Susan O'Brien, M.D., Professor, Dept. of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center: Newest Strategies in the Treatment of CML/CLL presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center.
1. CLL
Issues About Therapy
- Why do we watch and wait
- What is the best front line regimen
- Is it different for different subsets
- Does FISH affect choice of frontline
therapy?
- What are promising new agents?
2. Why Not Treat CLL at Diagnosis
- indolent disease
- patients often asymptomatic
- median age early 70’s
- no cure
4. Newer Prognostic Factors Associated
With Inferior Survival in CLL
FISH cytogenetic abnormalities
17p deletion
11q deletion
Complex abnormalities
Unmutated (<2% homology with germline)
immunoglobulin heavy chain variable gene
(IgVH)
Expression of ZAP-70 (≥ 20% positive)
Expression of CD38 (≥ 30% positive)
5. Early Treatment With FCR vs Deferred
Treatment in High-Risk Binet Stage A
GCLLSG CLL7
Diagnosed within 1 year All tested for 4 risk factors:
No pretreatment Cytogenetics by FISH
Age ≥ 18 years Serum thymidine kinase > 10 U/L
Enrollment ~ 825 Predicted LDT < 12 months
Unmutated IgVH
≥ 2 risk factors
N = 200 0-1 risk factors
N = 600
R
COHORT I COHORT II COHORT III
FCR 6 Watch & wait Watch & wait
Primary objectives: Event-free survival and definition of new prognostic system
Available at: http://dcllsg.web.med.uni-muenchen.de/en/cll7/index.php.
6. CLL8 Study Design
Patients with 6 courses
untreated, active FCR
CLL and Follow
good physical R
up
fitness
(CIRS ≤ 6,
FC
creatinine clearance
≥ 70 ml/min)
Updated results of the 2nd analysis
Median observation time 37.7 months.
Hallek et al Lancet 2010;376:1164-74
7. FC vs FCR: Response
FC (%) FCR (%) p
CR 23 45 <0. 01
CRu 5 3 0.22
CRi 2 3 0.52
nPR 5 3 0.15
PR 50 40 <0.01
OR 85 93 <0.01
Hallek et al Lancet 2010;376:1164-74
8. CLL8: Progression-free Survival
Median observation time 25.5 months
Median PFS:
FCR: 51.8 months
FC: 32.8 months
(N=790
Hazard ratio 0.563,
ranges 0.460-0.689,
p<0.001)
PFS rate 3 yrs
post
randomization:
FCR: 64.9%
FC: 44.7%
P<0.001
Hallek et al Lancet 2010;376:1164-74
9. CLL8: Overall Survival
Overall survival 3
years post
randomization:
FCR: 87.2%
FC: 82.5%
n=817, HR 0.664,
p=0.012
12. CAM307: Response to First-line Therapy With
Alemtuzumab vs Chlorambucil (N = 297)
IRRP Response Rate to First-line B-CLL Therapy
100 P<0.0001
90 83% ORR
80
CR
70 24% CR
PR
% Response
60
55% ORR
2%
50
40
30 59% PR 53% PR
52.7
20
10
0
Alemtuzumab Chlorambucil
Hillmen P et al. J Clin Oncol. 2007;25(35):5553-5.
13. CAM307: PFS by Cytogenetic
Abnormality and Treatment Arm
Alemtuzumab Chlorambucil
Median PFS Median PFS P-value for
Deletion N (mo) N (mo) PFS
17p del 11 10.7 10 2.2 0.2034
11q del
23 8.5 31 8.5 0.3895
(no 17p del)
Trisomy 12
(no 17p del, 24 18.3 10 12.9 0. 0815
no 11q del)
Normal 25 19.9 26 14.3 0.3477
Sole 13q del 33 24.4 34 13.0 0.0107
[Data presented according to hierarchical model of Döhner (NEJM 2000; 343: 1910-6)]
P value is calculated using log-rank test
14. Alemtuzumab for Fludarabine-Refractory
B-CLL: Study Results
• OR 33% (CR 2%, PR 31%)
• 59% of patients had stable disease
• Median TTP of responders 9+ months
• Fever, chills: 76% Gr 1-2, 20% Gr 3-4
• Grade 3-5 infections in 33% of patients
Keating et al. Blood 99 (10), 3554-61, 2002.
