Diffuse large B‐cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era

The addition of rituximab has improved outcomes in diffuse large B‐cell lymphoma (DLBCL ), however, there remains limited information on the impact of rituximab in those with testicular involvement. All patients with diffuse large cell lymphoma and testicular involvement treated with curative intent were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. In total, 134 patients diagnosed between 1982 and 2015 with diffuse large cell lymphoma involving the testis were identified: 61 received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)‐like chemotherapy and 73 received CHOP plus rituximab (R‐CHOP ). A greater proportion of R‐CHOP treated patients had higher International Prognostic Index (IPI , P  =  0·005). In multivariate analysis, the protective effect of rituximab on progression‐free survival (hazard ratio (HR ) 0·42, P  <  0·001), overall survival (HR 0·39, P  <  0·001) and cumulative incidence of progression (HR 0·46, P  =  0·014) were independent of the IPI . However, in a competing risk multivariate analysis including central nervous system (CNS ) prophylaxis and the CNS ‐IPI , rituximab was not associated with a decreased risk of CNS relapse. The addition of rituximab has reduced the risk of lymphoma recurrence in testicular DLBCL , presumably through improved eradication of systemic disease. However, CNS relapse risk remains high and further studies evaluating effective prophylactic strategies are needed.     

Impact of central nervous system (CNS) prophylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature

Central nervous system (CNS) prophylaxis for diffuse large B‐cell lymphoma (DLBCL) is controversial with even less evidence in the era of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. We reviewed the impact of CNS prophylaxis in DLBCL patients treated with R‐CHOP at a tertiary care centre over a 7‐year period. CNS prophylaxis was recommended for ‘higher risk’ patients and consisted of intrathecal methotrexate and/or high‐dose methotrexate. Of 214 patients 12·6% received CNS prophylaxis. With a median follow‐up of 27 months, eight patients (3·7%) developed CNS relapse (75% isolated to the CNS and 62·5% as parenchymal brain disease) at a median time of 17 months. Patients who did not receive CNS prophylaxis had lower events (2·7%) than those who did (11·1%). Half of the CNS relapses occurred in testicular lymphoma patients, 75% of whom had received CNS prophylaxis. In multivariate analysis, testicular involvement was the only significant prognostic factor for CNS relapse (hazard ratio 33·5, P < 0·001). In conclusion, CNS relapse in DLBCL appears to present as a later, more isolated parenchymal event and at a lower rate in the rituximab era compared with historical data. R‐CHOP may negate the need for CNS prophylaxis with the exception of testicular lymphoma.     

The lymphocyte to monocyte ratio improves the IPI‐risk definition of diffuse large B‐cell lymphoma when rituximab is added to chemotherapy

The peripheral blood lymphocyte to monocyte ratio (LMR) at diagnosis can be clinically relevant in patients with diffuse large B‐cell lymphoma (DLBCL). We reviewed the outcome of 1,057 DLBCL patients followed from 1984 to 2012 at four centers. LMR was analyzed as a clinical biomarker by receiver‐operating characteristic (ROC) analysis and Harrell's C‐statistics. Patients were characterized by a median age of 61 years, International Prognostic Index (IPI) score of >2 in 39%, and were treated with a rituximab‐containing chemotherapy in 66%. LMR proved strongly predictive for survival in patients treated with rituximab‐based programs, but not in those receiving chemotherapy alone. Additionally, an LMR value of ≤2.6 (as determined by ROC analysis) was associated with a worst performance status, a higher lactate dehydrogenase (LDH) level, an advanced clinical stage, and a higher IPI score (P = 0.000). In patients treated with rituximab‐supplemented chemotherapy programs, an LMR value of <2.6 was found in most of the primary refractory patients (75%) which proved as the best cutoff to predict both response and survival (P = 0.018). Finally, multivariate analysis and Harrell's C‐statistics confirmed the IPI‐independent role of LMR on survival (P = 0.0000). In conclusion, LMR is a potent predictor of clinical response and survival in DLBCL treated with rituximab‐containing chemotherapy. Am. J. Hematol. 88:1062–1067, 2013. © 2013 Wiley Periodicals, Inc.     

