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WaldenstromWaldenstromssmacroglobulinemiamacroglobulinemia
Xavier LELEUXavier LELEU
Service des Maladies du Sang
Hpital Huriez, CHRU, Lille, France
IMPRT Institut de Mdecine Prdictive
et de Reherches Thrapeutique
IFR 114
INSERM U837, quipe 3
IRCL, CHRU, Lille, France
Introduction
GhobrialGhobrial et al, BJH 2006et al, BJH 2006
Overall survival: 6.4 yearsOverall survival: 6.4
yearsDiseaseDisease--specific survival: 11.2 yearsspecific
survival: 11.2 years
Consensus panel recommendation on the clinicopathological
definition of WM
Presence of a monoclonal IgM protein, irrespective of serum
level
Underlying pathological diagnosis of lymphoplasmacyticlymphoma
using REAL/WHO criteria
ATHENS 2002
Owen et al. Semin Oncol, 2003
Other criteria
The clonal tumoral population can represent a Continuum of
lymphocytes, lymphoplasmocytes or plasmacytoid/plasma cells
Intertrabecular Infiltration on BM biopsy Other Immunological
characteristics: IgM+, CD19+, CD20+,
CD22+, FMC7+, Matutes 1 ou 2 And: CD38+(CD20+), CD25+, CD27+,
CD5, CD23, CD10-,
CD103-, CD138-(If CD138+(CD20+))
Differential diagnostics
CaracteristicsIgM MGUS MGUS and not WM
No del6qMZL CD22, CD11c strong, CD43 and CD103 possible
CD25 rarely as compared to WMOther cytogenetic abnormalities
7q-, +3, +18, et +5
B-LLCMultiple Myeloma IgM
isotypeMCL
FL
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MGUS SWM Symptomatic WM
Asymptomatic/Indolent Symptomatic
Progression of WM
NO TREATMENT TREATMENT
WM a true entity (?)
A
B
MYD88 gene alteration
(A) Sanger sequence of MYD88 exon 5 in WM patient characterized
with UPD on the 3p22 locus.
(B) UPD (uniparental disomy, loss of heterozygosity without
variation of copy number) of the short arm of chromosome 3
including MYD88 gene observed in one WM with MYD88 mutation using
SNP array
Hunter et al ASH 2012; Poulain et al. Submitted 2012
Overview of copy number alterations (CNA) and acquired
uniparentaldisomy (UPD) distribution in Waldenstroms
macroglobulinemia.
Poulain et al. Submitted 2012
Overview of acquired uniparental disomy (UPD) distribution in
Waldenstroms macroglobulinemia.
Poulain et al. Submitted 2012
(A)MCDR located on chromosome 6q21- 6q25 in 9 WM patients
characterized with deletion 6q. We alsopointed out one WM that
presented withgain on 6p in parallel with deletion 6q
Delineation of 6q MCDRs, detected by SNP arrays in WM
Poulain et al. Submitted 2012; Braggio et al. Cancer Res.
2009
(B) Rq DNA PCR quantification confirmed A20/TNFAIP3 gene
deletionin one WM with deletion 6q as comparedto 5 patients with
absence of A20deletion. Interestingly, none of the patient
demonstrated homozygousdeletion of A20/TNFAIP3.
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CytogeneticCC / FISH Incidence rate (%)
Abnormal CC 35 58
Deletion 6qMonosomy 6
CC / FISH 20 60FISH 1
Trisomy 4 (partial total) CC / FISH 12 20Deletion 13q14 CC /
FISH 2 16Deletion 11q23 (ATM) FISH 8Deletion 17p (P53) CC / FISH 7
15Translocation /
Rearrangement en 14q32 / IgH
CC / FISH 0 5
Trisomy 12 CC / FISH 0 10Trisomy 5 ; 18 ; 3q ; 14 CC / FISH 0
10Monosomy 7 CC / FISH 0
Terre C et al. Leukemia 2006
Overview of genomic alterations distribution, CNA and UPD,
detected by SNPa, in SWM versus ASW.Black boxes represent 3
abnormalities, Grey boxes represent 3 abnormalities, light grey
boxes represent from 1 to 2 abnormalities. Finally the remaining
white boxes represent no genomic abnormality. The 2 grey boxes with
vertical bars correspond to patients with telomeric UPD.
Poulain et al. Submitted 2012 Herbault et al. Submitted 2012
ASW SW
Overview of genetic alterations, using GEP, in SWM versus
ASW.
Identifying SWM from ASWM
Resveratrol
miRNA in WMA B
Roccaro et al, Blood 2008
Targeting the PI3K and NFKB pathways in WM Rle du
microenvironnement tumoral ?
WM
Adamia et col, Blood 2009Ngo et al, Blood, 2008
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Novel agents in WM
Irene GhobrialDana Farber Cancer Institute
Harvard Medical SchoolBoston, MA
Kirsch Lab for WM
Genetic Basis, Pathogenesis and Therapy of Waldenstrms
Macroglobulinemia
Steven P. Treon.Bing Center for WM
Dana Farber Cancer Institute Harvard Medical School
Prognostic index: ISSWM
Risque Score Total Evts MedianSurvival
0.95 CI< 0.95 CI>
Low 0 or 1 (exceptage)
155 (27%) 38 142.5 120.3 195.7
Intermediate Age>65or 2
216 (38%) 87 98.6 81.7 137.2
Hih 3 or more 203 (35%) 134 43.5 36.6 55.1
Age >65
hb3 mg/L
Plt70 g/L
Targeting WM-Mast Cell Interactions in
Waldenstrmsmacroglobulinemia
Mast Cells Lymphoplasmacytic cells
Soluble CD27CD70
APRIL
CD40L
SGN-70
Anti-BCMA, TACI mAb
CD52Campath
Anti-CD40L mAb
GleevecCD117
Stone MJ and Pascual V. Haematologica 2010
Clinicopathological Manifestations of Waldenstrms
macroglobulinemia
Adenopathy, SM 1.8 CP (72%)>4.0 CP (6%)
IgM Neuropathy (20%)Autoimmune D/O (15%)Cryoglobulinemia (
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Consensus panel recommendations for Consensus panel
recommendations for initiation of therapy in WM.initiation of
therapy in WM.
A high A high IgMIgM level is not by itself an indication to
initiate level is not by itself an indication to initiate
therapy.therapy.
HctHct
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Combination Therapy with Rituximabin WM
No. of patients Regimen
Major RR (%)
Response duration (months)
WMCTG1 43 Fludara/rituximab 82 NR Weber2
17 Cladribine/cyclophosphamide/
rituximab 94 NR Hensel3
17 Pentostatin/cyclophosphamide/
Rituximab 90 NR Dimopoulos4
34 Dex/cyclophosphamide/
Rituximab 78 NR Hunter5 13 CHOP/rituximab 77 NR GLSG6 72
CHOP/rituximab (vs. CHOP) 94 NR
1Treon, et al. ASH 2004; 2Weber DM, et al. Semin Oncol 2003;
3Hensel et al, ASCO 2004;4Dimopoulos MA, et al. ASH 2004; 6Hunter,
et al. ASH 2004; 6Buske et al, ASH 2004.
Treon et al. Blood 2006; Vijay and Gertz. Blood, 2007.
