Acute myeloid leukemia

Author:

Abstract

Nelson Hamerschlak, MD PhD

Acute myeloid leukemia (AML) occurs with

Hematology and Bone Marrow

a frequency of 3.5/1,000,000/year cases.

Transplant Dept

AML patients have an invasion of diseased

Hospital Israelita Albert Einstein

cells

Av. Albert Einstein, 627/520

microenvironmental dysfunction, defects in

São Paulo (SP) - Brazil

the

CEP 05651-901

remaining

(blasts)

medullary

proliferation

and

normal

insufficiency,

function

cells,

of

and

the

global

dysfunction of the immune system, and may present fatigue, fever, blotches on the body, and bone or joint pain. The diagnosis must be made based on clinical, morphological, immunophenotypical,

molecular,

and

cytogenetic findings. Prognostic assessment can determine the choice of treatment for the patient, and it depends on many different patient-related

factors.

Traditionally,

the

karyotype has been used as the principal prognostic factor in de novo leukemias. The conventional treatment for AML is divided between induction and consolidation. The future of AML treatment, particularly in cases of more reserved prognoses, should count on the assistance of genomics with panels of genetic changes or sequencing, new drugs, and targeted therapy. This paper describes the various alternatives available and under investigation, in Brazil and worldwide.

Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

the body, and bone or joint pain. The

1. Introduction

physical Acute myeloid leukemia (AML) occurs with a frequency of 3.5 cases per million people per year, and its incidence increases with age. This increase is significant after 60 years of age and the average age of occurrence is around 65 years of age.1-3 In Brazil, according to

exam

paleness,

should

check

mucocutaneous

for

bleeding,

fever, and visceromegalies. More rarely, patients may experience infiltration of the skin, gums, extramedullary tumors, and signs of infiltration of the central nervous system, manifested as headache or paralysis of the cranial nerves.6

the National Cancer Institute (Inca), For

there are an estimated 8000 to 9000

counts

cases per year.4

a

of

morphological 200

leukocytes

analysis, in

the

peripheral blood and 500 nucleated cells It is known that the occurrence of AML can be linked to different factors, such as ionizing radiation, exposure to chemical products, prior exposure to chemotherapy drugs, genetic factors, congenital

diseases,

and

medullary

failure syndromes. But, in most cases, these factors are not identified.5

in the bone marrow are recommended. According to World Health Organization criteria, when the number of blasts is equal to or greater than 20% it is considered to be AML, except in cases of

t(15:17),

the effects of the disease occur through the invasion of diseased cells (blasts), medullary

insufficiency,

microenvironmental dysfunction, defects in the proliferation and function of the remaining normal cells, and global dysfunction of the immune system. The

inversion

of

7

chromosome 16, or t(16:16). The

From a physiological perspective,

t(8:21),

objectives

of

immunophenotyping are to analyze cell lines, to characterize the state of cell maturation, and to detect anomalous immunophenotypical expressions that could be useful in monitoring minimal residual disease. Table 1 displays the principal markers for a diagnosis of AML.8-10

disease is characterized, at the end, by Various cytogenetic changes can

peripheral cytopenias and invasion by occur

blastic cells. 6

in

AML,

among

which

monosomal and complex changes are described as very serious. Chart 1

2. Diagnosis The diagnosis must be made based on

clinical,

morphological,

shows the cytogenetic changes of special interest in AMLs.8-10

and

We usually classify AMLs as de

cytogenetic findings.7 Clinically, patients

novo or secondary to myelodysplasia

may present fatigue, fever, blotches on

and/or chemotherapy or radiotherapy,

immunophenotypical,

molecular,

Copyright 2016 KEI Journals. All Rights Reserved

Page │2

Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

the latter having a worse prognosis. The

about the variability of their evolution in

French-American-British

(FAB)

