Transcript HIV JO Slide Template - ANCO On-Line

ASH 2006
Leukemia Review
Steven Coutre MD
Associate Professor of Medicine
Stanford University School of Medicine
Acute Myeloid Leukemia
Gemtuzumab + Chemotherapy in
Frontline AML
 Reduction in relapse risk remains clinical goal of
induction/consolidation in AML
 MRC pilot study of gemtuzumab ozogamicin +
chemotherapy in AML
– 3-mg dose safe, associated with > 80% remission rate
 MRC AML 15 study: preliminary results
– Evaluated safety and efficacy of gemtuzumab addition to
induction chemotherapy in AML patients < 60 years of age
Kell WJ, et al. Blood. 2003;102:4277-4283.
Burnett AK, et al. ASH 2006. Abstract 13.
MRC AML 15 Trial: Study Design
Risk assessment
Induction:
Course 1
Induction:
Course 2
ADE ± GO
(n = 160)
ADE
DA ± GO
(n = 474)
DA
Patients with
untreated AML
< 60 years of age
CR
(N = 1115)
FLAG-Ida ± GO
(n = 479)
FLAG-Ida
*Consolidation arms included gemtuzumab + chemotherapy.
Burnett AK, et al. ASH 2006. Abstract 13.
Second
randomization,
then
consolidation*
MRC AML 15 Trial: Relapse and DFS
No gemtuzumab
Relapse
DFS
P = .027
P = .007
60
54
Relapse (%)
50
39
40
30
20
10
0
Disease Free (%)
60
Gemtuzumab
49
50
40
38
30
20
10
0
3 Years From CR
Burnett AK, et al. ASH 2006. Abstract 13.
3 Years From CR
MRC AML 15 Trial: Preliminary Results
 Similar rates of postinduction CR with gemtuzumab + induction vs
induction chemotherapy alone
– 84% vs 86%
 Similar mortality, resistant disease rate in both groups
– 8% to 7%
 Gemtuzumab increased DFS in patients with favorable or intermediate
cytogenetics (P < .02) without improvement in overall survival
 Treatment generally tolerable with similar rates of adverse events in
each arm
 Addition of gemtuzumab to induction chemotherapy may benefit those
with favorable/intermediate cytogenetics
Burnett AK, et al. ASH 2006. Abstract 13.
Gene Mutations as Prognostic Markers
in AML
 Genetic mutations have prognostic significance in normal
karyotype AML
 Meta-analysis of 4 AMLSG trials evaluated incidence,
prognostic significance of specific mutations
– Gene mutation analysis: CEBPA, FLT3 ITD/TKD, MLL,
NPM1, NRAS
 Other study aims
– Evaluation of potential interactions between markers
– Influence of mutation on response to postremission therapy
 N = 872; all patients ≤ 60 years of age
Schlenk RF, et al. ASH 2006. Abstract 4.
Gene Mutations as Prognostic Markers
in AML: Results
 Improved RFS, OS with NPM1+/FLT3 ITD- and CEBPA+ vs other
genotypes without MSD allo SCT (P < .0001 for both)
– Poor prognosis with FLT3 ITD+, NPM1-FLT3 ITD- genotype
Characteristic
Frequency, %
Response
NPM1+/FLT3 ITD-
33
CR: 88%; HR: 3.1
CEBPA+
14
CR: 83%; HR: 2.0
Relapse HR (Cox Regression HR)
P Value
Age (per 10-year increase)
1.16
.04
Donor available
0.65
.01
CEBPA+
0.36
< .0001
NPM1+/FLT3 ITD-
0.34
< .0001
Characteristic
Schlenk RF, et al. ASH 2006. Abstract 4.
Gene Mutations as Prognostic Markers
in Normal Karyotype AML
 Analysis of CR outcome by genotype and MSD availability (n = 666)
 Improved RFS with MSD allo SCT in patients without NPM1+/FLT3
ITD- and CEBPA+ genotypes
– MRD Allo SCT analyzed by ITT based on donor availability
MSD Availability
NPM1+/FLT3 ITD-
Other Genotypes
RFS, HR
0.89
0.56
OS, HR
0.93
0.69
61
47
57
23
MSD
4-year RFS, %
No MSD
4-year RFS, %
Schlenk RF, et al. ASH 2006. Abstract 4.
