Deok-Hwan Yang

Association between folate-metabolizing pathway polymorphism and non-Hodgkin lymphoma

Polymorphisms in the genes coding folate‐metabolizing enzymes affect the risk of some forms of cancer. We investigated the association between these polymorphisms and non‐Hodgkin lymphoma (NHL) risk in a population‐based study (583 cases and 1700 controls). The MTHFR 677TT and CT genotypes were associated with reduced risk for NHL [odds ratios (OR) = 0·79; 95% confidence intervals (CI) = 0·65–0·98 for 677CT and 0·61; 0·45–0·82 for 677TT] and diffuse large B‐cell lymphoma (DLBCL) (OR = 0·68; 0·51–0·88 for 677CT; OR = 0·56; 0·38–0·83 for 677TT). The MTHFR 1298CC genotype was associated with increased risk for NHL (OR = 1·71; 1·07–2·75) and T‐cell lymphoma (OR = 3·05; 1·53‐6·11). The MTRR 66GG genotype was associated with increased risk for DLBCL (OR = 1·56; 1·03‐2·38) and the TYMS 2R2R genotype was associated with increased risk for T‐cell lymphoma (OR = 2·83; 1·33–6·01). Using subjects with 3RG3RG as a reference group, TYMS 2R2R was associated with increased risk for T‐cell lymphoma (OR = 2·46; 1·04–5·79). Interestingly, we observed a reduced association between the TYMS 2R3RG genotype and DLBCL (OR = 0·61; 0·38–0·99). These results suggest that MTHFR, MTRR and TYMS polymorphisms may play a significant role in the risk for NHL.

Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies

Several genetic polymorphisms in the genes coding folate-metabolizing enzymes have been associated with susceptibility to hematology malignancies. We conducted a Korean population-based case-control study to examine the relationship between the polymorphisms of folate-metabolizing enzymes and the risk of AML (acute myelogenous leukemia), CML (chronic myelogenous leukemia), MDS (myelodyspastic syndrome), and ALL (acute lymphoblastc leukemia). The MTHFR 677TT genotype was associated with an increased risk for ALL (odds ratios (OR)=1.77; 95% confidence intervals (CI)=1.02-3.09, p=.044). The MTRR 66 AG genotype was associated with an increased risk for MDS (OR=1.59; 1.06-2.38, p=.026) and the MTRR 66 GG genotype was associated with increased risk for AML (OR=1.51; 1.03-2.23, p=.037). The TYMS 2R3R genotype was associated with a decreased risk for AML (OR=0.76; 0.60-0.96, p=.022). The TYMS hap3 (2R-6bp) and hap4 (2R-0bp) were associated with decreased risk (OR=0.69; 0.53-0.90, p=.006) and increased risk (OR=1.65; 1.20-2.27, p=.002), respectively for AML. Hap C (677T-1298A) was associated with an increased risk (OR=1.40; 1.02-1.92, p=.04) for ALL. The risk for ALL appears to be associated with the MTHFR 677 polymorphism. The results are supportive of a risk modification by folate polymorphisms in several hematologic malignancies in Korea. The pattern of results suggests that MDS was associated with the DNA methylation status and the risk for AML was associated with both the DNA synthesis and DNA methylation status.

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation : comparison with BuCy2

A regimen of busulfan and cyclophosphamide (BuCy2) is regarded as the standard myeloablative regimen for SCT. This study evaluated the hypothesis that fludarabine can replace cyclophosphamide for myeloablative allogeneic SCT. Ninety-five patients underwent allogeneic SCT from HLA-identical donors, following BuCy2 (n=55) or busulfan+fludarabine (BF, n=40). The efficacy of fludarabine compared to cyclophosphamide was retrospectively evaluated. The BF group exhibited a shorter duration until engraftment (P=0.001), lower incidence of acute and chronic GVHD (P<0.001 and P=0.003, respectively), and non-relapse mortality (NRM) (P=0.039). Furthermore, the event-free survival and overall survival were significantly higher for the BF group compared to the BuCy2 group (P=0.004 and 0.002, respectively). After adjusting for age, the risk status of disease, GVHD prophylaxis and donor type, the BF regimen was found to be an independent favorable risk factor for event-free survival (hazard ratio (HR), 0.181; 95% confidence interval, 0.045–0.720; P=0.016) and overall survival (HR, 0.168; 0.035–0.807; P=0.026). The replacement of cyclophosphamide with fludarabine for myeloablative conditioning seems to be more effective in terms of short-term NRM, and GVHD compared to BuCy2 regimen in allogeneic transplantation.

