Anthracycline‐fludarabine‐containing regimens with or without rituximab in the treatment of patients with advanced follicular lymphoma

BACKGROUND:

Recent experience has suggested that there has been a stepwise improvement in the survival outcomes of patients who have follicular lymphoma with the introduction of new treatment options. In the current study, the authors report the results of 2 subsequent phase 2 trials of 238 previously untreated patients.

METHODS:

In a trial of bleomycin, epidoxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP) plus fludarabine, mitoxantrone, and dexamethasone (FND), 144 patients received 2 BACOP treatments followed by 4 FND treatments. In a trial of BACOP plus fludarabine and rituximab (FR), 94 patients received 3 BACOP treatments followed by 4 FR treatments.

RESULTS:

The complete remission (CR) rate for BACOP/FND was 62%. After a median follow‐up of 60 months, the failure‐free survival (FFS) and overall survival (OS) rates at 4 years were 53% and 77%, respectively. The CR rate for BACOP/FR was 79%. After a median follow‐up of 36 months, the FFS and OS rates at 4 years were 56% and 97%, respectively, which were significant compared with the CR and OS rates achieved with BACOP/FND. Twenty‐five of 42 bcl‐2‐positive patients attained a molecularly negative CR and had improved FFS. No significant differences were observed between the 2 trials in the percentage of infections or neutropenia.

CONCLUSIONS:

The CR and OS rates achieved with BACOP/FR were better, and overall toxicity did not increase. Furthermore, patients who received rituximab had a better FFS compared with patients who received chemotherapy alone. Finally, although conclusions between nonrandomized groups may depend on differences in observed and unobserved prognostic features, the current results suggested that the addition of rituximab to anthracycline‐fludarabine–containing regimens have a favorable effect on the prognosis of patients with advanced follicular lymphoma. Cancer 2009. © 2009 American Cancer Society.     

Fludarabine–Mitoxantrone–Rituximab regimen in untreated indolent non‐follicular non‐Hodgkin's lymphoma: experience on 143 patients

Indolent non‐follicular lymphomas (inFLs) are generally regarded as incurable, apart from extranodal mucosa‐associated lymphatic tissue lymphomas, which can be partially cured by surgery, local radiotherapy, or antibiotic treatment. The aim of the present study was to test the degree of effectiveness and the safety of the regimen containing fludarabine, mitoxantrone, and rituximab (FMR) in inFL patients considering all the different entities belonging to this group. An observational retrospective study was conducted on 143 inFL patients providing that their first chemoimmunotherapy performed was FMR regimen and diagnosis from September 2000 to March 2011. There were 32 small lymphocytic lymphomas and 111 marginal zone lymphomas. At the end of treatment, overall response rate was 96.5% with 88% of complete responses (CR) and 8.5% of partial responses. With a median follow‐up of 48 months, 10 out of 125 (8%) CR patients had disease relapse, yielding an estimated 9‐year disease‐free survival (DFS) of 74.9% and an estimated 10‐year overall survival of 92.8%. The estimated 9‐year progression free survival was 70.5%. The 10 relapsed patients showed lymphoma recurrence within 52 months: after this time, the DFS curve presented a plateau configuration. Only two (1.4%) patients developed a secondary hematological neoplasia. This study showed promising findings for the use of a fludarabine‐based regimen in combination with rituximab in the front‐line treatment of symptomatic inFL with a noteworthy high percentage of CR associated to an interesting long‐term DFS and favorable acute and long‐term safety profile. Copyright © 2014 John Wiley & Sons, Ltd.     

Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma

BACKGROUND: The current study was conducted to asses the safety profile and clinical activity of rituximab in combination with fludarabine and cyclophosphamide in patients with recurrent follicular lymphoma (FL). METHODS: This study was a noncomparative, multicenter, phase II study. Between March 2000 and December 2002, 54 patients with recurrent FL were enrolled in the FC+R trial. Patients received fludarabine at a dose of 25 mg/m(2) and cyclophosphamide at a dose of 300 mg/m(2) daily for 3 consecutive days, every 3 weeks for 4 cycles. Rituximab was administered at a dose of 375 mg/m(2) beginning 2 weeks after the first course of fludarabine and cyclophosphamide and then on Day 1 of each cycle thereafter. The planned treatment duration was 10 weeks. RESULTS: Overall, 92% of patients completed the planned therapy in 10 to 14 weeks and 74% achieved a complete response (CR). Among patients with BCL2-positive bone marrow, 86% obtained a molecular disease remission (MR). The median survival from treatment (SFT), the duration of disease remission (DR), and time to disease progression (TTP) had not been reached after a median follow-up of 45 months. Of the baseline characteristics, >2 previous treatments, BCL2-positive bone marrow, and low Follicular Lymphoma International Prognostic Index (FLIPI) score were found to be associated with better DR and/or TTP. Hematologic toxicity was transient and reversible, with the exception of 3 patients with severe and prolonged neutropenia. Three patients presented with infections, 1 of whom died of bronchopneumonia. CONCLUSIONS: The FC+R scheme, a nonanthracycline-containing regimen lasting up to 10 weeks, was found to be relatively well-tolerated and demonstrated significant antilymphoma activity with excellent clinical CR and molecular response rates.     

Management of localized low‐grade follicular lymphomas

Long‐term follow‐up data from Stanford and other centres suggest that 40–50% of patients with clinical stages I and II follicular low‐grade lymphoma can be cured by radiotherapy (RT). Relapse generally occurs outside radiation fields and most relapsed patients ultimately die from lymphoma. No randomized data exist to support adjuvant chemotherapy but only one trial of low‐intensity chemotherapy was sufficiently powerful to address the question. Nevertheless, data from a large phase‐II study from MD Anderson suggest that combined chemotherapy and RT can produce progression‐free survival results that are far superior to historical series, with survival at 10 years to be approximately 20% superior to radiation alone. These results have encouraged the development of a joint phase III study by the Trans Tasman Radiation Oncology Group (TROG) and the Australasian Leukaemia and Lymphoma Group (ALLG) in which patients with clinical stage I/II follicular lymphoma are randomized to involved field RT with or without six cycles of cytotoxic chemotherapy. In an era of rapid development in immunological and molecular therapies the potential for improved results with new combinations of more established treatment modalities should not be forgotten. This report reviews the literature on the management of localized low‐grade lymphoma and discusses the rationale for the TROG/ALLG study, which began recruitment in early 2000.     

Introduction of rituximab in front-line and salvage therapies has improved outcome of advanced-stage follicular lymphoma patients

BACKGROUND: It is unclear whether new treatment modalities have improved the survival of follicular lymphoma patients. Some data show that there has been no improvement in survival in the last 3 decades of the 20th century, whereas the results of recent retrospective studies suggest that evolving therapy has improved the outcome for follicular lymphoma patients. METHODS: To evaluate the impact of evolving therapies for follicular lymphoma, particularly the introduction of rituximab, the overall survival (OS), failure-free survival (FFS), and survival after recurrence (SAR) was analyzed in 438 advanced-stage follicular lymphoma patients enrolled in consecutive Gruppo Italiano Studio Linfomi (GISL) trials between 1988 and 2004. RESULTS: A stepwise improvement in FFS and a significant reduction in the hazard ratio was observed with succeeding studies. Cox regression analysis showed an improvement over time for OS, with a decline in the hazard ratio particularly evident in the group treated with rituximab. Furthermore, the SAR significantly improved in the group of patients treated with chemotherapy + rituximab. CONCLUSIONS: After adjusting for all parameters with an impact on FFS and OS, the results of multivariate analysis suggest that rituximab therapy has a favorable effect on the prognosis of follicular lymphoma. The data show that FFS and OS have significantly improved in advanced-stage follicular lymphoma patients treated on GISL protocols during the last 18 years. These improvements are related to evolving front-line and salvage therapies, particularly the introduction of rituximab in combination with chemotherapy.     

Long‐term outcomes for patients with limited stage follicular lymphoma

BACKGROUND:

Given the indolent behavior of follicular lymphoma (FL), it is controversial whether limited stage FL can be cured using radiotherapy (RT). Furthermore, the optimal RT field size is unclear. The authors of this report investigated the long‐term outcomes of patients with limited stage FL who received RT alone and studied the impact of reducing the RT field size from involved regional RT (IRRT) to involved node RT with margins up to 5 cm (INRT≤5 cm).

