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Transcript of Novel Strategies for the Treatment of AML: Tailoring Treatment For Specific Genetic Subtypes Martin...
Novel Strategies for the Treatment of AML: Tailoring
Treatment For Specific Genetic Subtypes
Martin S. Tallman, M.D. Northwestern University Feinberg School of
MedicineRobert H. Lurie Comprehensive Cancer Center
Chicago, IL
Topics To Address• Introduction and epidemiology
• Overview of current therapy
• Distinguishing genetic subtypes
• Novel strategies for specific genetic subtypes
• Future Directions
Introduction
• New patients/deaths in 2004: 12,000/9,000
• Median age of AML: 68 years
• Heterogeneity in genetics and clinical manifestations
• Outcome varies by prognostic factors
Epidemiology• Therapy-related (alkylating agent or topo II
active agents)
• Evolving from MDS or MPD
• Congenital chromosomal instability syndromes
• Higher frequency of APL in Latin Americans1
• Higher frequency of t(8;21) in Japan2
1Douer Blood, 1996, Br J Haematol, 2003; 2Nakase Leukemia, 2000
Current Treatment Results In Younger Adults
STUDY N CR % ED % OS % (3-5 yr)
CALGB 474 72 9 34
GAMLCG
HOVON
535
253
74
77
11
7
39
38
ALFA 345 82 9 38
Current Treatment Results In Older Adults
STUDY N CR % ED % OS % (2-7 yr)
CALGB 388 52 25 15
ECOG 348 42 17 10
SWOG 328 43 7 19
MRC 1,314 55 19 10
Prognostic Factors
• Age
• Intensity of postremission therapy (younger adults)
• Cytogenetics (distinguish fav- intermed- and unfav-risk groups)
Overall Survival by Cytogenetic Group
Slovak Blood, 2000
Years After Entering Study
0
20
40
60
80
100
0 2
Cu
mu
lati
ve P
erce
nt
84 6
Favorable 121 53 55% Intermediate 278 168 38% Unfavorable 184 162 11%
Estimate At Risk Deaths at 5 Years
Heterogeneity of 3 Groups: p<.0001
Prognostic FactorsMolecular Markers
• Transmembrane transporter proteins which confer multidrug resistance (MDR1)
• Mutations in or overexpression of specific genes-unfav. prognosis: WT1, BAX, BCL-2/BAX, BAALC, EVI1, KIT, FLT3, MLL, ERG; fav. prognosis: C/EBP, NMP1
Expressed in cells from pts with normal karyotype
Outcome For AML with Fav-risk Cytogenetics
N CR % DFS % OS %
CBF 3731
3122
86
88
40
47
43
50
1613 96 52 59
APL 4634 91 88 85
2985 94 90 871Castaigne Blood, 2002; 2Appelbaum Proc ASCO, 2005; 3Marcucci J Clin Oncol,
2005; 4Sanz Pro ASCO, 2005; 5Lo Coco Blood, 2004
Outcome For AML in Older Adults with
Unfavorable Cytogenetics
N CR% OS% (5-yr)
MRC1 145 26 2.0
ECOG2 61 23 2.5
1Grimwade Blood, 2004; 2Rowe Blood, 2004
Current Therapeutic Strategies
• Induction with anthracycline 45-60 mg/m2/day for 3 days + cytarabine 100 mg/m2/day for 7 days c.i.
• Multiple cycles of high-dose ara-C consolidation
• No maintenance (except APL)
Strategies To Improve Outcome
• Dose intensification (anthracyclines)
• Alternative chemotherapy
• Priming with growth factors
• New agents
Daunorubicin Dose Intensification
1Appelbaum Ann Int Med, 1984; 2Castaigne Blood, 2003; 3Kolitz Blood, 1998
Study Dauno Dose CR%
FHCRC1 70 mg/m2 80
ALFA2 80 mg/m2 76
CALGB3 90-95 mg/m2 80
ECOG Priming StudiesRecruiting Leukemic Cells into Cell
Cycle
GM-CSF Placebo
CR 38% 40%
Induction mortality 26% 17%
OS, median 5.3 mo. 8.5 mo.
DFS, median 6.9 mo. 5.1 mo.
