waldenström´s makroglobulinemi eva kimby m.d. ph.d professor karolinska institute center of...
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Waldenström´s makroglobulinemi
Eva Kimby M.D. Ph.D
Professor
Karolinska Institute
Center of Hematology Karolinska University Hospital
Stockholm, Sweden
Fortbildningsdagarna i hematologiLinköping 2 oktober 2014
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Fortbildningsdagarna 2-4 oktober 2013 Sundsvall
Disclosures Eva Kimby
• Advisory board : Celgene, Pharmacyclics, Gilead, Jansen, Teva
• Föreläsararvode: Roche, Mundipharma, Jansen
• Forskningsstöd: Pfizer, Roche
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Professor Jan WaldenströmActa Med Scand 1944
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Incipient myelomatosis or essential hyperglobulinemia with fibrinogenopenia • Oronasal bleeding
• Lymphadenopathy/enlarged lymphnodes
• Anemia and thrombocytopenia
• Hyperviscosity
• Elevated erythrocyte sedimentation rate (SR)
• Lymphoid cells and mast-cells in bone marrow
Waldenström J. Acta Med Scand 1944
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Sjukdomssymptom
• Anemi/trombocytopeni• Relativ anemi (hög plasmavolum)
• Lymfadenopati
• B-symptom
• Hyperviskositet • Kryoglobulinemi
• Cold agglutinin disease (CAD)
• Neuropati• Amyloidos
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WM – diagnos kriterierInternationaI Workshop on WM Athens 2002* Paris 2004 Stockholm 2008 Venice 2010 Newport 2012 London 2014
*Owen RG, et al. Clinicopathological definition of WM Semin Oncol. 2003Athens 2002
Enl WHO-klassifikationen 2008:“WM is a lymphoplasmacytic lymphoma”
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WM – diagnos kriterier
Benmärgsinfiltration– Små lymfoplasmacytiska
lymfocyter– Intertrabekulär växt – Typisk immunfenotyp
Biopsi med immunfärgning (IHC) Aspiration och flödescytometri
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WM immunofenotyp
Positivitet för
Light chain restricted IgM
CD19, CD22, (dim), CD25, CD27 och CD52
CD5 positivitet i 5-20% av fallen
Negativitet för
CD10, CD23, CD103 och CD138 En subklon, främst plasmaceller , är CD20-negativ och CD138-positiv
Paiva B, et al. Leukemia. 2014 Jan;28(1):166-73.Multiparameter flow cytometry for the identification of the WM's clone inIgM-MGUS and WM: new criteria for differential diagnosis and risk stratification.
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• May have prognostic significance more aggressive clinical features
FISH: 6q deletion (gen: BLIMP-1)
6q21 deletion
-10% Konventionell cytogenetics
34% med FISH
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M-spike in serum required for WM
Splenomegaly+IgM spike
Differential diagnosis: Splenisk marginal zons lymfom CD22+ and CD11c+
Irrespective of IgM concentration
MYD88 mutations status till hjälp vid differentiering från• Marginal zons lymfom (7-10%)• IgM- myeloma • KLL med plasmacytisk
differentiering (4%)
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MYD88 L265P mutation in WM
Whole genome sequencing of lymphoplasmacytic cells
from 30 WM-pts (paired normal tissue sequencing in 10 pts)
A recurring sequence variant on chr 3p22.2 identified with
a single nucleotide change in the myeloid differentiation primary response (MYD88) gene
Sanger sequencing confirmed the MYD88 L265P variant in tumor samples from 26 patients
Treon SP, Xu L, Yan G et al. NEJM. 2012;367826-33
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Allele-specific PCR i blod:Circulating WM-cells –• High concordance BM-blood if CD19+ selected cells are used for allele-specific PCR
patient-friendly, but not specific
Metod för MYD88 L265P
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IgM MGUS Asymtomatic WM Symtomatic WM
M-component, type IgM < 30g/L, and/or
M-component, type IgM ≥30g/L, and/or
M-component, type IgM ≥30g/L, and/or
LPL in BM <10% LPL in BM ≥10% LPL in BM ≥10%
No WM related symtom* No WM related symtom
WM relaterad symtom or end-organ -failure*
Diagnostic criteria (Mayo):
*B-symtom, anemia, hyperviscosity, lymphadenopathy/hepatosplenomegaly
MYD88 L265P vid IgM MGUS: 10-87%Vid förekomst av mutation större risk för “malignant evolution”
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C-X-C chemokine receptor typ 4 (CXCR4)
Hunter Z et al, Blood 2014
Somatisk ”WHIM-syndrome like” mutation avCXCR4 hos 27% av WM patienter
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The CXCR4 plays a role for cell trafficking of hematopoietic stem cells and also for clonal B-cells• CXCR4 WHIM mutation is related to high tumor
proliferation and extramedullary dissemination and decreased survival in WM patients
A prognostic marker?
