Clinical Outcomes and Pharmacokinetics of Targeted Intravenous Busulfan in Children Receiving Stem Cell Transplantation for Thalassemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1117-1117 ◽  
Author(s):  
Javi d Gaziev ◽  
Luca Spitaleri ◽  
Alessia Mozzi ◽  
Laurent Nguyen ◽  
Christian Puozzo ◽  
...  
Keyword(s):  
Univariate Analysis ◽  
Iron Concentration ◽  
Conditioning Regimen ◽  
Systemic Exposure ◽  
Thalassemia Major ◽  
Individual Variability ◽  
Target Range ◽  
High Dose ◽  
Liver Iron ◽  
Transplant Outcomes

Abstract Background: High dose busulfan (BU) in combination with cyclophosphamide (BUCY) is a preferred conditioning regimen for patients with hemoglobinopathies. Recently introduced intravenous BU (IVBU) has decreased intra-and inter-individual variability of BU systemic exposure (AUC) when compared to oral dosing. There are no data available on IVBU pharmacokinetics (PK) in a large group of patients with thalassemia to date. Purpose: to asses the IVBU PK in relation to patient and disease-related (hepatomegaly, blood transfusion, ferritin, liver iron concentration, hepatitis, liver fibrosis) variables and the relationship of BU exposure to toxicities and transplant outcomes in children and young adults given SCT for thalassemia from HLA-matched related donors. Methods: 57 patients with thalassemia major with median age of 9 years (range, 1.6–24) received IVBU (Busilvex, Pierre Fabre Medicament, France) as a part of conditioning regimen between 2006 and 2008. BU doses were based on actual body weight: <9–16= 1.2 mg/kg (n=10); 16–23= 1.1 mg/kg (n=13); 23–34= 0.95 mg/kg (n=23) and >34=0.8 mg/kg (n=11) and were given every 6 hours for 4 days. Valproic acid (Depakin) was administered before and during BU treatment as anticonvulsant prophylaxis. Most patients had liver disease and moderate to severe iron overload. Class 1 and class 2 patients (n=24) received IVBU in combination with CY200 ± thiotepa as conditioning regimen. Class 3 patients (n=33) before conditioning with IVBU/CY160 ± thiotepa were given cytoreduction/immunosuppression with hydroxyurea, azathioprine and fludarabine between −45 and −12 days pretransplant. GVHD prophylaxis consisted of CSA+ short MTX. Blood samples were drawn just before and 2h, 4h, and 6h after BU administration following the 1st, 5th, 9th, and 13th doses for PK assessment by HPLC-MS. Dose adjustment (DA) was made at the 3rd dose as needed, to target an AUC range of 900–1350 μol/L/min. The influence of patient and disease-related variables on IVBU PK was investigated by a population PK-based approach using the NONMEM program. Results: PK parameters following the 1st dose are reported in Table. Overall, 58% of patients AUC were within, 37% were below and 5% were above the target range following the 1st dose of IVBU. Dose elevations of 5.2–54% (median, 18.8%) were made in 17 patients and dose reductions of 5–34.2% (median,9.2%) in 19 patients. Following DA 79 % of patients after the 5th and 9th doses and 91 % after the 13th dose reached the target range. The inter-patient variability in IV BU clearance was moderate (CV=19%) and the intra-patient variability was low (CV=7%). Only weight or body surface area significantly explained the PK variability. Fifty three patients had sustained engraftment, 4 had primary (n=2) or secondary (n=2) graft failure. Forty eight (89%) of 54 evaluable patients were complete and 6 (11%) mixed chimeras. One patient had moderate hepatic VOD resolved with supportive care. Seventeen patients developed grade 2–4 acute GVHD. None of patients had seizure within 30 days post-transplant. Grade 1 or 2 ALT/AST increases were observed in 19,3% and 44% of patients and stomatitis/diarrhoea in 47% and 19% of patients respectively. Five patients died. There was no relationship between busulfan exposure and toxicities, engraftment time, chimerism, rejection, GVHD and survival in univariate analysis. No association was found between PK parameters and transplant outcomes in a subgroup of patients (n=19) who never needed DA. This study demonstrates that IVBU in children with thalassemia who have important organ damage due to their disease and treatment is well tolerated with no increase in organ system toxicity. IVBU exposure did not predict rejection, liver VOD or death in patients with thalassemia who received HLA-matched related SCT. AUC, μol/min Css, ng/ml Cmax, ng/ml Cmin, ng/ml Cl, ml/min/kg Vd, L T ½, h Mean ± sd 982± 203 672± 139 1071± 207 239± 72 4.23± 0.95 16.8±6.8 1.8±0.2 Range 630–1621 431–1109 735–1614 101–450 2.31–6.43 7.3–43.6 1.2–2.3