Prognostic significance of interim 18F-FDG PET/CT after three or four cycles of R-CHOP chemotherapy in the treatment of diffuse large B-cell lymphoma

PURPOSE (18)F-fluoro-2-dexoy-D-glucose-positron emission tomography (FDG-PET)/computerised tomography (CT) has been used for staging and monitoring responses to treatment in patients with diffuse large B cell lymphoma (DLBCL). The sequential interim PET/CT was prospectively investigated to determine whether it provided additional prognostic information and could be a positive predictable value within patients with the same international prognostic index (IPI) after the use of rituximab in DLBCL. METHODS One hundred and sixty-one patients with newly diagnosed DLBCL were enroled; the assessment of the PET/CT was performed at the time of diagnosis and mid-treatment of rituxibmab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). RESULTS Sixty-seven patients (41.6%) presented with advanced stage disease and 27 (16.8%) had bulky lesions. Forty-three patients (26.7%) continued to have positive metabolic uptakes with a significantly high relapse rate (62.8%) compared to the patients with a negative interim PET/CT (12.1%) (P<0.01). After a median follow-up of 30.8months, the positivity of interim PET/CT was found to be a prognostic factor for both overall survival (OS) and progression-free survival (PFS), with a hazard ratio of 4.07 (2.62-6.32) and 5.46 (3.49-8.52), respectively. In the low-risk IPI group, the 3-year OS and PFS rates were significantly different in the patients with positive (53.3% and 52.5%) and negative (93.8% and 88.3%) interim PET/CT, respectively (P<0.01). These significant prognostic differences of interim PET/CT responses were consistent with the results of the patients with high-risk IPI group (P<0.01). CONCLUSIONS Interim PET/CT scanning had a significant predictive value for disease progression and survival of DLBCL in post-rituximab treatment; it might be the single most important determinant of clinical outcome in patients with the same IPI risk.

The dysfunction and abnormal signaling pathway of dendritic cells loaded by tumor antigen can be overcome by neutralizing VEGF in multiple myeloma

We investigated whether dendritic cells (DCs) from multiple myeloma (MM) patients were affected by loading tumor antigens and whether the defective DC function associated with MM could be overcome by the neutralization of VEGF. MM-specific DCs were generated by loading tumor lysates from myeloma cells at diagnosis or relapsed/progressive state, respectively. DCs loaded with tumor lysates showed lower phenotypic maturation, less T cell stimulatory capacity, less cytotoxic T lymphocyte activities, and highly abnormal cytokine secretions of IL-6 and IL-12, compared to myeloma lysate-unloaded DCs. The levels of VEGF, phospho-STAT3 and phospho-ERK1/2 in DCs were significantly higher with loading myeloma lysates. After the neutralization of VEGF activity, the DC function, signal transduction and cytokine production returned to normal. The defective function of DC in patients with MM is significantly affected by loading tumor antigens, correlating with abnormal STAT3 and the NF-kappaB signaling pathway, and neutralization of VEGF can overcome this DC dysfunction through the elimination of abnormal signal transduction.

Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia

We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10(-3) and MR5 for ratios <10(-5). Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.

Induction of multiple myeloma-specific cytotoxic T lymphocyte stimulation by dendritic cell pulsing with purified and optimized myeloma cell lysates

We investigated the possibility of immunotherapy for multiple myeloma (MM) using myeloma-specific cytotoxic T lymphocytes (CTLs) that were stimulated in vitro by dendritic cells (DCs) pulsing with purified and optimized myeloma lysates. CD14+ cells were cultured in the presence of GM-CSF and IL-4. On day 6, the immature DCs were pulsed with the purified myeloma cell lysates, and then maturation of the DCs was induced by the addition of a cytokine cocktail. There were no differences in the phenotypic expressions of mature DCs that were generated by pulsing with CD138+ cell lysates or total cell lysates. In optimization of the concentration of myeloma lysates, DCs pulsed with 10 µg/mL of myeloma lysate had greater allogeneic T-cell stimulatory capacities than those pulsed with higher concentrations of myeloma lysates. The CTL lines generated by DCs pulsed with myeloma lysates demonstrated potent cytotoxic activities against autologous target cells, but not against HLA-A2− cell lines or K562 cell lines. The DCs pulsed with myeloma lysates demonstrated a higher stimulatory capacity for autologous CTL compared with mature nonpulsed DCs. These results suggested that the DCs pulsed with purified and optimized myeloma cell lysates could generate potent myeloma-specific CTLs for approaches in MM.

