A New Salvage Regimen for Aggressive Lymphomas Based on Gemcitabine,Rituximab, and Oxaliplatin Followed by Lenalidomide (GROC-Rev)

PurposeTo evaluate the impact of lenalidomide in patients with aggressive lymphoma who experienced less than complete response (CR) or as maintenance therapy after CR after gemcitabine, rituximab, and oxaliplatin salvage chemotherapy (GROC-Rev regimen).Patients and MethodsPatients with relapsed/refractory non-Hodgkin lymphoma received up to 6 GROC-Rev courses: rituximab (375 mg/m² provided intravenously) on day 1, oxaliplatin (100 mg/m² provided intravenously; 2 hours), gemcitabine (provided 1250 mg/m² intravenously; 30 minutes) on day 2, and pegfilgrastim (6 mg provided subcutaneously) on day 3. Patients switched to lenalidomide if they did not experience at least partial response (PR) after their second GROC-Rev course, or if they experienced less than a CR after 6 courses.ResultsIn 33 patients, overall response was 61% (CR = 39%). Of 17 patients with PR who continued to 6 courses, 10 (59%) experienced CR and 7 PR as maximum response; of these 7, 1 died before receiving lenalidomide, 1 experienced CR while receiving lenalidomide (17%), and 2 experienced a further PR (33%). Of 16 with disease that failed to respond to GROC-Rev after their second course, 2 died before lenalidomide could be administered, and 2 experienced CR (14%) and 1 PR (7%) after lenalidomide. Overall survival and progression-free survival were 47% and 33% at 2 years. Grade 3/4 adverse events included neutropenia, thrombocytopenia, and/or anemia (n = 5), neutropenic infection (n = 3), urinary tract infection (n = 3), pneumonia (n = 2), cellulitis (n = 2), and seizure (n = 1). Eight went on to receive transplants.ConclusionGROC-Rev is an effective and well-tolerated salvage regimen consisting of chemotherapy followed by lenalidomide maintenance in patients with relapsed/refractory non-Hodgkin lymphoma. Simultaneous administration of these agents is worth exploring in future studies.     

Maintenance therapy following induction chemoimmunotherapy in patients with diffuse large B-cell lymphoma: current perspective

BackgroundMaintenance therapy has proven efficacy in indolent non-Hodgkin lymphoma (NHL), yet its role in diffuse large B-cell lymphoma (DLBCL) is an area of ongoing investigation. While DLBCL is potentially curable, >30% of patients relapse following front-line therapy and have a poor prognosis, especially those with refractory disease. Maintenance therapy holds promise to maintain response post-induction.Patients and methodsKeyword searches were carried out in PubMed and congress abstracts of ‘diffuse large B-cell lymphoma’ and ‘maintenance’ and focused on phase II/III studies of maintenance following front-line induction.ResultsAlthough used in indolent forms of NHL, studies of maintenance therapy with rituximab in patients with DLBCL responding to front-line R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) have not improved efficacy and are not recommended. Targeted agents enzastaurin and everolimus reported results from the phase III studies PRELUDE and PILLAR-2, respectively, both of which showed no proven maintenance benefit following front-line chemoimmunotherapy induction. Overall, the reported efficacy results with these agents in the maintenance setting do not outweigh the risks. Lenalidomide for maintenance has been reported in three studies. Results from two phase II trials on lenalidomide maintenance revealed positive outcomes in higher-risk patients following induction, resulting in improved progression-free survival in relapsed DLBCL patients who were ineligible for transplantation. First analysis from the phase III REMARC trial showed a significant improvement in progression-free survival for lenalidomide versus placebo, with no difference in overall survival, following front-line R-CHOP induction in elderly patients.ConclusionsBased on currently available studies of DLBCL maintenance therapies, initial results in front-line, as well as the relapsed setting, with immunomodulators such as lenalidomide show promise for further research to identify appropriate patients who would most benefit. Overall, this review of maintenance studies underscores the need for additional analyses of patient subtypes, clinical risk status, and molecular profiles, with careful consideration of study end points.     

