CHOP followed by involved field radiotherapy for localized primary gastric diffuse large B-cell lymphoma: results of a multi center phase II study and quality of life evaluation

We aimed to define the role of cyclophosphamide, vincristine, doxorubicin, prednisone (CHOP) followed by involved field radiotherapy (IFRT) for treating localized primary gastric diffuse large B-cell lymphoma (DLBCL). Newly diagnosed patients with localized primary gastric DLBCL were to receive four cycles of CHOP followed by IFRT of 40.0 Gy. At 1 year after the completion of treatment, patients filled out the EORTC Quality of Life Questionnaire specified for stomach cancer (QLQ-C30-STO22). Fifty evaluable patients (25 men, 25 women) were included. The median age was 54.5 years (range, 21 - 73 years. The overall response rate to the CHOP was 94% (95% confidence interval [CI], 87 - 100) in the intent-to-treat population. Forty-one of the 50 patients (82%; 95% CI, 71 - 93) achieved complete remission (CR). After the completion of radiotherapy, five patients who were in PR following chemotherapy eventually attained CR. The overall complete response rate was thus 92% (95% confidence interval, 84 - 99). With a median follow-up period of 30 months, the 2-year progression-free and overall survival rate was 92% and 92%, respectively. The gastric function was well preserved with negligible stomach-related symptoms at 1 year after the completion of treatment. This organ-preserving combined treatment is highly effective and well tolerated for the patients with localized gastric DLBCL.     

A phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diffuse large B-cell lymphoma patients

Background: A prospective, single-arm, open-label, nonrandomizedphase II combination chemotherapy with cyclophosphamide, doxorubicin,vincristine, and prednisone (CHOP) plus radioimmunotherapy trialwas conducted to evaluate the efficacy and safety in untreatedelderly diffuse large B-cell lymphoma (DLBCL) patients. Patients and methods: From February 2005 to April 2006, in ourinstitute we treated 20 eligible elderly (age 60 years) patientswith previously untreated DLBCL using a novel regimen consistingof six cycles of CHOP chemotherapy followed 6–10 weekslater by ⁹⁰Y ibritumomab tiuxetan. Results: The overall response rate to the entire treatment regimenwas 100%, including 95% complete remission (CR) and 5% partialremission. Four (80%) of the five patients who achieved lessthan a CR with CHOP improved their remission status after radioimmunotherapy.With a median follow-up of 15 months, the 2-year progression-freesurvival was estimated to be 75%, with a 2-year overall survivalof 95%. The ⁹⁰Y ibritumomab tiuxetan toxicity included grade3 hematologic toxicity in 12 of 20 patients; the most commongrade 3 toxic effects were neutropenia (12 patients) and thrombocytopenia(7 patients). Transfusions of red blood cells and/or plateletswere given to one patient. Conclusion: This study has established the feasibility, tolerability,and efficacy of this regimen for elderly patients with DLBCL. Key words: Chemotherapy, DLBCL, elderly patients, yttrium 90 ibritumomab tiuxetan Received for publication April 30, 2007. Revision received July 25, 2007. Revision received September 13, 2007. Accepted for publication November 12, 2007.     

Prospective clinical study of surgical resection followed by CHOP in localized intestinal diffuse large B cell lymphoma

This study aimed to assess the efficacy of surgical treatment followed by post-surgical CHOP chemotherapy and to analyze the impact of T and N stage on survival in localized intestinal diffuse large B cell lymphoma (DLBL) patients. A prospective non-randomized study was conducted and 40 patients received primary surgical resection with lymph node dissection and post-operative CHOP chemotherapy. After a median follow-up duration of 33.3 months (range, 5.1-75.9 months), an estimated 5-year overall survival rate was 88.9% and a 5-year disease-free survival rate was 83.1%. Primary surgical resection followed by post-operative CHOP chemotherapy showed high efficacy in intestinal DLBL patients.     

