Systemic Treatment of Acute Myeloid Leukemia (AML)

253 Pages·2016·3.38 MB·English

by  Glenn Fletcher

Guideline 12-9

A Quality Initiative of the
Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO)

Systemic Treatment of Acute Myeloid Leukemia (AML)
Andre C Schuh, Glenn G Fletcher, Brian Leber, Mitchell Sabloff, and members of the
Hematology Disease Site Group1

Report Date: February 2, 2016

For information about this document, please contact Andre Schuh,
the senior author, through the PEBC via:
Phone: [phone] ext. 42822 Fax: [phone] E-mail: [email protected]

For information about the PEBC and the most current version of all reports, please visit the
CCO website at http://www.cancercare.on.ca/ or contact the PEBC office at:
Phone: [phone] ext. 42822 Fax: [phone] E-mail: [email protected]

PEBC Report Citation (Vancouver Style): Schuh AC, Fletcher GG, Leber B, Sabloff M, and
members of the Hematology Disease Site Group. Systemic treatment of acute myeloid
leukemia (AML). Toronto (ON): Cancer Care Ontario; 2016 Feb 2. Program in Evidence-Based
Care Guideline No.:12-9.

Copyright
This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced
without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any
time, and at its sole discretion, to change or revoke this authorization.

Disclaimer
Care has been taken in the preparation of the information contained in this report. Nevertheless, any person
seeking to consult the report or apply its recommendations is expected to use independent medical judgment in
the context of individual clinical circumstances or to seek out the supervision of a qualified clinician. Cancer Care
Ontario makes no representations or guarantees of any kind whatsoever regarding the report content or its use or
application and disclaims any responsibility for its use or application in any way.