Somatic ”WHIM-syndrome like” CXCR4 C1013G mutation: 20-30 % of WM cases, thus not a diagnostic marker
C-X-C chemokine receptor type 4 (CXCR4)
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IgM-MGUS
• 15% to 20% of all MGUS
• Distinct biological and clinical entity, different from IgG-IgA MGUS for nature and rate of progression:Evolution into lymphoma (WM) or other related
disordersHigher risk of progression than IgG-IgA MGUS
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MGUS: risk factors for evolution
N Isotype Risk Factors
Cesana, 2001 1,014 All BM infiltration, BJ, High ESR,
Polyclonal Ig Reduction
Gregersen, 2001 1,247 All BM infiltration, BJ, Polyclonal Ig
Reduction, MC size
Kyle, 2003 213 IgM MC Size, Serum Albumin
Rakjumar, 2005 1,384 All Abnormal Free Light Chain Ratio, MC
size, IgA-IgM isotype
Baldini, 2005 217 IgM MC Size, Hemoglobin, Male sex
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Asymptomatisk Waldenström:
Any size of serum IgM MC Any degree of BM-LP infiltration at BM biopsy No symptoms attributable to IgM MC/tumour infiltration No evolution to overt LPD for at least 12 months from
diagnosis
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IgM-MGUS och A-WM
Risk faktorer för evolution:
Hb nivå och serum MC
Uppföljning:
Var 4-6 månad : Klinisk undersökning
Hb och serum Ig M
OBS! Tänk på sekundära problem;
neuropati, amyloidos
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• Blodstatus • Elektrolytstatus + albumin + urat • Leverstatus + LD • Beta-2-mikroglobulin • Serum protein elektrofores med immunfixation (termos) • Hepatit C serologi
• Dygns samling av urin för protein elektrofores
Bildundersökning• Datotomografi hals, thorax, buk• Rtg pulm vid övre luftvägssymtom eller tidigare infektion
Histologisk undersökning • Benmärgsbiopsi och aspiration (morfologi, immunfärgningar, flödesytometri)
Utredning vid misstänkt Waldenströms makroglobulinemi
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Fler prover:• DAT = direkt antiglobulin test
– ev prov i termos för köldagglutininer• Kryoglobuliner (vid misstanke om kryoglobulinemi,
prov i termos) • Serum viskositet (vid hyperviskositetsymtom eller
hög M-komponent >40g/L)• P-FLC = fria lätta kedjor?
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Symtom orsakade av benmärgsinfiltration• Trötthet, yrsel pga anemi• Blödningar, hud, näsa, blåmärken pga trombocytopeni• Infektionskänslighet pga leukopeni och hypogammaglobulinemi
Symtom orsakade av M-komponent• Huvudvärk, synrubbningar, blödningar, dyspné, pga hyperviskositet• Njursvikt, Raynaudfenomen, hudutslag, led- muskel-smärta, • neuropati (pga Kryoglobulinemi typ I och II)
• Hemolytisk anemi pga autoantikroppar (I-antigen)• Trombocytopeni pga autoantikroppar
• Perifer neuropati pga autoantikroppar • mot MAG (myelin-associerad glycoprotein) eller GM1 (ganglioside M1)
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Andra symtom • Lymfknuteförstoring • Hepatosplenomegali • Hud (bullösa hudutslag, papuler, Schnitzler syndrom) • Gastrointestinala (diarré, malabsorbtion) • Njurar (proteinuri, njursvikt) • Trötthet, viktnedgång, macroglossia och dysfunktion av involverade organ pga infiltration av amyloida fibriller
• CNS påverkan (Bing-Neels syndrom)
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När ska behandling inledas?
Watchand wait
Serum IgM i sig är inte en behandlingsindikation
• Anaemia/trombocytopenia • Adenopati/organomegaly• Hyperviskositet• Kryoglobulinaemi• Köld agglutinin• Neuropati• Amyloidos• Transformation
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The International prognostic Scoring System for WM (ISSWM)
Risk group Adverse covariates* 5-year survival
Low1
(except age) 87%
Intermediate2
Or only age > 65 years 68%
High > 2 36%
*Adverse covariates: IgM > 70 g/l Age > 65 years β2M > 3mg/l Hb ≤ 11.5 g/dl Plts ≤ 100 x109/l
Morel P, et al. Blood 2009; 113:4163–4170.
