Acute myeloid leukemia: prognosis and treatment · Acute myeloid leukemia Prognosis, 18-60 years ... Improvement of supportive care Infectious Disease (profylaxis, treatment) ...

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