Multicenter phase II study of bendamustine for relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Bendamustine is a unique cytotoxic agent that has demonstrated efficacy in the treatment of indolent B‐cell non‐Hodgkin lymphomas (B‐NHLs). In this multicenter phase II trial, the efficacy and safety of bendamustine were evaluated in Japanese patients with relapsed or refractory indolent B‐NHL or mantle‐cell lymphoma (MCL). Patients received bendamustine (120 mg/m²) on days 1–2 of a 21‐day cycle, for up to six cycles. The primary endpoint was the overall response rate (ORR) as assessed by an extramural committee according to International Workshop Response Criteria (IWRC). Secondary endpoints included complete response (CR) rate, ORR according to Revised Response Criteria (revised RC), progression‐free survival (PFS), and safety. Fifty‐eight patients with indolent B‐NHL and 11 with MCL were enrolled. By IWRC, bendamustine produced an ORR of 91% (95% confidence interval [CI], 82–97%; 90% and 100% in patients with indolent B‐NHL and MCL, respectively), with a CR rate of 67% (95% CI, 54–78%). ORR and CR rates according to revised RC were 93% (95% CI, 84–98%) and 57% (95% CI, 44–68%), respectively. After a median follow‐up of 12.6 months, median PFS had not been reached. Estimated PFS rates at 1 year were 70% and 90% among indolent B‐NHL and MCL patients, respectively. Bendamustine was generally well tolerated. Reversible myelosuppression, including grade 3/4 leukopenia (65%) and neutropenia (72%), was the most clinically significant toxicity observed. Common non‐hematologic toxicities included mild gastrointestinal events and fatigue. These results demonstrate the high efficacy and tolerability of single‐agent bendamustine in relapsed patients with indolent B‐NHL or MCL histologies. (ClinicalTrials.gov ID: NCT00612183). (Cancer Sci 2010;)     

Phase I and pharmacokinetic study of bendamustine hydrochloride in relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Bendamustine is a cytotoxic agent with a novel mechanism of action. This phase I, dose‐escalation study evaluated the safety, tolerability, efficacy, and pharmacokinetics of bendamustine in Japanese patients with relapsed/refractory indolent B‐cell non‐Hodgkin lymphoma (B‐NHL) or mantle cell lymphoma (MCL) without major organ dysfunction. Bendamustine 90 or 120 mg/m² (dose escalation) was administered intravenously over 60 min on days 1 and 2 every 3 weeks for up to three cycles. Nine patients (eight indolent B‐NHL and one MCL) received per‐protocol treatment, three at 90 mg/m² and six at 120 mg/m². No dose‐limiting toxicities were observed; thus, the maximum‐tolerated dose was not reached. Grade 3/4 hematologic toxicities were neutropenia (33%) and leukopenia (33%). Non‐hematologic toxicities were grade 1/2 and included gastrointestinal events and fatigue. Peak plasma concentrations of bendamustine occurred near the end of infusion in both dose groups and were equivalent to therapeutic concentrations observed in vitro. Bendamustine was rapidly eliminated, with a mean elimination half‐life (t_1/2) of 29 min. Plasma concentrations of active metabolites M3 and M4 were approximately 4 and <1% of the plasma concentration of the parent molecule, with t_1/2 of 42 and 33 min, respectively. Two unconfirmed complete responses and six partial responses were observed for an overall response rate (ORR) of 89%. The recommended dose for this schedule in phase II trials is 120 mg/m². The acceptable safety profile and high ORR warrant further investigation of bendamustine in relapsed or refractory indolent B‐NHL and MCL. (ClinicalTrials.gov ID: NCT00389051). (Cancer Sci 2010)     

Bendamustine in Indolent Non‐Hodgkin's Lymphoma: A Practice Guide for Patient Management

For patients with advanced indolent non‐Hodgkin's lymphoma (NHL) or elderly patients with mantle cell lymphoma (MCL), the recently reported results of the German StiL NHL‐1 2003 and the international BRIGHT phase III trials showed that, as first‐line treatment, the combination of bendamustine and rituximab is at least as effective as rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone or rituximab/cyclophosphamide/vincristine/prednisone, possibly with a better therapeutic index. Bendamustine is therefore increasingly used in clinical practice. Because bendamustine has been used for many years in Germany and in Switzerland, our institutions have had extensive experience with bendamustine, both as a single agent and in combination with rituximab. In this comprehensive review, we summarize the most important clinical data from phase II/III trials with bendamustine in patients with indolent NHL and MCL, both in the relapsed/refractory setting and in the first‐line setting. In addition, this review provides practical advice on how to optimally manage bendamustine therapy in patients with NHL.     

