Oral isobutyramide reduces transfusion requirements in some patients with homozygous β-thalassemia

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3357-3363 ◽  
Author(s):  
Susanne Reich ◽  
Christoph Bührer ◽  
Günter Henze ◽  
Dieter Ohlendorf ◽  
Michael Mesche ◽  
...  
Keyword(s):  
Bitter Taste ◽  
Fetal Hemoglobin ◽  
Response To Treatment ◽  
Trial Period ◽  
Epigastric Discomfort ◽  
Day Range ◽  
Iron Load ◽  
Transfusion Requirements ◽  
Parenteral Iron ◽  
Pretreatment Phase

The butyrate derivative isobutyramide (IBT) increases fetal hemoglobin (HbF) in patients with β-hemoglobinopathies, but little is known about its usefulness for prolonged therapeutic use. We treated 8 patients with transfusion-dependent β-thalassemia with 350 mg/kg of body weight per day of oral IBT for 126 to 384 days. During the trial period, the hemoglobin level was maintained between 85 g/L (range 82-87 g/L) (pretransfusion) and 115 g/L (range 110-119 g/L) (post-transfusion) (median, interquartile range), corresponding to 4-week transfusion intervals in all patients during the pretreatment phase. Adverse effects (bitter taste, epigastric discomfort) did not cause discontinuation of IBT. HbF increased in all patients from 3.1% (range 1.9%-4.8%) to 6.0% (range 3.3%-8.7) (P = .0017), while free Hb dropped from 0.48 g/L (range 0.39-0.81 g/L) to 0.19 g/L (range 0.16-0.24 g/L) (P < .0001). Transfusion intervals were consistently extended to 8 or 9 weeks in 1 patient, resulting in a decrease of daily iron load from 455 μg/kg per day (range 451-459 μg/kg per day) before therapy to 211μg/kg per day (range 203-286 μg/kg per day) during the 12-month treatment period. Prolongation of transfusion intervals achieved by IBT was less consistent in another patient, whose parenteral iron load nevertheless decreased from 683 μg/kg per day (range 618-748 μg/kg per day) to 542 μg/kg per day (340-596 μg/kg per day). In the other 6 patients, no prolongation of transfusion intervals was achieved. Response to treatment was associated with high pretreatment HbF (> 4.5%), high parental HbF, and increased erythropoietin levels (> 150 IU/L). We conclude that IBT prolongs transfusion intervals and reduces parenteral iron burden in some patients with transfusion-dependent β-thalassemia.

Oral isobutyramide reduces transfusion requirements in some patients with homozygous β-thalassemia

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3357-3363 ◽  
Author(s):  
Susanne Reich ◽  
Christoph Bührer ◽  
Günter Henze ◽  
Dieter Ohlendorf ◽  
Michael Mesche ◽  
...  
Keyword(s):  
Bitter Taste ◽  
Fetal Hemoglobin ◽  
Response To Treatment ◽  
Trial Period ◽  
Epigastric Discomfort ◽  
Day Range ◽  
Iron Load ◽  
Transfusion Requirements ◽  
Parenteral Iron ◽  
Pretreatment Phase

Abstract The butyrate derivative isobutyramide (IBT) increases fetal hemoglobin (HbF) in patients with β-hemoglobinopathies, but little is known about its usefulness for prolonged therapeutic use. We treated 8 patients with transfusion-dependent β-thalassemia with 350 mg/kg of body weight per day of oral IBT for 126 to 384 days. During the trial period, the hemoglobin level was maintained between 85 g/L (range 82-87 g/L) (pretransfusion) and 115 g/L (range 110-119 g/L) (post-transfusion) (median, interquartile range), corresponding to 4-week transfusion intervals in all patients during the pretreatment phase. Adverse effects (bitter taste, epigastric discomfort) did not cause discontinuation of IBT. HbF increased in all patients from 3.1% (range 1.9%-4.8%) to 6.0% (range 3.3%-8.7) (P = .0017), while free Hb dropped from 0.48 g/L (range 0.39-0.81 g/L) to 0.19 g/L (range 0.16-0.24 g/L) (P &lt; .0001). Transfusion intervals were consistently extended to 8 or 9 weeks in 1 patient, resulting in a decrease of daily iron load from 455 μg/kg per day (range 451-459 μg/kg per day) before therapy to 211μg/kg per day (range 203-286 μg/kg per day) during the 12-month treatment period. Prolongation of transfusion intervals achieved by IBT was less consistent in another patient, whose parenteral iron load nevertheless decreased from 683 μg/kg per day (range 618-748 μg/kg per day) to 542 μg/kg per day (340-596 μg/kg per day). In the other 6 patients, no prolongation of transfusion intervals was achieved. Response to treatment was associated with high pretreatment HbF (&gt; 4.5%), high parental HbF, and increased erythropoietin levels (&gt; 150 IU/L). We conclude that IBT prolongs transfusion intervals and reduces parenteral iron burden in some patients with transfusion-dependent β-thalassemia.

