acute myeloid leukemia: prognosis and treatment · acute myeloid leukemia prognosis, 18-60 years...
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Acute myeloid leukemia:prognosis and treatment
Dimitri A. Breems, MD, PhDInternist-HematoloogZiekenhuis Netwerk AntwerpenCampus Stuivenberg
Patient
Female, 39 years
History: hypothyroidism
Present: fatigue and hematomas
Peripheral bloodPatient
ReferenceHemoglobin 11.4 g/dl 10.8-14.2
Thrombocytes 83 x109/l 142-330
Leukocytes 20.2 x109/l 3.5-9.8Blasts 1.0 % 0.0Neutrophils 3.9 % 40.2-74.7Eosinophils 0.0 % 0.9-8.4Basophils 0.0 % 0.0-1.5Lymphocytes 20.9 % 17.6-47.6Monocytes 40.7 % 4.0-11.3
3
Bone marrowPatient
Acute myeloid leukemiaPrognosis, 18-60 years
Complete remission rate after intensive chemotherapy?
1: 80%
2: 60%
3: 40%
Acute myeloid leukemiaPrognosis, 18-60 years
Overall survival at 5 years after intensive treatment?
1: 60%
2: 40%
3: 20%
Age Complete remission
Overall survival
18 - 60 years 80% 40% at 5 years
>60 years 65% 28% at 2 years
Acute myeloid leukemiaPrognosis according age
Acute myeloid leukemiaPrognosis, 18-60 years
Mortality:Relapse of disease 40% Primary refractory disease 10%Complications induction therapy 5%Complications consolidation treatment 5%
Acute myeloid leukemiaPrognosis, 18-60 years
Cytogenetic abnormalities
Favorable:t(8;21)(q22;q22) or AML1-ETOt(16;16)/inv(16)(p13;q22) or MYH11-CBFβt(15;17)(q22;q11-12) or PML-RARα
Unfavorable:complex (≥3 abnormalities)-7 or -5del 5q or del 7qabn 3qt(6;9)(q23;q34) or DEK-CANt(9;22)(q34;q11) or BCR-ABLabn 11q23
Acute myeloid leukemiaPatient
inv(16)(p13;q22) or MYH11-CBFβ
Acute myeloid leukemiaPrognosis, patient with inv(16)
Overall survival at 5 years after intensive treatment?
1: 90%
2: 70%
3: 50%
Cytogenetic analysis of 1975 patients, 18-60 years
Breems et al. J Clin Oncol 2008
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)
Prognostic value of cytogeneticsin acute myeloid leukemia
Cytogenetic analysis of 1975 patients, 18-60 years
Breems et al. J Clin Oncol 2008
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)
Prognostic value of cytogeneticsin acute myeloid leukemia
719 AML patients with abnormal karyotype(-X, -Y, inv(16), t(16;16), t(8;21) excluded)
Numerical abnormalitiesMonosomiesTrisomies
Structural abnormalities
Effect of cytogenetic abnormalitieson overall survival
Frequencies of autosomal chromosome monosomies in 719 cases of AML with
cytogenetic abnormalities
Chromosome
0
10
20
30
40
50
60
70
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 2122
Single monosomy
With additional monosomy
Overall survival of 719 cases of AML with cytogenetic abnormalities according to the
number of autosomal monosomies
months
Cumulativepercentage
P<0.0010
25
50
75
100
0 4812 24 36
No autosomal monosomies (n=494)Single autosomal monosomy (n=109)Two or more monosomies (n=116)
Overall survival of 719 cases of AML with cytogenetic abnormalities according to the
number of autosomal monosomies
months
Cumulativepercentage
P<0.0010
25
50
75
100
0 4812 24 36
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=46
+/- extra chromosome
+/- structural abnormality
+/- marker or ring chromsome
No autosomalmonosomy
P=0.58 P=0.82 P=0.56
Single autosomalmonosomy
P=0.23 P<0.001 P=0.23
Two or more monsomies
P=0.11 P=0.02 P=0.13
Overall survival of 719 cases of AML with cytogenetic abnormalities according to the number of autosomal
monosomies with or without other chromosomal abnormalities
0
25
50
75
100
0 48
months
Cumulativepercentage
P<0.001
Overall survival of 719 cases of AML with cytogenetic abnormalities with
autsomal monosomy / structural abnormality
No autosomal monosomy or1 auto monosomy without structural abn (n=535)
Two or more autosomal monosomy or1 auto monosomy with structural abn (n=184)= monosomal karyotype
p<0.0010
25
50
75
100
0 48
Overa
ll s
urv
ival
(%)
inv(16), t(8;21)
12 24 36
other abnormal karyotype
monosomal karyotype
normal karyotype, -X, -Y
Overall survival in AML patients categorized into favorable, intermediate, adverse and very adverse
