Front‐line,dose‐escalated immunochemotherapy is associated with a significant progression‐free survival advantage in patients with double‐hit lymphomas: a systematic review and meta‐analysis

‘Double‐hit lymphomas’ (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard‐risk, diffuse large B‐cell lymphomas (DLBCL). Consequently, dose‐intensive (DI) therapies and/or consolidation with high‐dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta‐analysis compared survival outcomes in DHL patients receiving dose‐escalated regimens [DI: R‐Hyper‐CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R‐CODOX‐M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate‐dose: R‐EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard‐dose regimens (R‐CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first‐line setting. Data were synthesized to estimate hazard ratios of dose‐escalated treatments versus R‐CHOP using a Weibull proportional hazards model within a Bayesian meta‐analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front‐line R‐CHOP (n = 180), R‐EPOCH (n = 91), or R‐Hyper‐CVAD/rituximab, methotrexate, cytarabine (R‐M/C), R‐CODOX‐M/R‐IVAC (DI) (n = 123). Our meta‐analysis revealed that median progression‐free survival (n = 350) for the R‐CHOP, R‐EPOCH and DI groups was 12·1, 22·2, and 18·9 months, respectively. First‐line treatment with R‐EPOCH significantly reduced the risk of a progression compared with R‐CHOP (relative risk reduction of 34%; P = 0·032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary.     

Rituximab,cyclophosphamide, doxorubicin,vincristine and prednisolone (R‐CHOP) in the management of primary mediastinal B‐cell lymphoma: a subgroup analysis of the UK NCRI R‐CHOP 14 versus 21 trial

We performed a subgroup analysis of the phase III UK National Cancer Research Institute R‐CHOP‐14 versus R‐CHOP‐21 (two‐ versus three‐weekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) trial to evaluate the outcomes for 50 patients with World Health Organization 2008 classified primary mediastinal B‐cell lymphoma identified from the trial database. At a median follow‐up of 7·2 years the 5‐year progression‐free survival and overall survival was 79·8% and 83·8%, respectively. An exploratory analysis raised the possibility of a better outcome in those who received R‐CHOP‐14 and time intensification may still, in the rituximab era, merit testing in a randomised trial in this subgroup of patients.     

Long‐term follow‐up of dose‐adjusted EPOCH plus rituximab (DA‐EPOCH‐R) in untreated patients with poor prognosis large B‐cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group

This prospective multi‐institutional phase II study was designed to assess the efficacy and safety of dose‐adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab (DA‐EPOCH‐R) in untreated patients with poor prognosis large B‐cell lymphomas. Eighty‐one patients diagnosed with diffuse large B‐cell lymphoma (DLBCL, n = 68), primary mediastinal DLBCL (n = 6) and follicular lymphoma Grade 3b (n = 7), with an age‐adjusted International Prognostic Index >1, were eligible for analysis. Median age was 60 years (range: 21–77). Sixty‐five patients (80·2%) achieved complete response. After a median follow‐up time of 64 months, 10‐year event‐free survival and overall survival (OS) were 47·8% and 63·6%, respectively. None of the studied clinical and biological characteristics were associated with poorer outcome. Interestingly, patients with BCL6 rearrangement achieved a 10‐year OS of 100%, while patients with BCL2 rearrangement exhibited a poorer outcome compared to activated B‐cell tumours and germinal centre B‐cell without BCL2 rearranged tumours. Results achieved with DA‐EPOCH‐R showed a good long‐term outcome and a tolerable toxicity profile in high‐risk large B cell lymphoma patients. Outcome was not affected by tumour cell proliferation or by cell of origin, highlighting the requirement of new biological markers for patient subclassification of high‐risk DLBCL patients.     

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.     

