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

Abstract 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 &amp;gt;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&amp;lt;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. </jats:sec

Thromboprophylaxis in Multiple Myeloma: Indian Perspective

Abstract Background: Hypercoagulability has been observed in patients of multiple myeloma and has been associated with deep venous thrombosis (DVT). There is growing evidence of increased rate of venous thromboembolism associated with use of thalidomide, an anti angiogenesis drug, especially when combined with other agents such as dexamethasone and doxorubicin. Currently there is no consensus on the most appropriate prophylactic approach for thrombotic episodes in patients of multiple myeloma treated with thalidomide containing regimen. Although newer thalidomide derivatives with less thrombogenic adverse effects are being used in the developed countries, in developing countries like India due to financial constraints thalidomide remains the 1st line drug for multiple myeloma. Further there are scant reports of multiple myeloma related thrombosis and thrombo prophylactic regimen from developing countries. Objectives: To evaluate the incidence of symptomatic as well as asymptomatic thrombosis at onset of the disease as well as during treatment, the efficacy of low dose aspirin and low molecular weight heparin as thromboprophylaxis and their adverse effects in multiple myeloma patients treated with thalidomide and dexamethasone regimen. Patients and Methods: 30 patients of multiple myeloma reporting to our centre from May 2006 to March 2008 comprised the study group. Patient with past history of bleeding, thrombocytopenia and deranged coagulation parameters were excluded from the study. The male to female ratio was 3:2. The median age was 56 years (39–70). 23 patients were de-novo and 7 patients were relapse cases. Before starting therapy in addition to diagnostic and prognostic work up, all patients were evaluated for symptomatic as well as asymptomatic DVT with the help of Color Doppler Flow Index (CDFI) study and d-dimer estimation. Patients were randomized to low dose aspirin (Aspirin 150 mg once a day) and low molecular weight heparin (Enoxapirin 40 mg once a day). All patients were administered dexamethasone pulses of 40 mg once a day from day 1 to 4 in each cycle of 28 days. Thalidomide was started at a dose of 100mg once a day and increased to maximum of 400 mg depending on tolerability (median dose 200 mg). None of the patients received erythropoietin. All patients were evaluated for DVT at the beginning of each cycle during the first three cycles. Thromboprophylaxis was administered for first three cycles only. The response to therapy was evaluated at completion of 3rd and 6th cycles. Criteria for response were as previously reported by Blade et al. Results: The overall response (OR) after 3 cycles was 18/30 (60%), complete response (CR)-10/30(33.3%), partial response (PR)-8/30(26.7%) and after 6 cycles was 22/28 (78.5%), CR-16/28(57.1%), PR-6/28(21.4%). 2 patients who had progressive disease after 3 cycles were changed to Bortezumib containing regimen. Out of 30 patients only one patient (3.3%) a 70 yr old male had deep vein thrombosis at diagnosis which was asymptomatic and the diagnosis was based on CDFI findings. One patient on low dose aspirin had one episode of upper GI bleed on 5th day of the first cycle and thromboprophylaxis was stopped. During the follow up, none of the patient had any evidence of symptomatic as well as asymptomatic DVT. Conclusion: This study suggests that the incidence of venous thrombosis in our cohort of patients were much lower than reported from the west. Both low doses Aspirin as well as low molecular weight heparin are effective agents for thromboprophylaxis. The adverse effects were acceptable. Larger trials would be required to confirm these findings.</jats:p

Autologous Stem Cell Transplantation in Patients of High and Intermediate Risk Acute Myeloid Leukemia:-Perspective of a Developing Country.

Abstract Abstract 4364 Introduction Most patients with acute myeloid leukemia (AML) who achieve a complete remission after induction chemotherapy will relapse if they do not receive effective consolidation therapy particularly patients of high and intermediate risk. Standard chemotherapy only achieves less than 30% overall survival at 2 years. The most effective consolidation for high risk and intermediate risk patients is allogeneic stem cell transplantation (allo-SCT) which may be related or unrelated. However in the developing world availability of a human leucocyte antigen (HLA) matched donor for those lacking a sibling match is rarely available due to minority of voluntary donors from Indian subcontinent in various registries. Hence autologous stem cell transplant (auto-SCT) is one option that has been studied extensively. The question as to whether auto-SCT after consolidation chemotherapy improves the probability of survival of patients with AML has not been settled. In view of the above considerations, we carried out a retrospective study aimed at analyzing the impact of disease, patient, and transplantation-related factors on relapse, non–leukemia-related death, and LFS of patients with AML. Patients and methods We present here retrospective data of 16 patients of AML who undergone auto SCT in our centre from Jan 2005 to Jan 2009. The median age of patients was 24 yrs with a range from 10 to 40 years. Male: Female ratio was 11:5. The diagnosis was established on both bone marrow morphology and immunophenotyping study. Morphologically there was 1 case each of AML-M1, AML-M4, AML-M5, AML-M6 and rest 13 cases were of AML-M2. Bone marrow karyotyping was done in 11 cases. Out of 11 cases where karyotyping was done, 2 were metaphase failures; 1 was deletion 7; 1 was trisomy 8 and rest had normal cytogenetics. All cases were classified as high risk or intermediate risk either by cytogenetics or by other standard criteria. All patients received standard induction chemotherapy (Idarubicin x 3days, Cytosine CI x 7days) followed by 2 or 3 high dose Cytosine. Fourteen patients were in first remission (CR-1) while 2 patients were in CR-2 (one case of AML-M5 with deletion 7 and one AML-M4 with normal cytogenetics). None of the patients had a related HLA matched donor and all patients underwent auto-SCT, the graft being peripheral blood stem cell. The conditioning regimen for initial 6 cases were Busulfan(16mg/kg over 4 days) and Cyclophosphamide(120mg/kg over 2 days)(BuCy) and the remaining 10 cases were adminstered Idarubicin (60mg/mt2 over 3days) and Busulfan (16mg/kg over 4 days) (IBu). All cases engrafted except one patient who died due to sepsis on 6th day post SCT prior to engraftment. The median engraftment for neutrophil was day10 (9-14) and platelet was on day 16 (13 - 20). Results Nine out of 16 patients are alive and free from leukemia on median follow up of 38 (18 to 56 months). Five patients died due to leukemia relapse; 1 patient had transplant related mortality (Sepsis) and 1 patient died due to unrelated cause (Severe heat exertion with multiorgan failure). The overall (OS) and leukemia free survival (LFS) on a median follow up of 38 months was 56.25% which is better than the chemotherapy group. The treatment related mortality (TRM) was 6.25%. Both patients transplanted in CR-2 relapsed and died. Three out of 6 patients from BuCy and 6 out 10 from IBu conditioning are alive. Out of 9 patients surviving, 5 had normal karyotype while in 4 same was not known. The patients with deletion 7 and trisomy 8 died due to leukemia relapse. Conclusion Auto-SCT is a viable option for AML patients who are in need of a allo-SCT but do not have a donor. However larger studies would be required to establish the exact role of auto-SCT in AML. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Monitoring Response to Therapy with Imatinib Mesylate in Chronic Myeloid Leukemia Using Indian Generic Molecule of Imatinib

