Akut myeloid leukemia AML 1 2 3 4

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Akut myeloid leukemia (AML) 1. 2. 3. 4. 5. 6. Epidemiology Diagnostics Treatment Indications

Akut myeloid leukemia (AML) 1. 2. 3. 4. 5. 6. Epidemiology Diagnostics Treatment Indications allo-tx Prognosis Trends/future AML_2014 -05 -28

Proportion AML of all adult acute leukemias (Swedish acute leukemia registry) AML_2014 -05 -28

Proportion AML of all adult acute leukemias (Swedish acute leukemia registry) AML_2014 -05 -28

AML – one disease or rather a group of different diseases? 29% other abnormalities

AML – one disease or rather a group of different diseases? 29% other abnormalities 5% t(15; 17) 7% inv(16) 6% t(8; 21) 5% t(11 q 23) 42% normal karyotype FLT 3, NPM 1, CEBPA, MLL 1, NRAS, WT 1, DNMT 3 A, IHD 1, IDH 2, KIT, SHP 2, CBL …. AML_2014 -05 -28

240 220 200 180 160 140 120 100 80 60 40 20 0 16

240 220 200 180 160 140 120 100 80 60 40 20 0 16 - 20 - 25 - 30 - 35 - 40 - 45 - 50 - 55 - 60 - 65 - 70 - 75 - 80 - 8590+y 19 y 24 y 29 y 34 y 39 y 44 y 49 y 54 y 59 y 64 y 69 y 74 y 79 y 84 y 89 y 2. 33170347260598 Total 5. 31946927655028 6. 64181811031535 8. 32016507207503 10. 1202715205597 13. 291575633219 20. 3366391670113 29. 5992121110271 37. 2378068407864 57. 8911391122013 91. 1999846400026 130. 959346875088 160. 686276478999 184. 104673469241 153. 377013247591 127. 449324073992 1. 43742184018743 F 4. 65326397384866 6. 05159662477538 8. 49502191715655 11. 6521634992742 14. 9101140386518 23. 7137034274893 25. 1682678478974 39. 594337400608 52. 585242526836 77. 9035378917938 110. 610647946886 134. 219789986134 155. 417479548175 132. 515941352231 120. 027126130505 3. 1794480478189 M 5. 95936902200795 7. 21116948342962 8. 15236136282398 8. 65697538883732 11. 7346674346354 17. 051324486705 33. 9396687168148 34. 9218332964714 63. 2284966288467 105. 538846696686 155. 001534819119 195. 643713727337 228. 538460991532 194. 397625867293 148. 664025021299 AML_2014 -05 -28

AML - utgår (i de flesta fall) från den hematopoetiska stamcellen AML_2014 -05 -28

AML - utgår (i de flesta fall) från den hematopoetiska stamcellen AML_2014 -05 -28

Types av genetic changes in AML • Relocalisation of genetic material (gene fusions )

Types av genetic changes in AML • Relocalisation of genetic material (gene fusions ) translokations/inversions/insertions • Addition or loss of genetic material trisomies/monosomies duplikations/amplifications/deletions • Point mutations TP 53, RAS, FLT 3 etc. • Epigenetic changes Metylations of CDKN 2 A/B etc AML_2014 -05 -28

Leukemic transformation? Normal Leukemic stem cell AML Self renewal STEM CELL Self renewa COM

Leukemic transformation? Normal Leukemic stem cell AML Self renewal STEM CELL Self renewa COM STEM CELL BLAST STAGE Block in maturation MATURE CELLS AML_2014 -05 -28

AML-epidemiology – risk factors (I) – Not a heriditary disease • familiar aggregations –

AML-epidemiology – risk factors (I) – Not a heriditary disease • familiar aggregations – Previous exposure to organic solvents (e. g. bensene) – Smoking? ? ? AML_2014 -05 -28

AML-epidemiology – risk factors (II); “secondary AML” – Previous treatment with DNA-damaging agents (t-AML)

AML-epidemiology – risk factors (II); “secondary AML” – Previous treatment with DNA-damaging agents (t-AML) • alkylating chemotherapy and/or radiation therapy • topoisomeras II-inhibitors (etoposide, antracyklines) – Antecendent chronic hematological disease (AHD-AML) • myelodysplastic syndrome (MDS) • myeloproliferative neoplasm (MPN) • others (congenital neutropenia, aplastic anemia etc) AML_2014 -05 -28

de novo AML (80%) sekundär AML (20%) Hematopoetisk stamcellssjukdom Mutagen exposition Alkylerande cytostatika (exv.

