Bhausaheb Bagal

Comparison of the efficacy and safety of Rituximab (Mabthera™) and its biosimilar (Reditux™) in diffuse large B-cell lymphoma patients treated with chemo-immunotherapy: A retrospective analysis

Background: Rituximab (Mabthera™) have been in use in India since 2000. A biosimilar molecule of rituximab (Reditux™) was approved in India in 2007. This retrospective audit was done to compare the efficacy and safety of Mabthera™ with Reditux™. Materials and Methods: We reviewed the charts of 223 adult diffuse large B-cell lymphoma patients who had received cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab chemotherapy. Tumor recurrence, survival and toxicities experienced during chemotherapy were obtained from the patient charts. The survival analysis was restricted to patients who received at least 4 cycles of the same brand. Results: Of the 223 patients evaluated, 101 received Mabthera™, 72 received Reditux™. There were no differences in the infusional reaction rates, grades 3 and 4 neutropenia and oral mucositis between the two brands. Complete-remission (CR) rates were similar with Mabthera™ and Reditux™ (75% and 82%, respectively; P = 0.294). The progression free survival (PFS) rate at 5 years were 72% in Mabthera™ and 81% in Reditux™ (P = 0.382). The overall survival (OS) at 5 years were comparable in the two groups (66% in Mabthera™ and 76% in Reditux™; P = 0.264). Conclusion: We observed no significant differences in the toxicity, tumor response rates, PFS and OS between the two available brands of rituximab.

Hepatitis B-related serological events in hematopoietic stem cell transplant patients and efficacy of lamivudine prophylaxis against reactivation

Reactivation of remote hepatitis B infection (RHBI) is an important cause of morbidity in hematopoietic cell transplant (HCT) patients. We analyzed the prevalence of RHBI in 205 patients who underwent HCT in our centre, serological events related to hepatitis B virus (HBV) reactivation and role of lamivudine prophylaxis in HCT patients with RHBI. The prevalence of RHBI was 14% (28/205 patients). Of these 28 patients, 15 received lamivudine prophylaxis (14 anti‐HBcIgG positive and 1 only anti‐HBs positive) while 13 did not receive lamivudine prophylaxis (12 anti‐HBs positive and 1 anti‐HBcIgG positive). None in prophylaxis group developed HBV reactivation while 12 of 13 in no‐prophylaxis group reactivated (P < 0.001). The rate of HBV reactivation was 10% (21/205 patients), which included 9 patients with no evidence of RHBI pre‐transplant. We conclude that lamivudine prophylaxis protects against HBV reactivation in HCT patients with evidence of RHBI. Lamivudine prophylaxis should be used not only in patients with anti‐HBcIgG positivity but also in those with isolated anti‐HBs positivity pre‐transplant given the high rate of HBV reactivation in these patients. HBV serology cannot identify all cases with RHBI and therefore does not preclude HBV reactivation post‐transplant. Copyright

MYD88 mutant lymphoplasmacytic lymphoma/Waldenström macroglobulinemia has distinct clinical and pathological features as compared to its mutation negative counterpart

Abstract In a first series from India, we report 32 cases of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) over 7 years. Here, we analyzed 32 patients with LPL/WM for MYD88 L265P mutation and correlated mutation staus with hematological and biochemical parameters and also with the International Prognostic Scoring System (ISSWM) and treatment response. Twenty-seven out of 32 cases of LPL/WM (84.3%) harbored the MYD88 L265P mutation. MYD88 wild-type WM was associated with a lower number of tumor cells (p < 0.01) and older age (p = 0.02) and a lower ISSWM score at presentation (p = 0.03) as compared to mutated LPL/WM. On evaluation of response (n = 23), 44.4% of patients with MYD88 mutated LPL/WM had progressive disease, whereas no patient in the MYD88 unmutated group changed their baseline status. We confirm the high frequency of MYD88 mutations in LPL/WM. Although the number of MYD88 wild-type cases was limited, our data indicate that MYD88 may represent an adverse prognostic marker for LPL/WM.