Acute Lymphoblastic
Leukemia
Allo BMT vs Auto BMT in Patients With
Ph- ALL: MRC UKALL XII/ECOG E2993
High-Dose
Methotrexate
(3 doses)
Patients with
Ph- ALL aged < 55 yrs
in complete remission
after induction therapy
HLA-matched sibling
donor available?
(N = 919)
No
Yes
High-Dose
Methotrexate
(3 doses)
Rowe JM, et al. ASH 2006. Abstract 2.
Sibling Allo BMT
(n = 389)
Auto BMT
(n = 530)
Consolidation/Maintenance
Chemotherapy:
2.5 years
Allo BMT vs Auto BMT in Patients With
Ph- ALL: 5-Year Results
 Improved OS with allo BMT vs auto BMT or postinduction
chemotherapy in standard-risk Ph- patients
– 5-year OS for allo BMT vs chemotherapy only: 54% vs 44% (P <
.02)
– No advantage in high-risk patients (aged > 34 years, WBC
>30,000 [B-cell] or > 100,000 [T-cell])
Outcome by Risk Group, %
Donor
(n = 389)
No Donor
(n = 530)
P Value
Overall 5-yr survival
53
45
.02
 High risk
40
36
.50
 Standard risk
63
51
.01
 High risk
39
62
< .0001
 Standard risk
27
50
< .0001
10-yr relapse rate
Rowe JM, et al. ASH 2006. Abstract 2.
Allo BMT vs Auto BMT in Patients With
Ph- ALL: 5-Year Results (cont’d)
 Better EFS, OS with consolidation/maintenance
chemotherapy vs auto BMT
– No role for auto BMT in postremission Ph- ALL
– Allo BMT treatment of choice in standard-risk patients
Outcome by Risk Group, %
Chemotherapy
Auto BMT
P Value
Overall 5-yr survival
47
37
.06
 High risk
40
32
.2
 Standard risk
49
41
.2
Overall EFS
42
33
.02
Rowe JM, et al. ASH 2006. Abstract 2.
Chronic Lymphocytic Leukemia:
Induction/Consolidation Therapy
Alemtuzumab Consolidation in CLL:
Phase III Study of the GCLLSG
Patients in complete
or partial remission
Patients ≤ 65
years of age
with previously
untreated CLL
Induction
F
Induction
FC
(N = 21)
Median FU: 48 mos
Consolidation:
Alemtuzumab* 30 mg IV
3 times weekly for up to 12 weeks
(n = 11)
Observation
(n = 10)
Primary endpoint: PFS
*Standard trimethoprim/sulfamethoxazole and famciclovir prophylaxis used in alemtuzumab arm
Schweighofer M, et al. ASH 2006. Abstract 33.
Alemtuzumab Consolidation in CLL:
PFS
Median progression-free survival
Alemtuzumab: not yet reached
Observation: 20.6 mos
Progression-Free Survival
Alemtuzumab
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Observation
Censored
P = .0035
0
6
12
18
Schweighofer M, et al. ASH 2006. Abstract 33.
24
30
36
Time (Months)
42
48
54
60
66
Alemtuzumab Consolidation in CLL:
Other Results
 Higher response rate at 48 months with consolidation
– 73% vs 20%
– Markedly lower levels of MRD in consolidation group
 Hematologic events more common in consolidation group
 High rate of infections in alemtuzumab arm led to
premature study discontinuation
– Infections successfully treated
 Optimal alemtuzumab regimen for consolidation has yet to
be determined
Schweighofer M, et al. ASH 2006. Abstract 33.
Chronic Lymphocytic Leukemia:
Relapsed/Refractory Disease
Lenalidomide in Relapsed/Refractory
CLL
 Lenalidomide: novel, potent thalidomide analogue
– Active in hematologic malignancies (eg, MDS, MM)
 2 phase II studies assessed the activity of lenalidomide in
relapsed/refractory CLL
– Ferrajoli and colleagues (N = 35)
– 10 mg daily dose, increased by 5 mg every 28 days (max 20 mg daily)
– Chanan Khan and colleagues (N = 45)
– 25 mg daily on Days 1-21 of 28-day cycle; ± rituximab
Ferrajoli A, et al. ASH 2006. Abstract 305.
Chanan Khan A, et al. ASH 2006. Abstract 306.
