1. A Focus on AML: Applying the Latest Research to Individualize Therapy
AML, acute myeloid leukemia.
Supported by educational grants from AbbVie, Agios Pharmaceuticals, Celgene Corporation, Daiichi Sankyo Inc., and Jazz Pharmaceuticals.

2. Current Management of Relapsed Acute Myeloid Leukemia
Harry P. Erba, MD, PhD
Albert F. LoBuglio Endowed Chair for Translational Cancer Research
Chair, SWOG Leukemia Committee
Professor, Internal Medicine
Director, Hematologic Malignancy Program
Division of Hematology and Oncology
University of Alabama at Birmingham Birmingham, Alabama

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4. Program Director
Richard M. Stone, MD Professor of Medicine Dana-Farber Cancer Institute Harvard Medical School Boston, Massachusetts
This slide lists the faculty who were involved in the production of these slides.

5. Faculty
Harry P. Erba, MD, PhD Albert F. LoBuglio Endowed Chair for Translational Cancer Research Chair, SWOG Leukemia Committee Professor, Internal Medicine Director, Hematologic Malignancy Program University of Alabama at Birmingham Birmingham, Alabama Keith W. Pratz, MD Assistant Professor of Oncology Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland
B. Douglas Smith, MD Professor of Oncology Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland
This slide lists the faculty who were involved in the production of these slides.

6. Faculty Disclosures
Harry P. Erba, MD, PhD, has disclosed that he has received consulting fees from Amgen, Ariad, Celgene, Daiichi Sankyo, Glycomimetics, Incyte, Novartis, Pfizer, Seattle Genetics, and Sunesis; funds for non-CME/CE services from Incyte and Novartis; and funds for research support from Agios, Amgen, Astellas, Celator, Janssen, Juno, Seattle Genetics, and Takeda Oncology. Keith W. Pratz, MD, has disclosed that he has received funds for research support from AbbVie, Astellas, and Takeda Oncology. B. Douglas Smith, MD, has disclosed that he has received consulting fees from Ariad and Celgene. Richard M. Stone, MD, has disclosed that he has received consulting fees from AbbVie, Agios, Amgen, Celator, Celgene, Janssen, Juno, Karyopharm, Merck, Novartis, Pfizer, Roche, Seattle Genetics, and Sunesis.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

7. Agenda Overview: Relapsed AML Prognostic Factors in Relapsed AML
Treatment Options in Relapsed AML
AML, acute myeloid leukemia.

8. Overview: Relapsed AML
AML, acute myeloid leukemia.

9. Introduction: AML Therapeutic Overview
The majority of adults with AML who achieve a CR eventually relapse and few are cured
Primary consideration is suitability for intensive reinduction chemotherapy and allogeneic HSCT
Prognostic factors include CR1 duration, age, prior allogeneic HSCT, AML karyotype, and AML mutational status
Therapeutic strategy: palliative or bridge to transplant
AML, acute myeloid leukemia; CR1, first CR; HSCT, hematopoietic stem cell transplantation.
Slide credit: clinicaloptions.com

10. AML Outcomes by Age Pts n CR1, % Relapse, % 5-Yr OS, % ECOG data
55 yrs of age or younger
1699 68 53 16
Older than 55 yrs of age
742 49 72 8
AML, acute myeloid leukemia; CR1, first CR; ECOG, Eastern Cooperative Oncology Group.
Slide credit: clinicaloptions.com
Rowe JM, et al. ASH Abstract 546.

11. Survival for Pts With Relapsed AML
1.0
0.8
0.6
Probability of Survival
0.4
0.2 26 52 78
104
130
156
182
208
234
260
Wks
AML, acute myeloid leukemia; CR1, first CR.
Wks of CR1
Pts Censored
at > 1, 2 Yrs
Pts
Deaths
0-26
436
413
0, 0
27-52
175
162
2, 0
53-78 98 86
6, 3
79-104 37 34
1, 1
 104 56 38
8, 7
Slide credit: clinicaloptions.com
Estey E. Leukemia. 1996;10:

12. HOVON Index for AML in First Relapse: OS
100
Favorable (score 1-6)
Intermediate (score 7-9)
Poor (score 10-14) 80 60
Group A (n = 57; 27 events)
OS (%) 40
Group B (n = 165; 119 events) 20
P < .001
Group C (n = 455; 418 events) 15 30 45 60
Mos
Risk Group
Risk Score Points, n
1-Yr OS, %
5-Yr OS, %
All -- 29 11
Low
1-6 70 46
Intermediate
7-9 49 18
High
10-14 16 4
AML, acute myeloid leukemia; HOVON, Stichting Hemato-Oncologie voor Volwassenen Nederland; OS, overall survival.
AML, acute myeloid leukemia; CR1, first CR; HOVON, Haemato Oncology Foundation for Adults in the Netherlands; SCT, stem cell transplantation.
Prognostic factors: age, short duration CR1, unfavorable karyotype, prior SCT
Slide credit: clinicaloptions.com
Breems DA, et al. J Clin Oncol. 2005;23:

13. Survival After Myeloablative Allo SCT for AML in Relapse or Primary Induction Failure
1.0
0.9
Score = 0
Score = 1
Score = 2
Score = ≥ 3
Poor Risk Factors
Duration CR1 < 6 mos
Poor-risk karyotype
KPS < 90%
Circulating blasts
Non-HLA identical donor
Mismatch URD, 1 point
Related donor, but not HLA identical sibling, 2 points
0.8
0.7
0.6
Probability of Survival
0.5
42%
0.4
0.3
28%
Allo, allogeneic; AML, acute myeloid leukemia; CIBMTR, Center for International Blood and Marrow Transplant Research; CR1, first CR; HLA, human leukocyte antigens; KPS, Karnofsky performance score; SCT, stem cell transplantation; URD, unrelated donors.
0.2
15%
0.1 6%
CIBMTR study (N = 2255): 1 2 3
Yrs
Slide credit: clinicaloptions.com
Duval M, et al. J Clin Oncol. 2010;28:

14. Prognostic Factors in Relapsed AML
AML, acute myeloid leukemia.

15. Retrospective Analysis: Prognostic Factors After First Relapse in Adult AML Pts
AML in CR1
N = 2029
Allo HSCT in CR1
n = 494
CTx in CR1
n = 1535
1st relapse
n = 1015
Detailed information
n = 931
Allo, allogeneic; AML, acute myeloid leukemia; CR1, first CR; CR2, second CR; HSCT, hematopoietic stem cell transplantation.
CR2
n = 463 (50%)
No CR2
n = 468 (50%)
Salvage allo HSCT
n = 305 (66%)
No HSCT
n = 158 (34%)
Salvage allo HSCT
n = 189 (40%)
No HSCT
n = 279 (60%)
Slide credit: clinicaloptions.com
Kurosawa S, et al. Haematologica. 2010;95:

16. OS After First Relapse in Adult AML Pts
1.0 B
1.0 C
1.0
P < .001
P < .001
All pts
Age
CR1 duration
Induction courses to achieve CR1
Karyotype
Salvage HSCT
0.8
0.8
0.8
0.6
0.6
≤ 49
0.6
≥ 1 yr
Probability of OS
0.4
0.4
0.4
0.2
0.2
0.2
≥ 50
< 1 year 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 D
1.0 E
1.0
P < .001 Intermediate F
1.0
P < .001
P < .001
0.8
0.8
0.8
Favorable
AML, acute myeloid leukemia; CR1, first CR; HSCT, hematopoietic stem cell transplantation.
0.6
0.6
0.6
Salvage HSCT
1 course
Probability of OS
0.4
0.4
0.4
0.2
0.2
0.2
2 courses
Unfavorable
No HSCT 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
Yrs From Relapse
Yrs From Relapse
Yrs From Relapse
Slide credit: clinicaloptions.com
Kurosawa S, et al. Haematologica. 2010;95:

17. OS After First Relapse in Adult AML by Risk Group
1.0
inv (16)
1.0
t(8;21)
HSCT in CR2
CR2/no HSCT in non-CR2
NR/no HSCT
0.8
0.8
0.6
0.6
Probability of OS
0.4
0.4
0.2
0.2 1 2 3 4 5 1 2 3 4 5
Unfavorable Risk
Intermediate Risk
1.0
1.0
0.8
0.8
AML, acute myeloid leukemia; CR2, second CR; HSCT, hematopoietic stem cell transplantation; NR, no response.
Probability of OS
0.6
0.6
0.4
0.4
0.2
0.2 1 2 3 4 5 1 2 3 4 5
Yrs From Relapse
Yrs From Relapse
Slide credit: clinicaloptions.com
Kurosawa S, et al. Haematologica. 2010;95:

18. OS Based on Disease Status at Time of Allogeneic HSCT
1.0
1.0
P < .001
P < .001
0.8
HSCT in CR1
0.8
CR2
0.6
0.6
Probability of OS
Probability of OS
0.4
0.4
CR2 → Relapse
HSCT after relapse
0.2
0.2
Nonremission
CR1, first CR; CR2, second CR; HSCT, hematopoietic stem cell transplantation. 1 2 3 4 5 1 2 3 4 5
Yrs From CR1
Yrs From First Relapse
Pts undergoing allogeneic HSCT after first relapse are less likely to have a poor-risk karyotype and dysplasia and more likely to have a favorable-risk karyotype
Slide credit: clinicaloptions.com
Kurosawa S, et al. Haematologica. 2010;95:

19. Outcomes Following Allogeneic HSCT for AML Pts in CR1 vs CR2
Cumulative Incidence of Nonrelapse Mortality
Cumulative Incidence of Relapse OS
1.0
P = .090
1.0
P = .316
1.0
P = .061
0.8
HSCT in CR1
0.8
0.8
0.6
0.6
0.6
HSCT in CR2
0.4
0.4
0.4
HSCT in CR2
HSCT in CR2
AML, acute myeloid leukemia; CR1, first CR; CR2, second CR; HSCT, hematopoietic stem cell transplantation.
0.2
0.2
0.2
HSCT in CR1
HSCT in CR1 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
Yrs From HSCT
Yrs From HSCT
Yrs From HSCT
Slide credit: clinicaloptions.com
Kurosawa S, et al. Haematologica. 2010;95:

20. Favorable/ intermediate
Leukemia Prognostic Score for Rel/Ref AML Adult Pts (Aged Yrs): OS
Adverse Factors 1
2-3
2-Yr OS, % 59 37 12
Risk Factor
Not Adverse Risk
Adverse Risk
FLT3-ITD
Absent
Present
Karyotype
Favorable/ intermediate
Poor risk
CR1 duration
> 12 mos
< 12 mos or refractory
1.0
0.8
0.6
Probability of OS
0.4
GOELAMS study (N = 138)
Similar number of pts underwent allogeneic HSCT in each group
AML, acute myeloid leukemia; CR1, first CR; HSCT, hematopoietic stem cell transplantation; Rel/Ref, relapsed/refractory.
0.2 1 2 3
Yrs
Slide credit: clinicaloptions.com
Chevallier P, et al. Leukemia. 2011;25:

21. Allogeneic BMT in AML: Leukemia-Free Survival by Disease Status
1.0
CR1 (n = 16): 0.50
CR2 (n = 40): 0.28
0.8
P = .0001
Primary induction failure (n = 16): 0.19
Relapse (n = 81): 0.87
0.6
Probability of Leukemia-Free Survival
0.4
AML, acute myeloid leukemia; BMT, bone marrow transplantation; CR1, first CR; CR2, second CR.
0.2 2 4 6 8 10 12 14
Yrs After Transplant
Slide credit: clinicaloptions.com
Sierra J, et al. Bone Marrow Transplant. 2000;26:

22. Prognostic Factors in Relapsed AML
Adverse Risk
RFS
< 1 yr
Age
Older than 50 yrs
CR2
Not achieved
Salvage allogeneic transplant
No transplant
AML karyotype
Unfavorable
FLT3-ITD
Positive
AML, acute myeloid leukemia; CR2, second CR; RFS, relapse-free survival.
Kurosawa S, et al. Haematologica. 2010;95: Chevallier P, et al. Leukemia. 2011;25:
Slide credit: clinicaloptions.com

23. Treatment Options in Relapsed AML
AML, acute myeloid leukemia.

24. Treatment Algorithm for Relapsed/Refractory Acute Myeloid Leukemia
Evaluation:
Performance status (including HSCT-CI score)
Cytogenetics
Molecular analysis
Refractory/relapsed AML
Fit (go go)
Unfit (slow go/no go)
Salvage therapy, eg, FLA-IDA, MEC
Clinical trial for fit pts
Clinical trial for unfit pts
LDAC
Demethylating agents
Hydroxyurea
TKI (for FLT3-ITD)
AML, acute myeloid leukemia; DLI, donor lymphocyte infusion; FLA-IDA, fludarabine, cytarabine, idarubicin; HCT-CI, Hematopoietic Stem Cell Transplantation Comorbidity Index;; LDAC, low-dose cytarabine; MEC, mitoxantrone, cytarabine, etoposide; TKI, tyrosine kinase inhibitor.
Allogeneic stem cell transplantation
LDAC
Demethylating agents
Hydroxyurea
TKI (for FLT3-ITD)
Tentatively, eg, DLI, targeted therapy
Slide credit: clinicaloptions.com
Thol F, et al. Blood. 2015;126:

25. AML Regimens Over Time Yr Regimen N Ref/Rel Median Age, Yrs CR, % 1985
HiDAC vs HiDAC + DXR/DNR 78
42/36 37
63 v 65
1988
MTZ, etoposide (ME) 61
21/20 47 43
1991
MTZ, etoposide, IDAC (MEC) 32
18/14 24 66
1993
IDA, etoposide, IDAC 97
36/61
1994
MEC ± G-CSF priming 50
6/44
43 vs 47
54 vs 42
HiDAC vs HiDAC + etoposide
131
---
31 vs 38
1995
Etoposide, MTZ, Ara-C (EMA)
133
22/111 60
1998
Fludarabine, HiDAC, G-CSF (FLAG) 38
16/22 41 55
1999
HiDAC vs HiDAC + MTZ
162
56/106
48 vs 53
32 vs 44
EMA ± GM-CSF
192
120/72
47 vs 46
65 vs 59
2001 83
44/21
47/48
30/81
2003
Fludarabine, HiDAC, G-CSF, IDA 46
10/36 52
2008
Cladribine, HiDAC, MTZ (CLAG-M)
118
78/40 45 58
2009
FLAG-IDA ± GO 71
10/61 48
29 vs 39
2012
Clofarabine + IDAC vs IDAC
326
171/148 67
35 vs 18
AML, acute myeloid leukemia; CTX, cyclophosphamide; DNR, daunorubicin; DXR, doxorubicin; GO, gemtuzumab ozogamicin; HiDAC, high-dose cytarabine; IDAC, intermediate-dose cytarabine; LDAC, low-dose cytarabine; MEC, mitoxantrone, cytarabine, etoposide; MTZ, mitoxantrone; TKI, tyrosine kinase inhibitor.
Thol F, et al. Blood. 2015;126: Jackson G, et al. Br J Haematol. 2001;112:
Montillo M, et al. Am J Hematol. 1998;58:
Slide credit: clinicaloptions.com

26. CLAG-M for Refractory/Relapsed AML
CLAG-M 2-CdA 5 mg/m2 IV Days 1-5 Ara-C 2 g/m2 IV Days 1-5
MIT 10 mg/m2 IV Days 1-3 G-CSF 300 µg SC Days 0-5 NR
Off protocol PR
PR/NR CR
Off protocol
CLAG-M CR
Consolidation I
Disease Status Before CLAG-M
Primary induction failure: 78 (66%)
Relapse after CR1 < 6 mos: 40 (34%)
HAM Ara-C 1.5 g/m2 IV Days 1-3
Mitox 10 mg/m2 IV Days 3-5
CLAG-M
AML, acute myeloid leukemia; CLAG-M, cladribine, high-dose cytarabine; mitoxantrone; CR1, first CR; HAM, cytarabine, mitoxantrone; HiDAC, high-dose cytarabine; NR, no response; PR, partial response. or
Consolidation II HiDAC Ara-C 4 g/m2 IV Days 1, 3, 5
± 2-CdA 5 mg/m2 IV Days 1, 3, 5
Slide credit: clinicaloptions.com
Wierzbowska A, et al. Eur J Haematol. 2008;80:

27. CLAG-M for Refractory/Relapsed AML: Outcomes
1.0
After 1 course CLAG-M: CR 53%, PR 9%
Overall CR rate: 58%
Early death: 7%
Median OS: 9 mos
Allogeneic HSCT: 30% of CR pats
0.8
0.8
0.7
0.6
Probability of OS
0.5
0.4
0.3
AML, acute myeloid leukemia; CLAG-M, cladribine, high-dose cytarabine; mitoxantrone; CR, CR; HSCT, hematopoietic stem cell transplantation; PR, partial response.
0.2
14% (4% to 23%)
0.1 12 24 36 48 60 72
Mos
Slide credit: clinicaloptions.com
Wierzbowska A, et al. Eur J Haematol. 2008;80:

28. Azacitidine for AML in Italian Compassionate Use Program: Responses
Overall
Untreated
Pretreated
Pts, n 82 35 47
ORR, % 32 48 19
CR, % 15 23 8
CRi, % 5 3
PR, % 12 17
Only WBC > 10,000/μL and pretreated AML negatively affected response in multivariate analysis
AML, acute myeloid leukemia; CRi, CR with incomplete hematologic recovery; WBC, white blood cell count.
Slide credit: clinicaloptions.com
Maurillo L, et al. Cancer. 2012;118:

29. Cumulative Proportion Surviving Cumulative Proportion Surviving
Azacitidine for AML in Italian Compassionate Use Program: OS by Prior Treatment
Untreated AML
Pretreated AML
1.0
1.0
0.9
0.9
0.8
0.8
Median OS: 9 mos
Median OS: 7 mos
0.7
0.7
0.6
0.6
Cumulative Proportion Surviving
0.5
Cumulative Proportion Surviving
0.5
0.4
0.4
0.3
0.3
AML, acute myeloid leukemia.
0.2
0.2
0.1
0.1 6 12 18 24 30 36 6 12 18 24 30 36 42
Mos
Mos
Slide credit: clinicaloptions.com
Maurillo L, et al. Cancer. 2012;118:

30. Azacitidine for AML in Austrian Azacitidine Registry: Responses
ITT
Evaluable
Plt transfusion independence
24/60 (40%)
24/43 (56%)
RBC transfusion independence
35/97 (36%)
35/69 (51%)
Any hematologic improvement
49 (32%)
49/107 (46%)
CR (best response)
15 (10%)
20%
Marrow CR (best response)
5 (3%) 7%
PR (best response)
32 (21%)
43%
AML, acute myeloid leukemia; ITT, intent to treat; RBC, red blood cell count.
Slide credit: clinicaloptions.com
Pleyer L, et al. J Hematol Oncol. 2013;6:32

31. Azacitidine for AML in Austrian Azacitidine Registry: OS by Response
HI-Any
HI-Ery
HI-PLT
No-HI
HI-Neotroph
First Response vs Best Response
Median OS, Mos
Median OS, Mos
1.0
1.0
No response 1st – best response 1st < best response
4.5
6.0
13.7
18.9
24.7
0.8
0.8
20.3
P < .001
24.7
P = .001
0.6
0.6
20.2
Probability of OS
Probability of OS
0.4
0.4
0.2
0.2
AML, acute myeloid leukemia; Ery, erythrocytes; HI, hematologic improvement; Neutroph, neutrophils; PLT, platelets. 3 6 9 12 15 18 21 24 27 30 33 35 38 41 3 6 9 12 15 18 21 24 27 30 33 35 38 41
Mos
Mos
Achievement of any hematologic response (left) and deepening of first response with continued azacitidine therapy (right) were associated with improvement in OS
Slide credit: clinicaloptions.com
Pleyer L, et al. J Hematol Oncol. 2013;6:32

32. Baseline Characteristics
Decitabine for Elderly Pts With AML Ineligible for Intensive Chemo: Results of 2 Early Studies
Study
Baseline Characteristics
Treatment
Response
Survival
Ganetsky et al[1]
Pts, n: 60
Median age, yrs (range): 62 (28-80)
Prior chemotherapy, y/n: 78%/22%
Of pts who received prior chemotherapy
Mean chemotherapy regimens: 2.5
Post HSCT: 30%
Decitabine 20 mg/m2/day for 5 days
Overall
ORR: 13%
CR: 12%
PR: 2%
Mean cycles to achieve maximal response, n = 3.25
Relapsed/refractory AML
CR: 8.5%
Untreated
CR: 23%
Not reported
George et al[2]
Pts, n: 19
Median age, yrs (range): 61 (22-78)
All pts had intermediate or poor risk cytogenetics
> 3 chemotherapy regimens: 79%
Post HSCT: 21%
Median cycles, n = 2
No pts achieved CR or CRi
Discontinuation due to disease progression or death: 95%
Median OS, mos: 3.1
Mortality at 30 days, n = 0
AML, acute myeloid leukemia; CRi, CR with incomplete hematologic recovery; HSCT, hematopoietic stem cell transplantation.
Slide credit: clinicaloptions.com
1. Ganetsky A, et al. ASCO Abstract George TJ, et al. ASH Abstract 2186.

33. Summary: Treatment of Relapsed/Refractory AML
Consider goals of therapy: curative vs palliative
Allogeneic HSCT currently remains only potentially curative option
Aggressive supportive care required regardless of therapeutic intent (transfusions, antibiotics)
Clinical trials preferred
AML, acute myeloid leukemia; HSCT, hematopoietic stem cell transplantation.

34. Go Online for More CCO Coverage of Acute Myeloid Leukemia!
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clinicaloptions.com/oncology