Anant Gokarn

Is long term storage of cryopreserved stem cells for hematopoietic stem cell transplantation a worthwhile exercise in developing countries

Background Stem cell units (SCUs) that are cryopreserved prior to both autologous and allogeneic hematopoietic stem cell transplants (for donor lymphocyte infusion) remain unused or partially used several times, and become an increased burden to blood banks/SCU repositories. Because of the scarcity of data regarding the duration for which the storage is useful, there is no general consensus regarding disposal of SCUs. Methods We conducted a retrospective audit of SCU utilization in 435 patients who planned to undergo either autologous stem cell transplantation (auto-SCT) (N=239) or allogeneic stem cell transplantation (allo-SCT) (N=196) at a tertiary cancer care center between November 2007 to January 2015. Results Our cohort consisted of 1,728 SCUs stored for conducting auto-SCT and 729 SCUs stored for conducting donor lymphocyte infusions (DLIs) after allo-SCT. Stem cells were not infused in 12.5% of patients who had planned to undergo auto-SCT, and 80% of patients who underwent allo-SCT never received DLI. Forty-one percent of SCUs intended for use in auto-SCT remained unutilized, with a second auto-SCT being performed only in 4 patients. Ninety-four percent of SCUs intended for carrying out DLIs remained unused, with only minimal usage observed one year after undergoing allo-SCT. Conclusion The duration of storage of unused SCUs needs to be debated upon, so that a consensus can be reached regarding the ethical disposal of SCU.

Antibiotic Lock Therapy for Salvage of Tunneled Central Venous Catheters with Catheter Colonization and Catheter-Related Bloodstream Infection

Central venous catheters (CVCs) represent a significant source of infection in patients undergoing hematopoietic stem cell transplantation and can add to the cost of care, morbidity, and mortality. Organisms forming biofilms on the inner surface of catheters require a much higher local antibiotic concentration to clear the pathogen growth. Antibiotic lock therapy (ALT) represents one such strategy to achieve such high intraluminal concentrations of antibiotics and can facilitate catheter salvage. Patients with catheter colonization (CC) or hemodynamically stable catheter‐related bloodstream infection (CRBSI) received ALT per institutional policy. We analyzed the incidence of CC and CRBSI and salvage rate of tunneled CVCs (Hickman) with ALT in patients undergoing hematopoietic stem cell transplant in this retrospective study. Catheter colonization was noted in 9.8% and CRBSI in 10.7% patients. Gram‐negative bacilli (GNB) accounted for 45% and 83% of isolates in CC and CRBSI, respectively. In patients with CRBSI, the rate of catheter salvage with the use of ALT in addition to systemic antibiotics was 86% compared to 55% in patients with systemic antibiotics use only (P = 0.06). There was no CRBSI related mortality, and no increase in resistant strains was noted at subsequent CRBSI. In conclusion, ALT represents an important strategy for catheter salvage, especially for gram‐negative infections, in a carefully selected patient population.

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.

Killer Immunoglobulin like Receptor-Human Leukocyte Antigen Ligand Match/Mismatch in Graft Loss Post Transplant Cyclophosphamide Based Hap loidentical Transplant

Background: Killer Immunoglobulin like receptor (KIR) genes that modulate Natural Killer cell alloreactivity have been linked with predicting haploidentical hematopoietic stem cell transplant outcomes. Study design and methods: We present two haploidentical hematopoietic stem cell transplant (HHSCT) scenarios, wherein after engraftment there was graft loss. We hypothesized that this phenomenon was due to KIR ligand matches/mismatches. The KIR ligand matches/mismatches were examined in both patient donor pairs. Results: Patient 1 and 2 were 11/12 and 12/12 match for HLA A, B, C, DRB1, DQB1 and DPB1 in GvH respectively, and their donors were 6/12 and 7/12 HLA match in HvG directions. It was observed that there was KIR activating receptor (aKIR) match and stronger KIR inhibitory receptor (iKIR) mismatch in GvH direction which resulted in removal of leukemic cells. Moreover, in the HvG direction, the stronger aKIR match led to graft rejection. Conclusion: This study highlights the implication of KIR-HLA interaction in predicting graft survival. Citation: D’Silva SZ, Diwedi P, Punatar S, Gokarn A, Bonda A, et al. (2018) Killer Immunoglobulin like Receptor-Human Leukocyte Antigen Ligand Match/Mismatch in Graft Loss Post Transplant Cyclophosphamide Based Hap loidentical Transplant. J Blood Lymph 8: 225. doi: 10.4172/2165-7831.1000225

