Novel treatment options for
Waldenstrom
Macroglobulinemia
Irene Ghobrial, MD
Associate Professor of Medicine
Harvard Medical School
Dana Farber Cancer Institute
Boston, MA
Ghobrial et al, Lancet Oncol 2004, Treon et al, Blood 2009
MYD88 in WM
Treon et al, NEJM 2012
Molecular characteristics
• 30-50% of patients: deletion 6q by FISH
• BLIMP (on 6q21): a tumor-suppressor
gene, is the master gene regulator for
B-lymphocytic cell proliferation.
• 70-90% of patients have MYD88
mutation.
• CXCR4 somatic mutation in 24% of
samples
Treon et al NEJM 2012
Consensus recommendations of the 4th
International WM meeting
• First Line therapy:
– Combination therapy
• (RCD or CPR; Cytoxan+nucleoside analogues+R; R-CHOP, R-CVP)
– Rituximab single agent
– Nucleoside analogues
– Alkylators
• Salvage therapy:
–
–
–
–
–
Re-use therapies
Bortezomib
Thalidomide+steroids
Alemtuzumab
AHSCT
Dimopoulos, JCO 2009, Treon et al Clin
Lymph and Myeloma 2009
Primary Therapy of WM with RituximabBased Options
Regimen
ORR
CR
Rituximab x 4
25-30%
0%
Rituximab x 8
40-45%
0%
Rituximab/cyclophosphamide
i.e. CHOP-R, CVP-R, CPR, RCD
70-80%
8-10%
Rituximab/nucleoside analogues
i.e. FR, FCR, CDA-R
70-90%
5-10%
Rituximab/thalidomide
70%
5%
Rituximab/bortezomib
i.e. BDR, VR
70-90%
10-25%
90%
NA
Rituximab/bendamustine
Courtesy of Dr. Steven Treon
Primary treatment of Waldenström
macroglobulinemia with dexamethasone, rituximab,
and cyclophosphamide.
• 72 patients
• cyclophosphamide 100 mg/m2 orally bid on days 1 to
5 (total dose, 1,000 mg/m2).
• 83% of patients achieved a response
• Including 7% complete, 67% partial, and 9% minor
responses.
• The median time to response was 4.1 months.
• The 2-year progression-free survival rate for all
patients was 67%
Dimopoulos, JCO 2007
Bendamustine plus Rituximab versus CHOP plus Rituximab
in the First-Line- Treatment of Patients with Waldenstrom
disease: Randomized Phase III Study of the Studygroup
Indolent Lymphomas (StiL)
•42 pts with WM, report on 40 evaluable in interim
analysis, BR=23 and CHOP-R=17.
•The ORR for pts treated with B-R was similar to
that associated with CHOP-R (96% vs 94%,
respectively).
•The median follow-up time for both groups is 26
months.
•Progressive or relapsed disease: 2 in pts treated
with B-R and 7 in the CHOP-R group.
•Less toxicity and non-inferior response.
Rummel, WM-Workshop2012
PFS: Benda-R vs CHOP-R in
Frontline WM
1.0
Probability
0.9
Bendamustine-R
0.8
0.7
0.6
0.5
0.4
0.3
0.2
CHOP-R
0.1
0.0
0
12
24
36
48
60
72
months
Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston,
Massachusetts, United States.
Phase II trial of bortezomib+ rituximab in
upfront or R/R WM
•ORR 80-90%. CR 10-15%
•Minimal peripheral neuropathy
V
V
V
R
R
R
V
V
V
V
V
R
V
V
R
•A total of 6 cycles, a cycle= 28 days
V
R
V
R
V
V
V
V
V
V
R
Maintenance
1 VR treatment q3M
x 2 years
•No
rituximab maintenance
---V Bortezomib 1.6 mg/m2 days 1, 8, 15 q 28 days x 6 cycles
Ghobrial et al, JCO 2010
---R Rituximab 375 mg/m days 1, 8, 15, 22 on cycles 1 and 4
•No
dexamethasone
Ghobrial et al, AJH 2011
1 cycle =28 days
2
New developments
 PI3K/mTOR inhibitors
 Proteasome inhibitors
 BTK inhibitors
 HDAC inhibitors
 IMIDs
The PI3K/mTOR pathway
Phase II trial of RAD001 in WM
Maximum decrease from baseline in IgM (%)
60
40
20
0
-20
-40
-60
-80
-100
-120
15
14
+
13
+
+
+
+
+
12
+
+
+
+
+
+
+
+
+
11
+
+
+
+
+
+
10
+
+
+
9
+
+
8
0
50
1
50
2
44
3
37
4
33
5
28
6
26
7
19
Cycle
Number of patients
8
18
9
15
10
12
11
11
12
10
Partial response
B
Stable disease
Partial response
A
C
Phase I/II Study of Everolimus,
Bortezomib and/or Rituximab in Relapsed/Refractory WM
Study Design
Phase I study
Registration
•
•
Everolimus/rituximab
Everolimus/bortezomib/rituximab
Determine maximum
tolerated dose (MTD)
Phase II study ongoing with 3 drug combination
The RVR phase I study
Response
CR
PR
MR
ORR (CR+PR+MR)
Stable Disease
N= 23 evaluable
1 (5%)
7 (30%)
9 (39%)
17 (74%)
6 (26%)
MLN128
• TORC1 and 2 inhibitor
• Oral agent
before
after 6 months
Maiso, Blood 2010
Targeting PKC in WM
Phase II study
38% ORR in 42
patients
relapsed/ref
Ghobrial, CCR 2012
N=37
% with
Phase II trial of perifosine
in patients
Clinical response
relapsed/refractory WM
CI
9
MR 35%, with another 54% showing stabilization
•ORR
of their 24
disease(11.8, 41 . 2 )
PR
•Only
SD
PD
3
8
(1.7, 21. 9 )
21
57
(39.5, 72 . 9 )
11
(3.0,
CI 25. 4 )
11% of patients demonstrated progression.
