Real-world Study in Acute Leukemia: Epidemiology, Treatment Patterns and Outcomes for B-cell ALL and AML in Adult Patients From Latin America - LOYAL Study
Conditions: Acute Myeloid Leukemia, Acute Lymphoid Leukemia
Sponsor: Pfizer

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PPD 
PPD 
PPD 
Co-author 
Author 
Research question and objectives 
20 April 2021 
Date 
1.0 
Protocol version identifier 
X9001302 
Protocol number 
Real-world Study in Acute Leukemia: 
Epidemiology, Treatment Patterns and 
Outcomes for B-cell ALL and AML in Adult 
Patients From Latin America – LOYAL 
Study 
Title 
PPD 
PPD 
PPD 
PPD 
– PPD 
PPD 
To describe the current epidemiology, 
treatment patterns, outcomes and healthcare 
resource use of adult patients diagnosed with 
B-cell ALL R/R and de novo AML in 4 
Latin American countries. 
H&V – 
– Pfizer 
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
 
 
 
NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
 
Study Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS ....................................................................................................... 2 
2. LIST OF ABBREVIATIONS ................................................................................................ 4 
3. RESPONSIBLE PARTIES .................................................................................................... 7 
4. ABSTRACT ........................................................................................................................... 8 
5. AMENDMENTS AND UPDATES ..................................................................................... 10 
6. MILESTONES ..................................................................................................................... 11 
7. RATIONALE AND BACKGROUND ................................................................................ 11 
7.1. Acute Myeloid Leukemia ........................................................................................ 11 
7.2. Acute Lymphoblastic Leukemia .............................................................................. 13 
7.3. Treatment for AML and ALL .................................................................................. 14 
7.4. Rationale .................................................................................................................. 15 
8. RESEARCH QUESTION AND OBJECTIVES .................................................................. 16 
8.1. Primary Objective(s) ................................................................................................ 16 
8.2. Secondary Objective(s) ............................................................................................ 16 
9. RESEARCH METHODS ..................................................................................................... 17 
9.1. Study Design ............................................................................................................ 17 
9.2. Setting ...................................................................................................................... 17 
9.2.1. Inclusion Criteria ......................................................................................... 18 
9.2.2. Exclusion Citeria ......................................................................................... 18 
9.2.3. Study Definitions......................................................................................... 18 
9.3. Variables .................................................................................................................. 21 
9.3.1. Outcomes .................................................................................................... 22 
9.3.1.1. Primary Outcomes ..................................................................... 22 
9.3.1.2. Secondary Outcomes ................................................................. 22 
9.3.2. Variables and Epidemiological Measurements ........................................... 23 
9.4. Data Sources ............................................................................................................ 24 
9.5. Study Size ................................................................................................................ 24 
9.6. Data Management .................................................................................................... 24 
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic 
Data Record ...................................................................................................... 25 
9.6.2. Record Retention ......................................................................................... 25 
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9.7. Data Analysis .......................................................................................................... 26 
9.8. Quality Control ....................................................................................................... 27 
9.9. Limitations of the Research Methods ..................................................................... 27 
9.10. Other Aspects........................................................................................................ 28 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................ 28 
10.1. Patient Information ............................................................................................... 28 
10.2. Patient Consent ..................................................................................................... 29 
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............ 29 
10.4. Ethical Conduct of the Study ................................................................................ 29 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ...................................................................................................................... 31 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ....... 32 
13. REFERENCES .................................................................................................................. 34 
14. LIST OF TABLES ............................................................................................................ 42 
15. LIST OF FIGURES ........................................................................................................... 42 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS ..........................................................42 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ......................................... 42 
ANNEX 3. ADDITIONAL INFORMATION ........................................................................ 43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
6MTP 
mercaptopurine 
AE 
adverse event 
AEM 
adverse event monitoring 
ALL 
acute lymphoblastic leukemia 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukemia 
AraC 
cytarabine 
ATRA 
all-trans retinoic acid 
AYA 
adolescents and young adults 
BFM 
German Berlin, Frankfurt, Muenster 
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
central nervous system 
CR 
complete remission; complete response 
CRF 
case report form 
CRi 
complete remission with incomplete hematological recovery or Complete 
response with incomplete blood count recovery 
CRMRD- 
complete remission without minimal residual disease 
CSA 
clinical study agreement 
CVAD 
cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride 
(Adriamycin), and dexamethasone 
DCT 
Data collection tools 
ECOG 
Eastern Cooperative Oncologic Group 
eCRF 
electronic case report forms 
EDC 
electronic data capture 
EFS 
event-free survival 
ELN 
European LeukemiaNet 
EMA 
European Medicines Agency 
EMD 
extramedullary disease 
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
ESMO 
European Society for Medical Oncology 
FAB 
French-American-British 
FDA 
Food and Drug Administration 
FLAG-IDA 
fludarabine, cytarabine, G-CSF and idarubicin 
 
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Abbreviation 
Definition 
G-CSF 
Granulocyte colony stimulating factor 
GPP 
Good Pharmacoepidemiology Practices 
GvHD 
graft-versus-host disease 
HCT 
hematopoietic cell transplantation 
HSCT 
hematopoietic stem cell transplantation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committees 
IQR 
interquartile range 
IRB 
institutional review board 
ISPE 
International Society for Pharmacoepidemiology 
ISPOR 
International Society for Pharmacoeconomics and Outcomes Research 
IWG 
International Working Group 
KPS 
Karnofsky performance status 
LA 
Latin America 
LOYAL 
Real-world Study in Acute Leukemia: Epidemiology, Treatment Patterns 
and Outcomes for B-cell ALL and AML in Adult Patients From Latin 
America 
MDR- 
complete remission without minimal residual disease 
MFC or MPFC 
multiparameter flow cytometry 
MLFS 
morphologic leukemia-free stat 
MRD 
minimal residual disease 
MTX 
methotrexate 
NCCN 
National Comprehensive Cancer Network 
NIS 
non-interventional study 
OS 
overall survival 
PD 
progressive disease 
Ph- 
Philadelphia chromosome - negative 
Ph+ 
Philadelphia chromosome - positive 
Ph1 
Philadelphia chromosome 
PPPY 
per patient per year 
PR 
partial remission 
R/R 
relapsed/refractory 
RFS 
relapse-free survival 
RT-qPCR 
Real-time polymerase chain reaction 
SAP 
statistical analysis plan 
 
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Abbreviation 
Definition 
SD 
standard deviation 
TdT 
nuclear terminal deoxynucleotide transferase 
TKI 
tyrosine kinase inhibitors 
TLS 
tumor sysis syndrome 
TTNT 
time to next treatment 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
Name, degree(s) 
Job Title 
Affiliation 
Address 
PPD 
PPD  
PPD 
 
H&V – PPD 
PPD  
PPD 
 
Consultant 
PPD  
PPD 
Analyst 
PPD  
PPD 
Sr. Consultant 
PPD  
PPD 
PPD 
 
 
PPD 
 
 
 
PPD 
PPD 
PPD 
3. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
 
 
 
The list of each Center Coordinating Investigators will be provided during the study and 
maintained separately. Available upon request. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PPD 
PPD 
4. ABSTRACT 
 
Title 
Real-world Study in Acute Leukemia: Epidemiology, Treatment 
Patterns and Outcomes for B-cell ALL and AML in Adult Patients 
From Latin America – LOYAL Study 
Version 
1.0 
Date of the protocol 22 March 2021 
Main author 
PPD 
,PPD 
Emerging Markets 
PPD 
, H&V –PPD 
– Pfizer Oncology 
Co-author 
– Pfizer 
Rationale and 
background 
Acute myeloid leukemia (AML) is the most frequent leukemia 
among adults, while acute lymphoblastic leukemia (ALL) affects 
mainly children and young adults. To date there is scarce data on the 
epidemiology and treatment patterns of patients with acute 
leukemias in Latin America (LA). 
Research question 
and objectives 
What is the epidemiology, treatment patterns and outcomes and 
healthcare resource utilization of ALL and AML patients in LA? 
The aim of this study is to describe the current epidemiology, 
treatment patterns, outcomes and healthcare resource use of adult 
patients diagnosed with B-cell ALL relapsed/refractory (R/R) and de 
novo AML in four Latin American countries. 
Study design 
This is a retrospective multicenter non-interventional study using 
real-world data collected from medical records of newly diagnosed 
AML or with relapsed/refractory B-cell ALL diagnosed between 
01 January 2015 and 31 December 2019 in 4 Latin American 
countries: Argentina, Brazil, Chile, and Colombia. In addition, as 
secondary objectives, the study will also describe molecular profile, 
cytogenetic risk, clinical outcomes, and healthcare resource 
utilization of treated B-cell ALL R/R and AML patients. 
Population 
Patients ≥18 years old at diagnosis, with confirmed diagnosis of 
relapsed/refractory B-cell ALL or newly diagnosis of AML between 
01 January 2015 and 31 December 2019, as documented in the 
medical chart and according to the physician’s notes, and with at 
least 1 line of treatment for B-cell ALL or AML within the study 
period will be eligible. Exclusion criteria includes patients with no 
medical chart available, with unreliable data as per investigator’s 
opinion (eg, excessive missing data or inconsistence data) and that 
have participated in any interventional clinical trial for 
 
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relapsed/refractory R/R B-cell ALL or denovo AML at any moment. 
Patients under any compassionate use is allowed. Patients with 
secondary AML or acute promyelocytic leukemia (APL) are also 
excluded. 
Variables 
Data on demographics, clinical characteristics, and treatment 
regimens, among others, will be collected. Healthcare resource 
utilization will be captured to understand the management pattern of 
both patient populations. 
Data sources 
All data will be extracted from patients’ medical charts and entered 
into an electronic case report form (CRF) specifically designed to 
capture relevant information in accordance with the study outcomes 
Study size 
It is expected the study will enroll approximately 700 patients with 
B-cell ALL R/R and AML in a consecutive manner, in 
approximately 15 sites distributed across Argentina, Brazil, Chile, 
and Colombia 
Data analysis 
All relevant data reported in the medical chart since diagnosis date 
(index date) until the study enrollment, last visit, contact date or 
death, whichever comes earlier, will be assessed. Follow-up period, 
time to next treatment (TTNT), overall survival (OS), relapse-free 
survival (RFS), event-free survival (EFS) will be assessed. 
Milestones 
- CRF and electronic CRF (eCRF): June 2021 
- Study documents (data management plan, data validation plan, 
statistical analysis plan): May 2021 
- Start of data collection: July 2021 
- End of data collection: August 2022 
- Data analysis: August 2022 
- Final study report: November 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5. AMENDMENTS AND UPDATES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. MILESTONES 
The timeline starts after the protocol approval and consider the approval and consider the 
milestones below. It is important to highlight that the dates may change during the study 
conduction 
 
Milestone 
Planned date 
Case report form (CRF) and electronic CRF (eCRF) 
June 2021 
Study documents: data management plan, data 
validation plan, statistical analysis plan 
May 2021 
Start of data collection 
July 2021 
End of data collection 
August 2022 
Data analysis 
August 2022 
Final study report 
November 2022 
 
7. RATIONALE AND BACKGROUND 
7.1. Acute Myeloid Leukemia 
Although acute leukemias are rare diseases, accounting for less than 3% of all cancers, they 
are the leading cause of death among children and young adults with cancer.1 Acute myeloid 
leukemia (AML) is the most frequent leukemia among adults, accounting for 90% of all 
cases of acute leukemia in adults and representing 23.1% of all leukemia cases.2,3 It is a 
disease with high mortality rate among patients over 65 years old, which is of special concern 
since its incidence has a J-shaped age-pattern.1,4 Globally, the age-standardized incidence 
rate of AML increased from 1.35/100,000 in 1990 to 1.54/100,000 in 2017, being more 
commonly diagnosed in high-income countries located in Europe and North America.5 In 
Latin America the epidemiology data on AML patients are scarce. 
 
Acute myeloid leukemia is a heterogeneous hematologic malignancy characterized by the 
clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other 
tissues. In most cases, it is a de novo malignancy in previously healthy individuals, however, 
it can also arise in patients with an underlying hematological disorder, or due to a prior 
alkylating therapy or radiotherapy.4 
Regardless of its etiology, several chromosomal rearrangements and gene mutations were 
closely associated to the AML pathogenesis and prognosis. Indeed, the presentation of AML 
depends heavily on the interactions between different somatic alterations and chromosomal 
rearrangements. A meta-analysis of the AML genomic patterns identified 5234 driver 
mutations involving 76 genes or regions.6 Among AML patients, around 20% were defined 
 
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according to fusion genes, 31% by chromosomal aneuploidies (including at least 
1 aneuploidy), 46% by gene mutations only (in the absence of gene fusions and chromosomal 
aneuploidies), and 3% with no events.7 With the advance of molecular and sequencing 
technologies the identification of key cytogenetic abnormalities and the molecular profiling 
have become a standard for an accurate diagnose of AML patients.7 The pattern of co- 
existing mutations and cytogenetic abnormalities at diagnosis can determine therapeutic 
approaches to induce remission and is associated with the risk of presenting worse response.8 
Besides older age, poor-risk prognostic parameters for AML include secondary disease, and 
adverse cytogenetics.8 Although age, performance status at diagnosis, and other clinical 
factors have been used as important parameters for management decision, cytogenetics 
abnormalities are the strongest prognostic factors for complete remission (CR) and OS in 
AML.4 Several classification systems are available for AML, including French-American- 
British (FAB) system; the World Health Organization (WHO) and the European 
LeukemiaNet. The FAB system was the first attempt to classify the AML according to the 
morphological and cytochemical characteristics of the leukemic cells.4 Comprising genetic, 
morphology, immunophenotyping, and clinical presentation information, the WHO 
classification is already stabilized in the clinical practice of high-income countries, where the 
molecular and cytogenetic screening are part of the routine.9 As for European LeukemiaNet 
system, later adopted in the clinical practice, AML patients can be stratified into favorable, 
intermediate or adverse prognostic risk groups based on the cytogenetic and gene 
abnormalities.10,11 However, low-income countries have limited access to these costly and 
complex test which hampered a more complete diagnosis classification of AML patients. A 
national survey conducted in Brazil, showed that among private and public institutions, the 
karyotype analysis and the screening of gene mutations were available in 88% and 71% of 
institutions, respectively. Next generation sequencing analysis was used in only 7% of 
institutions.12 Therefore, in many regions, the FAB classification is still under use.13-15 
In this scenario, cytogenetics has been widely used to provide the framework for risk-adapted 
treatment approaches. In certain situations, cytogenetics is also a predictor of treatment 
effectiveness: in patients with the t(15;17)(q22;q21) /PML-RARA, for instance, the 
combination of all-trans retinoic acid (ATRA) and anthracycline-based protocols has resulted 
in a markedly improved outcome. In contrast patients with complex karyotype (≥3 or 
≥5 abnormalities depending on the classification system), monosomal karyotype (such as 
monosomy 5/del(5q) or monosomy 7/del(7q)), or abnormalities of 3q have been shown to 
have inferior complete remission rates and overall survival and are currently considered for 
allogeneic stem cell transplant in first remission.8 Despite the genetic abnormalities at 
diagnosis, the continued presence of particular gene mutations during or after treatment 
carries prognostic information for certain genetically defined AML subtypes. Therefore, 
minimal residual disease (MRD) detection, either by genetics or by multiparameter flow 
cytometry (MPFC), is also an important risk factor for relapse.16 
 
 
 
 
 
 
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7.2. Acute Lymphoblastic Leukemia 
Unlike AML, acute lymphoblastic leukemia (ALL) affect mainly children and young adults. 
It is a disease with higher incidence in developing countries, with Honduras presenting the 
highest incidence rate in 2017 (3.83/100,000), followed by Mexico.5 The pathogenesis of 
ALL involves the abnormal proliferation and differentiation of a clonal population of 
lymphoid cells. In the majority of cases, it appears as a de novo malignancy in previously 
healthy individuals. Chromosomal aberrations are the hallmark of ALL, but are not sufficient 
to generate leukemia. Characteristic translocations include t(12;21)[ETV6-RUNX1], t(1;19) 
[TCF3-PBX1], t(9;22) [BCR-ABL1], rearrangement of MLL and a variant with a similar 
gene expression profile to (Philadelphia) Ph-positive ALL but without the BCR-ABL1 
rearrangement.17 
Most of the clinical manifestations of ALL reflect the accumulation of malignant, poorly 
differentiated lymphoid cells within the bone marrow, peripheral blood, and, extramedullary 
sites. In general, it is observed signs of bone marrow failure (anemia, thrombocytopenia, 
leukopenia) associated with general symptoms such as fever, weight loss, bleeding, fatigue, 
dyspnea and infection. Similarly, to the AML, the ALL can be also classified according to 
the WHO and FAB criteria. 
 
The ALL can be originated from a progenitor cell of the B- or T-cell.18 The malignant cell 
expresses surface antigens according to their respective lineage developments and may 
influence the choice of the treatment. Therefore, precursor B-cell ALL cells (B-cell ALL) 
typically express on their surface membrane peptidase CD10, CD19, CD34, and nuclear 
terminal deoxynucleotide transferase (TdT), while precursor T-cell ALL cells are mainly 
CD2, CD3, CD7, CD34, and TdT.19 
The genetic information of the leukemia cell can provide prognostic expectations and 
treatment directions.20 About 20% of adults and a small percentage of children with ALL 
present BCR-ABL fusion gene, which characterizes the Philadelphia chromosome (Ph1).21 In 
contrast, the Ph1 occurs in only 1% to 2% of patients with AML. The identification of Ph1 
by molecular analysis, such as reverse-transcriptase polymerase chain reaction (RT-PCR), is 
mostly important for B-cell disease.22 Besides Ph1, other chromosomal abnormalities are 
associated with poor prognosis and may also be investigated, such as myc gene 
rearrangements (in Burkitt leukemia), and MLL gene rearrangements.23-26 
Additionally, other factors affect prognosis and survival such as age, central nervous system 
impairment, and cellular morphology.27 Studies show that younger patients, less than 
35 years old, have better prognosis when compare to other ages.28,29 Moreover, the 
involvement of central nervous system influence both treatment and prognosis for leukemia, 
with the needed for a more aggressive therapy strategy.30 That aggressiveness in 
chemotherapy regimens can also be applied for patients that are identified with L3 cell 
morphology.31,32 
 
 
 
 
 
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7.3. Treatment for AML and ALL 
Among the therapeutic approaches, patients can be selected for an intensive treatment, which 
consists of either systemic or local (including intrathecal) chemotherapy.33 Besides 
chemotherapy, other types of treatment can be recommended according to patient status, 
including hematopoietic stem cell transplantation (HSCT); investigational products offered in 
clinical trials and targeted therapy. According to the patient´s characteristics, patients should 
first undergo an induction therapy to achieve complete remission, with a subsequent 
consolidation therapy in order to achieve a negative minimal residual disease (MRD). 
 
Although advances in the treatment of AML have led to significant improvements in 
outcomes for younger patients, prognosis in the elderly who account for the majority of new 
cases remains poor. Even with current treatments, as much as 70% of patients 65 years or 
older will die of their disease within 1 year of diagnosis.4 Except for those with acute 
promyelocytic leukemia, approximately 50% of patients under 60 years and 90% of patients 
over 60 years will.3 
The main induction therapy for AML changed minimally over the past 40 years and consist 
of the 7+3 regimen, which combines 7 days of continuous infusion cytarabine with 3 days of 
anthracycline.34,35 The combination of fludarabine, cytarabine, Granulocyte colony 
stimulating factor (G-CSF) and idarubicin (FLAG-IDA), which was traditionally used for the 
treatment of relapse, has also been shown to be a reasonable alternative to standard induction 
regimens and results in similar CR rates and overall survival (OS) with higher rates of CR 
after a single course.4 Nevertheless, the treatment approach for elderly patients with AML are 
not a consensus. These patients usually have a poor response to the conventional regimens, 
and in some cases are indicated for supportive care and palliative chemotherapy. 
 
Recently, new therapies approved or in clinical trials are being combined with the standard 
care, including intensive (gemtuzumab, ozogamicin, midostaurin) and non-intensive 
regimens such as improved chemotherapies (glasdegib), mutationally targeted inhibitors 
(sorafenib, midostaurin, lestaurtinib, quizartinib, crenolanib, and gilteritinib), pro-apoptotic 
agents (venetoclax), microenvironment targeting molecules (uproleselan), cell cycle 
checkpoint inhibitors (alisertib, barasertib, palbociclib, dinaciclib), and epigenetic regulators 
(bromodomain and clinical studies with extraterminal protein family inhibitors).35-40 
As for ALL, treatment usually differs for Ph+ and Ph- patients and according to age.41-43 For 
induction therapy in adolescents and young adults (AYA) – defined by the National Cancer 
Institute as cancer care or research focused on those diagnosed with cancer between the ages 
of 15 to 39 years old – with Ph+, the treatment are frequently tyrosine kinase inhibitors (TKI) 
associated with chemotherapy, considering hematopoietic cell transplantation (HCT) as 
consolidation therapy whenever possible.44 For Ph+ adults, the treatment could be similar, 
with the increase of corticosteroids for adults with comorbidities.41-43,45 For adults 
Ph- patients with less than 60 or even 65 years old without comorbidities, induction usually 
includes 4 to 6 drugs: vincristine, anthracycline, corticosteroids, asparaginase, 
cyclophosphamide, cytarabine (AraC) and mercaptopurine (6MTP); consolidation may 
include methotrexate (MTX) at high doses or divided doses, and long-term maintenance 
 
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(6MTP continuous and MTX weekly).41-43,45 For AYA Ph- patients, pediatric protocols are 
generally used, such as German Berlin, Frankfurt, Muenster (BFM) or cyclophosphamide, 
vincristine sulfate, doxorubicin hydrochloride (Adriamycin), and dexamethasone 
(HyperCVAD), which includes the drugs cyclophosphamide, vincristine sulfate, doxorubicin 
hydrochloride, and dexamethasone. Depending on the physical evaluation, adult Ph- patients 
could receive asparaginase, MTX and Ara-C in consolidation therapy.45,46 
Induction therapy aims to achieve complete remission, after which patients may undergo 
allogeneic (HSCT) – usually the best option for long-term survival – or progress to the 
consolidation and maintenance phases.47 In order to start the HSCT, a complete response to 
therapy is typically required. Unfortunately, only approximately 40% of patients after the 
first salvage therapy achieve a complete response.17,48-50 
Currently, immunotherapies have emerged as a novel treatment option for ALL and AML 
patients, including monoclonal antibodies, conjugated monoclonal antibodies, bispecific T 
cell engagers, and chimeric antigen receptor T cell therapies.38,39,46,48 Among 
immunotherapies, inotuzumab ozogamicin (Pfizer, Philadelphia, PA, USA) and 
blinatumomab (Amgen, Thousand Oaks, CA, USA) are both approved by Food and Drug 
Administration (FDA), and demonstrated efficacy in their respective phase III studies.51-53 
The are several treatment guidelines for AML and ALL, including those developed by each 
country; however, some of the most cited guidelines in literature include National 
Comprehensive Cancer Network (NCCN) guidelines for AML54,55 and ALL;41-43 European 
LeukemiaNet (ELN) recommendations and revised versions10,11 and Clinical Practice 
Guidelines developed in accordance with the European Society for Medical Oncology 
(ESMO) for AML;56,57 Guías de Diagnóstico y Tratamiento developed by Sociedad 
Argentina de Hematología for both AML and ALL.45 
7.4. Rationale 
To date there is scarce data on the epidemiology and treatment patterns of patients with acute 
leukemias in Latin America. Despite the various guidelines and recommendations for 
diagnosis, risk assessment, and therapy strategies most of them are not feasible in the clinical 
practice of a low/middle-income region. The lack of access to technologies for cytogenetic 
analysis and molecular profiling, besides the limit access to target therapies are important 
hurdles in the care of patients with AML and ALL. 
 
