Deferasirox: Oral, once daily iron chelator - An expert opinion.

Iron overload is a serious and potentially fatal condition that results from multiple blood transfusions required over a long period of time to treat certain types of anemias such as, that caused by β-thalassemia, sickle cell disease and myelodysplastic syndrome. Deferoxamine, which has been used since four decades as an iron chelator has limited efficacy due to its demanding therapeutic regimen, leading to poor compliance. Deferasirox, once daily oral iron chelator provides an effective alternative to Deferoxamine in the treatment of transfusional hemosiderosis. In this review, the role of Deferasirox as an ideal iron chelator has been discussed. Pubmed searches on Deferasirox were carried out for the same. Several studies demonstrated the safety and efficacy of Deferasirox in reducing iron burden in iron-overloaded patients with β-thalassemia, sickle cell anemia and myelodysplastic anemia. Thus, convenient, effective and tolerable chelation therapy with oral Deferasirox is likely to be a significant development in the treatment of transfusional iron overload, due to its ability to provide constant chelation coverage and the potential to improve compliance.

Advances in management of thalassemia.

Thalassemias represent the most common single-gene disorder causing a major public health problem in India. Thalassemia and hemoglobinopathies probably developed over 7000 years ago as a defense against malaria. In simple terms, thalassemia is caused by a mutation in either the â-globin chain or the á-globin chain which combine equally in red cells to form hemoglobin. These mutations lead to varying degree of anemia resulting into thalassemia minor, intermedia or major. Present write up relates to advances in the management of â-thalassemia major.

Clinical applications of molecular haematology: JAK2 in myeloproliferative disorders.

Molecular markers are helpful in diagnosis, prognosis and management of haematological malignancies. Recently, a single point mutation in the Janus Kinase 2 (JAK2) gene in the Philadelphia-negative myeloproliferative disorders, including polycythemia vera (over 95%), essential thrombocythemia (50%) and primary myelofibrosis (50%) was identified by several groups. This mutation is now considered to have a fundamental role in the pathogenesis of these disorders. A PCR-based test from peripheral blood has become available in India to detect this mutation. Present article discusses the basic aspects of this mutation and its value in diagnosing, prognosticating and treating patients of suspected chronic myeloproliferative disorders.

Conventional and fluorescence in situ hybridization analysis of three-way complex BCR-ABL rearrangement in a chronic myeloid leukemia patient.

Chromosomal analysis was carried out in bone marrow sample of an 11-year-old girl suspected of myeloproliferative disorder. Conventional G-banding study detected a complex three-way translocation involving 7, 9 and 22, which has resulted in the formation of a variant Philadelphia chromosome causing rearrangement of abl and bcr genes in 87% cells. Fluorescence in situ hybridization (FISH) confirmed the fusion of bcr-abl oncogene. Thus the bone marrow karyotype was observed as 46,XX (13%)/46,XX,t(7;9;22)(q11;q34;q11) (87%). Hyperdiploidy was present in two cells. In this study, both conventional cytogenetic and FISH diagnosis proved to be significant to identify the variant nature of the Philadelphia chromosome and hyperdiploid condition for introduction of a suitable treatment regimen and estimation of life expectancy of the young girl.

Caspofungin: a major breakthrough in treatment of systemic fungal infections.

Invasive fungal infections are difficult to eradicate especially in immuno-compromised host. Amphotericin B and voriconazole have been the mainstay of treatment but both have significant toxicity. Caspofungin belongs to a new class of antifungal agents, the echinocandins. It acts on the fungal cell wall by selective inhibition of beta-(1,3)-D-glucan syntheses, which is not present in mammalian cells. In vitro data and experimental studies have demonstrated that it has antifungal activity against yeasts of the genus Candida (including those resistant to amphotericin B and azoles), severe species of filamentous fungi, including aspergillosis and certain dimorphic fungi. As an empirical antifungal therapy in neutropenic patients, it has comparable clinical efficacy but superior tolerability compared with liposomal amphotericin B. In patients with invasive candidiasis, it is as effective as amphotericin B deoxycholate. In addition, it showed a significantly superior safety profile. Same has been shown in patients with oropharyngeal/oesophageal candidiasis. In patients with invasive aspergillosis refractory to or intolerant to other antifungal agents, 45% showed a partial or complete response to Caspofungin given as a salvage treatment. Caspofungin is cidal for all Candida species and is static against Aspergillus species. It also possesses activity against Pneumocystis jiroveci. In vitro and in animals, Caspofungin shows additive or synergic antifungal activity with amphotericin B and triazoles. Recently, it's use in paediatric patients, including after bone marrow transplantation, has also been shown to be safe. With compare to other antifungal agents known to be effective in systemic fungal infections, Caspofungin has the best safety profile, tolerability with very low potential for drug interactions. This makes Caspofungin an interesting and extremely valuable new antifungal agent that broadens the available therapeutic armamentarium for the treatment of systemic fungal infections.

Exjade (ICL 670): A new oral iron chelator.

ICL670(deferasirox) is a tridentate oral iron chelator that has shown high efficacy and theraputic safety in preclinical and currently ongoing phase III clinical evaluation. The drug has been just approved by US FDA for use in iron-loading anaemias. It is an ideal once-daily oral chelator, the effective dose of which is between 20 and 40 mg/kg. Iron is chelated & excreted almost exclusively via the feces. This is a major advance in the field of iron chelation.

Umbilical cord blood transplantation: newer trends.

