PracticeUpdate: Haematology & Oncology

VOL. 2 • NO. 1 • 2017

RESEARCH NEWS AND VIEWS FROM ELSEVIER

ISSN 2206-463X

2016 Top Stories in Oncology

EDITOR’S PICKS Atezolizumab for advanced urothelial carcinoma, adjuvant sunitinib for high- risk RCC after nephrectomy and 10-year outcomes for localised prostate cancer 8 Complete remissions with anti-CD22 CAR-T in children with relapsed/refractory ALL Patients who reached target second-maintenance- dose antithrombin III level achieved complete response of veno-occlusive disease Serial evaluation of plasma circulating tumour DNA can detect molecular response to treatment for metastatic breast cancer PIK3CA mutation testing from ctDNA may potentially be used as a surrogate for unknown or wild-type mutation status when tissue is unavailable SABCS 2016 22 ASH 2016 10

Interventions for preventing cardiomyopathy due to anthracyclines: a Bayesian Network meta-analysis Annals of Oncology This systematic review and meta-analysis found that dexrazoxane (based on moderate- quality data) and angiotensin antagonists (based on low-quality data) are potentially effective in preventing cardiotoxicity associated with anthracycline treatment.

Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas: a randomized clinical trial JAMA Oncology For the prevention of advanced colorectal adenomas, the benefits of vitamin D3 supplementation may vary based on the vitamin D receptor genotype.

Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy New England Journal of Medicine The study results showed that sunitinib

significantly lengthened disease-free survival in patients with locoregional clear cell RCC at high risk for tumour recurrence following nephrectomy, although this benefit was accompanied by increased adverse events. 9

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Continuing our series capturing the top stories in oncology for 2016, PracticeUpdate Oncology Editorial andAdvisory Boardmembers and contributors, Dr Isabel Cunningham, Dr SumantaKumarPal andDrRafael Fonseca share their toppicks for 2016. Featuredare the CABOSUN trial in renal cell carcinoma, monoclonal antibodies as anti-myeloma therapies, and the impact of minimal residual disease in acute myeloid leukaemia. 2016 TOP STORIES IN ONCOLOGY 3

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CABOSUN clinical trial By Sumanta Kumar Pal, MD T he renal cell carcinoma top story of 2016 is the CABOSUN clinical trial.

I hope that the CABOSUN results will stimulate enthusiasm for efforts to potentially combine cabozantinib with novel immunotherapeutic agents or other novel classes of drugs.

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he CABOSUN study is a trial led by the Alliance cooperative group. The data were just pre- sented at the European Society for Medical Oncology (ESMO) Congress this year and a fol- low-up was published in the Journal of Clinical Oncology . 1 The study included 157 pa- tients who were randomised to either cabozantinib or sunitinib therapy in the front-line setting. These previously untreated pa- tients all had intermediate- or poor-risk disease as defined by International Metastatic Renal Cell Carcinoma Database Con- sortium criteria. P atients received cabozan- tinib at a standard dose of 60 mg once daily or su- nitinib at 50 mg, 4 weeks on, 2 weeks off. The primary endpoint of this study was progression-free survival, and this endpoint was met with an improvement from 5.6 months to 8.2 months with cabozantinib. There was also a 34% reduction in the rate of progression or death (HR, 0.66). The objective response rate was 46% with cabozantinib versus 18% with sunitinib. It is apparent from assessment of the waterfall plots that a number of patients benefitted from system- ic therapy with cabozantinib in the front-line setting. In my mind, these data represent an important breakthrough for patients with previously untreated metastatic renal cell carcinoma with intermediate- or poor-risk disease. At the present time, there are few options for these patients. Temsirolimus represented a standard of care for

therapy with a checkpoint in- hibitor. I would propose that cabozantinib would represent a reasonable comparator arm, and I hope that the CABOSUN re- sults will stimulate enthusiasm for efforts to potentially com- bine cabozantinib with novel immunotherapeutic agents or other novel classes of drugs. Reference 1. Choueiri TK, Halabi S, Sanford BL, et al. J Clin Oncol [published online November 14, 2016] DOI: 10.1200/JCO.2016.70.7398.

patients with poor-risk disease; however, the overall survival estimated with temsirolimus in the poor-risk setting was only 10.4 months. This is profoundly different from the overall survival estimates closer to 30 months observed in this front- line trial of cabozantinib versus sunitinib. Admittedly, the study populations are different. Having said that, cabozantinib should remain a standard of care in the second-line setting and should also be considered for those patients with intermediate- and poor-risk in the front-line setting. It is curious to note that many of the clinical trials that are being designed currently randomise patients to either sunitinib or a novel combination of immu- notherapeutic strategies, either dual checkpoint inhibitors or combination of VEGF-directed

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VOL. 2 • NO. 1 • 2017

2016 TOP STORIES IN ONCOLOGY 4

Minimal residual disease assessment inAML By Isabel Cunningham, MD W ith no breakthrough therapies for acute myeloid leukaemia (AML) this year, again, and no AML clini- by excision or radiation before it has time to metastasise.

