Acute Leukemias

A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia

Article metrics

Abstract

The development of new treatments for older patients with acute myeloid leukaemia (AML) is an active area, but has met with limited success. Sapacitabine is a novel orally administered nucleoside analogue that has shown encouraging activity in unrandomised early-stage trials. We randomised 143 untreated patients with AML or with high-risk myelodysplastic syndrome (>10% marrow blasts) between sapacitibine and low-dose ara-C (LDAC) in our ‘Pick a Winner’ trial design. At the planned interim analysis there was no difference between LDAC and sapacitibine in terms of remission rate (CR/CRi, 27% vs 16% hazard ratio (HR) 1.98(0.90–4.39) P=0.09), relapse-free survival (10% vs 14% at 2 years, HR 0.73(0.33–1.61) P=0.4) or overall survival (OS; 12% vs 11% at 2 years, HR 1.24(0.86–1.78) P=0.2). Sapacitibine was well tolerated, apart from more grade 3/4 diarrhoea. On the basis of these findings sapacitibine did not show sufficient evidence of benefit over LDAC for the trial to be continued.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  1. 1

    Burnett AK, Hills RK, Hunter A, Milligan D, Kell J, Wheatley K et al. The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome. Leukemia 2011; 25: 1122–1127.

  2. 2

    Kantarjian HM, Erba HP, Claxton D, Arellano M, Lyons RM, Kovascovics T et al. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol 2010; 28: 549–555.

  3. 3

    Burnett AK, Russell NH, Kell J, Dennis M, Milligan D, Paolini S et al. European development of clofarabine as treatment for older patients with acute myeloid leukemia not considered unsuitable for intensive chemotherapy. J Clin Oncol 2010; 28: 2389–2395.

  4. 4

    Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood 2013; 122: 1384–1394.

  5. 5

    Burnett AK, Russell NH, Culligan D, Cavanagh J, Kell J, Wheatley K et al. The addition of the farnesyl transferase inhibitor, tipifarnib, to low dose cytarabine does not improve outcome for older patients with AML. Br J Haematol 2012; 158: 519–522.

  6. 6

    Fenaux P, Mufti GJ, Hellstrom-Liindberg E, Santini V, Gattermann N, Germing U et al. Azacytidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010; 28: 562–569.

  7. 7

    Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH et al. Results of a Phase 3, Multicenter, Randomised, Open-label Study of Azacitidine (AZA) vs. conventional Care Regimens (CCR) in Older Patients with Newly Diagnosed Acute Myeloid Leukaemia (AML). Haematologica 2014; 99 (s1): 788 (abstract LB2433).

  8. 8

    Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012; 30 (21): 2670–2677.

  9. 9

    Matsuda J, Nakajima Y, Azuma A, Tanaka M, Sasaki T . Nucleosides and nucleotides: 100. 2’-C-cyano-2’-deoxy-1-β-arabinofuranosylcytosine (CNDAC):Design of a potential mechanism-based DNA-strand-breaking antineoplastic nucleoside. J Med Chem 1991; 34: 2917–2919.

  10. 10

    Azuma A, Huang P, Matsuda A, Plunkett W . 2’-C-cyano-2-deoxy-β-D- arabinopentafuranosyl cytosine: a novel anticancer nucleoside analog that causes both DNA strand breaks and G2 arrest. Mol Pharmacol 2001; 59: 725–731.

  11. 11

    Serova M, Galmarini CM, Ghoul A, Benhadji K, Green SR, Chiao J et al. Antiproliferative effects of sapacitabine (CYC682), a novel2'-deoxycytidine-derivative, in human cancer cells. Br J Cancer 2007; 97: 628–636.

  12. 12

    Katz MH, Bouvet M, Takimoto S, Spivack D, Moossa AR, Hoffman RM . Selective antimetastatic activity of cytosine analog CS-682 in a red fluorescent protein orthotopic model of pancreatic cancer. Cancer Res 2003; 63: 5521–5525.

  13. 13

    Kantarjian H, Garcia-Manero G, O’Brien S, Faderl S, Ravandi F, Westwood R et al. Phase I clinical and pharmacokinetic study of oral sapacitabine in patients with acute leukemia and myelodysplastic syndrome. J Clin Oncol 2010; 28: 285–291.

  14. 14

    Kantarjian H, Faderl S, Garcia-Manero G, Luger S, Venugopal P, Maness L et al. Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study. Lancet Oncol 2012; 13: 1096–1104.

  15. 15

    Hills RK, Burnett AK . Applicability of a ‘Pick a Winner’ trial design to acute myeloid leukemia. Blood 2011; 118: 2389–2394.

  16. 16

    Sorror ML, Giralt S, Sandmaier BM, de Lima M, Shahjahan M, Maloney DG et al. Hematopoietic cell transplantation-specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood 2007; 110: 4606–4613.

  17. 17

    Wheatley K, Brookes CL, Howman AJ, Goldstone AH, Milligan DW, Prentice AG et al. Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials. Br J Haematol 2009; 145: 598–605.

  18. 18

    Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.

  19. 19

    Kantarjian H, O'Brien S, Cortes J, Giles F, Faderl S, Jabbour E et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 2006; 106: 1090–1098.

  20. 20

    Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE et al. Age and acute myeloid leukemia. Blood 2006; 107: 3481–3485.

  21. 21

    Kantarjian H, Ravandi F, O'Brien S, Cortes J, Faderl S, Garcia-Manero G et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 2010; 116: 4422–4429.

