Response‐adapted therapy for aggressive non‐Hodgkin's lymphomas based on early [18F] FDG‐PET scanning: ECOG‐ACRIN Cancer Research Group study (E3404)

A persistently positive positron emission tomography (PET) scan during therapy for diffuse large B‐cell lymphoma (DLBCL) is predictive of treatment failure. A response‐adapted strategy consisting of an early treatment change to four cycles of R‐ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET‐positive patients received four cycles of R‐ICE, PET‐negative patients received two more cycles of R‐CHOP. A ≥45% 2‐year progression‐free survival (PFS) for mid‐treatment PET‐positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two‐year PFS was 70%; 42% [90% confidence interval (CI), 19–63%] for PET‐positives and 76% (90% CI 65–84%) for PET‐negatives. Three‐year overall survival (OS) was 69% (90% CI 43–85%) and 93% (90% CI 86–97%) for PET‐positive and ‐negative cases, respectively. The 2‐year PFS for mid‐treatment PET‐positive patients intensified to R‐ICE was 42%, with a wide confidence interval due to the low proportion of positive mid‐treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials.     

Ki‐67 expression as a prognostic factor in diffuse large B‐cell lymphoma patients treated with rituximab plus CHOP

Background: Assessment of tumor cell proliferation based on Ki‐67 expression yielded conflicting prognostic predictions of patients with diffuse large B‐cell lymphoma (DLBCL). The introduction of rituximab to the DLBCL treatment regime has led to alterations in the significance of previous prognostic factors. Methods: We analyzed Ki‐67 expression and its correlation with prognosis in 144 patients with DLBCL treated with rituximab plus CHOP (R‐CHOP) between July 2003 and January 2008. Results: The complete response (CR) rates following R‐CHOP administration were not significantly different, based on Ki‐67 expression status (P = 0.104). However, higher rates of relapse were observed in the high Ki‐67 expression group (Ki‐67 ≥ 85%, n = 46) with 25.0%, compared to 10.0% in the low Ki‐67 expression group (Ki‐67 < 85%, n = 88) (P = 0.040). The 2‐yr event‐free survival (EFS) rates were 44.3% and 74.1% in the high and low Ki‐67 expression groups, respectively (P = 0.011). The 2‐yr overall survival (OS) rate was 66.4% in the high Ki‐67 expression group and 82.2% in the low Ki‐67 expression group (P = 0.016). In multivariate analysis, Ki‐67 expression was a significant prognostic factor for EFS [hazard ratio (HR) = 2.909; 95% confidence interval (CI) 1.261–6.708; P = 0.012]. Ki‐67 was associated with OS but with borderline significance (HR = 2.876; 95% CI, 0.972–8.508; P = 0.056). Conclusion: Elevated Ki‐67 expression seems to be associated with higher relapse after CR and inferior EFS in patients with DLBCL treated with R‐CHOP.     

Serum concentration of L‐kynurenine predicts the clinical outcome of patients with diffuse large B‐cell lymphoma treated with R‐CHOP

Purpose: Introduction of rituximab has largely improved the prognosis of patients with diffuse large B‐cell lymphoma(DLBCL). Such change in therapeutic outcome necessitates the identification of additional prognostic factors to conventional indexes that have been validated for CHOP without rituximab. Indoleamine 2,3‐dioxygenase (IDO) exerts intense immunomodulatory effects because of enzymatic activities that catalyze the breakdown of the essential amino acid L‐tryptophan. The activity of IDO can be estimated by measuring the serum concentration of L ‐kynurenine. Here, we investigated the role of L ‐kynurenine as a prognostic marker in R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) therapy. Experimental design: Data from 73 consecutive patients treated with eight cycles of R‐CHOP or R‐THP (tetrahydropyranyl adriamycin)‐COP between December 2002 and March 2007 were analyzed. L ‐kynurenine concentrations in serum samples obtained at admission were measured by high‐performance liquid chromatography. Results: The median serum L ‐kynurenine level was 1.575 μm (range 0.537–9.588). The complete response (CR) rates of patients with L ‐kynurenine <1.5 and ≥1.5 μm were 83% and 61%, respectively (P < 0.05). The three‐yr overall survival (OS) rates for patients with L ‐kynurenine <1.5 and ≥1.5 μm were 89% and 58%, respectively (P < 0.005). In addition, higher age, poor performance status, elevated serum lactate dehydrogenase, and unfavorable as well as revised International Prognosis Index were significantly worse factors for CR rate and OS. Multivariate analyses revealed only L ‐kynurenine as an independent prognostic factor for OS. Conclusions: Serum L ‐kynurenine might be a novel prognostic factor to determine the treatment outcome of DLBCL with the R‐CHOP regimen.     

