Acute myeloid leukemia: prognosis and treatment. Dimitri A. Breems, MD, PhD Internist-Hematoloog Ziekenhuis Netwerk Antwerpen Campus Stuivenberg
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1 Acute myeloid leukemia: prognosis and treatment Dimitri A. Breems, MD, PhD Internist-Hematoloog Ziekenhuis Netwerk Antwerpen Campus Stuivenberg
2 Patient Female, 39 years History: hypothyroidism Present: fatigue and hematomas
3 Peripheral blood Patient Reference Hemoglobin 11.4 g/dl Thrombocytes 83 x10 9 /l Leukocytes 20.2 x10 9 /l Blasts 1.0 % 0.0 Neutrophils 3.9 % Eosinophils 0.0 % Basophils 0.0 % Lymphocytes 20.9 % Monocytes 40.7 %
4 Bone marrow Patient
5 Acute myeloid leukemia Prognosis, years Complete remission rate after intensive chemotherapy? 1: 80% 2: 60% 3: 40%
6 Acute myeloid leukemia Prognosis, years Overall survival at 5 years after intensive treatment? 1: 60% 2: 40% 3: 20%
7 Acute myeloid leukemia Prognosis according age Age Complete remission Overall survival years 80% 40% at 5 years >60 years 65% 28% at 2 years
8 Acute myeloid leukemia Prognosis, years Mortality: Relapse of disease 40% Primary refractory disease 10% Complications induction therapy 5% Complications consolidation treatment 5%
9 Acute myeloid leukemia Prognosis, years Cytogenetic abnormalities Favorable: t(8;21)(q22;q22) or AML1-ETO t(16;16)/inv(16)(p13;q22) or MYH11-CBFβ t(15;17)(q22;q11-12) or PML-RARα Unfavorable: complex ( 3 abnormalities) -7 or -5 del 5q or del 7q abn 3q t(6;9)(q23;q34) or DEK-CAN t(9;22)(q34;q11) or BCR-ABL abn 11q23
10 Acute myeloid leukemia Patient inv(16)(p13;q22) or MYH11-CBFβ
11 Acute myeloid leukemia Prognosis, patient with inv(16) Overall survival at 5 years after intensive treatment? 1: 90% 2: 70% 3: 50%
12 Prognostic value of cytogenetics in acute myeloid leukemia Cytogenetic analysis of 1975 patients, years Karyotype Number of patients (%) Four-year overall survival, % (SE) Normal 987 (50) 41 (2) inv(16)/t(16;16) 120 (6) 70 (4) t(8;21) 134 (7) 63 (4) Abnormal 733 (37) 21 (2) Breems et al. J Clin Oncol 2008
13 Prognostic value of cytogenetics in acute myeloid leukemia Cytogenetic analysis of 1975 patients, years Karyotype Number of patients (%) Four-year overall survival, % (SE) Normal 987 (50) 41 (2) inv(16)/t(16;16) 120 (6) 70 (4) t(8;21) 134 (7) 63 (4) Abnormal 733 (37) 21 (2) Breems et al. J Clin Oncol 2008
14 Effect of cytogenetic abnormalities on overall survival 719 AML patients with abnormal karyotype (-X, -Y, inv(16), t(16;16), t(8;21) excluded) Numerical abnormalities Monosomies Trisomies Structural abnormalities
15 Frequencies of autosomal chromosome monosomies in 719 cases of AML with cytogenetic abnormalities Single monosomy With additional monosomy Chromosome
16 Overall survival of 719 cases of AML with cytogenetic abnormalities according to the number of autosomal monosomies Cumulative percentage P<0.001 No autosomal monosomies (n=494) Single autosomal monosomy (n=109) Two or more monosomies (n=116) months
17 Overall survival of 719 cases of AML with cytogenetic abnormalities according to the number of autosomal monosomies Cumulative percentage P<0.001 No autosomal monosomies (n=494) Single autosomal monosomy (n=109) Two or more monosomies (n=116) Four-year overall survival Single monosomy 7 13% n=63 Other single monsomy 12% n= months
18 Overall survival of 719 cases of AML with cytogenetic abnormalities according to the number of autosomal monosomies with or without other chromosomal abnormalities +/- extra chromosome +/- structural abnormality +/- marker or ring chromsome No autosomal monosomy P=0.58 P=0.82 P=0.56 Single autosomal monosomy P=0.23 P<0.001 P=0.23 Two or more monsomies P=0.11 P=0.02 P=0.13
19 Overall survival of 719 cases of AML with cytogenetic abnormalities with autsomal monosomy / structural abnormality 100 Cumulative percentage P<0.001 No autosomal monosomy or 1 auto monosomy without structural abn (n=535) Two or more autosomal monosomy or 1 auto monosomy with structural abn (n=184) = monosomal karyotype 0 48 months
20 Overall survival in AML patients categorized into favorable, intermediate, adverse and very adverse cytogenetic risk groups Overall survival (%) inv(16), t(8;21) 50 normal karyotype, -X, -Y other abnormal karyotype 25 monosomal karyotype p< months 66% 41% 26% 4% Breems et al. J Clin Oncol 2008
