ABSTRACT
In order to improve the outcome observed with azacitidine (AZA) in higher-risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA-PLUS was a phase II trial that, in a "pick a winner" approach, randomly assigned patients with higher-risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six cycles, 69 (21.4%) CR + PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7 months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six cycles were higher in the AZA-LEN And AZA-IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy-related MDS and, in the case of TP53, PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our "pick a winner" randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Azacitidine , Leukemia, Myeloid, Acute , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azacitidine/therapeutic use , Humans , Idarubicin/therapeutic use , Lenalidomide/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation , Treatment Outcome , Valproic Acid/therapeutic useABSTRACT
High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response (P=0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high (P=0.03) primary versus secondary azacitidine failure (P=0.01) and a high rate of demethylation in blood during the first cycle of treatment (P=0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered at clinicaltrials.gov identifier: 02197676).
Subject(s)
Azacitidine/analogs & derivatives , Azacitidine/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Myelodysplastic Syndromes/drug therapy , Aged , Female , Humans , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/mortality , Risk , Survival Analysis , Treatment OutcomeABSTRACT
OBJECTIVES: To assess the reduction of transfusions rate in transfusion-dependent patients with low-risk myelodysplastic syndrome (MDS) with iron overload treated with deferasirox. METHODS: Prospective observational study. Primary endpoint was reduction in transfusion requirements (RTR) at 3 months, (assessed on 8-week period). Secondary endpoints were hematologic improvement according to International Working Group (IWG) 2006 criteria at 3, 6, and 12 months. RESULTS: Fifty-seven patients were evaluable. After 3 months of chelation, no effect was seen on transfusion requirement (5.9 packed red blood cells (PRBC) vs 5.8 before chelation). According to the Kaplan-Meier analysis, the probability of RTR at 3, 6, and 12 months was assessed as 3.5%, 9.1%, and 18.7%, respectively. Median duration of RTR was 182 days. However, during the 12-month follow-up after deferasirox initiation, 17 patients (31.5%) achieved minor erythroid response [HI-E] according to IWG criteria, 10 of whom having achieved Hb improvement at month 12. CONCLUSION: After 3 months of treatment, deferasirox had no impact on transfusion requirement in regularly transfused patients with low-risk MDS. However, deferasirox could induce 31% of erythroid response during the 12-month follow-up period thus suggesting that iron chelation therapy with deferasirox may induce an effect on hematopoiesis in a subset of patients with MDS and iron overload.
ABSTRACT
Acute myeloid leukemia is driven by leukemic stem cells which can be identified by cross lineage expression or arrest of differentiation compared to normal hematopoietic stem cells. Self-renewal and lack of differentiation are also features of stem cells and have been associated with the expression of embryonic genes. The aim of our study was to evaluate the expression of embryonic antigens (OCT4, NANOG, SOX2, SSEA1, SSEA3) in hematopoietic stem cell subsets (CD34+CD38- and CD34+CD38+) from normal bone marrows and in samples from acute myeloid leukemia patients. We observed an upregulation of the transcription factors OCT4 and SOX2 in leukemic cells as compared to normal cells. Conversely, SSEA1 protein was downregulated in leukemic cells. The expression of OCT4, SOX2, and SSEA3 was higher in CD34+CD38- than in CD34+CD38+ subsets in leukemic cells. There was no correlation with biological characteristics of the leukemia. We evaluated the prognostic value of marker expression in 69 patients who received an intensive treatment. The rate of complete remission was not influenced by the level of expression of markers. Overall survival was significantly better for patients with high SOX2 levels, which was unexpected because of the inverse correlation with favorable genetic subtypes. These results prompt us to evaluate the potential role of these markers in leukemogenesis and to test their relevance for better leukemic stem cell identification.
