Rajan Kapoor

Rituximab in Steroid Refractory Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia is rare in children and infants and steroids are the corner stone of therapy. Management of the patients with steroid refractory/dependent disease is difficult .Rituximab is being used in the treatment of a variety of autoimmune diseases including Autoimmune hemolytic anemia (AIHA),especially in adults but there is scarce data regarding the use of this agent in pediatric AIHA patients.The authors report two cases of steroid refractory AIHA, who responded to rituximab with review the literature of its use in pediatrics.

Monitoring of response to therapy with imatinib mesylate in Chronic Myeloid Leukemia in chronic phase (CML-CP)

BACKGROUND The BCR-ABL tyrosine kinase is a well validated therapeutic target in Chronic Myeloid Leukemia (CML). Imatinib mesylate (IM), a tyrosine kinase inhibitor is highly effective in the treatment of chronic phase CML. BCR - ABL transcripts have been well established as a molecular marker to document response to therapy in CML. Periodic monitoring of this marker helps in evolving therapeutic strategies with IM and also in diagnosing early relapse. This study was undertaken to monitor therapeutic response to IM in CML in chronic phase (CML-CP) by assessing BCR-ABL by real time quantitative PCR (RQ-PCR) techniques and to determine the effectiveness of the Indian generic IM. METHODS One hundred consecutive patients of CML in chronic phase (CML-CP) were treated with an Indian generic of IM. Eighty-five patients were evaluable at 12 months of therapy. At entry, diagnosis of CML-CP was confirmed by FISH and RQ-PCR. Response to therapy was monitored by assessing BCR-ABL levels by RQ-PCR at 6 and 12 months of therapy. Regular follow up of patients was done to evaluate the safety profile of IM used in these patients. RESULTS Complete hematological response (CHR) rates at 3, 6, 9 and 12 months were 92%, 94%, 100% and 100% respectively. The total molecular response at 12 months was 43.52% of which complete molecular response (CMR) was noted in 17.64% and major molecular response (MMR) was observed in 25.88%. A cumulative survival probability of 0.8 was observed. CONCLUSION The Indian generic molecule of IM is effective in the treatment of CML-CP. The cost of Indian generic molecule is less than Rs. 10,000 per month there by making this affordable for large number of CML-CP patients in India.

Acute renal failure following antithymocyte globulin therapy for aplastic anaemia—report of two cases and review of literature

Dear Editor, Immunosuppressive therapy with antithymocyte globulin (ATG) with ciclosporine is the standard of care in patients with aplastic anaemia who are not eligible for bone marrow transplantation. ATG is an animal protein and its predominant toxicities include allergic reactions and serum sickness. Acute renal failure attributable to ATG has rarely been described. We report two patients with aplastic anaemia who developed acute renal failure during ATG therapy. Both patients developed oliguric acute renal failure with temporal relation to ATG administration and absence of other etiological factors. One of the patients had complete recovery of renal function with supportive treatment while the other died of sepsis and multi-organ dysfunction.

Lymphoma in ‘India’ at the Dawn of Targeted Therapies

Thomas Hodgkin, in 1832, as the ‘Inspector of the Dead and Curator of the Museum’ at the medical school of Guys hospital published a paper on ‘‘On Some Morbid Appearances of the Absorbant Glands and the Spleen’’, what later on Samuel Wilks in the true spirit of peer recognition named as ‘Hodgkin’s disease’ in 1865 [1]. Hodgkin tried cascarilla, soda and iodine to treat his initial 07 patients with obvious lack of success and who went on to become the subjects of autopsy. The long journey in the management of lymphomas to the current day success story has been phenomenal. We are beginning to look at a chemotherapy and radiotherapy free treatment protocol as the cobweb of signal transduction pathways becomes clearer and we are able to unravel the ways to use the targeted therapies in various combinations to achieve the goal of ‘cure’. While Hodgkins lymphoma achieved much success with the introduction of ABVD in 1970s [2], the heterogenous Non Hodgkin lymphoma (NHL) group has lagged behind with the backbone R-CHOP giving moderate results. Intensification of chemotherapy with protocols like Hyper CVAD, DA-EPOCH-R, etc., have improved the landscape of chemotherapy. However, the long-term effects of chemoradiotherapy has been a major hurdle in increasing the long-term survival of these patients. The increasing understanding of the pathobiology of the various lymphomas, their pathway dependencies and tumor-host interface, has provided new opportunities to use this knowledge to generate targeted therapies. The introduction of monoclonal antibodies and the success of Rituximab was a major breakthrough in improving the survival of patients with CD20 ? NHL [3]. Similarly anti CD30 Brentuximab Vedotin (BV) became a major success story in relapse-refractory Hodgkins disease. BV now threatens to replace the conventional Bleomycin, ‘‘B’’ of ABVD, a drug attributed to the most sinister long term pulmonary toxicity of ABVD, as a first line therapy [4]. Moving ahead from surface targets, the pathway dependencies of lymphomas were extensively studied and lead to the approval of Ibrutinib, a BTK inhibitor and a first drug of its kind, for Chronic Lymphocytic Leukemia with del17p. This success story has opened the pandora’s box for targeted therapies with various drugs like Idelalisib, venetoclax, panabinostat, etc., providing good results in relapse refractory cases, which were considered incurable. The introduction of tongue-twister CAR-T cell therapies like axicabtagene ciloleucel and tisagenlecleucel has brought Immunotherapy to the forefront of management of lymphoproliferative disorders. PD-L1 inhibitors like Nivolumab and Pembrolizumab can be considered as a major breakthrough in our understanding of the tumorimmunity cross talk and the benefits of their exploitation in treating these malignancies. The rapid strides in this field comes with its challenges of a continuously changing landscape of management guidelines. Anyone who is dealing with the management of lymphomas in India finds it difficult to remain abreast with the latest in this field. The need for an India-specific guideline may be partially fulfilled by the updated consensus statement presented in the current issue of IJHBT [5]. The consensus document on the management of & Rajan Kapoor majrkapoor@gmail.com