1 See Appendix 1 for a full list of participants
Guideline 12-9

TABLE OF CONTENTS

TABLE OF CONTENTS ............................................................................ ii
LIST OF ABBREVIATIONS ......................................................................... v
LIST OF FIGURES ................................................................................ vii
LIST OF TABLES................................................................................. viii
SECTION 1: RECOMMENDATIONS SUMMARY ................................................. 1
GUIDELINE OBJECTIVES .............................................................................. 1
RESEARCH QUESTIONS ................................................................................ 1
RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE ................ 1
Preamble ............................................................................................ 1
Question 1. Induction for Previously Untreated AML ........................................ 2
Question 2. Post-Remission Treatment ........................................................ 3
Question 3. Relapsed or Refractory AML ...................................................... 5
Question 4. Which patient characteristics are most important when making
treatment decisions? .............................................................................. 6
SECTION 2: GUIDELINE RECOMMENDATIONS AND KEY EVIDENCE ....................... 7
GUIDELINE OBJECTIVES .............................................................................. 7
TARGET POPULATION ................................................................................ 7
INTENDED USERS ...................................................................................... 7
RESEARCH QUESTIONS ................................................................................ 7
BACKGROUND .......................................................................................... 7
RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE ................ 9
Preamble ............................................................................................ 9
Question 1. Induction for Previously Untreated AML ........................................ 9
Question 2. Post-Remission Treatment ....................................................... 15
Question 3. Relapsed or Refractory AML ..................................................... 19
Question 4. Which patient characteristics are most important when making
treatment decisions? ............................................................................. 21
IMPLEMENTATION CONSIDERATIONS .............................................................. 21
RELATED GUIDELINES ................................................................................ 21
SECTION 3: GUIDELINE METHODS OVERVIEW .............................................. 22
THE PROGRAM IN EVIDENCE-BASED CARE ........................................................ 22
JUSTIFICATION FOR GUIDELINE .................................................................... 22
GUIDELINE DEVELOPERS ............................................................................ 22
GUIDELINE DEVELOPMENT METHODS ............................................................. 23
GUIDELINE REVIEW AND APPROVAL ............................................................... 23
Internal Review ................................................................................... 23
External Review ................................................................................... 24
ACKNOWLEDGEMENTS ............................................................................... 24
SECTION 4: SYSTEMATIC REVIEW ............................................................. 25
INTRODUCTION ....................................................................................... 25
RESEARCH QUESTIONS ............................................................................... 25
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METHODS .............................................................................................. 25
Study Selection Criteria and Process .......................................................... 26
Data Extraction and Assessment of Study Quality and Potential for Bias ................ 26
Synthesizing the Evidence ....................................................................... 27
RESULTS ................................................................................................ 27
Search for Existing Systematic Reviews ....................................................... 27
Literature Search Results ........................................................................ 27
Study Design and Quality ........................................................................ 29
Trial Descriptions ............................................................................ 29
Randomization and Prospective Design ................................................... 29
Allocation Concealment ..................................................................... 29
Blinding ........................................................................................ 29
Power and Sample Size Calculations ...................................................... 30
Appropriate and Complete Outcome Assessment ....................................... 30
Source of Funding ............................................................................ 31
Appropriate Analysis ........................................................................ 31
Overall Quality and Bias Assessment ...................................................... 31
Outcomes .......................................................................................... 32
1. What is the most effective systemic induction treatment for adults with
previously untreated AML? ...................................................................... 32
Induction, Cytarabine Dose or Comparison .............................................. 32
Induction, Nucleoside Analogues other than Cytarabine .............................. 33
Induction, Anthracycline Dose or Schedule .............................................. 34
Induction, Anthracycline Comparison: IDA versus DNR ................................. 34
Induction, Anthracycline Comparison: MTZ versus DNR ................................ 36
Induction, Anthracyclines other than IDA or MTZ compared with DNR .............. 37
Induction, Other Anthracycline Comparisons ............................................ 38
Induction, Etoposide ......................................................................... 38
Induction, ATRA .............................................................................. 39
Induction, Gemtuzumab Ozogamicin ...................................................... 40
Induction, GCSF or GM-CSF ................................................................. 41
Induction, Agents not in other Tables .................................................... 42
2. What is the most effective systemic post-remission treatment (consolidation
and/or maintenance, excluding stem cell transplant) for adults with previously
untreated AML? ................................................................................... 44
Consolidation ................................................................................. 44
Consolidation and Maintenance ............................................................ 46
Maintenance .................................................................................. 47
3. What is the most effective systemic treatment (reinduction, consolidation,
maintenance; not including stem cell transplant) for adults with relapsed or
refractory AML? ................................................................................... 48
4. Which patient characteristics are most important when making treatment
decisions? .......................................................................................... 51
Ongoing, Unpublished, or Incomplete Studies ................................................ 52
DISCUSSION ............................................................................................ 52
Induction in de novo AML ........................................................................ 52
Post-Remission Therapy ......................................................................... 55
Consolidation ................................................................................. 55
Maintenance .................................................................................. 56
Relapsed or Refractory AML ..................................................................... 57
Patient Characteristics .......................................................................... 58
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TABLES ................................................................................................. 60
SECTION 5: INTERNAL AND EXTERNAL REVIEW ......................................... 195
INTERNAL REVIEW .................................................................................. 195
RAP Review and Approval ...................................................................... 195
Expert Panel Review and Approval ............................................................ 197
EXTERNAL REVIEW BY ONTARIO CLINICIANS AND OTHER EXPERTS ....................... 197
Targeted Peer Review .......................................................................... 197
Professional Consultation ....................................................................... 202
Conclusions ....................................................................................... 203
REFERENCES ................................................................................... 204
APPENDICES .................................................................................... 242
APPENDIX 1. MEMBERS OF THE WORKING GROUP AND EXPERT PANEL .................. 242
APPENDIX 2. CONFLICT OF INTEREST .......................................................... 243
APPENDIX 3. LITERATURE SEARCH STRATEGY ............................................... 244
Page iv
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LIST OF ABBREVIATIONS

6MP, 6-mercaptopurine (mercaptopurine)
ACR, aclarubicin
ADE, AraC + DNR + etoposide
A-HAM, ATRA + HAM = all-trans retinoic acid + high-dose cytarabine + mitoxantrone
A-ICE, ATRA + ICE
AML, acute myeloid (myelogenous) leukemia
ANLL, acute non-lymphoid leukemia
AMSA, amsacrine
AraC, cytarabine = arabinofuranosyl cytidine = cytosine arabinoside
ATRA, all-trans retinoic acid
AZA, azacitidine
BHAC, N4-behenoyl-1-β-D-arabinosylcytosine
CBF, core-binding factor
CI, continuous iv infusion
CN-AML, cytogenetically normal AML
COAP, cyclophosphamide, vincristine, AraC, prednisone
CPX-351, a liposomal formulation of cytarabine and daunorubicin (5:1 molar ratio)
CR, complete remission (complete response)
CRi, complete remission with incomplete recovery
CRp, complete remission without full platelet recovery
CsA, cyclosporin A (cyclosporine)
DA, DNR + AraC
DAT, DNR +AraC + 6-thioguanine (TG)
DClo, DNR + clofarabine
DFS, disease-free survival
DNR, daunorubicin
DNX, DaunoXome, a liposomal formulation of daunorubicin
EFS, event-free survival
ELN, European LeukemiaNet
EMA, etoposide + MTZ + AraC
FAI, fludarabine + AraC + IDA
FLAG, fludarabine + high dose AraC + GCSF
FLAI, fludarabine + AraC + IDA
FLAM, flavopiridol + AraC + MTZ
GCSF, granulocyte-colony stimulating factor
GM-CSF, granulocyte-macrophage colony-stimulating factor
GO, gemtuzumab ozogamicin
HAA, homoharringtonine + AraC + ACR
HAD, homoharringtonine + AraC + DNR
HAM, high-dose cytarabine + mitoxantrone
HCT, hematopoietic cell transplantation
HDAC, high-dose cytarabine
HR, hazard ratio
HSCT, hematopoietic blood stem cell transplantation
Page v
Guideline 12-9