Impact of comorbidities on outcomes of elderly patients with diffuse large B‐cell lymphoma

International prognostic index (IPI) has remained the primary prognostic tool in diffuse large B cell lymphoma (DLBCL) for more than 20 years. Even though the disease is more common in older population, the impact of comorbidities, dose reductions, and treatment‐related adverse events (TAEs) on the outcome in elderly DLBCL patients has not been well established. We studied 413 consecutive patients aged ≥ 60 years who were treated at the Cleveland Clinic. The median age at diagnosis was 69 years, 58% of patients had high IPI score, and 85% had low Charlson comorbidity index (CCI). Forty percent of patients required dose reductions during treatment, 78% achieved CR, and 70% experienced at least one grade II‐IV TAE. High IPI score, high CCI, reduced dose chemotherapy, TAE, and hospitalization were significant predictors of death and relapse. In multivariable analysis, high IPI and CCI were independent predictors of overall and progression free survival. A simple model combining IPI and CCI could reliably distinguish three prognostically separate risk groups. Our results suggest that incorporation of CCI in current prognostic models can improve prognostication of older DLBCL patients and CCI might be a valuable tool in evaluating the eligibility of older patients for clinical trial enrollment.     

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.     

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.     

Prognostic value of complete remission status at end‐of‐treatment FDG‐PET in R‐CHOP‐treated diffuse large B‐cell lymphoma: systematic review and meta‐analysis

This study systematically reviewed and meta‐analysed the prognostic value of complete remission status at end‐of‐treatment ¹⁸F‐fluoro‐2‐deoxy‐d ‐glucose positron emission tomography (FDG‐PET) in diffuse large B‐cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP). The systematic PubMed/MEDLINE search yielded seven suitable studies comprising a total of 737 R‐CHOP‐treated DLBCL patients who were in complete remission at end‐of‐treatment FDG‐PET. Overall, the methodological quality of included studies was reasonable. The disease relapse rate among all patients with complete remission status according to end‐of‐treatment FDG‐PET ranged from 7·0% to 20·0%, with a weighted summary proportion of 13·7%. Five of seven studies reported progression‐free survival (PFS) of these patients at various specific time points, i.e., 2‐year PFS (n = 1), estimated 3‐year PFS (n = 3) and 5‐year PFS (n = 1), which was 83%, 85–86·4% and 75%, respectively. Three of seven studies reported overall survival (OS) of these patients at various specific time points, i.e., estimated 3‐year OS (n = 2) and estimated 5‐year OS (n = 1), which were 90%, 93·6% and 83%, respectively. In conclusion, a non‐negligible proportion of R‐CHOP‐treated DLBCL patients who achieve complete remission according to end‐of‐treatment FDG‐PET experiences disease relapse during follow‐up.     

A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B‐cell lymphoma

Bendamustine in combination with rituximab (BR) has been associated with high response rates and acceptable toxicity in older patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL). Evaluation of BR is warranted in the front‐line setting for DLBCL patients not eligible for anthracyclines or for the elderly. In this phase II study, we enrolled DLBCL patients aged ≥65 years who were poor candidates for R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to determine the efficacy and safety of BR in previously untreated stage II–IV DLBCL. Twenty‐three patients were enrolled with a median age of 80 years. 52% of patients presented with poor functional status (Eastern Cooperative Oncology Group performance score of ≥2). The overall response rate was 78% with 12 complete responses (52%). At a median follow up of 29 months, the median overall survival was 10·2 months and the median progression‐free survival was 5·4 months. The most common grade 3/4 adverse events were haematological. Combination therapy with BR demonstrates high response rates as front‐line therapy in frail older patients with DLBCL, but survival rates were low. BR should be used with caution in future clinical trials involving older DLBCL patients with poor functional status.     

