A Detailed Analysis of Myelodysplastic Syndrome Complicated By Autoimmune or Inflammatory Disorders: A Possible Efficacy of Low-Dose Lenalidomide

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3256-3256
Author(s):  
Yasunobu Takeoka ◽  
Akiko Miura ◽  
Koji Nakamura ◽  
Junko Nakamura ◽  
Ryosuke Yamamura ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Clinical Features ◽  
Steroid Therapy ◽  
Research Funding ◽  
Low Dose ◽  
Progression Rate ◽  
Trisomy 8 ◽  
Inflammatory Disorders ◽  
Kaplan Meier ◽  
Significant Difference

Abstract [Background] Approximately 10-20 % of the patients with myelodysplastic syndrome (MDS) are known to be complicated by autoimmune or inflammatory disorders (ADs) such as vasculitis. However, most of the reports on such MDS were published before 2000, in which the diagnosis of MDS was made with previous criteria; about 20% (range 9-43%) of the patients in these reports may not be diagnosed as MDS with the present criteria. In addition, many of these reports do not offer sufficient information on cytogenetic analysis, a presently known critical factor that affect pathophysiology of MDS. These facts could make difficult to discuss its characteristics, prognosis and treatment options. Therefore, we made a detailed retrospective analysis on clinical features and treatment outcomes of MDS complicated by ADs based on more recent knowledge. [Results] A total of 102 Japanese patients with MDS (70 males and 32 females, median age of 73), diagnosed between June 2007 and June 2014, were evaluated. The diagnosis was made with WHO (2008) classification. Bone marrow G-band chromosome analysis was available in 95 % of the patients. "Very High" risk category of IPSS-R criteria comprised 29% of the patients. As summarized in Table 1, 14 episodes of AD were observed in 13 (13%) patients; 4 with Sweet syndrome, 2 each with Bechet like symptoms, interstitial pneumonia, large vessel vasculitis and myelitis, and 1 each with HPS and seronegative arthritis. As in the previous reports, the patients who developed ADs (AD group) were characterized by younger age and higher frequency of complex cytogenetics compared with those who did not (non-AD group). In addition, patients of AD group showed lower neutrophil count and higher frequency of trisomy 8 (p=.034 and <.01, respectively). Of note, despite no significant difference in median IPSS-R score, the progression rate to AML in AD group was more than two-times higher compared with non-AD group (p=.01). Survival rates were not significantly different between two groups. Corticosteroids were given to 8 patients of AD group and 6 of them (75 %) showed a certain degree of responses. Six patients with relapsed or refractory AD after the steroid therapy were treated with low-dose Lenalidomide (LEN) (10mg/day for 21 days). Interestingly, 5 of them responded to LEN with 3 achieving complete remission. Furthermore, the patients of AD group received LEN showed better survival compared with those treated without LEN (1.2y vs. 3.1y, p=.017) (Figure 1). [Conclusion] The present observation indicated that MDS with AD may be associated with cytogenetic abnormalities including trisomy 8 and higher progression rate to AML. Of note, LEN might be a possible treatment option for those resistant to steroid therapy. Table 1. Clinical features of the patients who were complicated by autoimmune or inflammatory disorders (AD) and those who were not (non-AD) Table 1. Clinical features of the patients who were complicated by autoimmune or inflammatory disorders (AD) and those who were not (non-AD) Figure 1 Comparison of Kaplan-Meier estimates of survival in the presence or absence of Lenalidomide treatment Figure 1. Comparison of Kaplan-Meier estimates of survival in the presence or absence of Lenalidomide treatment Disclosures Nakamae: Novartis: Honoraria, Research Funding, Speakers Bureau, Travel/accomidations/meeting expenses Other. Hino:Nippon Shinyaku CO.,LTD: Research Funding; astellas CO.,LTD: Research Funding.

scholarly journals Clinical features and long-term outcomes of moyamoya disease: a single-center experience with 528 cases in China

2015 ◽  
Vol 122 (2) ◽  
pp. 392-399 ◽  
Author(s):  
Xing-ju Liu ◽  
Dong Zhang ◽  
Shuo Wang ◽  
Yuan-li Zhao ◽  
Mario Teo ◽  
...  
Keyword(s):  
Clinical Features ◽  
Moyamoya Disease ◽  
Positive Impact ◽  
Chinese Patients ◽  
Single Center ◽  
Long Term Outcomes ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Revascularization Procedures