Impact of Holmium-DOTMP on Transplant Outcomes. Results of a Retrospective Single Institution Analysis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 426-426
Author(s):  
Anna Christoforidou ◽  
Patricia Williams ◽  
Linda Roden ◽  
Ana Aleman ◽  
Donna Weber ◽  
...  
Keyword(s):  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
Phase Iii ◽  
High Dose ◽  
Free Survival ◽  
Transplant Outcomes ◽  
Phase Iii Trials ◽  
Total Body ◽  
High Dose Melphalan

Abstract Background:166Holmium-DOTMP is a beta emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Phase I/II trials have shown feasibility and tolerability when combined with a standard conditioning regimen of melphalan with or without total-body irradiation (TBI) in pts with multiple myeloma (MM) undergoing autologous stem cell transplantation (SCT). Purpose: To define the potential impact of 166Holmium-DOTMP (HO) in combination with melphalan when compared to a standard conditioning regimen of melphalan 200 mg/m2 (M200) in MM patients undergoing auto SCT. Methods: We performed a retrospective review of transplant outcomes among patients with MM who received an auto SCT between 1/98-12/01 with either M200 or a melphalan-HO combination and were in a 1ry refractory or 1st remission consolidation state. Univariate analysis was performed for response, survival and event free survival. Results: 104 pts were identified. Patient characteristics are summarized in Table 1. In brief the HO group had a higher percentage of patients with IgA disease, otherwise there were no siginificant differences in prognostic factors among the groups. Transplant outcomes are summarized in Table 2. The HO group had a trend towards a higher conversion to CR rate (51% vs 32%) for all patients, (23% vs 12.5%) for 1ry refractory patients and similar OS rates and a higher NRM rate of 12% vs 3% when compared to MEL200. When the analysis was limited to patients receiving <2400 mCi the HO group had a trend towards longer PFS (33 months vs 24 months) with no difference in NRM rates. The OS rate at 5 yrs was 54% for the HO group vs 43% for the MEL200 group, among the 21 patients in the HO group receiving <2400 mCi the 5 yr OS was 61% (Figure 1). Conclusion: 166Holmium-DOTMP in combination with high dose melphalan can result in higher CR rates than melphalan 200 mg/m2 alone, when given in optimal doses (<2400 mCi) the results seem to be superior and the toxicities are minimal. Targeted skeletal radiotherapy with 166Holmium-DOTMP in combination with melphalan 200 mg/m2 is safe and effective and should be further studied in Phase III trials in all patients with MM undergoing autologous SCT, based on these data other methods of targeted skeletal radiotherapy should also be pursued. Patient Characteristics HO <2400 mCi HO ≥ 2400 mCi Melphalan 200 p MEL200 vs HO N 21 20 63 Median Age 52 (45–61) 53 (36–64) 55 (35–69) NS IgA Type 33% 40% 14% .03 Median B2M @ Dx 3.15 3.15 3.5 NS Durie Salmon III 43% 55% 67% NS Number with Δ13 0 0 3 NS CR/PR @ SCT 5%/57% 5%/70% 6%/68% NS 1ry Refractory 38% 25% 25% NS Transplant Outcomes HO <2400 mCi HO ≥ 2400 mCi MEL200 MEL 200 vs HO ORR/CR conversion 95%/55% 90%/48% 92%/32% NS/.06 NRM 5% 20% 3% .07 Median OS NR 31 months 52 months NS Median EFS 30 months 23 months 19 months .3

