4 Acute Leukemias
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ACUTE LEUKEMIAS
• Acute leukemias (AL)
– A heterogeneous group of diseases characterized by proliferation of immature (blastic) cells in bone marrow and extramedullary tissues.
• Normally, blasts are absent in peripheral blood (PB) and are <5% in the bone marrow (BM)
• The cytological criterium for AL diagnosis: >20% blasts in BM
– Blastic proliferation results in suppression of normal clones and bone marrow failure:
• Anemia• Infection• Hemorrhage
Hematopoiesis in Humans Multipotential hematopoietic stem cell(Hemocytoblast)
Myeloblast
Common myeloid
progenitor
Common lymphoid
progenitor
Megakaryoblast
Promegakaryoblast
Megakaryocyte
Thrombocytes
Proerythroblast(Pronormblast)
Basophilic erythroblast
Polychromatic erythroblast
Orthochromatic erythroblast(Normoblast)
Polychromatic erythrocyte
(Reticulocyte)
Erythrocyte
Mast cell Lymphoid dendritic cell
Myeloid dendritic cell Plasma cellMacrophage
Small lymphocyte Natural killer cell
T lymphocyte B lymphocyte
Prolymphocyte
Lymphoblast
MonoblastB. promyelocyte N. promyelocyte E. promyelocyte
B. myelocyte N. myelocyte E. myelocyte
B. metamyelocyte N. metamyelocyte E. metamyelocyte
B. band N. band E. band
Basophil Neutrophil Eosinophil
Promonocyte
Monocyte
2211187
• AL ~ 10% of hematological malignancies• The first cause of death by cancer in subjects <35 years old.
• According to the origin of blastic cells, AL are subdivided in 2 large groups:
A. Acute lymphoblastic leukemia (ALL), resulting from the transformation of the multipotent lymphoid stem cell. B. Acute myeoid leukemia (AML) resulting from the transformation of the multipotent myeloid stem cell
• Epidemiology1. ALL
• Incidence: 0,5-1,5/100.000/year. • ALL affects mostly children and young adults• It is the most frequent malignancy <15 years • Afterwards, ALL incidence decreases gradually: in the
elderly, ALL is very rare
– 2. AML • Incidence: 5-8/100.00/y – increases with age• 2/100,000/year < 40 years• 10-12/100,000/year > 65 years• Currently, in developed countries, AML median age at
onset is ~ 65 years
• Etiology.
– Unknown
– Genetic factors:• AL is more frequent in children with congenital diseases such as
Down syndrome, Fanconi anemia, Li-Fraumeni syndrome, Klinefelter syndrome.
– Environmental factors• ALL – the “exaggerate hygiene” hypothesis• AML
– Exposure to radiation, solvents– Previous chemotherapy/radiotherapy for other cancers
» Secondary AML
• Pathogenesis– Genomic abnormalities appearing in a single stem cell
(leukemic stem cell). • Loss of differentiation capacity (maturation arrest) • Increased proliferative capacity
– Emergence of a “growth advantage” for the leukemic clone compared to normal clones: gradual replacement of hematopoiesis by leukemic cells
– AL requires several sequential genomic abnormalities: • Example: the most frequent genetic abnormality in ALL, the
t(12 ;21) transocation, results in the formation of a hybrid gene (TEL-AML1). This abnormality alone is not leukemogenic but leads to genetic instability with the appearance of new myutations that ultimately lead to the leukemic phenotype.
1st hit
Class II mutations
CEBPA, RARA, RUNX1, MLL, WT1
2nd hit
Class II mutations
FLT3, RAS, KIT
Normal hematopoiesis
Leukemic clone
AML pathogenesis – The 2-hit theory (2002)
MATURATION ARREST PROLIFERATION
Class III mutations(epigenetic changes)
• IDH 1,2
• DNMT
• TET2
• MLL
AML Pathogenesis 2014 – Complex picture
Class I mutations (proliferation)
• FLT3
• RAS
• Kit
• JAK2
Class II mutations(maturation arrest)
• RUNX1
• PML-RARA
• CBF
• CEBPA
Class IV mutations(Intercellular adhesion/interactions)
Class V mutations(DNA repair – tumor suppressor genes)
• NPM1
• TP53
• Clinical picture
– Usually sudden onset - main symptoms: • Anemia • Bleeding: petechiae, echymoses, mucosal bleeding• Infections
– Other frequently encountered symptoms:• Bone, joint pain• Lymphadenopathy, hepatosplenomegaly - ALL• Rarely cutaneous infiltration - purple nodules – ALL, AML (monocytic)• Neurologic symptoms due to CNS leukemic infiltration - ALL• Testicular infiltration – more frequent in children, ALL• Gingival hypertrophy – more common in AML (monocytic)
ALL – Clinical aspects
AML – Clinical aspects
• Laboratory data
– Blood counts:• Anemia • Thrombocitopenia• WBC: high, normal or low.