OBJECT The aim of this study was to describe the baseline clinical features and long-term outcomes of patients with moyamoya disease (MMD) based on a 25-year period at a single center in China. METHODS  Data obtained in 528 consecutive patients with MMD treated at the authors' hospital from 1984 to 2010 were reviewed retrospectively. Events of transient ischemic attack, new infarction, and hemorrhage were included. The Kaplan-Meier risk of stroke was calculated. RESULTS  The mean (± SD) patient age was 26 ± 13 years (range 2–67 years), and the female/male ratio was 0.9:1. There were 332 cases of ischemia and 196 hemorrhages. Adults had a higher rate of bleeding than children (50.7% vs 14.0%, respectively; p < 0.001). One hundred twenty-two patients were treated conservatively, and 406 patients underwent revascularization procedures. Of 528 patients, 331 (62.7%) had at least 1 year of follow-up (median 39.5 months) and data from these patients were analyzed. Rebleeding and mortality rates in patients with hemorrhagic MMD (n = 104) were higher than in those with ischemic MMD (n = 227) (26.9% vs 2.2% [p < 0.001] and 4.8% vs 0.4% [p < 0.05], respectively). Twenty-five of 60 (41.7%) conservatively treated patients and 8 of 271 (2.9%) surgically treated patients experienced rebleeding events, a difference that was significant in the Kaplan-Meier curve of rebleeding (p < 0.01). An improvement in perfusion was found in 164 of 224 (73.2%) surgically treated patients 1 month after discharge. However, there was no significant difference in the rate of ischemic events in the surgical and conservative groups (18.8% and 28.3%, respectively; p = 0.09). Among the 104 hemorrhagic cases, rebleeding attacks were observed in 25 patients in the nonsurgical group (n = 60) and 3 patients in the surgical group (n = 44) (41.7% and 6.8%, respectively; OR 9.7 [95% CI 2.7–35.0]; p < 0.01). CONCLUSIONS  There was no difference in the sex distribution of Chinese patients with MMD. Patients with hemorrhagic MMD had a much higher rate of rebleeding and poorer prognosis than those with the ischemic type. Surgical revascularization procedures can improve cerebral perfusion and have a positive impact in preventing rebleeding in patients with hemorrhagic MMD.

scholarly journals Pharmacological Myopia Control Influence on Quality of Life and Psyche among Adolescents

2020 ◽  
Vol 9 (12) ◽  
pp. 3920
Author(s):  
Andrzej Michalski ◽  
Małgorzata Rogaczewska ◽  
Magdalena Maleszka-Kurpiel ◽  
Marcin Stopa
Keyword(s):  
Quality Of Life ◽  
Low Dose ◽  
Self Esteem ◽  
Progression Rate ◽  
Myopia Progression ◽  
Significant Difference ◽  
High Level ◽  
Near Work ◽  
Myopia Control

Myopia is a global problem affecting all aspects of patients’ lives. Objectives: The aim of the study was to evaluate the influence of low dose atropine (LDA) myopia control on the quality of life in patients with myopia. Material and Methods: A self-constructed questionnaire, including eight questions, was distributed among 40 patients. The questionnaire was divided into two subsections: (1) influence of LDA on visual functions and (2) influence of LDA on self-esteem. Answers were collected separately for boys (18 patients) and girls (22 patients) and compared considering spherical equivalent (SE) and myopia progression rate. Results: Girls reported more issues with near activities and pupil size. Boys and girls complained similarly, regarding the sun glare. We found a high level of certainty about the efficacy of LDA therapy among both examined groups and a little improvement in self-esteem. Girls recommended LDA therapy more often than boys, especially when the progression rate was low. There was no statistically significant difference in answer scores between groups with different myopia progression rates for boys. Girls with lower progression rates reported more issues with near work and sun glare and less trust in LDA therapy’s effectiveness than girls with a higher progression rate. There was no statistically significant correlation between SE and the total answer score for both genders. Conclusions: Findings concerning childrens’ and adolescents’ psyche are a new aspect of myopia control. We prove that patients during pharmacological myopia control did not report significant problems caused by LDA therapy and they were convinced about its efficacy, had greater self-esteem, and recommended it to peers.

scholarly journals Lenalidomide and Low Dose Dexamethasone Plus Elotuzumab or Carfilzomib for Relapsed or Refractory Multiple Myeloma: A Comparison of Progression-Free Survival with Reconstructed Individual Participant Data

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Shuo Li ◽  
Xiang-Yu Meng ◽  
Souraka Tapara Dramani Maman ◽  
Yong-Nong Xiao ◽  
Sheng Li
Keyword(s):  
Multiple Myeloma ◽  
Survival Analysis ◽  
Low Dose ◽  
Progression Free Survival ◽  
Disease Stage ◽  
Free Survival ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Baseline Status ◽  
Individual Participant

Background. Refractory and relapsed multiple myeloma (RRMM) remains a clinical challenge. We compared the progression-free survival (PFS) of RRMM patients treated with lenalidomide and low dose dexamethasone plus elotuzumab or carfilzomib (ELD vs. CLD), using reconstructed individual patient data (IPD) based on two published trials reports. Methods. We extracted data of study-level characteristics from original trial reports. We evaluated the comparability between the two treatment groups in terms of baseline status. Digitization of PFS Kaplan-Meier curves, reconstruction of IPD data, and subsequent survival analysis were performed. Distribution of progression and death events over time was visualized as histograms and corresponding kernel density lines, and Kaplan-Meier survival curves were plotted. Hazard ratio (HR) and corresponding 95% confidence interval (95% CI) were calculated. Results. Significant difference in race and disease stage distribution was found (P < 0.0001). Higher proportion of white patients and patients with advanced disease in the carfilzomib group was identified. Survival analysis revealed better PFS in the carfilzomib group (elotuzumab group vs. carfilzomib group: HR = 1.36, 95% CI = [1.11-1.67]). Conclusion. The CLD regimen may result in better PFS as compared with the ELD regimen in RRMM patients.

scholarly journals Diagnosis, treatment of Type Ⅰ autoimmune pancreatitis and management of relapse and side effects after steroid treatment in China