Serum interleukin-18 level is associated with the outcome of patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP regimens

Background: We have previously reported that serum interleukin‐18 (IL‐18) concentration predicted the clinical outcome of patients with aggressive non‐Hodgkin’s lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). When rituximab (R) was added to this regimen, the prognosis of diffuse large B‐cell lymphoma (DLBCL) was markedly improved. Patients and Methods: In this study, we re‐evaluated the prognostic significance of serum IL‐18 in 227 DLBCL patients. Seventy‐three patients received CHOP before R‐era, and 154 patients received rituximab‐cyclophosphamide, doxorubicin, vincristine, and prednisolone (R‐CHOP) recently. Result: Four‐year overall survival (4‐yr OS) rates for patients in CHOP group with IL‐18 ≥ 720 pg/mL and <720 pg/mL were 8.2% and 67.3% (P < 0.0001), respectively, and 4‐yr OS rates with IL‐18 ≥ 590 and <590 pg/mL in R‐CHOP group were 53.4% and 77.8% (P = 0.0008), respectively. Multivariate analysis revealed that serum IL‐18 correlated most significantly with OS and progression‐free survival (PFS) in both groups (OS: P < 0.0001, PFS: P < 0.0001, in CHOP group; OS: P = 0.0147, PFS: P = 0.0084 in R‐CHOP group). The high serum IL‐18 patients with poor prognostic group in revised IPI or with non‐germinal center B‐cell phenotype had a very poor prognosis. Conclusion: Serum IL‐18 might be a powerful prognostic factor for DLBCL in R‐era.     

Higher fungal infection rate in elderly patients (more than 80 years old) suffering from diffuse large B cell lymphoma and treated with rituximab plus CHOP

Although adding rituximab to standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy is an efficacious and well-tolerated regimen in elderly patients with diffuse large B cell lymphoma (DLBCL), it may increase susceptibility to opportunistic infections, and such cases have been reported. Our study was to identify the risk factors for fungal infection in a retrospective case-control matched study of 34 elderly DLBCL patients treated with rituximab plus CHOP (R-CHOP) and 35 control patients treated with the standard CHOP regimen at the Taipei Veterans General Hospital, Taiwan. The rate of overall infection was similar in both groups. However, subgroup analysis found that the fungal infection rate was significantly different, 41.7 and 17.1%, in the R-CHOP and CHOP groups, respectively, (P = 0.03). Univariate analysis identified the rituximab plus CHOP chemotherapy regimen (P = 0.03), age older than 80 years (P = 0.04), and bone marrow involvement (P = 0.04) as risk factors for development of fungal infection, whereas, multivariate regression analysis identified only rituximab plus CHOP and old age. Adding rituximab to the standard CHOP regimen in elderly DLBCL patients might increase the incidence of fungal infection especially in those older than 80 years old.     

High Ki67 index and bulky disease remain significant adverse prognostic factors in patients with diffuse large B cell lymphoma before and after the introduction of rituximab

The aim of this study was to evaluate the impact of clinical variables and biologic features on response rate (RR), overall survival (OS) and progression-free survival (PFS) in 111 patients with de novo diffuse large B cell lymphoma (DLBCL). Fifty-three patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and 58 patients were treated with R-CHOP (rituximab + CHOP). The variables predictive of RR in the CHOP group were B symptoms, age, clinical stage, bone marrow involvement, bulky disease, International Prognostic Index (IPI) and Bcl-2; in the R-CHOP group, these variables were bulky disease, bone marrow involvement, IPI and Ki67 expression >80%. Multivariate analysis showed that in patients treated with CHOP, the independent prognostic factors associated with PFS were age, bulky disease, IPI and Bcl-2 and those associated with OS were performance status, clinical stage, IPI and bone marrow involvement. In contrast, in patients treated with R-CHOP, the variable shown by multivariate analysis to be an independent prognostic factor associated with PFS was bulky disease, whereas Ki67 expression >80% was associated with OS and PFS. Our data show that a high Ki67 expression and bulky disease could represent possible predictive factors of poor prognosis, which would help to identify a high-risk subgroup of newly diagnosed DLBCL.     

