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Introduction: In the treatment of advanced Hodgkin lymphoma (aHL), based on guidelines a multitude of treatment options are available. The availability of PET-guided decision-making and new therapeutic agents increase the complexity of the decision-making process. Methods: Thirteen experts of Swiss university and cantonal hospitals in Switzerland were asked to describe their institutional decision-making practice in aHL. Variables influencing the decision-making process were identified, standardized, and converted into decision trees for analysis of consent and discrepancies. The algorithms of all participating experts were analyzed with the objective consensus methodology. Results: Four decision criteria (age, fertility preservation, fitness, and interim PET) and 12 unique treatment regimens were identified. Consensus for the treatment of aHL for young and fit, as well as for older patients without comorbidity, was found. Large heterogeneity was identified with use of a variety of different regimens for unfit patients with aHL and for young female patients with a desire of fertility preservation. Conclusions: Four major decision criteria were identified allowing the representation of expert’s approach to first-line treatment of aHL. Among Swiss experts, consensus for a PET-guided curative treatment of aHL was identified. The use of a multitude of treatment regimens was observed for older and comorbid (unfit) aHL patients, highlighting the need for clinical trials and recommendations for this group of patients.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

This phase 1 study evaluated safety, tolerability, and preliminary efficacy of obinutuzumab in combination with venetoclax in patients with previously untreated grade 1-3a follicular lymphoma in need of systemic therapy. Two DLs of venetoclax were evaluated with an expansion cohort at the recommended phase 2 dose. Twenty-five patients were enrolled. The recommended phase 2 dose was venetoclax 800 mg OD continuously for 6 cycles starting on day 2 of cycle 1, with obinutuzumab 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 to 6, followed by obinutuzumab maintenance every 2 months for 2 years. Only 1 patient had a DLT consisting of grade 4 thrombocytopenia after the first obinutuzumab infusion. Neutropenia was the most common adverse event of grade ≥3 at least possibly attributed to study treatment. Twenty-four patients were evaluable for response after cycle 6 by computed tomography (CT) and 19 by positron emission tomography/CT (PET/CT): overall and complete response rates were 87.5% (95% CI, 67.6% to 97.3%) and 25% (95% CI, 9.8% to 46.7%) in the CT-evaluated patients and 84.2% (95% CI, 60.4% to 96.6%) and 68.4% (95% CI, 43.4% to 87.4%), respectively, in the PET/CT-evaluated patients. One-year progression-free survival was 77.8% (95% CI, 54.6% to 90.1%) and 79% (95% CI, 47.9% to 92.7%) for CT and PET/CT-evaluable patients, respectively, whereas progression-free survival at 30 months was 73.2% (95% CI, 49.8%, 87.0%) as assessed by CT and 79.0% (95% CI, 47.9%, 92.7%) by PET/CT. Despite the activity observed, our results do not support further development of the combination in this patient population. This trial was registered at www.clinicaltrials.gov as #NCT02877550.

The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.

Hairy cell leukemia (HCL) remains an incurable disease. However, first-line treatment with either intravenous or subcutaneous cladribine generally leads to long-lasting remissions. Although there are excellent long-term data for intravenous application, similar data regarding subcutaneous administration are lacking. We therefore analyzed the long-term outcome of 3 prospective multicenter clinical trials on subcutaneous cladribine performed by the Swiss Group for Clinical Cancer Research (SAKK), which recruited 221 patients with classical HCL between 1993 and 2005. Median overall survival from start of treatment was not reached. Pretreatment anemia, higher Eastern Cooperative Oncology Group score, and higher age were associated with poorer overall survival in multivariable analysis, whereas early progression at 24 and 36 months had no significant impact on overall survival. Second-line treatment was necessary in 53 (23.7%) patients after a median of 5 (range, 0.2-20.4) years, and first retreatment was mainly monotherapy with cladribine (66%) or rituximab (15.1%) or a combination of these drugs (15.1%). A total of 44 (19.9%) patients developed second primary malignancies with a median time to occurrence of 5.7 (range, 0.01-17.5) years. Second primary malignancies were the main cause for death (14; 27.5%). Compared with a matched normal Swiss population, the incidence of second primary malignancies was not increased. However, survival of patients with HCL was slightly inferior by comparison (P = .036). In conclusion, the outcome of HCL patients treated with subcutaneous cladribine is excellent, and in most patients, 1 cycle of subcutaneous cladribine is sufficient for long-term disease control.

