Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo.

Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 µM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-κB activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-κB activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.

Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103.

Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with rituximab and lenalidomide in previously untreated follicular lymphoma (overall response rate [ORR] 90%-96%) and ibrutinib in relapsed disease (ORR 30%-55%), the Alliance for Clinical Trials in Oncology conducted a phase 1 trial of rituximab, lenalidomide, and ibrutinib. Previously untreated patients with follicular lymphoma received rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, and 10; lenalidomide as per cohort dose on days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 3+3 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further investigation of the regimen in this setting seems unwarranted. The study was registered with www.ClinicalTrials.gov as #NCT01829568.

An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era.

The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with aggressive non-Hodgkin lymphoma (NHL) for the past 20 years. Using raw clinical data from the National Comprehensive Cancer Network (NCCN) database collected during the rituximab era, we built an enhanced IPI with the goal of improving risk stratification. Clinical features from 1650 adults with de novo diffuse large B-cell lymphoma (DLBCL) diagnosed from 2000-2010 at 7 NCCN cancer centers were assessed for their prognostic significance, with statistical efforts to further refine the categorization of age and normalized LDH. Five predictors (age, lactate dehydrogenase (LDH), sites of involvement, Ann Arbor stage, ECOG performance status) were identified and a maximum of 8 points assigned. Four risk groups were formed: low (0-1), low-intermediate (2-3), high-intermediate (4-5), and high (6-8). Compared with the IPI, the NCCN-IPI better discriminated low- and high-risk subgroups (5-year overall survival [OS]: 96% vs 33%) than the IPI (5 year OS: 90% vs 54%), respectively. When validated using an independent cohort from the British Columbia Cancer Agency (n = 1138), it also demonstrated enhanced discrimination for both low- and high-risk patients. The NCCN-IPI is easy to apply and more powerful than the IPI for predicting survival in the rituximab era.

High Body Mass Index in Elderly Patients With DLBCL Treated With Rituximab-Containing Therapy Compensates for Negative Impact of Male Sex.

BACKGROUND: The impact of patient body habitus and sex on outcomes in diffuse large B-cell lymphoma (DLBCL) remains controversial. We investigated the impact of body mass index (BMI), body surface area (BSA), age, and sex on clinical outcomes in patients with DLBCL treated in the rituximab era. PATIENTS AND METHODS: Patients with de novo DLBCL (n=1,386) diagnosed between June 2000 and December 2010 treated with rituximab-containing chemotherapy were identified from the NCCN Oncology Outcomes Database for Non-Hodgkin's Lymphoma. Progression-free survival (PFS) and overall survival (OS) at 3 years were analyzed based on sex, age, and baseline BMI/BSA. RESULTS: High BMI was associated with a lower risk of disease progression or death than low or normal BMI, whereas male sex was associated with poor clinical outcomes, especially among elderly patients (age >60 years). Compared with elderly women, elderly men experienced worse PFS (3-year hazard ratio [HR], 1.5) and OS (3-year HR, 1.6), but these differences diminished with increases in BMI and BSA. In multivariable analysis, normal BMI compared with high BMI was independently associated with poor outcomes (3-year PFS HR, 1.5; OS HR, 1.6) after adjusting for sex. Notably, only 13% of elderly men had BMI less than 25 kg/m2 and only 26% had BSA less than 2 m2 CONCLUSIONS: Analysis of unselected patients with DLBCL treated with rituximab-containing chemotherapy confirmed an age-dependent disadvantage to male sex in treatment outcomes, but this effect is abrogated by higher levels of BMI and BSA in most North American men.

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). METHODS: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. FINDINGS: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. INTERPRETATION: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. FUNDING: Genentech.

Radiation for diffuse large B-cell lymphoma in the rituximab era: analysis of the National Comprehensive Cancer Network lymphoma outcomes project.

