Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines.

Doxorubicin plays an integral role in the treatment of patients with diffuse large B-cell lymphoma (DLBCL) but can be associated with significant toxicity. Treatment guidelines of British Columbia (BC) Cancer recommend the substitution of etoposide for doxorubicin in standard-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (R-CEOP) for patients who have a contraindication to anthracyclines; however, it is unknown if this compromises treatment outcome. We identified all patients with newly diagnosed DLBCL who were treated in BC with curative intent with R-CEOP (n = 70) within the study period. Outcome in this population was compared with a 2:1 case-matched control group (n = 140) treated with R-CHOP and matched for age, clinical stage, and International Prognostic Index score. The 10-year time to progression and disease-specific survival were not significantly different for patients treated with R-CEOP compared with patients in the R-CHOP control group (53% vs 62% [P = .089] and 58% vs 67% [P = .251], respectively). The 10-year overall survival was lower in the R-CEOP group (30% vs 49%, P = .002), reflecting the impact of underlying comorbidities and frailty of this population. R-CEOP represents a useful treatment alternative for patients with DLBCL and an absolute contraindication to the use of anthracyclines, with curative potential.

Gemcitabine, dexamethasone, and cisplatin (GDP) is an effective and well-tolerated salvage therapy for relapsed/refractory diffuse large B-cell lymphoma and Hodgkin lymphoma.

The optimal choice of salvage therapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) remains unknown. Based on promising results of phase II trials, the preferred salvage regimen in British Columbia since 2002 has been the out-patient regimen, gemcitabine, dexamethasone, and cisplatin (GDP). We conducted a retrospective analysis including all patients with relapsed/refractory DLBCL or HL who received GDP as salvage therapy between September 2002 and June 2010. We identified 235 patients: 152 DLBCL, 83 HL. Overall response rates were 49% and 71% for patients with DLBCL and HL, respectively. Within the transplant-eligible population, 52% of patients with DLBCL and 96% of patients with HL proceeded to stem cell transplantation. The 2-year progression-free survival and overall survival were 21% and 28% in the DLBCL cohort, and 58% and 85% in the HL group. GDP is an effective and well-tolerated out-patient salvage regimen for relapsed/refractory DLBCL and HL.

Outcome of primary cutaneous anaplastic large cell lymphoma: a 20-year British Columbia Cancer Agency experience.

Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a rare CD30+ lymphoproliferative disorder with excellent outcomes reported despite frequent cutaneous relapses. Limited information exists on the development of systemic lymphoma. The British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database was searched to identify all adults diagnosed with PCALCL from 1993 to 2013. From 2005, the BCCA endorsed radiotherapy (RT) alone for limited stage with data failing to support chemotherapy. Forty-seven patients were identified with a male predominance (n = 31, 66%), median age of 64 years and predominantly limited stage (n = 40, 85%). Median follow-up was 8·4 years. The 5-year time to progression (TTP) was 58% (64% limited versus 29% advanced stage). The 5-year disease-specific survival (DSS) and overall survival was 86% and 75%, respectively. In an as-treated analysis, the 5-year DSS for limited stage patients was similar comparing RT to combined modality treatment or chemotherapy alone but the 5-year TTP favoured RT (82% vs. 33%, P = 0·004). The 5-year cumulative risk of developing systemic lymphoma was 14%. Our results confirm the favourable prognosis of PCALCL despite a high relapse rate. Limited stage patients treated with RT alone have excellent outcomes. There is a small risk of systemic lymphoma in PCALCL.

Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era.

The addition of rituximab has improved outcomes in diffuse large B-cell lymphoma (DLBCL), however, there remains limited information on the impact of rituximab in those with testicular involvement. All patients with diffuse large cell lymphoma and testicular involvement treated with curative intent were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. In total, 134 patients diagnosed between 1982 and 2015 with diffuse large cell lymphoma involving the testis were identified: 61 received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like chemotherapy and 73 received CHOP plus rituximab (R-CHOP). A greater proportion of R-CHOP treated patients had higher International Prognostic Index (IPI, P = 0·005). In multivariate analysis, the protective effect of rituximab on progression-free survival (hazard ratio (HR) 0·42, P < 0·001), overall survival (HR 0·39, P < 0·001) and cumulative incidence of progression (HR 0·46, P = 0·014) were independent of the IPI. However, in a competing risk multivariate analysis including central nervous system (CNS) prophylaxis and the CNS-IPI, rituximab was not associated with a decreased risk of CNS relapse. The addition of rituximab has reduced the risk of lymphoma recurrence in testicular DLBCL, presumably through improved eradication of systemic disease. However, CNS relapse risk remains high and further studies evaluating effective prophylactic strategies are needed.