Double hit lymphoma: the MD Anderson Cancer Center clinical experience

We report our experience with 129 cases of double hit lymphoma (DHL), defined as B‐cell lymphoma with translocations and/or extra signals involving MYC plus BCL2 and/or BCL6. All cases were reviewed for histopathological classification. Median age was 62 years (range, 18–85), 84% of patients had advanced‐stage disease, and 87% had an International Prognostic Index score ≥2. Fourteen patients (11%) had a history of low‐grade follicular lymphoma. MYC translocation was present in 81%, and extra signals of MYC in 25% of patients. IGH‐BCL2 translocation was present in 84% and extra signals of BCL2 in 12% of patients. Two‐year event‐free survival (EFS) rates in all patients and patients who received R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R‐HyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate) were 33%, 25%, 67% and 32%, respectively. In patients achieving complete response with initial therapy (n = 71), 2‐year EFS rates in patients who did (n = 23) or did not (n = 48) receive frontline stem cell transplantation were 68% and 53%, respectively (P = 0·155). The cumulative incidence of central nervous system involvement was 13% at 3 years. Multivariate analysis identified performance status ≥2 and bone marrow involvement as independent adverse prognostic factors for EFS and OS. Further research is needed to identify predictive and/or targetable biological markers and novel therapeutic approaches for DHL patients.     

Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B‐cell lymphoma: Characteristics,outcomes, and prognostication among a large multicenter cohort

Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B‐cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease (MGZL). We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients recently treated across 19 North American centers. Forty‐three percent of patients presented with MGZL, whereas 57% had non‐MGZL (NMGZL). NMGZL patients were older (50 versus 37 years, P = 0.0001); more often had bone marrow involvement (19% versus 0%, P = 0.001); >1 extranodal site (27% versus 8%, P = 0.014); and advanced stage disease (81% versus 13%, P = 0.0001); but they had less bulk (8% versus 44%, P = 0.0001), compared with MGZL patients. Common frontline treatments were cyclophosphamide‐doxorubicin‐vincristine‐prednisone +/? rituximab (CHOP+/?R) 46%, doxorubicin‐bleomycin‐vinblastine‐dacarbazine +/? rituximab (ABVD+/?R) 30%, and dose‐adjusted etoposide‐doxorubicin‐cyclophosphamide‐vincristine‐prednisone‐rituximab (DA‐EPOCH‐R) 10%. Overall and complete response rates for all patients were 71% and 59%, respectively; 33% had primary refractory disease. At 31‐month median follow‐up, 2‐year progression‐free survival (PFS) and overall survival rates were 40% and 88%, respectively. Interestingly, outcomes in MGZL patients seemed similar compared with that of NMGZL patients. On multivariable analyses, performance status and stage were highly prognostic for survival for all patients. Additionally, patients treated with ABVD+/?R had markedly inferior 2‐year PFS (22% versus 52%, P = 0.03) compared with DLBCL‐directed therapy (CHOP+/?R and DA‐EPOCH‐R), which persisted on Cox regression (hazard ratio, 1.88; 95% confidence interval, 1.03–3.83; P = 0.04). Furthermore, rituximab was associated with improved PFS on multivariable analyses (hazard ratio, 0.35; 95% confidence interval, 0.18–0.69; P = 0.002). Collectively, GZL is a heterogeneous and likely more common entity and often with nonmediastinal presentation, whereas outcomes seem superior when treated with a rituximab‐based, DLBCL‐specific regimen. Am. J. Hematol. 90:778–783, 2015. © 2015 Wiley Periodicals, Inc.     

