scholarly journals Increased Bone Marrow Iron at Diagnosis Is Associated with Inferior Prognosis in Patients with Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3700-3700
Author(s):  
Annika Kasprzak ◽  
Sandra Becker ◽  
Martina Rudelius ◽  
Corinna Strupp ◽  
Kathrin Nachtkamp ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Median Survival ◽  
Myelodysplastic Syndromes ◽  
Iron Uptake ◽  
Research Funding ◽  
Blue Staining ◽  
Prognostic Impact ◽  
Iron Stores ◽  
Bone Marrow Iron

Abstract Introduction: Iron storage in patients (pts) with myelodysplastic syndromes at the time of diagnosis may vary from normal to iron overload. Even before the first blood transfusion, storage iron can be increased due to down-regulation of hepcidin and subsequent increase in duodenal iron uptake. Iron overload is known to worsen the prognosis of MDS patients, partly due to iron-related organ damage after long-term transfusion therapy, and partly due to an increased risk of infections. However, it is unclear whether increased storage iron at the time of diagnosis already has a prognostic influence. We assessed bone marrow iron stores at the time of MDS diagnosis and correlated them with clinical outcome. Methods: In a retrospective analysis of 3762 adult MDS patients from the Düsseldorf MDS Registry, Prussian blue staining of marrow smears was performed in our cytology lab to assess iron stores according to the following categories: normal or decreased iron stores versus increased iron stores versus iron overload. Patients were followed up for survival and AML evolution until June 2021. Median time of follow-up was 20 months. 67.4% of the patients died during the course of the disease. Results: The study included 3.762 adult patients who received their initial diagnosis of MDS between 1970 and 2021. 58% were diagnosed as non-blastic MDS ( MDS SLD (RS) (n=240), MDS MLD (RS) (n=350), MDSdel(5q) (n=107), and MDS-U (n=25). Iron stores were decreased in 8% of the patients, normal in 44%, increased in 41%, and strongly increased in 7% (massive iron overload). In 282 cases, histologic assessment of storage iron was available. When comparing cytologic and histologic assessment, we found a strong correlation (p<0.0005), since 87% of the patients with increased iron on cytomorphology also showed increased iron as assessed by histopathology. However, 37% of the patients who cytologically showed normal iron stores, were reported to have slightly increased iron as assessed by histopathology. Median and mean serum ferritin values of patients with normal or decreased iron stores were 295 and 629 µg/l, respectively, as compared to 548 and 902 µg/l, respectively, in patients with increased iron stores. The cumulative risk of AML evolution was not associated with the results of iron staining. Regarding survival, we found that patients with decreased or normal storage iron had a median survival of 31 months, whereas those with increased iron had a median survival of 28 months (p=0.007). Focusing on patients with non-blastic MDS, the difference was not significant (46 vs 44 ms). However, patients who presented as EB I (n=435), EBII (n=510), AML MRC (n=264), CMML I (n=254), or CMML II (n=77), showed a prognostic impact of storage iron; patients with increased iron had a median survival of 11 months, as compared to 16 months in patients with normal or decreased iron (p<0.0005). Conclusion: Increased tissue iron in the bone marrow at the time of diagnosis is associated with inferior survival in patients with MDS, primarily in patients with higher risk MDS. At diagnosis, patients are not yet transfusion-dependent. This suggests that increased iron reflects a prolonged period of increased duodenal iron uptake as a consequence of ineffective erythropoiesis. Therefore, increased marrow iron at the time of MDS diagnosis seems to be a surrogate parameter of hematopoietic insufficiency, which is the real cause of inferior prognosis. Disclosures Nachtkamp: Jazz: Honoraria; Bsh medical: Honoraria; Celgene: Other: Travel Support. Gattermann: Novartis: Honoraria; Takeda: Research Funding; Celgene: Honoraria. Germing: Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding.