MRI-Guided Iron Assessment and Oral Chelator Use Improve Iron Status In Thalassemia Major Patients: a Six-Year Single Center Retrospective Cohort Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 563-563 ◽  
Author(s):  
Diana X Nichols-Vinueza ◽  
Matthew T White ◽  
Andrew J Powell ◽  
Puja Banka ◽  
Ellis J. Neufeld
Keyword(s):  
Side Effects ◽  
Iron Overload ◽  
Research Funding ◽  
Iron Status ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Target Range ◽  
Single Center ◽  
Liver Iron ◽  
Cardiac Iron

Abstract Background Patients (pts) with thalassemia major (TM) require regular red blood cell transfusions. Adequate iron chelation prevents morbidity and mortality due to transfusional iron overload, and must be guided by accurate assessment of tissue iron levels. Magnetic resonance imaging (MRI) can non-invasively measure liver iron content (LIC) and cardiac iron, and has almost entirely supplanted liver biopsy for LIC at our center. The therapeutic goal is to either (a) maintain iron status within a consensus target range, or (b) decrease the iron burden in pts above the target. Three chelators are FDA approved in the US: deferoxamine (DFO), deferasirox (DFX), and deferiprone (DFP), (approval years 1968, 2005 and 2011 respectively). The aim of this study was to evaluate our ability to improve iron status over time in the MRI and oral chelator era. Methods This IRB-approved, single-center, retrospective observational study covered the period from Jan 2005, when MRI iron assessments became standard at our center, to Dec 2012. The study population included all TM pts followed for chelation at our center who had >2 MRI studies during the study period. LIC was measured by calculating T2* and, starting April 2006, also by measuring T2 using the commercial Ferriscan® technique. Liver T2* was converted to LIC using a regression equation (Wood et al. Blood, 2005; 106:1460). Cardiac iron concentration was measured by calculating cT2*; in this abstract both T2* in msec and its reciprocal R2* (1000/cT2* in Hz, which varies proportionally to iron) are reported. The target for LIC was <7 mg/g dry wt (dw), (mean of T2* and Ferriscan LIC) and for cardiac iron, cR2*<50 Hz (i.e. cT2* >20 msec). Statistical analyses were performed in SAS. Results 42 pts (55% male) met the inclusion criteria and had a median age at first MRI of 17.5y (range 1.9-43). Over a mean follow-up period of 5.2±1.9 y, 190 MRIs were performed with median of 4.5 MRIs per pt, interquartile range 3-6. In 2005, DFO was the predominant chelator (70% vs 26% on research use of chelators, DFX; n=27); DFX predominated after its commercial launch. 29/40 (73%) were on DFX by 2009, but this proportion dropped to 23/36 (64%) by 2012. 13/42 pts (31%) remained within the target ranges for cardiac T2* and LIC throughout the study period. 29/42 pts (69%) had at least one cardiac T2* or LIC out of the target range in a total of 97 MRIs. 38/97 (40%) of these out-of-range MRIs prompted a change in chelation strategy: 61% dose change only, 34% change of monotherapy agent, and 5% change from monotherapy to combination. Two pts died of heart failure due to iron overload during the study period; both had taken DFP before their deaths, but for divergent duration (3 days vs 5 y). The median number of chelation changes was 1.4 per pt/y (IQR 0.9-1.9). 175/229 (76%) dosing changes were for iron status as assessed by MRI or ferritin; 7/229 (3%) were dose decreases for side effects, and 2% were due to weight change only. Change in chelators occurred 82 times during the study. 34% of chelator changes were due to low or high iron status by MRI or Ferritin. 11% of changes were for side effects to a prior chelator and 54% were for other reasons (commercial launch of DFX or clinical trials). From initial to final MRI, both LIC and T2* status of our pts improved significantly (figure). At the initial MRI, 16/41 (40%) of pts were in target range for both LIC and cR2*, 4/41 (10%) were in the highest (undesirable) range of LIC>15 mg/g dw, and/or cardiac T2* <10 msec. From first to last cardiac T2* assessment (n=38), 63% of pts started and ended within the target range, 13% improved from abnormal to target range, 24% remained out of the target range. The two pts who died were among the persistent abnormal cardiac T2* group. For LIC (n=42), 45% remained in the target range throughout, 33% started out of target range and ended within, 12% improved but not to the target, 7% worsened, and one outlier remained severe. Conclusions The introduction of routine MRI assessments of LIC and cardiac R2* (T2*), together with the introduction of oral chelators, has improved the fraction of TM pts with liver and cardiac iron within the target range at our center. Annual MRIs facilitate chelation changes when necessary. Legend: A: Cardiac iron status from first to last MRI for each subject. Reciprocal cR2* and cT2* are on left and right Y-axes. B: Liver iron status. P-values are by Wilcoxon signed-rank test. Disclosures: Neufeld: Shire: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Apopharma: Consultancy.