Primary gastric diffuse large B‐cell Lymphoma (DLBCL): analyses of prognostic factors and value of pretreatment FDG‐PET scan

Objectives: We report a single institution experience with gastric diffuse large B‐cell lymphoma (DLBCL) in an attempt to evaluate the roles of different treatment modalities, to assess the value of pretreatment positron emission tomography (PET) scan, and to identify potential prognostic factors. Methods: Among 384 patients diagnosed with DLBCL between 1995 and 2008, 75 patients had primary gastric DLBCL and were reviewed and analyzed. Results: The median age was 66. International prognostic index (IPI) risk was low in 52%, low‐intermediate in 23%, high‐intermediate in 9%, and high in 16%. Pretreatment PET scan was highly sensitive in detecting gastric lesions except stage I gastric DLBCL without detectable mass by CT or gastroscopy. As a general rule, patients with limited‐stage disease were treated with three times of CHOP (with or without rituximab) and radiotherapy, and those with advanced‐stage disease were treated with eight cycles of CHOP (with or without rituximab), and radiotherapy was given to residual diseases after chemotherapy. Three‐year overall survival (OS) rate was 78%. Multivariate analysis revealed that low albumin, hemoglobin <12.0 g/dL, and treatment without rituximab were independently associated with shorter OS. Low albumin, hemoglobin <12.0 g/dL,and advanced stage were independently associated with shorter progression‐free survival. Conclusion: We showed the survival benefit of rituximab and potential prognostic value of pretreatment hemoglobin and serum albumin levels in gastric DLBCL.     

Risk factors for poor treatment outcome and central nervous system relapse in diffuse large B-cell lymphoma with bone marrow involvement

Although several studies have described the prognostic implication of bone marrow (BM) involvement (BMI) in lymphoma, studies focused on BM-involved diffuse large B-cell lymphoma (DLBCL) are very rare and small-sized. This study was performed to examine the prognostic impact of morphologic findings of BMI by lymphoma and risk factors for central nervous system (CNS) relapse in BM-involved DLBCL. Between 1993 and 2005, 675 patients were diagnosed with DLBCL, and 88 patients who had BMI at initial diagnosis were eligible for this study. The median overall survival (OS) and failure-free survival (FFS) of 88 patients were 36.6 and 20.1 months, respectively. When three variables from BM morphologic findings (the pattern of BM infiltration, extent of BMI by lymphoma, and percentage of large cells in the infiltrate) were simultaneously included into multivariate model, the increased extent of BMI by lymphoma (≥10%) in BM area was the only negative prognostic factor, independent of the International Prognostic Index (IPI). Patients with both lower IPI scores and less extent of BMI showed an excellent prognosis with chemotherapy alone (5-year OS and FFS rates, 80% and 69%). However, morphologic BM features were not independent predictive factors for CNS recurrences. An increased lactate dehydrogenase (LDH) level at initial diagnosis was the only independent predictive factor for CNS relapse. Further efforts should be directed toward finding optimal treatment modalities based on the IPI and the extent of BMI by lymphoma. CNS prophylaxis may be considered only in patients with initial elevated LDH levels. K.-W. Lee and J. Yi equally contributed to this study.     

Outcome prediction by extranodal involvement,IPI, R‐IPI,and NCCN‐IPI in the PET/CT and rituximab era: A Danish–Canadian study of 443 patients with diffuse‐large B‐cell lymphoma

18F‐fluorodeoxyglucose PET/CT (PET/CT) is the current state‐of‐the‐art in the staging of diffuse large B‐cell lymphoma (DLBCL) and has a high sensitivity for extranodal involvement. Therefore, reassessment of extranodal involvement and the current prognostic indices in the PET/CT era is warranted. We screened patients with newly diagnosed DLBCL seen at the academic centers of Aalborg, Copenhagen, and British Columbia for eligibility. Patients that had been staged with PET/CT and treated with R‐CHOP(‐like) 1^st line treatment were retrospectively included. In total 443 patients met the inclusion criteria. With a median follow‐up of 2.4 years, the 3‐year overall (OS) and progression‐free survival (PFS) were 73% and 69%, respectively. The Ann Arbor classification had no prognostic impact in itself with the exception of stage IV disease (HR 2.14 for PFS, P<0.01). Extranodal involvement was associated with a worse outcome in general, and in particular for patients with involvement of >2 extranodal sites, including HR 7.81 (P < 0.001) for PFS for >3 sites. Bone/bone marrow involvement was the most commonly involved extranodal site identified by PET/CT (29%) and was associated with an inferior PFS and OS. The IPI, R‐IPI, and NCCN‐IPI were predictive of PFS and OS, and the two latter could identify a very good prognostic subgroup with 3‐year PFS and OS of 100%. PET/CT‐ascertained extranodal involvement in DLBCL is common and involvement of >2 extranodal sites is associated with a dismal outcome. The IPI, R‐IPI, and NCCN‐IPI predict outcome with high accuracy. Am. J. Hematol. 90:1041–1046, 2015. © 2015 Wiley Periodicals, Inc.     

