(CPG) Acute Myeloid Leukemia National Clinical Practice Guidelines

ACUTE MYELOID LEUKEMIA
NATIONAL CLINICAL PRACTICE GUIDELINES
NATIONAL INTEGRATED
CANCER CONTROL PROGRAM
Acute Myeloid Leukemia National Clinical Practice Guidelines
© Department of Health 2022
Published by
National Integrated Cancer Control Program
Disease Prevention and Control Bureau
Department of Health
San Lazaro Compound, Rizal Avenue, Sta. Cruz
Manila 1003, Philippines
An electronic copy of this publication can be downloaded at: www.doh.gov.ph
Suggested citation. Department of Health. (2022). Acute Myeloid Leukemia National

Clinical Practice Guidelines. Manila, Philippines.
General disclaimers
This document has been produced with the assistance of the Department of Health.
The contents of this publication are the sole responsibility of the Guideline
Development Group, and does not necessarily reflect the opinions, recommendations,
or advice of the Department of Health.
Editorial and Publication Team
Acute Myeloid Leukemia Guideline Development Group
Technical Advisory Group
Chair: Dr. Nilo C. de los Santos

East Avenue Medical Center
Co-chair: Dr. Clarito U. Cairo, Jr.

Members: Ms. Alma B. Abainza-Sanchez

Philippine Health Insurance Corporation
Dr. Allan Troy D. Baquir

Dr. Samuel S. Duran

Steering Committee
Chair: Dr. Lucille Osias
Members: Dr. Lynn Bonifacio

Dr. Prerna Vaswani
Dr. Chrystal Catli-Burog
Dr. Ma. Clariza Santos
Dr. Camille Ariadne Tanchanco
Dr. Mary Shayrel Lagan-Ragas
Dr. Ma. Regina De Leon
Dr. Alma Calavera
Dr. Roxan Perez
Dr. Alejandro Arevalo
Dr. Rose Lou Marie Agbay
Consensus Panel
Chair: Dr. Lucille Osias
Members: Dr. Milflordeliza Gonzaga

Dr. Connie Rose Benjamin
Dr. Karen Kate Tobias
Dr. Noel Pingoy
Dr. Haidee Michelle Lim-Chua
Dr. Januario Veloso
Dr. Marjorie Rose Bravo
Lead Guideline Development Team
Principal Investigator: Dr. Lucille Osias

Principal Co-investigator: Dr. Lynn Bonifacio
Technical Lead: Dr. Ian Theodore Cabaluna
Technical Co-lead: Mr. Teddy Dizon
Support Team: Dr. Jeriel De Silos

Ms. Hygeia Grace C. Agosto
Ms. Jessica A. Hernandez
Implementing Agencies

Healthcare Practice and Policy Management (HPPM), Inc.
Funding Agency
Supporting Agency
Partner Agencies and Societies

Table of Contents
Abbreviation and Acronym i
Acknowledgements ii
Contributors iii
Executive Summary iv
Acute Myeloid Leukemia NCPG Summary v
Introduction 2
Guideline Development Process 4

Phase 1 – Preparation Phase 4
Establishment of the Guideline Development Group 4
Declaration and Management of Conflicts of Interest 5
Identification of the Scope of the NCPG 5
Generation of NCPG questions 5
Phase 2 – Evidence synthesis 6
Overview of evidence synthesis methods 6
Phase 3 – Evidence to Recommendation 7
Phase 4 – Consensus Development 8
Patient Values, Preferences, and Other Considerations 9
Dissemination and Use of the Guideline 9
References 11
Clinical Practice Guidelines 14
Acute Myeloid Leukemia National Clinical Practice Guidelines

Recommendations 15
Diagnosis 15
Question 1. Among patients suspected to have AML, should histopathology (bone
marrow core biopsy and aspirate smears) with Immunohistochemical (IHC)
staining of blasts for MPO, CD34, CD117, CD68 alone be a surrogate test to
diagnose AML compared to histopathology (bone marrow core biopsy and aspirate
smears) with tri-color flow cytometry (CD45, CD34, HLADR, CD45, CD117, MPO,
CD13, CD33, CD56, CD4, CD14)? 15
Recommendation 1a. 15
Consensus Issues 15
Summary of Evidence 15
Research Recommendation 16
References 17
Question 2. Among newly diagnosed AML patients, should conventional
karyotyping compared to FISH [inversion 3 (GATA2/MECOM), 5q del, 7q del,
t(6;9), 11q23 (MLL) or KMT2A, del17p, trisomy 8, BCR ABL1, t(8;21)
(RUNX1/RUNX1T1, t(15;17) (PML/RARA), inv 16, t(16;16) (CBFB)] be used to risk
stratify patients with AML? 18
Consensus Issues 18
References 20
Question 3. Among newly diagnosed AML patients, should a baseline screening
with molecular analysis (FLT3-ITD, c-KIT, ASXL1, FLT-3 ITD, CEBPA, RUNX1,
NPM1, TP53, IDH1, IDH2) be done to risk stratify patients and guide treatment
plan? 21
Consensus Issues 21
References 23
Question 4. Among newly diagnosed AML patients who will undergo
chemotherapy, should HBsAg, anti HBc total, anti HBs, anti HCV, and HIV testing
be done for all patients to improve patient outcomes (i.e., decrease infectious
complications)? 24
Consensus Issues 24
References 25
Question 5. Among patients who have undergone induction chemotherapy, can
histopathology (bone marrow core biopsy and aspirate smears) with IHC staining
of blasts for MPO, CD34, CD117, CD68 with tri-color flow cytometry (CD45, CD34,
HLADR, CD45, CD117, MPO, CD13, CD33, CD, CD 56, CD4, CD14) be a
surrogate to detect minimal residual disease in AML compared to bone marrow
aspirate alone for multi-color (8 color) flow cytometry with BULK lysis? 27
Consensus Issues 27
References 28
Treatment and Care 29
Question 6. Among AML patients who are fit to receive intensive therapy, should
we use Doxorubicin with cytarabine compared to idarubicin with cytarabine for
frontline induction treatment to improve patient outcomes (i.e., remission rate,
disease-free survival, overall survival)? 29
Consensus Issues 29
References 31
Question 7. Among AML patients with intermediate or high-risk cytogenetics in first
remission, should allogeneic hematopoietic stem cell transplant compared to
consolidation chemotherapy be done to improve patient outcomes (i.e., disease-
free survival, overall survival)? 33
Recommendation 7b. 33
Consensus Issues 34
References 37
Question 8. Among newly diagnosed patients unfit for intensive induction
chemotherapy, how effective is HMA monotherapy compared to HMA plus
Venetoclax or LDAC plus Venetoclax in improving clinical outcomes (i.e., overall
survival)? 39
Consensus Issues 39
References 41
Question 9. Among newly diagnosed AML patients with FLT3-ITD mutation, how
effective is standard chemotherapy compared to standard chemotherapy with
FLT3 inhibitor in achieving complete remission? 43
Consensus Issues 43
References 45
Post-treatment Evaluation 46
Question 10. Among patients who are undergoing induction chemotherapy, how
accurate is a day 14 to 21 bone marrow histopathology (bone marrow core biopsy
and aspirate smears) with IHC staining of blasts for MPO, CD34, CD117, CD68
with tri-color flow cytometry (CD45, CD34, HLADR, CD45, CD117, MPO, CD13,
CD33, CD, CD 56, CD4, CD14) compared to bone marrow aspirate alone for multi-
color flow cytometry (8 color) with BULK lysis in predicting clinical outcome (i.e.
remission rate, overall survival) and treatment modification? 46
Consensus Issues 46
References 48
ANNEXES 49
Annex A: GDG COI Declaration and Management 49

Annex A.1. Technical Advisory Group COI Declaration and Management 49
Annex A.2. Steering Committee COI Declaration and Management 50
Annex A.3. Consensus Panel COI Declaration and Management 52
Annex B: Summary of ADAPTE evidence 52

Annex B.1. NCPG PIPOH framework 52
Annex B.2. Search Terms and Search Criteria 52
Annex B.3. PRISMA Flow 54
Annex B.4. Guideline Characteristics 55
Annex B.5. Guideline Assessment and Selection 56
Annex C. CPG Questions in PICO Framework 58

Annex C.1. Diagnosis 58
Annex C.2. Treatment and Care 62
Annex C.3. Post-treatment Evaluation 64
Annex C.4. Source Guideline Content Comparison 65
Annex D: AGREE II Reporting Checklist (Self Evaluation) 68

Abbreviation and Acronym
AML Acute Myeloid Leukemia
AGREE Appraisal of Guidelines for Research and Evaluation
COI Conflict of Interest
CP Consensus Panel
ICPG Interim Clinical Practice Guideline
ERE Evidence Review Experts
GDG Guideline Development Group
GRADE Grading of Recommendations, Assessment, Development and
Evaluation
PG Practice Guideline
NCPG National Clinical Practice Guideline
PICO Population, Intervention, Comparison, Outcome
PIPOH Population, Interventions, Professionals, Outcome, Healthcare Setting
QoE Quality of Evidence
SC Steering Committee
SoR Strength of Recommendation
TAG Technical Advisory Group
i
Acknowledgements
The Department of Health (DOH) with technical assistance from East Avenue Medical
Center (EAMC) and Healthcare Practice and Policy Management, Inc. developed the
Acute Myeloid Leukemia (AML) National Clinical Practice Guideline.
The Technical Advisory Group composed of EAMC, DOH, and PhilHealth

representatives serves as the oversight committee ensuring quality and inclusive
development of the guideline.
EAMC contracted Healthcare Practice and Policy Management, Inc. (HPPM) as an

independent study group to provide highly technical assistance to develop the AML
NCPG through a series of consultations and evidence reviews.
The following partner organizations contributed to the success of this publication:

• East Avenue Medical Center
• National Kidney and Transplant Institute (NKTI)
• Philippine College of Hematology and Transfusion Medicine (PCHTM)
• Philippine Society for Blood and Marrow Transplantation (PSBMT)
• Philippine Society of Pathologists (PSP)
• Philippine College of Physicians (PCP)
ii
Contributors
In collaboration with members of the medical community, national government
agencies, and clinical experts we developed the Acute Myeloid Leukemia National
Clinical Practice Guidelines (AML NCPG). The Consensus Panel (CP) includes
hematologists, pathologists, policy program managers, and primary health care
providers. All contributors completed the declaration of interest form.
The Technical Advisory Group (TAG) was composed of the following representatives:
Dr. Nilo C. de los Santos (EAMC), Dr. Clarito U. Cairo, Jr. (DOH), Ms. Alma B.
Abainza-Sanchez (PhilHealth), Dr. Allan Troy D. Baquir (EAMC) and Dr. Samuel S.
Duran (EAMC).
The Steering Committee (SC) was composed of the following representatives: Dr.
Lucille Osias (EAMC), Dr. Lynn Bonifacio (NKTI), Dr. Prerna Vaswani (PCHTM), Dr.
Chrystal Catli-Burog (PCHTM), Dr. Ma. Clariza Santos (PCHTM), Dr. Camille Ariadne
Tanchanco (PCHTM), Dr. Mary Shayrel Lagan-Ragas (PCHTM), Dr. Ma. Regina De
Leon (PSBMT), Dr. Alma Calavera (PSBMT), Dr. Roxan Perez (PSBMT), Dr.
Alejandro Arevalo (PSP), and Dr. Rose Lou Marie Agbay (PSP).
The Evidence Review Experts (ERE) included the following representatives: Dr. Ian
Theodore G, Cabaluna, Dr. Jeriel de Silos, Mr. Teddy S. Dizon, Ms. Hygeia C. Agosto,
Ms. Jessica A. Hernandez, Dr. Howell Bayona, and Dr. Flordeluna Mesina.
The Consensus Panel was composed of the following representatives: Dr. Lucille
Osias (EAMC)1, Dr. Milflordeliza Gonzaga (PCHTM), Dr. Connie Rose Benjamin
(PCHTM), Dr. Karen Kate Tobias (PCHTM), Dr. Noel Pingoy (PCHTM), Dr. Haidee
Michelle Lim-Chua (PCHTM), Dr. Januario Veloso (PSP) and Dr. Marjorie Rose Bravo
(PSBMT).
1
Non-voting member
iii
Executive Summary
Acute Myeloid Leukemia (AML) is a common type of leukemia among the adult
population. Delayed treatment and diagnosis of AML result in life-limiting and life-
threatening conditions.
The AML National Clinical Practice Guidelines (NCPG) aim to provide evidence-based
standards of diagnosis and treatment that meet all the quality requirements stipulated
in the Appraisal of Guidelines Research and Evaluation (AGREE) II instrument. It
includes high-priority questions on the diagnosis and treatment protocol for this
disease.
The Guideline Development Group (GDG) employed the ADAPTE process in

developing this NCPG. The Technical Advisory Group (TAG) provided the Population,
Intervention, Professionals, Outcomes, and Healthcare setting (PIPOH) framework for
selecting and framing clinical questions. The Steering Committee used this framework
in developing, prioritizing, and rationalizing the practice guideline questions.
The Evidence Review Experts (ERE) conducted evidence-gathering, appraisal, and

synthesis to answer the priority practice guideline questions. Finally, the Consensus
Panel (CP) scrutinized the summary of evidence and participated in the eDelphi
consensus-building process to finalize the recommendation for each practice guideline
question.
iv
Acute Myeloid Leukemia NCPG Summary
The Guideline Development Group used the ADAPTE methodology to generate and finalize the recommendations for AML NCPG,
covering diagnosis and clinical management. The ADAPTE process results in the adoption and adaption of recommendations from
the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines on Acute Myeloid Leukemia and supplemented
from The National Institute for Health and Care Excellence (NICE), American Society of Hematology (ASH), Japanese Society of
Hematology (JSH), Medical Journal of Australia (MJA), American College of Physicians (ACP), and American Society of Clinical
Oncology (ASCO).
Table 1. Acute Myeloid Leukemia NCPG Summary

