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Purpose: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes., Patients and Methods: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1)., Results: Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥175 mutations/exome and PD-L1 CPS ≥10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone., Conclusions: These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis with current treatment options including chemotherapy and androgen receptor signaling inhibitor (ARSI) medications. Poly-ADP ribose polymerase (PARP) inhibitors alone and in combination with ARSI has recently been incorporated in management for mCRPC deficient in BRCA1/2 genes. However, downregulating androgen-receptor signaling using ARSIs can upregulate the PI3K/AKT/mTOR pathway, promoting tumor cell survival. This creates a rationale for co-targeting both these pathways. This systematic review aimed to investigate AKT inhibitors and ARSI combination therapy., Methods: EMBASE, MEDLINE, and Scopus were searched from database inception to July 2023. Primary outcomes included objective response rate (ORR), prostate-specific antigen (PSA) response rate, adverse events (AEs), overall survival (OS), and radiographic progression-free survival (rPFS). Quality was assessed using the risk of bias tool (ROB2) and certainty of evidence with GRADE., Results: Six clinical trials with 3 Phase I, 1 Phase II, 1 Phase III were included with 771 patients and a median age ranging from 67 years to 70 years. The pooled ORR was 30% (n = 5 studies, 95% CI, 3%-84%) and PSA response rate was 43% (n = 5 studies, 95% CI, 15%-77%). The median duration of rPFS ranged from 8.2 to 19.2 months in the intervention compared with 6.4 to 16.6 months in the placebo group. A 16% reduction in radiographic progression or death was reported in patients receiving dual therapy compared with those receiving placebo. This reduction was greater by PTEN-loss status, ranging from 23% to 61%. The median OS ranged from 15.6 to 18.9 months. No significant difference was reported in survival relative to placebo. 98.8% (767/776) of patients experienced AEs of any grade, with GRADE ≥3 AEs occurring in 65.9% (512/776) of patients. The most common AE and GRADE ≥3 AEs were diarrhoea (pooled prevalence = 70%, 95% CI, 57%-81%), and hyperglycaemia (pooled prevalence = 12%, 95% CI, 6%-20%), respectively., Conclusion: Combined therapy reduced the risk of rPFS, with the response higher in PTEN-loss subgroup, with a modest but not significant increase in OS. Our AE estimates showed consistency with other studies. AEs of any grade were common with the majority experiencing at least 1 AE. (PROSPERO Registration Number: CRD420202352583)., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The optimal therapeutic approach for relapsed/refractory (R/R) Waldenström's Macroglobulinaemia (WM) has not been clearly defined, especially after treatment with chemoimmunotherapy (CIT) and covalent Bruton's tyrosine kinase inhibitors (cBTKi). The PembroWM trial is a multi-centre, phase II, single-arm study assessing the safety, tolerability and efficacy of rituximab with pembrolizumab in R/R WM patients who had received at least one prior line of treatment, with all having relapsed post-CIT and most also exposed to cBTKi. A total of 17 patients were enrolled, with a median age of 70, and median of three prior lines of therapy with 15 either refractory or intolerant of a cBTKi. A significant proportion was identified as genomically high risk with BTKC481, CXCR4 and MYD88 L265P wild-type aberrations. Twenty-four-week overall response rate was 50% (60% CI 39.3%-60.7%), and median duration of response was 11.6 months (IQR: 6.3-17). The median progression-free survival was 13.6 months (95% CI 3-19.8), and the median overall survival (OS) was not reached. Treatment was well tolerated, with minimal numbers of immune-mediated AEs typically seen with checkpoint inhibitors. PembroWM is the first study to evaluate the feasibility of PD-1 axis modulation in WM and has shown that in combination with Rituximab the combination is safe and deliverable., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy. VEGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in mCRC in combination with immune checkpoint inhibitors (ICIs), particularly in patients without liver metastases. The TKI zanzalintinib (XL092) targets VEGFR, MET and TAM kinases, proteins that are involved in tumor growth, angiogenesis, metastasis and immunosuppression. Zanzalintinib has immunomodulatory properties that may enhance response to ICIs. Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases. Clinical Trial Registration: NCT05425940 (ClinicalTrials.gov).

Background: Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability., Methods: MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m 2 for 5 days), cytarabine (2 g/m 2 for 5 days), and idarubicin (8 mg/m 2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib-FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented., Findings: Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36-48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3-4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia)., Interpretation: Ponatinib-FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers., Funding: Blood Cancer UK and Incyte., Competing Interests: Declaration of interests MC has received research funding from Novartis, Bristol Myers Squibb, Cyclacel, and Takeda/Incyte; is an advisory board member for Bristol Myers Squibb, Novartis, Incyte, Daiichi Sankyo, and Pfizer; has received honoraria from Astellas, Bristol Myers Squibb, Novartis, Incyte, Pfizer, and Gilead. JLB is on the advisory board for and has received honoraria from Incyte. KR is on the advisory board for Novartis; and has received honoraria from Novartis, Incyte, Pfizer, and Daiichi Sankyo. KB is employed by UCB; has received personal fees from Eli Lilly and Invex Therapeutics; has received reimbursement from Merck and Roche; and holds shares in AstraZeneca and GlaxoSmithKline. HDL has received research funding from Incyte and Bristol Myers Squibb; and has received speaker fees from Incyte, Bristol Myers Squibb, and Pfizer. REC has received research support and honoraria from Novartis and Bristol Myers Squibb; and has received honoraria from Pfizer in the past 3 years. MLS is on the advisory board for Daiichi Sankyo and Pfizer; and has received honoraria from ARIAD. DM has received honoraria and been part of the speakers bureau for Novartis, Incyte, Bristol Myers Squibb, and Pfizer. CY has received personal fees from Celgene and Faron Pharmaceuticals, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: The comparative cardiovascular risk profiles of available hormone therapies for the treatment of prostate cancer is not known., Materials and Methods: We queried the U.S. Food and Drug Administration Adverse Event Reporting System, a retrospective, pharmacovigilance database, for cardiovascular adverse event reports in men with prostate cancer receiving gonadotropin releasing hormone (GnRH) agonists, GnRH antagonists, androgen receptor antagonists, and/or androgen synthesis inhibitors from January 2000 to April 2020., Results: Cardiovascular adverse events accounted for 6,231 reports (12.6%) on hormone monotherapy and 1,793 reports (26.1%) on combination therapy. Arterial vascular events were reported most commonly, followed by arrhythmias, heart failure, and venous thromboembolism. Compared to GnRH agonists, GnRH antagonists were associated with fewer cardiovascular adverse event reports as monotherapy (adjusted reporting odds ratio [ROR]=0.70 [95% CI 0.59-0.84], p <0.001) and as combination therapy (ROR=0.47 [0.34-0.67], p <0.0001), driven by reductions in arterial vascular events. Second generation androgen receptor antagonists and abiraterone were associated with more reports of hypertension requiring hospitalization (ROR=1.21 [1.03-1.41], p=0.02 and ROR=1.19 [1.01-1.40], p=0.03, respectively), and more heart failure events when used in combination with GnRH antagonists (ROR=2.79 [1.30-6.01], p=0.009 and ROR=2.57 [1.12-5.86], p=0.03)., Conclusions: In this retrospective analysis of a pharmacovigilance database, arterial vascular events were the most commonly reported cardiovascular adverse events in men on hormone therapy for prostate cancer. GnRH antagonists were associated with fewer reports of overall cardiovascular events and arterial vascular events than GnRH agonists. Additional study is needed to identify optimal strategies to reduce cardiovascular morbidity among men with prostate cancer receiving hormone therapy.