ICE, idarubicin + cytarabine + etoposide
IDA, idarubicin
IEiv, IDA + etoposide, iv
IEpo, IDA + etoposide, orally
IFN, interferon
IL-2, interleukin-2
ITT, intention to treat
iv, intravenously
KRN, KRN8602 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride)
LFS, leukemia-free survival
MAC, MTZ + AraC
MACE, amsacrine + AraC +etoposide
MAE, MTZ + AraC + etoposide
MICE, MTZ + AraC + etoposide
MDS, myelodysplastic syndromes
MidAC, MTZ + AraC
MTZ, mitoxantrone
NR, not reported
ns, not significant (not statistically significant)
OR, odds ratio
OS, overall survival
po, oral administration (per os)
PR, partial response/remission
RAEB-t, refractory anemia with excess of blasts in transformation
RD, remission duration
RFI, relapse-free interval (after induction)
RFS, recurrence-free survival
s-AML, secondary AML arising from MDS or myeloproliferative disease
S-HAM, sequential HAM: 2nd course after three days, i.e., HDAC (d 1+2, 8,9) + MTZ (d 3, 4, 10,
11)
SAE, severe adverse effect
sc, subcutaneously
SCT, stem cell transplant
std, standard
t-AML, therapy-related AML following treatment of primary malignant disease
TAD, thioguanine + cytarabine + daunorubicin
TG, 6-thioguanine
TTF, time to treatment failure
VPA, valproic acid
TRM, treatment-related mortality
TSC, timed-sequential chemotherapy
VCR, vincristine
WBC, white blood cell

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Guideline 12-9

LIST OF FIGURES

Figure 4-1. Interrelationship of AML stages and research questions .............................. 28
Figure 4-2. Meta-analysis of trials comparing complete remission rates with idarubicin
versus daunorubicin ....................................................................................... 35
Figure 4-3. Meta-analysis of trials comparing overall survival (four-year OS or five-year
OS) with idarubicin versus daunorubicin ............................................................... 35
Figure 4-4. Meta-analysis of trials comparing complete remission rates with
mitoxantrone versus daunorubicin ...................................................................... 37
Figure 4-5. Meta-analysis of trials comparing complete remission rates with
aclarubicin versus daunorubicin ......................................................................... 38
Figure 4-6. Meta-analysis of trials comparing complete remission rates with etoposide
versus other treatments .................................................................................. 39
Figure 4-7. Meta-analyses of trials comparing complete remission rates with and
without GO ................................................................................................. 40

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Guideline 12-9

LIST OF TABLES

Table 4-1. Induction, cytarabine dose or comparison ............................................... 60
Table 4-2. Induction, nucleoside analogues other than cytarabine ................................ 67
Table 4-3. Induction, anthracycline dose or schedule .............................................. 72
Table 4-4. Induction, anthracycline comparison: IDA versus DNR ................................. 79
Table 4-5. Induction, anthracycline comparison: MTZ versus DNR ................................ 86
Table 4-6. Induction, anthracyclines other than IDA or MTZ compared with DNR .............. 93
Table 4-7. Induction, Other anthracycline comparisons ............................................ 96
Table 4-8. Induction, etoposide .......................................................................102
Table 4-9. Induction, ATRA ............................................................................111
Table 4-10. Induction, gemtuzumab ozogamicin (GO) ..............................................114
Table 4-11. Induction, GCSF or GM-CSF ..............................................................119
Table 4-12. Induction, agents not in other tables ..................................................133
Table 4-13. Induction, planned or ongoing trials ...................................................144
Table 4-14. Consolidation trials (Including those with Induction plus second
randomization) ............................................................................................146
Table 4-15. Consolidation and maintenance trials (or consolidation versus
maintenance) .............................................................................................158
Table 4-16. Maintenance trials (including those with induction plus second
randomization) ............................................................................................165
Table 4-17. Ongoing post-remission trials ...........................................................176
Table 4-18. Relapsed or refractory AML ..............................................................179

