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Rituximab (Mabthera)

Web Resources: Rituximab (Mabthera)
Latest Research Publications

Web Resources: Rituximab (Mabthera) (6 links)

Latest Research Publications

Jacobs I, Ewesuedo R, Lula S, Zacharchuk C
Biosimilars for the Treatment of Cancer: A Systematic Review of Published Evidence.
BioDrugs. 2017; 31(1):1-36 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Biologic treatments for cancer continue to place a significant economic burden on healthcare stakeholders. Biosimilar therapies may help reduce this burden through cost savings, thereby increasing patient access.
OBJECTIVES: The purpose of this study was to collate all published data to assess the weight of available evidence (quantity and quality) for proposed monoclonal antibody biosimilars and intended copies, for the treatment of cancer.
METHODS: MEDLINE(®), Embase(®), and ISI Web of Science(®) databases were searched to September 2015. Conference proceedings (17) were searched (2012 to July 2015). Searches of the United States National Library of Medicine ClinicalTrials.gov registry were also conducted. Risk of bias assessments were undertaken to assess data strength and validity.
RESULTS: Proposed biosimilars were identified in 23 studies (36 publications) in oncology and ten studies in 14 publications in oncology and chronic inflammatory diseases for bevacizumab, rituximab, and trastuzumab originators. Based on our review of the included published studies, and as inferred from the conclusions of study authors, the identified proposed biosimilars exhibit close similarity to their originators. Published data were also retrieved on intended copies of rituximab. It remains unclear what role these agents may have, as publications on rigorous clinical studies are lacking for these molecules.
CONCLUSION: While biosimilar products have the potential to improve patient access to important biologic therapies, robust evidence of outcomes for monoclonal antibody biosimilars in treating cancer patients, including data from comparative efficacy and safety trials, is not yet available in the published literature. Significant data gaps exist, particularly for intended copies, which reinforces the need to maintain a clear differentiation between these molecules and true biosimilars. As more biosimilars become available for use, it will be important for stakeholders to understand fully the robustness of overall evidence used to demonstrate biosimilarity and gain regulatory approval.

Alrifai T, Grant Szymanski K, Venugopal P, et al.
Bendamustine and Rituximab: Complete Response in a 62-Year-Old Female with an Aggressive Lymphoma and an Ejection Fraction of 20.
Chemotherapy. 2017; 62(2):140-146 [PubMed] Related Publications
The treatment of diffuse large B-cell lymphoma in the presence of cardiac comorbidities can be challenging considering that the standard treatment regimen used for this aggressive subtype of non-Hodgkin lymphoma (NHL) consists of a combination of rituximab, cyclophosphamide, doxorubicin hydrochloride, Oncovin (vincristine), and prednisone (R-CHOP). The use of the anthracycline doxorubicin has been associated with arrhythmias and cardiomyopathy, making patients with cardiac dysfunction poor candidates for R-CHOP. As such, it is imperative to find alternative regimens that omit cardiac toxicity without compromising efficacy for this patient population. We report a case of composite NHL in a patient who received frontline bendamustine with rituximab with encouraging results. Our patient had a left ventricular ejection fraction of 20%, making her a poor candidate for anthracycline-based therapy. We opted to administer bendamustine with rituximab for a total of 6 cycles. She remains disease free 18 months after the completion of therapy.

Cummin T, Johnson P
Lymphoma: turning biology into cures.
Clin Med (Lond). 2016; 16(Suppl 6):s125-s129 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is the commonest aggressive non-Hodgkin lymphoma with approximately 5,000 cases annually in the UK. The R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) regimen has become the international standard of care with cure rates of around 75% and despite extensive studies aimed at improving the outcomes, R-CHOP has not been superseded. Those patients that do not respond to R-CHOP have a poor outlook. DLBCL is a disease with marked molecular heterogeneity; advances in gene expression profiling and mutational analysis can be used to increase our understanding of the disease and identify new therapeutic targets. Precision medicine using new agents, including small molecule inhibitors, is now being investigated for DLBCL. Progress in this disease is likely to come by targeting heterogeneous subtypes through novel combinations. Where R-CHOP fails, we hope that these new approaches can succeed by providing personalised medicine using precision diagnostics to guide new treatment paradigms.

Cheson BD, Trask PC, Gribben JG, et al.
Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone.
Ann Hematol. 2017; 96(2):253-259 [PubMed] Free Access to Full Article Related Publications
We present health-related quality of life (HRQoL) data from GADOLIN, comparing bendamustine (B) alone or combined with obinutuzumab (G-B) in rituximab-refractory indolent non-Hodgkin lymphoma patients. The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire was administered on day 1 of cycles 1, 3, and 5 during treatment, at end of induction (EOI), bi-monthly for 2 years during maintenance/follow-up, and annually during extended follow-up until progression/death. Time to first ≥6-point worsening from baseline in the FACT-Lym trial outcome index (TOI) was estimated. Minimally important differences at individual subscale and total score level were used to define the proportion of patients reporting improvement on the FACT-Lym lymphoma-specific subscale (≥3 points), FACT-Lym TOI (≥6 points), and FACT-Lym total score (≥7 points). Overall, 396 patients were randomized. Analysis was conducted when 175 Independent Review Committee-assessed progression-free survival (PFS) events were observed. Questionnaire completion rates were generally balanced between arms at baseline, EOI, and final follow-up. Median time to ≥6-point worsening from baseline on the FACT-Lym TOI was 8.0 months in the G-B arm and 4.6 months in the B arm (HR 0.74; 95% CI 0.56-0.98). More G-B patients reported meaningful improvements on the FACT-Lym questionnaire subscales. Results were similar when follicular lymphoma patients were analyzed separately. The delayed time to worsening and greater proportion of patients reporting meaningful improvement in HRQoL in the G-B arm suggest that benefit in PFS is not at the expense of an increase in treatment-related toxicity that could lead to reduced HRQoL.

