Red Blood Cell Transfusion Requirement at Diagnosis Adversely Affects Both Overall and Leukemia-Free Survival in Primary Myelofibrosis - Increased Serum Ferritin or Total Transfusion Burden Does Not

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5232-5232
Author(s):  
Ayalew Tefferi ◽  
Ruben A. Mesa ◽  
Jocelin Huang ◽  
Animesh D. Pardanani ◽  
Kebede Hussein ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Prognostic Value ◽  
Serum Ferritin Level ◽  
Transfusion Requirement ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Primary Myelofibrosis ◽  
Disease Course ◽  
Kaplan Meier ◽  
Rbc Transfusion

Abstract BACKGROUND: In myelodysplastic syndromes (MDS) without excess blasts, red blood cell (RBC) transfusion requirement has been associated with poorer overall (OS) and leukemia-free (LFS) survival, suggesting that transfusion dependency is a marker of more severe disease (JCO2005;23:7594). We recently reported similar results in refractory anemia with ring sideroblasts (RARS): RBC transfusion requirement was an IPSS-independent adverse prognostic factor, but neither serum ferritin nor transfusion burden had prognostic value (AJH2008;83:611). Here, we examine the prognostic relevance of serum ferritin, need for RBC transfusions at time of diagnosis, and total transfusion burden in primary myelofibrosis (PMF). METHODS: We reviewed medical records to ascertain the clinical and laboratory features of 185 consecutive patients diagnosed with PMF according to the 2001 World Health Organization (WHO) criteria. Patients were excluded if ferritin measurements at time of diagnosis were unavailable. OS and LFS curves were constructed by Kaplan-Meier method, taking the interval from the date of diagnosis to death, leukemic transformation, or last contact. Log-rank test was used to test the homogeneity of survival curves over different groups. Cox proportional hazards model was utilized to determine the impact of various clinical and laboratory variables on OS and LFS. RESULTS: Clinical characteristics at diagnosis: Median age was 58 years (range 15–81; 110 males). Median serum ferritin level at diagnosis was 164 ng/mL (range 1–3903) and was ≥1000 ng/mL in 22 patients (12%). 101 (55%), 65 (35%) and 19 (10%) patients were assigned low, intermediate- and high-risk disease category (Blood1996;88:1013). In addition, 32 (17%) patients required RBC transfusions, 33% had constitutional symptoms and 39% displayed ≥ 1% circulating blasts. Where evaluated, 40% of the patients had cytogenetic abnormalities and 56% JAK2V617F. Events during the disease course: At a median follow-up of 28 months (range 0.5–231), 79 (43%) deaths and 15 (8%) leukemic transformations were documented. During this period, 126 (68%) patients required some form of therapy other than transfusion, including splenectomy in 33 (18%); only 4 underwent allogeneic stem cell transplantation. Causes of death were documented in 33 instances and none were attributed to iron overload. Median peak serum ferritin level during the disease course was 231ng/mL (range 9–13,080); 144 (78%) patients had peak levels <1000 ng/mL, 28 (15%) between 1000 and 3000 ng/mL, and 13 (7%) above 3000 ng/mL. Number of total RBC transfusions ranged from none to 121. Iron chelation therapy was reported in 62 patients (34%). Prognostic factors for OS and LFS: Kaplan-Meier projected median survival was 72 months. By univariate analysis, increased serum ferritin level at diagnosis considered as either a continuous (p<0.0001) or categorical (≥ 1000 ng/mL) variable (p<0.0001), RBC transfusion requirement at diagnosis (p<0.0001) and higher number of total RBC units transfused during the course of the disease (p=0.004) were all associated with inferior survival. However, only RBC transfusion requirement at diagnosis sustained its prognostic significance when age and conventional prognostic risk scores were added to the multivariable model as covariates. Similarly, a peak serum ferritin level of > 3000 ng/mL documented during the disease course was not detrimental to survival. History of iron chelation therapy was associated with shortened survival (p=0.003). Multivariable analysis that included previously described risk factors for LFS also identified RBC transfusion requirement at diagnosis as an additional and independent risk factor. CONCLUSIONS: Serum ferritin level at time of diagnosis or during the disease course of PMF lacks independent prognostic value for either OS or LFS. The same is true for total transfusion burden. However, although hemoglobin <10 g/dL is a component of all currently utilized prognostic scoring systems for PMF, the presence of a more severe erythropoietic defect as indicated by RBC transfusion need at time of diagnosis has an additional adverse prognostic value for both OS and LFS.