含聚乙二醇脂质体多柔比星的CHOP样方案治疗初治老年晚期弥漫大B 细胞淋巴瘤的Ⅱ期临床研究*

目的：评价含聚乙二醇脂质体多柔比星（PLD ）的CHOP 样方案治疗初治老年晚期弥漫大B 淋巴瘤（DLBCL）的疗效和安全性。方法：2011年11月至2014年3 月共入组30例患者,中位年龄70（63～80）岁,24例（80.0%）国际预后指数≥3 分;21例联合应用利妥昔单抗。进行前瞻性II 期临床研究,以含PLD 的CHOP 样方案治疗初治老年晚期DLBCL。PLD 剂量为30mg/m2,环磷酰胺、长春新碱和强的松采用标准CHOP 方案中的剂量。CD20阳性的患者可联合利妥昔单抗,计划完成6 个周期。结果：客观缓解率为86.7% ,其中完全缓解率为66.7% 。中位随访20.1（0.7～38.5）个月,18个月总生存率及无进展生存率分别为 82.4% 及70.1% 。主要不良反应为中性粒细胞减少。24例（80.0%）发生3～4 级中性粒细胞减少。研究中患者左室射血分数及血清肌钙蛋白T 无显著变化。4 例（13.3%）在PLD 输注后新发无症状性心电图异常。结论：含PLD 的CHOP 样方案是治疗初治老年晚期DLB-CL患者毒性可接受的备选方案,缓解率较高,心脏安全性较好。

     

A phase II study of the survivin suppressant YM155 in patients with refractory diffuse large B-cell lymphoma

BACKGROUND:

Few effective therapeutic options exist for patients with refractory diffuse large B‐cell lymphoma (DLBCL). YM155 is a survivin suppressant with activity against DLBCL in a phase I trial. This phase II study was conducted to better characterize the toxicity and efficacy of this small molecule in patients with refractory DLBCL.

METHODS:

Forty‐one patients with a median age of 66 years and 3 prior regimens were enrolled and treated with a YM155 dose of 5 mg/m²/d by continuous infusion for 168 hours every 21 days for up to 15 cycles of treatment. The median number of completed cycles was 3.

RESULTS:

One patient had a complete remission (CR) (2.4%) with an additional 2 patients (5.9%) responding, with a median progression‐free survival of 58 days.

CONCLUSIONS:

YM155 was well tolerated with major toxicities including anemia and fatigue. Whereas YM155 had limited single‐agent activity, preclinical data suggest its role in combination with other agents, including rituximab, and a study of that combination in ongoing. Cancer 2012;118: 3128–34. © 2011 American Cancer Society.     

Evolution of therapy for limited stage diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), with limited-stage DLBCL defined as stage I or II disease. Risk stratification, initial treatment options, and relapse patterns are distinct from advanced-stage DLBCL, but there is limited data on the impact of biologic features on outcome. Patients have excellent outcomes, with ~90% survival at 2 years. Over the past several years, sequential prospective trials and large registry studies have evaluated the optimal number of chemotherapy cycles and implemented PET-adapted approaches to reduce the need for radiotherapy. Special consideration must still be given to cases of bulky disease, extranodal disease, fully resected scenarios, and adverse biologic features such as high-grade B-cell lymphoma with double/triple hit rearrangements. This review presents the evolution of a modern management approach, with a discussion of recent treatment-defining studies.Subject terms: Cancer immunotherapy, Radiotherapy     

Prognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era

BackgroundThe introduction of rituximab (R) to conventional CHOP chemotherapy for newly diagnosed diffuse large B-cell lymphoma (DLBCL) led to an unequivocal improvement in survival, establishing RCHOP as the standard of care. Still, nearly 40% of DLBCL patients will eventually die of relapsed disease. Efforts to improve outcomes by addition of new biologic agents (X) to the RCHOP backbone are underway. In this era of R(X)CHOP, it is imperative to develop prognostic and predictive markers, not only to identify patients who will suffer a particularly aggressive course, but also to accurately select patients for clinical trials from which they will most benefit.DesignThe following review was undertaken to describe prognostic factors in DLBCL, with emphasis on markers that are accurate, relatively available, and clinically applicable in 2014.ResultsThe International Prognostic Index retains its validity in the era of RCHOP, although with limited ability to predict those with <50% chance of long-term survival. Gene expression profiling has provided novel insights into the biology of DLBCL and led to the development of immunohistochemistry (IHC) algorithms that are in routine practice. Identification of a ‘double-hit’ (DH) lymphoma by fluorescent in situ hybridization with aberrations involving MYC and/or BCL2 and BCL6 genes has important implications due to its extremely dismal prognosis with RCHOP. Other markers such as the absolute lymphocyte count (ALC), serum immunoglobulin free light chains, vitamin D levels, serum cytokines/chemokines, and imaging with positron emission tomography (PET) have all shown promise as future predictive/prognostic tests.ConclusionsThe future for new treatment options in DLBCL is promising with current clinical trials testing novel targeted agents such as bortezomib, lenalidomide, and ibrutinib as the ‘X’ in R(X)CHOP. Predictive factors are required to select and randomize patients appropriately for these trials. We envision the day when ‘X’ will be chosen based on the biological characteristics of the tumor.     