METHODS:

Eligible patients had limited stage, grade 1 through 3A FL diagnosed between 1986 and 2006 and treated were with curative‐intent RT alone. IRRT encompassed the involved lymph node group plus ≥1 adjacent, uninvolved lymph node group(s). INRT≤5 cm covered the involved lymph node(s) with margins ≤5 cm.

RESULTS:

In total, 237 patients were identified (median follow‐up, 7.3 years) and included 48% men, 54% aged >60 years, stage IA disease in 76% of patients, elevated lactate dehydrogenase (LDH) in 7% of patients, grade 3A tumors in 12% of patients, and lymph node size ≥5 cm in 19% of patients. The 2 RT groups were IRRT (142 patients; 60%) and INRT≤5 cm (95 patients; 40%). At 10 years, the progression‐free survival (PFS) rate was 49%, and the overall survival (OS) rate was 66%. Only 2 patients developed recurrent disease beyond 10 years. The most common pattern of first failure was a distant recurrence only, which developed in 38% of patients who received IRRT and in 32% of patients who received INRT≤5 cm. After INRT≤5 cm, 1% of patients had a regional‐only recurrence. Significant risk factors for PFS were lymph nodes ≥5 cm (P = .008) and male gender (P = .042). Risk factors for OS were age >60 years (P < .001), elevated LDH (P = .007), lymph nodes ≥5 cm (P = .016), and grade 3A tumors (P = .036). RT field size did not have an impact on PFS or OS.

CONCLUSIONS:

Disease recurrence after 10 years was uncommon in patients who had limited stage FL, suggesting that a cure is possible. Reducing RT fields to INRT≤5 cm did not compromise long‐term outcomes. Cancer 2010. © 2010 American Cancer Society.     

Infectious disease associations in advanced stage, indolent lymphoma (follicular and nonfollicular): developing a lymphoma prevention strategy.

BACKGROUND: Eradication of Helicobacter pylori in gastric mucosa-associated lymphoid tumor can result in lymphoma remission. We prospectively identified/treated infections in nonbulky, advanced stage indolent lymphoma (follicular; nonfollicular lymphoma) eligible for observation. Materials and methods: Stool H. pylori, hepatitis C and Borrelia serologies, Borrelia and Chlamydia fixed tissue PCR, Chlamydia peripheral blood mononuclear cell PCR and hydrogen breath test for small bowel bacterial overgrowth (SBBO) were obtained. RESULTS: Fifty-six patients were enrolled. Positive infections: H. pylori (13); hepatitis C (3); SBBO (11). Negative: Borrelia (13); Chlamydophila psittaci (12, except one PCR). Lymphoma responses to antimicrobial therapy: H. pylori [one complete response (CR), 24+ months; one transient near CR]; hepatitis C [two CRs, 18+ and 30+ months; one partial response (PR) but hepatitis C virus persistent]; SBBO (one PR, 30+ months). Patients with associated infections, but without lymphoma CR, have required lymphoma treatment sooner than those without initial infections (treatment-free survival at 23.4 months median follow-up, 40.5% versus 74.7%, P = 0.01), indicating a different biology. CONCLUSION: Infections are common in advanced stage indolent lymphoma (37.5% in our series). Anecdotal lymphoma responses have been seen and three have been durable CRs (18 to 30+ months) with infection eradication alone. The identification and treatment of associated infections may be a first step towards developing a lymphoma prevention strategy.     

