Role of daratumumab in the frontline management of multiple myeloma: a narrative review.

INTRODUCTION: The prevalence of multiple myeloma (MM) has gradually increased over the last few decades in India due to growing population, better disease awareness, and improved diagnostic procedures. Despite such advances, MM remains an incurable and relapsing disease due to its heterogeneity and genomic instability. With the inclusion of monoclonal antibodies, especially daratumumab in the frontline regimen, the management landscape of MM has improved significantly resulting in better disease control and patient outcomes. AREAS COVERED: This review aims to provide an in-depth summary of efficacy and safety of frontline daratumumab therapy in treatment of MM including patients with high-risk cytogenetic profile. EXPERT OPINION: Based on the review of literature, daratumumab in frontline therapy has demonstrated improved efficacy in terms of reduction in disease progression or death, and superior minimal residual disease (MRD)-negativity rates with an acceptable safety profile in patients with newly diagnosed MM (NDMM) including patients with high-risk cytogenetic profile. Daratumumab alone or in combination with other drugs has shown similar clinical outcomes in patients with relapsed/refractory MM. Hence, daratumumab can be used upfront in patients with MM.

Rare Case of Hemolytic Anemia and Distal Renal Tubular Acidosis in an adult due to Homozygous SLC4A1 Mutation.

In this case study, we report an adult patient presenting with generalized weakness, marked anemia, spherocytosis, and no features of thalassemia. The patient was treated for suspicion of autoimmune hemolytic anemia but was recalcitrant to treatment. Genetic analysis revealed the patient to be homozygous for SLC4A1 c.2573C>A (p.Ala858Asp). Distal renal tubular acidosis (dRTA) can be caused by mutations in SLC4A1, which encodes the Cl-/HCO3- exchanger of the renal type A intercalated cell, kidney AE1. SLC4A1 variants have been reported in dRTA patients from North America, Europe, and Southeast Asia. In some rare instances, SLC4A1 dRTA can present with hemolytic anemia resulting in marked anemia that is not responsive to standard interventions. This report identifies an autosomal recessive inheritance pattern for SLC4A1 variants in a patient presenting with dRTA and hemolytic anemia.

Enoxaparin Induced Skin Lesions in Pregnancy: A Rare But Clinically Recognizable Association.

We report the case of a 29 year old pregnant female who experienced itching with erythematous plaques on prophylactic enoxaparin for recurrent fetal losses. These lesions generalized on rechallenge but erythema and itching gradually resolved after 4 weeks of discontinuation. Cutaneous adverse events with heparin have been reported (Villanueva et al. in Actas Dermosifiliogr 103:816-819, 2012; Neloska et al. in Acta Dermatovenerol Croat 23:223-224, 2015; Maldonado et al. in Clin Exp Dermatol 37:707-711, 2012; Schindewolf et al. in Lancet 380:1867-1879, 2012; Tassava and Warkentin in Am J Hematol 90:747-750, 2015), some specifically with enoxaparin (Villanueva et al. 2012; Neloska et al. 2015).

Current Perspective on Use of NOAC in Clinical Practice in India.

Oral vitamin K antagonists (VKA) such as warfarin have been the mainstay of therapy for stroke prevention in patients with non valvular atrial fibrillation (NVAF) while low-molecular-weight heparin, fondaparinux and adjusted-dose warfarin or aspirin have been routinely used for thromboembolism (VTE) prophylaxis in patients undergoing total hip or knee replacement. However, VKAs are associated with considerable limitations, including increased risk of bleeding and narrow therapeutic window. Novel oral anticoagulants (NOACs, now referred as Non Vit K dependent oral anticoagulants), including the direct thrombin inhibitor dabigatran and direct Factor Xa inhibitors such as rivaroxaban and apixaban are now approved alternatives to warfarin for prophylaxis of stroke and systemic embolic events (SEE) in patients with NVAF and treatment and prophylaxis of VTE. The efficacy and safety of NOACs have been proven in several clinical trials. The advantages offered by NOACs such as rapid onset and termination of action, predictable anticoagulant effect, less frequent laboratory monitoring make them promising alternatives to warfarin. However, clinicians in India seek more information over the practical aspects that require due consideration to ensure proper use of these drugs. The article addresses some crucial aspects of NOAC therapy such as measurement of anticoagulant effects, transition between different agents, ensuring drug intake compliance, dealing with dosing errors, management of bleeding complications etc based on the guidance offered by the European Heart Rhythm Association in 2013.