Background: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma., Methods: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m 2 ] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m 2 ] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305., Findings: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group., Interpretation: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma., Funding: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA., Competing Interests: Declaration of interests TP reports honoraria and research funding from Merck Sharp and Dohme (a subsidiary of Merck, Kenilworth, NJ, USA), AstraZeneca, and Roche; honoraria from BMS, Seattle Genetics, Ipsen, Merck Sharp and Dohme, Novartis, and Pfizer; fees for a consultant or advisory role for AstraZeneca, BMS, Exelexis, Incyte, Ipsen, Merck Sharp and Dohme, Novartis, Pfizer, and Seattle Genetics; and travel expenses and accommodations from AstraZeneca and Roche. TC reports research funding from Merck Sharp and Dohme. MO reports research funding from Merck Sharp and Dohme; personal honoraria from Roche, Sanofi Aventis, and Astellas; institutional honoraria from Janssen; fees for a consultant or advisory role for Janssen, Sanofi Aventis, and Astellas; speaker bureau or expert testimony role for AstraZeneca; and travel expenses and accommodations from BMS, Janssen, and AstraZeneca. NM reports research funding from Merck Sharp and Dohme, Astellas, Chugai, Eli Lilly, Janssen, Pfizer, and Taiho; and fees for a consultant or advisory role for Chugai, Janssen, Merck Sharp and Dohme, and Sanofi Aventis. LG reports research funding from Merck Sharp and Dohme; fees for a consultant or advisory role for Janssen, Merck Sharp and Dohme, and Pfizer; and travel expenses and accommodations from Janssen, and Pfizer. SY-SC reports research funding from Merck Sharp and Dohme; and fees for a consultant or advisory role for AstraZeneca, BMS, and Merck Sharp and Dohme. YF reports research funding from Merck Sharp and Dohme, Tersera, Janssen, Astellas, and IMV; fees for a consultant or advisory role for AstraZeneca, Merck Sharp and Dohme, Sanofi Aventis, and Tersera; and fees for travel for Sanofi Aventis, and Tersera. SO reports research funding from Merck Sharp and Dohme, BMS, Sanofi Aventis, Pfizer, Novartis, Bayer, and Ipsen; personal honoraria from BMS, Merck, Sanofi Aventis, Pfizer, Novartis, Janssen, Astellas, Bayer, and Ipsen; institutional honoraria from Bayer and Pfizer; and travel expenses and accommodations from BMS, Merck, Sanofi Aventis, Pfizer, Novartis, Janssen, Astellas, Bayer, and Ipsen. CV reports research funding from Merck Sharp and Dohme, and Leo Pharma; fees for a consultant or advisory role for AstraZeneca, Merck Sharp and Dohme, GSK, Astellas, Ipsen, Roche, and BMS; and travel expenses and accommodations from Roche. RMB reports research funding from Merck Sharp and Dohme; honoraria from Sanofi Aventis, Roche, and Merck Sharp and Dohme; fees for a consultant or advisory role for Sanofi Aventis, Bayer, Janssen, AstraZeneca, Merck Sharp and Dohme, Roche, and Asofarma; and travel expenses and accommodations from Roche, Sanofi Aventis, Astellas, Janssen, Merck Sharp and Dohme, Bayer, Pharmacyclics, Clovis, and Eli Lilly. AF reports research funding from Merck Sharp and Dohme; honoraria from Merck Sharp and Dohme, AstraZeneca, Pfizer, and Seattle Genetics; and travel expenses and accommodations from Merck Sharp and Dohme, AstraZeneca, Pfizer, and Seattle Genetics. SG reports research funding from Merck Sharp and Dohme, and travel expenses and accommodations from Roche. YL reports research funding from Merck Sharp and Dohme, Sanofi Aventis, and Janssen; personal honoraria from Roche, Astellas, Janssen, Seattle Genetics, AstraZeneca, BMS, Merck Sharp and Dohme, Pfizer, Sanofi Aventis, and Ipsen; institutional honoraria from Janssen and Pfizer; and travel expenses and accommodations from Roche, Janssen, AstraZeneca, Merck Sharp and Dohme, and Sanofi Aventis. AR-V reports research funding from Merck Sharp and Dohme, Pfizer, and Takeda; honoraria from Astellas, AstraZeneca, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Roche, Ipsen, and Sanofi Aventis; fees for a consultant or advisory role for Astellas, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Ipsen, Clovis, and Roche; and travel expenses and accommodations from Astellas, AstraZeneca, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Roche, Ipsen, and Sanofi Aventis. RM reports research funding from Merck Sharp and Dohme; honoraria from MedLearning and Flatiron; and fees for a consultant or advisory role for Roche, Seattle Genetics, and Astellas. EYY reports research funding from Merck Sharp and Dohme, Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Pharmacyclics, Seattle Genetics, and Taiho; and fees for a consultant or advisory role for Abbvie, Advanced Accelerator Applications, Bayer, Clovis, Janssen, Merck Sharp and Dohme, and Sanofi Aventis. KN, KI, and BHM are employees of Merck Sharp and Dohme and report stock ownership. AA reports research funding from Merck Sharp and Dohme, Clovis, BMS, AstraZeneca, Bayer, Progenics, Janssen, Genentech, Esanik, Ionis, Arcus Biosciences, and Prometheus; honoraria from Merck Sharp and Dohme, BMS, and AstraZeneca; fees for a consultant or advisory role for Merck Sharp and Dohme, BMS, AstraZeneca, Pfizer, and Merck Serono; speaker bureau or expert testimony role for AstraZeneca; and travel expenses and accommodations from Merck Sharp and Dohme, BMS, and AstraZeneca., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990., Materials and Methods: Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set., Results: Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update)., Conclusion: The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors., Competing Interests: Silke GillessenConsulting or Advisory Role: Astellas Pharma, Janssen, Bayer, Orion Pharma GmbH, Tolero Pharmaceuticals, MSD Oncology, Roche, Amgen, PfizerSpeakers' Bureau: Janssen-CilagPatents, Royalties, Other Intellectual Property: Method for biomarker (WO 3752009138392 A1)Travel, Accommodations, Expenses: ProteoMedixOther Relationship: ProteoMediX, Aranda Pharma Gedske DaugaardConsulting or Advisory Role: Sanofi/Aventis, Astellas Pharma, Bayer, MSD Oncology, Bristol-Myers Squibb/PfizerTravel, Accommodations, Expenses: Astellas Pharma Ronald De WitHonoraria: Sanofi, Merck Sharp and DohmeConsulting or Advisory Role: Sanofi, Merck Sharp and Dohme, Janssen, Bayer, Astellas PharmaResearch Funding: Sanofi, BayerTravel, Accommodations, Expenses: Bayer Costantine AlbanyStock and Other Ownership Interests: AdvaxisHonoraria: Sanofi, AstraZeneca, Seattle GeneticsConsulting or Advisory Role: Seattle Genetics, AstraZeneca/MedImmuneSpeakers' Bureau: SanofiResearch Funding: Astex Pharmaceuticals, Merck, Bristol-Myers Squibb, Lilly, BayerTravel, Accommodations, Expenses: Sanofi Alexey TryakinConsulting or Advisory Role: BioCad, Roche/Genentech, Bristol-Myers Squibb, Eisai, Merck Sharp and DohmeSpeakers' Bureau: Bayer Health, BioCad, Lilly, Merck Serono, Sanofi, Amgen, Bristol-Myers Squibb, Eisai, Merck Sharp and DohmeTravel, Accommodations, Expenses: Novartis, BioCad, Bayer, Veropharm, Sanofi Karim FizaziHonoraria: Janssen, Sanofi, Astellas Pharma, BayerConsulting or Advisory Role: Janssen Oncology, Bayer, Astellas Pharma, Sanofi, Orion Pharma GmbH, Curevac, AstraZeneca, ESSA, Amgen, Bristol-Myers Squibb, Clovis OncologyTravel, Accommodations, Expenses: Janssen, MSD Olof StahlHonoraria: Bayer Ugo De GiorgiConsulting or Advisory Role: Pfizer, Janssen, Astellas Pharma, Sanofi, Bristol-Myers Squibb, Bayer, Ipsen, Merck, MSD, PharmaMar, NovartisResearch Funding: Sanofi, AstraZeneca, RocheTravel, Accommodations, Expenses: Bristol-Myers Squibb, Ipsen, Janssen, Pfizer, Roche Aaron HansenConsulting or Advisory Role: Merck, GlaxoSmithKline, Bristol-Myers Squibb, EisaiResearch Funding: Karyopharm Therapeutics, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Janssen, AstraZeneca/MedImmune, Astellas Pharma, Macrogenics Robert HuddartEmployment: Aspen Parkside HopsitalLeadership: Cancer Clinic London Limited liability partnershipHonoraria: Janssen OncologyConsulting or Advisory Role: Bristol-Myers Squibb, Roche, Merck Sharp and Dohme, Janssen Oncology, Nektar, BayerSpeakers' Bureau: Roche, MSD, RocheResearch Funding: Merck Sharp and Dohme, Roche, Bristol-Myers Squibb, JanssenPatents, Royalties, Other Intellectual Property: Royalties for drug discovery from JanssenTravel, Accommodations, Expenses: Janssen Oncology, Roche/Genentech, MSD Oncology, Nektar Andrea NecchiEmployment: BayerStock and Other Ownership Interests: BayerHonoraria: Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, Bristol-Myers SquibbConsulting or Advisory Role: Merck Sharp and Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Rainier Therapeutics, GlaxoSmithKline, FerringResearch Funding: Merck Sharp and Dohme, AstraZeneca, IpsenTravel, Accommodations, Expenses: Roche, Merck Sharp and Dohme, AstraZeneca, Janssen, Rainier TherapeuticsOther Relationship: Bayer Christopher SweeneyStock and Other Ownership Interests: LeuchemixConsulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, Celgene, LillyResearch Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, PfizerPatents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination Xavier Garcia Del MuroConsulting or Advisory Role: Pfizer, Bristol-Myers Squibb, Ipsen, Roche, Lilly, PharmaMar, EUSA Pharma, GlaxoSmithKlineSpeakers' Bureau: Pfizer, Bristol-Myers Squibb, Astellas Pharma, EisaiResearch Funding: AstraZenecaTravel, Accommodations, Expenses: Pfizer, Roche Daniel HengConsulting or Advisory Role: Pfizer, Novartis, Bristol-Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai, MerckResearch Funding: Pfizer, Novartis, Exelixis, Bristol-Myers Squibb, Ipsen Anja LorchHonoraria: MSD Oncology, Merck, MSDConsulting or Advisory Role: Bristol-Myers Squibb, Novartis, AstraZeneca, Roche, MSD Oncology, Janssen Oncology, Ipsen, Merck, PfizerTravel, Accommodations, Expenses: Ipsen, AstraZeneca Eric WinquistHonoraria: Merck, Bayer, Eisai, Amgen, RocheResearch Funding: Roche/Genentech, Merck, Pfizer, Eisai, Ayala Pharmaceuticals Peter GrimisonResearch Funding: Tilray, Pfizer, MSD, Gilead Sciences, Boston Biomedical, Tigermed, Halozyme, Specialised Therapeutics, Medimmune, Pfizer, ASLAN Pharmaceuticals, Genentech, Eisai, Five Prime Therapeutics, QED Therapeutics, Janssen-Cilag Darren FeldmanResearch Funding: Novartis, Seattle Genetics, Decibel Therapeutics, Astellas PharmaOther Relationship: UpToDate Angelika TerbuchResearch Funding: Roche, AstraZeneca, MSD, Bristol-Myers Squibb Marcus HentrichConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Hexal, Jazz Pharmaceuticals, TakedaSpeakers' Bureau: Amgen, Janssen-Cilag, Sanofi, Takeda, Bristol-Myers Squibb, Gilead SciencesTravel, Accommodations, Expenses: Celgene, Janssen-Cilag, Takeda Carsten BokemeyerHonoraria: Merck KGaA, Sanofi, Roche, Bayer, Bristol-Myers Squibb, AstraZeneca, Merck Sharp and DohmeConsulting or Advisory Role: Lilly/ImClone, Merck Serono, Sanofi, Bayer Schering Pharma, Merck Sharp and Dohme, GSO, AOK Health InsuranceResearch Funding: Abbvie, ADC Therapeutics, Agile Therapeutics, Alexion Pharmaceuticals, Amgen, Apellis Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BerGenBio, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Gilead Sciences, Glycotope GmbH, GlaxoSmithKline, Incyte, iOMEDICO, Isofol Medical, Janssen-Cilag, Karyopharm Therapeutics, Lilly, Millennium, MSD, Nektar, Novartis, Rafael Pharmaceuticals, Roche, Springworks Therapeutics, Taiho PharmaceuticalTravel, Accommodations, Expenses: Merck Serono, Sanofi, Pfizer, Bristol-Myers Squibb Jonathan ShamashSpeakers' Bureau: Pfizer/EMD Serono David VaughnResearch Funding: Merck Sharp and Dohme, Roche/Genentech, Astellas Pharma Cora SternbergConsulting or Advisory Role: Bayer, MSD, Pfizer, Roche, Incyte, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Genzyme, Immunomedics, Foundation Medicine Axel HeidenreichHonoraria: Amgen, Astellas Pharma, Bayer, Ferring, Ipsen, Janssen-Cilag, Sanofi, TakedaConsulting or Advisory Role: Astellas Pharma, Bayer, Janssen-Cilag, Clovis Oncology, BMS Global, AstraZeneca, MSD OncologySpeakers' Bureau: Amgen, Astellas Pharma, Bayer, Ipsen, Johnson and Johnson, Sanofi, Takeda, PfizerResearch Funding: Astellas Pharma, Bayer, Sanofi, Bristol-Myers Squibb Joerg BeyerHonoraria: Roche, Janssen Oncology, AstraZeneca, Astellas Pharma, Bayer, IpsenNo other potential conflicts of interest were reported.