2021 ◽  
Author(s):  
Neng Tang ◽  
Xiao-lin Dou ◽  
Qun He ◽  
Xue-jun Gong ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Side Effects ◽  
Steroid Therapy ◽  
Autoimmune Pancreatitis ◽  
Low Dose ◽  
Age Of Onset ◽  
Effective Rate ◽  
Expectant Treatment ◽  
Significant Difference ◽  
Cyclophosphamide Treatment ◽  
Central South

Abstract Background: Type Ⅰ autoimmune pancreatitis (AIP) have a dramatic response to steroid therapy, but the relapse rates (RRs) is very high, and the side effects of steroid therapy are inevitable. However, the management of relapse and side effects of steroid therapy have been poorly investigated and no series have been reported previously, so this article focuses on the management of relapse and side effects. Methods: A single-centre, retrospective, cohort study of the type Ⅰ AIP patients admitted to Xiangya Hospital Central South University from September 2008 to September 2019. Collection and retrospectively analyzed the clinicopathologic data and outcomes of type Ⅰ AIP patients. Results: 82 patients with type Ⅰ AIP were included. The ratio of male with female was 2.73: 1 with median age of onset of 52 years old. 73.2% were histologically confirmed, 62.2% were showed other organ involvement (OOI). 78.0% treated by medications: 40 cases (62.5%) prednisolone, 24 cases (37.5%) prednisolone plus cyclophosphamide. The effective rate of prednisolone and prednisolone plus cyclophosphamide was no significant difference (37/40 vs 22/24, P = 0.904). The RRs of prednisolone and prednisolone plus cyclophosphamide after remission have no significant difference (14/40 vs 7/24, P = 0.630). Increasing the dosage of prednisolone, the effective rate of the prednisolone treatment and prednisolone plus cyclophosphamide treatment relapsed patients were 78.57% and 71.43%, respectively. The side effects were diabetes mellitus (DM) in 12.5%; central obesity in 15.6%; hyperlipidemia in 18.8%; gastric ulcer in 6.3%; osteoporosis in 9.4%; bone fracture in 1.6%. For those side effects patients performed low dose prednisolone and expectant treatment have a ideal results. Conclusions: There was no significant difference between prednisolone and prednisolone plus cyclophosphamide in the treatment of type Ⅰ AIP. Increasing the dose of prednisolone can effectively treat relapsed patients. Low dose steroid and expectant treatment should be performed when side effects arised.

scholarly journals Development of Somatic NRAS Mutation Associated with Rapid Transition from Germline GATA2 Mutation Associated Myelodysplastic Syndrome to Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3616-3616 ◽  
Author(s):  
Yanqin Yang ◽  
Yubo Zhang ◽  
Jun Zhu ◽  
Catherine E. Lai ◽  
Jingrong Tang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Bone Marrow Aspirate ◽  
Nras Mutation ◽  
Trisomy 8 ◽  
Acute Myeloid

Abstract There is increasing recognition of the role of inherited germline predisposition for myeloid disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The additional somatic genetic events required for development of a malignant phenotype are however poorly understood. A 25 year old woman was referred to the NHLBI hematology branch in March 2014 for a seven year history of pancytopenia. Her medical history included recurrent pneumonias, oral ulcers, severe varicella infection and arthralgias. Prior bone marrow examinations at ages 21 and 23 at outside institutions reported normocellular marrow, tri-lineage hematopoiesis and mild dyspoiesis. Cytogenetics were remarkable for trisomy 8 in 80% (aged 21) or 90% (aged 23) of metaphases. Previously unrecognized lymphedema was noted on examination. Peripheral blood counts showed WBC 2.28 K/ul [normal range: 3.98-10.04], HGB 9.9 g/dL [11.2-15.7], PLT: 67 K/ul [173-369], ALC: 0.36 K/ul [1.18-3.74] and AMC: 0.06 [0.24-0.86]. Peripheral blood flow cytometry demonstrated decreased CD3+ CD4+ (T) cells, CD19+ (B) cells and NK cells. HLA-DR15 negative. Bone marrow examination showed trilineage hematopoiesis, 50-60% cellularity, mild erythroid predominance and mildly increased, mildly atypical megakaryocytes. Blasts less than 5%. Bone marrow flow cytometry revealed severely decreased B-cells and monocytes, absent B-cell precursors, absent dendritic cells, inverted CD4:CD8 ratio, and atypical myeloid maturation pattern. Cytogenetics demonstrated stable trisomy 8 in 90% of metaphases. On the basis of this assessment the diagnosis of MDS was confirmed. Sanger sequencing revealed a GATA2 L375S mutation in the second zinc finger of known pathogenic significance. Four months later she developed increased fatigue and easy bruising with worsening thrombocytopenia (PLT: 10K/ul). Bone marrow was dramatically changed; now markedly hypercellular (90-100%) with diffuse sheets of immature cells consistent with blasts having fine chromatin, distinct or prominent nucleoli, and visible cytoplasm. Blasts were positive for CD33, CD56, CD64, CD123, and CD163; and were negative for CD34, CD14, and myeloperoxidase. Cytogenetics showed a new trisomy 20 in 65% of metaphases, in addition to previously seen trisomy 8 in 100%. A diagnosis of acute monoblastic leukemia (M5a subtype) was made. At both clinic visits bone marrow aspirate was collected on an IRB approved research sample acquisition protocol. Whole exome sequencing of 1ug DNA was performed using Agilent SureSelect v5 Exome enrichment Kits on an Illumina HiSeq 2000 with 100-bp paired-end reads (Macrogen, Rockville, MD). Data was mapped to hg19 (BWA) and processed using an in-house pipeline (Samtools/Picard/GATK/VarScan/Annovar). Mean read depth of target regions was 157 and 149. There was high correlation between both samples with the exception of a NRAS:NM_002524:exon3:c.C181A:p.Q61K mutation (57 of 180 reads) seen only in the later sample. Confirmatory ultra-deep sequencing for NRAS was performed using Illumina TruSight Myeloid Sequencing Panel on an Illumina MiSeq. No evidence of the NRAS Q61K mutation was found in the earlier March MDS bone marrow sample even when sequenced to a depth greater than 1750 reads (see figure). The mutation was confirmed in the August AML sample at a variant allele frequency of 35%. If heterozygous this would reflect a clone size of 70%, consistent with data from both cytogenetics (new trisomy 20 in 65% of metaphases) and the 76% blasts documented by bone marrow aspirate smear differential. We report here the rapid progression to AML in a patient with germline GATA2 MDS associated with development of a new trisomy 20 karyotype and a NRAS Q61K mutation. The NRAS mutation was not detectable after the patient achieved a complete remission following induction chemotherapy further supporting this association. This NRAS mutation has been implicated in the pathogenesis of multiple cancers by constitutive activation of proliferative signaling. GATA2 associated MDS is a high-risk pre-leukemic condition with the potential for rapid evolution to AML. This is the first report of acquired somatic mutations in the RAS/RTK signaling pathway in the context of germline GATA2 insufficiency associated with acute leukemic transformation. Figure 1. Figure 1. Disclosures Townsley: Novartis: Research Funding; GSK: Research Funding.