Reversal agents for NOACs: Connecting the dots.

OBJECTIVE: The objective of this review is to provide an overview on the current development of the specific reversal agents for Non-vitamin K Oral Anticoagulants (NOACs). METHODS: We conducted a systematic literature search strategy to identify potential studies on Medline, Embase, and the Cochrane register. CONCLUSIONS: These new reversal agents for NOACs, will help address the unmet need for the management of major or life threatening bleeds, and the management of emergency surgical procedures in patients taking NOACs. It will increase confidence in the use of NOACs; thereby extending treatment to a wider range of patients.

The Indian consensus guidance on stroke prevention in atrial fibrillation: An emphasis on practical use of nonvitamin K oral anticoagulants.

The last ten years have seen rapid strides in the evolution of nonvitamin K oral anticoagulants (NOACs) for stroke prevention in patients with atrial fibrillation (AF). For the preparation of this consensus, a comprehensive literature search was performed and data on available trials, subpopulation analyses, and case reports were analyzed. This Indian consensus document intends to provide guidance on selecting the right NOAC for the right patients by formulating expert opinions based on the available trials and Asian/Indian subpopulation analyses of these trials. A section has been dedicated to the current evidence of NOACs in the Asian population. Practical suggestions have been formulated in the following clinical situations: (i) Dose recommendations of the NOACs in different clinical scenarios; (ii) NOACs in patients with rheumatic heart disease (RHD); (iii) Monitoring anticoagulant effect of the NOACs; (iv) Overdose of NOACs; (v) Antidotes to NOACs; (vi) Treatment of hypertrophic cardiomyopathy (HCM) with AF using NOACs; (vii) NOACs dose in elderly, (viii) Switching between NOACs and vitamin K antagonists (VKA); (ix) Cardioversion or ablation in NOAC-treated patients; (x) Planned/emergency surgical interventions in patients currently on NOACs; (xi) Management of bleeding complications of NOACs; (xii) Management of acute coronary syndrome (ACS) in AF with NOACs; (xiii) Management of acute ischemic stroke while on NOACs.

Unusual immunophenotype of T-cell large granular lymphocytic leukemia: report of two cases.

Large granular lymphocytes (LGL) leukemias are commonly of the T-cell or NK-cell type. T-cell LGL leukemia is typically a disorder of mature CD3, CD8 and T-cell receptor TCR (TCR - T cell receptor)-αß positive cytotoxic T-cells. Rare variants include TCRγδ+ variants and CD4 + TCRαß+ cases. We report a case of each of these rare variants. An 83-year-old female presented with anemia and lymphocytosis with LGLs on peripheral smear. Six-color multiparametric flowcytometric analysis showed expression of CD3, heterogeneous CD7, dim CD2 and TCRγδ and lacked expression of CD5, TCRαß, CD56, CD4 and CD8. A final diagnosis of TCRγδ+ T-cell LGL leukemia was made. Differentiation between TCRγδ+ T-cell LGL leukemia and other γδ+ T-cell malignancies is of utmost importance due to the indolent nature of the former as compared to the highly aggressive behavior of the latter. An 85-year-old male diagnosed with liposarcoma was identified to have lymphocytosis during preoperative evaluation. Peripheral smear showed presence of LGLs. Flowcytometric immunophenotyping showed expression of TCRαß, CD3, CD2, CD5, CD4, dim CD8, CD56 with aberrant loss of CD7 expression. Vß repertoire analysis by flowcytometry showed 97% cells with Vß14 clonality. A final diagnosis of TCRαß+ CD4 + T-cell LGL leukemia was made. CD4 + T-cell large granular lymphocytic leukemias have an indolent, less aggressive course when compared to their CD8 + counterparts and are not necessarily associated with cytopenias. However, their association with secondary neoplasia (29% of the cases) warrants a high degree of suspicion in the diagnosis as also noted in the index case. Use of a wide panel of antibodies and newer modalities such as Vß repertoire analysis helps in accurate subtyping of LGL leukemia.

Tc 99m Sestamibi Scanning in Multiple Myeloma--a New look with SPECT-CT.