Liu D, Wang Y, Dong M, et al.
Polymorphisms in cytokine genes as prognostic markers in diffuse large B cell lymphoma patients treated with (R)-CHOP.
Ann Hematol. 2017; 96(2):227-235 [PubMed] Related Publications
To investigate whether cytokine genetic polymorphisms influence the outcome of diffuse large B cell lymphoma (DLBCL), we tested 337 consecutive DLBCL treated with CHOP or rituximab-CHOP (R-CHOP) from interleukin 10 (IL10), Bcl-2, and tumor necrosis factor (TNF)-α polymorphisms. Patients who carried the IL10 rs1800871 TT or rs1800872 AA genotype showed higher complete response (CR) and overall response rate (ORR) significantly. A longer progression-free survival (PFS) was observed in patients with IL10 rs1800871 TT (P = 0.017) or rs1800872 AA (P = 0.017) genotype after rituximab-based chemotherapy, and better PFS was also noted with Bcl-2 rs1801018 AA genotype in the CHOP group (P = 0.048). Furthermore, the R-CHOP group patients who carried the IL10 non-CCA haplotype had longer PFS (P = 0.030). Cox proportional hazards analyses demonstrated that the genotype TT of IL10 rs1800871 and AA plus AC of rs1800872 were predictive of longer PFS and event-free survival (EFS) in DLBCL patients treated with R-CHOP. And the Bcl-2 rs2279115 AA plus AC genotypes and rs1801018 GG genotype were risk factors for EFS in DLBCL patients treated with CHOP. In conclusion, the results reminded us those DLBCL patients with IL10 rs1800871 TT, rs1800872 AA, or IL10 non-CCA haplotype are likely to benefit from the therapy of rituximab-based chemotherapy.

Bari A, Marcheselli R, Marcheselli L, et al.
A Multicenter Phase II Study of Twice-Weekly Bortezomib plus Rituximab in Patients with Relapsed Follicular Lymphoma: Long-Term Follow-Up.
Acta Haematol. 2017; 137(1):7-14 [PubMed] Related Publications
Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.

Yuda S, Maruyama D, Maeshima AM, et al.
Influence of the watch and wait strategy on clinical outcomes of patients with follicular lymphoma in the rituximab era.
Ann Hematol. 2016; 95(12):2017-2022 [PubMed] Free Access to Full Article Related Publications
We analyzed the effects of the initial approach to patients with follicular lymphoma (FL) on outcomes in order to investigate whether the watch and wait (WW) strategy is still an acceptable approach in the rituximab era. We retrospectively analyzed 348 patients who were initially diagnosed with FL between 2000 and 2012. We compared the clinical outcomes of the WW cohort and immediate treatment cohort. Among 348 patients (median age of 57 years, range: 19-85), 101 were initially managed with WW and 247 were immediately treated. The median follow-up duration was 75 months (range: 7-169). The estimated median time to treatment failure (TTF) in the treatment following WW cohort and immediate treatment cohort were 92 months (95 % CI, 60.1-NA) and 77 months (95 % CI, 65.1-107.6), respectively, which were not significantly different (P = 0.272) . In a multivariate analysis, clinical stage was identified as a predictive factor of TTF (HR 1.19, 95 % CI, 1.03-1.38, P < 0.05). Neither overall survival rate nor cumulative risk of transformation between the WW cohort and immediate treatment cohort was significant. The results of the present study suggested that the WW strategy is still an acceptable approach for selected FL patients in the rituximab era.

How J, Blattner M, Fowler S, et al.
Chemotherapy-associated Posterior Reversible Encephalopathy Syndrome: A Case Report and Review of the Literature.
Neurologist. 2016; 21(6):112-117 [PubMed] Related Publications
INTRODUCTION: There are increasing reports of posterior reversible encephalopathy syndrome (PRES) associated with the use of chemotherapeutic agents. Recognition of PRES is crucial given its reversibility with appropriate supportive management. We report a patient presenting with PRES after treatment with Rituximab, Cyclophosphamide, Hydroxydaunorubicin/Adriamycin, Oncovin/Vincristine, Prednisone (R-CHOP) and intrathecal methotrexate. We also perform a systematic review of the literature on chemotherapy-associated PRES.
CASE REPORT: A 72-year-old man with recently diagnosed diffuse large B-cell lymphoma became unresponsive 4 days after initiation of R-CHOP and intrathecal methotrexate. Brain magnetic resonance imaging showed interval development of occipital and temporal fluid attenuation inversion recovery hyperintensities consistent with PRES. The patient's blood pressure was aggressively controlled and he received 5 days of high-dose methylprednisone. He subsequently regained consciousness and his mental status gradually improved. Repeat magnetic resonance imaging showed interval resolution of the bilateral fluid attenuation inversion recovery hyperintensities.
REVIEW SUMMARY: We performed a systematic review of the literature and included a total of 70 unique cases involving chemotherapy-associated PRES. Platinum-containing drugs, Cyclophosphamide, Hydroxydaunorubicin/Adriamycin, Oncovin/Vincristine, Prednisone/R-CHOP regimens, and gemcitabine were the agents most commonly used in patients who developed suspected chemo-associated PRES. Median onset of symptoms occurred 8 days after chemotherapy. Hypertension was the most commonly reported risk factor associated with the development of chemotherapy-associated PRES. In most cases, PRES improved with supportive management alone within 2 weeks.
CONCLUSIONS: Chemotherapy-associated PRES is an increasingly encountered syndrome. Both neurologists and non-neurologists should be familiar with the most commonly implicated agents, symptoms, risk factors, and clinical course of chemotherapy-associated PRES, given its favorable prognosis with appropriate management.