de novo AML (80%) sekundär AML (20%) Hematopoetisk stamcellssjukdom Mutagen exposition Alkylerande cytostatika (exv. MDS) Övriga cytostatik a AML_2014 -05 -28

Secondary AML – 25% of all AML_2014 -05 -28

Secondary AML – 25% of all AML_2014 -05 -28

Clinical signs&symptoms Morphology Diagnostics Prognostics Cytogenetics Immunophenotypning AML_2014 -05 -28

Clinical signs&symptoms Morphology Diagnostics Prognostics Cytogenetics Immunophenotypning AML_2014 -05 -28

AML - clinical picture Stable not-so-sick to severely ill patients ! • Unspecific constitutional

AML - clinical picture Stable not-so-sick to severely ill patients ! • Unspecific constitutional symptoms – – fatigue weight loss fever nightly sweatings • Infections (immunodeficient due to neutropeni etc) • Bleeding tendency (thrombocytopenia, coagulations defects) • Extramedullary leukemia (5 -10%) AML_2014 -05 -28

Leukemic cutanous infiltrates AML_2014 -05 -28

Leukemic cutanous infiltrates AML_2014 -05 -28

An Gingival infiltrationold Mani A and Lee D. N Engl J Med 2008; 358:

An Gingival infiltrationold Mani A and Lee D. N Engl J Med 2008; 358: 274 AML_2014 -05 -28

Most patients have circulating blasts AML_2014 -05 -28

Most patients have circulating blasts AML_2014 -05 -28

AML_2014 -05 -28

AML_2014 -05 -28

AML AML_2014 -05 -28

AML AML_2014 -05 -28

Immunophenotypning (flow cytometry) • Differentiate AML from ALL • Subtyping of AML • ”Finger

Immunophenotypning (flow cytometry) • Differentiate AML from ALL • Subtyping of AML • ”Finger print” of AML-cells facilitating later MRD -diagnostics (MRD=minimal residual disease) AML_2014 -05 -28

Cytogenetics (karyotyping) AML_2014 -05 -28

Cytogenetics (karyotyping) AML_2014 -05 -28

Cytogenetics –risk of relapse • Low risk (≈10% of all pts) – t(15; 17),

Cytogenetics –risk of relapse • Low risk (≈10% of all pts) – t(15; 17), inv(16), t(8; 21) • Intermediate (≈60%) – normal karyotype – other changes • High risk (≈30%) – -5, -5 q, -7, inv(3), -komplex karyotype AML_2014 -05 -28

Recurrent mutations in AML_2014 -05 -28

Recurrent mutations in AML_2014 -05 -28

Akut myeloid leukemia (AML) 1. 2. 3. 4. 5. 6. Epidemiology Diagnostics Treatment Indications

Akut myeloid leukemia (AML) 1. 2. 3. 4. 5. 6. Epidemiology Diagnostics Treatment Indications allo-tx Prognosis Future prospects AML_2014 -05 -28

Life threatening initial complications • Septicaemia – ”fever=infection” • Bleeding – trombocytopenia – hyperfibrinolysis

Life threatening initial complications • Septicaemia – ”fever=infection” • Bleeding – trombocytopenia – hyperfibrinolysis – disseminated intravascular coagulation (DIC) AML_2014 -05 -28

Extremely risky patients (early death risk ≈20%) • Hyperleukocytosis (WBC>100 x 10 e 9/L)

Extremely risky patients (early death risk ≈20%) • Hyperleukocytosis (WBC>100 x 10 e 9/L) • Acute promyelocytic leukemia (APL) AML_2014 -05 -28

AML – upfront treatment strategies • Curative – intense, remission induction chemotherapy • ”Semipalliative”

AML – upfront treatment strategies • Curative – intense, remission induction chemotherapy • ”Semipalliative” (relieve symptoms, prolong life) – hypomethylating drugs (azacitidine, decitabine) – low dose cytarabine s. c. – hydroxyurea p. o. • Palliation – basic supportive care, no chemo AML_2014 -05 -28

AML- curative treatment COMPLICATIONS INDUCTION RESISTENT LEUKEMI COMPLETE REMISSION (CR) CONSOLIDATION CURE AML_2014 -05

AML- curative treatment COMPLICATIONS INDUCTION RESISTENT LEUKEMI COMPLETE REMISSION (CR) CONSOLIDATION CURE AML_2014 -05 -28

Remission induction chemoterapy in AML - golden standard (except APL) • Cytarabine – standard