Leflunomide: Is It the Game Changer in Musculoskeletal Chronic Graft Versus Host Disease?

Musculoskeletal involvement in chronic graft versus host disease (cGVHD) can be extremely crippling. Manifestations of musculoskeletal cGVHD are varied and can include fasciitis, myositis, weakness, cramping, joint stiffness and contractures. Pathogenetically, in musculoskeletal GVHD there is accumulation of alloimmune donor T-cells in the muscles, joints, and soft tissues. Release of cytokines by these activated T-cells results in fibroblast proliferation and activation. Cross talk between these alloimmune T-cells with macrophage will further augment the fibrosis. Alloimmune donor T cells also activate B-cells resulting in the production of auto antibodies directed against joints and muscular tissues [1]. Thus, pathophysiology of musculoskeletal GVHD closely mimics many autoimmune disorders. Though systemic steroids may improve clinical manifestations of musculoskeletal GVHD, prolonged usage of steroids is associated with several long term complications and predisposition to infections. Steroid sparing agents like Cyclosporine, Tacrolimus, Sirolimus, Mycophenolate mofetil, Etanercept, Low dose Methotrexate have been used with variable success. Olivieri et al. [2] described the role of Imatinib in chronic GVHD associated with fibrotic changes. Many of these drugs are associated with adverse effects like reactivation of infections, organ toxicities and some of them are costly. Leflunomide with its anti-T cell proliferative action has shown to be useful in rheumatoid arthritis [3]. Leflunomide has been shown to be effective in prevention and treatment of GVHD in various animal models [4, 5]. We describe our patient with Musculoskeletal GVHD who responded to single agent Leflunomide. A 46 year old female with Myelodysplastic syndrome (RAEB2) with progression to acute myeloid leukemia underwent haploidentical stem cell transplant with her 8/10 HLA matched son. Her baseline comorbidities included remote hepatits B infection for which she was on prophylaxis with lamivudine. Her conditioning regimen was reduced intensity with fludarabine, and treosulfan. GVHD prophylaxis consisted of cyclosporine (CsA), mycofenolate mofetil (MMF) and post-transplant cyclophosphamide. Her immediate post-transplant period was complicated by febrile neutropenia, voriconazole induced visual hallucinations and CsA related headache. She engrafted on day ? 11 and developed engraftment related fever needing low dose steroids for few days. MMF was stopped on day ? 36 and CsA tapering was started from day ? 91. On Day ? 125 her liver enzymes were found to be mildly elevated on routine blood workup. Virology testing did not show any seroconversion. HBV DNA and HCV RNA PCR were negative. She was continued on lamivudine. Suspecting liver GVHD, cyclosporine tapering was withheld temporarily. Her liver enzymes showed a declining trend by day ? 130. On day ? 133 she started having bilateral shoulder pain with some restriction of movements. This worsened gradually and 2 weeks later (day ? 144), she had severe restriction of movements, increased pain, joint stiffness in small joints of hand and difficulty in getting up from sitting position. MRI of shoulder joints ruled out avascular necrosis. A clinical diagnosis of musculoskeletal GVHD was made. Her baseline PROM score was 21 and NIH joint score was 2. Since her manifestations resembled rheumatoid arthritis, she was started on oral leflunomide (100 mg once a day for first 3 days followed by 20 mg & Navin Khattry nkhattry@gmail.com

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.