Zhang XY, Xu J, Zhu HY, et al.
Negative prognostic impact of low absolute CD4(+) T cell counts in peripheral blood in mantle cell lymphoma.
Cancer Sci. 2016; 107(10):1471-1476 [PubMed] Free Access to Full Article Related Publications
Tumor microenvironment and host immunity are closely related to outcome in patients with mantle cell lymphoma (MCL). However, few researchers have focused on the prognostic value of peripheral blood lymphocyte subsets counts. The purpose of this study was to investigate the prognostic value of lymphocyte subsets and absolute monocyte counts. Sixty-eight patients were analyzed retrospectively. Absolute CD4(+) T cell counts (ACD4C), CD8(+) T cell counts, nature killer cell counts, and CD4/CD8 ratios were assessed by peripheral blood flow cytometry and correlated with clinical parameters and long-term outcomes. The median follow-up for all patients was 21 months and the median survival time was 44 months. The overall survival (OS) rate at 1, 3, and 5 years was 80%, 51%, and 41%, respectively. In our cohort, high absolute monocyte count, and low ACD4C and CD4/CD8 ratio were associated with unfavorable OS (P = 0.029, P = 0.027, and P = 0.045, respectively) by univariate analysis. Multivariate analysis indicated that low ACD4C was a significant predictor of unfavorable OS (P = 0.004) independent of the simplified MCL International Prognostic Index (P = 0.048) in patients treated with or without rituximab (P = 0.011). Low CD4(+) T cell counts proved to be a significant predictor of unfavorable OS in patients with MCL.

Samarghandi A, Ahuja S, Gupta S, et al.
A case report of mantle cell lymphoma manifesting as a foot lesion.
Tumori. 2016; 102(Suppl. 2) [PubMed] Related Publications
INTRODUCTION: Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma that most commonly affects men above the age of 60 years. The disease is called MCL because the tumor cells originate from the mantle zone of the lymph node. The most commonly affected sites are the lymph nodes, bone marrow, gastrointestinal tract, Waldeyer's ring and rarely the skin, breast and central nervous system. Only 22 cases with skin manifestation of MCL have been reported so far.
CASE: We report the case of a 73-year-old woman who was diagnosed with MCL and underwent treatment, but later relapsed and presented with an ulcerated mass over her right foot. She underwent 6 cycles of chemotherapy with bendamustine plus rituximab and responded with resolution of the foot lesion.
DISCUSSION AND CONCLUSIONS: MCL is an aggressive lymphoma with a median overall survival of 3-5 years for advanced disease, while early-stage disease has a better prognosis. It rarely involves the skin. Since cutaneous lesions can be the first manifestation of MCL, awareness of this less common presentation is crucial to establish an early diagnosis and pursue treatment as early as possible, as it significantly impacts the survival rate.

Wudhikarn K, Bunworasate U, Julamanee J, et al.
Secondary central nervous system relapse in diffuse large B cell lymphoma in a resource limited country: result from the Thailand nationwide multi-institutional registry.
Ann Hematol. 2017; 96(1):57-64 [PubMed] Related Publications
Secondary central nervous system (CNS) relapse is a serious and fatal complication of diffuse large B cell lymphoma (DLBCL). Data on secondary CNS (SCNS) relapse were mostly obtained from western countries with limited data from developing countries. We analyzed the data of 2034 newly diagnosed DLBCL patients enrolled into the multi-center registry under Thai Lymphoma Study Group from setting. The incidence, September 2006 to December 2013 to represent outcome from a resource limited pattern, management, and outcome of SCNS relapse were described. The 2-year cumulative incidence (CI) of SCNS relapse was 2.7 %. A total of 729, 1024, and 281 patients were classified as low-, intermediate-, and high-risk CNS international prognostic index (CNS-IPI) with corresponding 2-year CI of SCNS relapse of 1.5, 3.1, and 4.6 %, respectively (p < 0.001). Univariate analysis demonstrated advance stage disease, poor performance status, elevated lactate dehydrogenase, presence of B symptoms, more than one extranodal organ involvement, high IPI, and high CNS-IPI group as predictive factors for SCNS relapse. Rituximab exposure and intrathecal chemoprophylaxis offered no protective effect against SCNS relapse. At the time of analysis, six patients were alive. Median OS in SCNS relapsed patients was significantly shorter than relapsed patients without CNS involvement (13.2 vs 22.6 months) (p < 0.001). Primary causes of death were progressive disease (n = 35, 63.6 %) and infection (n = 9, 16.7 %). In conclusion, although the incidence of SCNS relapse in our cohort was low, the prognosis was dismal. Prophylaxis for SCNS involvement was underused even in high-risk patients. Novel approaches for SCNS relapse prophylaxis and managements are warranted.