Effect of transfusional iron intake on response to chelation therapy in β-thalassemia major

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 583-587 ◽  
Author(s):  
Alan R. Cohen ◽  
Ekkehard Glimm ◽  
John B. Porter
Keyword(s):  
Chelation Therapy ◽  
Iron Concentration ◽  
Chelating Agent ◽  
Thalassemia Major ◽  
Phase Iii ◽  
Iron Loading ◽  
Iron Intake ◽  
Liver Iron ◽  
Iron Stores ◽  
Using Data

The success of chelation therapy in controlling iron overload in patients with thalassemia major is highly variable and may partly depend on the rate of transfusional iron loading. Using data from the 1-year phase III study of deferasirox, including volumes of transfused red blood cells and changes in liver iron concentration (LIC) in 541 patients, the effect of iron loading on achieving neutral or negative iron balance was assessed in patients receiving different doses of deferasirox and the comparator deferoxamine. After dose adjustment, reductions in LIC after 1 year of deferasirox or deferoxamine therapy correlated with transfusional iron intake. At a deferasirox dose of 20 mg/kg per day, neutral or negative iron balance was achieved in 46% and 75% of patients with the highest and lowest transfusional iron intake, respectively; 30 mg/kg per day produced successful control of iron stores in 96% of patients with a low rate of transfusional iron intake. Splenectomized patients had lower transfusional iron intake and greater reductions in iron stores than patients with intact spleens. Transfusional iron intake should be monitored on an ongoing basis in thalassemia major patients, and the rate of transfusional iron loading should be considered when choosing the appropriate dose of an iron-chelating agent. This study is registered at http://clinicaltrials.gov as NCT00061750.

scholarly journals Longitudinal analysis of heart and liver iron in thalassemia major

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2973-2978 ◽  
Author(s):  
Leila J. Noetzli ◽  
Susan M. Carson ◽  
Anne S. Nord ◽  
Thomas D. Coates ◽  
John C. Wood
Keyword(s):  
Longitudinal Analysis ◽  
Time Lag ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Accumulation ◽  
Liver Iron ◽  
Cross Sectional ◽  
Cardiac Iron ◽  
Cardiac Iron Overload ◽  
Magnetic Resonance Imaging Mri