A Multi-Center, Open Label Study Evaluating the Efficacy of Iron Chelation Therapy with Deferasirox in Transfusional Iron Overload Patients with Myelodysplastic Syndromes or Aplastic Anemia Using Quantitative R2 MRI

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3649-3649 ◽  
Author(s):  
Yoo-Hong Min ◽  
Hyeoung Joon Kim ◽  
Kyoo Hyung Lee ◽  
Sung-Soo Yoon ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Chelation Therapy ◽  
Transfusion Requirement ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Dry Weight ◽  
Mean Value ◽  
One Year

Abstract Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). Measurement of liver iron concentration (LIC) is used as a surrogate for total iron burden to guide chelation therapy in transfusion-dependent patients. Although deferasirox (Exjade®, ICL670) is an oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis, the clinical data on its specific benefits of iron chelation, including reduction of LIC, in transfusion-related iron overload patients with MDS or AA has been limited. We have prospectively investigated the efficacy of deferasirox for iron chelation by serial measurement of serum ferritin level and LIC, which is measured in vivo using quantitative tissue proton transverse relaxation rates (R2) magnetic resonance imaging (MRI), in transfusional iron overload patients with MDS or AA. Here we report the interim analysis data. A total of 79 patients with de novo MDS (n = 29) or idiopathic AA (n = 50) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a median of 30 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (10.3%), 20 (69.0%), and 4 cases (13.8%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64%) were severe form. Mean value of serum ferritin level in enrolled patients was 4,417 ± 3,378 (4,788 ± 3,996 in MDS, 4,185 ± 2,962 in AA) ng/ml at the time of deferasirox initiation. LIC value was measured using quantitative R2 MRI and FerriScan (Resonance Health, Australia) analysis. Mean value of LIC was 23.9 ± 13.8 (26.1 ± 15.0 in MDS, 22.8 ± 13.2 in AA) mg Fe/g dry weight. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p<0.001). Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin falls below 500 ng/ml, treatment was withheld. A consistent decrease in the serum ferritin level was demonstrated during the first 6 months in vast majority of patients despite of continued transfusion (209.7 ± 159.9 ng/ml and 324.0 ± 289.4 ng/ml per month in MDS and AA, respectively). Over the study period, patients with MDS or AA received a mean of 3.7 and 2.7 units RBC per month, respectively. After 6 months of medication, a slower decrease in the serum ferritin level was observed in MDS patients. In 30 cases, one-year medication of deferasirox was completed. At the end of study (EOS), the serum ferritin levels were significantly decreased to 3,085 ± 2,150 ng/ml (64.4% of baseline level) and 2,913 ± 2,232 ng/ml (69.6% of baseline level, p<0.01) in MDS and AA, respectively. One-year follow-up R2 MRI could be evaluated in 24 cases, and LIC was significantly decreased to the level of 19.3 ± 13.6 mg Fe/g dry weight (67.4% of baseline value, p=0.01). Decrease in the level of LIC at EOS in MDS (64.3% of baseline) was comparable to that in AA cases (68.5% of baseline). The most common drug-related adverse events (AE) were gastrointestinal disturbances, non-progressive increase in serum creatinine, and skin rash. However, AE were transient and mild-to-moderate in severity. Deferasirox was discontinued in 28 (35.4%) cases because of death (7 in MDS and 6 in AA), patient refusal (11 cases), and decrease in the serum ferritin level below 500ng/ml (4 cases). All death was ascribed to disease-related causes including cytopenia in nine (11.4%) and disease progression in one (1.3%). This study clearly shows that deferasirox is effective in reducing LIC and serum ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Careful assessment of patient’s transfusion requirement will be important in making dose adjustment according to purpose of iron chelation. Data from extension phase of this clinical trial may expand our knowledge about the beneficial effects of deferasirox on prolonging survival and improving quality of life in these patients.

A Multi-Center, Open Label Study Evaluating the Efficacy of Iron Chelation Therapy with Deferasirox In Transfusional Iron Overload Patients with Myelodysplastic Syndromes or Aplastic Anemia Using Quantitative R2 mri.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1125-1125
Author(s):  
Yoo-Hong Min ◽  
Hyeoung Joon Kim ◽  
Kyoo-Hyung Lee ◽  
Jae Hoon Lee ◽  
Hee-Sook Park ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Myelodysplastic Syndromes ◽  
Serum Ferritin Level ◽  
Chelation Therapy ◽  
Transfusion Requirement ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Dry Weight ◽  
Mean Value

Abstract Abstract 1125 Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). Measurement of liver iron concentration (LIC) is used as a surrogate for total iron burden to guide chelation therapy in transfusion-dependent patients. Although deferasirox (Exjade®, ICL670) is an oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis, the clinical data on its specific benefits of iron chelation, including reduction of LIC, in transfusion-related iron overload patients with MDS or AA has been limited. We have prospectively investigated the efficacy of deferasirox for iron chelation by serial measurement of serum ferritin level and LIC, which is measured in vivo using quantitative tissue proton transverse relaxation rates (R2) magnetic resonance imaging (MRI), in transfusional iron overload patients with MDS or AA. Here we report the interim analysis data. A total of 97 patients with de novo MDS (n = 44) or idiopathic AA (n = 53) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a mean of 28.6 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (8.3%), 25 (69.4%), and 4 cases (11.1%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64.2%) were severe form. Mean value of serum ferritin level in enrolled patients was 3,482.6±436.7 ng/ml in MDS, and 3,904.4±399.2 ng/ml in AA at the time of deferasirox initiation. LIC value was measured using quantitative R2 MRI and FerriScan (Resonance Health, Australia) analysis. Mean value of LIC was 20.8 ± 3.5 mg Fe/g dry weight in MDS and 22.6 ± 2.2 mg Fe/g dry weight in AA. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p<0.001). Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin falls below 500 ng/ml, treatment was withheld. Over the study period, patients with MDS and AA received a mean of 24.2 and 22.0 units RBC per year, respectively. At the end of study (EOS), the serum ferritin levels were significantly decreased to 3,045.1±446.5 ng/ml and 2,614.7±311.9 ng/ml (p=0.005) in MDS and AA, respectively. One-year follow-up R2 MRI could be evaluated in 55 cases, and at the end of study (EOS), the LIC were significantly decreased to 14.3±2.9 mg Fe/g dry weight (p=0.05) and 15.3±2.3 mg Fe/g dry weight (p=0.001) in MDS and AA, respectively. The most common drug-related adverse events (AE) were gastrointestinal disturbances, non-progressive increase in serum creatinine, and skin rash. However, AE were transient and mild-to-moderate in severity. Deferasirox was discontinued in 30.9% cases because of death, patient refusal, and decrease in the serum ferritin level below 500ng/ml. All death was ascribed to disease-related causes. This study clearly shows that deferasirox is effective in reducing LIC and serum ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Careful assessment of patient's transfusion requirement will be important in making dose adjustment according to purpose of iron chelation. Data from extension phase of this clinical trial may expand our knowledge about the beneficial effects of deferasirox on prolonging survival and improving quality of life in these patients. Disclosures: No relevant conflicts of interest to declare.