Kim EJ, Kim BS, Choi DB, et al.
Improved In Vivo Stability of Radioiodinated Rituximab Using an Iodination Linker for Radioimmunotherapy.
Cancer Biother Radiopharm. 2016; 31(8):287-294 [PubMed] Related Publications
PURPOSE: Directly radioiodinated [(131)I]-rituximab has been developed as a radioimmunotherapeutic agent in patients with CD20-positive B cell non-Hodgkin's lymphoma. However, there are concerns over its in vivo catabolism and deiodination. A novel radioiodination linker, N-(4-isothiocyanatobenzyl)-2-(3-(tributylstannyl)phenyl) acetamide (IBPA), was synthesized for the preparation of stable radioiodinated proteins.
METHODS: The authors evaluated the potential of IBPA as a stable radioiodinated linker for rituximab. [(125)I]-IBPA was purified and conjugated with rituximab, and in vitro stability testing was performed in serum and liver microsomes. In vivo studies were performed after i.v. injection of [(125)I]-rituximab or [(125)I]-IBPA-rituximab to nude mice.
RESULTS: In in vitro studies, [(125)I]-IBPA-rituximab was stable in serum and liver microsomes. In static scans, high radioactivity was evident in the thyroid following injection of [(125)I]-rituximab, but low radioactivity was seen in the thyroid following injection of [(125)I]-IBPA-rituximab. In biodistribution studies, radioactivity uptake in thyroid glands of [(125)I]-IBPA-rituximab was decreased by approximately sevenfold compared to [(125)I]-rituximab. In pharmacokinetics, the half-life of [(125)I]-rituximab was shorter than that of [(125)I]-IBPA-rituximab in plasma of nude mice.
CONCLUSIONS: The authors demonstrate that [(125)I]-IBPA-rituximab is more stable to metabolic deiodination in vivo than is [(125)I]-rituximab. Radioiodination of rituximab using IBPA is thus preferable to direct labeling in terms of in vivo stability.

Li C, Li L, Zhang P, et al.
Multifocal extranodal lymphoma: A case report.
Medicine (Baltimore). 2016; 95(40):e5029 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: We report an unusual and interesting case of non-Hodgkin lymphoma involving 7 extranodal sites.In this case, a 43-year-old woman with diffuse large B-cell lymphoma, including stomach, breasts, pancreas, adrenal glands, ovary and bones, was confirmed by biopsy and positron emission tomography/computed tomography scan. The patient achieved a complete response after 2 cycles of chemotherapy with combined rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, but subsequently developed central nervous system involvement.
CONCLUSION: This case illustrated the usefulness of positron emission tomography/computed tomography in diagnosis, disease staging, and assessment of response to therapy. Selection of the optimal treatment regimen is challenging and needs further research.

Mayerhoefer ME, Karanikas G, Kletter K, et al.
Can Interim 18F-FDG PET or Diffusion-Weighted MRI Predict End-of-Treatment Outcome in FDG-Avid MALT Lymphoma After Rituximab-Based Therapy?: A Preliminary Study in 15 Patients.
Clin Nucl Med. 2016; 41(11):837-843 [PubMed] Related Publications
PURPOSE: To determine whether interim F-FDG PET or interim diffusion-weighted magnetic resonance imaging (DWI) can predict the end-of-treatment (EOT) outcome after immunotherapy in patients with FDG-avid extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT).
MATERIALS AND METHODS: Patients with untreated MALT lymphoma prospectively underwent whole-body F-FDG PET/CT and DWI before treatment (baseline), and after three cycles (interim) of rituximab-based immunotherapy. Maximum and mean standardized uptake values (SUVmax, SUVmean), and minimum and mean apparent diffusion coefficients (ADCmin, ADCmean), were measured for up to three target lesions per patient. Rates of change between baseline and interim examinations (ΔSUVmax, ΔSUVmean, ΔADCmin, and ΔADCmean) were compared, using ANOVAs, between the four end-of-treatment (EOT, after six cycles of immunotherapy) outcomes: complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD).
RESULTS: Fifteen patients with 25 lesions were included. Lesion-based post hoc tests showed significant differences between CR and PR for ΔSUVmax (P < 0.001), ΔSUVmean (P < 0.001), and ΔADCmin (P = 0.044), and between CR and SD for ΔSUVmax (P < 0.001), ΔSUVmean (P < 0.001), ΔADCmin (P = 0.021), and ΔADCmean (P = 0.022). No lesion showed PD at EOT.
CONCLUSIONS: Both quantitative interim F-FDG PET and interim DWI may possibly be useful to predict complete remission at end-of-treatment in MALT lymphoma patients after immunotherapy.

Liu G, Luan J, Li Q
CD4(+)Foxp3(-)IL-10(+) Tr1 Cells Promote Relapse of Diffuse Large B Cell Lymphoma by Enhancing the Survival of Malignant B Cells and Suppressing Antitumor T Cell Immunity.
DNA Cell Biol. 2016; 35(12):845-852 [PubMed] Related Publications
Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy. Complete remission can be achieved in most patients by conventional treatment with rituximab and chemotherapy. However, a subset of remission individuals will develop a relapsed disease for obscure reasons. CD4(+)Foxp3(-)IL-10(+) cell (Tr1) is a novel cell subtype with the capacity to suppress pro-inflammatory responses, but has not been extensively studied in most tumors. In this study, we investigated the potential role of Tr1 cells in DLBCL. We found that compared to that in healthy controls, the frequency of Tr1 cells was significantly increased in DLBCL patients, even during complete remission. Further study showed that these Tr1 cells were enriched in the CD25(low/-)Foxp3(-)CD49b(+)LAG-3(+) fraction and could be developed in vitro from naive CD45RA(+) CD4(+) T cells. To examine the effect of Tr1 upregulation, we cocultured the enriched in vitro-induced Tr1 cells (iTr1) with autologous primary DLBCL cells and CD3(+) T cells and found that iTr1 cells both enhanced the survival of CD20(+) DLBCL tumor cells and suppressed the antitumor response of CD3(+) T cells through the production of IL-10. Furthermore, the frequency of CD4(+)Foxp3(-)IL-10(+) Tr1 cells in DLBCL patients during complete remission is directly associated with the risk of relapse. Together, these results suggested that Tr1 cells contributed to tumor cell maintenance and may serve as a prognostic marker and therapeutic target.