Bone Marrow Hypocellularity Does Not Impair the Tolerability or Efficacy of Azacitidine (AZA) in Patients with Higher-Risk Myelodysplastic Syndromes Treated in the AZA-001 Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3808-3808
Author(s):  
John F Seymour ◽  
John M. Bennett ◽  
Alan F List ◽  
Ghulam J. Mufti ◽  
Steven D. Gore ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Supportive Care ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Prognostic Impact ◽  
Effective Treatment Option ◽  
Employment Equity ◽  
Post Hoc Analysis ◽  
Equity Ownership ◽  
Post Hoc

Abstract Abstract 3808 Background: Approximately 10–15% of patients with myelodysplastic syndromes (MDS) have a hypocellular bone marrow (BM) at diagnosis. Some studies have suggested hypocellular MDS may have an adverse prognostic impact, but this is controversial. In the Phase 3 randomized AZA-001 study, AZA prolonged overall survival (OS) in patients with higher-risk MDS compared with conventional care regimens (CCR) (Lancet Oncol, 2009). However, the efficacy and tolerability of AZA in the subset of patients with hypocellular MDS has not been determined. Purpose: This post hoc analysis was conducted to determine whether the prolongation of OS observed with AZA compared with CCR in the AZA-001 study is influenced by baseline BM cellularity. We also sought to explore the tolerability of AZA treatment in patients with higher-risk MDS and hypocellular BM. Methods: Study design of AZA-001 is reported elsewhere (Lancet Oncol, 2009). Briefly, patients with higher-risk MDS (FAB: RAEB, RAEB-t, or CMML, and IPSS Int-2 or High risk disease) were randomized to AZA (75 mg/m2/d SC × 7d q 28d) or to CCR (supportive care, low-dose Ara-C [LDAC], or intensive chemotherapy [IC]). In the current analysis, patients were divided into 2 groups based on centrally reviewed baseline BM biopsy samples which confirmed the diagnosis of MDS (J. Bennett): a hypocellular (≤30%) group and a non-hypocellular (>30%) group. OS was assessed using Kaplan-Meier methods and treatments were compared by log-rank analysis. Results: Of 358 patients in AZA-001 (AZA n=179, CCR n=179), BM cellularity data were available for 299 patients (AZA n=154, CCR n=145). At baseline, 87% of patients (n=260) had non-hypocellular BM and 13% of patients (n=39) had hypocellular BM. Of patients with hypocellular BM in the CCR group (n=18), 7 patients (39%) received supportive care, 9 (50%) LDAC, and 2 (11%) IC. In general, baseline characteristics were similar between the hypocellular and non-hypocellular BM groups. Similarly, age, % BM blasts, cytogenetics, cytopenias, and transfusion dependence, were generally balanced across treatments within the 2 cellularity groups (Table). Median (range) duration of AZA treatment cycles in hypocellular patients was 35.5 (28–54) days and in non-hypocellular patients was 33.0 (15–75) days. Response (complete or partial response [CR+PR]) rates in hypocellular patients treated with AZA were 0% and with CCR were 5.6% (p=0.4615); and hematologic improvement (HI) rates were 52% and 41%, respectively (p=0.532). In non-hypocellular patients treated with AZA or CCR, rates of CR+PR were 7.5% and 0.8%, respectively (p=0.010); and HI rates were 48% and 28% (p=0.001), respectively. The improvement in OS in AZA-treated patients was more pronounced in the hypocellular group than the non-hypocellular group, whereas OS in CCR-treated patients was similar regardless of BM cellularity (Figure). Median OS was significantly prolonged with AZA vs. CCR in both the hypocellular and non-hypocellular groups. In patients with hypocellular BM, at 33 months median OS was not reached (NR; 95% CI: 19.2, NR) in the AZA arm vs. 16.9 months (95% CI: 11.1, 19.3) in the CCR arm (p=0.001). In patients with non-hypocellular BM, median OS in the AZA arm was 21.1 months (95% CI: 16.2, 34.7) vs. 15.3 months (95% CI: 9.3, 17.6) in the CCR arm (p=0.012). Safety and tolerability in the two BM cellularity groups were similar to that seen in the overall AZA-001 study (Lancet Oncol, 2009). Frequencies of grade 3–4 hematologic AEs in AZA-treated patients in the hypocellular and non-hypocellular groups were similar: anemia (9.5% vs 14.7%, respectively), febrile neutropenia (9.5% vs 11.6%), leukopenia (14.3% vs 13.2%), neutropenia (61.9% vs 60.5%), and thrombocytopenia (61.9% vs 58.1%). Conclusions: In this post hoc analysis, the prevalence of patients with hypocellular MDS was 13%, consistent with the reported prevalence in the general MDS population (Bennett, 2009). The survival advantage with AZA vs. CCR in both baseline BM cellularity groups observed in this analysis was consistent with the overall OS advantage with AZA shown in AZA-001. These findings suggest AZA is a safe and effective treatment option for patients with BM hypocellularity. Disclosures: Seymour: Celgene Corporation: Consultancy, Honoraria, Speakers Bureau, Travel support Other. Bennett:Celgene Corporation: Consultancy. List:Celgene Corporation: Consultancy. Mufti:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Gore:Celgene Corporation: Consultancy, Research Funding. Fenaux:Celgene: Honoraria, Research Funding. Hetzer:Celgene Corporation: Employment, Equity Ownership. Songer:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.

