Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients

A randomised phase 2 study

Hagop Kantarjian, Stefan Faderl, Guillermo Garcia-Manero, Selina Luger, Parameswaran Venugopal, Lori J Maness-Harris, Meir Wetzler, Steven Coutre, Wendy Stock, David Claxton, Stuart L. Goldberg, Martha Arellano, Stephen A. Strickland, Karen Seiter, Gary Schiller, Elias Jabbour, Judy Chiao, William Plunkett

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Background: Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. Methods: In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. Results: Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. Interpretation: Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. Funding: Cyclacel Limited.

Original languageEnglish (US)
Pages (from-to)1096-1104
Number of pages9
JournalThe Lancet Oncology
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2012

Fingerprint

Acute Myeloid Leukemia
Therapeutics
Appointments and Schedules
sapacitabine
Pneumonia
Safety
Recurrence
Febrile Neutropenia
Survival
Cytosine
Random Allocation
Neutropenia
Nucleosides
Thrombocytopenia

ASJC Scopus subject areas

  • Oncology

Cite this

Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients : A randomised phase 2 study. / Kantarjian, Hagop; Faderl, Stefan; Garcia-Manero, Guillermo; Luger, Selina; Venugopal, Parameswaran; Maness-Harris, Lori J; Wetzler, Meir; Coutre, Steven; Stock, Wendy; Claxton, David; Goldberg, Stuart L.; Arellano, Martha; Strickland, Stephen A.; Seiter, Karen; Schiller, Gary; Jabbour, Elias; Chiao, Judy; Plunkett, William.

In: The Lancet Oncology, Vol. 13, No. 11, 01.11.2012, p. 1096-1104.

Research output: Contribution to journalArticle

Kantarjian, H, Faderl, S, Garcia-Manero, G, Luger, S, Venugopal, P, Maness-Harris, LJ, Wetzler, M, Coutre, S, Stock, W, Claxton, D, Goldberg, SL, Arellano, M, Strickland, SA, Seiter, K, Schiller, G, Jabbour, E, Chiao, J & Plunkett, W 2012, 'Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: A randomised phase 2 study', The Lancet Oncology, vol. 13, no. 11, pp. 1096-1104. https://doi.org/10.1016/S1470-2045(12)70436-9
Kantarjian, Hagop ; Faderl, Stefan ; Garcia-Manero, Guillermo ; Luger, Selina ; Venugopal, Parameswaran ; Maness-Harris, Lori J ; Wetzler, Meir ; Coutre, Steven ; Stock, Wendy ; Claxton, David ; Goldberg, Stuart L. ; Arellano, Martha ; Strickland, Stephen A. ; Seiter, Karen ; Schiller, Gary ; Jabbour, Elias ; Chiao, Judy ; Plunkett, William. / Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients : A randomised phase 2 study. In: The Lancet Oncology. 2012 ; Vol. 13, No. 11. pp. 1096-1104.
@article{13a3582b49b24d239b7f21cf423eab9c,
title = "Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: A randomised phase 2 study",
abstract = "Background: Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. Methods: In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20{\%} or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. Results: Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35{\%} (95{\%} CI 16-59) in group A, 10{\%} (2-33) in group B, and 30{\%} (13-54) in group C. 14 (13{\%}) of 105 patients died within 30 days and 27 (26{\%}) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. Interpretation: Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. Funding: Cyclacel Limited.",
author = "Hagop Kantarjian and Stefan Faderl and Guillermo Garcia-Manero and Selina Luger and Parameswaran Venugopal and Maness-Harris, {Lori J} and Meir Wetzler and Steven Coutre and Wendy Stock and David Claxton and Goldberg, {Stuart L.} and Martha Arellano and Strickland, {Stephen A.} and Karen Seiter and Gary Schiller and Elias Jabbour and Judy Chiao and William Plunkett",
year = "2012",
month = "11",
day = "1",
doi = "10.1016/S1470-2045(12)70436-9",
language = "English (US)",
volume = "13",
pages = "1096--1104",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "11",

}

TY - JOUR

T1 - Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients

T2 - A randomised phase 2 study

AU - Kantarjian, Hagop

AU - Faderl, Stefan

AU - Garcia-Manero, Guillermo

AU - Luger, Selina

AU - Venugopal, Parameswaran

AU - Maness-Harris, Lori J

AU - Wetzler, Meir

AU - Coutre, Steven

AU - Stock, Wendy

AU - Claxton, David

AU - Goldberg, Stuart L.

AU - Arellano, Martha

AU - Strickland, Stephen A.

AU - Seiter, Karen

AU - Schiller, Gary

AU - Jabbour, Elias

AU - Chiao, Judy

AU - Plunkett, William

PY - 2012/11/1

Y1 - 2012/11/1

N2 - Background: Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. Methods: In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. Results: Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. Interpretation: Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. Funding: Cyclacel Limited.

AB - Background: Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. Methods: In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. Results: Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. Interpretation: Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. Funding: Cyclacel Limited.

UR - http://www.scopus.com/inward/record.url?scp=84868093252&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868093252&partnerID=8YFLogxK

U2 - 10.1016/S1470-2045(12)70436-9

DO - 10.1016/S1470-2045(12)70436-9

M3 - Article

VL - 13

SP - 1096

EP - 1104

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 11

ER -