Patterns of Hypomethylating Agent and Transfusion Use in Myelodysplastic Syndrome: a Claims Database Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2490-2490
Author(s):  
Hind T Hatoum ◽  
Swu-Jane Lin ◽  
Deborah Buchner ◽  
Edward Kim
Keyword(s):  
Logistic Regression ◽  
Myelodysplastic Syndrome ◽  
Poisson Regression ◽  
Research Funding ◽  
Myelogenous Leukemia ◽  
Transfusion Rate ◽  
Inclusion Criteria ◽  
Significant Difference ◽  
To Receive

Abstract Abstract 2490 Poster Board II-467 Introduction: Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis, multilineage dysplasia, peripheral cytopenias, and susceptibility to leukemic transformation. Supportive treatments include red blood cell (RBC) and platelet (PLT) transfusions as well as erythrocyte stimulating agents (ESAs) to correct disease-induced cytopenias. Active treatment with hypomethylating agents (HMAs) have been shown in clinical trials to reduce transfusion dependence and leukemic progression among patients with MDS. The purpose of this study is to describe the patterns of care among patients with MDS, and outcomes associated with HMA treatment options. Methods: Data were obtained from the MarketScan® database, which contains pharmacy, medical, hospital, and laboratory claims for several million members, from January 2002 through June 2008. Inclusion criteria included: age 18 or older; at least 2 claims with an ICD-9 diagnosis of MDS in 2006 or later; at least 6 months of pre-diagnosis health plan enrollment; at least 4 months of enrollment after initial HMA treatment; at least 1 complete cycle of decitabine (DAC; 5 treatments) or azacitidine (AZA, 7 treatments). Patients were excluded if they were treated with lenalidomide, had a prior cancer diagnosis, prior treatment with DAC or AZA, or had other isolated cytopenia or myeloproliferative diagnoses. Patients with a diagnosis of acute myelogenous leukemia within the first 28 days of treatment were also excluded. Descriptive statistics characterized patient demographics, including time between diagnosis and treatment, days per cycle, use of ESA, and number of treatment cycles. Logistic regression assessed predictors of HMA treatment using age at MDS diagnosis, gender, Charlson Comorbidity Index (CCI), and calendar year as predictors. Poisson regression compared the risk of RBC or PLT transfusion between DAC and AZA, controlling for age, gender, CCI, treatment cycles, time to initiating treatment, and follow-up duration. Results: 2525 patients met full inclusion criteria (51% female), of whom 95.4% received no HMA treatment. Logistic regression revealed that females were less likely to receive HMA therapy (OR 0.486, p<0.001). There was no significant difference in follow-up duration between the DAC and AZA groups. Over 50% of HMA-treated patients received 4 or more treatment cycles, with no significant difference between DAC (n=37) and AZA (n=60). Mean (SD) days from MDS diagnosis to first treatment was 93.7 (101.4) for DAC vs. 50.8 (73.4) for AZA (p=0.03). Median treatment days per cycle were 4.86 for DAC and 5.00 for AZA (p>0.05). Mean (SD) days to discontinuation of RBC/PLT transfusion was 15.8 (48.3) for DAC and 70.1 (136.1) for AZA (p<0.05). The RBC/PLT transfusion rate was lower for DAC than for AZA (0.06 vs 0.17 per month, p<0.05). Poisson regression found a significantly lower likelihood of RBC/PLT transfusion in the DAC group (OR=0.206, p<0.05). Use of ESA did not differ between treatments (p>0.05). Discussion: Only a small portion of MDS patients receive HMA treatments, with females less likely to receive drug therapy. Initiation of decitabine occurs later than azacitadine after MDS diagnosis for unclear reasons. Decitabine is associated with lower rates of RBC/PLT transfusion and shorter time to discontinuation of transfusions, consistent with a prompt time to clinical response. Further research is needed to clarify optimal initiation timing for HMA treatment to maximize therapeutic benefits. Disclosures: Hatoum: Eisai Inc.: Research Funding. Lin:Eisai Inc.: Research Funding. Buchner:Eisai Inc.: Employment. Kim:Eisai Inc.: Employment.

