R-CHOP Induction Research Articles

Comparing R-Bendamustine vs. R-CHOP Plus Maintenance Therapy as First-Line Systemic Treatment in Follicular Lymphoma: A Multicenter Retrospective GELTAMO Study.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77-86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72-86) for R-bendamustine vs. 67% (95% CI: 61-73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86-96) for R-B vs. 91% (95% CI: 87-94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality.

Matched control analysis suggests that R-CHOP followed by (R)-ICE may improve outcome in non-GCB DLBCL compared with R-CHOP

AbstractRituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score–matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score–matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.

Co-Expression of C-MYC/BCL2 Is Associated with Inferior Survival Outcomes in Relapsed/Refractory Diffuse Large B-Cell Lymphoma after Autologous Stem Cell Transplantation - a Nationwide Retrospective Analysis in Singapore

Introduction Co-expression of C-MYC and BCL2 in diffuse large b-cell lymphomas (DLBCL), also termed double-expressor lymphomas (DEL), has been shown to be associated with poorer outcomes after standard R-CHOP induction therapy. Approximately 70% of DEL will relapse within 5 years. The subsequent traditional approach with potential for cure has been high dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). Whilst factors such as remission status after front-line treatment and early relapse have been associated with poorer outcomes after ASCT, data are limited regarding significance of DEL status on survival outcomes post-ASCT. We retrospectively studied the prognostic impact of DEL status on outcomes in patients with relapsed or refractory (R/R) DLBCL who underwent ASCT. Methods This was a retrospective, nationwide study of adults patients, >18 years old, with R/R DLBCL who underwent autologous hematopoietic stem cell transplantation (ASCT) between 2010 and 2022 at the only 2 transplant centers in Singapore - Singapore General Hospital and National University Cancer Institute. Patients with double/triple hit lymphoma, defined as concurrent rearrangements of MYC and BCL2 and/or BCL6 by fluorescence in situ hybridization (FISH) analysis, were not included in this study. Patients with transformed indolent B-cell NHL (non hodgkin lymphoma), primary mediastinal B-cell lymphoma, primary CNS (central nervous system) lymphoma, or Richter transformation of chronic lymphocytic leukemia were excluded. Only patients that had available MYC and BCL-2 immunohistochemistry (IHC) were included in this study. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to assess associations between covariates of interest and OS or PFS. Results A total of 72 patients were included, 44 (61.1%) non-double expressor DLBCL (non-DEL) and 28 (38.9%) double expressor DLBCL (DEL). Patient demographics and disease characteristics at relapse were similar in both groups aside from a higher incidence of CNS involvement in the non-DEL group as compared to DEL group, 34.1% vs 10.7% (Table 1). Both groups achieved a >90% response (CR and PR) after second-line salvage chemotherapy as well as a >90% response post-transplant (CR and PR). Patients with DEL however were more likely to relapse post-transplant, 69.7% vs 40.9% (p = 0.032) and were also associated with increased odds of all-cause mortality, 60.7% vs 36.4% (p=0.043). This significance was maintained on multivariable analysis, HR 4.22 95% CI 1.20 - 14.84 (p=0.025) and HR 4.32 95% CI 1.10 - 17.15 (p=0.038) respectively. The median follow up for survivors were 42 months (range, 26 to 64 months) in the DEL patients and 60 months (range, 46 to 88 months) in the non-DEL patients. The 5-year PFS in patients with DEL was inferior to non-DEL patients, 23.3% vs 49.6% respectively, p=0.022. DEL patients were also associated with inferior 5-year OS, 40.2% vs 65.7%, p=0.041. In multivariable model, DEL status remained significantly associated with inferior PFS and OS. We also observed that patients with CNS involvement at relapse had inferior PFS and OS. Male gender and a less than complete metabolic response (CR) status prior to transplant, assessed on PET-CT, was also associated with inferior OS. Conclusion Co-expression of C-MYC/BCL2 was associated with inferior outcomes after ASCT in patients with R/R DLBCL. While ASCT has been the standard curative approach in the R/R setting, considerations for novel targeting therapies to achieve a deeper response prior to transplant or the upfront use of chimeric antigen receptor T-cell therapy at first relapse may be further explored in this high-risk subset of patients.