Serum Ferritin Level At Referral Provides Independent Prognostic Information For Overall Survival In Primary Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2824-2824
Author(s):  
Animesh D. Pardanani ◽  
Terra L Lasho ◽  
Christy Finke ◽  
Ramy A. Abdelrahman ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Serum Ferritin ◽  
Prognostic Value ◽  
Ferritin Level ◽  
Primary Myelofibrosis ◽  
Light Chains ◽  
Circulating Biomarkers ◽  
Free Light Chains ◽  
Free Survival ◽  
Rbc Transfusion

Abstract Background Recent studies have suggested that increased circulating free light chains, inflammatory cytokines, hepcidin, ferritin, and ASXL1 mutated status have independent prognostic value for survival in primary myelofibrosis (PMF). In the current retrospective study, we studied all the aforementioned variables in the context of DIPSS-plus to examine their relative prognostic contributions for overall and leukemia-free survival. Methods The diagnosis of PMF was according to WHO criteria. The study population included all consecutive referrals to the Mayo Clinic, Rochester, MN where complete information on clinical and laboratory parameters and bone marrow karyotype was available. Inclusion to the study required availability of a research blood sample collected at referral. Levels of circulating free light chains (FLC) (J Clin Oncol. 2012 Apr 1;30(10):1087), inflammatory cytokines (J Clin Oncol. 2011 Apr 1;29(10):1356), hepcidin and ferritin (Am J Hematol. 2013 Apr;88(4):312) were determined as previously described. Disease-relevant mutations (ASXL1, SRSF2, EZH2, IDH-1/2, SF3B1, JAK2V617F and MPLW515) were identified as previously described (Leukemia. 2013 Apr 26. doi: 10.1038/leu.2013.119). Results A total of 224 PMF patients were studied (66% male; median age 63 years, range 18-83 years). The DIPSS-plus distribution was: Low 23 (10%), Int-1 26 (12%), Int-2 98 (44%), and High 77 (34%). Clinical characteristics were: unfavorable karyotype 13%, hemoglobin <10 g/dL 58%, leukocyte count >25 x 109/L 13%, platelet count <100 x 109/L 20%, peripheral blasts ≥1% 62%, red blood cell transfusion-dependent 38%, and constitutional symptoms 36%. Mutation frequencies were: JAK2V617F 61% (n=220), MPLW515 6% (n=204), ASXL1 34% (n=154), SRSF2 16% (n=189), IDH-1/2 3% (n=209), EZH2 1.5% (n=134), SF3B1 5% (n=91) and SETBP1 4% (n=114). Distribution of circulating biomarkers was: FLC >receiver operating characteristic (ROC) cutoff of 3.78 mg/dL 37% (n=222), interleukin (IL)-2R and/or IL-8 >3 standard deviations above normal mean (SD) 75% (n=197), ferritin ≥1000 mcg/L 18% (n=146), ferritin ≥500 30% (n=146), and hepcidin >3SD 72% (n=203). Median follow up from the time of referral was 45 months (range 1-317 months); during this period, 139 deaths (62%) and 27 (12%) leukemic transformations have been documented. The median overall survival of the entire cohort was 61 months. The following variables had DIPSS-plus independent predictive value for inferior survival: ferritin ≥1000 mcg/L (HR 1.9), ASXL1 mutated status (HR 1.7) and FLC >ROC cutoff (HR 2.0) and IL-2R and/or IL-8 >3SD (HR 1.6) (all p<0.05). When the aforementioned variables were added to the multivariate model (sequentially or altogether), only serum ferritin >1000 mcg/L retained its significance for overall survival independent of DIPSS-plus (HR 2.1; p=0.03). The predictive significance for increased ferritin level was maintained in RBC transfusion-dependent (ferritin ≥1000 mcg/L; n=26/54; median survival 21 versus 59 months; p=0.03) and -independent (ferritin >500 mcg/L; n=5/92; median survival 20 versus 80 months; p=0.0002) patients. Multivariable analysis identified the following predictors for inferior leukemia-free survival: SRSF2 mutated status (HR 4.8), unfavorable karyotype (HR 4.0), and circulating blasts ≥1% (HR 3.0) (p<0.05). Conclusions When considering composite risk-assessment in PMF where input variables were disease-relevant mutations and circulating biomarkers in addition to traditional clinical parameters, only increased serum ferritin levels at time-of-referral retained adverse predictive value for overall survival independent of DIPSS-plus. The prognostic value of serum ferritin was independent of anemia and RBC transfusion need. It appears to more fully capture the severity of the underlying erythropoietic defect in PMF by also likely reflecting (as an acute-phase reactant) the marrow-suppressive effect of disease-related inflammation. The shortened survival in patients with increased ferritin levels was unrelated to iron overload since none of the deaths, where information was available, were caused by cardiac siderosis. Serum ferritin levels were not associated with leukemic transformation risk. In the latter analysis, only SRSF2 mutations, unfavorable karyotype and presence of circulating blasts were independently associated with inferior leukemia-free survival. Disclosures: No relevant conflicts of interest to declare.