Clinical Questions Recommendations SoR QoE
Diagnosis
Among patients suspected to have AML, can If available, multiparameter flow cytometry, a laser-
histopathology (bone marrow core biopsy and based technique, should be offered.
aspirate smears) with immunohistochemical
(IHC) staining of blasts for MPO, CD34, CD117 Immunohistochemistry, a microscopy-based
and CD68 alone be a surrogate test to diagnose technique, is recommended as auxiliary to diagnose Strong Low
AML compared to histopathology (bone marrow patients suspected to have AML.
core biopsy and aspirate smears) with tri-color
flow cytometry (CD45, CD34, HLADR, CD45,
CD117, MPO, CD13, CD33, CD56, CD4, CD14)?
Among newly diagnosed AML patients, should We recommend the use of cytogenetic study using
conventional karyotyping compared to FISH conventional karyotyping for risk stratification of
[inversion 3 (GATA2/MECOM), 5q del, 7q del, patients and to guide individualized therapy. In Strong Low
t(6;9), 11q23 (MLL) or KMT2A, del17p, trisomy 8, cases with inadequate karyotype analysis, we
BCR ABL1, t(8;21) (RUNX1/RUNX1T1, t(15;17)
v
(PML/RARA), inv 16, t(16;16) (CBFB)] be used to recommend addition of fluorescence in situ
risk stratify patients with AML? hybridization (FISH).
Among newly diagnosed AML patients, should a We suggest testing for baseline molecular analysis
baseline screening with molecular analysis of c-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA,
(FLT3-ITD, c-KIT, ASXL1, FLT-3 TKD, CEBPA, IDH1, IDH2, RUNX1, ASXL1, and TP53 for gene Weak Low
RUNX1, NPM1, TP53, IDH1, IDH2) be done to mutations to risk stratify patients and guide
risk stratify patients and guide treatment plan? individualized therapy.
Among newly diagnosed AML patients who will
undergo chemotherapy, should HBsAg, anti HBc We suggest testing for HBsAg, anti-HBc total, anti-
Good Practice
total, anti HBs, anti HCV, and HIV testing be HBs, anti-HCV, and HIV especially among high-risk
Statement
done for all patients to improve patient outcomes population group.
(i.e., decrease infectious complications)?
Among patients who have undergone induction
chemotherapy, can histopathology (bone marrow
core biopsy and aspirate smears) with IHC
staining of blasts for MPO, CD34, CD117, CD68
We suggest offering multi-color flow cytometry
with tri-color flow cytometry (CD45, CD34,
among post-induction patients with AML to monitor Weak Low
HLADR, CD45, CD117, MPO, CD13, CD33, CD,
for minimal residual disease, if available.
CD 56, CD4, CD14 be a surrogate to detect
minimal residual disease in AML compared to
bone marrow aspirate alone for multi-color (8
color) flow cytometry with BULK lysis?
Treatment
We recommend standard dose cytarabine with
Among AML patients who are fit to receive
either idarubicin or daunorubicin* or doxorubicin
intensive therapy, should we use doxorubicin with
among patients less than 60 years old with Strong High
cytarabine compared to idarubicin with cytarabine
favorable or intermediate risk cytogenetics, if
for frontline induction treatment to improve patient
available.
vi
outcomes (i.e., remission rate, disease-free
survival, overall survival)?
For patients age <60 years with intermediate-risk
cytogenetics and/or molecular abnormalities
(including MRD positive), we suggest the following
options:
a. matched sibling or alternative donor HCT;
b. HIDAC with or without oral Midostaurin;
c. Cytarabine on days one to four + daunorubicin*
Weak Low
on day one (1st cycle) or days one to two (2nd
cycle) + gemtuzumab ozogamicin* on day one x
two cycles (CD33-positive);
Among AML patients with intermediate or high-
d. Maintenance therapy with oral azacitidine PO
risk cytogenetics in first remission, should we do
OD on days one to 14 of each 28-day cycle until
allogeneic hematopoietic stem cell transplant
progression or unacceptable toxicity (if patients
compared to consolidation chemotherapy to
decline or not fit/eligible for allogenic HCT).
improve patient outcomes (i.e., disease-free
For patients age <60 years with unfavorable
cytogenetics, we suggest the following options:
a. Matched sibling or alternative donor HCT;
c. Dual-drug liposomal encapsulation* of
cytarabine and daunorubicin on days and three Weak Low
x q12 hours;
d. Maintenance therapy with oral azacitidine PO
OD on days one to 14 of each 28-day cycle until
progression or unacceptable toxicity (if patients
decline or not fit/eligible for allogenic HCT).
vii
Among newly diagnosed patients unfit for
We recommend the use of either hypomethylating-
intensive induction chemotherapy, how effective
agent monotherapy with Venetoclax or low-dose-
is HMA monotherapy compared to HMA plus
cytarabine with Venetoclax for older adults with Strong Low
Venetoclax or LDAC plus Venetoclax in
AML considered appropriate for antileukemic
improving clinical outcomes (i.e., overall
therapy but not for intensive antileukemic therapy.
survival)?
Among newly diagnosed AML patients with FLT3-
ITD mutation, how effective is standard
We recommend addition of FLT3-inhibitor in the
chemotherapy compared to standard
management of newly diagnosed adults with acute Strong Low
chemotherapy with FLT3 inhibitor in achieving
FLT3-mutation-positive myeloid leukemia.
complete remission?
Among patients who are undergoing induction

chemotherapy, how accurate is a day 14 to 21
bone marrow histopathology (bone marrow core
biopsy and aspirate smears) with IHC staining of
blasts for MPO, CD34, CD 117, CD 68 with tri- We suggest offering a bone marrow evaluation
color flow cytometry (CD45, CD34, HLADR, (bone marrow aspirate with multicolor flow
CD45, CD117, MPO, CD13, CD33, CD, CD 56, cytometry) 14 to 21 post-therapy to categorize the Weak Low
CD4, CD14) compared to bone marrow aspirate patient according to the presence of blasts or
alone for multi-color flow cytometry (8 color) with hypoplasia.
BULK lysis in predicting clinical outcome (i.e.
remission rate, overall survival) and treatment
modification?
viii
Background
1
Introduction
Leukemia begins in one of the bone marrow's immature cells, wherein a cell's DNA
undergoes one or more mutations, transforming into a type of cancer cell known as a
"leukemia cell" (Leukemia & Lymphoma Society (LLS), 2021). Classification of
leukemia subtypes is according to the rate of progression and the type of cells involved
in the disease.
Acute Myeloid Leukemia (AML) evolved from a single acute leukemia entity to a
complex array of AML sub-entities. AML has distinct pathophysiologic, clinical,
cytogenetic, and molecular characteristics (Kantarjian et al., 2021).
Additionally, AML is a heterogeneous malignancy defined by clonal proliferation and

improper differentiation of myeloid precursors (Yang & Wang, 2018). There are well-
known chromosomal translocations, such as t(8:21) in core-binding factor AML (CBF-
AML) and t(15:17) in Acute Promyelocytic Leukemia (APL). These result in chimeric
proteins – RUNX1-RUNX1T1 and PML-RARA, respectively – that disrupt the normal
maturation process of myeloid precursor cells (De Kouchkovsky & Abdul-Hay, 2016).
Patients diagnosed with AML often experience non-specific symptoms such as fatigue,
weight loss, fever, night sweats, and loss of appetite (Leukemia & Lymphoma Society
(LLS), 2021). These symptoms generally appear over a few weeks and become more
severe as the number of immature white blood cells increases (National Health
Service, 2019). Other signs or symptoms such as but are not limited to include pale or
"washed-out" skin, exhaustion, breathlessness, fever, excessive sweating, weight
loss, frequent infections, unusual and frequent bleeding, easily bruised skin, flat red or
purple spots on the skin, bone and joint pain, a feeling of fullness or discomfort in the
tummy, and swollen glands in the neck (National Health Service, 2019).
A lack of normal blood cells causes many signs and symptoms of AML. It occurs when
the leukemia cells in the bone marrow crowd out the normal blood-making cells. As a
result, normal red blood cells, white blood cells, and blood platelets are in short supply.
While individuals with AML may have elevated white blood cell counts due to an
overabundance of leukemia cells, these cells may not provide the same level of
protection against infection that normal white blood cells do (American Cancer Society,
2018).
Myelodysplastic syndrome, myelofibrosis, aplastic anemia, Down's syndrome, Bloom

syndrome, and exposure to radiation, tobacco, and benzene are risk factors for AML
(Vakiti & Mewawalla, 2019).
The Global Cancer Observatory (2020a) identified leukemia as the 10th leading cause
of cancer death worldwide, with up to 311,594 of all deaths. The global incidence of
2
AML has risen steadily over the last 28 years, from 63,840 cases in 1990 to 119,570
cases in 2017 (Yi et al., 2020). Subgroup analysis by geographical zone revealed the
highest prevalence of AML in Western Europe and South Asia (Yi et al., 2020).
In the Philippines, cancer is among the top three leading causes of mortality (Philippine
Statistics Authority, 2021). Leukemia ranks 5th among all cases of cancer-related
mortalities, with up to 4,370 deaths (Globocan, 2020b).
The five-year survival rate of AML for individuals under 20 years old is only 68%; this
rate decreases to 26% for those 20 years old and above (American Society of Clinical
Oncology, 2021).
3
Guideline Development Process
Phase 1 – Preparation Phase
Establishment of the Guideline Development Group
The guideline development group was composed of policy makers, program

managers, hematologists, blood and bone marrow transplant specialists, and
pathologists. The multidisciplinary and multispecialty professionals composed the
relevant working groups of the AML NCPG, the Technical Advisory Group (TAG), the
Steering Committee (SC), the Evidence Review Experts (ERE), and the Consensus
Panel (CP).
The TAG and the SC comprised the lead NCPG developers. The TAG has the
oversight function to ensure a quality and inclusive NCPG development process.
Nominated members for the TAG included representatives from East Avenue Medical
Center, the Department of Health, and the Philippine Health Insurance Corporation.
The multidisciplinary SC drafted the scope and target audience of the NCPG. They
also identified, ranked, and finalized the clinical questions on diagnosis and clinical
management of AML in the Philippines. The SC identified, invited, reviewed, and
managed the COI of the relevant working groups, such as the steering committee,
evidence reviewers, consensus panelists, and facilitators.
The ERE provided technical assistance in evidence review ranging from the
development of the clinical questions, search and identification of evidence, appraisal
of relevant literature to answer clinical questions, and synthesis of evidence
summaries as the basis of recommendation statements. The ERE for this Guideline
included consultants with backgrounds in clinical epidemiology, information
specialists, medical informatics, and public health.
The CP was a wider group of AML stakeholders. Establishing a more open and diverse
group of stakeholders for the CP — including multidisciplinary healthcare practitioners,
patient advocates, DOH program managers, and other technical content experts —
was aimed at promoting transparency, introducing different perspectives to AML
management, and safeguarding against conflicts of interest. The CP reviewed and
revised the recommendation statements and voted on adopting these statements into
the Guideline.
4
Declaration and Management of Conflicts of Interest
The AML NCPG Guideline Development Group utilized the PhP 1,000,000 DOH sub-
allotment to develop the guideline. The stakeholder of the working groups that
composed the Guideline Development Group (GDG) declared no true conflict interests
related to this material. The stakeholders included in the guideline development
groups were requested to provide a summary of their conflicts of interest (COI) related
to AML. These COIs may be classified into financial and non-financial (or intellectual)
COI. COIs were reviewed by the ERE, and admission of a stakeholder to the GDG
was contingent on the stakeholder having no or minimal COI, following
recommendations in the DOH CPG Manual (DOH [Philippines] 2018). Conflicts of
interest(s) and how COIs were managed are presented in Annex A.
Identification of the Scope of the NCPG
The PIPOH framework was used by the TAG and the SC in defining the scope of this
Guideline, which refers to Population, Intervention, Professionals, Outcomes and
Health Care Setting (ADAPTE Collaboration, 2009). These five items aided the
selection and framing of clinical questions on Population; Intervention of interest –
screening, diagnostics, and treatment/management; Professionals to whom the
guideline will be targeted; specific Outcomes; and Health care setting and context that
the guideline will be implemented.
Generation of NCPG questions
The methodology of clinical question generation is based on frameworks of clinical

practice guidelines (CPG), agenda-setting, and consensus-building (Murphy et al,
1998; The James Lind Alliance, 2020; WHO, 2014). For CPG question development
guidelines, we specifically referred to guidance published by the WHO in 2014. Due
to the COVID-19 pandemic and mobility restrictions at the time of guideline
development, all methods of communication were virtual; no face-to-face, physical
gatherings were conducted.
PIPOH framework was used by the TAG and the SC in defining the scope of this
Guideline, which refers to Population, Intervention, Professionals, Outcomes, and
Health Care Setting (ADAPTE Collaboration, 2009).
Table 2. PIPOH Framework for the AML NCPG Development

Adult (19 years old and above), including elderly, newly
Population
diagnosed, not relapse patients
Intervention Diagnostics, treatment and management
Professionals Medical specialist and allied health professionals
5
Overall survival rate, disease-free survival, recurrence, and
Outcomes
remission
Healthcare Setting Tertiary level of care (hospital or medical centers)
These guidelines included relevant questions on diagnosis and treatment of AML. The
objectives are the following:
1. To present and synthesize the best available evidence on the diagnosis and
treatment of Acute Myeloid Leukemia;
2. To standardize the diagnosis and treatment of Acute Myeloid Leukemia in the
Philippines for the reduction of the burden of disease; and,
3. To complement the existing DOH program mandates on cancer control by
providing evidence to its statements for policy implementation.
The generation of CPG questions is an essential early step in CPG development.