Erythrocyte Protoporphyrin in the Detection of Iron Deficiency

1975 ◽  
Vol 21 (8) ◽  
pp. 1121-1127 ◽  
Author(s):  
Gordon D McLaren ◽  
John T Carpenter ◽  
Hipolito V Nino
Keyword(s):  
Bone Marrow ◽  
Iron Deficiency ◽  
Prussian Blue ◽  
Blue Staining ◽  
Comparable Group ◽  
Iron Stores ◽  
Erythrocyte Protoporphyrin ◽  
Bone Marrow Iron ◽  
The Mean ◽  
Mean Concentration

Abstract Any decrease in the availability of iron for incorporation into the heme moieties of hemoglobin results in an increase in the erythrocyte protoporphyrin concentration. Our aim was to compare protoporphyrin concentrations, determined spectrophotometrically, with body iron stores, as assessed from the amount of iron demonstrable by Prussian blue staining of bone marrow aspirates. The mean protoporphyrin concentration (175 µg/dl) in the erythrocytes of a group of patients with markedly decreased stainable marrow iron or no iron Was Significantly Greater (P < .001) than the mean concentration (76 µg/dl) in a comparable group with adequate bone marrow iron stores, except in the presence of certain interfering conditions. These results suggest that the erythrocyte protoporphyrin test may be a useful addition to the methods now available for assessing disorders of heme synthesis, the most common of which is iron deficiency.

Prognostic Impact of Monosomy 7 as a Single Anomaly In Primary MDS – Reclassification From Poor to Intermediate Prognosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1861-1861
Author(s):  
Julie Schanz ◽  
Heinz Tüchler ◽  
Francesc Sole ◽  
Mar Mallo ◽  
Barbara Hildebrandt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Median Survival ◽  
Working Group ◽  
Research Funding ◽  
Prognostic Impact ◽  
Partial Monosomy ◽  
Monosomy 7 ◽  
The Poor

Abstract Abstract 1861 Introduction: Total or partial Monosomy 7 (-7/del(7q)) is one of the most frequent cytogenetic abnormalities in MDS, occurring in about 11% of abnormal cases in patients (pts) with primary MDS. The cytogenetic module of the IPSS defines any abnormality of chromosome 7 as unfavourable and classifies them, combined with complex abnormalities, into the poor risk cytogenetic subgroup. However, in previous publications from other groups, the prognosis of isolated -7/del(7q) was described as intermediate. The aim of the present study was to re-analyze the prognostic impact of -7/del(7q) as a single anomaly based on a large, international MDS database which was previously presented at the 2009 ASH-meeting (Schanz et al. abstract #2772). Materials and Method: Patients with -7/del(7q), derived from the international MDS database were examined. The large international data collection contains 2901 patients with MDS, originating from the German-Austrian (GA)-, the International MDS Risk Analysis Workshop (IMRAW)- and the Spanish Cytogenetic Working group (GCECGH) and the International Cytogenetics Working Group of the MDS Foundation (ICWG). Inclusion criteria for the study were defined as follows: Primary MDS, age >=16, and bone marrow blasts <=30%. Regarding therapy, patients with primary MDS who received supportive care, short courses of oral chemotherapy or hemopoietic growth factors were included. Univariate and multivariate analysis were performed for overall survival (OS) and risk of AML-transformation (AML-t). In multivariate analysis, site, age, gender, bone marrow blast count, date of first diagnosis and number of peripheral cytopenias were defined as co-variables. Results: In total, 60 patients (2.1% of all pts/4.4% of abnormal cases) with an isolated -7/del(7q) were detected. The median age of these pts was 66.1 years, which is significantly lower compared to pts without monosomy 7 (70.0 years; p<0.01; t-test, 2-sided). Regarding peripheral blood count, the mean hemoglobin in -7/del(7q) pts (9.2 g/dl) as well as ANC (1.7*103/ul) did not differ significantly as compared to pts without -7/del(7q) whereas the platelet count in pts with -7/del(7q) was significantly lower (82*103/ul vs. 125*103/ul; p<0.01). The median overall survival in -7/del(7q) pts was 16.0 (95% CI 14.0–21.4) months and the Hazard ratio (HR; as compared to a normal karyotype with a median survival of 47.4 (44.0-53.4) months as the reference category) was 1.6 (1.1-2.3; <0.01). Regarding the risk of AML-transformation, the median time to AML was 42.2 (14.4-not reached) months and the HR 1.7 (0.9-3.2; p<0.01). In comparison, this differed significantly from the median survival- (p<0.0001) and time to AML-transformation (p=0.027) for complex abnormalities, which are included with -7/del(7q) in the poor risk IPSS cytogenetic subgroup and were 5.7 (4.7-6.8) and 8.2 (6.4-14.0) months, respectively. The HR for complex abnormalities was 4.3 (3.4-5.4; p<0.01) for OS and 5.2 (3.8-7.5; p<0.01) for AML-transformation. Conclusions: The re-analysis of -7/del(7q), based on the largest MDS patient cohort yet published, confirms that the prognostic impact of an isolated total or partial monosomy 7 for overall survival as well as the risk of AML-transformation is intermediate, rather than poor. This finding is anticipated to be considered in the upcoming revision of the IPSS. Acknowledgments: The authors like to thank the MDS-Foundation for its support. Disclosures: Valent: Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Bennett:Johnson & Johnson: Consultancy.

