1. REVIEW
AML RECURRENCE
R3 조경민

2. AML의 발생률 세계적으로는 연간 10만명당 2명~3명이 발생.
세계적으로는 연간 10만명당 2명~3명이 발생.
나이가 많을수록 발생이 증가하여 65세 이상은 10만명당 12명 정도로 발생빈도 증가-

3. 급성 골수성 백혈병
2.6%
44.6%
2002년 한국 중앙암등록 사업본부

4. Karnofsky score >60 percent CD34-negative phenotype
AML
Favorable factors
Age <50
Karnofsky score >60 percent
CD34-negative phenotype
WBC <30,000/µl
t(8;21), inv(16)/t(16;16), t(15;17)

5. AML Unfavorable factors Age >60 Karnofsky score <60 percent
WBC >30,000/µl
CD34-positive phenotype
Complex karyotypic abnormalities, -5, -7, 3q26 aberrations,
t(6;9), 11q23 aberrations except for t(9;11),

6. AML Prognosis risk classification based upon karyotype Favorable
25 percent
t(8;21), inv(16), t(16;16)
Intermediate
65 percent
normal cytogenetics, t(9;11)
Unfavorable
10 percent
3q21q26 abnormalities, del (5q), del (7q), t(6;9), other 11q23 abnormalities, 12p abnormalities, 17p abnormalities

7. Overall survival in AML
median survival 7.6 years
median survival 1.3 years
median survival 0.5 years
Data from Byrd, JC, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8641).
Blood 2002; 100:4325

8. AML
Treatment
Age 18 to 60
years
Age 60 to 74
Years
Age 75 or older

9. Induction Therapy Three days of an anthracycline
Age 18 to 60 years
Age 60 to 74
Years
Age 75 or older
Induction Therapy
Three days of an anthracycline
7 days of cytarabine ( mg/m2 continuous IV)
daunorubicin, at least 60 mg/m2
idarubicin, mg/m2,
anthracenedione mitoxantrone,
10-12 mg/m2

10. Favorable-risk AML. Intermediate-risk AML
Age 18 to 60 years
Age 60 to 74
Years
Age 75 or older
Postremission therapy
according to cytogenetic
and molecular genetic risk
Favorable-risk
AML.
cycles of HiDAC
(3 g/m2 per q12h on days 1, 3, and 5)
autologous or allogeneic HSCT No advantage
Intermediate-risk
AML
Repetitive cycles of HiDAC
(3-4 cycles; 3 g/m2 per q12h on days 1, 3, and 5)
allogeneic HSCT is an option for those patients who are at high risk of relapse.

11. Postremission therapy according to cytogenetic
Age 18 to 60 years
Age 60 to 74
Years
Age 75 or older
Postremission therapy
according to cytogenetic
and molecular genetic risk
Adverse-risk
AML
most patients with high-risk cytogenetics, outcome remains dismal with conventional consolidation therapy
An allogeneic HSCT from a matched donor
is currenty considered the treatment of choice for patients with unfavorable cytogenetics

12. AML Treatment Age 18 to 60 Age 60 to 74 Years Age 75 or older
Older patients : those 60 or older.
Older patients are more likely to suffer treatment related early death and to exhibit therapeutic resistance

13. Induction Therapy Three days of an anthracycline
Age 18 to 60 years
Age 60 to 74
Years
Age 75 or older
Induction Therapy
Three days of an anthracycline
7 days of cytarabine ( mg/m2 continuous IV)
daunorubicin, at least mg/m2
idarubicin, mg/m2,
anthracenedione mitoxantrone, mg/m2

14. Favorable, intermediate, Adverse risk
Age 18 to 60 years
Age 60 to 74
Years
Age 75 or older
Postremission therapy according to cytogenetic and molecular genetic risk
Favorable, intermediate, Adverse risk
seven days of continuous infusion cytarabine (ara-C, 100 mg/m2 per day)
Three days of daunorubicin
(60 or 90 mg/m2 per day)
Allogeneic HSCT in older patients has become an active promising field of investigation

