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What is New and Exciting in AML in 2019
Hagop KantarjianMDACC
COC Florida – April 4, 2019
AML—The Times They Are A’ Changing (and Very Rapidly)
•Situation similar to: –HCL and APL in 2000–CML in 2000 (TKIs)–CLL in 2015 (ibrutinib+venetoclax)–ALL in 2010 (ponatinib, CD19 and CD22 antibodies)
The Genomic Landscape of AML
Genomic Classification and Prognosis in AML
Papaemmanuil .NEJM. 2016;374:2209
Gene Overall Frequency, %FLT3(ITD, TKD) 37 (30, 7)
NPM1 29DNMT3A 23NRAS 10CEBPα 9TET2 8WT1 8IDH2 8-12IDH1 7-10KIT 6RUNX1 5MLL-PTD 5ASXL1 3PHF6 3KRAS 2PTEN 2TP53 2 - 20HRAS 0EZH2 0
Prognostic Relevance of Integrated Genomic Profiling
Patel JP et al. N Engl J Med. 2012;366:1079-1089.
Molecular Studies in AMLMarker % Prognosis• FLT3 ITD/mutation 30 Worse• NPM1 mutation 50 Better• IDH1-2 mutations 20-30 Worse or neutral• C-kit mutation- CBF 15 Worse• BCL2 10-20 Worse• MLL PTD 7 Worse• DNMT3A mutation 22 Worse• ASXL1;TET2 10 Worse; epigenetic modulation• P53 mutation 5-20 Very poor• EVI1 expression 10 Very poor
Clinical Applications of Molecular Studies in AML
• FLT3-ITD mutations - Add FLT3 inhibitor (midostaurin, sorafenib, quizartinib), consider allo-SCT
• IDH1-2 mutations - Add IDH inhibitor –enasidenib (AG-221/IDH2 inhibitor), ivosidenib (AG-120/IDH1 inhibitor)
• NPM1 mutation in diploid CG - ara-C sensitivity• TP53 mutation - Consider decitabine 10 days ±
others (GO, venetoclax); refer to allo-SCTNCCN guidelines. Acute Myeloid Leukemia; v2.2018
And Suddenly in 2017-2018, FDA Approvals….• Midostaurin ( RYDAPT) for de novo younger AML (< or = 60 yrs), FLT3
mutation—April 2017• Gilterinib ( FLT3 inhibitor) for FLT-3 + R-R AML• Enasidenib (AG-221; IDHIFA) for R-R AML and IDH2 mutation—August
2017• Ivosidenib (AG-221) for R-R AML—August 2018• CPX 351 (Vyxeos) for newly Dx Rx-related AML and post MDS AML—
August 2017• Gemtuzumab ozogamycin revival for frontline AML Rx— August 2017• Venetoclax for newly Dx older/unfit for intensive chemo, with AZA/DAC,
ara-C• Glasdegib for newly Dx older/unfit, with ara-C • Data + with FLT3 inhibitor quizartinib
ATRA + As2O3 without Chemotherapy in APL. MD Anderson Experience
• Induction–ATRA 45 mg/m2/D until CR–As2O3 0.15 mg/kg/D until CR–Gemtuzumab (GO) 9 mg/m2x1 if WBC> 10x109/L
• Maintenance–ATRA 45 mg/m2/D x 2 wks Q mo x 6–As2O3 0.15/kg/D x 4 wks Q2 mo x 3–GO in PCR+
Ravandi. JCO 27:504, 2009
APL-Outcome with ATRA + AS2O3 vs AIDA
Platzbecker. JCO 35: 605; 2016
MDACC - FLAG-GO in CBF AML• Induction:Fludarabine (FL) 30 mg/m2 Days 1-