TO THE EDITOR: Treatment of proteasome inhibitor (PI)–refractory multiple myeloma (MM) is challenging, with response rates of only 15% to 35% being achieved with next-generation drugs such as pomalidomide, carfilzomib, and daratumumab, alone or in combination.[1][1][⇓][2]-[3][3] The oral HIV

Background Pomalidomide (POM) with dexamethasone (DEX) is approved in patients (pts) with relapsed and refractory (RRMM) myeloma and achieved a progression free survival (PFS) between 4.0 and 4.6 months in two pivotal phase III trials (MM-003 and MM-010). In addition, POM-DEX is a current standard backbone for triplet combinations in RRMM. However, POM-DEX with registered POM dosing (4mg daily, 21/28 day cycle) has significant toxicity with G3/4 neutropenia (48%), anemia (33%), infections (34%) and thrombocytopenia (22%) in MM-003, and up to 85% G3/4 neutropenia in triplets containing CD38 antibodies. The relationship between dose, efficacy and toxicity of POM is poorly established and POM delivered on a 2mg daily continuous schedule was similarly active compared to the standard schedule, but less toxic. Half life time of POM (7.5h) is significantly longer compared to lenalidomide (3h) with a slow decline of the POM plasma concentration at the terminal phase. Alternate day dosing of POM 4mg may therefore maintain efficacy while mitigating toxicity. This multicenter, open label, non-randomized phase II study investigated the activity and toxicity of POM 4mg given continuously every second day in RRMM pts. Methods Inclusion criteria matched MM-003. Pts with RRMM must have had ≥ 2 prior lines including bortezomib (BORT), lenalidomide (LEN), adequate alkylator treatment, and progressive myeloma on or within 60 days of the last MM treatment. Continuous oral POM 4mg on alternate days 1 to 28 was combined with weekly oral DEX 40mg (pts > 75 years 20mg) until intolerance or progression (PD). Pts received prophylaxis with acyclovir/valacyclovir, cotrimoxazole and ASS. Prophylactic G-CSF was not allowed. Primary endpoint was overall response rate (ORR, minimal response (MR) or better by IMWG criteria). Secondary objectives were overall survival (OS), 12 months OS, PFS and adverse events (AE). Results 34 patients were enrolled (median age 75 yrs, range 52-87) with time from diagnosis of 5.1 yrs (range 1.9-16.8). Prior treatments included LEN (100%), BORT (100%), alkylator (100%), carfilzomib (29%) and daratumumab (27%); 14 (41%) pts had high-risk cytogenetic features. Median treatment duration was 3.6 months. G3/4 AE occurred in less than one quarter of patients: (neutropenia 24%; anemia 18%; infections 18%; thrombocytopenia 12%). Neutropenic fever was not observed. ORR was 29 % (95% confidence interval [CI], 16%-50%; 3 (9%) VGPRs, 6 (8%) PRs and 1 (3%) MR; 15 pts (44%) achieved SD. 9 pts (26%) progressed. Median PFS was 4.2 months (95% CI, 1.9-5.5 months). OS at 12 months was 66.5% (95% CI, 47.6-79.9). Conclusion POM 4mg on an alternate day continuous dosing schedule is an active and well-tolerated option to deliver POM-DEX to RRMM pts and is especially reasonable for patients at increased risk of toxicity. This dosing schedule may have comparable efficacy, improved safety and should be explored in triplet combination.

Summary Background Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPP escalated ) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. Methods In this open-label, international, randomised, phase 3 study, we recruited patients aged 18–60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPP escalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPP escalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPP escalated (BEACOPP escalated group) or BEACOPP escalated plus rituximab (R-BEACOPP escalated group). PET-2 was assessed using a 5-point scale with 18 FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPP escalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPP escalated (day 0 and day 3 in cycle 4, day 1 in cycles 5–8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. Findings Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPP escalated group (n=220) or the R-BEACOPP escalated group (n=220). With a median follow-up of 33 months (IQR 25–42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0–95·7) for patients in the BEACOPP escalated group and 93·0% (89·4–96·6) for those in the R-BEACOPP escalated group (difference 1·6%, 95% CI −4·0 to 7·3; log rank p=0·99). Common grade 3–4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPP escalated group vs 211 [96%] of 220 patients in the R-BEACOPP escalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPP escalated group and ten (5%) of 220 in the R-BEACOPP escalated group died; fatal treatment-related toxic effects occurred in one ( escalated group and three (1%) in the R-BEACOPP escalated group, all of them due to infection. Interpretation The addition of rituximab to BEACOPP escalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. Funding Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.