HLA Antigens as Risk Factors for Acute and Chronic Graft Versus Host Disease in Allogenic Stem Cell Transplant – A Single Centre Experience from India

Christophe Willekens, Alina Danu, Julien Lazarovici, David Ghez, Eric Solary, Vincent Ribrag, Jean-Henri Bourhis, Cristina Castilla-Llorente Department of Hematology, Gustave Roussy Cancer Center, Villejuif, France; Gustave Roussy Cancer Center, INSERM U1170, Villejuif, France; Faculty of Medicine, Université Paris-Sud, Le Kremlin-Bicêtre, France; Gustave Roussy Cancer Campus, Villejuif, France Context: Allogeneic hematopoietic stem cell transplant (HCT) represents a curative option in elderly acute myeloid leukemia (AML) patients. Reduced intensity conditioning regimens (RIC) have decreased treatment related toxicity. In 2014, Sorror et al., proposed a risk-adapted approach integrating AML-, HCTand patient-specific risk factors guiding decisions about HCT versus no HCT in elderly patients. Objective: To determine overall survival (OS); Relapse-free survival (RFS); Non-relapse mortality (NRM) and cumulative incidence of relapse (RI). To evaluate, after stratifying patients according to the risk-adapted approach, the NRM, relapse and survival rates according to the HCT-CI comorbidity score. Design: In our center, we analyzed retrospectively, between 2010 and 2016, a cohort of AML patients aged more than 60 years. We classified them according to the risk-adapted model into 3 categories: favorable, intermediate and unfavorable risk. Results: 47 patients were included. Median age was 64 years. The median follow-up was 6 years. At 3 years, OS was 63% (95% CI: 48-79%), RFS 57% (95% CI: 42-72%), RI 30% (95% CI: 18-49%) and NRM 16% (95% CI: 8-31%). Using the risk-adapted strategy, two patients had a favorable risk, 17 patients an intermediate and 28 patients an unfavorable risk. In the intermediate risk group, all patients had low HCT-CI (score 0-2). The NRM was 25% (4 patients). 75% (13 patients) were still alive, free from disease. In the unfavorable risk group, 20 patients had a low and 8 patients a high (score>3) HCT-CI. In patients with a low HCT-CI, the relapse and NRM were 21% (n1⁄46) and 7% (n1⁄42) respectively, and 43% (n1⁄4 12) were still alive at the last follow-up. In patients with a high HCT-CI, the relapse and NRM were 4% (n1⁄41) and 11% (n1⁄43) respectively, and 14% (n1⁄44) were still alive at the last followup. Conclusion: Our study shows a low transplant-related toxicity with promising long-term outcome in elderly patients. The observed RFS and OS, especially in the unfavorable risk AML patients, compares favorably with the results obtained with chemotherapy alone and suggest clear benefits from allogeneic HCT regardless of the HCT-CI comorbidity score.

Daratumumab at the frontiers of post-transplant refractory T-acute lymphoblastic leukemia—a worthwhile strategy?

