Background: Iron overload is the main cause of morbidity and mortality especially from heart failure in patients with beta thalassemia major [TM]. Successful iron chelation is thus essential for the optimal management of TM. Although desferrioxamine [DFX] has been the major iron-chelating treatment of transfusional iron overload, compliance is a major hindrance. The availability of oral iron chelation with deferiprone [L1] since 1987 was welcome but showed poor efficacy when used alone as compared to DFX. Aim: To compare DFX and prospective combined therapy with DFX and L1 in beta thalassemia major patients with iron overload. Methods: We studied 69 patients with beta thalassemia major (Mean age ± SD, 15.02± 5.8; Range 4–28 years) attending the Day Care unit for regular transfusional support. They received packed red cells every 3–4 weeks to maintain pre-transfusion hemoglobin concentration above 9 g/dl. They were receiving DFX at a daily dose of 40mg/kg/day by subcutaneous infusion for 8–10 hrs on 4–5 nights each week for past several years. However, owing to various reasons, they developed considerable transfusional iron overload. These patients were enrolled prospectively to receive additional therapy with oral iron chelator L1 at 75 mg/kg body weight in three divided doses with food after informed consent and also continued to receive treatment with DFX as per the above dosage. Results: Of the 69 patients, 6 developed severe GI upset, 2 developed persistently raised liver enzymes, 2 died [sepsis], two underwent bone marrow transplantation and 2 developed agranulocytosis and so did not continue in the study. In the remaining 55 evaluable patients, [3–48 months on combination therapy; mean(±SD) 22±12 months] the mean serum ferritin(±SD) fell dramatically from 3088(±1299) [DFX alone] to 2051(±935)ng/ml [DFX+L1; p<0.001], with the mean of lowest serum ferritin being 1731(±828) ng/ml in this group. Interestingly, there was also a significant improvement in the Ejection fraction [p<0.004]and Fractional shortening[p<0.0436] in these patients. Sustained successful iron chelation on combination therapy Ferritin pretherapy[DFX] 6mths[DXF+L1] 12 mths [DXF+L1] 18mths [DXF+L1] 24mths [DXF+L1] 36mths [DXF+L1] 48 mths [DXF+L1] No of Patients n=55 n=54 n=42 n=32 n=24 n=12 n=7 Mean± SD 3088±1299 2530±1221 2495±1175 2433±1154 2165±889 1686±917 997±318 Range-Max 7534 6070 5559 5126 4130 3172 1471 Range-Min 1072 599 776 408 712 473 559 Students t test[DFX v/s DFX+L1] p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 Improved myocardial performance on combination therapy Pretherapy [DFX] Combination Therapy [DFX+L1] p value Ejection Fraction [%] 69.04±5.182 72.99±5.54 p<0.0004 Fractional Shortening [%] 32.19±4.32 34.89±5.4 p<0.0436 Summary/Conclusion: The study emphasizes that beta thalassemia major patients with transfusional iron overload can be successfully treated with a combination of DFX and L1. The results also demonstrate significant statistical improvement as early as 6 months of combination therapy. Furthermore, this improvement was sustained leading to a progressive fall in the mean serum ferritin. Lastly, the study also demonstrates significant improvement in echocardiographic parameters of myocardial performance in these patients receiving combination therapy.
Objective: The aim of the study was to establish neonatal cord blood screening in the Sultanate of Oman, in an effort to determine the prevalence of haemoglobinopathies by a cost-effective method. Background: Oman is a country with a two million population comprising of a wide range of ethnic groups, high rates of consanguinity and increased incidences of inter-cousin marriages all leading to an increased prevalence of haemoglobinopathies. High performance liquid chromatography [HPLC] is a powerful tool to screen newborns for haemoglobinopathies. Neonatal screening includes cord blood samples collection, screening and follow up of all newborns with abnormal results. Methods: A total of 7837 consecutive cord blood samples were screened for the presence of possible haemoglobinopathies by HPLC using Biorad Variant II program between April 2005 & March 2007. Complete blood counts [CBC] were also obtained on Cell Dyn 4000 automated blood cell counter. All samples were then processed to isolate and store mononuclear leukocytes for subsequent molecular diagnostics. Results: The findings indicated a 47.07% incidence of α-thalassaemia, based on low mean cell volume [MCV] & mean cell haemoglobin [MCH] on the CBC and significant amounts of Hb Barts on HPLC. Furthermore, the overall incidence of other haemoglobinopathies was 9.87%, with 5.47% incidence of sickle haemoglobin. On HPLC, D-window, E-window and C-window were present in 0.93%, 0.77% and 0.06% of the samples respectively. Figure Figure Since HPLC cannot diagnose beta thalassemia major at birth, in samples with HbA below 10%, the beta globin gene was directly sequenced including the promoter, all exons and introns in these samples. Amongst 206(2.62%) samples sequenced, beta thalassaemia trait was confirmed in 201 cases and 5 cases were homozygous for beta thalassaemia. Additionally, direct sequencing of all abnormal samples with HbS,[n=429] HbD,[n=73], HbE[n=42] and HbC[n=5] was also performed on ABI 3100 Genetic Analyzer to assign the genotype status to these subjects and to validate the HPLC results. Amongst the 429 samples with HbS sequenced, 24 samples were homozygous (0.3%) and were referred for comprehensive clinical care programme. Conclusions: The significantly high incidence of haemoglobinopathies in newborns in the Sultanate of Oman emphasizes the value of neonatal cord blood screening to be implemented as the first step in the national strategy towards total management of haemoglobinopathies including early diagnosis, comprehensive clinical care and counseling of the affected families. The results of this large study indicate that using HPLC [<2 USD/sample] and prescreening of parents to select only abnormal samples for neonatal cord blood screening [<10% samples] can be recommended as a highly cost-effective method targeted to screen only the abnormal samples.
4105 Introduction: Conditioning chemotherapy prior to allogeneic bone marrow transplantation (BMT) can induce impairment in gonadal function. Patients with beta-thalassemia major generally undergo BMT at a young age and long-term data on its effects on gonadal function in this patient population are limited. Aims and objectives: To address the effect of BMT on gonadal function in long term survivors with beta-thalassemia major following successful BMT. Materials and methods: The hormonal profiles of gonadotrophins (LH and FSH), sex hormones (total and free testosterone in males, and 17 beta-estradiol in females) and inhibin B were assayed yearly after BMT. We analyzed data on patients who underwent BMT between January 1996 and June 2009 in whom the pubertal process should have started. Results: A total of 84 patients received BMT for thalassemia major; 51 (20 females and 31 males) have reached the age of puberty at the time of this analysis. Median age at transplant was 10 years (range: 3 – 17). With a median follow-up of 8 years (range: 2–15), the median age at last follow-up was 18 years (range: 13 – 26). All transplants were from matched sibling donors. Conditioning was myeloablative and consisted of: Busulfan, total dose of 600mg/m2 and Cyclophosphamide, total dose 200mg/kg (BuCy) before January 2005 and Busulfan, total dose 520mg/m2, Fludarabine, total dose 180mg/m2 and ATG, total dose 40mg/kg (BuFluATG) from January 2005 onwards. The impact of BMT appears to be different in the two sexes. 18 of 20 (80%) female patients had evidence of primary ovarian failure. Leydig cell failure was seen in only two male patients. However, injury to the germinal epithelium (as shown by low inhibin B levels which is predictive of oligo- or azoospermia) was seen in 22 of 31 (70%) male patients. A correlation was not found between the low inhibin B levels and age at BMT or type of conditioning regimen. Conclusion: Our data confirm that gonads in male and female thalassemic patients are affected by the cytotoxic effects of the preparative regimens of BMT, albeit at different levels. These findings emphasize the need for vigilant long term follow up of thalassemic patients post-BMT so that those requiring hormone replacement therapy can be identified and treated early. These findings are also important for pre- and post-BMT counseling. Disclosures: No relevant conflicts of interest to declare.