Known limitations with the use of Nucleoside
Analogues
AutoAuto--immune diseasesimmune diseases
InfectionsInfections
LongLong--term toxicity on stem cells.term toxicity on stem
cells. Potential long term side effectsPotential long term side
effects
Transformation into high grade B cell NHLTransformation into
high grade B cell NHL
(Richter Syndrome)TherapyTherapy--related MDS/AMLrelated
MDS/AML
Long term Side Effects in literature in NA treated WM
3033272-cdaDelannoy. 1999
00-252-cdaBetticher. 1997
00-222-cdaHellmann. 1999
0041182FDhodapkar. 2001
053471FLeblond. 1998
25
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10
52
18
20
Follow-up(Months)
Protocol N TransformationN
MDS/AMLN
Liu et al. 1998 2-cda 20 0 0
Foran. 1999 F 19 0 0
Leblond. 2001 F vs CAP 92 3 4
Lewandowski. 2002 F (resistant to 2cda) 6 0 0
Weber. 2003 2-cda -/+Cy-Rit-Pred 90 0 0
Tamburini. 2005 F+Cy 49 2 2
Leleu et al. JCO
Survival from Long term Side Effects
nana36/181 (20)36/181 (20)No complicationNo complication
0.0010.0014 (44 (4--5)5)3/3 (100)3/3
(100)MDS/AMLMDS/AMLNSNSnana2/9 (22)2/9
(22)TransformationTransformation
pMedian Median (range, years)(range, years)
O/N O/N (%)(%)
From onset of NA
TransformationMDS/AMLUntreated
Leleu et al. JCO
Thalidomide and Rituximab in WM :Responses
N=25 patients; 23/25 received intended therapy Of evaluable
patients: CR= 1 ( 4.0%) PR= 15 (65.0%) MR= 2 ( 8.0%) SD = 1 (
4.0%)
Median follow-up of 19 months, 12/18 responding patients remain
in remission.
Median time to best response = 18 months
69.0% 78.0%
Treon et al, ASH 2005
Revlimid and Rituximab in WM: Responses N=12 patients; 4 pts
prematurely off study due to
toxicity from CC-5013 (n=3) and rituximab (n=1)and therefore not
evaluable for response;
PR = 3 ( 25.0%) MR= 4 ( 25.0%) SD = 1 ( 16.6%)
Median follow-up of 7 months* Included 2 patients with bulky
adenopathy/SM
37.5% 87.5%
Treon et al, ASH 2005
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Revlimid induced anemia in WM
Decreased Hct observed in 10/12 pts following first week of
Revlimid monotherapy;
Median Hct decrease: 3.9% (31.9% to 28%; p=0.003)
No evidence for hemolysis; concurrent thrombocytopenia observed
in 1 pt
4 patients hospitalized for anemia related complications (Afib,
syncope, CHF)
20
22
24
2628
30
3234
3638
1 2 3 4 5 6 7 8 9 10 11 12
Pre-Rx
Post-Rx
Treon et al, ASH 2005
Pomalidomide
Essai de phase II Mayo Clinic 60 patients Pomalidomide : 2
mg/jour en continu per os Dexamthasone : 40 mg J1, 8, 15, 22
Rponse: 63% de rponse globale (33% CR + VGPR)
Next
Bortezomib in MW
Rech/Refr: Rechute et rfractaires, R: Rituximab; D:
Dexamthasone
Studies Protocol N CyclesResponse
%RC%
TTPmonths
DimopoulosHematologica 2005
Bortezomib (Btz) Rech/Refr
10 6 60 - >11
WMCTG 03-248Treon et al, CCR 2007
BtzRech/Refr
27 6 85 - 7.9
NCI-CanadaChen et al, JCO 2007
Btz1ere Line 27 6 78 0 16.3
WMCTG 05-180Treon et al, CCR 2007
R-Dex Btz1ere Line
23 8 96 21 >24
DFCI 2010Ghobrial et al, JCO 2010
R- BtzRech/Refr 37 4 81 5 16.4
BDR Europen 1ere Line 100 5 - - -
WM2 Rech/Refr 30 6 - - -
Immunoproteasome
Roccaro et al, Blood 2010
Survie - MTT
Resveratrol
Novel agent in WM
Bendamustine + Rituximab
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Back to reality
IgM
Definition of WM (Owen et al. Semin Oncol 2003): Presence of a
monoclonal IgM protein, irrespective of serum level = serum IgM
level is not sensitive enough to differentiate WM from MGUS
Criteria for initiation of therapy (Treon et al. Blood 2006): A
high IgM level is not by itself an indication to initiate therapy =
= IgM does not correlate to tumour mass
Response criteria (Kimby et al. Clin Lymph Myelom 2006): IgM is
part of response criteria while serum IgM level is not correlated
to tumour mass
Serum IgM flare (Ghobrial et al. Cancer 2004): increase serum
IgM level post rituximab = progression or flare + need for
plasmapheresis for some patients
Delayed response (Kimby et al. Clin Lymph Myelom 2006):
following nucleoside analogues
IPSS WM score (Morel et al. Blood 2009): IgM >7.0g/dL is of
adverse prognostic impact = IgM is not a sensitive prognostic
marker
Biologic properties: IgM has a prolonged half-life, IgM
clearance from the serum takes about 3 weeks= not sensitive for
early response
Measurement of IgM: IgM M-spike by SPEP or IgM by nephelometry =
none are the exact concentration of IgM
IgM is the compelling marker of Waldenstrom, BUT
MedianeMediane sFLCsFLC estest superieursuperieur dansdans la WM
compare la WM compare aux aux IgMIgM--MGUSMGUS
Median (range) Involved Median (range) Involved sFLCsFLCWM. 36.3
mg/L (16WM. 36.3 mg/L (16--141)141)>60mgL 39.7% >60mgL
39.7%
IgMIgM MGUS. 20 mg/L (16MGUS. 20 mg/L
(16--30)30)P=0.0003P=0.0003
Abnormal Abnormal sFLCsFLC K/L RatioK/L RatioWM. 76.5% WM.
