Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

BACKGROUND:

B‐cell lymphoma, Unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma, for convenience referred to here as unclassifiable B‐cell lymphoma, is a category in the 2008 World Health Organization system used for a group of histologically aggressive neoplasms that are difficult to classify definitively. Currently, there is no established standard therapy for these neoplasms.

METHODS:

The authors assessed MYC status and correlated it with treatment response and outcome in a group of 52 patients with unclassifiable B‐cell lymphoma treated with either a standard DLBCL regimen (R‐CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone‐related therapy]) or more intensive regimens, such as R‐hyper‐CVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high‐dose methotrexate and cytarabine). The regimens were selected by the treating clinicians based on the overall clinical and pathological findings.

RESULTS:

Thirty (58%) unclassifiable B‐cell lymphomas had MYC abnormalities (MYC⁺) including 27 with rearrangement, 2 with amplification, and 1 with both. The MYC⁺ and MYC^? groups were similar in their age distribution and International Prognostic Index scores. Progression‐free survival of patients with MYC⁺ unclassifiable B‐cell lymphoma treated initially with R‐CHOP was significantly worse than patients treated with R‐hyper‐CVAD (P = .0358). In contrast, for the MYC^? unclassifiable B‐cell lymphoma group, some patients responded to R‐CHOP, and others were refractory to R‐hyper‐CVAD.

CONCLUSIONS:

MYC aberrations are common in unclassifiable B‐cell lymphoma. The presence of MYC aberrations identifies a patient subset that requires more aggressive therapy than R‐CHOP. In contrast, MYC^? unclassifiable B‐cell lymphoma patients responded variably to either R‐CHOP or aggressive therapy, and the latter showed no survival advantage. Cancer 2011;. © 2011 American Cancer Society.     

Immunophenotype and intermediate‐high international prognostic index score are prognostic factors for therapy in diffuse large B‐cell lymphoma patients

BACKGROUND.

The development of gene expression profiling and tissue microarray techniques have provided more information about the heterogeneity of diffuse large B‐cell lymphoma (DLBCL), enabling categorization of DLBCL patients into 3 prognostic groups according to cell origin (but independently from the International Prognostic Index [IPI] score): germinal center (GCB), activated B‐cell (ABC), and not classified (NC) diffuse large B‐cell lymphoma. This study investigated the role of immunohistochemical discrimination between GCB and ABC&NC‐DLBCL subtypes in identifying those high‐risk patients who may benefit from a more aggressive first‐line therapeutic approach.

METHODS.

From February 2003 to August 2006, 45 newly diagnosed DLBCL patients, with IPI≥2, were considered eligible for this study: 13 had a GCB, 8 an ABC, and 24 a NC‐DLBCL. GCB patients received 6 courses of rituximab, cyclophophosphamide, doxorubicin, vinicristine, and prednisone (R‐CHOP) chemotherapy, with a subsequent, autologous stem cell transplantation in case of partial response. All ABC and NC‐DLBCL patients received 6 R‐CHOP cycles and autologous stem cell transplantation.

RESULTS.

Complete response rate for each treatment arm was 84.6% for GCB and 89.7% for ABC&NC‐DLBCL (P = .50), with a continuous complete response rate of 81.8% and 84.6%, respectively (P = .59). Projected 4‐year overall survival is 100% for GCB and 82% for ABC&NC patients (P = .12). Progression‐free survival is 77% and 79% (P = .7), respectively.

CONCLUSIONS.

The autologous stem cell transplantation consolidation in the ABC&NC‐DLBCL subtypes induced the same rate of complete response (and similar progression‐free survival rate) compared with GCB‐DLBCL. In ABC&NC‐DLBCL patients the authors observed a complete response rate of 89.7% vs. 84.6% in the GCB‐DLBCL subset, without any significant difference in progression‐free survival rate. Cancer 2010. © 2010 American Cancer Society.     