scholarly journals P0861THE RELATIONSHIP BETWEEN HEPCIDIN-25 AND BONE MARROW IRON IN ANEMIC, NON-DIALYSIS, CHRONIC KIDNEY DISEASE PATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Cristina-Stela Capusa ◽  
Ana-Maria Mehedinti ◽  
Gabriela-Adriana Talimba ◽  
Ana Stanciu ◽  
Liliana Viasu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Bone Marrow ◽  
Kidney Disease ◽  
Linear Regression ◽  
Iron Content ◽  
Blood Smear ◽  
Transferrin Saturation ◽  
Peripheral Blood Smear ◽  
Iron Stores ◽  
Bone Marrow Iron

Abstract Background and Aims Hepcidin-25 (Hep25) is a key known regulator of iron metabolism and its interactions with inflammation, iron stores and erythropoietic activity were involved in the pathogenesis of chronic kidney disease (CKD)-associated anemia. Therefore, our aim was to assess the determinants of serum Hep25 level in non-dialysis CKD patients. Method In this cross-sectional, single-center study, 52 subjects (56% men, 65±13 years) with CKD [estimated glomerular filtration rate, eGFR 14.5 (95%CI 16 to 25) mL/min] and anemia [hemoglobin, Hb 9.8 (95%CI 9.2 to 9.9) g/dL], not treated with erythropoiesis-stimulating agents (ESA) or iron in the previous 6 months, were enrolled. Patients with anemia of other causes than CKD, active infectious and inflammatory diseases, malignancy, severe hyperparathyroidism, transfusions during the last 3 months, and immunosuppressive therapy were excluded. The iron status was evaluated using both peripheral and central parameters. The iron stores were assessed by serum ferritin (Fer) and iron content in bone marrow macrophages (iMf, measured quantitively on a scale from 0 to 6). The iron available for erythropoiesis was assessed by transferrin saturation (TSAT) and the percentage of sideroblasts (%Sb). Anemia was further evaluated by a peripheral blood smear, erythrocytes indices and reticulocyte index. Serum Hep25 and erythropoietin (Epo) were assessed by ELISA (Bachem®, and Abcam® 119522, respectively). C-reactive protein (CRP), albumin, and parameters of kidney disease (eGFR, proteinuria) were also measured. Mann-Whitney, Kruskal-Wallis, Chi2 tests, Spearman bivariate correlation and multiple linear regression were used for statistical analysis. Results The median serum Hep25 of the whole cohort was 82.1 (95%CI 68.7 to 92.1) ng/mL. According to median Hep25, subjects were clustered in Group 1 (below median - G1) and Group 2 (above median - G2). %Sb and reticulocyte index had higher levels in G2 than in G1 [9 (95%CI 5 to 14) vs. 5 (95%CI 4 to 7) %, p=0.003 and 0.55 (95%CI 0.39 to 0.77) vs. 0.41 (95%CI 0.32 to 0.58), p=0.05, respectively], while the proportions of subjects with iMf suggestive for iron deficiency or iron overload were similar in G2 and G1 (38% vs. 50%, p=0.40, and 26% vs. 23%, p= 0.75, respectively). Peripheral blood smear, peripheral iron indices and all the other studied parameters were also alike. In bivariate analysis, Hep25 was positively associated both with indices of iron stores, i.e. Fer (rs = 0.30, p=0.03) and iMf (rs = 0.34, p=0.01) and indices of iron available for erythropoiesis, i.e. %Sb (rs = 0.55, p&lt;0.001) and (marginally) with TSAT (rs = 0.26, p=0.06). Meanwhile, Hep25 was not related to serum Epo, CKD parameters or inflammation markers. In a multivariate linear regression model that explained 28% of Hep25 variation, the percentage of bone marrow sideroblasts, i.e. the tissue iron available for erythropoiesis, was the only independent determinant of Hep25: Variables entered in the first step: reticulocyte index, percentage of medullary sideroblasts (%Sb), iron content in the bone marrow macrophages (iMf), serum ferritin, and transferrin saturation Conclusion In stable patients with advanced CKD, not treated with ESA or iron, with low to moderate inflammation, serum hepcidin was related only to bone marrow iron available for erythropoiesis, suggesting that in this clinical setting the need of iron for erythropoiesis prevails over inflammation in regulation of hepcidin synthesis.