BACKGROUND: The role of consolidation radiotherapy was examined for patients with diffuse large B-cell lymphoma who were treated at institutions of the National Comprehensive Cancer Network during the rituximab era. METHODS: Failure-free survival (FFS) and overall survival (OS) were analyzed in terms of patient and treatment characteristics. Potential associations were investigated with univariate and multivariate survival analysis and matched pair analysis. RESULTS: There were 841 patients, and most (710 or 84%) received 6 to 8 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); 293 (35%) received consolidation radiation therapy (RT). Failure occurred for 181 patients: 126 patients (70%) who did not receive RT and 55 patients (30%) who did. At 5 years, both OS and FFS rates were better for patients who had received RT versus those who did not (OS, 91% vs 83% [P = .01]; FFS, 83% vs 76% [P = .05]). A matched pair analysis (217 pairs matched by age, stage, International Prognostic Index [IPI] score, B symptoms, disease bulk, and response to chemotherapy) showed that the receipt of RT improved OS (hazard ratio [HR], 0.53 [P = .07]) and FFS (HR, 0.77 [P = .34]) for patients with stage III/IV disease, but too few events took place among those with stage I/II disease for meaningful comparisons (HR for OS, 0.94 [P = .89]; HR for FFS, 1.81 [P = .15]). A multivariate analysis suggested that the IPI score and the response to chemotherapy had the greatest influence on outcomes. CONCLUSIONS: There was a trend of higher OS and FFS rates for patients who had received consolidation RT after R-CHOP (especially for patients with stage III/IV disease), but the difference did not reach statistical significance.

Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents.

Histone deacetylases (HDACs) inhibitors are active in T-cell lymphoma and are undergoing pre-clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half-life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B-cell lymphoma we studied its anti-tumour activity in several rituximab-sensitive or -resistant pre-clinical models. We demonstrated that entinostat is active in rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl-XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms-of-action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma-bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B-cell lymphoma.

Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20(+) rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre-B-ALL): potential targeted therapy in patients with poor risk CD20(+) BL and pre-B-ALL.

Obinutuzumab is a novel glycoengineered Type-II CD20 monoclonal antibody. CD20 is expressed in approximately 100% of children and adolescents with Burkitt lymphoma (BL) and 40% with precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL). We evaluated the anti-tumour activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and -sensitive (Raji) BL and pre-B-ALL (U698-M) cells in vitro and in human BL or Pre-B-ALL xenografted mice. We demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35·6 ± 3·1% vs. 25·1 ± 2·0%, (P = 0·001), Raji4RH 19·7 ± 2·2% vs. 7·9 ± 1·5% (P = 0·001) and U-698-M 47·3 ± 4·9% vs. 23·2 ± 0·5% (P = 0·001), respectively. Obinutuzumab versus rituximab also induced a significant increase in antibody-dependent cellular cytotoxicity (ADCC) with K562-IL15-41BBL expanded NK cells against Raji 73·8 ± 8·1% vs. 56·81 ± 4·6% (P = 0·001), Raji-4RH 40·0 ± 1·6% vs. 0·5 ± 1·1% (P = 0·001) and U-698-M 70·0 ± 1·6% vs. 45·5 ± 0·1% (P = 0·001), respectively. Overall survival in tumour xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in BL; Raji (P = 0·05), Raji4RH (P = 0·02) and U698-M (P = 0·03), respectively. These preclinical data suggest obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab-sensitive/-resistant BL and pre-B-ALL xenografted mice. Taken together, these preclinical results provide evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20(+) BL and/or pre-B-ALL.

Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma.

Standard treatment of transplant-eligible patients with relapsed diffuse large B-cell lymphoma (DLBCL) consists of rituximab and platinum-based chemotherapy, either ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP), with autologous transplant consolidation for those with chemosensitive disease. Nonetheless, outcomes are suboptimal for patients failing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We performed a multi-center phase II trial investigating the safety and efficacy of ofatumumab, a monoclonal antibody against CD20, combined with ICE or DHAP second-line therapy in patients with relapsed or refractory DLBCL, grade 3b follicular lymphoma, or transformed follicular lymphoma. Sixty-one patients were treated with either ofatumumab-ICE (35) or ofatumumab-DHAP (26). The overall response rate (ORR) was 61%, and the complete response (CR) rate was 37%. In patients with 2 or 3 adverse risk factors according to the second-line, age-adjusted, international prognostic index, the ORR was 59% and CR 31%, and in patients with early-relapsing or primary refractory disease, the ORR was 55% and CR 30%. Toxicity was largely hematologic, and stem cell mobilization was successful in 43 of 45 patients. Substitution of ofatumumab for rituximab in standard second-line regimens following failure of R-CHOP is a promising approach. This trial was registered at www.clinicaltrials.gov as NCT00823719.

