Uday Kulkarni

Clinical Outcomes in Multiple Myeloma Post-Autologous Transplantation—A Single Centre Experience

There is paucity of data from developing countries on the clinical outcomes in myeloma post-autologous transplantation. In this retrospective study, we used hospital records to retrieve data of patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) from January 1995 to December 2014 at our centre. During the study period, 245 patients underwent ASCT for myeloma. Of these, 19%, 37% and 37% were in complete response, very good partial response and partial response respectively at the time of ASCT. Only in 14 (5.7%) patients, the stem cells were cryopreserved. The transplant related mortality was 2.86%. The median follow up was 40.7 months (range 0–237.4 months). The 5-year overall survival (OS) and progression-free survival (PFS) for the entire cohort was 61.6% ± 3.8% and 37.2% ± 3.9% respectively. Independent predictors of OS included mononuclear cell dose infused, pre- and post-transplant response; and the use of maintenance therapy. Independent predictors of PFS included age at diagnosis, pre- and post-transplant response; and the use of maintenance therapy. In a resource limited setting, ASCT for myeloma is associated with low transplant related mortality. Pre- and post-transplant response and maintenance therapy are predictors of survival.

Arsenic Trioxide Enhances the NK Cell Cytotoxicity Against Acute Promyelocytic Leukemia While Simultaneously Inhibiting Its Bio-Genesis

Natural killer cells (NK) contribute significantly to eradication of cancer cells, and there is increased interest in strategies to enhance it’s efficacy. Therapeutic agents used in the treatment of cancer can impact the immune system in a quantitative and qualitative manner. In this study, we evaluated the impact of arsenic trioxide (ATO) used in the management of acute promyelocytic leukemia (APL) on NK cell reconstitution and function. In patients with APL treated with single agent ATO, there was a significant delay in the reconstitution of circulating NK cells to reach median normal levels from the time of diagnosis (655 days for NK cells vs 145 and 265 days for T cells and B cells, respectively). In vitro experiments demonstrated that ATO significantly reduced the CD34 hematopoietic stem cell (HSC) differentiation to NK cells. Additional experimental data demonstrate that CD34+ sorted cells when exposed to ATO lead to a significant decrease in the expression of IKZF2, ETS1, and TOX transcription factors involved in NK cell differentiation and maturation. In contrast, exposure of NK cells and leukemic cells to low doses of ATO modulates NK cell receptors and malignant cell ligand profile in a direction that enhances NK cell mediated cytolytic activity. We have demonstrated that NK cytolytic activity toward NB4 cell line when exposed to ATO was significantly higher when compared with controls. We also validated this beneficial effect in a mouse model of APL were the median survival with ATO alone and ATO + NK was 44 days (range: 33–46) vs 54 days (range: 52–75). In conclusion, ATO has a differential quantitative and qualitative effect on NK cell activity. This information can potentially be exploited in the management of leukemia.

Management of Relapse in Acute Promyelocytic Leukemia Treated with Upfront Arsenic Trioxide Based Regimens

S210 dnAML, while TP53 (OR 0.39, p 1⁄4 0.001) mutations were more enriched in stAML. NPM1 (OR2.18, p 1⁄4 0.036) and NRAS (OR 2.58, p 1⁄4 0.049) mutations were more enriched in previouslyuntreated patients, whereas WT1 (OR 0.44, p 1⁄4 0.02) and U2AF1 (OR 0.23, p 1⁄4 0.012) mutations were more enriched in R/R AML. Class 1 mutations (NPM1, FLT3, PTPN11, NRAS) were associated with proliferative disease (high WBC, blast, LDH), whereas patients with mutations in TP53, STAG2, BCOR, and ASXL1 had non-proliferative disease. We detected rare mutations in MYC (8 hotspot SNVs in exon 2 and 1 ITD) and MYCN (1 SNV) in 9 (2%) patients. Patients with MYC mutations showed significantly higher MYC expression than those without by IHC staining (median H score 22 vs. 15, p < 0.001). Conclusion: We identified significant association between mutations and certain clinical phenotype. MYC mutations were associated with MYC protein overexpression in AML.

Post-Transplant Cyclophosphamide as Sole Graft-versus-Host Disease Prophylaxis Is Feasible in Patients Undergoing Peripheral Blood Stem Cell Transplantation for Severe Aplastic Anemia Using Matched Sibling Donors

High-dose cyclophosphamide (PTCY) after allogeneic hematopoietic cell transplantation (HSCT) has been shown to be effective in preventing graft-versus-host disease (GVHD) after HLA-matched bone marrow transplantation. We performed a phase II study of PTCY given at 50 mg/kg i.v. on days 3 and 4 as the sole GVHD prophylaxis after HSCT for severe aplastic anemia (SAA) in patients receiving granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (PBSC) grafts from HLA-matched related donors after conditioning with fludarabine, CY, and single-dose total body irradiation. Thirty patients with a median age of 29 years (range, 16 to 49) were enrolled in this study. Engraftment was seen in 27 patients (90%) at a median of 16 days (range, 12 to 21) post-HSCT. None of the patients developed veno-occlusive disease of the liver or hemorrhagic cystitis. Grades II to IV acute GVHD was seen in 22% of patients with grades III to IV GVHD in 11.1%. The 2-year cumulative incidence of chronic GVHD was 22.7%. Fourteen patients (46.6%) did not require any further immunosuppression after receiving PTCY. Comparing with 2 historical cohorts of 30 patients each who received cyclosporine and methotrexate (MTX; at 15 mg/m2 [MTX15] and 10 mg/m2 [MTX10]), the incidence of grades II to IV acute GVHD was lower, albeit not significantly, with the use of PTCY (PTCY, 22.2%, vs MTX15, 37.1%, vs MTX10, 53.8%; P = .056), whereas rates of chronic GVHD were significantly reduced (PTCY, 22.7%, vs MTX15, 63.6%, vs MTX10, 76.2%; P = .013). Viral infections including cytomegalovirus were significantly higher with the use of PTCY (60%) compared with cyclosporine and MTX (MTX15, 23.3%, vs MTX10, 33.3%; P = .008). Overall survival was similar between the 3 groups. We conclude that PTCY as the sole GVHD prophylaxis is associated with low rates of acute and chronic GVHD in patients undergoing PBSC transplant for SAA using HLA-matched donors. This trial is registered at CTRI/2010/091/001480.