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.     

Non‐Hodgkin lymphoma in Romania: a single‐centre experience

Epidemiologic studies of non‐Hodgkin lymphoma (NHL) in Eastern Europe are scarce in the literature. We report the experience of the “Ion Chiricuta” Institute of Oncology in Cluj‐Napoca (IOCN), Romania, in the diagnosis and outcome of patients with NHL. We studied 184 consecutive NHL patients diagnosed in the Pathology Department of IOCN during the years 2004–2006. We also obtained epidemiological data from the Northwestern (NW) Cancer Registry. In the IOCN series, the most common lymphoma subtype was diffuse large B‐cell lymphoma (43.5%), followed by the chronic lymphocytic leukaemia/small lymphocytic lymphoma (21.2%). T‐cell lymphomas represented a small proportion (8.2%). The median age of the patients was 57 years, with a male‐to‐female ratio of 0.94. Patients with indolent B‐cell lymphomas had the best overall survival, whereas those with mantle cell lymphoma had the worst survival. The NW Cancer Registry data showed that the occurrence of NHL in the NW region of Romania was higher in men [world age‐standardized incidence rate/100 000 (ASR)—5.9; 95% CI 5.1–6.6] than in women (ASR—4.1; 95% CI 3.5–4.7) with age‐standardized male‐to‐female ratio of 1.44 (p = 0.038). Chronic lymphocytic leukaemia/small lymphocytic lymphoma was the most common NHL in the NW region of Romania, accounting for 43% of all cases, followed by diffuse large B‐cell lymphoma (36%). The 5‐year, age‐standardized cumulative relative survival for NHL in the County of Cluj in NW Romania, for the period of 2006–2010, was 51.4%, with 58.4% survival for men and 43.2% for women. Additional studies of NHL in Eastern Europe are needed. Copyright © 2015 John Wiley & Sons, Ltd.     

Classifying B‐cell non‐Hodgkin lymphoma by using MIB‐1 proliferative index in fine‐needle aspirates

BACKGROUND:

MIB‐1 proliferation index (PI) has proven helpful for diagnosis and prognosis in non‐Hodgkin lymphomas (NHLs). However, validated cutoff values for use in fine‐needle aspiration (FNA) samples are not available. We investigated MIB‐1 immunocytochemistry as an ancillary technique for stratifying NHL and attempted to establish PI cutpoints in cytologic samples.

METHODS:

B‐cell NHL FNA cases with available cytospins (CS) MIB‐1 immunocytochemistry results were included. Demographic, molecular, immunophenotyping and MIB‐1 PI data were collected from cytologic reports. Cases were subtyped according to the current World Health Organization classification and separated into indolent, aggressive, and highly aggressive groups. Statistical analysis was performed with pairwise Wilcoxon rank sum test and linear discriminant analysis to suggest appropriate PI cutpoints.

RESULTS:

Ninety‐one NHL cases were subdivided in 56 (61.5%) indolent, 30 (33%) aggressive, and 5 (5.5%) highly aggressive lymphomas. The 3 groups had significantly different MIB‐1 PIs from each other. Cutpoints were established for separating indolent (<38%), aggressive (≥38% to ≤80.1%) and highly aggressive (>80.1%). The groups were adequately predicted in 76 cases (83.5%) using the cutpoints and 15 cases showed discrepant PIs.

CONCLUSIONS:

MIB‐1 immunohistochemistry on CS can help to stratify B‐cell NHL and showed a significant increase in PI with tumor aggressiveness. Six misclassified cases had PIs close to the cutpoints. Discrepant MIB‐1 PIs were related to dilution of positive cells by non‐neoplastic lymphocytes and to the overlapping continuum of features between diffuse large B‐cell lymphoma and Burkitt lymphoma. Validation of our approach in an unrelated, prospective dataset is required. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.     