Monocyte Ferritin as a Possible Index of Bone Marrow Iron Stores in Patients on Chronic Hemodialysis

Nephron ◽  
1990 ◽  
Vol 54 (1) ◽  
pp. 7-11 ◽  
Author(s):  
Nuha Nuwayri-Salti ◽  
F. Jabre ◽  
G. Sa’ab ◽  
Majida Daouk ◽  
Z. Salem
Keyword(s):  
Bone Marrow ◽  
Chronic Hemodialysis ◽  
Iron Stores ◽  
Bone Marrow Iron

Acute Myeloid Leukemia (AML) Treated with Azacitidine: Survival Outcomes for Patients Who Complete More Than Six Cycles Are Similar to High-Risk Myelodysplastic Syndrome/Low Blast Count AML

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5156-5156
Author(s):  
Jill Fulcher ◽  
Zahra Abdrabalamir Alshammasi ◽  
Nathan Cantor ◽  
Christopher Bredeson ◽  
Grace Christou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Median Survival ◽  
Research Funding ◽  
Survival Outcomes ◽  
Advisory Committees ◽  
Ottawa Hospital ◽  
Funding Agencies ◽  
Progression Of Disease ◽  
Refractory Aml

INTRODUCTION: Despite accumulating evidence supporting the efficacy of hypomethylating agents in patients with AML and > 30% bone marrow blasts as well as in relapsed/refractory AML, this therapy is not yet funded by National Health Plans / Healthcare Funding Agencies in a number of countries including Canada. The assistance of an industry-sponsored compassionate program has enabled provision of azacitidine for this group of patients at The Ottawa Hospital. We report here our local "real-world" experience of azacitidine efficacy in this diverse group of AML patients and identify a sub-group whose outcomes are equivalent to that of patients with higher-risk Myelodysplastic Syndrome (MDS) and AML with 20-30% blasts for whom azacitidine therapy has funding approval in Canada. METHODS: All patients who received azacitidine at The Ottawa Hospital between 2009 and 2016 were included in this single-center, retrospective analysis. Azacitidine was administered at a dose of 75mg/m2 subcutaneously daily for 7 consecutive days every 28 days. Response was evaluated with a repeat bone marrow aspirate and trephine biopsy after the 6th cycle. In those patients confirmed to have stable or responsive disease, azacitidine was continued until progression of disease, intolerable side-effects of the drug or the patient chose to discontinue therapy. Overall survival curves were generated using the Kaplan-Meier method and log-rank tests were used to compare subgroups of patients. Actuarial median survival months were calculated with 95% confidence intervals (CI). P-values less than 0.05 were considered statistically significant. RESULTS: During the study period, 109 patients received azacitidine: 54 had MDS /AML with 20-30% blasts (the 'funded' group) and 55 had either AML with > 30 % blasts (n=23), AML relapsed post-intensive chemotherapy (n=14), AML relapsed post-allogeneic stem cell transplant (n=10) or primary refractory AML (n=8) (the 'unfunded' group). Median survival of the 'funded' group was 12.2 months while median survival of the 'unfunded' group was 5.6 months (95% CI 3.3-7.7; p=0.0058). Of the AML patients in the 'unfunded' group, 24% completed more than 6 cycles of azacitidine compared to 52% of patients in the 'funded' group. In both the 'funded' and 'unfunded' groups, patients who completed more than 6 cycles of azacitidine had similar survival outcomes (p=0.7277): the 'funded' group had a median survival of 19 months (95% CI 14.4-25.3) while the median survival of this sub-population of the 'unfunded' AML group was 22 months (95% CI 11.7-24.9). Patients in both groups who failed to complete more than 6 cycles of azacitidine also had a similar outcome (p=0.39), with a median survival of 5.7 months (95% CI 4.0-6.3) for patients with MDS/AML 20-30% blasts and 3.6 months (95% CI 2.2-5.1) for AML patients with > 30% blasts or relapsed/refractory disease. Reasons for patients not completing at least 6 cycles of azacitidine included progression of disease (25%), bacterial infections most commonly pneumonia (53%) and patient preference (7%). CONCLUSION: A significant sub-population of AML patients with > 30% blasts or refractory/relapsed AML can achieve a meaningful survival benefit with the hypomethylating agent, azacitidine. A higher proportion of this AML patient population discontinued azacitidine as a result of infective complications. The provision of routine prophylactic antibiotics may enable more patients with AML to receive an adequate amount of azacitidine to achieve therapeutic benefit and warrants further investigation. Our results add to the growing body of 'real-world' evidence that supports healthcare funding agencies to provide coverage of azacitidine for patients with AML who in some countries at present do not fulfill government funding criteria. Disclosures Bredeson: Otsuka: Research Funding. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sabloff:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding.

