Satyaranjan Das

Survival after immunosuppressive therapy in children with aplastic anemia

ObjectiveTo determine the survival of children≤18y, treated with immunosuppresive therapy (IST) using equine antithymocyte globulin (e-ATG) and cyclosporine (CsA).DesignProspective data entry as per a specified format.SettingTertiary care hospital.PatientsFrom January 1998 to December 2009, 40 children were diagnosed with acquired aplastic anemia; 33 patients, who received IST, were analyzed. 31 children (94%) received one course of e-ATG and CsA. 2 patients (6%) received two courses of ATG.InterventionImmunosuppressive therapy using equine ATG and cyclosporine.Main Outcome MeasuresOverall response and overall survival.ResultsThe overall response (complete response + partial response) to IST at 6 months was 87.9%. 8 (24.2%) patients achieved CR, 21 (63.6%) patients had PR and 4 (12.1%) patients did not respond to IST. Median follow-up was 24 (6–102) months. Overall survival at 24 months was 90%, with an acturial survival of 85.4% at 5 years. Seventeen patients (51.5%) received G-CSF for a median duration of 32 (23–64) days. The patients who received G-CSF had fewer infectious complications (P=0.002), but G-CSF administration did not influence survival/outcome. No patient developed myelodysplastic syndrome or acute leukemia.ConclusionsThe survival of patients who respond to IST is excellent. Also, G-CSF reduces the infectious complications without conferring any survival advantage.

A clinicopathological analysis of 26 patients with infection-associated haemophagocytic lymphohistiocytosis and the importance of bone marrow phagocytosis for the early initiation of immunomodulatory treatment

Objective To analyse the clinicopathological presentation, outcome and importance of bone marrow haemophagocytosis in patients with infection-associated haemophagocytic lymphohistiocytosis (IA-HLH) in a tertiary care hospital in Northern India. Study design Between January 2007 and December 2009, 26 consecutive patients meeting the diagnostic criteria for IA-HLH, based on the HLH2004 protocol of the Histiocyte Society, were followed up for between 12 and 34 months (median 20 months). Results IA-HLH was diagnosed in three of the five patients who died 5–6 weeks after the onset of the illness, whereas diagnosis in the remaining group was made a median of 2 weeks after the onset of the illness. The predominant presenting features were fever (100%), hepatomegaly (69%), splenomegaly (58%) and anaemia (96%). All patients showed >3% haemophagocytosis on bone marrow studies—in four cases after serial aspiration/biopsies. Twenty-one (80.8%) cases were non-fatal and five (19.2%) patients died. The non-fatal cases included eight (38.1%) cases of viral infection, seven (33.3%) bacterial infections, two (9.6%) fungal and four (19.0%) protozoal infections; whereas four (80%) bacterial infections and one (20%) viral infection were associated with the fatal cases. The mean of the nadir blood counts of white blood cells, absolute neutrophil counts and platelets; the mean of all the peak biochemical parameters of liver function tests, lactate dehydrogenase and ferritin and the lowest fibrinogen values before treatment, differed significantly (p<0.05) between the non-fatal and the fatal group, being worse in the latter. Conclusions IA-HLH is important because it can obscure the typical clinical features of the underlying primary disease, thus delaying the diagnosis and having a negative effect on the outcome. Although bone marrow haemophagocytosis is not a mandatory diagnostic criterion, we found it to be a useful tool together with biochemical parameters for early recognition of HLH, especially in developing countries lacking molecular and flow laboratories. The severity of pancytopenia and derangement in biochemical markers were significantly higher in the patients who died.

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.