Characteristics of BCR-ABL kinase domain mutations in chronic myeloid leukemia from India: not just missense mutations but insertions and deletions are also associated with TKI resistance

Abstract We document the characteristics of BCR-ABL kinase domain mutations (KDM) in the largest study from India comprising of 385 patients and demonstrate that more than half (51.9%) of these patients have detectable abnormalities in the KD both in adult and in pediatric chronic myelogenous leukemia (CML). These comprise singly occurring missense mutations (25.5%), polyclonal/compound point mutations (4.9%), and insertions/deletions (29.6%). Missense mutations were most commonly seen in the imatinib-binding region followed by the P-loop. The commonest mutation in our dataset was T315I. Other common missense mutations were Y253H, M244V, and F317L. A high prevalence of BCR-ABL exon7 deletion (p.R362fs*) was also seen (25.5% of the entire cohort), whereas the 35bpintron-derived insertion/truncation mutation detected in 12 patients. In the pediatric age group, 58.8% of patients harbored missense mutations, polyclonal/compound mutations as well as insertions and deletions. We detected 11 novel mutations (seven missense mutations and four insertions/deletions).

Immunogenetics of chronic lymphocytic leukemia

Introduction: Cytogenetic aberrations as well as presence of IGVH mutations are the underlying reason for clinical heterogeneity in Chronic Lymphocytic Leukemia (CLL). The presence of IGVH mutations as well as the predominant gene usage shows geographical variations. However, there is no study from India addressing immunogenetics of CLL. In a first Indian study we document the immunogenetics of CLL in a large tertiary hospital. Methods: We analyzed IGVH mutation status, VH gene usage, cytogenetic abnormalities using FISH, immunophenotyping data and correlated them with standard clinical variables in 84 patients of CLL. Results: Advanced Rai stage (Stage 3/4) was seen in 45% of our patients, where as 13q deletion was the commonest clonal cytogenetic abnormality detected in 48.4% of the cases. IGVH unmutated cases (55.2%) showed higher proportion expressing CD38 and CD49d, a preferential usage for VH1 and VH3 families (55.2%), presentation at an advanced Rai stage (52.8%) as well as more frequent presence of p53 deletions. As compared to the IGVH mutated cases greater proportion of IGVH unmutated patients (70%) required treatment. However, there was no significant difference in the time to treatment between mutated and unmutated cases which can be attributed to relatively short median follow up of 10 months. Conclusion: To summarize, we have seen a higher proportion of IGVH unmutated patients in our cohort (55.2%). The commonly used VH genes in the Indian population are IGVH 2-5, IGVH 1-2 and IGVH 1-69. Longer clinical follow up and a larger cohort is necessary to confirm the prognostic value of IGVH mutation analysis in Indian Patients with CLL.

Low, fixed dose defibrotide in management of hepatic veno-occlusive disease post stem cell transplantation

OBJECTIVE/BACKGROUND Hepatic veno-occlusive disease (VOD) is well recognized potentially serious regimen-related toxicity seen after stem cell transplantation. Severe VOD is associated with poor long-term outcomes with very high mortality. Besides supportive care, only defibrotide has been found to be effective in the management of VOD. The recommended dose of defibrotide is 25mg/kg/d but there has been no classical dose finding study done for this drug. A higher dose of defibrotide is associated with increased risk of bleeding and this drug is prohibitively expensive. We report our experience of using fixed low dose of defibrotide in patients with VOD. METHODS We retrospectively evaluated 511 patients who underwent stem cell transplant at our center from November 2007 and December 2015. All patients received ursodeoxycholic acid as VOD prophylaxis. Modified Seattle criterion was used for diagnosis and severity grading of VOD. Patients developing VOD were initially treated with furosemide and adequate analgesia. Defibrotide was started within 12 to 24 hours of diagnosis of VOD. All adult patients received defibrotide at a fixed dose of 200mg twice daily while two children were given dose of 100mg and 50mg twice daily. RESULTS Nine (1.7%) of our patients developed VOD. Daily dose of defibrotide ranged from 5mg/kg/d to 20mg/kg/d till resolution of VOD. All patients had complete resolution of VOD. None of our patients required ventilator support or dialysis. No episodes of bleeding were observed. No dose response relationship was observed between defibrotide dose and time to resolution of VOD. CONCLUSION Low fixed dose defibrotide initiated early seems to be effective and safe in treatment of VOD. This is relevant in a resource limited setting and warrants prospective evaluation.