5;Cytarabine (A) 2 g/m2 IV Days 1 to 5;Gemtuzumab Ozogamicin (GO) 3 mg/m2 Day 1; G-CSF (G) 5 mcg/kg Day -1 till neutrophils recovery ( can use neulasta 6 mgx1 Day 4)
• Consolidation: FL and A for 4 (amended to 3) days, GO (in cycle 2/3 and 5/6) and G as in induction for 6 cycles
• Peg-GCSF instead of G-CSF allowed beyond day 5 (induction) or day 4 (consolidation)Replaced GO by low dose Idarubicin 6mg/m2 days 3and 4 after patient 50
MRC. FLAG-IDA x 2, HD ara-C x 2-Survival in Fav. and Interm. Risks
Burnett. JCO, 2013 (e-Pub)
Therapy of AML-The Old Standard3+7
± HD araC x 1-2
CRAge, PS, comorbidities, CG, molecular, donor
Low risk of relapseHigh risk of SCT
HD ara C X 4 total
High risk of relapseLow risk of SCT
Allo SCT
No maintenance
3+7…50 year Anniversary
Yates JW, et al Cancer Chemo Rep. 57;4. 1973; 485-8
What is “3 + 7”• Induction
DNR 45-90 mg/m2 [60mg/m2] daily x 3 Ara-C 100-200mg/m2 CI daily x 7D14 BM AML → 2 + 5
• Consolidations x 4Ara-C 3g/m2 Q 12h D1, 3, =18g/m2/courses
Actual Results of “3 + 7”
• 5-yr survival 20-35% in young, 10% in old Fernandez. NEJM 36: 1256; 2009; Lowenberg. NEJM 36: 1235; 2009
AML.SurvivalbyAgeandTreatmentEra
Kantarjian H et al. Cancer. 2010;21:4896-4901.
MRC FLAG-IDA
Burnett. JCO 31: 3360-3368; 2013
•Fludarabine-30mg/m2/Dx5AraC 2g/m2/Dx5IDA 10mg/m2/Dx32 inductions
•FLAG-IDAx2 → HD Ara C 1.5-3g/m2 Q12h D1, 3, 5—x2
FLAG-IDA vs ADE. Survival and RFS
Burnett. JCO 31: 3360-3368; 2013
MRC AML 15. ADE/DA vs FLAG-IDA-4 Courses
Burnett. JCO, 2013 (e-Pub)
FAI+GO in AML (Italy)• 130 pts with newly Dx
AML; age <65 yrs (median 52 yrs; range 18-65) Rx with FAI-GO
• GO (3mg/m2 D6 x 1)• CR 106/130 = 82%• 5-yr OS 52%; 5-yr DFS
52%• Allo SCT in 60/130 =
46%
Candoni. AJH. 2018
Randomized Maintenance with Azacitidine in AML-MDS ≥ 60 yrs (HOVON 97)
• 117 pts post 2 courses of intensive chemo randomized to AZA x 12 vs observation
• 12-mos DFS 63% with AZA 63% vs 39% (p .005)
• Censoring for allo SCT, survival better with AZA (p=.04)
Huls. Blood 130: abst 463; 2017
AML FLT3-ITD. Sorafenib post Allo-SCT• 83 pts, median age
54 yr, post allo-SCT• Randomization to
sorafenib 200-400mg BID vs placebo
• 2-yr RFS 85% with sorafenib vs 53% with placebo
• Also significant survival benefit
Burchert. Blood 132: abst 661; 2018
Patients at risk (n)
Sorafenib 43 35 31 25 18 0Placebo 40 24 19 17 14 0
time (months)
Abbreviations: CI, confidence interval; HR, hazard ratio; IQR, interquartal range, RFS, relapse free survival; EOT, end of treatment; EOS, end of study.