Subject(s)
Biomarkers, Tumor/biosynthesis , Fucosyltransferases/biosynthesis , Leukemia, Myeloid, Acute/drug therapy , Lewis X Antigen/biosynthesis , Octamer Transcription Factor-3/biosynthesis , SOXB1 Transcription Factors/biosynthesis , ADP-ribosyl Cyclase 1/genetics , Adult , Aged , Antigens, CD34/genetics , Bone Marrow Cells/metabolism , Cell Differentiation/genetics , Embryonic Stem Cells/metabolism , Embryonic Stem Cells/pathology , Female , Flow Cytometry , Gene Expression Regulation, Neoplastic/drug effects , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/pathology , Humans , Immunophenotyping , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , PrognosisABSTRACT
Patients with acute myeloblastic leukemia or higher risk myelodysplastic syndromes with 5q deletion (generally within a complex karyotype) respond poorly to intensive chemotherapy and have very poor survival. In this population, we evaluated escalating doses of lenalidomide combined with intensive chemotherapy in a phase II study. Treatment consisted of daunorubicin (45 mg/m2/day, days 1-3 in cohort 1, escalated to 60 mg/m2/day, days 1-3 in cohorts 2 and 3) combined with cytosine arabinoside (200 mg/m2/day, days 1-7) and lenalidomide (10 mg/day, days 1-21 in cohorts 1 and 2, escalated to 25 mg/day, days 1-21 in cohort 3). Eighty-two patients with 5q deletion were enrolled, including 62 with acute myeloblastic leukemia, 62/79 (78%) of whom had a complex karyotype (median 7 cytogenetic abnormalities, all but 2 of them monosomal) and three had unknown karyotypes. Thirty-eight patients (46%) achieved complete remission and the overall response rate was 58.5%. Among the 62 patients with a complex karyotype, 27 achieved complete remission (44%) and 21 had cytogenetic responses. A lower response rate was observed in patients with acute myeloblastic leukemia but other pretreatment factors, including cytogenetic complexity and treatment cohort, did not significantly influence response. Fifteen patients underwent allogeneic stem cell transplantation, including 11 patients in first remission. The 1-year cumulative incidence of relapse was 64.6% and the median overall survival was 8.2 months. By comparison with conventional intensive chemotherapy, the treatment protocol we used appeared to produce higher hematologic and cytogenetic complete remission rates in patients with very poor cytogenetics, but response duration was short in this very poor risk population, highlighting the need for better post-induction strategies. Clinical trial registry number: NCT00885508.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chromosome Deletion , Chromosomes, Human, Pair 5 , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Humans , Lenalidomide , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/mortality , Prognosis , Thalidomide/administration & dosage , Thalidomide/analogs & derivatives , Treatment OutcomeABSTRACT
Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Herein, we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy. Median age was 55.3 years. Diagnostic was secondary AML for 33% of them. Seven patients had favorable risk, 8 had intermediate-1 or intermediate-2, and 6 had unfavorable risk of AML according to the European LeukemiaNet prognostic index. Complete remission was achieved in 50% of cases (46% in refractory and 55% in relapsed AML) without excessive toxicity. Thirteen patients could be referred for transplant. Only allogeneic hematopoietic stem cell transplantation provided a benefit in this patient cohort with a 1-year overall survival of 50.7 versus 18.1% in the absence of transplantation. Patients treated with reduced intensity conditioning (RIC) showed a longer survival as compared to those undergoing myeloablative conditioning regimen mainly because of decreased toxicity.Our data suggest that salvage therapy with fractionated GO combined with intermediate-dose cytarabine and daunorubicin in very high-risk patients may serve as a potential bridge therapy to RIC transplant.
Subject(s)
Aminoglycosides/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cytarabine/administration & dosage , Daunorubicin/administration & dosage , Leukemia, Myeloid, Acute/therapy , Salvage Therapy/methods , Transplantation Conditioning/methods , Adult , Aged , Cohort Studies , Female , Gemtuzumab , Hematopoietic Stem Cell Transplantation/methods , Humans , Leukemia, Myeloid, Acute/diagnosis , Male , Middle Aged , Retrospective Studies , Risk Factors , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: Little data exist regarding long-term survival in elderly patients with acute myeloid leukemia (AML). METHODS: In view of the fact that most deaths occurred during the first 3 yr, this study examined long-term survival in this patient population, defined as overall survival for at least 3 yr with the aim to determine the number of long-term survivors and to identify factors that might impact on longer survival. RESULTS: The criterion for entry into this cohort was fulfilled by 57 patients among 302 seen over a 14-yr period (19%): 12 patients who never achieved complete remission (CR), 21 patients who relapsed after CR achievement, and 24 patients who achieved CR and did not relapse, including three patients who died while in CR and 21 patients still alive in first CR at the time of analysis. The pretreatment prognostic importance of cytogenetics was still apparent. However, some patients with secondary AML and/or unfavorable-risk markers belonged to long survivors. The cohort involved mainly patients treated by intensive chemotherapy, but also some patients receiving low-intensity therapies. CONCLUSION: Improved results should come from a better selection of patients to a more 'personalized' therapeutic approach combined with better supportive care assessment.