Type I and II interferons enhance dendritic cell maturation and migration capacity by regulating CD38 and CD74 that have synergistic effects with TLR agonists

The major limitation for the maturation of dendritic cells (DCs) using Toll-like receptor (TLR) agonists is their decreased ability to migrate into lymph nodes compared with conventional DCs. CD38 can be used as a multifunctional marker to modulate migration, survival and Th1 responses of DCs. CD74 has been shown to negatively regulate DC migration. The goal of this study was to investigate the combinations of TLR agonists and interferons (IFNs) that most effectively regulate CD38 and CD74 expression on DCs. Synergistic TLR agonist stimulation in combination with IFN-α and IFN-γ was the best method for regulating CD38 and CD74 expression and inducing the highest secretion of IL-12p70. An in vitro migration assay showed that DCs treated with this combination had significantly enhanced migratory ability, similar to that observed in cells expressing CD38, CD74 and CCR7. The results of this study suggest that an alternative maturation protocol in which two TLR ligands are combined with type I and II IFNs generates potent DCs that have both a high migratory capacity and high IL-12p70 production.

Treatment Outcomes with CHOP Chemotherapy in Adult Patients with Hemophagocytic Lymphohistiocytosis

The objective of the current study was to investigate the treatment outcomes for the use of cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) chemotherapy in adult patients with hemophagocytic lymphohistiocytosis (HLH). Seventeen HLH patients older than 18 yr of age were treated with CHOP chemotherapy. A response evaluation was conducted for every two cycles of chemotherapy. With CHOP chemotherapy, complete response was achieved for 7/17 patients (41.2%), a partial response for 3/17 patients (17.6%), and the overall response rate was 58.8%. The median response duration (RD) was not reached and the 2-yr RD rate was 68.6%, with a median follow-up of 100 weeks. Median overall survival (OS) was 18 weeks (95% CI, 6-30 weeks) and the 2-yr OS rate was 43.9%. Reported grade 3 or 4 non-hematological toxicities were increased serum liver enzyme levels and stomatitis. Grade 3 or 4 hematological toxicities were leukopenia (50.8%), anemia (20%), and thrombocytopenia (33.9%). Neutropenic fever was observed in 21.6% of patients (14/65 cycles), and most of the cases were resolved with supportive care including treatment with broad-spectrum antibiotics. CHOP chemotherapy seems to be effective in adult HLH patients and the toxicities are manageable.

Clinical outcome of elderly patients with Epstein–Barr virus positive diffuse large B-cell lymphoma treated with a combination of rituximab and CHOP chemotherapy

Several studies have suggested the possibility of a prognostic relationship between Epstein–Barr virus (EBV) and diffuse large B‐cell lymphoma (DLBCL). The clinical outcome of EBV‐associated DLBCL is not clear, especially since the introduction of rituximab. We retrospectively analyzed 222 elderly patients (≥50 years) with DLBCL who received R‐CHOP chemotherapy and evaluated the state of EBV‐encoded RNA‐1 (EBER). Eighteen cases (8.1%) were EBER‐positive (+). After a median of six cycles of R‐CHOP chemotherapy, the response rate (≥partial response) was 72.2% (13/18) in the EBV (+) patients and 90.2% (184/204) in the EBV (−) DLBCL patients (P = 0.021). Four of 18 (22.2%) EBV (+) DLBCL patients received two or fewer cycles of R‐CHOP chemotherapy. R‐CHOP chemotherapy was also interrupted early more frequently compared with the EBV (−) group (2.5%) (P = 0.00). At a median follow‐up of 32.8 months, there was no significant difference in the overall survival between the groups (P = 0.627). The EBV (+) DLBCL patients with early interruption of R‐CHOP chemotherapy showed a trend toward a high EBV‐DNA titer (≥1,000 copies/mL) (P = 0.091). The results suggest that the EBV (+) tumoral status of elderly DLBCL patients who undergo R‐CHOP chemotherapy does not predict their survival but that their EBV status may contribute to the early interruption of R‐CHOP chemotherapy. Am. J. Hematol. 88:774–779, 2013.