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MYD88 L265P as a prognostic marker?
WM-cells harboring the L265P mutation, exhibit constitutive signaling leading to the hyperactivation of NF-κB
WM patients without the mutation have worse prognosis?
Level of mutation of importance?
Quantitative PCR?
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Treatment options for WM
Single agentsRituximab (standard or extended schedule)Cladribine/fludarabineChlorambucilBortezomib
Rituximab-based combinationsR + fludarabine/cladribine/pentostatin +cyclophosphamide
R + bendamustine R + cyclophosphamide + dexamethasone (DRC)R+ bortezomib
Treatment recommendations by the 4th International Workshop on WMDimopoulos MA, et al. J Clin Oncol 2009; 27:120–126Updated at last International Workshop on WM, Newport 2012, in manuscript
.
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Single-agent therapy
Single-agentchlorambucil
Low Ig M and cytopenias
Old age and slow progression
.
Single-agentrituximab
High Ig M - risk of “flare” Plasmapheresis
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Plasmapheresis for removal of IgM
Hyperviscosity-related symptoms
Prevention Reduce IgM before rituximab
Reversing (rapid effect needed) Headache, breathlesness Retinopathy Venous dilatation Bleeding Anemia
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One randomized trial: WM1 Final results ASH 2011
WM 1- prospective randomized trial
Previously untreated WM (339), MZL(37) and LPL
Median age: 68 years (40-89)
NCRI Lymphoma Clinical Studies Group (UK) Groupe d’Etudes sur la Leucémie Lymphoïde Chronique et la maladie de Waldenström (France)
Leblond V et al. J Clin Oncol. 2013. 20;31(3):301-7.
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WM 1- prospective randomized trial 07/01-12/09 (n=414)
Chlorambucil: 8 mg/m2 x10 days/28 days (max 12 cycles)
CR+PR: 38.6%
Oral Fludara: 40 mg/m2 orally x5 days/28 days (max 6 cycles)
CR+PR: 47.8 %
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WM1 progression-free survival
0 20 40 60 80 100
0.0
0.2
0.4
0.6
0.8
1.0
Months
PF
S
FAMPCHB
N Median (Months)
Fludarabine 207 36.3
Chlorambucil 207 27.1
P=0.01
Factors influencing PFS Negatively: Clb, albumin<35g/l, ptls<100, age>70y
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Survival
OS 5 years • Chlorambucil: 61.4% [52.9;71.3] • Fludarabine: 70.3% [62.7-78.8]
(p=0.04)
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CD20 + tumor cells Rituximab of value?
The addition of R to front-line therapy with CHOP in Lymphoplasmacytic lymphoma (including WM)• A higher response rate • Longer time to treatment failure
Buske C, et al. Leukemia. 2009;23:153-61
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Fludarabine/combinations FC and FCR good efficacy
• Hematologic toxicities Grade 3/4
NeutropeniaThrombocytopenia
• Infections• Transformation • MDS/AML
Purinanalogues No indication in younger patients if autologous ASCT is a later alternative
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Other less toxic combinationsDexamethasone + rituximab + cyclophosphamide (DRC)1
Cyclophosphamide+prednisone+rituximab (CP-R)2
Bendamustine + rituximab3
1. Dimopoulos MA, et al. J Clin Oncol 2007; 25:3344–3349.2. Ioakomidis L et al, Clin Lymphoma Myeloma. 2009 Mar;9(1):62-63. Rummel MJ. Lancet. 2013 Apr 6;381(9873):1203-10.
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Dimopoulos et al. J Clin Oncol 2007; 25: 3344-9
• CR = 7%• PR = 67%• MR = 9%• SD = 8% • PD = 8%
ORR = 83%
Median time to 50% IgM reduction: 4.1 mo (range 0.7–14)
IgM flare: 32% (>25% IgM increase in 11% of patients)
DRC regimen (n=72)
Dexamethasone 20 mg IV day 1Rituximab 375 mg/m2 IV day 1Cyclophosphamide 100 mg/m2 PO BID days 1–5courses repeated every 21 days X6
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Rummel MJ et al.: Blood 2009.114: 168 (abs#405). Lancet. 2013 Apr 6;381(9873):1203-10
R-Benda vs R-CHOP: Progression free survival
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Other drugs• Proteosominhibitors = bortezomib
carfilzomib
• Everolimus decrease in serum IgM level, but increase in BM involvement
• Lenalidomide unclear anemia
• Carfilzomib, Rituximab and Dexamethasone (CaRD) Highly active neuropathy sparing approach for proteasome-inhibitor based therapy in WM
Treon et al, ASH 2013 , abstract 757
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Bortezomib Multicenter protocol (BDR) Cycle 1 (21-days): bortezomib 1.3 mg/m2 on days 1, 4, 8, 11
Cycles 2-5 (35-days): bortezomib 1.6 mg/m2 d 1,8,15, 22
Rituximab 375 mg/m2 + Dexa 40 days 1, 8, 15, 22 (8
infusions R)
..