  22. 22

    Burnett AK, Milligan D, Goldstone A, Prentice A, McMullin MF, Dennis M et al. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. Br J Haematol 2009; 145: 318–332.

  23. 23

    Krug U, Rollig C, Koschmieder A, Heinecke A, Sauerland MC, Schaich M et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet 2010; 376: 2000–2008.

  24. 24

    Juliusson G, Billstrom R, Gruber A, Hellström-Lindberg E, Höglunds M, Karlsson K et al. Attitude towards remission induction for elderly patients with acute myeloid leukemia influences survival. Leukemia 2006; 20: 42–47.

  25. 25

    Cheson BD, Japerse DM, Simon R, Friedman MA . A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes. J Clin Oncol 4: 1857–1864 1986.

  26. 26

    Tilly H, Castaigne S, Bordessoule D, Casassus P, Le Prisé PY, Tertian G et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 1990; 8: 272–279.

  27. 27

    Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007; 109: 1114–1124.

  28. 28

    Burnett AK, Hills RK, Hunter AE, Milligan D, Kell WJ, Wheatley K et al. The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia 2013; 27: 75–81.

  29. 29

    Ravandi F, Faderl S, Cortes J, Garcia-Manero G, Jabbour E, Boone PA et al Phase I/II study of Sapacitabine and Decitabine administered sequentially in elderly patients with newly diagnosed AML. Abstract #81934. ASCO Annual Meeting 2011.

Download references

Acknowledgements

We are grateful to Cyclacel Ltd for the provision of Sapacitabine for the duration of the study, and to the Haematology Clinical Trials Unit, Cardiff University, for supervising the trial. The following investigators contributed patients to the trial: Aberdeen Royal Infirmary: Dr C Duncan; Addenbrooke's Hospital: Dr C Crawley, Dr J Craig; Airedale General Hospital: Dr A C Cuthbert, Dr C Patalappa; Belfast City Hospital: Dr M F McMullin, Dr R J G Cuthbert; Blackpool Victoria Hospital: Dr P A Cahalin, Dr P R Kelsey; Bradford Royal Infirmary: Dr N Sood, Dr S Ackroyd; Castle Hill Hospital (Hull): Dr S Ali; Cheltenham General Hospital: Dr A Rye; Churchill Hospital: Dr P Vyas; City Hospitals Sunderland: Dr A Nicolle, Dr M J Galloway; Colchester General Hospital: Dr G Campbell, Dr M T Hamblin; Derriford Hospital: Dr T J Nokes; Dorset County Hospital: Dr A Moosa; Gartnavel General Hospital: Dr P McKay; Gloucestershire Royal Hospital: Dr R Frewin; Guy's Hospital: Dr R Carr; Hillingdon Hospital: Dr K Patel, Dr R Kaczmarski; James Paget University Hospital: Dr C Gomez; Kent & Canterbury Hospital: Dr K Saied; Leicester Royal Infirmary: Dr A E Hunter, Dr A M Martin; Medway Maritime Hospital: Dr W Nagi; Musgrove Park Hospital: Dr D Mannari; Norfolk & Norwich University Hospital: Dr M Lawes; North Manchester General Hospital: Dr D Osbourne; North Middlesex Hospital: Dr J Luckit; Northwick Park Hospital: Dr C Kyriakou, Dr N Panoskaltsis; Nottingham University Hospital: Dr E Das-Gupta, Dr J L Byrne, Prof N H Russell; Poole General Hospital: Dr F Jack; Queen Alexandra Hospital (Portsmouth): Dr H Dignum, Dr M Ganczakowski, Dr R Corser; Queen Elizabeth Hospital (Kings Lynn): Dr A J Keidan; Queen's Hospital, Romford: Dr C Hemmaway; Rigshospitalet University Hospital: Dr Lars Kjeldsen, Dr Ove Juul Nielsen; Russells Hall Hospital: Dr S Jenkins; Salford Royal Hospital: Dr S Ravenscroft; Salisbury District Hospital: Dr E Grand, Dr T Everington; Sandwell Hospital: Dr F Wandroo; Singleton Hospital: Dr H Sati, Dr S Al-Ismail; Southampton General Hospital: Dr S Narayanan; St Bartholomew's Hospital: Dr H Oakervee, Dr J Cavenagh; St Helens & Knowsley (Whiston): Dr T Nicholson; St James's University Hospital: Prof D T Bowen; Stoke Mandeville Hospital: Dr A Watson; The James Cook University Hospital: Dr D Plews; The Royal Bournemouth Hospital: Dr J Chacko; The Royal Liverpool Hospital: Dr R Salim; The Royal Oldham Hospital: Dr Allameddine Allameddine, Dr D Osbourne; University College Hospital London: Dr A Khwaja, Dr K G Patterson; University Hospital Aintree: Dr B Hammer, Dr W Sadik; University Hospital of North Tees: Dr Z Maung; University Hospital Of Wales: Dr S Knapper; Victoria Hospital: Dr P Williamson; Western General Hospital: Dr P R E Johnson; Wycombe General Hospital: Dr R Aitchison; York Hospital: Dr L R Bond; Ysbyty Gwynedd: Dr M Hamilton.

Author information

Correspondence to A K Burnett.

Ethics declarations

Competing interests

AKB has acted on a data monitoring committee for Cyclacel Ltd. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading