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Acute Promyelocytic and Other Acute Myeloid Leukemias:
The Slaying of the Old Dragon?
Martin S. Tallman, M.D. Memorial Sloan Kettering Cancer Center
Weill Cornell Medical College 14th Annual Indy Hematology Review
Acute Promyelocytic Leukemia Distinguishing Features
• 10-15% of adult AML • Leukopenia (85%) • Complex coagulopathy • t(15;17) chrom translocation • Sensitivity to anthracyclines • PML-RARα fusion transcript • Differentiation with retinoic acid • Apoptosis with arsenic trioxide
Initial Studies of ATRA in APL
Group Year N CR% D(E)FS% Therapy
Euro. APL 1999 99 94 84 ATRA/DA
GIMEMA 1997 240 95 79 ATRA/Ida
North Am. 1997 172 72 75 Maint.
PETHEMA 1999 123 89 92 No ara-C
GAMLCG 2000 51 92 88 HiDAC
GIMEMA & PETHEMA Study Relapse-free survival
0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 Months
Prob
abili
ty
P <0.0001
High WBC >10,000/µL Intermediate WBC ≤10,000/µL & Plt ≤40,000/µL Low WBC ≤10,000/µL & Plt >40,000/µL
n = 53
n = 49
n = 115 Low risk
Sanz et al. Blood, 2000
Most Important Questions in APL in 2017
1. How can early death rate be reduced?
2. Is ATRA/ATO standard of care?
3. What is best treatment for high-risk disease?
4. Is maintenance needed?
Early Death Rate in APL Population-Based Studies
Study N ED
Jeddi 41 16%
Lehmann 99 31%
Alizadeh 137 14%
McClellan 70 26%
Park 1,400 18%
Jeddi et al. Hematology, 2008; Lehmann et al. Leukemia, 2010; Alizadeh et al. ASH, 2009; McClellan et al. Haematologica, 2012; Park et al. Blood, 2011
Pathogenesis of the Coagulopathy
elastase TAT F1+2 FPA
COAGULATION FIBRINOLYSIS PROTEOLYSIS
ACTIVATION
u-PA plasminogen a-2-antiplasmin D-dimer D-dimer Annexin II
Prevention of Early Death in APL
• Early death as emerged as the major cause of treatment failure
• Start ATRA at first suspicion (based on clinical hx and review of peripheral smear), BEFORE MARROW AND BEFORE DIAGNOSIS CONFIRMED (in ER)
• Frequent plt transfusion to >50,000/µL
• Cryo to maintain fibrinogen >150 mg/dL
• No heparin, although not studied in ATRA era
• No antifibrinolytics
Rodeghiero et al. Blood, 1990; Tallman et al. Leukemia Res, 2004; Sanz et al. Blood, 2008
Important (and Provocative) Concepts in APL
• No treatment modification based on additional cyto abn, therapy-related, FLT3 mutations, CD56, PML isoform, or morphology (M3V)
• Bone marrow not needed on day 14 AND not at CR
– No primary resistance
– No prognostic importance of cyto/molecular genetics when CR1 first achieved at end of induction
• Maybe marrow not needed at diagnosis, if diagnosis unmistakable
Dual Mechanisms of Action of Arsenic Trioxide
Apoptosis Differentiation
RARa release
Caspase activation
Release of cytochrome c from the mitochondria
PML/RARa degradation
Transcription of RARa target genes
Arsenic Trioxide
GIMEMA /SAL/AMLSG-APL0406
Low-risk (wbc<10x109/L)
R
AIDA 2000 (anthracycline-based consolidation)
ATRA + ATO
ATRA + ATO ATRA + Chemo No. of patients 75 79
CR, (%) 75 (100%) 75 (95%)
Induction death 0 4*
Resistant disease 0 0
Induction Outcome
*Differentiation syndrome (2), ischemic CVA (1) and pneumonia (1)
Lo Coco et al. NEJM, 2013
Event-Free Survival Primary objective
98%
84.9%
97.1%
85.6%
p=0.02 p=<0.001
Initial series Final series
Lo Coco et al. NEJM, 2013 and ASH, 2014
ATRA
IDA
ATRA
ATO ATO
APML4
Induction Consolidation Maintenance
ATRA MTX 6MP
APML4 Trial
Iland et al. ASH, 2014