these patients, the description of genetic-

classification was used for many years,

molecular factors and mutations, such as

taking

morphological

NPM1 in 55% of cases, FLT3-ITD

characteristics into account and dividing

(40%), MLL-PTD (6%), NRAS (8-

the AMLs into M0, M1, M2, M3, M4,

10%), CEBPA (10%), and FLT3-TKD

M5, M6, and M7 (Table 2), while the

(6%), can contribute to the improvement

World Health Organization classification

of prognostic measurements.12-15 Of

of 2008 is currently in effect and is

these, FLT3-ITD, NPM1, and CBPA are

based on risk (Chart 2).11

the ones that have been more often used

only

in clinical practice.12-15 The presence of 3. Prognostic factors

the c-Kit mutation has also been used in

In AML, perhaps one of the most

order to demonstrate cases of t (8:21) or

important

steps

is

the

prognostic

inv(16) with poor prognosis.16 15

assessment, because this can determine

Therefore, a normal karyotype

the choice of treatment for the patient.

with negative FLT3 and positive NPM1

Several studies have been published in

and those with CBPA and with inv16,

this regard and they usually consider

t(8:21) without mutation of the c-Kit are

patient-related

as

considered to be factors for good patient

performance status, age, comorbidities,

prognosis. The others are considered to

the existence of a compatible donor,

be of an intermediate or unfavorable

factors related to the biology of the

prognosis.16 The European Leukemia

disease such as chromosomal changes,

Net17 then went on the classify AMLs as

response to therapy, secondary versus de

having

novo

intermediate

leukemia,

factors,

morphology

classification), genetic-molecular

such

(FAB

immunophenotype, factors,

II,

intermediate and

I,

unfavorable

prognoses, as displayed in Table 4. In

even

our service, we have adopted the

factors related to the environment, such

algorithm in Figure 1 for an indication

as

of consolidation chemotherapy with

socioeconomic

and

favorable,

resources

and

conditions.

autologous or allogeneic bone marrow

Traditionally, the karyotype has

transplants. We take the c-Kit into

been used as the principal prognostic

account for cases of t(8;21), inv(16), or

factor in de novo leukemias. Table 3

t(16;16).

separates the cases

into favorable,

unfavorable, and intermediate prognoses according to karyotype.

8-10

New changes have been identified and

their

value

in

the

clinical

Keeping in

management of AML has been studied:

mind that more than 40% of the AMLs

mutations of TET2, ASXL1, IDH1 and

have a normal karyotype and knowing

IDH2, PHF6, and DNMT3A.18-22 It

Copyright 2016 KEI Journals. All Rights Reserved

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

appears that the mutation of IDH2 R140,

assistance of genomics with panels of

but not of IDH2 R172 or IDH1, was

genetic changes or sequencing, new

associated with an improvement in

drugs, and targeted therapy. Today,

overall survival. Mutations of ASXL1

some of these strategies are already

and PHF6, on the other hand, were

being used in clinical studies, such as the

associated with a worsening of overall

use of FLT3 inhibitors, ATRA (all-trans

survival.18-22 Recently, a meta-analysis

retinoic

of studies including more than 4500

chemotherapy in the presence of NPM1,

patients

that

the use of hypomethylation agents for

DNMT3A is associated with subtypes

secondary leukemias and in elderly

M4 and M5 and that it was an

patients, histone deacetylase inhibitors,

independent adverse marker. The authors

AKT/m

of

apoptopic agents, such as genasense, and

with

that

AML

study

incorporating

this

showed

recommended mutation

in

the

decision algorithms for patients with

acid)

Tor

MDR

together

inhibitors,

modulators,

with

clofarabine,

such

as

zosuquidar.27,28

AML.23 5. Acute myeloid leukemia 4. Treatment

Acute

myeloid

leukemia,

The conventional treatment for

designated as FAB classification subtype

AML is divided between induction and

M3, accounts for between 10% and 15%

consolidation.

of

The

conventional

AMLs.

