Bendamustine is effective therapy in patients with rituximab‐refractory,indolent B‐cell non‐Hodgkin lymphoma

BACKGROUND:

Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single‐agent bendamustine in patients with rituximab‐refractory, indolent B‐cell lymphoma.

METHODS:

Eligible patients (N = 100, ages 31‐84 years) received bendamustine at a dose of 120 mg/m² by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0‐6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression‐free survival (PFS).

RESULTS:

An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

CONCLUSIONS:

Single‐agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab‐refractory indolent B‐cell lymphoma. Cancer 2010. © 2010 American Cancer Society.     

Chlorambucil–rituximab as first‐line therapy in patients affected by follicular non‐Hodgkin's lymphoma: a retrospective single‐centre study

Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has been shown to be active in newly diagnosed and relapsed patients with follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. Many studies suggest that the prognosis of patients with FL may improve when it is used in combination with chemotherapy. Despite these advances, the disease remains essentially incurable with standard therapy, and novel approaches to treatment are needed because optimal therapy is not defined. The combination of chlorambucil–rituximab is one of several standard treatment options for FL. Here, we considered data arising from 75 patients with newly diagnosed FL at the European Institute of Oncology treated with the combination of rituximab plus chlorambucil. The aim of this study was to evaluate the efficacy and safety of chlorambucil and rituximab, delivered 6 mg/m²/day orally for 6 weeks and 375 mg/m² in a standard 4‐weekly schedule, respectively. Patients responding to the induction therapy received a prolonged therapy with four additional cycles of chlorambucil plus rituximab. Seventy‐one patients (94.6%) completed the treatment; four patients discontinued treatment because of grade 3–4 hematological toxicity. The overall response rate was 97.3% including 74.7% of complete responses. Only two patients had a stable disease at revaluation after treatment. With a median follow‐up of 57 months, 72 patients (96%) are alive. Median event‐free survival (EFS) and median overall survival (OS) were not reached; 5‐year OS rate was 98.4%. The 5‐year EFS was 71.3%. By univariate and multivariate analyses, elevated beta‐2 microglobulin levels and partial responses to therapy were correlated with worse EFS. These results suggest that the combination of chlorambucil and rituximab is an active and safe regimen in patients with newly diagnosed FL, principally in those with low tumour burden and favourable prognostic factors. Copyright © 2014 John Wiley & Sons, Ltd.     

Combination of rituximab and nonpegylated liposomal doxorubicin (R‐NPLD) as front‐line therapy for aggressive non‐Hodgkin lymphoma (NHL) in patients 80 years of age or older: a single‐center retrospective study

The incidence of non‐Hodgkin lymphoma in patients 80 years of age or older is 50 times higher than in 20‐ to 24‐year‐olds. Very elderly patients are often not treated with standard immunochemotherapy because of poor performance status, comorbidities, and toxicity concerns. We retrospectively analyzed data for 29 patients diagnosed with diffuse large B‐cell lymphoma or grade 3B follicular lymphoma and treated with rituximab in combination with nonpegylated liposomal doxorubicin between January 2010 and August 2015. The median age was 84 years. The overall 3‐year survival, cause‐specific survival, and progression‐free survival rates were 46%, 55%, and 44%, respectively. Among prognostic factors, only the achievement of complete remission strongly correlated with overall survival, cause‐specific survival, and progression‐free survival rates. Treatment caused very mild toxicity, without treatment‐related hospitalization or toxic deaths.     

Autografting followed by rituximab for chemosensitive mantle cell lymphoma: A pilot study and literature review

Mantle cell lymphoma (MCL) is rarely cured with either conventional-dose chemotherapy or autografting. Recent evidence suggests that anti-CD20 monoclonal antibody therapy (rituximab) in combination with chemotherapy may improve the response rate. We report a pilot study of autografting using busulfan - melphalan conditioning followed by rituximab in 9 patients (median age 52 years) with chemosensitive MCL. Rituximab was given for 4 doses of 375 mg/m² between 4 and 10 weeks post-transplant. Three of 5 patients autografted after induction therapy remain alive in clinical and molecular complete remission at 33 - 50 months post-transplant. Only 1 of 4 patients autografted after relapse remains in complete remission. Two of the 3 patients with persistent marrow molecular positivity post-autograft became negative after rituximab therapy. Molecular negativity was first observed in 2 patients only after rituximab therapy. Overall, 2 patients have relapsed and the remaining 3 died of late-onset respiratory failure, probably reflecting infection and/or aggressive conditioning in an older patient population. These preliminary results, together with a review of the literature, suggest that the combination of autografting and rituximab may lead to durable molecular remissions in patients with chemosensitive MCL. Further studies are required to clarify whether the administration of rituximab: (1) is optimal pre- or post-autograft and (2) impacts on the incidence of infection and idiopathic pneumonitis in this context.     

