[Show abstract][Hide abstract] ABSTRACT: Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ⩾2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125-3.11 mg/m(2) on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1-36). MTD was determined to be 2.34 mg/m(2). Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ⩾3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ⩾3 events were reported. Plasma exposure increased dose proportionally from 0.5-3.11 mg/m(2); terminal half-life was 4-12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ⩾32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma.
Blood Cancer Journal 10/2014; 4:e251. · 2.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent advances in imaging, use of prognostic indices, and molecular profiling techniques have the potential to improve disease characterization and outcomes in lymphoma. International trials are under way to test image-based response-adapted treatment guided by early interim positron emission tomography (PET) -computed tomography (CT). Progress in imaging is influencing trial design and affecting clinical practice. In particular, a five-point scale to grade response using PET-CT, which can be adapted to suit requirements for early- and late-response assessment with good interobserver agreement, is becoming widely used both in practice- and response-adapted trials. A workshop held at the 11th International Conference on Malignant Lymphomas (ICML) in 2011 concluded that revision to current staging and response criteria was timely.
Journal of Clinical Oncology 08/2014; · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this work was to modernize recommendations for evaluation, staging, and response assessment of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). A workshop was held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, in June 2011, that included leading hematologists, oncologists, radiation oncologists, pathologists, radiologists, and nuclear medicine physicians, representing major international lymphoma clinical trials groups and cancer centers. Clinical and imaging subcommittees presented their conclusions at a subsequent workshop at the 12th International Conference on Malignant Lymphoma, leading to revised criteria for staging and of the International Working Group Guidelines of 2007 for response. As a result, fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) was formally incorporated into standard staging for FDG-avid lymphomas. A modification of the Ann Arbor descriptive terminology will be used for anatomic distribution of disease extent, but the suffixes A or B for symptoms will only be included for HL. A bone marrow biopsy is no longer indicated for the routine staging of HL and most diffuse large B-cell lymphomas. However, regardless of stage, general practice is to treat patients based on limited (stages I and II, nonbulky) or advanced (stage III or IV) disease, with stage II bulky disease considered as limited or advanced disease based on histology and a number of prognostic factors. PET-CT will be used to assess response in FDG-avid histologies using the 5-point scale. The product of the perpendicular diameters of a single node can be used to identify progressive disease. Routine surveillance scans are discouraged. These recommendations should improve evaluation of patients with lymphoma and enhance the ability to compare outcomes of clinical trials.
Journal of Clinical Oncology 08/2014; · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT CALGB designed a phase II trial of lenalidomide+bortezomib for relapsed/refractory mantle cell lymphoma (MCL). Induction therapy was lenalidomide (days 1-14) plus bortezomib (days 1/4/8/11), every 21 days for eight cycles. Complete and partial responders (CR, PR) received maintenance lenalidomide (days 1-14) and bortezomib (days 1/8), every 21 days. Primary endpoint was overall response rate; secondary endpoints were CR rate, progression-free- (PFS), event-free- (EFS), and overall survival (OS). Fifty-three eligible patients, median age 67 years, were accrued. Median number of cycles received was 4 (range, 1-82). Median follow-up is 46 (range, 12-67) months. Best response was CR (n=8, 15%), PR (n=13, 25%). 5/8 CR and 4/13 PR patients received maintenance therapy. Of responders, 6 CR/1 PR patients remain in remission at a median of 3.2 years. Thirty-three (62%) patients have died. One-year PFS, EFS, OS are 40%, 25%, and 68%, respectively. This combination will not be pursued further at this dose/schedule.
