Michio Sawada

Prevalence of hepatitis B and C virus infection in haematological malignancies and liver injury following chemotherapy

Abstract:  The aim of this study was to determine the carrier rate of hepatitis virus in patients with haematological malignancies and the incidence of liver injury in these patients following chemotherapy. From January 1996 to September 2002, we studied 601 consecutive, unselected series of patients with haematological malignancies admitted in our hospital unit (Japan). They consisted of 246 cases of acute leukaemia, 218 non‐Hodgkins lymphoma (NHL), 13 adult T‐cell leukaemia, and 124 multiple myeloma. Of these 601 patients, 373 were men and 228 were women; their mean age was 61 yr, with a range from 18 to 89 yr. The prevalences of hepatitis B virus (HBV) and hepatitis C virus (HCV) were 7.3% and 10.1%, respectively, in NHL, both higher than those in acute leukaemia (1.7% and 2.9%, P < 0.005) and in general Japanese population (1.2% and 2.6%). The incidence of post‐chemotherapy liver injury in 25 HBV carriers (36.0%) was significantly higher than that in 539 non‐hepatitis virus carriers (12.6%, P = 0.003) and 37 HCV carriers (10.8%, P = 0.026). Liver injury in HBV carriers was more often present in patients who had been treated with steroids than in those without steroids (72.7% and 0%, P = 0.013). After lamivudine became available in our institution, the incidence of liver injury in HBV carriers was reduced from 53.3% to 10.0% (P = 0.041). The therapeutic strategy for haematological malignancies in hepatitis virus carriers should be further investigated.

Serum-Soluble Fas Level Determines Clinical Symptoms and Outcome of Patients With Aggressive Non-Hodgkin's Lymphoma

Soluble Fas (sFas) blocks apoptosis induced by Fas ligand in vitro. The serum concentration of sFas is elevated in lympho‐proliferative diseases. We hypothesized that higher levels of sFas worsen the clinical symptoms and outcome of patients with aggressive non‐Hodgkins lymphoma (NHL). We prospectively measured the serum concentrations of sFas in 67 consecutive patients with aggressive NHL (59 with diffuse large cell lymphoma and 8 with diffuse small cleaved cell lymphoma). sFas was significantly elevated in patients with aggressive NHL compared to healthy controls (N = 36, P< 0.005), while sFas in patients with B symptoms (4.20 ± 2.12 μg/l) was significantly higher than in those without B symptoms (2.66 ± 1.08 μg/l, P < 0.005). No significant difference was observed between B‐cell lymphoma and T‐cell lymphoma or between patients with clinical stage I or II and those with clinical stage III or IV. Significant correlations were found between sFas concentration and both soluble interleukin‐2 receptor (R = 0.400, P < 0.001) and C‐reactive protein (R = 0.340, P < 0.01) levels in patients with aggressive NHL. No correlation was observed between sFas and either white blood cell count or lactate dehydrogenase. Generalized Wilcoxon analysis revealed that NHL patients with sFas less than 4 μg/l had better overall survival than those with sFas above 4 μg/l (P < 0.001). The serum concentration of sFas might be associated with clinical symptoms and the prognosis of patients with aggressive NHL. Am. J. Hematol. 64:257–261, 2000.

A prospective study of P‐IMVP‐16/CBDCA: a novel salvage chemotherapy for patients with aggressive non‐Hodgkin's lymphoma who had previously received CHOP therapy as first‐line chemotherapy

Abstract:  The purpose of this study was to determine the efficacy of salvage chemotherapy with, P‐IMVP‐16/CBDCA, consisting of carboplatin (CBDCA), etoposide (VP‐16), ifosfamide (IFM), and methotrexate (MTX), for patients with aggressive non‐Hodgkins lymphoma (NHL) who had previously received CHOP [a regimen of cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), and prednisolone], as first‐line chemotherapy. The 45 consecutively enrolled patients received methylprednisolone (mPSL) 1000 mg per body for 3 d (from day 1 to day 3), IFM 1000 mg/m2 for 5 d (from day 1 to day 5), MTX 30 mg/m2 on day 3 and day 10, VP‐16 80 mg/m2 for 3 d (from day 1 to day 3), and CBDCA 300 mg/m2 on day 1, with granulocyte colony‐stimulating factor every 21 d. Patients 70 yr of age or older were given 75% of the standard dose. The response rate [complete response (CR) plus partial response (PR)] was 55.6% (25/45), including 12 (26.7%) CR and 13 (28.9%) PR. The overall survival rate for the 45 patients was 31.1% at 1 yr and 17.3% at 2 yr. The failure‐free survival rate for the 45 patients was 6.7% at 1 yr and 4.4% at 2 yr. The survival rate for the 25 responders was 48.0% at 1 yr and 24.0% at 2 yr, and the survival rate for the 20 non‐responders was 10.0% at 1 yr (P<0.001). Multivariate analysis demonstrated that prior chemotherapy (reduced‐dose CHOP for age 70 yr or older) and the number of cases of extranodal involvement (>1) were significant unfavorable factors for overall survival. Although the major toxicity was neutropenia, no patient died of infection related to neutropenia. Non‐hematological adverse effects were predominantly mild and tolerable. Unfortunately, the clinical outcome with P‐IMVP‐16/CBDCA was unfavorable, possibly because the study comprised consecutive patients who had received identified intensive chemotherapy, such as biweekly CHOP. Salvage chemotherapy with P‐IMVP‐16/CBDCA is not sufficient to cure relapsed or refractory aggressive NHL. Aggressive NHL should be cured by first‐line chemotherapy with or without hematopoietic stem cell transplantation.