Phase II study of bendamustine combined with rituximab in relapsed/refractory mantle cell lymphoma: efficacy, tolerability, and safety findings.

In most cases of relapsed/refractory mantle cell lymphoma (MCL), patients respond to salvage therapy, though typically responses are partial and/or transient followed by disease progression, even with newer agents (e.g., ibrutinib). In this multicenter, open-label, single-arm, phase II study, patients with relapsed/refractory non-blastoid MCL received bendamustine 90 mg/m(2) (days 1 and 2) and rituximab 375 mg/m(2) (day 1) for 6 planned 28-day cycles. Functional imaging with 18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) was conducted at baseline and after cycle 6. Forty-five patients were enrolled (median age, 70 years; 82 % stage IV disease; median number of prior chemotherapies, 2 [range, 1-4]), showing an overall response rate (ORR; primary efficacy measure) of 82 % (complete response [CR], 40 %; partial response, 42 %). In the 32 patients with complete 18F-FDG PET/CT data, 75 % achieved a complete metabolic response. Median duration of response was 1.6 years, 1-year progression-free survival was 67 %, and 3-year overall survival was 55 %. Main non-hematologic adverse events were nausea (69 %), fatigue (56 %), decreased appetite (42 %), constipation (38 %), diarrhea (36 %), vomiting (36 %), and decreased weight (31 %). Grade 3/4 neutropenia and lymphopenia occurred in 44 and 89 % of patients, respectively. ORR and CR rate compared favorably with single-agent ibrutinib (ORR, 67 %; CR, 23 %); bendamustine-rituximab is an effective therapy with manageable toxicity in relapsed/refractory MCL.

Results of a phase II study of bendamustine and ofatumumab in untreated indolent B cell non-Hodgkin's lymphoma.

The efficacy/tolerability of bendamustine, a unique alkylator, plus ofatumumab, a human anti-CD20 monoclonal antibody, was evaluated for previously untreated indolent B cell non-Hodgkin's lymphoma (NHL). The study investigated whether the overall response rate (ORR) for bendamustine-ofatumumab was similar to historical bendamustine-rituximab ORRs (≥90 %). In this multicenter, open-label, single-arm, phase II study, patients received six planned 28-day cycles of bendamustine (90 mg/m(2) on days 1 and 2 of each cycle) and ofatumumab (300 mg on day 1, 1000 mg on day 8 of cycle 1, and on day 1 of subsequent cycles). The primary outcome was ORR. Secondary objectives included safety and tolerability. Exploratory evaluations included percentage of patients with positive baseline [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans who converted to negative postbaseline and quality of life (QOL) scores. The treated/safety analysis population received ≥1 dose of either therapy. The bendamustine-ofatumumab ORR was 90 % (95 % confidence interval, 77.8-96.6) in 49 treated patients (67 % complete response, 22 % partial response). No patients had progressive disease. Bendamustine-ofatumumab was acceptably tolerated. All 49 patients had ≥1 adverse event, the most common being nausea (61 %), fatigue (55 %), and infusion-related reactions (45 %, all but 1 occurring during cycle 1). The proportion of patients whose FDG-PET scans converted to negative postbaseline was 88 %. Changes in QOL scores were minor. In patients with treatment-naive, indolent B cell NHL, bendamustine-ofatumumab exhibited a high degree of activity (90 % ORR), comparable with historical bendamustine-rituximab ORRs (≥90 %), and was adequately tolerated ( ClinicalTrials.gov identifier: NCT01108341).

Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL.

Circulating CD4(+)CXCR5(+) T Cells Exacerbate B Cell Antibody Production in Crohn's Disease Through IL-21 Secretion.