Leukemia and Lymphoma 07/2014; · 2.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Natural killer (NK) cells contribute to clinical responses in patients treated with rituximab, but the rules determining NK cell responsiveness to mAb therapies are poorly defined. A deeper understanding of the mechanisms responsible for antibody-dependent cellular cytotoxicity (ADCC) could yield useful biomarkers for predicting clinical responses in patients. Unlicensed NK cells, defined as NK cells expressing inhibitory KIR for non-self-HLA class I ligands, are hypo-responsive in steady-state, but are potent effectors in inflammatory conditions. We hypothesized that anti-tumor antibodies such as rituximab can overcome NK cell dependence on licensing, making unlicensed NK cells important for clinical responses. Here we examined the influences of variations in KIR and HLA class I alleles on the in vitro responses to rituximab. We further tested the clinical significance in a cohort of follicular lymphoma patients treated with rituximab-containing antibody combinations. We show that rituximab triggers responses from all NK cell populations regardless of licensing. Neither IL-2 nor accessory cells are required for activating unlicensed NK cells, but both can augment rituximab-mediated ADCC. Moreover, in 101 follicular lymphoma patients treated with rituximab-containing mAb combinations, a "missing ligand" genotype (predictive of unlicensed NK cells) is associated with higher progression-free survival. Our data suggest that the clinical efficacy of rituximab may be driven, in part, by its ability to broaden the NK cell repertoire to include previously hypo-responsive, unlicensed NK cells. A "missing ligand" KIR and HLA class I genotype may be predictive of this benefit, and useful for personalizing treatment decisions in lymphomas and other tumors.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Despite initial responses >90% with fludarabine and rituximab-based regimens, patients with CLL invariably relapse and require further treatment. Ofatumumab (O) and bendamustine (B) have each shown efficacy in relapsed/refractory CLL with ORRs of 58% and 76%, respectively. Given excellent data with bendamustine and rituximab in relapsed/refractory CLL/SLL, this phase II study evaluated the combination of ofatumumab and bendamustine in previously treated patients. Patients received O 300 mg IV D-7, followed by O 1000 mg IV D1 and B 70 mg/m(2) D1, 2 of each 28-day cycle. Patients received 4-6 cycles depending on number of prior therapies, as long as well-tolerated or until progression. Of 10 patients enrolled, the ORR was 40% and complete response rate was 20%. The median progression-free and overall survivals were 8.1 months and 16.2 months. Three patients developed Richter's transformation. The study was closed early due to unexpected adverse events including infusion-related reactions, infection, and neurotoxicity.
Leukemia and Lymphoma 06/2014; · 2.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study.
[Show abstract][Hide abstract] ABSTRACT: PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody with increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab. In this phase I study, PRO131921 was administered as a single agent to patients with CD20+, relapsed or refractory, indolent non-Hodgkin's lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The primary aim of this study was safety and tolerability of PRO131921. The secondary aim of the study, and focus of this report, was to determine the pharmacokinetics (PK) profile of PRO131921 and establish a correlation between drug exposure and clinical efficacy. Patients were treated with PRO131921 by intravenous infusion weekly for 4 weeks and the dose was escalated based on safety in a 3+3 design. Twenty-four patients were treated with PRO131921 at doses from 25 mg/m(2) to 800 mg/m(2). Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and tumor shrinkage (p=.0035). Also, normalized AUC levels were higher among responders and subjects displaying tumor shrinkage versus subjects progressing or showing no regression (p=0.030). In conclusion, PRO131921 demonstrated clinical activity in rituximab-relapsed and refractory indolent NHL patients. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy.
[Show abstract][Hide abstract] ABSTRACT: The majority of patients with advanced Hodgkin lymphoma are cured with current standard therapy such as Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). However, almost 20 % of patients fail to achieve complete remission, and depending upon risk group, 20-30 % experience relapse with prolonged follow-up. BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, prednisone, procarbazine) was developed by the German Hodgkin Study Group (GHSG) to improve upon standard therapy by intensifying treatment and substituting etoposide and procarbazine for vinblastine and dacarbazine, respectively. In the HD9 trial, escalated BEACOPP was shown to be superior to COPP/ABVD with regard to time to treatment failure, but was associated with increased risk of secondary malignancies. Modifications of BEACOPP were developed to maintain efficacy while reducing the adverse effects. While several randomized trials have confirmed prolongation of progression-free survival with BEACOPP compared to ABVD, a survival advantage has been difficult to demonstrate. Given the comparable survival between BEACOPP and ABVD, as well as the greater toxicities of the former, including infertility, myelosuppression, and secondary malignancies, ABVD should remain the standard regimen for patients in the U.S. Newer regimens incorporating novel agents such as brentuximab vedotin may further improve the efficacy of current regimens.