Familial nodular lymphocyte predominant Hodgkin lymphoma: Successful treatment with CHOP plus rituximab

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare tumor type distinct from classical Hodgkin lymphoma and its familial form is unusual. The two cases (mother at age 48 and son at age 30 years) of NLPHL in advanced clinical stage are described. The patients were successfully treated with an immunochemotherapy schedule consisting CHOP plus rituximab (CHOP-R). This chemotherapy was well tolerated and the patients reached complete remission. These remissions were for 34 and 40 months for mother and son, respectively. In patients with NLPHL, CHOP-R regimen should be used as an alternative treatment regimen to obtain a good long-lasting response without any adverse events.     

Phase 2 study of gemcitabine in combination with rituximab in patients with recurrent or refractory Hodgkin lymphoma

BACKGROUND: The management of recurrent or refractory Hodgkin lymphoma (HL) remains challenging. The objective of this phase 2 trial was to investigate the activity of gemcitabine in combination with rituximab in patients with recurring or refractory HL. METHODS: Patients were considered eligible if they had recurring or refractory HL, had received >or=2 prior chemotherapy regimens, had an Eastern Cooperative Oncology Group (ECOG) performance status 相似文献   

Anthracycline‐fludarabine‐containing regimens with or without rituximab in the treatment of patients with advanced follicular lymphoma

BACKGROUND:

Recent experience has suggested that there has been a stepwise improvement in the survival outcomes of patients who have follicular lymphoma with the introduction of new treatment options. In the current study, the authors report the results of 2 subsequent phase 2 trials of 238 previously untreated patients.

METHODS:

In a trial of bleomycin, epidoxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP) plus fludarabine, mitoxantrone, and dexamethasone (FND), 144 patients received 2 BACOP treatments followed by 4 FND treatments. In a trial of BACOP plus fludarabine and rituximab (FR), 94 patients received 3 BACOP treatments followed by 4 FR treatments.

RESULTS:

The complete remission (CR) rate for BACOP/FND was 62%. After a median follow‐up of 60 months, the failure‐free survival (FFS) and overall survival (OS) rates at 4 years were 53% and 77%, respectively. The CR rate for BACOP/FR was 79%. After a median follow‐up of 36 months, the FFS and OS rates at 4 years were 56% and 97%, respectively, which were significant compared with the CR and OS rates achieved with BACOP/FND. Twenty‐five of 42 bcl‐2‐positive patients attained a molecularly negative CR and had improved FFS. No significant differences were observed between the 2 trials in the percentage of infections or neutropenia.

CONCLUSIONS:

The CR and OS rates achieved with BACOP/FR were better, and overall toxicity did not increase. Furthermore, patients who received rituximab had a better FFS compared with patients who received chemotherapy alone. Finally, although conclusions between nonrandomized groups may depend on differences in observed and unobserved prognostic features, the current results suggested that the addition of rituximab to anthracycline‐fludarabine–containing regimens have a favorable effect on the prognosis of patients with advanced follicular lymphoma. Cancer 2009. © 2009 American Cancer Society.     

The dog as a possible animal model for human non‐Hodgkin lymphoma: a review

Lymphoma represents the most frequent hematopoietic cancer in dogs, and it shows significant overlap with the human disease. Several environmental factors have been associated with canine lymphoma, suggesting that they may contribute to lymphomagenesis. Canine lymphoma often presents in advanced stage (III–V) at diagnosis and, most commonly, has an aggressive clinical course requiring prompt treatment, which relies on the use of polychemotherapy. In this review, we will summarize the state‐of‐the‐art of canine lymphoma epidemiology, pathobiology, diagnostic work‐up and therapy, and will highlight the links to the corresponding human disease, providing evidence for the use of dog as an animal model of spontaneous disease. Copyright © 2012 John Wiley & Sons, Ltd.     