Interleukin-21 (IL-21) upregulation was observed in Crohn's disease (CD) patients and was shown to contribute to ongoing mucosal inflammation in CD patients through stabilizing Th1 cell differentiation and IFN-γ production. Given the role of IL-21 in mediating adaptive B cell antibody responses in healthy individuals, we examined the effect of IL-21 upregulation in B cell responses in patients with active CD, including ileum, ileocolonic and colon subtypes, defined by the primary site of CD involvement. We first observed an upregulation of blood plasma IL-21 concentration and IL-21 production from CD4(+) T cells in CD patients compared to healthy individuals. The IL-21-expressing T cells were more concentrated in the CD4(+)CXCR5(+) compartment, both in unstimulated medium and after stimulation with SEB. ICOS and PD-1 expressions were also concentrated in the CD4(+)CXCR5(+) subset in CD patients. Since peripheral blood CD4(+)CXCR5(+) T cell-mediated antibody secretion is IL-21-dependent, we examined the plasma antibody concentration in CD patients and healthy controls. We found that CD patients had significantly higher plasma Ig level than healthy patients, with no significant differences between different CD subtypes. Higher plasma IL-21 concentration and increased IL-21 production from CD4(+) T cells were directly correlated with higher plasma antibody levels. Moreover, we found that IL-21 and CD4(+)CXCR5(+) T cells can directly enhance B cell antibody response in CD patients. Depletion of secreted IL-21 by sIL-21R addition compromised the CD4(+)CXCR5(+) T cell-mediated increase in antibody production. Together, our results demonstrated a novel role of IL-21 in mediating B cell inflammation in CD development.

Comparison of referring and final pathology for patients with T-cell lymphoma in the National Comprehensive Cancer Network.

BACKGROUND: T-cell lymphomas (TCLs) are uncommon in the United States. The accurate diagnosis of TCL is challenging and requires morphologic interpretation, immunophenotyping, and molecular techniques. The authors compared pathologic diagnoses at referring centers with diagnoses from expert hematopathology review to determine concordance rates and to characterize the usefulness of second-opinion pathology review for TCL. METHODS: Patients in the National Comprehensive Cancer Network non-Hodgkin lymphoma database with peripheral TCL, not otherwise specified (PTCL-NOS), angioimmunoblastic TCL (AITL), and anaplastic lymphoma kinase (ALK)-positive and ALK-negative anaplastic large cell lymphoma (ALCL) were eligible if they had prior tissue specimens examined at a referring institution. Pathologic concordance was evaluated using available pathology and diagnostic testing reports and provider progress notes. The etiology of discordance and the potential impact on treatment were examined. RESULTS: Among 131 eligible patients, 57 (44%) had concordant results, totaling 64% of the 89 patients who were referred with a final diagnosis. Thirty-two patients (24%) had discordant results, representing 36% of those who were referred with a final diagnosis. The rates of discordance among patients with of PTCL-NOS, AITL, ALK-negative ALCL, and ALK-positive ALCL were 19%, 33%, 34%, and 6%, respectively. In 14 patients (44% of discordant results), pathologic reclassification could have resulted in a different therapeutic strategy. Forty-two patients (32%) were referred for classification with a provisional diagnosis. CONCLUSIONS: In a large cohort of patients with TCL who were referred to National Comprehensive Cancer Network centers, the likelihood of a concordant final diagnosis at a referring institution was low. As current and future therapies target TCL subsets, these data suggest that patients with suspected TCLs would benefit from evaluation by an expert hematopathologist.

Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database.

Few randomized trials have compared therapies in mantle cell lymphoma (MCL), and the role of aggressive induction is unclear. The National Comprehensive Cancer Network (NCCN) Non-Hodgkin Lymphoma (NHL) Database, a prospective cohort study collecting clinical, treatment, and outcome data at 7 NCCN centers, provides a unique opportunity to compare the effectiveness of initial therapies in MCL. Patients younger than 65 diagnosed between 2000 and 2008 were included if they received RHCVAD (rituximab fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone), RCHOP+HDT/ASCR (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone + high-dose therapy/autologous stem cell rescue), RHCVAD+HDT/ASCR, or RCHOP. Clinical parameters were similar for patients treated with RHCVAD (n = 83, 50%), RCHOP+HDT/ASCR (n = 34, 20%), RCHOP (n = 29, 17%), or RHCVAD+HDT/ASCR (n = 21, 13%). Overall, 70 (42%) of the 167 patients progressed and 25 (15%) expired with a median follow-up of 33 months. There was no difference in progression-free survival (PFS) between aggressive regimens (P > .57), which all demonstrated superior PFS compared with RCHOP (P < .004). There was no difference in overall survival (OS) between the RHCVAD and RCHOP+HDT/ASCR (P = .98). RCHOP was inferior to RHCVAD and RCHOP+HDT/ASCR, which had similar PFS and OS. Despite aggressive regimens, the median PFS was 3 to 4 years. Future trials should focus on novel agents rather than comparing current approaches.

Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study.

New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, 300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.

Non-Hodgkin's lymphomas, version 4.2014.