These questions were used as the basis for the subsequent systematic review of the
evidence base on AML (WHO, 2014). CPG questions generated by the SC were
agreed to focus on evidence uncertainties, areas of controversy in the management
of AML and known variations of clinical practice and care especially in the resources
available in the Philippine setting. The SC was then convened in virtual workshops
where the final questions were formulated in PICO (Population, Intervention,
Comparator, and Outcome) format, reviewed, and prioritized according to a
consensus. Technical working groups were assigned for further review and revision to
reach the final PICO format of the clinical questions. The final list of PICO elements
for each CPG question is located in Annex C.
Phase 2 – Evidence synthesis
Overview of evidence synthesis methods
Considering the time and resources to produce quality CPGs, it is recommended that
existing guidelines be adapted to reduce duplication of effort and update existing
guidelines in a shorter period of time. In this CPG development process, guideline
adaptation by the ADAPTE method was considered to address specific health
questions generated. Independent methodologists and reviewers determined if
adaptation of any existing CPG was feasible and consequently created the evidence
base and recommendation matrix.
The ERE utilized the ADAPTE method to review existing guidelines for inclusion in the
evidence base and drafting of recommendation matrix. The ADAPTE collaboration has
developed a systematic approach to aid in the adaptation of guidelines (ADAPTE
Collaboration, 2009). The systematic approach aids in the use and modification of
existing guidelines to customize an existing guideline to suit the local context while
6
addressing relevant health questions. A systematic search of existing guidelines in
multiple databases, including PubMed, Google Scholar and Scopus®. Search terms
and limits are provided in Annex B. Updated versions of the guidelines were also
searched to ensure currency of the recommendations. Assessment of the guidelines
yielded from the systemic search were then given consideration for adaptation by
assessment if it meets the qualities of a high-quality guideline using the Appraisal of
Guidelines Research and Evaluation (AGREE) instrument as well as if it can address
the specific clinical questions. The AGREE II instrument provides a framework for
assessing the quality of CPGs (Brouwers et al, 2013). The 23 items in the AGREE
instrument assess the methods used for developing the guideline and quality of
reporting. Assessment is focused on the rigor and overall score. The domains and
criteria for the AGREE II tool are shown in Annex B. The guidelines were assessed for
guideline quality, currency, content, consistency, and applicability (ADAPTE
Collaboration, 2009). The characteristics and contents of the source guidelines are
summarized in Annex B.
Phase 3 – Evidence to Recommendation
The ERE drafted the initial recommendation statements to include level of evidence
based on the source guidelines and its references. All guidelines included utilized by
recommended Grading of Recommendations, Assessment, Development and
Evaluation (GRADE) for evaluation of level of evidence (Schünemann et al, 2013).
This is the tool developed by the GRADE working group in evaluating the quality of
the evidence and is summarized and defined in Table 3 below.
Table 3. Quality of Evidence Grades (Schünemann et al, 2013)

Grade Definition
We are very confident that the true effect lies close to that of
High
the estimate of the effect.
We are moderately confident in the effect estimate. The true
Moderate effect is likely to be close to the estimate of the effect, but there
is a possibility that it is substantially different.
Our confidence in the effect estimate is limited. The true effect
Low
may be substantially different from the estimate of the effect.
We have very little confidence in the effect estimate. The true
Very Low effect is likely to be substantially different from the estimate of
effect.
The recommendation matrix developed was for finalization of the CP who were
provided by the ERE with a guide on determining the strengths of recommendation
(Schünemann et al, 2013). Recommendations may either be strong or weak. Strong
recommendations refer to issues where the guideline development group may be
confident that the benefits outweigh the risks or costs of an intervention, or vice versa,
whereas weak recommendations are those where there is appreciable uncertainty on
7
the calculus of benefits and risks. A summary of the implication of recommendation
strength on each type of guideline user based on WHO which is reproduced in full in
Table 4.
Table 4. Implications of Strong and Weak Recommendations for Different Users of

Guidelines (WHO, 2014)
Guideline Strong Recommendation Weak Recommendation

Users
Most individuals in this situation The majority of individuals in this
For would want the recommended situation would want the
patients course of action and only a small suggested course of action, but
proportion would not. many would not.
Most individuals should receive Recognize that different choices
the recommended course of will be appropriate for different
action. Adherence to this patients, and that you must help
recommendation according to the
each patient arrive at a
guideline could be used as a
quality criterion or performance management decision consistent
indicator. Formal decision aids with her or his values and
For are not likely to be needed to help preferences. Decision aids may
clinicians individuals make decisions well be useful helping individuals
consistent with their values and making decisions consistent with
preferences. their values and preferences.
Clinicians should expect to
spend more time with patients
when working towards a
decision.
The recommendation can be Policymaking will require
adapted as policy in most substantial debates and
situations including for the use as involvement of many
performance indicators.
stakeholders. Policies are also
For policy more likely to vary between
makers regions. Performance indicators
would have to focus on the fact
that adequate deliberation about
the management options has
taken place.
Phase 4 – Consensus Development
The consensus panel facilitator led the asynchronous consensus-building process

through the eDelphi process. The facilitator sent out the two batches of
recommendations from the ADAPTE evidence evaluation and synthesis for scrutiny
by the consensus panelists. There are three iterations for comments discussions
8
followed by a presentation of the evidence and nominal group technique discussions
(NGT) of recommendations (Delbecq et al., 1986).
Following the NGT discussions, the CP was allowed to revise the recommendation
statements for adaptation and contextualization within reasonable limits as long as the
revision did not alter the value of the underlying evidence. The facilitator was allowed
only to clarify the comments by asking probing exploratory questions. There were no
leading questions asked.
The CP set the 80% consensus agreement on every content and strength of each
recommendation. The CP repeated the cycle of discussions for content and strength
and recommendations that could not reach the consensus marker.
The invited patient and advocacy group did not attend any consensus panel meeting.
To ensure inclusivity, the SC and CP provided email updates and encouraged email
comments or feedback through the project management team.
Patient Values, Preferences, and Other Considerations
As there are no patient nor patient groups present within the SC or CP, results based
on a systematic review of patient or family values, was assessed vis-à-vis the
recommendations of the GDG after consensus made.
The SC and CP thoroughly discussed the applicability of the recommendations using

several criteria, such as improvement of treatment outcomes through availability of
quality affordable drugs and medicines, acceptability to local professional practice,
public health impact, and cost of specialist care based on lived experiences.
Ethics review was sought and approved by the DOH Single Joint Review Board.
External evaluation was sought by the guideline development group through a public
forum with the hematologists where feedbacks were documented and directly
incorporated in the final manuscript.
The DOH as funding agency and EAMC as fund manager did not influence the editorial
independence of the GDG.
Dissemination and Use of the Guideline
The value of a CPG is fully appreciated when it is widely adopted, and adoption is
contingent on access and distribution of the CPG to its target audience. This clinical
practice guideline is available on the DOH website.
The GDG will work closely with DOH and other partners to ensure wide dissemination
of the guideline through different events: (1) Presentation in professional society’s
9
scientific fora; (2) Distribution of the guideline will be done electronically through DOH
and partner society websites; (3) Monitoring/assessment on the uptake of the
guideline will be done through monitoring the number of downloads and request for
distribution, and; (4) Health outcomes will be monitored during the first three years of
guideline distribution specifically on number of cases identified, treated and
surveillance for recurrence reported.
The NCPG recommendations are valid until new significant evidence emerges that
would require a change in recommendation. The ERE recommends revisiting the
Guidelines regularly every three years. The research recommendations may be
considered by policymakers and program managers for future research funding as
part of the continuous quality improvement of healthcare services in the country.
10
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Delbecq, A.L., Van de Ven, A.H., & Gustafson, D.H. (1986). Group techniques for
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(2018). Manual for Clinical Practice Guideline Development (1st ed.). Manila,
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Kantarjian, H., Kadia, T., DiNardo, C., Daver, N., Borthakur, G., Jabbour, E., Garcia-
Manero, G., Konopleva, M., & Ravandi, F. (2021). Acute myeloid leukemia:
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Marteau, T. (1998). Consensus development methods, and their use in clinical
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https://doi.org/10.1186/s13045-020-00908-z
13
Clinical Practice Guidelines
14
Acute Myeloid Leukemia National Clinical Practice
Guidelines Recommendations
Diagnosis
Question 1. Among patients suspected to have AML, should histopathology (bone

marrow core biopsy and aspirate smears) with Immunohistochemical (IHC) staining of
blasts for MPO, CD34, CD117, CD68 alone be a surrogate test to diagnose AML
compared to histopathology (bone marrow core biopsy and aspirate smears) with tri-
color flow cytometry (CD45, CD34, HLADR, CD45, CD117, MPO, CD13, CD33, CD56,
CD4, CD14)?
Recommendation 1a.
If available, multiparameter flow cytometry, a laser-based technique, should be
offered.
Immunohistochemistry, a microscopy-based technique, is recommended as

auxiliary to diagnose patients suspected to have AML.
Strong recommendation, Low quality of evidence
Consensus Issues
The Consensus Panel (CP) voted to adapt and modify the recommendations. A
suggestion was made to indicate the number of white blood cells (WBC) or percent
blasts in the peripheral blood that is considered suitable or acceptable for
immunotyping and cytogenetic testing.
Summary of Evidence
As stated in the National Comprehensive Cancer Network (NCCN) guidelines, bone

marrow core biopsy, aspirate analyses (including immunophenotyping and
cytochemistry), and cytogenetic analyses are useful procedures in planning treatment
for AML patients. Döhner et al. (2017), Ley et al. (2013), and Papaemmanuil et al.
(2016) have demonstrated that gene mutations are associated with prognoses for
certain patients, which have implications in their management.
The application of circulating leukemic blasts from peripheral blood may also be an
alternative specimen in detecting molecular abnormalities. According to the 2016
World Health Organization (WHO) classification, AML diagnosis is established on the
presence of ≥20% blasts in the marrow or peripheral blood. In a clinical setting, it may
15
be with <20% blasts in patients with recurrent cytogenetic abnormalities including
t(15;17), t(8;21), t(16;16), or inv(16) or the corresponding transcript.
With this, the NCCN AML Panel advocated for complementary diagnostic techniques
to be utilized at the discretion of the pathology unit in the institution. Multidisciplinary
diagnostic studies (e.g., immunohistochemistry, cytochemistry, or both), together with
molecular genetics analysis, are necessary in the accurate classification of AML
(NCCN, 2019).
Research Recommendation
The GDG recommended no additional research.
16
References
Cancer Genome Atlas Research Network. (2013). Genomic and epigenomic

landscapes of adult de novo acute myeloid leukemia. New England Journal of
Medicine, 368(22), 2059-2074.
Döhner, H., Estey, E., Grimwade, D., Amadori, S., Appelbaum, F.R., Büchner, T., ...
& Bloomfield, C.D. (2017). Diagnosis and management of AML in adults: 2017
ELN recommendations from an international expert panel. Blood, The Journal
of the American Society of Hematology, 129(4), 424-447.
National Comprehensive Cancer Network. (2019). Acute Myeloid Leukemia Version

3.2019. Journal of the National Comprehensive Cancer Network (JNCCN),
17(6). United States, Pennsylvania.
Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V. I., Paschka, P., Roberts,
N. D., ... & Campbell, P. J. (2016). Genomic classification and prognosis in
acute myeloid leukemia. New England Journal of Medicine, 374(23), 2209-
2221.
17
Question 2. Among newly diagnosed AML patients, should conventional karyotyping
compared to FISH [inversion 3 (GATA2/MECOM), 5q del, 7q del, t(6;9), 11q23 (MLL)
or KMT2A, del17p, trisomy 8, BCR ABL1, t(8;21) (RUNX1/RUNX1T1, t(15;17)
(PML/RARA), inv 16, t(16;16) (CBFB)] be used to risk stratify patients with AML?
Recommendation 2a.
We recommend the use of cytogenetic study using conventional karyotyping for risk
stratification of patients and to guide individualized therapy. In cases with
inadequate karyotype analysis, we recommend addition of fluorescence in situ
hybridization (FISH).
Strong recommendation, Low quality of evidence
Consensus Issues
The Panel members adapted the recommendation but specified that there are areas
in the country with inadequate resources/facilities for investigating genetic
abnormalities in AML.
Summary of Evidence
The molecular pathogenesis of AML has been determined by cytogenetic analysis. It

has been shown that recurrent chromosomal structural variations denote diagnostic
and prognostic markers, implying the significant role of acquired genetic abnormalities
(i.e., somatic mutations) in pathogenesis. (Mrózek et al., 2004; Rowley, 2008). As
such, the WHO 2016 Classification of AML highlighted the importance of testing AML
patients for genetic abnormalities to correctly classify AML (Arber et al, 2016).
Together with molecular testing, cytogenetic analyses (karyotype with fluorescence in

situ hybridization) are beneficial in stratification and treatment guidance among AML
cases (NCCN, 2019). Depending on the genetic abnormalities, the prognosis and
management may differ.
Aside from the above, the 2016 WHO Classification of AML also incorporated all
diagnostic approaches of clinical history, cytogenetics, molecular genetics,
morphology and immunophenotype. Additionally, it included two full entities regarding
specific gene mutations – AML with mutated NPM1 and AML with biallelic mutations
of CEBPA – which are usually early events that are disease-defining.
Data obtained from the said diagnostic strategies are currently important to properly
classify cases of AML, as the collaboration among hematologists, pathologists,
reference laboratories, cytogeneticists and/or molecular pathologists is needed. This
18
ensures diagnoses that have clearer definitions of disease groups, including
prognostic features and potential new targets for treatment (Arber, 2019).
19
References
Arber, D. (2019). The 2016 WHO classification of acute myeloid leukemia: What the
practicing clinician needs to know. Seminars in Hematology, 56(2), 90-95.
https://doi.org/10.1053/j.seminhematol.2018.08.002