Four doses of unpegylated versus one dose of pegylated filgrastim as supportive therapy in R‐CHOP‐14 for elderly patients with diffuse large B‐cell lymphoma

The primary objective of this prospective, randomized study was to compare the efficacy of a reduced regimen of only four doses of unpegylated filgrastim from day +8 to +11 per cycle with a standard once per cycle administration of pegylated filgrastim to maintain dose‐intensity of R‐CHOP‐14 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone given every 14 d) in previously untreated elderly patients with diffuse large B‐cell lymphoma (DLBCL). We included 51 patients (median age 66 years, range 60–76). Median dose intensity did not differ between the group of 24 patients receiving four doses of unpegylated filgrastim of each cycle (87·5%) and the group of 27 patients receiving pegylated filgrastim once per cycle on day 2 (89·4%) (P = 0·9). There was also no difference in the frequency of adverse events, such as episodes of neutropenic fever and unplanned hospitalizations. Patient characteristics that negatively influenced dose intensity were reduced performance status, advanced stage disease and poor‐risk International Prognostic Index, with Eastern Cooperative Oncology Group performance status ≥2 being the most significant factor. In conclusion, a limited support with 4 d of filgrastim appears to be equivalent to pegylated filgrastim administered once per cycle, and appears to be sufficient to maintain dose‐intensity of the R‐CHOP‐14 regimen in elderly patients with DLBCL without risk factors.     

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.     

Improved treatment outcome of primary mediastinal large B-cell lymphoma after introduction of rituximab in Korean patients

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) improved the outcome of patients with diffuse large B-cell lymphoma (DLBCL). However, the impact of rituximab (R-CHOP) is still not determined in primary mediastinal large B-cell lymphoma (PMBCL), a subtype of DLBCL, especially in Asian patients. Thus, we analyzed the treatment outcome of PMBCL patients (n = 21) treated with R-CHOP and compared it with the historical group treated with CHOP (n = 14). The rate of complete response for R-CHOP was higher than that of CHOP (17/21, 81.0% vs. 8/14, 57.2%), although the difference was not statistically significant (P = 0.151). The number of patients with disease progression or relapse was higher in the CHOP group (6/14, 42.9%) than the R-CHOP group (2/21, 9.5%). Thus, patients treated with R-CHOP had higher 2-year progression-free survival (79.0%) than those treated with CHOP (50.0%, P = 0.043). Although the 2-year overall survival of the R-CHOP was also superior to that of the CHOP group (82.7% vs. 57.1%), this survival benefit did not reach statistical significance (P = 0.081). In conclusion, our comparison suggests that R-CHOP may increase response and reduce relapse resulting in prolongation of progression-free survival of patients with PMBCL.     

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.     

Obesity negatively impacts outcome in elderly female patients with aggressive B‐cell lymphomas treated with R‐CHOP: results from prospective trials of the German high grade non‐Hodgkin's lymphoma trial group

To study if obesity is a risk factor in elderly patients (>60 years) with aggressive B‐cell lymphoma, the outcomes of 576 elderly patients treated with rituximab in the RICOVER‐60 trial were analysed in a retrospective study with regard to body mass index (BMI) and gender. Of the 576 patients, 1% had low body weight (BMI < 18·5), 38% were normal weight (18·5 ≤ BMI < 25), 42% were overweight (25 ≤ BMI < 30) and 19% were obese (BMI ≥ 30). Event‐free (EFS), progression‐free (PFS) and overall survival (OS) according to BMI showed no significant differences for all and for male patients. EFS (P = 0·041), PFS (P = 0·038) and OS (P = 0·031) were significantly better for female non‐obese patients. A multivariate analysis adjusted for International Prognostic Index risk factors confirmed these results, with the following hazard ratios (HR) for obesity (BMI ≥ 30) for EFS/PFS/OS: all patients – 1·4/1·4/1·4 (not significant); male patients – 1·2/1·2/1·0 (not significant) and female patients – 1·7 (P = 0·032)/1·9 (P = 0·022)/2·0 (P = 0·017). In conclusion, obesity is a risk factor that influences treatment outcome in elderly female patients with aggressive B‐cell lymphoma treated with R‐CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisolone). The inferior outcomes in obese female patients may be due to faster rituximab clearance in obese females.     

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.     