15. Local Injection-Site Reaction Following SC
Alemtuzumab Administration
Disappeared within 2 weeks of continued therapy
Skin reactions appear to be much less
pronounced in pretreated CLL patients
16. CAM307: Safety
Summary of Infection-Related Adverse Events
100
90 IV Alemtuzumab (n=147)
80 Oral Chlorambucil (n=147)
70
CMV incidence
% of Patients
60
50
40
30
20
46 50 53
10 5 3 3 2 16
8
0
Febrile Bacteremia Total Positive CMV Positive CMV
Neutropenia /Sepsis Infections* PCR with PCR without
symptoms symptoms
(*Total infections is excluding patients with any CMV events)
Hillmen et al. JCO 2008;25:5616-23
17. CMV Viremia with Alemtuzumab
Trial % Pts Time of Organ
No. Pts. with CMV CMV Involv. Deaths
Keating
93 8 on therapy no 0
Nguyen
34 10 28 days no 0
Ferrajoli
78 20 1st month no 0
Lundin*
41 10 on therapy no 0
*initial therapy
Keating et al Blood 99(10) 3554-3561 2002, Nguyen et al Clinical Lymphoma 3(2) 105-110, 2002,
Ferrajoli et al Cancer 98:773-8 2003, Lundin et al Blood 100:768-773 2002
19. Results
CMV
Total Reactivation
Valtrex 20 7
p = .004
Valcyte 20 0
O’Brien et al. Blood 2008;111(4):1816-19
20. Lymphadenopathy Predicts Poor
Response to Alemtuzumab in
Relapsed/Refractory CLL
Response according to size of largest lymph node
% of patients
MRD-
Largest NCI Response
negative
node No. CR OR response
None 33 72 87 39
<5cm 47 17 40 11
>5cm 11 0 9 0
Moreton P et al. J Clin Oncol. 2005;23:2971-2979.
21. Bendamustine
Bifunctional Antineoplastic Agent?
CH3
N
ClH2C
N
N
CO2H
ClH2C Purine-like
Alkylating Group Benzimidazole Ring
Available in Germany, 1971 - 1992
Unique in vitro anti-tumor profile
21
Rummel M, et al. J Clin Oncol. 2005;23:3383-3389.
22. Bendamustine combined with rituximab in
first-line therapy of advanced CLL:
mutlicenter phase II trial of the German
CLL SG
Kirsten Fischer, MD, Paula Cramer, MD, Stephan Stilgenbauer,
MD, Raymonde Busch, Leopold Balleisen, MD, Julia Kilp, MD,
Anna-Maria Fink, MD, Sebastian Böttcher, MD, Matthias
Ritgen, MD, Michael Kneba, MD, PhD, Peter Staib, MD,
Hartmut Döhner, MD, Silke Schulte, Barbara F. Eichhorst, MD,
Michael Hallek, MD and Clemens-Martin Wendtner, MD
ASH 2008 Abstract 205
23. BR Front-line Response Rate
Response N %
ORR 100 90.9
CR 36 32.7
nPR 3 2.7
PR 61 55.5
* N=110 (7 pts not yet evaluable)
Fischer et al; ASH 2008 Abstract 205: Bendamustine and rituximab
25. CLL10 protocol of the GCLLSG
Fludarabine Fludarabine 25 mg/m² i.v., days 1–3
Cyclophosphamide Cyclophosphamide 250 mg/m², days 1–3,
Rituximab: 375 mg/ m2 i.v. day 0, cycle 1
Rituximab
Rituximab: 500 mg/m² i.v. day 1, cycle 2–6
(FCR)
R
Bendamustine Bendamustine 90mg/m² day 1–2
Rituximab Rituximab 375 mg/m² day 0, cycle 1
(BR) Rituximab 500 mg/m² day 1, cycle 2–6
Similar efficacy of BR in comparison with FCR?
Lower toxicity rate of BR?
