Multiple Myeloma: Treatment is Getting Individualized.

Multiple myeloma (MM) is a heterogeneous disease with varied outcome. The novel agents including two major classes of drugs; the immunomodulatory drugs and the proteasome inhibitors with unprecedented response rates, have replaced conventional chemotherapy. With monoclonal antibodies on the horizon, outcome of this disorder will further improve. Progression in risk stratification systems has made it possible to predict the disease course as well as outcome in myeloma patients with disease categorization into low to high risk. In addition, detection of minimal residual disease by serum free light chain assay, flow cytometry, molecular techniques like polymerase chain reaction and positron emission tomography scan is playing an important role in modifying the treatment. An extensive research in the disease biology has improved our knowledge regarding interplay between myeloma cells and elements of the bone marrow microenvironment which contribute to sustain proliferation and survival as well as de novo drug resistance. Again, insight into the role of genetic and epigenetic interactions in MM has exposed new molecular targets. All these have opened the gateway for novel therapeutic strategies with focus on risk based individualized therapy.

Safety and efficacy of indigenous equine antithymocyte globulin along with cyclosporine in subjects with acquired aplastic anemia.

To confirm the safety and efficacy of an indigenous equine antithymocyte globulin (eATG) along with cyclosporine in Indian subjects with acquired aplastic anaemia. Subjects >2 years old with acquired aplastic anaemia were enrolled at six hospitals between April 2011 and February 2013, after approval from respective Ethics Committees. Equine ATG at a dose of 40 mg/kg/day was infused for 4 days. Efficacy analysis defined a priori, was in subjects, who had completed eATG treatment and followed-up on day 90 and/or 180. Complete response (CR) was defined as-transfusion independent, haemoglobin ≥11 g/dL, absolute neutrophil count (ANC) >1.5 10(9)/L and platelet ≥150 10(9)/L; partial response (PR) was transfusion independent, haemoglobin ≥8 g/dL, ANC >0.5 10(9)/L and platelet ≥20 10(9)/L; non responders were transfusion dependent. Lymphocyte subsets (CD 2, 3, 4 and 8) in the blood were tested on days 0 (pre eATG infusion), 3, 5, 7, 14 and 21 after eATG. Of the 30 subjects (two children <12 years old) enrolled, 19 completed day 90 and 18 completed day 180 visit. Of the remaining 11 subjects, two died on days 12 and 45 due to septicaemia and pneumonia, one was withdrawn after the first dose of eATG due to jaundice and eight were lost to follow-up. The median age was 30 (9-58) years and weight was 57 (26-84) kg. On day 90, 12 of 30 subjects responded (CR 1, PR 11) and 15 of 30 (CR 2, PR 13) on day 180. The most common adverse event was fever related to eATG infusion. There were two serious adverse events (acute renal failure, febrile neutropenia) and both recovered with treatment. There were no unusual adverse events noted during the study period. Blood T lymphocytes showed a mean decrease of 91 % from baseline that recovered by day 21. We conclude that eATG is safe and in combination with cyclosporine showed overall response in 50 % of enrolled subjects. The trial was registered with the clinical trial registry-india (Registration no. CTRI/2012/03/002498).

Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia.

According to the 2008 revision of the World Health Organization (WHO) classification of myeloid malignancies, philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) include clonal, hematologic disorders such as polycythemia vera, primary myelofibrosis, and essential thrombocythemia.Recent years have witnessed major advances in the understanding of the molecular pathophysiology of these rare subgroups of chronic, myeloproliferative disorders. Identification of somatic mutations in genes associated with pathogenesis and evolution of these myeloproliferative conditions (Janus Kinase 2; myeloproliferative leukemia virus gene; calreticulin) led to substantial changes in the international guidelines for diagnosis and treatment of Ph-negative MPN during the last few years.The MPN-Working Group (MPN-WG), a panel of hematologists with expertise in MPN diagnosis and treatment from various parts of India, examined applicability of this latest clinical and scientific evidence in the context of hematology practice in India.This manuscript summarizes the consensus recommendations formulated by the MPN-WG that can be followed as a guideline for management of patients with Ph-negative MPN in the context of clinical practice in India.

Report of chronic myeloid leukemia in chronic phase from Ashirwad Hematology Centre, Mumbai, 2002-2009.

We have analyzed our experience regarding use of tyrosine kinase inhibitors especially imatinib mesylate in patients of chronic myeloid leukemia-chronic phase over last 7 years at our center (2002-2009). The object was to report long-term efficacy (hematological, cytogenetic and molecular) and toxicity. Overall, 775 patients were treated. Out of these, 576 were analyzable with a median follow-up of 3.6 years. The median age was 42 years. Complete cytogenetic response (CCyR) was achieved in 351/576 patients, i.e., 62.1%. Grade 3/4 adverse effects were observed in 36 patients, i.e., 6.25%. Age under 40 years, low Sokal score, complete hematological response and CCyR were significant predictive factors for event free survival (EFS) on univariate analysis while low Sokal score and early chronic phase were significant predictive factors for EFS on multivariate analysis. Our results are almost similar to those reported from various studies from western population.

Balancing efficacy and bleeding risk in the prevention of stroke due to atrial fibrillation with newer oral anticoagulants.

With the evaluation and approval of newer oral anticoagulants such as the factor IIa inhibitor, dabigatran etexilate and the factor Xa inhibitors, rivaroxaban and apixaban, strategies for stroke prevention in atrial fibrillation need a thorough re-evaluation of current options. Clinicians are naturally excited about the imminent introduction of these newer drugs that do not need international normalized ratio (INR) monitoring, besides having no drug-food and minimal drug-drug interactions. However, as with all new drugs, it is always prudent to use these judiciously so that they stay in our therapeutic armamentarium for a long time. More than 56 years after the introduction of warfarin we now have three drugs, viz., dabigatran 150 mg bid, rivaroxaban 20 mg od, and apixaban 5 mg bid which were effective in comparison with warfarin in reducing the risk of stroke and bleeding in the landmark trials, RE-LY, ROCKET-AF, and ARISTOTLE respectively. There is a thin dividing line between physiological hemostasis and pathological thrombosis. Routine INR monitoring may not be required but in special situations, such as prior to major surgery, overdose, non-compliance or stroke while on the anticoagulant, one may wish to know whether there are any laboratory measures of efficacy or means of reversal of over anticoagulation. Similar questions may be raised about other situations such as renal dysfunction, cardioversion, ablation procedures, post-stenting, or switch to and from warfarin, heparin or LMWH? This document is an attempt to address these concerns based on available evidence and give physicians a perspective and practice guidelines on how best to use these agents, both old and new, for optimal patient outcomes, maximizing efficacy and minimizing risk.

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 beta-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 beta-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.

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.

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.

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.

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.

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.