Statin-independent prognosis of patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy

BackgroundA recent laboratory study indicated that statins impaired the antitumor effects of rituximab by inducing conformational changes in CD20. Although these findings raised significant concerns about statin use during rituximab treatment, their clinical significance is unclear.Patients and methodsWe conducted a retrospective study investigating the effects of statins on the prognosis of diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). Newly diagnosed DLBCL patients were analyzed (n = 256), including 35 patients taking statins.ResultsThe 3-year progression-free survival rates were 84% and 73% (P = 0.38), while the overall survival rates were 89% and 78% (P = 0.28) for those patients treated with and without statins, respectively. After adjusting for the International Prognostic Index and serum cholesterol level, statin use was not associated with prognosis.ConclusionsThese results indicate that statins do not influence the clinical prognosis of DLBCL treated with RCHOP. Further studies with larger numbers of patients are warranted to confirm the prognostic significance of statins for patients with DLBCL receiving rituximab-containing chemotherapy.     

Surgical debulking is associated with improved survival in stage I-II diffuse large cell lymphoma

Tumor burden is an important predictor of survival in patients with diffuse large cell lymphoma (DLCL). The authors reviewed the charts of 147 patients with early stage presentation (Stage I-IE and II-IIE) seen from 1974 through 1984. The 10-year survival for the 85 patients with bulky disease was 54% compared with 76% for those who did not have bulky disease. Of the 62 with nonbulky disease, 14 had been rendered so by removal of greater than 80% of the initial tumor mass (surgical debulking). The authors compared these 14 patients with a matched control group of 14 patients selected from the 85 with bulky disease who had equivalent stage, therapy, site, size of initial mass, performance status, and sex and age. All had received similar therapy with cyclophosphamide, Adriamycin (doxorubicin), vincristine, prednisone, bleomycin, and radiotherapy to the involved field. At a 7-year follow-up, the 14 debulked patients had a better survival when compared with the matched controls (93% versus 35%, P = 0.003). The authors also analyzed the initial serum lactate dehydrogenase (LDH) levels. Preoperative LDH values were available in six of 14 debulked patients. In the three with elevated LDH levels at presentation, surgical debulking was associated with subsequent decreased LDH levels, which is known to be associated with better prognosis. The other three presented with normal values that remained normal after surgery. These data suggest a potentially important role for surgery as front-line therapy in patients with Stage I-IE and II-IIE bulky DLCL whose disease is deemed resectable. More studies are needed in order to better define this role as well as to determine how frequently and safely surgical debulking can be performed.     

Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma.

BACKGROUND: To evaluate the efficacy and feasibility of rituximab monotherapy in Japanese patients with relapsed or refractory aggressive B-cell lymphoma. PATIENTS AND METHODS: Sixty-eight patients were treated with rituximab at 375 mg/m(2) by eight consecutive weekly infusions. Pretreatment variables affecting overall response rate (ORR) and progression-free survival (PFS) and the relationship between pharmacokinetic parameters and efficacy were analyzed. RESULTS: The ORRs of 68 enrolled patients and 57 eligible patients were 35% [95% confidence interval (CI) 24% to 48%] and 37% (95% CI 25% to 51%), respectively. Median PFS of 53 evaluable patients was 52 days, whereas time to progression of 21 eligible responders was 245 days. Mild to moderate infusion-related toxicities were observed frequently at the first infusion, but all of them were reversible. Elevated lactate dehydrogenase (LDH) and refractoriness to prior chemotherapy were unfavorable factors affecting ORR and PFS (P <0.01). Serum trough levels of rituximab and area under the concentration-time curve for responders were higher than for non-responders (P <0.05). CONCLUSIONS: Eight consecutive weekly infusions of rituximab have significant anti-lymphoma activity for relapsed or refractory aggressive B-cell lymphoma. Several pretreatment variables and serum rituximab levels are useful for predicting its efficacy.     

MACOP-B treatment for advanced stage diffuse large cell lymphoma: A multicenter Italian study

Seventy-one patients with advanced stage diffuse large cell lymphoma were treated with MACOP-B. Sixty-nine per cent of patients achieved a complete response (CR), 10% a partial remission, while 11% had no response and 10% died because of toxicity. The CR rate was adversely affected by immunoblastic type, poor performance status and bone marrow involvement.Two-year survival for all 71 patients was 55% and 2-year disease-free survival (DFS) for the 49 CRs was 73%. Relapses were lower (P < 0.05) in patients achieving CR in 8 weeks or less (DFS 83% vs. 59%) and in patients without tumor bulk (DFS 87% vs. 54%).Overall toxicity was acceptable with mucositis proving to be the most frequent severe side-effect. However, treatment-related deaths were unacceptably high in patients over 59 years of age (30% vs. 7%). Thus for the elderly MACOP-B is potentially lethal and must be used cautiously.These preliminary results confirm the effectiveness of MACOP-B. The delay of response and/or the presence of tumor bulk may be important prognostic factors in identifying a subset of poor risk patients with a high incidence of relapse.     