Purpose: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches., Methods: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019., Results: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively., Conclusion: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

Context: Immune therapy has emerged as a powerful treatment of metastatic urothelial carcinoma. Over 20 ongoing studies are exploring this strategy in the neoadjuvant setting in patients with localized muscle-invasive bladder cancer., Objective: To summarize the rationale and the clinical outcomes regarding the use of immune checkpoint blockade in the neoadjuvant setting before radical cystectomy., Evidence Acquisition: A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, mice, human, immunotherapy, neoadjuvant therapy, atezolizumab, pembrolizumab, durvalumab, nivolumab, avelumab, ipilimumab, and tremelimumab. The search was limited to publications between January 2008 and February 2020. Publicly available relevant abstracts from recent meetings were also included., Evidence Synthesis: Phase II trials investigating neoadjuvant immune checkpoint blockade as a single agent before radical cystectomy reported a rate of pathological complete response (CR), ranging from 31% with an anti-PD-L1 monoclonal antibody (mAb) atezolizumab (n = 27/88) to 37% with anti-PD-1 mAb pembrolizumab (n = 42/114). Overall, 92% (n = 87/95) and 98% (n = 112/114) of the patients underwent radical cystectomy. Neoadjuvant immune checkpoint blockade did not delay planned surgery. Checkpoint inhibitor monotherapy was well tolerated, with no unexpected toxicity in the presurgical setting. Early phase I/II trials investigating neoadjuvant combination chemotherapy strategies with immune checkpoint blockers reported enhanced antitumor efficacy, with a pathological CR ranging from 33% to 50%., Conclusions: Although limited clinical data are available on long-term survival, neoadjuvant immune checkpoint blockade demonstrated effective antitumor efficacy for localized muscle-invasive bladder cancer. Phase III trials are currently investigating this strategy in the presurgical setting., Patient Summary: Immunotherapy prior to surgery has been evaluated for patients with muscle-invasive bladder cancer. Although long-term survival benefit is unknown, such treatment strategy revealed a promising antitumor response rate for patients who underwent radical cystectomy. Ongoing prospective clinical trials will define the potential advantage of this approach over current cisplatin-based chemotherapeutic regimens alone or in combination., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance., Methods: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety., Results: Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively., Conclusions: Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.)., (Copyright © 2020 Massachusetts Medical Society.)