abnormal karyotypes. Only small numbers of the 152 studied for MRD had been fol- lowed over a year, but the early results are encouraging. The authors documented that less than a 4-log reduction in NPM1-mutated cells after induction eventuated in the early relapses and near 60% relapse rate at 1 year that is all too familiar in studies of unstratified AML patients. However, relapse within 2 years occurred in only 20% of those patients in whom reduction exceeded 5 logs. The benefits of our being able to recognise inadequate cell kill right after induction are tremendous. Knowing such results in an individual patient could lead to making earlier decisions about risking transplant or going to experimental therapies. It should also prompt doctors to search for an unrecognised leukaemic tumour that could have grown silently in any organ through therapy. Finding a resistant tumour using PET/CT or gallium would enable ablation

Another valuable feature of this French study is its requirement that the search for a transplant donor be started at the time of diagnosis. Delay after remission attainment that often occurs in identifying a suitable donor is a variable con- tributing to post-transplant relapse often not detailed in reports. More large studies such as this one are likely to improve outcomes as more markers of residual leukaemia are identified. Reference 1. Balsat M, Aline Renneville A, Thomas X, et al. J Clin Oncol DOI: 10.1200/JCO.2016.67.1875.

cal reports in the ASH 2016 plenary session, it is hard to choose one story for 2016. In- stead, I’m choosing to highlight a theme of growing importance – the increase in reports of minimal residual disease (MRD) assess- ment in AML. MRD in AML was the subject of several ASH presentations. I cite this recent Journal of Clinical Oncology study of many French centres that shows how the depth of cell kill after induction can potentially help doctors to estimate prognosis and make the decision about recommending transplant in first re- mission, somewhat akin to what has already happened in CML. 1 The study concerns patients with NPM1 mutations that occur in approximately 30% of AML and 60% of AML patients without

Dr Cunningham is Adjunct Associate Research Scientist in the Division of Hematology Oncology at Columbia University

College of Physicians and Surgeons, New York, and Associate Editor of the PracticeUpdate Oncology Editorial Board.

Monoclonal antibodies as therapeutic tools for myeloma By Rafael Fonseca, MD A lthough many new drugs have been approved in the last years as tools against

relapsed and refractory setting, and also the longest projected progression-free survival in any trial of myeloma that is relapsed or refractory. 3 Daratumumab is here to stay and is quickly gaining a foothold at the bedside. My colleague Dr Sagar Lonial pointed out a few years ago what he called “oncologic irony”; that is, that myeloma, the only disease that produces a monoclonal anti- body, had no available therapeu- tic monoclonal. The “oncologic irony” is finally over. References 1. Lonial S, Dimopoulos M, Palumbo A, et al. N Engl J Med 2015;373:621-631. 2. Palumbo A, Chanan-Khan A, Weisel K, et al. N Engl J Med 2016;375:754-766. 3. Dimopoulos MA, Oriol A, Nahi H, et al. N Engl J Med 2016;375:1319-1331.

now FDA- and TGA-approved and is being used in lenalido- mide-naive patients, including those with high-risk cytogenet- ics. Some questions remain, such as whether it will be useful in patients progressing on lenalid- omide maintenance or whether it will work in combination with pomalidomide. The second monoclonal anti- body approved is daratumumab, which targets the CD38 receptor in cells. While CD38 is not ex- clusively in myeloma cells, the antibody has shown evidence of anti-myeloma activity as a single agent. While this was impres- sive, the most notable results are those seen in the context of combinations with bortezomib and dexamethasone and also with lenalidomide and dexameth- asone. 2,3 The latter combination has now resulted in the clinical trial with the greatest rate of complete responses (43%) in the

myeloma, a whole new class of drugs has joined the toolbox: monoclonal antibodies. These antibodies have greatly aug- mented the capacity of myeloma doctors to control disease. First, elotuzumab is a monoclonal anti- body that targets the cell surface receptor SLAMF7 (previously known as CS1), which is mainly present in the surface of natural killer cells and myeloma cells. Elotuzumab alone has no direct anti-myeloma activity; but, when combined with lenalidomide and dexamethasone, it was associated with higher than anticipated re- sponse rates. This led to a phase 3 clinical trial that was published in 2016 wherein the three-drug combination demonstrated a superior outcome over lenalido- mide and dexamethasone alone (ELOQUENT-2). 1 This drug is

My colleague pointed out a few years ago what he called “oncologic irony”; that is, that myeloma, the only disease that produces a monoclonal antibody, had no available therapeutic monoclonal. The “oncologic irony” is finally over.

Dr Fonseca is a haematologist and Site Director of the

Hematologic Malignancies Program at the Mayo Clinic Cancer Center in Arizona.

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EDITOR’S PICKS 5

Introducing Editor’s Picks , a new section featuring the most recent top clinical trials in oncology and haematology specially selected by the PracticeUpdate Oncology Editorial and Advisory Board members.

