How I Treat Waldenstrom Macrobulinemia - Winship Cancer Institute ...

7/17/2012
How I Treat: Waldenström Macroglobulinemia
Leonard T. Heffner, Jr., M.D.
Winship Cancer Institute of Emory University
What I need to know before starting
treatement for Waldenström
• Does the patient really have WM.
• Is there an indication for starting treatment
• What risk factors are present
• Is there a standard treatment
• What are the treatment options
• Is there a clinical trial available
• Should the patient receive maintenance
• Is there a role for stem cell transplant
Demographics
Incidence Age-adjusted : 3.8/million persons/yr.(1500/yr)
Amyloidosis: 8/mil persons/yr
Myeloma: 40/mil persons/yr
Age: 65-73 yo (median at Dx)
Gender: Males: 5.4/mil
Females: 2.7/mil
Race: Caucasian- 4.1/mil
African-American- 1.8/mil
Wang H, et al. Cancer 2011;doi:10.1002/cncr.26627
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106.5 vs 94 mos
p = 0.37
Kastritis E, et al. AmJHem 2011;86:479
120 mos vs not reached
p = 0.987
Kastritis E, et al. AmJHem 2011;86:479
1944: Jan Waldenström described 2 pts with
lymphadenopathy, but also oranasal
bleeding, anemia, thrombocytopenia,
increased viscosity, elevated ESR, normal
bone survey, and bone marrow showing
predominantly lymphoid cells.
Waldenström, J: Incipient myelomatosis or essential hyperglobulinemia with
fibrinogenopenia--A new syndrome Acta Medica Scand 117:217, 1944.
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WHO 2008: The Mature B-cell Neoplasms
• Lymphoplasamacytic lymphoma
a. Bone marrow infiltration by small lymphocytes,
plasmacytoid cells, and plasma cells
b. diffuse, interstitial or nodular pattern of bone
marrow infiltration
c. Immunophenotype: CD5-,CD10-, usually CD23-,
CD19+,CD20+,sIg+
1. Waldenström macroglobulinemia
IgM monoclonal gammopathy of any
concentration
The IgM Disorders
• Waldenström (WM):
-IgM monoclonal gammopathy(any amt)
-BM infiltration with lymphoplasmacytic
cells
• Smoldering WM:
->3 g/dL monoclonal protein
and/or
->10% BM lymphoplasmacytic cells
but also no evidence of symptoms or lab
findings due to the disease
The IgM Disorders
• IgM MGUS:
-IgM monoclonal protein

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Diagnostic Approach for Suspected WM
-SPEP with immunofixation
-Quantitative immunoglobulins
-24hr urine for electrophoresis
-Beta-2 microglobulin and LDH (for prognostic scoring)
-Bone marrow with cytogenetic analysis and FISH
-CT imaging of chest/abdomen/pelvis (bone survey only if suspected myeloma)
-Serum viscosity
-Based on clinical presentation: consider cryoglobulins, cold agglutinins, other
medical causes of anemia, tissue stains for amyloid, detailed fundoscopic exam,
hepatitisB and C, anti-MAG and anti-GM1 antibodies
Indications for treatment of WM
Bone Marrow/Node Related
1. Hgb

7/17/2012
International prognostic scoring system
for Waldenström
Variables
Age >65
Hgb 7.0
For pts. needing therapy
Score Med surv 5-yr surv
Low 0-1 142.5 mos. 87%
except age
Int 2 98.6 mos. 68%
or age
High >3 43.5 mos. 36 %
nl LDH = 94 mos
Inc LDH = 36 mos
Morel P, et al. Blood 2009;113:4163
Kastritis E, et al Leu Res 2010;doi:10;1016
Making the decision to treat WM
• There is NO one standard of care regimen.
• Does the patient meet the criteria for
symptomatic disease
• How urgent is response needed
- immediate
- non-immediate
• Are there any high-risk features
• Is the patient a potential candidate for stem cell
transplant
Treatment Options in WM
Single Agents
• Rituximab
• Chlorambucil
• Fludarabine
• Cladribine
• Bortezomib
• Cyclophosphamide
• Thalidomide
• Bendamustine
Combinations
• Flu or Clad/Rituxan
• FCR
• R-CHOP
• R-CVP
• R-CD
• Benda/Rituxan
• Bortez/Rituxan/Dex
• Stem cell Transplant
And plasmapheresis
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The IgM Flare
• A rapid rise in IgM level following rituximab (up to
60% incidence)
• May aggravate pre-existing hyperviscosity or
precipitate new sxs of hyperviscosity
• Also occurs with combination drug therapy, but
less common with bortezomib
• Use TPE (with albumin) prophylactically for IgM
level >4000mg/dL or any symptomatic viscosity
• Generally 1-3 TPE required to reduce IgM by 30-
60%, but follow IgM levels. Follow with additional
planned therapy within 1 week optimally.