Rowe Blood, 2004
Priming With Growth Factor (GF) in Younger Patients with Intermediate
Cytogenetics
Study N CR % DFS % OS %GF/No GF GF/No GF GF/No GF
HOVON1 464 87/86 45/33 (p=.006)
45/35 (p=.02)
ALFA2 259 91/87 50/35 (p=.05)
56/47(p=.07)
1Lowenberg NEJM, 2003; 2Thomas Blood, 2005
Specific Genetic Subtypes of AML To Which Therapy Can Be
Tailored• APL
• CBF AML
• CD33 pos AML
• AML with FLT3 mutatations
• AML with c-kit mutations
• AML with MLL PTD
Curative Strategies in APLInduction: ATRA + anthracycline-based
chemotherapy
Consolidation: Anthracycline-based chemotherapy for 2-3 cycles to molecular negativity
Intermediate-dose ara-C for high-risk
Maintenance: ATRA +/- low-dose chemo for 1-2 years; ? Role in PCR neg after consol
Mol. Monitoring: RT-PCR from PB every 3-6 months for 2-3 years, prob for high-risk only
Relapse: Arsenic followed by ASCT (allo if PCR pos) (consider prophylactic IT
therapy)
GIMEMA AIDA 2000
Years
Su
rviv
al
0 .5 1.0 2.0 3.0 4.0
0
.25
.50
.75
1.0
N=3383 years: 87%
1.5 2.5 3.5
Overall Survival
Courtesy of F. Lo Coco
Advances in Therapy in APLParadigm for tailoring therapy to
specific genetic subtypeStudy Group ContributionNo. Am. Intergroup Maintenance
PETHEMA Elimination of ara-C
PETH/GIMEMA ATRA in consolidation
No. Am. Intergroup ATO in consolidation
GIMEMA Gemtuzumab
Shanghai ATRA + ATO
Iran ATO single agent
Will chemotherapy be eliminated?
Arsenic Trioxide for Rel/Ref APLPilot and US Multicenter Trial
Overall and Relapse-Free Survival
Years
0
20
40
60
80
100
0
Pro
bab
ility
(%
)
1 4
OS - 1st Relapse
2 3
OS - > 1st RelapseRFS - 1st RelapseRFS - > 1st Relapse
Soignet J Clin Oncol, 2001; Douer, Tallman J Clin Oncol, 2005
< .02*
0
11.1
26.3
Relapse (%) (median follow-up 18 months)
< .01
119
32
6.7
PML/RARα (fold)
< .05
25 5
35 3
40 10
Time to CR (days)
NS
95
90
95
(%)
CR
—P
21ATRA + ATO
20ATO
20ATRA
N
Induction/ maintenance therapy
*All patients also treated with consolidation chemotherapy and 6-MP + MTX as maintenance
Randomized Trial of Arsenic Trioxide and ATRA in Untreated APL
Shen Proc Natl Acad Sci,U S A, 2004
Time of Follow-up (months)
0
0.2
0.4
0.6
0.8
1.0
0 8
Probability
3216 244 2812 20
ATRA + arsenic trioxide (n = 20)arsenic trioxide (n = 18)ATRA (n = 19)
Shen PNAS, 2004
Disease-Free Survival by Treatment Group
1Zhang J Biol Regul Homeost Agents, 19992Ghavamzadeh ASCO, 2003[abst]3Ghavamzadeh EHA, 2004[abst]
Induction With Single-Agent Arsenic Trioxide: Untreated APL
51
111
124
N
95
92
NR
PCR neg (%)
ATO 6
ATO 1
Chemotherapy
Postremission therapy
80
86
88
CR (%)
Chandy – India5,6,7
Ghavamzadeh – Iran2,3,4
Zhang – China1
Study
4Ghavamzadeh Ann Oncol, 20055George Haematologica, 20046George European Hematol Assoc, 20047Mathews Blood, 2005 (abstr)
North American Intergroup Trial C9710
Induction Consol #1 Consol #2 Maint
ATRA DaunoAra-C
ATOATRADauno
CR
ATRA6-MPMTX
ATRA7 days, QOW
UntreatedAPL
No ATO
Tests arsenic as early consolidation and 2 maint regimens
Proposed North American Intergroup Study-Phase III
Low- and Intermediate-Risk
Induction Consol #1 Consol #2 Maint
ATRA Daunorubicin
Ara-CATO
ATRADaunorubicin
PCR
ATRA6-MPMTXneg
pos
OBS
GemtuzumabOzogamicin
HSCTTests benefit of maint in PCR neg patients
Proposed North American Intergroup Study-Phase II
High-Risk
Induction Consol #1 Consol #2 Consol #3 Maint
ATRAATO
GemtuzumabOzogamicin
ATO ATRADaunorubicin
GemtuzumabOzogamicin
ATRA6-MPMTX
Tests benefits of 3 nonchemotherapy agents in induction
Incidence of CBF AML by Age
Age Total inv(16) t(8;21) P-value
16-30 27% 43% 57% 0.056
31-40 26% 55% 45%
