Liang-Tsai Hsiao

Randomized Controlled Trial of Entecavir Prophylaxis for Rituximab-Associated Hepatitis B Virus Reactivation in Patients With Lymphoma and Resolved Hepatitis B

PURPOSE The role of antiviral prophylaxis in preventing hepatitis B virus (HBV) reactivation before rituximab-based chemotherapy in patients with lymphoma and resolved hepatitis B is unclear. PATIENTS AND METHODS Eighty patients with CD20(+) lymphoma and resolved hepatitis B were randomly assigned to receive either prophylactic entecavir (ETV) before chemotherapy to 3 months after completing chemotherapy (ETV prophylactic group, n = 41) or to receive therapeutic ETV at the time of HBV reactivation and hepatitis B surface antigen (HBsAg) reverse seroconversion since chemotherapy (control group, n = 39). RESULTS Fifty-eight patients (72.5%) were positive for hepatitis B surface antibody, and HBV DNA was undetectable in 50 patients (62.5%). During a mean 18-month follow-up period, one patient (2.4%) in the ETV prophylactic group and seven patients (17.9%) in the control group developed HBV reactivation (P = .027). The cumulative HBV reactivation rates at months 6, 12, and 18 after chemotherapy were 8%, 11.2%, and 25.9%, respectively, in the control group, and 0%, 0%, and 4.3% in the ETV prophylactic group (P = .019). Four patients (50%) in the control group had HBsAg reverse seroconversion after HBV reactivation. The cumulative HBsAg reverse seroconversion rates at months 6, 12, and 18 since chemotherapy were 0%, 6.4%, and 16.3% in the control group, respectively, which were significantly higher than those in the ETV prophylactic group (P = .032). Patients with detectable or undetectable viral load could develop HBV reactivation and HBsAg reverse seroconversion. CONCLUSION Undetectable HBV viral load before chemotherapy did not confer reactivation-free status. Antiviral prophylaxis can potentially prevent rituximab-associated HBV reactivation in patients with lymphoma and resolved hepatitis B.

Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma

Background:Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.Methods:Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg–1 on day 1 and capecitabine 800 mg m–2 twice daily on days 1–14 every 3 weeks as first-line therapy.Results:A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.Conclusion:The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.

Stevens-Johnson syndrome after treatment with STI571: a case report.

Summary.  Between seven and 21% of patients treated with the specific tyrosine kinase inhibitor STI571 have been reported to develop mild‐to‐moderate severity of adverse cutaneous reactions. We report a patient in the blast crisis phase of chronic myeloid leukaemia who developed a life‐threatening cutaneous reaction, Stevens–Johnson syndrome, following 1 week of STI571 therapy. This report may serve to remind the clinician about the possible severe cutaneous side‐effects of STI571 before instituting more extensive clinical application of this agent in the future.

High prevalence of occult hepatitis B virus infection in patients with B cell non-Hodgkin’s lymphoma

Several reports recently found that patients with B cell non-Hodgkin’s lymphoma (NHL) had a higher carrier rate of hepatitis B surface antigen (HBsAg). The current study aimed to examine the hepatitis B virus (HBV) infection status of NHL patients in Taiwan, an HBV-endemic area. Serum HBV and serum hepatitis C virus were measured in 471 NHL patients and 1,013 non-lymphoma cancer patients enrolled between February 2000 and March 2007. Furthermore, nested polymerase chain reaction of HBV-DNA was used to examine the sera from selected patients in these two populations and healthy volunteers for the presence of occult HBV infection. The infection rates (as indicated by the rates of HBsAg and occult HBV) were compared between different groups. There was a higher incidence of HBV infection in B cell NHL patients (23.5%), especially patients with diffuse large B lymphoma, than solid tumor patients (15.6%, P = 0.001). Among HbsAg-negative patients, those with B cell NHL had a higher prevalence of occult HBV infection (6%) than those with non-lymphoma solid tumors and healthy volunteers, 0% and 0.9%, respectively (P = 0.005). B cell NHL patients, even HBsAg-negative B cell NHL patients, but not T cell NHL patients, have a higher incidence of HBV infection than patients with solid tumors. Our findings support the etiologic role of HBV infection in B cell NHL.