Secondary central nervous system involvement in 599 patients with diffuse large B-cell lymphoma: are there any changes in the rituximab era?

The introduction of rituximab has improved the overall prognosis of diffuse large B-cell lymphoma (DLBCL). However, the impact of rituximab on central nervous system (CNS) involvement in DLBCL remains a matter of debate. Patients with DLBCL and no CNS involvement at initial diagnosis were eligible for this analysis. Patients must have received treatment either with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP). We analyzed the incidence, clinical features and outcomes of CNS involvement that developed during or after completion of therapy. A cohort of 599 patients was eligible for this analysis. With a median follow-up of 26 and 21 months, respectively, 19 of 294 (6.5 %) in the CHOP group and 13 of 305 (4.3 %) in the R-CHOP group developed CNS involvement. Rituximab did not significantly reduce the risk of CNS involvement either in the univariate (P = 0.354) or in the multivariate analysis (RR 0.632, 95 % CI 0.301–1.327, P = 0.225). No patient developed CNS disease after 19 months in the R-CHOP group whereas four patients (21.1 %) in the CHOP group developed CNS disease 2 years after initial diagnosis (range 34–83 months). Systemic disease prior to or coincident with CNS occurrence was more common in the CHOP group than in the R-CHOP group (73.7 versus 38.5 %, P = 0.046). Isolated CNS events were more common in the R-CHOP group than those in the CHOP group (53.8 versus 10.5 %, P = 0.015). This study indicates that isolated CNS events are more common in DLBCL patients treated with R-CHOP than those treated with CHOP alone. Our data also suggest that the time and pattern of CNS events and systemic disease status differ with the addition of rituximab. Better methods for earlier detection and prophylaxis of CNS involvement are needed in the rituximab era.     

Diffuse large B-cell lymphoma with central nervous system relapse: prognosis and risk factors according to retrospective analysis from a single-center experience

The introduction of rituximab for diffuse large B-cell lymphoma (DLBCL) has improved the disease’s overall prognosis. However, relapse in the central nervous system (CNS) is still an issue. We investigated the prognosis and risk factors of CNS recurrence in DLBCL. A total of 403 patients who were diagnosed with DLBCL without CNS involvement between January 1996 and April 2007 at our institution were included in the study. Subsequently, 42 experienced CNS relapse. Clinical information was gathered by chart review. The median disease-free interval to CNS relapse was 625 days. The mean survival periods after relapse in the cases with CNS and extra-CNS involvement were 513 and 1,615 days, respectively (P = 0.0004). Multivariate analysis identified age >60 years (P = 0.031), involvement in two or more extranodal sites (P = 0.040), bone marrow involvement (P = 0.036), an elevated serum lactate dehydrogenase (LDH) level (P = 0.016), and treatment without rituximab before CNS relapse (P = 0.027) as independent predictors of CNS relapse. We have shown that cases of DLBCL occurring in advanced age, involving two or more extranodal sites or the bone marrow, or showing an elevation of LDH have a higher risk of CNS relapse. Rituximab may prevent CNS relapse by reducing the recurrence of DLBCL at all sites. An effective CNS prophylaxis strategy should be determined according to the risk assessment of CNS relapse. This work was done in the Department of Hematology/Oncology, Kurashiki Central Hospital, Okayama. Part of this study was presented at the 49th Annual Conference of the American Society of Hematology, 2008 (Abstract No. 955341).     