The role of rituximab and positron emission tomography in the treatment of primary mediastinal large B‐cell lymphoma: experience on 74 patients

Regarding primary mediastinal large B‐cell lymphoma (PMLBCL), there are several controversial topics that warrant further investigation: the superiority of third‐generation regimens, the impact of rituximab, the use of involved field radiotherapy (RT) and the assessment of clinical response by positron emission tomography (PET). We report our experience on 74 PMLBCL patients treated with a combination of a third‐generation chemotherapy regimen (MACOP‐B) and rituximab: an observational retrospective single‐centre study was conducted on patients diagnosed and treated between February 2002 and July 2011. All patients were evaluated by computed tomography scan and PET scan; after the final PET evaluation, PET‐negative patients were observed, whereas PET‐positive patients underwent mediastinal RT. Sixty‐one (82.4%) patients achieved a complete response after the MACOP‐B plus rituximab regimen; 68.9% presented a positive final PET and were treated with local RT, whereas 31.1% had a negative PET. Five patients relapsed within 12 months. At 10 years, overall survival was 82%, progression‐free survival was 87.6% and disease‐free survival (DFS) was 90.5% (median follow‐up 4 years). No statistically significant differences were observed in DFS between the patients treated also with RT (PET positive) and patients only observed (PET negative): 90.7% vs 90% (p = 0.85), respectively. In our experience, adding rituximab does not change the final results in terms of complete response and DFS utilizing third‐generation regimen. Furthermore, the introduction of the PET‐guided RT approach leads to a patient‐tailored treatment, which preserves the outcome and, at the same time, allows reducing the use of RT. Copyright © 2014 John Wiley & Sons, Ltd.     

Prognostic value of interim 18F-FDG PET/CT in diffuse large B-cell lymphoma

Objective: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. The prognostic factor currently used is not accurate enough to predict the outcomes of patients with DLBCL. The prognostic significance of interim PET/CT in DLBCL remains controversial. The aim of this study is to determine the predictive value of interim 18F-FDG PET/CT after first-line treatment in patients with DLBCL. Methods: Thirty-two patients with DLBCL underwent baseline, interim and post-treatment 18F-FDG PET/CT scans. Imaging results were analyzed for the survival of patients via software SPSS 13.0, retrospectively. Results: Thirty-one of the 32 patients were treated with R-CHOP regimen, and interim 18F-FDG PET/CT of 24 patients was performed after 2 cycles of treatment. After a median follow-up period of 16.7 months, the 2-year progression-free survival (PFS) rates were significantly different between the groups above and below SUV max cut-off value of 2.5 (P=0.039). No significant differences were found in the 2-year PFS rates if SUV max cut-off values were set as 2.0 and 3.0, respectively (P=0.360; P=0.113). Conclusions: Interim PET/CT could predict the prognosis of DLBCL patients with the SUV max cut-off value of 2.5, but more clinical data should be concluded to confirm this conclusion.     

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.     

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high‐risk patients with diffuse large B‐cell lymphoma

BACKGROUND:

The outcome of patients with systemic diffuse large B‐cell lymphoma (DLBCL) had improved over the past decade with the addition of monoclonal antibody therapy. Unfortunately, approximately 5% of these patients still developed a secondary central nervous system (CNS) recurrence followed invariably by rapid death. This rate is substantially increased in patients with certain high‐risk features. Although prophylaxis against CNS recurrence with either intrathecal or intravenous methotrexate is commonly used for such patients, to the authors' knowledge, there is no standard of care. Retrospectively evaluated was the role of high‐dose systemic methotrexate combined with standard cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (R‐CHOP) chemotherapy to decrease CNS recurrence in high‐risk patients.

METHODS:

A total of 65 patients with DLBCL and CNS risk factors were identified at the study institution between 2000 and 2008 who received intravenous methotrexate as CNS prophylaxis concurrent with standard systemic therapy with curative intent. CNS recurrence rate, progression‐free survival, and overall survival were calculated.

RESULTS:

Patients received a median of 3 cycles of methotrexate at a dose of 3.5 gm/m² with leucovorin rescue. The complete response rate was 86%, with 6% partial responses. At a median follow‐up of 33 months, there were only 2 CNS recurrences (3%) in this high‐risk population. The 3‐year progression‐free and overall survival rates were 76% and 78%, respectively. Complications associated with methotrexate therapy included transient renal dysfunction in 7 patients and a delay in systemic chemotherapy in 8 patients.

CONCLUSIONS:

Intravenous methotrexate can be safely administered concurrently with R‐CHOP and is associated with a low risk of CNS recurrence in high‐risk patients. Cancer 2010. © 2010 American Cancer Society.     