Remission induction chemoterapy in AML - golden standard (except APL) • Cytarabine – standard dose, 100 -200 mg/m 2 kont iv inf x 7 -10 d – intermediate dose, 1 -2 g/m 2/1 -4 h x II x 4 -5 d – high dose, 3 g/m 2 1 -4 h x 2 x 4 -6 d • Antracyklin – daunorubicin 30 -90 mg/kvm bolus-8 h x 3 d – idarubicin 10 -12 mg/kvm bolus-1 h x 3 d – mitoxantron 8 -12 mg/kvm bolus-1 h x 3 d AML_2014 -05 -28

Why combine chemotherapeutic drugs? • Maximal cytotoxicity due to more targets • Decreases the

Why combine chemotherapeutic drugs? • Maximal cytotoxicity due to more targets • Decreases the risk of resistance However, the value of adding a third drug (e. g. etoposid, purine analogues) to daunorubicin-cytarabin is not yet proven AML_2014 -05 -28

Intensive vs palliative treatment by age (Sw AML-registry) 100% 90% 80% 70% 60% 50%

Intensive vs palliative treatment by age (Sw AML-registry) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Palliative Intensive <65 yrs 35 294 65 -69 yrs 24 79 70 -74 yrs 40 90 75 -79 yrs 84 77 AML_2014 -05 -28 80+ yrs 207 34 All 390 574

AML non-APL 1997 -2006 CR rate with Intensive Treatment by Age 120% 100% 80%

AML non-APL 1997 -2006 CR rate with Intensive Treatment by Age 120% 100% 80% 60% 40% 20% 0% no CR CR <40 yrs 34 156 40 -49 yrs 36 160 50 -59 yrs 114 262 Juliusson et al, Blood 2009; 113: 4179 60 -64 yrs 83 171 65 -69 yrs 104 188 AML_2014 -05 -28 70 -74 yrs 149 163 75 -79 yrs 125 110 80 -84 yrs 68 38 85+ yrs 9 4

Chemo induced neutropeni - infektions AML_2014 -05 -28

Chemo induced neutropeni - infektions AML_2014 -05 -28

AML non-APL: Early Death Rate (8 wks) by Palliative vs Intensive Treatment and Age

AML non-APL: Early Death Rate (8 wks) by Palliative vs Intensive Treatment and Age AML_2014 -05 -28

AML- curative treatment COMPLICATIONS (7 -15%) INDUCTION CR (60 -85%) RESISTENT LEUKEMIA (10 -20%)

AML- curative treatment COMPLICATIONS (7 -15%) INDUCTION CR (60 -85%) RESISTENT LEUKEMIA (10 -20%) CONSOLIDATION CURE? AML_2014 -05 -28

Consolidation – main options AIM: Eradicate persisting tumour cells (minimal residual disease=MRD) in order

Consolidation – main options AIM: Eradicate persisting tumour cells (minimal residual disease=MRD) in order to minimise the risk of relapse • 1 -3 intensive chemotherapy cycles (optimal number not known) or • allogeneic hematopoietic stem cell transplantation; allo. SCT (matched sibling donor, unrelated donor) AML_2014 -05 -28

Consolidation by chemo • What number is optimal? – Sweden: 3 consolidations – MRC:

Consolidation by chemo • What number is optimal? – Sweden: 3 consolidations – MRC: randomisering totalt 5 vs 4 kurer, similar restults – US: often only 1 konsolidering AML_2014 -05 -28

Allo-SCT in AML + Most efficient therapy in minimising the risk of relapse -

Allo-SCT in AML + Most efficient therapy in minimising the risk of relapse - Transplantation related mortality - Transplantation related morbidity, in particular severe chronic GVHD AML_2014 -05 -28

Allo. SCT Rates by Age and Dx (Sw AMLreg) AML_2014 -05 -28

Allo. SCT Rates by Age and Dx (Sw AMLreg) AML_2014 -05 -28

Indications for allo-SCT in AML CR 1 Pts <55 -70 yrs, well informed about

Indications for allo-SCT in AML CR 1 Pts <55 -70 yrs, well informed about risks, no severe comorbidity, good performance status • High risk cytogenetics • Intermediate risk cytogenetics with FLT 3 ITD-mutation • Secondary AML • Slow responders AML_2014 -05 -28 39 39

Not indications for allo-SCT in AML CR 1 • Pts with t 15; 17

Not indications for allo-SCT in AML CR 1 • Pts with t 15; 17 (i. e. acute promyelocytic leukemia =APL) • Pts with other typer of low risk cytogenetics and good response to induction chemotherapy – t: 8; 21 – inv(16) – normal karyotype and NPMI 1 pos/FLT 3 -ITDneg AML_2014 -05 -28 40 40