MYC and BCL2 protein expression predicts survival in patients with diffuse large B‐cell lymphoma treated with rituximab

Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disease and “double‐hit” DLBCL, with both MYC and BCL2 translocations has a poor prognosis. In this study, we investigated whether MYC and BCL2 protein expression in tissue would predict survival in DLBCL. The study included 106 cases of de novo DLBCL treated with rituximab and cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) or CHOP‐like regimens. The results were validated on an independent cohort of 205 DLBCL patients. Patients with low expression of BCL2 (≤30%) and MYC (≤50%) had the best prognosis, whereas those with high BCL2 (>30%) and MYC (>50%) had the worst outcome. In multivariate analysis, the combination of the BCL2 and MYC was an independent predictor of overall survival (OS) and event‐free survival (EFS) (P = 0·015 and P = 0·005, respectively). The risk of death was nine times greater for patients with high BCL2 and MYC compared to those with low expression. High BCL2 and MYC was a strong predictor of poor OS (P < 0·001) and EFS (P = 0·0017) in patients with the germinal centre B‐cell (GCB) type, but not in the non‐GCB type. In DLBCL, high co‐expression of MYC and BCL2 was an independent predictor of poor survival, and could be used to stratify patients for risk‐adapted therapies.     

Phase II trial of R‐CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601

Bortezomib is active in mantle cell lymphoma (MCL), with approval in upfront and relapsed settings. Given inevitable recurrence following induction chemoimmunotherapy, maintenance approaches are a rational strategy to improve clinical outcomes. We conducted a phase II study to evaluate the safety and efficacy of six cycles of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus bortezomib (1·3 mg/m² days 1 and 4 of 21 d cycles) followed by bortezomib maintenance (1·3 mg/m² days 1, 4, 8, and 11 every 3 months for 2 years). Sixty‐five eligible patients were enrolled. The treatment was well tolerated and toxicities were mainly haematological. The rate of grade ≥3 peripheral neuropathy was low (5%). With a median follow‐up of 6·8 years, 2‐year progression‐free survival (PFS) was 62%, and 2‐year overall survival (OS) was 85%. At 5 years, PFS was 28% and OS was 66%. MCL International Prognostic Index scores were significantly associated with 2‐year PFS, but did not predict long‐term (≥5‐year) PFS. Baseline Ki‐67 index was significantly associated with survival. Combination R‐CHOP with bortezomib followed by maintenance bortezomib appears to improve outcomes compared historically with R‐CHOP alone, with prolonged remissions in a subset of patients. These results suggest that inclusion of bortezomib with induction chemotherapy and/or maintenance is promising in MCL and warrants further exploration.     

CD30 expression in de novo diffuse large B‐cell lymphoma: a population‐based study from British Columbia

Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disease with variable therapeutic responses and alternative therapies are needed for patients with unfavourable treatment outcomes after standard treatment with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). One promising candidate is brentuximab vedotin, an antibody‐drug conjugate targeting CD30‐expressing cells. However, CD30 (TNFRSF8) expression patterns in DLBCL are not well described thus far. Here, we examined CD30 expression in a population‐based cohort of immunocompetent patients from British Columbia with de novo DLBCL using immunohistochemistry. 385 cases of formalin‐fixed paraffin‐embedded DLBCL in tissue microarrays were evaluated. 95 cases (25%) harboured CD30+ tumour cells. Using a > 0% cut‐off, CD30 expression was predictive of superior 5‐year progression‐free survival within R‐CHOP treated germinal centre B‐cell‐like (GCB) DLBCL (86% vs. 64%, P = 0·020), which was independent of the International Prognostic Index. Epstein‐Barr virus (EBV) was identified in 11 (3%) cases, all of which were non‐GCB (P = 0·001) and almost exclusively positive for CD30 expression (10/11) (P < 0·001). We conclude CD30 is expressed in a substantial proportion of DLBCL and CD30 immunohistochemistry may be a useful prognostic marker in R‐CHOP treated GCB‐DLBCL. The significant association of CD30 with EBV‐positive non‐GCB DLBCL suggests a distinct pathobiology for these cases.     