Burkitt post-transplantation lymphoma in adult solid organ transplant recipients: Sequential immunochemotherapy with rituximab (R) followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or R-CHOP is safe and effective in an analysis of 8 patients

BACKGROUND:

Burkitt lymphoma post‐transplantation lymphoproliferative disorder (Burkitt‐PTLD) is a rare form of monomorphic B‐cell PTLD for which no standard treatment has been established. Currently, the treatment of Burkitt lymphoma outside the post‐transplantation setting involves high doses of alkylating agents, frequent dosing, and intrathecal and/or systemic central nervous system prophylaxis. In PTLD, however, such protocols are associated with considerable toxicity and mortality.

METHODS:

The authors present a retrospective series of 8 adult patients with Burkitt‐PTLD. Six patients were reported to the prospective German PTLD registry or were enrolled in the PTLD‐1 trial, and 2 patients had received treatment before 2000, thus allowing for comparison with the pre‐rituximab era.

RESULTS:

Seven of the 8 patients were men. The median age at presentation was 38 years, and the median time since transplantation was 5.7 years. Five of 8 patients had histologically established, Epstein‐Barr virus‐associated disease, and 7 of 7 patients were positive for a MYC translocation. Five of 8 patients received sequential immunochemotherapy (4 courses of rituximab [R] followed by 4 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP] or R plus CHOP [R‐CHOP]). In this group, 5 of 5 patients reached complete remission (CR), and their overall survival (OS) was significantly longer (P = .008) compared with the OS for 2 of 8 patients who received first‐line CHOP and did not respond. One of 8 patients (who had stage IV disease with meningiosis) received combination therapy (cyclophosphamide pretreatment, rituximab, intrathecal chemotherapy, whole‐brain irradiation, and radioimmunotherapy) and reached CR. Overall, 6 of 8 patients reached CR; and, after a median follow‐up of 4.7 years (range, 1.7‐4.8 years), the median OS was 36.7 months. There was no treatment‐related mortality under first‐line therapy.

CONCLUSIONS:

In the largest adult case series in Burkitt‐PTLD to date, sequential immunochemotherapy with rituximab followed by standard CHOP or R‐CHOP was a both safe and effective treatment. Cancer 2012. © 2012 American Cancer Society.     

Response and survival benefit with chemoimmunotherapy in Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma

Epstein‐Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) is a haematologic malignancy with poor prognosis when treated with chemotherapy. We evaluated response and survival benefits of chemoimmunotherapy in EBV‐positive DLBCL patients. A total of 117 DLBCL patients were included in our retrospective analysis; 33 were EBV‐positive (17 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R‐CHOP] and 16 with CHOP), and 84 were EBV‐negative (all treated with R‐CHOP). The outcomes of interest were complete response (CR) and overall survival (OS) in EBV‐positive DLBCL patients (R‐CHOP versus CHOP) and in DLBCL patients treated with R‐CHOP (EBV‐positive vs EBV‐negative). There were no differences in the clinical characteristics between EBV‐positive and EBV‐negative DLBCL patients. Among EBV‐positive DLBCL patients, R‐CHOP was associated with higher odds of CR (OR 3.14, 95% CI 0.75‐13.2; P = .10) and better OS (hazard ratio 0.30, 95% confidence interval [CI] 0.09‐0.94; P = .04). There were no differences in CR rate (OR 0.52, 95% CI 0.18‐1.56; P = .25) or OS (hazard ratio 0.93, 95% CI 0.32‐2.67; P = .89) between EBV‐positive and EBV‐negative DLBCL patients treated with R‐CHOP. Based on our study, the addition of rituximab to CHOP is associated with improved response and survival in EBV‐positive DLBCL patients. Epstein‐Barr virus status does not seem to affect response or survival in DLBCL patients treated with R‐CHOP.     

Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy: involved-field versus involved-node radiotherapy

BACKGROUND:

For limited‐stage diffuse large B‐cell lymphoma (DLBCL), treatment decisions are often influenced by toxicity profiles. One strategy that minimizes chemotherapy‐induced toxicities is abbreviated chemotherapy plus consolidation involved‐field radiotherapy (IFRT). Involved‐node radiotherapy (INRT) is a new concept to DLBCL, aimed to reduce radiotherapy‐induced toxicities. We retrospectively review the long‐term outcomes of limited‐stage DLBCL treated with abbreviated systemic therapy and radiotherapy focusing on field size: IFRT versus INRT.

METHODS:

The British Columbia Cancer Agency Lymphoid Cancer Database was used to identify patients diagnosed with limited‐stage DLBCL (stage I/II, without B‐symptoms; bulk < 10 cm) from 1981 to 2007. Patients were prescribed 3 cycles of chemotherapy plus IFRT (1981‐1996) or INRT≤5 cm (1996‐2007), defined as INRT to the prechemotherapy involved nodes with margins ≤ 5 cm.

RESULTS:

A total of 288 patients were identified: 56% were aged >60 years, 34% had stage II disease, 55% had extranodal disease, 19% had elevated lactate dehydrogenase levels, and 15% received rituximab. The two radiotherapy groups were IFRT (138 patients; 48%) and INRT≤5cm (150 patients; 52%); median follow‐up was 117 and 89 months, respectively. Distant relapse was the most common site of failure in both groups. After INRT≤5 cm, marginal recurrence was infrequent (2%). Time to progression (P = .823), progression‐free survival (P = .575), and overall survival (P = .417) were not significantly different between the radiotherapy cohorts. Radiotherapy field size was not a significant prognostic factor on multivariate analyses.

CONCLUSIONS:

This research is the first known body of work to apply the concept of INRT to limited‐stage DLBCL. Reducing the field size from IFRT to INRT≤5 cm maintains a low marginal recurrence risk with no impact on overall outcome. Cancer 2012. © 2012 American Cancer Society.     

Addition of rituximab is not associated with survival benefit compared with CHOP alone for patients with stage I diffuse large B-cell lymphoma

Background

The role of rituximab in combination with CHOP regimen in patients with stage I diffuse large B-cell lymphoma (DLBCL) remains to be defined. We aimed to compare CHOP plus rituximab (R-CHOP) with CHOP alone and determine the value of radiotherapy in these patients.

Methods

Between 2003 and 2009, 140 untreated patients with stage I DLBCL were retrospectively analyzed in this study.

Results

Seventy-eight patients were treated in R-CHOP group and 62 in CHOP group. Ninety-one patients received additional radiotherapy at the end of chemotherapy. The different treatment groups were well-balanced with respect to baseline characteristics. Complete response (CR) rate was 77% both in R-CHOP and CHOP groups (P=0.945). After a median follow-up period of 56 months, patients received R-CHOP regimen had similar 5-year progression-free survival (PFS) (76% vs. 85%; log-rank P=0.215) and 5-year overall survival (OS) (90% vs. 96%; log-rank P=0.175) compared with those with CHOP alone. Patients with radiotherapy had significantly increased 5-year PFS compared with those who had chemotherapy alone (86% vs. 71%; log-rank P=0.005). At multivariate analysis, patients who had CR (P=0.008) and received radiotherapy (P=0.003) were significantly associated with superior PFS.

Conclusions

CHOP alone could be as effective as R-CHOP regimen and additional radiotherapy would be necessary for stage I or stage I non-bulky DLBCL patients.     

Lack of benefit of central nervous system prophylaxis for diffuse large B-cell lymphoma in the rituximab era: findings from a large national database

BACKGROUND:

Little is known about the utility of central nervous system (CNS) prophylaxis for diffuse large B‐cell lymphoma (DLBCL) in the rituximab era. The objective of this study was to characterize patterns of CNS prophylaxis for patients who received combined rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) chemotherapy using the National Comprehensive Cancer Network Non‐Hodgkin Lymphoma Outcomes Database, a prospective cohort study that collects clinical and outcomes data for patients at 7 participating centers.

METHODS:

Patients who were eligible for this analysis presented with newly diagnosed DLBCL between January 2001 and July 2008, had no evidence of baseline CNS disease, and had received R‐CHOP within 180 days of diagnosis. The authors assessed incidence and covariates of prophylaxis, prophylaxis modality, and, using propensity score analysis, outcomes such as overall survival.

RESULTS:

Of 989 eligible patients, 117 received CNS prophylaxis (11.8%), most intrathecally (71.8%). Involvement of bone marrow, other high‐risk site, >1 extranodal site, higher International Prognostic Index score, and higher stage were associated individually with the receipt of prophylaxis (all P < .0001). At a median follow‐up of 2.5 years, there were 20 CNS recurrences (2% [95% confidence interval, 1.1%‐2.9%]) among all patients, and overall survival was not affected by prophylaxis.

CONCLUSIONS:

Given the overall low rate of CNS recurrence and lack of prophylaxis‐associated survival benefit, the current data called into question the practice of CNS prophylaxis in the rituximab era. Cancer 2011. © 2011 American Cancer Society.     

Prognostic impact of extranodal involvement in diffuse large B-cell lymphoma in the rituximab era

BACKGROUND:

Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B‐cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated.

METHODS:

The authors retrospectively analyzed 1221 patients treated uniformly with standard R‐CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax‐associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15‐91 years).

RESULTS:

Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04).

CONCLUSIONS:

Extranodal involvement affects the prognosis of patients undergoing R‐CHOP therapy for DLBCL. Cancer 2012. © 2011 American Cancer Society.     

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma

BACKGROUND:

Improved outcomes have recently been reported for rituximab (R) plus rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R‐EPOCH) chemotherapy in patients with human immunodeficiency virus (HIV)‐associated, aggressive B‐cell, non‐Hodgkin lymphoma (NHL). The objective of the current analysis was to assess whether patient selection or other factors contributed to this improvement and to identify patients who are at the greatest risk for lethal toxicity.

METHODS:

The authors performed a pooled analysis of 2 consecutive trials that included 150 patients with HIV‐associated NHL who received either R‐CHOP (n = 99; Acquired Immunodeficiency Syndrome [AIDS] Malignancy Consortium Trial 010 [AMC010]) or R‐EPOCH (n = 51; AMC034). Age‐adjusted International Prognostic Index (aaIPI), CD4 count at lymphoma diagnosis (<100/μL vs ≥100/μL), and treatment (R‐CHOP vs R‐EPOCH) were included as variables in a multivariate logistic regression model for complete response (CR) and in a Cox proportional hazards regression models for event‐free survival (EFS) and overall survival (OS).

RESULTS:

Features that were associated significantly with an improved CR rate and improved EFS and OS included a low aaIPI score and a baseline CD4 count ≥100/μL. When the analysis was adjusted for aaIPI and CD4 count, patients who received concurrent R‐EPOCH had improved EFS (hazard ratio [HR] 0.40; 95% confidence intervals [CI], 0.23, 0.69; P < .001) and OS (HR, 0.38; 95% CI, 0.21, 0.69; P < .01). Treatment‐associated death occurred significantly more often in patients with CD4 counts <50/μL (37% vs 6%; P < .01).

CONCLUSIONS:

The current analysis provided additional level 2 evidence supporting the use of concurrent R‐EPOCH in patients with HIV‐associated lymphoma and a CD4 count >50/μL, and the results support the design of an ongoing phase 3 trial comparing concurrent R‐EPOCH with R‐CHOP in immunocompetent patients with diffuse large B‐cell lymphoma (National Clinical Trial no. NCT00118209). Cancer 2012. © 2011 American Cancer Society.     

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.     

Efficacy and toxicity of 2 schedules of frontline rituximab plus cyclophosphamide,doxorubicin, vincristine,and prednisone plus bortezomib in patients with B‐cell lymphoma

BACKGROUND:

Bortezomib demonstrated promising activity in lymphomas. The authors conducted a randomized phase 2 trial of frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) with the addition of bortezomib in patients with B‐cell lymphoma.

METHODS:

Patients were randomized between 2 schedules of bortezomib, Arm A (Days 1, 4, 8, and 11) and Arm B (Days 1 and 8), combined with 6 cycles of R‐CHOP. For the first patients (Step 1), bortezomib was given at a dose of 1 mg/m² in Arm A and 1.3 mg/m² in Arm B. For the next patients (Step 2), doses were increased to 1.3 mg/m² and 1.6 mg/m² in Arms A and B, respectively. The primary endpoint was the rate of complete response (CR) and unconfirmed CR (CR/CRu) after 6 cycles.

RESULTS:

Forty‐nine patients were included in the study, and 41 patients (84%) achieved a CR/CRu, ie, 18 of 20 patients (90%) in Arm A and 23 of 29 patients (79%) in Arm B. There were 6 partial responses and 2 patients with progressive disease. Neurologic toxicity occurred in 21 patients (43%) and was grade 2 in 11 patients (7 patients in Step 2) and grade 3 in 10 patients (9 patients in Step 2). Other grade 3 and 4 toxicities included constipation (n = 1), infections (n = 3), and cardiac events (n = 2). Grade 3 and 4 thrombocytopenia and leucopenia occurred in 14% and 41% of cycles, respectively.