UNLABELLED: A variety of diagnostic tools including biochemistry, radiological imaging bone marrow studies and recently metabolic imaging with FDG PET are used for assessment of disease extent in myeloma. AIM: To evaluate the role of metabolic imaging with Tc99m Sestamibi (Mibi) SPECT-CT in Multiple myeloma. MATERIALS AND METHODS: Patients in various stages of Myeloma were scanned after 20mCi Tc99m Sestamibi was injected i/v. Whole body planar scans were obtained with a dual head gamma camera and SPECT-CT imaging was done. Images were analyzed for degree and extent of abnormal Mibi uptake, extent of lesions seen on low-dose CT and fusion of these images. RESULTS: 112 Whole body Sestamibi Scans were performed in 84 patients (46 Males; 38 Females). Out of these 24 (28.5%) were recently diagnosed cases (Pre-therapy); 35 (41.7 %) were follow-up cases who had received Chemotherapy in the past (Post-therapy), there were 2 cases (2.3%) of Smouldering Myeloma, 4 cases (4.7%) of Plasmacytoma, 13 cases (15.5%) of MGUS (Monoclonal gammopathy of Unknown Significance) and 3 cases (3.6%) of suspected Myeloma (not biopsy confirmed). Myeloma lesions showed good concentration of Mibi. Additionally, the CT scan component of SP.ECT-CT allowed visualization of osteolytic lesions of myeloma. Mibi uptake becomes positive on scan earlier than radiological changes and in follow-up cases, the presence or absence of Mibi uptake could differentiate active from old burnt-out lesions. Whole body scan could detect additional lesions in Plasmacytoma patients. Patients of MGUS showed poor concentration of Sestamibi. CONCLUSION: Whole body Sestamibi Imaging (WBSI) is very useful for evaluating the extent of disease in multiple myeloma. Being a metabolic imaging modality it is superior to radiological (X-ray or CT) assessment alone, and where FDG PET scan is not available, it is a valuable tool for myeloma assessment at a much lower cost.

Hb Koln [ß98(FG5) [GTG → ATG, Val → Met]: the first report from India.

BACKGROUND: The group of unstable hemoglobins are associated with congenital non-spherocytic hemolytic anemia due to instability of the hemoglobin molecule. They often lead to formation of the characteristic inclusion bodies or Heinz bodies. AIM: To identity the cause of mild anemia, reticulocytosis, and hepatosplenomegly in a case of non-spherocytic hemolytic anemia. MATERIALS AND METHODS: A 34-year-old female patient originating from Maharashtra, western India presented with mild anemia and jaundice which had persisted since childhood. Investigations included a complete blood count, screening for red cell membrane protein defects, Hb analysis by high-performance liquid chromatography (HPLC) and cellulose acetate electrophoresis (pH 8.9), heat instability test and DNA sequencing. RESULTS: Hemoglobin analysis by HPLC showed an abnormal peak in the Hb C window (9.8%) with a retention time of 4.90 minutes. Cellulose acetate electrophoresis (pH 8.9) showed a slow moving band (6.15%) between Hb A2 and Hb S. The heat instability test was positive. DNA analysis of α globin genes showed absence of both deletional and non- deletional α thalassemia. DNA sequencing of the ß globin gene revealed heterozygosity for a mutation at codon 98 [GTG → ATG, Val → Met], which gives rise to Hb-Koln. CONCLUSION: Hb Koln is the commonest unstable Hb variant reported from many populations in the world. However, this is the first report of this unstable Hb variant from India.

Refractory anaemia in an immunocompromised patient--what is it?

Anaemia is common among human immunodeficiency virus (HIV)-infected patients. It may be directly attributable to the virus or may be caused by opportunistic infections, neoplasms or drugs that cause either bone marrow suppression or haemolysis. Pure red cell aplasia (PRCA) is an uncommon haematological disorder that causes severe transfusion dependant anaemia. We report a 36 year-old female with HIV infection who developed anaemia which did not improve even after discontinuing the offending drug, namely Zidovudine. Routine investigations were unhelpful but her bone marrow study was consistent with pure red cell aplasia. She showed dramatic improvement with steroids with subsequent transfusion independence.

Warfarin therapy--why one dose does not fit all!

We report an Indian adult female patient with Deep Vein Thrombosis (DVT), in whom it was difficult to achieve and maintain target INR on warfarin (oral anticoagulant) by conventional doses. Pharmacogenomics study for warfarin revealed that she had Homozygous mutant for CYP2C9 *3(CYP2C9 *3/*3) and Heterozygous mutant for VKORC 1(1639G >A) {genetic polymorphism double defect}. This conferred a greater sensitivity to her warfarin therapy in an otherwise conventional dose regime used in most patients, making her management challenging. This sensitivity (or resistance in other cases) can be assessed by this evidence based test and warfarin dosing could be individualised to avoid toxicity.

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.