Hematologic Improvement with Iron Chelation using therapy Deferasirox in Patients with Aplastic Anemia: A Subgroup Analysis of KAMS0112 Prospective Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3424-3424
Author(s):  
Yoo-Hong Min ◽  
Sung-Soo Yoon ◽  
Hyeoung Joon Kim ◽  
Kyoo-Hyung Lee ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Platelet Count ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Research Funding ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Hemoglobin Level ◽  
Hematopoietic Stem ◽  
Wbc Count

Abstract Abstract 3424 Patients with aplastic anemia (AA) are suffered from various complications related to bone marrow failure and peripheral cytopenia. Although immunosuppressive therapy or hematopoietic stem cell transplantation has been performed for curative purpose, the majority of patients have been treated only by supportive cares including repeated transfusion. However, because continued transfusion eventually induces iron overload in many tissues and organs, transfusional iron overload and its consequences are another life-threatening problems for AA patients. Previous reports about iron chelation therapy (ICT) have mainly shown its efficiency for decreasing tissue iron and safety. However, improvement in hematopoiesis after iron chelation therapy has been limitedly reported as case reports or trials involving small number of patients without objective tools for measuring tissue iron content. In the KAMS0112 study (a multi-center, open label, prospective study evaluating the efficacy of ICT with deferasirox in transfusional iron overload with myelodysplastic syndrome or AA using quantitative R2-MRI, Ferriscan), a total of 54 patients with AA showing serum ferritin level over 1,000 ng/ml were enrolled from 19 institutes, and further analyzed for the changes in hemogram during ICT as well as efficacy and safely of deferasirox. During the study, the specific treatments for AA, such as immunosuppressive therapy or hematopoietic stem cells transplantation, were not undertaken. During 1 year prior to study, patients received 23.7±16.9 units of red blood cell (RBC) product, and the baseline serum ferritin level and liver iron content (LIC) were 4,164±447 ng/ml and 20.1±12.0 mg Fe/g DW, respectively. Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin level falls below 500 ng/ml, treatment was withheld. In spite of continued transfusional support during the study, serum ferritin level and LIC were significantly decreased after 1 year of ICT with deferasirox (Ds-ferritin=−3,076.7±489.9 ng/ml, p=0.0003; DLIC=−7.73 mg/Fe/g DW, p=0.001). To evaluate the improvement of each parameter in hemogram by ICT, patients with baseline hemoglobin level less than 8.0 g/dl (n=28), with baseline WBC count less than 4/ml (n=43), and with baseline platelet count less than 20/ml (n=31) were selected separately. At the end of study, hemoglobin level and platelet count (8.2±3.0 g/dl and 22.2±31.4/ml, respectively) was significantly increased from the baseline value (6.1±1.1 g/dl, p=0.001; 12.5±12.4/ml, p=0.05, respectively). WBC count was also slightly increased (from 2.1±0.9/ml to 2.3±0.9/ml, p=0.457). Considering the relatively uniform criteria of transfusion, the finding that hemoglobin level and platelet count could increase above 8 g/dl and 20/ml, respectively, after 1 year of deferasirox treatment is clinically significantly. Due to gradual improvement of anemia, requirement of RBC transfusion had continuously decreased during the study period (R2=0.31). This subanalysis of KAMS0112 study demonstrates that ICT using deferasirox can be effective in improving anemia and thrombocytopenia in the transfusional iron overload patients with AA, as well as reducing serum ferritin level and LIC. Further studies might be required to elucidate the mechanism involved in the improvement of hematopoiesis associated with correction of deranged intracellular iron homeostasis. Disclosures: Min: Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Lee:Novartis: Research Funding. Won:Novartis: Research Funding. Shim:Novartis: Research Funding. Kim:Novartis: Research Funding. Seung:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Chung:Novartis: Research Funding. Hyun:Novartis: Research Funding. Jo:Novartis: Research Funding. Jung:Novartis: Research Funding. Sohn:Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Joo:Novartis: Research Funding. Cheong:Novartis: Research Funding.

Significant Impact Of Iron Chelation After Allogeneic Hematopoetic Stem Cell Transplantation On Disease Recurrence: Potential Anti-Leukemic Activity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 180-180 ◽  
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Helene Labussiere ◽  
Marie Y. Detrait ◽  
...  
Keyword(s):  
Stem Cell ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Disease Recurrence ◽  
Hazard Ratio ◽  
Iron Chelators ◽  
Myeloid Leukemias

Abstract Iron overload (IO), primarily related to multiple red blood cell transfusions, is a relatively common complication in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Elevated pre-transplant ferritin level, a surrogate marker of iron overload, was demonstrated to be an important cause of mortality and morbidity in patients who have undergone allo-HSCT. Excessive iron accumulation results in tissue damage and organ failure, mainly as a result of the generation of free radicals that cause oxidative damage and organ dysfunction. Iron chelators have been widely used leading to normalisation for ferritine level and lower IO-related complications. As iron has a fundamental role in cell survival affecting pathways involved in DNA synthesis, cell differentiation, and apoptosis, some studies evaluated the anti-proliferative activity of iron chelators in cancer and leukemia patients on disease recurrence. The objective of this study was to determine at a first time the impact of serum ferritin level measured at time of allogeneic HSCT in adult patients with hematological disorders on the different outcomes and to investigate at a second time the role of iron chelation on relapse incidence. We included 158 patients, 100 males and 58 females with a median age of 45 years (18-67) who underwent allo-HSCT between 2002 and 2010. There were 83 acute myeloid leukemias, 10 chronic myeloid leukemias, 11 myelodysplastic syndromes, 7 myeloproliferative disorders, 19 myelomas, 9 non-Hodgkin lymphomas, 6 Hodgkin diseases, 5 aplastic anemias and 3 hemoglobinopathies. Sixty-seven (42%) patients were sex mismatched (F→M:37; M→F:30); for ABO compatibility, 61% were compatible, 18% had minor incompatibility and 21% had major incompatibility. Concerning the HSCT procedures, 60 patients (38%) received peripheral blood stem cell and 98 (62%) received bone marrow from 97 (61%) HLA related donors [matched, n=76; mismatched, n=21], and 61 (39%) HLA unrelated donors [matched, n=36; mismatched, n=25] after myeloablative [n=64, (41%)] or reduced intensity conditioning [n=94, (59%)]. At transplantation, 91 (58%) were in complete remission (CR) or chronic phase [CR1: n=61 (67%); ≥CR2: n=30 (33%)]. The median serum ferritin level at HSCT was 1327 microg./l (26-14136); 31(20%) patients had a level 26-500, 33 (21%) had a level 500-2500, and 94 (59%) >2500. There was no significant correlation between the different ferritin levels, disease kind and status at HSCT. After transplantation, 23 patients received iron chelating agents after a serum ferritin level of 1000 microg/l and stopped when the level decreased below 1000. The cumulative incidence of acute GVHD ≥ II at 3 months was 14% (11-16.5) with 10.5% (8-13) for grade III and 7% (5-9) for grade IV; the 1 year cumulative incidence of limited and extensive chronic GVHD were 4% (2-6) and 12.4% (9-16) respectively. After a median follow-up of 18 months (1-106), the 5 years OS probability was 65% for patients with ferritin level below 500 microg./l, 39% for level between 500 and 2500 microg./l and 28% for level > 2500 micog./l, [Hazard ratio= 3.5 (1.5-8.1), p=0.002]; this was explained by a significant higher TRM in patients with level >2500 [Hazard ratio= 4.3 (1.02-18), p=0.04]. Interestingly, we found in multivariate analysis that patients receiving iron chelators had significantly better OS [5 years OS= 59% vs. 34% for non-chelated patients, Hazard ratio= 0.34 (0.15-0.76), p=0.008], (Figure 1a), and experienced less disease relapse [5 years relapse incidence= 18% vs. 41% for non-chelated patients, Hazard ratio= 0.22 (0.07-0.73), p=0.012], (Figure 1b). In conclusion, we confirmed the negative impact of iron overload on the outcomes allo-HSCT recipients. More importantly, we demonstrated that iron chelators have a positive impact in reducing disease relapse by the possible mechanism of iron deprivation in leukemic cells. This clinical observation needs to be confirmed by prospective randomized trials.Figure 1a: Overall survival probability and b: relapse incidence in patients with or without iron chelationFigure 1. a: Overall survival probability and b: relapse incidence in patients with or without iron chelation Disclosures: Michallet: Novartis: Honoraria, Research Funding. Nicolini:Novartis: Consultancy, Honoraria, Research Funding.

The role of iron chelation activity of wheat grass juice in patients with myelodysplastic syndrome

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7012-7012 ◽  
Author(s):  
S. Mukhopadhyay ◽  
J. Basak ◽  
M. Kar ◽  
S. Mandal ◽  
A. Mukhopadhyay
Keyword(s):  
Myelodysplastic Syndrome ◽  
Serum Ferritin ◽  
Crude Extract ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Performance Status ◽  
Iron Chelation ◽  
Iron Chelator ◽  
The Mean ◽  
Age Range