– Peripheral blood• Presence of immature cells (blasts)• Usually low neutrophil count (<1500/μl)
– Bone marrow• Blasts >20%• Reduced normal precursors
Lymphoid blasts in a case of “common” ALL
Vacuolated blasts in a case of Burkitt – type ALL
Lymphoblast vs. mature lymphocyte
Myeloblast vs. neutrophil
Monoblast vs. monocyte
Blast with Auer body – AML2
Promyelocyte with multiple Auer bodies – AML3
Monoblasts – AML5
Abnormal erythroblast – AML6
– Immunophenotyping by flow cytometry: esential for diagnosis
• Lymphoid markers:– B lymphoid markers (CD10, CD19, CD20)– T lymphoid markers (CD3, CD7)– Early lymphoid markers (HLA-DR, TdT)
• Mieloid markers – Granulocytic – CD13, CD33– Monocytic – CD14, CD68– Megacaryocytic – CD41, CD61– Erythrocytic – glycophorin 1 (CD235)
• Stem cell marker - CD34
Flow citometry in in a case of precursor B ALL: CD10, CD19, TDT, HLA-DR poz, CD20, CD7, CD3, CD33 neg
Flow-cytometry in AML: CD13, CD33, CD117 poz, HLA-DR, CD10, CD7 neg
• Cytogenetic aspects (karyotype).
– ALL • Hyperdiploidia (>47 chromosomes) – in children – no impact on
prognosis.
• Translocations:– t(12 ;21) - good prognosis – t(9;22), (Ph1) - 15% of ALL in adults – like in CML leads to the
BCR-ABL fusion gene – good response to TKI but most cases relapse – bad prognosis
– t(4;11) – bad prognosis
• Normal karyotype – good prognosis
• AML – Karyotype defines 3 prognostic groups: – Good prognosis: t(8;21), t(15;17), inv16, t(16;16): 10-15% of cases– Bad prognosis: abnormalities of chromosomes 3, 5, 7, multiple abnormalities
(complex karyotype): 25-30% din cazuri– Intermediate prognosis: normal karyotype, other abnormalities: 40-50%
• AML – Molecular genetics (PCR, sequencing): detects genomic abnormalities that are not visible by karyotyping – useful especially in “normal cytogenetic” cases (NC-AML)– FLT3 (FMS-like tyrosine kinase-3) mutations
• 20-30% af all cases• 25-40% of NC-AML• Bad prognosis.
– NPM1 (nucleophosmin 1) mutations • 20-30% of all cases• 40-55% of NC-AML• Good prognosis (when not associated with FLT3 mutations)
– Many other mutations…..
AML - t(8;21) translocation with the formation of the AML1-ETO fusion gene (RUNX1-RUNX1T) on chr 21
AL Classification• ALL – Immunophenotipic criteria
– B-cell ALL ~ 80% of cases• Precursor B type (pB)
– proB - (5% of children, 10% of adults) – HLA-DR+, TdT+, CD19+, CD34+– common - (65% of children, 50% adults) – HLA-DR+, TdT+, CD19+,
CD10+– preB – (15% children, 10% adults) – HLA-DR+, TdT+, CD19+, CD10+/-,
cytoplasmatic IgM (cIgM) +• “Matur” B type (3% of children, 5% of adults) – HLA-DR+, CD19+,
CD20+/-, CD10+/-, sIgM + ; cytologically Burkitt-like
– T-cell ALL ~ 20% of cases• Precursor T – (1% of children, 7% of adults) – TdT+, CD3+, CD7+• “Mature” T – (11% of children, 17% of adults) – TdT+, CD3+, CD1a+,
CD5+
• AML – 2 classifications are used