scholarly journals Impact of Available Therapies on Survival of Very Elderly Myelodysplastic Syndrome (MDS) Patients (Age above 75 yrs)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4611-4611
Author(s):  
Uma Borate ◽  
Vipin Lohiya ◽  
Garrett Sherwood ◽  
Bradford E Jackson ◽  
Harry P. Erba
Keyword(s):  
Research Funding ◽  
Rank Test ◽  
Very Elderly ◽  
Data Safety ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Study Population ◽  
The Mean

Abstract Objective: Very elderly MDS patients (≥75 years) have limited therapeutic options and are usually ineligible for allogeneic stem cell transplantation. We aimed to study the impact of available MDS therapies on very elderly MDS patients and their correlation with patient demographics, performance status(PS) disease characteristics and patient outcomes. Methods: We performed a retrospective analysis of MDS patients ≥75 years diagnosed and treated at the University of Alabama at Birmingham from 2008 to 2014, with a minimum followup of 12 months. We analyzed demographics, ECOG PS, karyotypic risk categories as defined by the IPSS scoring system, blast percentage, IPSS and R-IPSS scores and overall survival (OS) in this population. We stratified patients based on therapy into two groups - the hypomethylating agent (HMA) group (defined as receiving therapy with ≥ 1 cycle of HMA; Azacitidine or Decitabine or both) and the non-HMA group, which included treatment with supportive transfusions, erythropoietin stimulating agents (ESAs), lenalidomide and cytotoxic chemotherapy. We analyzed group differences for all the parameters mentioned above using chi square test for categorical variables, and t test and Mann Whitney u-test for mean and medians respectively. In addition, OS was examined using Kaplan Meier curves using the log rank test. We used univariate and multivariate analysis to examine the effects of variables of interest on OS.All results were considered statistically significant at α=0.05 level. Results: The study population included 58 patients of which 35 patients were males (60%). Median age was 78 years. Forty patients (71%) of patients had good, 6% had intermediate and 23% had poor karyotypic profiles by the IPSS scoring system. ECOG ≥2 was observed in 44% of the patients with no significant differences in both groups. Average IPSS and R-IPSS scores were 1.2 and 4.5 respectively. Median OS for the entire study population was noted to be 15.5 months (7-34m). There were 25 patients in the HMA group and 33 patients in the non-HMA group. The blast percentage was higher in HMA group (20.5% vs 9.4%) compared to non-HMA group. More patients had a good karyotypic profile in the non-HMA group when compared to HMA group (80% vs 60%). There was a statistically significant difference between the mean IPSS and R-IPSS prognostic scores in non-HMA and HMA group (0.9 vs 1.7, p=0.010 and 3.5 vs 5.5, p=0.002) respectively. There was no significant difference in median overall survival between the non-HMA and HMA group (16.5 m (7-53) vs 15.5 m (5-19) p=0.278) respectively but the mean survival rates between non-HMA and HMA group were statistically different (32.81 vs 15.85, p=0.034). According to the log rank test, a statistical difference (p=0.027) in survival estimates was observed between the two groups on Kaplan Meier curve, where the HMA group had a significantly shorter survival compared to the non-HMA group. In the univariate analysis for the entire sample, higher IPSS score; R-IPSS score, and higher blast percentage were associated with increased rate of events. Moreover, rates of events were found to be lower in patients who did not receive HMA therapy (HR - 0.45, p=0.033), however in multivariable analysis, only higher blast percentage was associated with increased rate of events (HR - 1.06 p=0.025 95% CI - 1.004-1.11). Patients in the HMA group received average of 7.8 cycles. After stopping HMA therapy, 10 patients received other therapies including cytotoxic chemotherapy, hydroxyurea and lenalidomide, 4 were enrolled in a clinical trial, 9 received supportive transfusions and ESAs while 2 died immediately afterwards. Conclusion: Our study did not find a difference in median OS between patients who received HMA therapy versus non-HMA therapy in this population of very elderly MDS patients. Patients who received HMA therapy had a higher risk karyotypic profile, increased blast percentage and higher IPSS and R-IPSS scores. The average number of HMA cycles they received was 7.8, indicating adequate therapy. However, we could not evaluate transfusion needs, hospitalizations or other quality of life measures in these 2 groups. In conclusion, further studies need to be done to better evaluate various MDS therapies and their impact on quality of life and survival in this very elderly population with a higher comorbidity burden, possibly limiting the benefit of these treatments typically seen in younger MDS patients. Disclosures Borate: Genoptix: Consultancy; Seattle Genetics: Research Funding; Gilead: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau. Erba:Millennium/Takeda: Research Funding; Jannsen (J&J): Other: Data Safety and Monitoring Committees; Ariad: Consultancy; Millennium/Takeda: Research Funding; Celgene: Consultancy, Speakers Bureau; Astellas: Research Funding; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy; Astellas: Research Funding; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Incyte: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees; Jannsen (J&J): Other: Data Safety and Monitoring Committees; Amgen: Consultancy, Research Funding; Celator: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Ariad: Consultancy; Novartis: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees; Celator: Research Funding.