Rowley, J. D. (2008). Chromosomal translocations: Revisited yet again. Blood, The

Journal of the American Society of Hematology, 112(6), 2183-2189.
Mrózek, K., Heerema, N. A., & Bloomfield, C. D. (2004). Cytogenetics in acute

leukemia. Blood reviews, 18(2), 115-136.
20
Question 3. Among newly diagnosed AML patients, should a baseline screening with
molecular analysis (FLT3-ITD, c-KIT, ASXL1, FLT-3 ITD, CEBPA, RUNX1, NPM1,
TP53, IDH1, IDH2) be done to risk stratify patients and guide treatment plan?
Recommendation 3a.
We suggest testing for baseline molecular analysis of c-KIT, FLT3-ITD, FLT3-TKD,
NPM1, CEBPA, IDH1, IDH2, RUNX1, ASXL1, and TP53 for gene mutations to risk
stratify patients and guide individualized therapy.
Weak recommendation, Low quality of evidence
Consensus Issues
The Panel members adapted the recommendation on using molecular testing in

stratifying patients. This was based on the NCCN guidelines in testing for gene
mutation to stratify and guide recommendations. The Panel also noted that this
recommendation is subject to the availability of tests.
Summary of Evidence
According to NCCN and European LeukemiaNet (ELN), all AML cases should be
assessed for the following gene mutations: c-KIT, FLT3-ITD, FLT3-TKD, NPM1,
CEBPA, IDH1, IDH2, RUNX1, ASXL1, and TP53. Multiple studies have demonstrated
that mutations in these genes, along with multiplex gene panels and comprehensive
next-generation sequencing (NGS) analysis, are beneficial for the management of
various phases of treatment among patients. (Döhner et al., 2017; Lindsley et al.,
2015; Papaemmanuil et al., 2016).
Genetic analysis among AML patients undergoing intensive therapy showed that the
above gene mutations and their interactions were drivers of pathogenesis and clinical
prognosis. Döhner et al. (2017) stratified the genetic abnormalities among AML
patients according to their prognosis derived from several studies (Bullinger et al.,
2017; Meyer et al., 2014; Papaemmanuil, 2016; Patel et al., 2012). These may change
as new treatment protocols emerge.
Table 2. Genetic abnormalities and their prognosis (adapted from Döhner et al., 2017)
Favorable Intermediate Adverse/Unfavorable
t(8;21)(q22;q22.1); Mutated NPM1 and t(6;9)(p23;q34.1); DEK-
RUNX1-RUNX1T1 FLT3-ITDhigh† NUP214
inv(16)(p13.1q22) or Wild-type NPM1 without t(v;11q23.3); KMT2A
t(16;16)(p13.1;q22); FLT3-ITD or with FLT3- rearranged
CBFB-MYH1 ITDlow† (without
21
adverse-risk genetic
lesions)
Mutated NPM1 without t(9;11)(p21.3;q23.3); t(9;22)(q34.1;q11.2); BCR-
FLT3-ITD or with FLT3- MLLT3-KMT2A ABL1
ITDlow
Biallelic mutated CEBPA Cytogenetic inv(3)(q21.3q26.2) or
abnormalities not t(3;3)(q21.3;q26.2);
classified as favorable or GATA2,MECOM(EVI1)
adverse −5 or del(5q); −7;
−17/abn(17p)
Complex karyotype
monosomal karyotype
Wild-type NPM1 and FLT3-
ITD high
Mutated RUNX1
Mutated ASXL1
Mutated TP53
22
References
Arber, D.A., Orazi, A., Hasserjian, R., Thiele, J., Borowitz, M.J., Le Beau, M.M.,
Bloomfield, C.D., Cazzola, M., & Vardiman, J.W. (2016). The 2016 revision to
the World Health Organization classification of myeloid neoplasms and acute
leukemia. Blood, 127(20), 2391–2405. https://doi-org.ezp-
prod1.hul.harvard.edu/10.1182/blood-2016-03-643544
Bullinger, L., Döhner, K., & Döhner, H. (2017). Genomics of acute myeloid leukemia
diagnosis and pathways. Journal of Clinical Oncology, 35(9), 934-946.
Döhner, H., Estey, E., Grimwade, D., Amadori, S., Appelbaum, F.R., Büchner, T., ...
& Bloomfield, C.D. (2017). Diagnosis and management of AML in adults: 2017
ELN recommendations from an international expert panel. Blood, The Journal
of the American Society of Hematology, 129(4), 424-447.
Grimwade, D., Ivey, A., & Huntly, B. J. (2016). Molecular landscape of acute myeloid
leukemia in younger adults and its clinical relevance. Blood, The Journal of the
American Society of Hematology, 127(1), 29-41.
Lindsley, R. C., Mar, B. G., Mazzola, E., Grauman, P. V., Shareef, S., Allen, S. L., ...
& Ebert, B. L. (2015). Acute myeloid leukemia ontogeny is defined by distinct
somatic mutations. Blood, The Journal of the American Society of Hematology,
125(9), 1367-1376. https://www.ncbi.nlm.nih.gov/pubmed/25550361
Meyer, S. C., & Levine, R. L. (2014). Translational implications of somatic genomics

in acute myeloid leukaemia. The Lancet Oncology, 15(9), e382-e394.

Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V. I., Paschka, P., Roberts,
N. D., ... & Campbell, P. J. (2016). Genomic classification and prognosis in
2221.
Patel, J. P., Gönen, M., Figueroa, M. E., Fernandez, H., Sun, Z., Racevskis, J., ... &
Levine, R. L. (2012). Prognostic relevance of integrated genetic profiling in
1089.
23
Question 4. Among newly diagnosed AML patients who will undergo chemotherapy,
should HBsAg, anti HBc total, anti HBs, anti HCV, and HIV testing be done for all
patients to improve patient outcomes (i.e., decrease infectious complications)?
Recommendation 4a.
We suggest testing for HBsAg, anti-HBc total, anti-HBs, anti-HCV, and HIV
especially among high-risk population group2.
Good Practice Statement
Consensus Issues
The CP members adapted the recommendation of providing hepatitis B surface

antigen (HBsAg), anti-hepatitis B core antibody (HBc) total, anti-hepatitis B surface
antibody (HBs), anti-hepatitis C virus (HCV), and human immunodeficiency virus (HIV)
testing to patients, particularly those who belong in high-risk population groups.
Summary of Evidence
Based on several studies (Bruix, 2011; Terrault, 2016), the American College of
Physicians (ACP) Guidelines (2017) stated that it is best practice for patients with
chronic hepatitis B virus (HBV) infection to be routinely tested. Patients who are given
this type of care can have significant reductions in HBV-associated morbidity and
mortality (Cohen et al., 2017; Gordon et al., 2014; Lai et al., 2013; Ward et al., 2012).
2
Men who have sex with men, persons who inject drugs, HIV-positive persons, household and sexual
contacts of HBV-infected persons, persons requiring immunosuppressive therapy.
24
References
Abara, W. E., Qaseem, A., Schillie, S., McMahon, B. J., Harris, A. M., & High Value
Care Task Force of the American College of Physicians and the Centers for
Disease Control and Prevention. (2017). Hepatitis B vaccination, screening,
and linkage to care: best practice advice from the American College of
Physicians and the Centers for Disease Control and Prevention. Annals of
Internal Medicine, 167(11), 794-804. doi: 10.7326/M17-1106
Bruix, J., & Sherman, M. (2011). Management of hepatocellular carcinoma: A update.

Hepatology (Baltimore, Md.), 53(3), 1020. doi: 10.1002/hep.24199
Cohen, C., Holmberg, S. D., McMahon, B. J., Block, J. M., Brosgart, C. L., Gish, R.
G., ... & Block, T. M. (2011). Is chronic hepatitis B being undertreated in the
United States? Journal of Viral Hepatitis, 18(6), 377-383. doi: 10.1111/j.1365-
2893.2010.01401.x
Gordon, S. C., Lamerato, L. E., Rupp, L. B., Li, J., Holmberg, S. D., Moorman, A. C.,
... & CHeCS Investigators. (2014). Antiviral therapy for chronic hepatitis B virus
infection and development of hepatocellular carcinoma in a US population.
Clinical Gastroenterology and Hepatology, 12(5), 885-893. doi:
10.1016/j.cgh.2013.09.062
Lai, C. L., & Yuen, M. F. (2013). Prevention of hepatitis B virus–related hepatocellular

carcinoma with antiviral therapy. Hepatology, 57(1), 399-408. doi:
10.1002/hep.25937
Lok, A. S., McMahon, B. J., Brown Jr, R. S., Wong, J. B., Ahmed, A. T., Farah, W., ...
& Mohammed, K. (2016). Antiviral therapy for chronic hepatitis B viral infection
in adults: a systematic review and meta-analysis. Hepatology, 63(1), 284-306.
doi: 10.1002/hep.28280
Lok, A. S., & McMahon, B. J. (2007). Chronic hepatitis B. HEPATOLOGY-

BALTIMORE THEN ORLANDO-, 45(2), 507
Mast, E. E., Margolis, H. S., Fiore, A. E., Brink, E. W., Goldstein, S. T., Wang, S. A.,
... & Alter, M. J. (2005). A Comprehensive immunization strategy to eliminate
transmission of hepatitis B virus infection in the United States;
recommendations of the Advisory Committee on Immunization Practices
(ACIP); Immunization of infants, children and adolescents; Part I.
Terrault, N. A., Bzowej, N. H., Chang, K. M., Hwang, J. P., Jonas, M. M., & Murad, M.
H. (2016). AASLD guidelines for treatment of chronic hepatitis B. Hepatology
(Baltimore, Md.), 63(1), 261. doi: 10.1002/hep.28156
25
Ward, J. W., Lok, A. S., Thomas, D. L., El-Serag, H. B., & Kim, W. R. (2012). Report
on a single-topic conference on “Chronic Viral Hepatitis–Strategies to Improve
Effectiveness of Screening and Treatment.” Hepatology, 55(1), 307-315. doi:
10.1002/hep.24797
26
Question 5. Among patients who have undergone induction chemotherapy, can
histopathology (bone marrow core biopsy and aspirate smears) with IHC staining of
blasts for MPO, CD34, CD117, CD68 with tri-color flow cytometry (CD45, CD34,
HLADR, CD45, CD117, MPO, CD13, CD33, CD, CD 56, CD4, CD14) be a surrogate
to detect minimal residual disease in AML compared to bone marrow aspirate alone
for multi-color (8 color) flow cytometry with BULK lysis?
Recommendation 5a.
We suggest offering multi-color flow cytometry among post-induction patients with
AML to monitor for minimal residual disease, if available.
Weak recommendation, Low quality of evidence
Consensus Issues
The CP adapted the recommendation of the Japan Society of Hematology (JSH),

wherein the use of multi-color flow cytometry on bone marrow aspirate was an option
due to emerging evidence.
Summary of Evidence
The JSH cited a sub-study of the COG AAML03P1 study, which is a prospective cohort
study involving 340 children and young adults with AML. The presence of residual
disease post-induction as detected by multi-color flow cytometry was a significant
prognostic factor for overall survival (OS) and residual-free survival (RFS) [OS HR
2.46 (95%CI, 1.35 to 4.47) and RFS HR 2.38 (95%CI, 2.46 (1.51 to 3.97) (Loken et
al., 2012). Patients with positive minimal residual disease (MRD) had lower OS and
RFS.
In another study conducted among 202 children and adolescents, presence of MRD
detected by flow cytometry of bone marrow specimens after induction therapy was
correlated with a much lower five-year event free survival compared to those without
(Inaba et al., 2012).
A recent systematic review including 24 studies (n=11,151 patients) showed a