A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma

Lenalidomide is an oral non-chemotherapy immunomodulator with direct and indirect effects on non-Hodgkin lymphoma (NHL) cells and with single-agent activity in relapsed/refractory aggressive and indolent B-cell NHL, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, and follicular lymphoma. Based on the pivotal phase II MCL-001 trial of lenalidomide in heavily pretreated patients with relapsed/refractory MCL, lenalidomide was approved by the US Food and Drug Administration for the treatment of relapsed/refractory MCL after failure of two prior therapies, one of which includes bortezomib, at a recommended starting dose of 25 mg on days 1–21 of each 28-day cycle. Lenalidomide enhanced the survival benefit in combination with rituximab in preclinical models, prompting clinical evaluation of the lenalidomide–rituximab (R2) combination. In phase II trials, lenalidomide 20 mg on days 1–21 in combination with different standard-dose rituximab schedules exhibited promising activity in both first-line and relapsed/refractory disease across multiple B-cell NHL subtypes. The feasibility of combining lenalidomide with immunochemotherapy, including R-CHOP and rituximab–bendamustine, has been demonstrated in phase I/II trials. These latter regimens are currently being evaluated in ongoing phase II and III trials. The role of lenalidomide monotherapy and R2 in maintenance therapy is also being examined. Based on available evidence, a comprehensive review of lenalidomide in all treatment phases of B-cell NHL—relapsed/refractory disease, first-line, and maintenance—is presented here.     

An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma

BackgroundLenalidomide is an immunomodulatory agent with antitumor activity in B-cell malignancies. This phase II trial aimed to demonstrate the safety and efficacy of lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular grade 3 lymphoma (FL-III), or transformed lymphoma (TL).MethodsPatients received oral lenalidomide 25 mg on days 1–21 every 28 days as tolerated or until progression. The primary end point was overall response rate (ORR).ResultsTwo hundred and seventeen patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13% (29/217) complete remission (CR), 22% (48/217) partial remission, and 21% (45/217) with stable disease. The ORR for DLBCL was 28% (30/108), 42% (24/57) for MCL, 42% (8/19) for FL-III, and 45% (15/33) for TL. Median progression-free survival for all 217 patients was 3.7 months [95% confidence interval (CI) 2.7–5.1]. For 77 responders, the median response duration lasted 10.6 months (95% CI 7.0–NR). Median response duration was not reached in 29 patients who achieved a CR and in responding patients with FL-III or MCL. The most common adverse event was myelosuppression with grade 4 neutropenia and thrombocytopenia in 17% and 6%, respectively.ConclusionLenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma.     

Peripheral Blood Lymphocyte-to-Monocyte Ratio at Relapse Predicts Outcome for Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma in the Rituximab Era

BackgroundPatients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis, even in the rituximab era. Several studies have reported the clinical importance of the peripheral blood lymphocyte-to-monocyte ratio (LMR) in various malignancies, including lymphoma. However, the prognostic value of the LMR in relapsed/refractory DLBCL has not been well evaluated. The purpose of the present study was to investigate whether the LMR at relapse can predict clinical outcomes for relapsed/refractory DLBCL patients treated with rituximab.Patients and MethodsWe analyzed data on 74 patients with relapsed/refractory DLBCL, who were initially treated with R-CHOP (rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone) or an R–CHOP-like regimen.ResultsThere was a significant association between a low LMR (≤ 2.6) and shorter overall survival (OS; P < .001) and progression-free survival (PFS; P < .001) compared with the high LMR group (> 2.6). Multivariate analysis showed that LMR was an independent prognostic factor for OS (P < .001) and PFS (P < .001), as was the international prognostic index (IPI) at relapse for OS. In addition, the LMR had an incremental value for OS and PFS compared with the IPI at relapse.ConclusionThe LMR predicts OS and PFS outcomes in relapsed/refractory DLBCL patients treated with rituximab, and might facilitate better stratification among patients in low- and intermediate-risk IPI groups.     