0 10 20 30 40 50
100
80
60
40
20
0
Rel
apse
free
surv
ival
(%)
off treatmenton treatment EOT EOS
24
SORMAIN – Results: Relapse free survival
SorafenibPlacebo
on treatment
off treatment
Burchert.Blood132:abst 661;2018
25
100
80
60
40
20
0
Cum
ulat
ive
Inci
denc
e(%
)
p=0.981*
SORMAIN – Results: Relapse mortality at 2 years
0 10 20 30 40 50
time (months)
SorafenibPlacebo
100
80
60
40
20
0
Cum
ulat
ive
Inci
denc
e(%
)
p=0.011*
0 10 20 30 40 50
time (months)
SorafenibPlacebo
relapse mortality non-relapse mortality
*Gray‘s test
Burchert.Blood132:abst 661;2018
Abbreviations: CI, confidence interval; HR, hazard ratio; EOS,end of study
Patients at risk (n)
Sorafenib 43 38 28 12 7 0Placebo 40 25 19 9 3 0
time (months)0 20 40 60 80 100
100
80
60
40
20
0
Ove
rall
surv
ival
(%)
off treatmenton treatment EOS
55.4 months (median follow up)
SORMAIN – Results: Overall survival
SorafenibPlacebo
on treatment
off treatment
30 months – OS (end of study) HR=0.447 (95% CI: 0.20, 0.97), p=0.03
Burchert.Blood132:abst 661;2018
Older AML. Low Intensity RegimensClo-araC-
DACCDA-ara C-
DACAZA/DAC+VEN LD araC +
VEN
No Rx 118 118 145 71% CR 60 58 - 26% CR + CRi/p 68 68 67 62Median OS (mos)
11 13.8 17.5 11.4
% 2-yr OS 25 28 45 25-30
% 4-wk death 3 1 - 3
Kadia. Cancer 121: 2375; 2015. Kadia. November 2017. DiNardo. ASH. 2017.; Wei. ASH 2017. Abst. 890.
AML. What Definitely Works
•FLT3 inhibitors•IDH1-2 inhibitors•CD33 and CD123 antibodies•Venetoclax•? Checkpoint inhibitors•CPX351
Target Antigens and Novel Antibodies in AML--225Ac-Lintuzumab (Actimab-A)-Gemtuzumab ozogamicin-IMGN779-AMG 330 (BiTE; CD33/CD3)
-SGN-CD123 (Halted)-IMGN632-XmAb (CD3/CD123)-MGD006 (CD3/CD123)
Gemtuzumab ozogamicin (GO)Humanized murine anti CD33 monoclonal antibody
(hP67.6) conjugated to NAc-calicheamicin
Me
O
O
NH
S
H
HOO
OCH3
NH O
O
OCH3
N
CH3CH2O
OHOCH3HOCH3
OCH3
HNHO
OO
OH
CH3S
CH3
OCH3
OCH3
I
O
O
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S
O
NHN
Me Me
O
CH3
hP67.6
Hills, RK, et al. Lancet Oncology, 2014; 15(9), 986
Gemtuzumab Ozogamycin in induction Therapy Meta-analysis of 5 Randomized Trials
Tagraxofusp (SL-401) in BPDCN
•45 pts Rx; SL401 7-12 mcg/kg IV/Dx5•CR+CRc 54%; OR 90%•LFTs 44%; low plts 26%; capillary leak 17%
(3 deaths/183)
Pemmaraju. Blood 132: abst 765; 2018
P ValueQuartile 1(0.01-0.20)
Quartile 2(0.20-0.53)
Quartile 2(0.53-0.80)
Quartile 4(0.80-10.19)
CR, % 81.5 79.8 69.1 57.5 .003
Median OS, years 2.19 2.15 1.2 0.9 .0006
Median EFS, years 0.75 0.81 0.49 0.25 .001
Prognosis (CR, OS, EFS)
Effect of Allelic Ratio on Outcomes (in pts Rx with induction, without a FLT3i)
• Higher allelic ratio associated with worseoutcome , in induction without FLT3i
Schlenk RF, Kayser S. Blood. 2014;124(23):3441-3449.
34
NOT FOR DISTRIBUTION
ImprovingOverallSurvivalinFLT3-ITDAML(#1):AlloHSCT inFLT3-ITDMutatedPatients
Schlenk .NEngl JMed.2008;358:1909-1918.