1. FAB (French-American-British) classification (the ’80).– M1 = myeloblastic undifferentiated– M2 = mieloblastic with differentiation (>10% maturation)– M3 = promyelocytic (APL)– M4 = myelo-monocytic: monocytic component (monoblasts -
monocytes) >20% in BM– M5 = monoblastic: monocytic component >80%– M6 = erythroleukemia: Ebl represent >50% of BM cells – M7 = megakaryoblastic
• The FAB classification is no longer used:– Does not take into consideration cytogenetic abnormalities– Is not useful in taking decision (except APL - M3)
2. The 2008 WHO AML classification • AML with recurrent genetic abnormalities
– AML with t(8;21) (q22;q22 – [RUNX1-RUNX1T1]– AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22) - [CBFβ/MYH11]– Acute promyelocytic leukemia with t(15;17) (q12;q22) – [PML/RARA]– AML with t(9;11)(p22;q23) – [MLLT3-MLL] – Provisional entities – molecularly defined:
» AML with NPM1 mutations» AML with CEBPA mutations
• AML with myelodysplasia - related changes (MRC)
• AML and MDS, therapy related
• AML not otherwise categorized– AML minimally differentiated– AML without maturation– AML with maturation– Acute myelomonocytic leukemia– Acute erythroid leukemia– Acute megakaryocytic leukemia– Acute basophilic leukemia– Acute panmyelosis with myelofibrosis
Vardiman et al. 2008
• Acu leukemia prognosis
1. ALL– Very good prognosis in children: 70-80% cure after chemotherapy.– In adults prognosis is much worse:
• 20-30% cure after chemotherapy• 40-50% after allogeneic stem cell transplant (SCT)
– Prognostic factors in ALL• Bad:
– WBC > 40.000/μl– T and B mature phenotype– CNS involvement
• Good:– “Common” immunophenotype
2. AML – bad prognosis – median survival <1 year – Prognostic factors
• Good – cure in 30-50%:– Age <60 years– FAB M3 (APL) with t(15;17) – 70-80% cure– t(8;21) and inv16 – cure 40-60%– NPM1 mutations
• Bad – cure 5-10%:– Age >60 de ani – AML with myelodysplasia - related changes (MRC) – AML therapy related – “Bad” karyotype– FLT3 mutations
• AL treatment– Treatment is very complex: supportive measures, chemotherapy,
transplant – The first step towards cure: Complete Remission (CR) – CR can be defined as “apparent cure” (1000X reduction of number of
tumor cells).
– CR criteria:• No lymphadenopathy, no hepato/splenomegaly.• PB: neutrophils >1500/μl, platelets >100.000/μl, no blasts• <5% blasts în BM • Normal cerebrospinal fluid (CSF). • Normal karyotype
• General supportive measures: – Isolation– Hygene– Hyperuricemia prophylaxis: allopurinol, rasburicase,
alcalinisation. – Antibiotics, antifungals, antivirals– Transfusions:
• Red cells : Hgb<7g/dl • Platelets: Plt <10-20.000/µl.
– Growth factors. • In severe neutropenia (<500/µl): G-CSF
• Chemotherapy
1. ALL – standard chemotherapy– Several steps:
– Remission induction» Combinations: antracyclines, vincristine, L-asparaginase,
corticoids– CNS prophylaxis
» MTX, Ara-C i.t.– Consolidation
» High dose MTX, Ara-C– Maintenance – up to 3 years
» Low dose 6MP, MTX
GMALL protocol• 1. Induction 1.