Ito K, Okamoto M, Inaguma Y, et al.
Influence of R-CHOP Therapy on Immune System Restoration in Patients with B-Cell Lymphoma.
Oncology. 2016; 91(6):302-310 [PubMed] Related Publications
OBJECTIVE: To assess the immunosuppressive effect of R-CHOP in patients with B-cell lymphoma at 2 years.
METHODS: Parameters of humoral and cell-mediated immunity were assessed in 89 patients with diffuse large B-cell lymphoma or follicular lymphoma before and after 6-8 cycles of R-CHOP-14 or R-CHOP-21 regimen.
RESULTS: Data on pre- and posttreatment serum IgG (sIgG) levels were available for all 89 patients, while the corresponding data on serum CD20+, CD3+, CD4+, and CD8+ lymphocyte counts were available in only 43. Median sIgG levels significantly decreased from 1,221 mg/dl (baseline) to 733 mg/dl (after chemotherapy) (p < 0.001). Although CD20+ and CD4+ cell counts decreased (p < 0.001), no significant effect of chemotherapy on CD3+ and CD8+ cell counts was observed. CD20+ cell counts were restored to baseline levels at the 12-month follow-up. sIgG levels and CD4+ cell counts were not completely restored at 24 months, indicating a sustained immunosuppressive effect of R-CHOP in these patients. The incidence of infections over the 2-year period was 16.3-23.6%.
CONCLUSION: The immunosuppressive effect of R-CHOP in newly diagnosed cases of B-cell lymphoma tends to persist for >2 years, although sIgG levels were restored more quickly than CD4+ cell counts.

Song MK, Chung JS, Shin DY, et al.
Tumor necrosis could reflect advanced disease status in patients with diffuse large B cell lymphoma treated with R-CHOP therapy.
Ann Hematol. 2017; 96(1):17-23 [PubMed] Related Publications
Tumor necrosis (TN) can lower responsiveness to chemotherapy and confer basic resistance to anti-cancer therapy. We investigated the association of TN with poor clinical features and outcome in diffuse large B cell lymphoma (DLBCL). We examined the presence or absence of TN in 476 DLBCL patients of who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Eighty-nine (18.7 %) patients had TN at diagnosis. Patients with TN had a progression-free survival (PFS) and overall survival (OS) of 39.3 and 46.7 %, whereas patients without TN had a PFS and OS of 73.4 and 82.6 %. Adverse clinical factors of poor Eastern Cooperative Oncology Group performance status ≥ grade 2 (p = 0.005), elevated lactate dehydrogenase ratio >1 (p < 0.001), advanced Ann Arbor stage (p = 0.002), and bulky disease (p = 0.026) were more prevalent in the TN group than the non-TN group. Cox regression model analysis revealed TN as an independent prognostic factor for PFS and OS in DLBCL (PFS, hazard ratio [HR] = 1.967, 95 % confidence interval [CI] = 1.399-2.765, p < 0.001; OS, HR = 2.445, 95 % CI = 1.689-3.640, p < 0.001). The results indicate that TN could reflect adverse clinical features and worse prognosis in DLBCL patients receiving R-CHOP therapy.

Wang J, Zhou M, Xu JY, et al.
Prognostic role of pretreatment neutrophil-lymphocyte ratio in patients with diffuse large B-cell lymphoma treated with RCHOP.
Medicine (Baltimore). 2016; 95(38):e4893 [PubMed] Free Access to Full Article Related Publications
This study aims to investigate whether neutrophil to lymphocyte ratio (NLR) is an independent predictor in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. Data from newly diagnosed DLBCL patients at Nanjing Drum Tower Hospital from 2006 to 2015 were retrospectively reviewed. We used the receiver operating characteristic (ROC) curve analysis to generate the optimal cutoff value for NLR. Among those 156 patients enrolled, the NLR was < 3.0 in 46.8% (73/156) of the patients, and the remaining 53.2% (83/156) had an NLR ≥ 3.0. Patients with higher pretreatment NLR were found to correlate with poorer OS and PFS than these with lower NLR (hazard ratio [HR] = 2.66, 95% confidence interval [CI] = 1.43-4.97, P = 0.002 and HR = 1.79, 95% CI = 1.05-3.07, P = 0.034, respectively). The multivariate Cox proportional hazard model analysis further showed that high NLR was found independently predictive of poor OS (HR = 0.40; CI = 0.19-0.84, P = 0.015) and PFS (HR = 0.57; CI = 0.33-0.98, P = 0.042). Consequently, pretreatment NLR was an independent prognostic predictor in patients with DLBCL in the rituximab era.

Ochi Y, Kazuma Y, Hiramoto N, et al.
Utility of a simple prognostic stratification based on platelet counts and serum albumin levels in elderly patients with diffuse large B cell lymphoma.
Ann Hematol. 2017; 96(1):1-8 [PubMed] Related Publications
Few studies have examined the prognostic impact of blood markers [other than the five factors in the enhanced International Prognostic Index (NCCN-IPI)] in elderly patients with diffuse large B cell lymphoma (DLBCL). We retrospectively analyzed 391 DLBCL patients receiving rituximab plus anthracycline-containing chemotherapy to examine the prognostic impact of simple blood markers. The NCCN-IPI was more accurate for discriminating prognoses than the original IPI. Multivariate analysis identified platelet count (<100,000/μl) and albumin (<3.5 g/dl) levels as significantly associated with lower overall survival (OS), independently of the NCCN-IPI. These parameters stratified patients into three risk groups: platelet-albumin (PA) score low (platelet count ≥100,000/μl, albumin ≥3.5 g/dl, n = 243); intermediate (platelet count <100,000/μl, albumin ≥3.5 g/dl or platelet count ≥100,000/μl, albumin <3.5 g/dl, n = 125); and high (platelet count <100,000/μl, albumin <3.5 g/dl, n = 23). The 5-year OS rates were 81.5, 48.6, and 20.2 %, respectively (p < 0.001). Notably, most patients with a low platelet count (n = 30) were stratified into the high-risk subgroup, suggesting that platelet count was prognostic for high-risk patients with a dismal outcome. In elderly patients (n = 291), the prognostic value of the NCCN-IPI might be diminished because the low-risk category was excluded; however, the PA score was predictive of survival: the 5-year OS rates for PA score low (n = 171), intermediate (n = 101), and high (n = 19) groups were 77.6, 47.9, and 19.0 %, respectively (p < 0.001). Platelet count and albumin levels are useful prognostic factors, and their combined use can predict survival, even in elderly patients.