cytogenetic risk groups
66%
41%
26%
4%
months
Breems et al. J Clin Oncol 2008
Cytogenetic analysis of 1975 patients, 18-60 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)
Prognostic value of cytogeneticsin acute myeloid leukemia
Acute myeloid leukemiaPrognosis, 18-60 years
Gene mutations in AML with normal karyotype
Favorable:NPM1 mutation in absence of FLT3-ITD mutationCEPBA-biallelic mutation
Unfavorable:High EVI1 expressionMutant p53Mutant RUNX1Mutant ASXL1Biallelic FLT3-ITD mutation with FLT3-ITD/FLT3wt ratio of >0.6
Acute myeloid leukemiaPrognosis, 18-60 years
Micro-RNAs
Micro-RNAsShort noncoding RNAsHybridize to target mRNAsRepress expression of encoded proteinsInvolved in cellular differentiation, proliferation, survivalRole in development of malignant tumors
Favorable outcome of AML patients with FLT3-ITD and/or NPM1wt and higher miR-181a expression
Schwind et al. J Clin Oncol 2010
Hickey et al. Blood 2013
Lenalidomide treatment in vivo induces miR-181a-mediated inhibition in xenograft AML
tumor growth
Acute myeloid leukemiaPrognosis, 18-60 years
Flow cytometric minimal residual disease
517 AML patients, 18-60 years85% of all AMLs:
Leukemia-associated phenotype by immunoflowcytometry is determined at diagnosisMinimal residual disease assessment in complete remission:
After chemotherapy induction cycle 1After chemotherapy cycle 2After consolidation treatment
Terwijn et al. J Clin Oncol 2013
Relapse incidence by minimal residual disease
A: After chemotherapy induction cycle 1B: After chemotherapy cycle 2C: After consolidation treatment
Relapse incidence by minimal residual disease
After chemotherapy cycle 2D: Good riskC: Intermediate riskF: Poor risk
Treatment of AMLGoals
Hematological remission, <5% blasts in bone marrowNormal peripheral blood countsNo symptomsNo extramedulary diseaseImproving survival and quality of life
No minimal residual disease (flowcytometry, molecular)
Treatment of AMLRemission-induction treatment
Combination chemotherapyCytarabineAnthracyclines (idarubicin, daunorubicin)MitoxantroneAmsacrine
Treatment of AMLRemission-induction treatment
VariationsThird cytostatic drug (thiguanine, etoposide)Local radiotherapy for extramedulary disease (CNS)Intrathecal chemotherapy (meningeal leukemia)G-CSF primingAddition of a new drug (trial)
Treatment of AMLImprovement of supportive care
Infectious Disease (profylaxis, treatment)AntibioticsAntifungals (amphotericin B, azoles, echinocandins)Antiviral
Growth factors (G-CSF)Blood products (packed cells, platelets)
Leukocyte reducedIrradiateCMV screeningHLA-identical platelets
Tumor lysis syndromeAllopurinolRasburicase
Treatment patient inv(16)
Idarubicin 12 mg/m2
3 hrs infusion
days 5, 6 and 7
Cytarabine 200 mg/m2
24 hrs cont. infusion
days 1 thru 7
Induction cycle I
Induction cycle II
Daunorubicin 60 mg/m2
1 hr infusion
days 3, 5 and 7
Cytarabine 1000 mg/m2
3 hrs inf., q 12 hrs x 12
days 1 thru 6
Treatment of AMLRemission-induction treatment
Response evaluationEarly bone marrow examination on day 10-21 to asses refractory diseaseBone marrow examination after recovery of peripheral blood
Morphologic remissionImmunologic remissionCytogenetic remissionMolecular remission
Treatment of AMLRemission-induction treatment
Patient inv(16)
Response evaluationBM day 17: no cells, no blastsBM after cycle 1: 3,1% blasts, 1-log inv(16) reductionBM after cycle 2: 1,7% blasts, 2-log inv(16) reduction
Treatment of AMLPost-remission treatment
Treatment modalitiesChemotherapyAutologous stem cell transplantation
Higher dose chemotherapyFaster hematologic recoveryLower relapse riskNo improved overall survival
Allogeneic stem cell transplantationGraft versus leukemiaLower relapse riskMore toxic treatment (infections, graft versus host disease)
Overall survival of patients with AML in first CR according to donor availability
Cornelissen et al. Blood 2007
Cornelissen et al. Blood 2007
Overall survival hazard ratio of patients with AML in first CR according to donor availability
Risk adapted postremission therapy