Publisher's Note: There is a Blood Commentary on this article in this issue.

Recommendations for the Second Phase of the COVID-19 Pandemic in Clinical Practice Guidelines for the Management of Malignant Lymphoma

Summary The combination of lenalidomide (Revlimid®, R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose-limiting haematotoxicity restricted its use in extensively pre-treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46–83]) and were treated with B 75 mg/m2 days 1, 2; R 25 mg days 1–21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28-day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol-defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.

BRAF mutations are present in a variety of cancers and cause constitutive activation of the Ras-Raf-MEK-ERK signaling pathway. In cutaneous malignant melanoma, combined treatment with BRAF and MEK inhibitors is associated with high response rates and has been shown to improve progression free as well as overall survival compared to BRAF inhibition alone. In multiple myeloma, BRAF mutations are detectable only in a minority of patients. Only few data are available regarding the clinical activity of BRAF inhibitors in BRAF-positive multiple myeloma patients, including some anecdotal reports on remarkable responses in individuals being resistant to all other available anti-myeloma treatment approaches. We here present the first report on the combination of vemurafenib and cobimetinib in a young patient with highly resistant and rapidly progressing multiple myeloma harboring the BRAF V600E mutation who achieved a rapid and sustained response to this combination therapy.

This analysis reports on 72 patients with relapsed or refractory non-Hodgkin lymphoma who were treated with R-DHAP salvage chemotherapy regimen followed by high-dose chemotherapy and stem cell transplantation. The overall remission rate was 58.3%. Median time of follow-up was 28.7 months. Median progression-free survival was 29 months, estimated median overall survival was 37 months. Within a matched pair analysis these results were compared to a group that received DHAP salvage therapy without rituximab showing similar overall response rates and better estimated five-year overall survival of 59.2% versus 43.5%. R-DHAP therapy was shown to be effective and feasible with acceptable toxicity.

An increasing number of older patients are suffering from aggressive lymphoma. Effective and more tolerable treatment regimens are urgently needed for this growing patient population. Patients with aggressive lymphoma not eligible for anthracycline-based first-line therapy or intensive salvage regimens were treated with the rituximab-bendamustine-lenalidomide (R-BL) regimen (rituximab 375 mg/m(2) day 1, bendamustine 70 mg/m(2) d 1, 2, lenalidomide 10 mg d 1-21) for six cycles every 4 weeks. Forty-one patients with a median age of 75 (range 40-94) years were enrolled: 33 patients had substantial co-morbidities. 13 patients were not eligible for anthracycline-based first-line chemotherapy, 28 patients had relapsed/refractory disease. The primary endpoint, overall response, was achieved by 25 (61%) patients (95% confidence interval 45-76%). Grade ≥ 3 toxicity comprised haematological (59%), skin (15%), constitutional (15%) and neurological (12%) events. 9 patients died during trial treatment: 5 from lymphoma progression, 2 from toxicity, 2 with sudden death. After a median follow-up of 25·9 (interquartile range 20·4-31·6) months, 13 patients were still alive. Median overall survival was 14·5 months. In conclusion, R-BL can be considered a treatment option for elderly patients with treatment naïve or relapsed/refractory aggressive lymphoma not eligible for standard aggressive regimens.

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).

Background There is evidence linking metformin to improved prostate cancer–related outcomes. Patients and Methods Twenty-five men with metastatic castration-resistant prostate cancer and prostate-specific antigen (PSA) progression while receiving treatment with abiraterone from 3 Swiss centers were included in this single-arm phase 2 trial between November 2013 and September 2016. Metformin was added to abiraterone continuously at 1000 mg twice daily in uninterrupted 4-week cycles. The primary end point was the absence of disease progression at 12 weeks (PFS12). The Fleming single-stage design was applied. With a 5% significance level and 80% power, 25 patients were required to test PFS12 ≤ 15% (H0) compared to ≥ 35% (H1). Secondary end points included toxicity and safety issues. The study was registered at ClinicalTrials.gov ( NCT01677897 ). Results The primary end point PFS12 was 12% (3 of 25 patients) (95% confidence interval, 3-31). Most patients had PSA progression, almost half had radiographic progression, but only 1 patient had symptomatic progression. Eleven (44%) of 25 patients had grade 1 and 2 patients each grade 2 (8%) or grade 3 (8%) gastrointestinal toxicity (nausea, diarrhea, loss of appetite). One patient discontinued treatment at week 5 because of intolerable grade 3 diarrhea. Conclusion The addition of metformin to abiraterone for patients with metastatic castration-resistant prostate cancer and PSA progression while receiving abiraterone therapy does not affect further progression and has no meaningful clinical benefit. A higher-than-expected gastrointestinal toxicity attributed to metformin was observed.