APML4 DFS by Sanz Risk Category
% a
live
and
rela
pse-
free
100
80
60
40
20
0 1 2 3 4 5 6 7 8 0
Years from documented HCR
P [ trend ] = .30
Low 100%
High 95% Intermediate 93%
Iland et al. ASH, 2014
Sanz et al. Blood, 2010; Adès et al. Am J Hematol, 2013; Lo Coco et al. Blood, 2010; Sanz et al. Best Pract Res Clin Haematol, 2003; Iland et al. ASH, 2014
High-Risk APL ATRA + Risk-Adapted Chemo vs APML4
Number Median follow-up
(months)
IDA equivalent
(mg/m2)
AraC
(g/m2)
DFS CIR OS
PETHEMA LPA2005 118 28 122 5.8
82%
14%
79%
European APL2000 74 103 99 22.8 -
7%
88%
GIMEMA AIDA2000 129 59 122 6.3
85%
9%
83%
ALLG
APML4 23 50 48 0
95%
5%
87%
MRD Monitoring
• Low- and intermediate-risk: 1% OS benefit at 5 yrs
• High-risk: 10% OS benefit at 5 years
• Low- and intermediate-risk: MRD monitoring can be reasonably discontinued and pts followed once molecularly negative
• High-risk: continue MRD monitoring every three months for 3 years
Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010
Future Directions
• Decrease early death
• Optimize/refine treatment for high-risk patients
• Novel strategies
–Oral arsenic
Lu et al. Blood, 2006; Au et al. Blood, 2011
Oral Arsenic
• Outcome
– newly dx’d: CHR 100%, CCR 88%, DFS 78%
– Relapsed: CCR and CMR 71%
• Similar bioavailability to IV
• Crosses into CSF about 30% serum level (by itself may not be enough to prevent CNS relapse)
Lu et al. Blood, 2002; Kumana et al. Eur J Clin Pharmacol, 2002; Au et al. Leukemia Res, 2007; Au et al. Blood 2006, 2008, 2011
Overall Survival 1.0
.90
.95
.85
.80 0 10 20 30 40 50 60 70
Time (months)
RIF ATO
P =.18
Ove
rall
Surv
ival
(pro
babi
lity)
Zhu et al. J Clin Oncol, 2013
Future Treatment
APL likely will be treated and cured with all oral therapy (ATRA + oral ATO)
Imagine that!
• Defined by cytogenetic and molecular interactions
• Intensified induction may be important
• Less intensive chemotherapy consolidation under study
• Increased importance of minimal residual disease
• Expanded availability of allogeneic transplantation
• Novel strategies for older patients
• Incorporation of novel agents
Acute Myeloid Leukemia State-of-the-Art 2017
14% Other adverse 5% MLL-PTD
12% FLT-ITD/ NPM1 wt
INTERMEDIATE 21% CEBPα mut (biallelic)/ FLT3-ITD neg 3%
NPM1 mut/ FLT3-ITD neg/WT1 wt 18%
Inv(16)/t(16;16)/ CBFB-MYH11 5%
3% inv(3)/t(3;3)/EVI-1
t(8;21)/RUNX1-RUNX1-T1 8%
t(15;17)/PML-RARA 11%
ADVERSE 34% FAVORABLE
45%
Grimwade Hematology Am Soc Hematol Educ Program, 2009
Distribution of Cytogenetically and Molecularly Defined Risk Groups in AML
Gene Incidence Associations Impact
FLT3-ITD 25% NPM1 Unfavorable
NPM1 33% FLT3 Favorable
dCEBPα 8% FLT3 Favorable
C-KIT 15% CBF Unfavorable [in t(8;21), but less clear
in inv(16)]; 1D816 worse than others
IDH1 and 2 22% NPM1 Favorable
Gene Mutations Clinically Important in Everyday Practice Today
1Yui et al. ASH abstr 2785, 2016
Multivariate Risk Classification For FLT3-ITD-neg,
Intermediate Risk AML
• Group 1 (favorable): IDH2/NPM1 mutant
• Group 3 (poor-risk): TET2, PHF6, ASXL1, MLL-PTD mutations
• Group 2: all others
Patel et al. New Engl J Med, 2012
P<0.001
Cytogentic Classification Mutations Overall
Risk
Inversion (16), t(8:21) Any
Favorable
Normal Karyotype or Intermediate Risk
Cytogenetic Lesions
FLT3-ITD negative
NPM1 and IDH1/2 mutant
FLT3-ITD negative
ASXL1, MLL-PTD, PHF6 and TET2-wildtype
Intermediate FLT3-ITD