scholarly journals Gene therapy of hemoglobinopathies: progress and future challenges

2019 ◽  
Vol 28 (R1) ◽  
pp. R24-R30 ◽  
Author(s):  
Yasuhiro Ikawa ◽  
Annarita Miccio ◽  
Elisa Magrin ◽  
Janet L Kwiatkowski ◽  
Stefano Rivella ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Ex Vivo ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Specific Expression ◽  
Widespread Application ◽  
Hematopoietic Stem ◽  
Transfusion Requirements ◽  
Future Challenges

Abstract Recently, gene therapy clinical trials have been successfully applied to hemoglobinopathies, such as sickle cell disease (SCD) and β-thalassemia. Among the great discoveries that led to the design of genetic approaches to cure these disorders is the discovery of the β-globin locus control region and several associated transcription factors, which determine hemoglobin switching as well as high-level, erythroid-specific expression of genes at the ß-globin locus. Moreover, increasing evidence shows that lentiviral vectors are efficient tools to insert large DNA elements into nondividing hematopoietic stem cells, showing reassuring safe integration profiles. Alternatively, genome editing could restore expression of fetal hemoglobin or target specific mutations to restore expression of the wild-type β-globin gene. The most recent clinical trials for β-thalassemia and SCD are showing promising outcomes: patients were able to discontinue transfusions or had reduced transfusion requirements. However, toxic myeloablation and the high cost of current ex vivo hematopoietic stem cell gene therapy platforms represent a barrier to a widespread application of these approaches. In this review, we summarize these gene therapy strategies and ongoing clinical trials. Finally, we discuss possible strategies to improve outcomes, reduce myeloablative regimens and future challenges to reduce the cost of gene therapy platform.

Activated Recombinant Factor VII (rFVIIa/NovoSeven®) in the Treatment of Bleeding Complications Following Hematopoietic Stem Cell Transplantation (HSCT).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1135-1135 ◽  
Author(s):  
Benjamin Brenner ◽  
Markus Pihusch ◽  
Andrea Bacigalupo ◽  
Jeff Szer ◽  
Mario von Depka Prondzinski ◽  
...  
Keyword(s):  
Adverse Events ◽  
Initial Dose ◽  
Factor Vii ◽  
Bleeding Complications ◽  
Controlled Study ◽  
Severe Bleeding ◽  
Trial Period ◽  
Hematopoietic Stem ◽  
Coagulation Parameters ◽  
Transfusion Requirements