Subject(s)
Leukemia, Myeloid, Acute/epidemiology , Survivors , Age Factors , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/pathology , Female , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Population Surveillance , Remission Induction , Retreatment , Treatment OutcomeABSTRACT
After allogeneic hematopoietic stem cell transplantation (HSCT), BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication. Although supportive measures have been the standard of care for many years, several studies suggested the efficacy of cidofovir. The aim of this study was to assess the safety profile and efficacy of cidofovir. A retrospective study was conducted on all patients treated with cidofovir in our HSCT unit between March 2011 and May 2013. Data for efficacy (partial [PR] or complete response [CR]), prescription (dose, frequency, number of doses, and administration route), and toxicity were collected from published reports and medical files. Renal toxicity was evaluated using creatinine clearance calculated with the Cockcroft and Gault formula. A parallel literature search using PubMed (last search, May 2015) was performed. From March 2011 to June 2013, 27 of 181 patients undergoing allogeneic HSCT in our department received cidofovir for BKV-HC: 24 (88.9%) intravenously, 1 intravesically, and 2 via both routes. Mean dose was 5 mg/kg per administration, for a median of 4 injections (range, 1 to 11), from twice a week to once every 2 weeks. CR was achieved in 22 patients (81.5%), PR in 2, and no response in 2 patients. Eight patients presented renal failure (29.6%): 6 moderate (creatinine clearance < 60 mL/min) and 2 severe (creatinine clearance < 30 mLmin). Mean decrease in creatinine clearance after cidofovir was 27% (35 mL/min; range, 2 to 159). In 3 cases renal insufficiency and hematologic toxicity led to discontinuation of treatment or switch to intravesical instillation. For 3 patients cidofovir dose was reduced because of nephrotoxicity. Thirteen studies have reported on the use of cidofovir for BKV-HC (204 patients) since 2005. Intravenous cidofovir was used for 91.3% of patients, with doses ranging from .5 to 5 mg/kg. The main toxicity reported was renal failure (9% to 50% in 9 studies). Between 60% and 100% of CRs were observed independently of cidofovir dose or administration route. Cidofovir is an effective therapy for BKV-HC but requires very precise renal function management to avoid toxicity. Cidofovir treatment modalities (high dose, intravesical instillation, or low dose [≤1 mg/kg]) needs to be investigated in randomized controlled trials.
Subject(s)
Antiviral Agents/therapeutic use , Cystitis/therapy , Cytosine/analogs & derivatives , Hematologic Neoplasms/therapy , Hemorrhage/therapy , Organophosphonates/therapeutic use , Polyomavirus Infections/therapy , Tumor Virus Infections/therapy , Adult , BK Virus/drug effects , BK Virus/physiology , Cidofovir , Cystitis/etiology , Cystitis/immunology , Cystitis/mortality , Cytosine/therapeutic use , Drug Administration Schedule , Female , Glomerular Filtration Rate , Graft Survival , Hematologic Neoplasms/immunology , Hematologic Neoplasms/mortality , Hematologic Neoplasms/pathology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Hemorrhage/etiology , Hemorrhage/immunology , Hemorrhage/mortality , Humans , Male , Middle Aged , Myeloablative Agonists/therapeutic use , Polyomavirus Infections/etiology , Polyomavirus Infections/immunology , Polyomavirus Infections/mortality , Retrospective Studies , Survival Analysis , Transplantation Conditioning , Transplantation, Homologous , Tumor Virus Infections/etiology , Tumor Virus Infections/immunology , Tumor Virus Infections/mortality , Viral Load/drug effectsABSTRACT
The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-ß. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-ß arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-ß arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one "epigenetic mutation" and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azacitidine/therapeutic use , Drug Resistance , Myelodysplastic Syndromes/drug therapy , Aged , Azacitidine/administration & dosage , Biomarkers , Cytogenetic Analysis , DNA Mutational Analysis , Erythropoietin/administration & dosage , Female , Hematinics/therapeutic use , Humans , Male , Middle Aged , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Polymorphism, Single Nucleotide , Recombinant Proteins/administration & dosage , Survival Analysis , Treatment OutcomeABSTRACT
Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy, however, remains poorly understood, especially as viral mRNA/protein are tightly silenced in tumors. Here, using deep sequencing of broad windows of small RNA sizes in the bovine leukemia virus ovine model of leukemia/lymphoma, we provide in vivo evidence of the production of noncanonical RNA polymerase III (Pol III)-transcribed viral microRNAs in leukemic B cells in the complete absence of Pol II 5'-LTR-driven transcriptional activity. Processed from a cluster of five independent self-sufficient transcriptional units located in a proviral region dispensable for in vivo infectivity, bovine leukemia virus microRNAs represent â¼40% of all microRNAs in both experimental and natural malignancy. They are subject to strong purifying selection and associate with Argonautes, consistent with a critical function in silencing of important cellular and/or viral targets. Bovine leukemia virus microRNAs are strongly expressed in preleukemic and malignant cells in which structural and regulatory gene expression is repressed, suggesting a key role in tumor onset and progression. Understanding how Pol III-dependent microRNAs subvert cellular and viral pathways will contribute to deciphering the intricate perturbations that underlie malignant transformation.
Subject(s)
Enzootic Bovine Leukosis/genetics , Enzootic Bovine Leukosis/virology , Leukemia Virus, Bovine/genetics , Leukemia, B-Cell/genetics , Leukemia, B-Cell/virology , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/virology , MicroRNAs/genetics , RNA, Viral/genetics , Animals , Argonaute Proteins/metabolism , Base Sequence , Cattle , Cell Line, Tumor , Disease Models, Animal , Gene Expression , High Mobility Group Proteins/genetics , Human T-lymphotropic virus 1/genetics , Humans , Leukemia, B-Cell/veterinary , Leukemia-Lymphoma, Adult T-Cell/genetics , Leukemia-Lymphoma, Adult T-Cell/virology , Lymphoma, B-Cell/veterinary , MicroRNAs/chemistry , MicroRNAs/metabolism , Molecular Sequence Data , Nucleic Acid Conformation , RNA Polymerase III/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , RNA, Viral/chemistry , RNA, Viral/metabolism , Sequence Analysis, RNA , Sequence Homology, Nucleic Acid , Sheep , Sheep Diseases/genetics , Sheep Diseases/virology , Terminal Repeat SequencesABSTRACT
BACKGROUND: Reprogramming cellular gene transcription sustains HTLV-1 viral persistence that ultimately leads to the development of adult T-cell leukemia/lymphoma (ATLL). We hypothesized that besides these quantitative transcriptional effects, HTLV-1 qualitatively modifies the pattern of cellular gene expression. RESULTS: Exon expression analysis shows that patients' untransformed and malignant HTLV-1(+) CD4(+) T-cells exhibit multiple alternate exon usage (AEU) events. These affect either transcriptionally modified or unmodified genes, culminate in ATLL, and unveil new functional pathways involved in cancer and cell cycle. Unsupervised hierarchical clustering of array data permitted to isolate exon expression patterns of 3977 exons that discriminate uninfected, infected, and transformed CD4(+) T-cells. Furthermore, untransformed infected CD4+ clones and ATLL samples shared 486 exon modifications distributed in 320 genes, thereby indicating a role of AEUs in HTLV-1 leukemogenesis. Exposing cells to splicing modulators revealed that Sudemycin E reduces cell viability of HTLV-1 transformed cells without affecting primary control CD4+ cells and HTLV-1 negative cell lines, suggesting that the huge excess of AEU might provide news targets for treating ATLL. CONCLUSIONS: Taken together, these data reveal that HTLV-1 significantly modifies the structure of cellular transcripts and unmask new putative leukemogenic pathways and possible therapeutic targets.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , Exons , Gene Expression Regulation , Host-Pathogen Interactions , Human T-lymphotropic virus 1/physiology , Leukemia-Lymphoma, Adult T-Cell/pathology , Human T-lymphotropic virus 1/growth & development , Humans , Transcription, GeneticABSTRACT