Years
Relapse-FreeSurvival(%)
Relapse-FreeSurvival(%)
OverallSurvival(%
)
Years Years
OtherGenotypes
NPM1,CEBPA,FLT3evaluatedinstudyOthergenotypes:FLT3-ITDwithanyCEBPA/NPM1,NPM1WT,CEBPAwt
• 1. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT01831726 (accessed April 2017);2. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT01207440 (accessed April 2017);
• 3. Wander SA, et al. Ther Adv Hematol 2014; 5:65–77;4.ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02039726 (accessed May 2017);5.PerlAE,etal.JClinOncol 2016;34:AbstractTPS7072;6.Rydapt® USPI.Availableat:https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf(accessedMay2017).
FLT3 inhibitors under development in AMLPhase 2
CrenolanibPLX3397Dovitinib
Phase 3Quizartinib Sorafenib
FDA approvedMidostaurin
Gilterinib
Phase 3 RATIFY Study: Chemotherapy ± Midostaurin in Newly Diagnosed AML
• CALGB 10603
Treatment-naïve
patients with AML with activating
FLT3 mutations(N = 514)
Midostaurin group
Control group
Cytarabine(200 mg/m2/d, days 1-7) +
Daunorubicin(60 mg/m2/d, days 1-3) +
Midostaurin(50 mg BID, days 8-21)
Cytarabine(200 mg/m2/d, days 1-7) +
Daunorubicin(60 mg/m2/d, days 1-3) +
Placebo(BID, days 8-21)
High-dose cytarabine(3 g/m2/d BID, days 1,3,5)
+Midostaurin
(50 mg BID, days 8-21)
High-dose cytarabine(3 g/m2/d BID, days 1,3,5)
+Placebo
(50 mg BID, days 8-21)
Midostaurin
(50 mg BID, days 1-28)
Placebo(BID, days
1-28)
R
CR
CR
Induction(1-2 cycles)
Consolidation(4 cycles)
Continuation(12 cycles)
Stone. NEJM 377: 454-464; 2017
Chemo Rx ± Midostaurin in AML (RATIFY)
Stone. NEJM 377: 454-464; 2017
1st Salvage Phase 3: Quizartinib vs Standard Chemotherapy
QuANTUM-R Study Design
Primary endpoint: overall survival (ITT population)
FLT3-ITD AML (N = 367)
• Age, ≥ 18 years • Refractory AML or
relapse within 6 months of first remission (±HSCT)
• ≥ 1 cycle of standard-dose anthracycline- or mitoxantrone-containing induction therapy
• ≥ 3% FLT3-ITD allelic ratio
Long
-term
follo
w-u
p
Quizartinib continuatio
n
Quizartinib (n = 245)
30 mg × 15 days à 60 mg if QTcF ≤ 450 ms on day 16a
Salvage chemotherapy (n = 122)
LoDAC (n = 29)
MEC (n = 40) or FLAG-IDA (n = 53)
HSCT
2:1
Rand
omiz
atio
n HSCT
Cortes. EHA: LB2600; 2018
1st Salvage Phase 3: Quizartinib vs Standard Chemotherapy
39
1.0
0.8
0.6
0.4
0.2
0.0
No. at Risk:
Quizartinib
Salvage chemotherapy
0 4 6 8 10 12 14 16 18 20 22 24 26 28 302
245 173 122 89 71 53 48 38 36 27 20 20 16 11 10224
122 59 38 28 21 15 13 13 12 12 10 9 7 7 677
Time (months)
Prop
ortio
n of
Pat
ient
s Al
iveHR, 0.76 (95% CI, 0.58-0.98)P = 0.0177 (1-sided, stratified log-rank)
Median overall survival: Quizartinib (n = 245): 6.2 months Salvage chemotherapy (n = 122): 4.7 monthsMedian follow-up: 23.5 months
27%
20%