Abstract HSCT is a common treatment of hematological or oncological disorders. Many HSCT-associated complications, including prolonged aplasia, infection and graft-versus-host disease (GVHD) predispose to bleeding, resulting in increased morbidity and mortality. Platelet concentrates, fresh frozen plasma, antifibrinolytic agents or prothrombin complex concentrates are often ineffective. Although licensed for use in hemophilia pts with inhibitors, rFVIIa has been reported to be effective for the treatment of bleeding related to thrombocytopenia, thrombasthenia and other coagulation disorders. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rFVIIa in treatment of bleeding from days 2 to 180 after HSCT (F7BMT-1360 trial). Patients received rFVIIa (40, 80, 160 μg/kg) or placebo every 6h for 36h and were followed up for 96h after the initial dose. Exclusion criteria were recent thromboembolic events, atherosclerotic disease, DIC, thrombotic microangiopathy, venoocclusive disease and active AML (M3, M4, M5). The primary efficacy endpoint was the change in bleeding from 0h to 38h after initial dose. Secondary endpoints were transfusion requirements, change of coagulation parameters, and adverse events (AEs). One hundred patients (64 m; 36 f; 97 allogeneic; 3 autologous; 67 PBSC; 30 bone marrow; 2 cord blood; 1 unknown) with moderate or severe bleeding were included (38 lower GI; 26 hemorrhagic cystitis; 14 upper GI; 7 pulmonary; 1 intracerebral; 14 other). 80 μg/kg rFVIIa was effective, however no significant reduction in bleeding was seen at 160 μg/kg. There were no differences in transfusion requirements and changes in coagulation parameters across dose groups. Thirteen serious adverse events (SAEs) were reported within the trial period; there was no apparent drug or dose-related trend in the type or number of SAEs. One thromboembolic SAE (catheter thrombosis, 160 μg/kg) was observed within the trial period (2 days after last dosing) and two thromboembolic SAEs (cerebral infarction, 80 μg/kg; myocardial infarction, 40 μg/kg) were reported 4 and 14 days after last dosing. In this first controlled study on the use of rFVIIa after HSCT we found a significant effect of 80 μg/kg rFVII versus the standard hemostatic treatment. The diversity of the hemostatic disturbances and the heterogeneity of the patient population may have contributed to the lack of an increasing effect with increased dose. No safety issues were identified. Further trials with higher numbers of patients should focus upon optimizing the dose regimen of rFVIIa and on severe bleeding complications Bleeding status 38h after initial dose Treatment Gp N Stopped Decreased Unchanged/worse Cumulative odds ratio 97.1% CI p All data based on ITT. p&lt;0.029 considered sig. Overall treatment effect: p=0.003. *Status unknown for 2 pts Placebo 22 5 (23%) 8 (36%) 9 (41%) 1.00 - - 40μg/kg 20 6 (30%) 4 (20%) 10 (50%) 0.94 [0.24; 3.64] 0.923 80μg/kg 26 14 (54%) 7 (27%) 5 (19%) 4.20 [1.05; 16.84] 0.021 160μg/kg 30 4 (13%) 9 (30%) 17 (57%) 0.54 [0.16; 1.83] 0.269 Total 98* 29 (30%) 28 (29%) 41 (42%) - - -

Hydroxyurea can eliminate transfusion requirements in children with severe β-thalassemia

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1529-1530 ◽  
Author(s):  
Mohamed Bradai ◽  
Mohand Tayeb Abad ◽  
Serge Pissard ◽  
Fatima Lamraoui ◽  
Laurent Skopinski ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Chelating Agents ◽  
Fetal Hemoglobin ◽  
Thalassemia Major ◽  
Thalassemia Intermedia ◽  
Cell Disease ◽  
Marked Elevation ◽  
Transfusion Requirements

Abstract Hydroxyurea (HU) enhances fetal hemoglobin (Hb) production. An increase in total Hb level has been repeatedly reported during HU treatment in patients with sickle cell disease and in several patients with β-thalassemia intermedia. Effects in patients with β-thalassemia major are controversial. We now report a marked elevation of total Hb levels with HU that permitted regular transfusions to be stopped in 7 children with transfusion-dependent β-thalassemia. The median follow-up was 19 ± 3 months (range, 13-21 months). We conclude that HU can eliminate transfusional needs in children with β-thalassemia major, which could be particularly useful in countries such as Algeria, where supplies of blood or chelating agents are limited.

scholarly journals Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1109-1112 ◽  
Author(s):  
Steffen E. Meiler ◽  
Marlene Wade ◽  
Ferdane Kutlar ◽  
Shobha D. Yerigenahally ◽  
Yongjun Xue ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Ex Vivo ◽  
Fetal Hemoglobin ◽  
Structural Analog ◽  
Hematologic Malignancies ◽  
Similar Efficacy ◽  
Novel Therapy ◽  
New Class ◽  
Transfusion Requirements ◽  
Hbf Induction

Abstract Pharmacologic induction of fetal hemoglobin (HbF) expression is an effective treatment strategy for sickle cell disease (SCD) and β-thalassemia. Pomalidomide is a potent structural analog of thalidomide and member of a new class of immunomodulatory drugs. Recent reports demonstrated that pomalidomide reduced or eliminated transfusion requirements in certain hematologic malignancies and induced HbF ex vivo in CD34+ progenitor cells from healthy and SCD donors. We investigated the effects of pomalidomide on erythropoiesis and hemoglobin synthesis in a transgenic mouse model of SCD. We found that 8 weeks of treatment with pomalidomide induced modest increases of HbF with similar efficacy as hydroxyurea. However, in stark contrast to hydroxyurea's myelosuppressive effects, pomalidomide augmented erythropoiesis and preserved bone marrow function. Surprisingly, combinatory therapy with both drugs failed to mitigate hydroxyurea's myelotoxic effects and caused loss of HbF induction. These findings support further evaluation of pomalidomide as a novel therapy for SCD.