Adjuvant radiotherapy in stage IV diffuse large cell lymphoma improves outcome

The role of adjuvant radiotherapy to sites of nodal bulky disease in patients with aggressive diffuse large cell lymphoma (DLCL), and stage IV remain undefined. We began a prospective controlled clinical trial to evaluate impact in event free survival (EFS) and overall survival (OS) in a large cohort of patients with a longer follow-up. Between 1989 and 1995; 341 patients with aggressive DLCL and presence of nodal bulky disease (tumor mass > 10 cm) in pathological proven complete response after intensive chemotherapy were randomized to received either radiotherapy (involved fields, 40 Gy) or not. The 5-year EFS and OS in radiated patients were respectively: 82% (95% Confidence interval (CI): 70-89%) and 87% (95% 80-99%), that were statistically significant to control group: 55% (41-64%) (P < 0.001) and 66% (95% CI: 51-73%) (P < 0.01) respectively. Radiotherapy was well tolerated, acute toxicity was mild and until now late toxicity did not appear. The use of adjuvant radiotherapy improve EFS and OS and probably the possibility of cure in patients diffuse large cell lymphoma with worse prognostic factors. Thus, we felt that adjuvant radiotherapy will be considered as part of the initial treatment in this setting of patients.     

Rituximab in Combination with CHOP, an Effective and Well-tolerated Salvage Regimen for Diffuse Large B-Cell Lymphoma

OBJECTIVE To evaluate the clinical effect of the R-CHOP regimen (rituximab in combination with cyclophosphamide, epirubicin, vincristine and prednisone) in treating refractory or relapsed diffuse large B-cell lymphoma (DLBCL), as a salvage therapy for DLBCL. METHODS Eighteen patients with refractory or relapsed DLBCL who were treated with the R-CHOP regimen from 2001 to 2006 in hospitals in Jilin Province were analyzed retrospectively. The response rate, change of serum lactate dehydrogenase (LDH), time to progression (TTP) and toxicity were observed. RESULTS The R-CHOP regimen can achieve a higher response rate, decrease serum LDH to a larger extent and obtain longer TTP than a con- ventional secondary regimen. The main adverse effects were similar to con- ventional chemotherapy. CONCLUSION The R-CHOP regimen is one of the most effective sec- ondary therapies for DLBCL.     

Obinutuzumab and miniCHOP for unfit patients with diffuse large B-cell lymphoma. A phase II study by Fondazione Italiana Linfomi

ObjectiveTo evaluate activity and safety of obinutuzumab-miniCHOP (Ga101-miniCHOP) combination in older patients with Diffuse Large B-Cell Lymphoma (DLBCL) unfit to receive full dose immunochemotherapy.Materials and MethodsWe conducted a Simon's two-stage phase II multicenter trial to investigate response rate (primary endpoint) and safety of six courses of Ga101-miniCHOP in older patients with DLBCL (≥65 years), prospectively defined as unfit according to a simplified Comprehensive Geriatric Assessment (sCGA).ResultsOverall, 34 patients were enrolled (median age 82 years; range 68–89), with 27 out of the 33 eligible patients completing all six planned courses. Complete Remission (CR) rate was reported in fourteen patients (42%). After a median follow-up of sixteen months, the two-year Progression Free and Overall Survival (PFS and OS) were 49% (95% Confidence Interval (CI), 28 to 67) and 68% (95% CI, 49 to 81), respectively. The most frequent grade 3–4 adverse event was neutropenia in thirteen patients (26%).ConclusionsBased on the observed CR rate, study accrual was interrupted due to the very low probability of demonstrating the initial study hypothesis that Ga101-miniCHOP could improve results of historical data obtained with R-miniCHOP in this group of patients. Nonetheless, results achieved with the 33 treated patients confirm activity and good tolerability of the Ga101-miniCHOP regimen for older unfit adult patients with DLBCL.     

