Junning Cao

Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group.

BACKGROUND Hepatitis B virus (HBV) reactivation is increasing, as rituximab has become widely used for B-cell lymphoma. Thus, prevention and management of HBV reactivation are important in HBV-endemic areas. METHODS Hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-positive patients and HBsAg-negative/HBV core antibody (HBcAb)-positive patients who received rituximab-containing chemotherapy was investigated by the Asia Lymphoma Study Group via retrospective (n=340), and the results were compared to cross-sectional analysis with patients who were prospectively monitored in a single institute (n=127). The goal of the study was to define the frequency of HBV reactivation and the efficacy of antiviral prophylaxis. RESULTS HBV reactivation was found in 27.8% of HBsAg-positive patients (45/162) in the retrospective analysis, being significantly less frequent in patients receiving antiviral prophylaxis than those not (22.9%, 32/140 versus 59.1%, 13/22; p<0.001). Lamivudine was most commonly used (96/162, 59.3%), but more than 20% of HBsAg-positive patients showed breakthrough HBV reactivation. In the cross-sectional analysis, a reduced rate of HBV reactivation occurred for entecavir as compared with lamivudine prophylaxis (6.3% versus 39.3%; p<0.05). HBV DNA monitoring of HBsAg-negative/HBcAb-positive patients in the cross-sectional analysis showed HBV reactivation in only 2.4% of cases. CONCLUSIONS This is the largest study of HBV reactivation in patients receiving rituximab-containing chemotherapy to date, and we defined the probability of HBV reactivation in an HBV-endemic region.

Recombinant human endostatin in combination with CHOP regimen for peripheral T cell lymphoma.

Peripheral T cell lymphoma (PTCL) has a poor prognosis. Overexpression of vascular endothelial growth factor (VEGF) might contribute to the poor prognosis of PTCL and could be the target of novel therapy. The efficacy and safety of recombinant human endostatin (Endostar) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (ECHOP) have been explored in 15 PTCL patients. The objective response rate was 80%, with 53.3% patients having achieved complete response (CR) rate. The CR rate was 100% (3/3) in angioimmunoblastic T cell lymphoma (AITL) patients compared to only 36.4% (4/11) in PTCL not otherwise specified (PTCL-NOS) patients. With a median follow-up of 69 months, the 5-year progression-free survival and overall survival (OS) were 53% and 60%, respectively. The 5-year OS was 100% in AITL but was only 45% in PTCL-NOS. Seven out of 11 patients showed overexpression of VEGFR2 in their tumor vessels and had a better efficacy than those with low expression of VEGFR2. Grade 3 or 4 neutropenia is the most common toxicity observed. ECHOP was safe and might display potential benefit in AITL patients.

Phase I Dose‐Escalation Study of Ramucirumab in Chinese Patients with Advanced Solid Tumors

Abstract Lessons Learned. Ramucirumab was well tolerated in Chinese patients with advanced solid tumors, and adverse events were manageable in this study. Pharmacokinetics characteristics in Chinese patients were similar to those in other populations. Immunogenicity was not detected. No efficacy conclusion could be drawn, and further randomized studies are warranted. Background. This single‐arm, nonrandomized, open‐label, dose‐escalation, phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of ramucirumab in Chinese patients with advanced solid tumors that were resistant to standard therapy or no standard therapy was available. Methods. Dose escalation was a 3 + 3 design, with expansion in Cohorts 2 and 3 for PK. Ramucirumab was given intravenously at three different dosages: 6 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 8 mg/kg every 2 weeks. Safety analyses included all patients. PK, immunogenicity, and antitumor activity were also assessed. Results. Among 28 patients treated, 2 experienced dose‐limiting toxicity, possibly related to ramucirumab. No maximum tolerated dose was determined. All patients experienced at least one treatment‐emergent adverse event. Grade ≥3 adverse event was reported for 53.6% (n = 15) of patients. PK analyses indicated that ramucirumab had low clearance, small volume of distribution, and long half‐life in Chinese patients, as in other populations. Immunogenicity was not detected. No patient had complete/partial response, and 64.3% (n = 18) had stable disease with a median duration of 5.55 months (95% confidence interval: 3.38−7.13 months). Conclusion. Ramucirumab appeared to be well tolerated in Chinese patients with advanced solid tumors. PK characteristics in Chinese patients were similar to those in other populations.

