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Tyrosine kinase inhibitors (TKI) have changed the natural course of chronic myeloid leukemia (CML). With the advent of second-generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM). 1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years, 965 patients (64%) still received IM. At 10 years, progression-free survival was 82%, overall survival 84%, 59% achieved MR 5 , 72% MR 4.5 , 81% MR 4 , 89% major molecular remission and 92% MR 2 (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR 5 . Eight-year probabilities of adverse drug reactions (ADR) were 76%, of grades 3–4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800 mg and IM 400 mg+IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.

The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18–60 years were randomly assigned to receive either eight cycles of BEACOPPescalated (8×Besc group), six cycles of BEACOPPescalated (6×Besc group), or eight cycles of BEACOPP14 (8×B14 group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×Besc group, 711 in the 6×Besc group, and 710 in the 8×B14 group. Freedom from treatment failure was sequentially non-inferior for the 6×Besc and 8×B14 groups as compared with 8×Besc. 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0–87·7) for the 8×Besc group, 89·3% (86·5–92·1) for 6×Besc group, and 85·4% (82·1–88·7) for the 8×B14 group (97·5% CI for difference between 6×Besc and 8×Besc was 0·5–9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×Besc than with 8×Besc (97·5% CI 0·2–6·5). The 8×Besc group showed a higher mortality (7·5%) than the 6×Besc (4·6%) and 8×B14 (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1–96·1); and 225 (11%) of 2126 patients received additional radiotherapy. Treatment with six cycles of BEACOPPescalated followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPPescalated should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. Deutsche Krebshilfe and the Swiss Federal Government.

The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. In the randomised open-label MInT study, patients from 18 countries (aged 18–60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II–IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03–119), 6-year event-free survival was 55·8% (95% CI 50·4–60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3–78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5–25·4, log-rank p<0·0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84·3% [95% CI 74·2–90·7] vs 71·0% [65·1–76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6–6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2–6·2) in the chemotherapy and rituximab group (Fisher's exact p=0·730). Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. Hoffmann–La Roche.

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day ( n =400) could be optimized by doubling the dose ( n =420), adding interferon (IFN) ( n =430) or cytarabine ( n =158) or using IM after IFN-failure ( n =128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients’ and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection. Results: (i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P =0.001); (iii) at 3 months, a 6% BCR-ABL IS cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P =0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)—a subtype of Hodgkin lymphoma (HL)—is characterized by a low content of tumor cells, the lymphocyte predominant (LP) cells. Transformation into diffuse large B-cell lymphoma (DLBCL) occurs in about 10% of patients. We performed whole-genome mutation analysis of the DLBCL components from two composite lymphomas consisting of clonally related NLPHL and DLBCL as a means to identify candidate tumor suppressor genes and oncogenes in NLPHL. The analysis of LP cells for selected mutations of the DLBCL revealed that most mutations are also present in the LP cells, indicating a close relationship between the two components. The analysis of 62 selected genes in NLPHL by targeted ultra-deep sequencing revealed three novel highly recurrently mutated genes (each mutated in ~50% of cases), that is, DUSP2 , SGK1 and JUNB . SGK1 was expressed in the LP cells of primary NLPHL cases and in the NLPHL cell line DEV. Administration of an SGK1 inhibitor induced apoptosis in the NLPHL cell line DEV and the DLBCL cell line Farage, suggesting a pathogenetic role of SGK1 in the LP and DLBCL cells. In summary, the present study identifies SGK1 , DUSP2 and JUNB as novel key players in the pathogenesis of NLPHL.

This international prospective study showed that maintenance therapy with rituximab was more effective than interferon alfa in prolonging the duration of remission and extending survival in older patients with mantle-cell lymphoma. Patients with mantle-cell lymphoma typically present with extensive disease and involvement of multiple lymph nodes as well as the spleen, bone marrow, blood, and gastrointestinal tract. The median age at diagnosis is about 65 years. 1 , 2 Standard therapy for these patients consists of chemotherapy (e.g., the CHOP regimen, consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone) combined with the anti-CD20 monoclonal antibody rituximab (e.g., R-CHOP). 2 – 4 Only a minority of patients have a complete remission, and relapse or progression usually occurs within 2 to 3 years, resulting in an overall survival of less than 5 years. To improve this grim prognosis, . . .

The role of rituximab in combination with different CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diffuse large-B-cell lymphoma remains to be defined. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients. 824 patients who were from 18 countries; aged 18–60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II–IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116. After a median follow-up of 34 months (range 0·03–61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75–83] vs 59% [54–64]; difference between groups 20% [13–27], log-rank p<0·0001), and had increased 3-year overall survival (93% [90–95] vs 84% [80–88]; difference between groups 9% [3–13], log-rank p=0·0001). Event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defined from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not differ in the frequency of adverse events. Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.

To investigate safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT) in relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL), we conducted a single-arm multicentre study for immunocompetent patients (<66 years) with PCNSL failing high-dose methotrexate)-based chemotherapy. Induction consisted of two courses of rituximab (375 mg/m 2 ), high-dose cytarabine (2 × 3 g/m 2 ) and thiotepa (40 mg/m 2 ) with collection of stem cells in between. Conditioning for HCT-ASCT consisted of rituximab 375 mg/m 2 , carmustine 400 mg/m 2 and thiotepa (4 × 5 mg/kg). Patients commenced HCT-ASCT irrespective of response after induction. Patients not achieving complete remission (CR) after HCT-ASCT received whole-brain radiotherapy. Primary end point was CR after HCT-ASCT. We enrolled 39 patients; median age and Karnofsky performance score are 57 years and 90%, respectively. About 28 patients had relapsed and 8 refractory disease. About 22 patients responded to induction and 32 patients commenced HCT-ASCT. About 22 patients (56.4%) achieved CR after HCT-ASCT. Respective 2-year progression-free survival (PFS) and overall survival (OS) rates were 46.0% (median PFS 12.4 months) and 56.4%; median OS not reached. We recorded four treatment-related deaths. Thiotepa-based HCT-ASCT is an effective treatment option in eligible patients with r/r PCNSL. Comparative studies are needed to further scrutinise the role of HCT-ASCT in the salvage setting.

Recent retrospective studies of heterogeneously treated patients have suggested that chromosomal aberrations of the MYC gene locus indicate an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL). Here, we investigated the prognostic impact of MYC aberrations analyzed by interphase fluorescence in situ hybridization in 177 patients with de novo DLBCL treated within the two prospective, randomized trials non-Hodgkin's lymphoma NHL-B1 and NHL-B2. MYC aberrations were detected in 14 DLBCL (7.9%). In a univariate analysis compared with MYC -negative DLBCL, MYC -positive cases showed a significantly shorter overall survival (OS) ( P =0.047) and relevantly, though not significantly, shorter event-free survival (EFS) ( P =0.062). In a Cox model adjusted for the international prognostic index, the presence of a MYC gene rearrangement was the strongest statistically independent predictor of OS (relative risk 3.4, P =0.004) and EFS (relative risk 2.5, P =0.015), and this also held true when the cell-of-origin signature detected by immunohistochemistry was included in the model.