Friedberg, Jonathan W.

SummaryThe International Prognostic Score (IPS‐7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS‐7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS‐7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS‐7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS‐3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P < 0·0001)]. IPS‐3 outperformed the IPS‐7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS‐7 low risk patients were re‐classified as intermediate risk and 13% of IPS‐7 intermediate risk patients as low risk. For patients with advanced HL, the IPS‐3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.

SummaryData from the National LymphoCare Study (a prospective, multicentre registry that enrolled follicular lymphoma (FL) patients from 2004 to 2007) were used to determine disease characteristics, treatment patterns, outcomes and prognosis for elderly FL (eFL) patients. Of 2650 FL patients, 209 (8%) were aged >80 years; these eFL patients more commonly had grade 3 disease, less frequently received chemoimmunotherapy and anthracyclines, and had lower response rates when compared to younger patients. With a median follow‐up of 6.9 years, 5‐year overall survival (OS) for eFL patients was 59%; 38% of deaths were lymphoma‐related. No treatment produced superior OS among eFL patients. In multivariate Cox models, anaemia, B‐symptoms and male sex predicted worse OS (P < 0·01); a prognostic index of these factors (0, 1 or ≥2 present) predicted OS [hazard ratio (95% CI): ≥2 vs. 0, 4·72 (2·38–9·33); 1 vs. 0, 2·63 (1·39–4·98)], with a higher concordance index (0·63) versus the Follicular Lymphoma International Prognostic Index (0·55). The index was validated in an independent cohort. In the largest prospective US‐based eFL cohort, no optimal therapy was identified and nearly 40% of deaths were lymphoma‐related, representing baseline outcomes in the modern era.

Key Points Elevated IL-2R, IL-1RA, and CXCL9 are associated with shorter event-free survival in newly diagnosed FL, treated with chemoimmunotherapy. Increased serum IL-12 and IL-1RA is associated with shorter event-free survival in patients who were observed or treated with rituximab alone.

BACKGROUNDThe authors examined the “real‐world” effectiveness of rituximab (R) maintenance therapy (R‐maintenance) compared with observation after R‐based induction therapy in patients with previously untreated follicular lymphoma (FL) in the United States.METHODSThe National LymphoCare Study is a prospective, multicenter, observational study that enrolled > 2700 untreated patients with FL diagnosed from 2004 to 2007 at 265 sites in the United States. Among these, patients who achieved at least stable disease after R‐based induction therapy were eligible for the current analysis. Patients who initiated R‐maintenance within 215 days of completing induction therapy were categorized as the R‐maintenance group, and those who did not initiate therapy during this period were categorized as the observation group. The objective of the current study was to determine the effect of R‐maintenance on progression‐free survival (PFS), time to next treatment (TTNT), and overall survival (OS).RESULTSA total of 1439 patients completed R‐based induction therapy, 1186 of whom met all inclusion criteria (541 patients received R‐maintenance and 645 patients were observed). Characteristics that were found to be predictive of receiving R‐maintenance were histology grade (1/2), Ann Arbor stage of disease (III/IV), geographic region (region other than the West), and practice setting (community practice). With a median follow‐up of 5.7 years, R‐maintenance was associated with superior PFS (hazards ratio [HR], 0.68; 95% confidence interval [95% CI], 0.56‐0.84 [P = .0003]) and TTNT (HR, 0.66; 95% CI, 0.52‐0.84 [P = .0007]). No significant difference in OS was observed (HR, 0.81; 95% CI, 0.58‐1.14 [P = .23]).CONCLUSIONSR‐maintenance in patients with FL and at least stable disease after R‐based induction therapy provided significantly longer PFS and TTNT in comparison with observation, but no significant difference in OS was observed with 5‐years of follow‐up. This comparative effectiveness study aligns with the results of randomized trials suggesting that similar outcomes occur with R‐maintenance in FL with the treatment variations observed in clinical practice. Cancer 2014;120:1830–1837. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

BACKGROUNDDrug choice and delivered dose of treatment potentially influence outcome in patients treated for follicular lymphoma (FL). Historically, observational studies have evaluated drug choice. The National LymphoCare Study (NLCS) is a prospective, observational study of patients with FL who were enrolled at academic and community practice sites in the United States between 2004 and 2007. In the current study, the authors report on measures of delivered dose and its impact on outcomes for the most common first‐line regimens.METHODSAll evaluable patients with FL who were treated with initial rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP); rituximab plus cyclophosphamide, vincristine, and prednisone (R‐CVP); or rituximab plus a fludarabine‐containing regimen (R‐Flu) were included. Associations between baseline factors, choice of treatment, number of cycles received, completion of therapy, and patient outcomes were assessed.RESULTSA total of 646 patients received R‐CHOP, 297 received R‐CVP, and 222 received R‐Flu. Characteristics were similar between the 3 groups with the following exceptions. Patients receiving R‐CHOP were more often found to have grade 3 FL and patients receiving R‐CVP were older and had higher Follicular Lymphoma International Prognostic Index scores. The majority of patients (80%) received ≥ 5 cycles of treatment. Toxicity, but not disease progression, was commonly cited as the reason for the early discontinuation of treatment (51% vs 6%). Time to retreatment was shorter for patients receiving ≤ 4 cycles, regardless of the treatment regimen used. The number of cycles was associated with overall survival, progression‐free survival, and lymphoma‐related mortality for patients receiving R‐CVP.CONCLUSIONSThe majority of patients with FL receiving chemoimmunotherapy in the NLCS completed ≥ 5 cycles of treatment. Strategies to improve dose delivery appear unlikely to impact outcomes, except possibly in patients receiving R‐CVP. Although early treatment discontinuation appears to be associated with survival, this analysis does not implicate causality. Cancer 2013;119:4129–4136. © 2013 American Cancer Society.

PurposeThe optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT).Patients and MethodsWe analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database.ResultsOf 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival.ConclusionIn this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation.

AbstractCertain malignant B cells rely on B-cell receptor (BCR)–mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.

Purpose Optimal therapy of follicular lymphoma (FL) is not defined. We analyzed a large prospective cohort study to identify current demographics and patterns of care of FL in the United States. Patients and Methods The National LymphoCare Study is a multicenter, longitudinal, observational study designed to collect information on treatment regimens and outcomes for patients with newly diagnosed FL in the United States. Patients were enrolled between 2004 and 2007. There is no study-specific prescribed treatment regimen or intervention. Results Two thousand seven hundred twenty-eight subjects were enrolled at 265 sites, including the 80% of patients enrolled from nonacademic sites. Using the Follicular Lymphoma International Prognostic Index (FLIPI), three distinct groups independent of histologic grade could be defined. Initial therapeutic strategy was: observation, 17.7%; rituximab monotherapy, 13.9%; clinical trial 6.1%; radiation therapy, 5.6%; chemotherapy only, 3.2%; chemotherapy plus rituximab, 51.9%. Chemotherapy plus rituximab regimens were: rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone, 55.0%; rituximab plus cyclophosphamide, vincristine, and prednisone, 23.1%; rituximab plus fludarabine based, 15.5%; other, 6.4%. The choice to initiate therapy rather than observe was associated with age, FLIPI, stage, and grade (P < .01). Significant differences in treatment (P < .01) across regions of the United States were noted. Contrary to practice guidelines, treatment of stage I FL frequently omits radiation therapy. Conclusion Widely disparate therapeutic approaches are utilized for FL. Initial therapy is deferred in a small subset of patients. There is no single standard of care for the treatment of de novo FL, although antibody use is ubiquitous when therapy is initiated. These disparate approaches to the initial care of patients with FL render a heterogeneous group of patients at relapse.