Abstract High hepatic iron concentration (HIC) is associated with cardiac iron overload. However, simultaneous measurements of heart and liver iron often demonstrate no significant linear association. We postulated that slower rates of cardiac iron accumulation and clearance could reconcile these differences. To test this hypothesis, we examined the longitudinal evolution of cardiac and liver iron in 38 thalassemia major patients, using previously validated magnetic resonance imaging (MRI) techniques. On cross-sectional evaluation, cardiac iron was uncorrelated with liver iron, similar to previous studies. However, relative changes in heart and liver iron were compared with one another using a metric representing the temporal delay between them. Cardiac iron significantly lagged liver iron changes in almost half of the patients, implying a functional but delayed association. The degree of time lag correlated with initial HIC (r = 0.47, P < .003) and initial cardiac R2* (r = 0.57, P < .001), but not with patient age. Thus, longitudinal analysis confirms a lag in the loading and unloading of cardiac iron with respect to liver iron, and partially explains the weak cross-sectional association between these parameters. These data reconcile several prior studies and provide both mechanical and clinical insight into cardiac iron accumulation.

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 884-893 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Mohamed Bejaoui ◽  
Leyla Agaoglu ◽  
Duran Canatan ◽  
Marcello Capra ◽  
...  
Keyword(s):  
Adverse Events ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Efficacy And Safety ◽  
Liver Iron ◽  
Median Serum

Abstract Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

Consequences and management of iron overload in sickle cell disease

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 447-456 ◽  
Author(s):  
John Porter ◽  
Maciej Garbowski
Keyword(s):  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Loading ◽  
Cell Disease ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.

scholarly journals Characteristics and prognosis of hepatocellular carcinoma in multi-transfused patients with thalassemia major. Experience of a single tertiary center.

2020 ◽  
Vol 12 (1) ◽  
pp. e2020013
Author(s):  
Nikolaos Papadopoulos ◽  
Dimitrios Kountouras ◽  
Katerina Malagari ◽  
Maria Tampaki ◽  
Maria Theochari ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Proportional Hazard ◽  
Liver Iron ◽  
Cox Proportional Hazard ◽  
Tertiary Center

Background: In this retrospective study, records of patients with thalassemia major (TM) diagnosed with hepatocellular carcinoma (HCC) from 2008‐2018 were reviewed in order to determine the survival rate and evaluate possible etiological factors associated with survival. Methods: Forty-two TM patients who were diagnosed with HCC have been included in the study. Most of our patients (78.5%) were anti-HCV positive, while 16.5% had evidence of resolved HBV infection. At the time of HCC diagnosis, 78.5% of our patients were diagnosed with cirrhosis, while the vast majority (98%) had normal or mild elevated liver iron concentration (LIC) values. According to Barcelona Clinic Liver Cancer (BCLC) grading system patients were classified as 0-A: 28.5%, B: 57% and as C-D: 14.5%.  HCC has been treated with loco-regional treatment in 78.5% of our patients, while the rest have been treated with sorafenib. Results: Twenty-eight patients (66.5%) have eventually died with a median survival time of 6 months (range: 2-60). Using the Cox proportional hazard model, the only factors who have been associated with poor survival were BCLC stages C and D. Conclusions: In conclusion, BCLC staging is the main prognostic factor of survival in patients with TM who develop HCC, with a median survival time of six months.

Transplant Outcomes after Topotecan-Melphalan-Cyclophosphamide (TMC) Conditioning for Autologous Stem Cell Transplantation for Multiple Myeloma. Comparison to Melphalan 200 mg/M2 (MEL200).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1177-1177
Author(s):  
Michele Donato ◽  
Ana Aleman ◽  
Donna Weber ◽  
Michael Wang ◽  
Muzaffer Qazilbasch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
High Dose ◽  
Transplant Outcomes ◽  
Transplant Program ◽  
Preparative Regimen