41-55 27% 59% 41%
56-65 9% 50% 50%
66-83 10% 62% 38%
Appelbaum FR, Kopecky KJ, Tallman MS, et al (submitted)
Outcome of t(8;21) AMLStudy N CR OS Postrem
Palmeri 17 82% 79% HiDACx3
Nishii 85 95% 52% No I-or HDAC
Baer 29 90% 45% >/=1 HiDAC
Marcucci 139 89% 46% S-, I-, HiDAC
Appelbaum
Schlenk
174
191
85%
87%
45%
65%
Variable
HiDAC
Palmeri Leuk Res, 2002; Nishii Leukemia, 2003; Baer Blood, 1997; Marcucci J Clin Oncol, 2005; Appelbaum (submitted); Schlenk J Clin Oncol, 2004
Outcome of inv16/t(16;16) AML
Study N CR OS Postrem
Marcucci 164 87% 54% S-, I-HiDAC
Delaunay 110 93% 58% variable
Appelbaum 196 89% 50% variable
Schlenk 201 89% 60% HiDAC
Marcucci J Clin Oncol, 2005; Delaunay Blood 2003; Appelbaum (submitted); Schlenk J Clin Oncol 2004
Overall Survival
Years0 10 20 25
100
Per
cent
0
40
60
80
20
5 15
5YearN Deaths Estimate
All Patients 370 197 48%
Overall Survival by Abnormality
Years0
100
Per
cent
0
40
60
80
20
5YearN Events Estimate
inv 16 196 97 50%t(8;21) 174 100 45%
10 20 255 15
Disease-Free Survival by Treatement
Years After Start of Post-CR Regimen0
100
Per
cent
0
40
60
80
20
5YearN Events Estimate
FA 53 20 61%HCT 31 12 61%HDAC 44 23 50%Other 136 96 31%
10 20 255 15
Outcome for CBF Leukemias
Appelbaum et al.(submitted)
CALGB Protocol 19808: Induction +/- MDR Modulation Followed by Cytogenetic Risk-
Adapted Intensification in Younger Adults
ADE
ADEP
Favorable Cytogenetics
Unfavorable Cytogenetics
HiDACConsolidationTherapy x 3
If able toReceive PSCT
If unable toReceive PSCT
HiDACG-CSF VP-16
Stem CellMobilize
VP-16HiDACG-CSF
BU/VP-16PSCT
HiDACConsolidationTherapy x 2
Obs.
IL-2
Tests HiDAC for fav. Cyto and IL-2 post-ASCT
Specific Genetic Subtypes Are Heterogeneous: t(8;21)
• CD56 expression may confer poor prognosis
• Associated trisomy 4 is a distinct subtype with poor prognosis
• Receptor tyrosine kinase pathway mutations in 49% and confer poor prognosis
Baer Blood, 1997; Nishii Leukemia 2003; Nanri Leukemia 2005
New AgentsClass Agent Target
Antibodies Gemtuzumab CD33
MDR inhibitors PSC833, Zosuquidar P-gp
FT inhibitors Tipifamib Lamin A, HJJ-2
FLT3 inhibitors PKC-412, CEP-701, MLN518, SU11248
FLT3 ITD
HDAC inhibitors Valproic acid, SAHA, depsipeptide
HDAC
Antiangio agents Bevacizumab VEGF
Apoptosis inhibitors Genasense BCL-2
Deoxyadenosine analogs
Nucleoside analogs
Clofarabine
Tiazofurin
DNA
IMPDH
S
H
HOO
OCH
NH O
O
OCH 3
N
EtO
OHOCH 3
HOCH3
OCH3
HNHO
OO
OH
CH3
S
CH3
OCH 3
OCH 3
I
O
O
O
O
O
CH 3
S
O
NHN
Me Me
Me
OO
HN
hP67.6
Gemtuzumab Ozogamicin
• Approved for adults > 60 in first relapse
• Induces CR + CRp in ~ 30%1,2
• Rare VOD/SOS if allo < 3.5 mo.3
•Structure hP67.6 - humanized anti-CD33 antibody Blue- linker Periwinkle - calicheamicin
1Sievers J Clin Oncol, 2001; 2Larson Leukemia, 2002; 3Wadleigh Blood, 2003
Gemtuzumab OzogamicinCR
MD Anderson1
Single Agent 8%
With IL-11 36%
Northwestern2 27%
EORTC3
Single Agent 23%
Followed by Chemo 35%
1Estey Blood, 2002; 2Nabhan Leukemia Res, 2004; 3Amadori Blood, 2004 [abstr]
Gemtuzumab Ozogamicin in Induction
DeAngelo Blood, 2003 (abstr); Kell Blood, 2003
Study Chemotherapy GO Dose CR
DeAngelo Dauno/Ara-C 6 mg/m2 d4 83%
Kell DAT or FLAG-ida 3 mg/m2 d1 85%
Prompts SWOG Phase III trial of chemotherapy +/- GO d4
ECOG Protocol E1900: Dose Intensification in Induction and Gemtuzumab Ozogamicin (GO) pre-ASCT in Younger Adults with
Untreated AML
Daunorubicin45 mg/m2/day
+Cytarabine
Allogeneic HSCT
CR
Daunorubicin90 mg/m2/day
+Cytarabine
High Risk
HiDAC x 2PBSH after 2nd
courseGO
6 mg/m2 IV day 1
AutologousASCT
Tests anthracycline dose intens and GO as in vitro purge pre- ASCT
