Management of newly diagnosed high-risk and intermediate-risk follicular lymphoma with 90 Y ibritumomab tiuxetan in a phase II study.

Five-year overall survival for high-risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high-risk follicular lymphoma. Front-line treatment with chemo-immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio- immunotherapy with 90-Yttrium ibritumomab tiuxetan consolidation, and 2 years of rituximab maintenance. The 5-year overall survival for intermediate and high-risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio-immunotherapy. Three months post radio-immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo-immunotherapy and converted to complete response after radio-immunotherapy. The 5-year progression-free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow-up of 48 months (range 3-84 months). Post radio-immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%-36% and 10%-24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4 years post treatment. Whereas many patients had prolonged B-cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov: NCT01446562.

Gemcitabine/dexamethasone/cisplatin vs cytarabine/dexamethasone/cisplatin for relapsed or refractory aggressive-histology lymphoma: cost-utility analysis of NCIC CTG LY.12.

BACKGROUND: The NCIC CTG LY.12 study showed that gemcitabine, dexamethasone, and cisplatin (GDP) were noninferior to dexamethasone, cytarabine, and cisplatin (DHAP) in patients with relapsed or refractory aggressive histology lymphoma prior to autologous stem cell transplantation. We conducted an economic evaluation from the perspective of the Canadian public healthcare system based on trial data. METHODS: The primary outcome was an incremental cost utility analysis comparing costs and benefits associated with GDP vs DHAP. Resource utilization data were collected from 519 Canadian patients in the trial. Costs were presented in 2012 Canadian dollars and disaggregated to highlight the major cost drivers of care. Benefit was measured as quality-adjusted life-years (QALYs) based on utilities translated from prospectively collected quality-of-life data. All statistical tests were two-sided. RESULTS: The mean overall costs of treatment per patient in the GDP and DHAP arms were $19 961 (95% confidence interval (CI) = $17 286 to $24 565) and $34 425 (95% CI = $31 901 to $39 520), respectively, with an incremental difference in direct medical costs of $14 464 per patient in favor of GDP (P < .001). The predominant cost driver for both treatment arms was related to hospitalizations. The mean discounted quality-adjusted overall survival with GDP was 0.161 QALYs and 0.152 QALYs for DHAP (difference = 0.01 QALYs, P = .146). In probabilistic sensitivity analysis, GDP was associated with both cost savings and improved quality-adjusted outcomes compared with DHAP in 92.6% of cost-pair simulations. CONCLUSIONS: GDP was associated with both lower costs and similar quality-adjusted outcomes compared with DHAP in patients with relapsed or refractory lymphoma. Considering both costs and outcomes, GDP was the dominant therapy.

Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12.

PURPOSE: For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS: We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS: For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). CONCLUSION: For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.

Impact of central nervous system (CNS) prophylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature.

Central nervous system (CNS) prophylaxis for diffuse large B-cell lymphoma (DLBCL) is controversial with even less evidence in the era of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. We reviewed the impact of CNS prophylaxis in DLBCL patients treated with R-CHOP at a tertiary care centre over a 7-year period. CNS prophylaxis was recommended for 'higher risk' patients and consisted of intrathecal methotrexate and/or high-dose methotrexate. Of 214 patients 12·6% received CNS prophylaxis. With a median follow-up of 27 months, eight patients (3·7%) developed CNS relapse (75% isolated to the CNS and 62·5% as parenchymal brain disease) at a median time of 17 months. Patients who did not receive CNS prophylaxis had lower events (2·7%) than those who did (11·1%). Half of the CNS relapses occurred in testicular lymphoma patients, 75% of whom had received CNS prophylaxis. In multivariate analysis, testicular involvement was the only significant prognostic factor for CNS relapse (hazard ratio 33·5, P < 0·001). In conclusion, CNS relapse in DLBCL appears to present as a later, more isolated parenchymal event and at a lower rate in the rituximab era compared with historical data. R-CHOP may negate the need for CNS prophylaxis with the exception of testicular lymphoma.

High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphoma.

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL). However, combined therapy is associated with increased neurotoxicity. In an effort to limit this toxicity, we treated a series of non-immunocompromised patients with HDMVP, a HD-MTX based regimen, with deferral of WBRT until progression. Twenty-three patients were treated with the HDMVP regimen consisting of MTX, vincristine, and procarbazine. The mean age at diagnosis was 60.9 years (range 45-79 years). The overall response rate was 65% (14 complete responses and one partial response). For patients achieving an initial response with HDMVP the median response duration was 40.4 months (95% confidence interval [CI] 19.5-61.3). The median progression-free survival was 4.6 months (95% CI 0.0-20.4) and median overall survival was 41.4 months (95% CI 0.0-95.5). Fourteen patients received WBRT for relapsed or progressive disease. The conclusion of this trial is that HDVMP results in good initial response rates but only moderate disease control. Ultimately the majority of the patients in this series required WBRT for salvage treatment, potentially enabling a delay in treatment-associated neurotoxicity.

The impact of follicular (FL) and other indolent non-Hodgkin's lymphomas (NHL) on work productivity-a preliminary analysis.