significantly higher five-year OS and disease-free survival (DFS) among those who
are MRD-negative. MRD-negative had a pooled OS of 68% whereas MRD-positive
patients only had 34% OS rate (Short et al., 2020).
27
References
Inaba, H., Coustan-Smith, E., Cao, X., Pounds, S.B., Shurtleff, S.A., Wang, K.Y., ... &
Campana, D. (2012). Comparative analysis of different approaches to measure
treatment response in acute myeloid leukemia. Journal of Clinical Oncology,
30(29), 3625. https://doi.org/10.1200/JCO.2011.41.5323
Loken, M.R., Alonzo, T.A., Pardo, L., Gerbing, R.B., Raimondi, S.C., Hirsch, B.A., ...
& Meshinchi, S. (2012). Residual disease detected by multidimensional flow
cytometry signifies high relapse risk in patients with de novo acute myeloid
leukemia: a report from Children's Oncology Group. Blood, The Journal of the
American Society of Hematology, 120(8), 1581-1588.
https://doi.org/10.1182/blood-2012-02-408336
Short, N.J., Zhou, S., Fu, C., Berry, D.A., Walter, R.B., Freeman, S.D., ... & Ravandi,
F. (2020). Association of measurable residual disease with survival outcomes
in patients with acute myeloid leukemia: a systematic review and meta-analysis.
JAMA Oncology, 6(12), 1890-1899.
https://doi.org/10.1001/jamaoncol.2020.4600
28
Treatment and Care
Question 6. Among AML patients who are fit to receive intensive therapy, should we
use Doxorubicin with cytarabine compared to idarubicin with cytarabine for frontline
induction treatment to improve patient outcomes (i.e., remission rate, disease-free
Recommendation 6a.
We recommend standard dose cytarabine with either idarubicin or daunorubicin or
doxorubicin among patients less than 60 years old with favorable or intermediate
risk cytogenetics, if available.
Strong recommendation, High quality evidence
Consensus Issues
The CP members adapted the recommendation but raised the concern on the cost of
idarubicin and availability of daunorubicin in the Philippines. Doxorubicin more
accessible hence is also prescribed to AML patients.
Although the recommendation is applicable and acceptable to both patients and

clinicians, it must be considered that idarubicin is more costly compared to
doxorubicin. In cases where cost is an issue (i.e., resources of patient are limited), an
alternative anthracycline should be offered.
Summary of Evidence
The standard induction treatment for patients less than 60 years old is formed on a
combination of cytarabine and anthracycline. The anthracycline regimen that is used
frequently is daunorubicin with a dosage of 45 to 60 mg/m2 for three days.
Nevertheless, idarubicin with a dosage of 12 mg/m2 for three days has equivalent
outcomes with fewer patients needing another treatment at the 15th day to complete
remission (CR).
For patients less than 60 years old with previously untreated AML, a study done by
the Eastern Cooperative Oncology Group (ECOG) showed significant increases in CR
rate (71% vs 57%; P<0.001) and median OS (vs 16 months; P=0.003) for those given
daunorubicin at a dosage of 90 mg/m2 for three days (n=327) compared to those who
took it for 45 mg/m2 in three days (n=330). However, the advantage in survival was
seen among patients with favorable and intermediate-risk cytogenetics.
Moreover, studies including a phase III trial conducted in newly diagnosed AML
patients aged 15 to 65 years old, imply that a higher dose of daunorubicin (90 mg/m2)
29
provides improved OS and event-free survival (EFS) rates for FLT3-ITD mutation-
positive cases (Burnett et al., 2016; Lee et al., 2011, 2017).
On a retrospective study of Sherif et.al (2021), 143 patients with de novo AML received
full dose of standard induction therapy using anthracyclines and cytarabine, idarubicin
did not provide a clear advantage over doxorubicin in achieving complete remission.
The GDG recommended the conduct of a costing study on the anthracycline regimen
that will be used for each AML patient, considering their financial capability and age.
30
References
Burnett, A.K., Russell, N.H., & Hills, R.K. (2016). United Kingdom National Cancer
Research Institute Acute Myeloid Leukemia Study Group. Higher daunorubicin
exposure benefits FLT3 mutated acute myeloid leukemia. Blood, 128(3), 449-
452.
Fernandez, H.F., Sun, Z., Yao, X., Litzow, M.R., Luger, S.M., Paietta, E.M., ... &
Tallman, M.S. (2009). Anthracycline dose intensification in acute myeloid
leukemia. New England Journal of Medicine, 361(13), 1249-1259.
Fischer, T., Stone, R.M., DeAngelo, D.J., Galinsky, I., Estey, E., Lanza, C., ... & Giles,
F.J. (2010). Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine
kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with
acute myeloid leukemia and high-risk myelodysplastic syndrome with either
wild-type or mutated FLT3. Journal of Clinical Oncology, 28(28), 4339.
Lee, J.H., Joo, Y.D., Kim, H., Bae, S.H., Kim, M.K., Zang, D.Y., ... & Cooperative Study
Group A for Hematology. (2011). A randomized trial comparing standard versus
high dose daunorubicin induction in patients with acute myeloid leukemia.
Blood, The Journal of the American Society of Hematology, 118(14), 3832-
3841.
Lee, J.H., Kim, H., Joo, Y.D., Lee, W.S., Bae, S.H., Zang, D.Y., ... & Cooperative Study
Group A for Hematology. (2017). Prospective randomized comparison of
idarubicin and high dose daunorubicin in induction chemotherapy for newly
diagnosed acute myeloid leukemia. Journal of Clinical Oncology, 35(24), 2754-
2763.

Sherif, H. A., Magdy, A., Elshesheni, H. A., Ramadan, S. M., & Rashed, R. A. (2021).
Treatment outcome of doxorubicin versus idarubicin in adult acute myeloid
leukemia. Leukemia research reports, 16, 100272.
https://doi.org/10.1016/j.lrr.2021.100272
Stone, R.M., Fischer, T., Paquette, R., Schiller, G., Schiffer, C.A., Ehninger, G., ... &
Giles, F. (2012). Phase IB study of the FLT3 kinase inhibitor Midostaurin with
chemotherapy in younger newly diagnosed adult patients with acute myeloid
leukemia. Leukemia, 26(9), 2061-2068.
31
Stone, R.M., Mandrekar, S.J., Sanford, B.L., Laumann, K., Geyer, S., Bloomfield, C.
D., ... & Döhner, H. (2017). Midostaurin plus chemotherapy for acute myeloid
leukemia with a FLT3 mutation. New England Journal of Medicine, 377(5), 454-
464.
32
Question 7. Among AML patients with intermediate or high-risk cytogenetics in first
remission, should allogeneic hematopoietic stem cell transplant compared to
consolidation chemotherapy be done to improve patient outcomes (i.e., disease-free
Recommendation 7a.
For patients age <60 years with intermediate-risk cytogenetics and/ or molecular
abnormalities (including MRD positive), we suggest the following options:
a. matched sibling or alternative donor HCT;
c. Cytarabine on days 1-4 + daunorubicin* on day one (1st cycle) or days one
to two (2nd cycle) + gemtuzumab ozogamicin* on day one x two cycles
(CD33-positive);
d. Maintenance therapy with oral azacitidine PO OD on days one to 14 of each

28-day cycle until progression or unacceptable toxicity (if patients decline or
not fit/ eligible for allogenic HCT).
Weak recommendation, Low quality evidence
Recommendation 7b.
For patients age <60 years with unfavorable cytogenetics, we suggest the following
options:
a. Matched sibling or alternative donor HCT;
c. Dual-drug liposomal encapsulation* of cytarabine and daunorubicin* on days

and three x q12 hours;
d. Maintenance therapy with oral azacitidine PO OD on days one to 14 of each

28-day cycle until progression or unacceptable toxicity (if patients decline or
not fit/ eligible for allogenic HCT).
33
Consensus Issues
Consolidation chemotherapy (patients <60 years old)
The CP adapted the NCCN recommendation on the use of consolidation

chemotherapy among patients less than 60 years old with complete response after
therapy. This included the use of Allogeneic HCT, or chemotherapy, for patients over
60 years old who have had a complete response to previous intensive therapy.
In addition, it was noted that daunorubicin, gemtuzumab ozogamicin, midostaurin and

oral azacitidine are not readily available.
Patients <60 years old with intermediate-risk or unfavorable cytogenetics
The CP adapted the NCCN recommendation for people less than 60 years old with
intermediate, and unfavorable cytogenetics.
In addition, it was noted that dual-drug liposomal encapsulation of cytarabine,

daunorubicin, midostaurin and oral azacitidine are not readily available.
Summary of Evidence
Post-remission Therapy and Intensive Antileukemic Therapy
According to the ASH, patients receiving more post-remission therapy seem to do

better than those who receive less therapy. In the clinical trial of Büchner et al. (2003),
which consisted of 832 patients with de novo AML, 69.2% of the patients went into
CR. Although no statistically significant survival benefit was observed in CR patients
(P=0.085), it was discovered that more patients in the maintenance arm than in the S-
HAM arm remained in initial CR (P=0.026).
In the clinical trial of Willemze et al., (2014), CR patients underwent a single

consolidation cycle consisting of daunorubicin and intermediate dose cytarabine (500
mg/m2 every 12 hours for six days). Those who were assigned randomly to standard-
dose cytarabine had a 38.7% OS rate, while patients assigned randomly to high-dose
(HD) cytarabine had a 42.5% OS rate (log-rank test P =0.06). Survival rates were
43.3% and 51.9%, respectively, for patients less than 46 years old (P=0.009;
multivariable analysis P=0.003), and 33.9% and 32.9%, respectively, for patients 46
to 60 years old (P=0.91).
Mayer et al. (1994) treated 1,088 newly diagnosed AML individuals aged 16 and up
with daunorubicin for three days, cytarabine for seven days, and assigned randomly
34
patients who had a CR to receive four sessions of cytarabine at one of three doses.
After 52 months of follow-up, 693 patients had achieved CR, whereas 596 were given
post-remission cytarabine, and the DFS rates in the three groups were considerably
different. The likelihood of remaining alive and disease-free after four years was 21%
in the 100-mg group (95% CI, 15-26%), 25% in the 400-mg group (95% CI, 19-32%),
and 39% in the 3-g group for the 596 patients who were assigned randomly to the
medication (95% CI 32-46%). Furthermore, in each of the three post-remission
cytarabine groups, patients aged 60 and higher had a 16% or lower likelihood of
remaining disease-free after four years.
Cairoli et al. (2006) conducted an Italian retrospective analysis to examine the

prognostic significance of 67 adult patients with the c-KIT mutation. When compared
to the 17 c-KIT unmutated (c-KIT) patients, the 12 TKD816 (tyrosine kinase domain)
mutant patients had a significantly higher recurrence rate and lower OS at 24 months.
There was no difference in relapse rate or OS between c-KIT patients with mutations
other than TKD816 (n = 7) and c-KIT patients without mutations.
To assess the prognostic significance of mutant KIT in core-binding factor acute

myeloid leukemia (AML), 110 patients with de novo CBF AML from Cancer and
Leukemia Group B (CALGB) were studied (Paschka et al., 2006). The study revealed
that KIT mutations were found in 29.5% of the inv(16) and 22% of the t(8;21) AML
participants. For those with mutKIT (P 0.05; 5-year cumulative incidence of relapse
(CIR), 56% v 29%) and mutKIT17 (P=0.002; 5-year cumulative incidence of relapse
(CIR), 80% v 29%) had a greater CIR than wtKIT patients in inv(16). It was observed
that after adjusting for sex, mutKIT predicted a worse OS rate. This confirmed that
those with mutKIT17 had a higher relapse risk.
Chen et al. (2015) conducted a study evaluating the impact of KIT (a proto-oncogene)
mutations on CBF-AML CR and recurrence, as well as the OS and mentioned that KIT
mutations in CBF-AML should be considered in the initial diagnostic workup and
classification of patients with t(8,21) AMP. The probability of relapse in CBF-AML and
t(8;21) AML was shown to be negative. KIT mutations had a deleterious influence on
non-Caucasians' CR (OR, 2.03; 95% CI: 1.02–4.05), relapse risk (RR, 1.89; 95% CI:
1.51–2.37), and OS (RR, 2.26; 95% CI: 1.35–3,78). However, it was also stated that
larger prospective clinical studies are required to assess their findings.
In the prospective study of Jourdan et al. (2013), on days one to three, a 30-minute IV
infusion of daunorubicin (DNR) at 60 mg/m2/d was given, followed by a continuous IV
infusion of cytarabine. On days eight and nine, DNR at 35 mg/m2/d by 30-minute IV
infusion was followed by cytarabine at 1000 mg/m2/12 h by 2-hour IV infusion. For
treatment B, on days one to three, DNR was administered IV for 30 minutes, and
cytarabine was given IV daily from days one to seven. On day 15, patients in arm B
35
had a blood and BM test. Chemotherapy was restarted on day 16 for patients with
more than 5% marrow blasts or Auer rods on day 15. Despite a faster drop in MRD,
reinforced induction had no effect on RFS (64% in both groups; P=0.91). At 36 months,
patients who had a 3-log MRD drop had a 22% recurrence rate and a 73% RFS rate,
respectively. These findings imply that MRD, rather than gene mutations, should be
employed to stratify individuals with CBF-AML in the future.
Based on the systematic review of Dholaria et.al (2020) allo-HCT offers survival
benefit in patients with intermediate- and high-risk AML. On a meta-analysis of 4
intent-to treat AML-CR1 trials with over 3500 allo-HCT recipients and showed
significant relapse-free survival for those whose cytogenetics were adverse risk (HR,
0.76; 95% CI, 0.68 to 0.85) rather than favorable risk (HR, 1.06; 95% CI, 0.80 to 1.42)
the same with the overall survival.
36
References
Post-remission Therapy and Intensive Antileukemic Therapy
Büchner, T., Hiddemann, W., Berdel, W. E., Wormann, B., Schoch, C., Fonatsch, C.,
... & Heinecke, A. (2003). 6-Thioguanine, cytarabine, and daunorubicin (TAD)
and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for
consolidation, and either prolonged maintenance by reduced monthly TAD or
TAD-HAM-TAD and one course of intensive consolidation by sequential HAM
in adult patients at all ages with de novo acute myeloid leukemia (AML): a
randomized trial of the German AML Cooperative Group. Journal of Clinical
Oncology, 21(24), 4496-4504.
Gardin, C., Turlure, P., Fagot, T., Thomas, X., Terre, C., Contentin, N., ... & Dombret,
H. (2007). Postremission treatment of elderly patients with acute myeloid
leukemia in first complete remission after intensive induction chemotherapy:
results of the multicenter randomized Acute Leukemia French Association
(ALFA) 9803 trial. Blood, The Journal of the American Society of Hematology,
109(12), 5129-5135.
Sekeres, M. A., Guyatt, G., Abel, G., Alibhai, S., Altman, J. K., Buckstein, R., ... &
Brignardello-Petersen, R. (2020). American Society of Hematology 2020
guidelines for treating newly diagnosed acute myeloid leukemia in older adults.
Blood advances, 4(15), 3528-3549. doi: 10.1182/bloodadvances. 2020.
Mayer, R. J., Davis, R. B., Schiffer, C. A., Berg, D. T., Powell, B. L., Schulman, P., ...
& Frei, E. (1994). Intensive postremission chemotherapy in adults with acute
myeloid leukemia. New England Journal of Medicine, 331(14), 896-903.

