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.     

Guidelines for the management of diffuse large B‐cell lymphoma

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8–10 months. We conducted a phase II trial of standard CHOP‐21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2–6: 1000 mg day 1) (CHOP‐O) followed by 12 months ofatumumab maintenance (1000 mg given 8‐weekly for up to six cycles). Forty‐three patients were recruited of whom 37 were evaluable. Seventy‐three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide‐based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression‐free survival was 6·2 months (95% confidence interval [CI] 4·9–14·0 months) and median OS was 11·4 months (95% CI 6·4–25·6 months). Treatment‐naïve and TP53‐intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non‐neutropenic infections were observed. There were no treatment‐related deaths. Seven patients received platinum‐containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP‐O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.     

Bortezomib in combination with infusional dose‐adjusted EPOCH for the treatment of plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is a rare and aggressive CD20‐negative lymphoma. Despite improvements of the biology behind PBL, it still represents a challenge from the diagnostic and therapeutic perspectives for pathologists and clinicians. PBL is characterized by high rates of relapse and short median survival with standard approaches. Here, we report the use of the combination of bortezomib and infusional etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (V‐EPOCH) in three patients with PBL; two were HIV‐positive and one was HIV‐negative. All three patients obtained a durable complete response to V‐EPOCH with survival times of 24, 18 and 12 months respectively.     

High ten‐year remission rates following rituximab,fludarabine, mitoxantrone and dexamethasone (R‐FND) with interferon maintenance in indolent lymphoma: Results of a randomized Study

We report a single‐centre, randomized study evaluating the efficacy and safety of concurrent fludarabine, mitoxantrone, dexamethasone (FND ) and rituximab versus sequential FND followed by rituximab in 158 patients with advanced stage, previously untreated indolent lymphoma, enrolled between 1997 and 2002. Patients were randomized to 6–8 cycles of FND followed by 6 monthly doses of rituximab or 6 doses of rituximab given concurrently with FND . All patients who achieved at least a partial response received 12 months of interferon (IFN ) maintenance. Median ages were 54 and 55 years. The two groups were comparable with the exception of a higher percentage of females (65% vs. 43%) and baseline anaemia (23% vs. 11%) in the FND followed by rituximab group. Complete response/unconfirmed complete response rates were 89% and 93%. The most frequent grade ≥ 3 toxicity was neutropenia (86% vs. 96%). Neutropenic fever occurred in 21% and 16%. Late toxicity included myelodysplastic syndrome (n  = 3) and acute myeloid leukaemia (n  = 5). With 12·5 years of follow‐up, no significant differences based on treatment schedule were observed. 10‐year overall survival estimates were 76% and 73%. 10‐year progression‐free survival estimates were 52% and 51%. FND with concurrent or sequential rituximab, and IFN maintenance in indolent lymphoma demonstrated high response rates and robust survival.     

B‐cell lymphoma,unclassifiable, with features intermediate between diffuse large B‐cell lymphoma and burkitt lymphoma: study of 39 cases

B‐cell lymphoma, unclassifiable (B‐UCL), with features intermediate between diffuse large B‐cell lymphoma and Burkitt lymphoma, is a poorly characterized entity. Therefore, we investigated cases of B‐UCL treated by the Nebraska Lymphoma Study Group (NLSG). We searched the NLSG registry for years 1985–2010 for cases of B‐UCL. Immunohistochemical stains and fluorescence in situ hybridization studies for MYC, BCL2 and BCL6 gene rearrangements were performed. Among the 39 cases studied, 54% were male and 46% were female, with a median age of 69 years. The majority of patients presented with advanced‐stage disease (62%) and had high (3–5) International Prognostic Index (IPI) scores (54%). The median overall survival (OS) was only 9 months and the 5‐year OS was 30%. Patients with low IPI scores (0–2) had a better survival than those with high scores (3–5). The cases were genetically heterogeneous and included 11 ‘double‐hit’ lymphomas with rearrangements of both MYC and BCL2 or BCL6. None of the immunohistochemical or genetic features was predictive of survival. This B‐cell lymphoma is a morphologically‐recognizable entity with a spectrum of genetic abnormalities. New and better treatments are needed for this aggressive lymphoma.     

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.     

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.     