21 Prognostic value of cytogenetics in acute myeloid leukemia Cytogenetic analysis of 1975 patients, years Karyotype Number of patients (%) Four-year overall survival, % (SE) Normal, -X, -Y 1001 (51) 41 (2) inv(16)/t(16;16) 120 (6) 70 (4) t(8;21) 134 (7) 63 (4) Abnormal, no monosomal karyotype 535 (27) 26 (2) Monosomal karyotype 184 (9) 4 (1)
22 Acute myeloid leukemia Prognosis, years Gene mutations in AML with normal karyotype Favorable: NPM1 mutation in absence of FLT3-ITD mutation CEPBA-biallelic mutation Unfavorable: High EVI1 expression Mutant p53 Mutant RUNX1 Mutant ASXL1 Biallelic FLT3-ITD mutation with FLT3-ITD/FLT3wt ratio of >0.6
23 Acute myeloid leukemia Prognosis, years Micro-RNAs Micro-RNAs Short noncoding RNAs Hybridize to target mrnas Repress expression of encoded proteins Involved in cellular differentiation, proliferation, survival Role in development of malignant tumors
24 Favorable outcome of AML patients with FLT3-ITD and/or NPM1wt and higher mir-181a expression Schwind et al. J Clin Oncol 2010
25 Lenalidomide treatment in vivo induces mir- 181a-mediated inhibition in xenograft AML tumor growth Hickey et al. Blood 2013
26 Acute myeloid leukemia Prognosis, years Flow cytometric minimal residual disease 517 AML patients, years 85% of all AMLs: Leukemia-associated phenotype by immunoflow cytometry is determined at diagnosis Minimal residual disease assessment in complete remission: After chemotherapy induction cycle 1 After chemotherapy cycle 2 After consolidation treatment Terwijn et al. J Clin Oncol 2013
27 Relapse incidence by minimal residual disease A: After chemotherapy induction cycle 1 B: After chemotherapy cycle 2 C: After consolidation treatment
28 Relapse incidence by minimal residual disease After chemotherapy cycle 2 D: Good risk C: Intermediate risk F: Poor risk
29 Treatment of AML Goals Hematological remission, <5% blasts in bone marrow Normal peripheral blood counts No symptoms No extramedulary disease Improving survival and quality of life No minimal residual disease (flowcytometry, molecular)
30 Treatment of AML Remission-induction treatment Combination chemotherapy Cytarabine Anthracyclines (idarubicin, daunorubicin) Mitoxantrone Amsacrine
31 Treatment of AML Remission-induction treatment Variations Third cytostatic drug (thiguanine, etoposide) Local radiotherapy for extramedulary disease (CNS) Intrathecal chemotherapy (meningeal leukemia) G-CSF priming Addition of a new drug (trial)
32 Treatment of AML Improvement of supportive care Infectious Disease (profylaxis, treatment) Antibiotics Antifungals (amphotericin B, azoles, echinocandins) Antiviral Growth factors (G-CSF) Blood products (packed cells, platelets) Leukocyte reduced Irradiate CMV screening HLA-identical platelets Tumor lysis syndrome Allopurinol Rasburicase
33 Treatment patient inv(16) Induction cycle I Idarubicin 12 mg/m 2 3 hrs infusion days 5, 6 and 7 Cytarabine 200 mg/m 2 24 hrs cont. infusion days 1 thru 7 Induction cycle II Daunorubicin 60 mg/m 2 1 hr infusion days 3, 5 and 7 Cytarabine 1000 mg/m 2 3 hrs inf., q 12 hrs x 12 days 1 thru 6
34 Treatment of AML Remission-induction treatment Response evaluation Early bone marrow examination on day to asses refractory disease Bone marrow examination after recovery of peripheral blood Morphologic remission Immunologic remission Cytogenetic remission Molecular remission
35 Treatment of AML Remission-induction treatment Patient inv(16) Response evaluation BM day 17: no cells, no blasts BM after cycle 1: 3,1% blasts, 1-log inv(16) reduction BM after cycle 2: 1,7% blasts, 2-log inv(16) reduction
36 Treatment of AML Post-remission treatment Treatment modalities Chemotherapy Autologous stem cell transplantation Higher dose chemotherapy Faster hematologic recovery Lower relapse risk No improved overall survival Allogeneic stem cell transplantation Graft versus leukemia Lower relapse risk More toxic treatment (infections, graft versus host disease)
37 Overall survival of patients with AML in first CR according to donor availability Cornelissen et al. Blood 2007