QUANTUM-R : Overall Survival
Cortes. EHA: LB2600; 2018
Quizartinib + Azacitidine or Low-Dose Cytarabine
Study Design
MDS, CMML or AMLFLT3-ITD and one of the following:• Age ≥60 yrs with previously untreated disease
• Age ≥18 yrs with refractory or relapse disease with ≤1 prior treatment regimen (i.e., 1st
salvage)• Any age who received HMA and progressed to AML
Quizartinib +
AZA
Quizartinib +
LDAC
Phase I: n = 6Phase II: n = 31
Phase I: n = 6Phase II: n = 18
Physician’s Choice
N=61
N=37
N=24
• Primary endpoint: Overall response (CR+CRi+PR+HI)
• Secondary endpoints: CRc (CR+CRp+CRi); overall survival and relapse free survival
Swaminathan. Blood 130: abst 723; 2017
Quizartinib+AzacitidineorLow-DoseCytarabineResponsetoTherapy
Best Response N (%)Q+AZA Q+LDAC Total
CR 8 (22) 2 (8) 10 (16)CRp 2 (5) 5 (21) 7 (12)CRi 15 (41) 7 (29) 22 (36)
CRc (CR+CRp+CRi) 25 (68) 14 (58) 39 (64)OR (CRc+HI+PR) 26 (70) 16 (67) 42 (69)
NR 9 (24) 8 (33) 17 (28)60-day mortality 2 (5) 0 2 (3)
Swaminathan. Blood 130: abst 723; 2017
42
Antileukemic Response to ≥80 mg/day Gilteritinib in FLT3mut+ Patients by Mutation Type and TKI Status
ORR=55%CRc=43%
ORR=62%CRc=54%
ORR=17%CRc=8%
ORR=42%CRc=31%
ORR=56%CRc=44%
N=141 N=13 N=12 N=45N=124
Perl AE, et al. Lancet Oncol. 2017;18(8):1061-1075
43
Overall Survival in FLT3mut+ Patients Treated With Gilteritinib (N=191)*
Gilteritinib ≥80 mg/day in FLT3mut+ PatientsMedian OS: 31 weeks (range: 1.7–61 weeks)Median Duration of Response: 20 weeks (range: 1.1–55 weeks)Median Time to Best Response: 7.2 weeks (range: 3.7– 52 weeks)
Perl . Lancet Oncol. 2017;18(8):1061-1075
44
StudyDesignandTreatment
• Phase1study(NCT02236013):– Multicenter,open-label,3+3design– Adultpatientsaged≥18yearswithnewlydiagnosedAML
wereenrolled• Dose-escalationcohortsof40,80,and120mg/daygilteritinibwith3–6patientspercohort• Morethan20patientsinthedose-expansioncohort,including≥15FLT3Mut+ patients
Patientsaged≥18yearswithnewlydiagnosedAML
Maintenance(upto26cycles)Gilteritinib(oncedaily)
DLTObservatio
nRemissioninduction(1–2cycles)Cytarabine(100mg/m2;Days1–7)
+Idarubicin(12mg/m2;Days1–3)
+Gilteritinib(oncedaily,Days1–14or4–17*)
Consolidation(1–3cycles)Cytarabine(1.5g/m2 q12h;Days1,3,and5)
+Gilteritinib(oncedaily,Days1–14)
DoseEscalation
Response Parameter*, n (%) FLT3Mut+ (n=21)†
CR 19 (90.5)CRp 1 (4.8)CRi 1 (4.8)PR 0
CRc‡ 21 (100)
• IDH: critical enzymes of citric acid cycle
• mIDH2 and IDH1produce 2-HG-- alters DNA methylation and blocks cellular differentiation
• mIDH2 in ~15% of AML/MDS; mIDH1 in 7%
• Enasidenib (AG-221 )is a selective, oral, potent inhibitor of mIDH2 enzyme
• Ivosidenib, IDH-305, FT2102, and Bay-6032 are potent inhibitors of IDH1
IDHMutationsasaTargetTumor Cell
Prensner. Nat Med. 2011;17:291-293.