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.     

Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced‐dose ibrutinib: results from a multi‐centre study

Richter Syndrome, an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia (CLL), has a generally poor prognosis and anthracycline‐based chemoimmunotherapy regimens designed to treat de novo diffuse large B‐cell lymphoma achieve modest clinical benefit. R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) has demonstrated greater activity against aggressive B‐cell histologies but has not been studied in Richter Syndrome. We conducted a retrospective cohort study of 46 Richter Syndrome patients treated with first‐line R‐EPOCH at our institution between 1 January 2006 and 31 May 2014. The median progression‐free survival (PFS) was 3·5 months [95% confidence interval (CI): 2·0–7·6] and median overall survival (OS) was 5·9 months (95% CI: 3·2–10·3). Toxicity was high and 30% of patients died without progression or response. Patients with a complex CLL karyotype had significantly shorter PFS and OS (P = 0·005 and P = 0·002, respectively). Multivariable analysis identified complex CLL karyotype as the most significant predictor of decreased survival [Hazard ratio (HR) 2·72, 95% CI: 1·14–6·52, P = 0·025], adjusting for number of prior CLL treatments (P = 0·036). Richter Syndrome patients with complex CLL karyotype experience poor survival with R‐EPOCH treatment and novel approaches are needed for these patients. In contrast, survival of patients without a complex CLL karyotype was similar to patients with de novo diffuse large B‐cell lymphoma.     

The efficacy and safety of gemcitabine,cisplatin, prednisone,thalidomide versus CHOP in patients with newly diagnosed peripheral T‐cell lymphoma with analysis of biomarkers

We compared the efficacy and safety of gemcitabine, cisplatin, prednisone and thalidomide (GDPT) with standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) for patients with newly diagnosed peripheral T‐cell lymphoma (PTCL) in a prospective randomized controlled and open‐label clinical trial. Between July 2010 and June 2016, 103 patients were randomly allocated into two groups, of whom 52 were treated with GDPT therapy and 51 with CHOP therapy. The 2‐year progression‐free survival (PFS) and overall survival (OS) rates were better in the GDPT group than in the CHOP group (57% vs. 35% for 2‐year PFS, P = 0·0035; 71% vs 50% for 2‐year OS, P = 0·0001). The complete remission rate (CRR) and the overall response rate (ORR) in the GDPT group were higher than in the CHOP group (52% vs. 33%, P = 0·044 for CRR; 67% vs. 49%, P = 0·046 for ORR). Haemocytopenia was the predominant adverse effect, and acute toxicity was moderate, tolerable and well managed in both arms. mRNA expression of ERCC1, RRM1, TUBB3 and TOP2A genes varied among patients but the difference did not reach statistical significance, mainly due to the relatively small sample size. The precise characters of these biomarkers remain to be identified. In conclusion, GDPT is a promising new regimen as potential first‐line therapy against PTCL. This study was registered at www.clinicaltrials.gov as #NCT01664975.     

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.     

Favourable outcomes of poor prognosis diffuse large B‐cell lymphoma patients treated with dose‐dense Rituximab,high‐dose Methotrexate and six cycles of CHOP‐14 compared to first‐line autologous transplantation

The optimal therapeutic approach for young diffuse large B‐cell lymphoma (DLBCL) patients with high‐intermediate and high‐risk age‐adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10‐year single‐centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R‐CHOP‐21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first‐line high‐dose chemotherapy with autologous stem‐cell support (HDCT‐ASCT), resulting in 2‐year progression‐free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP‐14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose‐dense rituximab and high‐dose methotrexate resulting in promising overall response‐ (93·3%) and complete remission (90%) rates and sustained survival (2‐year PFS and OS: 93·3%). In an intention‐to‐treat analysis, 2‐year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox‐regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83–35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28–26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor‐prognosis DLBCL patients appears superior after early therapy intensification.