The use of a fludarabine-based conditioning regimen in patients with severe aplastic anemia – a retrospective analysis from three Indian centers

Between 2001 and 2009, 121 patients with severe aplastic anemia (SAA) underwent hematopoietic stem cell transplantation (HSCT) using a conditioning protocol of fludarabine and cyclophosphamide at three Indian hospitals. Donors were HLA‐identical sibling or family donors. Seventy‐six patients were considered “high risk” as per criteria. The graft source included peripheral blood stem cells in 109 and G‐CSF‐stimulated bone marrow in 12. GVHD prophylaxis consisted of cyclosporine and mini‐methotrexate. Engraftment occurred in 117 (96.6%) while two had graft failure and two expired in the first two wk. Neutrophil engraftment was seen at 12.3 d (range: 9–19) while platelet engraftment occurred at 12.4 d (range: 8–32). Grade II–IV acute GVHD was seen in 26.7% and grade IV GVHD in 8.6%. Chronic GVHD occurred in 44% and was extensive in 10%. The five‐yr overall survival for the entire cohort is 75.8 ± 3.9% with a survival of 95.6 ± 3.1% in the low‐risk group (n = 45) and 64.0 ± 5.6% in the high‐risk group (n = 76). Conditioning with fludarabine and cyclophosphamide is associated with very good long‐term survival in patients undergoing HSCT for SAA.

Successful bone marrow transplantation in a patient with Diamond-Blackfan anemia with co-existing Duchenne muscular dystrophy: a case report

IntroductionDiamond-Blackfan anemia and Duchenne muscular dystrophy are two rare congenital anomalies. Both anomalies occurring in the same child is extremely rare. Allogeneic hematopoietic stem cell transplantation is a well-established therapy for Diamond-Blackfan anemia. However, in patients with Duchenne muscular dystrophy, stem cell therapy still remains experimental.Case presentationWe report the case of a nine-year-old boy of north Indian descent with Diamond-Blackfan anemia and Duchenne muscular dystrophy who underwent successful allogeneic hematopoietic stem cell transplantation. He is transfusion-independent, and his Duchenne muscular dystrophy has shown no clinical deterioration over the past 45 months. His creatine phosphokinase levels have significantly decreased to 300 U/L from 14,000 U/L pre-transplant. The patient is 100% donor chimera in the hematopoietic system, and his muscle tissue has shown 8% to 10.4% cells of donor origin.ConclusionOur patients Diamond-Blackfan anemia was cured by allogeneic hematopoietic stem cell transplantation. The interesting clinical observation of a possible benefit in Duchenne muscular dystrophy cannot be ruled out. However, further clinical follow-up with serial muscle biopsies and molecular studies are needed to establish this finding.

Rare Case of Acquired Haemophilia and Lupus Anticoagulant

Acquired haemophilia or factor VIII (FVIII) deficiency, caused by FVIII inhibitor antibodies, is a very rare condition that commonly results in severe haemorrhagic complications. We report a case of acquired haemophilia presenting with multiple bluish patches affecting face, neck, upper & lower limbs, history of gum bleeding and left knee haemarthrosis. The patient was found to have acquired FVIII inhibitor and lupus anticoagulant (LAC). The simultaneous presence of LAC and FVIII inhibitor is exceedingly rare. The differentiation between these two conditions is crucial, because both result in a prolongation of the activated partial thromboplastin time test, which does not correct when mixed with the plasma of a normal control; however, the clinical manifestations range from thrombosis in the presence of LAC to massive haemorrhage with FVIII inhibitors.

Immunosuppressive therapy in adults with aplastic anaemia: single-institution experience from India