Over the last few years, there have been many changes in the management of patients with follicular lymphoma, resulting in improvements in progression-free survival and quality of life. In addition to established regimens such as radiotherapy and immunochemotherapy, new treatment options are on the horizon. Furthermore, even the use of established chemotherapy agents has evolved, with new combinations moving to the forefront of the current treatment strategy. Nevertheless, there remains an unmet need for patients who have early relapses, those who are not responsive to anti-CD20 treatment regimens and for those in whom minimal residual disease persists even after immunochemotherapy. This review provides a summary of current developments in the diagnosis, treatment and management of follicular lymphoma, focusing on the clinical issues from a Swiss perspective.

The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use, and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically-relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were presented to the entire panel and a consensus was reached. This consensus, which was further developed in continuous post-meeting discussions, formed the basis of three manuscripts, each covering one of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript.

Multiple myeloma (MM) is the most common hematologic malignancy in Europe. Although remaining an incurable disease, substantial progress has been made within the last two decades. However, until recently, improvement in overall survival (OS) was only documented in younger, transplant-eligible patients. In this analysis, we retrospectively investigated the outcome of older patients with newly diagnosed MM in an unselected patient population with a special focus on the use of novel agents in a routine care community-based, non-university setting. A total of 107 patients older than 65 years of age or patients aged 60-65 years with relevant comorbidities precluding the use of autologous stem cell transplantation diagnosed with MM between 2000 and 2011 at the two largest non-university hospitals of Eastern Switzerland were analyzed. Patients were grouped into two six-year periods by date of initial diagnosis, 2000-2005 and 2006-2011. The median follow-up was 6.9 (range of 2.1 to 9.4) years. The median OS for the entire cohort was 3.0 years (95% confidence interval, 2.4-4.4). The median OS was significantly longer for patients in the 2006-2011 group (4.3 years) compared with the 2000-2005 group (2.6 years, p = 0.04). The 5-year estimated OS improved from 26% to 38%; 1-year survival was similar in both groups (86% in the 2000-2005 group and 84% in the 2006-2011 group respectively). The use of novel agents showed a statistically significant correlation with OS, whereas the impact of age was only of borderline significance. In conclusion, we demonstrate improved OS outcomes in an unselected population of older patients with MM during the last decade. This improvement is associated with an increased use of novel agents for the treatment of transplant-ineligible MM patients in daily clinical practice. Copyright © 2015 John Wiley & Sons, Ltd.

PURPOSE To evaluate the efficacy and tolerability of chemotherapy, a geriatric assessment is recommended in elderly patients with cancer. We aimed to characterize and compare patients with aggressive lymphoma by objective response and survival status based on pre-treatment cancer-specific geriatric (C-SGA) and quality of life (QoL) assessments. METHODS Patients not eligible for anthracycline-based first-line therapy or intensive salvage regimens completed C-SGA and QoL assessment before and after a rituximab-bendamustine-lenalidomide (R-BL) treatment in a phase II clinical trial. Clinical outcomes were compared based on pre-treatment individual and summary C-SGA measures, their cutoff-based subcategories and QoL indicators, using Wilcoxon rank sum or chi-square tests. RESULTS A total of 57 patients (41 included in the clinical trial) completed a C-SGA. Participants with pre-treatment impaired functional status (Vulnerable Elders Survey-13 score ≥3) were more likely to experience worse outcomes: a higher proportion were non-responders, died before the median follow-up of 31.6 months (interquartile range (IQR) 27.9-37.9) or died during treatment. Non-responders were patients categorized as having possible depression (Geriatric Depression Scale-5 score ≥2) and with worse QoL scores for functional performance. Patients with worse C-SGA summary scores and with greater tiredness were more likely to die during treatment. CONCLUSION A pre-treatment impaired functional status is an important factor with respect to clinical outcomes in patients receiving an R-BL regimen. Individual geriatric and related QoL domains showed similar associations with clinical outcomes. Whether interventions targeting specific geriatric dimensions also translate in better symptom- or domain-specific QoL warrants further research.

Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPPIn this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPPBetween May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPPThe addition of rituximab to BEACOPPDeutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.

SummaryBackground: The triplet combination of fluorouracil, oxaliplatin and irinotecan for metastatic colorectal cancer improves efficacy at the cost of increased toxicity. Preliminary reports indicate that triplet combination regimens might improve outcome in the RAS/RAF-mutated subgroup. Patients and Methods: This retrospective analysis included 25 patients with metastatic colorectal cancer, who received treatment with OCX (oxaliplatin, irinotecan, capecitabine). The regimen consisted of oxaliplatin 70 mg/m2 on days 1 and 15, irinotecan 100 mg/m2 on days 8 and 22, and capecitabine 1,400 mg/m2 on days 1-29 every 5 weeks. KRAS, NRAS, and BRAF mutations were determined by Sanger sequencing. Results: 23 patients received at least 1 cycle and were evaluable for efficacy. In 10 patients, a KRAS or BRAF mutation was detected. Partial remission rate was 61%, median progression-free survival 9.8 months, and median overall survival 32.9 months for all evaluable patients. No difference in efficacy was detected between the RAS/RAF wild-type and the mutant group. OCX was well tolerated with no grade 3/4 haematological events. Diarrhoea was the major non-haematological toxicity (24% grade 3). Conclusion: In this retrospective analysis, triplet chemotherapy with OCX was well tolerated and achieved encouraging efficacy in metastatic colorectal cancer irrespective of RAS/RAF mutation status.

Background: Mantle cell lymphoma (MCL) is a distinct subtype of lymphoma with a wide variation of clinical course. Based on randomized trials of our network, current standard of care is a cytarabine-containing immunochemotherapy induction (Hermine, Lancet 2016) followed by autologous stem cell transplantation (SCT; Zöllner, ICML 2019) and rituximab maintenance for 3 years (Le Gouill, NEJM 2018). In relapsed MCL the BTK inhibitor ibrutinib achieves high response rates and ongoing remissions (Wang, NEJM 2013; Dreyling, Lancet 2016). This approach achieved especially longer remission durations in earlier treatment lines (Rule, Hamatologica 2019). We aim to clarify whether ibrutinib added to induction and as maintenance with or without autologous stem cell transplantation might improve outcome. Study design and methods: In this international, randomized three-arm phase III trial (EudraCT-no. 2014-001363-12) young, fit patients ( up to 65 years) with histologically confirmed, untreated mantle cell lymphoma advanced stage II-IV qualify for 1:1:1 randomization after written informed consent according to ICH/EU GCP. In the control arm A, patients receive an alternating R-CHOP/R-DHAP induction followed by myeloablative consolidation (either BEAM or THAM: TBI, high dose Ara-C and melphalan). In arm A+I Ibrutinib is added to the R-CHOP cycles (560 mg day 1-19) and applied as maintenance (continuous dosing) for 2 years. In arm I the same induction and maintenance is applied but high dose consolidation and autologous SCT is skipped. A rituximab maintenance (single doses every 2 months up to 3 years) may be added in all study arms according to national clinical routine. The primary study aim is to show superiority of one of three study arms as future standard of care based on the comparison of the investigator-assessed failure-free survival (FFS), i.e. to investigate if the addition of ibrutinib improves the efficacy of standard 1st line treatment, and can even challenge the use of high-dose chemotherapy with autologous SCT. Secondary study aims include the efficacy of the three treatment arms and the safety and tolerability of ibrutinib during induction immuno-chemotherapy and maintenance. Accordingly, overall and complete response rates, progression-free and overall survival will be determined as well as adverse events during induction immuno-chemotherapy and follow-up including the cumulative incidence rates of SPMs. In addition, minimal residual disease is regularly determined based on patient-specific PCR assay according to the standardized Biomed-2 procedure. Results: As of July 30th, 511 of up to 870 patients have been randomized from 12 different European countries. In a meanwhile completed safety run-in of the initial 50 patients, feasibility of the two experimental arms was confirmed with no major differences in hematological and other toxicities and no major delays during induction. Disclosures Dreyling: Acerta: Other: Scientific advisory board; Novartis: Other: Scientific advisory board; Mundipharma: Other: Scientific advisory board, Research Funding; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Bayer: Other: Scientific advisory board, Speakers Bureau; Sandoz: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau. Ladetto:Roche: Honoraria; AbbVie: Honoraria; J&J: Honoraria; Celgene: Honoraria; Pfizer: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; ADC Therapeutics: Honoraria. Doorduijn:Roche: Honoraria, Research Funding. Gine:Janssen: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Roche: Other: Travel expenses, Research Funding. Jerkeman:Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Mey:Janssen-Cilag: Consultancy; Roche: Consultancy, Research Funding. Hutchings:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding. Kolstad:Merck: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding. Trneny:Roche: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Gilead sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Gomes da Silva:AbbVie: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support; Janssen-Cilag: Consultancy, Other: Travel support; Celgene: Consultancy; Gilead Siences: Other: Travel support, Research Funding. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Unterhalt:F. Hoffmann-La Roche: Research Funding. Hoster:Janssen: Research Funding; Roche Pharma AG: Other: Travel Support.