scholarly journals Azacitidin Is Effective in the Therapy Related Myelodysplastic Syndrome.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5554-5554
Author(s):  
Hirofumi Yamauchi ◽  
Masahiro Yokoyama ◽  
Yuko Mishima ◽  
Noriko Nishimura ◽  
Kyoko Ueda ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Research Funding ◽  
Poor Prognosis ◽  
De Novo ◽  
Genetic Alterations ◽  
Poor Risk ◽  
Significant Difference ◽  
One Year

Abstract Introduction: Myelodysplastic syndromes (MDS) are clonal hematopoietic neoplasms characterized by abnormal maturation of precursor cells which often translates into peripheral blood cytopenias and a high rate of transformation to acute myeloid leukemia (AML) due to accumulation of genetic alterations. The AZA-001 trial showed azacitidine (AZA) significantly prolonged median overall survival compared with conventional care regimens (24.5 vs 15.0 months; P=0.0001). AZA is standard first-line treatment for Intermediate-2 and High-risk myelodysplastic syndrome patients who are not immediate candidates for allogeneic stem cell transplantation, but this study included no cases of therapy related MDS (t-MDS). T-MDS is known to have poor prognosis, therefore it is very important to analyze the outcome of patients with t-MDS treated in the front-line with AZA. Methods: We studied newly diagnosed 29 MDS patients who were treated by AZA in our hospital from July, 2010 to April, 2016, retrospectively. AZA was given subcutaneously at 75 mg/㎡per day for 5 or 7 days every 28 days. Results: We analyzed 29 MDS patients. According to the WHO classification, there were 12 RA, 15 RCMD, 10 RAEB-1, 2 RAEB 2 and 1 MDS-U. The median age was 70 year (range 49-88), and men was 12 (41.3%). There were 12 de novoMDS cases (41.3%) and 17 t-MDS cases (58.6%). All of the t-MDS patients had previously received chemotherapy (17 patients, 100%) and 9 patients had also received radiotherapy (9 patients, 53%). Very poor risk group was 47.1% (9/17) in t-MDS group compared to 25.0% (3/12) in de novo MDS group (P=0.26). Median follow up time was 11.4 months (range 1.4-47.8). Twenty five patients (86.3%) were treated by AZA for 5 days. Four patients (13.7%) were treated by AZA for 7 days, but all 4 patients decreased the dosing period to 5 days due to unacceptable toxicity. AZA was given for a median of 4 cycles (range 1-33). In 29 MDS patients, 1-year overall survival (OS) was 60.5% (95% CI, 38.7-76.7%) and 1-year PFS was 40.1% (95% CI, 18.8-60.6%). After a median follow-up of 11.4 months, median OS was 18.7 months (95% CI, 9.4-21). One-year OS was 59.3% in t-MDS group compared to 63.6% in de novo MDS group (P=0.294). 1-year PFS was 38.4% in t-MDS group compared to 40.4% in de novo MDS group (P=0.626). One-year OS was 37.5% in very poor risk karyotype group (R-IPSS) compared to 74.6% in not very poor risk karyotype group (P=0.000748). 1-year PFS was 43.2% in very poor risk karyotype group compared to 39.0% in not very poor risk karyotype group (P=0.594). Focusing on t-MDS group, 1-year OS was 46.9% in very poor risk karyotype group (8/17 47%) compared to 74.1% in not very poor risk karyotype group (9/17 53%) (P=0.054). 1-year PFS was 48.0% in very poor risk karyotype group compared to 26.0% in not very poor risk karyotype group (P=0.339). Conclusions: In our study, 1-year OS in all MDS patients was 60.5%. It was slightly poor prognosis than 1-year OS in AZA-001 trial (about 70%). Our study include t-MDS cases (58.6%). Additionally, AZA was given for a median of 4 cycles in our study but 6 cycles in the AZA-001 trial. It showed severe patient's background of our study. These difference may cause the lower median OS and poorer prognosis. There trended to be more patients who had very poor risk karyotype in t-MDS group, but there was no significant difference between t-MDS and de novoMDS for the 1-year OS and PFS. Azacitidin is effective in the therapy related myelodysplastic syndrome. Disclosures Yokoyama: Chugai: Consultancy. Mishima:Chugai: Consultancy. Nishimura:Chugai: Consultancy. Terui:Yanssen: Honoraria. Hatake:Kyowa Kirin: Honoraria, Research Funding; Chugai: Research Funding; Otsuka: Consultancy; Meiji-Seika: Consultancy.