Fatal Fulminant Hepatitis B after Withdrawal of Prophylactic Lamivudine in Hematopoietic Stem Cell Transplantation Patients

Hepatitis B virus (HBV) reactivation can give rise to acute hepatitis and even fatal fulminant hepatitis in patients receiving immunosuppressive or cytostatic treatment. Recently, the prophylactic use of lamivudine for HBV reactivation in HBV surface antigen-positive chronic-disease patients undergoing hematopoietic stem cell transplantation (HSCT) has been reported. However, the appropriate duration for this prophylactic therapy is unclear. Here, we report 2 cases of fatal fulminant hepatitis B reactivation in HSCT patients after lamivudine withdrawal. One patient with non-Hodgkin’s lymphoma completed 6 courses of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone) and autologous peripheral blood SCT (PBSCT). Lamivudine was discontinued 3 months after transplantation. The second patient had acute myeloid leukemia. He received induction chemotherapy and postremission allogeneic PBSCT as late intensified consolidation therapy. Lamivudine treatment was discontinued 10 months after transplantation. In both patients, HBV reactivation 2 to 3 months following lamivudine cessation led to fatal fulminant hepatitis. We suggest that the duration of prophylactic use of lamivudine in chronic HBV carriers receiving HSCT be prolonged until the patient’s immune system has been reconstituted.

Low absolute lymphocyte count and addition of rituximab confer high risk for interstitial pneumonia in patients with diffuse large B-cell lymphoma

Several small-scale studies have reported pulmonary toxicity among patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-containing chemotherapy, though whether the use of rituximab predisposes to interstitial pneumonia (IP) remains unclear. This retrospective study was intended to identify the characteristics and risk factors of IP in patients with DLBCL. Between 2000 and 2009, 529 consecutive patients with DLBCL receiving first-line tri-weekly COP- or CHOP-based chemotherapy with or without rituximab were enrolled as subjects. IP was defined as diffuse pulmonary interstitial infiltrates found on computed tomography scans in conjunction with respiratory symptoms. IP was observed in 26 patients (4.9%), six of whom were confirmed with Pneumocystis jirovecii pneumonia. The median number of chemotherapy courses before IP was four cycles. Using multivariate analysis, absolute lymphocyte count less than 1 × 109/l at diagnosis [odds ratio (OR) 2.75, p = 0.014] and the addition of rituximab to chemotherapy (OR 4.56, p = 0.003) were identified as independent risk factors for IP. In conclusion, the incidence of IP is increased in patients with DLBCL receiving rituximab-containing chemotherapy. Specific subgroups with lymphopenia at diagnosis may justify close scrutiny to detect pulmonary complications.

Detection of reactivation and genetic mutations of the hepatitis B virus in patients with chronic hepatitis B infections receiving hematopoietic stem cell transplantation.

Background. This study elucidates the profiles for hepatitis B virus (HBV) reactivation and genetic mutation of the core promoter and precore regions for HBV-carriers receiving hematopoietic stem cell transplantation (HSCT). Methods. Sera from 20 HSCT patients diagnosed with hematological diseases, 13 donors and 36 healthy HBV-carriers, were collected regularly for analysis. The hepatic biochemistry profiles, serological HBV markers, and HBV-DNA titers were checked regularly, and primer-amplification of the HBV core promoter or precore region and sequencing were performed once the mutations were identified. Results. Deteriorated liver function was demonstrated for 13 of 20 post-HSCT patients, compared with none of the 36 controls (P <0.01). The HBV-DNA was detected more frequently for post-HSCT subjects than for controls (P =0.001). Incidence of the HBV precore nucleotide 1896 G-to-A mutation was significantly higher for HSCT patients (P =0.004), and a significant association was demonstrated for carriage of core promoter or precore mutations and the development of hepatitis (P =0.015). Different HBV genotypes were revealed in post-HSCT patients and the respective donors. Conclusions. Intensive chemotherapy and immunosuppression may cause HBV reactivation in HBV carriers receiving HSCT, and more frequent core promoter or precore mutations could be detected in HBV carriers receiving HSCT than healthy HBV carriers, with the chemotherapy/immunosuppression-induced immunocompromise possibly contributing to this effect. Donor HBV genotype did not interfere with that of the recipient after HSCT. Core promoter or precore region mutations were associated with a higher incidence of liver dysfunction than wild-type HBV carriers in the HSCT patients.

High serum hepatocyte growth factor level in patients with non-Hodgkin's lymphoma

Abstract: Higher pretreatment serum hepatocyte growth factor (HGF) levels were observed in patients with multiple myeloma and Hodgkins disease, but not in those with non‐Hodgkins lymphoma (NHL). We examined patients’ serum levels at diagnosis using enzyme‐linked immunosorbent assay and histological expression of HGF in pathological specimens of lymphoma, in relation to clinical features. The subjects were 77 NHL patients and 40 healthy controls. The serum levels of HGF in NHL patients at diagnosis were significantly higher than those in healthy controls (median 1019 vs. 689 pg/mL, P < 0.001). At diagnosis, patients with more than two sites of extranodal involvement (P = 0.001), higher scores of international prognostic index (P = 0.015), and advanced Ann Arbor stage (P = 0.023) had a higher level of serum HGF. Although the association of pretreatment serum HGF level and survival was not significant, a correlation of serial change of serum HGF levels with treatment response was found in limited cases. Furthermore, HGF expression of lymphoma tissues was shown in 18 of 24 (75%) different NHL subtypes, including most of the diffuse large B cell lymphoma (12 of 15, 80%). In conclusion, our study showed higher pretreatment serum HGF levels in NHL patients, which was related to clinical features; and the serial change of HGF seemed to parallel the treatment response. The pathogenic role of HGF in NHL patients was further highlighted by a modest expression of HGF in most of the diffuse large B cell lymphoma.