R‐CHOP therapy alone in limited stage diffuse large B‐cell lymphoma

Long‐term observation has identified a pattern of continuing relapse in limited stage diffuse large B‐cell lymphoma (DLBCL) treated by three cycles of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved‐field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R‐CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full‐dose R‐CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R‐CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5‐year progression‐free survival and 5‐year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the ‘standard’ strategy of three cycles of R‐CHOP followed by involved‐field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R‐CHOP alone.     

Treatment of diffuse large B‐cell lymphoma with secondary central nervous system involvement: encouraging efficacy using CNS‐penetrating R‐IDARAM chemotherapy

Diffuse large B‐cell lymphoma with secondary involvement of the central nervous system (SCNS‐DLBCL) is a rare condition carrying a poor prognosis. No optimal therapeutic regimen has been identified. We retrospectively analysed 23 patients with SCNS‐DLBCL treated with R‐IDARAM (rituximab 375 mg/m² IV day 1; methotrexate 12·5 mg by intrathecal injection day 1; idarubicin 10 mg/m²/day IV days 1 and 2; dexamethasone 100 mg/day IV infusion over 12 h days 1–3; cytosine arabinoside 1000 mg/m²/day IV over 1 h days 1 and 2; and methotrexate 2000 mg/m² IV over 2 h day 3. Ten out of 23 (44%) patients had CNS involvement at initial presentation (‘new disease’), 10/23 (44%) had relapsed disease and 3/23 (13%) had primary refractory disease. 14/23 (61%) of patients responded ‐ 6 (26%) complete response, 8 (35%) partial response. Grade 3–4 haematological toxicity was seen in all cycles, with no grade 3–4 or long‐term neurological toxicity. Median follow‐up for surviving patients was 49 months. At 2 years, estimated progression‐free survival (PFS) was 39% and overall survival (OS) was 52%. Encouraging outcomes were reported in patients with new disease, with 5‐year estimated PFS of 50% and OS 75%. R‐IDARAM is a well‐tolerated regimen with encouraging efficacy in patients with SCNS‐DLBCL, although patients with relapsed or refractory disease continue to fare poorly.     

R‐CHOP versus dose‐adjusted R‐EPOCH in frontline management of primary mediastinal B‐cell lymphoma: a multi‐centre analysis

Primary mediastinal (thymic) large B‐cell lymphoma (PMBCL) is an uncommon subtype of non‐Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose‐adjusted (DA) R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R‐CHOP versus DA‐R‐EPOCH. 132 patients were identified from 11 contributing centres (56 R‐CHOP and 76 DA‐R‐EPOCH). The primary outcome was overall survival. Secondary outcomes included progression‐free survival, complete response (CR) rate, and rates of treatment‐related complications. Demographic characteristics were similar in both groups. DA‐R‐EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA‐R‐EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA‐R‐EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment‐related toxicities. At 2 years, 89% of R‐CHOP patients and 91% of DA‐R‐EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R‐CHOP to DA‐R‐EPOCH for PMBCL.     

Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo®) substituted for non‐liposomal vincristine in cyclophosphamide,doxorubicin, vincristine,prednisone with or without rituximab for patients with untreated aggressive non‐Hodgkin lymphomas

Vincristine sulfate liposome injection (VSLI; Marqibo^®; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m² without dose cap) substituted for non‐liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non‐Hodgkin lymphoma patients, including 60 with diffuse large B‐cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression‐free survival (PFS) and overall survival (OS) were not reached at median follow‐up of 8 and 10·2 years, respectively. The 5‐ and 10‐year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R‐CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R‐CHMP versus R‐CHOP in elderly patients with untreated DLBCL is ongoing.     

Prospective phase II study of rituximab with alternating cycles of hyper‐CVAD and high‐dose methotrexate with cytarabine for young patients with high‐risk diffuse large B‐cell lymphoma

We conducted a prospective randomized phase II study to evaluate two chemotherapy regimens: (i) rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R‐HCVAD) alternating with rituximab, high‐dose methotrexate, and cytarabine (R‐MA) and (ii) rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) in diffuse large B‐cell lymphoma (DLBCL). This study randomized patients aged ≤60 years with DLBCL and an age‐adjusted international prognostic index ≥2 to R‐HCVAD/R‐MA or R‐CHOP based on a Bayesian adaptive algorithm. Interim analysis of the first 26 eligible patients showed that the complete response rate (CRR) was higher with R‐HCVAD/R‐MA than R‐CHOP (P = 0·03); thus, R‐CHOP arm was closed. In the final analysis, 49 and 10 eligible patients were treated in R‐HCVAD/R‐MA and R‐CHOP arms respectively; CRR were 82% and 60% respectively (P = 0·13); 3‐year progression‐free survival (PFS) rates were 75·7% and 77·8% respectively (P = 0·53). In the R‐HCVAD/R‐MA arm, 3‐year PFS rates in patients aged 46–60 years and ≤45 years were 70·3% and 87·1% respectively (P = 0·13), and the treatment‐associated early mortality rate in patients >45 years was 12%. In conclusion, R‐HCVAD/R‐MA is associated with excellent outcome in patients ≤45 years old. However, in patients >45 years old, R‐HCVAD/R‐MA is associated with unacceptable mortality rates.     

Weekly rituximab consolidation following four cycles of R‐CHOP induction chemotherapy in very elderly patients with diffuse large B‐cell lymphoma: Consortium for improving survival of lymphoma study (CISL)

This study aimed to determine the objective response, toxicity, and clinical outcome of weekly rituximab consolidation after four cycles of R‐CHOP21 in very elderly patients with DLBCL. A prospective, multi‐institutional phase II trial was conducted on patients with previously untreated CD20⁺ DLBCL who were older than 70 yr. Patients were treated with four cycles of R‐CHOP21 followed by weekly consolidation with rituximab (375mg/m², four times infusion) (NCT01181999). We also compared the clinical outcomes with an historical case‐matched control group treated conventionally with six cycles of R‐CHOP21. A total of 51 patients with newly diagnosed DLBCL were enrolled at 15 institutes between June 2010 and September 2013 . The median age was 76 yr (range: 70–89). Forty‐one of the 51 patients completed the planned rituximab consolidation (R‐consolidation). The overall response rate was 78.4%, comprising 74.5% with a complete response and 3.9% with a partial response. After a median follow‐up of 20.3 months, 2‐yr progression‐free survival and overall survival were 63.9% and 68.7%, respectively. No serious toxicities were reported during rituximab consolidation. Weekly rituximab consolidation following four cycles of R‐CHOP21 resulted in an acceptable response with high tolerability and could be a good compromise between efficacy and safety for elderly patients with DLBCL.     

Chemotherapeutic intensity and survival differences in young patients with diffuse large B‐cell lymphoma: a Swedish Lymphoma Registry study

Young patients with diffuse large B‐cell lymphoma (DLBCL) are variably treated with rituximab combined with cyclophosphamide‐doxorubicin‐vincristine‐prednisone (R‐CHOP), CHOP‐etoposide (R‐CHOEP), and anthracycline‐based regimens with the addition of high‐dose cytarabine/methotrexate (R‐HDA/M). Using the nationwide, population‐based Swedish Lymphoma Registry, we evaluated outcome, by treatment and Healthcare Region, in all 751 DLBCL patients aged ≤60 years without central nervous involvement, diagnosed in Sweden between 2007 and 2012. Overall survival was estimated using multivariate Cox analysis. In patients with age‐adjusted international prognostic index (aaIPI) ≥ 2, the 5‐year overall survival (OS) was 70%, 76% and 85% after R‐CHOP, R‐CHOEP and R‐HDA/M, respectively (P = 0·002); the corresponding estimates were 40%, 55%, and 92% in aaIPI = 3 (P = 0·014). There were large therapeutic differences between Sweden's six Healthcare Regions for aaIPI ≥ 2: three were “Moderate” (more R‐CHOP) and three “Intensive” (more R‐CHOEP and R‐HDA/M). Patients with aaIPI ≥ 2 who were treated in the Intensive Regions, showed better OS (P < 0·00005), particularly those with aaIPI = 3 (5‐year OS, 62% vs. 30%; P < 0·00005). There were no regional differences in therapy or survival in patients with aaIPI < 2. We conclude that in younger high‐risk patients, survival appears superior after more intensive therapy than R‐CHOP.     

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.     