Adult ALL is a heterogeneous disease both clinically and genetically. The management of ALL in adults remains a daunting task. The therapeutic options in relapsed / refractory setting post allogeneic hematopoietic stem cell transplantation are limited. The emergence of targeted immunotherapeutic strategies in cancers paved way for the detection of suitable targets and drugs with cytotoxic abilities. However no safe and effective immunotherapies have been developed for T ALL. CD 38, also referred to as T10, was identified in 1980 in a project investigating cell surface molecules of human WBC using thymocyte-specific murine monoclonal antibodies [1]. It is recognized as a marker of both differentiation and activation of lymphocytes. It is expressed at high levels on the cell surface of activated T cells and terminally differentiated B cells, but at relatively low levels on normal lymphoid and myeloid cells [2]. Most notably, CD 38 is expressed in a large number of hematological malignancies [3–12]. Daratumumab is a human IgG1κ monoclonal antibody that binds to a unique CD 38 epitope and recently FDA approved for the treatment of refractory multiple myeloma. Preclinical studies have shown that CD 38 is a relevant target in T ALL and its surface expression does not change with chemotherapy [13]. Hence daratumumab with its broad antitumor spectrum may be used in T ALL. We report a patient with early precursor T cell acute lymphoblastic leukemia who relapsed post allogeneic hematopoietic stem cell transplantation and was salvaged with daratumumab. A 32-year-old lady presented to our center in June 2013, with generalized lymphadenopathy. On evaluation she was diagnosed to have an acute leukemia of ambiguous lineage (CD 13, CD 33, CD 38, CD 45 and CD 7 positive). She received induction chemotherapy with 3+ 7 (cytarabine and daunorubicin) followed by three cycles of high dose cytarabine consolidation. She was in morphological complete remission. After a treatment-free interval of 2 months, she relapsed with an early precursor T cell phenotype (CD 1a negative, TdT, CD 10, CD 34, CD 38 positive). She was then given ALL like induction therapy and achieved a complete remission without measurable residual disease (MRD negative). She underwent allogeneic stem cell transplantation from a matched sibling donor with myeloablative conditioning (cyclophosphamide with total body irradiation) in January 2014. She relapsed after 21 months. The marrow revealed 76% lymphoid blasts expressing CD 34, CD 7, CD 10, CD 38 and negative for CD 1a, CD 4, and CD8. She received salvage induction with vincristine, etoposide, bortezomib, dexamethasone, adriamycin and L asparaginase. With this, she did not achieve remission. This was followed by one cycle of FLAG IDA with which she achieved complete remission morphologically (but with MRD of 0.17% by flow cytometry). As she had another fully HLA matched sibling donor, she underwent second allogeneic stem cell transplant with reduced intensity conditioning (fludarabine+ treosulfan) in February 2016. In view of a high risk of relapse, she received prophylactic donor lymphocyte infusion (DLI) on day +94 along with lenalidomide 10 mg per day subsequently. She developed skin and liver GVHD which was managed with systemic steroids and topical tacrolimus. Bone marrow studies done at day 90 and 1 year after 2nd allogeneic transplant showed MRD negativity. She developed a relapse after 18 months with marrow showing 86% lymphoid blasts with CD 7 bright, CD 1a negative, CD 20 negative, CD 34 bright, and CD 38 bright while CD 4 and CD 8 were negative. In view of her young age and good performance status, she received salvage chemotherapy with pegylated L asparaginase, dexamethasone, bortezomib and vincristine. During this chemotherapy she developed sub-acute bilateral lower * Navin Khattry nkhattry@gmail.com

Comparison of isolates and antibiotic sensitivity pattern in pediatric and adult cancer patients; is it different?

BACKGROUND Infection is a common cause of mortality and morbidity in cancer patients. Organisms are becoming resistant to antibiotics; age appears to be one of the factors responsible. We analyzed common organisms and their antibiotic sensitivity pattern in the correlation with age. METHODS This is a single institutional, retrospective analysis of all culture positive adult and pediatric cancer patients from January 2007 to December 2007. For statistical analysis, Chi-square test for trend was used and P values were obtained. Of 1251 isolates, 262 were from children <12 years of age and 989 were from adolescents and adults (>12 years of age). Gram-negative organisms were predominant (64.95) while Gram-positive constituted 35.09% of isolates. RESULTS The most common source in all age groups was peripheral-blood, accounting to 47.8% of all samples. The most common organisms in adults were Pseudomonas aeruginosa (15.3%) while in children it was coagulase negative Staphylococcus aureus (19.8%). Antibiotic sensitivity was different in both groups. In pediatric group higher sensitivity was seen for Cefoparazone-sulbactum, Cefipime, Amikacin, and Tobramycin. No resistance was found for Linezolid. CONCLUSIONS The isolates in both children and adults were predominantly Gram-negative though children had proportionately higher Gram-positive organisms. High-dose cytarabine use, cotrimoxazole prophylaxis, and frequent use of central lines in children especially in hematological malignancies could explain this observation. Children harbor less antibiotic resistance than adults; Uncontrolled, cumulative exposure to antibiotics in our community with increasing age, age-related immune factors and variable bacterial flora in different wards might explain the higher antibiotic resistance in adults. Thus age is an important factor to be considered while deciding empirical antibiotic therapy.