Background: Several distinct subtypes of breast cancer (Luminal, Basal-like and Her-2+) have been identified by gene expression profiling of breast cancers and cell lines. Although much is known about the regulation of cell signaling in each breast cancer subtype, little is known about subtype-specific energy metabolism and its regulation. The majority of cancers, including breast cancer, acquire an accelerated metabolic index as part of the transformation process. One of the most studied metabolic changes in cancer, referred to as the Warburg effect, is the increased uptake of glucose and its conversion to lactate; which is released from the cell, thus creating an astringent tumor microenvironment with high lactate and low pH. Accumulation of lactate in the tumor microenvironment presents cancer cells with a potential rich carbon source that could be exploited when the preferred nutrient sources, glucose and glutamine, are not abundant or available. Thus uptake and conversion of lactate to pyruvate and then entry into the TCA cycle and oxidative phosphorylation could generate energy that could potentially allow cancer cells to survive until other nutrients become available or until the cancer cells can invade and migrate toward nutrient rich environments, in other words, until they spread locally and metastasize. Methods and Results: Examination of 59 breast cancer cell lines shows differences in expression of numerous proteins and enzymes involved in cellular metabolism, including the lactate transporters (MCT), the enzyme lactate dehydrogenase (LDH), and glucose transporter proteins (GLUT). We found that MCT1 expression is lost in the Luminal subtype and correlates with loss of LDHB and the regulator and chaperone of MCT1, CD147 (Basigin). Conversely, MCT1 is highly expressed in Basal-like and normal cell lines, along with CD147 and LDHB. While monocarboxylate transporter proteins can transport bi-directionally, MCT1 preferentially transports lactate into the cell, while MCT4 transports lactate out of the cell. The loss of MCT1 in luminal cells suggests a distinct energy metabolism in this subtype versus basal-like cells. The basal-like subtype has been further categorized into Basal and Claudin-low subtypes. Claudin-low cells express stem-like markers such as CD44+/CD24-, EMT markers such as vimentin, and are low expressers of the Claudin proteins. We found that MCT1 and CD147 are highly expressed and differentially regulated in Claudin-low cell lines as compared to normal cells. We have evidence that high lactate (10mM) as a sole energy source delays ATP loss and apoptosis in MCT1 expressing cells, but not in luminal cell lines that lack MCT1. Thus, claudin-low tumors may benefit from local lactate production providing an unexpected energy source. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-05-03.
Bone marrow transplantation is the only curative treatment modality available for patients with homozygous beta thalassemia. Although the transplant outcome for good-risk patients is uniformly excellent, rejection continues to remain a serious complication with reported incidences ranging from 10–40%. Since mixed hematopoietic chimerism (MC) has been shown to be a risk factor for rejection in homozygous beta thalassemia, we investigated the relationship between MC and busulfan pharmacokinetics (Bu PK). Between May 1999 and April 2004, we retrospectively analyzed 24 consecutive patients with homozygous beta thalassemia transplanted in this center, for whom data on Bu PK was available. The median age was 9.5yr (3–15 yr). Sixteen (67%) patients were Class II, six (25%) Class III, one patient (4%) Class I and one patient (4%) Class II or III as per the Lucarelli classification for transplant outcome. The conditioning regimen consisted of busulfan/cyclophosphamide in 21/24 (88%) and busulfan/cyclophosphamide/ATG in 3/24 (12%) patients. All patients received a standard dose of cyclophosphamide (200mg/kg) but had varying doses of busulfan, ranging from 15 to 29mg/kg (mean 21mg/kg). Nine out of the 24 patients (38%) received the intravenous preparation of busulfan. Cyclosporine and short-course methotrexate were used as graft versus host disease (GVHD) prophylaxis. Bu PK was performed by liquid chromatography mass-spectrometry on frozen plasma samples obtained after doses 1, 5 and 13. Chimerism was assessed after BMT by DNA fingerprinting using a panel of informative markers. Acute GVHD was seen in 13/23 (56%) evaluable patients, 9/13 were grade I & II and 3/13 grade III & IV. Veno-occlusive disease of the liver (VOD) as per the Seattle and Baltimore criteria occurred in 14/24 (58%) and 3/24 (12%) respectively. MC was documented in 5/24 (21%) patients while graft rejection occurred in 2/23 (9%) evaluable patients. Non-rejection mortality was 4% (1/24). Thalassemia-free survival was 88% (21/24) with a median follow up of 31 months. MC significantly predicted for rejection (p=0.04). Analysis of Bu PK showed that patients with MC had significantly lower minimum and steady state busulfan concentrations (Cmin and Css) and faster clearance of the drug (CL/F) when compared to patients with complete chimerism. REJECTION [n=2] NO REJECTION [n=21] MIXED CHIMERISM 2 [100%] 3 [14%] p = 0.04 MIXED CHIMERISM [n=5] COMPLETE CHIMERISM [n=19] Dose 1 Bu PK Cmin (ng/ml) 201.00±44.21 298.16±98.08 p < 0.05 Css (ng/ml) 616.2±108.4 842.83±252.2 p < 0.05 Cl/F (L/h/kg) 0.343±0.087 0.260±0.058 p < 0.05 Mean Bu PK Cmin (ng/ml) 207.6±48.3 288.4±86.3 p < 0.05 Cl/F (L/h/kg) 0.345±0.091 0.289±0.045 p < 0.05 Although the number of patients is small, this study confirms MC to be a risk factor for rejection, and further demonstrates the occurrence of MC post BMT to be associated with low busulfan systemic exposure during conditioning. Individualizing busulfan dosage based on Bu PK may therefore be one strategy to minimize rejection in bone marrow transplantation for homozygous thalassemia.
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