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A.K. Burnett et al.
observed excess toxicity, which was primarily gastroin- testinal (mucositis and diarrhea), and biochemical evi- dence of liver toxicity at the dose chosen. Infection was a major issue in the first 6 months of treatment with 12 ver- sus 1 deaths attributed to infection in the everolimus and control arms, respectively. This did not appear to be the result of prolonged neutropenia but may be attributable to the immunosuppressive effects of everolimus when given with chemotherapy, which reflects what has been seen with the use of the mTOR inhibitor in solid tumors.15 This in turn contributed to sub-optimal drug delivery for many patients. The chosen schedule of 10 mg daily was not fea- sible in this setting, but drug delivery improved when a 5 mg daily dose was introduced. Other studies in leukemia have used equivalent schedules16,17 or a loading dose (12 mg) followed by 4 mg/day for 7 days per cycle11 or lower doses in combination with low-dose Ara-C.18 However even when the subgroup of good compliers was compared separately, there was no evidence of improved disease control.
We had hoped that the development of an assay to quantitate plasma inhibitory activity would provide insight into response or toxicity, but unlike the experience of plasma inhibitory activity in the setting of an FLT3 inhibitor,19,20 consistent correlations were not found. In a phase 2 study of patients with relapsed AML treated with clofarabine and temsirolomus, correlation of response to dephosphorylation of pS6RP (S6 ribosomal protein) was demonstrated.21 However the target cells were the patients’ own blasts, which were not available in the cur- rent study and it was unclear whether the clinical out- come was superior to that which clofarabine alone could achieve.
Finally the mTOR inhibitors tested to date have been inhibitors of the TORC1 pathway. This may be by-passed by the TORC2 pathway which is insensitive to this class of mTOR inhibitors, but may be sensitive to agents which produce dual inhibition.
Acknowledgments
The authors are grateful to Novartis for the provision of everolimus, to Cancer Research UK for research funding of the trial and to the investigators, research staff and patients in the participating sites:
Aalborg Hospital: Maria Kallenbach; Aarhus University Hospital: Hans Beier Ommen, Jan Maxwell Norgaard; Aberdeen Royal Infirmary: Dominic Culligan; Addenbrookes Hospital: George Follows, Jenny Craig; Auckland City Hospital: Lucy Pemberton, Richard Doocey, Sophie Lee, Timothy Hawkins; Barnet General Hospital: Andres Virchis; Barts and the London NHS Trust: Jamie Cavenagh, Matthew Smith; Basingstoke and North Hampshire Foundation NHS Trust: Sylwia Simpson; Beatson West of Scotland Cancer Centre: Mark Drummond; Belfast City Hospital: Claire Arnold, Mary Francis McMullin, Robert Cuthbert; Birmingham Heartlands Hospital: Donald Milligan, Guy Pratt, Matthew Lumley, Shankara Paneesha; Blackpool Victoria Hospital NHS Foundation Trust: Paul Cahalin; Borders General Hospital: John Tucker; Bradford Royal infirmary: Adrian Wiliams, Lisa Newton, Sam Ackroyd; Bristol Haematology and Oncology Centre: Priyanka Mehta; Chesterfield Royal Hospital: Mark Wodzinski, Robert Cutting; Christchurch Hospital: Ruth Spearing, Steve Gibbons; Christie Hospital NHS Trust: Mike Dennis; Countess of Chester Hospital: Salah Tuegar; Crosshouse Hospital: Julie Gillies; Derby Hospitals NHS