Table 5-1. Summary of the Working Group’s responses to comments from RAP ...............195
Table 5-2. Summary of the Working Group’s responses to comments from the Expert
Panel .......................................................................................................197
Table 5-3. Responses to nine items on the targeted peer reviewer questionnaire. ...........198
Table 5-4. Responses to comments from targeted peer reviewers. ..............................198
Table 5-5. Responses to four items on the professional consultation survey. ..................202
Table 5-6. Modifications/actions taken/responses regarding main written comments
from professional consultation. ........................................................................203

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Systemic Treatment of Acute Myeloid Leukemia (AML)

Section 1: Recommendations Summary
SECTION 1: RECOMMENDATIONS SUMMARY

GUIDELINE OBJECTIVES
The primary objective was to make recommendations regarding the most effective
intensive systemic treatment of acute myeloid leukemia (AML) in adult patients. A secondary
objective was to make recommendations regarding use of patient characteristics to
determine appropriate treatment.

TARGET POPULATION
The target population is adult patients with AML (excluding acute promyelocytic
leukemia) who are deemed suitable for intensive treatment.

INTENDED USERS
The intended users are hematologists, oncologists, nurses, and pharmacists.

RESEARCH QUESTIONS
1. What is the most effective systemic induction treatment for adults with previously
untreated AML who can tolerate intensive treatment?

2. What is the most effective systemic post-remission treatment (consolidation and/or
maintenance, excluding stem cell transplant) for adults with previously untreated AML?

3. What is the most effective systemic treatment (reinduction, consolidation, maintenance;
not including stem cell transplant) for adults with relapsed or refractory AML who can
tolerate intensive treatment?

4. Which patient characteristics are most important when making treatment decisions?

RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE

Preamble
After reviewing the literature to arrive at these recommendations there are two important
background issues that will affect their implementation:
1. Fitness or frailty is a key determinant in assessing whether a patient should be offered
induction chemotherapy with curative intent because of the potential toxicity of this
approach. The selection criteria for entry into most of the studies mentioned do not
explicitly address this issue other than age and performance status. In studies
specifying young or elderly patients, the cut-off is often 60 years of age, but 50 to 65
years have been used in some trials. It is becoming clear that age alone is not an
accurate way of determining treatment tolerability and other tools are emerging that
may refine the evaluation of this important factor. These types of studies are either
Section 1: Recommendations Summary– February 2, 2016 Page 1
Guideline 12-9

in progress or in design and will hopefully better define the target population for these
recommendations (1).

2. Due to the complex nature of treatment of AML and the heterogeneous way in which it
is treated in different countries, these recommendations must be considered in the
broader context of the jurisdiction in which the treatments were administered. For
example, comparing the outcomes of different induction regimens may depend on
when bone marrow evaluations were performed to confirm treatment response, and
the number of induction courses that are considered standard (one versus two). Dosing
of agents may also be influenced by the other agents used in the regimen. Similarly,
the outcomes of consolidation regimens may be influenced by the preceding induction
regimen, which is not uniform.

Question 1. Induction for Previously Untreated AML

Recommendation 1
 Cytarabine (cytosine arabinoside, AraC) plus an anthracycline (or anthracenedione) is
recommended as standard induction treatment for AML.
 Conventional-dose AraC at 100-200 mg/m2/day for seven days is recommended
for routine use
 High-dose AraC (HDAC) (1-3 g/m2/day) may be considered in younger patients
and those with poor-risk factors*.
 Idarubicin (IDA), daunorubicin (DNR), and mitoxantrone (MTZ), are the
recommended anthracyclines (anthracenediones) for use with AraC.
 The recommended dose for DNR is 60 mg/m2/day.
 It is recommended that IDA or DNR be administered for three days. Various
regimens with MTZ have been used and are considered acceptable.

*See Preamble above for age considerations and Background (Section 2) for a summary of the
European LeukemiaNet subgroups (2)

Recommendation 2
Addition of gemtuzumab ozogamicin (GO) at 3 mg/m2 to 7+3 regimens is recommended.

Qualifying Statements for Recommendation 2
 Increase in veno-occlusive disease (more recently designated sinusoidal obstructive
syndrome [SOS]) has been reported with GO at 6 mg/m2 (3,4). This was not evident
with doses at 3 mg/m2. The risk of SOS needs to be weighed against the benefit of
receiving GO in patients who are destined to receive an allogeneic cell transplant.
 While the ALFA-0701 trial (5) suggested greater benefit in patients with
cytogenetically normal or with favourable/intermediate genetics, there was
insufficient evidence to restrict the recommendation based on cytogenetics or other
defined subgroups.
 While evidence indicates GO may improve OS and RFS, it is currently not approved for
use in Canada.

Section 1: Recommendations Summary– February 2, 2016 Page 2