Overexpression of cyclin D1 in accelerated-phase chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a bi- or triphasic disease. Molecular markers distinct for the phase evolution would be clinically helpful. For signaling transformation and proliferation activities in CML, Bcr-Abl is the pivotal protein. As downstream signals of Bcr-Abl, RAS, PI3-K, and Stat 5 may lead to cell cycle progression mediated by increased expression of cyclin Ds. We analyzed copy numbers of bcr-abl and cyclin D1 transcripts by reverse transcription (RT) and competitive PCR titration in bone marrow cells of 20 patients with CML, 10 in chronic phase (CP) and the other 10 in accelerated phase (AP). The level of bcr-abl transcripts in the AP was not significantly higher than that in the CP; in contrast, the level of cyclin D1 transcripts in the AP was significantly higher than that in the CP (p < 0.001). Cyclin D1 RNA expression in the CP of CML was also found to have clinical relevance to time to AP transformation. The median time to AP transformation for the CP patients with cyclin D1 transcripts of ⩾̸ 1.50 × 104/μg RNA was significantly shorter than that for those with cyclin D1 transcripts < 1.50 × 104/μg RNA (15 vs. 67 months, p = 0.0354) although confirmation to conduct in a larger patient group is required. These results suggest that the expression level of cyclin D1 RNA in bone marrow cells is predictive of the phase evolution in CML and may be helpful in treatment decision-making.

Sustained remission and long-term survival of secondary central nervous system involvement by aggressive B-cell lymphoma after combination treatment of systemic high-dose chemotherapy and intrathecal rituximab

In the era of targeted anti-cancer treatment, chemotherapy plus intravenous rituximab significantly improves the treatment response and survival of elderly patients with aggressive B-cell lymphoma [1]. However, the administration of rituximab does not alter the incidence of central nervous system (CNS) recurrence, which, on the basis of recent studies, has been reported to be up to 5% [2]. The CNS relapse occurs in the forms of leptomeningeal involvement or isolated parenchymal involvement, and sometimes both. Managing this secondary CNS involvement remains a great challenge; in particular, elderly patients who have manifestation of leptomeningeal relapse on therapy or after achieving a complete remission usually carry a dismal prognosis [3]. Highdose methotrexate (HD-MTX) based systemic chemotherapy and/or brain irradiations may yield an initial satisfactory treatment response, but eventually they fail to show a favourable outcome [4]. Bokstein et al. was able to demonstrate an initial response rate of 100% in the CNS relapse in 23 patients using systemic HD-MTX based combination chemotherapy, but the responses were not durable, with a 1year survival of 32% and 2-year survival of 15% [5]. Recently, salvage monotherapy using intrathecal (IT) or intraventricular administration of rituximab to increase the concentration of rituximab in the cerebrospinal fluid (CSF) has shown its safety and efficacy in animal models [6,7], several case reports [8–11] and one phase I trial [12]. However, the durability of responses and long-term safety has been rarely described. We describe an elderly patient with diffuse large B-cell lymphoma, who developed CNS relapse following initial successful treatment. After shortened cycles of systemic HD-MTX based chemotherapy in conjunction with IT rituximab, the patient has achieved a complete remission with a long relapse-free survival. The addition of IT rituximab was highlighted and suggested to contribute to the favourable outcome. A 69-year-old female was diagnosed with diffuse large B-cell lymphoma of Ann Arbor stage IV in December 2003. She first presented to us with disease involvement in the neck lymph nodes (bilateral levels II to IV), intra-abdominal lymph nodes and lung and hepatic parenchyma. Meanwhile, an elevated lactate dehydrogenase (LDH) of 324 U/L was noted on presentation. The score of International Prognostic Index (IPI) was 4. She achieved complete remission in July 2004 after eight cycles of R-CEOP (rituximab; cyclophosphamide, epirubicin, vincristine and prednisolone). In October 2004, she suffered from disease recurring in the CNS, with symptoms of drooling, dysphagia requiring nasogastric tube feeding and dysarthria. The magnetic resonance imaging study of the brain