Activity Of Single Agent Temsirolimus and Associated Impact On Bone Marrow Vascularization and T-Cell Composition In Patients With Myelodysplastic Syndromes – Result Of The Prospective Temds Trial Of The German MDS-SG

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2808-2808
Author(s):  
Martin Wermke ◽  
Claudia Schuster ◽  
Claudia Schönefeldt ◽  
Christiane Jakob ◽  
Malte von Bonin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Adverse Events ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Single Agent ◽  
Infectious Complications ◽  
T Cell Subsets ◽  
Concentration Data ◽  
Cell Composition

Abstract Introduction Enhanced progenitor proliferation, bone marrow (BM) hypervascularization and disturbed immune regulation contribute to the pathogenesis of myelodysplastic syndromes (MDS). Inhibition of mammalian-target of rapamycin (mTor) by temsirolimus (TEM) might be a promising strategy to target these disease-specific cellular alterations. We report on the effects of single agent TEM on the clinical course as well as on immune composition and BM vascularization of MDS patients treated within the prospective, multicenter “TEMDS”-trial (NCT01111448). Patients, Materials and Methods Twenty patients being either IPSS low/int-1 MDS (n = 9) or IPSS int-2/high after azacitidine failure were treated with TEM at a dose of 25 mg/week in the absence of toxicity or disease progression. BM was reevaluated after 4 months of treatment with the option of TEM continuation for a maximum of 12 months in responding patients. Translational research within this study included flowcytometry-based measurement of changes in T-cell composition as well as determination of cytokine levels and BM-vascularization prior to and after TEM. Results Of 20 patients treated, 15 discontinued TEM treatment prematurely due to intolerable side effects (n = 11), infectious complications (n = 3), or progression to AML (n = 1). Fatigue, stomatitis and profound leukopenia were the most frequent adverse events. A total of 13 severe adverse events were encountered in 10 patients and 1 patient died of infectious complications during TEM treatment. Of the 5 patients who were treated for at least 4 months and underwent regular BM reevaluation, none showed signs of response according to IWG criteria. TEM treatment resulted in a remarkable, although non-significant, decrease in total number of lymphocytes in the pB (pre: 74.6%, post: 48.4%, p = 0,083) and BM (pre: 23.5% post: 20.1%, p = 0.123). Within the T-helper cell compartment a trend towards an increase in regulatory T-cell (Treg) frequency was observed (pB: pre: 6.0 %, post: 6.4 %, p = 0.083). Moreover, the balance between naive (CD45RA+/CD45RO-) and activated/memory (CD45RA-/CD45RO+) Treg shifted significantly in favor of the latter (p = 0.004). Plasma analysis in BM and pB revealed, that these changes were obviously not mediated by alterations in TGFβ plasma levels. In a total of 12 assessable patients, a significant (p = 0.006) decrease of BM vascularization was observed after treatment with TEM for a median of 5 weeks (Fig. 1). There were, however, no changes in the medullary or peripheral blood VEGF concentration (data not shown). Conclusions Selective inhibition of the mTOR signaling cascade in MDS patients results in specific alterations of the composition of T-cell subsets as well as BM vascularization. Given the absence of any hematological response we suggest that these drug-induced modifications cannot alter the natural course of the disease. Disclosures: Wermke: Pfizer: Research Funding. Off Label Use: Temsirolimus is licensend for the treatment of MCL and RCC but not MDS. Platzbecker:Pfizer: Research Funding.