Azacitidine (AZA) Combination Therapy with Low-Dose AraC Is Well Tolerated and Highly Effective for MDS with Overt Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3260-3260
Author(s):  
Manabu Hirai ◽  
Mizuki Aimoto ◽  
Atsushi Inoue ◽  
Mitsuharu Hashimura ◽  
Erina Sakamoto ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Research Funding ◽  
Low Dose ◽  
Progressive Disease ◽  
Single Agent ◽  
In Vivo Studies ◽  
Risk Category ◽  
Significant Difference ◽  
Overt Leukemia

Abstract Introduction: Conversion to overt leukemia is the final, progressive and most aggressive stage in myelodysplastic syndromes (MDS). Azacitidine (AZA) is a promising agent for improving prognosis in higher-risk MDS, but inadequate as a single agent for progressive disease, for example with AML and the aggressive stage of MDS (aMDS), defined by clinical progression with the presence of disease-related symptoms such as fever, edema and effusions. For disease control in aMDS we have used low-dose AraC prior to AZA therapy (AraC→AZA), which was well tolerated by elderly patients. Significant benefits were observed not only in aMDS but also in MDS patients with overt leukemia, compared with single agent AZA therapy (sAZA). However two-week duration of the cyclic AraC and AZA therapy (AraC→AZA) was inconvenient for patients. We therefore combined AraC with AZA (AraC+AZA) for seven days. Five to eight hours after administration of 75 mg/m2 of AZA, 20 mg/m2 of AraC (s.c.) was given. Six of ten (60%) patients with overt AML achieved complete remission after single course of AraC+AZA therapy. We present a clinic-based pilot study of very simple, convenient, and effective combination therapy with AZA and AraC that can be used in older patients with MDS and overt AML. Method: We evaluated a total of 50 patients with MDS (29), CMML (4), overt AML (14) and relapsed AML (3) between March 2011 and July 2014. Those patients with MDS and CMML all had disease-related symptoms or disease progression in the previous three months (the so-called aggressive stage of MDS: aMDS). Twenty-two eligible patients with a median age of 73 years (55–87 years) were treated with single AZA (sAZA) 75 mg/m2/day i.v. on days 1–5, 8 and 9, every four weeks. With AraC→AZA (CA→AZA) therapy, AraC 10 mg/m2 was given twice daily on days 1–5 and Aclarubicin hydrochloride (Aclacinon) 14 mg/m2/day on days 1 and 2, followed by AZA 75 mg/m2/day i.v. for seven days (on days 8–12, 15 and 16). With AraC+AZA therapy (CA+AZA), 75 mg/m2 of AZA (i.v. / s.c.) was given in the morning, and 20 mg/m2 of AraC (s.c.) was administered 5–8 hours after the AZA on days 1–5, 8 and 9, every four weeks. Aclarubicin hydrochloride 14 mg/m2/day was given i.v. on days 1 and 2. With a persistently high WBC count after AraC+AZA therapy, 20 mg/m2 of AraC (s.c.) daily was continued until WBC decreased to 1–2x109 /L. After one cycle of (CA→/+AZA) as an induction therapy, 27 eligible patients with a median age of 74 years (62–86 years) were treated with AraC+AZA (one or two cycles) as consolidation therapy, and maintained on sAZA therapy. Responses were scored according to IWG 2006 criteria for MDS. Results: In those who received sAZA the diagnoses were RCMD n=3, RAEB1 n=5, RAEB2 n=9, CMML n=1, overt AML n=3, relapsed AML n=1; for CA→/+AZA (CA-AZA) the corresponding numbers were RCMD n=1, RAEB1 n=2, RAEB2 n=9, CMML n=3, overt AML n=10, and relapsed AML n=2. With sAZA, the IPSS-R risk category was intermediate in six, high in two, and very high in eight; for CA-AZA the numbers were respectively one, three and eight. The overall response rates for sAZA vs. CA-AZA were 27% and 74%. In the sAZA group progressive disease was seen in nine (40.9%) and failure (death) in two (9.1%), after one to three courses. Median overall survival (OS) in months was 5.8 vs. 19.0 for sAZA and CA-AZA respectively (P=0.002). In overt AML, CA-AZA also resulted in a significant improvement in OS (P=0.012) (median OS: sAZA 7.7 mo vs. CA-AZA 24.2 mo), with 60% CR rates after CA-AZA. In the CA-AZA group with favorable karyotypes, there was a significant difference in OS compared with sAZA (median OS in months: 9.0 vs. 24.2, P=0.005). The observed rate of adverse events in the CA-AZA group was no higher than the sAZA group. Conclusions: CA+AZA therapy was established based on both in vitro and in vivo studies (R.L. Momparler Cancer Res. 1975;35, G.L. Neil Cancer Res. 1976;3). After 2.5 years of observation of sAZA vs. CA-AZA therapy for aMDS, we found CA-AZA to be of significant benefit, even in patients with overt AML. Effects were observed after just one or two courses of CA+AZA. Greater benefit was seen in MDS patients with favorable karyotypes. AZA may work as a hypomethylating drug for epigenetic disorders and act in synergy with AraC. Because of failures (deaths) with sAZA and difficulties with planning a comparative clinical study in MDS patients, we now favor CA+AZA therapy for aMDS. We have presented our clinical evidence and methodology for treating MDS patients with AZA. Disclosures Hirai: Nippon shinyaku CO.,LTD: Speakers Bureau. Nakamae:Nippon Shinyaku CO.,LTD: Research Funding. Hino:Nippon Shinyaku CO.,LTD: Research Funding; astellas CO.,LTD: Research Funding.