[Show abstract][Hide abstract] ABSTRACT: To improve long-term outcomes for Burkitt leukaemia/lymphoma (BL) or aggressive lymphomas in adults, we assessed the benefit of adding rituximab and filgrastim support to a dose-dense modified chemotherapy regimen from the Cancer and Leukemia Group B (CALGB) 9251 trial. One hundred and five patients (aged 19–79 years) were enrolled; 27% were >60 years old; 47% had high or high-intermediate risk by International Prognostic Index (IPI) criteria. Common severe toxicities included stomatitis/upper gastrointestinal toxicity (69%), renal insufficiency (10%), neurological events (25%) and pulmonary events (18%). Seven died from treatment-related causes (one central nervous system bleed, four infections, two respiratory failure); five were >60 years old. Results in this adult population are encouraging as complete response (CR) was observed in 83% and 4-year event-free (EFS) and overall survivals (OS) were 74% and 78%, respectively. Results compare favourably to our prior chemotherapy alone study (CALGB 9251) but despite this, high-risk patients still had worse outcomes. In conclusion, short duration, intensive chemo-immunotherapy is feasible and should be considered in adults with BL as it results in high remission rates and durable remissions.
British Journal of Haematology 04/2014; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL).
A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories.
Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58).
BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.
Annals of Oncology 03/2014; 25(3):669-74. · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the management of follicular lymphomas (FL) major changes have taken place within the last few years leading to a substantial improvement of prognosis and overall survival. For some patients with limited disease stages I and II, radiotherapy may be associated with durable responses, however, whether patients are cured is controversial and new approaches such as the combination of irradiation with rituximab or even single agent rituximab need to be explored. Whereas watch and wait is the current standard for stage III and IV disease with low tumor burden, better indices are warranted to potentially select patients for whom early intervention is preferred. For advanced stages with a high tumor burden immuno-chemotherapy followed by 2 years of rituximab maintenance is widely accepted as standard therapy, although retreatment at recurrence may be an alternative option. Highly attractive new therapeutic options have recently arisen from new antibodies and particularly from new agents targeting oncogenic pathways such as B-cell receptor signalling pathways or inhibiting bcl 2. Furthermore, immunomodulatory drugs may add to the therapeutic armamentarium and may lead to "chemotherapy-free" therapies in the near future. Hence, the management of follicular lymphomas has become a moving target and the hope is justified that the long term perspectives of patients suffering from the disease will be further improved in the near future.Leukemia accepted article preview online, 28 February 2014; doi:10.1038/leu.2014.91.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2014; · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The management approach in Hodgkin's (HL) and high-grade non-Hodgkin's lymphomas (NHL) has shifted towards reducing the toxicity and long-term adverse effects associated with treatment while maintaining favorable outcomes in low-risk patients. The success of an individualized treatment strategy depends largely on accurate diagnostic tests both at staging and during therapy. In this regard, positron emission tomography (PET) using fluorodeoxyglucose (FDG) with computed tomography (CT) has proved effective as a metabolic imaging tool with compelling evidence supporting its superiority over conventional modalities, particularly in staging and early evaluation of response. Eventually, this modality was integrated into the routine staging and restaging algorithm of lymphomas. This review will summarize the data on the proven and potential utility of PET/CT imaging for staging, response assessment, and restaging, describing current limitations of this imaging modality.
European Journal of Nuclear Medicine 02/2014; 41(5). · 4.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. Methods In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. Results The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. Conclusions The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512 .).
New England Journal of Medicine 01/2014; · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Bendamustine is a byfunctional molecule with both alkylating and antimetabolite properties, synthetized in 1963 by Ozegowski and Krebs in East Germany (German Democratic Republic). Widely used in east Europe for lymphoma and myeloma therapy during '70 and '80, Bendamustine was never studied in well designed clinical trials, until the 2000s. Unique among other recently developed antineoplastic drugs, Bendamustine shows high activity and is now approved by FDA and EMA being part of the therapeutic armamentarium in indolent and aggressive B-cell non-Hodgkin lymphomas (NHL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), multiple myeloma (MM). "Bendamustine: role and clinical evidences in lymphoma therapy" is the title of a workshop which took place in Bologna, Italy, on January 28, 2013. This meeting, focused on the development, mechanisms of action, and evidence supporting the use of Bendamustine in lymphoma therapy. This report will summarize drug development steps, mechanisms of action, clinical results and rationale of use of Bendamustine in different lymphoma subtypes, as discussed during the meeting, with the aim to help the clinician for an optimal use of this compound in a wide spectrum of lymphoproliferative disorders.