Thalidomide enhanced the efficacy of CHOP chemotherapy in the treatment of diffuse large B cell lymphoma: A phase II study

Cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab (R-CHOP) is the standard treatment for patients with diffuse large B cell lymphoma (DLBCL). However, rituximab cannot be popularly applied in a considerable number of patients with DLBCL because of economic reasons. To develop a new regimen to improve the outcome of these patients is extremely important. In our study, sixty five patients with DLBCL were randomly assigned to thalidomide plus CHOP group (n=32) or to CHOP alone group (n=33). Objective response rates (ORR) and complete remission rates (CRR) were 96.7% and 80.6% in T-CHOP group versus 78.9 % and 57.8 % in CHOP group, respectively (P <0.05). At a median follow-up of 96 months, median PFS for T-CHOP group was still not reached yet, and in CHOP group it was 22.9 months (95% CI [0-50.4]). (P=0.163). Median overall survival (OS) for T-CHOP group was also not reached, and the estimated median OS for CHOP group was 83.5 months, the difference of OS between the two groups is not significant (p=0.263). But, in patients with Bcl-2 positive and Bcl-6 negative, the median PFS in T-CHOP group was longer than that in CHOP group (111.0 vs 8.5 months (P=0.017). In addition, thalidomide did not significantly increase the grade 3/4 toxicity of CHOP. We concluded that the addition of thalidomide to the CHOP regimen significantly improved the CRR and showed a trend of improving clinical outcome in patients with DLBCL, especially for patients with Bcl-2 positive and Bcl-6 negative B-cell phenotype, without increased toxicity.

Cardiotoxicity as indicated by LVEF and troponin T sensitivity following two anthracycline-based regimens in lymphoma: Results from a randomized prospective clinical trial

Anthracycline-induced cardiotoxicity influences treatment selection and may negatively affect clinical outcomes in lymphoma patients. While epirubicin induced cardiotoxicity less often than the same dose of doxorubicin in breast cancer, higher doses of epirubicin are required in lymphoma regimens for equivalent efficacy. Whether a higher dosage of epirubicin also induces cardiotoxicity less often than doxorubicin in lymphoma remains unknown. We therefore administered 6-8 cycles of cyclophosphamide, vincristine and prednisone (CEpOP) +/− rituximab (R) with either epirubicin (CEpOP) or doxorubicin (CHOP) to patients (N=398) with untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade 3 (FLG3). Left ventricular ejection fraction (LVEF) and high-sensitivity serum cardiac troponin T (HsTnT) were assessed at baseline and after 4 cycles of treatment. Epirubicin (70 mg/m2/dose) was equivalent to doxorubicin (50 mg/m2/dose) in terms of 3-year progression-free survival. The risk of decreased LVEF was similar between the two regimens. CEpOP+/−R induced HsTnT elevation less often than CHOP+/−R. We conclude that CEpOP+/−R is a more acceptable regimen with short-term efficacy similar to CHOP+/−R in lymphoma patients. Longer follow-up is needed to monitor the risk of cardiac dysfunction and determine whether differences in the induction of elevated HsTnT between epirubicin and doxorubicin justify changes in clinical practice.

Role of radiotherapy in patients with limited diffuse large B-cell lymphoma of Waldeyer's ring in remission after R-CHOP immunochemotherapy

The standard treatment of waldeyers ring DLBCL remains controversial. This retrospective study was designed to evaluate the role of consolidation radiotherapy (RT) in patients with stage I/II diffuse large B-cell lymphoma (DLBCL) limited in Waldeyers ring (WR). We included 72 patients, 42 were treated with immunochemotherapy alone (CT group) and 30 were treated with immunochemotherapy followed by radiotherapy (CT + RT group). All patients received at least 3 cycles of R-CHOP regimen and achieved complete remission (CR) after immunochemotherapy. After 53 months median follow-up time, the 5-year progression-free survival (PFS) rates in CT + RT group vs. CT group were 93.3% vs. 92.5% (P = 0.896), the 5-year overall survival (OS) rates were 96.7% vs. 94.4% (P = 0.649). Patients with oropharyngeal primary had relatively better 5-year PFS and OS rates compared to nasopharyngeal primary (PFS: 98.2% vs. 73.3%, p = 0.001; OS: 100% vs. 79.0%, p < 0.001). Moreover, the primary site was the only independent prognostic factor for PFS in the multivariate analysis (p = 0.012, HR 16.858 [95% CI: 1.883-150.933]).