4
N=37
%
Clinical response
Response by M spike
MR
MR
PR
PR
99
24
24
(11.8, 41.2)
4
11
(3.0, 25. 4 )
20
54
(36.9,70.5)
21
4
57
11
(39.5,
72.9)
(3.0, 25.
4)
4
11
(3.0, 25. 4 )
3
SD
SD
PD
PD
Response by IgM
MR
PR
SD
Response
PD
(11.8,41 . 2 )
by M spike
8
(1.7, 21. 9 )
11
30
(15.9, 47 . 0 )
2
5
(0.7,18.2 )
20
54
(36.9,70
.5)
(11.8,41.2)
11
24
(3.0, 25. 4 )
MR
PR
49
SD
PD
20
4
11
(3.0, 25. 4 )
Ghobrial54
et al, CCR
2010
(36.9,70.5)
CAL-101
PI3K delta (p110)
Oral
Well tolerated
Significant Lymph node response but
increase in peripheral blood
lymphocytes in CLL
60% ORR in indolent lymphomas, 86%
in MCL, 95% ORR in CLL in lymph
nodes
Roccaro et al, Blood 2011
New Proteasome inhibitors
 Upfront therapy with
Carfilzomib/dex/rituxan
(CARD study)
 Onyx 0912 in relapsed
WM
Roccaro et al, Blood 2010
Sacco et al, CCR 2011
IMIDs in WM
•
•
•
Thalidomide and rituximab:
– Thalidomide 200-400 mg, rituximab weeks 2-5, 13-16
– 25 pts (20 untreated)
– 70% ORR
– TTP ≥38 months observed among responders.
– 44% >G2 PN
Lenalidomide and rituximab:
– 25 mg lenalidomide 21 days, and rituximab weeks 2-5, 13-16
– 16 pts (12 untreated)
– 50% response rate, TTP of 18.9 months
– 88% discontinuation of therapy
– Most due to anemia that occurred early with therapy
– Median decrease in Hct from 32 to 27%, 4 pts required
hospitalization
Phase I trials of lenalidomide ongoing, phase I
pomalidomide/rituximab ongoing.
Treon et al, Blood 2008, CCR 2008
Phase II Study of Panobinostat in WM
Best overall
response
CR
VGPR
PR
MR
SD
PD
Unevaluable
N
%
0 0
1 3
10 27
9 25
14 39
1 3
1 3
Total
36
PR or better
30
11 (90%CI:18, 46)
55
20 (90%CI:41,70)
MR or better
Ghobrial I, et al. Blood. 2010;116:3952.[Oral Presentation].
IgM response to Panobinostat
Bruton’s Tyrosine Kinase (BTK)
IgM
• 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
• Inhibitors of Btk block BCR signaling and induces apoptosis
Nat Rev Imm 2:945
Ibrutinib
• Breakthrough designation by the FDA
for WM.
• Over 80% response rate.
• Very well tolerated.
• Currently, no trials available. Awaiting
approval and more trials or expanded
access in the next few months.
New Proteasome inhibitors
Oprozomib in relapsed
WM
Roccaro et al, Blood 2010
Sacco et al, CCR 2011
Oprozomib
• Oral agent.
• Proteasome inhibitor without
neuropathy.
• Over 80% response rate so far in WM
• Considering breakthrough designation
in WM.
• Study open in multiple sites and
accruing now.
Future developments
• MYD88 targeting (IRAK4)
• CXCR4 targeting
• miRNA155 targeting (MiRNA LNA)
miRNA expression in bone marrow CD19+ WM cells
vs CD19+ normal counterpart
Roccaro et al. Blood 2009
Association between microRNAs
and clinical prognostic features
P = .009
P = .004
P = .001
Roccaro et al. Blood 2009
Summary
 Significant advances in WM specifically MYD88
 miRNA155 as a prognostic maker and therapeutic target
 New agents including mTOR inhibitors, BTK inhibitors,
PI3K inhibitors, HDAC inhibitors, new proteasome
inhibitors
 Can we personalize therapy in WM?
 Should we treat earlier to prevent complications/clonal
heterogeneity and resistance
 FDA approval for agents in WM
Acknowledgement
•
Ken Anderson, MD, Steven Treon, MD, Paul Richardson, MD, Nikhil Munshi,
MD, Jacob Laubach, MD, Claudia Paba-Prada, MD
•
Supported by the NIH, FDA, IWMF, LLS, Kirsch Lab for WM, Heje Fellowship, All
our patients.