Colin Phipps Diong

Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.

BACKGROUND Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. METHODS We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. FINDINGS Associations exceeding the genome-wide significance threshold (p<5 × 10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10(-19), odds ratio [OR] 1·84 [95% CI 1·61-2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection. INTERPRETATION To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. FUNDING Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).

CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes

Antibody-dependent cellular cytotoxicity (ADCC) is exerted by immune cells expressing surface Fcγ receptors (FcγRs) against cells coated with antibody, such as virus-infected or transformed cells. CD16, the FcγRIIIA, is essential for ADCC by NK cells, and is also expressed by a subset of human blood monocytes. We found that human CD16− expressing monocytes have a broad spectrum of ADCC capacities and can kill cancer cell lines, primary leukemic cells and hepatitis B virus-infected cells in the presence of specific antibodies. Engagement of CD16 on monocytes by antibody bound to target cells activated β2-integrins and induced TNFα secretion. In turn, this induced TNFR expression on the target cells, making them susceptible to TNFα-mediated cell death. Treatment with TLR agonists, DAMPs or cytokines, such as IFNγ, further enhanced ADCC. Monocytes lacking CD16 did not exert ADCC but acquired this property after CD16 expression was induced by either cytokine stimulation or transient transfection. Notably, CD16+ monocytes from patients with leukemia also exerted potent ADCC. Hence, CD16+ monocytes are important effectors of ADCC, suggesting further developments of this property in the context of cellular therapies for cancer and infectious diseases.

Multicenter study of comparative outcomes of hematopoietic stem cell transplant for peripheral T cell lymphoma and natural killer/T-cell lymphoma

Department of Haematology, Singapore General Hospital, Singapore, Duke-NUS Graduate Medical School, Singapore, Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, National Cancer Centre, Singapore, Department of Haematology, St George’s Hospital and Medical School, London, UK, Department of Clinical Research, Singapore General Hospital, Singapore, and Singapore Clinical Research Institute, Singapore

Methotrexate-induced myelopathy mimicking subacute combined degeneration of the spinal cord

Methotrexate (MTX), a folate antagonist, is widely used to treat hematological malignancies. Although it is known to cause myelopathy, little is known about the pathophysiology and natural history of this myelopathy. We describe a 42-year-old woman with acute lymphoblastic leukemia who was treated with chemotherapy consisting of intrathecal MTX who developed a progressive myelopathy. The myelopathy mimicked, radiologically, subacute combined degeneration (SACD) of the spinal cord. This myelopathy mimicking SACD could be explained by the folate antagonism of MTX. The progressive clinical signs and serial MRI in this patient further our understanding of the natural progression of this myelopathy.

Pre-transplant achievement of negativity in minimal residual disease and French–American–British L1 morphology predict superior outcome after allogeneic transplant for Philadelphia chromosome positive acute lymphoblastic leukemia: an analysis of Southeast Asian patients

Abstract To better understand predictive factors and improve the clinical outcome of allogeneic transplant for patients with Philadelphia positive acute lymphoblastic leukemia, we analyzed 67 Southeast Asian patients transplanted in our institutions. Multivariate analysis showed that disease status before transplant, year of transplant and, interestingly, French–American–British (FAB) subtype had a significant impact on overall survival (OS) and non-relapse mortality. Patients who were minimal residual disease (MRD) negative at transplant had a 3-year OS of 73% compared to those who were MRD positive (45%) and refractory (0%). The 3-year cumulative incidence of relapse was 18% and 36% for the MRD negative and positive groups, respectively. FAB L1 subtype had a significantly superior 3-year OS of 63% vs. 29% for L2 subtype. Pre-transplant use of a tyrosine kinase inhibitor significantly improved outcomes in univariate but not multivariate analysis, as it served to induce more patients into MRD negativity, which was the factor that directly improved transplant outcome.

Subcutaneous bortezomib combined with weekly cyclophosphamide and dexamethasone is an efficient and well tolerated regime in newly diagnosed multiple myeloma

