1. Current Treatment Paradigms in Acute Myeloid Leukemia
Richard Stone, MD
Professor of Medicine
Harvard Medical School
Chief of Staff
Director, Adult Acute Leukemia Program
Dana-Farber Cancer Institute
Boston, Massachusetts

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Content presented live on 6/3/17

3. Acute Myeloid Leukemia (AML): The Basics
Unbridled proliferation of hematopoietic stem cells (myeloid lineage)
Results in marrow failure and patient death unless successfully treated
Risk factors
AGE (median age = 69)
Prior chemo for other cancers
Ionizing radiation
Industrial solvents
20K new US cases w/10K deaths annually

4. Basic Facts: AML Older patient population1 Heterogenous2
Most patients diagnosed after age 60
Heterogenous2
Based on disease- and patient-related features
Therapy is adapted accordingly3
Percent of New Cases by Age Group: All Races, Both Sexes; SEER
1NCI website. 2Medinger M, et al. Leuk Res Rep. 2016;6: NCCN. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version

5. AML: Current Treatment Paradigms
APL: The major success story and the goal: Chemo-free cures
Unmet needs: Disease resistance is common
Younger patients: Most need allo SCT
Older patients: Cure rate is very low
Relapsed/refractory disease
Highly unsatisfactory therapeutic results
Current goal: Achieve a deep response at a level undetectable by sensitive means (MRD negative)

6. AML: Not Much Improvement Over Time, Especially in Older Adults
Ages years
Ages ≥60 years
Older adults have a worst prognosis than younger patients; almost all will die of their disease. In younger adults the cure rate is %, unacceptable low. Little improvement in outcomes has been seen over the last few decades. Improvements came from optimizing dose and regimens of approved chemotherapies and due to improvements on supported care. Current treatments are myelosuppressive, toxic and have a negative impact on QOL. Patients are care for by a multidisciplinary team that is resource (hospitalization and transfusion) intensive
Burnett A, et al. J Clin Oncol. 2011;29:

7. Treatment of Acute Promyelocytic Leukemia
Key Principles of APL Management
Suspect the Disease!
Risk of death is greatest in the first two weeks after diagnosis, especially if ATRA initiation is delayed…
So, if the clinical setting suggests the possibility of APL (eg, clefted blasts, strong CD33+, DIC, low WBC/PLTS) do not wait for molecular confirmation to start ATRA
Document Disease
Use cytogenetics or FISH for t(15;17), or RT-PCR for PML-RARA fusion
Variant translocations are rare, but important to know about, since several do not respond to ATRA
Assess Risk
If WBC >10 x 109/L: high risk: Use CALGB 9710 or APML4 or similar
If WBC ≤10 x 109/L: standard risk (lowest risk if platelets also >40 x 109/L): Use GIMEMA regimen

8. 21/11/12
ATRA Plus Arsenic Trioxide the New Standard for APL, Based on APL 0406 Study
Acute Promyelocytic Leukemia
Low/intermediate risk patients
(WBC ≤10 x 109/L, AGE 16-70) R
ATRA +
ATO
ATRA +
Chemotherapy
Per MD Anderson
Per PETHEMA
Lo-Coco F, et al. New Engl J Med. 2013;369(2): 8

9. Event-Free and Overall Survival in APL
21/11/12
Event-Free and Overall Survival in APL
Event-free survival probability
Months from diagnosis
97.1%
85.6%
P = .02
ATRA+ATO
ATRA+Chemo
Overall survival probability
Months from diagnosis
98.7%
91.1%
P = .02
ATRA+ATO
ATRA+Chemo
Lo-Coco F, et al. New Engl J Med. 2013;369(2): 9

10. Current Risk Assessment in AML
Key Prognostic Factors in AML in 2017
Patient age (FH, bleeding hx; ? Therapy related; ? Prior MDS)
Cytogenetics/fusion mRNA (screen for APL, Ph+, CBF)
Multiparameter flow
Molecular studies:
FLT3 ITD (internal tandem duplication) mutation
Unfavorable
NPM1 mutation
Favorable
CEBPA biallelic mutation
RUNX1, TP53, ASXL1 (? KIT in CBF)
Of future importance: Mutation status of IDH1/2, DNMT3A, TET2, etc. 10