Although the incidence of HIV-associated lymphomas decreased after the introduction of effective combination antiretroviral therapy, they became the most common AIDS-related cancer in high-income countries. Moreover, as people living with HIV live longer, a wide range of non-AIDS-related cancer has emerged, including other haematological malignancies. Nonetheless, combination antiretroviral therapy has offered people with HIV the opportunity to receive the same therapies as those provided to the general population, and intensive curative therapies have become the standard. However, several population-based studies highlight a major health-care disparity between people with HIV and those without, with people who are HIV positive often excluded from using innovative therapies and participating in prospective trials. In addition, patients from low-income countries frequently receive inappropriate treatment. The hope is that with increased awareness of effective curative options these disparities will decrease, and people with HIV will be given the same therapeutic opportunities and enrolled in clinical trials alongside patients who are HIV negative., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Clinical stage I (CSI) nonseminoma (NS) is a disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant chemotherapy. Little is known about the outcome of patients who experience relapse after such treatment., Patients and Methods: Data from 51 patients with CSI NS who experienced a relapse after adjuvant bleomycin, etoposide, and cisplatin (BEP) from 18 centers/11 countries were collected and retrospectively analyzed. Primary outcomes were overall and progression-free survivals calculated from day 1 of treatment at first relapse. Secondary outcomes were time to, stage at, and treatment of relapse and rate of subsequent relapses., Results: Median time to relapse was 13 months, with the earliest relapse 2 months after start of adjuvant treatment and the latest after 25 years. With a median follow-up of 96 months, the 5-year PFS was 67% (95% CI, 54% to 82%) and the 5-year OS was 81% (95% CI, 70% to 94%). Overall, 19 (37%) of 51 relapses occurred later than 2 years. Late relapses were associated with a significantly higher risk of death from NS (hazard ratio, 1.10 per year; P = .01). Treatment upon relapse was diverse: the majority of patients received a combination of chemotherapy and surgery. Twenty-nine percent of patients experienced a subsequent relapse. At last follow-up, 41 patients (80%) were alive and disease-free, eight (16%) had died of progressive disease, and one patient (2%) each had died from therapy-related or other causes., Conclusion: Outcomes of patients with relapse after adjuvant BEP seem better compared with patients who experience relapse after treatment of metastatic disease but worse compared with those who have de-novo metastatic disease. We found a substantial rate of late and subsequent relapses. There seem to be three patterns of relapse with different outcomes: pure teratoma, early viable NS relapse (< 2 years), and late viable NS relapse (> 2 years).

Background: Up to 50% of men with poor prognosis, non-seminoma germ cell tumours (GCTs) die with standard BEP (bleomycin, etoposide and cisplatin) chemotherapy. An intensive regimen, CBOP/BEP (carboplatin, bleomycin, vincristine and cisplatin/BEP), met response targets in a randomised, phase II trial (74% complete response or partial response marker negative, 90% confidence interval (CI) 61%-85%)., Aim: To assess long-term outcomes and late toxicity associated with CBOP/BEP., Methods: Patients with poor prognosis extracranial GCT were randomised to 4xBEP or CBOP/BEP (2xCBOP, 2xBO, 3xBEP with 15,000iu of bleomycin). Low-dose, stabilising chemotherapy before entry was permitted. Response rates (primary outcome) were reported previously. Here, we report secondary outcomes: progression-free survival (PFS), overall survival (OS) and late toxicity. Prognostic factors and the impact of marker decline are assessed in exploratory analysis., Results: Eighty-nine patients (43 CBOP/BEP) were randomised. After median 63 months follow-up, 3-year PFS is 55.7% (95% CI: 39.7%, 69.0%) for CBOP/BEP and 38.7% (95% CI: 24.7%, 52.4%) for BEP (hazard ratio [HR]: 0.59 (0.33, 1.06), p = 0.079). Three-year OS is 65.0% (48.8%, 77.2%) and 58.5% (43.0%, 71.2%), respectively (HR: 0.79 (0.41, 1.52), p = 0.49). Twelve-month toxicity was affected by subsequent treatments, with no clear differences between arms. Stabilising chemotherapy was associated with poorer PFS (HR: 2.09 (1.14, 3.81), p = 0.017), whereas unfavourable marker decline, in 60 (70%) patients, was not., Conclusion: Although not powered for PFS, results for CBOP/BEP are promising. Impact on OS was less clear (and will be affected by subsequent therapy). Further study in an international phase III trial is warranted., Trial Registration: ISRCTN 53643604., Competing Interests: Conflict of interest statement R.A.H. reports activities outside the submitted work, including receiving non-financial support from Janssen, grants and personal fees from MSD, personal fees from Bristol Myers Squibb, grants from CRUK, advisory board fees and travel expenses from Nekta and personal fees and non-financial support from Roche. F.H.C., J.D.W., J.S., I.H. and S.P.S. have nothing to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Salvage options for patients who relapse after allogeneic stem-cell transplantation (allo-SCT) for acute myeloid leukemia (AML) and myelodysplasia (MDS) remain limited, and novel treatment strategies are required. Both lenalidomide (LEN) and azacitidine (AZA) possess significant antitumor activity effect in AML. Administration of LEN post-transplantation is associated with excessive rates of graft-versus-host disease (GVHD), but AZA has been shown to ameliorate GVHD in murine transplantation models. We therefore examined the tolerability and activity of combined LEN/AZA administration in post-transplantation relapse., Patients and Methods: Twenty-nine patients who had relapsed after allo-SCT for AML (n = 24) or MDS (n = 5) were treated with sequential AZA (75 mg/m 2 for 7 days) followed by escalating doses of LEN on days 10 to 30. Dose allocation and maximum tolerated dose (MTD) estimation were guided by a modified Bayesian continuous reassessment method (CRM)., Results: Sequential AZA and LEN therapy was well tolerated. The MTD of post-transplantation LEN, in combination with AZA, was determined as 25 mg daily. Three patients developed grade 2 to 4 GVHD. There was no GVHD-related mortality. Seven of 15 (47%) patients achieved a major clinical response after LEN/AZA therapy. CD8+ T cells demonstrated impaired interferon-γ/tumor necrosis factor-α production at relapse, which was not reversed during LEN/AZA administration., Conclusion: We conclude LEN can be administered safely post-allograft in conjunction with AZA, and this combination demonstrates clinical activity in relapsed AML/MDS without reversing biologic features of T-cell exhaustion. The use of a CRM model delivered improved efficiency in MTD assessment and provided additional flexibility. Combined LEN/AZA therapy represents a novel and active salvage therapy in patients who had relapsed post-allograft.

A recent shortage of melphalan has prompted the use of alternatives to BEAM (BCNU, Etoposide, Cytarabine, Melphalan) conditioning for autologous stem cell transplantion (ASCT). The BEAC (BCNU, Etoposide, Cytarabine, Cyclophosphamide) regimen has been employed as a conditioning regimen in lymphoma patients. However, there have been recent concerns about the toxicity of BEAC. We conducted a retrospective analysis of the EBMT database comparing the outcome of patients conditioned using BEAC with a matched cohort of patients conditioned with BEAM. In the BEAC cohort (n = 383), 25 patients died from non-relapse mortality (NRM) events (32% owing to MOF or cardiac toxicity). In the BEAM cohort (n = 766) there were 34 NRM events (23% owing to MOF or cardiac toxicity). The 1-year cumulative incidence of NRM was 4% in the BEAC cohort and 3% in the BEAM group (p = ns). The 2-year relapse/progression rate was 32% with BEAC and 33% with BEAM (p = ns). At 2 years the progression-free survival (PFS) and overall survival (OS) were 63% and 78% for BEAC and 63% and 77% for BEAM-conditioned patients (p = ns for PFS and OS). The toxicity observed with BEAC conditioning as measured by NRM was similar to that seen with BEAM. The outcomes following BEAC were similar to those seen with BEAM, suggesting that BEAC is a safe conditioning regimen.