Evaluation of the Risk of Relapse in Classical Hodgkin Lymphoma at Event-Free Survival Time Points and Survival Comparison With the General Population in British Columbia.

PURPOSE: Studies in classical Hodgkin lymphoma (cHL) typically measure the time to events from diagnosis. We evaluated the risk of relapse at event-free survival time points in cHL and compared the risk of death to expected mortality rates in British Columbia (BC). METHODS: The BC Cancer Agency Lymphoid Cancer Database was screened to identify all patients age 16 to 69 years diagnosed with cHL between 1989 and 2012 treated with the chemotherapy regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (or equivalent). We compared the observed mortality to the general population using age-, sex-, and calendar period-generated expected mortality rates from BC life-tables. Relative survival was calculated using a conditional approach and expressed as a standardized mortality ratio of observed-to-expected deaths. RESULTS: One thousand four hundred two patients were identified; 749 patients were male (53%), the median age was 32 years, and 68% had advanced-stage disease. The median follow-up time was 8.4 years. Seventy-two percent of relapses occurred within the first 2 years of diagnosis. For all patients, the 5-year risk of relapse from diagnosis was 18.1% but diminished to 5.6% for patients remaining event free at 2 years. For advanced-stage patients who were event free at 2 years, the 5-year risk of relapse was only 7.6%, and for those who were event free at 3 years, it was comparable to that of limited-stage patients (4.1% v 2.5%, respectively; P = .07). Furthermore, international prognostic score ≥ 4 and bulky disease were no longer prognostic in patients who were event free at 1 year. Although the relative survival improved as patients remained in remission, it did not normalize compared with the general population. CONCLUSION: Patients with cHL who are event free at 2 years have an excellent outcome regardless of baseline prognostic factors. All patients with cHL had an enduring increased risk of death compared with the general population.

Impact of time from diagnosis to initiation of curative-intent chemotherapy on clinical outcomes in patients with classical Hodgkin lymphoma.

The impact of treatment delays on outcomes in Hodgkin lymphoma (HL) is currently unknown. Time from definitive histologic diagnosis to first ABVD treatment (TDT) was calculated in 810 adults with HL: 365 (45%) TDT ≤4 weeks, 369 (46%) TDT 5-8 weeks, 76 (9%) TDT >8 weeks. The 5-year overall survival (OS) was 92% TDT ≤4 weeks, 92% TDT 5-8 weeks, and 83% TDT >8 weeks (p = 0.007). The 5-year disease-specific survival (DSS) was 93% TDT ≤4 weeks, 95% TDT 5-8 weeks, and 87% TDT >8 weeks (p = 0.094). The 5-year progression-free survival (PFS) was similar between groups (p = 0.139). In the multivariate analysis, TDT >8 weeks was not associated with worse OS, DSS, or PFS. Despite the univariate association between initiation of ABVD >8 weeks and worse OS, these data do not support such cut-off to improve outcomes. Nevertheless, clinicians should make every effort possible to initiate curative-intent chemotherapy as soon as a diagnosis of HL is established.

Impact of time from diagnosis to initiation of curative chemotherapy on survival of patients with diffuse large B-cell lymphoma.

Although it is generally regarded appropriate to start chemotherapy promptly after a diagnosis of diffuse large B-cell lymphoma (DLBCL), the optimal time from diagnosis to treatment (TDT) is unknown. A total of 689 patients diagnosed with DLBCL and treated with ≥ 1 cycle of CHOP-R with curative intent during 2003-2008 in British Columbia were identified: 347 (50%) TDT ≤ 4 weeks, 277 (40%) TDT 5-8 weeks, 65 (10%) TDT > 8 weeks. For the respective TDT groups, 5-year OS estimates were 61%, 74%, 63% (p = 0.006); 5-year PFS 57%, 70%, 61% (p = 0.006); and 5-year DSS 64%, 80%, 77% (p <0.001). In multivariate analysis, TDT >8 weeks was associated with worse OS (HR 1.20 (95% CI 1.03, 1.41), p = 0.020), PFS (HR 1.33 (95% CI 1.15, 1.54), p < 0.001), and DSS (HR 1.40 (95% CI 1.10, 1.78), p = 0.006). Clinicians should endeavor to initiate curative chemotherapy as soon as possible after a diagnosis of DLBCL is established.