Efficacy and Safety of Eltrombopag for Treatment of Patients with Myelodysplastic Syndromes after Hypomethylating-Agent Failure: A Phase 2 Clinical Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1691-1691 ◽  
Author(s):  
Maliha Khan ◽  
Bodden Kristy ◽  
Tapan Kadia ◽  
Alessandra Ferrajoli ◽  
Yesid Alvarado ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Phase 2 ◽  
Open Label ◽  
Bone Marrow Fibrosis ◽  
First Response ◽  
Transfusion Requirements ◽  
Marrow Fibrosis

Abstract Background: Myelodysplastic syndromes (MDS) are malignant clinical disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, peripheral cytopenias and a property to transform into acute myeloid leukemia (AML). Standard of care for MDS includes the hypomethylating agents (HMAs) (i.e. azacitidine, decitabine) to improve quality of life, decrease transfusion requirements and improve clinical outcome. However not all patients (pts) respond to HMAs and even in responding pts, cytopenias may persist. HMA-failure MDS has extremely poor prognosis and currently there are no approved therapeutic options for such pts who are often of advanced age with frequent comorbidities. Objectives: The dual primary objectives of this study evaluate the safety and efficacy of the second-generation thrombopoietin-receptor agonist (TPO-RA) eltrombopag (EPAG) for the treatment of MDS pts at the time of HMA-failure. Secondary objectives include incidence of transformation to AML and evaluation of bone marrow fibrosis during therapy. Methods: Eligible pts for this 2-arm phase 2 open-label clinical trial included adults with MDS after completing >4 HMA cycles with failure to achieve at least a partial response, or the presence of ongoing cytopenias per IWG criteria. Arm A includes eltrombopag monotherapy and Arm B includes eltrombopag with continuation of the HMA at the previous dosing schedule. The starting eltrombopag dose is 200mg orally daily, which can be increased to 300mg in the absence of toxicity. First response is assessed after 2 cycles with each cycle lasting 28 days. The primary efficacy endpoint was overall response rate based on the IWG-2006 criteria. Results: To date, 23 pts with a median age of 72 years (range 42-84 years) have been enrolled. Prior to study entry, pts had received a median of 6 (range 4-25) HMA cycles. Cytogenetics were diploid in 12 (53%), intermediate in 7 (30%), and high risk in 4 (17%) pts by IPSS. Median bone marrow blasts at study start was 3% (range 0-15%). Arm A has enrolled 7 pts with a median age of 74 years; Arm B has enrolled 16 pts with median age of 69 years. In Arm B, ongoing HMA therapy includes azacitidine in 7 (44%) and decitabine in 9 (56%). Nine (39%) pts increased to 300mg EPAG after median of 8 weeks on study. Median total cycles received on study is 5 (1-17); median OS has not been reached. Overall, 16 pts are response-evaluable; 7 pts discontinued prior to the first response assessment at 2 months (4 due to AEs including myalgias/fatigue (n=2), hyperbilirubinemia (n=1), and pneumonia (n=1), 2 per pt request and 1 for pt inability to comply with protocol requirements). Of the 16 response-evaluable pts, 3 (19%) in Arm B demonstrated platelet improvement, including one pt necessitating EPAG dose-reduction to 100mg due to platelet count exceeding 450 x10⁹/L with concomitant ANC recovery at 200mg EPAG dose level. An additional 8 (35%) pts have remained on study for a median of 5 cycles (2-17) with stable disease. Two pts discontinued therapy due to disease progression, including 1 (4%) that progressed to AML. The most common non-hematologic AEs regardless of attribution included hyperbilirubinemia (n=14, 61%), fatigue (n=13, 56%) myalgias (n=11, 48%), fever (7, 30%), dyspnea (7, 30%), nausea (6, 26%) and transaminitis (4, 17%). No significant increase in bone marrow fibrosis has been observed. Conclusion: Eltrombopag orally daily appears to be a safe and beneficial supportive adjunct for pts with MDS while receiving HMA-therapy or after HMA-failure due to persistent cytopenias. Treatment on this study continues and larger prospective clinical trials are needed to confirm these preliminary findings. Disclosures Off Label Use: Eltrombopag for the treatment of MDS-related cytopenias". Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. DiNardo:Novartis: Research Funding.