The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphoma (MZL) is debatable. This study investigated the outcome and prognostic factors affecting the outcome of patients undergoing ASCT for MZL. Eligible patients had non-transformed nodal, extra-nodal (MALT) or splenic MZL (SMZL), aged ≥18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, [111 MALT lymphoma, 55 nodal MZL (NMZL) and 33 SMZL]. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1-8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy-based high-dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub-group and more transplants performed in recent years in the other sub-groups. After a median follow-up of 5 years, 5-year cumulative incidence of relapse/progression and non-relapse mortality were 38% and 9%, respectively. Five-year event-free survival (EFS) and overall survival (OS) were 53% and 73%, respectively. Five-year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age ≥65 years was associated with a shorter EFS and OS. In addition, patients with SMZL had a shorter OS than those with MALT. ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients., Methods: We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0-3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , and vincristine 1·4 mg/m 2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1-5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m 2 on days 1, 8, and 15, cisplatin 100 mg/m 2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1-5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18)., Findings: Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6-38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95% CI 0·21-1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections., Interpretation: The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma., Funding: Bloodwise and the UK National Institute of Health Research., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The treatment of poor prognosis chemotherapy naïve or relapsed testicular cancer is challenging. In poor prognosis treatment naïve disease, the outlook for patients with standard approaches utilising three weekly cisplatin based regimens, most commonly bleomycin, etoposide and cisplatin (BEP) is suboptimal, and one can expect more than half of patients to relapse or progress and need salvage treatment. Recent randomised studies have lent weight to the use of dose intensified treatments in these selected patient groups. In relapsed testicular cancer, post platinum based chemotherapy controversy exists as to the optimum relapse regimen as significant cure rates can be expected by re-treating with both conventional dose and high dose or dose intense regimens. Areas covered: This review seeks to outline the evidence for alternative approaches beyond standard three weekly cisplatin based regimens in poor risk metastatic disease. It also explores the evidence available for selection between conventional dose and high dose strategies on relapse. Expert commentary: An overview of the data is presented to support personalising therapy selection in both poor risk and relapsed metastatic germ cell tumors.

Over the last few years, the developments around cancer immunotherapy (CIT) have led to a paradigm shift in the treatment of many different cancers, in particular melanoma, renal, bladder and lung cancers with a remarkable impact on response rate and, most importantly, overall survival. Breast cancer is most commonly considered to be a 'non-inflamed' cancer and so this shift has been less marked within its treatment. However, some subsets of breast cancer, most notably triple negative breast cancer, are deemed to be more 'inflamed' and therefore may prove to be an appropriate cohort for CIT. This review looks back at the theory of the cancer immunity cycle and mechanism of action behind immune checkpoint inhibitors and goes on to explore their role within the various subtypes of breast cancer. It looks at the first trials performed using CIT monotherapy which demonstrated that breast cancer could respond to CIT with a small population reaping considerable benefit. It then examines the continuing body of work being undertaken to explore CIT in combination with chemotherapy to try to increase the proportion of patients who might reap the considerable rewards on offer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: KW-2478 is a novel non-ansamycin Hsp90 inhibitor with modest single-agent activity in relapsed/refractory myeloma but which shows synergistic antimyeloma activity with bortezomib (BTZ) in preclinical studies. This study determined the safety, preliminary clinical activity, and pharmacokinetics of KW-2478, an Hsp90 inhibitor, in combination with BTZ in patients with relapsed/refractory multiple myeloma (MM)., Methods: Phase I dose escalation determined the recommended phase II dose (RP2D) of KW-2478 plus BTZ, which was then used during phase II., Results: The maximum tolerated dose was not reached during phase I and the RP2D was KW-2478 175 mg m -2 plus BTZ 1.3 mg m -2 on days 1, 4, 8, and 11 every 3 weeks. In the efficacy evaluable phase I/II population treated at the RP2D (n=79), the objective response rate was 39.2% (95% confidence interval: 28.4-50.9%), clinical benefit rate 51.9% (40.4-63.3%), median progression-free survival 6.7 (5.9-not reached (NR)) months, and median duration of response 5.5 (4.9-NR) months. In the phase I/II safety population (n=95), the most frequently observed treatment-related grade 3/4 adverse events were diarrhoea, fatigue, and neutropenia (each in 7.4% of patients), and nausea and thrombocytopenia (each in 5.3%)., Conclusions: KW-2478 plus BTZ was well tolerated with no apparent overlapping toxicity in patients with relapsed/refractory MM. The antimyeloma activity of KW-2478 in combination with BTZ as scheduled in this trial appeared relatively modest; however, the good tolerability of the combination would support further exploration of alternate dosing schedules and combinations.

Relapse remains the most common cause of treatment failure in patients receiving autologous stem cell transplantation (ASCT) for follicular lymphoma (FL). The aim of this study was to evaluate the effect of adding radioimmunotherapy or rituximab (R) to BEAM (carmustine, etoposide, ara-c, melphalan) high-dose therapy for ASCT in patients with relapsed FL. Using the European Society for Blood and Marrow Transplantation registry, we conducted a cohort comparison of BEAM (n=1973), Zevalin-BEAM (Z-BEAM) (n=207) and R-BEAM (n=179) and also a matched-cohort analysis of BEAM vs Z-BEAM including 282 and 154 patients, respectively. BEAM, Z-BEAM and R-BEAM groups were well balanced for age, time from diagnosis to ASCT and disease status at ASCT. The cumulative incidences of relapse (IR) at 2 years were 34, 34 and 32% for Z-BEAM, R-BEAM and BEAM, respectively. By multivariate analysis, there were no significant differences with Z-BEAM or R-BEAM compared with BEAM for IR, non-relapse mortality, event-free survival or overall survival. With the caveat that the limitations of registry analyses have to be taken into account, this study does not support adding radioimmunotherapy or R to BEAM in ASCT for relapsed FL. However, we cannot rule out the existence a particular subset of patients who could benefit from Z-BEAM conditioning that cannot be identified in our series, and this should be tested in a randomized trial.

Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non-small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m 2 , 27 mg/m 2 , or 36 mg/m 2 , together with pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m 2 plus three-weekly cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 .

Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose should be 3 mg/m(2) or 6 mg/m(2) In this study, we randomized 788 patients to a single dose of gemtuzumab ozogamicin 3 mg/m(2) or 6 mg/m(2) with the first course of induction therapy. We found that the rate of complete remission was higher with 3 mg/m(2) [82% vs 76%; odds ratio 1.46 (1.04-2.06); P=0.03], but this was balanced by a higher rate of complete remission with incomplete peripheral blood count recovery in the 6 mg/m(2) treatment (10% vs 7%) resulting in similar overall response rate [89% vs 86%; hazard ratio 1.34 (0.88-2.04); P=0.17]. There was no overall difference in relapse or survival at four years between the arms: 46% vs 54%; hazard ratio 1.17 (0.94-1.45), P=0.5, and 50% versus 47%; hazard ratio 1.10 (0.90-1.34), P=0.3, respectively. The 30- and 60-day mortality was significantly higher in the 6 mg/m(2) recipients: 7% versus 3%; hazard ratio 2.07 (1.11-3.87), P=0.02, and 9% versus 5%; hazard ratio 1.99 (1.17-3.39), P=0.01, respectively, which in addition was associated with a higher rate of veno-occlusive disease (5.6% vs 0.5%; P<0.0001). Our conclusion from this trial is that there is no advantage in using a single dose of 6 mg/m(2) of gemtuzumab ozogamicin in combination with induction chemotherapy when compared with a 3 mg/m(2) dose, with respect to response, disease-free and overall survival, either overall, or in any disease subgroup. (AML17 was registered as ISRCTN55675535)., (Copyright© Ferrata Storti Foundation.)

