Therapy In Myelodysplastic Syndromes Patients Research Articles

Prognosis and Therapy of Myelodysplastic Syndrome

Prognosis and Therapy of Myelodysplastic Syndrome Abstract. The myelodysplastic syndromes (MDS) represent a heterogeneous group of diseases affecting the hematopoietic stem cells, which are characterized by reduced blood cells (cytopenia), maturation disorders (dysplasia) and an increased risk of transformation into acute myeloid leukemia (AML). For adequate treatment, disease and patient-related factors must be taken into account and the therapies are very different for lower- and higher-risk diseases, respectively. In the case of lower-risk diseases, the focus is on improving cytopenias and quality of life, while in the case of higher-risk diseases the prolongation of survival with a delay of transformation to AML. Only a small proportion of higher-risk MDS patients qualify for the only potentially curative treatment of hematopoietic stem cell transplantation. This review article summarizes the most important aspects of prognosis and therapy in MDS patients for the practicing physician.

Immunological Correlates of Treatment with the CTLA-4 Inhibitor Ipilimumab in Patients with Refractory Myelodysplastic Syndromes (MDS)

Introduction: Failure of hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS) is associated with dismal survival and there are no currently approved therapies in this setting. We recently presented the results of a multi-center phase 1b study of the immune checkpoint blocker (ICB) ipilimumab given as monotherapy after HMA failure in 29 MDS patients. Eight doses of 3mg/kg administered in induction and maintenance phases were safe and well tolerated. Very limited data has been reported on immunologic correlates of response after ICB therapy among patients with hematologic malignancies. Here we present a detailed analysis of the immunological correlates of achieving clinical benefit with ipilimumab.Methods: We defined patients who achieved marrow complete response (mCR) or prolonged stable disease (PSD) for ≥46 weeks as having achieved meaningful clinical benefit (MCB) for analyses of immunologic studies. 11 patients were treated during the dose escalation phase (6 patients at 3mg/kg dose and 5 patients at 10 mg/kg), while another 18 patients were treated in the dose expansion part at the 3 mg/kg dose. Correlative immunologic studies were performed on mononuclear cells from both peripheral blood (PBMC) and bone marrow (BMMC) samples that were collected at baseline and at pre-determined timepoints after ipilimumab treatment (after induction cycle 2 and 4; after each maintenance cycle 1-4, and end of treatment or study discontinuation). Correlative assays included immunophenotyping of PBMCs and BMMCs by multicolor flow cytometry, as well as high throughput sequencing of the T cell antigen receptor (TCR) repertoire. T cell percentages, absolute numbers, and ratios were summarized by time point for patients and overall for healthy controls using descriptive statistics (mean, SD). Differences in log-transformed T cell values were compared between healthy controls and patients at pre-treatment using two-sample t tests. Differences from pre-treatment to cycle 2 and cycle 4 were estimated for patients and tested for positive or negative changes with paired t tests. Analyses were completed using R version 3.3.2.Results: MCB was observed in 28% of patients, 2 (7%) patients with mCR and 6 (21%) patients with PSD, respectively. Immunologic studies were performed on 16 patients who had samples available from at least two time points. Compared to solid tumor literature, we did not observe a correlation between early dynamic changes in serial absolute lymphocyte count and probability of achieving MCB. Expression of co-stimulatory molecules (ICOS - Inducible T Cell CO-Stimulator) and co-inhibitory molecules (PD-1 and CTLA-4) showed that a higher fraction of CD4+ and CD8+ T-cells in PB expressed ICOS in patients who achieved MCB following ipilimumab treatment (P=0.05 and P=0.01, respectively, Figure 1]. Similarly, expression of the immune co-inhibitory receptor CTLA-4 followed a similar pattern showing a trend of increased expression in both CD4+ and CD8+ T-cells (average increase of 6% and 2.4% respectively, P=ns.) over the first 4 cycles of ipilimumab treatment among patients who achieved MCB, followed by a gradual decrease. In contrast to CTLA-4, there was a wide range in frequencies of CD4+ and CD8+ T-cells expressing PD-1 in both patients and HC and PD-1 levels remained stable throughout ipilimumab treatment suggesting that the lack of T-cell activation in non-responders was not due to increased expression of other co-inhibitory molecules. There was a significantly higher frequency of CD3+CD4+Foxp3+ and activated effector Tregs (eTregs) prior to treatment which persisted throughout the examined time points and neither their levels, nor the CD8 T-cell to Treg (CD8/Treg) ratio were impacted by ipilimumab treatment.Conclusions: These data represent, to our knowledge, the first detailed analysis of immunologic correlates of response to ICB therapy in MDS patients. Our data suggest that ICOS expression is positively correlated with achievement of MCB with single agent ipilimumab in patients with MDS and should be further explored as a biomarker for response. The results of the high throughput sequencing of the T cell antigen receptor (TCR) repertoire are currently being analyzed and will be presented at the meeting. [Display omitted] DisclosuresSmith:Celgene: Other: DSMB member; Jazz: Membership on an entity's Board of Directors or advisory committees. Zeidner:Tolero Pharmaceuticals: Honoraria; Agios: Honoraria; Tolero Pharmaceuticals: Research Funding; Takeda: Research Funding; Merck: Research Funding; Celgene: Honoraria. Frattini:Astellas: Honoraria; Lin Bioscience: Consultancy. Levy:Actinium Pharmaceuticals: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Takeda: Consultancy, Speakers Bureau. Zeidan:AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau; Otsuka: Consultancy.