Recruitment of virus-infected T lymphocytes into the CNS is an essential step in the development of virus-associated neuroinflammatory diseases, notably myelopathy induced by retrovirus human T leukemia virus-1 (HTLV-1). We have recently shown the key role of collapsin response mediator protein 2 (CRMP2), a phosphoprotein involved in cytoskeleton rearrangement, in the control of human lymphocyte migration and in brain targeting in animal models of virus-induced neuroinflammation. Using lymphocytes cloned from infected patients and chronically infected T cells, we found that HTLV-1 affects CRMP2 activity, resulting in an increased migratory potential. Elevated CRMP2 expression accompanies a higher phosphorylation level of CRMP2 and its more pronounced adhesion to tubulin and actin. CRMP2 forms, a full length and a shorter, cleaved one, are also affected. Tax transfection and extinction strategies show the involvement of this viral protein in enhanced full-length and active CRMP2, resulting in prominent migratory rate. A role for other viral proteins in CRMP2 phosphorylation is suspected. Full-length CRMP2 confers a migratory advantage possibly by preempting the negative effect of short CRMP2 we observe on T lymphocyte migration. In addition, HTLV-1-induced migration seems, in part, supported by the ability of infected cell to increase the proteosomal degradation of short CRMP2. Finally, gene expression in CD69(+) cells selected from patients suggests that HTLV-1 has the capacity to influence the CRMP2/PI3K/Akt axis thus to positively control cytoskeleton organization and lymphocyte migration. Our data provide an additional clue to understanding the infiltration of HTLV-1-infected lymphocytes into various tissues and suggest that the regulation of CRMP2 activity by virus infection is a novel aspect of neuroinflammation.
Subject(s)
Cell Movement , Human T-lymphotropic virus 1/physiology , Intercellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/metabolism , T-Lymphocytes/virology , Antigens, CD , Antigens, Differentiation, T-Lymphocyte , Cytoskeleton/virology , Humans , Inflammation/virology , Intercellular Signaling Peptides and Proteins/physiology , Lectins, C-Type , Nerve Tissue Proteins/physiology , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , T-Lymphocytes/physiology , Viral ProteinsABSTRACT
Upon antiretroviral therapy (ART) human immunodeficiency virus (HIV)/human T-cell lymphotropic virus type 1 (HTLV-1) co-infected individuals frequently develop neurological disorders through hitherto unknown mechanisms. Here, we show that effective anti-HIV ART increases HTLV-1 proviral load through a polyclonal integration pattern of HTLV-1 in both CD4(+) and CD8(+) T-cell subsets that is reminiscent of that typically associated with HTLV-1-related inflammatory conditions. These data indicate that preventing ART-triggered clonal expansion of HTLV-1-infected cells in co-infected individuals deserves investigation.
Subject(s)
Anti-Retroviral Agents/administration & dosage , Antiretroviral Therapy, Highly Active/methods , HIV Infections/drug therapy , HTLV-I Infections/virology , Human T-lymphotropic virus 1/drug effects , Human T-lymphotropic virus 1/pathogenicity , Virus Replication , Anti-Retroviral Agents/adverse effects , Antiretroviral Therapy, Highly Active/adverse effects , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/virology , Coinfection/drug therapy , HIV Infections/complications , Human T-lymphotropic virus 1/isolation & purification , Humans , Proviruses/drug effects , Proviruses/isolation & purification , Viral Load , Virus Integration/drug effectsSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Myelodysplastic Syndromes/drug therapy , Aged , Azacitidine/administration & dosage , Disease-Free Survival , Humans , Kaplan-Meier Estimate , Myelodysplastic Syndromes/mortality , Risk Factors , Treatment Outcome , Vorinostat/administration & dosageABSTRACT
PURPOSE: Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML). PATIENTS AND METHODS: Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m2/d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression. RESULTS: One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 109/L and 31.2 × 109/L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System-mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients (P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm (P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04). CONCLUSION: Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407).