11. Genetic-Cytogenetic Prognostic Subgroups New European Leukemia Net (ELN) 2017
Favorable Genetic Risk
Frequency: 15%
Survival: 65%
Subset:
t(8;21)(q22;q22); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD or FLT3-ITD low
Biallelic Mutated CEBPA
Intermediate Genetic Risk
Frequency: 55%
Survival: 50%
Subset:
Mutated NPM1 and FLT3-ITD high
Wild-type NPM1 without FLT3-ITD or FLT3-ITD low (without adverse-risk genetic lesions)
Wild-type NPM1 and FLT3-ITD (normal karyotype)
t(9;11)(p22;q23); MLLT3-MLL
Any cytogenetics not classified as favorable or adverse
Adverse Genetic Risk
Frequency: 30%
Survival: 20%
Subset:
t(6;9)(p23;q34); DEK-NUP214
t(v;11)(v;q23); MLL (KMT2A) rearranged
Inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 (GATA2, MECOM (EVI1)
t(9;22)(q34.1;q11.2) BCR-ABL1
Monosomy 5 or del(5q); monosomy 7; monosomy 17; abnormal 17p
Complex karyotype(≥ 3 abnormalities) or monosomal karyotype
Wild-type NPM1 and FLT3-ITD high
Mutated RUNX1
Mutated ASXL1
Mutated TP53
Döhner H, et al. Blood. 2017;129(4):

12. AML: General Treatment Principles
Goal 1: Induction chemotherapy to reduce gross leukemia to measurably (by morphology traditionally but ideally by PCR or multiparameter flow) undetectable levels (eg, CR)
Goal 2: Reduce the residual cells present at CR, to a level low enough to achieve prolonged disease-free survival (“cure”) using “consolidation chemo” and/or allogeneic SCT
NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version

13. AML Therapy: Patients Age <60 Years
Standard induction chemo: “3+7”
Daunorubicin mg/m2/d x 3 or idarubicin 12 mg/m2/d x 3 plus
Cytarabine mg/m2/d x 7 continuous infusion
Ida plus high-dose ara-C (IA) inferior to standard 3+7 (SWOG 1203 study)1
Post-remission (consolidation) therapy
If adverse risk cytogenetics: allo SCT
Maybe DUCB or haploidentical SCT
If favorable risk: 4 cycles HiDAC
If intermediate risk: allo SCT if sibling or MUD; HiDAC otherwise
DUCB=double umbilical cord blood; HiDAC=high-dose cytarabine
1Garcia-Manero G, et al. ASH 2016.

14. Intensified Induction in AML: ECOG E1900 ‒ Overall Survival
——— MRD-positive
——— MRD-negative
All patients
High dose
P = .003
Standard dose
Probability OS
Months
Favorable cytogenetics
High dose
Standard dose
P = .004
Probability OS
Months
Unfavorable cytogenetics
High dose
P = .45
Standard dose
Probability OS
Months
Comparison:
Daunorubicin 90 mg/m2/d x 3 vs
Daunorubicin 45 mg/m2/d x 3
Fernandez HF, et al. N Engl J Med. 2009;361:

15. Is There a Role for Chemotherapy in CR1 in AML Patients With Normal Cytogenetics?
Mutant NPM1, No FLT3-ITD
No benefit from allo SCT in patients with: mutated NPM1 and wild-type FLT3
Donor
No Donor
P = .71
Years
Relapse-free Survival (%)
Other Genotypes
In all other cases: allo SCT may be superior
Donor
No Donor
P = .003
Years
Relapse-free Survival (%)
Schlenk RF, et al. N Engl J Med. 2008;358:1909:1918.

16. FLT3 WILD-TYPE not eligible for enrollment
C10603/RATIFY Established New Standard: Add Midostaurin to Standard Chemo in Mutant FLT3 AML
DNR
Ara-C
Midostaurin
Midostaurin
MAINTENANCE
12 months CR
HiDAC
Midostaurin
X 4
PRE-REGISTER
FLT3 SCREENa,b
R FLT3+
DNR
Ara-C
Placebo
Placebo
MAINTENANCE
12 months CR
HiDAC
Placebo
X 4
Note that transplant not specified in treatment plan. Study enrolled from Patients who left study for HSCT were followed for EFS and OS.
Eligible patients: previously untreated AML, age with demonstration of FLT3-ITD or D835 in central lab
Induction:
Daunorubicin 60 mg/m2 d1-3
Cytarabine 200 mg/m2 CIVI d1-7
Midostaurin 50 mg bid days 8-21
Repeat above after d24 if persistent marrow blasts on D21 aspirate.
Marrow to document response required before day 60, regardless of number of cycles delivered. Patients entering CR1 thereafter could continue on protocol
Post-remission therapy:
AraC 3 gm/m2 q12h d1, 3, 5
Midostaurin d8-21
Maintenance:
Midostaurin 50 mg BID d1-28 x 12 cycles
FLT3 WILD-TYPE not eligible for enrollment
aStratification: FLT3 ITD or TKD; bStratification: TKD; ITD with allelic ratio <0.7 vs ≥0.7 R=randomize
Stone RM, et al. Blood. 2015;126:6.