Regimens that combine bortezomib and steroids with thalidomide, lenalidomide or cyclophosphamide have resulted in high response rates and are now considered standard treatments in newly diagnosed, transplant-eligible multiple myeloma (Reeder et al, 2009; Cavo et al, 2010; Richardson et al, 2010). The comparison between bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy is important given the significantly lower drug costs of these regimens compared to bortezomib-lenalidomide-dexamethasone (VRD). We aim to highlight certain aspects of the cyclophosphamide dosing and the route of administration of bortezomib that are crucial in the success of VCD as an upfront treatment regime for multiple myeloma. We read with interest the meta-analysis by Leiba et al (2014), which concluded that patients treated with VTD had significantly higher near complete or complete response (nCR/CR) (34% vs. 6%) and very good partial response (VGPR) or better (62% vs. 27%), compared to VCD-treated patients. Studies included in the VCD arm used heterogeneous regimens with different dosing of cyclophosphamide, and regimens using less cyclophosphamide led to lower CR rates, a point also noted by the authors (Leiba et al, 2014). In particular, support for a higher dosing of cyclophosphamide to deepen response comes from the EVOLUTION trial that achieved better nCR/CR (12% vs. 3%) and ≥ VGPR rates (41% vs. 13%) with an additional dose of cyclophosphamide (Kumar et al, 2012), albeit limited by the small sample size of 17 patients in the higher cyclophosphamide arm. In our institution in Singapore, we routinely use VCD treatment with a higher dosing of cyclophosphamide and subcutaneously administered bortezomib. We retrospectively analysed 46 transplant-eligible patients in our hospital with newly diagnosed symptomatic multiple myeloma who were initiated on VCD treatment (Table I). Treatment consisted of 28-d cycles of bortezomib, given subcutaneously at a concentration of 1 3 mg/m on days 1, 8, 15 and 22, oral cyclophosphamide at 500 mg on days 1, 8, 15and 22, and oral dexamethasone at 40 mg on days 1, 8, 15 and 22. All patients had prophylaxis with co-trimoxazole and acyclovir. The primary endpoint was the best response at the end of VCD therapy prior to transplant. The number of cycles used, and dose modification for haematological or non-haematological toxicities were at the discretion of the treating physician. Responses were assessed according to the International Myeloma Working Group (IMWG) criteria (Durie et al, 2006). Using the intensified regimen of VCD with additional cyclophosphamide and subcutaneous bortezomib led to high response rates with a favourable side-effect profile. 39% of Table I. Patient baseline characteristics and response.

Single center retrospective analysis of BU-based conditioning regimens in allogeneic transplantation

We performed a single institution retrospective analysis of 114 patients treated with BU-based pretransplant conditioning regimens. Oral BU was administered to 76 patients (total dose 16 mg/kg or 8 mg/kg) and i.v. BU to 38 others (total dose 12.8 mg/kg or 6.4 mg/kg). Either CY (n=74) or fludarabine (n=40) was given in combination with BU. Median age was 35 years in the oral BU group and 48.5 years with i.v. BU (P<0.001). OS and PFS rates at 3-years post HSCT were not different in patients who received either i.v. or oral BU (OS: 41.3 vs 44.0% (P=0.981); PFS: 52.7 vs 54.7% (P=0.526), respectively). The i.v. BU, however, was associated with a significantly shorter time to engraftment (13.5 days vs 16 days, respectively; P<0.001). There were no significant differences in survival or 100-day mortality for patients who received either CY or fludarabine, in combination with BU. After adjustment for confounders, multivariate analysis showed that age of transplant (P=0.002), donor type (sibling or unrelated; P=0.003), GVHD (P<0.05) and route of administration (P=0.023) were significant risk factors for OS. The i.v. BU used in an older age group yielded equivalent survival compared with oral BU used in a younger population.

Respiratory virus infection after allogeneic hematopoietic stem cell transplant in a tropical center: Predictive value of the immunodeficiency scoring index

Respiratory virus infection (RVI) is a prevalent infection in patients after allogeneic hematopoietic stem cell transplant (allo‐HSCT) and can result in significant morbidity and mortality. Ability to assess the potential severity of RVI is important in the management of such patients.

Long‐term renal outcome after allogeneic hemopoietic stem cell transplant: A comprehensive analysis of risk factors in an Asian patient population

Allogeneic hemopoietic stem cell transplantation (allo‐HSCT) poses a significant challenge to renal function due to multiple drug‐ and complication‐related renal toxicity. In this single‐center series of 216 adult Asian patients with a long and complete follow‐up, 41 developed chronic kidney disease (CKD) giving a cumulative incidence of 19.0% at 25 years (median follow‐up duration 7.84 years, range 2.0‐27.7 years), but only two of the 41 patients reached stage 4 CKD and another two required dialysis. In contrast, acute kidney injury occurred in most patients, where glomerular filtration rate (GFR) suffered a mean fall of 50 mL/min/1.73 m2 at 6 months post‐transplant compared with baseline. Suppression of renal function may last beyond 6 months but is potentially reversible, although not to baseline level in most patients. Analysis of a comprehensive range of 18 risk factors showed that older age, lower GFR at transplant, unrelated donor, diagnosis of AML, presence of diabetes mellitus at transplant, and duration of foscarnet use were significantly associated with CKD development, with the first three remaining as independent risks for CKD in multivariate analysis. Long‐term survival is not affected by renal function, being 78.6% as compared to 85.5% for patients with low vs normal GFR at 2 years, respectively.