Morphologically,

presence

of

characterized

and cytarabine has been in use for more

abnormal promyelocytes, with eccentric

than 40 years. Studies with the addition

nuclei and granulations in the cytoplasm,

of other drugs or increased doses of

as well as numerous Auer rods in bundle

cytarabine

formations.

not

reported

any

Immunophenotypically,

increase in remission rates, which ranged

there

from 60 to 80%.24,25 The anthracyclines

myelomonocytic antigens (CD13, CD15

traditionally used are idarubicin and

and

daunorubicin.24,25

expression

In

consolidation

is

the

is

induction treatment with anthracycline

have

by

it

high

CD33)

and of

expression

the

absence

monocytic

of

of

antigens

therapy, the use of two to four cycles of

(CD14, including My4, Leu M3, and

cytarabine in high doses, autologous

Mo2) and HLA-DR. The presence of the

transplants, and allogeneic transplants

t(15:17) (q22: q21) translocation occurs

have been used depending on the

in practically all cases and results in the

prognosis of the patient.

26,27

fusion of the PML and RARa genes.29

The future of AML treatment,

Clinically,

promyelocytic

particularly in cases of more reserved

leukemia

prognoses,

disseminated intravascular coagulation,

should

count

on

the

Copyright 2016 KEI Journals. All Rights Reserved

is

acute

characterized

Page │4

by

Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

with hemorrhage being the main cause

under the proper clinical conditions, is

of death in these patients. Treatment has

forcing the world to adapt to more

changed significantly with the advent of

aggressive

treatment

ATRA

Adequate

geriatric

evaluation,

comorbidity

rates,

less

associated

chemotherapy.

with

29,30

The Spanish group (PETHEMA) developed a treatment protocol showing

strategies.

and

toxic

treatment schemes are making curative treatment possible for these patients.35

the importance of anthracyclines in

In induction, we must consider the

combination with ATRA in the evolution

standard

and cure of the disease and established a

cytarabine) regimen, with remission

risk classification based on leukocyte

rates of 60%, always remembering that

and

providing

progression-free survival is short (5 to

individualized therapy for each case with

10 months) and that remission is

platelet

counts, 31

good chances of a cure.

3

+

7

(anthracycline

+

maintained for more than 2 years in less

Conventional treatment consists of

than 10% of cases.36-38 It is important to

and

consider using hypomethylating agents,

maintenance. Arsenic trioxide (ATO) is

such as 5-azacytidine and decitabine,

often used in patients suffering from

mainly in more fragile patients or those

recurrent disease, but there are several

with secondary leukemias. Of note here

induction,

consolidation,

studies that combine ATRA and ATO in

are the studies with high doses of

the first line, mainly for low-risk cases,

decitabine

with outcomes similar to those from the

remission of around 50%.39

use of ATRA and chemotherapy.32

and

rates

of

complete

In the consolidation of elderly patients, those with favorable prognoses

6. Leukemias in the elderly

should be considered, i.e., those who do

Normally,

treatment

not present t(15;17), t(8:21), and inv16,

outcomes in the elderly are very bad.

with negative c-Kit, or normal karyotype

Many

with negative FLT3 and positive NPM1.

times

AML

these

patients

have

compromised performance status, a high

They

incidence of minimum residual disease

consolidations with intermediate doses

following

unfavorable

of cytarabine, with 1 to 1.5 g every 12

treatment-related

hours for 3 days or an autologous

treatment,

cytogenetics,

high

should

submitted

transplant.

failure, shorter remissions, and shorter

prognoses and a good overall geriatric

overall survival.33,34

assessment should be selected (if under

most cases reaches an advanced age

with

to

mortality, higher incidence of induction

The aging population, which in

Those

be

unfavorable

80 years of age) for non-myeloablative or reduced intensity transplants.40-42

Copyright 2016 KEI Journals. All Rights Reserved

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

interesting piece of information and

7. Acute myeloid leukemia and

should be analyzed within the context

bone marrow transplants in Brazil Brazilian

that, at least during this period, Brazil

authors report discouraging outcomes

followed the more European than North

from the treatment of AML in Brazil.43

American trend to value this type of

41

procedure. The similarity of the survival

Data

from

several

Since 2005, the Brazilian Bone

Marrow Transplant Society (SBTMO)

data

has encouraged multicenter studies and

modalities was explained by higher

the evaluation of various treatment

mortality in the autologous transplants

centers in Brazil with the goal of

from

monitoring and trying to improve bone

toxicity (40%), with the percentages

marrow transplant outcomes.

reversed for allogeneic transplants.44.

