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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

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
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

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

Adult, Age Factors, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cyclosporins, Cytarabine, Cytogenetic Analysis, Daunorubicin, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Female, Humans, Leukemia, Myeloid, Acute, Leukocyte Count, Male, Middle Aged, Multivariate Analysis, Myelodysplastic Syndromes, Prognosis, Remission Induction, Survival Rate, Journal Article, Randomized Controlled Trial
0007-1048
318-332
Burnett, Alan K.
50a1c448-e723-4da8-9b36-5074383e66de
Milligan, Donald
8b40f81d-a5ba-467f-a944-c127256174d3
Goldstone, Anthony
18a96978-b2e4-4911-904f-d6af5d915c39
Prentice, Archibald
a834a471-b816-4c3a-a3d4-70fa8dd2c982
McMullin, Mary-Frances
feeaf619-229b-4827-ae20-29b9b2b03bf9
Dennis, Michael
ed592cb2-79a8-4141-a402-6c0ea6bcb646
Sellwood, Elizabeth
4498de1f-6127-40ed-9373-e83b4f8872a1
Pallis, Monica
995e1c71-2d32-4878-b565-fd613afa3c44
Russell, Nigel
50041bba-1fd0-47a5-948b-cd8d3e40e426
Hills, Robert K.
0bad705f-3cf8-46cb-80f9-28ce9e75e80d
Wheatley, Keith
7593db84-279b-4f04-886d-ad214fa91b52
Orchard, Kim
794654ab-d6cc-488a-ac11-c9217433c7a2
United Kingdom National Cancer Research Institute Haematological Oncology Study Group
Burnett, Alan K.
50a1c448-e723-4da8-9b36-5074383e66de
Milligan, Donald
8b40f81d-a5ba-467f-a944-c127256174d3
Goldstone, Anthony
18a96978-b2e4-4911-904f-d6af5d915c39
Prentice, Archibald
a834a471-b816-4c3a-a3d4-70fa8dd2c982
McMullin, Mary-Frances
feeaf619-229b-4827-ae20-29b9b2b03bf9
Dennis, Michael
ed592cb2-79a8-4141-a402-6c0ea6bcb646
Sellwood, Elizabeth
4498de1f-6127-40ed-9373-e83b4f8872a1
Pallis, Monica
995e1c71-2d32-4878-b565-fd613afa3c44
Russell, Nigel
50041bba-1fd0-47a5-948b-cd8d3e40e426
Hills, Robert K.
0bad705f-3cf8-46cb-80f9-28ce9e75e80d
Wheatley, Keith
7593db84-279b-4f04-886d-ad214fa91b52
Orchard, Kim
794654ab-d6cc-488a-ac11-c9217433c7a2

Burnett, Alan K., Milligan, Donald, Goldstone, Anthony, Prentice, Archibald, McMullin, Mary-Frances, Dennis, Michael, Sellwood, Elizabeth, Pallis, Monica, Russell, Nigel, Hills, Robert K., Wheatley, Keith and Orchard, Kim , United Kingdom National Cancer Research Institute Haematological Oncology Study Group (2009) 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. British Journal of Haematology, 145 (3), 318-332. (doi:10.1111/j.1365-2141.2009.07604.x).

Record type: Article

Abstract

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

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More information

Accepted/In Press date: 15 December 2008
e-pub ahead of print date: 8 March 2009
Published date: May 2009
Keywords: Adult, Age Factors, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cyclosporins, Cytarabine, Cytogenetic Analysis, Daunorubicin, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Female, Humans, Leukemia, Myeloid, Acute, Leukocyte Count, Male, Middle Aged, Multivariate Analysis, Myelodysplastic Syndromes, Prognosis, Remission Induction, Survival Rate, Journal Article, Randomized Controlled Trial

Identifiers

Local EPrints ID: 413855
URI: https://eprints.soton.ac.uk/id/eprint/413855
ISSN: 0007-1048
PURE UUID: 1649bcb0-558f-4b2f-a528-84ed49877356
ORCID for Kim Orchard: ORCID iD orcid.org/0000-0003-2276-3925

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Date deposited: 07 Sep 2017 16:33
Last modified: 14 Mar 2019 01:45

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Contributors

Author: Alan K. Burnett
Author: Donald Milligan
Author: Anthony Goldstone
Author: Archibald Prentice
Author: Mary-Frances McMullin
Author: Michael Dennis
Author: Elizabeth Sellwood
Author: Monica Pallis
Author: Nigel Russell
Author: Robert K. Hills
Author: Keith Wheatley
Author: Kim Orchard ORCID iD

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