CONCLUSIONS:

R‐CHOP + bortezomib was an effective regimen and produced an 84% CR rate. However, the dose‐limiting neurotoxicity should be kept in mind for further trials with vinca alkaloids or other potentially neurotoxic drugs combination therapies. Cancer 2009. © 2009 American Cancer Society.     

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy in primary mediastinal large B-cell lymphoma: the emerging standard of care

More aggressive treatment approaches (methotrexate, cytarabine, cyclophosphamide, vincristine, prednisone, and bleomycin [the MACOP-B regimen] or consolidation with high-dose therapy and autologous stem cell transplantation) have been considered to be superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with primary mediastinal large B-cell lymphoma (PMLBCL). Rituximab-CHOP (R-CHOP) is the standard of care for diffuse large B-cell lymphoma, whereas efficacy in PMLBCL has not been adequately confirmed.

Patient and Methods.

Seventy-six consecutive PMLBCL patients who received R-CHOP with or without radiotherapy (RT) were compared with 45 consecutive historical controls treated with CHOP with or without RT. Baseline characteristics of the two groups were balanced.

Results.

The rate of early treatment failure was much lower with R-CHOP with or without RT (9% versus 30%; p = .004). The 5-year freedom from progression rate after R-CHOP with or without RT was 81%, versus 48% for CHOP with or without RT (p < .0001). The 5-year event-free survival rates were 80% and 47% (p < .0001) and the 5-year overall and lymphoma-specific survival rates were 89% and 69% (p = .003) and 91% and 69% (p = .001), respectively, with only seven of 76 lymphoma-related deaths. Among R-CHOP responders, 52 of 68 received RT.

Conclusions.

Based on these results, most patients with PMLBCL appear to be cured by R-CHOP in 21-day cycles with or without RT, which could be the current standard of care. Therefore, the need for more aggressive treatment strategies is questionable unless high-risk patients are adequately defined. Further studies are required to establish the precise role of RT.     

Total lesion glycolysis in positron emission tomography is a better predictor of outcome than the International Prognostic Index for patients with diffuse large B cell lymphoma

BACKGROUND:

This study was undertaken to evaluate the prognostic value of quantitative metabolic parameters in [¹⁸F]2‐fluoro‐2‐deoxyglucose (FDG)‐positron emission tomography (PET) for diffuse large B cell lymphoma (DLBCL).

METHODS:

A total of 140 DLBCL patients underwent FDG‐PET scans before rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R‐CHOP) chemotherapy. The maximal standardized uptake value (SUV_max) and total lesion glycolysis (TLG) were calculated, with the margin thresholds as 25%, 50%, and 75% of SUV_max of all lesions. Treatment outcomes were compared between groups according to metabolic parameters and the International Prognostic Index (IPI).

RESULTS:

After a median follow‐up of 28.5 months (range, 5‐81 months), the 2‐year progression‐free survival (PFS) and overall survival (OS) were 83% and 87%, respectively. Among metabolic parameters, TLG at the threshold of 50% (TLG₅₀) was significantly associated with treatment outcomes. High TLG₅₀ values (>415.5) were associated with reduced survivals compared with low TLG₅₀ values (≤415.5) (2‐year PFS of 73% versus 92%, P = .007; and 2‐year OS of 81% versus 93%, P = .031). High IPI score (≥3) significantly reduced OS (2‐year OS of 79% versus 90%, P = .049). Ann Arbor stage III/IV adversely affected PFS (P = .013). However, high IPI score and Ann Arbor stage of III/V did not significantly shorten PFS (P = .200) and OS (P = .921), respectively. High TLG₅₀ values independently predicted survivals by multivariate analysis (hazard ratio = 4.4; 95% confidence interval = 1.5‐13.1; P = .008 for PFS and hazard ratio = 3.1; 95% confidence interval = 1.0‐9.6; P = .049 for OS).

CONCLUSIONS:

Combined assessment of volume and metabolism (ie, TLG) is predictive of survivals in DLBCL patients who are treated with R‐CHOP. Cancer 2013. © 2012 American Cancer Society.     