Safety and efficacy of combination therapy with fludarabine, mitoxantrone, and rituximab followed by yttrium-90 ibritumomab tiuxetan and maintenance rituximab as front-line therapy for patients with follicular or marginal zone lymphoma

BackgroundWe conducted a single-institution phase II clinical trial evaluating the safety and efficacy of combination chemoimmunotherapy followed by radioimmunotherapy consolidation and rituximab maintenance as front-line treatment in indolent lymphomas.Patients and MethodsWe enrolled 20 patients with intermediate- to high-risk follicular lymphoma and 2 patients with marginal zone lymphoma. Treatment consisted of 4-6 cycles of FM (fludarabine 25 mg/m² on days 1-3, mitoxantrone 12 mg/m² on day 1 of each 28-day cycle). The protocol was amended after enrolling the first 4 patients to include rituximab 375 mg/m² on day 1. After 6-8 weeks, responders received ⁹⁰Y-ibritumomab tiuxetan (Zevalin) followed by maintenance rituximab (375 mg/m² weekly × 4 doses, repeated every 6 months for 2 years).ResultsAfter R-FM, the overall response rate was 95% with a complete response rate (CR) of 45% (n = 10), a partial response (PR) rate of 50% (n = 11), and stable disease in 1 patient. Nineteen patients received ⁹⁰Y-ibritumomab tiuxetan with a 60% conversion rate of PR to CR, resulting in an improved CR of 79% (n = 15) and a PR of 21% (n = 4). Fifteen patients proceeded to rituximab maintenance resulting in 3 patients with PR converting to CR. At median follow-up of 49.6 months, median progression-free survival (PFS) was 47.2 months and median overall survival (OS) was not reached in an intent-to-treat analysis. The most common adverse effects were hematologic, with 2 patients experiencing treatment-related myelodysplastic syndrome (MDS), evolving to acute myelogenous leukemia (AML) in 1 patient.ConclusionR-FM with ⁹⁰Y-ibritumomab tiuxetan consolidation and rituximab maintenance is well tolerated, improving CR rates and maintaining durable responses in patients with untreated indolent lymphomas.     

Impressive and durable response in a case of multiple relapsed mantle cell lymphoma treated with bortezomib and rituximab

Relapsed mantle cell lymphoma (MCL) usually represents a hard challenge, especially after the failure of high-dose therapy or in elderly patients, and although new agents have been investigated, responses are often short and a significant proportion of patients finally die from progressive disease. Here, we report a case of a relapsed MCL patient that achieved durable response with bortezomib and rituximab. Treatment regimen consisted of bortezomib 1.6 mg/m² and rituximab 375 mg/m² intravenously on days 1–8–15–22 for the 1st course, followed by 2 courses of bortezomib with the same schedule. After the third course, patients in CR, PR or SD received other 3 courses. The patient achieved a CR, but because of the high risk of relapse we started a 4-week maintenance therapy with rituximab and bortezomib for 4 courses administered at six month interval. After a follow-up of 62 months, the patient maintained CR. We suggest rituximab plus bortezomib could play an important role in the treatment of patients with relapsed/refractory MCL. Maintenance therapy could be an interesting option, especially for patients with a high relapse risk rate.     

Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype

BACKGROUND:

There is a need to develop novel therapies for relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) and to identify biomarkers predictive for therapeutic response. Lenalidomide was previously shown to induce an overall response rate (ORR) of 28% in patients with relapsed/refractory DLBCL. It is currently unknown if response rates differ between patients with different DLBCL subtypes.

METHODS:

The authors retrospectively evaluated clinical outcomes of patients with germinal center B‐cell–like versus nongerminal center B‐cell–like DLBCL treated with salvage lenalidomide at 4 academic institutions.