Improved therapeutic outcomes of DLBCL after introduction of rituximab in Korean patients

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been shown to improve the outcome in all age groups with newly diagnosed diffuse large B-cell lymphoma (DLBCL). We conducted a retrospective analysis to evaluate the impact of this combination therapy on DLBCL outcomes in Korea. From October 2001 to June 2004, newly diagnosed DLBCL patients in nine Korean institutes were included. All of these 81 patients were treated with three or more cycles of rituximab plus CHOP (R-CHOP) combination chemotherapy (R group), and followed for a minimum of 12 months. For comparison, a historical cohort of patients was used and analyzed for “Clinicopathologic characteristics of Korean non-Hodgkin’s lymphomas (NHLs) based on Revised American Lymphoma (REAL) classification” in 1999. Among the 1,098 NHL patients, the data of 214 DLBCL patients, who were treated with CHOP chemotherapy in first-line, were analyzed (C group). We compared outcomes between the C group and the R group. A total of 295 patients were evaluated (C group, 214; R group, 81). The complete response (CR) rate was higher in R group (73 vs 91%, p=0.001). The 2-year event-free survival (EFS) rate was significantly higher in R group (78 vs 85%, p=0.0194). This survival benefit was maintained in high-risk patients according to the international prognostic index (IPI) (p=0.0039), regardless of age. However, there was no significant difference in low-risk patients. The addition of rituximab to CHOP combination chemotherapy for DLBCLs showed improved outcomes, particularly in high-risk group according to the IPI. Long-term follow-up results will be needed to confirm these results.     

Uterine,but not ovarian,female reproductive organ involvement at presentation by diffuse large B‐cell lymphoma is associated with poor outcomes and a high frequency of secondary CNS involvement

Involvement of the internal female reproductive organs by diffuse large B‐cell lymphoma (DLBCL) is uncommon, and there are sparse data describing the outcomes of such cases. In total, 678 female patients with DLBCL staged with positron emission tomography/computed tomography and treated with rituximab‐containing chemotherapy were identified from databases in Denmark, Great Britain, Australia, and Canada. Overall, 27/678 (4%) had internal reproductive organ involvement: uterus (n = 14), ovaries (n = 10) or both (n = 3). In multivariate analysis, women with uterine DLBCL experienced inferior progression‐free survival and overall survival compared to those without reproductive organ involvement, whereas ovarian DLBCL was not predictive of outcome. Secondary central nervous system (CNS) involvement (SCNS) occurred in 7/17 (41%) women with uterine DLBCL (two patients with concomitant ovarian DLBCL) and 0/10 women with ovarian DLBCL without concomitant uterine involvement. In multivariate analysis adjusted for other risk factors for SCNS, uterine involvement by DLBCL remained strongly associated with SCNS (Hazard ratio 14·13, 95% confidence interval 5·09–39·25, P < 0·001). Because involvement of the uterus by DLBCL appears to be associated with a high risk of SCNS, those patients should be considered for CNS staging and prophylaxis. However, more studies are needed to determine whether the increased risk of secondary CNS involvement also applies to women with localized reproductive organ DLBCL.     

Clinical outcome of elderly patients with Epstein–Barr virus positive diffuse large B‐cell lymphoma treated with a combination of rituximab and CHOP chemotherapy

Several studies have suggested the possibility of a prognostic relationship between Epstein–Barr virus (EBV) and diffuse large B‐cell lymphoma (DLBCL). The clinical outcome of EBV‐associated DLBCL is not clear, especially since the introduction of rituximab. We retrospectively analyzed 222 elderly patients (≥50 years) with DLBCL who received R‐CHOP chemotherapy and evaluated the state of EBV‐encoded RNA‐1 (EBER). Eighteen cases (8.1%) were EBER‐positive (+). After a median of six cycles of R‐CHOP chemotherapy, the response rate (≥partial response) was 72.2% (13/18) in the EBV (+) patients and 90.2% (184/204) in the EBV (?) DLBCL patients (P = 0.021). Four of 18 (22.2%) EBV (+) DLBCL patients received two or fewer cycles of R‐CHOP chemotherapy. R‐CHOP chemotherapy was also interrupted early more frequently compared with the EBV (?) group (2.5%) (P = 0.00). At a median follow‐up of 32.8 months, there was no significant difference in the overall survival between the groups (P = 0.627). The EBV (+) DLBCL patients with early interruption of R‐CHOP chemotherapy showed a trend toward a high EBV‐DNA titer (≥1,000 copies/mL) (P = 0.091). The results suggest that the EBV (+) tumoral status of elderly DLBCL patients who undergo R‐CHOP chemotherapy does not predict their survival but that their EBV status may contribute to the early interruption of R‐CHOP chemotherapy. Am. J. Hematol. 88:774–779, 2013. © 2013 Wiley Periodicals, Inc.     