scholarly journals Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial

Blood ◽  
1995 ◽  
Vol 85 (1) ◽  
pp. 43-49 ◽  
Author(s):  
AF Collins ◽  
HA Pearson ◽  
P Giardina ◽  
KT McDonagh ◽  
SW Brusilow ◽  
...  
Keyword(s):  
Fetal Hemoglobin ◽  
Cell Number ◽  
Response To Treatment ◽  
Beta Thalassemia ◽  
Thalassemia Patient ◽  
Alpha Globin ◽  
Pill Counts ◽  
Sodium Phenylbutyrate

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta- thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion- dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.

The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS)

Blood ◽  
2010 ◽  
Vol 115 (12) ◽  
pp. 2354-2363 ◽  
Author(s):  
Ersi Voskaridou ◽  
Dimitrios Christoulas ◽  
Antonios Bilalis ◽  
Eleni Plata ◽  
Konstantinos Varvagiannis ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Hospital Admissions ◽  
Fetal Hemoglobin ◽  
Acute Chest Syndrome ◽  
Prolonged Administration ◽  
Probability Of Survival ◽  
Transfusion Requirements ◽  
History Of

The aim of this prospective study was to evaluate the long-term efficacy and safety of hydroxyurea (HU) in patients with sickle cell disease (SCD). Thirty-four patients with sickle cell anemia (hemoglobin S [HbS]/HbS), 131 with HbS/β0-thal, and 165 with HbS/β+-thal participated in this trial. HU was administered to 131 patients, whereas 199 patients were conventionally treated. The median follow-up period was 8 years for HU patients and 5 years for non-HU patients. HU produced a dramatic reduction in the frequency of severe painful crises, transfusion requirements, hospital admissions, and incidence of acute chest syndrome. The probability of 10-year survival was 86% and 65% for HU and non-HU patients, respectively (P = .001), although HU patients had more severe forms of SCD. The 10-year probability of survival for HbS/HbS, HbS/β 0-thal, and HbS/IVSI-110 patients was 100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and 66%, for non-HU patients. The multivariate analysis showed that fetal hemoglobin values at baseline and percentage change of lactate dehydrogenase between baseline and 6 months were independently predicted for survival in the HU group. These results highlight the beneficial effect of HU, which seems to modify the natural history of SCD and raise the issue of expanding its use in all SCD patients.

Role of parenteral iron in transfusion requirements after total hip replacement. A pilot study

2006 ◽  
Vol 0 (0) ◽  
pp. 060518042006001
Author(s):  
M. Munoz ◽  
E. Naveira ◽  
J. Seara ◽  
J. H. Palmer ◽  
J. Cuenca ◽  
...  
Keyword(s):  
Pilot Study ◽  
Total Hip Replacement ◽  
Hip Replacement ◽  
Total Hip ◽  
Transfusion Requirements ◽  
Parenteral Iron

Chemotherapy as the initial treatment of spinal cord compression due to disseminated neuroblastoma

1989 ◽  
Vol 70 (5) ◽  
pp. 688-690 ◽  
Author(s):  
I. R. Sanderson ◽  
Jon Pritchard ◽  
Henry T. Marsh
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Compression ◽  
Initial Treatment ◽  
Cord Compression ◽  
Response To Treatment ◽  
Trial Period ◽  
Content Type ◽  
Sick Children ◽  
Spinal Cord Function ◽  
Fine Print

✓ During a 12-month trial period, all children attending the Hospitals for Sick Children, London, England, for management of spinal cord compression due to disseminated neuroblastoma were given chemotherapy as initial treatment rather than radiotherapy or laminectomy. Response to treatment was evaluated by a neurosurgeon as well as by oncologists. Four children were treated in this way and all made a full recovery of spinal cord function.