17. Overall Survival (Primary Endpoint) 23% Reduced Risk of Death in the MIDO Arm
4-year Survival
MIDO
51.4% (95%CI: 46, 57)
PBO
44.2% (95%CI: 39, 50)
Hazard ratio*: 0.77
1-sided log-rank P value*: .0074
+ Censor
Median OS: MIDO 74.7 (31.7-NE); PBO 25.6 ( ) months
NE=not estimable
*Controlled for FLT3 subtype (TKD, ITD-Low, ITD-High)
Stone RM, et al. Blood. 2015;126:6.

18. Importance of Achieving an MRD Negative CR (Using PCR for NPM1 Mutation After Two Induction Cycles)
Figure 2. Minimal Residual Disease in Peripheral Blood after the Second Cycle of Chemotherapy and Clinical Outcomes. Shown are the rates of overall survival (Panel A) and the cumulative incidence of relapse in all patients (Panel B), in those without FLT3-ITD mutations (Panel C) and those with FLT3-ITD mutations (Panel D), and in those without DNMT3A mutations (Panel E) and those with DNMT3A mutations (Panel F) among patients who were found to have minimal residual disease (MRD-positive) or no minimal residual disease (MRD-negative) in peripheral-blood samples. Censoring of data is indicated by black tick marks, and death during remission is indicated by green tick marks.
MRD=minimal residual disease; PCR=polymerase chain reaction
Ivey A, et al. N Engl J Med. 2016;374:

19. Older Patients with AML Have Inferior Outcomes
Age group
Complete remission rate (with “3&7”-like regimens)
Early mortality
Disease-free survival
Long-term overall survival
Median survival
<60 years
70%
10%
45%
30%
24 months
≥60 years
>25%
<20%
10 months
Data are based on CALGB & MRC trials for which adults of all ages were eligible
Mayer RJ, et al. N Engl J Med. 1994;331: ; Rees JK, et al. Br J Haematol. 1996;94:89-98. 19

20. Why Do Older Patients With AML Experience Inferior Outcomes?
Decreased host tolerance of intensive therapy
Impaired hematopoietic stem cell reserve
Presence of comorbid diseases
Decreased chemotherapy clearance
Increased resistance of disease to therapy
Ratio of favorable (eg, t[8;21]) to unfavorable (eg, -7) cytogenetics is lower than for younger patients
Higher expression of drug resistance proteins (eg, PGP)
Higher incidence of antecedent hematologic disorders (and secondary mutations)
PGP=p-glycoprotein

21. Event-free Survival (%)
In Elderly De Novo AML, Secondary-Type Mutations Are Associated With Adverse Outcomes
de novo AML, Age ≥60 y
Genetic Subtype
Event-free Survival (%)
Months
Lindsley RC, et al. Blood. 2015;125:

22. AML Therapy: Patients Age >60 Years
Standard induction: 3+7 (if patient likely to tolerate)1,2
Daunorubicin mg/m2/d x 3 d plus
Cytarabine mg/m2/d x 7 d by continuous infusion
Idarubicin or mitoxantrone are not better than daunorubicin3
Adding etoposide or increasing daunorubicin dosage is possible, but not clearly better4,5
Recent trials6-8 have assessed whether “tolerable” single-agent therapy (eg, clofarabine, decitabine, azacitidine) might replace 3+7 in those destined to do very poorly with 3+7, for example:
Age >70 years
Performance status ≥2 +/- comorbid disease
Adverse cytogenetics
Antecedent hematological disorder (eg, myelodysplastic syndrome, myeloproliferative neoplasms)
Daunorubicin and cytosine arabinoside remain the standard induction regimen for older patients with acute myeloid leukemia. While idarubicin was apparently superior to daunorubicin based on several randomized trials conducted in the 1980s, recent trials in which various anthracyclines (idarubicin, mitoxantrone) have been compared during induction specifically in older patients have not shown a benefit compared to daunorubicin. There is no basis for reducing the dose of daunorubicin in this cohort.
The benefit of adding etoposide to standard anthracycline and cytosine arabinoside induction for acute myeloid leukemia is debated in younger patients. Randomized trials have suggested a benefit in disease-free, but not overall survival. The use of etoposide is not recommended in older patients with acute myeloid leukemia due to increased potential toxicity without added benefit.
AML Collaborative Group. A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia. Br J Haematol. 1998;103:
Lowenberg B, Suciu S, Archimbaud E, et al for the European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. J Clin Oncol. 1998;16:
Rowe J, Neuberg D, Friedenberg W, et al. A Phase III study of daunorubicin vs idarubicin vs mitoxantrone for older adult patients (>55 years) with acute myelogenous leukemia (AML): A study of the Eastern Cooperative Oncology Group (E3993) {Abstract]. Blood. 1998; 92:1284a.
Kahn SB, Begg CB, Mazza JJ, Bennett JM, Bonner H, Glick JH. Full dose versus attenuated dose daunorubicin, cytosine arabinoside, and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol. 1984;2:
Bishop JF, Matthews JP, Young GA, Bradstock K, Lowenthal RM. Intensified induction chemotherapy with high-dose cytarabine and etoposide for acute myeloid leukemia: a review and updated results of the Australian Leukemia Study Group. Leuk Lymphoma. 1998;28:
[AU: Please identify the 3 most important references to include on the slide.]
1Estey EH. Blood. 2000;96: NCCN Clinical Practice Guidelines. AML. V Rowe JM, et al. Blood. 2004;103: Baer MR, et al. Blood. 2002;100: Lowenberg B, et al. N Engl J Med. 2009;361: Cashen AF, et al. J Clin Oncol. 2010;28: Kantarjian HM, et al. J Clin Oncol. 2010;28: Schiller GJ, et al. J Clin Oncol. 2010;28:

23. Phase III Trial of Azacitidine vs
Phase III Trial of Azacitidine vs. Conventional Care in Older AML Patients With >30% BM Blasts
Age ≥65 y
ECOG PS 0-2
>30% blasts
Int/poor karyotype
Azacitidine 75 mg/m2 sq x 7 d every 28 d
Randomization
N = 241
Conventional care (7+3, LDAC, supportive care)
N = 247
Azacitidine
Conventional Care
CR/Cri (%)
28%
25%
Median OS (months)
10.4
6.5
Median EFS (months)
6.7
4.8
Median RFS (months)
9.3
10.5
1-year OS (%)
46.5%
34.2%
Because of the possibility that these results reflected more indolent AML disease and may not be applicable to the majority of AML pts, these investigators recently performed a f/u phase III study randomizing older AML pts with >30% BM blasts with the same schema. Of note, all of the pts in this study had inter/poor karyotype. As shown here, CR rates were again similar; however the differences in overall survival in the two groups were much closer than in the prior study.
BM=bone marrow; CRi=complete remission with incomplete blood count recovery; EFS=event-free survival; LDAC=low-dose Ara-C; RFS=relapse-free survival
Dombret H, et al. Blood. 2015;126:

24. Correlation Between Somatic Mutations and Clinical Responses
10 d decitabine upfront in 116 AML patients
Figure 2 Correlation between Somatic Mutations and Clinical Responses. Panel A shows the results of enhanced exome sequencing in the discovery cohort among patients who had a response (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) or no response (partial response, stable disease, or progressive disease). Panel B shows the results of gene-panel sequencing (264 genes in 15 patients and 8 genes in 45 patients) in patients in the extension cohort. ND denotes not done. Panel C shows the proportions of patients among all those in whom samples were sequenced (99 patients) who had a response or did not have a response, according to the presence of the indicated mutations. Panel D shows the locations and predicted consequences of TP53 mutations identified in this trial and in patients with AML in the Cancer Genome Atlas Research Network cohort.20
Welch JS, et al. N Engl J Med. 2016;375:

25. TP53 and 10-Day Decitabine in AML: Interesting, Not Yet a New Paradigm
NA=not applicable; PD=progressive disease; PR=partial remission; SD=stable disease
Welch JS, et al. N Engl J Med. 2016;375:

26. AML: Relapsed Disease
No clear best regimen (MEC, FLAG-ida, HMA commonly used)
Outcome dependent on age, leukemia-specific factors, prior treatment (? allo SCT), and duration of initial CR (highly variable CR rates in patients fit for multi-agent salvage)
10% CR rate with HMA1 largely in patients considered unfit for multi-agent salvage
The goal is to achieve response and proceed to allo SCT if feasible
1Stahl M, et al. ASH 2016.

27. AML: Burden and Unmet Needs
Older adults: Almost all die of their disease
Little improvement in outcome over the last few decades
Younger adults: 40%-50% cure rate
Unacceptably low
All patients: Current treatments are myelosuppressive/toxic/neg impact on QOL, resource (hospital and transfusion) intensive

28. 2017: The Year of Hope
Approved: Midostaurin (+ chemo) in upfront mut FLT3 AML
May be approved:
CPX-351 for secondary AML
Enasidenib in IDH2 mutant advanced AML
Gemtuzumab (antiCD33 Ab-toxin conjugate) + chemo in upfront and/or single- agent in relapse
Not far behind
Vadastuximab (antiCD33), ivosidenib (IDH1 mutant), venetoclax (bcl-2 inhib), glasdegib (hedgehog inhib)

29. A Resource for Information and Education in AML
A Resource for Information and Education in AML