Exteriorisation of the Ommaya Reservoir Secondary to Wound Dehiscence in a Case of ALL

A 41-year-old male a case of acute lymphoblastic leukaemia with C3 disease (CNS involvement) was being managed with modified BFM-90 protocol. For his CNS positive disease, he was planned for intensive triple intrathecal therapy. For the ease of administration of intrathecal and to ensure adequate distribution of chemotherapeutic agents, he was subjected to Ommaya reservoir placement. There were no immediate postoperative complications. The patient received 04 intrathecal therapies through the reservoir as inpatient and was subsequently discharged after CSF was negative and managed as an outpatient. He presented to OPD on D40 of Ommaya insertion with complaints of wetness of the scalp near the site of insertion. Physical examination revealed exteriorisation of Ommaya with CSF leak. CSF examination revealed no evidence of meningitis. Patient hasn’t received any radiation to lead to wound dehiscence. An Ommaya reservoir is a synthetic dome that is surgically placed beneath the scalp and attached to a catheter directed into a ventricle. Complications associated with Ommaya reservoir include technical complications such as misplacement of the catheter, intraventricular haemorrhage, malfunctioning reservoirs, and bacterial meningitis [1]. Other complications included wound dehiscence, ventricular catheter associated cerebral oedema and leakage of cerebrospinal fluid. With wound dehiscence, a superficial wound infection can easily track to the CSF and intracranial cavity resulting in serious intracranial complications. Countersinking is a good technique to prevent wound dehiscence, device extrusion and in irradiated patients with very thin skin, it also enables tension-free closure of the wound [2]. Our patient had wound dehiscence and CSF leak with our associated meningitis in the absence of radiation to scalp at D40 which is an uncommon complication. It is thus mandatory to do a regular local physical examination of the scalp in a patient with Ommaya reservoir (Figs. 1, 2).

Primary imatinib failure rescued by dasatinib and maintained by reintroduction of imatinib

The availability of multiple tyrosine kinase inhibitors (TKIs) for the management of chronic myeloid leukemia (CML) has created the debate on which one to use frontline.1,2 This debate would have been a straightforward one had there not been the huge cost differences between the first and second generation TKIs. The importance of early and deeper molecular responses on the risk of progression and blast crisis has been proven in the DASISION and ENESTnd trials leading to the approval of both dasatinib and nilotinib as first line TKIs along with imatinib in both the National Comprehensive Cancer Network (NCCN) and European Leukemia Net (ELN) guidelines.3–5 However, imatinib continues to be the most commonly used first line TKI for CML, especially in developing countries like India. Patients with CML who are started on imatinib at diagnosis and fail to achieve the appropriate milestones as defined in the ELN guidelines are shifted to any one of the second generation TKIs and then continued on the same indefinitely until progression to blast crisis or allogeneic stem cell transplantation.6

Detection of balanced translocations in acute lymphoblastic leukemia by a novel multiplex reverse transcriptase reverse transcription-polymerase chain reaction

Fusion transcripts detection is essential for subtyping and diagnosis of acute lymphoblastic leukemia (ALL). This enables institution of appropriate therapy and provides a parameter to monitor disease progression and response to therapy. This study endeared to detect and analyze various balanced translocations known in ALL by using a novel polymerase chain reaction (PCR) method. A pilot study was done in which 16 consecutive cases of ALL were analyzed and followed-up for a period of 1 year. Diagnosis of ALL was established after subjecting blood/bone marrow aspirate samples to morphological examination, immunophenotyping, and detection of fusion transcripts by multiplex reverse transcription (RT)-PCR using HemaVision kit. Results were analyzed by correlating with morphology, immunophenotype, and response to therapy. Epi-Info statistical software was used. 43% (seven cases) showed balanced translocations, with all seven cases being B-ALL and t(9;22) being the most common. There was a consistent association of CD25 cases with t(9;22). Analyses of relation to other parameters were as expected by their respective WHO 2008 subtype. No significant correlation in terms of survival benefit was seen between cases with and without balanced translocations (P = 0.7472). The study demonstrated the utility of multiplex RT-PCR in the initial evaluation, subtyping, and monitoring minimal residual disease in ALL cases with balanced translocations, thereby guiding both therapy and prognosis. The consistent association of CD25 in cases of t(9;22) ALL indicated that CD25 could be used as a surrogate marker.