The anti‐lymphoma activity of antiviral therapy in HCV‐associated B‐cell non‐Hodgkin lymphomas: a meta‐analysis

Many epidemiological studies provide solid evidence for an association of chronic hepatitis C virus (HCV) infection with B‐cell non‐Hodgkin's lymphoma (B‐NHL). However, the most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B‐NHL regression after HCV eradication by antiviral therapy (AVT). We conducted a literature search to identify studies that included patients with HCV‐associated B‐NHL (HCV‐NHL) who received AVT, with the intention to treat lymphoma and viral disease at the same time. The primary end point was the correlation of sustained virological response (SVR) under AVT with lymphoma response. Secondary end points were overall lymphoma response rates and HCV‐NHL response in correlation with lymphoma subtypes. We included 20 studies that evaluated the efficacy of AVT in HCV‐NHL (n = 254 patients). Overall lymphoma response rate through AVT was 73% [95%>confidence interval, (CI) 67–78%]. Throughout studies there was a strong association between SVR and lymphoma response (83% response rate, 95%>CI, 76–88%) compared to a failure in achieving SVR (53% response rate, 95%>CI, 39–67%, P = 0.0002). There was a trend towards favourable response for AVT in HCV‐associated marginal zone lymphomas (response rate 81%, 95%>CI, 74–87%) compared to nonmarginal zone origin (response rate 71%, 95%>CI, 61–79%, P = 0.07). In conclusion, in the current meta‐analysis, the overall response rate of HCV‐NHL under AVT justifies the recommendation for AVT as first‐line treatment in patients who do not need immediate conventional treatment. The strong correlation of SVR and lymphoma regression supports the hypothesis of a causal relationship of HCV and lymphomagenesis.     

A phase II study of dose‐dense and dose‐intense ABVD (ABVDDD‐DI) without consolidation radiotherapy in patients with advanced Hodgkin lymphoma

We explored activity and safety of a dose‐dense/dose‐intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (ABVD_DD‐DI) in 82 patients with advanced Hodgkin Lymphoma. Patients entered a two‐stage Bryant‐Day Phase II study to receive six cycles of ABVD_DD‐DI without consolidation radiotherapy. Cycles were supported with granulocyte colony‐stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard ABVD except for doxorubicin (35 mg/m²; first four cycles only). Co‐primary endpoints were complete response (CR) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event‐free (EFS) and disease‐free survival (DFS). All patients received the four doxorubicin‐intensified courses and 96% concluded all six cycles (82·3% within the intended 18 weeks). This translated into a 66·9% increase of received dose‐intensity for doxorubicin and 31·8% for the other agents over standard ABVD. The CR rate was 95·1% (78/82) and 87·8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14·6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five‐year EFS and DFS was 88·3% and 93·7%, respectively. ABVD_DD‐DI regimen was well‐tolerated and ensured substantial CR and EFS rates without radiotherapy.     

Peripheral T‐cell lymphoma in HIV‐infected patients: a study of 17 cases in the combination antiretroviral therapy era

Most cases of human immunodeficiency virus (HIV)‐associated non‐Hodgkin Lymphoma (NHL) are of B‐cell origin; T‐cell NHLs are rarely reported. Within a single centre prospective cohort of 370 HIV‐NHL, 17 (5%) were of T‐cell origin (82% male; median age, 39 years). Median CD4+ cell count was 0·194 × 10⁹/l and 41% had undetectable plasma HIV‐RNA at lymphoma diagnosis. All patients received combination antiretroviral therapy during chemotherapy. All histological samples were centrally reviewed. The distribution of the histological subtypes differed from the general population with absence of angioimmunoblastic subtype. Lymphoma was disseminated in 14 patients, and seven patients had performance status >2. All patients received full‐dose chemotherapy: eight standard and nine intensive regimens. Two patients who received intensive chemotherapy died during therapy. The complete remission rate was 53%; 62·5% with standard therapy and 44% with intensive therapy. After a median follow‐up of 7·2 years, the median overall survival was 9·4 months. Most deaths (85%) occurred within the first year following diagnosis, as a consequence of lymphoma progression in 10/13 cases. In this rare but severe complication of HIV infection the use of intensive chemotherapy does not appear to be beneficial for response, with increased toxicity.     

A phase 2 study of inotuzumab ozogamicin in patients with indolent B‐cell non‐Hodgkin lymphoma refractory to rituximab alone,rituximab and chemotherapy,or radioimmunotherapy

This phase 2 study evaluated the efficacy and safety of inotuzumab ozogamicin (InO) in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL) refractory to rituximab alone, rituximab plus chemotherapy or anti‐CD20 radioimmunotherapy. Patients received InO 1·8 mg/m² intravenously on a 28‐d cycle for a planned 4–8 cycles. The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a complete response (CR). The primary endpoint was overall response. Eighty‐one patients were enrolled, among whom 48 (59%) received ≥3 InO cycles and 13 (16%) completed the treatment phase. The overall response rate was 67% (CR, 31%). Median (95% confidence interval) progression‐free survival was 12·7 (8·9–26·9) months; median overall survival was not reached. Haematological adverse events (AEs) were common, particularly thrombocytopenia (74%) and neutropenia (56%). These were also the most common AEs leading to treatment discontinuation (37% and 11%, respectively); 58% of patients reported AEs leading to treatment discontinuation. InO demonstrated robust activity in these heavily pretreated patients, although treatment duration was limited by haematological toxicities. Additional studies may determine dosing regimens that allow for reduced toxicity.