Retrospective Analysis of Clinical Outcomes of Utilizing R-CHOP Plus Zanubrutinib for High-Risk Diffuse Large B Cell Lymphoma Patients with Extranodal Involvement or MYC/BCL2 Double Expression

Background: Diffuse large B-cell lymphoma (DLBCL) patients with extranodal involvement and double expression of MYC and BCL2 often have a poorer prognosis when treated with the standard first-line R-CHOP regimen. The 5-year progression-free survival (PFS) and overall survival (OS) rates are both below 40% for these high-risk DLBCL cases. In this study, we perform a retrospective analysis of the clinical outcomes and adverse events of the high-risk DLBCL patients with extranodal involvement and double expression, who were admitted to our center and used Bruton's tyrosine kinase inhibitor (BTKi) zanubrutinib on the basis of R-CHOP regimen. Methods: We conducted a retrospective analysis of 26 DLBCL patients with extranodal involvement or MYC/BCL2 double expression who were admitted to our center and used R-CHOP regimen in combination with zanubrutinib between 1 st January 2021 and 30 th April 2023 (Figure A). Of these patients, 19 had extranodal involvement, and 7 were identified as double expression cases. The patients had a median age of 70 years, ranging from 34 to 87. Among them, 20 cases (77%) were aged over 60, and 8 cases (30%) were aged over 75. Moreover, 20 cases (76.9%) exhibited an Eastern Cooperative Oncology Group (ECOG) performance status score higher than 2 points. All the patients received an induction regimen consisting of zanubrutinib in combination with R-CHOP for a total of 4 cycles. After the fourth cycle, treatment efficacy was assessed using 18FDG-PET/CT scans. Patients achieving partial response (PR) or better continued with rituximab in combination with zanubrutinib for consolidation maintenance therapy, lasting for 1 year. For patients at risk of central nervous system involvement, oral administration of zanubrutinib continued for 2 years. During the treatment period, imaging evaluations were performed every 3 months to assess treatment response (Figure B). Results: After the induction therapy, a mid-term PET/CT evaluation showed that all patients achieved PR or above, resulting in an overall response rate (ORR) of 100%. Among them, 19 patients (73.1%) achieved complete response (CR), while 7 patients (26.9%) achieved PR. During the consolidation and maintenance therapy, 7 patients who were initially in PR converted to CR. As of the latest follow-up, with a median follow-up duration of 11 months (ranging from 4.1 to 30.0 months), 2 patients (7.7%) were lost to follow-up, and 2 patients (7.7%) experienced disease progression. The median PFS and OS were not reached. The 2-year PFS was 69.7±13.4% (Figure C), and the 2-year OS was 77.4±12.2% (Figure D). Non-hematological adverse events included fatigue (38.5%), hypertension (15.38%), neurological symptoms (7.7%), and infections (100%). Among the infections, 3 cases (11.5%) were of >3-grade and led to treatment discontinuation. Additionally, one patient experienced immune encephalitis and went into a coma. Hematological adverse events included granulocytopenia (55%), anemia (26%), thrombocytopenia (42.3%), and bleeding (38.5%). Among them, >3-grade granulocytopenia occurred in 4.5% of the patients. Five patients who were on long-term anticoagulant therapy due to concurrent cardiovascular diseases experienced a reduction in zanubrutinib dosage during the follow-up period, resulting in an improvement in bleeding symptoms. Conclusions: The combination of 4 cycles of R-CHOP regimen with zanubrutinib in the induction treatment of DLBCL patients with high-risk factors, such as extranodal involvement or MYC/BCL2 double expression, has shown promising clinical outcomes especially in older or unfit/frail patients. This approach allows for a reduction in the number of cytotoxic drug cycles, thereby improving the patients' tolerance to the treatment. Moreover, the efficacy of this regimen is superior to the traditional 6-8 cycles of R-CHOP induction therapy. Furthermore, the consolidation and maintenance therapy with rituximab in combination with zanubrutinib has demonstrated good safety and manageable adverse effects. This approach exhibits hope for further enhancing the prognosis of high-risk DLBCL patients.