GBV‐C/hepatitis G virus infection and non‐Hodgkin lymphoma: a case control study

We investigated whether there was an association between GBV‐C viremia and the development of non‐Hodgkin lymphoma (NHL) in 553 NHL cases and 438 controls from British Columbia, Canada. Cases were aged 20–79, diagnosed between March 2000 and February 2004, and resident in Greater Vancouver or Victoria. Cases and controls were tested for GBV‐C RNA by RT‐PCR and positive samples were genotyped. Overall, GBV‐C RNA was detected in 4.5% of NHL cases vs. 1.8% of controls [adjusted odds ratio (OR) = 2.72, 95% confidence interval (CI) = 1.22–6.69]. The association between GBV‐C RNA detection and NHL remained even after individuals with a history of prior transfusion, injection drug use and hepatitis C virus sero‐positivity were excluded. GBV‐C viremia showed the strongest association with diffuse large B cell lymphoma (adjusted OR = 5.18, 95% CI = 2.06–13.71). Genotyping was performed on 29/33 GBV‐C RNA positive individuals; genotypes 2a (n = 22); 2b (n = 5) and 3 (n = 2) were identified, consistent with the distribution of genotypes found in North America. This is the largest case‐control study to date associating GBV‐C viremia and NHL risk. As GBV‐C is known to be transmitted through blood products this may have important implications for blood safety.     

Cardiovascular mortality among patients with non‐Hodgkin lymphoma: Differences according to lymphoma subtype

Survival rates of patients with non‐Hodgkin lymphoma (NHL) have improved over the last decade. However, cardiotoxicities remain important adverse consequences of treatment with chemotherapy and radiation, although the burden of cardiovascular mortality (CVM) in such patients remains unknown. We conducted a retrospective cohort study of patients greater than or equal to 20 years of age diagnosed with diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) between 2000 and 2013 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. Our primary endpoint was CVM. The association between NHL and CVM was evaluated using multivariable Cox regression analysis after adjusting for other patient characteristics. We calculated standardized mortality ratios (SMRs) for CVM, comparing NHL patients with the general population. We identified 153 983 patients who met the inclusion criteria (69 329 with DLBCL, 48 650 with CLL/SLL, and 36 004 with FL). The median follow‐up was 37 months (interquartile range, 10‐78 months); the mean patient age was 66.24 (±14.69) years; 84 924 (55.2%) were men; 134 720 (87.5%) were White, and 131 912 (85.7%) did not receive radiation therapy. Overall, 9017 patients (5.8%) died from cardiovascular disease, and we found that NHL patients had a higher risk of CVM than the general population, after adjusting for age (SMR 15.2, 95% confidence interval: 14.89‐15.52). The rates of CVM were 5.1%, 8%, and 4.4% in patients with DLBCL, CLL/SLL, and FL, respectively. Furthermore, across all NHL subtypes, older age, higher stage at the time of diagnosis (particularly stage 4), male sex, and living in the south were associated with higher risks of CVM. Our data suggest that risk assessment and careful cardiac monitoring are recommended for NHL patients, particularly those with the CLL/SLL subtypes.     

Impact of the introduction of rituximab in first‐line follicular lymphoma: a retrospective study of 247 unselected patients referred to a single institution with a long‐term follow‐up

Rituximab was approved in France in 2004, following randomized trials that demonstrated efficacy in newly diagnosed high tumour burden follicular lymphoma (FL). This retrospective study compared the management and outcome of FL in unselected patients treated in a single institution before and after rituximab approval. Two hundred and forty‐seven adult patients were referred with first‐line FL between 1996 and 2010 and are included in this study. The 103 pre‐rituximab patients comprising cohort 1 were diagnosed between January 1996 and December 2003; cohort 2 includes the 144 patients diagnosed after the approval of rituximab between January 2004 and December 2010. Baseline clinical and biological data, type of therapy, treatment response, progression‐free survival (PFS) and overall survival (OS) rates were compared. There were no statistically significant differences between the two cohorts with respect to baseline clinical and disease characteristics, including FL International Prognostic Index score. The major difference between the two cohorts is the use of rituximab in first line. Seventy‐one per cent of patients in cohort 2 received rituximab (19% alone, 52% with chemotherapy) versus 10% in cohort 1 (2% alone, 8% with chemotherapy; p < 0.0001). The objective response rate (ORR) was significantly higher for cohort 2 (ORR 84% compared with 72% for cohort 1; p = 0.03). The PFS and OS rates were also significantly better: 3‐year PFS 72% [95% confidence interval (CI) 64–80%] versus 55% (95% CI 45–64%), p = 0.0039 and 3‐year OS 98% (95% CI 94–99%) versus 83% (95% CI 74–90%), p = 0.0007. Effect of period of study is significant when using multivariate analysis on PFS and OS and lactate dehydrogenase level (PFS and OS) and age (OS). These data from everyday practice confirm the benefit for patients with FL treated in the last decade through availability of rituximab in first line used alone or in association with various chemotherapy regimens. Copyright © 2014 John Wiley & Sons, Ltd.     