Subject(s)
Leukemia, Myelomonocytic, Acute , Leukemia, Myelomonocytic, Chronic , Humans , Aged , Leukemia, Myelomonocytic, Chronic/drug therapy , Leukemia, Myelomonocytic, Chronic/diagnosis , Decitabine , Hydroxyurea/adverse effects , Leukemia, Myelomonocytic, Acute/drug therapy , Proportional Hazards ModelsABSTRACT
Untransformed HTLV-1 positive CD4(+) cells from infected individuals are selected for expressing tax and displaying morphological features consistent with telomere dysfunctions. We show that in resting HTLV-1 positive CD4(+) cells cloned from patients, hTERT expression parallels tax expression and cell cycling. Upon activation, these cells dramatically augment tax expression, whereas their increase in telomerase activity is about 20 times lower than that of their uninfected counterpart. Activated HTLV-1 positive CD4(+) but not uninfected CD4(+) or CD8(+) clones also repress the transcription of TRF1, TPP1, TANK1, POT1, DNA-PKc and Ku80. Both infected and uninfected lymphocytes from infected individuals shared common telomere gene deregulations toward a pattern consistent with premature senescence. ATLL cells displayed the highest telomerase activity (TA) whereas recovered a telomere gene transcriptome close to that of normal CD4(+) cells. In conclusion HTLV-1-dependent telomere modulations seem involved in clonal expansion, immunosuppression, tumor initiation and progression.
Subject(s)
CD4-Positive T-Lymphocytes/virology , HTLV-I Infections/enzymology , Human T-lymphotropic virus 1/isolation & purification , Telomerase/genetics , Telomere , Base Sequence , Clone Cells , DNA Primers , HTLV-I Infections/genetics , HTLV-I Infections/immunology , Homeostasis , Humans , Lymphocyte Activation , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Shelterin Complex , Telomere-Binding Proteins , Transcription, Genetic , TranscriptomeABSTRACT
Lenalidomide (LEN) has been shown to yield red blood cell (RBC) transfusion independence in about 25% of lower risk myelodysplastic syndromes (MDS) without del(5q), but its efficacy in patients clearly refractory to erythropoiesis-stimulating agents (ESA) is not known. We report on 31 consecutive lower-risk non-del(5q) MDS patients with anaemia refractory to ESA and treated with LEN in a compassionate programme, 20 of whom also received an ESA. An erythroid response was obtained in 15 patients (48%), including 10 of the 27 (37%) previously transfusion-dependent (RBC-TD) patients, who became transfusion-independent (RBC-TI). Nine of the responders relapsed, whereas 6 (40%) were still responding and transfusion-free after 11(+)-31(+) months. Median response duration was 24 months. The erythroid response rate was lower in refractory cytopenia with multilineage dysplasia (27% vs. 60%) and tended to be higher in patients treated with LEN + ESA (55% vs. 36%). Response duration was significantly longer in responders who obtained RBC-TI and in patients treated with LEN after primary resistance to ESA. The main toxicity of LEN was cytopenias. We confirm that, in a patient population of lower risk MDS without del 5q clearly resistant to ESA, LEN is an interesting second line therapeutic option. Its combination with ESAs in this context warrants prospective studies.
Subject(s)
Antineoplastic Agents/therapeutic use , Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Myelodysplastic Syndromes/drug therapy , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Blood Transfusion , Drug Administration Schedule , Drug Therapy, Combination , Female , Hematinics/therapeutic use , Humans , Karyotype , Lenalidomide , Male , Middle Aged , Myelodysplastic Syndromes/genetics , Prognosis , Recurrence , Thalidomide/administration & dosage , Thalidomide/adverse effects , Thalidomide/therapeutic use , Treatment Failure , Treatment OutcomeABSTRACT
Approximately 3% of all human T-lymphotropic virus type 1 (HTLV-1)-infected persons will develop a disabling inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis, against which there is currently no efficient treatment. As correlation exists between the proviral load (PVL) and the clinical status of the carrier, it is thought that diminishing the PVL could prevent later occurrence of the disease. We have conducted a study combining valproate, an inhibitor of histone deacetylases, and azidothymidine, an inhibitor of reverse transcriptase, in a series of baboons naturally infected with simian T-lymphotropic virus type 1 (STLV-1), whose PVL was equivalent to that of HTLV-1 asymptomatic carriers. We show that the combination of drugs caused a strong decrease in the PVL and prevented the transient rise in PVL that is seen after treatment with histone deacetylases alone. We then demonstrate that the PVL decline was associated with an increase in the STLV-1-specific cytotoxic T-cell population. We conclude that combined treatment with valproate to induce viral expression and azidothymidine to prevent viral propagation is a safe and effective means to decrease PVL in vivo. Such treatments may be useful to reduce the risk of HAM/TSP in asymptomatic carriers with a high PVL.