Interventions for preventing cardiomyopathy due to anthracyclines By Reshma Mahtani, DO A nthracyclines are commonly used for the treatment of breast cancer. Dose-dependent risks of cardiotox-

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data are not an overwhelming endorsement of any specific approach. It is interesting to note that, despite the identification of risk factors, some patients with little exposure and no risk factors can develop considera- ble cardiac damage while others with higher exposure and risk factors do not develop any problems. This suggests a possible role of genetic susceptibility. A large number of polymorphisms have been reported in genes that mediate the metabolism, trans- port, and pharmacological activity of doxo- rubicin. The clinical significance of these findings is still under investigation, but may be the key to identifying patients at most risk. Once these patients are identified, the use of cardio-protectants such as ACE inhibitors, angiotensin-receptor blockers, and beta blockers may be used as part of an individualised plan for the prevention of anthracycline-induced cardiotoxicity.

icity and congestive heart failure are well- known. Risk factors for the development of cardiotoxicity have been investigated and include cumulative dose greater than >300 mg/m 2 ; age >65 years; history of hy- pertension, diabetes, or hyperlipidaemia; lifestyle factors such as smoking and obe- sity; history of prior radiation involving the chest; and the use of trastuzumab. Recent research has focused on early monitoring and risk stratification. The aim is to iden- tify patients at higher risk for the develop- ment of cardiotoxicity based on the use of biochemical markers and the prophylactic use of cardio-protectants. The current article is a systematic review of 16 randomised controlled trials evaluating the primary prevention of anthracycline-as- sociated toxicity with the use of various agents. The authors indicate that “moder- ate quality data suggest that dexrazoxane, and low quality data suggest angiotensin antagonists are likely to be effective for cardiotoxicity prevention.” The presented

The Rare Haematology Resource Centre is funded by Sanofi Genzyme and developed by Elsevier. Sanofi Genzyme has no editorial control over the content of the Resource Centre. All content therein has been subject to an independent editorial review.

Dr Mahtani is Assistant Clinical Professor of the Division of Hematology/ Oncology at the Sylvester Comprehensive Cancer Center, University of Maimi.

Sanofi Genzyme is the specialty care global business unit of Sanofi, focused on rare diseases, multiple sclerosis, oncology and immunology. 12–24 Talavera Road, Macquarie Park NSW 2113 Australia.

Interventions for preventing cardiomyopathy due to anthracyclines: a Bayesian Network meta-analysis Ann Oncol 2016 Dec 26;[EPub Ahead of Print], H Abdel-Qadir, G Ong, R Fazelzad, et al Take-home message • This systematic review used a Bayesian network meta-analysis to examine the effects of interventions to prevent cardiomyopathy in adult cancer patients treated with anthracyclines. A total of 16 randomised controlled trials including 1918 patients were identified for inclusion; these examined the use of dexrazoxane, beta blockers, angiotensin antagonists, beta blockers with angiotensin antagonists, prenylamine, N-acetylcysteine, coenzyme Q10, and statins. Only dexrazoxane treatment was demonstrably superior to placebo in reducing total cardiotoxicity events (pooled OR, 0.26), with 33% probability of being the most effective agent. When a single outlying study was removed, angiotensin antagonists had an 84% probability of being the most effective agent. When heart failure alone was considered, the dexrazoxane and angiotensin antagonists had odds ratios of 0.12 and 0.18, respectively. No evidence was found for increased risk of death or for effects on malignancy response rate with dexrazoxane or angiotensin antagonists. • This systematic review and meta-analysis found that dexrazoxane (based on moderate- quality data) and angiotensin antagonists (based on low-quality data) are potentially effective in preventing cardiotoxicity associated with anthracycline treatment.

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EDITOR’S PICKS 6

Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas By Sonia S. Kupfer, MD, Marc Bissonnette, MD, Yan-Chun LI, PhD V itamin D regulates a plethora of biological processes mediated by