Outcome for young high-risk aggressive B-cell lymphoma patients treated with CHOEP-14 and rituximab (R-CHOEP-14)

Purpose To study the effectiveness and tolerability of a dose-intensified treatment including rituximab for patients, not older than 65 yr, with high-risk aggressive B-cell lymphoma. Patients Thirty-eight patients with high-risk aggressive B-cell lymphoma, the majority classified as grade 2 or 3 using age-adjusted International Prognostic Index, were treated with six courses of CHOEP+rituximab on a 2-wk schedule with G-CSF d 4-11. CNS prophylaxis was administered using intravenous Ara-C as a single dose at the end of treatment. Results All patients were considered responders after three courses. Thirty-one patients (82%) achieved a complete remission or a complete remission unverified. With a median follow up of 27 mo, overall and event-free survival are 79% and 60%, respectively. Treatment was given on an outpatient basis. There were no treatment-related unexpected toxic events or mortalities. Large-cell lymphoma involvement of the bone marrow was a poor prognostic sign even with this intensified treatment and 4/6 patients relapsed. CNS relapse occurred in three patients, two of whom had large cell bone marrow involvement. Conclusion Although only a short follow up, the R-CHOEP-14 regimen is promising and could be an improvement compared to conventional treatment, with acceptable toxicity. The value of intravenous Ara-C at the end of treatment can be questioned, as it did not prevent CNS relapse or affect treatment outcome.     

Temozolomide plus rituximab in the treatment of recurrent central nervous system lymphoma： Case report and literature review

Objective  

The aim of our study was to investigate the treatment of recurrent central nervous system lymphoma.     

Factors affecting toxicity, response and progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with rituximab: a Japanese phase II study.

BACKGROUND: The aim of the study was to determine factors affecting the toxicity and efficacy of rituximab monotherapy in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma (MCL). PATIENTS AND METHODS: A total of 90 patients were enrolled and treated with rituximab infusions at 375 mg/m2 once weekly for 4 weeks. Central pathology review revealed that histologically, 81 patients had indolent B-cell lymphoma or MCL: 59 with follicular lymphoma, 17 with MCL, four with marginal zone lymphoma and one with lymphoplasmacytoid lymphoma. Of these, four were ineligible due to violation of other eligibility criteria. Pre-treatment variables affecting toxicities were analyzed for all 90 patients, and those affecting response and progression-free survival (PFS) were analyzed for 77 eligible patients with confirmed indolent B-cell lymphoma or MCL. The relationship between serum rituximab levels and efficacy was also analyzed for 66 eligible patients. RESULTS: Hematological toxicities (grade > or =3) occurred more frequently in females (P <0.05), and thrombocytopenia and leukopenia were more frequent in patients with high lactate dehydrogenase (LDH) levels (P <0.05). Non-hematological toxicities (grade > or =2) were more frequent in patients with extranodal disease or bone marrow involvement. The overall response rate (ORR) in patients receiving one prior chemotherapy regimen was higher than those receiving two or more regimens (P <0.05). The median PFS was shorter in MCL patients, in those with extranodal disease, or in those receiving two or more prior chemotherapy regimens (P <0.01). The PFS intervals of patients with higher serum rituximab levels (> or =70 microg/ml) immediately before the third infusion were longer than in other patients (P <0.01). CONCLUSIONS: Several prognostic factors and serum rituximab levels are useful for predicting the toxicity and efficacy of rituximab monotherapy.     

Fludarabine–Mitoxantrone–Rituximab regimen in untreated indolent non‐follicular non‐Hodgkin's lymphoma: experience on 143 patients