7012 Background: A pilot study with wheat grass juice in major thalassaemia patients was done by a group of clinicians in IPGMR, Chandigarh, India. We performed a study of 200 patients of intermediate thalassaemia with wheat grass juice and found 80% patients becoming transfusion independent. During the study in majority of the patients, serum ferritin level was significantly less as compared to pretreatment values. The aim of our study was to see the effect of wheat grass juice in reducing Ferritin level in myelodysplastic syndrome and also do the biochemical analysis of the wheat grass juice. Methods: During period from January 2003 to December 2007 we selected 20 patients of transfusion dependent myelodysplastic syndrome in the oncology department of Netaji Subhash Chandra Bose Cancer Research Institute. The age range of the patients was 42 years to 72 years (median 55 years). The fresh leaves of 5–7-day-old wheat grasss including stems were made fresh juice and had given 30 mL of juice daily to all 20 patients for continuous 6 months. Wheat grass juice was analyzed by column chromatography and found to be rich in oxalic and malic acid which might have some role in dietary absorption of iron from intestine. Beside that the wheat grass juice was found to contain two unique active ingredients with iron chelating property which was performed by deoxyribose degradation assay. We compared aqueous soluble extract of 5–7-day-old plant and dose-dependent study showed a significant iron chelating activity of crude extract in comparison to known standard iron chelator desferroxamine (DFO). The active compounds of crude extract of wheat grass may chelate catalytic iron in iron overload disorders when taking systematic dose. Result: The mean serum Ferritin level of the patients was 2,250 (range 650–4,800) before wheat grass treatment. The mean reduced to 950 (range 68–1680) (p < 0.0001). The performance status was improved from 60% to 80% (Karnofsky) after wheat grass treatment. The mean interval between transfusions was found increased. Conclusions: Wheat grass juice is an effective iron chelator and its use in reducing serum ferritin should be encouraged in myelodysplastic syndrome and other diseases where repeated blood transfusion is required. No significant financial relationships to disclose.

Multidisciplinary Evaluation Improves Efficacy and Safety of Iron Chelation Therapy with Deferasirox in MDS Elderly Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4558-4558
Author(s):  
Lisette Del Corso ◽  
Elisa Molinari ◽  
Andrea Bellodi ◽  
Riccardo Ghio ◽  
Andrea Bacigalupo ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Chelation Therapy ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Group A ◽  
Group B

Abstract BACKGROUND: Iron overload from chronic transfusion therapy can be extremely toxic and most patients (pts) do not receive adequate iron chelation therapy (ICT) despite evidence of transfusional iron overload (IOL). Deferasirox (DFX) is the principal option currently available for ICT in the management of IOL due to transfusion dependent anemia, such as in MDS pts. The most common adverse events (AEs) are gastrointestinal disorders, skin rash, elevations in liver enzymes levels and non-progressive transient increases in serum creatinine also in MDS pts, most of whom are elderly with significant comorbidities and side effects of other concomitant therapies. In order to achieve effective ICT with minimal toxicity in individual pts, regular monitoring to assess IOL and adverse effects of DFX treatment is essential. METHODS: The safety and efficacy of DFX were examined in a retrospective multicenter observational study of transfusion-dependent (TD) MDS pts with International Prognostic Scoring System (IPSS) low-or Int-1-risk. We included all pts treated with DFX up to 12 months, divided into two groups; the first one (group A) not under a multidisciplinary assessment, including pts not adequately treated, in terms of dosing and discontinuation of ICT and the second one (group B) with pts under multidisciplinary control. The DFX starting dosing was 10 mg/kg/die in all pts. The aim of our retrospective analysis was to assess the effectiveness of ICT in relation of dosing and right management of AEs. RESULT: We evaluated 45 MDS pts (12F/33M); 27 belonging to the group A and 18 to group B. The age was 74.2±8.8 and 77.3±4.8 respectively. The ECOG 0-1 was 85,1% in group A and 88,9% in group B. The transfusion episodes prior starting DFX were22.1±12.1 and 24.5±35.4 in the first and in the second group, respectively. The serum ferritin level at baseline was respectively 1285.1±489.6 ng/mL and 1452.6±748.1 ng/mL. The mean serum ferritin level increased from 1285.1+489.6 ng/mL to 1412.1+842.8 ng/mL in group A while decreased from 1452.6+748.1 ng/mL to 1166.1+ 723.4 ng/mL in group B. The rate of inadequate therapy, in terms of dosing and/or discontinuation ICT, was 85% in group A compared to 60% in group B (p= 0.086).The rate of severe SAE observed in all pts was 10%.The most common AEs were diarrhea, nausea, upper abdominal pain, serum creatinine increase. The positive hematological response rate was observed in 15% of all pts. CONCLUSIONS: The study showed that group B obtained advantage in terms of efficacy and toxicity. The difference between the two groups derived from the ability to manage comorbidities, concomitant therapies and AEs, in particular the rise in serum creatinine, the most common cause DFX discontinuation or dosing reduction. In this setting, the most important specialist was the nephrologist. In our multidisciplinary group experts in management of ICT were hematologist, internist, immune-hematologist and nephrologist. We shared how we monitored kidney function and managed a possible nephrotoxicity (table.2), in order to ensure DFX efficacy. Positive hematological responses were observed, and a subset of pts achieved transfusion independence. The timing of future multidisciplinary evaluation is set on 24 and 36 months, time in which we expect the best response to DFX therapy. Table 1. Ferritin trend group A (n27) group B (n18) Ferritin N mean±SD Median (range) N mean±SD Median (range) Baseline 27 1285.1±489.6 1134 (388-2099) 18 1452.6±748.1 1515 (160-3018) 3 months 22 1451.5±720.5 1247.5 (529-2791) 13 1312.7±909.8 1064 (521-3859) 6 months 23 1850.5±1079.1 1419 (374-4185) 11 1168.4±648.4 1300 (160-2409) 12 months 17 1412.1±842.8 1372 (111-3127) 9 1166.1±723.4 930 (277-2536) Table 2. Management of renal changes during therapy with DFX Creatinine and urine examination:1) in two successive determinations prior to initiation of therapy, then every month 2) in pts with other risk factors for kidney disease, every week for 1 month after start of DFX or dose increase and, subsequently, every month Changes in creatinine:1) increased by 33% in two successive determinations: reduce DFX dose of 5 mg/kg 2) progressive increase of creatinine: interrupt DFX and then re-challenge it at a lower dose with gradual increase if the clinical benefits outweigh the risks Disclosures No relevant conflicts of interest to declare.