Objective To determine overall survival and factors predicting survival after immunosuppressive therapy in patients with acquired aplastic anaemia. Design Retrospective. Setting Tertiary care hospital. Patients 120 adults diagnosed as having acquired aplastic anaemia between 1 January 1996 and 31 December 2009. Interventions Anti-thymocyte globulin (ATG) followed by ciclosporin was administered to all patients for 15–18 months as the initial treatment. Haematological response was assessed 6 months after ATG administration and 6-monthly thereafter. Platelets were transfused if levels were <10 × 103/l and for symptomatic bleeding. Transfusions of red blood cells were given for haemoglobin levels <70 g/l or symptomatic anaemia. Febrile neutropenia was managed with antibiotics, with the addition of antifungal agents after 3–4 days of unresponsive fever. Granulocyte colony-stimulating factor was administered at a dose of 5 µg/kg/day (maximum 300 µg/day) subcutaneously for infective episodes. Main outcome measures Primary outcome: overall survival. Secondary outcome: response to immunosuppressive therapy, failure-free survival, relapse and clonal evolutions. The response and relapse criteria were defined in accordance with the British Council for Standards in Haematology guidelines. Results Overall response at 6 months after initiation of treatment was 85.8% (103/120). Overall survival at 76 months was 83.4%. Overall survival correlated with presence of response (complete response or partial response) at 6 months after ATG administration (HR=0.021, 95% CI 0.006 to 0.079, p<0.001). The occurrence of infectious complications adversely affected the overall survival (HR=5.71, 95% CI 1.22 to 26.77, p=0.027). Six patients relapsed. There were no deaths or adverse events 12 months after treatment among responders. Conclusions In our study, overall survival was 83.4% at a median follow-up of 76 months. The two variables that significantly affected overall survival were response to therapy at 6 months and occurrence of infectious complications.

A Rare Case of a Mixed Phenotypic Acute Leukemia (Mpal) - Report From a Tertiary Care Hospital

The term mixed phenotype acute leukemia (MPAL) applies to both acute bilineal leukemia, that is, leukemias containing a separate population of blasts of more than one lineage and biphenotypic leukemia containing a single population of blasts co expressing antigens of more than one lineage. Here we report a rare case of MPAL –NOS T/Megakaryocytic type in a 4 year old female child which has not been reported so far. She presented with fever, generalized weakness and right calf pain. Her peripheral blood picture revealed a leuco-erythroblastic blood picture with two population of blasts .Bone marrow biopsy revealed scattered lymphoblast amidst clusters of megakaryoblast. Immunohistochemical examination was done which revealed one population to be positive for CD3 and other population to be CD61 positive. Patient was diagnosed as a case of MPAL-NOS T/megakaryocytic type and was subsequently given AML chemotherapy. Patient achieved complete morphological remission and thereafter received an allogeneic bone marrow transplant. Patient is presently doing well after eighteen months of bone marrow transplant and has had no episode of relapse. This case report highlights the shortcomings of the WHO 2008 requirements for assigning more than one lineage to a leukemia as there is no inclusion criteria for megakaryocytic lineage which is myeloperoxidase negative.

Consensus Statement of the Indian Academy of Pediatrics in Diagnosis and Management of Hemophilia

JustificationDespite having standard principles of management of hemophilia, treatment differs in various countries depending on available resources. Guideline for management of hemophilia in Indian setting is essential.ProcessIndian Academy of Pediatrics conducted a consultative meeting on Hemophilia on 18th September, 2016 in New Delhi, which was attended by experts in the field working across India. Scientific literature was reviewed, and guidelines were drafted. All expert committee members reviewed the final manuscript.ObjectiveTo bring out consensus guidelines in diagnosis and management of Hemophilia in India.RecommendationsSpecific factor assays confirm diagnosis and classify hemophilia according to residual factor activity (mild 5-40%, moderate 1-5%, severe <1%). Genetic testing helps in identifying carriers, and providing genetic counseling and prenatal diagnosis. Patients with hemophilia should be managed by multi-specialty team approach. Continuous primary prophylaxis (at least low-dose regimen of 10–20 IU/kg twice or thrice per week) is recommended in severe hemophilia with dose tailored as per response. Factor replacement remains the mainstay of treating acute bleeds (dose and duration depends on body weight, site and severity of bleed). Factor concentrates (plasma derived or recombinant), if available, are preferred over blood components. Other supportive measures (rest, ice, compression, and elevation) should be instantly initiated. Long-term complications include musculoskeletal problems, development of inhibitors and transfusion-transmitted infections, which need monitoring. Adequate vaccination of children with hemophilia (with precautions) is emphasized.

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).