Objectives: To determine the outcome of an expanded cohort of patients with relapsed germ cell tumours (GCTs) treated with a salvage chemotherapy regimen consisting of irinotecan, paclitaxel and oxaliplatin (IPO) and assess the role of IPO as an alternative to standard cisplatin-based chemotherapy regimens in this setting., Patients and Methods: The results of 72 consecutive patients were reviewed retrospectively. IPO was used either as a second-line treatment (29 patients), of which 20 patients subsequently received high-dose chemotherapy (HDCT), or third-line (43), of which 32 patients proceeded to HDCT., Results: The 2-year progression-free survival (PFS) and 3-year overall survival (OS) rates for the whole cohort were 30.2% (95% confidence interval [CI] 17.3-40.5%) and 33.4% (95% CI 20.1-43.8%), respectively. Complete remission was achieved in 3%, marker-negative partial response (PR) in 41%, marker-positive PR in 18%, stable disease in 17% and progressive disease in 20%. In the second-line setting, the 2-year PFS rate was 43.5% (95% CI 21.7-60.8%) and 3-year OS 49.1% (95% CI 24.2-65.1%). In the third-line setting, the 2-year PFS rate was 21.0% (95% CI 9.5-35.4%) and the 3-year OS rate was 23.9% (95% CI 11.7-38.2). According to the current international prognostic factor study group criteria for first relapse for the high- and very high-risk group the 2-year PFS rates were 50% and 30%, respectively. There were two treatment-related deaths from IPO, and four from HDCT. Grade 3 or 4 toxicities included neutropenia (35%), thrombocytopaenia (18%), infection (15%), diarrhoea (11%) and lethargy (8%)., Conclusions: IPO offers an effective, well-tolerated, non-nephrotoxic alternative to cisplatin-based salvage regimens for patients with relapsed GCTs. It appears particularly useful in high-risk patients and for those in whom cisplatin is ineffective or contra-indicated., (© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.)

Objective: To conduct a cost-effectiveness assessment of lenalidomide plus dexamethasone (Rd) vs bortezomib plus melphalan and prednisone (VMP) as initial treatment for transplant-ineligible patients with newly-diagnosed multiple myeloma (MM), from a U.S. payer perspective., Methods: A partitioned survival model was developed to estimate expected life-years (LYs), quality-adjusted LYs (QALYs), direct costs and incremental costs per QALY and LY gained associated with use of Rd vs VMP over a patient's lifetime. Information on the efficacy and safety of Rd and VMP was based on data from multinational phase III clinical trials and a network meta-analysis. Pre-progression direct costs included the costs of Rd and VMP, treatment of adverse events (including prophylaxis) and routine care and monitoring associated with MM. Post-progression direct costs included costs of subsequent treatment(s) and routine care and monitoring for progressive disease, all obtained from published literature and estimated from a U.S. payer perspective. Utilities were obtained from the aforementioned trials. Costs and outcomes were discounted at 3% annually., Results: Relative to VMP, use of Rd was expected to result in an additional 2.22 LYs and 1.47 QALYs (discounted). Patients initiated with Rd were expected to incur an additional $78,977 in mean lifetime direct costs (discounted) vs those initiated with VMP. The incremental costs per QALY and per LY gained with Rd vs VMP were $53,826 and $35,552, respectively. In sensitivity analyses, results were found to be most sensitive to differences in survival associated with Rd vs VMP, the cost of lenalidomide and the discount rate applied to effectiveness outcomes., Conclusions: Rd was expected to result in greater LYs and QALYs compared with VMP, with similar overall costs per LY for each regimen. Results of this analysis indicated that Rd may be a cost-effective alternative to VMP as initial treatment for transplant-ineligible patients with MM, with an incremental cost-effectiveness ratio well within the levels for recent advancements in oncology.

Background: Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly to conventional chemotherapy (response achieved in 20-30% of patients) with an overall survival of less than 1 year. High tumour angiogenesis and high concentrations of intratumoural VEGF are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGFR1, 2, and 3. In this trial, we aimed to assess the effect of the addition of cediranib to carboplatin and paclitaxel chemotherapy in patients with metastatic or recurrent cervical cancer., Methods: In this randomised, double-blind, placebo-controlled phase 2 trial, which was done in 17 UK cancer treatment centres, patients aged 18 years or older initially diagnosed with metastatic carcinoma or who subsequently developed metastatic disease or local pelvic recurrence after radical treatment that was not amenable to exenterative surgery were recruited. Eligible patients received carboplatin AUC of 5 plus paclitaxel 175 mg/m(2) by infusion every 3 weeks for a maximum of six cycles and were randomised centrally (1:1) through a minimisation approach to receive cediranib 20 mg or placebo orally once daily until disease progression. The stratification factors were disease site, disease-free survival after primary therapy or primary stage IVb disease, number of lines of previous treatment, Eastern Cooperative Oncology Group performance status, and investigational site. All patients, investigators, and trial personnel were masked to study drug allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat, and the safety analysis included all patients who received at least one dose of study drug. This trial is registered with the ISCRTN registry, number ISRCTN23516549, and has been completed., Findings: Between Aug 19, 2010, and July 27, 2012, 69 patients were enrolled and randomly assigned to cediranib (n=34) or placebo (n=35). After a median follow-up of 24·2 months (IQR 21·9-29·5), progression-free survival was longer in the cediranib group (median 8·1 months [80% CI 7·4-8·8]) than in the placebo group (6·7 months [6·2-7·2]), with a hazard ratio (HR) of 0·58 (80% CI 0·40-0·85; one-sided p=0·032). Grade 3 or worse adverse events that occurred in the concurrent chemotherapy and trial drug period in more than 10% of patients were diarrhoea (five [16%] of 32 patients in the cediranib group vs one [3%] of 35 patients in the placebo group), fatigue (four [13%] vs two [6%]), leucopenia (five [16%] vs three [9%]), neutropenia (10 [31%] vs four [11%]), and febrile neutropenia (five [16%] vs none). The incidence of grade 2-3 hypertension was higher in the cediranib group than in the control group (11 [34%] vs four [11%]). Serious adverse events occurred in 18 patients in the placebo group and 19 patients in the cediranib group., Interpretation: Cediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer. This finding was accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia)., Funding: Cancer Research UK and AstraZeneca., (Copyright © 2015 Symonds et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: Salvage high-dose chemotherapy (HDCT) along with autologous stem cell transplant (ASCT) plays an important role in the management of patients with germ cell tumors (GCT) and progression after first-line cisplatin-based chemotherapy. In this review, the authors will discuss the history of HDCT as salvage management of patients with GCT, improvement in efficacy and safety over the past 25 years, prognostic factors for outcome, and the conflicting data on the optimal initial salvage approach., Methods: The authors performed a PubMed search of HDCT and GCT to identify articles relevant to this review. After discussion, the articles felt to have contributed most notably to the field were selected for inclusion and summarized., Results: Depending on patient selection and timing of HDCT, durable remission rates with salvage HDCT range between 30% and 63%. The combination of carboplatin and etoposide is the standard regimen for the high-dose cycles with more variability in the regimens used for stem cell mobilization. Adding a third agent, particularly an oxazophosphorine (cyclophosphamide and ifosfamide), may add toxicity without increasing efficacy. In addition, sequential (2 or 3 cycle) HDCT regimens appear more effective and safer than single-cycle HDCT regimens. The optimal initial salvage approach (HDCT or conventional-dose chemotherapy) remains an unanswered question and highly controversial., Conclusions: Salvage HDCT with ASCT can cure a significant proportion of patients with GCT and progression after one or more lines of cisplatin-based chemotherapy and thus plays an important role in the contemporary management of high-risk patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

There is a significant unmet need in effective therapy for relapsed myeloma patients once they become refractory to bortezomib and lenalidomide. While data from the front line setting suggest bendamustine is superior to melphalan, there is no information defining optimal bendamustine dose in multiply-treated patients. We report a multi-centre randomized two-stage phase 2 trial simultaneously assessing deliverability and activity of two doses of bendamustine (60 mg/m2 vs. 100 mg/m2) days 1 and 8, thalidomide (100 mg) days 1-21 and low dose dexamethasone (20 mg) days 1, 8, 15 and 22 of a 28-d cycle. Ninety-four relapsing patients were treated on trial, with a median three prior treatment lines. A pre-planned interim deliverability and activity assessment led to closure of the 100 mg/m2 arm due to excess cytopenias, and led to amendment of entry criteria for cytopenias. Non-haematological toxicities including thromboembolism and neurotoxicity were infrequent. In the 60 mg/m2 arm, treatment was deliverable in 61.1% subjects and the partial response rate was 46.3% in the study eligible population, with 7.5 months progression-free survival. This study demonstrates bendamustine at 60 mg/m2 twice per month with thalidomide and dexamethasone is deliverable for repeated cycles in heavily pre-treated myeloma patients and has substantial clinical activity., (© 2015 John Wiley & Sons Ltd.)