Use of Deferasirox in Transfusion-Dependent Myelodysplastic Syndromes with Iron Overload

SUMMARY In myelodysplastic syndromes (MDS), transfusion-dependent anemia has been established as an independent risk factor for decreased survival. Although evidence from prospective studies is still lacking, several guidelines recommend iron-chelating therapy in MDS patients with a longer life expectancy. With the recent introduction of deferasirox, an oral active iron-chelating drug, which has shown dose-dependent efficacy and acceptable tolerability, this therapeutic option has become feasible even in the elderly. Several retrospective and prospective studies showed that in MDS patients deferasirox is effective in reducing iron burden and in maintaining the circulating toxic iron fraction within the normal range. Moreover, in a substantial fraction of patients treated with deferasirox a significant improvement of peripheral cytopenias may occur.

Serum microRNA-21 as a Potential Biomarker for Response to Hypomethylating Agents in Myelodysplastic Syndromes

Identification of biomarkers that predict responses to hypomethylating agents (HMAs) will allow optimal strategies for epigenetic therapy in myelodysplastic syndromes (MDS) to be established. Serum miR-21 was quantitatively measured in 58 MDS patients treated with HMAs and 14 healthy controls. Serum miR-192 was an internal control, and diagnostic performance was evaluated according to receiver operating characteristics (ROCs). ROC analysis indicated that serum miR-21 levels differentiated responders from non-responders with an area under the curve of 0.648 (95% confidence, 0.49 to 0.72). The baseline level of serum miR-21 was significantly lower in the responder group than in the non-responder group (P = 0.041). The overall response rate (ORR) of the high miR-21 group was significantly lower than that of the low miR-21 group (41.2 vs. 73.2%, P = 0.021). Progression-free survival (PFS) was significantly inferior in the high group versus the low group (14.0 vs. 44.5 months, P = 0.001). Multivariate analyses revealed that the initial serum miR-21 level (P = 0.001) and circulating blasts (P = 0.007) were prognostic factors for PFS. Serum miR-21 level was significantly associated with ORR and PFS in MDS patients treated with HMAs. Although validation with a large prospective study is required, serum miR-21 is a potential biomarker of epigenetic therapy in MDS patients.