Indolent non‐follicular lymphomas (inFLs) are generally regarded as incurable, apart from extranodal mucosa‐associated lymphatic tissue lymphomas, which can be partially cured by surgery, local radiotherapy, or antibiotic treatment. The aim of the present study was to test the degree of effectiveness and the safety of the regimen containing fludarabine, mitoxantrone, and rituximab (FMR) in inFL patients considering all the different entities belonging to this group. An observational retrospective study was conducted on 143 inFL patients providing that their first chemoimmunotherapy performed was FMR regimen and diagnosis from September 2000 to March 2011. There were 32 small lymphocytic lymphomas and 111 marginal zone lymphomas. At the end of treatment, overall response rate was 96.5% with 88% of complete responses (CR) and 8.5% of partial responses. With a median follow‐up of 48 months, 10 out of 125 (8%) CR patients had disease relapse, yielding an estimated 9‐year disease‐free survival (DFS) of 74.9% and an estimated 10‐year overall survival of 92.8%. The estimated 9‐year progression free survival was 70.5%. The 10 relapsed patients showed lymphoma recurrence within 52 months: after this time, the DFS curve presented a plateau configuration. Only two (1.4%) patients developed a secondary hematological neoplasia. This study showed promising findings for the use of a fludarabine‐based regimen in combination with rituximab in the front‐line treatment of symptomatic inFL with a noteworthy high percentage of CR associated to an interesting long‐term DFS and favorable acute and long‐term safety profile. Copyright © 2014 John Wiley & Sons, Ltd.     

The role of maintenance therapy in patients with diffuse large B cell lymphoma: A systematic review and meta‐analysis

Randomized trials of maintenance therapy (MT) in diffuse large B cell lymphoma (DLBCL) are inconclusive regarding its effect on overall survival (OS) and disease control. We aimed to examine the efficacy and safety of MT in this meta‐analysis. Systematic review and meta‐analysis of randomized controlled trials comparing MT with observation or placebo, in patients with DLBCL, who achieved complete response (CR) or partial response (PR) after first‐line chemotherapy with or without rituximab. Primary outcome was OS. Secondary outcomes included relapse rate, disease control (defined as progression‐free survival, event‐free survival, or disease‐free survival, as reported in the original trials), and safety. Our search yielded 14 trials including 5122 patients. Median age of patients was 49 to 70 years. Six trials included rituximab as the MT; three included Interferon alfa; other trials include thalidomide, lenalidomide, cyclophosphamide and prednisone, serine threonine kinase inhibitor enzastaurin, and mTOR inhibitor everolimus. MT did not improve OS compared to observation, OR 0.91, (95% CI 0.78‐1.07). Results were the same in a subgroup analysis by the type of maintenance (rituximab vs other). MT did decreased relapse rate, RR 0.76 (95% CI 0.65‐0.89) and improved disease control, OR 0.74 (95% CI 0.65‐0.84). Disease control was significantly improved in the subgroup of studies evaluating rituximab as maintenance OR 0.61 (95% CI 0.47‐0.79) and in the subgroup of R‐CHOP induction studies OR 0.77 (95% CI 0.67‐0.88). Serious or grade III/IV adverse events including neutropenia and infections were significantly more common in the maintenance arm, RR = 1.69 (95% CI 1.29‐2.22). MT in patients with DLBCL achieving CR or PR after induction therapy did not affect OS, yet it decreased relapse rate and improved disease control at the cost of higher infection rate. Our data do not support routine administration of MT in patients with DLBCL.     

Use of non‐steroidal anti‐inflammatory drugs and risk of non‐Hodgkin lymphoma: a systematic review and meta‐analysis

Epidemiological study findings regarding the association between use of non‐steroidal anti‐inflammatory drugs (NSAIDs) and risk of non‐Hodgkin lymphoma (NHL) have been inconsistent. We aimed to systematically review epidemiological studies of the association and calculate pooled relative risks using meta‐analytic methods. We searched eight electronic literature databases and three clinical trial registers to identify all studies (including observational studies and randomized clinical trials) of the association published prior to October 2013. Identified studies were independently reviewed by two researchers. We used a random effects model to calculate pooled odds ratio (PORs). Heterogeneity amongst studies was examined using Cochran's Q and I‐squared (I²) tests; and sources of heterogeneity were explored using subgroup and meta‐regression analyses. A total of 17 studies (12 case‐control studies and five cohort studies), all adult studies, were included. Use of NSAIDs was not associated with overall risk of NHL [POR = 1.05, and 95% confidence interval (95% CI) 0.90–1.22] or NHL subtypes including B‐cell lymphoma, T‐cell lymphoma, follicular lymphoma, diffuse large B‐cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Aspirin use was associated with reduced risk of CLL/SLL (POR = 0.70, 95% CI 0.54–0.91) but not with the risk of all NHLs (POR = 1.02, 95% CI 0.89–1.17). Use of non‐aspirin NSAIDs was associated with increased risk of NHL (POR = 1.41, 95% CI 1.01–1.97) amongst females only. The epidemiologic evidence remains inconclusive. Effects of NSAIDs may differ by drug type, NHL subtype, and sex and more studies taking into consideration these differences are needed. Copyright © 2014 John Wiley & Sons, Ltd.