Reference
CR PR MR SD PD ORR
Dimopoulos et al Blood 2009; 114: 2886a
3% 52% 16% 13% 16% 71%Dimopoulos et al. *Blood. 2013 Nov 7;122(19):3276-82
3% 58% +7% VGPR
17% 9% 11% 85%
* Progression-free survival: 42 months
Peripheral neuropathy in 46% (grade ≥3 in 7%) 8% discontinued bortezomib due to neuropathy
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WM therapy
Single-agentchlorambucil
Low Ig M and cytopenias
Old age and slow progression
.
Single-agentrituximab
High Ig M ....risk of “flare”
Plasmapheresis
DRCBortezomib
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Proposed European trial:
DRC versus DRC+ bortezomib sc
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• MYD 88 L265P - trigger NFκB signaling by direct
interaction with BTK in WM cells
• Ibrutinib 420mg/dag under 2 år, eller tills progress eller toxicitet
• Mutations MYD88 L265P hos 49/43 (93%) WHIM-like CXCR4 hos 10/40
(25%) MYD88
Treon et al, ASH 2013, abstract 251
Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib in patients with relapsed/refractory WM
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Ibrutinib in relapsed/refractory WM
Response impacted by mutations in CXCR4
but not in MYD88
Major response rate:
77% for patients with wild-type CXCR4 vs
30% in those with WHIM-like CXCR4 mutations (p=0.018)
Decreases in serum IgM M-spike (p=0.012) and improvements in hemoglobin (p=0.058) greater in patients with wild-type CXCR4
Treon et al ASH 2013, abstract 251
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PI3K inhibitors
• GS1101/idelalisib inhibits PI3K-delta – a role in lymphocyte activation and mast cell
degranulation• Rituximab and alkylating agent-refractory iNHL• 125 enrolled patients: 58% FL, 22% SLL, 12% MZL,
8% LPL/WM
Ajay Gopal et al ASH 2013,abstract 85
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PI3K-Delta Inhibitor Idelalisib in Patients With Double Refractory Indolent B-Cell Lymphoma
• ORR: 57% , LPL/WM - ORR :80%• ORR consistent across all subgroups, regardless
of number of prior regimens, refractoriness to bendamustine or tumor bulk
• Short median FU 9.4 months
Gopal G, Salles G, et al 2013, abstract 85
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Relapse-studier hos oss: Indolent lymphoma
Randomiserad, double-blind, placebo-controllerad Fas 3 Studier
Idelalisib i kombination med Bendamustin och rituximab (BR) (Gilead Study
125) eller med
Rituximab alone (Gilead Study 124)
Patienter som ej är aktuella för högdos kemoterapi/SCT
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Recommendations on
Response Criteria
WM Consensus Panel :
Weber D et al. Semin Oncol. 2003;30:127-31.
UpdatesKimby E, et al. Clin Lymphoma Myeloma. 2006:6:380-3.
Owen RG, et al. Br J Haematol. 2013;160:171-6
Timepoint for response evaluation is crucial
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Delayed response
Conversion from PR to CR
PR
CR
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Moderna response kriterier
Allele specific PCR for MYD88 L265p in CD19+ selected blood cells?
NO: Quicker and greater reduction of tumor-cells in blood than in BM, why BM is required
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Schnitzler Syndrom
Monoclonal IgM gammopathy without features of lymphoproliferative disease• ~ Chronic Uticaria- vascular reaction of the upper dermis
(wheals, severe itching)
• ~Bone pain• ~Intermittent fever• ~Arthritis• ~Enlarged lymph nodes• ~Hepato/splenomegali• ~Elevated ESR
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Bing-Neel syndrome
1936 Jens Bing and Axel Neel reported the association hyperglobulinemia and CNS symptoms
• paresthesia, headache, gaitproblems, paralysis
Brain infiltration: plasmacells and lymphocytes
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Definition- Infiltration of malignant lymphoplasmacytoid/WM cells
in the central nervous system.