Bystander release of IL-6 by Monocytes may
account for the Rituximab IgM flare.
Rituximab
IVIg
FcγRIIA
IgM (ng/ml)
IL-6
IL-6R
Monocytes
WM-LPC
IgM
Treon, SP. Used by permission
Single-Agent Treatment in WM
Regimen No. Responses (%)
>PR >MR CR
CB 46-128 70-75 NR 2
Cladribine 16-46 43-94 NR 2
Fludarabine 28-183 30-36 NR 0-3
Rituximab 17-69 32-48 55-69 0
Bortezomib 10-27 48-60 59-85 0-4
Thalidomide 20 25 25 0
Rourke M, et al Leuk&Lymp, 2010;51:1779-92. (modified)
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Combination Treatment in WM
Regimen
Responses (%)
(No. pts 31-72) >PR >MR CR
Flu/Ctx 55-78 NR 0
Flu/R 82 95 5
FCR 74 79 12
Clad/Ctx 84 NR 5
Mel/Ctx/Pred 77 NR NR
Mel/Ctx/CB/Pred 74 NR 26
Ctx/R/Dex 74 83 7
R-CHOP 91 NR 9
Rourke M, et al Leuk&Lymp, 2010;51:1779-92.(modified)
Phase III Trials in WM
Yr.
pub
Regimen No. Pop. Yrs to
complete
Kyle 1999 Daily vs intermit CB 46 Upfront 22
Leblond 2001 Flu vs CAP 92 Rel/Ref 4
Buske 2009 CHOP vs R-CHOP 48 Upfront 3
Rummel 2009 R-CHOP vs BR 41 Upfront 6
Owen NYR Flu vs CB 337 Upfront 8.5
Rourke M, et al Leuk&Lymp, 2010;51:1779-92.(modified)
Event Analysis in WM Trials
• Numerous studies with small numbers of
patients; absence of randomized trials
• Patient populations not uniform: untreated, rel/ref,
no. of prior lines of treatment; age gps; risk stratification
• Lack of uniform response criteria or not given:
PR vs MR vs VGPR vs nCR
• Absence of consistent defined events: PFS, EFS, TTNT,
DOR
• Definitions of response not consistent: IgM vs M-
spike; bone marrow; nodal response
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Phase III Study of Chlorambucil vs
Fludarabine in Untreated WM
• 414 patients: 337 WM (34 MZL, 43 LPL)
• Chlorambucil 8mg/m2 x10d every 4 wks
• Fludarabine 40mg/m2 x5d every 4 wks
• Med age: 68; study required 8.5 years to complete
WM CB FLU signif
PFS 27mo 35 mo
TTF 19 mo 38 mo
5yr OS 65% 70% ns
CR+PR* 40% 51% p=.06
Owen, R. United Kingdom * CR = 3.6%
Phase II Study of Fludarabine,
Cyclophosphamide and Rituximab in Untreated
and Prev Treated WM
• 43 pts. (65% untreated); med age 65
– Flu 25mg/m2 IV d 2-4
– Cyclophos 250mg/m2 IV d 2-4
– Rituximab 375mg/m2 IV d 1
• ORR: 79%
-12% CR - 21% VGPR
- 42% PR - 4% MR
• 87.6% med TTP at med of 24.8 mos.