Impact of Circulating Lymphoma at Diagnosis on Outcomes in Patients with Diffuse Large B-Cell Lymphoma

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma. The risk stratification tools continue to evolve and currently, there are various known prognostic factors including revised international prognostic index (R-IPI), MYC/BCL2 overexpression by IHC, MYC/BCL2, and or BCL6 rearrangement (double hit/triple hit lymphomas [DHL/THL]), CD5 expression, and metabolic tumor volume. Outside of case reports and small case series (Muringampurath-John, D et al BJH 2012), the relevance of circulating lymphoma (CL) in patients with DLBCL at diagnosis is largely unknown. Hence, we sought to evaluate the impact of CL at diagnosis on outcomes in patients with DLBCL. Methods This is a single-center, retrospective cohort study of DLBCL patients treated at Ohio State University and included patients who were ≥18 years old, diagnosed with DLBCL from 2010-2021, and had information on flow cytometry at diagnosis. Patients were grouped according to positive or negative flow cytometry results as CL+ and CL-, respectively. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was overall survival (OS) in CL+ and CL- groups. PFS was defined as the time from the start of first-line therapy until lymphoma relapse/progression or death from any cause, censoring at the last clinical assessment. OS was defined as the time from the start of first-line therapy until death or last follow-up. The first-line therapy was categorized into two groups, R-CHOP, and intensive induction therapy (R-EPOCH, R-hyperCVAD, and R-CODOX-M/R-IVAC). Results Among the 181 eligible patients with newly diagnosed DLBCL, 30 (17%) had detectable CL at diagnosis, while 151 (83%) did not. Patients in the CL+ group had a higher median age (66 vs 64 years), more advanced stage disease (97% vs 83%), and R-IPI score of 3-5 (89% vs 62%) compared to the CL- group. The two groups were balanced in regard to gender, race, ECOG performance status, bulky disease, presence of B symptoms, cell of origin, synchronous central nervous system (CNS) involvement, DHL/THL, and first-line therapy. The median PFS was 4.2 years (95%CI=0.9-not reached [NR]) in the CL+ group compared to 10.9 years (95%CI=4.8-NR) in the CL- group (p=0.20, Figure 1). While the median PFS was not significantly different between CL+ and CL- groups among patients treated with R-CHOP chemotherapy (median PFS NR vs 10.9 years, respectively, p=0.99). However, compared to the CL+ group, the median PFS was significantly longer in the CL- group receiving intensive induction therapy (median PFS 1.8 years vs NR, respectively, p=0.04). After adjusting for factors associated with PFS in multivariable cox regression (gender, R-IPI, first-line therapy, synchronous CNS involvement, and DHL/THL), there was no difference in PFS between CL+ and CL- groups (HR=1.48, 95%CI=0.77-2.85, p=0.24). The median OS was 4.2 years (95%CI=1.7-NR) in the CL+ group while it was NR in the CL- group (p=0.05, Figure 2). After adjusting for factors associated with PFS in multivariable cox regression (gender, R-IPI, first-line therapy, synchronous CNS involvement, and DHL/THL), there was no difference in OS between CL+ and CL- groups (HR=1.85, 95%CI=0.90-3.79, p=0.09). Conclusions This is the first study to compare the outcomes of patients with CL+ and CL- groups in newly diagnosed DLBCL. In this largest study to date evaluating the prognostic relevance of CL in patients with DLBCL, we found that CL at diagnosis was not associated with a shorter PFS but trended towards inferior OS. The CL+ group represents a potentially high-risk patient population and needs to be prioritized for experimental and cellular therapies at first relapse. Future prospective studies should include testing for CL and validate the findings found in our study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Favorable Outcomes with R-CHOP Induction and Consolidative Autologous Stem Cell Transplantation for Double-Hit Lymphoma