Willemze, R., Suciu, S., Meloni, G. R., Labar, B., Marie, J. P., Halkes, C. J., ... & De
Witte, T. (2014). High-dose cytarabine in induction treatment improves the
outcome of adult patients younger than age 46 years with acute myeloid
leukemia: results of the EORTC-GIMEMA AML-12 trial. Journal of Clinical
Oncology, 32, 219–228.
37
Cairoli, R., Beghini, A., Grillo, G., Nadali, G., Elice, F., Ripamonti, C.B., ... & Morra, E.
(2006). Prognostic impact of c-KIT mutations in core binding factor leukemias:
an Italian retrospective study. Blood, 107(9), 3463-3468.
Chen, W., Xie, H., Wang, H., Chen, L., Sun, Y., Chen, Z., & Li, Q. (2016). Prognostic
significance of KIT mutations in core-binding factor acute myeloid leukemia: a
systematic review and meta-analysis. PloS One, 11(1), e0146614.
Dholaria, B., Savani, B., Hamilton, B… Hamandi, M., Carpenter, P., & Nagler, A.
(2020). Hematopoietic Cell Transplantation in the Treatment of Newly
Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from
the American Society of Transplantation and Cellular Therapy. Transplantation
and Cellular Therapy, 27(1), 6–20. https://doi.org/10.1016/j.bbmt.2020.09.020
Jourdan, E., Boissel, N., Chevret, S., Delabesse, E., Renneville, A., Cornillet, P., ... &
Dombret, H. (2013). Prospective evaluation of gene mutations and minimal
residual disease in patients with core binding factor acute myeloid leukemia.
Blood, The Journal of the American Society of Hematology, 121(12), 2213-
2223.
Paschka, P., Marcucci, G., Ruppert, A.S., Mrózek, K., Chen, H., Kittles, R.A., ... &
Bloomfield, C.D. (2006). Adverse prognostic significance of KIT mutations in
adult acute myeloid leukemia with inv (16) and t (8; 21): A Cancer and Leukemia
Group B Study. Journal of Clinical Oncology, 24(24), 3904-3911.
38
Question 8. Among newly diagnosed patients unfit for intensive induction
chemotherapy, how effective is HMA monotherapy compared to HMA plus Venetoclax
or LDAC plus Venetoclax in improving clinical outcomes (i.e., overall survival)?
Recommendation 8a.
We recommend the use of either hypomethylating-agent with Venetoclax or low-
dose-cytarabine with Venetoclax for older adults with AML considered appropriate
for antileukemic therapy but not for intensive antileukemic therapy.
Strong recommendation, Low quality evidence
Consensus Issues
The CP decided to recognize the AML-ASH2020 guidelines recommending the use of

hypomethylating agents (HMA; monotherapy) or low-dose cytarabine (LDAC;
monotherapy).
In addition, the CP considered and preferred the addition of Venetoclax to standard

HMA or LDAC for older adults considered appropriate for antileukemic therapy but not
for intensive therapy.
Summary of Evidence
Based on the ASH recommendation, giving HMAs or LDAC in combination with other
drugs do not give any significant benefit over HMA or LDAC monotherapy.
In a study comparing the use of LDAC plus arsenic trioxide (ATO) against LDAC
monotherapy among AML patients (median age = 74 years, range 36-86 years), no
significant difference was noted in terms of CR between the LDAC + ATO and LDAC
groups (LDAC + ATO 12% vs LDAC 15%, OR = 1.25, 95% CI [0.51, 3.06]; P=0.6), as
well as in terms of 12-month OS (HR = 1.17, 95% CI [0.83, 1.65]; P=0.4) (Burnett et
al., 2011). One RCT compared the effect of gemtuzumab ozogamicin (GO) + LDAC to
LDAC alone in older patients with AML.
In terms of remission rate, GO + LDAC has a significantly better outcome (GO + LDAC
30% vs LDAC 17%, OR = 0.48, 95% CI [0.32, 0.73]; P=0.006). However, the 12-month
OS rate between the two groups is not significant (GO + LDAC 27% vs LDAC 25%,
HR = 0.99, 95% CI [0.83, 1.16]) (Burnett et al., 2012).
Vosaroxin + LDAC has no significant benefit against LDAC, both in terms of 12-month
survival (Vosaroxin + LDAC 33% vs LDAC 37%, HR = 1.30, 95% CI [0.81, 2.07], P =
0.3) and response rate (Vosaroxin + LDAC 38% vs LDAC 34%, OR = 0.83, 95% CI
[0.37, 1.84], P = 0.6). A reason to this lack of benefit was the Vosaroxin + LDAC
39
group’s excess early mortality, most notably in the second month following
randomization (Dennis et al., 2015).
A randomized, Phase II trial of LDAC and LDAC + volasertib in AML patients (median
age = 75 years) resulted to a significantly higher EFS for LDAC + volasertib (LDAC +
volasertib 5.6 months vs LDAC 2.3 months, HR = 0.57, 95% CI [0.35, 0.92], P = 0.021).
The median OS is also higher for LDAC + volasertib (LDAC + volasertib 8.0 months
vs LDAC 5.2 months, HR = 0.63, 95% CI [0.40, 1.00], P = 0.47) Response rate is also
higher (but insignificant) for LDAC + volasertib (LDAC + volasertib 31.0% vs LDAC
13.3%, OR = 2.91, P = 0.052) (Döhner et al., 2014).
In a randomized, Phase IIb study of LDAC + lintuzumab against LDAC + placebo,

adding lintuzumab to LDAC did not improve survival (LDAC + lintuzumab 14%, LDAC
+ placebo 9%, HR = 0.96, 95% CI [0.72, 1.28], P = 0.7585) (Sekeres et al., 2013).
Combining glasdegib with LDAC for patients with newly diagnosed AML resulted to a
higher median OS (glasdegib + LDAC 8.8 months vs LDAC 4.9 months, HR = 0.51,
80% CI [0.39-0.67], P = 0.0004) and CR (glasdegib + LDAC 17% vs LDAC 2.3%, OR
= 5.03, 80% CI [1.59-15.88], P = 0.0152, and can be an option for AML patients
unsuitable for intensive chemotherapy (Cortes et al., 2019).
In an RCT comparing azacitidine (AZA) + vorinostat (VOR) versus AZA alone, no

difference was seen in the overall response rate (AZA + VOR 42% vs AZA 41%, OR
= 1.05, 95% CI [0.64, 1.72]); P = 0.84) and in the median OS (AZA + VOR 11.0 months
vs AZA 9.6 months, HR = 1.15, 95% CI [0.87, 1.51]; P = 0.32) (Craddock et al., 2017).
A randomized Phase II trial comparing ten days of decitabine with bortezomib against
decitabine alone among elderly patients with AML (median age = 72.4 years, range =
60.5-92.3 years) did not show any improvement in terms of median OS (decitabine +
bortezomib 9.3 months vs 8.9 months, HR = 1.7, 95% CI [0.84, 1.63]; P = 0.18).
Currently, gemtuzumab ozogamicin, vosaroxin, volsertab, vorinostat, and lintuzumab

are not available in the local market, while arsenic trioxide is formerly available but is
no longer distributed in the country.
Bewersdorf et.al (2020) systematic review and meta-analysis, the addition of

Venetoclax has demonstrated promising outcomes but inconclusive.
40
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Stahl, M. (2020). Venetoclax as monotherapy and in combination with
hypomethylating agents or low dose cytarabine in relapsed and treatment
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analysis. Haematologica, 105(11), 2659–2663.
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Burnett, A.K., Hills, R.K., Hunter, A.E., Milligan, D., Kell, W.J., Wheatley, K., Yin, J.,
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gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does
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Burnett, A.K., Hills, R.K., Hunter, A., Milligan, D., Kell, J., Wheatley, K., Yin, J.,
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Cortes, J.E., Heidel, F.H., Hellmann, A., Fiedler, W., Smith, B.D., Robak, T.,
Montesinos, P., Pollyea, D.A., DesJardins, P., Ottmann, O., Ma, W.W., Shaik,
M.N., Laird, A.D., Zeremski, M., O’Connell, A., Chan, G., & Heuser, M. (2019).
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Craddock, C.F., Houlton, A.E., Quek, L.S., Ferguson, P., Gbandi, E., Roberts, C.,
Metzner, M., Garcia-Martin, N., Kennedy, A., Hamblin, A., Raghavan, M.,
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41
Döhner, H., Lübbert, M., Fiedler, W., Fouillard, L., Haaland, A., Brandwein, J.M.,
Lepretre, S., Reman, O., Turlure, P., Ottmann, O.G., Müller-Tidow, C., Krämer,
A., Raffoux, E., Döhner, K., Schlenk, R.F., Voss, F., Taube, T., Fritsch, H., &
Maertens, J. (2014). Randomized, phase 2 trial of low dose cytarabine with or
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Jurcic, J.G. (2013). Randomized phase IIb study of low-dose cytarabine and
lintuzumab versus low-dose cytarabine and placebo in older adults with
untreated acute myeloid leukemia. Haematologica, 98(1), 119–128.
https://doi.org/10.3324/HAEMATOL.2012.066613
42
Question 9. Among newly diagnosed AML patients with FLT3-ITD mutation, how
effective is standard chemotherapy compared to standard chemotherapy with FLT3
inhibitor in achieving complete remission?
Recommendation 9a.
We recommend addition of FLT3-inhibitor in the management of newly diagnosed
adults with acute FLT3-mutation-positive myeloid leukemia.
Strong recommendation, Low quality evidence
Consensus Issues
The CP voted to adopt the recommendation, with a suggestion to include other FLT3
inhibitors aside from Midostaurin, such as in Wei et al. (2020). Sorafenib did not
improve EFS when combined with intensive chemotherapy in adults with newly
diagnosed FLT3-ITD AML. Although not powered for significance, sorafenib showed
a trend for improved OS among patients with higher FLT3-ITD AR or receiving HCT in
CR1.
Summary of Evidence
According to the NICE guidelines (2021), evidence from RATIFY indicated that
individuals taking Midostaurin with chemotherapy live longer than those given
chemotherapy alone. It compared Midostaurin with intensive chemotherapy
(daunorubicin plus cytarabine), followed by Midostaurin monotherapy (n=360) with
chemotherapy alone (n=357).
In the said trial, participants aged 18 to 59 years old were randomized to receive
standard cytarabine therapy (200 mg/m2 daily for seven days via continuous infusion)
and daunorubicin (60 mg/m2 on days one to three) with placebo or Midostaurin (50
mg, twice daily on days eight to 21).
Patients who experienced CR were given four 28-day cycles of HiDAC (3 g/m2 every
12 hours on days one, three, and five) with placebo or Midostaurin (50 mg, twice a day
on days eight to 21), followed by a year of maintenance therapy with placebo or
Midostaurin (50 mg twice a day) (Tallman et al., 2019). The median OS was 74.7
months (95% CI, 31.5–not reached [NR]) in the Midostaurin group and 25.6 months
(95% CI, 18.6–42.9) in the placebo group (P=0.009). It was also found that patients
who were provided with Midostaurin with standard induction and consolidation therapy
had significant improvement in OS (HR for death, 0.78; P=0.009) and EFS (HR for
event or death, 0.78; P=0.002) compared to the placebo group.
43
Studies such as Fischer et al. (2010) and Stone et al. (2012, 2017) have demonstrated
the advantage of including Midostaurin to standard chemotherapy as part of frontline
treatment for patients with newly diagnosed FLT3-mutation-positive AML. Based on
the cost-effectiveness analysis done by NICE, Midostaurin plus chemotherapy
compared with chemotherapy alone are considered an efficient use of resources, as
such Midostaurin is recommended.
In FLT3-mutant cases, of whom majority are found in patients with intermediate-risk