Lomustine, cytarabine, cyclophosphamide, etoposide – An effective conditioning regimen in autologous hematopoietic stem cell transplant for primary refractory or relapsed lymphoma: Analysis of toxicity, long-term outcome, and prognostic factors

Background: High-dose chemotherapy followed by autologous hematopoietic stem cell transplant (HSCT) is the treatment of choice for patients with relapsed and refractory (RR) lymphoma. We analyzed toxicity and long-term outcome with lomustine, cytarabine, cyclophosphamide, etoposide (LACE) conditioning in patients with primary refractory or relapsed lymphoma undergoing autologous transplant. Materials and Methods: One-hundred patients with primary refractory (23), chemotherapy sensitive relapse (74) or RR (3) Hodgkin lymphoma (HL - 70 patients), and non-HL (NHL - 30 patients) underwent HSCT with LACE (lomustine 200 mg/m 2 day-7, etoposide 1000 mg/m 2 day-7, cytarabine 2000 mg/m 2 day-6 to day-5, and cyclophosphamide 1800 mg/m 2 day-4 to day-2) conditioning between November 2007 and December 2013. At transplant, 68 patients were in complete remission (CR), 29 in partial remission, 2 had stable disease, and 1 had progressive disease. Patients were followed up for development of transplant-related toxicities and long-term survival outcome. Results: The incidence of grades 3–4 oral mucositis and grades 3–4 diarrhea was 8% and 4%, respectively. Median days to myeloid and platelet engraftment were 10 and 13. Transplant-related mortality was 7%. At median follow-up of 3 years, probability of overall survival (OS) and progression-free survival (PFS) at 3 years was 70% and 58% in entire cohort, 78% and 62% in HL and 51% and 46% in NHL subgroup, respectively. International Prognostic Score (IPS) >2 at relapse prognosticated for poor OS (P = 0.002) and PFS (P < 0.001) in HL subgroup. Positron emission tomography positivity pretransplant (HL subgroup) and at day + 100 (NHL subgroup) predicted for poor survival. Conclusion: We conclude that LACE is effective and well-tolerated conditioning regimen. IPS at relapse is the most important prognostic factor in HL transplant.

Successful Treatment of Transplant Associated Thrombotic Microangiopathy (TA-TMA) with Low Dose Defibrotide

Transplant associated microangiopathy (TA-TMA) is a potentially serious complication of stem cell transplantation. Though stopping calcineurin/mTOR inhibitor is the first step in managing TA-TMA, this is not always adequate. The pathophysiology of TA-TMA is different from microangiopathy seen in other settings. Many drugs have been used in TA-TMA with modest responses. Defibrotide has been explored in TA-TMA in the past with good results. However, its availability is erratic and cost of therapy very high. Hence its routine use in low middle income country (LMIC) is financially demanding. We report the use of low dose defibrotide safely and successfully in this case series. This is pertinent more to LMIC’s and warrants prospective evaluation.