Double-hit lymphoma (DHL) is an aggressive large B cell lymphoma associated with a poor prognosis with R-CHOP chemotherapy. The optimal treatment is unknown, but outcomes might be improved with intensive induction regimens or consolidative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT). The purpose of this study was to determine the real-world outcomes of patients with DHL treated with primarily R-CHOP induction and consolidative HDT/ASCT. This retrospective, multicenter study included consecutive patients age 18 to 70 years with newly diagnosed DHL intended for consolidative HDT/ASCT in Alberta, Canada. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method. The cohort comprised 58 patients with a median age of 59.5 years (range, 30 to 69 years). High-risk features at diagnosis included International Prognostic Index score 3 to 5 in 45 patients (78%), transformed indolent lymphoma in 25 (43%), and central nervous system involvement in 3 (5%). Forty-six patients (79%) patients received R-CHOP induction, and 45 (78%) proceeded to consolidative HDT/ASCT. With a median follow-up of 4.6 years, the 4-year PFS and OS rates were 67% (95% confidence interval [CI], 53% to 78%) and 68% (95% CI, 54% to 79%), respectively, for all patients and 86% (95% CI, 72% to 93%) and 88% (95% CI, 73% to 95%) for those undergoing HDT/ASCT. R-CHOP induction and consolidative HDT/ASCT result in excellent outcomes for patients with chemosensitive DHL, whereas patients with primary refractory disease might benefit from alternative strategies, such as earlier use of chimeric antigen receptor T cell therapy.

Impact of Immunochemotherapy with R-Bendamustine or R-CHOP in the Post-Induction Management of Treatment Naïve Advanced Stage Follicular Lymphoma Patients: A Subset Analysis of the FOLL12 Trial By the Fondazione Italiana Linfomi (FIL)

Impact of Immunochemotherapy with R-Bendamustine or R-CHOP in the Post-Induction Management of Treatment Naïve Advanced Stage Follicular Lymphoma Patients: A Subset Analysis of the FOLL12 Trial By the Fondazione Italiana Linfomi (FIL)

Ibrutinib- and bortezomib-extended R-CHOP induction in elderly higher-risk patients newly diagnosed with diffuse large B-cell lymphoma – first analysis of toxicity and efficacy signals

Diffuse large-cell B-cell lymphoma (DLBCL) is the most common lymphoid malignancy. About 30–40% of the patients will not be cured by standard Rituximab (R)-CHOP-like immune-chemotherapy, and many of them experience relapse and eventually succumb to their disease. Enhancing first-line efficacy in patients at higher risk, among them many elderly, is key to improve long-term outcomes. Numerous attempts to combine R-CHOP with targeted agents failed in large randomized phase III trials. The addition of Ibrutinib enhanced survival in younger patients, but increased toxicity across all age groups, especially in the elderly. Older DLBCL patients impose particular challenges, since they often present with more advanced disease, and exhibit treatment-relevant comorbidities. ImbruVeRCHOP trial aims at identifying patients who need that benefit from rationally augmented first-line regimens without experiencing overt toxicity and detecting their molecular signatures of response. This first analysis presents encouraging feasibility, safety, and preliminary response data in elderly high-risk DLBCL patients.

Rituximab Maintenance after First-Line Immunochemotherapy in Mantle Cell Lymphoma: Long-Term Follow-up of the Randomized European MCL Elderly Trial

Rituximab Maintenance after First-Line Immunochemotherapy in Mantle Cell Lymphoma: Long-Term Follow-up of the Randomized European MCL Elderly Trial

Value of PD-L1 Protein Expression in the Combined Prognostic Model of Diffuse Large B-Cell Lymphoma

Aim. To study the value of PD-L1 protein expression in the combined model of diffuse large B-cell lymphoma (DLBCL) after administration of R-CHOP induction immunochemo-therapy. Materials & Methods. A retrospective analysis was based on the data of 85 DLBCL patients. The median age was 59 years (Q-Q<sub>3</sub>: 29-83). Each patient received at least 2-6 courses of R-CHOP immunochemotherapy. The median follow-up period was 17 months. The optimal cut-off threshold for assessing the proportion of tumor cells expressing PD-L1 protein was determined by the CART (Classification and Regression Tree) method. Results. Patients were divided into three groups depending on IPI (International Prognostic Index) risk and immunohis-tochemical subtype (Hans algorithm) using CART. In group 1 with immunohistochemical GCB subtype and any IPI risk, except for the high one, low PD-L1 expression measured in terms of the DLBCL expressing tumor cell count, was identified in 21 (84 %) patients, 4 (16 %) patients showed overexpression. In case of low PD-L1 expression the 2-year progression-free survival (PFS) was 76 % (median not reached). In 4 patients with protein overexpression, the life duration after DLBCL diagnosed was 4, 16, 2, and 6 months, respectively. In group 2 with immunohistochemical non-GCB subtype and any IPI risk, except for the high one, 27 (67.5 %) patients showed low, and 13 (32.5 %) patients showed high PD-L1 expression. The analysis of the 2-year PFS resulted in no significant differences in groups with different relative counts of PD-L1 expressing tumor cells, i.e., 46 % and 49 %, respectively (p = 0.803). In case of low (< 24.5 % tumor cells) PD-L1 expression, the 2-year overall survival (OS) was better than in patients with overexpression (> 24.5 % tumor cells), i.e., 87 % vs. 52 %, respectively (p = 0.049). In group 3 with IPI high risk irrespective of immunohistochemical subtype, the proportion of PD-L1 expressing cells was higher than cut-off threshold (> 24.5 %) in 9 (45 %) patients, low protein expression was identified in 11 (55 %) patients. Deaths were reported in all patients of group 3 showing PD-L1 overexpression. In case of low protein expression the proportion of patients alive was 46 % (p = 0.002). None of the patients with high PD-L1 expression lived longer than 2 years. In those with low PD-L1 expression the 2-year OS was 66 % (p = 0.008). Conclusion. Overexpression of PD-L1 by DLBCL tumor cells together with high IPI progression risk and non-GCB tumor subtype is associated with the worst OS and PFS. It can probably be accounted for by insufficient efficacy of R-CHOP induction immunochemotherapy in patients with high IPI risk. With this presumption, the PD-L1 expressing tumor cell count can be regarded as an important additional criterion for stratification of DLBCL patients into risk groups. Adding this new parameter to already established ones would probably contribute to differentiated approach to the choice of chemotherapy strategy at the onset of this aggressive lymphoma.

Lenalidomide As Maintenance Therapy after R-CHOP Has No Protecting Effect for Central Nervous System Relapse in Frontline Treatment of Diffuse Large B-Cells Lymphoma. an Ancillary Studies of the Remarc Study

Lenalidomide As Maintenance Therapy after R-CHOP Has No Protecting Effect for Central Nervous System Relapse in Frontline Treatment of Diffuse Large B-Cells Lymphoma. an Ancillary Studies of the Remarc Study

Recovery of central memory and naive peripheral T cells in Follicular Lymphoma patients receiving rituximab-chemotherapy based regimen

Preclinical models and clinical studies have shown that anti-CD20-based treatment has multifaceted consequences on T-cell immunity. We have performed a prospective study of peripheral T-cell compartment in FL patients, all exhibiting high tumor burden and receiving rituximab-chemotherapy-based regimen (R-CHOP). Before treatment, FL patients harbor low amounts of peripheral naive T cells, but high levels of CD4+ TEM, CD4+ Treg and CD8+ TEMRA subsets and significant amounts of CD38+ HLA-DR+ activated T cells. A portion of these activated/differentiated T cells also expressed PD-1 and/or TIGIT immune checkpoints. Hierarchical clustering of phenotyping data revealed that 5/8 patients with only a partial response to R-CHOP induction therapy or with disease progression segregate into a group exhibiting a highly activated/differentiated T cell profile and a markedly low proportion of naive T cells before treatment. Rituximab-based therapy induced a shift of CD4+ and CD8+ T cells toward a central memory phenotype and of CD8+ T cells to a naive phenotype. In parallel, a decrease in the number of peripheral T cells expressing both PD-1 and TIGIT was detected. These observations suggest that the standard rituximab-based therapy partially reverts the profound alterations observed in T-cell subsets in FL patients, and that blood T-cell phenotyping could provide a better understanding of the mechanisms of rituximab-based treatment.

The role of maintenance therapy in patients with diffuse large B cell lymphoma: A systematic review and meta-analysis.