Mantle cell lymphoma (MCL) is a rare non-Hodgkin's lymphoma entity with a heterogeneous clinical presentation. Various therapeutic considerations in MCL for younger and elderly patients were used over the past decade. We retrospectively analyzed all 44 patients consecutively treated in a tertiary hospital between 2000 and 2010 with newly diagnosed MCL. Patient characteristics, treatment regimens and biological markers were evaluated with regard to overall survival (OS). Treatment regimens were categorized into internationally accepted intensive standard therapies and less intensive alternative treatment regimens given with palliative intent. Biological markers were correlated with clinical outcome by univariate analysis. The median age of the entire study group was 66 years (range: 42–88), with 23 (52%) patients ≥65 years. Thirty-one (70%) patients received standard regimens, the remaining 13 (30%) patients were treated with other, less intensive regimens with palliative intent. With a median follow-up of 5.25 years, the three-year OS rate was 60% [95% confidence interval (CI) 0.47–0.77]. Patients treated with standard regimens had a three-year survival rate of 77% (range: 64–94%). Of these, patients younger than 65 years were observed to have better OS (83% at 3 years; 95% CI 68–100%) than those older than 65 years (69% at 3 years; 95% CI 48–99%). In univariate analysis, the only parameters with a statistically significant prognostic impact on OS were absolute monocyte count as a continuous variable, lactate dehydrogenase and absolute lymphocyte count (>0.5 × 109/l) at diagnosis. In conclusion, our data of an unselected group of patients with newly diagnosed MCL treated at a single centre tertiary hospital are in line with results from larger randomized trials demonstrating an improved OS rate of younger as well as elderly MCL patients within the last decade. Copyright © 2013 John Wiley & Sons, Ltd.

Die Einführung monoklonaler Antikörper stellt einen Meilenstein in der Optimierung der Therapie hämatologischer Neoplasien dar. Der CD20-Antikörper Rituximab nimmt eine Vorreiterrolle ein und ist inzwischen ein etablierter Kombinationspartner verschiedener Erst- und Zweitlinien-Chemotherapien bei CD20-positiven B-Zell Non-Hodgkin-Lymphomen (NHL). Als Monosubstanz wird er zur Erhaltungstherapie bei follikulären B-Zell-Lymphomen eingesetzt. Im Bereich der nicht-malignen hämatologischen Erkrankungen liegen auch Daten für den Einsatz bei der Immunthrombozytopenie (ITP) vor. In der Folge wurden der CD52-Antikörper Alemtuzumab und kürzlich der CD20-Antikörper Ofatumumab für die Therapie der chronischen lymphatischen Leukämie (CLL) sowie das Radioimmunkonjugat Ibritumomab-Tiuxetan zur Behandlung refraktärer und rezidivierter CD20-positiver follikulärer NHL bzw. zur Konsolidierung nach Induktion einer Remission zugelassen. In nächster Zeit werden viele neue monoklonale CD20-Antikörper Eingang in die klinische Praxis finden. In der Behandlung refraktärer oder rezidivierter Hodgkin-Lymphome und systemischer großzelliger anaplastischer Lymphome (sALCL) stellt der CD30-Antikörper Brentuximab Vedotin eine aussichtsreiche neue Therapieoption dar.