RESULTS:

Forty patients with relapsed/refractory DLBCL were included (24 men; 16 women; median age, 66 years; median of 4 prior treatments, including rituximab chemotherapy). Patients were classified as germinal center B‐cell–like (n = 23) or nongerminal center B‐cell–like (n = 17) DLBCL according to the Hans algorithm. The subgroups were similar in terms of stage, international prognostic index score, prior number of treatments, and rituximab resistance. A significant difference in clinical response to lenalidomide was observed in nongerminal center B‐cell–like versus germinal center B‐cell–like patients. ORR was 52.9% versus 8.7% (P = .006); complete response rate was 23.5% versus 4.3%. Median progression‐free survival was 6.2 versus 1.7 months (P = .004), although no difference in OS was observed between nongerminal center B‐cell–like and germinal center B‐cell–like DLBCL patients.

CONCLUSIONS:

The data suggest that the 2 major subgroups of patients with DLBCL (germinal center B cell and nongerminal center B cell) have different antitumor responsiveness to lenalidomide in the relapsed/refractory setting. A large international trial (NCT01197560) has been opened to enrollment in an attempt to prospectively validate these retrospective observations. Cancer 2011;. © 2011 American Cancer Society.     

Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective ‘proof of concept’ phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)

BackgroundPrimary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R²) in DLBCL–PCNSL.Patients and methodsPatients with refractory/relapsed (R/R) DLBCL–PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R² (rituximab 375/m² i.v. D1; lenalidomide 20 mg/day, D1-21 for cycle 1; and 25 mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10 mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0 = 10%; P1 = 30%).ResultsFifty patients were included. Forty-five patients (PCNSL, N = 34; PVRL, N = 11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9–51.2) in assessable patients and 32.0% (95% CI 21.9–51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2 months (range 1.5–31), the median progression-free survival (PFS) and overall survival (OS) were 7.8 months (95% CI 3.9–11.3) and 17.7 months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS = 9.5 months (95% CI, 8.1–14.8] for CD4/CD8 ≥ 1.6; median PFS = 2.8 months, [95% CI, 1.1–7.8) for CD4/CD8 < 1.6, P = 0.03).ConclusionsThe R² regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R² combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL.Clinical trials numberNCT01956695.     

Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 study

BackgroundMantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma with poor overall prognosis, requiring the development of new therapies. Lenalidomide is an immunomodulatory agent demonstrating antitumor and antiproliferative effects in MCL. We report results from a long-term subset analysis of 57 patients with relapsed/refractory MCL from the NHL-003 phase II multicenter study of single-agent lenalidomide in patients with aggressive lymphomaDesignLenalidomide was administered orally 25 mg daily on days 1–21 every 28 days until progressive disease (PD) or intolerability. The primary end point was overall response rate (ORR).ResultsFifty-seven patients with relapsed/refractory, advanced-stage MCL had a median of three prior therapies. The ORR was 35% [complete response (CR)/CR unconfirmed (CRu) 12%], with a median duration of response (DOR) of 16.3 months (not yet reached in patients with CR/CRu) by blinded independent central review. The median time to first response was 1.9 months. Median progression-free survival was 8.8 months, and overall survival had not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), and anemia (13%).ConclusionsThese results show the activity of lenalidomide in heavily pretreated, relapsed/refractory MCL. Responders had a durable response with manageable side-effects. Clinical trial number posted on www.clinicaltrials.gov NCT00413036.     

Late Relapses After High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Diffuse Large B-cell Lymphoma in the Rituximab Era