Lenalidomide in Relapsed/Refractory
CLL: Results
 Lenalidomide active in relapsed/refractory CLL, with
response seen at different dose levels
– Dramatic response in high-risk patients (ORR in ZAP70+
CLL: 60%)
Characteristic
Lenalidomide 10-25 mg
Daily (n = 35)[1]
Lenalidomide 25 mg Daily
± Rituximab
(n = 45)[2]
ORR
37
58
 CR
6
13
 PR
29
44
 SD
29
5
 Studies in frontline, consolidation settings being planned
1. Ferrajoli A, et al. ASH 2006. Abstract 305.
2. Chanan Khan A, et al. ASH 2006. Abstract 306.
Chronic Myeloid Leukemia:
Chronic-Phase Disease
Phase II Study of Dasatinib in CP-CML
Patients After Failure of Imatinib
 Phase II study (N = 387) of dasatinib in patients resistant
to or unable to tolerate imatinib
– 70 mg twice daily
 Dasatinib active in this setting
– Dose reductions: 70%; grade 3/4 pleural effusion: 6%
Response, %
All Patients
(n = 387)
Imatinib Resistant
(n = 288)
Imatinib Intolerant
(n = 99)
CHR
91
NR
NR
MCyR
59
80
52
CCyR
49
75
40
Baccarani M, et al. ASH 2006. Abstract 164.
Dasatinib in CP-CML: CA180-034 Study
Primary endpoint: 6-mo CyR of
100 mg vs 140 mg daily doses
Dasatinib 50 mg twice daily*
(n = 166)
Patients with CP-CML
resistant or intolerant
to imatinib
(N = 670)
Dasatinib 100 mg once daily*
(n = 166)
Dasatinib 70 mg twice daily*
(n = 167)
Dasatinib 140 mg once daily*
(n = 163)
100 mg daily
arms
140 mg daily
arms
*In poor responders, dose escalation to 90 mg twice daily/180 once daily allowed; dose reductions to
40 mg twice/80 mg once daily allowed for adverse events.
Hochhaus A, et al. ASH 2006. Abstract 166.
CA180-034 Study: Results
 Similar CHR, MCyR across treatment arms; CCyR ~ 30%
– > 80% patients remain in MCyR at 8 months
 Significant differences in rates of grade 3/4 cytopenias;
lowest incidence with 100-mg once-daily dose
Grade 3/4
Cytopenias, %
100 mg QD
(n = 166)
50 mg BID
(n = 166)
140 mg QD
(n = 163)
70 mg BID
(n = 167)
P Value*
Anemia
10
16
17
16
.032
Leukopenia
16
25
20
23
.079
Neutropenia
33
43
42
41
.035
Thrombocytopenia
22
31
39
37
.001
*100-mg once-daily arm compared with all other treatment arms.
Hochhaus A, et al. ASH 2006. Abstract 166.
Nilotinib in CP-CML Patients After
Failure of Prior Imatinib
 Nilotinib: novel tyrosine kinase inhibitor
– Highly active and specific to Bcr-Abl
 Phase II study evaluated safety, efficacy, in CP-CML
patients with imatinib resistance or intolerance
– N = 316
– 400 mg twice daily; escalation to 600 mg twice daily allowed
for nonresponders
 Primary endpoint: MCyR
le Coutre P, et al. ASH 2006. Abstract 165.
Nilotinib in CP-CML Patients After
Failure of Prior Imatinib
 ~ 50% of nilotinib-treated patients achieved MCyR
– Nilotinib well tolerated at higher doses
– Transient, manageable myelosuppression, elevated liver
transaminases
Response
6 Mos of Follow-up
(n = 279)
10 Mos of Follow-up
(n = 132)
CHR, % (n)
74 (185)
77 (86)
52 (46-58)
49 (40-58)
Imatinib resistant, % (n)
51 (193)
49 (91)
Imatinib intolerant, % (n)
55 (86)
49 (41)
34
32
MCyR, % (95% CI)
CCyR, %
le Coutre P, et al. ASH 2006. Abstract 165.
Chronic Myeloid Leukemia:
Novel Agents
MK-0457 in BCR-ABL T315I Mutant
CML
 MK-0457: aurora kinase inhibitor with T315I and JAK2 activity
 Phase I study presented at ASH 2006
– Evaluated safety of 5-day continuous IV dose, DLTs, PK and PD, in
chronic/acute leukemia
– 8-40 mg/m2/hr, 8 cohorts
– 15 CML patients, 11 with T315I
 MK-0457 active in CML: response in 8 of 9 T315I patients
– CCyR: 1; PCyR: 2; minor CyR: 1
 No grade 4 toxicity observed; events included mucositis,
myelosuppression
Giles F, et al. ASH 2006. Abstract 163.