There are guidelines developed by the Ministries of Health and the local 
hematology/oncology medical societies for ALL and AML in Brazil,3,58-60 Argentina,45 
Colombia 61 e Chile.62-64 However, the understanding of ALL and AML in the real-world 
context of developing countries is very limited. Progress in being made in the real-world 
setting, leading to improvements in the way the diseases are managed.65 Therefore, this 
non-interventional study aims to describe the current epidemiology, treatment patterns and 
health care resource use of adult patients diagnosed with B-cell ALL relapsed/refractory 
(R/R) and de novo AML in four Latin American countries. 
 
 
 
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8. RESEARCH QUESTION AND OBJECTIVES 
The aim of this study is to describe the current epidemiology, treatment patterns, outcomes 
and healthcare resource use of adult patients diagnosed with B-cell ALL R/R and de novo 
AML in four Latin American countries. 
 
8.1. Primary Objective(s) 
• To describe the clinical and demographics characteristics of newly diagnosed AML 
(and follow up treatment for R/R disease when available) and relapsed/refractory 
B-cell ALL patients. 
• To assess treatment patterns in current practice of newly diagnosed AML and 
relapsed/refractory B-cell ALL patients. 
8.2. Secondary Objective(s) 
• To describe the cytogenetic and molecular profile of newly diagnosed AML and 
relapsed/refractory B-cell ALL patients, when available. 
• To evaluate the risk stratification of newly diagnosed AML and relapsed/refractory 
B-cell ALL patients. 
• To describe the clinically relevant events of newly diagnosed AML and 
relapsed/refractory B-cell ALL patients. 
• To estimate event-free survival (EFS) of newly diagnosed AML and 
relapsed/refractory B-cell ALL patients. 
• To assess patient response rate to treatment for newly diagnosed AML and 
relapsed/refractory B-cell ALL patients. 
• To describe, for relapsed/refractory B-cell ALL patients, treatment received when 
newly diagnosed for ALL (frontline B-cell ALL treatment). 
• To estimate the overall survival (OS) and the 1, 3- and 5-year overall survival (OS) of 
newly diagnosed AML and relapsed/refractory B-cell ALL patients. 
• To estimate relapse-free survival (RFS) for newly diagnosed AML patients. 
• To describe healthcare resource utilization of newly diagnosed AML and 
relapsed/refractory B-cell ALL patients. 
 
 
 
 
 
 
 
 
 
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9. RESEARCH METHODS 
9.1. Study Design 
The current study is a retrospective multicenter non-interventional study using real-world 
data collected from medical records to describe the epidemiology of acute leukemias and 
treatment patterns among patients diagnosed with B-cell ALL R/R or AML in 4 Latin 
American countries: Argentina, Brazil, Chile, and Colombia. In addition, as secondary 
objectives, the study will also describe molecular profile, cytogenetic risk, clinical outcomes, 
and healthcare resource utilization of treated B-cell ALL R/R and AML patients. 
 
All patients with newly diagnosed AML or with relapsed/refractory B-cell ALL diagnosed 
between 01 January 2015 and 31 December 2019 will be included in the study for medical 
chart abstraction. Data on demographics, clinical characteristics, treatment regimens, among 
others will be collected. Healthcare resource utilization will be captured to understand the 
management pattern of both patient’s population. All relevant data reported in the medical 
chart since diagnosis date (index date) until the study enrollment or death, whichever comes 
earlier, will be assessed. 
 
9.2. Setting 
For this study, data from patients treated at public or private healthcare facilities in 
Argentina, Brazil, Chile, Colombia, diagnosed with R/R B- cell ALL or AML between 
01 January 2015 and 31 December 2019 will be considered for the analysis. 
 
The eligibility period of 5 years was determined to increase the overall patient 
representativeness, and to allow ample follow-up to assess survival outcomes. 
 
The study will be conducted in approximately 15 sites distributed across Argentina, Brazil, 
Chile, and Colombia, and is expected to enroll approximately 700 patients with R/R B-cell 
ALL and AML in a consecutive matter. To assure the representativeness of each country, the 
number of sites and the total expected enrolled patients will be limited according to the 
country, considering the prevalence/incidence of the diseases. These will be estimated after a 
country level feasibility assessment. 
 
Data collection will occur in a period of up to 12 months following the independent ethics 
committee (IEC)/ institutional review board (IRB) approval and study set up. Patients will be 
consecutively enrolled, considering both target population, with no set proportion of AML 
and R/R B-cell ALL patients to be included in the study. However, it is expected a higher 
proportion of AML patients in the cohort. The study period will comprise since diagnosis 
date (index date) until the study enrollment or death, whichever comes earlier. 
 
 
 
 
 
 
 
 
 
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9.2.1. Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
 
1. Patients with ≥18 years old at diagnosis; 
 
2. Confirmed diagnosis of relapsed/refractory B-cell ALL or newly diagnosed of AML 
between 01 January 2015 and 31 December 2019, as documented in the medical chart 
and according to the physician’s notes; 
 
3. Patients that received at least one line of treatment for R/R B-cell ALL or denovo AML 
within the study period; for R/R B-cell ALL patients, data on previous therapy will also 
be collected if available. 
 
9.2.2. Exclusion Citeria 
Patients meeting any of the following criteria will not be included in the study: 
 
1. Patients with no medical chart available. 
 
2. Patients with unreliable data as per investigator’s opinion (eg, excessive missing data 
or inconsistence data). 
 
3. Patients that have participated in any interventional clinical trial for 
relapsed/refractory B-cell ALL or AML at any moment. Patients under any 
compassionate use is allowed. 
 
4. Patients with secondary AML. 
 
5. Patients with any concomitant primary malignancy. 
 
6. Patients with acute promyelocytic leukemia (APL). 
 
9.2.3. Study Definitions 
• Patients with AML: patients with diagnosis of AML according to the physician´s note in 
the medical chart participants. 
• Patients with B-cell ALL R/R: B-cell ALL R/R is defined as ALL patients with 
type B - cell that are classified as relapsed and/or refractory according to medical chart. 
• Concomitant medications: drug treatment for comorbidities, supportive and prophylaxis 
therapies, or to treat adverse events. 
• Consolidation therapy: according to the medical chart. A shorter and more intense 
treatment phase to further reduce the number of cancer cells. Also called intensification 
therapy and postremission therapy.66 
 