Indications for allo-SCT in AML CR 1 – controversy Pts <55 -70 yrs with

Indications for allo-SCT in AML CR 1 – controversy Pts <55 -70 yrs with intermediate risk cytogenetics (FLT 3 -ITDneg) 1. ”All these pts should be considered for allo-SCT” 2. ”These pts should only be transplanted after relapse” 3. ”These pts should be considered for allo-SCT except those who have a normal karyotype and are MRD-negative post consolidation (i. e. very good responders)” AML_2014 -05 -28 41 41

Prognostic factors in AML • Patient related – ålder – comorbidity (andra svåra sjukdomar)

Prognostic factors in AML • Patient related – ålder – comorbidity (andra svåra sjukdomar) – performance status • Leukemia related – de novo or secodndary AML – cytogenetics • Response related – bone marow morphology – minimal residual disease AML_2014 -05 -28 42 42

Akut myeloid leukemia (AML) 1. 2. 3. 4. 5. 6. Epidemiology Diagnostics Treatment Indications

Akut myeloid leukemia (AML) 1. 2. 3. 4. 5. 6. Epidemiology Diagnostics Treatment Indications allo-tx Prognosis Future prospects AML_2014 -05 -28

AML - overall survival in different age groups AML_2014 -05 -28

AML - overall survival in different age groups AML_2014 -05 -28

Elderly AML pts ofte have multiple negative prognostic faktors • High proportion secondary AML,

Elderly AML pts ofte have multiple negative prognostic faktors • High proportion secondary AML, i. e. MDSAML – more chemo resistent • High proportion high risk cytogenetics – more chemo resistent • Poor performance status – inceased treatment related mortality • Comorbidities – inceased treatment related mortality AML_2014 -05 -28

AML, survival, gender AML_2014 -05 -28

AML, survival, gender AML_2014 -05 -28

De novo versus secondary AML_2014 -05 -28

De novo versus secondary AML_2014 -05 -28

Cytogenetics and prognosis prognos Byrd et al, Blood 2002 1213 AML patients AML_2014 -05

Cytogenetics and prognosis prognos Byrd et al, Blood 2002 1213 AML patients AML_2014 -05 -28

Prognostisk impact of FLT 3 -ITD och NPM 1 mutation status in AML FLT

Prognostisk impact of FLT 3 -ITD och NPM 1 mutation status in AML FLT 3 -, NPM 1+ FLT 3+, NPM 1 - AML_2014 -05 -28 Gale et al. , Blood, 2008 1425 AML-patienter

Response related risk factors for relapse in AML • Leukemic blasts in bone marrow

Response related risk factors for relapse in AML • Leukemic blasts in bone marrow >15% following first chemo cycle • >2 cycles needed to achieve CR • Minimal residual disease (MRD) – by flow cytometry – by molecular genetics • Remaining ”leukemic stem cells” after consolidation (LSC) ? – area of intense research AML_2014 -05 -28

Relapse incidence by minimal residual disease (MRD). Terwijn M et al. JCO 2013; 31:

Relapse incidence by minimal residual disease (MRD). Terwijn M et al. JCO 2013; 31: 3889 -3897 AML_2014 -05 -28 © 2013 by American Society of Clinical Oncology

AML - summary • AML is a biologically and prognostically heterogenous disease • Good

AML - summary • AML is a biologically and prognostically heterogenous disease • Good initial diagnostic work-up and MRDmonitoring important for decision making (tx or not) • Approx half of the younger pts cured with intensive, toxic chemotherapy +/- allo-SCT • Only a minority of elderly pts are cured, but substantial proportion obtain 1 -3 yrs disease free survival with good quality of life AML_2014 -05 -28 52 52

AML – three interesting trends • Developments in molecular genetics has given us new

AML – three interesting trends • Developments in molecular genetics has given us new prognostic markers (but we are wating for predictive markers…!) • MRD-monitoring • Post transplant treatment in high risk AML in order to reduce relapse AML_2014 -05 -28 53 53

Emerging therapies – some examples • Chemotherapy – asacytidin (Vidaza®), decitabin (Dacogen®), clofarabin (Evoltra®)

Emerging therapies – some examples • Chemotherapy – asacytidin (Vidaza®), decitabin (Dacogen®), clofarabin (Evoltra®) • Immunocytotherapy – gemtuzumab ozogamicin (Mylotarg®) • Immunotherapy – histamin (Ceplene®) + interleukin-2 – vaccination strategies • Signal transduction modulators AML_2014 -05 -28 54 54