Transfused Myelodysplastic Syndromes (MDS) Patients Have Severe Iron Overload and Relevant Improvements in Iron Burden and Liver Function with Deferasirox Treatment: Results From a Pooled Analysis

Abstract 5019 Background:MDS patients receiving chronic transfusions can develop significant iron accumulation in key organs such as the liver following 10–20 transfusions (Porter et al. BJH 2001). The diagnosis and monitoring of iron overload, as well as the effect of iron chelation therapy in MDS patients, is often based on serum ferritin (SF), with limited data on liver iron concentration (LIC), primarily due to the biopsy-related increased risk of bleeding and infections in these patients. However, LIC is clinically a more robust and direct measure of body iron burden and with the availability of non-invasive determination of LIC by MRI, LIC assessment has become more practical in MDS patients. This pooled analysis focuses on LIC assessments from a population of 71 MDS patients who completed 1 year of treatment with deferasirox (Exjade®), including assessment of the relationship between LIC vs SF and alanine aminotransferase (ALT). Methods:Analysis is based on 1-year pooled data from iron-overloaded patients with MDS who were enrolled in 4 open-label single-arm deferasirox studies: US02 (Low/Int-1 MDS patients, starting dose 20 mg/kg/day); 2409 (MDS patients with life expectancy >1 yr, starting dose 10–30 mg/kg/day); 108 (MDS patients with life expectancy >1 yr, dosing 5–40 mg/kg/day), and 2204 (Low/Int-1 MDS patients, starting dose 10–30 mg/kg/day). LIC was assessed in the US02, 2409 and 2204 studies using R2 MRI (St Pierre et al. Blood 2004). In the 108 study, LIC was assessed by magnetic liver susceptometry using a superconducting quantum interference device (SQUID) or ultrasound-guided percutaneous liver biopsy; LIC values obtained by SQUID were multiplied by a factor of 2 to correct for the underestimation of LIC by SQUID compared to biopsy (Porter et al. EJH 2008). Datasets were pooled for baseline (BL) characteristics, as well as LIC, SF and ALT at BL and end of study (EOS). Correlations were evaluated on a Pearson’s correlation coefficient. Results:71 patients (56.3% male) were assessed with a mean age of 65 years (range 16.5–82.0). Mean transfusional iron intake ± SD was 0.31 ± 0.12 mg/kg/day. Mean actual deferasirox dose was 19.6 ± 6.5 mg/kg/day. At BL, mean ± SD LIC was 20.5 ± 14.6 mg Fe/g dw (BL LIC <7 mg Fe/g dw, 21.1%; ≥7 mg–≤15 mg Fe/g dw, 23.9%; and >15 mg Fe/g dw, 54.9%). Median BL SF was 2620 ng/mL (range 538–12,639) (BL SF ≤2500 ng/mL, 47.9%; >2500–≤5000 ng/mL, 32.4%; and >5000 ng/mL, 15.5%). With 1 year of DFX, mean ± SD LIC decreased to 13.9 ± 13.1 mg Fe/g dw (mean absolute change –6.6 mg Fe/g dw). In patients with BL LIC <7 mg Fe/g dw (n=15), LIC was maintained with a mean absolute change of 1.0 ± 2.8 mg Fe/g dw, whereas in patients with BL LIC ≥7 mg Fe/g dw (n=56), LIC was reduced by –8.6 ± 10.7 mg Fe/g dw from BL. The proportion of MDS patients with LIC ≥7 mg Fe/g dw reduced from 78.9% at BL to 59.2% at EOS, with 50.7% of patients achieving a decrease in LIC of ≥30%.Median SF decreased to 2035 ng/mL (range 158–10520 ng/mL) with median absolute change from baseline of –630 ng/mL. There was a significant correlation between BL LIC and SF (R=0.548; P<0.0001). Change in LIC significantly correlated with change in serum ferritin (R=0.336; P=0.0042, Figure A). Mean ALT decreased from 55.9 to 38.9 U/L (absolute change –17.0). The change in LIC correlated with the change in ALT (R=0.397, P=0.0006, Figure B). [Display omitted] Conclusions:This pooled analysis in a large cohort of transfusion-dependent MDS patients with LIC assessment shows significantly elevated LIC, with a high proportion of patients (55%) having severely elevated LIC of >15 mg Fe/g dw, a level known to markedly increase liver dysfunction and other iron overload-related complications. One year of treatment with deferasirox produced relevant reductions in LIC, an outcome possibly indicative of a clinical benefit. SF and ALT (an important indicator of liver function) also decreased, with reductions correlating with those of LIC. These findings indicate that correction of moderate-to-severe iron overload in MDS patients is associated with a parallel improvement in liver function. Disclosures:Gattermann:Novartis Pharma: Honoraria, Research Funding. Greenberg:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Habr:Novartis Pharma: Employment. Kpamegan:Novartis Pharma: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Role of flow cytometry in diagnostics of myelodysplastic syndromes—beyond the WHO 2008 classification