 
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• Death in aplasia: according to the medical chart. Deaths occurring ≥7 days following 
completion of initial treatment while cytopenic; with an aplastic or hypoplastic bone 
marrow obtained within 7 days of death, without evidence of persistent leukemia.10 
• Death from indeterminate cause: according to the medical chart. Deaths occurring before 
completion of therapy, or <7 days following its completion; or deaths occurring ≥7 days 
following completion of initial therapy with no blasts in the blood, but no bone marrow 
examination available.10 
• Genetic classification and response to therapy for patients with AML and 
relapsed/refractory treatments for patients with B cell ALL: according to the medical 
chart and exemplifications are described in ANNEX 3. ADDITIONAL INFORMATION: 
Appendix 3 and Appendix 4.10 
• Induction therapy: according to the medical chart. The first treatment that is given to 
greatly reduce the extent of cancer.66 
• Intrathecal therapy: according to the medical chart. A treatment with cell-killing drugs 
that are injected into the brain and spinal fluid.66 
• Maintenance therapy: according to the medical chart. A treatment phase that is given to 
prolong good treatment results.66 
• Palliative therapy. according to the medical chart. Health care that includes symptom 
relief but not cancer treatment. Also sometimes called supportive care.66 
• Primary chemotherapy: one or more cell-killing drugs that are used to rid the body of 
cancer.66 
• Relapsed disease: according to the medical chart. The return or worsening of cancer after 
a period of improvement. 
o Hematologic relapse (after CRMRD, CR, CRi) 
Bone marrow blasts ≥5%; or 
reappearance of blasts in the blood; or development of extramedullary disease. 
o Molecular relapse (after CRMRD) 
If studied pretreatment, reoccurrence of MRD 
as assessed by Real-time polymerase chain reaction (RT-qPCR) or by MFC. 
• Re-admission: according to the medical chart, generally defined as a hospital admission, 
occurring ≤30-days after the index admission. 
• Re-induction therapy: according to the medical chart. After the first induction therapy 
fails.67 
• Refractory disease: a cancer that does not improve with treatment.66 
• Regimen: a plan for the dose, schedule, and length of treatment. A regimen can be a 
treatment that consists of one or combined (two or more) drugs.66 
 
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• Remission: the absence of cancer signs and symptoms after treatment.66 
• Recurrence therapy: according to the medical chart. Treatment for cancer that has 
returned after a cancer-free period.66 
• Treatment failure: according to the medical chart. Refractory disease or Death in aplasia 
or Death from indeterminate cause.10 
• Treatment lines: lines will be defined as distinct combinations. The initial treatment or 
regimen administered will be first line. Do not include a stem cell transplant, induction, 
consolidation or maintenance therapies in your counting of lines. A line of therapy ends 
and a new line of therapy begins when the patient discontinued treatment with a regimen; 
if a regimen was added to the ongoing treatment this should be considered a new line of 
therapy. If a drug within a combination is held or discontinued this should not be 
considered a new line of therapy. 
• Treatment response 
o Complete remission or complete response (CR): a patient’s response to treatment 
according to the medical chart. Usually, AML complete remission defined as no 
physical signs of leukemia, bone marrow with active hematopoiesis, <5% bone 
marrow blasts and more than 1 × 109/l granulocytes and more than 
100 × 109/l platelets in the blood and no circulating leukemic blasts or evidence of 
extramedullary leukemia.10 
o Complete response with incomplete blood count recovery (CRi): also known as CR 
with incomplete hematologic recovery, also a patient’s response to treatment 
according to the medical chart. Definition includes all CR criteria except for residual 
neutropenia (<1.0 × 109/L [1000/µL]) or thrombocytopenia (<100 × 109/L 
[100 000/µL]).10 
o Partial remission: a patients response to treatment according to the medical chart. All 
hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; 
and decrease of pretreatment bone marrow blast percentage by at least 50%.10 
o Progressive disease (PD): according to the medical chart. Progressive disease is 
usually accompanied by a decline in ANC and platelets and increased transfusion 
requirement and decline in performance status or increase in symptoms. Evidence for 
an increase in bone marrow blast percentage and/or increase of absolute blast counts 
in the blood is defined by European LeukemiaNet (ELN).10 as: 
 
 
 
 
 
 
 
 
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− 
>50% increase in marrow blasts over baseline (a minimum 15% point increase is 
required in cases with <30% blasts at baseline; or persistent marrow blast 
percentage of >70% over at least 3 months; without at least a 100% 
improvement in absolute neutrophil count (ANC) to an absolute level 
(>0.5 × 109/L [500/µL], and/or platelet count to >50 × 109/L [50 000/µL] 
nontransfused). According to ELN recommendations, the date of progression 
should then be defined as of the first observation date; or 
− 
>50% increase in peripheral blasts (white blood cell (WBC) × % blasts) to 
>25 × 109/L (>25 000/μL) (in the absence of differentiation syndrome); or 
− 
New extramedullary disease. 
o Refractory disease: according to the medical chart. No CR or CRi after 2 courses of 
intensive induction treatment; excluding patients with death in aplasia or death due 
to indeterminate cause.10 
o Relapse from CR or CRi: according to the medical chart.40,53 
− 
Appearance of leukemic blasts in the peripheral blood. 
− 
Appearance of extramedullary disease. 
− 
≥5% blasts in the bone marrow not attributable to another cause (eg, recovery of 
normal cells following chemotherapy-induced aplasia). 
− 
If there are no circulating blasts and no extramedullary disease and the bone 
marrow blast percentage is ≥5% 
• Tumor Lysis Syndrome (TLS): according to the medical chart. Descriptive TLS 
criteria are described in ANNEX 3. ADDITIONAL INFORMATION: Appendix 268 
9.3. Variables 
 
This is an observational study to access the real-world treatment practices and clinical 
outcomes in a Latin American population of adults’ patients with acute leukemias. All 
treatment, procedures and overall management information of the target population will be 
collected according to the availability on the medical chart. 
 
 
 
 
 
 
 
 
 
 
 
 
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9.3.1. Outcomes 
9.3.1.1. Primary Outcomes 
• Description of demographic and clinical presentation characteristics at the moment of 
relapsed/refractory B-cell ALL or AML diagnosis. 
• Treatment description considering the front-line therapy and subsequent regimen(s) 
required for patients with relapsed/refractory B-cell ALL and AML, including any 
systemic chemotherapy, target therapy, hematopoietic stem cell transplantation 
(autologous/allogenic), intrathecal chemotherapy and palliative management. 
9.3.1.2. Secondary Outcomes 
• Description of subtypes of AML and B-cell ALL based on the cytogenetic and molecular 
abnormalities, according to the WHO classification. 
• Proportion of patients of each prognostic-risk group (favorable, intermediate, adverse) 
among newly diagnosed AML patients, based on cytogenetic profile 
• Description of the treatment standard from diagnosis to inclusion of R/R ALL patients. 
• Description of clinically relevant events presented by AML and relapsed/refractory B-cell 
ALL patients since treatment initiation until loss of follow-up or death from any cause. 
• The EFS will be the measure of time since treatment initiation until failure to achieve 
complete remission (CR), or disease progression after CR, or death from any cause for 
both AML and relapsed/refractory B-cell ALL patients. 
• The OS will be the measure of median time since treatment initiation until death from 
any cause for both AML and relapsed/refractory B-cell ALL patients. 
• The OS will also assess the proportion of AML and relapsed/refractory B-cell ALL 
patients alive after 1, 3 and 5 years since treatment initiation. 
• For AML patients who achieved CR, the RFS will be the measure of time since the CR 
attainment until relapse or death from any cause. 
• For AML patients the response to induction and consolidation therapy will assess the 
proportion of patients who achieve complete remission (CR), complete remission with 
incomplete hematological recovery (CRi), complete remission without minimal residual 
disease (MDR-), partial remission (PR), and progressive disease. 
• For relapsed/refractory B-cell ALL patients the response to the rescue treatment will 
access the proportion of patients with complete remission (CR), complete remission 
without minimal residual disease (MRD-), partial remission (PR), and progressive 
disease. 
 
