome; Vidarabine
PubMed: 30125597
DOI: 10.1016/j.taap.2018.08.007 -
Bone Marrow Transplantation Dec 2021Myeloablative conditioning with fludarabine/busulfan (Flu/Bu4) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective for acute myeloid...
Myeloablative conditioning with fludarabine/busulfan (Flu/Bu4) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective for acute myeloid leukemia. However, the effectiveness of Flu/Bu4 for myelodysplastic syndrome (MDS) remains poorly understood. Therefore, we retrospectively analyzed nationwide registry data in Japan from 2006 to 2018 and compared transplant outcomes of adult MDS patients receiving Flu/Bu4 and busulfan/cyclophosphamide (Bu4/Cy) using propensity score (PS) matching. The primary endpoint was overall survival (OS). Among 2,482 MDS patients, 153 patients were assigned each to the Flu/Bu4 and Bu4/Cy groups. The 3-year OS rates were 52.7% (95% confidence interval [CI], 43.8-60.8%) and 49.5% (95% CI, 40.8-57.6%) in the Flu/Bu4 and Bu4/Cy group, respectively (P = 0.548). The 3-year progression-free survival (P = 0.858), the cumulative incidence of relapse (P = 0.536), and cumulative incidence of non-relapse mortality (P = 0.684) were not significantly different between the two groups. According to the findings of subgroup analyses, no patient had a favorable OS when using either of the two regimens. In conclusion, although our PS-matched cohort mainly comprised older patients who had a low hematopoietic cell transplantation-comorbidity index and low-risk disease status, Flu/Bu4 could be an alternative to Bu4/Cy for MDS patients prior to allo-HSCT.
Topics: Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Propensity Score; Retrospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 34489555
DOI: 10.1038/s41409-021-01447-y -
Scientific Data May 2020Acquired resistance to chemotherapy is an important clinical problem and can also occur without detectable cytogenetic aberrations or gene mutations. Chronic lymphocytic...
Acquired resistance to chemotherapy is an important clinical problem and can also occur without detectable cytogenetic aberrations or gene mutations. Chronic lymphocytic leukemia (CLL) is molecularly well characterized and has been elemental for establishing central paradigms in oncology. This prompted us to check whether specific epigenetic changes at the level of DNA methylation might underlie development of treatment resistance. We used Illumina Infinium HumanMethylation450 BeadChips to obtain DNA methylation profiles of 71 CLL patients with differential responses. Thirty-six patients were categorized as relapsed/refractory after treatment with fludarabine or bendamustine and 21 of them had genetic aberrations of TP53. The other 35 patients were untreated at the time of sampling and 15 of them had genetic aberration of TP53. Although we could not correlate chemoresistance with epigenetic changes, the patients were comprehensively characterized regarding relevant prognostic and molecular markers (e.g. IGHV mutation status, chromosome aberrations, TP53 mutation status, clinical parameters), which makes our dataset a unique and valuable resource that can be used by researchers to test alternative hypotheses.
Topics: Bendamustine Hydrochloride; DNA Methylation; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Tumor Suppressor Protein p53; Vidarabine
PubMed: 32358561
DOI: 10.1038/s41597-020-0456-0 -
Leukemia Research Nov 2021Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown to induce apoptosis in many types of cancer cells. In this study, we aimed to...
INTRODUCTION
Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown to induce apoptosis in many types of cancer cells. In this study, we aimed to determine the effects of DHA on apoptosis in human chronic lymphocytic leukemia (CLL) cell lines.
METHODS
The cells were treated separately and combined by DHA and Fludurabine (FLU) during 24, 48 and 72 hours. The cell viabilities determined by XTT method. Following separate and combined treatment of IC50 concentrations of DHA and FLU to the cells during 24 hours, the cells were analyzed by flow cytometry to determine the effects on apopotis staining with AnnexinV FITC and PI. mRNA and protein expression levels of TCTP, Mcl-1, Bcl-2, Bax and Caspase-3 were analyzed to find out the molecular mechanisms of apoptosis by using quantitative real-time PCR and flow cytometric methods.
RESULTS
Treatment with DHA alone or in combination with FLU induced apoptosis in a dose dependent manner in CLL cells. DHA alone was more effective than FLU alone or combined treatment with DHA and FLU. Our results suggest that Bcl-2 protein family member Bax was active in the apoptotic response of CLL cells after DHA treatment. Moreover, the apoptotic response induced by DHA was independent from the p53 mutation status of the CLL cells.
CONCLUSION
DHA might be a potential anti-cancer therapeutic for CLL.
Topics: Antimalarials; Antineoplastic Agents; Apoptosis; Artemisinins; Biomarkers; Cell Proliferation; Drug Therapy, Combination; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Tumor Cells, Cultured; Tumor Protein, Translationally-Controlled 1; Vidarabine
PubMed: 34571432
DOI: 10.1016/j.leukres.2021.106702 -
Leukemia & Lymphoma Apr 2018Fludarabine and melphalan (Flu/Mel) has emerged as a more tolerable chemotherapy-based conditioning regimen compared with busulfan and cyclophosphamide (Bu/Cy) for... (Comparative Study)
Comparative Study
Myeloablative busulfan/cytoxan conditioning versus reduced-intensity fludarabine/melphalan conditioning for allogeneic hematopoietic stem cell transplant in patients with acute myelogenous leukemia.
Fludarabine and melphalan (Flu/Mel) has emerged as a more tolerable chemotherapy-based conditioning regimen compared with busulfan and cyclophosphamide (Bu/Cy) for allogeneic stem cell transplant (allo-hematopoietic stem cell transplantation (HSCT)) patients with acute myelogenous leukemia (AML). We conducted a retrospective review of a single-institution database including patients with AML who received allo-HSCT following conditioning with Mel/Flu or Bu/Cy-based regimens. We performed descriptive statistical analysis to examine patient demographics and clinical outcomes. We identified 156 patients meeting criteria between 2005 and 2014. Overall, patients conditioned with Bu/Cy were significantly younger, but more likely to be treated in an earlier era than those receiving Flu/Mel. Regimen choice was not associated with relapse rates (RR), relapse-free survival (RFS), or overall survival (OS) on both univariate and multivariable analyses. Bu/Cy was associated with increased non-relapse mortality (NRM) on multivariable analysis. These findings demonstrate that Flu/Mel provides non-inferior disease control and could be an appropriate regimen for selected patients.
Topics: Adult; Age Factors; Busulfan; Cyclophosphamide; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myeloablative Agonists; Patient Selection; Retrospective Studies; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine
PubMed: 28782395
DOI: 10.1080/10428194.2017.1361027 -
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