Several

initiatives

can

between

recurrence

The

be

the

two

(60%)

Brazilian

than

from

post-transplant

highlighted here. Between 2005 and

survival

2007, data from 1289 patients in 17

validated by Marcelo Pasquini of the

treatment centers in São Paulo, Rio de

CIBMTR, who published the curves for

Janeiro, Paraná, Pernambuco, and Rio

early,

Grande

disease

do

Sul

were

evaluated

retrospectively. Transplants for AML accounted for 16% of the transplants

data

transplant

were

intermediate, from

the

subsequently

and

advanced

Brazilian

data

forwarded to the CIBMTR, as shown in Figure 4.*

performed in Brazil, and in the same

From

2007

to

2012,

several

period, the data of the Center for

initiatives in Brazil in this area deserve

International

mention:

Blood

and

Marrow

Transplant Research (CIBMTR) was

- Experience with the use of oral or

27%.

intravenous busulfan in association

The

results

were

partially

published and can be seen in Figures 2

with fludarabine;45,46

and 3 for allogeneic and autologous

- A study to evaluate how patients

transplants,

with AML were treated in Brazil;47

conditioning busulfan

respectively. regimens and

were

The mainly

- A study of elderly patients with

cyclophosphamide,

bone marrow transplants with a

busulfan and melphalan, and TBI (total body

irradiation)

regimen of reduced toxicity;48

and

cyclophosphamide.44 In this study, there was no prognostic cytogenetic classification and

*

Pasquini M. Resultados de transplantes de

medulla

óssea

de

centros

de

transplante

brasileiros através dos registros do Center for International Blood and Marrow Transplant

in general the autologous transplant had

Research (CIBMTR). [Presented during the

interesting results very similar to those

Brazilian Bone Marrow Transplant Conference-

of the allogeneic transplant. This is an

SBTMO 2007].

Copyright 2016 KEI Journals. All Rights Reserved

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

- Two consensuses (2009 and 2012)

and the NPM1 by less than 15% of

on bone marrow transplants from

them;

the

- Induction therapy with cytarabine

Brazilian

Bone

Marrow

Transplant Society.49,50 The

group

and idarubicin was used by 36% of

known

as

the

the institutions, and daunorubacin

“Conexão Caipira”, led by the Centro de

and cytarabine by 64% of them;

Transplantes de Jaú, showed that the use

- In consolidation, 91% of the

of

fludarabine

institutions indicated allotransplant

produced a survival curve of 64% in two

for intermediate risk and 100% for

years (Figure 5).45 The results with

high risk patients, when a donor was

intravenous busulfan and fludarabine,

identified;

mainly

were

- In low risk patients, 70% were

published by our group, showing their

consolidated with high doses of

effectiveness (Figure 6) and low toxicity

cytarabine and 30% with bone

(Figure 7).46

marrow autotransplants.

oral

busulfan

in

and

elderly

patients,

With the objective of evaluating

Transplants in the elderly are

the conditions under which patients with

becoming an increasingly more common

AML are diagnosed and treated in

practice in Brazil. The first Brazilian

Brazil, a questionnaire was sent to the

initiative

Brazilian treatment centers. The results

was

conducted

by

our

institution in association with the MD Anderson Cancer Center, in a study

obtained showed that:47

published in 2011, the results of which - The centers considered to be references and that perform bone marrow transplants use diagnostic and prognostic methods for more than 90% of their patients, while in other

