Daver 7 3 Thank you Jk Basic Facts Unbridled proliferation of hematopoietic stem cells myeloid linage resulting in marrow failure and patient death unless successfully
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Slide1
AML
Elizabeth Ellent
Some slides borrowed from Dr. Richard Stone and Dr. Naval
Daver
Slide27 + 3
Slide3Thank you
Slide4Jk
Slide5
Basic Facts
Unbridled proliferation of hematopoietic stem cells (myeloid linage) resulting in marrow failure and patient death unless successfully treated
20 K new US cases with 10 K death annually
Risk factors:
Age (median age 67)
Prior chemo for other cancers
Ionization radiation
Industrial solvents
Slide6Age, Survival, and Treatment Era in AML
1
1. Kantarjian
H et al.
Cancer
. 2010;116:4896-4901.
%
%
Slide7Gene
Overall Frequency, %
FLT3
(ITD, TKD)
37 (30, 7)
NPM1
29
DNMT3A
23
NRAS
10
CEBP
α
9
TET2
8
WT1
8
IDH2
8IDH17KIT6RUNX15MLL-PTD5ASXL13PHF63KRAS2PTEN2TP532HRAS0EZH20
Prognostic Relevance of
Integrated
Genomic Profiling
1
1. Patel JP et al. N Engl J Med. 2012;366:1079-1089.
Slide12New Therapies and Emerging Agents for AML
… For many populations, including those at high risk or defined by molecular abnormalities
Novel cytotoxics
(
CPX-351
, vosaroxin)
Emerging/next-generation HMAs
(
SGI-110
, CC-486,
ASTX727)
Targeted therapies
(
FLT3i
,
IDHi
,
Bcl-2
, SINE, HDAC)
Immune checkpoint
inhibitors on the horizon(nivolumab, pembrolizumab)Novel antibodies(gemtuzumab, IMGN 33 and 123, AMG-330, Xmab-CD33/CD123)AML with actionable mutations, molecular, or high-risk features (eg, age, secondary AML)Combination therapy with HMAs for older patients
Slide13General Treatment
Goal 1: induction therapy
Remove morphologic evidence of leukemic cells in blood, bone marrow,
extramedullary
sites
Goal 2: reduce 10
9
- 10
10
cells
Undetectable at CR to low enough level to achieve prolonged disease free survival
Slide15Targeted agents
Midostaurin
is a potent FLT3 inhibitor of both ITD and TKD. (also inhibits VEGFR, PKC, KIT, PDGFR)
Specifically inhibits growth of leukemic cell lines made factor independent by transfection of activating FLT3 mutation.
Slide23RATIFY: DFS
1
Using a landmark analysis from the end of maintenance, there was no difference in DFS between the 2 arms
(HR = 1.4
[95% CI, 0.63-3.3];
P
= .38)
DFS at 1-year from end of maintenance was 75% (
95
% CI,
62%-
84
%)
for
midostaurin
and 91%
(95
% CI,
77%-
96%) for placeboThere was no difference between the arms in OS from the time starting maintenance (HR = 0.96 for midostaurin [95% CI, 0.58-1.59]; P = .86)1. Larson RA et al. 59th American Society of Hematology Annual Meeting and Exposition (ASH 2017). Abstract 145.
Slide291.
Hills RK et al.
Lancet
Oncol.
2014;15:986-996.
Gemtuzumab Ozogamicin
Meta-Analysis
of 5
AML Randomized
Trials
1
Addition of GO
No ↑ CR rate: OR, 0.91;
P
= .3
Did not increase mortality: OR, 1.13;
P
= .4
Improved survival: OR, 0.89;
P = .01Reduced relapse: OR, 0.81; P = .001Improved survival: OR, 0.90; P = .01Highly significant survival benefit for favorable risk (OR, 0.47; P = .006) and int risk (OR, 0.84; P = .005)5 randomized trials of 3,325 pts: SWOG, ALFA, UK-MRC AML15 and 16, GOELAMS
Slide34Primary R/R AML (N = 125)
CR + CRh rate, n (%) [95% CI]
38 (30.4%) [22.5-39.3]
Time to CR/CRh, median (range) mo
2.7 (0.9-5.6)
Duration of CR/CRh, median [95% CI] mo
8.2 [5.5-12.0]
CR rate, n (%)
[95% CI]
27 (21.6%)
[14.7-29.8]
Time to CR,
median (range) mo
2.8 (0.9-8.3)
Duration of CR,
median [95% CI] mo
9.3 [5.6, 18.3]
CRh rate, n (%)
11 (8.8%)
Overall Response Rate, n (%) [95% CI]
52 (41.6%) [32.9-50.8]Time to first response, median (range) mo1.9 (0.8-4.7)Duration of response, median [95% CI] mo6.5 [4.6-9.3]Best response, n (%) CR27 (21.6) CRi or CRp16 (12.8) MLFS9 (7.2) SD44 (35.2) PD
13 (10.4)
NA
16 (12.8)
a
Data cut-off: May 12, 2017.
b
CRh
:
6 patients with investigator-assessed responses of
CRi
/
CRp
and 5 with MLF.
1.
DiNardo
CD et al. ASH 2017. Abstract 725
.