Subject(s)
Antiviral Agents/administration & dosage , Deltaretrovirus Infections/veterinary , Histone Deacetylase Inhibitors/administration & dosage , Monkey Diseases/drug therapy , Papio , Reverse Transcriptase Inhibitors/administration & dosage , Simian T-lymphotropic virus 1 , Animals , Antiretroviral Therapy, Highly Active , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Deltaretrovirus Infections/drug therapy , Deltaretrovirus Infections/immunology , Deltaretrovirus Infections/virology , Disease Models, Animal , Drug Therapy, Combination , Female , HTLV-I Infections/drug therapy , HTLV-I Infections/virology , Humans , Male , Monkey Diseases/immunology , Monkey Diseases/virology , Paraparesis, Tropical Spastic/drug therapy , Paraparesis, Tropical Spastic/virology , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , Valproic Acid/administration & dosage , Viral Load/drug effects , Zidovudine/administration & dosageABSTRACT
BACKGROUND: Although lenalidomide is very effective in the treatment of anemia of lower risk myelodysplastic syndromes with 5q deletion (del 5q), concerns have been raised over the fact that this drug could trigger progression to acute myeloid leukemia in some patients. DESIGN AND METHODS: Ninety-five transfusion-dependent patients with lower risk myelodysplastic syndromes with del 5q were treated with lenalidomide (10 mg/day, for 3 weeks every 4 weeks); six (6.3%) of the patients progressed to acute myeloid leukemia. This cohort of 95 lenalidomide-treated patients was compared to a historical control cohort of 99 patients with lower risk myelodysplastic syndromes with del 5q who never received lenalidomide, using a propensity score approach that can control for potential confounders in non-randomized comparisons. RESULTS: The 4-year estimated cumulative incidence of leukemia was 9% in patients treated with lenalidomide and 15.8% in controls who did not receive lenalidomide (P=0.16). CONCLUSIONS: Using a propensity score approach, we found no significant difference in acute myeloid leukemia progression and survival from diagnosis between the cohort treated with lenalidomide and the control cohort.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Disease Progression , Myelodysplastic Syndromes/epidemiology , Myelodysplastic Syndromes/genetics , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , France/epidemiology , Humans , Lenalidomide , Male , Middle Aged , Myelodysplastic Syndromes/chemically induced , Survival Rate , Thalidomide/adverse effects , Thalidomide/therapeutic use , Treatment OutcomeABSTRACT
Adult T-cell leukemia/lymphoma (ATL) is resistant to chemotherapy and carries a dismal prognosis particularly for the acute and lymphoma subtypes. Promising results were obtained with the combination of zidovudine and interferon-alpha. Chronic ATL has a relatively better outcome, but poor long-term survival is noted when patients are managed with a watchful-waiting policy or with chemotherapy. In ATL cell lines, arsenic trioxide shuts off constitutive NF-kappaB activation and potentiates interferon-alpha apoptotic effects through proteasomal degradation of Tax. Clinically, arsenic/interferon therapy exhibits some efficacy in refractory aggressive ATL patients. These results prompted us to investigate the efficacy and safety of the combination of arsenic, interferon-alpha, and zidovudine in 10 newly diagnosed chronic ATL patients. An impressive 100% response rate was observed including 7 complete remissions, 2 complete remissions but with more than 5% circulating atypical lymphocytes, and 1 partial response. Responses were rapid and no relapse was noted. Side effects were moderate and mostly hematologic. In conclusion, treatment of chronic ATL with arsenic, interferon-alpha, and zidovudine is feasible and exhibits an impressive response rate with moderate toxicity. Long-term follow up will clarify whether this will translate to disease cure. Overall, these clinical results strengthen the concept of oncogene-targeted cancer therapy.