Randomized trials of maintenance therapy (MT) in diffuse large B cell lymphoma (DLBCL) are inconclusive regarding its effect on overall survival (OS) and disease control. We aimed to examine the efficacy and safety of MT in this meta-analysis. Systematic review and meta-analysis of randomized controlled trials comparing MT with observation or placebo, in patients with DLBCL, who achieved complete response (CR) or partial response (PR) after first-line chemotherapy with or without rituximab. Primary outcome was OS. Secondary outcomes included relapse rate, disease control (defined as progression-free survival, event-free survival, or disease-free survival, as reported in the original trials), and safety. Our search yielded 14 trials including 5122 patients. Median age of patients was 49 to 70years. Six trials included rituximab as the MT; three included Interferon alfa; other trials include thalidomide, lenalidomide, cyclophosphamide and prednisone, serine threonine kinase inhibitor enzastaurin, and mTOR inhibitor everolimus. MT did not improve OS compared to observation, OR 0.91, (95% CI 0.78-1.07). Results were the same in a subgroup analysis by the type of maintenance (rituximab vs other). MT did decreased relapse rate, RR 0.76 (95% CI 0.65-0.89) and improved disease control, OR 0.74 (95% CI 0.65-0.84). Disease control was significantly improved in the subgroup of studies evaluating rituximab as maintenance OR 0.61 (95% CI 0.47-0.79) and in the subgroup of R-CHOP induction studies OR 0.77 (95% CI 0.67-0.88). Serious or grade III/IV adverse events including neutropenia and infections were significantly more common in the maintenance arm, RR=1.69 (95% CI 1.29-2.22). MT in patients with DLBCL achieving CR or PR after induction therapy did not affect OS, yet it decreased relapse rate and improved disease control at the cost of higher infection rate. Our data do not support routine administration of MT in patients with DLBCL.

Maintenance Therapy in Diffuse Large B Cell Lymphoma and Mantle Cell Lymphoma.

Maintenance therapy has evolved as a strategy to prolong remissions in patients with diffuse large B cell lymphoma (DLBCL) or mantle cell lymphoma (MCL), typically following a more intensive therapy, such as induction therapy or stem cell transplantation. In randomized, controlled clinical trials, this approach has successfully prolonged overall survival in some MCL clinical settings, including after autologous stem cell transplantation and after R-CHOP induction, but has generally been unsuccessful in DLBCL. This most likely reflects differences in the biology and natural history of each disease. In DLBCL, a majority of patients are cured with frontline therapy, leaving fewer who can potentially benefit from maintenance. When the disease relapses, it is usually within the first 2years and is usually clinically aggressive and difficult to control with low-intensity therapy. In contrast, nearly all patients with MCL will eventually relapse, and the disease may remain quiescent for many years. There may also be differences in sensitivity of minimal residual disease to maintenance treatments. Thus, future strategies to improve DLBCL treatments should focus on improved induction and possibly consolidation regimens rather than maintenance. In MCL, maintenance therapy will continue to play a role in the near future, although in both diseases, applying novel immunotherapies with the potential to eradicate residual disease clones persisting after induction may be the most successful strategy to improve patient outcomes.

Beyond rituximab maintenance. relapsing follicular lymphoma during or after end of rituximab maintenance: analysis of Czech Lymphoma Study Group (CLSG) database

Introduction: Rituximab maintenance (RM) improves progression-free survival (PFS) in advanced indolent follicular lymphoma (FL). Despite this fact, some proportion of patients relapse during or after RM. This cohort is not well described and its outcome and prognosis are unknown. Methods: Between 01/2002 and 12/2012, 1456 patients with initialy diagnosed FL grade 1-3A were registered in the prospectively maintained multicentric CLSG database. For the analysis, relapsed FLs during (at least one dose given) or after end of RM and initially treated with R-CHOP induction were selected. Results: There were 519 patients treated with RM in first line, 117 pts relapsed during maintenance or after the last dose, and 88 cases of them received RCHOP induction. Global 5-year PFS was in RCHOP/RM arm about 74%. For 88 relapsed pts, median of administered RM doses was 8 (1-29), and median duration of maintenance was 1.67 (0-2.1) yr. At the time of relapse, median of age was 62 ys, and 9/88 (10%) pts transformed into FL3B or DLBCL. Generally, at relapse there were observed less advanced lymhomas compared to initial FL diagnoses. Clinical stage I or II had 32/88 vs 3/88 (p < .001) pts, B-symptoms developed 14 vs 28 (p < .02) of them, bone marrow involvement was present in 13 vs 61 (p < .001) cases, elevated LDH was in 14 vs 42 (p. 013), and bulky disease >7.5 cm was in 13 vs 35 patients (p < .01). Twenty-nine (33%) relapses occured during RM with median 4 (1-9) doses given; 6 pts relapsed within 6 months since the end of RCHOP (double refractory patients). Totally, 13/88 (15%) relapsed pts remain without any therapy, whereas 75 (85%) received systemic treatment including 24 (27%) cases consolidated with autologous (ASCT) and 1 case with allogeneic stem cell transplantations. Rituximab alone or in combination was given to 59/88 (67%) patients. There were differences in subsequent therapy between cohort progressed “during RM” and arm relapsing “after end of RM.” Patients relapsed “during RM” were more often treated with platina-based regimens (59% vs 25%; p.005), and consolidated more with ASCT (48% vs 17%; p.014). From the relapse, OS in 5 yrs was about 90% and 5-yr PFS was 43%. There were no significant differences between cohort relapsing “during RM” or “after RM” in overal survival. However, PFS showed some trend to be better in “after RM” arm (p. 13). Keywords: follicular lymphoma (FL); R-CHOP; rituximab