The bendamustine plus rituximab regimen is active against primary nodal marginal zone B‐cell lymphoma

Primary nodal marginal zone lymphoma (NMZL) is a rare disease. There is no current consensus on how to treat it. The bendamustine plus rituximab (BR) regimen is effective for the treatment of follicular and other indolent lymphomas, but its efficacy in NMZL is not known. We analyzed the outcome of 14 patients diagnosed with NMZL (median age 67 years) who were treated with 375 mg/m² of rituximab on day 1 and 90 mg/m² of bendamustine on days 1 and 2. The overall and complete response rates were 93% and 71%, respectively. Major toxicity (grade 3/4 neutropenia) occurred in 5% of treatment courses. After a median follow‐up of 22 months (range: 18‐55), the overall survival and the free survival rates were 100% and 93%, respectively. None of the patients showing a complete or partial response developed secondary myelodysplastic syndrome/acute myeloid leukemia. Bendamustine plus rituximab was found to be an active and well‐tolerated regimen leading to the rapid control of disease.     

Concomitant high expression of Toll‐like receptor (TLR) and B‐cell receptor (BCR) signalling molecules has clinical implications in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive disease with frequent relapse. Targeted therapies against B‐cell receptor (BCR) molecules have demonstrated improved outcomes in relapsed cases. However, clinical responses are slow and selective, with failure to attain complete remission in a significant subset of patients. Complex interaction of BCR signal transduction with toll‐like receptor (TLR) and other pathways in MCL remains unknown, thus averting progress in development of targeted therapies. We have performed detailed digital quantification of BCR/TLR signalling molecules and their effector pathways in a cohort (n = 81) of MCL patients and correlated these data with overall survival. Hierarchical clustering model based on BCR/TLR genes revealed two distinct (BCR^high and BCR^low) subsets of patients (n = 32; 40%) with significant differences in expression (>1.5‐fold change; p < 0.05). Higher levels of BTK/SYK/BLNK/CARD11/PLCG signalosome and lower expression of MALT1/BCL10 genes suggested tonic pattern of BCR activation. Amplified expression of TLR6/TLR7/TLR9 was noted in concert with hyper‐responsiveness of BCR machinery. MYD88, a key TLR adaptor molecule, was not upregulated in any of these clusters, which may suggest a ‘cross‐talk’ between BCR and TLR pathways. In sync with BCR/TLR signalling, we recorded significantly enhanced expression of genes associated with NF‐kB pathway in BCR^high subset of MCL patients. On univariate analysis, the BCR^high patients showed a trend towards inferior clinical response to a standardized treatment protocol, compared with the BCR^low group (log rank, p = 0.043). In conclusion, we have identified hyperactive BCR/TLR signalling pathways and their effector downstream targets in a subset of MCL patients and associated it with poor clinical outcomes. Our study provides quantitative evidence at RNA expression level of possible concomitant collaboration between TLR and BCR signalling molecules in MCL. These data will provide further insights for future functional studies and, hence, development of targeted therapies for MCL patients. Copyright © 2015 John Wiley & Sons, Ltd.     

Serum beta‐2 microglobulin as a prognostic biomarker in patients with mantle cell lymphoma

Although serum beta‐2 microglobulin (B2M) has been suggested as a prognostic factor for mantle cell lymphoma (MCL), additional data are necessary to confirm its role. Between November 2005 and July 2014, a total of 52 patients with MCL were identified from the database of Asan Medical Center, Seoul, Korea. Pretreatment serum B2M information was available in 50 patients (96%). Overall survival (OS) was compared according to the serum B2M level with a cut‐off value of 2.5 mg/L. The median MCL international prognostic index (MIPI) score was 5.84 (range 4.72–7.80), and the median biologic MIPI (MIPI‐b) score was 6.27 (4.93–8.47). Pretreatment serum B2M was elevated in 30 patients (60%) and was significantly related to advanced stage (p = 0.02) and high MIPI (p = 0.03) and MIPI‐b (p = 0.03) scores. With median follow‐up duration of 29.8 months (range 0.8–87.0 months), the median OS was 56.2 months [95% confidence interval (CI) 36.6‐75.9 months] in all patients, and serum B2M was significantly associated with OS (p = 0.001). In multivariate analyses adjusted for MIPI or MIPI‐b scores and rituximab, elevated serum B2M was significantly associated with poor OS (when adjusting MIPI, hazard ratio = 26.4, 95% CI 2.9–241.3, p = 0.004; when adjusting MIPI‐b, hazard ratio = 20.1, 95% CI 2.4–170.1, p = 0.006). Thus, pretreatment serum B2M may be an independent and significant prognostic factor in patients with MCL. Copyright © 2015 John Wiley & Sons, Ltd.     