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.

Non-Hodgkin's lymphomas, version 2.2014.

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Follicular lymphoma (FL) is the most common subtype of indolent NHL, accounting for approximately 22% of all newly diagnosed cases of NHL. The incorporation of rituximab to chemotherapy regimens has become a widely accepted standard of care for first-line therapy for patients with FL. Maintenance and consolidation therapy with rituximab and radioimmunotherapy have also been associated with improved progression-free survival in patients experiencing response to first-line therapy. Despite therapeutic advances that have improved outcomes, FL is generally considered a chronic disease characterized by multiple recurrences with current therapies. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with FL.

Stem cell transplantation for follicular lymphoma relapsed/refractory after prior rituximab: a comprehensive analysis from the NCCN lymphoma outcomes project.

BACKGROUND: Stem cell transplant (SCT)-related outcomes and prognostication for relapsed/refractory follicular lymphoma (FL) are not well-defined in the post-rituximab era. METHODS: Through the National Comprehensive Cancer Network (NCCN) lymphoma outcomes study, 184 patients with relapsed/refractory FL who underwent autologous SCT (autoSCT) or allogenic SCT (alloSCT) following disease relapse after prior rituximab-based therapy were examined. RESULTS: Patients who underwent autoSCT (N=136) were older compared with patients who underwent alloSCT (N=48) (54 versus 51 years, respectively, P=.01) and more frequently had grade 3 FL (35% versus 8%, respectively, P=.006). Patients who underwent alloSCT received more prior therapies (4 versus 3, respectively, P<.0001) and more often had resistant disease at SCT (19% versus 6%, respectively, P=.008). Cumulative 100-day nonrelapse mortality (NRM) for autoSCT and alloSCT were 1% and 6%, respectively (P<.0001), whereas 3-year NRM rates were 3% versus 24%, respectively (P<.0001). For autoSCT and alloSCT, cumulative rates of relapse, progression, and/or transformation were 32% versus 16%, respectively (P=.03), whereas 3-year overall survival rates were 87% versus 61% (P<.0001); there were no differences in failure-free survival. AlloSCT was associated with increased risk of death on multivariate analysis (hazard ratio=2.77, 95% confidence interval=1.46-5.26, P=.002). This finding persisted on propensity scoring/matching. Multivariate analysis for autoSCT patients identified age>60 years and>3 prior therapies as adverse factors. Furthermore, a survival model was created for the autoSCT cohort based on number of factors present (0, 1, 2); 3-year failure-free survival was 72%, 47%, and 20%, respectively (P=.0003), and 3-year overall survival was 96%, 82%, and 62%, respectively (P<.0001). CONCLUSIONS: AutoSCT remains an effective therapy for patients with FL. For alloSCT, continued strategies to reduce NRM are needed.

The novel proteasome inhibitor carfilzomib induces cell cycle arrest, apoptosis and potentiates the anti-tumour activity of chemotherapy in rituximab-resistant lymphoma.

Targeting the proteasome system with bortezomib (BTZ) results in anti-tumour activity and potentiates the effects of chemotherapy/biological agents in multiple myeloma and B-cell lymphoma. Carfilzomib (CFZ) is a more selective proteasome inhibitor that is structurally distinct from BTZ. In an attempt to characterize its biological activity, we evaluated CFZ in several lymphoma pre-clinical models. Rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL), and primary tumour cells derived from B-cell lymphoma patients were exposed to CFZ or BTZ. Cell viability and changes in cell cycle were determined. Western blots were performed to detect PARP-cleavage and/or changes in Bcl-2 (BCL2) family members. CFZ was 10 times more active than BTZ and exhibited dose- and time-dependent cytotoxicity. CFZ exposure induced apoptosis by upregulation of Bak (BAK1) and subsequent PARP cleavage in RSCL and RRCL; it was also partially caspase-dependent. CFZ induced G2/M phase cell cycle arrest in RSCL. CFZ demonstrated the ability to overcome resistance to chemotherapy in RRCL and potentiated the anti-tumour activity of chemotherapy agents. Our data suggest that CFZ is able to overcome resistance to chemotherapeutic agents, upregulate pro-apoptotic proteins to promote apoptosis, and induce G2/M cell cycle arrest in lymphoma cells. Our pre-clinical data supports future clinical evaluation of CFZ in B-cell lymphoma.