Impact of rituximab on treatment outcomes of patients with diffuse large b-cell lymphoma: a population-based analysis

We conducted a multi-institutional population-based analysis of the survival and toxicity associated with the addition of rituximab to chemotherapy for patients with diffuse large B-cell lymphoma (DLBCL), including patients aged ≥ 80 years, who were excluded from published randomized trials. Using population-based registries in Ontario, we identified 4021 patients who received chemotherapy with or without rituximab (R-CHOP [rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone] or CHOP) for DLBCL between 1996 and 2007, including 397 patients aged ≥ 80 years. After propensity score matching, the overall survival (OS) and significant toxicities for R-CHOP and CHOP treatment groups were compared. R-CHOP was associated with a significant increase in 5-year OS compared to CHOP alone (62% vs. 54%; hazard of death = 0·78, P = 0·0004). Survival benefit was seen in all age groups, including those aged ≥ 80 years. Patients treated with rituximab did not have a significant increase in 1-year hospitalization rates for cardiac, pulmonary, gastrointestinal or neurological diagnoses compared to those treated with CHOP alone. The addition of rituximab to CHOP improves survival in the general population of patients with DLBCL and produces early survival benefit for very elderly patients, without any significant increase in the risk of serious toxicity.     

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.     

Analysis of very elderly (≥80 years) non-hodgkin lymphoma: impact of functional status and co-morbidities on outcome

Data on outcome, prognostic factors, and treatment for very elderly non‐Hodgkin lymphomas (NHL) is sparse. We conducted a multicentre retrospective analysis of NHL patients ≥80 years (at diagnosis) treated between 1999 and 2009. Detailed characteristics were obtained including geriatric syndromes, activities of daily living (ADLs), and co‐morbidities using the Cumulative Illness Rating Scale‐Geriatrics (CIRS‐G). We identified 303 patients: 170 aggressive NHL (84% B cell/16% T cell) and 133 indolent NHL (82% B cell/18% T cell). Median age was 84 years (80–95). A geriatric syndrome was present in 26% of patients, 18% had ≥1 grade 4 CIRS‐G, and 14% had loss of ADLs. At 49‐month median follow‐up, 4‐year progression‐free (PFS) and overall survival (OS) for aggressive NHLs were 31% and 44% respectively (stage I/II: PFS 53% and OS 66%; stage III/IV: PFS 20% and OS 32%; P < 0·0001 and 0·0002, respectively). Four‐year PFS and OS for indolent NHL were 44% and 66% respectively, regardless of stage. Multivariate regression analysis identified two key factors that predicted inferior PFS and OS for both NHL groups: lack of CR and loss of ADLs. Prospective studies for very elderly NHL that incorporate geriatric tools, especially ADLs, are warranted.     

High Ki-67 expression in diffuse large B-cell lymphoma patients with non-germinal center subtype indicates limited survival benefit from R-CHOP therapy

Objectives: Rituximab has significantly improved the survival of patients with DLBCL, especially those with non‐germinal center B‐cell‐like (non‐GCB) subtype. The impact of Ki‐67 expression, an index of proliferation, on the clinical outcomes of patients with DLBCL has largely been unexplored. This study aimed to investigate whether Ki‐67 expression is an indicator of outcome in DLBCL patients (especially non‐GCB DLBCL patients) treated with standard chemotherapy combined with rituximab. Methods: Expression of Ki‐67 protein was examined immunohistochemically in 118 tumor specimens from patients newly diagnosed with DLBCL and treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Results: Overall survival (OS) and progression‐free survival (PFS) were lower in patients with high Ki‐67 expression than in those with low Ki‐67 expression (3‐year OS: 65.2% vs. 81.7%, P = 0.030; 3‐year PFS: 56.4% vs. 73.3%, P = 0.020), similar in patients with GCB subtype and those with the non‐GCB subtype (OS: P = 0.330; PFS: P = 0.287). According to Ki‐67 expression status by immunophenotype subgroups, patients with high Ki‐67 expression in non‐GCB subgroup had the most unfavorable PFS and OS, comparing with the other three subgroups (P = 0.004 and P = 0.002, respectively). In multivariate analysis, non‐GCB with high Ki‐67 expression was an independent prognostic predictor of inferior survival in DLBCL patients treated with R‐CHOP. Conclusion: For DLBCL patients with non‐GCB DLBCL and high Ki‐67 expression, the survival benefit from R‐CHOP therapy is limited.