Outcomes of Patients with Splenic Marginal Zone Lymphoma Treated with Rituximab or Splenectomy: Report from Tertiary Cancer Center in India

S282 Context: Castleman ’s Disease (CD) is the rare lymphoproliferative disease masking a number of hematologic, oncological and autoimmune diseases. Objective: To determine the frequency of occurrence of the diseases which are followed by Castleman-like similar changes in lymph nodes. Materials and methods: Medical records of the 48 patients with preliminary diagnosis CD directed in outpatient department from 2016 to 2017. All patients were examined according to the recommendations of the international working group on the study of CD. Morphological study of lymph node tissue biopsies included the assessment of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, vascularization and polytypic plasmacytosis in the interfollicular spaces by the point system from 0 to 3 grades. Results: Morphological picture in 24 lymph node tissue biopsies, from 24 of 48 patients corresponded to the first large criterion of diagnosis of CD. In these cases, comparison of clinical and laboratory data allowed to confirm the diagnosis of C D. The greatest divergence was observed in cases with a generalized lymphadenopathy. From 15 patients with the preliminary diagnosis multicentric CD the diagnosis has been confirmed in 20%. Diagnosis CD was changed to the Hodgkin’s lymphoma (HL) in three cases, to NHL in three cases, to the connective tissue disease and solid tumors in two cases respectively, to primary amyloidosis in one patient, and to multiple myeloma in one patient. In cases with local specific involvement the diagnosis of CD has been confirmed in 63.6%. The range of the revealed diseases included: a reactive lymphadenopathy in 6 cases, a tumor not of the lymphoid nature in two cases, HL at the one patient and NHL at the three patients. Conclusion: Inspection of patients with suspected diagnosis of CD according to the recommendations of the international working group has shown that the frequency of occurrence of the diseases which are followed by Castleman-like similar changes in lymph nodes varies from 36,4 to 80% and depends on prevalence of process. The range of the diseases demanding an exception includes HL and NHL, connective tissue disease, other neoplastic processes and reactive conditions.

Study of stem cell homing & self-renewal marker gene profile of ex vivo expanded human CD34+ cells manipulated with a mixture of cytokines & stromal cell-derived factor 1

Background & objectives: Next generation transplantation medicine aims to develop stimulating cocktail for increased ex vivo expansion of primitive hematopoietic stem and progenitor cells (HSPC). The present study was done to evaluate the cocktail GF (Thrombopoietin + Stem Cell factor + Flt3-ligand) and homing-defining molecule Stromal cell-derived factor 1 (SDF1) for HSPC ex vivo expansion. Methods: Peripheral blood stem cell (n=74) harvests were analysed for CD34hi CD45lo HSPC. Immunomagnetically enriched HSPC were cultured for eight days and assessed for increase in HSPC, colony forming potential in vitro and in vivo engrafting potential by analyzing human CD45+ cells. Expression profile of genes for homing and stemness were studied using microarray analysis. Expression of adhesion/homing markers were validated by flow cytometry/ confocal microscopy. Results: CD34hi CD45lo HSPC expansion cultures with GF+SDF1 demonstrated increased nucleated cells (n=28, P< 0.001), absolute CD34+ cells (n=8, P=0.021) and increased colony forming units (cfu) compared to unstimulated and GF-stimulated HSPC. NOD-SCID mice transplanted with GF+SDF1-HSPC exhibited successful homing/engraftment (n=24, P< 0.001). Microarray analysis of expanded HSPC demonstrated increased telomerase activity and many homing-associated genes (35/49) and transcription factors for stemness/self-renewal (49/56) were significantly upregulated in GF+SDF1 stimulated HSPC when compared to GF-stimulated HSPC. Expression of CD44, CXCR4, CD26, CD14, CD45 and soluble IL-6 in expanded cultures were validated by flow cytometry and confocal microscopy. Interpretation & conclusions: Cocktail of cytokines and SDF1 showed good potential to successfully expand HSPC which exhibited enhanced ability to generate multilineage cells in short-term and long-term repopulation assay. This cocktail-mediated stem cell expansion has potential to obviate the need for longer and large volume apheresis procedure making it convenient for donors.