• Toxicity: a) 88% grade 3-4 neutropenia with
44% lasting med of 7 months
b) 3 deaths from infection
c) 2 developed myelodysplastic syndrome
Tedeschi A, et al. Cancer 2012:118:434
Randomized Phase III Trial of CHOP vs R-
CHOP in Previously Treated LPL/WM
• 64 with LPL and 48 with WM
CHOP R-CHOP
ORR 60% 91%
CR 4% 9%
TTF 22 mos 64 mos
OS* 33 mos 73 mos
* maint. Interferon-alpha
Buske C, et al. Leukemia 2009;23:153
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Phase III Randomized Trial of R-CHOP vs
R-Bendamustine as Front-line Treatment in
Indolent Lymphoma
• 513 Evaluable patients with FL, MZL,
MALT, and WM (41)
BR(22) R-CHOP(19)
ORR 95% 95%
PFS NR 35 mos*
Dec IgM ~500 ~900
Relapse 18%(4) 58%(11)
Deaths 1 4
Rummel, MJ Germany
* p=0.0024
Phase II Study of Bortezomib(Velcade) and
Rituxan as Primary Therapy for WM
• BZ 1.6mg/m2 IV d 1,8,15 for 28d cycles x6
• Rituximab 375mg/m2 IV weekly cycles 1&4
• 26 pts: CR- 1(4%) nCR-1(4%)
88%
PR- 15(58%) MR-6(23%)
• Med DOR and TTP = NR (>12mos)
• Toxicity: (grade 3 or 4) neutropenia(12%),
anemia(8%), low platelets(8%). No significant
peripheral neuropathy
Ghobrial I, et al. AmJHem; 2010;85:670
E1A10: Treatment
for Primary or
Relapsed WM
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7/17/2012
Treatment Options in WM
Investigational agents
1. Rad-001
mTOR inhibitors
2. Temsirolimus
3. Perifosine- AKT inhibitor
4. Btk inhibitors
5. Pomalidomide- immune modulator
5. Panobinostat- HDAC inhibitors
What about maintenance
Retrospective review comparing maintenance rituximab vs observation in 248
pts with rituximab-naïve WM who responded to a rituximab-containing regimen
No. PFS
Obs 162 28.6mos
Ritux 86 56.3 mos
P=0.0001
Treon SP, et al. BritJHaem. 2011;154:257
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Is Transplantation a Reasonable Option
Yes
1. Avoid toxicities of repeated drug therapy
2. Limited duration of response to salvage
therapy
3. Infrequent poor adverse cytogenetics-i.e., drug
resistance mutations
4. Low proliferative rate-i.e, less kinetically active
5. Outcomes favorable- a deep and durable
response to a single dose of myelosuppresive
therapy
Selected Largest Series of Autologous SCT in WM
Source No. Med
age
Response
>PR CR
RFS
EBMTR 158 49 85% 22% 40%
5 yr
Giralt 24 50 96% 38
OS
69%
5 yr
France 17 54 100% 12% 53%
10mo
France 2 32 56 med
32 mo
UK 9 56 100% 34% 43%
4 yr
65%
25+ mo
58%
5 yr
73%
4 yr
Modified from Gertz MA, et al. Bone Marrow Transp 2011;doi.1038/bmt.2011.175
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7/17/2012
How I Treat Waldenström
Macroglobulinemia
Waldenström Macroglobulinemia
Leonard T. Heffner, Jr., M.D.
Winship Cancer Institute of Emory University
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7/17/2012
Demographics
Age-adjusted incidence: 3.8/million persons/yr.
Amyloidosis: 8/mil
Myeloma: 40/mil
Gender: Males: 5.4/mil
Females: 2.7/mil
Race: Caucasian- 4.1/mil
African-American- 1.8/mil
WHO 2008: The Mature B-cell
Neoplasms
• Lymphoplasmacytic lymphoma
a. Immunophenotype: CD5-,CD10-,
CD19+,CD20+,sIg+
b. Bone marrow infiltration by small
lymphocytes, plasmacytoid cells, and plasma cells
c. diffuse, interstitial or nodular pattern of bone
marrow infiltration
1. Waldenström macroglobulinemia
IgM monoclonal gammopathy of
any concentration
Overall Survival
per ISSWM
Before 2000
Overall Survival
per ISSWM After
2000
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7/17/2012
Treatment Options in WM
Single Agents
• Rituximab
• Chlorambucil
• Fludarabine
• Cladribine
• Bortezomib
• Cyclophosphamide
• Thalidomide
• Bendamustine
Combinations
• Flu/Rituxan
• FCR
• R-CHOP
• R-CVP
• Benda/Rituxan
• Bortez/Rituxan/Dex
• Ctx/Dex/Rituxan
• Stem cell Transplant
Phase II Trial of Single Agent
Panobinostat(LBH589) in Rel/Ref WM
• 27 patients enrolled
• 30mg flat dose PO 3x/wk; 1 cycle = 4wks
• Med no. of cycles = 4 (1-12)
• Response: 15(60%) 6 PR, 9 MR, 9 SD
• Toxicity: Grade 3 or 4: anemia, neutropenia, low
platelets, GI bleed, elevated blood sugar.
Grade 2: low platelets, anemia, fatigue
• Protocol amended to decrease starting dose to 25mg
3x/wk
Ghobrial, I. Boston
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