A Phase I Study of Everolimus and Bendamustine in Patients With Relapsed/Refractory Lymphoid Hematologic Malignancies

IntroductionEverolimus and bendamustine both have single-agent activity against lymphoid hematologic malignancies. We examined this combination in a group of heavily pretreated patients with non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and multiple myeloma (MM).Patients and MethodsIn this phase I trial, 18 patients (8 with NHL, 6 with MM, and 4 with HL) were treated with bendamustine 90 mg/m² on days 1 and 2 and everolimus from 5 to 10 mg daily on a 28-day cycle, for up to 4 cycles.ResultsAdverse events were generally mild and mostly hematologic in nature. The most frequent grade 3/4 adverse events were lymphopenia (61%), thrombocytopenia (22%), leukopenia (22%), neutropenia (17%), and fatigue (17%). Overall response rate varied by malignancy: diffuse large B-cell lymphoma, 20% (1 of 5 patients); HL (2 of 4 patients), 50%; MM, 80% (4 of 5 patients); and indolent lymphomas, 100% (3 of 3 patients). The maximum tolerated dose of everolimus was determined to be 7.5 mg daily.ConclusionThe combination of everolimus and bendamustine appeared to be well-tolerated and relatively efficacious.     

Toll‐like receptor‐4 signaling in mantle cell lymphoma

BACKGROUND:

Mantle cell lymphoma (MCL) is an incurable B‐cell malignancy, and patients with this disease have the poorest prognosis among all patients with B‐cell lymphomas. The signaling pathways that trigger MCL escape from immune surveillance are unclear. Because Toll‐like receptors (TLRs) initiate innate and adaptive immune responses against invading pathogens, the authors investigated the impact of TLR signaling in MCL cells.

METHODS:

TLR expression was examined in MCL cell lines and in primary tumors. The examination focused on TLR4 and its ligand lipopolysaccharide (LPS) on MCL cells and their function on MCL proliferation and immune evasion.

RESULTS:

MCL cells expressed multiple TLRs, and TLR4 was among the highest expressed molecules. The activation of TLR4 signaling in MCL cells by LPS induced MCL proliferation and up‐regulated the secretion of cytokines like interleukin‐6 (IL‐6), IL‐10, and vascular endothelial growth factor (VEGF). LPS‐pretreated MCL cells inhibited the proliferation and cytolytic activity of T cells by secreted IL‐10 and VEGF, and neutralizing antibodies against these cytokines restored their functions. Similar results were observed in TLR4‐positive/myeloid differentiation 88 (MyD88)‐positive primary lymphoma cells but not in TLR4‐positive/MyD88‐negative primary lymphoma cells from patients with MCL. Knockdown of TLR4 on MCL cells abrogated the effect of LPS on MCL cells in term of cell growth or secretion of the cytokines and evasion of the immune system.

CONCLUSIONS:

The current results indicated that TLR4 signaling triggers a cascade that leads to MCL growth and evasion from immune surveillance. Thus, TLR4 signaling molecules may be novel therapeutic targets in patients with MCL. Cancer 2013. © 2012 American Cancer Society.     

Absolute monocyte count predicts overall survival in mantle cell lymphomas: correlation with tumour‐associated macrophages