15. Age 18 to 60 years
Age 60 to 74
Years
Age 75 or older
An alternative to standard-dose induction should be sought for patients 75 or older with a performance status of 2 or 3, comorbidities, or organ dysfunction.
low-dose cytarabine
Hydroxyurea
In a randomized trial
low-dose cytarabine (20 mg twice daily s.c. for 10 days) was associated with longer survival than hydroxyurea

16. 3 2 1 complete remission (CR)
absolute neutrophil count (>1000/microL) and
platelet count (>100,000/microL), and independence
from red cell transfusion.
A bone marrow biopsy which reveals no clusters or collections of blast cells.
A bone marrow aspiration revealing normal maturation of all cellular components (ie, erythrocytic, granulocytic, and megakaryocytic series). 1 2 3

17. Less than 5 percenct blast cell are present in the bone marrow
complete remission (CR)
Less than 5 percenct blast cell are present in the bone marrow
A bone marrow biopsy which reveals no clusters or collections of blast cells. Extramedullary leukemia must be absent.
A bone marrow aspiration revealing normal maturation of all cellular components (ie, erythrocytic, granulocytic, and megakaryocytic series). 4
Less than 5 percenct blast cell are present in the bone marrow

18. Relapsed AML In the majority of patients with AML who
achieve a CR, the leukemia will recur within 3 years
The prognosis of patients after relapse is poor and unsatisfactory.

19. (duration of CR1 <6 months)
Relapsed AML
poor outcome
adverse
cytogenetics
early relapse,
(duration of CR1 <6 months)
older age

20. INITIAL APPROACH AND PROGNOSIS
Relapsed AML
INITIAL APPROACH AND PROGNOSIS 

21. With long first remissions (greater than one year)
Relapsed AML
With long first remissions
(greater than one year)
Approximately 50 percent reinduction rate with
daunorubicin and cytarabine or with high-dose cytarabine
The duration of the second remission is usually shorter than the first
Hematopoietic cell transplantation (HCT) should be considered for any patient who has relapsed

22. Relapsed AML
Patients who achieve complete remission but relapse within 6 to 12 months of initial diagnosis
Considerable degrees of drug resistance and a lower rate of second CR
Candidates for experimental therapy or palliative care if an allogeneic HCT is not feasible

23. Relapsed AML
Allogeneic HCT remains the recommended treatment option for patients with relapsed or resistant disease

24. Relapsed AML Allogeneic hematopoietic cell transplantation (HCT)
only curative approach for relapsed or refractory disease
Biol Blood Marrow Transpl 2009;15:1431–1438.

25. Relapsed AML
Mitoxantrone
cytarabine

26. Mitoxantrone And High - cytarabine
Double Induction Strategy for Acute Myeloid Leukemia:
The Effect of High-Dose Cytarabine With Mitoxantrone Instead of Standard-Dose
Cytarabine With Daunorubicin and 6
Thioguanine: A Randomized Trial by the German AML Cooperative Group
Blood 1999 Jun 15;93(12):

27. Mitoxantrone And High - cytarabine
Blood 1999 Jun 15;93(12):
3g/m2 cytarabine by 3 hours of intravenous infusion every 12 hours on days 1 through 3
mitoxantrone by 30
minutes of intravenous infusion on days 3, 4, and 5

28. Mitoxantrone And High - cytarabine
Blood 1999 Jun 15;93(12):
Regimen proved highly effective by inducing 53% CR in patients with refractory AML by rigid criteria
2) Superior by producing significantly higher remission
rates in patients with unfavorable karyotype, with
highly elevated LDH.

29. intermediate-dose cytarabine
Mitoxantrone +
intermediate-dose cytarabine
Cancer 2000 May 1;88(9):
Treatment of patients with recurrent and primary refractory acute myelogenous leukemia using mitoxantrone and intermediate-dose cytarabine: a pharmacologically based regimen.