negative or positive CEBPA mutant
FLT3-ITD positive
MLL-PTD, TET2, DNMT3A R882, and
trisomy 8 negative
FLT3-ITD negative
TET2, MLL-PTD, ASXL1, PHF6 mutant
Unfavorable FLT3-ITD positive
TET2, MLL-PTD, DNMT3A R882 mutant
or trisomy 8
Unfavorable Any
Revised AML Risk Stratification Based on Integrated Mutational Profiling
Patel et al. New Engl J Med, 2012
Remission Induction and Escalated Daunorubicin Dose in AML
• DNR 90 mg benefits patients with any cytogenetic risk, and with FLT3-ITD, DNMT3A, or NPM1, including age 50-60.
• Whether or not dauno 60=90 mg dose requires further studies • DNR 90 mg standard for all patients up to age 60-65
• CRs after third attempt uncommon and short-lived
Fernandez et al. NEJM 2009, Patel et al. NEJM 2012;
Burnett et al Blood, 2015; Luskin et al. Blood, 2015; Zarabi et al. ASH, 2016
• Do we need 4 cycles? Probably not, but I do it
• Do we need 3g/m2 of Ara-C? Probably not, but I do it
• Do we need high-dose Ara-C? Probably not, but I do it
Consolidation Questions Remain Unanswered
Induction Consolidation
DA ± GO vs
ADE ± GO vs
FLAG-Ida ± GO
MACE-MiDAC ± GO vs
HiDAC ± GO (3.0 vs 1.5 mg/m2)
Burnett et al. J Clin Oncol, 2013
MRC AML15
Burnett et al. J Clin Oncol, 2013
100
75
50
25
0 1 2 3 4 5
Cumulative Incidence
of Relapse
%
0 Years
6
n=328 1.5g/m²
n=326 3g/m²
7 8
51%
60%
MRC: AML 15
p = 0.06
Less Intensive Consolidation 3g/m2 vs 1.5g/m2 Ara-C
Burnett et al. J Clin Oncol, 2013
100
75
50
25
0 1 2 3 4 5
Relapse Free
Survival %
0 Years
6
n=328 1.5g/m²
n=326 3g/m²
7 8
34%
42%
MRC: AML 15
p = 0.1
Less Intensive Consolidation 3g/m2 vs 1.5g/m2 Ara-C
Condensed vs Standard Schedule of HiDAC Consolidation
• HiDAC 3 gms/m2 twice daily D1,3,5 (G on D10) vs HiDAC 3 gms/m2 twice daily D1,2,3 (G on D8) (Third cohort 3 gms/m2 D1,3 5 without G)
• Time to count recovery shorter with D1,2,3 (median 4 days)
• Rates of infection lower with D1,2,3
• Days in hospital and plts transfusion reduced with D1,2,3
• RFS and OS not different
Jaramillo et al. ASH abstr 337, 2016
Relapse-free and Overall Survival According to Consolidation Schedule
Jaramillo et al. ASH abstr 337, 2016
Minimal Residual Disease
• Detected by increasingly sensitive techniques (immunophenotyping, PCR, sequencing)
• Most studied in patients with NPM1 mutation and CBF AMLs
• Complex due to genetic heterogeneity and multiple subclones
• Has prognostic implications following chemotherapy and before allogeneic transplantation
• Will rapidly become incorporated in routine clinical practice
Ivey et al. N Engl J Med, 2016
Minimal Residual Disease (by PCR) in Standard-Risk AML
100
75
50
25
0 0 1 2 3 4 5
Years since Entry
Sur
viva
l (%
) MRD-negative 73%
MRD-positive 24%
P<0.001
Overall Survival
100
75
50
25
0 0 1 2 3 4 5
Years since Remission
Rel
apse
(%)
MRD-negative 34%
MRD-positive 86%
P<0.001
Relapse in All Patients
Equivalent Post-Transplant Outcomes for Pre-transplant AML MRD (by FC) and Active AML
Araki et al. J Clin Oncol, 2016
Active disease Remission (MRD–) Remission (MRD+)
Active disease Remission (MRD–) Remission (MRD+)
Survival Landmarked from Time of Transplant
• CPX-351 median OS not reached vs 10.25 months for 7+3 – HR of 0.46 favoring CPX-351 (P=0.0046) – Cox proportional hazards HR, including transplant as a time-dependent
covariate, was 0.51 (95% CI, 0.35–0.75; P=0.0007), favoring CPX-351
CI, confidence interval; HR, hazard ratio; OS, overall survival.