Abstract Background: Topotecan at modest doses has activity in multiple myeloma (MM). The combination of high-dose topotecan, melphalan, and cyclophosphamide (TMC) has been used as a conditioning regimen for autologous SCT in patients with MM. We report the results of a phase II trial with this combination and perform a retrospective analysis comparing TMC to a standard preparative regimen of melphalan 200 mg/m2 (MEL200). Patients and Methods: Between 10/99 and 3/04, 55 patients with newly diagnosed MM were treated on a Phase II trial of topotecan 3.5 mg/m2 daily for 5 days in combination with cyclophoshamide 1 gm/m2 daily for 3 days, and melphalan 70 mg/m2 daily for 2 days followed by autologous SCT. Patient characteristics are summarized in table 1. In brief, median age was 55 (range, 37–67), median time to transplant was 6 months (range, 2-59); median B2M @diagnosis 3.3 (range, 1.4–17.2); 76% of patients had chemosensitive disease prior to transplant. Results: No treatment related deaths were observed, the regimen was well tolerated with grade 2 Bearman mucositis and diarrhea the most common toxicities, and no grade 3 or 4 toxicities observed. When compared to a group of patients who received MEL 200 the overall response rate was lower 75% vs 82% and a lower CR rate 11% vs 36%, but a similar median time to disease progression (14 m vs 13 m), with a trend towards a better 3 yr overall survival (87% vs 77%; p=.05) (Table 2 and Figure 1). Conclusion: TMC is a well tolerated conditioning regimen for myeloma, our results suggests that although no more effective than MEL200 as a single preparative regimen for MM, it warrants exploring as part of a tandem transplant program. Patient Characteristics TMC MEL200 N 55 157 Median Age (range) 55(37-67) 56(29-75) Median B2M @Dx 3.3 (1.4 - 17.2) 4 (0.5 - 49.8) % Abn Cytogenetics 15% 22% CR/PR @ SCT 4%/73% 10%/89% % 1ry Refractory 24% 27% Transplant Outcomes TMC MEL200 p ORR/CR conversion 75%/11% 82%/36% Non Relapse Mortality 0 2 Median OS NR 52 months .05 Figure Figure

Safety and Efficacy of High Dose Intravenous Desferoxamine for Reduction of Iron Overload Due to Chronic Transfusion in Sickle Cell Patients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1430-1430
Author(s):  
Ram Kalpatthi ◽  
Brittany Peters ◽  
David Holloman ◽  
Elizabeth Rackoffe ◽  
Deborah Disco ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Liver Tissue ◽  
Iron Concentration ◽  
P Value ◽  
High Dose ◽  
Liver Iron ◽  
Iron Storage