Inhibition of Multidrug Resistance
• P-gp-mediated MDR plays major role in clinical resistance to chemotherapy
• P-gp correlates inversely with CR
• 71% of patients > age 60 express moderate to high P-gp1
• Major limitation is alteration in pK of concomitant chemotherapy
1Leith Blood, 1994
Group Modulator Regimen Outcome
CALGB1 PSC-833 ADE+PSC-833 Closed due to
toxicity
HOVON2 PSC-833 DA+PSC-833 DFS, OS not
improved1Baer Blood, 1999; 2 Van der Holt Blood, 2004 (abstr)
MDR Modulation Studies in AMLDe novo > 60 years
Inhibition of Multidrug Resistance
• Selective P-gp inhibitor with high affinity1
• In vitro conc of 50-100nM circumvent P-gp-mediated resistance 2,3
• Does not alter PKs of co-administered drugs2
• Phase II trial in poor-risk AML CR or mCR 42%4
• ECOG phase III trial
LY335979 (Zosuquidar)
1Sato Cancer Res, 1991; 2Dantzig Cancer Res, 1996; 3Green Biochem Pharmacol, 2001; 4Cripe Blood, 2001 (abstr)
ECOG Protocol E3999: Dauno + Cytarabine+/- Zosuquidar in Older Adults
DaunorubicinCytarabine
Zosuquidar
Induction Consolidation I
Daunorubicin
Cytarabine
Placebo
V
A
L
U
A
T
E
E
CR or
MR
Cytarabine
Consolidation II
Daunorubicin
Cytarabine
Zosuquidar
Daunorubicin
Cytarabine
Placebo
Tests novel MDR modulator
Ras• Ras mutations
– Activating mutations in 10-30% of AML1,2 – Frequent in t(3;5) and inv(16)3
• Active inhibition of farnesyl transferase (FT), inhibits ras protein
• Inhibitors of FT active in AML4,5
• Gene expression profiling may predict response to Tipifarnib6
1Radich Blood, 1990; 2Neubauer Blood, 1999; 3Bowen Blood, 2005;
4Karp Blood, 2001; 5Lancet Blood, 2002; 6Raponi Blood, 2005
Tipifarnib-Phase II Trial in Untreated High-risk AML/MDS
• Med age 74 yrs (46-85)• CR in 21%• Med CR dur 5-8 mo. (1.5-11+)• Gr. 4 neutropenia 13%• Inhibition of FT in 74% of samples• Encouraged US Intergr Phase II trial of
2 different doses/schedules in older adults
Lancet Blood, 2003 (abstr)
S0432: US Intergroup Phase II Study Zarnestra for Previously Untreated AML in
Patients > Age 70
Randomization
Arm 1 Arm 2 Arm 3 Arm 4
Zarnestra 600 mg
bid x 21 daysq 28 days
Zarnestra 600 mg bid x 7 days every other week q 28
days
Zarnestra 300 mg
bid x 21 daysq 28 days
Zarnestra 300 mg
bid x 7 days every other week q 28
days
AML With Mutant RAS and Cytarabine Intensification
wtRAS mutRAS
LoDAC HDAC LoDAC HDAC
Yrs to relapse
0.8 1.1 0.6 NR
RR 82% 71% 100% 45%
Neubauer ASCO, 2005
0
40
20
60
100
0 1
Su
rviv
al (
%)
Years2 3 4 5
80
44%44%
32%32%
ITD- n=627ITD- n=627
ITD+ n=227ITD+ n=227
P<0.001P<0.001
Kottaridis Blood, 2001
Prognostic Significance of FLT3 ITD
Tyrosine Kinase Inhibitors
PKC412• Staurosporine-derived, targets PKC, KDR, VEGF-R2,
PDGFR, c-KIT, FLT3
• Phase II study1 – 28 pts with FLT3 mutation, HI in 50%, but no CR or PR
CEP-701• Indolcarbazole alkyloid-targets TrkA, VEGFR, FLT3
• Phase I/II study2-14 pts with FLT3 mutation, biologic activity in 35%, but no CR or PR
1Estey Blood, 2003; Smith Blood, 2004
FLT3 Inhibitors and Chemotherapy in AML
•CEP-7011
•N=34 in first relapse•MEC or HiDAC +/- CEP-701•10/17 CR with CEP-701
•PKC4122
•N=19 de novo•Dauno + Ara-C + PKC412•CR 71-75%•100% FLT3 mut•62% FLT3 wt
1Lewis, Blood, 2005 (abstr);
2 Stone, Blood, 2005 (abstr)
FLT3 Inhibitors• In vitro data strong
• Modest clinical activity-few, if any, CRs
• How best to develop? • Focus on combinations with chemotherapy1, 2;
Phase III US Intergroup trial planned (dauno + ara-C +/- PKC412)
• Will combining agents with in vitro activity, but modest clinical activity, be effective?