Serum‐soluble tumor necrosis factor receptor 2 (sTNF‐R2) level determines clinical outcome in patients with aggressive non‐Hodgkin's lymphoma

Abstract:  Background: Recently investigators have worked to identify prognostic factors in non‐Hodgkins lymphoma (NHL) so an appropriate therapeutic plan can be put in action. The aim of the present study was to assess the prognostic significance of serum soluble tumor necrosis factor receptor (sTNF‐R) 2 in aggressive NHL. Methods: One hundred and ten consecutive patients with aggressive NHL who were previously untreated (diffuse large B‐cell lymphoma; 94, peripheral T‐cell lymphoma; 16) were prospectively enrolled in this study between 1997 and 2002. The patients were treated with 6–8 cycles of CHOP or THP‐COP regimens. Results: High serum sTNF‐Rs level was associated with some poor prognostic factors and low complete remission rate. Patients with high sTNF‐R1 (4 ng/mL and over) and sTNF‐R2 (15 ng/mL and over) at onset had significantly lower survival rates (5 yr: 19%, 19%) than those with low sTNF‐R1 (under 4 ng/mL) and sTNF‐R2 (under 15 ng/mL) (62% and 69%), respectively (P < 0.0005 and 0.0001). Multivariate analysis employing sTNF‐R2 and some conventional prognostic factors demonstrated that a combination of sTNF‐R2 and performance status, and that of sTNF‐R2, sIL‐2R, and LDH were significant prognostic factors for poor overall survival and for poor event‐free survival, respectively. In addition, we attempted to use sTNF‐R2 in combination with the international prognostic index (IPI). The patients in the high risk group and those with high sTNF‐R2 in the low‐intermediate (LI)/high‐intermediate (HI) risk group had significantly lower survival rates than the patients in the low risk group and those with low sTNF‐R2 in LI/HI risk group (P < 0.0001). Conclusions: The results suggest that a high serum sTNF‐R2 level predicts a poor prognosis in aggressive NHL and may be a useful biomarker for selecting appropriate treatment when used in combination with the IPI.

Phase II study of the tetrahydropyranyl adriamycin–cyclophosphamide, vincristine, and prednisolone regimen combined with rituximab as first-line treatment for elderly patients with diffuse large B-cell lymphoma

The anthracycline drug pirarubicin (tetrahydropyranyl adriamycin; THP) apparently has fewer cardiotoxic effects than doxorubicin. We previously described the benefit of the THP-COP regimen comprising cyclophosphamide, THP, vincristine, and prednisolone for elderly patients with diffuse large B-cell lymphoma (DLBCL). However, that study was completed before rituximab (R) was introduced into clinical practice. Here we report a phase II study of the THP-COP regimen combined with R (R-THP-COP) every 3 weeks. The complete response and 3-year overall survival rates was 63% and 53%, respectively, and no deaths were related to the regimen. We conclude that the R-THP-COP regimen is safe and effective for patients with DLBCL. Based on these results, a randomized controlled trial of rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and R-THP-COP as a phase III study is ongoing.

