LMA

t (15;17(q22, q21), causa a fusao do gene do receptor do acido trans-retinoico alfa (RARA) ao chamado gene da leucemia promielocitica (PML) no cromossomo 15,

produzindo uma proteina de fusao, a PML-RARA

Combinando o ATRA e antraciclico, alcanca-se remissao molecular em ate 99% dos pacientes, com sobrevida livre de

doenca de 90% aos cinco anos do diagnostico.

LMA

LMA

LMA

LMA

LMA - WHO Classicication

LMA - WHO Classicication

AML Prognostic factors

Treatment-related mortality

Standard x increased treatment intensity

Consolidation chemotherapy x allogenic hematopoietic stem cell

transplant

Established x investigational therapies

AML Prognostic factorsClinical factors

Increased age

Poor performance status

Lower rates of complete remission (CR) and decreased overall survival (OS)

=> risk of TRM

platelet count, serum creatinine or albumin

TR AML and AML-MDS

Cytogenetic changes:

Single strongest prognostic factor for CR and OS in AML

…

LMA - Prognostic risk group

with a 3 year OS of 66% and 33% in patients

younger and older than 60 years

c-KIT mutation significantly increases the risk

of relapse, and decreases OS to levels

comparable to those of patient with

intermediate-risk AML

LMA - Prognostic risk group

LMA - Prognostic risk group

significantly higher risk of treatment failure and death

AML Established treatmentsEligible patients first undergo induction therapy to achieve CR.

Unfortunately, minimal residual disease often persists in CR, and

relapse will inevitably occur if treatment is discontinued.

Induction therapy should be followed by consolidation therapy in

order to eradicate any residual disease and achieve lasting

remission.

‘7+3’ regimen, which combines 7 days of continuous infusion

cytarabine with 3 days of anthracycline.

AML Established treatments

Intention-to-treat analyses:

Favorable Prognosis:

No benefit to allo-HSCT when compared with chemotherapy in

patients with cytogenetically favorable AML in first CR.

AML Established treatments

Intermediary:???

allo-HSCT significantly prolongs RFS and OS in some patients with

intermediate-risk and in most with adverse-risk AML

AML Established treatments

High Risc: Allo-HSCT has been shown to prolong RFS and improve

OS in patients with CN-AML and a high FLT3-ITD allelic ratio.

AML Novel agents

FLT3-ITD inhibitors ( inhibition of tyrosine kinase-TKI)

- Sorafenib (TKI of RAF kinase, c-KIT, VGFR, PGFR and FLT3-ITD)

Treatment failure: Emergence of D835Y and D835H mutations within the

FLT3 TKD

An encouraging phase II trial of sorafenib and azacitidine in 43 patients with

relapsed/refractory AML reported a response rate of 46%, including 16% CR and

27% CR

- Midostaurin

- Quizartinib

- Crenolanib

AML Novel agentsSTAT inhibitors

- STAT3 tyrosine phosphorylation is upregulated in up to 50% of AML cases and confers a worse

prognosis

IDH1/IDH2 small molecule inhibitors

- Enzymes are found in approximately 20% of cases.

Clofarabine

- Second-generation purine nucleoside analog

Monoclonal antibodies

CART therapy

- Synthetic T-cell receptors with antibody-like specificity

AML ConclusionAML is a biologically and clinically heterogeneous disease.

Although advances overall long-term survival remains poor.

Elderly patients are more likely to present with an adverse cytogenetic profile.

Increased risk of TRM

Novel targeted therapies offer the promise of effective anti-leukemic activity with reduced toxicity

from off-target effects.

Molecular diversity of AML: single ‘magic bullet’ ?

Improved genetic profiling, risk stratification and pathology

Development of well-tolerated oral therapies, such as oral clofarabine.

We are looking to a new era in the treatment of AML to begin with novel agents so we can

achieve better responses with prolong OS particularly for patients with relapsed or refractory

diseases and poor cytogenetic features.

ALL

80% of ALL occurs in children, it represents a devastating disease when it occurs in adults

ALL

ALLPathophysiology

Down syndrome

Fanconi anemia

Bloom syndrome

Ataxia telangiectasia

Nijmegen breakdown syndrome.

Ionizing radiation

Pesticides

Certain solvents

Epstein-Barr Virus

Human Immunodeficiency Virus

De novo malignancy

ALLPathophysiology

Chromosomal aberrations are the hallmark of ALL, but are not sufficient to generate

leukemia.

Characteristic translocations:

t(12;21) [ETV6-RUNX1], t(1;19) [TCF3-PBX1], t(9;22) [BCR-ABL1] and

rearrangement of MLL.

Similar gene expression profile to (Philadelphia) Ph-positive ALL but without the

BCR-ABL1 rearrangement has been identified. In more than 80% of cases of this so-

called Ph-like ALL, the variant possesses deletions in key transcription factors

involved in B-cell development including IKAROS family zinc finger 1 (IKZF1),

transcription factor 3 (E2A), early B-cell factor 1 (EBF1) and paired box 5 (PAX5).12

Petechiae, ecchymoses, and bleeding - PTI

Patients with ALL, or promyelocytic leukemia, or aplastic anemia can present with pancytopenia

In aplastic anemia, hepatosplenomegaly and lymphadenopathy are rare

skeletal pain associated with ALL is absent.

BMA hypocellular marrow that is later replaced by lymphoblasts. polymerase chain reaction (PCR)

ALL should be considered in the differential diagnosis of patients with hypereosinophilia, can precede its diagnosis by

several months.

Occasionally, hematogones in a regenerative marrow may mimic leukemic blast cells; flow cytometry

Infectious mononucleosis and other viral infections, especially those associated with thrombocytopenia or hemolytic

anemia.

Acute infectious lymphocytosis, pertussis, or parapertussis can have marked lymphocytosis, as high as 50 × 109/L, BUT

WITH mature lymphocytes

Bone pain, arthralgia, and occasionally arthritis mimic juvenile rheumatoid arthritis, rheumatic fever, other collagen

diseases, or osteomyelitis. BMA-CCE?

ALL should be distinguished from small, round cell tumors involving the marrow, including neuroblastoma,

rhabdomyosarcoma, and retinoblastoma.(PRIMARY TUMOR; IFT)

ALL DIFFERENTIAL DIAGNOSIS

Hyper-CVAD Regimen in Routine Management of Adult Acute Lymphoblastic Leukemia: A Retrospective Multicenter Study

Y. Buyukasik, K. Acar, Medicine Acta Haematologica