Outcomes in splenic marginal zone lymphoma: analysis of 107 patients treated in British Columbia.

Splenic marginal zone lymphoma (SMZL) accounts for less than 2% of all non-Hodgkin lymphomas. We identified 107 cases diagnosed with SMZL between 1985 and 2012 from the British Columbia Cancer Agency Centre for Lymphoid Cancer and Lymphoma Pathology Databases. Patient characteristics were: median age 67 years (range 30-88), male 40%, stage IV 98%, splenomegaly 93%, bone marrow involvement 96%, peripheral blood involvement 87%. As initial treatment, 52 underwent splenectomy (10 with chemotherapy), 38 chemotherapy alone (21 chemoimmunotherapy containing rituximab, 1 rituximab alone), two antivirals for hepatitis C, and 15 were only observed. The 10-year overall survival for first-line splenectomy versus chemotherapy was 61% and 42%, respectively [Hazard Ratio (HR) 0·48, 95% confidence interval (CI) 0·26-0·88, P = 0·017]. The 10-year failure-free survival (FFS) after first-line splenectomy vs chemotherapy was 39% and 14%, respectively (HR 0·48, 95% CI 0·28-0·80, P = 0·004). Among the 38 patients who received first-line chemotherapy, FFS was similar between those receiving rituximab (n = 22) and those who did not (n = 16) (HR 0·64, 95% CI 0·31-1·34, P = 0·238). Fifteen patients transformed to aggressive lymphoma with median time to transformation of 3·5 years (range 6 months to 12 years) and the 10-year transformation rate was 18%. In conclusion, splenectomy remains a reasonable treatment for patients with SMZL.

Advanced-stage nodular lymphocyte predominant Hodgkin lymphoma compared with classical Hodgkin lymphoma: a matched pair outcome analysis.

Due to disease rarity, there is limited information regarding the optimal therapy and outcome for patients with advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Forty-two patients with NLPHL by the Revised European-American Lymphoma/World Health Organization classification with advanced-stage disease were identified and paired 1:2 with a matched control with classical Hodgkin lymphoma (CHL) matched by age, gender, stage, decade of diagnosis, and treatment received. The median follow-up was 11.3 years (range, 1.9 to 35.5 years) for NLPHL patients and 10.7 years (range, 1.6 to 26.3 years) for CHL patients. The majority received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)-like chemotherapy. Although the 10-year overall survival (OS) (P = .579) and HL freedom from treatment failure (HL-FFTF) were similar between NLPHL and CHL patients (75% vs 73%; P = .610), the time to progression (TTP), which also includes the development of secondary aggressive lymphoma, was inferior in NLPHL (10-year, 63% vs 73%; P = .040). Splenic involvement was associated with an inferior 10-year TTP in patients treated with ABVD (48% vs 71%; P = .049) and an increased cumulative incidence of secondary aggressive lymphoma (P = .014) providing a rationale for further evaluation of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with rituximab in NLPHL.

Effect of place of residence and treatment on survival outcomes in patients with diffuse large B-cell lymphoma in British Columbia.

BACKGROUND: We examined the relationship between location of residence at the time of diagnosis of diffuse large B-cell lymphoma (DLBCL) and health outcomes in a geographically large Canadian province with publicly funded, universally available medical care. PATIENTS AND METHODS: The British Columbia Cancer Registry was used to identify all patients 18-80 years of age diagnosed with DLBCL between January 2003 and December 2008. Home and treatment center postal codes were used to determine urban versus rural status and driving distance to access treatment. RESULTS: We identified 1,357 patients. The median age was 64 years (range: 18-80 years), 59% were male, 50% were stage III/IV, 84% received chemotherapy with curative intent, and 32% received radiotherapy. There were 186 (14%) who resided in rural areas, 141 (10%) in small urban areas, 183 (14%) in medium urban areas, and 847 (62%) in large urban areas. Patient and treatment characteristics were similar regardless of location. Five-year overall survival (OS) was 62% for patients in rural areas, 44% in small urban areas, 53% in medium urban areas, and 60% in large urban areas (p = .018). In multivariate analysis, there was no difference in OS between rural and large urban area patients (hazard ratio [HR]: 1.0; 95% confidence interval [CI]: 0.7-1.4), although patients in small urban areas (HR: 1.4; 95% CI: 1.0-2.0) and medium urban areas (HR: 1.4; 95% CI: 1.0-1.9) had worse OS than those in large urban areas. CONCLUSION: Place of residence at diagnosis is associated with survival of patients with DLBCL in British Columbia, Canada. Rural patients have similar survival to those in large urban areas, whereas patients living in small and medium urban areas experience worse outcomes.

Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors.

INTRODUCTION: A number of novel therapies are under investigation in relapsed or refractory peripheral T-cell lymphoma (PTCL); however, their relative impact on outcome is unknown. We examined the survival of patients with PTCL after relapse or progression in the absence of hematopoietic stem-cell transplantation and explored factors influencing survival. The three most common subtypes encountered in North America were evaluated: PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL; anaplastic lymphoma kinase [ALK] positive and ALK negative. PATIENTS AND METHODS: After exclusions, 153 patients were analyzed (PTCL-NOS, n = 79 [52%]; AITL, n = 38 [25%]; ALK-positive ALCL, n = 11 [7%]; ALK-negative ALCL, n = 27 [16%; including ALK status unknown, n = 1]). RESULTS: Median time from initial diagnosis to relapse or progression after primary therapy was 6.7 months, and median age at relapse was 66 years (ALK-positive ALCL, 39 years). Median overall survival (OS) and median progression-free survival (PFS) after relapse or progression (second PFS) were 5.5 and 3.1 months, respectively, and were only marginally better in patients who received chemotherapy at relapse (n = 89 [58%]; 6.5 and 3.7 months, respectively). Patients with good performance status (PS) of 0 or 1 (n = 47) at relapse who received chemotherapy had a more favorable OS (P < .001; median OS, 13.7 months) and PFS (P = .006; median second PFS, 5.0 months), which remained significant in multivariate analysis (OS: hazard ratio [HR], 2.09; P = .002; second PFS: HR, 1.66; P = .030). CONCLUSION: Most patients with relapsed or refractory PTCL have poor outcomes with short survival. Select patients with good PS have more favorable outcomes with standard chemotherapy.

International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era.

PURPOSE: The International Prognostic Score (IPS) is the most widely used risk stratification index for Hodgkin's lymphoma (HL). It is based on patients treated before 1992 and predicts 5-year freedom from progression (FFP) and overall survival (OS) ranging from 42% to 84% and 56% to 89%, respectively. The IPS has not been validated in a recently treated population in which outcomes have improved compared with historic results. PATIENTS AND METHODS: By using the British Columbia Cancer Agency Lymphoid Cancer Database, we identified all patients age ≥ 16 years newly diagnosed with advanced-stage HL (stage III to IV, or stage I to II with "B" symptoms or bulky disease ≥ 10 cm) from 1980 to 2010, treated with curative intent with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or an ABVD-equivalent regimen with complete clinical information. RESULTS: In all, 740 patients were identified. Five-year FFP and OS were 78% and 90%, respectively. The IPS was prognostic for both FFP (P < .001) and OS (P < .001), with 5-year FFP ranging from 62% to 88% and 5-year OS ranging from 67% to 98%. Analysis limited to patients age 16 to 65 years (n = 686) demonstrated a narrower range of outcomes, with 5-year FFP ranging from 70% to 88% and 5-year OS ranging from 73% to 98%. CONCLUSION: The IPS remains prognostic for advanced-stage HL, but the range of outcomes has narrowed considerably. This improvement in outcome with ABVD should be acknowledged before consideration of alternate initial therapies and when comparing results from current trials with those of historic controls.

Multivalent rituximab lipid nanoparticles as improved lymphoma therapies: indirect mechanisms of action and in vivo activity.