scholarly journals Nerve conduction study in children with thalassemia

2018 ◽  
Vol 6 (6) ◽  
pp. 2138
Author(s):  
Banita Negi ◽  
Parveen Bhardwaj ◽  
Minoo Sharma ◽  
Sudhir Sharma ◽  
Neelam Grover
Keyword(s):  
Conduction Velocity ◽  
Serum Ferritin ◽  
Nerve Conduction Study ◽  
Nerve Conduction ◽  
Nerve Conduction Velocity ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Sensory Nerves ◽  
Motor Nerves

Background: Regular blood transfusion and iron chelation therapy has increased life span of children with Thalassemia and with prolongation of life expectancy the toxic effect of iron on nervous system are being increasingly reported. Aim was to study nerve conduction study in thalassemia children and effect of iron overload on NCV.Methods: 30 children with thalassemia on regular transfusions and iron chelation therapy and 30 healthy age and sex matched controls were subjected to nerve conduction study on three motor and sensory nerves. Statistical analysis used: means of quantitative variables were calculated in two groups and compared with student t- test. A p-value of <0.05 was taken as significant.Results: On comparing the results the between cases and controls, we found that, there was no significant difference in the distal latency, amplitude and nerve conduction velocity of all three motor nerves and sensory nerves which were evaluated. Cases were further divided in to two groups depending upon serum ferritin level of < and >1000ng/ml. On comparing these two groups it was noted that distal latency was increased, nerve conduction velocity was slow in all the motor nerves (i.e. median, ulnar and tibial nerves) and sensory nerves (i.e. median, ulnar and sural nerves) in group with serum ferritin level >1000ng/ml and these findings were statistically significant.Conclusions: We concluded that in children with thalassemia on regular transfusion and Iron chelation regime, nerve conduction study is normal in comparison to normal control but with progressive increase in serum ferritin level, the latency and conduction velocity is decreased and is statistically significant.

Positive Impact of Iron Chelation Therapy (CT) on Survival in Regularly Transfused MDS Patients. A Prospective Analysis by the GFM.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 249-249 ◽  
Author(s):  
Christian Rose ◽  
Sabine Brechignac ◽  
Dominique Vassilief ◽  
Odile Beyne-Rauzy ◽  
A. Stamatoullas ◽  
...  
Keyword(s):  
Chelation Therapy ◽  
Transfusion Requirement ◽  
Positive Impact ◽  
Iron Chelation ◽  
Prospective Analysis ◽  
Iron Chelation Therapy ◽  
Kaplan Meier ◽  
Survival Difference ◽  
Impact On Survival ◽  
Rbc Transfusion

Abstract Background: RBC transfusions are required in most MDS, leading to iron overload which probably contributes to shortened survival (Malcovati, JCO, 2005). Consensus for indications of iron chelation therapy (CT) in MDS patients are recent (Gattermann Hemato/Oncol Clin2005; 19:supp1). A positive impact on survival of CT, clearly demonstrated in thalassemia, has not yet been prospectively reported in large MDS cohorts. Methods: We performed in 2005 a survey on hematological data, RBC transfusion requirement and CT in 170 MDS referred for RBC transfusion during a month period (May 15–June 15, 2005) to 18 French GFM centers (Rose, ASH 2006, abstr:2661). Survival of this prospective cohort was reanalyzed at the reference date of May 15, 2007. Results: 5 pts were lost to follow up. Median age of the remaining 165 pts was 77 (range 14–95).M/F 1.4. WHO: 13 pure RA (10%), 30 pure RARS (23%), 6 RCMD (5%),5 RCMD-RS (4%), 28 RAEB I (21%), 10 RAEB II (8%),11 5q- Sd (7%), 8 CMML (6%); 21 MDS unclass (16%). Karyotype: fav (12%), int (36%), unfav (22%), failure or ND (30%) IPSS: low 27%, Int1 32%, Int2 10%, high 2%, unavailable 29%. 76 pts (46%) received CT for at least 6 months, including 65 before May 2005, and 11 since May 2005. Median interval from diagnosis to onset of CT was 30 months (range 0–192). CT included: DFO continuous s/c (8h) (40mg/kg/d, 3 – 5d/w) n= 41, deferiprone alone (30 to 75 mg/kg/d) n= 5, Deferiprone + DFO s/c n= 5, deferasirox (20 to 30 mg/kg/d) n= 6 (Defined as “standard” chelation) and DFO s/c bolus (2 to 3g/week) n = 12 or DFO IV (50 to 100mg/kg/d once after each RBC transfusion) n= 7 (defined as “low” chelation). Median duration of CT was 35 months (6–138+). Median serum ferritin (SF) level was 569ng/ml (range 9–2500), 1436ng/ml (range 436–6572) and 1498ng/ml (range 272–7502) at diagnosis, onset of CT and last evaluation, respectively (resp). By comparison to non chelated pts, chelated pts had significantly higher number of RBC units transfused (mean 104 vs 57) (p&lt;0.001), lower age (mean 70 vs 76) (p= 0.006) no difference in WHO classification (p=0.274) but differences in IPSS: IPSS 0; 0–1,&gt;1 in 27%, 53%, 20% of non chelated versus 49%,36%,15% of chelated pts with available IPSS, resp (p=0.044). Median overall survival from diagnosis (OS, Kaplan-Meier analysis) was 115 and 51 months in chelated and non chelated pts,resp (p&lt; 0.0001). After adjustment on other prognostic parameters (sex,age, IPSS, transfusion requirement) the survival difference remained significant. In IPSS 0 pts, median OS was not reached in chelated pts and 69 months in non chelated pts(p=0.002).In IPSS 0–1 pts, median OS was 115 months in chelated pts and 50 months in non chelated pts (p=0.003). Longer interval from diagnosis to onset of CT did not influence OS negatively but median OS was 120 months with “standard” chelation versus 69 months with “low “chelation (p&lt;0.001). Conclusions: This prospective analysis strongly suggests that chelation therapy (CT) provides survival benefit in heavily transfused, mainly low and int 1, MDS. Confirmatory randomized trials, theoretically required,(CT vs no CT) may be difficult to perform in this situation.