Prognostic significance of interim ¹⁸F-FDG PET/CT after three or four cycles of R-CHOP chemotherapy in the treatment of diffuse large B-cell lymphoma

Purpose

¹⁸F-fluoro-2-dexoy-d-glucose-positron emission tomography (FDG-PET)/computerised tomography (CT) has been used for staging and monitoring responses to treatment in patients with diffuse large B cell lymphoma (DLBCL). The sequential interim PET/CT was prospectively investigated to determine whether it provided additional prognostic information and could be a positive predictable value within patients with the same international prognostic index (IPI) after the use of rituximab in DLBCL.

Methods

One hundred and sixty-one patients with newly diagnosed DLBCL were enroled; the assessment of the PET/CT was performed at the time of diagnosis and mid-treatment of rituxibmab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP).

Results

Sixty-seven patients (41.6%) presented with advanced stage disease and 27 (16.8%) had bulky lesions. Forty-three patients (26.7%) continued to have positive metabolic uptakes with a significantly high relapse rate (62.8%) compared to the patients with a negative interim PET/CT (12.1%) (P < 0.01). After a median follow-up of 30.8 months, the positivity of interim PET/CT was found to be a prognostic factor for both overall survival (OS) and progression-free survival (PFS), with a hazard ratio of 4.07 (2.62-6.32) and 5.46 (3.49-8.52), respectively. In the low-risk IPI group, the 3-year OS and PFS rates were significantly different in the patients with positive (53.3% and 52.5%) and negative (93.8% and 88.3%) interim PET/CT, respectively (P < 0.01). These significant prognostic differences of interim PET/CT responses were consistent with the results of the patients with high-risk IPI group (P < 0.01).

Conclusions

Interim PET/CT scanning had a significant predictive value for disease progression and survival of DLBCL in post-rituximab treatment; it might be the single most important determinant of clinical outcome in patients with the same IPI risk.     

Prognostic significance of metabolic tumor burden by positron emission tomography/computed tomography in patients with relapsed/refractory diffuse large B‐cell lymphoma

The aim of the present study was to investigate the feasibility of measuring metabolic tumor burden using [F‐18] fluorodeoxyglucose (¹⁸F‐FDG) positron emission tomography/computed tomography (PET/CT) in patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) treated with bendamustine–rituximab. Because the standardized uptake value is a critical parameter of tumor characterization, we carried out a phantom study of ¹⁸F‐FDG PET/CT to ensure quality control for 28 machines in the 24 institutions (Japan, 17 institutions; Korea, 7 institutions) participating in our clinical study. Fifty‐five patients with relapsed or refractory DLBCL were enrolled. The ¹⁸F‐FDG PET/CT was acquired before treatment, after two cycles, and after the last treatment cycle. Treatment response was assessed after two cycles and after the last cycle using the Lugano classification. Using this classification, remission was complete in 15 patients (27%) and incomplete in 40 patients (73%) after two cycles of therapy, and remission was complete in 32 patients (58%) and incomplete in 23 patients (42%) after the last treatment cycle. The percentage change in all PET/CT parameters except for the area under the curve of the cumulative standardized uptake value–volume histogram was significantly greater in complete response patients than in non‐complete response patients after two cycles and the last cycle. The Cox proportional hazard model and best subset selection method revealed that the percentage change of the sum of total lesion glycolysis after the last cycle (relative risk, 5.24; P = 0.003) was an independent predictor of progression‐free survival. The percent change of sum of total lesion glycolysis, calculated from PET/CT, can be used to quantify the response to treatment and can predict progression‐free survival after the last treatment cycle in patients with relapsed or refractory DLBCL treated with bendamustine–rituximab.     

A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas

BACKGROUND:

Bortezomib has demonstrated efficacy in patients with relapsed B‐cell non‐Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R‐CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.

METHODS:

Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29‐71 years). Seven patients had a FL International Prognostic Index score ≥3. R‐CHOP with the vincristine dose capped at 1.5 mg was administered on a 21‐day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m² [n = 1], 1.3 mg/m² [n = 6], or 1.6 mg/m² [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.

RESULTS:

The maximum tolerated dose (MTD) of bortezomib with modified R‐CHOP was reached at 1.6 mg/m². Dose‐limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m², 1 patient at a bortezomib dose of 1.3 mg/m², and 3 patients at a bortezomib dose of 1.6 mg/m²). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow‐up of 32 months, the 3‐year progression‐free survival rate was 89.5%.

CONCLUSIONS:

Bortezomib combined with modified R‐CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R‐CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2012;3538–3548. © 2012 American Cancer Society.