Relationship between ambient ultraviolet radiation and non‐Hodgkin lymphoma subtypes: A U.S. population‐based study of racial and ethnic groups

Associations between ultraviolet radiation (UVR) exposure and non‐Hodgkin lymphoma (NHL) have been inconsistent, but few studies have examined these associations for specific subtypes or across race/ethnicities. We evaluated the relationship between ambient UVR exposure and subtype‐specific NHL incidence for whites, Hispanics and blacks in the United States for years 2001–2010 (n = 187,778 cases). Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quintiles using Poisson regression. Incidence was lower for the highest UVR quintile for chronic/small lymphocytic/leukemia (CLL/SLL) (IRR = 0.87, 95% CI: 0.77–0.97), mantle cell (IRR = 0.82, 95% CI: 0.69–0.97), lymphoplasmacytic (IRR = 0.58, 95% CI: 0.42–0.80), mucosa‐associated lymphoid tissue (MZLMALT) (IRR = 0.74, 95% CI: 0.60–0.90), follicular (FL) (IRR = 0.76, 95% CI: 0.68–0.86), diffuse large B‐cell (IRR = 0.84, 95% CI: 0.76–0.94;), peripheral T‐cell other (PTCL) (IRR = 0.76, 95% CI: 0.61–0.95) and PTCL not otherwise specified (PNOS) (IRR = 0.77, 95% CI: 0.61–0.98). Trends were significant for MZLMALT, FL, DLBCL, BNOS and PTCL, with FL and DLBCL still significant after Bonferroni correction. We found interaction by race/ethnicity for CLL/SLL, FL, Burkitt, PNOS and MF/SS, with CLL/SLL and FL still significant after Bonferroni correction. Some B‐cell lymphomas (CLL/SLL, FL and Burkitt) suggested significant inverse relationships in whites and Hispanics, but not in blacks. Some T‐cell lymphomas suggested the most reduced risk for the highest quintile of UVR among blacks (PNOS and MF/SS), though trends were not significant. These findings strengthen the case for an inverse association of UVR exposure, support modest heterogeneity between NHL subtypes and suggest some differences by race/ethnicity.     

Pixantrone dimaleate in combination with fludarabine, dexamethasone, and rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: phase 1 study with a dose-expansion cohort

BACKGROUND:

Pixantrone dimaleate (pixantrone) has been shown to have antitumor activity in leukemia and lymphoma in vitro models and to lack delayed cardiotoxicity associated with mitoxantrone in animal models. FND‐R, a combination regimen of fludarabine, mitoxantrone, dexamethasone, and rituximab, has been shown to be an effective regimen for low‐grade lymphomas.

METHODS:

This dose‐escalation study, with an expansion cohort, was conducted to evaluate the safety and preliminary efficacy of FPD‐R, in which pixantrone was substituted for mitoxantrone in the FND‐R regimen, in patients with relapsed or refractory indolent non‐Hodgkin lymphoma (NHL). Escalated doses of pixantrone were administered to newly enrolled patients on day 2 of each 28‐day cycle of FPD‐R.

RESULTS:

Twenty‐eight of 29 enrolled patients received at least 1 cycle of FPD‐R (median, 5 cycles). Pixantrone 120 mg/m² was identified as the recommended dose in this regimen. Grade 3‐4 adverse events were primarily hematologic; grade 3‐4 lymphopenia occurred in 89% of patients and leukopenia in 79%. No patients developed congestive heart failure or grade 3‐4 cardiac adverse events. Left ventricular ejection fraction decreases occurred in 8 (29%) patients, and most were grade 1 or 2, transient, and asymptomatic. The overall response rate was 89%. Estimated survival was 96% after 1 year and 92% after 3 years.

CONCLUSIONS:

The FPD‐R regimen was well‐tolerated and highly active in patients with relapsed or refractory indolent NHL. Cancer 2011;. © 2011 American Cancer Society.     

Presence of autoimmune disease affects not only risk but also survival in patients with B‐cell non‐Hodgkin lymphoma