Treatment of aggressive B-cell lymphomas.

Treatment of aggressive B-cell lymphomas.

Benefit of Consolidative Autologous Stem Cell Transplantation in First Complete Remission for Patients with Double Hit Lymphoma Appears Dependent on Induction Regimen Intensity

Benefit of Consolidative Autologous Stem Cell Transplantation in First Complete Remission for Patients with Double Hit Lymphoma Appears Dependent on Induction Regimen Intensity

Patients with "Single-Hit" but Not MYC -Amplified Non-Burkitt High-Grade B Cell Non-Hodgkin Lymphomas Experience Poor Survival Outcomes and May Benefit from Intensive Induction Therapy

Patients with "Single-Hit" but Not MYC -Amplified Non-Burkitt High-Grade B Cell Non-Hodgkin Lymphomas Experience Poor Survival Outcomes and May Benefit from Intensive Induction Therapy

Maintenance Rituximab Following R-CHOP Chemotherapy in Patients with Composite or Discordant, Indolent and Aggressive, B-Cell Non-Hodgkin Lymphomas

Background:Patients with follicular lymphoma (FL) who achieve a complete (CR) or partial (PR) response to rituximab-containing chemotherapy followed by maintenance rituximab (MR) experience improved progression-free survival (PFS). In contrast, MR does not improve outcomes in chemo-sensitive patients with diffuse large B-cell lymphoma (DLBCL). There are no published data describing the impact of MR in patients presenting with indolent and aggressive histology lymphoma simultaneously in the same biopsy (composite, COM) or two separate sites (discordant, DIS).Methods:Patients with newly-diagnosed COM/DIS lymphomas composed of an indolent B-cell non-Hodgkin lymphoma (excluding CLL/SLL, mantle cell lymphoma, and grade 3B FL) and DLBCL were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. All patients received first-line chemotherapy with R-CHOP. In early 2006, a treatment policy was introduced recommending MR 375 mg/m2 IV every 3 months for 2 years in patients with COM/DIS lymphomas achieving a CR/PR to R-CHOP induction. PFS, time to progression (TTP) and overall survival (OS) were calculated from the time of diagnosis and compared between treatment groups.Results:98 patients with COM/DIS lymphomas were identified between January 2001 and December 2013: median age 64 y (range 22 - 86), 56% male, 48% elevated LDH, 30% performance status ≥ 2, 87% stage III/IV, and 51% high-intermediate or high IPI. 58 (59%) and 40 (41%) patients had COM and DIS lymphoma, respectively. FL was the indolent component in 65% of all cases. 35/40 patients with DIS had low-grade histology in the bone marrow. Following R-CHOP, 77 (79%) and 21 (21%) patients achieved CR and PR, respectively. 43 patients were treated with R-CHOP alone before the MR policy introduction, and 55 were treated with R-CHOP+MR; the latter group received a median of 8 (range 1 - 8) MR doses. There were no significant differences in baseline characteristics or response rates between the two groups with the exception of a higher proportion of patients with poor performance status in the group not given MR.With a median follow-up of 10y (range 1.5 - 13.6) in living patients treated with R-CHOP and 6y (range 0.9-9.5) in patients treated with R-CHOP+MR, there were 20 (47%) and 15 (27%) relapses, respectively (p=0.26). Of these, 11 relapsed with indolent histology, 11 relapsed with DLBCL, 3 relapsed in the central nervous system (CNS), and 10 had no biopsy at relapse (8 had aggressive and 2 indolent clinical behavior on review of medical records). There were 6 (30%) indolent and 14 (70%) aggressive relapses in patients treated with R-CHOP, while there were 7 (47%) indolent and 8 (53%) aggressive relapses in patients treated with R-CHOP+MR (p=0.31). 