38 Overall survival hazard ratio of patients with AML in first CR according to donor availability Cornelissen et al. Blood 2007
39 Risk adapted postremission therapy Induction course I Induction course II No complete remission Complete remission Favorable risk Intermediate risk Poor risk Alternative therapy Consolidation chemotherapy Allogeneic SCT (sibling) Autologous SCT Allogeneic SCT (sibling or matched unrelated) Relapse
40 Treatment of AML Patient inv(16) Response evaluation BM day 17: no cells, no blasts BM after cycle 1: 3,1% blasts, 1-log inv(16) reduction BM after cycle 2: 1,7% blasts, 2-log inv(16) reduction No sibling donor Mitoxantrone/etoposide consolidation chemotherapy BM after cycle 3: 1,9% blasts, 3-log inv(16) reduction
41 Treatment of AML Patient inv(16) Response evaluation BM day 17: no cells, no blasts BM after cycle 1: 3,1% blasts, 1-log inv(16) reduction BM after cycle 2: 1,7% blasts, 2-log inv(16) reduction No sibling donor Mitoxantrone/etoposide consolidation chemotherapy BM after cycle 3: 1,9% blasts, 3-log inv(16) reduction Follow up BM after 3 months: 2,0% blasts, 3-log inv(16) reduction BM after 6 months: 20% blasts, 100% inv(16)
42 Prognostic factors in relapse acute myeloid leukemia 1540 newly diagnosed non-m3 AML patients age 18 to 60 years 667 patients with a relapse with a median follow up of 56 months Breems et al. J Clin Oncol 2005
43 Length of relapse free interval (RFI) from first CR and overall survival after first relapse 100 Overall survival (%) P<0.001 RFI >18 months RFI 7 to 18 months RFI <=6 months months
44 Cytogenetics at diagnosis and overall survival after first relapse 100 t(16;16) or inv(16) Overall survival (%) P<0.001 t(8;21) Other months
45 Age at relapse and overall survival after first relapse 100 <=35 years Overall survival (%) P< to 45 years >45 years months
46 SCT (autologous or allogeneic) before first relapse and overall survival after first relapse 100 Overall survival (%) P<0.001 No SCT Previous SCT months 6 0
47 Simplified prognostic score (0 14 points) for AML at first relapse Prognostic factor Coefficient Points Relapse free interval from first CR >18 months to 18 months <=6 months Cytogenetics at diagnosis t(16;16) or inv(16) 0 0 t(8;21) Other Age at first relapse <=35 years to 45 years >45 years STC before first relapse No 0 0 Yes
48 Simplified prognostic score (0 14 points) for AML at first relapse Prognostic factor Coefficient Points Relapse free interval from first CR >18 months to 18 months <=6 months Cytogenetics at diagnosis t(16;16) or inv(16) 0 0 t(8;21) Other Age at first relapse <=35 years to 45 years >45 years STC before first relapse No 0 0 Yes
49 Overall survival among patients with AML in first relapse according to prognostic group 100 Group A (1-6 points) Group B (7-9 points) Overall survival (%) P<0.001 Group C (10-14 points) months
50 Treatments applied following first relapse and second complete remission rates in the three prognostic groups Group Percentage treated patients Second complete remission rate of treated patients Favorable risk group A Intermediate risk group B Poor risk group C
51 Survival probabilities of patients attaining second CR in the three prognostic groups in relation to treatment Five-year overall survival 100% 75% Chemotherapy Autologous SCT Allogeneic SCT 50% 25% 0% Group A Group B Group C Breems et al. J Clin Oncol 2005
52 Treatment of AML Patient inv(16) Relapse treatment Fludarabine/high dose cytarabine/g-scf (FLAG) reinduction chemotherapy BM after chemotherapy: 0% blasts, no inv(16) No sibling donor, no matched unrelated donor Combined cord blood and haplo-identical (mother) stem cell transplantation Chronic graft versus host disease (skin) Five years after transplantation: molecular remission
53 HOVON 132 study Induction cycle I Idarubicin 12 mg/m 2 3 hrs infusion days 5, 6 and 7 Cytarabine 200 mg/m 2 24 hrs cont. infusion days 1 thru 7 +/- Lenalidomide, Day 1-21 Induction cycle II Daunorubicin 60 mg/m 2 1 hr infusion days 3, 5 and 7 Cytarabine 1000 mg/m 2 3 hrs inf., q 12 hrs x 12 days 1 thru 6 +/- Lenalidomide maintenance +/- Lenalidomide, Day 1-21
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