A new prognostic model identifies patients aged 80 years and older with diffuse large B‐cell lymphoma who may benefit from curative treatment: A multicenter,retrospective analysis by the Spanish GELTAMO group

The means of optimally managing very elderly patients with diffuse large B‐cell lymphoma (DLBCL) has not been established. We retrospectively analyzed 252 patients aged 80‐100 years, diagnosed with DLBCL or grade 3B follicular lymphoma, treated in 19 hospitals from the GELTAMO group. Primary objective was to analyze the influence of the type of treatment and comorbidity scales on progression‐free survival (PFS) and overall survival (OS). One hundred sixty‐three patients (63%) were treated with chemotherapy that included anthracyclines and/or rituximab, whereas 15% received no chemotherapeutic treatment. With a median follow‐up of 44 months, median PFS and OS were 9.5 and 12.5 months, respectively. In an analysis restricted to the 205 patients treated with any kind of chemotherapy, comorbidity scales did not influence the choice of treatment type significantly. Independent factors associated with better PFS and OS were: age < 86 years, cumulative illness rating scale (CIRS) score < 6, intermediate risk (1‐2) R‐IPI, and treatment with R‐CHOP at full or reduced doses. We developed a prognostic model based on the multivariate analysis of the 108 patients treated with R‐CHOP‐like: median OS was 45 vs. 12 months (P = .001), respectively, for patients with 0‐1 vs. 2‐3 risk factors (age > 85 years, R‐IPI 3‐5 or CIRS > 5). In conclusion, treatment with R‐CHOP‐like is associated with good survival in a significant proportion of patients. We have developed a simple prognostic model that may aid the selection patients who could benefit from a curative treatment, although it needs to be validated in larger series.     

Presence of a high-grade component in gastric mucosa-associated lymphoid tissue (MALT) lymphoma is not associated with an adverse prognosis

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B cell lymphoma (DLBCL) show a spectrum of disease characterized by varying proportions of low-grade and high-grade components. While the natural history and optimum treatment for low-grade gastric MALT lymphoma and DLBCL is well established, the prognosis and optimal treatment of patients with both low- and high-grade components is not well established. The purpose of our study was to evaluate the clinical characteristics, survival outcomes, and prognostic factors of patients with gastric MALT lymphoma and gastric DLBCL. A retrospective review of patients with gastric MALT lymphoma, gastric DLBCL, or MALT lymphoma with a high-grade component treated at our centers from 1994 to 2006 was performed. Patients were divided into three categories: “pure MALT lymphoma,” “MALT lymphoma with high-grade component” (mixed), and “pure DLBCL.” Seventy-six patients were included in our study—26 with pure MALT, 22 with MALT with high-grade component (“mixed”), and 28 with pure DLBCL. Pure MALT lymphoma and mixed lymphoma patients had similar clinical characteristics, whereas pure DLBCL patients had less favorable disease characteristics with significantly poorer performance status, higher number of extranodal sites of disease, higher stage, and larger proportion of bone marrow involvement and international prognostic index (IPI) scores compared with mixed lymphoma. The majority of mixed lymphoma (72.7%) and DLBCL patients (71.4%) were treated with chemotherapy. Of patients receiving chemotherapy, a higher proportion of mixed lymphoma and DLBCL patients received anthracycline-based combination chemotherapy regimens compared with MALT lymphoma (73% vs 71% vs 8%) whereas the proportion of mixed lymphoma and DLBCL patients was similar (p = 0.919). At a median follow-up of 37 months, the 5-year overall survival was 66.9%. The 5-year overall survival was 78% for MALT lymphoma, 84% for mixed lymphoma, and 45% for DLBCL. On univariate analysis, DLBCL histology, age, performance status, serum albumin, lactate dehydrogenase, bone marrow, number of extranodal sites, stage, and IPI score were prognostic for inferior survival. On multivariate analysis, DLBCL histology remained significantly prognostic for inferior survival, independent of chemotherapy regimen (hazard ratio (HR) 6.66, 95% confidence interval (CI) 2.01–21.41, p = 0.001). Mixed histology was not prognostic for inferior survival (HR 1.13, 95% CI 0.28–4.54, p = 0.868). Other factors prognostic for inferior survival were serum albumin <37 g/L (HR 3.22, 95% CI 1.11–13.22, p = 0.034) and treatment with non-cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy (HR 4.89, 95% CI 1.67–14.36, p = 0.004). In conclusion, the clinical characteristics of mixed histology MALT lymphoma are similar to low-grade MALT lymphoma and significantly different from pure DLBCL. The prognosis of mixed histology MALT lymphoma is significantly better than pure DLBCL, independent of IPI and chemotherapy regimen, and pure DLBCL histology is independently prognostic of inferior survival outcome.     