76.5%
IgM MGUS. 23.5% IgM MGUS. 23.5% p40 0.060.06
4.2(0.94.2(0.9--19.1)19.1)
>70>70Age(yrsAge(yrs)) >65 >65 HbHb ((g/dLg/dL)
)
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Elevated sFLC correlated to Shorter time to first treatment
R. Itzykson, V. Leblond, et al 2008
sFLC a new marker in WM
But not considered better than M-spike using SPEP
IgM Hevylite a potential new marker in WM
Elevated IgM HLR correlated to Shorter time to first
treatment
0 factors
1 factor
2 factors
3 factors
pmedian, b2m >5,5mg/L, abnormal LDH
The study was conducted in a series of 86 WM patients [71 at
diagnosis and 15 at relapse], of whom 10 patients with WM were
homogeneously treated at front line in the multicentric phase 3
trial, chlorambucil vs fludarabine that included WM.
All serum samples were collected prior to treatment and were
kept frozen since collection. Responses included partial response
(PR) or better, confirmed at 2 consecutive values.
Hevylite, a Novel M-component based Biomarkers of Response to
Therapy and Survival in Waldenstrom Macroglobulinemia (WM)Salomon
Manier and Julie Lejeune et al. ASH 2011,
The IgMi HL values correlated well with the M-spike (intra class
correlation (icc) coefficient = 0.48 [0.31; 0.60]), and with the
IgM neph (icc = 0.74 [0.52; 0.86]), right panel of the figure.
The IgM HLR also correlated to the M-spike (r=0.44, p
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The response rate was 60% at 14 months and 40% were stable
(including minor disease) on the 10 WM homogeneously treated.
The response rates and stable diseases were 40% and 60% using
IgMneph, and 50% and 50% using IgMi HL. The concordance between
IgMi HL with M-spike was quite good (k=0.61, p=0.13).
The median time to response was similar across the 3 IgM
techniques, 10.4 months as per protocol as compared to 12.9 months
with IgMneph, and 11.8 months using IgMi HL.
With a median follow-up of 45.7 months [40.7; 53.9], 50% of
patients had a progression in the protocol, with a median time to
progression (TTP) of 25.2 months. The median TTP was similar with
IgMi HL and IgMneph, 23.1 months and 13.8 months (p=NS). Similar
results were observed with the median time to next treatment, 4.43
months, 10.9 months and 10.9 months, respectively (p=NS).
Correlation between IgMi HL and responses/progression Summary WM
an Orphan Hemopathy regarding how poorly we know the
disease == Understanding the pathogenesis of WM cells and the
interaction of WM cells with the BM microenvironment== Preclinical
development of therapeutic agents
Drugs tested to date: bortezomib, perifosine, RAD001,
Enzastaurin, NPI-0052, PR-171, AZD0530, LBH-589, BEZ235, PKC412,
IGF-1 inhibitors, AMD3100, VLA-4 inhibitors
== But none appeared remarquable
Future challenge finding the best combinations that target the
critical pathways regulating WM growth and resistance
Future challenge to have better prognostic markers and
IgMmeasurement
Thanks a lot