Median follow-up: - CPX-351 = 531 days (96-983) - 7+3 = 442 days (316-650)
Lancet et al. ASH, 2016
RATIFY (C10603) Trial Schema
R A N D O M I Z E
DNR ARA-C Midostaurin
DNR ARA-C Placebo
HidAC Midostaurin
HidAC Placebo
Midostaurin MAINTENANCE 12 months
Placebo MAINTENANCE 12 months
Stratify* FLT3 ITD or
TKD
FLT3 WILD TYPE not eligible for enrollment
X 4
X 4
CR
CR
PRE-REGISTER
FLT3 SCREEN
Stratification: TKD; ITD with allelic ratio <0.7 ‘vs’ ≥0.7
Stone et al. ASH abstr 6, 2015
Overall Survival (Primary Endpoint) 23% reduced risk of death in the Mido arm
Arm 4-year Survival MIDO 51.4% (95%CI: 46, 57) PBO 44.2% (95%CI: 39, 50)
+ Censor
Hazard Ratio*: 0.77 1-sided log-rank p-value*: 0.0074
Stone et al. ASH abstr 6, 2015
0
10
20
30
40
50
60
70
80
90
100
Response in FLT3mut+ Patients by Gilteritinib Dose (N=191)
n=10 300 mg
Prop
ortio
n of
Pat
ients
Ach
ievin
g Re
spon
se (%
)
n=12 n=56 n=89 80 mg 120 mg 200 mg
n=2 450 mg
n=8 40 mg
n=14 20 mg
ORR=67%
ORR=47%
ORR=60% ORR=55%
ORR=38%
ORR=14%
ORR=50%
CRc=42%
CRc=39%
CRc=30% CRc=46%
CRc=0
CRc=7%
CRc=0
0
10
20
30
40
50
60
70
80
90
100
Response in FLT3mut+ and FLT3WT Patients (N=249)
CR CRp CRi PR
Antileukemic Activity of Gilteritinib
Gilteritinib ≥80 mg/day: CRc (CR+CRp+CRi)=41% ORR=52%
Prop
ortio
n of
Pat
ients
Ach
ievin
g Re
spon
se (
%)
FLT3mut+ (N=191)
FLT3WT (N=58)
ORR=12%
CRc=9%
ORR=49%
CRc=37%
Perl et al. ASH abstr 1069, 2016
Binds to CD33 antigen
Complex is internalized and traffics to lysosome
PBD dimer is released
PBD dimer crosslinks DNA
DNA repair failed
Apoptotic cell death
Vadastuximab Talirine (SGN-CD33A; 33A) Proposed Mechanism of Action
Anti-CD33 antibody, engineered cysteines to enable uniform site-specific conjugation Cleavable dipeptide linker, highly stable in circulation Pyrrolobenzodiazepine (PBD) dimer, binds DNA with high intrinsic affinity
Novel Treatments For AML Agent Target Mechanism Comment Status
Vadastuximab CD33 Immunoconjugate Phase I trial comb with 7 + 3; CR 60%, CRi18%,
74% MRD neg; CR/CRi 54% in older treat-naïve; CR/CRi 73%
with HMA
Alternative schedule w/ single day dosing
underway
Entospletinib SYK SYK inhibitor Phase I/II in untreated AML then chemo; CR in 11q23
rearranged pt
Phase II underway
Selinexor XPO1 Inhibits nuclear transport protein
exportin
1.Combined with chemo: ORR 60%in R/R AML
2. Phase I comb with DAC: ORR81%
Lower dose being explored
Eltrombopag TPO receptor
TPO receptor agonist Shortens plt recovery (mean peak plts 719,000, max
1,935,000), reduces plt transf
Accruing