Objectives: CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin-methatrexate/ifusamide, etoposide, cytarabine) chemotherapy is commonly used to treat Burkitt lymphoma and in the HIV-negative population. Rituximab is often added with suggested survival benefits. Concerns over increased toxicity in an already immunocompromized population have prevented its routine addition in people living with HIV (PLWH). This study evaluated the effect on treatment-related toxicity and efficacy of adding rituximab to CODOX-M/IVAC chemotherapy in PLWH., Design: Retrospective review of 91 PLWH (74 men) with Burkitt lymphoma treated in five London centers between 2003 and 2013. All patients received combination antiretroviral therapy., Results: Forty-nine patients received CODOX-M/IVAC and 42 rituximab (R)-CODOX-M/R-IVAC. The addition of rituximab did not confer any significant increase in grade 3/4 toxicities including infections, mucositis, diarrhea, renal impairment, and tumor lysis syndrome. There was no significant difference in toxic deaths between groups (P = 0.14). The 2-year overall survival (OS) was greater for patients receiving rituximab {2-year OS 72% [95% confidence interval (CI) 0.22-0.92, hazard ratio 0.46] vs. 55% [95% CI 1.1-4.5, hazard ratio 2.2]; log-rank P = 0.04}. Similarly, the 2-year progression-free survival (PFS) was greater in the rituximab cohort [2-year PFS 81% (95% CI 0.21-0.99, hazard ratio 0.46) vs. 55% (95% CI 1.0-4.8, hazard ratio 2.2); log-rank P = 0.04]., Conclusion: Our multicenter analysis is the largest to date in this population and showed that the addition of rituximab to CODOX-M/IVAC chemotherapy confers no increase in toxicity and results in significantly improved OS and PFS in PLWH with Burkitt lymphoma who receive concomitant combination antiretroviral therapy.

Background: It is unclear whether patients with early-stage Hodgkin's lymphoma and negative findings on positron-emission tomography (PET) after three cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) require radiotherapy., Methods: Patients with newly diagnosed stage IA or stage IIA Hodgkin's lymphoma received three cycles of ABVD and then underwent PET scanning. Patients with negative PET findings were randomly assigned to receive involved-field radiotherapy or no further treatment; patients with positive PET findings received a fourth cycle of ABVD and radiotherapy. This trial assessing the noninferiority of no further treatment was designed to exclude a difference in the 3-year progression-free survival rate of 7 or more percentage points from the assumed 95% progression-free survival rate in the radiotherapy group., Results: A total of 602 patients (53.3% male; median age, 34 years) were recruited, and 571 patients underwent PET scanning. The PET findings were negative in 426 of these patients (74.6%), 420 of whom were randomly assigned to a study group (209 to the radiotherapy group and 211 to no further therapy). At a median of 60 months of follow-up, there had been 8 instances of disease progression in the radiotherapy group, and 8 patients had died (3 with disease progression, 1 of whom died from Hodgkin's lymphoma); there had been 20 instances of disease progression in the group with no further therapy, and 4 patients had died (2 with disease progression and none from Hodgkin's lymphoma). In the radiotherapy group, 5 of the deaths occurred in patients who received no radiotherapy. The 3-year progression-free survival rate was 94.6% (95% confidence interval [CI], 91.5 to 97.7) in the radiotherapy group and 90.8% (95% CI, 86.9 to 94.8) in the group that received no further therapy, with an absolute risk difference of -3.8 percentage points (95% CI, -8.8 to 1.3)., Conclusions: The results of this study did not show the noninferiority of the strategy of no further treatment after chemotherapy with regard to progression-free survival. Nevertheless, patients in this study with early-stage Hodgkin's lymphoma and negative PET findings after three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy. (Funded by Leukaemia and Lymphoma Research and others; RAPID ClinicalTrials.gov number, NCT00943423.).

Background: Standard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required., Objective: To explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial., Design, Setting, and Participants: We conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres., Intervention: BEP (bleomycin 30,000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2×CBOP, 2×BO, and 3×BEP (bleomycin 15,000 IU)., Outcome Measurements and Statistical Analysis: Primary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates., Results and Limitations: A total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61-85) with CBOP/BEP, 61% with BEP (90% CI, 48-73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33-1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS., Conclusions: The primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial., Patient Summary: In this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration., Trial Registration: ISRCTN53643604; http://www.controlled-trials.com/ISRCTN53643604., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P <.001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma., Methods: PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308., Findings: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81-13·47) in the panobinostat group and 5·59 months (2·14-11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33-12·94] vs 8·08 months [7·56-9·23]; hazard ratio [HR] 0·63, 95% CI 0·52-0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34-not estimable) for the panobinostat group and 30·39 months (26·87-not estimable) for the placebo group (HR 0·87, 95% CI 0·69-1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7-65·6] for panobinostat vs 208 [54·6%, 49·4-59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2-32·4] vs 60 [15·7%, 12·2-19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76-14·92) in the panobinostat group and 10·87 months (9·23-11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41-1·64) in the panobinostat group and 2·00 months (1·61-2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%])., Interpretation: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival., Funding: Novartis Pharmaceuticals., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Uveal melanoma (UM) is the most common primary intraocular malignancy and the second most common form of melanoma. UM has a strong tendency for metastatic disease, and no effective treatments have yet been identified. Activating oncogenic mutations are commonly found in GNAQ and GNA11 in UM, and inhibiting key downstream effectors of the GNAQ/11 signaling pathway represents a rational therapeutic approach for treating metastatic UM. Chen et al., doi:10.1038/onc.2013.418, now confirm activation of the MAPK and PKC pathways as a result of GNAQ and GNA11 activating mutations in melanocytes, and they demonstrate that MAPK activation occurs downstream of PKC activation. PKC inhibitors disrupt MAPK signaling and block proliferation of GNAQ/11 mutant UM cell lines and slow the in vivo growth of xenografted UM tumors without inducing their shrinkage. However, a combination of PKC and MEK inhibition led to sustained MAPK pathway inhibition and tumor regression in vivo. Hence, the authors concluded that MEK and PKC inhibition is synergistic, with superior efficacy to treatment of GNAQ/GNA11 mutant UMs with either drug alone.

Hodgkin lymphoma (HL) is more frequent in patients with Human Immunodeficiency Virus (HIV) infection than in immunocompetent patients. The relationship between the immune system and HL is complex. Whilst the incidence of HL in HIV patients has most likely increased since the introduction of combined anti-retroviral therapy (cART), there is no doubt that the outcomes for patients with HIV and HL (HIV-HL) have improved since its introduction. Improved CD4 counts and risk-adapted treatment schedules have resulted in outcomes for patients with HIV-HL that are comparable to those in HIV-negative patients with HL. Thus, HIV-HL should be treated in the same way as HL in immunocompetent patients, including the use of salvage chemotherapy and autologous transplant in the relapsed setting in HIV-HL. Along the same lines, patients with HIV-HL should not be excluded from trials based on their immune status alone.

