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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