26. CLL8 Study Design
Patients with 6 courses
untreated, active FCR
CLL and Follow
good physical R
up
fitness
(CIRS ≤ 6,
FC
Creatinine
clearance
≥ 70 ml/min)
Updated results of the 2nd analysis
Median observation time 37.7 months.
Hallek et al Lancet 2010;376:1164-74
27. CLL8: Side effects: the effect of age
FC FCR
< 70 yrs ≥ 70 yrs < 70 yrs ≥ 70 yrs p
p
n = 359 n = 37 n = 361 n = 43
Total AEs gr 3/4 61.0% 78.4% 0.04 75.6% 83.7% 0.24
Anemia 6.7% 8.1% 0.74 5.5% 4.7% 0.81
AIHA 1.1% 0.0% 0.52 0.6% 2.3% 0.20
Leukocytopenia 12.0% 13.5% 0.79 24.9% 16.3% 0.21
Neutropenia 19.5% 35.1% 0.03 32.4% 44.2% 0.12
Thrombopenia 11.4% 5.4% 0.26 7.8% 4.7% 0.46
Infections,
9.5% 8.1% 0.79 13.0% 18.6% 0.31
unspecified
Infections,
0.7% 5.4% 0.02 1.9% 4.7% 0.26
bacterial
28. SOB’s Quick Survey
All patients with CLL > 70 years seen
by me in clinic last month: N = 14
Eligible for CLL8 trial?
3 too old, > 80 years, so N = 11
Meet creatinine clearance requirement?
N=4
So 4/14 = 29% eligible
Not counting CIR score
29. So if FCR not SOC for Patients with 17p
Deletion or Elderly, Then What Is?
17p-: clinical trial
elderly:
really old, poor PS
→ palliative, probably doesn’t
matter
older but good shape
→ reduced dose FCR
→ clinical trial
30. Bruton’s Tyrosine Kinase (Btk)
A Critical B-Cell Signaling Kinase
• B-cell antigen receptor (BCR) signaling is required for tumor
expansion and proliferation
• Bruton’s Tyrosine Kinase (Btk) is an essential element of the
BCR signaling pathway
• Mutations in Btk prevent B cell maturation
• Inhibitors of Btk block BCR signaling and induce apoptosis
30
31. PCI-32765: Novel Small Molecule Inhibitor of
BTK
• Forms a specific and irreversible bond
with cysteine-481 in Btk
O • Potent Btk inhibition at IC50 = 0.5 nM
• Orally bioavailable with daily dosing
NH 2
resulting in 24-hr target inhibition
• Inhibits BCR signaling and active in
N
N spontaneous canine B-cell lymphoma
N
N • In CLL cells promotes apoptosis, inhibits
ERK1/AKT phosphorylation, NF-κB DNA
N binding, CpG mediated proliferation
O • Inhibits CLL cell migration and adhesion
PCI-32765
Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010
Herman SEM et al: : Blood. 2011 Mar 21. [Epub]
Ponader, et al., Proc ASH, 2010 31
32. Pattern of Response:
Blood Lymphocytes vs Lymph Nodes
Treatment-Naïve Patients
600
1.5
% of Base SPD
ALC 109/L
400
1.0
200
0.5
0.0
0
0 50 100 150 200 250 300 0 50 100 150 200 250 300
Time (Days) Time (Days)
Relapsed/Refractory Patients
600
1.5
% of Base SPD
ALC 109/L
400
1.0
200
0.5
0.0
0
0 50 100 150 200 250 300 0 50 100 150 200 250 300
Time (Days)
Time (Day) Time (Days) 32
35. Best Response by Risk Features
Relapsed/Refractory Patients: 420 mg/d Cohort
Best Response (%)
Molecular Risk Feature N IWG Response Nodal Response
Overall 27 48 41
Del17p 9 4/9 (44) 3/9 (33)
Del11q 8 5/8 (63) 3/8 (38)
IgVH unmutated 17 9/17 (53) 5/17 (29)
35
36. Improvement in Hematologic Parameters
Platelets over time Hemoglobin over time
in subjects with plt <50x109/L in subjects with Hgb <9g/dL
at study entry at study entry
(n=12) (n=8)
150
14
Platelets (109/L)
HGB (g/dL)
12
100
10
50
8
0