Venetoclax BCL2 BCL2 inhibitor Phase 1/2 trial + LoDAC in untreated older pts; ORR 75%;
CR/CRi 70%
Phase I/II trial underway
Erba ASH abstr 211, 2016; Bixby ASH abstr 590, 2016; Fathi ASHabstr 591, 2016; Walker ASH abstr 2831, 2016; Wang ASH abstr 212, 2016; Bhatnager ASH abstr 1651, 2016; Mukherjee ASH abstr 447, 2016; Wei ASH abstr 102, 2016
Role of IDH in Malignancy
• IDH is critical metabolic enzyme in the citric acid cycle
• IDH1 in cytoplasm and IDH2 in mitochondria
• Cancer-associated IDHm produces 2-hydroxyglutarate (2-HG) and blocks normal cellular differentiation
Response
44
RR-AML (n = 159)
Untreated AML
(n = 24) MDS
(n = 14) All
(N = 209) Overall Response (CR, CRp, CRi, mCR, PR)
59 (37%) [95%CI: 30%,
45%] 10 (42%)
[22%, 63%] 7 (50%)
[23%, 77%] 79 (38%)
[31%, 45%]
CR 29 (18%)
[95%CI: 13%, 25%]
4 (17%) [5%, 37%]
3 (21%) [5%, 51%]
37 (18%) [13%, 24%]
CRp 1 (1%) 1 (4%) 1 (7%) 3 (1%)
CRi 3 (2%) 0 0 3 (1%)
mCR 9 (6%) 1 (4%) 3 (21%) 14 (7%)
PR 17 (11%) 4 (17%) 0 22 (11%)
SD 72 (45%) 9 (38%) 6 (43%) 96 (46%)
PD 10 (6%) 1 (4%) 0 11 (5%)
Not evaluable 18 (11%) 4 (17%) 1 (7%) 23 (11%)
• Overall response by IDH mutation type: R140Q 36% / R172K 42%
CR, complete response; CRp, CR with incomplete platelet recovery; CRi, CR with incomplete hematologic recovery; mCR, marrow CR; PR, partial response; SD, stable disease; PD, progressive disease
Stein et al. ASH abstr, 2015
Differentiation Syndrome
• 21 days of AG-221 at 100 mg daily • Fever, oxygen requirement • Normal BAL
Courtesy Dr. Stephane De Botton
• Dexamethasone 10 mg BID for 15 days • Resolution of clinical symptoms • Patient achieves a complete remission
How I Treat AML-2017
• Induction: dauno 90 mg/m2/d x 3d (or ida) + ara-C 100 mg/m2/d x 7d c.i. + targeted agent (HMA or novel agents in older adults or if not fit); LP for monocytic lineage or WBC > 40,000
• Consol: multiple cycles (3-4) of HiDAC in younger pts fav-risk, NK FLT3-/NPM+, or dCEBPα; 3-4 for CBF; no clear role in older adults (can give 1-2 cycles at 1-1.5 gm/m2) + targeted agent
• Allogeneic HCT for intermed- and high-risk (consider alternative donor if no sib); consider in CBF [esp t(8;21) with c-KIT]; not FLT3-/NPM1+ (esp if IDH+) or dCEBPα+; RIC for older adults
• No maintenance (except ? APL) except targeted agent
• Relapse: reinduction chemo + targeted agent or targeted agent alone
Paschka et al. J Clin Oncol, 2006; Schlenk et al. NEJM, 2008; Green et al. J Clin Oncol, 2010; Dohner et al. Blood, 2010
Coombs, Tallman, Levine. Nat Rev Clin Oncol, 2015
Coombs, Tallman, Levine. Nat Rev Clin Oncol, 2015