Comprehensive Genomic Analysis Provides Further Evidence That Iron Overload Can Induce Genetic Instability in Myelodysplastic Syndromes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2842-2842 ◽  
Author(s):  
Gina Westhofen ◽  
Christina Ganster ◽  
Fabian Beier ◽  
Tienush Rassaf ◽  
Haifa Kathrin Al-Ali ◽  
...  
Keyword(s):  
Iron Overload ◽  
Myelodysplastic Syndromes ◽  
Genetic Instability ◽  
Research Funding ◽  
Snp Array ◽  
Iron Chelation ◽  
Genomic Analysis ◽  
Array Analysis ◽  
Γh2ax Foci ◽  
Snp Array Analysis

Abstract Introduction: Experimental and clinical data have shown that iron overload (IO) has the potential to accelerate progression of myelodysplastic syndromes (MDS) towards secondary leukemia and coincides with a lower survival rate. While genetic instability is understood as a common driver of MDS progression, the mechanisms involved have not yet been fully explored, albeit that oxidative stress is considered to be a main factor for IO related genetic instability. We aimed to investigate the influence of IO, measured by serum ferritin (SF) as a suitable surrogate parameter, on the stability of the genome of MDS patients (pts). Patients/Methods: 60 pts with proven MDS were included, cut-off for elevated SF being 275 µg/l. 29 pts had normal SF levels (median 61 µg/l [range 8-256 µg/l]), 31 pts had elevated SF levels (median 1,246 µg/l [283-6,907]); 1 out of 8 patients with SF > 1,005 µg/l tested positive for labile plasma iron (LPI). Pts were investigated for possible correlations of IO with distinct manifestations of genetic instability as shown by TP53 mutations, chromosome banding analysis, and molecular karyotyping (SNP array analysis). DNA double-strand breaks were quantified by γH2AX immunostaining on enriched CD34+ peripheral blood cells (PB). In addition, telomere length (TL) in PB granulocytes and lymphocytes was analyzed using flow-FISH, PB of 104 healthy donors being used for age-adaption. Plasma nitric oxide metabolites (nitrite, nitrate, nitroso species) are pending but will be screened for a possible correlation with SF. Results: Parameters for genomic stability were determined in the group of pts with elevated SF levels and the group of pts with normal SF levels. Through SNP array analysis, pts with increased SF levels were found to have significantly bigger total genomic aberrations (TGA) size than the subgroup with normal SF levels (median 87.5 Mbp TGA [range 0-229] vs. 0 Mbp TGA [0-155]; p = 0.005; Fig. 1). Likewise, telomere analysis showed significant more age-adapted TL shortening in granulocytes, representing the myeloid compartment, in the subgroup with increased SF levels (mean -1.81 kb) compared to patients with normal SF (0,64 kb, p = 0.003; Fig. 2). No significant TL shortening in lymphocytes of pts with normal SF was observed compared to pts with elevated SF. When only pts with marrow blasts <10% were considered, the subgroup with increased SF levels exhibited higher numbers of γH2AX-foci per CD34+ cell (median 5.7 γH2AX foci [range 2.1-8.6] vs. 1.6 γH2AX foci [0.5-3.5]; p = 0.008; Fig. 3). Elevated SF levels had no impact on the number, or type of chromosome abnormalities. Sanger sequencing identified only one patient with a TP53 mutation (SF = 1,246 µg/l); a search for smaller TP53-mutated clones by ultra-deep-sequencing is under way. Conclusion: In this MDS cohort, higher SF levels were significantly associated with bigger TGA size, premature granulocyte TL shortening, and increased numbers of γH2AX foci in CD34+ cells. These results further support the assumption that IO might be causally related to genetic instability in pts with MDS. Furthermore, our data suggest that SF levels not only above 1,000 µg/l, but also between upper limit of normal value but below 1,000 µg/L adversely affect genetic stability. Additionally, our results imply that the biological relevance of LPI for IO in MDS might be overestimated and is in need of reevaluation. Therefore, iron chelation might be relevant for pts with MDS at lower SF levels than previously thought. Whether investigation of the level of genetic instability by comprehensive genomic analysis as indicated above may be beneficial for the therapeutic decision regarding the timing of iron chelation therapy in individual pts with MDS remains to be explored. Disclosures Al-Ali: Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Brümmendorf:Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: Patent on the use of imatinib and hypusination inhibitors, Research Funding. Gattermann:Novartis: Honoraria, Research Funding.

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