Bing Neel syndrome
Cerebrospinal fluid
Involved?
Intracerebral tumour
Meninges (dura & arachnoid)
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Neurologic symptoms in patients with the "Bing-Neel Syndrome"
Cases of hyperviscosity, malignant transformation, vasculitis, and ophthalmologic manifestations excluded
Diagnosis: CSF, imaging and histopathology:
(1) lymphoplasmacytoid/ic cells infiltrating the CNS
(2) a non-cellular form: IgM deposition
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BNS diagnostic work up
• Eye examination; fundoscopy• MRI brain and spine
– With contrast enhancement studies– FLAIR / diffusion weighted images
• CSF analysis– Cell count (lymphocytosis)– Morphology– Flow cytometry– MYD88, IgH rearrangement– Total protein– Protein electrophoresis and immunofixation– Biobanking (chemokines and interleukins)
• Brain biopsy if possible
Novel diagnostic approaches in BNSK. Ina Ly et al, IWWM 2010 proceedings
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Bing-Neel syndrome (BNS) –Orbital involvement - case
• Orbitopathy and optic neuropathy
• Orbital biopsy, cerebrospinal fluid studies, and neuroimaging can confirm a diagnosis of BNS involving the orbital soft tissues, optic nerves, meninges, and cauda equina
Stacy RC, Jakobiec FA, Hochberg FH, Hochberg EP, Cestari DM.
J Neuroophthalmol. 2010 Sep;30(3):255-9.
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Hydrocephalus in BNS
• Proliferation of a small clone of lymphoma cells in the subarachnoid room
• might give problems with resorption of spinal fluid and a risk of development of normotensive hydrocephalus
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Methotrexate• 3 g/m2
Cytarabine• Intermediate to high
dosing 2 g/m2
High dose intensive schemes as used in CNS DLBCL
Purine analogues• Fludarabine• Cladribine
• Pass blood brain barrier
• Dose related neurotoxicity
• 6 cases reports described so far
CNS penetrating chemotherapy
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Response• Hematological
– 3 CR, 1 PR
• CNS (MRI/CSF)– All CR; normalisation MRI and CSF
• Clinical – 2 complete response, in 2 patients mild
symptoms persisted (paresthesias, double vision)
Follow up (6 months – 9 years)• 1 patient with 2 relapses, second relapse CNS
only
Use of fludarabin in 4 BNS patients
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{Giampaolo [email protected]
Diagnosis and workup of the patient with Ig M monoconal gammopathy - amyloidosis
8th International Workshop on Waldenström’s Macroglobulinemia
August 14-16, 2014 London, United Kingdom
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AL amyloidosis associated with IgM monoclonal protein: a distinct clinical
entity
6% of AL amyloidosis
4% have AA amyloidosis
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Palladini & Merlini Clin Lymphoma Myeloma Leuk. 2013;13:244-6Terrier et al, Medicine, 2008;87:99-109
Survival of patients with IgM-related AL according
to NT-proBNP and albumin: a distinct staging system
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Impact of bortezomib based regime on overall survival
Treatment and outcome of 263 patients with IgM-related AL amyloidosis
Roussel et al, ASH 2012 Annual Meeting Abstract 4074*Palladini et al, Clin Lymphoma Myeloma Leuk. 2011 ;11:143-5.
*
Given the rapid activity in patients with non-IgM AL amyloidosis and in WM, bortezomib-based therapy could be used in carefully selected patients.
Dimopoulos et al, Blood. 2014 Jul 15
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Sammanfattning: Waldenström macroglobulinemia
Biologi: MYD88 och CXCR4-mutationer Terapi:
Rituximab-baserade kombinationsbehandlingar Bortezomib ger snabbt svar
New agents BTK inhibitors, new proteasome inhibitors PI3K inhibitors, Bcl-2 inhibitors, antibodies (PD-1,
CD38, SLAMF-7)
Risk-benefit ISSWM och CXCR4 för “risk-adapted” terapi
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Tack till alla kollegor ansvariga för Svenska Nationella riktlinjer för behandling av Waldenströms makroglobulinemi
Lena Brandefors, Norra Magnus Svensson, Uppsala-Örebro Monica Sender, Västra Elena Holm, Lund-Malmö Lotfi Kourosh, Linköping Magnus Björkholm, Elin Helgadottir, Sigurdur
Kristinsson, Eva Kimby, Stockholm