Ivosidenib
Monotherapy
:
Response
1,a,b
Slide37At a median time on study of 8.9
mo
(range, 0.2-31.6), the median
OS
in all treated patients
was 17.5
mo
(95
% CI, 12.3-NR)
Estimated
1-y
and
2-y
OS rates were 59% and 46
%, respectively
Response Rates by Cohorts
1
Cohort
NComposite Response Rate, CR/CRi, n (%)Overall Response Rate (CR + CRi + PR + MLFS), n (%)All patients14597 (67)120 (83)VEN 400 mg6044 (73)49 (82)VEN 400 mg + AZA2922 (76)24 (83)VEN 400 mg + DEC3122 (71)25 (81)VEN 800 mg7448 (65)63 (85)VEN 800 mg + AZA3721 (57)31 (84)VEN 800 mg + DEC3727 (73)32 (86)VEN 1,200 mg115 (45)8 (73)1. DiNardo CD et al. Lancet Oncol. 2018;19:216-228.
Slide41Immune-Based Approaches to AML/MDS
1
1.
Boddu
P et al.
Am J
Hematol
Oncol
. 2017;13:4-15.
Slide45Best
Response/Outcome
n (%)/Median [Range]
Evaluable
70
ORR
24
(
35)
CR/CRi/PR
16
(24)
HI
+ 50% blast reduction (
6 mo
+)
7
(10)
50% reduction in blast
17 (24)
Progression/stable dz (6 mo+)26 (37) [21/5]8-wk mortality8 (11)Median cycles to response2 [1-13]Median follow-up13.3 mo [8.2-25.5]AZA + NIVO in Relapsed AML: Response (N = 70)1,2Expected response rate with HMA alone in salvage: ORR = 20%-22%; CR/CRi = 16% 1. Daver N et al. EHA 2017. Abstract S474. 2. Stahl M et al. ASH 2018. Abstract 148.
Slide46Entity
Management
% Cure/Comments
APL
AIDA;
ATRA + ATO
95+
CBF
FLAG
+ gemtuzumab
80+ >> 90%
Younger AML
FLAG-
ida
,
CLIA
, 7
+3; HD DA +
ara
-CFLT3+: Chemo + FLT3i (SOC)IDH1/2+: Chemo + IDHi (clinical trials)No mutation: Add gemtuzumab (SOC)4-50 >>> 70%-75%Older AML, not fit for intensive chemoLow-intensity chemo Rx: AZA + VEN, AZA + CPI, AZA + mAb (clinical trials)Secondary AML: AZA + VEN10-20 >>> 40%-45%Secondary AML, therapy-related or AHDConsider CPX-351 (especially in s-AML aged >60 y)15%-20% >>> 40%Always check CG, molecular (FLT3, NPM1, CEBPA, IDH1/2, CKIT, CBF)Prognosis; to determine need for alloSCT in CR1 or maintenance and targeted RxNot determinedMRD by FCMPrognosis; need for alloSCT in CR1 or maintenanceMRD eradication: PD-1, revlimid, monoclonalMost important after intensive chemoFinal Thoughts on AML: Approach at MDACC11. Slide courtesy of Naval Daver, MD.
Slide47A 58 year old was recently dx with AML with inversion (16). He was started on standard 7+3 induction chemotherapy. A bone marrow biopsy is performed 21 days after induction is completed and shows hypoplasia. You await recovery and a repeat bone marrow
bx
reveals no leukemia and
cytogenetics
are negative for inversion 16. what do you offer for consolidation therapy
A. none
B. intermediate dose ARA C
C. high dose ARA C
D.Autologous
transplant
Allogenic
transplant
Slide48A 58 year old was recently dx with AML with inversion (16). He was started on standard 7+3 induction chemotherapy. A bone marrow biopsy is performed 21 days after induction is completed and shows hypoplasia. You await recovery and a repeat bone marrow
bx
reveals no leukemia and
cytogenetics
are negative for inversion 16. what do you offer for consolidation therapy
A. none
B. intermediate dose ARA C
C. high dose ARA C
D.Autologous
transplant
Allogenic
transplant
Favorable karyotype consider HIDAC ( not
tx
)- CALG trial enrolled 285 pts with AML and assigned standard,
int
, or high dose ARA-C. CBF AML benefitted greatly from high dose
Slide49A 52 year old male with AML undergoes induction chemotherapy with standard dose
cytarabine
200 mg/m2 x7 days along with
daunorubicin
90 mg/m2 x 3 days. BM
bx
done 7
dyas
after induction is completed and shows 18% cellularity and 1% residual blasts. What do you recommend next?
A. HIDAC 3 g/m2 every 12 hours x 5 days
B. standard dose
Cytarabine
with
Daunorubicin C. Await marrow recovery D. Gemtuzumab
E. Refer for allogeneic HSCT
Slide50A 52 year old male with AML undergoes induction chemotherapy with standard dose
cytarabine
200 mg/m2 x7 days along with
daunorubicin
90 mg/m2 x 3 days. BM
bx
done 7
dyas
after induction is completed and shows 18% cellularity and 1% residual blasts. What do you recommend next?
A. HIDAC 3 g/m2 every 12 hours x 5 days
B. standard dose
Cytarabine
with
Daunorubicin C. Await marrow recovery D. Gemtuzumab
E. Refer for allogeneic HSCT