Gordon, Leo I

PURPOSE Lymphomas are a heterogeneous group of diseases that develop in individuals of all ages and have variable prognoses. Improved survival resulting from therapy advances has led to the emergence of diverse late effects. Although several (US)–based organizations have developed survivorship guidelines, the distinct features of lymphoma subtypes and diverse therapies used raise concerns regarding their applicability to lymphoma survivors. We compared survivorship recommendations (outside primary disease monitoring) between US clinical guidelines. METHODS We extracted information from 17 guidelines from five US-based organizations: ASCO (n = 11), American Cancer Society (n = 1), Children's Oncology Group (n = 1), Center for International Blood and Marrow Transplant Research (n = 1), and the National Comprehensive Cancer Network (n = 3). Guidelines were evaluated to determine whether they offer recommendations on physical effects , psychosocial and quality of life ( QOL ), and health promotion and prevention . Comparisons were focused on second primary malignancy, cardiovascular complications, and vaccination. RESULTS Survivorship recommendations on physical effects and psychosocial and QOL mainly differ in the timing and approaches for screening. Vaccination recommendations were primarily derived from other cancer populations. Identified research gaps were a lack of understanding of the risk of late effects across lymphoma subtypes, the role of social determinants of health in survivorship, and the lack of a survivorship care model that integrates lymphoma subtypes and treatment exposures. CONCLUSION This study raises awareness about the complexity and challenges of managing survivors under the umbrella diagnosis of lymphoma. The inconsistency and incompleteness of existing guidelines may lead to suboptimal survivorship care. We propose expert-based research priorities to address gaps and unmet needs to help develop risk-based follow-up recommendations to optimize survivorship care for lymphoma survivors.

Abstract Purpose: To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA). Patients and Methods: ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. Results: The NA subgroup consisted of 497 subjects in the A+AVD (n = 250) and ABVD (n = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint [modified progression-free survival (PFS) per independent review] demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; P = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; P = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD. Conclusions: The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.

Purpose To determine the maximum-tolerated radiation-absorbed dose (RAD) to critical organs delivered by yttrium-90 (90Y) ibritumomab tiuxetan in combination with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with autologous transplantation. Patients and Methods Eligible patients had relapsed or refractory CD20+ non-Hodgkin's lymphoma (NHL). Individualized 90Y activities were based on dosimetry and were calculated to deliver cohort-defined RAD (1 to 17 Gy) to critical organs with three to six patients per cohort. The therapeutic dose of 90Y ibritumomab tiuxetan was followed by high-dose BEAM and autologous transplantation. Results Forty-four patients were treated. Thirty percent of patients had achieved less than a partial remission to their most recent therapy and would not have been eligible for autologous transplantation at most centers. The toxicity profile was similar to that associated with high-dose BEAM chemotherapy. Two dose-limiting toxicities occurred at the 17 Gy dose level, which made 15 Gy the recommended maximum-tolerated RAD. Although eight patients received at least twice the conventional dose of 0.4 mCi/kg, a weight-based strategy at 0.8 mCi/kg would have resulted in a wide range of RAD; nearly 25% of patient cases would have received 17 Gy or more, and many would have received less than 10 Gy. With a median follow-up of 33 months for all patients, the estimated 3-year progression-free and overall survivals were 43% and 60%, respectively. Conclusion Dose-escalated 90Y ibritumomab tiuxetan may be safely combined with high-dose BEAM with autologous transplantation and has the potential to be more effective than standard-dose radioimmunotherapy. Careful dosimetry is required to avoid toxicity and undertreatment.

Purpose To determine if maintenance rituximab (MR) after standard chemotherapy improves progression-free survival (PFS) in advanced-stage indolent lymphoma. Patients and Methods Patients with stage III-IV indolent lymphoma with responding or stable disease after cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy were stratified by initial tumor burden, residual disease after CVP (minimal or gross), and histology, and randomly assigned to observation (OBS) or MR 375 mg/m2 once per week for 4 weeks every 6 months for 2 years. PFS was the primary end point. Results Three hundred eleven (282 with follicular lymphoma) evaluable patients who received CVP were randomly assigned to OBS (n = 158) or MR (n = 153). Best response improved in 22% MR versus 7% OBS patients (P = .00006). Toxicity was minimal in both study arms. Three-year PFS after random assignment was 68% MR versus 33% OBS (hazard ratio [HR] = 0.4; P = 4.4 × 10−10 [all patients]) and 64% MR v 33% OBS (HR = 0.4; P = 9.2 × 10−8 [patients with follicular lymphoma]). There was an advantage for MR regardless of Follicular Lymphoma International Prognostic Index score, tumor burden, residual disease, or histology. In multivariate analysis of MR patients, minimal disease after CVP was a favorable prognostic factor. OS at 3 years was 92% MR versus 86% OBS (HR = 0.6; log-rank one-sided P = .05) and, among patients with follicular lymphoma, OS was 91% MR versus 86% (HR = 0.6; log-rank one-sided P = .08). A trend favoring MR was observed among patients with high tumor burden (log-rank one-sided P = .03). Conclusion The E1496 study provides the first phase III data in untreated indolent lymphoma that MR after chemotherapy significantly prolongs PFS.

Purpose To investigate the incidence of treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) after treatment with ibritumomab tiuxetan radioimmunotherapy. Patients and Methods Analysis of the incidence of t-MDS and t-AML in 746 patients with non-Hodgkin's lymphoma (NHL) treated with the ibritumomab tiuxetan regimen in registration and compassionate-use trials between 1996 and 2002. Results Nineteen patients (2.5%) developed t-MDS or t-AML at a median follow-up of 4.4 years (range, 0 to 9.3). These malignancies were diagnosed at a median of 5.6 years (range, 1.4 to 13.9) after the diagnosis of NHL and 1.9 years (range, 0.4 to 6.3) after radioimmunotherapy. The annualized rates were 0.3% per year after the diagnosis of NHL and 0.7% per year after treatment. Most patients with t-MDS or t-AML had multiple cytogenetic aberrations, commonly on chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. Conclusion Analysis of data from patients in registration and compassionate-use trials suggests that the annualized incidences of t-MDS and t-AML are consistent with that expected in patients with NHL who have had extensive previous chemotherapy treatment and do not appear to be increased after treatment with the ibritumomab tiuxetan regimen. Cytogenetic testing before treatment with radioimmunotherapy may identify existing chromosomal abnormalities in previously treated patients, particularly those who have been treated with alkylating agents and purine nucleoside analogs and would be at higher risk for t-MDS or t-AML.

PurposeThis multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma.Patients and MethodsPatients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2.ResultsThirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months).ConclusionThe favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.