19 patients eventually died from lymphoma (8 with DLBCL relapse, 5 without a biopsy at relapse, and all 3 with CNS recurrence).The 6-y PFS was 60% (standard error [SE] 5%) with no difference between patients treated with or without MR (Hazard ratio (HR) 0.74, 95% CI 0.39 - 1.37, p= 0.33). The 6-year TTP was 64% (SE 5%), again with no differences between the two groups (HR 0.68, 95% CI 0.34 - 1.33, p= 0.25). The 6-year OS was similar between the two groups (p= 0.89). In the subgroup of patients with FL (21 R-CHOP and 43 R-CHOP+MR) the addition of MR did not impact PFS (p= 0.90), TTP (p= 0.99), or OS (p=0.55).An additional 52 patients were diagnosed after the treatment policy introduction in 2006, but did not receive MR for several reasons including physician non-adherence, progressive disease on R-CHOP, toxicity from R-CHOP or patient refusal. In an intent-to-treat analysis (43 pre-policy and 107 post-policy) there were no differences in outcomes. In a per-protocol analysis (95 R-CHOP and 55 R-CHOP+MR), there were no significant differences in outcomes.Conclusion:The addition of MR does not appear to improve PFS, TTP or OS in patients with COM/DIS lymphomas achieving CR/PR to R-CHOP, although comparisons are likely underpowered and 6-year median length of follow-up in the MR group may not be sufficient. However, the majority (63%) of relapses are aggressive and unlikely to be impacted by MR. The role of MR in these uncommon lymphomas requires further exploration. DisclosuresConnors:Roche: Research Funding; Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Scott:Celgene: Consultancy, Honoraria; NanoString: Patents & Royalties: Inventor on a patent that NanoString has licensed. Gerrie:Roche: Honoraria, Other: Advisory board, Research Funding; Lundbeck: Honoraria, Other: Advisory board, Research Funding; Janssen: Other: Advisory board. Villa:Roche: Research Funding.

Induction chemotherapy followed by up-front autologous stem cell transplantation may have a survival benefit in high-risk diffuse large B-cell lymphoma patients

We compared the outcomes of patients with higher-risk diffuse large B-cell lymphoma (DLBCL) who were treated with either up-front autologous stem cell transplantation (ASCT) or salvage chemotherapy followed by delayed ASCT after relapse. Data for 122 DLBCL patients who underwent ASCT as up-front or salvage treatment were analyzed. The 3-year overall survival (OS) rate in DLBCL patients who underwent up-front ASCT was 76.6%, and the rate for those who underwent delayed ASCT was 60.9% (p = 0.017). In a subgroup analysis of patients with a high-intermediate/high-risk age-adjusted International Prognostic Index, achievement of complete remission translated into improved OS in the up-front ASCT group, whereas patients who achieved partial remission had similar OS rates in both groups. The up-front ASCT group had improved OS in patients aged <50 years or with good performance status, whereas the OS rates of both groups were similar in patients aged ≥ 60 years or with poor performance status. When the OS outcome is analyzed by the number of factors (no complete remission during R-CHOP induction chemotherapy, age ≥ 50 years, and performance status ≥ 2), the 3-year OS rates of patients with zero or one, two, and three clinical factors were 80.2%, 51.6%, and 0%, respectively (p < 0.001). In conclusion, in higher-risk DLBCL patients, induction chemotherapy followed by up-front ASCT may have a survival benefit compared with induction chemotherapy alone in highly selected patients who have achieved a complete remission, who are aged <50 years, and who have a good performance status at diagnosis.