Mantle cell lymphoma (MCL) is characterized by a variable clinical course in which patients can experience indolent disease or frequent relapses despite a good initial response to conventional therapy. Risk stratification of MCL is most frequently performed using the MCL International Prognostic Index (MIPI). Recent studies indicate that the peripheral blood absolute monocyte count (AMC) and tumour‐associated macrophages may reflect the state of the tumour microenvironment in lymphomas. The significance of AMC and tumour‐associated macrophages in the clinical course of MCL is unknown. The prognostic impact of the AMC, of CD68 expression and of CD163 expression was retrospectively examined in 103 MCL samples using the receiver operating characteristic curved. Patients with an AMC ≥ 375 cells/μL at diagnosis were more likely to present with advanced‐stage disease (p = 0.026), leukocytosis (p < 0.001), lymphocytosis (p = 0.01) and granulocytosis (p = 0.003). On univariate analysis, a high AMC (≥375 cells/μL) correlated with poorer overall survival (OS) (p = 0.01). Neither CD68 nor CD163 expression was significantly associated with either OS or event‐free survival. Multivariate analysis showed that a high AMC was a prognostic factor for OS, independent of the MIPI [hazards ratio (HR), 1.811; 95% confidence interval, 1.018–3.223; p = 0.043]. This study demonstrates that the AMC at the time of diagnosis is an independent prognostic factor for OS in MCL, which suggests the possibility that AMC may be used in addition to the MIPI to predict outcome in patients with MCL. Copyright © 2013 John Wiley & Sons, Ltd.     

Clinicopathologic characteristics and outcomes of transformed diffuse large B‐cell lymphoma in hepatitis C virus‐infected patients

Hepatitis C virus (HCV) causes a chronic but curable infection associated with the development of marginal zone lymphoma (MZL) and diffuse large B‐cell lymphoma (DLBCL). Preliminary data have shown frequent transformation of indolent lymphoma to DLBCL in HCV‐infected patients. To compare their clinicopathologic characteristics and oncologic outcomes, we reviewed the medical records and pathology reports of HCV‐infected and uninfected patients with DLBCL that transformed from indolent lymphoma seen at The University of Texas MD Anderson Cancer Center (June 2004 to May 2015). To identify predictors of DLBCL relapse, patients with relapse after first‐line chemotherapy were compared with those without it using univariate and logistic regression analyses. Compared with the uninfected patients (n = 63), HCV‐infected patients (n = 21) were younger (median age =54 years [interquartile range= 49–62 years] vs. 62 years [53–66 years]; p = 0.01) and more often had advanced DLBCL (Ann Arbor stage 3–4; 95% vs. 76%; p = 0.05). Immunophenotypically, more HCV‐infected than uninfected patients had CD10‐negative B cells (76% vs. 43%; p = 0.008), CD5‐positive B cells (39% vs. 7%; p = 0.004) and activated B‐cell phenotypes (57% vs. 31%; p = 0.07). Comparison of the patients who had relapse after first‐line chemotherapy (n = 42) and those who did not (n = 40) revealed that having CD5‐positive B cells was the only factor associated with DLBCL relapse in multivariate analysis (odds ratio= 10.7; p = 0.02). HCV‐infected patients with transformed DLBCL have unique clinicopathologic characteristics that make their lymphoma difficult to treat, potentially leading to unfavorable outcome. The impact of HCV eradication should be explored in such patients.     

Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B‐cell‐derived mantle cell lymphoma

Composite lymphomas (CL) represent the occurrence of two distinct lymphomas in the same patient. Often, CL share a common cellular origin, thus representing a unique model to investigate the multistep genetic path leading to lymphomagenesis in general and to the specific development of each distinct lymphoma component in particular. Here, we present the molecular analysis of a case consisting of an unusual Hodgkin lymphoma (HL) and a mantle cell lymphoma (MCL), intimately admixed within one another in lymph nodes and bone marrow yet phenotypically distinct, in a patient who first presented with splenic/leukemic MCL two years earlier. MCL and Hodgkin and Reed/Sternberg (HRS) cells harbored identical immunoglobulin (Ig) V_H gene rearrangements with shared somatic mutations, proving their common clonal origin from a (post‐)germinal center (GC) B cell. This also demonstrates the (post‐)GC origin of MCL with mutated IgV genes. Both lymphomas carried the same CCND1/IGH translocation and, unexpectedly for HL, expressed cyclin D1 and OCT2. Thus, HRS cells are able to preserve IGH locus activity (otherwise usually silenced in HL) to promote expression of an oncogene translocated into this locus. Both lymphoma populations further showed an identical TP53 function‐impairing mutation, and later acquired a TP53 heterozygous deletion independently from one another (convergent evolution). The surprisingly close genetic relationship of the lymphomas, together with their histological intermingling and the clinical history of the patient, suggests subclonal evolution of HL from MCL as a plausible pathway in alternative to that so far described in CL, i.e. separate development from a common precursor.     