R-CHOP和CHOP方案治疗两种亚型弥漫大B细胞淋巴瘤患者的近期疗效

背景与目的：根据肿瘤细胞起源不同,可将弥漫大B细胞淋巴瘤（diffuselarge Bcelllymphoma,DLBCL）分为生发中心来源（germinalcenter Bcell like,GCB）及非生发中心来源（non-GCB）两种亚型。在以CHOP方案为标准的化疗基础上,前者预后优于后者。本研究通过比较R-CHOP（Rituximab联合CHOP）和CHOP方案治疗不同亚型DLBCL患者的近期疗效,寻找初诊DLBCL患者最佳一线治疗方案。方法：将2006年11月至2008年2月中山大学肿瘤防治中心内科收治的83例初治DLBCL患者分为GCB和non-GCB两组。按照修订版淋巴瘤疗效评价标准,比较接受R-CHOP或CHOP方案治疗患者的近期疗效;观察Bcl-2在两种亚型中的表达情况,并分析其与近期疗效的关系。结果：83例DLBCL患者中GCB组35例（42．2％）,non-GCB组48例（57．8％）。GCB组一线化疗近期总缓解率74．3％,non-GCB组60．4％,两组相比差异有显著性（P=0．006）。Bcl-2在GCB和non-GCB两亚组的表达差异没有显著性：Bcl-2阳性患者采用R．CHOP方案治疗的近期缓解率（75．6％）明显高于用CHOP方案治疗者（47．8％）,两组相比差异有显著性（P=0．031）：采用不同方案化疗的Bcl-2阴性患者的近期缓解率则差异无显著性（P〉0．05）。结论：GCB组患者接受标准R—CHOP或CHOP方案治疗近期缓解率高于non-GCB组,提示预后良好。加用Rituximab可提高Bcl-2阳性患者的近期缓解率。     

Consolidation radiotherapy following brief chemotherapy for localized diffuse large B-cell lymphoma: a prospective study

Many physicians administer involved field radiation therapy (RT) following brief chemotherapy for localized aggressive non-Hodgkin's lymphoma. Involved field irradiation usually implies treatment to the involved nodal regions with and without the contiguous lymphatic region, however, there is no agreements about its definition. Here we assess the appropriateness of RT irrespective of lymph node regions (localized field) following chemotherapy for patients with early stage diffuse large B-cell lymphoma. The localized field encompassed all original gross tumor volumes before chemotherapy with at least a 2- to 3-cm margin irrespective of lymphatic regions. We also evaluated the suitable radiation dose on the basis of response to chemotherapy. Twenty five eligible patients were treated with 3 cycles of chemotherapy (CHOP) followed by RT. All 25 patients had disease confined to Waldeyer's ring and/or cervical lymph nodes. Twenty two patients in complete response following chemotherapy received 30 Gy, and the remaining 3 in partial response received 40 Gy. With a median follow up of 42 months, both event free and overall survival rates at 2 years were 96.0%. There were no in-field recurrences, however, two patients experienced relapses. One developed central nervous system involvement and subsequently died of his disease. The other had mediastinal and submental lymph node relapse at 32 months, and is alive after salvage chemotherapy. Our study demonstrated that it should be possible to reduce treatment volume to less than the conventional involved field, and to limit the dose of RT in the range of 30-40 Gy.     

Randomized phase II study of concurrent and sequential rituximab and CHOP chemotherapy in untreated indolent B-cell lymphoma

CHOP combined with rituximab (R-CHOP) is regarded as one of the most effective treatments for indolent B-cell non-Hodgkin lymphoma (B-NHL), however, its optimal combination schedule remains unknown. We performed a randomized phase II study to explore a more promising schedule in untreated, advanced indolent B-NHL. Patients were randomized to receive either six courses of CHOP concurrently with rituximab (Arm C), or six courses of CHOP followed by six courses of weekly rituximab (Arm S). A total of 69 patients received the concurrent (n=34) or sequential (n=35) regimen. Overall response rate (ORR) in Arm C was 94% (95% confidence interval [CI], 79 to 99), including a 66% complete response (CR) compared with 97% (95% CI, 85-100), including a 68% CR in Arm S. Patients in Arm C experienced more grade 4 neutropenia (85%versus 70%) and experienced more grade 3 or greater non-hematological toxicities (21%versus 12%). Both arms were tolerated well. With a median follow-up of 28.2 months, the median progression-free survival (PFS) time was 34.2 months in Arm C, and was not reached in Arm S. R-CHOP is highly effective in untreated indolent B-NHL, either concurrent or in a sequential combination. Both combination schedules deserve further investigation.     

Response-adapted therapy for limited stage diffuse large B-cell lymphoma based on interim PET-CT: preliminary results of a phase 2 study

Background

Limited stage diffuse large B-cell lymphoma is curable with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) immunochemotherapy. For patients achieving complete response by interim 18F-fluorodeoxyglucose PET-CT, a previous study showed therapy could be safely de-escalated by omitting the subsequent chemotherapy or radiotherapy. We aimed to adapt the therapy on the basis of the response as assessed by the interim PET-CT.