Although autoimmune diseases (AIDs) are known to predispose to non‐Hodgkin lymphoma (NHL), their association with NHL prognosis has rarely been investigated. We examined associations between autoimmunity and B‐cell NHL onset by comparing AID history (determined by self‐report and medication review and supplemented by chart review where possible) among 435 adult B‐NHL patients in Hadassah‐Hebrew University Medical Center, diagnosed 2009‐2014, and 414 age‐and‐sex frequency‐matched controls. We examined AIDs as a whole, B‐ and T‐cell–mediated AIDs, and autoimmune thyroid diseases. Among cases, we used Kaplan‐Meier and Cox regression models to assess the association of AID with overall survival and relapse‐free survival, adjusting for prognostically important patient and disease characteristics such as Ki67% staining, International Prognostic Index, rituximab treatment, and histological subgroup. Autoimmune diseases were associated with B‐NHL (odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.31‐2.92), especially AIDs mediated by B‐cell activation (OR = 5.20; CI, 1.90‐14.3), which were particularly associated with marginal zone lymphoma (OR = 19.3; CI, 4.59‐80.9). We found that time to relapse for all B‐NHL patients with AIDs was significantly shorter (mean of 49.21 mo [±3.22]) than among patients without AID (mean of 59.74 mo [±1.62]), adjusted hazard ratio [HR_adj] = 1.69 (CI, 1.03‐2.79). Specifically, in patients with diffuse large B‐cell lymphoma, of whom 91.8% had received rituximab, a history of B‐cell–mediated AIDs was associated with shorter relapse‐free survival and overall survival, HR_adj = 8.34 (CI, 3.01‐23.1) and HR_adj = 3.83 (CI, 1.20‐12.3), respectively. Beyond confirming the well‐known association between AIDs and B‐NHL, we found that AID is an adverse prognostic factor in B‐cell lymphoma, associated with a shortened time to relapse, suggesting that there are specific therapeutic challenges in the subgroup of patients suffering from both these diseases. Further work is required to address mechanisms of resistance to standard treatment in the setting of AID‐associated B‐NHL. In the era of immunotherapy, these findings have particular relevance.     

Cardiovascular mortality among patients with non‐Hodgkin lymphoma: Differences according to lymphoma subtype

Survival rates of patients with non‐Hodgkin lymphoma (NHL) have improved over the last decade. However, cardiotoxicities remain important adverse consequences of treatment with chemotherapy and radiation, although the burden of cardiovascular mortality (CVM) in such patients remains unknown. We conducted a retrospective cohort study of patients greater than or equal to 20 years of age diagnosed with diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) between 2000 and 2013 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. Our primary endpoint was CVM. The association between NHL and CVM was evaluated using multivariable Cox regression analysis after adjusting for other patient characteristics. We calculated standardized mortality ratios (SMRs) for CVM, comparing NHL patients with the general population. We identified 153 983 patients who met the inclusion criteria (69 329 with DLBCL, 48 650 with CLL/SLL, and 36 004 with FL). The median follow‐up was 37 months (interquartile range, 10‐78 months); the mean patient age was 66.24 (±14.69) years; 84 924 (55.2%) were men; 134 720 (87.5%) were White, and 131 912 (85.7%) did not receive radiation therapy. Overall, 9017 patients (5.8%) died from cardiovascular disease, and we found that NHL patients had a higher risk of CVM than the general population, after adjusting for age (SMR 15.2, 95% confidence interval: 14.89‐15.52). The rates of CVM were 5.1%, 8%, and 4.4% in patients with DLBCL, CLL/SLL, and FL, respectively. Furthermore, across all NHL subtypes, older age, higher stage at the time of diagnosis (particularly stage 4), male sex, and living in the south were associated with higher risks of CVM. Our data suggest that risk assessment and careful cardiac monitoring are recommended for NHL patients, particularly those with the CLL/SLL subtypes.     

No excess risk of follicular lymphoma in kidney transplant and HIV‐related immunodeficiency

Subtype‐specific incidence patterns in populations at high risk of lymphoma offer insight into lymphomagenesis. The incidence profiles for the 2 most common non‐Hodgkin lymphoma subtypes were compared for 2 immunodeficient populations, adults receiving a kidney transplant 1982–2003 (n = 7,730) or diagnosed with human immunodeficiency virus (HIV) infection 1982–2004 (n = 17,175). National, population–based registries were linked and standardized incidence ratios (SIRs) were computed for each cohort and lymphoma subtype. Risk of diffuse large B‐cell lymphoma was significantly increased after transplantation (SIR 17.83, 95% CI: 13.61–22.95) and after HIV infection (SIR 58.81, 95% CI: 52.59–65.56). Rates of follicular lymphoma (FL) were neither significantly increased nor decreased in transplant recipients (SIR 0.82, 95% CI: 0.10–2.96) and in people with HIV (SIR 1.25, 95% CI: 0.41–2.91). The findings argue against an infectious or other immunodeficiency‐related etiology for FL and clearly differentiate it from diffuse large B‐cell lymphoma.     