BackgroundThe standard of care for diffuse large B-cell lymphoma (DLBCL) relapsing after front-line therapy is high-dose chemotherapy and autologous stem cell transplantation (ASCT). Evidence has suggested that early relapses (ie, within 1 year) after this approach portends exceptionally poor outcomes. However, data examining relapses > 1 year after ASCT for patients with refractory or relapsed DLBCL are limited, in particular, in the rituximab era. We sought to examine the effect of early (≤ 1 year) and late (> 1 year) relapse after ASCT in a single-institution cohort of patients with relapsed and refractory DLBCL treated with chemoimmunotherapy.Materials and MethodsA retrospective analysis was performed on the data from 85 consecutive patients who had undergone ASCT for biopsy-confirmed relapsed or refractory DLBCL from 2001 to 2010 at the University of Rochester Medical Center. All patients had received rituximab as a part of treatment. Of the 85 patients, 35 developed relapse after ASCT. These 35 patients were divided into 2 groups according to the timing of the relapse (≤ 1 year and > 1 year after ASCT).ResultsThe median follow-up period was 6.4 years. For all patients, the overall survival (OS) from post-ASCT relapse was 5.2 years. For the 27 patients developing relapse at ≤ 1 year after ASCT, the median OS was 0.6 year and progression-free survival was 0.4 year. For the 8 patients developing relapse at > 1 year after ASCT, the median OS was 5.9 years and progression-free survival was 2.9 years.ConclusionPatients with relapsed or refractory DLBCL experiencing relapse > 1 year after ASCT had good outcomes. Despite the relative rarity in incidence, a significant risk of relapse of DLBCL after ASCT remains, suggesting the need for continued monitoring because of the possibility of later progression.     

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 70 years. 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.     

Hitting back at lymphoma: How do modern diagnostics identify high-risk diffuse large B-cell lymphoma subsets and alter treatment?

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Diagnostic tools in the clinic can now identify distinct subsets characterized by unique molecular features, which are increasingly transforming how these patients are managed. Activated B–cell-like DLBCL is characterized by NF-κB activation and chronic B-cell receptor signaling and may be targeted with lenalidomide or ibrutinib in the relapsed setting. Germinal center-like DLBCL is enriched for activating EZH2 mutations, and encouraging activity has been observed for the EZH2 inhibitor tazemetostat, which now has a fast-track US Food and Drug Administration designation. Double-hit lymphoma is a high-grade B-cell lymphoma characterized by translocations of MYC and BCL2 and/or BCL6 and carries a poor prognosis. Intensive chemoimmunotherapy strategies appear to be superior to standard R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone) as initial therapy, and anti-CD19 chimeric antigen receptor T cells are inducing remission in patients with relapsed/refractory disease who previously had few available options. Primary mediastinal (thymic) large B-cell lymphoma is a molecularly distinct large-cell lymphoma with clinical and molecular features that overlap with those of classical Hodgkin lymphoma. R-CHOP has been associated with an unacceptably high rate of primary treatment failure in this young population, whereas dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) produces durable remissions without the need for radiotherapy in most patients. For relapsed/refractory disease, immune checkpoint inhibitors targeting PD-1 have shown promising activity in chemotherapy-refractory disease, as have anti-CD19 chimeric antigen receptor T cells. Additional therapeutic targets, including JAK2, continue to be evaluated. The identification of discrete biological subsets is steadily moving us away from a “one-size-fits-all” approach in DLBCL.     

Phase II study of the CPT-11, mitoxantrone and dexamethasone regimen in combination with rituximab in elderly patients with relapsed diffuse large B-cell lymphoma

Standard treatment for elderly patients with relapsed or refractory DLBCL has not been established. CPT-11 has a broad spectrum of anticancer activities including a cytotoxic effect in a variety of malignant tumors. The results of combined treatment with CPT-11 and rituximab have not been reported. The R-CMD regimen was given to elderly patients with relapsed or refractory DLBCL. The safety and efficacy of this regimen were studied. In addition, the serum nm23-H1 level was determined to study whether or not it can serve as a prognostic factor. Thirty elderly patients with DLBCL were studied. The main non-hematological toxicities were infusion-related adverse events. Grade 3/4 hematological toxicity was seen in 19 patients. Following R-CMD treatment, the BNP and troponin T levels did not increase. The CR rate was 57%, PR rate was 17%, 2-year survival rate was 45.2%, and PFS rate was 37.2%. Patients with serum nm23-H1 levels of higher than 80 ng/mL before the treatment showed significantly poorer prognosis. The serum nm23-H1 level of the 30 subjects before the treatment was elevated at 39.4 +/- 41.3 ng/mL, but it significantly decreased only in the subset of patients who achieved CR. The R-CMD regimen was safe in elderly patients with DLBCL. No new signs of cardiotoxicity were observed with this regimen. It was also effective in patients with relapsed or refractory DLBCL who had previously used DXR.     

Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a retrospective analysis

For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy because of comorbidities, advanced age, or relapse after heavy salvage regimens, treatment options are very limited and prognosis is poor. We retrospectively analyzed 29 patients with relapsed/refractory DLBCL treated with combination bendamustine plus rituximab (BR) between July 2010 and January 2014 to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and treatment safety. Twenty-eight patients were available for this analysis. ORR was 50% (14 patients), with 39.3% CR (11 patients), and 10.7% PR (3 patients). SD was reported in 2 patients (7.2%) and PD in 12 patients (42.8%). At the median follow up of 8 months (range 1–37.4 months), the median PFS was 8 months for all patients (95% CI 5.5–26.6). The median DOR was 24.7 months (95% CI 3.2–24.7). Grade 3/4 toxicity observed included hematologic events: lymphopenia (42.8%), neutropenia (32.1%), anemia (17.2%), and thrombocytopenia (14.2%). BR can be considered to have a role in the treatment of patients with relapsed/refractory DLBCL with limited therapeutic options, in that it can induce long-term remission in some patients with an acceptable toxicity profile.     

R-CHOP方案治疗复发、难治弥漫大B细胞淋巴瘤的临床研究

 【摘要】　目的　观察R-CHOP方案治疗复发、难治弥漫大B细胞淋巴瘤（DLBCL）的临床疗效及患者不良反应。方法　选择30例经病理证实为CD20阳性的DLBCL患者,前期常规方案化疗（不含利妥昔单抗）2～6个疗程后评估为复发或难治患者,其中复发患者16例,难治患者14例。应用R-CHOP方案治疗4～6个周期,每个周期21 d。所有淋巴瘤患者均为Ⅲ～Ⅳ期,搜集治疗前后相关临床资料,采用回顾性分析方法,将R-CHOP方案疗效与文献及自身对照比较,评价其疗效及不良反应。结果　全组30例患者均可评价疗效,完全缓解15例,部分缓解10例,稳定3例,进展2例,完全缓解率为50.0 %（15／30）,总有效率83.3 %（25／30）。出现Ⅱ度白细胞减少3例,Ⅰ度血小板降低1例,恶心等轻微的消化道反应2例。结论　R-CHOP方案对复发、难治DLBCL仍有良好的治疗效果,完全缓解率与总有效率明显优于常规二线化疗方案。接受R-CHOP方案治疗患者不良反应轻微,与常规化疗方案无显著区别,患者耐受良好。     

A Phase I/II Trial of Panobinostat in Combination With Lenalidomide in Patients With Relapsed or Refractory Hodgkin Lymphoma

BackgroundLenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL.Patients and MethodsIn the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose-limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR).ResultsTwenty-four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg panobinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), thrombocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte-predominant HL and received 22 cycles. Median progression-free survival and overall survival were 3.8 and 16.4 months, respectively.ConclusionAlthough the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL.     

Radioimmunotherapy with (131)I-rituximab for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL)