30. intermediate-dose cytarabine
Mitoxantrone +
intermediate-dose cytarabine
intermediate-dose cytarabine
(0.5 g/m2 IV every 12 hours for 6 days)
mitoxantrone (5 mg/m2 per day for 5 days)
Cancer 2000 May 1;88(9):

31. intermediate-dose cytarabine
Mitoxantrone +
intermediate-dose cytarabine
Complete remission rate :62%
The median duration of remission was only 3.7 months .
62%
96 %
96% of those achieving CR eventually relapsed.
Cancer 2000 May 1;88(9):

32. Relapsed AML
Anthracycline
cytarabine

33. second-line treatment
cytarabine (3 g/m2 per q12h) 7 3 5 1
daunorubicin (50mg/m2) or idarubicin (10 mg/m2) 2 4 6

34. second-line treatment
cytarabine (3 g/m2 per q12h) 1 6
in patients aged 60 years or older
Regimens that include cytarabine at high doses cannot be safely applied
blood :

35. Cytarabine Anthracycline
Cancer 2001;92:7–14. © 2001 American Cancer Society.

36. Cytarabine Anthracycline cytarabine (1g/m2 IV for 4 days)
daunorubicin ( mg/m2 per day for 3 days)

37. Cytarabine Anthracycline 62patients were treated
18 patients achieving CR
complete remission : 29%
29%
Cancer 2001;92:7–14. © 2001 American Cancer Society.

38. Cytarabine Anthracycline 62 patients were treated 11 :
18 patients achieving CR
complete remission : 29%
11 :
daunorubicin and ara-C
7 :
allogeneic BMT
Cancer 2001;92:7–14. © 2001 American Cancer Society

39. Cytarabine Anthracycline
62 patients were treated
18 patients achieving C
11 : daunorubicin and ara-C
7 : allogeneic BMT
Acute myelogenous leukemia recurred in 7 patients
one died of sepsis after a consolidation
other died of graft-versus-host disease with a CR
Death
(2)
Cancer 2001;92:7–14. © 2001 American Cancer Society

40. Other Treatment A combination of fludarabine cytarabine and G-CSF
In two reports.
A complete remission was achieved in
46 to 55 percent of patients with
primary refractory or relapsing AML
Median survival was >16 months
A combination of cytarabine,
daunorubicin, and etoposide
A complete remission rate of 43
percent in a group of 235 patients
with relapsed, refractory, or
resistant disease

41. The treatment of relapsed or refractory -
Acute promyelocytic leukemia
ATRA, high-dose cytarabine,
autologous or allogeneic hematopoietic cell transplantation, Arsenic trioxide 
Chemotherapy and ATRA for relapse 
Patients who have received ATRA plus anthracycline treatment during first remission are less likely to be cured by the same treatment at the time of relapse
The best outcomes in these patients are likely to follow hematopoietic cell transplantation, either at the time of relapse or, preferably, soon after a second CR has been obtained.

42. Relapsed AML
HEMATOPOIETIC CELL
TRANSPLANTATION

43. HEMATOPOIETIC CELL TRANSPLANTATION
Autologous HCT
In the early days
Autologous HCT, marrow was sometimes collected in first complete remission (CR)
later reinfused at the time of relapse after myeloablative - chemotherapy

44. Autologous HCT high rate of second CR but few long-term survivors
Rarely used for primary treatment of relapse

45. Allogeneic HCT
Survival following allogeneic hematopoietic cell transplantation (allo-HCT) in patients with relapsed AML
 ≤35 percent
significantly less than that seen when allo-HCT is performed in first complete remission (CR).

46. Allogeneic HCT * sicker after relapse
*leukemia is more resistant to treatment.
transplantation-related mortality is higher and post-transplant relapses are more frequent