BCR-ABL and JAK2V617F Mutation Co-existence, Rare or Just Unexplored

Abstract Current hematology practice distinguishes chronic myeloid leukemia (CML) and other major chronic myeloproliferative neoplasms as different entities classically characterized by positivity of BCR-ABL fusion gene and JAK2V617F mutations. These are different in clinical presentation, molecular genetics, therapy and response to present treatments. Nevertheless, there have been occasional case reports of detection of both mutations in the same patient. Although some of these had been incidentally detected, most have manifested clinically while being treated for one disease. Here, we present two cases of co-existence of BCR-ABL and JAK2V617F positivity. The first one was initially managed as CML. On obtaining adequate molecular and hematological response, thrombocytosis persisted. Hence she was tested for JAK2V617F mutation. In the second case, when we noticed upfront very high platelet counts along with a clinical picture of CML, we tested her for both and was found to be positive for both. Till to date, no such clinical case has been reported from India. The current status and approach to BCR ABL and JAK2 coexistent mutations has been reviewed and discussed.

Presence of Essential Hypertension or Diabetes Mellitus Is a Predictor of Intracranial Bleeding in Elderly Patients: A Study of 108 Patients with Isolated Thrombocytopenia from a Single Reference Center.

Objective: Thrombocytopenia poses a significant problem in the elderly. Not only are there varied causes, but it is also associated with significant morbidity and mortality. We carried out a study to learn the causes of isolated thrombocytopenia in elderly patients and to correlate the severity of thrombocytopenia and bleeding manifestations with various etiologic factors and comorbidities. Materials and Methods: A total of 108 patients above 50 years of age presenting with isolated thrombocytopenia (platelet counts of <100x109/L with normal hemoglobin and total leukocyte counts) were enrolled in the study. Detailed history and clinical examinations were carried out for each patient. Complete blood counts were analyzed by automated cell counter. Peripheral smears were examined in all cases. HbsAg, anti-HCV, and anti-HIV testing by enzyme-linked immunosorbent assay was done in all patients. Wherever clinically indicated, bone marrow aspiration biopsy and cytogenetic studies were done. Results: Out of 108 patients, 102 (94.4%) presented with bleeding tendencies. Twenty-nine (26.8%) presented with serious (World Health Organization grade 3/4) bleedings. Major findings were immune thrombocytopenic purpura in 79 (73.1%), myelodysplastic syndrome in 7 (6.5%), drug-induced thrombocytopenia in 7 (6.5%), and connective tissue disorder in 4 (3.7%) cases. Ten patients presented with intracranial bleedings. Upon logistic regression analysis, comorbidities in the form of essential hypertension and diabetes mellitus were significantly associated with occurrence of intracranial bleeding. There was no correlation of serious bleedings with platelet counts. Conclusion: Isolated thrombocytopenia in the elderly is associated with significant morbidity. Diligent clinical and laboratory evaluation is required to elucidate the cause of thrombocytopenia in the elderly. Comorbidities in this population are associated with serious bleedings and not low platelet counts as is commonly thought.

A rare case of leukemic presentation of blastoid variant of mantle cell lymphoma with isolated splenic involvement: Flowcytometric revelation

Mantle cell lymphoma (MCL) is a B-cell neoplasm generally composed of monomorphic, small to medium-sized lymphoid cells with irregular nuclear contours and a CCND1 translocation. It comprises approximately 3–10% of non-Hodgkin lymphomas and occurs in middle-aged to older individuals with a median age of about 60 years and a variably marked male predominance (about 2:1 or greater). Lymph nodes are the most commonly involved site; spleen and bone marrow (BM), with or without peripheral blood (PBS) are the other frequently involved extranodal sites.1 Classical MCL is a monomorphic lymphoid proliferation with a vaguely nodular, diffuse, mantle zone or rarely follicular growth pattern. One of the variant is blastoid variant which is considered to be more aggressive and characterized by the cells which resemble lymphoblasts with dispersed chromatin and a high mitotic rate.1 The peripheral spill with massive spleen is frequently seen in the classical MCL and splenic marginal zone lymphoma where differential diagnosis is splenic lymphoma with villous lymphocytes, Hairy cell leukemia and Small lymphocytic lymphoma (SLL)/Chronic lymphocytic Leukemia (CLL). The differentiation is done on the basis of flowcytometry. They are usually positive for CD5, FMC-7 and CD 43, but negative for CD10 and BCL6. These cells express relatively intense surface IgM/lgD, more frequently with lambda than kappa restriction. CD23 is negative or weakly positive. Aberrant phenotypes have been described, sometimes in association with blastoid/pleomorphic variants, including absence of CD5 and expression of CD43 and BCL6. All cases are BCL2 protein positive and almost all express cyclin D1, including the minority of cases that are CD5 negative. Leukemic presentation of B-MCL is an exceedingly uncommon event. Largest case series of 23 cases is published so far however, from India there is only one case which has been reported to best of our knowledge.2,3