Introduction : Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with a very indolent clinical course and patients may survive for many decades. First-line treatment with purine analogues such as cladribine (Cld) is considered standard of care since it is very efficient and induces profound remissions. However, patients with HCL often relapse after purine analogues and repeated treatment may increase morbidity and mortality. Despite good clinical evidence of long term control of the disease by several mainly single center studies of patients treated with purine analogues, there is only one study analyzing mainly subcutaneous (sc) treated patients based on registry data. We therefore performed a pooled long-term follow-up analysis of our prospective multicenter studies treating patients with sc Cld focusing on survival, secondary malignancy and retreatment. Materials and Methods : The SAKK included patients treated for HCL in 4 studies between 1993 and 2005. Three studies focused on first-line regimens with sc Cld, whereas the fourth protocol focused on the effect of Rituximab monotherapy in patients pretreated with Cld. Classical morphologic, immunohistochemistry and flow cytometry criteria were used as inclusion criteria and response was assessed by established criteria. Treatment algorithms in the 4 studies were as follows: 1) 5 days of Cld 0.14mg/kg sc followed by max 2 cycles of 7 days of Cld 0.1mg/kg sc in case of minor response or no response (SAKK 32/93); 2) Single shot of Cld 0.25mg/kg sc followed by a maximum of 2 cycles of 0.14mg/kg sc for 5 day in case of minor response, no response or relapse (SAKK 32/95); 3) 5 consecutive days of Cld 0.14mg/kg sc versus the same dose in 5 weekly applications (SAKK 32/98); 4) Rituximab 375 mg/m2iv weekly for 4 weeks in relapsed patients (SAKK 31/98). SAKK 32/93 included 63, SAKK 32/95 74 and SAKK 32/98 100 patients. Of the 26 patients registered in 31/98 20 were already in SAKK 32/93, 32/95 and 32/98. Therefore, we also included the treatment information and follow-up data of these 20 patients. All patients were subject to life-long follow-up within the clinical trials. Further information including secondary malignancies and retreatments were obtained by sending out questionnaires to the treating physicians of the study patients. Of the 237 patients 4 patients were in two of the studies and 10 patients have been excluded because of non-classical HCL phenotype. Therefore, a total of 223 patients were included in the analysis. Overall survival and follow-up time were assessed by Kaplan-Meier and reverse Kaplan-Meier method, respectively. Results : The median age of patients at the time of diagnosis was 55 (range 21 to 96) years, 50 patients were female (22.4%) and 173 (77.6%) male. At the time of data analysis, the median follow-up time was 12.1 (95%-CI 10.0 to 14.0) years. A total of 129 (57.8%) patients had the last follow-up information more than two years prior to the data cut-off in May 2016, however, the available information of all patients was used for the sub-analyses including secondary malignancies or retreatment. By the cut-off date, 49 patients have died, 14 (28.6%) due to secondary malignancies and 7 (14.3%) due to HCL progression. Median overall survival from diagnosis was 31.6 (95%-CI 31.6 to 37.8) years. Retreatment was necessary in 53 (23.7%) patients after a mean of 6 (0.2 to 20.4) years and first retreatment was mainly Cld (64%), rituximab (19%) or Cld and rituximab (13%). 21 patients (9.4%) required more than one retreatment with a mean number of 1.57 (range 1 to 5) treatments. A total of 42 (18.8%) patients developed secondary malignancies with an average time to occurrence of 7.1 (range: 0.1 to 17.7) years. The majority of the secondary malignancies were of non-hematological origin (85.9%), most frequently skin cancer (31.0%), followed by prostate cancer (19.0%) and colorectal cancer (16.7%). Six patients (14.4%) developed hematological secondary malignancies with a predominance of B-lymphoid neoplasms. Conclusion : Long-term overall survival in HCL patients treated with sc Cld was excellent and comparable to studies using iv Cld. Despite the long follow-up, sc Cld had a curative potential and relapses requiring re-treatment were observed only in a minority of patients. Secondary malignancies were predominantly non-hematological. These data indicate that patients need to be followed carefully with a special focus on secondary malignancies. Disclosures Chalandon: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Oxaliplatin-associated neuropathy remains a dose-limiting toxicity of the standard chemotherapy regimen of oxaliplatin and capecitabine for metastatic colorectal cancer. No preventive strategy has definitively been established. Because this neuropathy is triggered by cold, we hypothesized that infusing oxaliplatin at 37 degrees C might reduce neuropathy.In this open-label pilot feasibility trial, patients with no prior chemotherapy for metastatic colorectal cancer were included. Treatment consisted of capecitabine 1,000 mg/m(2) bid on days 1-14 and oxaliplatin 130 mg/m2 on day 1 of a 21-day cycle. The oxaliplatin infusion was administered through a fluid-warming device at a constant temperature of 37 degrees C over 2 h. The primary endpoint was feasibility and drug reactions during the infusion. Secondary endpoints included acute and chronic neuropathy as well as response rate.Twenty patients were enrolled, and a total of 95 cycles administered. Median cumulative oxaliplatin dose was 735 mg/m(2). Apart from one patient with laryngeal spasm, no other infusion-related adverse events were observed. Of the patients, 35% reported grade 3/4 acute dysesthesia or paresthesia according to a patients questionnaire. Chronic neuropathy according to NCI CTC v3.0 was observed in 85% (grade 1) and 15% (grade 2), respectively. The overall response rate was 45% (95% CI 23-67%; 5% complete remission; 40% partial remission) and stable disease was achieved in another 30% of patients.Administration of heated oxaliplatin in combination with capecitabine is feasible and well tolerated without additional toxicity. While we have observed a relatively low rate of chronic cumulative neuropathy with heated oxaliplatin, this procedure appears not promising enough for us to recommend its further clinical evaluation.