cytogenetics, findings show that the inclusion of Midostaurin to standard
chemotherapy as frontline treatment improved survival, particularly for newly
diagnosed cases. Results of the CALGB 10603/RATIFY Alliance trial (n=717), which
was done in patients aged 18 to 59 years old indicated that those who received
Midostaurin with standard induction and consolidation therapy had significant
improvements in OS (HR for death, 0.78; P=0.009) and EFS (HR for event or death,
0.78; P=0.002), compared to those given placebo (Stone et al., 2017).
44
References
Fischer, T., Stone, R. M., DeAngelo, D. J., Galinsky, I., Estey, E., Lanza, C., ... & Giles,
F. J. (2010). Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine
kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with
acute myeloid leukemia and high-risk myelodysplastic syndrome with either
wild-type or mutated FLT3. Journal of Clinical Oncology, 28(28), 4339.
National Institute for Health and Care Excellence (NICE). 2021. Myeloid Leukemia.
London, United Kingdom.
Stone, R.M., Fischer, T., Paquette, R., Schiller, G., Schiffer, C.A., Ehninger, G., ... &
Giles, F. (2012). Phase IB study of the FLT3 kinase inhibitor Midostaurin with
chemotherapy in younger newly diagnosed adult patients with acute myeloid
leukemia. Leukemia, 26(9), 2061-2068.
Stone, R.M., Mandrekar, S.J., Sanford, B.L., Laumann, K., Geyer, S., Bloomfield, C.
D., ... & Döhner, H. (2017). Midostaurin plus chemotherapy for acute myeloid
leukemia with a FLT3 mutation. New England Journal of Medicine, 377(5), 454-
464.
Tallman, M. S., Wang, E. S., Altman, J. K., Appelbaum, F. R., Bhatt, V. R., Bixby, D.,
... & Ogba, N. (2019). Acute myeloid leukemia, version 3.2019, NCCN clinical
practice guidelines in oncology. Journal of the National Comprehensive Cancer
Network, 17(6), 721-749.
Wei, A. H., Kennedy, G. A., Morris, K. L., Grigg, A., He, S., Schwarer, A., ... & Roberts,
A. W. (2020). Results of a phase 2, randomized, double-blind study of sorafenib
versus placebo in combination with intensive chemotherapy in previously
untreated patients with FLT3-ITD acute myeloid leukemia (ALLG AMLM16).
Blood, 136, 36-38.
45
Post-treatment Evaluation
Question 10. Among patients who are undergoing induction chemotherapy, how
accurate is a day 14 to 21 bone marrow histopathology (bone marrow core biopsy and
aspirate smears) with IHC staining of blasts for MPO, CD34, CD117, CD68 with tri-
color flow cytometry (CD45, CD34, HLADR, CD45, CD117, MPO, CD13, CD33, CD,
CD 56, CD4, CD14) compared to bone marrow aspirate alone for multi-color flow
cytometry (8 color) with BULK lysis in predicting clinical outcome (i.e. remission rate,
overall survival) and treatment modification?
Recommendation 10a.
We suggest offering a bone marrow evaluation (bone marrow aspirate with
multicolor flow cytometry) 14 to 21 days post-therapy to categorize the patient
according to the presence of blasts or hypoplasia.
Consensus Issues
The CP decided to adapt the recommendation from NCCN, Acute Myeloid Leukemia,
Version 3.2019. No suggestions or issues from the Panel members were documented.
Summary of Evidence
The NCCN recommended a bone marrow evaluation 14 to 21 days post-therapy (i.e.,

standard cytarabine/anthracycline induction with or without Midostaurin or GO, or a
dual-drug encapsulation of daunorubicin and cytarabine) to categorize the patient
based on the presence of blasts or hyperplasia.
A retrospective analysis of 194 untreated AML patients found that a day-14 marrow
had a 90% sensitivity in predicting CR on day 28 but had a rather low 43% specificity
and 29% negative predictive value (NPV) (Hussein et al., 2008).
In another retrospective study involving 74 patients, the 14-day bone marrow biopsy
was assessed as to whether it was accurate in determining a patient’s need for re-
induction chemotherapy. Results showed a positive predictive value (PPV) of 15%
(95% CI [0.02; 0.45]) and an NPV of 93% (95% CI [0.81, 0.98]) for the 14-day bone
marrow biopsy. The sensitivity and specificity are observed to be at 40% (95% CI
[0.05, 0.85]) and 79% (95% CI [0.66, 0.89]), respectively (Morris et al., 2013).
A more recent retrospective study about 84 AML patients treated with standard
chemotherapy showed that the 14-day bone marrow biopsy had an 82% sensitivity in
46
predicting CR on Day 28. It also had a specificity of 60% in predicting failure of CR
(Alsaleh et al., 2018).
47
References
Alsaleh, K., Aleem, A., Almomen, A., Anjum, F., & Alotaibi, G.S. (2018). Impact of Day
14 Bone Marrow Biopsy on Re-Induction Decisions and Prediction of a
Complete Response in Acute Myeloid Leukemia Cases. Asian Pacific Journal
of Cancer Prevention : APJCP, 19(2), 421–425.
https://doi.org/10.22034/APJCP.2018.19.2.421
Hussein, K., Jahagirdar, B., Gupta, P., Burns, L., Larsen, K., & Weisdorf, D. (2008).
Day 14 bone marrow biopsy in predicting complete remission and survival in
acute myeloid leukemia. American Journal of Hematology, 83(6), 446–450.
https://doi.org/10.1002/AJH.21133
Morris, T.A., DeCastro, C.M., Diehl, L.F., Gockerman, J.P., Lagoo, A.S., Li, Z., ... &
Rao, A.V. (2013). Re-induction therapy decisions based on day 14 bone
marrow biopsy in acute myeloid leukemia. Leukemia Research, 37(1), 28-31.
https://doi.org/10.1016/J.LEUKRES.2012.09.016

48
ANNEXES
Annex A: GDG COI Declaration and Management
Annex A.1. Technical Advisory Group COI Declaration and Management
Conflict of Interest
Name Affiliation
Intellectual Financial Management
Dr. Nilo C. de los Santos East Avenue Medical Center None None May participate in the NCPG development
Dr. Clarito U. Cairo, Jr. Department of Health None None May participate in the NCPG development
Ms. Alma B. Abainza- PhilHealth None None May participate in the NCPG development
Sanchez
Dr. Samuel S. Duran East Avenue Medical Center None None May participate in the NCPG development
Dr. Allan Troy D. Baquir East Avenue Medical Center None None May participate in the NCPG development
49
Annex A.2. Steering Committee COI Declaration and Management
Name Qualifications
Dr. Lucille Osias East Avenue Medical Center None None May participate in the NCPG development
National Kidney and
Dr. Lynn Bonifacio None None May participate in the NCPG development
Transplant Institute
Philippine College of
Dr. Prerna Vaswani Hematology and Transfusion None None May participate in the NCPG development
Medicine
Dr. Chrystal Catli-Burog Hematology and Transfusion None None May participate in the NCPG development
Medicine
Dr. Ma. Clariza Santos Hematology and Transfusion None None May participate in the NCPG development
Medicine
Dr. Camille Ariadne
Hematology and Transfusion None None May participate in the NCPG development
Tanchanco
Medicine
Dr. Mary Shayrel Lagan-
Ragas
Medicine
Philippine Society for Blood
Dr. Ma. Regina De Leon None None May participate in the NCPG development
and Marrow Transplantation
Dr. Alma Calavera None None May participate in the NCPG development
50
Dr. Roxan Perez None None May participate in the NCPG development
Philippine Society of
Dr. Alejandro Arevalo Pathologists None None May participate in the NCPG development
Dr. Rose Lou Marie Agbay Pathologists None None May participate in the NCPG development
51
Annex A.3. Consensus Panel COI Declaration and Management
Name Qualifications
Dr. Milflordeliza Gonzaga Hematology and Transfusion None None May participate in the NCPG development
Medicine
Dr. Connie Rose Benjamin Hematology and Transfusion None None May participate in the NCPG development
Medicine
Dr. Karen Kate Tobias Hematology and Transfusion None None May participate in the NCPG development
Medicine
Dr. Noel Pingoy Hematology and Transfusion None None May participate in the NCPG development
Medicine
Dr. Haidee Michelle Lim-
Chua
Medicine
Dr. Januario Veloso None None May participate in the NCPG development
Pathologists
Dr. Marjorie Rose Bravo None None May participate in the NCPG development
52
Annex B: Summary of ADAPTE evidence
During the development of the Acute Myeloid Leukemia National Clinical Practice
Guideline (AML NCPG), ADAPTE methodology was used to take advantage of the
existing high-quality guidelines that can be modified or customized to suit the local
context while addressing relevant health questions This is a systematic approach that
was designed to aid in the adaptation of guidelines by the ADAPTE collaboration using
the Appraisal of Guidelines Research and Evaluation (AGREE) II instrument. This, in
turn, provides a framework for assessing the quality of clinical practice guidelines
ensuring that high quality guidelines are used for adaptation.
Annex B.1. NCPG PIPOH framework
Population Adult (19 years old and above), including elderly, newly
diagnosed, not relapse patients
Intervention Diagnostics and Management
Professionals Medical Specialist and Allied Health Professionals
Outcomes Overall survival rate, disease-free survival, recurrence, and
remission
Healthcare setting Tertiary Level of Care (Hospital or Medical Centers)
Annex B.2. Search Terms and Search Criteria
The eight previously identified databases were systematically searched for guidelines
on AML. The following were the inclusion criteria used for selection of applicable
guidelines:
Database Search String Used

PubMed Guideline [Publication Type] OR practice guideline
[Publication Type] or recommendation*[Title] OR standard*
[Title] OR standard* [Title] OR guideline* [Title]) AND
"Leukemia, Myeloid, Acute"[MeSH Terms]
Scopus Guideline [Publication Type] OR practice guideline
Google Scholar Guideline [Publication Type] OR practice guideline
52
Guidelines Guideline [Publication Type] OR practice guideline
International Network [Publication Type] or recommendation*[Title] OR standard*
(GIN) [Title] OR standard* [Title] OR guideline* [Title]) AND
The National Institute Guideline [Publication Type] OR practice guideline
for Health and Care [Publication Type] or recommendation*[Title] OR standard*
Excellence (NICE) [Title] OR standard* [Title] OR guideline* [Title]) AND
Scottish Intercollegiate Guideline [Publication Type] OR practice guideline
Guidelines Network [Publication Type] or recommendation*[Title] OR standard*
(SIGN) [Title] OR standard* [Title] OR guideline* [Title]) AND
EMBASE Guideline [Publication Type] OR practice guideline
Cochrane Guideline [Publication Type] OR practice guideline
Search Criteria in Scoping Review
Inclusion Criteria Exclusion Criteria

1. Clinical practice guidelines for 1. Articles with no available full-text access
Acute Myeloid Leukemia 2. Articles not written in English and without
published in the last 10 years English translation
(2011 – present)
53
Annex B.3. PRISMA Flow
*6 with AGREE II score on RIGOR Domain >75%, 1 with <75% AGREE II score
54
Annex B.4. Guideline Characteristics
Scope
Stakeholder Rigor of Clarity of Editorial
Guideline and Applicability OVERALL SCORE
Involvement Development Presentation Independence
Purpose
AML- 100 97.2
100 100 77.1 100 91.7
ASH2020
AML-
91.7 66.7 87.5 83.3 68.8 87.5 75
NCCN2019
AML-
94.4 100 85.4 100 100 79.2 83.3
NICE2021
AML-
91.7 66.7 87.5 83.3 68.8 87.5 75
NCCN2021
AML-JSH2018 47.2 11.1 18.8 72.2 39.6 33.3 33.3
AML-
97.2 77.8 81.3 100 77.1 91.7 83.3
ACP2017
AML-
91.7 66.7 87.5 83.3 68.8 87.5 75
NCCN2022
55
Annex B.5. Guideline Assessment and Selection
The tables below summarize the characteristics of the included guidelines that were evaluated for adaptation. The rigor dimension of
the AGREE II instrument was completed by two appraisers who were members of the ERE team for the seven guidelines.
Title Publisher Country/ Publication Search Recommendation AGREE II

Language Date Duration Standards Score (Rigor)
NCCN Acute Plymouth
National NCCN Categories
Myeloid Leukemia, Meeting, 07/21 to
Comprehensive 2019 of Evidence and 87.5
Version 3.2019 Pennsylvania/ 05/22
Cancer Network Consensus
English
NCCN Acute Myeloid Plymouth NCCN Categories
National
Leukemia, Version Meeting, 07/21 to of Evidence and
Comprehensive 2021 85.4
2.2021 Pennsylvania/ 05/22 Consensus
Cancer Network
English
NCCN Acute Myeloid Plymouth NCCN Categories
National
Leukemia, Version Meeting, 07/21 to of Evidence and
Comprehensive 2021 87.5
1.2022 Pennsylvania/ 05/22 Consensus
Cancer Network
English
JSH Practical
Guidelines For
Hematological Japanese Society
07/21 to
Malignancies, 2018: I. of Hematology Japan/ English 2020 N/A 18.8
05/22
Leukemia1. Acute
Myeloid Leukemia
(AML)
56
American Society
Of Hematology 2020
Guidelines Washington,
For Treating Newly American Society D.C., United March 25, 07/21 to
GRADE 100
Diagnosed of Hematology States/ 2020 05/22
Acute Myeloid English
Leukemia In
Older Adults
London,
National Institute
Myeloid Leukemia United 07/21 to
for Health and July 14, 2021 N/A 85.4
Kingdom/ 05/22
Care Excellence
English
Hepatitis B
Vaccination,
Screening, And
Linkage To Care: Best
Practice Philadelphia
American College December 5, 07/21 to
Advice From The PA/ English N/A 81.3
of Physicians 2017 05/22
American College Of
Physicians And The
Centers For
Disease Control And
Prevention
57
Annex C. CPG Questions in PICO Framework
Annex C.1. Diagnosis
1. Among patients suspected to have AML, can histopathology (bone marrow core biopsy and aspirate smears) with
Immunohistochemical (IHC) staining of blasts for MPO, CD34, CD117, CD68 alone be a surrogate test to diagnose AML
compared to histopathology (bone marrow core biopsy and aspirate smears) with tri-color flow cytometry (CD45, CD34,
HLADR, CD45, CD117, MPO, CD13, CD33, CD56, CD4, CD14)?
Population Intervention Comparator Outcomes

Patients suspected to Histopathology (bone marrow Histopathology (bone marrow Accuracy, Overall survival
have AML core biopsy and aspirate smear) core biopsy and aspirate smear) rate, disease-free survival
with flow cytometry (CD45, CD34, with IHC staining of blasts for
HLADR, CD117, MPO, CD13, MPO, CD34, CD 117, CD 68
CD33, CD56, CD4, CD14)
58
2. Among newly diagnosed AML patients, should conventional karyotyping compared to FISH [inversion 3 (GATA2/MECOM),
5q del, 7q del, t(6;9), 11q23 (MLL) or KMT2A, del17p, trisomy 8, BCR ABL1, t(8;21) (RUNX1/RUNX1T1, t(15;17)
(PML/RARA), inv 16, t(16;16) (CBFB)] be used to risk stratify patients with AML?
• NON-FAVORABLE: inversion 3 (GATA2/MECOM), 5q del, 7q del, t(6;9), 11q23 (MLL) or KMT2A, del17p, trisomy 8,
BCR ABL1
• FAVORABLE: t(8;21) (RUNX1/RUNX1T1, t(15;17) (PML/RARA), inv 16, t(16;16) (CBFB).

