acute myeloid leukemia myelodysplastic syndromes

Acute myeloid

leukemia

Myelodysplastic

syndromes

Acute leukemia in adults

70% myeloid, 30% lymphoid

Average age at presentation is 60 years.

60% of the patients is older than 55-60 years.

Clinical presentation: deficiency of functional blood cells( anaemia, thrombocytopenia, neutropenia) or infiltration of the organs by immature leukemic blasts

>20% blasts on the bone marrow (BM is usually hypercellular, rarely hypoplastic).

Flow cytometry/ citochemistry is required for further classification (ALL/AML)- therapy is different!!!

Survival is just weeks or months without treatment

Clinical presentation ♦ Pancytopenia:

fever, infection, anaemia, bleeding

♦ Signs og malignant proliferation:

pain in the bones, lymphadenomegaly, meningeal signs

♦ Compression signs

(MYELOID SARCOMA!)

AML

M0

M2

M1

M4-M5b

M5a

FAB subtype NameAdult AML patients

(%)

M0Undifferentiated acute

myeloblastic leukemia5%

M1

Acute myeloblastic

leukemia with minimal

maturation

15%

M2

Acute myeloblastic

leukemia with

maturation

25%

M3Acute promyelocytic

leukemia10%

M4Acute myelomonocytic

leukemia20%

M4eos

Acute myelomonocytic

leukemia with

eosinophilia

5%

M5Acute monocytic

leukemia10%

M6Acute erythroid

leukemia5%

M7Acute megakaryocytic

leukemia5%

AML WHO classification

AML with recurrent genetic abnormalities:

• t(8;21), inv(16) or t(16;16), t(15;17), t(9;11), t(6;9), inv(3)or t(3;3), t(1;22)

AML with myelodysplasia-related change

Therapy-related myeloid neoplasms

AML, not otherwise specified: M0-M7

Myeloid sarcoma

Myeloid proliferations related to Down syndrome:

• Transient abnormal myelopoiesis

• Myeloid leukemia associated with Down syndrome (50x incidence !!!)

Therapy

High dose therapy with the aim of cure

Palliative- to decrease malignant cell burden

Best supportive care

Favorable

t(8;21) (q22;q22); RUNX1-RUNX1T1

inv(16) (p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

Mutated NPM1 without FLT3-ITD (normal karyotype)

Mutated CEBPA (normal karyotype)

Intermediate-I

Mutated NPM1 and FLT3-ITD (normal karyotype)

Wild type NPM1 and FLT3-ITD (normal karyotype)

Wild type NPM1 without FLT3-ITD (normal karyotype)

Intermediate-II t(9;11)(p22;q23); MLLT3-MLL

Adverse

inv(3) (q21q26.2) or t(3;3) (q21;q26.2); RPN1-EVI1

t(6;9) (p23;q34); DEK-NUP214

t(v;11) (v;q23); MLL rearranged

-5 or del(5q);

-7;

del17p;

complex karyotype; monosomal karyotype

High dose therapy in non-M3 AML

Induction: aim is complete remission (CR):

<5% blasts in BM, no blast and normal cell

count in PB (10E8 leukemic cells left!)

„7+3” protocol: AraC+anthracyclin

Postremission treatment: aim is elimination of

residual cells (chemotherapy like high-dose

AraC or alloPBSCT)

Graft sources

HLA class II HLA class I

antigens

DP DQ DR B C A

6 9 19 46 10 21

MHC (224 genes)

6

Human Major Histocompatibility Complex

B1 A1 B1 A1 B3

B4

B5

A1B1

alleles(DNA) 126 81 559 851 276 506

(2400)

HLA genotypically

identical sib

DP ACwDQ DR B

related

A/B/C

DR/DQ/DP

A/B/C

DR/DQ

12/12

10/10

A/B/DR 6/6

unrelated

A/B/C/DR 8/8

HLA matching

Donor age

CMV (-) for CMV(-) patients

Gender (male)

Pregnancy

ABO

Body mass

Much of the benefit of alloSCT is

due to immune GVL effect

Transplant related mortality

Early effects: – Infection, sepsis

– Mucositis (etoposid, MTX)

– Haemorrhagic cystitis (cyclophosphamid, adenovirus, BK virus)

– GVHD

– Graft failure

– Transplant related lung injury, interstitial pneumonitis (CMV)

– Venoocclusive disease (damage of sinosoidal endothelium-jaundice,

fluid retention)

– Transplantation associated thrombotic microangiopathy

Graft Versus Host Disease

Acute (<100 days)

skin-mucosa

gut

liver

Chronic

skin, eye, mouth, lung, liver, etc. oral ulcerations (lichen planus), keratoconjunctivitis sicca, xerostomia, polyserositis, esophagitis and stricture, intrahepatic obstructive liver disease, obstructive pulmonary disease, scleroderma, morphea,

fasciitis and myositis

Acut Promyelocytic Leukemia

FAB M3

Distinct entity: t(15;17) PML-RARa

RARa keeps DNA and ligand binding properties:

Co-repressors dissociate with farmacologic

doses of retinoids

APL

Clinical:

• BM infiltration with promyelocytes

• first signs are DIC/hyperfibrinolysis

Therapy:

„urgency leukemia”

All-trans retinoic acid (ATRA) in case of APL suspicion

APL therapyInduction + consolidation + maintenance

Protocol:

AIDA (ATRA+Idarubicin)+ risk-adapted consolidation therapy

ATRA+ATO (arsenic trioxide)

(first chemo free regimen!!)