Foundation Trust: Juanah Addada; Derriford Hospital: Hannah Hunter, Tim Nokes; Doncaster Royal Infirmary: Stuti Kaul; Dorset County Hospital NHS Foundation Trust: Akeel Moosa; East Kent Hospitals University NHS Foundation Trust: Jindriska Lindsay, Vijay Ratnayake; East Sussex Hospitals NHS Trust: Richard Grace; Falkirk and District Royal Infirmary: Christopher Brammer, Marie Hughes; Glan Clwyd Hospital: Christine Hoyle, Earnest Heartin, Margaret Goodrick; Gloucestershire Royal Hospital: Adam Rye, Sally Chown; Great Western Hospital: Alex Sternberg, Atherton Gray, Norrbert Blessing; Guys and St Thomas' Foundation Trust: Kavita Raj, Robert Carr; Hairmyres Hospital: Iain Singer; Heatherwood and Wexham Park NHS Foundation Trust: Nicola Bienz, Simon Moule; Hereford County Hospital: Sara Willoughby; Herlev Hospital: Morten Krogh Jensen, Peter Moller; Hillingdon Hospital: Riaz Janmohamed, Richard Kaczmarski; Hull Royal Infirmary: Sahra Ali; James Cook University Hospital: Ray Dang; James Paget University Hospital: Cesar Gomez, Shala Sadullah; John Radcliffe Hospital: Paresh Vyas; Kettering General Hospital: Isaac Wilson-Morkeh, Matthew Lyttelten; Leicester Royal Infirmary: Ann Hunter, Murray Martin; Lincoln County Hospital: Kandeepan Saravanamuttu; Maidstone Hospital: Evangelia Dimitriadou; Manchester Royal Infirmary: Eleni Tholouli, Guy Lucas; Milton Keynes Hospital NHS Foundation Trust: Moez Dungarwalla; Monklands Hospital: John Murphy, Lindsey Mitchell, Pamela Paterson; New Cross Hospital: Sunil Hada, Supratik Basu; Ninewells Hospital and Medical Centre: Keith Gelly; Norfolk and Norwich University Hospital NHS Foundation Trust: Matthew Lawes; Northampton General Hospital: Angela Bowen, Sajan Mittal, Suchitra Krishnamurthy@Ngh.Nhs.Uk; Nottingham University Hospitals NHS Trust: Emma Dasgupta, Jenny Byrne, Kate Forman, Nigel Russell; Odense University Hospital: Claus Marcher, Lone Friis, Poul Gram Hansen; Peterborough District Hospital: Kanchan Rege; Pinderfields General Hospital: David Wright, Mary Chapple, Paul Moreton; Poole General Hospital: Fergus Jack; Queen Alexandra Hospital: Mary Ganczakowski, Tanya Cranfield; Queen Elizabeth Hospital, Birmingham: Charles Craddock, Jim Murray; Queen Elizabeth Hospital, Norfolk: Jane Keidan; Queens Hospital, Romford: Claire Hemmaway; Raigmore Hospital NHS Highland: Chris Lush, Peter Forsyth; Rigshospitalet: Carsten Niemann, Lars Kjeldsen, Ole Wei Bjerrum, Ove Juul Nielsen, Peter Kampmann; Rotherham General Hospital: Arun Alfred; Royal Berkshire Hospital: Henri Groch, Stuart Mucklow; Royal Cornwall Hospital: Bryson Pottinger, Richard Noble; Royal Devon and Exeter Hospital: Claudius Rudin, Malcolm Hamilton, Paul Kerr; Royal Free Hospital: Panos Kottaridis; Royal Hallamshire Hospital: Chris Dalley, John Snowden; Royal Liverpool University Hospital: Rahuman Salim, Richard Clark; Royal Marsden Hospital: Mark Ethell; Royal Oldham Hospital: Allameddine Allameddine, David Osborne, Hayley Greenfield, Sumaya Elhanash, Vivek Sen; Royal Surrey County Hospital: Johannes Devos, Louise Hendry; Royal Sussex County Hospital: Timothy Corbett; Russell’s Hall Hospital: Jeff Neilson; Salford Royal Hospital: John Houghton, Simon Jowitt, Sonya Zaman; Salisbury Hospital NHS Foundation Trust: Jonathan Cullis, Tamara Everington; Sandwell Hospital: Farooq Wandoo, Yasmin Hasan; Singleton Hospital: Saad Ismail; South Devon Healthcare NHS Foundation Trust: Deborah Turner, Nicholas Rymes; Southampton University Hospital NHS Trust: Deborah Richardson, Kim Orchard, Matthew Jenner; St Helens and Knowsley NHS Trust: Toby Nicholson; St James University Hospital: David Bowen; St Richard’s Hospital: Sarah Janes; Stafford Hospital: Andrew Amos; Stoke
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haematologica | 2018; 103(10)