Newly diagnosed AML FISH [inversion 3 Conventional Karyotyping Accuracy for risk
patients (GATA2/MECOM), 5q del, 7q del, stratification, Overall
t(6;9), 11q23 (MLL) or KMT2A, survival rate, disease-free
del17p, trisomy 8, BCR ABL1, survival
t(8;21) (RUNX1/RUNX1T1,
t(15;17) (PML/RARA), inv 16,
t(16;16) (CBFB)]
59
3. Among newly diagnosed AML patients, should a baseline screening with molecular analysis (FLT3-ITD, c-KIT, ASXL1,
FLT-3 TKD, CEBPA, RUNX1, NPM1, TP53, IDH1, IDH2) be done to risk stratify patients and guide treatment plan?

Newly diagnosed AML Baseline screening with No screening with molecular Accuracy for risk
patients molecular analysis analysis stratification, Overall
survival rate, disease-free
survival
4. Among newly diagnosed AML patients who will undergo chemotherapy, should HBsAg, anti HBc total, anti HBs, anti HCV,
and HIV testing be done for all patients to improve patient outcomes (i.e., decrease infectious complications)?

Newly diagnosed AML HBsAg, anti HBc total, anti HBs, No HBsAg, anti HBc total, anti Overall survival rate,
patients anti HCV, and HIV testing HBs, anti HCV, and HIV testing disease-free survival
60
5. Among patients who have undergone induction chemotherapy, can histopathology (bone marrow core biopsy and aspirate
smears) with IHC staining of blasts for MPO, CD34, CD117, CD68 with tri-color flow cytometry (CD45, CD34, HLADR,
CD45, CD117, MPO, CD13, CD33, CD, CD 56, CD4, CD14) be a surrogate to detect minimal residual disease in AML
compared to bone marrow aspirate alone for multi-color (8 color) flow cytometry with BULK lysis?

Newly diagnosed AML Submitting bone marrow aspirate Histopathology with IHC or Accuracy, Overall survival
patients alone for multi-color (8 color) flow Histopathology with tri-color flow rate, disease-free survival
cytometry using BULK lysis
technique
61
Annex C.2. Treatment and Care
6. Among AML patients who are fit to receive intensive therapy, should we use Doxorubicin with cytarabine compared to
idarubicin with cytarabine for frontline induction treatment to improve patient outcomes (i.e., remission rate, disease-free

AML patients fit to receive Doxorubicin with cytarabine Idarubicin with cytarabine Overall survival rate,
intensive therapy disease-free survival,
remission rate
7. Among AML patients with intermediate or high-risk cytogenetics in first remission, should we do allogeneic hematopoietic
stem cell transplant compared to consolidation chemotherapy to improve patient outcomes (i.e., disease-free survival,
overall survival)?

AML patients with Allogeneic hematopoietic stem Consolidation chemotherapy Overall survival rate,
intermediate or high-risk cell transplant disease-free survival
cytogenetics in first
remission
62
8. Among newly diagnosed patients unfit for intensive induction chemotherapy, how effective is HMA monotherapy compared
to HMA plus Venetoclax or LDAC plus Venetoclax in improving clinical outcomes (i.e., overall survival)?

Newly diagnosed patients Hypomethylating agent Hypomethylating agent Overall survival rate
unfit for intensive (Azacitidine or Decitabine) (Azacitidine or Decitabine) plus
induction chemotherapy monotherapy Venetoclax or Low dose
cytarabine (LDAC) plus
Venetoclax
9. Among newly diagnosed AML patients with FLT3-ITD mutation, how effective is standard chemotherapy compared to
standard chemotherapy with FLT3 inhibitor in achieving complete remission?

Newly diagnosed AML Standard chemotherapy Standard chemotherapy with Complete remission,
patients with FLT3-ITD FLT3 inhibitor overall survival
mutation
63
Annex C.3. Post-treatment Evaluation
10. Among patients who are undergoing induction chemotherapy, how accurate is a day 14 to 21 bone marrow histopathology
(bone marrow core biopsy and aspirate smears) with IHC staining of blasts for MPO, CD34, CD117, CD68 with tri-color
flow cytometry (CD45, CD34, HLADR, CD45, CD117, MPO, CD13, CD33, CD, CD 56, CD4, CD14) compared to bone
marrow aspirate alone for multi-color flow cytometry (8 color) with BULK lysis in predicting clinical outcome (i.e. remission
rate, overall survival) and treatment modification?

Patients undergoing Day 14 to 21 bone marrow No day 14 to 21 bone marrow Overall survival, remission
induction chemotherapy assessment using option 1: bone assessment rate
marrow histopathology (bone
marrow core biopsy and aspirate
smears) with IHC staining of
blasts for MPO, CD34, CD117,
CD68 and tri-color flow cytometry
(CD45, CD34, HLADR, CD45,
CD117, MPO, CD13, CD33, CD,
CD 56, CD4, CD14) VERSUS
option 2: bone marrow aspirate
alone for multi-color flow
cytometry (8 color) with BULK
lysis
64
Annex C.4. Source Guideline Content Comparison
Content Comparison
A check (✓) indicates inclusion of the relevant discussion in the guideline
AML NCPG Questions and Recommendations AML- AML- AML- AML- AML- AML- AML-
NCCN NCCN JSH ASH NICE ACP NCCN
2019 2021 2020 2020 2021 2017 2022
Diagnosis
Among patients suspected to have AML, can ✓ ✓
histopathology (bone marrow core biopsy and
aspirate smears) with immunohistochemical (IHC)
staining of blasts for MPO, CD34, CD117, CD68
alone be a surrogate test to diagnose AML
compared to histopathology (bone marrow core
biopsy and aspirate smears) with tri-color flow
cytometry (CD45, CD34, HLADR, CD45, CD117,
MPO, CD13, CD33, CD56, CD4, CD14)?
Among newly diagnosed AML patients, should ✓

conventional karyotyping compared to FISH
[inversion 3 (GATA2/MECOM), 5q del, 7q del,
t(6;9), 11q23 (MLL) or KMT2A, del17p, trisomy 8,
BCR ABL1, t(8;21) (RUNX1/RUNX1T1, t(15;17)
(PML/RARA), inv 16, t(16;16) (CBFB)] be used to
risk stratify patients with AML?
• NON-FAVORABLE: inversion 3 (GATA2/MECOM),

5q del, 7q del, t(6;9), 11q23 (MLL) or KMT2A,
del17p, trisomy 8, BCR ABL1
65
• FAVORABLE: t(8;21) (RUNX1/RUNX1T1, t(15;17)
(PML/RARA), inv 16, t(16;16) (CBFB)
Among newly diagnosed AML patients, should ✓

a baseline screening with molecular analysis
(FLT3-ITD, c-KIT, ASXL1, FLT-3 TKD,
CEBPA, RUNX1, NPM1, TP53, IDH1, IDH2)
be done to risk stratify patients and guide
treatment plan?
Among newly diagnosed AML patients who will ✓

undergo chemotherapy, should HBsAg, anti HBc
total, anti HBs, anti HCV, and HIV testing be done
for all patients to improve patient outcomes (i.e.,
decrease infectious complications)?
Among patients who have undergone induction ✓

chemotherapy, can histopathology (bone marrow
core biopsy and aspirate smears) with IHC staining
of blasts for MPO, CD34, CD 117, CD 68 with tri-
color flow cytometry (CD45, CD34, HLADR, CD45,
CD117, MPO, CD13, CD33, CD, CD 56, CD4,
CD14 be a surrogate to detect minimal residual
disease in AML compared to bone marrow aspirate
alone for multi-color (8 color) flow cytometry with
BULK lysis?
Treatment and Care

Among AML patients who are fit to receive intensive ✓
therapy, should we use Doxorubicin with cytarabine
compared to idarubicin with cytarabine for frontline
induction treatment to improve patient outcomes
66
(i.e., remission rate, disease-free survival, overall
survival)?
Among AML patients with intermediate or high-risk ✓ ✓ ✓

cytogenetics in first remission, should we do
allogeneic hematopoietic stem cell transplant
compared to consolidation chemotherapy to
improve patient outcomes (i.e., disease-free
Among newly diagnosed patients unfit for intensive ✓

induction chemotherapy, how effective is HMA
monotherapy compared to HMA plus Venetoclax or
LDAC plus Venetoclax in improving clinical
outcomes (i.e., overall survival)?
Among newly diagnosed AML patients with FLT3- ✓

ITD mutation, how effective is standard
chemotherapy compared to standard
chemotherapy with FLT3 inhibitor in achieving
complete remission?
Post-treatment Evaluation
Among patients who are undergoing induction ✓
chemotherapy, how accurate is a day 14 to 21
bone marrow histopathology (bone marrow core
biopsy and aspirate smears) with IHC staining of
blasts for MPO, CD34, CD117, CD68 with tri-color
flow cytometry (CD45, CD34, HLADR, CD45,
CD117, MPO, CD13, CD33, CD, CD 56, CD4,
CD14) compared to bone marrow aspirate alone for
multi-color flow cytometry (8 color) with BULK lysis
67
in predicting clinical outcome (i.e. remission rate,
overall survival) and treatment modification?
68
Annex D: AGREE II Reporting Checklist (Self Evaluation)
68
69
70
71
72
73

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ACUTE MYELOID LEUKEMIA

NATIONAL CLINICAL PRACTICE GUIDELINES

© Department of Health 2022

An electronic copy of this publication can be downloaded at: www.doh.gov.ph

Suggested citation. Department of Health. (2022). Acute Myeloid Leukemia National

Technical Advisory Group

Chair: Dr. Nilo C. de los Santos

Co-chair: Dr. Clarito U. Cairo, Jr.

Members: Ms. Alma B. Abainza-Sanchez

Dr. Allan Troy D. Baquir

Dr. Samuel S. Duran

Chair: Dr. Lucille Osias

Members: Dr. Lynn Bonifacio

Chair: Dr. Lucille Osias

Members: Dr. Milflordeliza Gonzaga

Lead Guideline Development Team

Principal Investigator: Dr. Lucille Osias

Technical Lead: Dr. Ian Theodore Cabaluna

Technical Co-lead: Mr. Teddy Dizon

Support Team: Dr. Jeriel De Silos

East Avenue Medical Center

East Avenue Medical Center

Partner Agencies and Societies

Abbreviation and Acronym i

Acute Myeloid Leukemia NCPG Summary v

Guideline Development Process 4

Clinical Practice Guidelines 14

Acute Myeloid Leukemia National Clinical Practice Guidelines

Annex A: GDG COI Declaration and Management 49

Annex B: Summary of ADAPTE evidence 52

Annex C. CPG Questions in PICO Framework 58

Annex D: AGREE II Reporting Checklist (Self Evaluation) 68

The Technical Advisory Group composed of EAMC, DOH, and PhilHealth

EAMC contracted Healthcare Practice and Policy Management, Inc. (HPPM) as an

The following partner organizations contributed to the success of this publication:

The Guideline Development Group (GDG) employed the ADAPTE process in

The Evidence Review Experts (ERE) conducted evidence-gathering, appraisal, and

Table 1. Acute Myeloid Leukemia NCPG Summary

Among patients who are undergoing induction

Additionally, AML is a heterogeneous malignancy defined by clonal proliferation and

Myelodysplastic syndrome, myelofibrosis, aplastic anemia, Down's syndrome, Bloom

Phase 1 – Preparation Phase

Establishment of the Guideline Development Group

The guideline development group was composed of policy makers, program

Identification of the Scope of the NCPG

Generation of NCPG questions

The methodology of clinical question generation is based on frameworks of clinical

Table 2. PIPOH Framework for the AML NCPG Development

The generation of CPG questions is an essential early step in CPG development.

Phase 2 – Evidence synthesis

Overview of evidence synthesis methods

Phase 3 – Evidence to Recommendation

Table 3. Quality of Evidence Grades (Schünemann et al, 2013)

Table 4. Implications of Strong and Weak Recommendations for Different Users of

Guideline Strong Recommendation Weak Recommendation

Phase 4 – Consensus Development

The consensus panel facilitator led the asynchronous consensus-building process

Patient Values, Preferences, and Other Considerations

The SC and CP thoroughly discussed the applicability of the recommendations using