 
 
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• Heath care resource utilization description, considering the outpatient utilization, 
inpatient admissions, hospitalization length of stay, and concomitant medication 
prescription since diagnosis until the loss of follow-up or death from any cause. 
9.3.2. Variables and Epidemiological Measurements 
The information will be extracted only if available in the medical chart. No assumptions or 
interpretation should be done in order to describe the parameter of interest. The following 
variables will be collected: 
 
• Patient demographics: age at diagnosis, gender at birth, country of residence. 
• Medical history: comorbidities, family history, prior exposure to toxic agents, prior 
malignancy, therapy for prior malignancy, information on smoking, history of bleeding 
episodes. 
• Clinical information at diagnosis: age at diagnosis, performance status (Karnofsky 
performance status [KPS] or Eastern Cooperative Oncologic Group [ECOG]). 
• Diagnosis information: hematological parameters (total blood count, differential count, 
hemoglobin level), bone marrow aspirate/biopsy, cytogenetics, screening for gene 
mutations and rearrangements, immunophenotyping assessment. 
• Treatment information: all treatment regimens used since diagnosis until loss of 
follow-up or death. It will include front-line induction therapies, consolidation therapies, 
rescue therapies, conditioning therapy, hematological stem cell transplantation 
(autologous/allogenic), intrathecal chemotherapy, palliative care. 
• Clinically relevant events: 
o Hematological toxicities described as: febrile neutropenia, anemia/thrombocytopenia 
that requires blood transfusion, bleeding events. 
o Hematological stem cell transplantation (autologous/allogenic) and transplant 
complications such as graft-versus-host disease (GvHD), stem cell (graft) failure. 
o Gastrointestinal toxicities: oral mucositis, nausea, vomiting, diarrhea. 
o Hepatotoxicity: hepatic enzymes elevation, jaundice, ascites, abdominal pain. 
o Other events: tumor lysis syndrome, fatigue, dysgeusia, alopecia, muscle spasm, 
Infections and sepsis. 
o Secondary malignancy or central nervous system (CNS) involvement. 
o Any serious adverse even.t 
• Patient response at the end of treatment: 
o Patient response according to International Working Group (IWG) criteria.69 
o Methodology for the assessment of minimal residual disease. 
 
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• Cytogenetic risk: 
o Favorable, intermediate, adverse for AML. 
o Good, intermediate, poor, undetermined for B-cell ALL. 
• Healthcare resource utilization: outpatient encounters (office visits, ancillary 
procedures, and ER visits), day-patient admission, inpatient admissions, hospitalization 
length of stay, concomitant medication (prophylactic therapy for infections, and other 
conditions related to the AML/ALL treatment or disease). 
9.4. Data Sources 
Given the noninterventional, observational nature of this study, its protocol does not 
recommend the use of any specific treatments, and no specific treatment is required for entry 
into the registry. Screening of data in medical records will be conducted retrospectively to 
identify study candidates, followed by data collection from registrants in a manner consistent 
with each investigator’s practice (with recording of data using electronic case report forms). 
 
All information will be capture from patient´s medical chart, since diagnosis until the most 
recent data available at study enrollment. 
 
9.5. Study Size 
As a descriptive study, sample size calculations are not applicable. The expected number of 
patients eligible for the study is approximately 700. An initial estimation of 15 sites across 
Argentina, Brazil, Chile and Colombia. The number for each disease will be estimated based 
on the feasibility assessment. Study size was estimated according to incidence of the diseases 
in Latin America and population size of each country.5 In Latin America, the incidence 
varied from 0.51/100,000 to 2.0/100,000 for AML and from 0.81/100,000 to over 
1.0/100,000 for ALL from 1990 until 2017.5 Considering all leukemia cases in 2017, global 
incidence trends corresponds to 23.1% and 12.4% for AML and ALL, respectively. Higher 
trends were found in Southern Latin America, with 27.7% and 14.9% for AML and ALL, 
respectively. 
 
9.6. Data Management 
A data management plan will be created before data collection begins and will describe all 
functions, processes, and specifications for data collection, cleaning and validation. The 
electronic case report forms (eCRFs) will include programmable edits to obtain immediate 
feedback if data are missing, out of range, illogical or potentially erroneous. Concurrent 
manual data review will be performed based on parameters dictated by the plan. Ad hoc 
queries will be generated within the electronic data capture (EDC) system and followed up 
for resolution. 
 
 
 
 
 
 
 
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9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to an electronic data 
record. 
 
A CRF is required and should be completed for each included patient. The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties. 
 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
 
The source documents are the hospital or the physician's chart. In these cases, data collected 
on the CRFs must match those charts. 
 
9.6.2. Record Retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), copies of all CRFs, 
safety reporting forms, source documents, detailed records of treatment disposition, and 
adequate documentation of relevant correspondence (eg, letters, meeting minutes, and 
telephone call reports). The records should be retained by the investigator according to local 
regulations or as specified in the clinical study agreement (CSA), whichever is longer. The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained. 
 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
 
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless IQVIA and Pfizer have expressly agreed to a different period of retention 
via a separate written agreement. Record must be retained for longer than 15 years if required 
by applicable local regulations. 
 
 
 
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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
 
9.7. Data Analysis 
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be dated, filed and maintained 
by the sponsor. The SAP may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment. 
 
Analyses will be descriptive in nature, as no hypothesis is being tested. Disease staging, 
comorbidities, demographic, clinical characteristics will be described at the date of diagnosis 
and/or treatment initiation for patients diagnosed with B-cell ALL R/R or AML. Treatment 
and clinical information will be assessed up to the most recent data available at the study 
enrollment. The treatments will be described in sequence according to the chronological 
order of administration. The duration through the number of cycles will be evaluated. Dose 
reduction information will also be collected. 
 
Continuous variables will be described as mean and standard deviation (SD), and/or as 
median, minimum, maximum, interquartile range (IQR, 25th and 75th percentiles). 
Categorical variables will be described by simple and cross contingency tabulation, with 
absolute frequencies and percentages. Missing values will be included in the denominators 
for the calculation of percentages and missing categories will be presented. 
 
All time-to-event analysis will be described using a Kaplan Meier plot, if appropriate. The 
following definition and parameter analysis will be considered: 
 
• Follow-up period – considered the time elapsed since B-cell ALL R/R or AML 
diagnosis until the study enrollment. It will be presented in years. 
• Time to next treatment (TTNT) – considered as the time from the start date of the 
front-line therapy to the start date of a subsequent line of therapy. It will be presented 
in months. 
• Overall survival (OS) – considered as death from any cause from the time of initiation 
of diagnosis or treatment.70,71 The median overall survival (OS) and the % of alive 
patients in 1, 3- and 5-years follow up of newly diagnosed AML and 
relapsed/refractory B-cell ALL patients will be assessed. 
• Relapse-free survival (RFS) for newly diagnosed AML patients – considered as 
measured from the date of achievement of a remission until the date of relapse or 
death from any cause; patients not known to have relapsed or died at last follow-up 
are censored on the date they were last examined. Defined only for patients achieving 
CR, or CRi. 
 
 
 
 
 
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• Event-free survival (EFS) of newly diagnosed AML and relapsed/refractory B-cell 
ALL patients – considered as the measured from the date of initiation of treatment to 
the date of primary refractory disease, or relapse from CR, or CRi, or death from any 
cause; patients not known to have any of these events are censored on the date they 
were last examined 
All computations and generation of tables, listings, graphics, and data for figures will be 
performed using R® version 3.5.3 or newer version (R Core Team), or a comparable 
statistical software package. 
 
Medical Dictionary for Regulatory Activities Terminology (MedDRA) version 2.1 (V2.1) or 
newer version will be used as a standardised medical terminology. Medicinal product names 
will be codified using World Health Organisation Drug Dictionary (WHODrug), a dictionary 
maintained and updated by Uppsala Monitoring Centre (UMC). 
 
The resource utilization (eg, number of hospital admissions, hospitalization period, 
procedures during hospital admissions) will be presented as mean number per patient per 
year (PPPY). According to the sample distribution, the data will be presented with a standard 
deviation (SD) or a 95% confidence interval (95% CI), which will be estimated either by 
Poisson regression or Gama distribution. The PPPY will be calculated as the sum of all event 
observed in the cohort divided by the total follow-up period (in years) of all patient in the 
cohort (including those who did not present the event). 
 