Abstract Background: Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by reciprocal t(9;22) translocation, which creates a juxtaposition of the BCR and ABL genes to form the p230-, p190- or p210- constitutively active tyrosine kinases. Imatinib mesylate (Gleevec) is a novel molecule, which inhibits the protein product of this fusion gene and hence has been used as a targeted therapy in CML. It is remarkably effective as a single agent therapy of newly diagnosed CML in chronic phase (CP). We report here an independent validation of therapeutic efficacy in CML-CP using an Indian generic of imatinib. Methods: At our institution from October, 2006 and March, 2008; 100 consecutive newly diagnosed CML-CP patients were started on imatinib mesylate (Indian generic molecules from Ms NATCO, Ranbaxy, CIPLA) 400mg PO within 6 months from diagnosis. The median age was 40.1years (age range: 9–80 years). The median follow-up was 12 months (range: 6–18 months). Monitoring of response was carried out by BCR-ABL dual colour dual fusion FISH and RT-PCR at diagnosis and thereafter by quantitative BCR-ABL FISH and RQ-PCR at 3 monthly intervals. All patients were treated with intention to treat and accordingly analysed. Non detectable BCR-ABL: ABL ratio was taken as complete molecular response and ratio &amp;lt; 0.1 % is considered as major molecular response. Of the 100 patients with CML-CP, 85 patients could be followed up for 12 months and remaining 15 were lost to follow-up. All 100 patients (100%) achieved complete hematological response (CHR) at 9 months (92% at 3 months and 94% at 6 months). Seven percent patients achieved complete molecular response and 8% major molecular response at 6 months. Of the 85 patients evaluable at 12 months, 22 (28 %) achieved complete molecular response (CMolR) and 15(18%) achieved major molecular response (MMolR) and 35(41%) patients showed a BCR-ABL:ABL of &amp;gt; 0.1% – 20%. The median BCR-ABL: ABL by Wilcoxon signed rank test was 12% at 6 months and 1% at 12 months (P = 0.003); whereas median BCR-ABL FISH was 65.75% at baseline and 14% at 6 months (P = 0.0006). The molecular response pattern conforms to all the published literature on the subject. Two patients showed molecular relapse followed by hematological relapse at 18 months. Kaplan- Meier Survival curve for CML Patients on imatinib projected a mean survival of 58.12 months (95% CI 54.17 – 62.10). Hypo-pigmentation (40%), wt gain(15%), leucopenia (11%), muscle cramps (10%), facial puffiness(10%), skin rashes (9%), fullness of stomach (6%), anemia (5%), raised trans-aminases (5%), pedal edema (3%), mucosal bleeding (2%), raised uric acid levels (2%) and decreased libido (1%) were toxicities encountered during our study. The drug was well tolerated and the adverse effects noted were manageable with supportive care. The results were comparable with trials from the West where Gleevec (Novartis) was used with comparable molecular responses and side effect profile. The cost of Indian generic molecule of imatinib is less than INR 10,000 (250 USD) while the cost of imatinib (Gleevec) is approx INR 1, 00,000 (2500 USD) per month. We conclude that the Indian generic of imatinib mesylate is effective and safe first line therapy for CML-CP. Kaplan- Meier Survival curve: CML Patients on Imatinib Mean Surv – 58.12 months (95% CI 54.17 – 62.10) Comparative Kaplan- Meier Survival curves:&amp;#x2028; Based on Molecular Remission Status Mean Surv – 58.12 months (95% CI 54.17 – 62.10) Comparative Kaplan- Meier Survival curves:&amp;#x2028; Based on Molecular Remission Status 1 − CMR + MMR, 2 − MI + NR Log Rank Chi Sq = 4.19, P=0.041 1 − CMR + MMR, 2 − MI + NR Log Rank Chi Sq = 4.19, P=0.041</jats:p