places,

cytogenetics

and

immunophenotyping for diagnosis are lacking, with only 50% of the institutions that treat patients but do

showed significant survival in patients between 60 and 80 years of age.48 The two-year survival of treated patients reached 71% in those in first remission, 44% in those in second remission, and 32% in those with active disease. Interestingly, we found that 58% died from recurring disease and not from the toxicity of the transplant (42%).48

not perform transplants using these The work of the Latin-American

methodologies; - In relation to molecular studies, the

consortium, coordinated by Professor

PML/RARa

or

Eduardo Rego, in collaboration with the

forwarded for execution by more

American Hematology Association, to

than

improve

80%

was

of

conducted

the

institutions

consulted, while the FLT3 by 45%

the

promyelocytic

outcomes

of

leukemias,

acute

was

a

significant milestone in the area of Copyright 2016 KEI Journals. All Rights Reserved

Page │7

Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

leukemia in Brazil. Using a protocol

allogeneic transplants, while those

from a Spanish risk-based classification

with

(PETHEMA)

and

consolidation chemotherapy with

centralized

molecular

from

agile

and

diagnosis

high

favorable

doses

prognoses

of

cytarabine

to

or

laboratories, it achieved outcomes in

autologous transplant;

developing countries similar to those

2. In spite of the knowledge that, in

observed at the international level, as

the second remission or in advanced

shown in Figure 8.51

or even refractory disease, the

Finally, during the period from

transplant has a worse prognosis,

2012 to 2015, initiatives such as

they

targeted-dose busulfan, improvements in

conditions;

our diagnostic/prognostic tools, the 2015

3. The main conditioning regimens

Consensus of the Brazilian Society of

recommended would be busulfan

Bone Marrow Transplants (SBTMO),

and cyclophosphamide and busulfan

consolidating the consensuses of 2009

and

and 2012 and as yet unpublished,49,50 and

possible, busulfan dosing would be

the design of a protocol to evaluate the

recommended;

autotransplant versus chemotherapy in

4. Transplants in the elderly are

the consolidation of low-risk patients,

indicated in patients in good overall

demonstrated that specialists continue to

condition

be active in Brazil, always seeking better

comorbidities, preferably with an

diagnostic, prognostic, and therapeutic

extensive geriatric assessment.

conditions.

accept

it

fludarabine,

and

under

and

these

whenever

with

few

Achieving the proper levels of expert

busulfan seems to influence the outcome

meetings in 2009, 2012, and 2015 to

of transplants. Therefore, doses in the

establish a consensus for bone marrow

area under the curve (AUC) of 6000

transplants in Brazil around indications,

µMol.min can be used in patients with

conditioning regimens, prophylaxis, and

more

treatment

graft-versus-host

patients, or even those with active

disease. The key recommendations for

disease, while doses of 4000 µMol.min

AML were:50,52

are ideal in transplants of low toxicity

The

SBTMO

of

the

held

aggressive

diseases,

younger

used in patients with myelofibrosis, in 1. To base indications of allogeneic transplants, autologous transplants,

AML with comorbidities, and in the elderly.53

and consolidation chemotherapy in the first remission on the prognostic

In Brazil, dosing of busulfan is

factors of the patients. Thus, patients

not routinely performed. It is indicated

with intermediate and unfavorable

especially when using oral busulfan,

prognoses would be directed to

where absorption is erratic. However,

Copyright 2016 KEI Journals. All Rights Reserved

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

few treatment centers have the HPLC

tools and these molecular findings, we

(high performance or pressure liquid

were able to classify out patients

chromatography)

according to the European Leukemia

or

UPLC

(ultra

performance) technology to perform the

Net,54 as shown in Figure 9.

dosing. With the goal of trying to obtain

Based on the excellent results

dosing prior to the transplants that would

obtained in the acute promyelocytic

be capable of predicting the dose to be

leukemia consortium and on the fact

administered to patients, the doctoral

that, for Brazil, the autologous transplant

thesis of Iracema Esteves was conducted

may be a more suitable consolidation

with technology developed at Einstein

strategy for low-risk patients, a group of

through

the

Ministry

PROADI program.