potentially important associa- tions but lacks the ability to make causal connections, emphasising the challenges of determining underlying mechanisms when studying interventions such as vi- tamin D in colon cancer preven- tion. Crispr-Cas9 genetic tools that are capable of making alter- ations to single DNA bases could be used to dissect molecular al- terations regulated by SNPs. 10,11 When applied to model systems or genetically engineered mice, such studies could determine whether targeted SNPs regulate VDR gene expression and vita- min D effects on colon cancer development. Such insights from cell and mouse models could strengthen the rationale to un- dertake chemoprevention studies in populations expressing SNPs predicted to respond to anti-can- cer effects of vitamin D or other agents. If such investigations are successful, we would be much closer to practicing personalised medicine. References 1. Carlberg C. Front Physiol 2014;5:167. 2. Lee JE, Li H, Chan AT, et al. Cancer Prev Res (Phila) 2011;4:735-743. 3. Lamprecht SA, Lipkin M. Nat Rev Cancer 2003;3:601-614 4. Dougherty U, Mustafi R, Sadiq A, et al. Clin Cancer Res 2014;20:5848-5859. 5. Zheng W, Wong KE, Zhang Z, et al. Int J Cancer 2012;130: 10-19. 6. Baron JA, Barry EL, Mott LA, et al. N Engl J Med 2015;373:1519-1530. 7. Kupfer SS, Li YC, Bissonnette. Nutr Cancer 2017;69(1):167. 8. Kang EY, Martin L, Mangul S, et al. Genetics DOI:1534/ genetics.115.177246. 9. Kupfer SS, Torres JB, Hooker S, et al. Carcinogenesis 2009;30:1353-1357. 10. Courtney DG, Moore JE, Atkinson SD, et al. Gene Ther 2016;23(1):108-112. 11. Beaudoin M, Gupta RM, Won HH, et al. Arterioscler Thromb Vasc Biol 2015;35:1472-1479. Dr Kupfer is Assistant Professor in the Section of Gastroenterology and Director of the Gastrointestinal Cancer Risk and Prevention clinic at the University of Chicago; Dr Bissonnette and Dr Li are Associate Professor of the Department of Medicine – Section of Gastroenterology, Cancer Research Centre and on the Committee on Molecular

examined 41 candidate SNPs in genes associated with vitamin D and calcium signalling. The in- vestigators identified two SNPs in the 3’ untranslated region (UTR) of VDR (rs7968585 and rs731236) in linkage disequilibri- um that varied significantly with effects of vitamin D3 supplemen- tation on advanced adenoma oc- currence. For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementa- tion reduced advanced polyp risk by 64%, whereas in those with 1 or 2 G alleles (74%), vitamin D3 supplementation increased advanced polyp risk by 41%. Therefore, the authors specu- lated that effects of vitamin D supplementation are dependent on VDR genotype. The effects of the SNPs were not related to changes in serum vitamin D lev- els, suggesting that these SNPs modulate risk independent of serum vitamin D levels. More work is obviously needed to determine the mechanisms of these genotypic effects. SNPs in the 3’ UTR could, for example, alter mRNA splicing or microR- NA binding, modulating mRNA stability or translational effi- ciency. This study has identified

the vitamin D receptor (VDR) and is postulated to inhibit colon cancer development. 1–5 However, a recent study of vitamin D and calcium intervention by Dr Baron’s group failed to support this hypothesis, with no differences in polyp recurrence noted in individuals randomised to vitamin D and/or calcium compared with those randomised to placebo. 6 Caveats were noted with the study, including the dose of vitamin D. 7 Growing evidence supports the hypothesis that single nucleo- tide polymorphisms (SNPs) can modulate gene expression and colon cancer risk. 8,9 To further explore potential confounders for the negative results, the authors

Such insights from cell and mouse models could strengthen the rationale to undertake chemoprevention studies in populations expressing SNPs predicted to respond to anti- cancer effects of vitamin D or other agents. If such investigations are successful, we would be much closer to practicing personalised medicine.

Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas: a randomized clinical trial JAMA Oncol 2016 Dec 15;[EPub Ahead of Print], EL Barry, JL Peacock, JR Rees, et al. Take-home message • In this randomised, double-blind, multisite study, 41 single-nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes were analysed in patients with colorectal adenomas. Based on data from 1702 non-Hispanic whites, two SNPs (rs7968585 and rs731236) in vitamin D receptors were significantly linked to the impact of vitamin D3 supplementation. Vitamin D3 supplementation decreased risk for advanced adenomas by 64% among individuals with the AA genotype (26%) at the rs7968585 SNP. Risk increased by 41% in individuals with one or two G alleles (74%). The benefits of supplementation with calcium were not significantly linked to genotype. • For the prevention of advanced colorectal adenomas, the benefits of vitamin D3 supplementation may vary based on the vitamin D receptor genotype.

Metabolism and Nutrition, The University of Chicago.