Fas and Fas ligand expression on germinal center type-diffuse large B-cell lymphoma is associated with the clinical outcome

Abstract:  In recent years, diffuse large B‐cell lymphoma (DLBCL) has been classified by DNA microarray analysis into the germinal center B‐cell‐like (GC) type, the activated B‐cell‐like (ABC) type and type 3. The latter two types can be collectively categorized as the non‐GC (NGC) type. From the prognostic perspective, the GC type has a favorable clinical outcome when compared with the NGC type. The protein Fas induces apoptosis of lymphocytes by binding with the Fas ligand (FasL), and escape from such apoptosis is considered to lead to malignant transformation of the cells and unrestricted growth of lymphoma. We proposed a hypothesis that Fas/FasL expression could be possibly related with a better survival of GC type DLBCL and evaluated 69 DLBCL cases immunohistochemically with CD10, Bcl‐6, MUM1, Fas and FasL. These lymphomas were classified as GC type (positive for CD10 or Bcl‐6 and negative for MUM1) or NGC type. The GC type had a better overall survival rate than the NGC type (P = 0.0723). Among markers as given above, positive CD10 was the most significant prognostic factor for overall survival in total DLBCL (P < 0.05). In the GC type, Fas and FasL expressions were significantly associated with a favorable overall survival (Fas: P < 0.005; FasL: P < 0.05). Hence, Fas or FasL expression might contribute to a better prognosis of this type of DLBCL.

Phase II study of Rituximab combined with THP-COP as first-line therapy for patients younger than 70 years with diffuse large B cell lymphoma

IntroductionWe previously described the effectiveness of the THP-COP regimen comprising cyclophosphamide, pirarubicin (tetrahydropyranyl adriamycin; THP), vincristine and prednisolone in patients with diffuse large B-cell lymphoma (DLBCL). The anthracycline drug THP was apparently less cardiotoxic than doxorubicin. However, that study was completed before rituximab was introduced into clinical practice. We conducted a phase II study to determine the effectiveness of a regimen incorporating rituximab (R-THP-COP) against DLBCL.PatientsSix to 8 courses of the regimen were administered every 2 weeks in 48 patients who were younger than 70 years.ResultsThe complete remission rate was 92%, the 3-year overall survival rate was 83% and 3-year progression free survival rate was 74%. No deaths were associated with the treatment regimen.ConclusionWe conclude that R-THP-COP regimen is very effective against DLBCL. The results of our study urge randomized trials of R-CHOP and R-THP-COP among patients with CD20+ DLBCL.

Serum interleukin‐18 level is associated with the outcome of patients with diffuse large B‐cell lymphoma treated with CHOP or R‐CHOP regimens

Background:  We have previously reported that serum interleukin‐18 (IL‐18) concentration predicted the clinical outcome of patients with aggressive non‐Hodgkin’s lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). When rituximab (R) was added to this regimen, the prognosis of diffuse large B‐cell lymphoma (DLBCL) was markedly improved.

Hypoplastic myelodysplastic syndromes can be distinguished from acquired aplastic anaemia by bone marrow stem cell expression of the tumour necrosis factor receptor

Summary. It is often difficult to distinguish hypoplastic myelodysplastic syndrome (h‐MDS) from acquired aplastic anaemia (AA), because of the considerable clinical, cytological and histological similarities between these two disorders. The distinction between AA and h‐MDS is important because there is a higher risk of progression to acute leukaemia in patients with h‐MDS compared with AA. Recent studies suggest that tumour necrosis factor‐alpha (TNF‐α) plays an important role in the development of AA. In order to determine the potential importance of TNF‐α in the differential diagnosis of hypoplastic bone marrow (BM) disorders, we examined whether analysis ofTNF‐receptor expression could be used as a tool to differentiate AA from h‐MDS. Flow cytometric analysis revealed that BM stem cells (CD34+) from AA patients have markedly greater TNF receptor (R) 1 and TNFR2 expression than those from patients with MDS and h‐MDS. We suggest that the BM stem cells with a high expression of TNFR in patients with AA may be potently sensitive to TNF‐α stimulation of differentiation. Thus, we propose that quantification of TNFR expression in BM stem cellsmay be a useful method to distinguish AA from h‐MDS.

Serum soluble CD27 level is associated with outcome in patients with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone

Abstract Since the introduction of rituximab (R), the prognosis for diffuse large B-cell lymphoma (DLBCL) has markedly improved. We evaluated the prognostic significance of serum soluble CD27 (sCD27) in 143 patients with DLBCL treated with cyclophosphamide, doxorubicin, vincristine and prednisolone plus rituximab (R-CHOP). Five-year overall survival rates for patients with sCD27≥213 U/mL or <213 U/mL were 38.7% and 76.8%, respectively (p =0.0005). Multivariate analysis revealed that serum sCD27 was significantly correlated with OS (p =0.047). Immunohistochemical staining for CD27 in lymphoma tissues revealed positive lymphoma cells in 22 cases (18.5%) and positive microenvironment T-cells in 62 cases (52.1%) and was negative in the remaining patients. In these three subgroups, median sCD27 levels were 336 U/mL, 242.6 U/mL and 109.9 U/mL, respectively (p =0.004). Thus, serum sCD27 level is associated with CD27 expression on lymphoma cells, and may be a powerful prognostic factor for DLBCL.