Enasidenib (AG221) in R-R AML• 239 pts Rx with enasidenib 50-650mg orally
daily; 153 pts Rx with 100 mg daily in Phase 2• ORR 70/239 = 40%; median RD 5.8 mos;
median OS 9.3 mos• CR 19%; median OS 19.7 mos• Grade 3-4 AEs: ↑ bili 12%; differentiation
syndrome 7%
Stein. Blood 130: 722; 2017
Enasidenib (AG221) in R-R AML
Stein. Blood 130: 722; 2017
Ivosidenib (AG120; IDH1 inhibitor) in R-R AML
• 258 pts Rx with ivosidenib 500mg/D; 125 R-R AML
• CR 22%, CRh 9%--CR + CRh 30%• Median OR duration 8.2 mos; median CRD 9.3
mos• Differentiation syndrome 11%; grade 3-4 5%
DiNardo. NEJM 378: 2386; 2018.
Overall Survival by Best Response in R/R AML (n=125)
DiNardo. NEJM 378: 2386; 2018.
Azacytidine +IDHinhibitor• Ivosidenib + AZA: 18/23 response, 10 CRs•Enasidenib + AZA: 4/6 response, 3 CRs
Ivosidenib + AZA(N=23)
Enasidenib + AZA(N=6)
Overall response, n (%) 18 (78) 4 (67)CR, n (%) 10 (44) 3 (50)CRi/CRp, n (%) 5 (22) 0MLFS, n (%) 3 (13) 1 (17)SD, n (%) 4 (17) 1 (17)PD, n (%) 0 1 (17)NE, n (%) 1(4) 0
DiNardo Abstract S1562 EHA 2018
IDH inhibitors+ChemoRx in Newly Dx AML• 134 pts Rx with 3+7 with ivosidenib (n=47) or enasidenib
(n=87)
• Mutation clearance in CR—41% on ivosidenib, and 30% on enasidenib
Parameter Ivosidenib EnasidenibMedian age 63 63No(%) CR/CRi/CRp - -- DeNovo 26/28 (93) 34/45 (73)- 2nd 6/13 (46) 20/32 (63)
Stein. Blood 132: abst 560; 2018
5252
Survival of Newly Dx IDH-mutated AML Rx with 3+7 + ivosidenib/enasidenib
• 79% probability of being alive at 1 year after Induction Day 1
• Median overall survival not yet estimable
Data cut 01AUG2018
• 75% probability of being alive at 1 year after Induction Day 1
• Median overall survival not yet estimable
Wei.Blood128:abst 102;2016
Venetoclax plus DAC/AZA in Rx-naïve AML• 145 pts median age 74 yr (65-86) Rx ; Venetoclax 400-1200mg/D
Patients N CR+CRi; n (%) ORR; n(%) Median OS (95% CI)
All Patients 145 [54+43], 97, (67) [54+43+2], 99 (68) 17.5
VEN 400mg + HMA
60 44 (73) 44 (73) NR
VEN 400mg + AZA 29 22 (76) 22 (76) NR
VEN 400mg + DEC
31 22 (71) 22 (71) 14.2
VEN 800mg + HMA
74 48 (65) 50 (68) 17.5
VEN 800mg + AZA 37 21 (57) 22 (59) 15.2
VEN 800mg + DEC
37 27 (73) 28 (76) 17.5
DiNardo. Lancet Oncol 2018; 19: 216-228. DiNardo. Blood 133: 7-17; 2019
Venetoclax in UnRx Elderly AML – Survival
DiNardo. Lancet Oncol 2018; 19: 216-228. DiNardo. Blood 133: 7-17; 2019
Venetoclax in UnRx Elderly AML – AZA/DAC +/-Venetoclax
Dombret H, et al. Blood 2015; 126:291–299. DiNardo. Lancet Oncol 2018; 19: 216-228. DiNardo. Blood 133: 7-17; 2019
Phase 2 DEC10-VEN in AML/MDSStudy Design