INTRODUCTION: Although much is known about the efficacy, toxicity, and direct costs of treatment for follicular lymphoma (FL), there is no data assessing the impact of this diagnosis on the work productivity of affected individuals. METHODS: We conducted a cross-sectional survey study of consecutive patients attending a malignant haematology clinic at a large multi-disciplinary cancer centre. Patients with a diagnosis of FL or other indolent non-Hodgkin's lymphoma completed questionnaires assessing health status, work productivity, and activity impairment. RESULTS: Eighty-four patients completed the survey study (95% response). Patients who continued to work reported a minimal impact on their work productivity (10%+/-standard deviation SD 20; 0%=no effect and 100%=complete impairment of activity) and on their daily activities (13%+/-SD 25) attributable to their cancer. Prior to lymphoma diagnosis, over 71% of patients were working while 14% were retired. At the time of survey administration, only 41% of patients were still able to work with a significant proportion of patients having transitioned to retirement (36%), sick leave (10%), or unemployment (4%). On multivariate analysis, significant activity impairment (daily activity impairment>50%) was predicted by poor self-rated health status (OR 32.1; 95% CI: 5.9-174.2; p<0.0001) and active chemotherapy treatment (OR 14.5; 95% CI: 0.91-230.9; p=0.059). CONCLUSIONS: Although few patients with indolent lymphoma identified significant impairment in productivity, many were unable to continue employment following diagnosis, needed to miss days from work, or imposed a significant burden on caregivers. The greatest impact on activity is apparent in patients who rate their health status as poor and in those who are currently receiving systemic therapy.

Physician perceptions and preferences in the treatment of acquired immunodeficiency syndrome (AIDS)-related lymphoma.

The optimal management of acquired immunodeficiency syndrome-related lymphoma (ARL) in the era of combination antiretroviral therapy (cART) is unclear. We administered a survey to determine physician preferences and perceptions in the management of ARL and to assess the variability in treatment in Canada. Of 196 lymphoma-treating physicians, 117 (63%) responded. The majority of respondents (98%) had a positive attitude towards the treatment of ARL. Most physicians (66%) recommended the concomitant use of cART in the care of their patients with ARL, and a majority (86%) recommended CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone) to form the backbone of chemotherapy. The addition of rituximab was preferred by 43% of physicians, while 39% and 18% would either not use rituximab or were unsure of the agent's role, respectively. In logistic regression analysis, use of rituximab was predicted only by location of practice (province); physicians from the province of British Colombia were much more likely to administer rituximab than practitioners from Ontario (odds ratio 41.8; 95% confidence interval 7.44-235.1, p < 0.001). In the current cART era, physicians have a positive attitude towards the treatment of ARL. The majority prefer to use cART in combination with CHOP for ARL. The use and perceived benefit of rituximab may be influenced by interprovincial formulary differences and regional variation in guideline recommendations.

Rituximab in lymphoma: a systematic review and consensus practice guideline from Cancer Care Ontario.

Rituximab is the first antibody-based therapy approved in cancer. The role of this treatment for non-Hodgkin's lymphoma has evolved significantly since its introduction. We aimed to systematically review the literature on rituximab in non-Hodgkin's lymphoma and provide consensus guidelines as to the rational use of this agent. Validated methodology from the Cancer Care Ontario Program in Evidence-Based Care was applied. A comprehensive literature search was completed by reviewers from the Hematology Disease Site Group of Cancer Care Ontario. Data were abstracted from randomized controlled trials of rituximab-containing regimens for patients with non-Hodgkin's lymphoma. Twenty-three randomized controlled trials (RCTs) of rituximab-based therapy were analyzed. Consistent and clinically important benefits in progression-free and overall survival and were seen in the following settings: (1) addition of rituximab to combination chemotherapy for initial treatment of diffuse large B-cell lymphoma and other aggressive B-cell lymphomas; (2) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; and (3) use of rituximab alone as extended maintenance therapy in patients with indolent B-cell lymphomas who have responded to initial treatment. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications.

Debate on the conservative and aggressive treatment options for the optimal management of indolent non-Hodgkin's lymphoma.

Indolent non-Hodgkin's lymphoma (NHL) is currently considered to be an incurable disease, with a median survival of 6-8 years. In the absence of a cure, the variety of therapeutic options available for patients with indolent NHL range from 'watchful waiting' to high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT). There is no current consensus on standard treatment. Conventional chemotherapy is clearly not curative, and many clinicians prefer to delay chemotherapy until the patient develops overt symptoms that require treatment. On the one hand, long-term studies indicate that 'watchful waiting' has no effect on overall survival. On the other hand, aggressive treatment strategies, such as HDT with ASCT, may increase disease-free survival in some patients, particularly when used early in the treatment algorithm, but are also associated with potential toxicity. Thus the selection of therapy for each patient involves balancing the benefit of the treatment with any side effects and detriment to quality of life. The development of innovative therapies for indolent NHL, such as monoclonal antibodies with or without chemotherapy, requires a reassessment of the treatment choices. Good clinical responses and time to progression have so far been achieved in clinical trials of rituximab and other agents including radiolabelled antibodies, but in view of the long median survival of patients with indolent NHL, it will be some years before it can be conclusively demonstrated whether such treatments have an effect on the natural history of the disease or produce a cure. This issue raises an important question: outside the setting of a clinical trial, should patients be treated aggressively with therapies that do not yet have proven curative ability? This article considers the evidence and relative merits for the conservative approach to indolent NHL, where patients are treated according to symptoms in order to maintain a normal quality of life wherever possible, and for the aggressive approach, where the lymphoma is targeted soon after the diagnosis.