Abstract Background: Patients with sickle cell disease (SCD) receiving chronic blood transfusions are at risk of developing iron overload and organ toxicity. Chelation therapy with either subcutaneous (SQ) desferoxamine (DFO) or oral deferasirox is effective in preventing and reducing iron overload but poses significant challenges with patient compliance. Intravenous (IV) infusions of high dose DFO (HDD) have been utilized in non compliant patients with heavy iron overload in small case series. We review our experience of high dose IV DFO in a large cohort of SCD patients with significant iron overload who are non compliant with SQ DFO. Methods: The medical records of SCD patients who received HDD in our center between 1993 and 2004 were reviewed. All of them were on chronic transfusion, had significant iron overload defined by serum ferritin &gt; 1500 and/or liver iron concentration (LIC) more than 10 μg/g of liver tissue and were non-compliant with SQ DFO. All patients underwent annual ophthalmologic, hearing, pulmonary and cardiac evaluation. Demographic data, treatment details, serum ferritin levels, liver iron concentration (LIC), liver enzymes, renal function tests, audiogram and other relevant clinical data were collected. Results: There were 27 patients (19 males, 8 females), 19 patients were on transfusion for history of cerebrovascular accident, 5 for abnormal transcranial Doppler flow velocity, 2 for transient ischemic attack and one for recurrent pain crises. All continued to receive packed red blood cell transfusions aimed to keep HbS levels below 30 or 50% during this time. They were treated in-hospital with DFO 15 mg/kg/hr IV for 48 hrs every 2 weeks (20 patients), 3 weeks (4 patients) and 4 weeks (3 patients). The mean age at start of high dose regimen was 14.6 years (range 9–27 years). The mean duration of HDD treatment was 8.9 months (range 3–49 months). Fourteen patients had LIC determined by liver biopsy. Significant reductions in LIC were observed after HD (table I). This was more pronounced in patients who had higher LIC and received at least 6 months of HDD. Histological examination of liver biopsies revealed a decrease in the grade of liver iron storage. Four patients had portal triaditis initially which resolved after starting HDD therapy. Also there was significant improvement in liver enzymes (ALT, AST) after HDD. There was a trend in decreasing ferritin levels after HDD but this did not achieve statistical significance. All patients tolerated HDD without any major reactions. No audiologic or ophthalmologic toxicity or acute or chronic pulmonary complications were observed. Blood urea nitrogen remained normal in all patients after HDD but there was mild increase in serum creatinine. One patient had high serum creatinine (1.2 mg/dL) after two doses HDD. This patient had focal segmental glomeurosclerosis which was most probably the cause for the rise in creatinine. There was no significant increase in serum creatinine in our series when this patient was excluded. Conclusions: In our cohort of SCD patients we observed a significant decrease in liver iron burden with high dose IV DFO. Our patients tolerated the therapy well without any major toxicity. This regimen is safe and may be an option for poorly compliant patients with significant iron overload. In addition, combination of this regimen with oral iron chelators may be of benefit to patients with significant iron overload and organ dysfunction. Table 1: Laboratory characteristics of sickle cell patients before and after high dose IV DFO Parameter No. of Patients Mean (SD) prior to HDD Mean (SD)after HDD p Value* * Changes in mean levels analyzed using two-tailed Paired T Test with significant p value ≤ 0.05. SD – Standard deviation + See text Liver iron (μg/g of liver tissue ) 14 16864 (10903) 12681 (8298) 0.04 Liver iron min of 6 months of HDD (μg/g of liver tissue ) 8 18677 (8319) 9362 (4521) 0.01 Liver iron &gt;10 mg & minimum 6 months of HDD (μg/g of liver tissue) 7 21181 (7054) 10092 (4443) 0.01 Grade of liver iron storage 14 3.57 (0.9) 3.07 (1) 0.05 Serum Ferritin (ng/mL) 27 3842 (2619) 3238 (1780) 0.06 Serum AST (IU/L) 27 54.1 (27.2) 44.6 (17.6) 0.04 Serum ALT (IU/L) 27 39.2 (36) 27.5 (14.2) 0.01 Blood urea nitrogen (mg/dL) 27 8.9 (2.9) 9.5 (4.3) 0.20 Serum Creatinine (mg/dL)+ 26 0.50 (0.1) 0.55 (0.2) 0.07

Safety of Deferasirox (Exjade®) in Patients with Transfusion-Dependent Anemias and Iron Overload Who Achieve Serum Ferritin Levels <1000 Ng/Ml during Long-Term Treatment

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5423-5423 ◽  
Author(s):  
John B Porter ◽  
Antonio Piga ◽  
Alan Cohen ◽  
John M Ford ◽  
Janet Bodner ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Abdominal Pain ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Safety Profile ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Liver Iron ◽  
Long Term Treatment ◽  
Baseline Characteristics