• DEC 20 mg/m2 x 10 days every 4-8 wks• Consolidation/maintenance: DECx5D post CR/CRi• VEN D1-28 for C1, D1-21 C2 onward
‒If C1D21 BM blasts <5%, VEN held for count recovery
‒Additional reduction in VEN allowed for myelosuppression
Maiti. Blood 132: Abst 286; 2018
Cohort n/N (%)CR/CRi
CRCRi
MRD negative by FCMComplete cytogenetic responseTime to response, days, median [range]30-day mortality90-day mortality
26/27 (96)16/27 (59)10/27 (37)13/25 (52)7/12 (58)
42 (24-157)00
DEC10-VEN in Newly Dx and UnRx Secondary AML ( n=27)Response Rates
Other regimens in Newly Dx AML CR/CRi %Decitabine 5 days + venetoclaxDecitabine 10 daysAzacitidine
614028
DiNardo. Lancet Oncol 2018. Ritchie. Leuk Lymphoma 2013. Dombret. Blood 2015
Management of Acute Leukemia In The Elderly-First a Definition
•Who is “elderly”?•Age cut-off 60, 65, 70, older?•My definition--any patient in whom expected
induction mortality (8-week mortality) more than 20-30% + short median survival/low cure rate with standard intensive chemo Rx
Adverse Prognostic Factors with Intensive ChemoRx in Elderly AML
•Age ≥ 75 yrs•Unfavorable kayotype•ECOG performance ≥ 2•AHD > 6-12 mos; prior MDS•Creatinine > 1.3 mg/dl•Poor supportive care (“Rx outside LAFR”)
Kantarjian. Cancer 106:1090, 2006
Outcome of Elderly AML by Adverse Factors
No Adverse Factors % CR
% 8-wk Mortality
% 1-yr Survival
0-1 60-70 10-20 50
2-3 40-50 30-40 20-35
≥ 4 20 60-65 < 10Kantarjian. Cancer 106:1090, 2006
Older AML. Low Intensity RegimensClo-
araC-DAC
CDA-ara C-DAC
AZA/DAC+VEN
LD araC + VEN
No Rx 118 118 145 71% CR 60 58 - 26% CR + CRi/p 68 68 67 62Median OS (mos)
11 13.8 17.5 11.4
% 2-yr OS 25 28 45 25-30% 4-wk death 3 1 - 3
Kadia. Cancer 121: 2375; 2015. Kadia. November 2017. DiNardo. ASH. 2017.; Wei. ASH 2017. Abst. 890.
Outcomes of AML by Rx Centers• National Cancer Data Base of 60,738 pts with AML
• MVA for adverse factors for mortality(p<.0001): non-academic (HR 1.52); increasing age; less income; not insured (HR 2.0; medicaid and other OK); co-morbidities; APL (HR≈1.3)
• Similar data from California (7007 pts; 1999-2014)—mortality in NCI-CC 12% vs non-NCI-CC 24%
Bhatt. AJH 92: 764; 2017. Ho. Cancer 124: 1938; 2018
Outcomes in AMLCenter 4-wk Mortality % 5-yr Survival %
Non-academic 29 16Academic 15 25
Non-NCI CC 24NCI CC 12
MDACCYounger 5 40-50
Older 2-3 30-40Bhatt. AJH 92: 764; 2017. Ho. Cancer 124: 1938; 2018
AML. Important Leads• FLT3 inhibitors; IDH1/2 inhibitors• Venetoclax• Antibodies: monoclonal, bispecific constructs
(CD33, CD123) [GO,IMGN632, AMG330, others]• CAR-T directed to CD33, CD123• CPX351• Checkpoint inhibitors• CD70 Ab• APR 246 for p53-mutated MDS/AML