Strikingly high false positivity of surveillance FDG‐PET/CT scanning among patients with diffuse large cell lymphoma in the rituximab era

Predictive value (PV) of surveillance fluorodeoxyglucose positron emission tomography (FDG‐PET) in patients with diffuse large B‐cell lymphoma (DLBCL) treated with chemotherapy‐rituximab (R) versus chemotherapy only, remains unclear. The aim of the current study was to compare the performance of surveillance PET in DLBCL patients receiving CHOP (cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, and prednisone) alone versus CHOP‐R. Institutional database was retrospectively searched for adults with newly diagnosed DLBCL, receiving CHOP or CHOP‐R, who achieved complete remission and underwent surveillance PETs. Follow‐up (FU) PET was considered positive for recurrence in case of an uptake unrelated to physiological or known benign process. Results were confirmed by biopsy, imaging and clinical FU. One hundred nineteen patients, 35 receiving CHOP and 84 CHOP‐R, who underwent 422 FU‐PETs, were analyzed. At a median PET‐FU of 3.4 years, 31 patients relapsed (17 vs. 14, respectively; P = 0.02). PET detected all relapses, with no false‐negative studies. Specificity and positive PV (PPV) were significantly lower for patients receiving CHOP‐R vs. CHOP (84% vs. 87%, P = 0.023; 23% vs. 74%, P < 0.0001), reflecting a higher false‐positive (FP) rate in subjects receiving CHOP‐R (77% vs. 26%, P < 0.001). In the latter group, FP‐rate remained persistently high up to 3 years post‐therapy. Multivariate analysis confirmed rituximab to be the most significant predictor for FP‐PET. In conclusion, routine surveillance FDG‐PET is not recommended in DLBCL treated with rituximab; strict criteria identifying patients in whom FU‐PET is beneficial are required. Am. J. Hematol. 88:400–405, 2013. © 2013 Wiley Periodicals, Inc.     

CD4+ Tumor infiltrating lymphocytes are prognostic and independent of R‐IPI in patients with DLBCL receiving R‐CHOP chemo‐immunotherapy