Purpose Rituximab has been shown to be active in follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. We conducted a randomized trial comparing mitoxantrone, chlorambucil, and prednisolone (MCP) chemotherapy plus rituximab with MCP alone. Patients and Methods Previously untreated patients with stage III or IV CD20+ indolent or mantle cell lymphoma were randomly assigned to either eight 28-day cycles of MCP plus rituximab (R-MCP; n = 181) or eight cycles of MCP alone (n = 177). All patients who achieved a complete or partial remission were treated with interferon maintenance until relapse. Herein, we report the results from the primary analysis population of patients with FL, who constituted the majority of patients (56%) recruited to the trial (n = 201; R-MCP, n = 105; MCP, n = 96). Results Rates of overall and complete response were significantly higher in the R-MCP arm than the MCP arm (overall response, 92% v 75%, respectively; P = .0009; complete response, 50% v 25%, respectively; P = .004). With a median follow-up time of 47 months, median event-free survival (EFS) and progression-free survival (PFS) times were significantly prolonged with R-MCP compared with MCP (EFS, not reached v 26 months, respectively; P < .0001; PFS, not reached v 28.8 months, respectively; P < .0001), and overall survival (OS) was significantly improved with R-MCP compared with MCP (4-year OS rate, 87% v 74%, respectively; P = .0096). Conclusion The R-MCP regimen significantly improves complete and overall response rates, EFS, PFS, and OS in patients with previously untreated advanced FL, without a clinically significant increase in toxicity.

Recently, 6 cycles of R-CHOP-14 have been recommended as the reference standard regimen for the treatment of elderly patients with diffuse large B-cell lymphoma (DLBCL). Pegfilgrastim has been shown to facilitate dose-dense chemotherapy schedules with a single administration per chemotherapy cycle. The aims of this study were to evaluate the use of pegfilgrastim in combination with the R-CHOP-14 regimen in a homogenous group of previously untreated elderly patients with DLBCL and to assess the pharmacokinetics of pegfilgrastim within this patient population. Ten patients with DLBCL between 60 and 80 years of age received a single subcutaneous injection of 6 mg pegfilgrastim 24 h after administration of R-CHOP chemoimmunotherapy, which was repeated for 6 to 8 cycles in two-weekly intervals. A total of 348 blood samples were collected. Pegfilgrastim plasma levels and absolute neutrophil counts were measured every other day during the first treatment cycle and twice weekly during all consecutive cycles. Sixty-three of 72 cycles (87.5%) could be delivered on time and at the planned dose. Median absolute neutrophil nadir was 0.32 g/l on day 9. Grade 3/4 granulocytopenia occurred in all patients. Febrile neutropenia occurred in two patients. Plasma levels of pegfilgrastim remained elevated during the neutropenic phase. At the start of hematologic recovery, plasma concentrations of pegfilgrastim decreased rapidly to baseline levels. Median pegfilgrastim trough plasma level was 0.43 ng/ml on the day preceding the next application. A single fixed dose of 6 mg of pegfilgrastim given once per cycle of R-CHOP-14 is effective in supporting neutrophil recovery to allow two-weekly drug administration in previously untreated elderly patients with DLBCL. However, close monitoring for infectious complications is mandatory in this patient population.