Bendamustine and rituximab is well-tolerated and efficient in the treatment of indolent non-Hodgkin's lymphoma and mantle cell lymphoma in elderly: A single center observational study

Bendamustine and rituximab (BR) is a preferred first-line therapy for indolent non-Hodgkin's lymphoma (iNHL) and mantle cell lymphoma (MCL); however, few reports on BR performance in elderly patients are available to date. We compared safety and efficacy of BR in patients ≥70 years (elderly) vs <70 years (younger) treated at our institution. Among 201 patients, 113 were elderly (median age: 77 years), including 38 patients ≥80 years, and 88 were younger (median age: 62 years). Elderly patients had more bone marrow involvement by lymphoma, anemia, ECOG status 3 and high-risk disease follicular lymphoma (P < .05 for all). Fifty-four percent of elderly received full dose of bendamustine vs 79.5% of younger patients. More elderly patients (54%) vs younger (43.2%) experienced treatment delay. Less elderly proceeded to rituximab maintenance. Overall, the number of adverse events per patient and transformed B-Cell lymphoma/secondary malignancies were similar between groups. Elderly patients had less febrile neutropenia, rituximab-associated infusion reactions, but more herpes zoster reactivation. There were more deaths in the elderly (37.2%) vs younger (10.2%) groups (P < .001), mainly due to non-lymphoma-related causes. With median follow-up of 42 months [4.0-97.0] disease-free survival for the elderly was similar to younger patients. There was no difference between patients <80 and ≥80 years (P = .274). In conclusion, the real-world elderly patients have more advanced disease and higher ECOG status. BR is well-tolerated; elderly patients had lower incidence of febrile neutropenia. Dose reduction and treatment delays are common, but BR efficacy was not affected even in very old patients (≥80 years).     

Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma

BACKGROUND:

In vitro studies in mantle cell lymphoma (MCL) cell lines and patient‐derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R‐bortezomib) compared with single‐agent bortezomib. Therefore, the authors of this report evaluated R‐bortezomib in a preclinical model and in a phase 2 clinical trial.

METHODS:

A Hu‐MCL‐severe combined immunodeficiency (SCID) model engrafted with the Jeko cell line was treated with R‐bortezomib, bortezomib, or rituximab. Twenty‐five patients with relapsed follicular lymphoma (n = 11) and MCL (n = 14) received 375 mg/m² rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m² bortezomib on Days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1‐5 cycles).

RESULTS:

R‐bortezomib resulted in a statistically significant improvement in overall survival in Hu‐MCL‐SCID mice. In the clinical trial, the overall response rate was 40% in all 25 patients, 55% in patients with follicular lymphoma, and 29% in patients with MCL. The estimated 2‐year progression‐free survival (PFS) rate was 24% (95% confidence interval [CI], 10%‐53%) in all patients and 60% (95% CI, 20%‐85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity, which consisted of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients who were heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (P = .009) after R‐bortezomib compared with HH and RR homozygotes.

CONCLUSIONS:

R‐bortezomib had significant activity in patients with relapsed or refractory follicular lymphoma and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity was a potential limiting factor with this combination. Cancer 2011. © 2010 American Cancer Society.     

A Canadian perspective on bendamustine for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma

Despite the success of standard treatments in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), patients are often unable to tolerate aggressive regimens, and they require effective alternatives. Bendamustine is a bifunctional alkylator with unique properties that significantly distinguish it from other agents in its class. In untreated CLL, bendamustine has demonstrated rates of response and progression-free survival (PFS) that are superior to those with chlorambucil, with an acceptable toxicity profile. In the relapsed setting, combination treatment with bendamustine-rituximab (BR) has demonstrated promising activity in high-risk patients such as those refractory to fludarabine or alkylating agents. In untreated patients with indolent NHL and mantle cell lymphoma, BR has demonstrated a PFS significantly longer than that achieved with R-CHOP (rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone), with significantly reduced toxicity. In the relapsed setting, br has demonstrated rates of response and PFS superior to those with fludarabine-rituximab, with comparable toxicity. In the United States and Europe, bendamustine has been approved for the treatment of CLL and indolent NHL; its approval in Canada is pending and eagerly awaited. Once available, bendamustine will benefit many Canadian patients with NHL and CLL.     