Aim: To evaluate the efficacy and safety of radioimmunotherapy (RIT) with radioiodinated human/murine chimeric anti‐CD20 monoclonal antibody rituximab (¹³¹I‐rituximab) for treating Korean patients with relapsed or refractory B‐cell non‐Hodgkin's lymphomas (NHL). Methods: All patients received unlabeled rituximab 70 mg immediately prior to the administration of a therapeutic dose (median dose: 7.3 GBq) of ¹³¹I‐rituximab. The tumor response was evaluated 1 month later by contrast enhanced ¹⁸F‐fludeoxyglucose positron emission tomography‐computed tomography. Results: Between May 2004 and October 2006, 24 patients received single treatment with ¹³¹I‐rituximab. The overall response rate (ORR) was 29%; 46% (three complete responses, two partial responses (PR) for patients with low grade B‐cell NHL (LGL) and 9% (one PR) for patients with diffuse large B‐cell lymphoma (DLBCL). After a median follow‐up of 55 months, the median progression‐free survival (PFS) for all the patients was 2.2 months. The median overall survival (OS) was 11.3 months. There were statistically significant differences between the LGL and the DLBCL for the median PFS (4.5 months vs 1.3 months, respectively, P = 0.0007) and the median OS (30.3 months vs 6.5 months, respectively, P = 0.0295). Grades 3–4 thrombocytopenia and neutropenia occurred in 33% (8/24) and 21% (5/24) of the patients, respectively. Conclusion: RIT with ¹³¹I‐rituximab seems to be effective and tolerable for patients with refractory LGL, although this treatment had modest activity in patients with refractory DLBCL. Further studies are warranted to determine the efficacy of ¹³¹I‐rituximab for treating the patients with DLBCL.     

弥漫性大B细胞淋巴瘤免疫治疗进展

弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）是最常见的非霍奇金淋巴瘤（NHL）亚型,其具有高度异质性和侵袭性。尽管许多患者应用R-CHOP(利妥昔单抗+环磷酰胺+阿霉素+长春新碱+泼尼松)方案一线治疗后达到完全缓解（CR）,但仍有部分患者之后发展为复发和难治性的DLBCL,而一旦发展为复发难治性的DLBCL,常规的放疗和化疗则收效甚微。近年来,免疫治疗逐渐成为研究热点,如单克隆抗体治疗、双特异性抗体治疗、抗体-药物偶连物（ADC）治疗和嵌合体抗原受体修饰T细胞（CAR-T）治疗等。本文现就弥漫性大B细胞淋巴瘤免疫治疗进展进行综述。     

Brief-Duration Rituximab/Chemotherapy Followed by Maintenance Rituximab in Patients With Diffuse Large B-Cell Lymphoma Who Are Poor Candidates for R-CHOP Chemotherapy: A Phase II Trial of the Sarah Cannon Oncology Research Consortium

Introduction:Patients with diffuse large B-cell lymphoma (DLBCL) who are very elderly or have poor performance status are difficult to treat with a full course of R-CHOP (rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone) therapy. In this phase II trial, we treated this group of patients with a novel regimen containing 3 courses of rituximab/chemotherapy followed by maintenance rituximab.Patients and Methods:Patients with newly diagnosed stage II-IV DLBCL were eligible if they were considered poor candidates for 6-8 cycles of R-CHOP therapy. Patients who were eligible for anthracycline therapy received 3 cycles of rituximab plus cyclophosphamide/mitoxantrone/vincristine/prednisone (CNOP); the remainder of patients received R-CVP (rituximab plus cyclophosphamide/vincristine/prednisone). Patients without progression after completion of 3 cycles received 4 courses of maintenance rituximab (375 mg/m² weekly × 4, repeated every 6 months) for 24 months.Results:Between May 2003 and July 2007, 51 patients were enrolled. The median age was 78 years, and 43% of patients were > 80 years of age. Nineteen patients (37%) had Eastern Cooperative Oncology Group performance status of 2, and 72% had high-intermediate or high-risk International Prognostic Index scores. After a median follow-up of 48 months, the 2-, 3-, and 4-year progression-free survival rates are 71%, 65%, and 56%, respectively. The 2-, 3-, and 4-year overall survival rates are 72%, 67%, and 67%, respectively. Treatment was well tolerated, with few severe toxicities and no treatment-related deaths.Conclusion:This abbreviated course of rituximab/chemotherapy, followed by maintenance rituximab, was active and well tolerated in these very elderly patients. Brief-duration rituximab/chemotherapy as well as maintenance rituximab merit further evaluation in this setting.