During last ten years, over 4000 umbilical cord blood transplantations have been performed worldwide. The interest in this modality of transplantation has been growing as this provides easy access to an alternative source of stem cells for treating cancer and serious genetic disorders with otherwise fatal outcome or immense morbidity. Umbilical cord blood is a commonly discarded source of useful stem cells. The outcome of transplantation using cells from this source in children mirrors the results of unrelated donor transplantation and hence the procedure is widely accepted by paediatric transplant community. Results are, however, hampered in adults due to low cell dose. Newer techniques, such as pooled or sequential cord blood transplantation, may help to increase progenitor cell numbers and improve immune reconstitution. In near future, non-haematopoietic uses will make this even more exiting area. In this write-up, we will review this treatment including cord blood banking issues and the ethical concerns. We will discuss both paediatric and adult transplantations including certain new indications.

Recombinant activated factor VII (rFVIIa, NovoSeven).

Recombinant activated factor VII (rFVIIa, NovoSeven) enhances haemostasis in individuals, with its predominant action limited to areas of injury, apparently without systemic activation of the coagulation cascade. rFVIIa is currently licensed in most countries worldwide, for its use in the treatment of bleeding episodes in patients with hemophilia and the presence of inhibitors. Recently in the European Union, rFVIIa, has been approved for use in congenital Factor VII deficiency and Glanzmann's thrombasthenia. Furthermore, a large number of case series studies and anecdotal evidences, from patients with different bleeding conditions, have now shown that rFVIIa is actually a very valuable general haemostatic agent. It has been reported to reduce bleeding in patients with liver disease, thrombocytopenia/thrombocytopathia, trauma, spontaneous intracerebral hemorrhage and in the reversal of anticoagulant overdosage or toxicity. A number of trials have been carried out, which have shown that it is a relatively safe and well tolerated drug with a few episodes of unwanted thrombosis.

Advances in management of sickle cell disease.

Sickle cell disease is numerically as common as thalassaemia. However, it affects relatively under privileged population i.e. tribal population belonging to economically poor class and having inadequate access to education and modern health facilities. A recent explosion acknowledged in understanding the pathogenesis of this disease has lead to newer dimensions in treatment. Some of these viz. prevention of overwhelming bacterial infection, present indications and controversies regarding blood transfusion, prevention of stroke, acute chest syndrome, hydroxyurea therapy--probably the best disease modifying agent at the moment, stem cell transplantation--a cure and certain promising experimental therapies including gene therapy have been discussed in this review.

Anti-lymphocyte globulin therapy in acquired aplastic anaemia.

Thirty five patients with acquired aplastic anaemia (AAA) were treated with anti-lymphocyte globulin (ALG). Fifteen (42.9%) had non-severe aplastic anaemia (NSAA), 14 (40%) severe aplastic anaemia (SAA) and 6 very severe aplastic anaemia (VSAA). There were 17 (48.6%) responders to the first course of ALG while 2 out of 5 (40%) responded to a second course, the overall response rate being 54.3%. Eleven out of 15 (73.3%) with NSAA responded, 8 out of 20 (40%) with SAA responded while none of VSAA responded. All the non-responders have died. Out of the responders, 1 died of non-A non-B hepatitis, and 1 with relapse of AA and sepsis. One has developed paroxysmal nocturnal haemoglobinuria (PNH) and one myelodysplasia. Another 2 needed infrequent red cell transfusion support. Remaining 13 (37.1%) are asymptomatic and without any external support since 18-78 months (35 +/- 21). We conclude that ALG is an effective modality of treatment for patients with AAA.

Antibody to hepatitis-C virus in multi-transfused thalassaemics--Indian experience.

Twelve out of 72 (16.7%) multi-transfused patients with thalassemia major (age range: 7-22 years) were found to be positive for antibody to hepatitis-C virus (anti-HCV). Nine (75%) of these 12 cases were positive for hepatitis B core antibody (anti-HBc) and/or hepatitis B surface antibody (anti-HBs). Out of the remaining 60 patients (83.3%), 27 patients (45%) were positive for anti-HBc and/or anti-HBs, while six (10%) were HBsAg positive Anti-HCV positive patients had significant higher levels of liver enzymes than those who were negative (p < 0.01). S. Ferritin was also significantly higher in those with seropositivity for anti-HCV than those who were negative (p < 0.01). It is concluded that HCV (besides HBV) is a major problem in multi-transfused thalassemia major patients and routine pre-transfusion screening of blood for anti-HCV must be introduced in the blood banks.

Thyroid dysfunction in multi-transfused iron loaded thalassemia patients.

Seventy-two transfusion-dependent iron loaded thalassemia patients were investigated for thyroid dysfunction by estimating circulating thyroid hormones (T4 and T3) and basal thyroid stimulating hormone (TSH). They were also evaluated for their liver function (biochemically) and iron overload by estimating serum ferritin. Thyroid failure (hypothyroidism) was documented in 14 patients (19.4%). In all, 3 groups were seen, i.e. Group 1: Normal T4, T3, TSH (58 patients: 80.6%); Group 2: Compensated hypothyroidism characterized by normal T4, T3 and raised TSH (9 patients: 12.5%); Group 3: Decompensated hypothyroidism characterized by decreased T4 and increased TSH (5 patients: 6.9%). Interestingly, impaired thyroid function could not be correlated with age, amount of blood transfused, liver dysfunction or degree of iron overload. It is postulated that an inter-play between chronic hypoxia, liver dysfunction and iron overload may be responsible for the thyroid damage.