Multiparameter flow cytometry (FCM) is an excellent method to follow the expression patterns of differentiation antigens using monoclonal antibodies to surface and cytoplasmic proteins. Although several authors described various aberrant immunophenotypic features in the bone marrow of patients with myelodysplastic syndromes (MDS), the World Health Organization 2008 classification recommended that, only if 3 or more phenotypic abnormalities are found involving 1 or more of the myeloid lineages can the aberrant FCM findings be considered suggestive of MDS. In the absence of conclusive morphologic and/or cytogenetic features, FCM abnormalities alone were considered not sufficient to establish MDS diagnosis and further follow-up of the patients was recommended. Review of the literature gives accumulating evidence that FCM has become an important part of the integrated diagnostic work-up of patients with suspected MDS. Several studies have also reported FCM findings significant for prognosis and therapy choice in MDS patients. Technical progress in multicolor FCM and new analysis programs, together with ongoing efforts to standardize the methodology, will make it possible to apply FCM in individual risk assessment and choice of best therapy for MDS patients.

Oxidative Stress and the Myelodysplastic Syndromes

The evolution of higher organisms from anaerobic to aerobic living has promoted an elaborate mechanism of defense against potentially toxic oxidants. Many environmental toxicants implicated in the pathogenesis of myelodysplastic syndromes (MDS), including benzene and ionizing radiation, exert toxicity via pro-oxidant mechanisms. The emerging data suggest a probable genetic susceptibility to environmental carcinogenesis through functional polymorphic variants in enzymes that metabolize toxicants and/or protect against oxidative stress. The most studied enzyme is NAD(P)H:quinone oxidoreductase (NQO1). CD34+ cells from individuals homozygous for the NQO1 C609T nonfunctional allelic variant are incapable of enzyme induction following exposure to benzene, thus potentially increasing the hematotoxicity of benzene metabolites. Serologic and molecular markers of oxidative stress are present in many patients with MDS and include an increased concentration of the lipid peroxidation product malondialdehyde and the presence of oxidized bases in CD34+ cells. Potential mechanisms of oxidative stress include mitochondrial dysfunction via iron overload and mitochondrial DNA mutation, systemic inflammation, and bone marrow stromal defects. The biological activity of the antioxidant aminothiol amifostine in vivo suggests that these pathways may be meaningful targets for future therapy in MDS patients.

Immunosuppressive Treatments for Myelodysplastic Syndromes

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell disorders, while, immunological abnormalities are frequently observed in patients with MDS. Several reports revealed that about 10% of MDS patients have clinical autoimmune disorders like skin vasculitis, rheumatic disease, or autoimmune hemolytic anemia. Furthermore, serological immunological abnormalities like hyper- or hypogammaglobulinemia, positivities of antinuclear antibody, positivities of direct Coombs test, or inverted CD4/8 ratios were found in 18-65% of patients with MDS. Recently immunosuppressive therapies including prednisolone, antithymocyte globulin, and cyclosporin A (CsA) are used to treat cytopenia in some patients with MDS. We examined the efficacy of CsA in 50 patients with MDS. Hematologic improvement was observed in 30 (60%) patients especially for erythroid lineage. There were significantly more responders with good karyotype or DRB1*1501 than with intermediate/poor karyotypes or with other HLA types. MDS with erythroid hypoplasia is a rare form of MDS, and has not yet been clearly defined. We reported four patients with MDS with erythroid hypoplasia who had morphological evidence of myelodysplasia and low percentage of erythroid precursors. Rearrangements of the TCR- β and - γ genes were seen in these patients using Southern blot and PCR analysis. Also they had skewed TCR usages using TCR repertoire analysis. Their anemia drastically improved with CsA therapy. We have to establish the clinical usefulness of immunosuppressive therapy in MDS patients and simple tools for revealing T-cell mediated myelosuppression in the individual patients for decision-making.