Background: Modern treatment of Hodgkin's lymphoma (HL) has transformed its prognosis but causes late effects, including premature menopause. Cohort studies of premature menopause risks after treatment have been relatively small, and knowledge about these risks is limited., Methods: Nonsurgical menopause risk was analyzed in 2127 women treated for HL in England and Wales at ages younger than 36 years from 1960 through 2004 and followed to 2003 through 2012. Risks were estimated using Cox regression, modified Poisson regression, and competing risks. All statistical tests were two-sided., Results: During follow-up, 605 patients underwent nonsurgical menopause before age 40 years. Risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea [BCNU], etoposide, cytarabine, melphalan) chemotherapy for stem cell transplantation, but was not statistically significantly raised after adriamycin, bleomycin, vinblastine, dacarbazine (ABVD). Menopause generally occurred sooner after ovarian radiotherapy (62.5% within five years of ≥5 Gy treatment) and BEAM (50.9% within five years) than after alkylating chemotherapy (24.2% within five years of ≥6 cycles), and after treatment at older than at younger ages. Cumulative risk of menopause by age 40 years was 81.3% after greater than or equal to 5Gy ovarian radiotherapy, 75.3% after BEAM, 49.1% after greater than or equal to 6 cycles alkylating chemotherapy, 1.4% after ABVD, and 3.0% after solely supradiaphragmatic radiotherapy. Tables of individualized risk information for patients by future period, treatment type, dose and age are provided., Conclusions: Patients treated with HL need to plan intended pregnancies using personalized information on their risk of menopause by different future time points., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Everolimus (mammalian target of rapmaycin (mTOR) inhibitor) and dovitinib (vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. The combination is explored in this phase Ib study., Methods: Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalating doses of everolimus and dovitinib. Dose-limiting toxicities (DLTs) were assessed to determine the maximum tolerated dose (MTD). An expansion cohort (n=15) was investigated to obtain additional efficacy information. Sequential fluorodeoxyglucose positron emission tomography (FDG-PET) was used as a surrogate marker of response., Results: Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5mg orally (PO) once daily (OD) and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (Common Toxicity Criteria (CTC) grade 1-4) of patients, respectively. Frequent biochemical abnormalities occurred (such as hypertriglyceridaemia in 67%). Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% confidence interval (CI) 2.2-11 months). Pharmacokinetic data at the MTD showed stable kinetics with time., Conclusion: Dovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Introduction/background: Patients with metastatic renal cell carcinoma (mRCC) in whom first-line therapies have failed might derive clinical benefit with sequential targeted agents. Limited data are available on the efficacy and toxicity of subsequent therapies after disease progression during pazopanib therapy., Patients and Methods: Patients with mRCC who received subsequent systemic treatment after pazopanib treatment failure were identified across 7 institutions. Pazopanib was given as first-line therapy in 28 patients and after cytokines therapy in 7 patients. Clinical outcome and toxicity analyses of 2 sequential treatment options (anti-vascular endothelial growth factor [VEGF] or mammalian target of rapamycin inhibitor [mTORi]) is presented., Results: Subsequent therapy was anti-VEGF in 22 patients and mTORi in 13. One patient who received bevacizumab and temsirolimus combination was excluded. VEGF-targeted therapies included sorafenib (n = 10), sunitinib (n = 3), bevacizumab (n = 2), cediranib (n = 4) and cabozantinib (n = 3). Patients treated with mTORi received everolimus. Median progression-free survival was 5.6 months from the start of subsequent therapy with anti-VEGF and 2.4 months with mTORi (P = .009). Overall survival (OS) was not significantly different (P = .68). Clinical benefit (including partial response and stable disease) on subsequent therapy was observed in 15 patients (64%) and 4 patients (31%) of anti-VEGF- and everolimus-treated patients, respectively (P = .021)., Conclusion: In this retrospective study, targeting VEGF was an effective strategy after disease progression during pazopanib treatment, although OS was not different among patients treated with VEGF or mTORi., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer., Methods: TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138., Findings: The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3; p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group)., Interpretation: Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy., Funding: Cancer Research UK and KAEL-GemVax., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To compare the outcome of patients diagnosed with HIV infection and diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP in the cART era with that of a HIV-negative control group., Methods: From 2003 to 2011, 305 patients (97 HIV-positive) were diagnosed with DLBCL and treated with R-CHOP. Clinical features were compared using chi-square or Fisher's exact test. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed using the Cox regression proportional hazards model., Results: HIV-positive patients had more B symptoms and extranodal sites of disease at diagnosis, but the proportion of patients with high-intermediate/high-risk disease according to the international prognostic index (IPI) was similar between groups. Response rate was 73%, both for patients with and without HIV infection. After a median follow-up of 48 months, 30 patients relapsed after achieving a complete remission, including four HIV-positive patients. Ninety-six patients have died (19 HIV-positive), 73 of them due to DLBCL. Three patients (one HIV-positive) died due to treatment toxicity. Patients with HIV infection had a significantly longer disease-free survival (DFS) (5-year: 94 vs. 77%; P = 0.03) and overall survival (OS) (78 and 64% for HIV-positive and HIV-negative patients, respectively; P = 0.03). These results were confirmed on multivariate analysis when controlled for other potential prognostic confounders., Conclusion: HIV-positive patients diagnosed with DLBCL in the cART era have an excellent outcome when treated with standard immunochemotherapy. Therefore, the choice of chemotherapy in patients with lymphoma should not be influenced by HIV status.

Background: Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine)., Methods: In our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278)., Findings: Between Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37-51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14-21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14-21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16-24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11-18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (<1%) had grade 4 infection., Interpretation: Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in standard neoadjuvant chemotherapy for breast cancer., Funding: Cancer Research UK, Eli Lilly, Bristol-Myers Squibb., (Copyright © 2014 Earl et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd. All rights reserved.)

Bendamustine is a unique bifunctional alkylating agent with promising activity in myeloma. Despite the increasing number of studies demonstrating its efficacy in both the upfront and relapse settings, including patients with renal insufficiency, the optimal use of bendamustine, in terms of dosage, schedule and combination with other agents, has yet to be defined. It is currently licensed for use as frontline treatment with prednisolone for patients with myeloma who are unsuitable for transplantation and who are contraindicated for thalidomide and bortezomib. Studies in relapsed/refractory patients are currently ongoing with other combinations. Given the increasing data to date, the UK Myeloma Forum believes that bendamustine with steroids alone or in combination with a novel agent could be considered for patients with multiply relapsed myeloma. This document provides guidance for the use of bendamustine for patients with myeloma until the results of definitive studies are available., (© 2013 John Wiley & Sons Ltd.)

Background and Objectives: Cisplatin-based chemotherapy is standard care for metastatic transitional cell carcinoma (TCC) of the urinary tract. However it is not appropriate for all patients, particularly those with poor renal function. There is no clear consensus on the optimal regimen for these individuals or for those after cisplatin failure. Here we present data using mitomycin, 5-fluorouracil, and irinotecan (MFI) in these patients., Materials and Methods: Patients with TCC, who had either received cisplatin-based chemotherapy previously or who were not deemed fit for cisplatin therapy (creatinine clearance was less than 60 ml/min) were eligible for treatment with the experimental combination chemotherapy regimen MFI., Results: Thirty-six patients were treated with MFI between 2001 and 2004. Overall response rate was 19% and median overall survival (OS) was 5.4 months (95% CI 3.3-8.4 months). The response rate and overall survival in both groups was 19% and 5.4 months, respectively, (95% CI 2.9-7.1 months) in the pretreated and 2.5- 9.3 months in the untreated. The most common toxicity was malaise (grade 3 or 4 = 28%)., Conclusions: MFI appear to be a combination which requires further investigation in patients where cisplatin and gemcitabine are not applicable., (Copyright © 2013 Elsevier Inc. All rights reserved.)