AIMS: The activity of therapeutic antibodies can be enhanced by creating multivalent constructs, such as antibody lipid nanoparticles (LNPs). Here, we examine differences between rituximab (Ritux) and Ritux-LNPs in terms of their indirect mechanisms of action: complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). MATERIALS & METHODS: We employed two mantle-cell lymphoma cell lines, Z138 and JVM2, which exhibit different in vivo sensitivities to Ritux along with variable expression levels of cell-surface proteins that regulate ADCC and CDC. RESULTS: In both cell lines, CDC and ADCC were found to be significantly enhanced after treatment with Ritux-LNPs compared with Ritux. In vivo efficacy studies, however, suggested that the therapeutic activities of Ritux and Ritux-LNPs were equivalent, which was subsequently explained in part by pharmacokinetic studies indicating rapid elimination of Ritux-LNP. CONCLUSION: Although indirect and direct mechanisms of multivalent Ritux are enhanced, its further development requires methods to improve its circulation lifetime.

A phase II study of bortezomib and gemcitabine in relapsed mantle cell lymphoma from the National Cancer Institute of Canada Clinical Trials Group (IND 172).

Bortezomib and gemcitabine have each shown activity as single agents in mantle cell lymphoma (MCL), which is incurable. The purpose of this phase II study was to determine the efficacy and safety of the previously unstudied combination of bortezomib and gemcitabine in patients with relapsed or refractory MCL. Patients were eligible if they had relapsed MCL with 1-3 prior therapies. Patients were treated with gemcitabine 1000 mg/m(2) on days 1 and 8 and bortezomib 1.0 mg/m(2) IV on days 1, 4, 8, and 11, on a 21-day schedule. Twenty-six patients were evaluable for toxicity and 25 for response. The overall response rate was 60% and the median progression free survival was 11.4 months. The main adverse effects were hematological, with 40% and 48% of patients experiencing grade 3/4 thrombocytopenia and granulocytopenia, respectively. Bortezomib and gemcitabine is an active combination in relapsed and refractory MCL with clinically meaningful results. It offers a chemotherapy backbone to which other agents, less myelosuppressive, may be added.

Prognostic implications of extranodal involvement in patients with diffuse large B-cell lymphoma treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone.

The addition of rituximab (R) to standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy has altered the significance of previously recognized prognostic factors. We sought to re-examine the prognostic utility of (1) the number of extranodal sites of disease involvement, and (2) a primary extranodal presentation in patients with DLBCL treated with immunochemotherapy. We retrospectively analyzed all patients with DLBCL diagnosed between January 1979 and May 2006 who were treated with an anthracycline-based therapy with curative intent. In all, 1781 patients were identified, of whom 513 (29%) received R-CHOP. In the R-CHOP group, extranodal involvement as defined by the International Prognostic Index (>or=2 sites) was not prognostic on multivariate analysis, but the presence of any extranodal involvement (>or=1 site) was associated with decreased progression-free survival (HR 1.6, 95% CI 1.1-2.4, p = 0.024) and overall survival (HR 1.8, 95% CI 1.1-2.7, p = 0.011). A total of 133 (26%) R-CHOP treated patients presented with primary extranodal DLBCL. There was no difference in outcome between patients with primary extranodal and nodal DLBCL, and no primary site of involvement was associated with an inferior outcome. In patients with DLBCL treated with R-CHOP, the presence of extranodal disease remains prognostic, whereas a primary extranodal presentation did not affect outcome.

Long-term survival in patients with metastatic melanoma treated with DTIC or temozolomide.

BACKGROUND: Patients with metastatic melanoma typically have a poor outcome; however, a small proportion of patients achieve long-term survival (LTS). It is unclear how often LTS is related to sensitivity to chemotherapy. METHODS: All patients with metastatic melanoma treated with either dacarbazine (DTIC) or temozolomide (TMZ) at the British Columbia Cancer Agency (BCCA) from January 1, 1988 to February 1, 2006 were identified through the BCCA pharmacy electronic database, which was then linked to the surveillance and outcomes unit to identify patients with LTS, defined as survival > or =18 months following chemotherapy. RESULTS: In total, 397 patients were treated with either DTIC (n = 349) or TMZ (n = 48) and 43 patients (10.8%) were identified with LTS. Two additional patients with LTS were added prior to 1988 for a total of 45 patients. The 5-year overall and progression-free survival rates for patients with LTS were 33% and 16%, respectively. In total, 16% had a complete response (CR) to chemotherapy, which was the only factor identified that correlated with survival in the multivariate analysis. However, most patients with LTS had an incomplete response to chemotherapy. CONCLUSIONS: LTS occurs in select patients who achieve a CR to chemotherapy. However, this occurs in only a minority of patients and, in most cases, the longer survival is likely the result of indolent disease biology or host factors.

Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study.

PURPOSE: In 2006, we published the results of the European Organisation for Research and Treatment of Cancer phase III trial EORTC 20981 on the role of rituximab in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). At that time, the median follow-up for the maintenance phase was 33 months. Now, we report the long-term outcome of maintenance treatment, with a median follow-up of 6 years. PATIENTS AND METHODS: Overall, 465 patients were randomly assigned to induction with either six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab plus CHOP (R-CHOP). Those in complete remission or partial remission after induction (n = 334) were randomly assigned to maintenance treatment with rituximab (375 mg/m(2) intravenously once every 3 months) or observation. RESULTS: Rituximab maintenance significantly improved progression-free survival (PFS) compared with observation (median, 3.7 years v 1.3 years; P < .001; hazard ratio [HR], 0.55), both after CHOP induction (P < .001; HR, 0.37) and R-CHOP (P = .003; HR, 0.69). The 5-year overall survival (OS) was 74% in the rituximab maintenance arm, and it was 64% in the observation arm (P = .07). After progression, a rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance. Rituximab maintenance was associated with a significant increase in grades 3 to 4 infections: 9.7% v 2.4% (P = .01). CONCLUSION: With long-term follow-up, we confirm the superior PFS with rituximab maintenance in relapsed/resistant FL. The improvement of OS did not reach statistical significance, possibly because of the unbalanced use of rituximab in post-protocol salvage treatment.

BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC 20981 phase III intergroup study.

PURPOSE: The prognostic value of residual BCL2/immunoglobulin heavy chain (BCL2/IgH) -positive cells in peripheral blood (PB) or bone marrow (BM) after induction treatment in follicular lymphoma (FL) is still controversial. In a prospective randomized phase III intergroup trial of 465 patients with relapsed/resistant follicular lymphoma (FL), we showed that addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone induction results in increased overall and complete response rates, and that rituximab maintenance strongly improves median progression-free survival (PFS) as well as overall survival. Here, we studied whether BCL2/IgH major break point levels in PB/BM correlated with response rates/quality for the induction phase and PFS for the maintenance phase. PATIENTS AND METHODS: Samples were obtained before and after induction therapy and at the end of the 2 years maintenance/observation period. BCL2/IgH major break point-positive cells were quantified by genomic quantitative polymerase chain reaction in 792 samples from 238 patients. RESULTS: Pretreatment BCL2/IgH levels had no significant prognostic value for overall response or complete remission rates after induction treatment, but pretreatment positive BM results had an adverse prognostic value for PFS from first randomization (P = .023). Importantly, BCL2/IgH levels at the end of induction treatment had no prognostic value for PFS from second randomization. The highly significant improved PFS by rituximab maintenance was observed in both BCL2/IgH PB/BM-positive and -negative groups. CONCLUSION: Postinduction BCL2/IgH major break point status in BM/PB is not useful for decisions on subsequent therapy for patients with relapsed/resistant FL.

The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation.

Previous studies of follicular lymphoma (FL) patients treated heterogeneously have suggested that decreased numbers of regulatory T cells correlates with improved survival. We studied advanced-stage FL patients from a single institution phase 2 trial. All patients were treated uniformly with multiagent chemotherapy and radiation. Tissue microarrays were constructed using diagnostic biopsies available in 105 patients and stained with CD4, CD8, CD25, and forkhead/winged helix transcription factor 3 (FOXP3) antibodies. Both cell content and cell distribution were evaluated. For all antibodies, there were cases with a predominant intrafollicular or perifollicular localization of cells (follicular pattern) while others displayed a diffuse pattern. The median follow-up of living patients was 17.1 years. The International Prognostic Index score predicted overall survival (OS; P = .004) but not risk of transformation (RT). Cell content did not impact survival, while immunoarchitectural patterns of CD4/CD8 were significant for progression-free survival (PFS; P = .056), CD25 for both PFS and OS (P = .002 and P = .024, respectively), and FOXP3(+) predicted PFS, OS, and RT (P = .001, P < .001 and p = .002, respectively). A Cox multivariate model showed both International Prognostic Index score and FOXP3(+) pattern were independent predictors of OS (P = .008 and P < .001, respectively), while only FOXP3(+) pattern predicted RT (P = .004). We conclude that FOXP3(+) cell distribution significantly predicts survival and RT in FL.