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Minimum Product Information: Abstral ® (fentanyl citrate) 100 µg, 200 µg, 300 µg, 400 µg, 600 µg & 800 µg sublingual tablets. Indication: ABSTRAL is indicated for the management of breakthrough pain in adults with cancer who are already receiving maintenance opioid therapy for chronic pain. Breakthrough pain is a transient exacerbation of otherwise controlled chronic background pain. Contraindications: Hypersensitivity to active substance or to any excipients; non-opioid tolerant patients due to risk of life-threatening respiratory depression; severe respiratory depression or severe obstructive lung conditions; use in patients not receiving opioid maintenance therapy for cancer-related pain. Precautions: Stabilisation of chronic opioid therapy required before initiation; use in patients not receiving maintenance opioid therapy for cancer-related pain carries a risk of dependence (in addition to risk of life-threatening respiratory depression); repeated administration can result in tolerance and physical and/or psychological dependence; cessation of treatment may cause symptoms of withdrawal such as anxiety, tremor, sweating, paleness, nausea and vomiting; clinically significant respiratory depression can occur in patients with chronic obstructive pulmonary disease or other conditions predisposing to respiratory depression (e.g. myasthenia gravis). Use with caution in patients with head injuries or raised intracranial pressure; history of bradyarrhythmia, hypovolaemia and hypotension; co-administration with a serotonergic agent; elderly patients; patients with hepatic and renal impairment; mouth wounds or mucositis; prolonged use may result in sexual dysfunction, infertility or impairment of fertility in both sexes and menstrual disturbance in women; pregnancy (Category C); lactation; use in children and adolescents below 18 years not recommended; driving or operating machinery not recommended. See full PI. Interactions: metabolised by CYP3A4; concomitant use with macrolide antibiotics (e.g. erythromycin); azole antifungal agents (e.g. ketoconazole, itraconazole); certain protease inhibitors (e.g. ritonavir); grapefruit juice; CNS depressants such as other morphine derivatives (analgesics and antitussives); general anaesthetics; skeletal muscle relaxants; sedative antidepressants; sedative H1 antihistamines; barbiturates; anxiolytics (i.e. benzodiazepines); hypnotics; antipsychotics; clonidine; alcohol; monoamine oxidase inhibitors within 14 days; or partial opioid agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) not recommended. Co-administration of fentanyl with a serotonergic agent may increase risk of serotonin syndrome, a potentially life-threatening condition. See full PI. Adverse Effects: nausea, dizziness, headache, somnolence, dyspnoea, stomatitis, vomiting, constipation, dry mouth, hyperhidrosis, fatigue. See full PI. Dosage and Administration: tablets should be administered directly under the tongue at the deepest part until fully dissolved; tablets should not be swallowed, chewed or sucked; do not eat or drink until tablet is completely dissolved. Initial dose: 100 µg, titrating upwards as necessary. See full PI for dose initiation, titration and maintenance. Approved Product Information: 27 July 2015. Date prepared: 24 August 2015. REFERENCE : 1. Abstral Product Information. November 2015. A. Menarini Australia Pty Ltd. Level 8, 67 Albert Avenue, Chatswood NSW 2067. ABN 62 116 935 758. Medical Information: 1800 644 542 or med.infoau@menariniapac.com. ABS-AU-0626. January 2017. MEAB11924/PU/FP.

EDITOR’S PICKS 8

Atezolizumab for advanced urothelial carcinoma, adjuvant sunitinib for high-risk RCC after nephrectomy and 10-year outcomes for localised prostate cancer

Atezolizumab as first-line in cisplatin-ineligible patients with advanced urothelial carcinoma C isplatin-based chemotherapy has been the mainstay in the treatment of metastatic urothelial cancer.

Drs Rajesh Nair and Homi Sagar share their top three recent clinical trials – S-TRAC, ProtecT and IMvigor210 – and their impact on patients with bladder, renal and prostate cancers.

diarrhoea (12%), and pruritis (8%). There was one treatment-associated mortality due to sepsis, and treatment was discontinued in 8%. Reassuringly, nephrotoxicity has been reportedly low in this cohort. This is a critical study; it reveals similar response rates to previous studies involving checkpoint inhibitors. Immunotherapy appears to be much easier to tolerate than chemotherapy, and this is especially important for elderly patients or those with significant renal impairment. However, with less than 30% of patients responding to the drug, future studies are essential in the predictive biomarkers field to determine response. The future also necessitates studies evaluating drug sequencing, combination therapy with chemotherapy, PD-1 inhibitors (eg, pembrolizumab), and the role of neoadjuvant therapy in muscle invasive disease. We remain at the tip of a very exciting iceberg.

Unfortunately, over 60% of patients are ineligible to receive this treatment. Reasons include poor performance status, impaired renal function or heart failure. Atezolizumab, a class of checkpoint inhibitor immunotherapy, targets the protein PD-L1 found on tumour cells. PD-L1 binding to PD-1 on immune cells supresses the host immune response. Balar and colleagues report the promising results of a multicentre, non-randomised single-arm, phase 2 study of atezolizumab in a cohort of patients with locally advanced or metastatic urothelial carcinoma not suitable for cisplatin-based chemotherapy. For the 119 patients who received one or more doses of atezolizumab, the overall response rate was 23%; complete response rate was 9% and 70% of responses were on-going. Median overall survival was 15.9 months. Treatment related adverse events included fatigue (30%),

Rajesh Nair, FRCS (Urol), FEBU, MSc is a UK-trained urological surgeon undergoing advanced fellowship training in robotics and uro-oncology at the Royal Melbourne Hospital.

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2016 Dec 7; [Epub ahead of print]. AV Balar, MD Galsky, JE Rosenberg, et al; IMvigor210 Study Group. Take-home message • This was a multicentre, single-arm, phase 2 study evaluating the safety and efficacy of first- line atezolizumab monotherapy (1200 mg fixed dose) in 123 cisplatin-ineligible patients with advanced urothelial carcinoma. The objective response rate was 23%. Tumour mutation load was associated with response. Median overall survival was 15.9 months. • Results indicated that atezolizumab is active in patients with advanced, untreated cisplatin- ineligible urothelial carcinoma.

Homayoun (Homi) Zargar, MD, FRACS is a urological surgeon with fellowship training in uro-oncology, and advanced laparoscopic and robotic surgery. He is Consultant Urologist at the Royal Melbourne Hospital and Senior Clinical Lecturer, Department of Surgery, University of Melbourne.

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EDITOR’S PICKS 9

Adjuvant sunitinib increases disease-free survival in patients with high-risk RCC after nephrectomy T he S-TRAC trial reported by Ravaud and colleagues is a phase 3 trial of the VEGF pathway inhibitor sunitinib

Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy N Engl J Med 2016;375:2246-2254. A Ravaud, RJ Motzer, HS Pandha, et al; S-TRAC Investigators Take-home message • This double-blind, phase 3 trial included 615 patients with locoregional, high-risk clear cell renal cell carcinoma who were randomised to receive sunitinib or placebo. Patients receiving sunitinib exhibited a significantly longer median disease-free survival compared with patients receiving placebo (6.8 vs 5.6 years; P = 0.03). Dose reductions, interruptions, and discontinuations were more frequent in patients receiving sunitinib. The occurrence of serious adverse events was similar between the groups, with no deaths attributed to treatment. • The study results showed that sunitinib significantly lengthened disease-free survival in patients with locoregional clear cell RCC at high risk for tumour recurrence following nephrectomy, although this benefit was accompanied by increased adverse events. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer N Engl J Med 2016;375:1415-1424. FC Hamdy, JL Donovan, JA Lane, et al; ProtecT Study Group. Take-home message • This was a multicentre, randomised trial including 1643 men with newly diagnosed localised prostate cancer, which was designed to compare three potential treatment strategies: active monitoring, radical prostatectomy, and external-beam radiotherapy. At a median follow- up of 10 years, there were only 17 prostate cancer-specific deaths in the three treatment groups combined (prostate cancer-specific survival of at least 98.8% in all groups at 10 years). There was no significant difference in overall survival among the patients whether treated with observation, prostatectomy, or external-beam radiotherapy. Metastatic disease was also rare irrespective of treatment arm (62 of 1643 patients) but was more common in the observation arm compared with either the upfront radiation or surgery arms (33 vs 13 vs 16 events for observation, surgery, and radiation groups, respectively). • The authors concluded that, while prostate cancer-specific mortality rates remained low despite the treatment strategy employed, surgery and radiotherapy resulted in lower incidences of disease progression and metastases.

survival data was not complete. Adverse events were responsible for dose reductions in 34.3% of the sunitinib group compared with only 2% of placebo patients. There were more treatment interruptions (46.4% vs 13.2%) as well as more treatment discontinuations (28.1% vs 5.6%) in the sunitinib group. Despite a similar number of serious adverse events, there were significantly more frequent grade 3 adverse events in the sunitinib arm (48.4% vs 12.1%). This is a positive trial promoting the use of adjuvant therapy. However, it is important to highlight that more than 50% of the patients in the placebo arm did not experience any recurrence. Furthermore, similar studies, including the ASSURE trial, have demonstrated no differences in disease free or overall survival in a similar setting. A number of comparable trials are underway and where there currently remains equipoise in outcomes and opinion, the future will tip the scales one way or another. It is important to recognise that modern day active surveillance regimens incorporate serial PSA testing, digital rectal examination, serial prostate biopsies or imaging. The trial protocol mandated only rectal examination and PSA testing. While the conclusions do allow for additional support using conservative management for select patients, however, one must not confuse modern day active surveillance and active monitoring used in the trial design. The vast majority of patients in the trial exhibited low-risk disease; many of these patients would be considered for modern day active surveillance. Today, active treatment would be reserved for intermediate and higher risk prostate cancer. It is important to note that although radical treatment is effective in reducing disease progression and metastases, based on the data presented, this did not translate into improved survival.

for adjuvant treatment of high-risk renal cell carcinoma after nephrectomy. It is one of the first studies demonstrating the benefit of adjuvant therapy in patients with renal cell carcinoma. Although one should be cautious when interpreting the results, the investigators have allowed for an optimistic view when managing the disease in the higher risk patient population, where recurrence rates after nephrectomy are approximately 50%. A total of 615 patients with high-risk clear cell renal cell carcinoma following nephrectomy were randomised to either placebo or full dose 50 mg of sunitinib for 4 weeks on, 2 weeks off for 1 year or until disease recurrence. Patients with suspected metastases were excluded from the study. The primary endpoint was met with a significantly longer disease-free survival of 6.8 years with sunitinib compared with 5.6 years with placebo. At 5 years, 59.3% were disease-free in the sunitinib group versus 51.3% in the placebo group. Overall monitoring, surgery or radiotherapy for localised PSA-detected prostate cancer. Many authors have failed to recruit to similar studies in the past. Both oncological and functional outcomes of patients were evaluated. A total of 545 patients were randomised to active monitoring, 553 to radical prostatectomy and 545 to radiotherapy. At a median follow-up of 10 years, there were no significant differences in prostate cancer- specific or overall survival between groups. Of note, there was a notable increase in disease progression and metastasis in men managed with active monitoring. With respect to functional outcomes, worse urinary continence and erectile function was observed following surgery, whereas voiding and bowel-related symptoms were worse after radiotherapy. There are a number of caveats one must consider when evaluating the data presented. The ProtecT authors assumed a prostate cancer mortality of 15% when powering the study. As the trial progressed,

Positive 10-year outcomes for localised prostate cancer across treatment strategies T he ProtecT trial is a highly commendable effort evaluating 10-year outcomes following active this figure was however significantly lower at 1%. Although the result is huge, conclusions are drawn from very few events (17 deaths).

VOL. 2 • NO. 1 • 2017

CONFERENCE COVERAGE 10

58th Annual Meeting of American Society of Hematology

3–6 DECEMBER 2016 • SAN DIEGO, USA

Drs David Straus and Isabel Cunningham discuss their top abstracts from the 58th Annual Meeting of the American Society of Hematology, while the PracticeUpdate Editorial Team bring you our coverage of ASH2016 on topics which included handheld devices for blood clotting assessment, CAR-T cell therapies for ALL, artificial red blood cells, reducing or stopping TKI in patients with CML, and many more. For more on ASH 2016, go to practiceupdate.com

The sensitivity and discriminatory ability of the device compared to standard coagulation tests is what excites me. >11

© ASH 2016/Todd Buchanan 2016

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

ASH 2016 11

Handheld device offers rapid, comprehensive assessment of blood clotting W ith less than a drop of blood, a prototype for ClotChip, a port- able, disposable sensor provides Willebrand factor defect; and one, mild congenital hypodysfibrinogenemia.

Taken together, these findings might indicate that some patients are being unnecessarily overtreated. The other important implication is that patients do not have to have extremely low levels of leukaemia on very sensitive tests to safely try reducing their dose of tyrosine kinase inhibitor. >19 Large percentage of patients who reached target second- maintenance-dose antithrombin-III level achieved complete response. Additional treatment strategies may be needed, however, for patients who do not reach the target second- maintenance-dose antithrombin-III level with their current antithrombin-III dosage. >20

Compared to the normal curve, all samples from patients with coagulopathy exhibited an abnormal curve with an extended rise to peak [range 7 to 15 minutes (P = 0.0004)]. A receiver operating characteristic curve was generated, and the true positive rate plotted against the false–positive rate. The area under the curve for ClotChip (1.00) was higher than those of both acti- vated partial thromboplastin time (0.7813) and partial thromboplastin time (0.5859), illustrating that the ClotChip rise-to-peak parameter exhibits superior sensitivity than conventional screening coagulation tests. Next, ClotChip measurements were per- formed with whole blood from four healthy donors after the samples were treated with 1 µM prostaglandin E2 to inhibit platelet aggregation. Dr Stavrou determined that prostaglandin E2-treated samples exhibited a statistically significant (P = 0.03) lower peak height than that of untreated samples while rise-to-peak values remained unchanged between treat- ed and untreated samples. This showed that the lower peak height parameter was sen- sitive in response to platelet function and that ClotChip was able to detect platelet function defects. Dr Stavrou said that ClotChip showed a higher degree of sensitivity than convention- al diagnostic tests for coagulation defects. Compared to conventional tests, ClotChip reduced the rate of false-negative results. ClotChip is sensitive to multiple coagu- lation factors and platelet activity, there- by allowing whole blood assessment of hemostasis in a single disposable sensor. The ClotChip will bring blood coagulation testing closer to the patient for time-sensi- tive applications such as diagnosis of the bleeding patient and in trauma-induced coagulopathy. “Our device gives you different informa- tion – and more information – than other devices out there,” Dr Stavrou said. “The sensitivity and discriminatory ability of the device compared to standard coagulation tests is what excites me.” Dr Stavrou and coinvestigators are recruit- ing volunteers to participate in an expanded round of testing. The team is also working to optimise the device’s construction to enhance its sensitivity.