53

of

Health’s

Brazilian researchers, led by Eduardo

A prior dosing was

Rego, intends to conduct a multicenter

performed from 48 hours to 15 days

study to evaluate the best consolidation

before the transplant, comparing it with

strategy, i.e., chemotherapy with high

the dosing during the procedure. She

doses

showed that this strategy was feasible for

autotransplant of hematopoietic stem

the use of intravenous busulfan, but not

cells.

accurate for oral use of the drug.

of

cytarabine

versus

an

53

After conducting a retrospective Another project conducted with PROADI

resources

implementation

results obtained in the treatment of AML and the efforts made in Brazil towards

CEBPA, and c-Kit prognostic molecular

this end, the scientific community is

tests

them

hopeful that we will continue to achieve

available to both public and private

better results. We should remember,

services. We were able to observe that

however, that in our country there exist

the incidence of FLT3, NPM1, and

enormous

CEBPA

unfavorable

Brazil

in

and

patients

FLT3,

the NPM1,

in

of

was

review of the literature regarding the

making

with

normal

inequalities

and

conditions,

often causing

karyotypes were 19%, 17%, and 1%,

distortions that should gain the attention

respectively. The c-Kit mutation among

of our authorities so they can be

cases of t(8:21) or chromosome 16

corrected.

inversion was 3%. Using cytogenetic

Copyright 2016 KEI Journals. All Rights Reserved

Page │9

Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Table 1. Principal immunophenotypical markers for acute myeloid leukemia Myeloid precursors

CD34, CD38, CD117, CD133, HLA-DR

Granulocytic line

CD13, CD 15, CD 16, CD33, CD65, MPOc

Monocytic line

CD11c, CD14, CD64, CD4, CD11b, CD36, lisozime

Megakaryocytic line

CD41, CD61, CD42

Erythroid line

CD235a (glicoforine A)

Chart 1. Principal cytogenetic changes found in acute myeloid leukemia (AML) t(8;21)(q22;q22); RUNX1-RUNX1T1: 5% of AML cases inv(16)(p13.1q22); t(16;16)(p13.1;q22); CBFB-MYH11: 5-8% of AML cases t(15;17)(q22;q12); PML-RARA: 5-8% of AML cases t(9;11)(p22;q23); MLLT3-MLL: 9-12% (children); 2% (adults) t(6;9)(p23;q34); inv(3)(q21q26.2); t(3;3)(q21;q26.2); t(1;22)(p13;q13)

Table 2. FAB (French-American-British) classification based on cytology in seven subtypes of acute myeloid leukemia (AML) M1

M2 M3 M4

M5

AML without maturation (more than 90% myeloid blasts, with less than 10% of maturing myeloid elements) AML with maturation (more than 30% blasts, up to 89% with more than 10% abnormal cells, from promyelocytic to more mature cells) Acute promyelocytic leukemia Acute myelomonocytic leukemia (the myeloid blasts must exceed 30% of the nonerythroid nucleated medullary cells, with 20% to 80% of them being monoblasts) Acute monocytic leukemia (more than 30% of the non-erythroid nucleated medullary cells are blasts, with more than 80% being monocyte precursors) Acute erythroleukemia or Di Guglielmo’s syndrome (more than 50% of the

M6

nucleated elements of the medulla must be erythroblasts and more than 30% of the non-erythroid elements must be myeloid blasts)