No completeremission
Alternative therapy
Completeremission
Intermediate risk
Allogeneic SCT (sibling)
Autologous SCT
Induction course II
Induction course I
Favorable risk
Consolidation chemotherapy
Poor risk
Allogeneic SCT (sibling or matched
unrelated)
Relapse
Treatment of AMLPatient inv(16)
Response evaluationBM day 17: no cells, no blastsBM after cycle 1: 3,1% blasts, 1-log inv(16) reductionBM after cycle 2: 1,7% blasts, 2-log inv(16) reductionNo sibling donorMitoxantrone/etoposide consolidation chemotherapyBM after cycle 3: 1,9% blasts, 3-log inv(16) reduction
Treatment of AMLPatient inv(16)
Response evaluationBM day 17: no cells, no blastsBM after cycle 1: 3,1% blasts, 1-log inv(16) reductionBM after cycle 2: 1,7% blasts, 2-log inv(16) reductionNo sibling donorMitoxantrone/etoposide consolidation chemotherapyBM after cycle 3: 1,9% blasts, 3-log inv(16) reduction
Follow upBM after 3 months: 2,0% blasts, 3-log inv(16) reductionBM after 6 months: 20% blasts, 100% inv(16)
Prognostic factors in relapse acute myeloid leukemia
1540 newly diagnosed non-M3 AML patientsage 18 to 60 years667 patients with a relapse with a median follow up of 56 months
Breems et al. J Clin Oncol 2005
Length of relapse free interval (RFI)from first CR and overall survival
after first relapse
0 60
0
25
50
75
100
12 24 36 48
P<0.001
RFI <=6 months
RFI >18 monthsRFI 7 to 18 months
Overa
ll s
urv
ival
(%)
months
0 60
0
25
50
75
100
12 24 36 48
P<0.001Overa
ll s
urv
ival
(%)
months
Other
t(16;16) or inv(16)t(8;21)
Cytogenetics at diagnosis and overall survival after first relapse
Age at relapse and overall survival after first relapse
0 60
0
25
50
75
100
12 24 36 48
P<0.001Overa
ll s
urv
ival
(%)
months
>45 years
<=35 years36 to 45 years
SCT (autologous or allogeneic) before first relapse and overall survival after first relapse
0 60
0
25
50
75
100
12 24 36 48
P<0.001Overa
ll s
urv
ival
(%)
months
Previous SCTNo SCT
60
Simplified prognostic score (0 – 14 points) for AML at first relapse
Prognostic factor Coefficient Points
Relapse free interval from first CR >18 months 0 0
7 to 18 months 0.69 3
<=6 months 1.28 5
Cytogenetics at diagnosis t(16;16) or inv(16) 0 0
t(8;21) 0.68 3
Other 1.19 5
Age at first relapse <=35 years 0 0
36 to 45 years 0.21 1
>45 years 0.47 2
STC before first relapse No 0 0
Yes 0.49 2
Simplified prognostic score (0 – 14 points) for AML at first relapse
Prognostic factor Coefficient Points
Relapse free interval from first CR >18 months 0 0
7 to 18 months 0.69 3
<=6 months 1.28 5
Cytogenetics at diagnosis t(16;16) or inv(16) 0 0
t(8;21) 0.68 3
Other 1.19 5
Age at first relapse <=35 years 0 0
36 to 45 years 0.21 1
>45 years 0.47 2
STC before first relapse No 0 0
Yes 0.49 2
Overall survival among patients with AML in first relapse according to prognostic group
Group C (10-14 points)
Group A (1-6 points)Group B (7-9 points)
0 60
0
25
50
75
100
12 24 36 48
P<0.001Overa
ll s
urv
ival
(%)
months
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
95 85
Intermediate risk group B
93 60
Poor riskgroup C
76 34
Survival probabilities of patients attaining second CR in the three prognostic groups in relation to treatment
0%
25%
50%
75%
100%
Group A Group B Group C
ChemotherapyAutologous SCTAllogeneic SCT
Five-year overall survival
Breems et al. J Clin Oncol 2005
Treatment of AMLPatient inv(16)
Relapse treatment
Fludarabine/high dose cytarabine/G-SCF (FLAG) re-induction chemotherapyBM after chemotherapy: 0% blasts, no inv(16) No sibling donor, no matched unrelated donorCombined cord blood and haplo-identical (mother) stem cell transplantationChronic graft versus host disease (skin)Five years after transplantation: molecular remission
HOVON 132 study
Idarubicin 12 mg/m2
3 hrs infusion
days 5, 6 and 7
Cytarabine 200 mg/m2
24 hrs cont. infusion
days 1 thru 7
Induction cycle I
Induction cycle II
Daunorubicin 60 mg/m2
1 hr infusion
days 3, 5 and 7
Cytarabine 1000 mg/m2
3 hrs inf., q 12 hrs x 12
days 1 thru 6
+/- Lenalidomide,Day 1-21
+/- Lenalidomide,Day 1-21
+/- Lenalidomide maintenance