Using primary site as a predictor of survival in mantle cell lymphoma

BACKGROUND:

Mantle cell lymphoma (MCL) is a rare B cell lymphoma that varies in clinical behavior with some patients experiencing aggressive disease with short survival, whereas others have indolent behavior. We examined the association between primary disease site and survival in MCL patients to identify subgroups with distinct characteristics.

METHODS:

We analyzed the United States Surveillance, Epidemiology and End Results Program database for MCL cases reported from 2000 through 2009. Kaplan‐Meier curves and Cox proportional hazard models were used to estimate the effect of primary site on survival.

RESULTS:

Among 4477 cases included in our study, 19.6% of patients presented with an extranodal primary site. The most common extranodal primary sites were of the gastrointestinal (GI) tract (7.8%), the head and neck (6.2%), and the hematologic/reticuloendothelial systems (3.6%). Asians/Pacific Islanders were more likely than whites or blacks to have GI tract or head and neck disease (P < .0001 and P = .002, respectively). Advanced disease and B symptoms were less common in those with primary disease of the GI tract or head and neck than in those with primary disease of the lymph nodes (both P < .0001). In a multivariate Cox regression model, patients with primary disease of the GI tract and head and neck had superior survival compared to those with primary disease of the lymph nodes; hazard ratios 0.75 (95% CI = 0.62‐0.90) and 0.68 (95% CI = 0.55‐0.85), respectively.

CONCLUSIONS:

Primary site of disease may be an important prognostic factor for patients with MCL. Further studies elucidating a biological basis for these differences are needed. Cancer 2013. © 2013 American Cancer Society.     

Associations between statin use and non‐Hodgkin lymphoma (NHL) risk and survival: a meta‐analysis

Evidence on the effect of statin use on non‐Hodgkin lymphoma (NHL) is not clear. We conducted a systematic review and meta‐analysis to examine the associations between statin use and NHL risk and survival. We searched multiple literature sources up to October 2014 and identified 10 studies on the risk of diagnosis with NHL and 9 studies on survival. Random effects model was used to calculate pooled odds ratio (PORs) for risk and pooled hazard ratio (PHR) for survival. Heterogeneity among studies was examined using the Tau‐squared and the I‐squared (I²) tests. Statin use was associated with reduced risk for total NHL (POR = 0.82, 95% CI 0.69–0.99). Among statin users, there was a lower incidence risk for marginal zone lymphoma (POR = 0.54, 95% CI 0.31–0.94), but this was not observed for other types of NHL. However, statin use did not affect overall survival (PHR = 1.02, 95% CI 0.99–1.06) or event‐free survival (PHR = 0.99, 95% CI 0.87–1.12) in diffuse large B‐cell lymphoma. There is suggestive epidemiological evidence that statins decrease the risk of NHL, but they do not influence survival in NHL patients. Copyright © 2015 John Wiley & Sons, Ltd.     

Clinical experience of bendamustine treatment for non-Hodgkin lymphoma and chronic lymphocytic leukemia in Spain

Bendamustine is a alkylating agent with a purine-like benzamidazole ring currently approved in Europe for indolent non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma. Our aim was to analyze retrospectively the efficacy and toxicity of bendamustine in NHL and CLL in Spain in the bendamustine Compassionate Use Program. Patients with relapsed/refractory NHL or CLL were eligible. Any regimen containing bendamustine was eligible. 109 patients were included from 22 institutions. Forty-nine patients had indolent NHL, 18 aggressive NHL and 42 CLL, being 44 patients (40%) refractory to previous treatment. 63% of patients had adverse events grade 3-4, mainly hematological. Overall response rate (ORR) was 66%, complete responses 30%. ORR observed in refractory patients was 45%. The median progression-free survival (PFS) was 13 months. Outcome was influenced by histology, number of previous treatments, resistance to previous chemotherapy and type of response achieved with bendamustine. Alone or in combination, bendamustine shows a meaningful clinical antitumor activity in patients with relapsed or refractory NHL or CLL, with an acceptable toxicity profile.