1Stone Blood, 2005; Levis, Blood 2005
Genasense (Oblimersen Sodium)• Bcl-2 associated with poor outcome in AML
• Phosphorothioate 18-mer antisense oligonucleotide directed at first 6 codons of Bcl-2
• Genasense + dauno/cytarabine in high-risk de novo pts– 26 pts, med. age 67 – CR in 45.4%; no unexpected toxicity
• CALGB phase III trial underway
Marcucci Blood, 2003
G3139+
Cytarabine +Daunorubicin
Cytarabine +Daunorubicin
High-Dose Cytarabine
G3139+
High-DoseCytarabine
CALGB 10201: Daunorubicin + Cytarabine +/- G3139 (Genasense)
in Older Adults
CR
RemissionInduction
ConsolI & II
CR
Tests bcl-2 antisense strategy
Clofarabine• Intentionally designed to incorporate
the favorable properties of fludarabine/cladribine
• Multiple mechanisms of action
– Inhibits DNA replication and repair
– Disrupts mitochondrial function leading to apoptosis
• Active in both dividing and non-dividing cells
Clofarabine Trials in AML
Regimen N Population
CR/OR %
Clo 31 Rel/Ref 01
Clo 28 Untreated 59/752
Clo +IDAC 25 Rel/Ref 22/383
Clo + IDAC 60 Untreated 52/604
Clo + LoDAC 32 Untreated 59/625
1Kantarjian Blood, 2003;2Faderl Blood, 2005; 3Burnett Blood, 2005; 4Faderl Blood, 2005; 5Faderl Blood, 2005
CClofarabine Low-dose cytarabine
DDaunorubicin Cytarabine
Clofarabine
CClofarabine Low-dose cytarabine
CCytarabine 1.5 mg/m2 IV Q12 d1-6
CCytarabine 1.5 g/m2 IV Q12 d1-3
CClofarabine
Age 60-69
R
R
No CR Off Study
Age 70-79
HLA-iden sibling Mini-MUD alloSCT
Proposed ECOG Trial
CR
Can we eliminate conventional chemotherapy in older adults?
Specific Genetic Subtypes Of AML To Target In The Very
Near Future
• C-KIT AML: Imatinib, Dasatinib, FLT3 inhibitors
• MLL PTD AML: HDAC and DMT inhibitors
• Bcr-abl pos AML: IMP dehydrogenous inhibitor (Tiazofurin )
Whitman Blood, 2005; Malek Leuk Res, 2004
Other Active Agents Awaiting Assignement
To Specific Genetic Subtypes
• Choretazine (VNP40101M): sulfonylhydrazine alkylating agent1
• Tandutinib: small molecule inhibitor or type II receptor tyrosine kinases2
• XL99: inhibits multiple receptor kinases(VEGFR-2, PDGFR-alpha, PDGFR-beta, c-KIT, SRC, FGFR1, FLT4, FLT3)
• Low-dose decitabine3
• Arsenic plus low-dose ara-C41Giles Blood 2005 (abstr); 2Deangelo Blood, 2004 (abstr);
3Lubbat Blood, 2005 (abtsr); 4Robosz Blood, 2005(abstr)
Future Directions
• Gene expression profiling to determine signatures characteristic of specific genetic subtypes, identify cooperating mutations and perturbed pathways and predict treatment response
• Further characterization of normal karyotype AML and adverse karyotype AML
• Increased collaboration among cooperative groups to study myriad of new agents to tailor to specific genetic subtypes