High Alpha-1 Antitrypsin Clearance Predicts Severity of Gut Graft Versus Host Disease (GVHD) In Children

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1242-1242
Author(s):  
Lorrie EM Hagen ◽  
Tal Schechter ◽  
Adam Gassas ◽  
John J Doyle
Keyword(s):  
Conflicts Of Interest ◽  
Response To Therapy ◽  
Stage Ii ◽  
Stage Iii ◽  
Response To Treatment ◽  
Protein Losing Enteropathy ◽  
Hematopoietic Stem ◽  
Day Range ◽  
Number Of Patients ◽  
Alpha 1 Antitrypsin

Abstract Abstract 1242 The clinical evaluation and management of gut GVHD is a significant challenge in pediatric hematopoietic stem cell transplantation (HSCT). It is often difficult to obtain pathological evidence to confirm the GVHD diagnosis and/or determine response to treatment. The severity of the disease itself may not just be related to the associated classic symptoms. Our objective herein was to prospectively study the effect of gut GVHD on protein losing enteropathy (PLE) as measured by alpha-1 antitrypsin clearance (AATC) in stools. Thirteen patients who were diagnosed with gut GVHD by clinical criteria were recruited; 5 patients were excluded as 4 had gut GVHD ruled out by biopsy and 1 was unable to complete study due to stool collection issues. Therefore, 8 patients; 6 males and 2 females, were studied. The median age was 9.5 years (range 6–17). Diagnoses included ALL (4), AML (2), Lymphoma (1) and Adrenoleukodystrophy (1). Donor types were; 7 unrelated (BM n=4 and cord n=3) one matched related BM donor. All patients received cyclosporine for GVHD prophylaxis, in addition 4 patients also received methotrexate and 3 others received prednisone as the second agent. All patients had negative stool EM for viruses and cultures for C.difficile on their first collection. Two 24 hour stool collections were taken from each patient at a mean of 8.5d (range 7–13d) apart. Patients’ gut GVHD staging is summarized in Table 1.Table 1:Summary of Stage gut GVHD and PLEPatientsAATC Median(range)normal = <22Stool outputml/kg/d Median(range)Stage of gutGVHD (n=)# with PLECollection #1831 (3-339)28 (10-109)Stg 1 (2) 4/8Stg 2 (3)Stg 3 (1)Stg 4 (2)Collection #2856 (8-561)19 (0-85) Stg 1 (0) 5/8Stg 2 (0)Stg 3 (3)Stg 4 (1) At the time of 1st collection, 6 patients had ≥ stage II gut GVHD and at 2nd collection 4 patients had ≥stage II gut GVHD and 4 collections were of non-diarrheal stool. A total of 7 stool collections were taken at a diagnosis of ≥stage III gut GVHD. Mean alpha-1 antitrypsin clearance (AATC) from all 16 collections was 143 mls/day (range 3–561), levels >22 mls/day indicate the diagnosis of protein-losing enteropathy (PLE). Nine of the collections (56%) showed PLE with a mean AATC of 247mls/day (range 31–561). Six out of the 7 samples from patients with ≥stage III gut GVHD were positive for PLE. Five collections with stool volumes >30 ml/kg/day were positive for PLE. Stool volumes were significantly higher on second collection (Wilcoxon signed ranks test, p = 0.003) consistent with the second stool collections being significantly more likely to have an elevated AATC, therefore more severe PLE over time (p<0.001). We conclude that a highly significant positive correlation exists between the severity of PLE and the stage of gut GVHD, particularly obvious in patients with stage 3–4 GVHD (ANOVA, p=0.015). See Table 2.Table 2:Stage of gut GVHD and AATCStage ofGVHDNumber ofcollectionsMeanAATCStd.Deviation0426.0020.801217.0019.802384.67136.2934171.50176.2143406.33134.32 When patients were grouped as stage 0–2 GVHD vs. stage 3–4 GVHD, those with stage 3–4 GVHD had significantly higher AATC values (p =0.02). Despite the small number of patients recruited, this study emphasizes the need to consider PLE as a useful aspect of the clinical picture. We suggest that in order to see a response to therapy and therefore a decrease in AATC, clinicians should not repeat stool collections before 2 weeks from the initiation of therapy. In light of the significant morbidity and mortality associated with grade 3 and 4 gut GVHD, and as an important therapeutic decision for these patients, one may consider escalating GVHD therapy if a patient's AATC is rising. Disclosures: No relevant conflicts of interest to declare.

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