Racial differences in presentation and management of follicular non-Hodgkin lymphoma in the United States: Report from the National LymphoCare Study

BACKGROUND:

Racial differences in follicular lymphoma (FL) in the United States have not been investigated.

METHODS:

The National LymphoCare Study is a multicenter, longitudinal, observational cohort study collecting data on treatment patterns and outcomes for patients with newly diagnosed FL in the United States between 2004 and 2007 without any predefined, study‐specific intervention. The authors investigated differences between white (W) patients, African American (AA) patients, and Hispanic (H) patients.

RESULTS:

Among 2744 enrolled patients, there were 95 (3%) AA patients, 125 (5%) H patients, and 2476 (90%) W patients. Compared with W patients, more AA and H patients were diagnosed at age <45 years (P < .0001). H patients more commonly were diagnosed with grade 3 FL compared with AA and W patients (29%, 13%, and 18%, respectively; P = .019) and more commonly received rituximab plus chemotherapy as initial therapy compared with W patients (66% vs 50%; P = .036), while AA patients less commonly received anthracyclines (49% vs 64% in W patients; P = .027). H and AA patients who received rituximab plus chemotherapy were less likely than W patients to receive maintenance rituximab (27% vs 31% vs 40%, respectively; P = .031). At a median follow‐up of 52 months, progression‐free survival was similar between AA and W patients but was longer in H patients, and there was no difference in overall survival.

CONCLUSIONS:

In the largest prospective cohort to date of AA and H patients with FL in the United States, AA and H patients were younger at presentation. Although racial differences in treatment patterns for FL were noted, additional follow‐up is needed to determine the impact of these differences on survival. Cancer 2012. © 2012 American Cancer Society.     

Pretransplantation [18‐F]fluorodeoxyglucose positron emission tomography scan predicts outcome in patients with recurrent Hodgkin lymphoma or aggressive non‐Hodgkin lymphoma undergoing reduced‐intensity conditioning followed by allogeneic stem cell transplantation

BACKGROUND:

The use of positron emission tomography (PET) scanning in Hodgkin lymphoma (HL) and aggressive non‐Hodgkin lymphoma (HG‐NHL) has recognized prognostic value in patients who are receiving chemotherapy or undergoing autologous stem cell transplantation (SCT). In contrast, the role of PET before reduced‐intensity conditioning (RIC) and followed by allogeneic SCT has not been investigated to date.

METHODS:

PET was used to assess 80 patients who had chemosensitive disease (34 patients with HG‐NHL and 46 patients with HL) before they underwent allogeneic SCT: 42 patients had negative PET studies, and 38 patients had positive PET studies. Patients underwent allograft from matched related siblings (n = 41) or alternative donors (n = 39).

RESULTS:

At the time of the last follow‐up, 48 patients were alive (60%), and 32 had died. The 3‐year cumulative incidence of nonrecurrence mortality and disease recurrence was 17% and 40%, respectively. The cumulative incidence of disease recurrence was significantly lower in the PET‐negative patients (25% vs 56%; P = .007), but there was no significant difference between the patients with or without chronic graft‐versus‐host disease (P = .400). The patients who had negative PET studies before undergoing allogenic SCT also had significantly better outcomes in terms of 3‐year overall survival (76% vs 33%; P = .001) and 3‐year progression‐free survival (73% vs 31%; P = .001). On multivariate analysis, overall survival was influenced by PET status (hazard ratio [HR], 3.35), performance status (HR, 5.15), and type of donor (HR, 6.26 for haploidentical vs sibling; HR, 1.94 for matched unrelated donor vs sibling).

CONCLUSIONS:

The current results indicated that PET scanning appears to be an accurate tool for assessing prognosis in patients who are eligible for RIC allografting. Cancer 2010. © 2010 American Cancer Society.