9.8. Quality Control 
In general, missing data will not be imputed and the data will be analyzed as they are 
recorded in the study CRFs. However, if more than 10% of data is missing for 1 or more key 
variables, the impact of missing data on the analysis will be discussed, and the pattern of 
missing data may be explored. If there is evidence of bias in the missing data, and variables 
that are considered good predictors of the missing data are available, the multiple imputation 
method at the study level may be used to replace missing values as secondary exploratory 
analyses. If the multiple imputation method is used, a sensitivity analysis will be carried out 
comparing results from the complete case analysis (where records with missing data will be 
dropped) and the full set analysis (with imputed data). Another potential strategy is a mixed- 
effects model repeated-measures analysis. This approach helps to conserve patient data in the 
event of missing observations. It is also potentially advantageous in registry studies with 
often irregularly spaced clinic visits and observations. 
 
9.9. Limitations of the Research Methods 
The limitation of retrospective study is that the data are often incomplete. Individual or entire 
series of records can be missing, either because the data were misplaced or because data were 
not recorded. Quality and completeness of data collected in this study will depend on the 
level of detail and accuracy with which patients’ medical charts are kept in participating 
sites. However, taking into consideration that patients are generally referred to and treated in 
specialized sites, these sites are likely to have the resources and systems working to keep 
patients’ records appropriately. 
 
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9.10. Other Aspects 
All efforts are made in this protocol to reduce inclusion bias. Potential sources of bias in this 
study, and the approach(es) for addressing and minimizing these biases are discussed below. 
 
Selection bias: may arise if the study sample differs substantively from the underlying target 
population of patients with B-cell ALL R/R or AML. To minimize selection bias, the study 
protocol has selected eligibility criteria that are as liberal as possible: age ≥18, newly 
diagnosed B-cell ALL R/R or AML, and willing to consent, in case ICF waiver is not 
approved by the ethics committee. Patients will also be recruited from a heterogeneous 
reservoir of study sites. Finally, where applicable, minimal de-identified information, 
including the reason for nonparticipation, will be collected for patients who are not enrolled 
in the study to assess whether there may be any systematic differences between participants 
and non-participants. 
 
Measurement bias: inaccurate assessment of study variables can occur in observational 
research. The present study will seek to limit measurement bias by instructing investigators 
to conduct their patient care in the customary fashion and that observations will be made in a 
nonintrusive manner that will focus on medical records and not infringe on Latin American 
healthcare provider’s and patient interactions. 
 
Bias due to Missing Data or Study Variables: reference is made to Section 9.9 regarding 
strategies for handling missing data. Briefly, the impact of missing data on the analysis will 
be evaluated, and appropriate measures will be taken to address the missing information if 
any bias is likely. 
 
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient Information 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
 
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access. The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster. In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law. 
 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code. 
 
 
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The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity. In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the clinical study agreement and applicable privacy laws. 
 
10.2. Patient Consent 
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required. 
 
This research presents no more than minimal risk of harm to patients and involves no 
physical procedures with patients, therefore, a waiver of informed consent will be requested 
as only retrospective collection of anonymized, non-personally identifiable data will be 
performed. Alternatively, patients will be informed accordingly, and will be asked to give 
their consent on data handling procedures in accordance with national regulations in place in 
each of the countries included in the study. 
 
All data will be extracted from patient´s medical chart and entered into an electronic CRF 
specifically designed to capture relevant information in accordance with the study outcomes. 
Prior to the enrollment of any patient, the study must be evaluated by the local independent 
ethics committees (IEC) and/or institutional review board (IRB) and a formal approval must 
be provided. 
 
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (eg, informed consent forms if applicable) from the relevant IRBs/IECs. 
All correspondence with the IRB/IEC must be retained. opies of IRB/IEC approvals must be 
forwarded to Pfizer. 
 
10.4. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in: 
 
• Guidelines for Good Pharmacoepidemiology Practices (GPP). Public Policy 
Committee, International Society of Pharmacoepidemiology. Pharmacoepidemiology 
and Drug Safety 2016; 25:2-10. 
https://onlinelibrary.wiley.com/doi/full/10.1002/pds.3891. 
 
• Good Practices for Outcomes Research issued by the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR) 
http://www.ispor.org/workpaper/practices_index.asp. 
 
 
 
 
 
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• Good practices for real-world data studies of treatment and/or comparative 
effectiveness: Recommendations from the joint ISPOR-ISPE Special Task Force on 
real-world evidence in health care decision making 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639372/. 
 
• International Ethical Guidelines for Epidemiological Studies issued by the Council 
for International Organizations of Medical Sciences (CIOMS) 
https://cioms.ch/shop/product/international-ethical-guidelines-for-epidemiological- 
studies/. 
 
• European Medicines Agency (EMA) European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological 
Standards in Pharmacoepidemiology 
http://www.encepp.eu/standards_and_guidances/methodologicalGuide.shtml. 
 
• The ENCePP Code of Conduct for scientific independence and transparency in the 
conduct of pharmacoepidemiological and pharmacovigilance studies 
http://www.encepp.eu/code_of_conduct/. 
 
• Food and Drug Administration (FDA) Guidance for Industry: Good 
Pharmacovigilance Practices and Pharmacoepidemiologic Assessment 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/gui 
dances/ucm071696.pdf. 
 
• FDA Guidance for Industry and FDA Staff: Best Practices for Conducting and 
Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G 
uidances/UCM243537.pdf. 
 
• FDA Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims 
http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. 
 
To ensure the quality and integrity of research, this study will be conducted under the 
guidelines good pharmacoepidemiology practices (GPPs) issued by the International Society 
for Pharmacoepidemiology (ISPE), the Declaration of Helsinki and its amendments, and any 
applicable national guidelines. 
 
 
 
 
 
 
 
 
 
 
 
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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database. The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information 
(defined per the patient population and study period specified in the protocol). Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE, 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE. 
 
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows: 
 
• All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the Case report form (CRF) 
and reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form. 
 
• Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form. 
 
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs. No follow-up on related AEs will be conducted. 
 
All the demographic fields on the NIS AEM Report Form may not necessarily be completed, 
as the form designates, since not all elements will be available due to privacy concerns with 
the use of secondary data sources. While not all demographic fields will be completed, at the 
very least, at least one patient identifier (eg, gender, age as captured in the narrative field of 
the form) will be reported on the NIS AEM Report Form, thus allowing the report to be 
considered a valid one in accordance with pharmacovigilance legislation. All identifiers will 
be limited to generalities, such as the statement “A 35-year-old female...” or “An elderly 
male...” Other identifiers will have been removed. 
 
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug 
Name” may be documented in month/year (mmm/yyyy) format rather than identifying the 
actual date of occurrence within the month /year of occurrence in the day/month/year 
(DD/MMM/YYYY) format. 
 
 
 
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All research staff members must complete the following Pfizer training requirements: 
 
• “YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”. 
 
These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Certificate” (for signature by 
the trainee) as a record of completion of the training, which must be kept in a retrievable 
format. Copies of all signed training certificates must be provided to Pfizer. 
 
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities training materials. 
 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately. 
 
This study aims to achieve quality results to be published in abstracts/posters at national and 
international scientific congresses and/or peer reviewed journals. The authors of all 
publications resulting from this study will be determined in accordance with the requirements 
of the International Committee of Medical Journal Editors (ICMJE), which states: 
 
• Authorship should be based on: (1) substantial contributions to the design and design 
of the study, data collection, or analysis and interpretation of data, (2) critical writing 
or review of its content, (3) final approval of the version to be (4) agree to be 
responsible for all aspects of the work to ensure that issues related to the accuracy or 
completeness of any part of the work are properly investigated and resolved. Authors 
must comply with conditions 1, 2, 3 and 4. All authors should be identified in 
accordance with ICMJE criterion 1 with the expectation that they will provide input 
on the publication to meet criteria 2-4. Criteria 1 stipulates that a substantial 
contribution prior to the publication is required.” 
 
• When the research is conducted in multiple centers, the group should identify 
individuals who accept direct responsibility for the manuscript. These individuals 
must fully comply with the authorship criteria defined above. A limit of seven authors 
from the seven centers with the largest number of participants will be invited as 
authors. 
 