Adams HJ, Kwee TC
Prognostic value of interim FDG-PET in R-CHOP-treated diffuse large B-cell lymphoma: Systematic review and meta-analysis.
Crit Rev Oncol Hematol. 2016; 106:55-63 [PubMed] Related Publications
This study aimed to systematically review and meta-analyze the prognostic value of interim (18)F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). MEDLINE and EMBASE were systematically searched for suitable studies. Included studies were methodologically appraised, and results were summarized both descriptively and meta-analytically. Nine studies, comprising a total of 996 R-CHOP-treated DLBCL patients, were included. Overall, studies were of moderate methodological quality. The area under the summary receiver operating curve (AUC) of interim FDG-PET in predicting treatment failure and death were 0.651 and 0.817, respectively. There was no heterogeneity in diagnostic odds ratios across available studies (I(2)=0.0%). At multivariable analysis, 2 studies reported interim FDG-PET to have independent prognostic value in addition to the International Prognostic Index (IPI) in predicting treatment failure, whereas 3 studies reported that this was not the case. One study reported interim FDG-PET to have independent prognostic value in addition to the IPI in predicting death, whereas 2 studies reported that this was not the case. In conclusion, interim FDG-PET in R-CHOP-treated DLBCL has some correlation with outcome, but its prognostic value is homogeneously suboptimal across studies and it has not consistently proven to surpass the prognostic potential of the IPI. Moreover, there is a lack of studies that compared interim FDG-PET to the recently developed and superior National Comprehensive Cancer Network-IPI. Therefore, at present there is no scientific base to support the clinical use of interim FDG-PET in R-CHOP-treated DLBCL.

Schirmbeck NG, Mey UJ, Olivieri A, et al.
Salvage Chemotherapy with R-DHAP in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma.
Cancer Invest. 2016; 34(8):361-72 [PubMed] Related Publications
This analysis reports on 72 patients with relapsed or refractory non-Hodgkin lymphoma who were treated with R-DHAP salvage chemotherapy regimen followed by high-dose chemotherapy and stem cell transplantation. The overall remission rate was 58.3%. Median time of follow-up was 28.7 months. Median progression-free survival was 29 months, estimated median overall survival was 37 months. Within a matched pair analysis these results were compared to a group that received DHAP salvage therapy without rituximab showing similar overall response rates and better estimated five-year overall survival of 59.2% versus 43.5%. R-DHAP therapy was shown to be effective and feasible with acceptable toxicity.

Kim J, Lee JO, Paik JH, et al.
Different predictive values of interim (18)F-FDG PET/CT in germinal center like and non-germinal center like diffuse large B-cell lymphoma.
Ann Nucl Med. 2017; 31(1):1-11 [PubMed] Related Publications
PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is a pathologically heterogeneous disease with different prognoses according to its molecular profiles. Despite the broad usage of (18)F-fluoro-2-dexoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT), previous studies that have investigated the value of interim (18)F-FDG PET/CT in DLBCL have given the controversial results. The purpose of this study was to evaluate the prognostic value of interim (18)F-FDG PET/CT in DLBCL according to germinal center B cell-like (GCB) and non-GCB molecular profiling.
METHODS: We enrolled 118 newly diagnosed DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Interim (18)F-FDG PET/CT scans performed after 2 or 3 cycles of R-CHOP treatment were evaluated based on the Lugano response criteria. Patients were grouped as GCB or non-GCB molecular subtypes according to immunohistochemistry results of CD10, BCL6, and MUM1, based on Hans' algorithm.
RESULTS: In total 118 DLBCL patients, 35 % were classified as GCB, and 65 % were classified as non-GCB. Interim PET/CT was negative in 70 %, and positive in 30 %. During the median follow-up period of 23 months, the positive interim (18)F-FDG PET/CT group showed significantly inferior progression free survival (PFS) compared to the negative interim (18)F-FDG PET/CT group (P = 0.0004) in entire patients. A subgroup analysis according to molecular profiling demonstrated significant difference of PFS between the positive and negative interim (18)F-FDG PET groups in GCB subtype of DLBCL (P = 0.0001), but there was no significant difference of PFS between the positive and negative interim (18)F-FDG PET groups in non-GCB subtype of DLBCL.
CONCLUSIONS: Interim (18)F-FDG PET/CT scanning had a significant predictive value for disease progression in patients with the GCB subtype of DLBCL treated with R-CHOP, but not in those with the non-GCB subtype. Therefore, molecular profiles of DLBCL should be considered for interim (18)F-FDG PET/CT practice.

Maury S, Chevret S, Thomas X, et al.
Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia.
N Engl J Med. 2016; 375(11):1044-53 [PubMed] Related Publications
BACKGROUND: Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial.
METHODS: We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions.
RESULTS: From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group.
CONCLUSIONS: Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .).

Song HN, Kim SJ, Ko YH, Kim WS
Mediastinal Gray Zone Lymphoma with Features Intermediate between Classical Hodgkin Lymphoma and Primary Mediastinal B-Cell Lymphoma.
Acta Haematol. 2016; 136(3):186-90 [PubMed] Related Publications
BACKGROUND: Mediastinal gray zone lymphoma (MGZL) shares clinical characteristics with primary mediastinal B-cell lymphoma (PMBCL) and nodular sclerosing Hodgkin lymphoma (NSHL). However, MGZL is extremely rare, and an appropriate treatment for it has not yet been established.
METHODS: We retrospectively analyzed 8 patients who were treated with systemic chemotherapy for MGZL between 2007 and 2014.
RESULTS: The patients with MGZL were predominantly young and male (median age 26 years), and 62.5% of patients had bulky disease. The overall response rate (ORR) and complete remission (CR) rate were both 75% (6/8) for all treated patients The median overall survival (OS) and progression-free survival (PFS) was 40.7 and 3.9 months, respectively. Most responders (4/6, 66.7%) were treated with R-CHOP (rituximab + cyclophosphamide, hydroxydaunorubicin, Oncovin and prednisolone) as the frontline therapy. The CR rate of patients who received R-CHOP and those who did not was 100% (4/4) and 50% (2/4), respectively. Particularly striking was the finding that the median PFS of patients who received R-CHOP frontline chemotherapy was 11.4 months, which was superior to the median PFS of patients who did not receive R-CHOP.
CONCLUSIONS: Of the 8 patients with MGZL who were treated with systemic chemotherapy, superior treatment responses were observed in patients who received R-CHOP as the frontline therapy.

Maeda-Sakagami Y, Tanaka Y, Koba Y, et al.
Mantle cell lymphoma presenting with spontaneous splenic rupture.
Rinsho Ketsueki. 2016; 57(8):1018-25 [PubMed] Related Publications
A 48-year-old man was transferred to our emergency room because of sudden-onset epigastric pain and nausea. Abdominal contrast-enhanced computed tomography (CT) showed splenomegaly with splenic infarction and intra-abdominal bleeding, suggestive of splenic rupture. An emergent open splenectomy was performed. His spleen was markedly swollen and showed continuous bleeding due to a laceration. On histopathological examination, his spleen was filled with abnormal tumor cells. He was diagnosed as having mantle cell lymphoma based on the findings of immunohistochemical and cytogenetic analyses of the spleen. Mantle cell lymphoma cells were identified in the bone marrow and ileum, and he was determined to be in stageIVA by positron emission tomography (PET)-CT. He was administered rituximab combined with hyper-CVAD/MA chemotherapy (R-hyper-CVAD/MA regimen). After two courses of the R-hyper-CVAD/MA regimen, he achieved complete response, as confirmed by PET-CT. He received four courses in total of the R-hyper-CVAD/MA regimen, followed sequentially by high-dose chemotherapy and autologous peripheral blood stem cell transplantation (auto-PBSCT). He is currently alive and free of disease. This is the 10(th) report of a mantle cell lymphoma case with spontaneous splenic rupture. We herein review previous reports and emphasize the importance of awareness of hematological malignancies when encountering a case with spontaneous splenic rupture.

Thakral P, Singla S, Vashist A, et al.
Preliminary Experience with Yttrium-90-labelled Rituximab (Chimeric Anti CD-20 Antibody) in Patients with Relapsed and Refractory B Cell Non-Hodgkins Lymphoma.
Curr Radiopharm. 2016; 9(2):160-8 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: The aim of the study is to evaluate the therapeutic efficacy and safety of Yttrium- 90 radiolabelled chimeric anti CD20 antibody-Rituximab in the treatment of patients with relapsed/ refractory B cell Non-Hodgkins Lymphoma (NHL).
METHODS: Twenty patients with relapsed/refractory CD20+ NHL in progressive state were included in the study. These patients had undergone a median of 2 (range 2-5) prior standard chemotherapy ± immunotherapy regimens. All the patients received rituximab 250 mg/m2 on days 1 and 8, and either 14 MBq/kg (0.4 mCi/kg) or 11 MBq/kg (0.3 mCi/kg) of Y-90 Rituximab on day 8 (maximum dose, 32 mCi) depending upon their platelet count. The patients were observed for systemic toxicity and response for at least 12 weeks after therapy.
RESULTS: No acute adverse effects were observed after the administration of 90Y-Rituximab. Overall response rate (ORR) was 45% of which complete response (CR) was observed in 2 patients, stable disease in 1 patient and partial response in 6 patients. The therapy was well tolerated with grade IV thrombocytopenia, neutropenia and anemia observed in 3, 4 and 2 patients respectively.
CONCLUSION: 90Y-Rituximab therapy is safe and well tolerated in high risk extensively pretreated NHL patients. Toxicity is primarily hematologic, transient and reversible.

Khan MA, Garg K, Bhurani D, Agarwal NB
Early manifestation of mild cognitive impairment in B-cell non-Hodgkin's lymphoma patients receiving CHOP and rituximab-CHOP chemotherapy.
Naunyn Schmiedebergs Arch Pharmacol. 2016; 389(12):1253-1265 [PubMed] Related Publications
Existing evidence suggests that pro-inflammatory cytokines increases during chemotherapy which plays an intermediary role in Chemotherapy related cognitive impairment (CRCI) and thyroid dysregulation. Previous studies suggest that thyroid hormones are essential for neuronal development and neurotransmitter release. CHOP regimen has been the backbone of Non-Hodgkin's lymphoma (NHL) treatment from a decade but rituximab addition to CHOP (R-CHOP) has improved cure rates. However, their adverse event profile on behavior is not well studied on patients. In this study total 68 NHL patients were enrolled and divided equally in 2 groups as CHOP receiving (n = 34) and R-CHOP receiving (n = 34). Effects of R-CHOP and CHOP regimen on thyroid function, pro-inflammatory cytokines and cognitive function were determined at four time points that was from one day before 1st (TP0), 2nd (TP1), 3rd (TP2) and 4th (TP3) cycle of chemotherapy. Results indicated significant increase in levels of pro-inflammatory cytokines after each time point from TP0 to TP3of chemotherapy. Thyroid hormone levels i.e. T3, T4 were found significantly decreased and TSH was increased after each time point of both groups. MMSE score was found significantly decreased after each cycle of both groups. However, an inverse association was found between IL-1β levels with TSH by applying correlation coefficient. Cognitive function was decreased in patients with decreased T3 and T4 levels and increased TSH. To conclude, patients receiving R-CHOP regimen were found to have more increased IL-6 and IL-1β with more cognitive decline and thyroid abnormality as comparison to CHOP receiving patients.