The size and depth of lesions measured by endoscopic ultrasonography are novel prognostic factors of primary gastric diffuse large B-cell lymphoma

Abstract Diffuse large B cell lymphoma is one of the predominant histological subtypes of primary gastric lymphomas. Factors that contribute to precise stratification and guide the treatment of this disease are still not well understood. We analyzed 73 primary gastric diffuse large B cell lymphoma patients retrospectively, and found that patients characterized by late stage, multiple localization, B symptoms, lower serum albumin level and elevated LDH level had a shorter overall survival through Univariate Cox regression analysis. Multivariate Cox regression analysis demonstrated that ALB ≤ 35g/L, staging ≥ IIE and multiple sites localization were independent adverse prognostic factors. Significantly, in 35 patients who received endoscopy at diagnosis, Kaplan–Meier analyses indicated that patients with large (≥3 cm) and deep lesions (≥11 mm) had an inferior OS (p = .01 and .039). These findings implicated that tumor size and depth are two indicators of prognosis under ultrasonography. Further randomized studies with large number of cases are needed.

Response-adapted therapy for limited stage diffuse large B-cell lymphoma based on interim PET-CT: preliminary results of a phase 2 study

Abstract Background Limited stage diffuse large B-cell lymphoma is curable with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) immunochemotherapy. For patients achieving complete response by interim 18F-fluorodeoxyglucose PET-CT, a previous study showed therapy could be safely de-escalated by omitting the subsequent chemotherapy or radiotherapy. We aimed to adapt the therapy on the basis of the response as assessed by the interim PET-CT. Methods We did this phase 2 study in patients with low risk (International Prognostic Index 0–2), limited stage diffuse large B-cell lymphoma. Patients were initially treated with four cycles of R-CHOP. PET-CT scans were done at baseline and after four cycles. Patients with negative PET (Deauville scores 1–2) received two cycles of rituximab monotherapy, unless they had any risk factors (primary mediastinal large B-cell lymphoma, primary extranodal non-Hodgkin lymphoma, and bulky disease). Patients with these risk factors received another two cycles of R-CHOP as routine practice. Patients with partial response received another four cycles of R-CHOP and a repeated PET-CT scan at the end of treatment. Patients with stable and progressive disease were managed by salvage chemotherapy. The primary endpoint was progression-free survival at 3 years. The trial is registered with ClinicalTrials, number NCT0180412 . Findings From December, 2012, to September, 2015, a total of 143 patients were enrolled and we analysed the 129 patients with baseline and interim PET-CT scans for efficacy. By local assessment, 114 PET-CT scans (88%) were reported as negative and 15 (12%) as positive. With a median follow-up time of 28·2 months (range 15·0–47·4), the estimated 3-year progression-free survival was 91%. Patients with negative interim PET-CT scans had a 3-year progression-free survival of 93% compared with 79% for patients with positive results (p=0·062). The estimated 3-year progression-free survival did not differ between patients with nodal and extranodal primaries (92% vs 91%, p=0·978). Interpretation For patients with limited stage diffuse large B-cell lymphoma, the results of interim PET-CT might predict progression-free survival and adapt the subsequent treatment. For complete response patients without risk factors, the extra two cycles of CHOP might be safely omitted without compromising the efficacy, which needs to be confirmed in a randomised study. Funding None.

A retrospective analysis of outcomes for primary mediastinal large B-cell lymphoma treated with RCHOP followed by radiotherapy or front-line autologous stem cell transplantation

ABSTRACT Objectives: Our aim was to retrospectively investigate the data from our institute the response rate and outcome in patients with primary mediastinal B-cell lymphoma (PMBL) who received the rituximab in combination with CHOP (RCHOP) followed by autologous stem cell transplantation (ASCT) or RCHOP followed by involved field radiation therapy (IFRT). Methods: Sixty five patients with PMBL received RCHOP as first-line chemotherapy between January 2005 and December 2010. Forty of the 65 patients completed the planned subsequent IFRT after initial chemotherapy. Thirteen of the 65 patients received the front-line ASCT after RCHOP. Twelve patients received RCHOP alone. Results: Thirty two of the 40 patients who received the RCHOP followed by IFRT have complete remission (CR) or CRu (CR/unconfirmed). All patients have CR or CRu after the ASCT. The progression free survival (PFS) and the estimated overall survival (OS) rate at 5 years for 32 CR/CRu patients in the RCHOP followed by IFRT group were 57 and 65%, respectively, as compared to RCHOP/ASCT group who were 94 and 100%, respectively. Twelve patients who received RCHOP alone had the same PFS and OS rate as the 40 patients who received RCHOP/IFRT (5-year PFS:62 vs. 65%, p = 0.068; 5-year OS:57 vs. 67%, p = 0.058). For all 65 patients, the age-adjusted international prognostic index (aaIPI) score remained the only predictor of a worse outcome. Conclusion: The PFS and OS rate of RCHOP/IFRT were found to be unsatisfied. RCHOP/ASCT showed a satisfactory PFS and OS rate.