a complete report on a patient’s coagula- tion status in less than 15 minutes, finds a comparative study of ClotChip versus conventional coagulation evaluations. Evi X. Stavrou, MD, of Case Western Re- serve School of Medicine, Cleveland, Ohio, explained that the miniaturised microfluidic dielectric sensor provides for point-of-care assessment of blood coagulation. Such results are now obtainable only with spe- cialised laboratory testing. Accurate information about coagulation status is associated with better survival. Early identification of coagulopathy carries crucial clinical implications in the man- agement of patients who are critically ill, severely injured, or taking anticoagulation therapy. Conventional laboratory-based coagulation tests are time-consuming, labour-intensive, and costly. Available point-of-care devices are intended for use in specific patient populations (those taking warfarin). Measurements are insensitive due to interference from the device surface. A low-cost, easy-to-use, portable platform is needed for point-of-care assessment of the complete haemostatic process outside of the laboratory setting. The device has the potential for use in health-care settings that lack easy access to specialised laboratory testing. Unlike standard blood coagulation and platelet testing procedures that use specially trained personnel, large machines, and collected blood samples, ClotChip uses dielectric spectroscopy to detect markers of coagu- lation activity in real time. Dr Stavrou and colleagues measured coagulation in whole blood from healthy volunteers (n=10) collected in 3.2% sodium citrate. Coagulation was induced with cal- cium chloride. ClotChip curves exhibited a reproducible rise to peak within 4.5 to 6 minutes. Conventional coagulation tests were also performed in each of the healthy samples in duplicate and confirmed normal activated partial thromboplastin time and partial thromboplastin values. ClotChip measurements were then per- formed in seven clinical samples obtained from patients with coagulopathy. These patients were referred to a specialised haematology clinic for workup of coagu- lopathy. Four patients suffered from intrin- sic pathway defects (two, haemophilia A; three, haemophilia B); one, acquired von

The findings will help inform the first guidelines on how to use and select central

venous lines in children and when anticoagulants might be recommended to prevent blood clots. >21

PracticeUpdate Editorial Team

VOL. 2 • NO. 1 • 2017

GET MORE PEOPLE WITH CML-CP WHERE THEY NEED TO BE 1-3†

PBS Information: Authority Required. Refer to PBS Schedule for full Authority Information.

Please review approved Product Information before prescribing. Approved Product Information can be accessed at http://www.novartis.com.au/products_healthcare.html. Please note change(s) in Product Information. Indications: Treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (Ph+CML) in chronic phase. Treatment of chronic or accelerated phase Ph+CML in adult patients resistant to or intolerant of at least one prior therapy including imatinib. Dosage: Patients with newly diagnosed Ph+CML-CP: 300 mg twice daily; patients with CP and AP Ph+CML resistant to or intolerant of at least one prior therapy including imatinib: 400 mg twice daily. Monitoring of response to therapy in Ph+ CML should guide appropriate CML management. Doses should be taken about 12 hours apart without food. No food should be consumed for at least two hours before and one hour after the dose. For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of applesauce (pureed apple) and should be taken immediately. Not more than one teaspoon of applesauce and no food other than applesauce must be used. Contraindications: Hypersensitivity to nilotinib or excipients. Precautions: Thrombocytopenia, neutropenia and anaemia managed by temporary withdrawal or dose reduction; complete blood counts every two weeks for the first two months, monthly thereafter or as clinically indicated; patients at risk of QTc prolongation (e.g. patients with hypokalaemia, hypomagnesaemia, congenital long QT syndrome, with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia; patients taking anti-arrhythmic drugs or other drugs that may lead to QT prolongation); ECG is recommended prior to treatment, repeat after 7 days and as clinically indicated; correct hypokalaemia or hypomagnesaemia prior to treatment; uncommon cases (0.1 to 1%) of sudden death have been reported in patients with past medical history of cardiac disease or significant cardiac risk factors (not in the newly diagnosed Ph+ CML-CP study). Cardiovascular events were reported in 48 month extended follow-up trial in newly diagnosed CML patients and observed in the post-marketing reports. Grade 3/4 cases of cardiovascular events included peripheral arterial occlusive disease, ischemic heart disease and ischemic cerebrovascular events. If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The CV of patients should be evaluated and the CV risk factors should be monitored and actively managed during therapy according to standard guidelines. It is recommended that the lipid profiles be determined before initiating treatment with Tasigna, assessed at month 3 and 6 after initiating therapy, and at least yearly during chronic therapy. Blood glucose levels should be assessed prior to initiating Tasigna therapy and monitored during treatment. Test for hepatitis B infection before initiating treatment with Tasigna. In patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for hepatitis B infection during treatment, consult experts before initiating treatment. Closely monitor for signs and symptoms of active hepatitis B infection in carriers of hepatitis B virus throughout therapy and for several months following termination of therapy. Unexpected, rapid weight gain should be carefully investigated. If signs of severe fluid retention appear during treatment with nilotinib, the etiology should be evaluated and patients treated accordingly. Comorbidities in addition to the underlying malignancy were also frequently present as were concomitant medications; ventricular repolarization abnormalities may have been contributory factors. Hepatic impairment or previous history of pancreatitis; interrupt treatment in case of lipase elevations accompanied by abdominal symptoms; should not be used during pregnancy; sexually active males or females/women of child-bearing potential should be advised to use highly effective contraception while receiving Tasigna and for up to 2 weeks after ending treatment; not recommended in breast-feeding and in patients with rare hereditary problems of galactose intolerance, or severe lactase deficiency or of glucose-galactose malabsorption; the bioavailability of nilotinib might be reduced in patients with total gastrectomy. Interactions: numerous (see full Product Information) including concomitant use with drugs known to prolong the QT interval