M7

Acute megakaryocytic leukemia

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Chart 2. World Health Organization (WHO) classification for acute leukemias11 Acute myeloid leukemia and related cancers Acute myeloid leukemia (AML) with recurrent genetic abnormalities AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) ou t(16;16)(p13.1;q22); CBFB-MYH11 AML with t(15;17)(q22;q12); PML-RARA AML with t(9;11)(p22;q23); MLLT3-MLL AML with t(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) ou t(3;3)(q21;q26.2); RPN1-EVI1 AML (megacarioblastic) with t(1;22)(p13;q13); RBM15-MKL1 Acute myelogenous leukemia related with myelodysplasia transformation Acute myeloid leukemia without other specific classification: AML with minimal differentiation AML without maturation LMA with maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic leukemia Acute erythroid leukemia Pure erythroid leukemia Erythroleukemia, erythroid/myeloid Acute megakaryoblastic leukemia Acute basophilic leukemia Panmielose with acute myelofibrosis Myeloid sarcoma Myelogenous proliferation related with Down syndrome Myelopoiesis transient abnormal Myelogenous leukemia associated with Down syndrome Blastic plasmacytoid neoplasia of dendritic cells

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Table 3. Prognosis of acute myeloid leukemia (AML) by karyotype t(15;17) Favorable prognosis

t(8;21) Inv(16) and t(16:16)

Intermediate prognosis

normal karyotype t(9;11), -y, +8, +6, del 12(p) t(6;9), -7, -5

Unfavorable prognosis

complex changes

Table 4. European Leukemia Net prognostic classification17 Genetic group

Changes t(8:21)(q22;q22),RUN X1-RUNX1T1

Favorable

Inv(16)(p13.1q22) or t(16;16) (p13.1;q22); CBFB- MYH11 NPM1 mutated without FLT3-ITD (normal karyotype) CEBPA mutated (normal karyotype) NPM1 e FLT3-ITD mutated (normal karyotype)

Intermediate I

NPM1 e FLT3 negativos (normal karyotype) NPM1 negative and FLT3 positive (normal karyotype)

Intermediate II

t(9:11) (p22;q23); MLLT3-MLL Cytogenetic findings not classified as favorable or adverse Inv(3) (q21q26.2) or t(3;3) (q21:q26.2); RPN1- EVI1 t(6;9)(p23;q34); DEK-NUP 214 t(v;11) (v;q23); rearrangement MLL

Adverse

-5 or del (5q) -7 anl (17p) complex karyotype

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Figure 1. Consolidation therapy for patients with acute myeloid leukemia (AML)

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Figure 2. Allogeneic transplants in Brazil. Overall survival, survival by first remission, second remission, and advanced disease and by de novo or secondary disease.

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Figure 3. Autologous transplants in Brazil. Overall survival, survival by first remission, second remission, and advanced disease and by de novo or secondary disease.

l

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Figure 4. Data presented by Marcelo Pasquini, of the Center for International Blood and

Sobrevida Global de pacientes com LMA apos transplante alogênico de doador HLA-idêntico that submitted data to the international registry. - Dados Brasileiros no CIBMTR -

Marrow Transplant Research (CIBMTR), classifying the transplants of Brazilian centers

Early (N=119) Intermediate (N=81)

Advanced (N=110)

P 

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Figure 5. Survival curve with the use of oral busulfan and fludarabine in a group study directed by the Centro de Transplantes de Jaú.

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Figure 6. Overall survival with intravenous busulfan (BU) and fludarabine (FLU) in patients with acute myeloid leukemia (AML).

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Figure 7. Main adverse effects from the use of busulfan (BU) and fludarabine (FLU) conditioning, showing few serious changes

25

IV

III

20

II 15 I 10 0 5

0 I II

0

l na Re I/M G

III

i os uc

te

t ic pa e H

c ia rd a C

IV

lm Pu

y ar on

CN

S

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Figure 8. A: Overall survival and disease-free survival. B: Cumulative incidence of recurrence and deaths unrelated to recurrence

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Medical Research Archives, Vol. 4, Issue 7, November 2016 Acute myeloid leukemia

Figure 9. European Leukemia Net risk classification in 100 patients with acute myeloid leukemia (AML) studied in the Brazil AML project.

Classificação de Risco : "Leukemia Net" 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Favorável

Intermediário I

Intermediário II

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Desfavorável

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