Despite the Revised International Prognostic Index's (R‐IPI) undoubted utility in diffuse large B‐cell lymphoma (DLBCL), significant clinical heterogeneity within R‐IPI categories persists. Emerging evidence indicates that circulating host immunity is a robust and R‐IPI independent prognosticator, most likely reflecting the immune status of the intratumoral microenvironment. We hypothesized that direct quantification of immunity within lymphomatous tissue would better permit stratification within R‐IPI categories. We analyzed 122 newly diagnosed consecutive DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) chemo‐immunotherapy. Median follow‐up was 4 years. As expected, the R‐IPI was a significant predictor of outcome with 5‐year overall survival (OS) 87% for very good, 87% for good, and 51% for poor‐risk R‐IPI scores (P < 0.001). Consistent with previous reports, systemic immunity also predicted outcome (86% OS for high lymphocyte to monocyte ratio [LMR], versus 63% with low LMR, P = 0.01). Multivariate analysis confirmed LMR as independently prognostic. Flow cytometry on fresh diagnostic lymphoma tissue, identified CD4⁺ T‐cell infiltration as the most significant predictor of outcome with ≥23% infiltration dividing the cohort into high and low risk groups with regard to event‐free survival (EFS, P = 0.007) and OS (P = 0.003). EFS and OS were independent of the R‐IPI and LMR. Importantly, within very good/good R‐IPI patients, CD4⁺ T‐cells still distinguished patients with different 5 year OS (high 96% versus low 63%, P = 0.02). These results illustrate the importance of circulating and local intratumoral immunity in DLBCL treated with R‐CHOP. Am. J. Hematol. 88:273–276, 2013. © 2013 Wiley Periodicals, Inc.     

Importance of maintaining the relative dose intensity of CHOP-like regimens combined with rituximab in patients with diffuse large B-cell lymphoma

CHOP-like regimen combined with rituximab is a standard chemotherapy for diffuse large B-cell lymphoma (DLBCL). The relative dose intensity (RDI) was proposed as an index of the dose and administration interval of agents. Previous studies reported that the maintenance of the RDI during CHOP therapy improved the treatment results. However, few studies regarding RDI have reviewed patients receiving combination therapy with CHOP and rituximab. We investigated the influence of RDI maintenance, involving combination therapy with rituximab, on therapeutic effects in patients with DLBCL. We retrospectively examined 152 DLBCL patients who were treated with CHOP-like regimen combined with rituximab in whom the RDI could be followed up. Multivariate analysis revealed that international prognosis index (IPI) high intermediate-high (HI-H) (p = 0.005) and RDI of less than 70% (p = 0.007) were independent prognostic factors for low progression free survival. Concerning overall survival, IPI HI-H (p = 0.027) and an RDI of less than 70% (p = 0.002) were involved in an unfavorable prognosis. In addition, age over 60 years (p = 0.003), R-THPCOP (p = 0.034), or the presence of febrile neutropenia (p = 0.004) made RDI maintenance difficult, and prophylactic G-CSF therapy (p = 0.026) was useful for maintaining the RDI. Maintaining the RDI is important even in the era of rituximab-combined chemotherapy for DLBCL.     

Low absolute lymphocyte count is a poor prognostic marker in patients with diffuse large B-cell lymphoma and suggests patients' survival benefit from rituximab

Objectives: To evaluate the prognostic value of absolute lymphocyte count (ALC) at diagnosis in patients with diffuse large B‐cell lymphoma (DLBCL). Methods: In a large cohort of patients with DLBCL treated with CHOP (n = 119) or RCHOP (n = 102) in our institution, we evaluated the prognostic value of ALC at diagnosis with regards to treatment response, overall (OS) and progression‐free survival (PFS). Use of rituximab, all International Prognostic Index (IPI) determinants, β2microglobulin level, presence of B symptoms or bulky disease, and ALC were evaluated. Results: Low ALC (<1.0 × 10⁹/L) was associated with advanced stage, performance status ≥2, elevated lactate dehydrogenase, number of extranodal involvement ≥2, B symptoms, elevated β2microglobulin and higher IPI risk group. Low ALC was associated with lower CR rate by univariate analysis (odds ratio = 3.29, P = 0.024) but not by multivariate analysis. By univariate analysis using Cox proportional hazard model, low ALC was associated with shorter OS [hazard ratio (HR) = 2.89, P < 0.001] and PFS (HR = 2.91, P < 0.001). Multivariate analysis revealed that low ALC was associated with shorter OS (HR = 2.51, P = 0.003) and PFS (HR = 2.72, P < 0.001), independent of above‐mentioned parameters. Subclass analyses revealed that the use of rituximab improves OS in patients with low ALC (HR = 0.42, P = 0.05) but not in those with high ALC (HR = 0.83, P = 0.71). This observation was most obvious in patients with higher IPI score. Conclusion: Low ALC is a poor prognostic marker in patients with DLBCL and suggests patients’ survival benefit from rituximab.