Laribi K, Denizon N, Bolle D, et al.
R-CVP regimen is active in frail elderly patients aged 80 or over with diffuse large B cell lymphoma.
Ann Hematol. 2016; 95(10):1705-14 [PubMed] Related Publications
Patients aged 80 or over with diffuse large B cell lymphoma (DLBCL) often have comorbidities that increase drug toxicity and prevent the use of otherwise optimal treatment. We performed a retrospective analysis of 43 patients aged 80 or over (median age: 83; range: 80-93) unable to receive treatment with anthracyclines, at diagnosis of DLBCL, treated with an R-CVP treatment (standard R-CHOP without doxorubicin). The patients had one or more comorbidities: 18 patients (41.9 %) had a performance status (PS) of 3; 23 patients (53.5 %) had low creatinine clearance; 12 patients (27.9 %) had low left ventricular ejection fraction; seven patients (16.3 %) had poor hepatic function; and 26 patients (60.5 %) had a Charlson index score ≥4. Thirty patients (70 %) had two or three adverse factors according to the age-adjusted International Prognostic Index. Twenty-five patients (58.1 %) received eight cycles of R-CVP, but the full eight cycles could not be given to 18 patients (41.9 %). The OR rate was 58.1 % (CR 37.2 %). There were 34 deaths (79 %) during treatment and follow-up. Ten patients (23.3 %) died early from toxicity before interim evaluation; all had PS 3. The median follow-up of surviving patients was 52.6 months. The overall 2-year survival rate was 31.9 % and the median OS was 12.6 months. The median OS for patients who completed the entire treatment was 26.4 months. The median PFS was 11.2 months. In multivariate analyses, OS was only affected by performance status ≥2 and Charlson index score ≥4. The R-CVP regimen can be active in elderly frail patients aged 80 or more with DLBCL, but systematic geriatric assessment is required so that those unsuitable for chemotherapy are excluded.

Nolasco-Medina D, Reynoso-Noveron N, Mohar-Betancourt A, et al.
Comparison of Three Chemotherapy Regimens in Elderly Patients with Diffuse Large B Cell Lymphoma: Experience at a Single National Reference Center in Mexico.
Biomed Res Int. 2016; 2016:9817606 [PubMed] Free Access to Full Article Related Publications
Background. Although chemotherapy added to rituximab is a standard of care for diffuse large B cell lymphoma (DLBCL), treatment of patients ≥65 years of age remains controversial due to comorbidities. Methods. This is a retrospective, comparative, nonrandomized study of patients ≥65 years of age, who were diagnosed with DLBCL but not previously treated. Demographic characteristics and comorbidities were analyzed. Three rituximab-containing treatment regimens (standard RCHOP, anthracycline dose-reduced RChOP, and RCOP) were compared. Descriptive analyses were conducted. Survival was calculated with the Kaplan-Meier method, and differences were compared with the log-rank test. Results. In total, 141 patients with a median age of 73.9 years were studied. The three treatment groups had comparable demographic characteristics. The overall response was 77%, 72.5%, and 59% in groups treated with RCHOP, RChOP, and RCOP, respectively. After multivariate analysis, the factors influencing the overall survival were the presence of B symptoms, poor performance status (ECOG ≥ 3), and febrile neutropenia. Factors influencing disease-free survival were febrile neutropenia, high-intermediate and high-risk IPI scores, and treatment without anthracycline. Conclusion. A higher ORR (overall response rate) was achieved with standard RCHOP, which influenced DFS and OS, although it was not statistically significant compared with the other groups. Interventional phase 3 trials testing new molecules in patients aged 70 to 80 years and older are required to improve the prognosis within this growing population.

Moura M, Silva-Dos-Santos A, Afonso J, Talina M
First-episode psychosis in a 15 year-old female with clinical presentation of anti-NMDA receptor encephalitis: a case report and review of the literature.
BMC Res Notes. 2016; 9:374 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Anti-NMDA receptor encephalitis is an autoimmune disease that was identified in 2007, and manifests in a stepwise manner with psychiatric, neurological and autonomic symptoms. The disease is caused by autoantibodies against NMDA receptors. It can have a paraneoplastic origin, mainly secondary to ovarian teratomas, but it can also be unrelated to the tumor. This disease can affect both sexes and all ages.
CASE PRESENTATION: Here, we present a case of a 15 year-old female adolescent with first-episode psychosis with anti-NMDA receptor encephalitis not related to tumor, which manifested with delusion, hallucinations, panic attacks, agitation, and neurological symptoms, and later with autonomic instability. She was treated with immunotherapy and psychiatric medication resulting in improvement of her main psychiatric and neurological symptoms.
CONCLUSION: Our main objective in presenting this case is to alert clinicians to this challenging and recent disease that has a clinical presentation that might resemble a functional psychiatric condition and can be underdiagnosed in the context of child and adolescent psychiatry.

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