Results: 90-95% Complete remission

CAVE: differentiation sy (fever, hypertension, oedema, pulmonal

infiltrate, pseudotumor cerebri)

Lo-Coco F et al. N Engl J Med 2013;369:111-121.

Elimination of leukemic blasts and LICs is necessary for definitive cure of APL. LICs posses high self-renewal capability and give rise to leukemic blasts that form the bulk of the disease

dos Santos G A et al. J Exp Med 2013;210:2793-2802

© 2013 dos Santos et al.

Treatment in patients over 60

Comorbidities: OH-Urea, haemosupportation

Low intensity chemotherapy:

hypomethylating agents: AzaC, Decitabin

sc low dose AraC

7+3: 100-200 mg/m2 AraC + 45-60 mg/m2 daunorubicin

clofarabine (monoth?, +AraC?,

+hypomethylating agent)

Myelodysplasia

Clonal disease of haematopoietic stem cells: insufficient

haemopoiesis and dysplasia in one or more cell lines

Clinical:

-ineffective haematopoiesis (increased apoptosis)- cytopenia

and progressive BM insufficiency

-leukemic transformation is possible

Epidemiology:

Average age around 70 years

3/100000/year

Can be due to previous radio- or chemotherapy

30% leukemic transformation

Diagnosis:

♦Peripheral blood count

♦BM biopsy and aspiration

♦Cytogenetic evaluation

Other CAUSES HAVE TO BE EXCLUDED:

♦Vitamin (B12,folic acid) deficiency

♦Chr. Liver diseases

♦Malignant diseases

♦HIV

♦Autoimmune diseases

♦Ring sideroblasts: alcoholism, As or Pb exposition,

drugs, congenital haematopoietic diseases

Etiology

Familiar: rare

Therapy related (t-MDS)

CAUSE IS USUALLY UNKNOWN

Peripheral blood

Heterogenous disease

Sine qua non: Quantitative deficiency in one or more cell lines

Anaemia:

– Isolated cytopenia without anaemia is rare(<5%)

Leukopenia: ~50%

Trombocytopenia: ~25%

Pancytopenia: 50% at diagnosis

Morphology in PB:

RBC: anisocytosis

macro-ovalocytosis

basophilic punctation

Granulocyte:

deficient granulation

hypo- or hyperlobulated nuclei

Thrombocytopenia (except 5q-)

Blasts

RBC

Anaemia

Retikulocyte count is low

Normocytic or macrocytic

Elliptocytes, dacrocytes

2 different RBC poplutation could be observed

Nucleated RBCs

MDS:

WBC Granulocytopenia:

~50% at dg

Nuclei:– Decreased

segmentation(“pseudo-Pelger-Huët” anomaly)

– Ring form

Cytoplasm: decreased or absent granulation

Platelets

Thrombocytopenia: ~25% at diagnosis

– Isolated thrombocytopenia rare as first

presentation sign

Giant thrombocytes

5q- sy: thrombocytosis could be seen.

WHO classification

Refractory anaemia (RA): cytopenia in one or two cell lines,

blasts <5%, ring sideroblasts<15%

RA with ring sideroblast (RARS): ring sideroblasts >15%

Refractory cytopenia with dysplasia in two or more cell lines (RCMD):

>10% dysplastic cells, <5% blasts,

RAEB-1: 5-9% blasts

RAEB-2: 10-19% blasts

MDS/MPDS

Del(5q): Anaemia, blasts <5%, normal or elevated platelet count

(female predominance, transformation is rare)

>20% blasts =ACUTE LEUKEMIA

WHO classification-based prognostic

scoring system for myelodysplasias

Karyotypes: Good = normal, -Y, del(5q-) only, del(20q-) only. Poor = complex (≥3

abnormalities), or chromosome 7 abnormalities. Intermediate = all others.

Transfusion dependency is defined as at least one red transfusion every 8 weeks

over a period of 4 months.

IPSS-R calculator: http://www.ipss-r.com

Pathogenesis of ring

sideroblasts

Cazzola M et al. Blood. 121(2):260-9

Treatment

♦ Supportive care: RBC and THR transfusion

Iron chelators: decreased organ damage and improved

hematological response

♦ Biologic response modifiers:

♦ Immune modulating agents (lenalidomide)

♦ Growth factors (Epo, G-CSF) TPO receptor antagonists???

♦ Immunosuppressive agents (cyclosporine, ATG)

♦ Hypomethylating agents (decitabin, azacitidin)

♦ High-dose chemotherapy

♦ AlloPBSCT

Therapeutic choices

Del5q: lenalidomide

Transfusion dependent, seEpo<500 U/l: Epo +/- G-CSF

Hypoplastic variant: ATG (anti-thymocyte globulin)/cyclosporin

Thr-penia/neutropenia, high risk: demethylating agents- Azacitidine, decitabin

High risk, suitable for high dose chemotherapy: chemotherapy -

alloPBSCT

Lenalidomide in del5q MDS