1 15 28 43 56 84 112 140 168 196 224 252 1 15 28 43 56 84 112 140 168 196 224 252
Days on Study Days on Study
Subjects from all treatment groups with low baseline measurements are included
36
37. In B-Cell Malignancies, PI3K Delta Is at the
Crossroads of Critical Signaling Pathways
Stromal cell
T-cell Signaling IL-6 BAFF
stimulus CXCL13
BCR IL-6R
CXCR5
CD40 BAFFR
Malignant B-cell membrane
LYN gp130 gp130
JAK
TRAF6 SYK JAK
LYN/SYK α β γ
PI3K
STAT BTK Delta STAT BTK
PLCγ2 PLCγ2
T308 AKT S473
PKC GSK-3
NF-kβ PI3K Delta Pathway Drives
pathway
Proliferation
mTOR Cell survival
p70s6k elf4E Trafficking
Slide 37 Reference: Lannutti, Blood, 2011
38. CAL-101 is an Orally Bioavailable Small Molecule
that Inhibits PI3K Delta Potently and Selectively
CAL-101
Class I
PI3K Alpha Beta Gamma Delta
Isoform
Cell- PDGF- LPA-induced fMLP-induced FcεR1-
Based induced pAKT pAKT CD63+ induced
Activity CD63+
EC50 (nM) >20,000 1,900 3,000 8
• Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions
• No off-target activity against Class II or III PI3K, mTOR, or DNA-PK
• No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™)
Slide 38 Reference: Lannutti, Blood, 2011
39. Single-Agent CAL-101 Resulted in Tumor Shrinkage in All
Evaluable Patients with CLL, Including Those with del (17p)
Best On-Treatment Change in Tumor Size
(ITT Analysis, N=55)
+100
+75
% Change in Lymph Node Area
+50
+25
0
-25
-50*
-75 Inevaluable (patients without a follow-up tumor assessment)
Patients with del (17p)
* Criterion for response [Hallek 2008]
-100
Slide 39
40. Marked Reductions in Peripheral
Lymphadenopathy Were Observed
Pretreatment With CAL-101 Treatment
38-year-old patient with refractory CLL and 5 prior therapies
Slide 40
41. CAL-101 Treatment Improved CLL-Related
Thrombocytopenia and Anemia
14
Hemoglobin and Platelet Counts 160
Mean Hemoglobin ± SEM (g/dL)
Mean Platelets ± SEM (K/µL)
13 140
12 120
11 Hemoglobin 100
Platelets
10 80
)
)
)
)
)
)
5)
2)
2
2
1
8
2
1
(2
(2
(5
(5
(5
(3
(3
(3
10
12
0
1
2
4
6
8
Cycle (28 days) (N)
Improved thrombocytopenia: Patients with baseline thrombocytopenia
(platelets<100,000/uL) had sustained improvement in mean platelet counts
Improved anemia: Patients with baseline anemia (hemoglobin <11 g/dL) had
sustained improvements in mean hemoglobin values
Slide 41
42. CAL-101 Has Been Well Tolerated in Patients with CLL
Over Exposure Periods Exceeding One Year
Grade 3-4 Adverse Events Occuring in ≥5%
of Patients Regardless of Causality (N=55)
100
80
Incidence, %
60
Non-Hematological Hematological
40
24%
20 18%
5% 7% 5% 7%
0 ia
ia
N
↑
↓
ia
F&
on
m
en
ST
et
ne
el
p
um
/A
ro
at
A
LT
Pl
e
t
eu
Pn
A
N
Adverse Event Type
• Grade 3-4 adverse events largely due to prior therapy or underlying CLL
• No maximum tolerated dose or dose-limiting toxicities
• No pattern of drug-related symptomatic adverse events
Slide 42
43. Conclusions - CLL
- FCR is standard of care
- 17p- is the mother of all bad prognostic
factors
• clinical trials
• allo SCT
- No real standard of care for elderly patients
• all regimens that are effective are also
toxic
- Several promising new agents in clinical trials