• Obtaining funding, data collection or general supervision of the research group does 
not justify the authorship; 
 
 
 
 
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• All persons designated as authors must be qualified for authorship, and all qualified 
persons should be listed; 
 
• Each author must have reasonably participated in the research in order to assume 
public responsibility for appropriate parts of the content. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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64. MINISTERIO DE SALUD. Guía Clínica LEUCEMIA EN PERSONAS DE 15 AÑOS 
Y MÁS. 2010; Available from: 
https://www.minsal.cl/portal/url/item/7221fa2ff9d5c9c5e04001011f016052.pdf. 
 
65. Hokland P, Cotter F. Real world data on acute myeloid leukaemia therapy from the 
developing world - an eye-opener. Br J Haematol [Internet]. 2015 Jul;170(1):1–2. 
Available from: http://doi.wiley.com/10.1111/bjh.13410. 
 
66. National Comprehensive Cancer Network. NCCN Dictionary (Patient and Caregiver 
Resources ) [Internet]. NCCN. 2021 [cited 2021 Mar 10]. p. 1. Available from: 
https://www.nccn.org/patients/resources/dictionary/default.aspx. 
 
 
 
 
 
 
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67. Buchanan G, Rivera G, Boyett J, Chauvenet A, Crist W, Vietti T. Reinduction therapy 
in 297 children with acute lymphoblastic leukemia in first bone marrow relapse: a 
Pediatric Oncology Group Study. Blood [Internet]. 1988 Oct 1;72(4):1286–92. 
Available from: 
https://ashpublications.org/blood/article/72/4/1286/166378/Reinduction-therapy-in-297- 
children-with-acute. 
 
68. Howard SC, Jones DP, Pui C-H. The Tumor Lysis Syndrome. N Engl J Med [Internet]. 
2011 May 12;364(19):1844–54. Available from: 
.http://www.nejm.org/doi/10.1056/NEJMra0904569. 
 
69. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. 
Revised Recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards 
for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol [Internet]. 2003 Dec 
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70. American Society of Clinical Oncology (ASCO). Understanding Statistics Used to 
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survival. 
 
72. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 
revision to the World Health Organization classification of myeloid neoplasms and 
acute leukemia. Blood. 2016. 
 
73. Kruse, Abdel-Azim, Kim, Ruan, Phan, Ogana, et al. Minimal Residual Disease 
Detection in Acute Lymphoblastic Leukemia. Int J Mol Sci [Internet]. 2020 Feb 
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14. LIST OF TABLES 
None. 
 
15. LIST OF FIGURES 
None. 
 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None. 
 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
None. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ANNEX 3. ADDITIONAL INFORMATION 
Appendix 1. WHO Classification of Myeloid Neoplasms and Acute Leukemia72 
 
WHO myeloid neoplasm and acute leukemia classification 
Acute myeloid leukemia (AML) and related neoplasms 
AML with recurrent genetic abnormalities 
AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1 
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11 
APL with t(15;17)(q22;q21)/ PML-RARA 
AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A 
AML with t(6;9)(p23;q34.1);DEK-NUP214 
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM 
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1 
Provisional entity: AML with BCR-ABL1 
AML with mutated NPM1 
AML with biallelic mutations of CEBPA 
Provisional entity: AML with mutated RUNX1 
AML with myelodysplasia-related changes 
Therapy-related myeloid neoplasms 
AML, NOS 
AML with minimal differentiation 
AML without maturation 
AML with maturation 
Acute myelomonocytic leukemia 
Acute monoblastic/monocytic leukemia 
Pure erythroid leukemia 
Acute megakaryoblastic leukemia 
Acute basophilic leukemia 
Acute panmyelosis with myelofibrosis 
Myeloid sarcoma 
Myeloid proliferations related to Down syndrome 
Transient abnormal myelopoiesis (TAM) 
Myeloid leukemia associated with Down syndrome 
Blastic plasmacytoid dendritic cell neoplasm 
Acute leukemias of ambiguous lineage 
Acute undifferentiated leukemia 
Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1 
MPAL with t(v;11q23.3); KMT2A rearranged 
MPAL, B/myeloid, NOS 
MPAL, T/myeloid, NOS 
B-lymphoblastic leukemia/lymphoma 
B-lymphoblastic leukemia/lymphoma, NOS 
 
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WHO myeloid neoplasm and acute leukemia classification 
B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities 
B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1 
B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged 
B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1 
B-lymphoblastic leukemia/lymphoma with hyperdiploidy 
B-lymphoblastic leukemia/lymphoma with hypodiploidy 
B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH 
B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1 
Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like 
Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2. 2017 ELN Risk Stratification by Genetics in AML10 
 
Risk 
category* 
Genetic abnormality 
Favorable 
t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow† 
Biallelic mutated CEBPA 
Intermediate Mutated NPM1 and FLT3-ITDhigh† 
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow† (without adverse- 
risk genetic lesions) 
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡ 
Cytogenetic abnormalities not classified as favorable or adverse 
Adverse 
t(6;9)(p23;q34.1); DEK-NUP214 
t(v;11q23.3); KMT2A rearranged 
t(9;22)(q34.1;q11.2); BCR-ABL1 
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) 
−5 or del(5q); −7; −17/abn(17p) 
Complex karyotype,§ monosomal karyotype|| 
Wild-type NPM1 and FLT3-ITDhigh† 
Mutated RUNX1¶ 
Mutated ASXL1¶ 
Mutated TP53# 
Frequencies, response rates, and outcome measures should be reported by risk category, and, if sufficient 
numbers are available, by specific genetic lesions indicated. 
*Prognostic impact of a marker is treatment-dependent and may change with new therapies. 
†Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5); semiquantitative assessment of FLT3-ITD allelic 
ratio (using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” divided by 
area under the curve “FLT3-wild type”; recent studies indicate that AML with NPM1 mutation and FLT3-ITD 
low allelic ratio may also have a more favorable prognosis and patients should not routinely be assigned to 
allogeneic HCT. 
‡The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations. 
§Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring 
translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); 
AML with BCR-ABL1. 
||Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 
additional monosomy or structural chromosome abnormality (excluding core-binding factor AML). 
¶These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML 
subtypes. 
#TP53 mutations are significantly associated with AML with complex and monosomal karyotype. 
 
 
 
 
 
 
 
 
 
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Appendix 3. Genetic Classification by Prognosis of B-cell Acute Lymphoblastic 
Leukemia73 
 
Good Prognosis 
Intermediate 
Prognosis 
Poor Prognosis 
Undetermined 
Prognosis 
Hyperdiploid 
karyotypes 
t(1;19); TCF3-PBX1 
Hypodiploid 
karyotypes 
t(5;14); IL3-IGH* 
t(12;21);ETV6- 
RUNX1 (TEL- 
AML1) 
t(9;22); BCR-ABL 
Philadelphia-like 
ALL 
11q23 MLL 
rearrangements 
* t(5;14);IL3-IGH is a World Health Organization classified acute leukemia and prognosis data has not been 
determined. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 4. Response to Therapy will be Classified According to the International 
Working Group (IWG) Criteria 200369 
 
Response 
Criterion 
Neutrophils 
(microL) 
Platelets 
(microL) 
Bone Marrow 
Blasts (%) 
Other 
Early treatment 
NA 
NA 
<5 
Morphologic 
leukemia-free 
state 
NA 
NA 
<5 
Flow 
cytometry 
EMD 
Morphologic CR 
>1,000 
>100,000 
<5 
Transfusion 
EMD 
Cytogenetic CR 
>1,000 
>100,000 
<5 
Cytogenics - 
normal, EMD 
Molecular CR 
>1,000 
>100,000 
<5 
Molecular - 
negative, 
EMD 
Partial remission 
>1,000 
>100,000 
>50 or decrease 
to 5-25 
Blasts <5% if 
Auer rod 
positive 
Abbreviations: CR, complete remission; EMD, extramedullary disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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