Complications and treatment of the myelodysplastic syndromes

The major complications of the myelodysplastic syndromes (MDS) are related to cytopenia and evolution to acute myeloid leukemia (AML). Hematopoietic growth factors are only of limited benefit to alleviate the cytopenia. Therapy in MDS patients over the age of 50 should aim at prolonging survival while limiting the risk of toxicity. Those with stable disease should only receive supportive care; those with progressive cytopenia should have a trial with low-dose chemotherapy. Aggressive chemotherapy should only be reserved for those failing low-dose therapy. Therapy in MDS patients under the age of 50 should aim at cure of the disease. Although aggressive chemotherapy can induce complete remission in the majority of these patients, remission is usually short. Allogeneic bone marrow transplantation is probably the only curative option in these patients and should be the treatment of choice.

Two Regression Models and a Scoring System for Predicting Survival and Planning Treatment in Myelodysplastic Syndromes: A Multivariate Analysis of Prognostic Factors in 370 Patients

AbstractTherapy planning in patients with myelodysplastic syndromes (MDSs) is complicated by its high prognostic heterogeneity. Forty-one patient and disease characteristics at onset of 370 patients with MDS were analyzed to identify significant prognostic factors for survival and transformation to acute myeloblastic leukemia (AML), and to develop and validate a regression model for predicting survival. Multivariate regression analysis showed that the total bone marrow percentage of blast cells, age, platelet count, WBC count, and hemoglobin level were the characteristics more significantly associated with survival in the overall series. The bone marrow percentage of type I blast cells was the most important factor predicting transformation into AML. Proportional hazards regression analysis in a randomly selected training sample of 240 patients demonstrated that the combination of total bone marrow percentage of blast cells, platelet count, and age had the strongest predictive relation to survival length. The resulting regression models, continuous and categorized, were validated in the remaining test sample of 130 patients by demonstrating its capability of segregating patients into low-, intermediate-, and high-risk groups, with distinctively different survival curves (P <.0001). A scoring system derived from the categorized model also had a great prognostic value (P <.0001). These regression models and the simpler scoring system may be accurately used for decision-making regarding therapy in MDS patients.

Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients

Therapy planning in patients with myelodysplastic syndromes (MDSs) is complicated by its high prognostic heterogeneity. Forty-one patient and disease characteristics at onset of 370 patients with MDS were analyzed to identify significant prognostic factors for survival and transformation to acute myeloblastic leukemia (AML), and to develop and validate a regression model for predicting survival. Multivariate regression analysis showed that the total bone marrow percentage of blast cells, age, platelet count, WBC count, and hemoglobin level were the characteristics more significantly associated with survival in the overall series. The bone marrow percentage of type I blast cells was the most important factor predicting transformation into AML. Proportional hazards regression analysis in a randomly selected training sample of 240 patients demonstrated that the combination of total bone marrow percentage of blast cells, platelet count, and age had the strongest predictive relation to survival length. The resulting regression models, continuous and categorized, were validated in the remaining test sample of 130 patients by demonstrating its capability of segregating patients into low-, intermediate-, and high-risk groups, with distinctively different survival curves (P less than .0001). A scoring system derived from the categorized model also had a great prognostic value (P less than .0001). These regression models and the simpler scoring system may be accurately used for decision-making regarding therapy in MDS patients.