Somatic Gene Mutations Serve As Molecular Biomarkers Predictive for Response to Immunosuppressive Therapy (IST) in Myelodysplastic Syndromes (MDS)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1664-1664 ◽  
Author(s):  
Rami S. Komrokji ◽  
Mintallah Haider ◽  
Najla H. Al Ali ◽  
Jeffrey E Lancet ◽  
Qing Zhang ◽  
...  
Keyword(s):  
Immunosuppressive Therapy ◽  
Lower Risk ◽  
Research Funding ◽  
Response Rate ◽  
Gene Mutations ◽  
Cancer Center ◽  
Trisomy 8 ◽  
Significant Difference ◽  
Somatic Gene ◽  
The Impact

Abstract Introduction Immunosuppressive therapy (IST) yields durable hematologic improvement (HI) in a subset of patients (pts) with lower risk MDS. Age, HLA-DR15+, and duration of transfusion dependence are the strongest independent clinical variables predictive for response. We investigated the impact of somatic gene mutations on response to IST in lower risk MDS pts. Methods MDS pts who received ATG +/- CSA were identified at the Moffitt Cancer Center. The National Institutes of Health (NIH) IST response model was calculated for each pt. Next Generation sequencing (NGS) for somatic gene mutations was conducted using DNA extracted from archived BM prior to therapy. All pts underwent mutation analysis by a 49 myeloid gene panel. The library was generated with the ThunderBolt (RainDance Technologies, Billerica, MA) and sequenced on a MiSeq instrument (Illumina, San Diego, CA). Alignment and variant calling was performed with NextGene (Soft Genetics, State College, PA). Results Sixty-six pts treated with ATG +/- CSA were identified. Median age was 61 and the majority of pts had IPSS lower risk disease with favorable risk karyotype. Median time to initiation of IST was 1 year. All pts received ATG (60% rabbit (r-ATG); 32% equine (e-ATG)), and CSA was used in 60% of pts. Overall frequency of HI was 42% with a trend favoring e-ATG vs. r-ATG (52% vs. 39%, p=0.09). Erythroid HI was evaluable in 30 pts with 60% responding, neutrophil improvement was evaluable in 15 pts and 39% responded, while platelet improvement was evaluable in 18 pts with 57% responding. Six of 18 (33%) pts with pancytopenia experienced trilineage response. Mean time from ATG to next therapy was 12 mo (median of 7.7 mo). Neither presence of an LGL clone, hypocellular BM or fibrosis, HLA DR15, trisomy 8, nor age influenced response to IST. Pts classified as IPSS-R Very high or high risk were unresponsive (n= 5), whereas 10 of 19 pts (53%) with intermediate risk responded. Poor risk IPSS karyotype was associated with a trend for lower response rate when compared to intermediate and good risk (25% vs. 41% vs. 44%; p=0.6). The response rate based on the NIH IST model was 38% for low response probability category pts and 45% for high probability category (p=0.5). Response rate to IST was higher if administered within 2 years from diagnosis, with an HI rate of 48% vs. 33% when treated after 2 years (p=0.04). Pts who received ATG as first line treatment or after lenalidomide had a trend for higher response rates than those treated after azacitidine (46%,75%, and 25% respectively). Addition of CSA significantly improved HI rate (51% vs. 27% for ATG alone, p=0.02). Transformation to AML occurred in 10 pts, 7% of responders and 24% of non-responders (p=0.08). Median OS was 67.2 mo with no significant difference based on IST response. Among 40 pts evaluated by NGS, 20 (50%) had at least one demonstrable somatic mutation (SM) and 9 pts (22.5%) had two or more SM. SF3B1 was the most common SM detected (n=9, 22.5%), followed by ASXL-1 (n=7, 17.5%), TET-2 (n= 5, 12.5%), and STAG2, EZH-2 and ZRSR2 (2 pts each, 5%), and 1 pt each with IDH-1, KDM6A, SETBP1, RAD2, GNAS or GATA-2. Absence of a SM was associated with a higher response to IST (70% vs. 40%, p=0.16), whereas number of SM (1 vs. 2+) did not influence response. The presence of an SF3B1 mutation was a significantly associated with IST nonresponse (1/9 SF3B1 SM, 11% vs. 21/31 WT, 68%; p=0.01). All pts with SF3B1 SM had ring sideroblasts >15% (RS) by morphology and the corresponding HI rate was 20% among pts with RS vs 50% for those without RS, p=0.09. Median OS in pts with an SF3B1 SM was 111 mo vs. 54 mo in SF3B1 WT (p=0.016). The two pts with EZH-2 and the single pt with WT-1 S achieved HI. Mean duration of response was 12 mo among pts with no SM vs. 9 mo in those harboring a SM (p=0.09). Rate of AML transformation among pts with a SM other than SF3B1 was higher in pts without SM (4/11 pts, 36%vs. 1/20, 5%; p =0.023, with a corresponding reduced median OS (52 mo vs. 96, p=0.24). Conclusions These findings support an improved response rate to ATG when administered in combination with CSA, and early in the disease course. The presence of an SF3B1 mutation adversely influences response to IST, suggesting a non-immunologic pathogenesis in this molecularly defined subset. The presence of non-SF3B1 somatic mutations adversely affects response duration and probability of AML transformation. SM should be considered in selection of IST in lower risk MDS patients. Disclosures Komrokji: Pharmacylics: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Incyte: Consultancy. Lancet:Seattle Genetics: Consultancy; Pfizer: Research Funding; Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. List:Celgene Corporation: Honoraria, Research Funding. Padron:Incyte: Research Funding; Novartis: Speakers Bureau.

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