Dose Optimization of Deferasirox in Chelation Naïve Children with Thalassemia Major

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5294-5294
Author(s):  
Surekha Tony ◽  
Murtadha K. Al-Khabori ◽  
Ashraf Abdullah Saad ◽  
Shahina Daar ◽  
Mathew Zachariah ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Iron Chelator ◽  
Once Daily ◽  
History Of ◽  
Oral Iron Chelator

Abstract Abstract 5294 Background: Deferasirox is a relatively new once-daily oral iron chelator widely used for patients with thalassemia major. Efficacy of deferasirox has been evaluated in pediatric and adult patients with thalassemia and transfusion-dependent anemias. Experience with deferasirox in pediatric patients with thalassemia major is mainly in heavily iron loaded patients with a history of prior iron chelation. There are no current reports available on its use in chelation naïve very young patients with thalassemia major. Material and Methods: Ten chelation naive children (mean age 17.7 ± 2.7 months), on hypertransfusion regimen at the Pediatric Thalassemia Day Care Center, Sultan Qaboos University Hospital, Muscat, Oman, were initiated on deferasirox at a dose of 20 mg/kg/day at serum ferritin levels >500 ng/ml at a minimum age of 14 months. Patients were monitored and evaluated for possible side effects. Complete blood count, renal function test, liver function test and urine dipstick were done monthly with serum ferritin analysis once every 2 months. Guided by serum ferritin level and safety markers (transaminases, serum creatinine, and clinical adverse effects), the dose of deferasirox was gradually increased to 40 mg/kg/day with increments of 5 mg/kg/day every 2 months, in order to maintain a safe serum ferritin level with no major hepatic or renal side effects. Results: After a median treatment duration of 13 months (2–38 months) with deferasirox at a mean dose of 33.22 ± 5.99 mg/kg/day, mean serum ferritin level is 985.8 ± 373.002 ng/ml, as compared to baseline level of 807.8 ± 182.766 ng/ml. The increase in mean serum ferritin is 178 ng/ml (95% confidence interval −9.72 to 365.72) which is statistically insignificant (p = 0.06, two sided paired t-test). Nausea and vomiting, abdominal pain, and rash were observed in 1 patient each. Increase in transaminases was mild (3 times upper limit of normal) and non-progressive in 3 of the patients. Two patients had single serum creatinine level increases >33% above baseline and >upper limit of normal, and one had 2 non-consecutive increases requiring dose modification. The adverse effects were mild and did not require drug interruption. None of the patients had leucopenia, neutropenia or thrombocytopenia. Compliance with chelation was optimal. Conclusions: Deferasirox is relatively well tolerated in very young chelation naïve patients with thalassemia major. Dose increments of 5 mg/kg/day at intervals of 2 months allowed the optimization of the drug to 40 mg/kg/day within 1 year of initiation of chelation with no major adverse effects. Inspite of initial rises in serum ferritin at doses < 25 mg/kg/day, serum ferritin levels showed a steady trend towards the end of 12 months of therapy, requiring the continuation of the drug at doses > 30 mg/kg/day to achieve safe ferritin levels. Appropriate drug dosing guided by serum ferritin levels and safety markers improve the efficacy of deferasirox. Disclosures: Off Label Use: Deferasirox is a once-daily oral iron chelator used for patients with thalassemia major and other transfusion-dependent anemias. Experience with deferasirox in pediatric patients with thalassemia major is mainly in heavily iron loaded patients with a history of prior iron chelation. There are no current reports available on its use in chelation naïve patients with thalassemia major. We evaluated the efficacy of deferasirox in 10 very young chelation naïve children with thalassemia major.

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