– Vincristine (iv) – 2mg, days 1, 8, 15, 22 – Doxorubicin (iv, 30 min), 25 mg/m2, days 1, 8, 15, 22 – L-Asparaginase (iv, 30 min), 5 000 IU/m2, days 15,17,19,21,23,25,27– Prednisone (po) 60 mg/m2, days 1-28– Methotrexate (i.t.) - 15 mg, day 1
• 2. Induction 2.– Cyclophosphamide (iv) - 650 mg/m2, days 29, 43, 57 – Ara-C (iv, 1 h) - 75 mg/m2, days 31-34, 38-41, 45-48, 52-55– 6-Mercaptopurine (po) - 60 mg/m2, days 29-57– Methotrexat (i.t.) – 15 mg, days 31, 38, 45, 52
• 3. Consolidation 1. (HDARAC+Mitox) + (HDMTX+Asp+6MP)– Ara-C (iv, 3 h, at 12h) - 1 000 mg/m2, days 1-4– Mitoxantrone (iv, 30 min) – 10 mg/m2, days 3-5, then, after hematological
recovery: – Methotrexate (iv, 24 h) - 1 500 mg/m2, days 1, 15 + Leucovorin – L-Asparaginase (iv, 30 min) - 10 000 U/m2, days 2,16– 6-Mercaptopurine (po) - 25 mg/m2, days 1-5, 15-19
• 4. Reinduction 1. – Vincristin (iv) – 2mg, days 1, 8, 15, 22 – Doxorubicin (iv, 30 min) - 25 mg/m2, days 1, 8, 15, 22 – Prednison (po) 60 mg/m2, days 1-28– MTX 15 mg + Ara-C 50 mg + Dexamethasone 4 mg (i.t.) – d 1
• 5. Reinduction 2. – Cyclophosphamida (iv) - 650 mg/m2, day 29– Ara-C (iv, 1 h) - 75 mg/m2, days 31-34, 38-41 – 6-Thioguanina (po) - 60 mg/m2, days 29-57– MTX 15 mg + Ara-C 50 mg + Dexametazona 4 mg (i.t.) – day 29
• 6. Consolidation 2. – Etoposide (iv, 1 h) - 100 mg/m2, days 1-5– Ara-C (iv, 1 h) - 150 mg/m2, days 1-5, then, after hematological recovery:– Cyclophosphamide (iv) - 1 000 mg/m2, day 1– Ara-C (iv, 24 h) - 500 mg/m2, day 1– MTX 15 mg + Ara-C 50 mg + Dexametasone 4 mg (i.t.) – day 1
• 7. Maintenance – 2 years.– 6-Mercaptopurine (po) – 60mg/m2, weekly, days 1-5– Methotrexate (po) – 12,5mg/m2, weekly, day 6
HyperCVAD protocol• 1. Cycle A.
– Cyclophosphamide (iv, 3h, at 12 h) – 300mg/m2, days 1,2,3
– Methotrexate (i.t.) – 15 mg, day 2– Doxorubicin (iv, 30min) – 50mg/m2, day 4– Vincristine (iv) – 2mg, days 4,11– Dexamethasone (iv or po) – 40mg days 1-4 and 11-14– Cytarabine (i.t.) - 70mg, day 7
• 2. Cycle B
– Methotrexate (iv, 24h) – 1000mg/m2, day 1– Leucovorin (iv, 24 h after MTX) – 6 doses every 6 h– Ara-C (iv, 2 f, at 12 h) – 3000mg/m2, days 2,3
• A total of 8 cycles (4A + 4B) • 3. Maintenance – POMP – 2 years
– Vincristine (iv) - 2mg, day 1– Prednisone (po) – 60mg/m2, days 1-5– 6-Mercaptopurine (po) – 60mg/m2, weekly, days 1-5– Methotrexate (po) – 12,5mg/m2, weekly, day 6
Treatment of certain ALL subtypes:
• Ph1-ALL [t(9;22)]: Tyrosine kinase inhibitors - imatinib 600-800mg/day or dasatinib 140mg/day are added, “a la longue”.
• B-ALL(Burkitt), CD20+: monoclonal anti-CD20 antibodies (rituximab) are added
2. AML – Standard chemotherapy (except M3):
– Remission induction: 1–2 cycles – 3/7 regimen• Idarubicin – 12mg/m2 days 1,3,5• Cytarabine (Ara-C) – 100-200mg/m2, days 1-7
– Remission consolidation: High-dose Ara-C – 3-4 cycles• Ara-C (iv 3h, every 12 ore) – 3g/m2 days 1,3,5
– M3 (Acute promylocytic leukemia, APL)• Induction:
– All-trans retinoic acid (ATRA) – 45mg/m2, p.o, day 1 till CR (usually 14-30 days) – induces leukemic cell differentiation
• Idarubicin 12mg/m2, days 2, 4, 6, 8• Consolidation:
– Idarubicin 5 mg/m2 days 1-4, repeated at 28 days, 3 cycles• Maintenance – up to 2 years from onset
- 6MP 90 mg/m2/day, p.o. Days 1-5 of every week- Methotrexate 15mg/m2, p.o., day 6- ATRA 45mg/m2/day, p.o., days 1-15, every 3 months
• Stem cell transplant• Allogeneic stem cell transplant (allo-SCT)
– Indicated as soon as possible, in 1st CR:• ALL
– ALL Ph+– In adults with bad prognostic factors (<60 years)
• AML– All intermediate/bad risk patients <60 years
– In relapse/refractory disease – all patients <60 ani
• Autologous stem cell transplant (auto-SCT)– When no donor is found for allo-SCT– It is not clear if there is an advantage over chemotherapy alone