Abstract Background: Maintaining serum ferritin (SF) levels below 1000 ng/mL has been reported to predict longer survival and a reduced risk of complications (eg heart failure) in patients with thalassemia major. Experience with deferoxamine (Desferal®, DFO) has indicated that the toxicity of DFO may increase as SF levels decrease. A target SF value in the deferasirox clinical trials was not specified per protocol, but was determined by the individual investigators. This analysis evaluates the safety of deferasirox (Exjade®) in a cohort of adult and pediatric patients with transfusion-dependent anemias and iron overload from two large clinical trials (107 and 108) who were chelated to SF levels &lt;1000 ng/mL. Methods: In core studies 107 and 108, frequently-transfused patients with chronic anemias ≥2 years old received deferasirox 5–30 mg/kg/day for 1 year. Eligible patients were then enrolled in 4-year extension trials, where initial dosing was based on the end of core study liver iron concentration; dose adjustments were based on SF levels. Patients eligible for this analysis had an initial SF ≥1000 ng/mL. Patients who achieved a SF level &lt;1000 ng/mL on ≥2 consecutive visits, any time after starting deferasirox, were identified. The number of days when SF was &lt;1000 ng/mL was calculated for each patient. AEs in these patients were calculated for the entire period on deferasirox, and for the period following the first SF measurement of &lt;1000 ng/mL, irrespective of future SF levels. Results: 474 patients were included in this analysis: underlying anemias were β-thalassemia (n=379), myelodysplastic syndromes (n=43), Diamond-Blackfan anemia (n=30) and other anemias (n=22). Overall, 13.5% patients achieved SF&lt;1000 ng/mL in year 1, 18.6% in year 2, 25.7% in year 3, 32.5% in year 4 and 36.7% by the time of this analysis. Therefore, overall 174 patients (36.7%) reached a SF level &lt;1000 ng/mL on ≥2 consecutive visits, while in 300 patients SF levels remained ≥1000 ng/mL. The median period for a SF value &lt;1000 ng/mL was 149 days [range 18–1726]. Patient demographics, baseline characteristics and safety profiles of the two groups throughout deferasirox treatment are shown in Table 1. At month 54, median SF levels in the &lt;1000 and &gt;1000 ng/mL groups were 872 and 2118 ng/mL, respectively. The incidence of drug-related AEs (gastrointestinal, renal and liver) did not appear to increase during the periods after SF levels first decreased below 1000 ng/mL (data not shown). Table 1. Demographics, baseline characteristics and safety profile of patients who achieved SF levels &lt;1000 ng/mL and patients who did not Patients who achieved SF &lt;1000 ng/mL Patients who did not achieve SF &lt;1000 ng/mL *Investigator-assessed; SCr, serum creatinine; ULN, upper limit of normal; ALT, alanine aminotransferase n 174 300 Male:female 85:89 145:155 Mean age ± SD, years 23.8 ± 16.7 23.5 ± 18.2 &lt;16, n (%) 65 (37.4) 123 (41.0) ≥16, n (%) 109 (62.6) 177 (59.0) Enrolled from study 107:108 120:54 175:125 Median exposure to deferasirox, months 56.3 45.2 Mean actual deferasirox dose, mg/kg/day 20.3 22.9 Median baseline SF, ng/mL 1791 2883 Drug-related AEs* (≥5% in either group), n (%) Nausea 26 (14.9) 38 (12.7) Diarrhea 17 (9.8) 42 (14.0) Vomiting 14 (8.0) 25 (8.3) Abdominal pain 12 (6.9) 32 (10.7) Upper abdominal pain 6 (3.4) 20 (6.7) Rash 9 (5.2) 16 (5.3) Audiological abnormalities 7 (4.0) 4 (1.3) Ophthalmological abnormalities 4 (2.3) 5 (1.7) Two consecutive SCr increases &gt;33% above baseline and above ULN 26 (14.9) 36 (12.0) Increase in ALT &gt;10×ULN on at least 1 visit 12 (6.9) 20 (6.7) Baseline levels elevated 6 (3.4) 16 (5.3) Conclusions: Over the core and extension phases of these clinical studies, the safety profile of patients achieving SF levels &lt;1000 ng/mL was similar to that observed in patients who did not achieve SF levels &lt;1000 ng/mL. There was also no apparent increase in AEs associated with a decrease in SF levels &lt;1000 ng/mL. In particular, no increase in the proportion of patients with creatinine increases &gt;33% above baseline and ULN or with ALTs &gt;10×ULN were observed in these patients. These findings suggest that ironoverloaded patients can be safely chelated with deferasirox to low SF levels.

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