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

Fortbildningsdagarna 2-4 oktober 2013 Sundsvall

Disclosures Eva Kimby

• Advisory board : Celgene, Pharmacyclics, Gilead, Jansen, Teva

• Föreläsararvode: Roche, Mundipharma, Jansen

• Forskningsstöd: Pfizer, Roche

Professor Jan WaldenströmActa Med Scand 1944

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

Sjukdomssymptom

• Anemi/trombocytopeni• Relativ anemi (hög plasmavolum)

• Lymfadenopati

• B-symptom

• Hyperviskositet • Kryoglobulinemi

• Cold agglutinin disease (CAD)

• Neuropati• Amyloidos

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”

WM – diagnos kriterier

Benmärgsinfiltration– Små lymfoplasmacytiska

lymfocyter– Intertrabekulär växt – Typisk immunfenotyp

Biopsi med immunfärgning (IHC) Aspiration och flödescytometri

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.

• May have prognostic significance more aggressive clinical features

FISH: 6q deletion (gen: BLIMP-1)

6q21 deletion

-10% Konventionell cytogenetics

34% med FISH

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%)

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

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

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”

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

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)

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

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

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

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

• 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

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?

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)

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)

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

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.

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?

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

.

Single-agent therapy

Single-agentchlorambucil

Low Ig M and cytopenias

Old age and slow progression

.

Single-agentrituximab

High Ig M - risk of “flare” Plasmapheresis

Plasmapheresis for removal of IgM

Hyperviscosity-related symptoms

Prevention Reduce IgM before rituximab

Reversing (rapid effect needed) Headache, breathlesness Retinopathy Venous dilatation Bleeding Anemia

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.

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 %

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

Survival

OS 5 years • Chlorambucil: 61.4% [52.9;71.3] • Fludarabine: 70.3% [62.7-78.8]

(p=0.04)

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

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

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.

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

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

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

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

WM therapy

Single-agentchlorambucil

Low Ig M and cytopenias

Old age and slow progression

.

Single-agentrituximab

High Ig M ....risk of “flare”

Plasmapheresis

DRCBortezomib

Proposed European trial:

DRC versus DRC+ bortezomib sc

• 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

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

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

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

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

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

Delayed response

Conversion from PR to CR

PR

CR

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

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

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

Definition- Infiltration of malignant lymphoplasmacytoid/WM cells

in the central nervous system.

Bing Neel syndrome

Cerebrospinal fluid

Involved?

Intracerebral tumour

Meninges (dura & arachnoid)

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

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

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.

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

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

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

{Giampaolo Merlinigmerlini@unipv.it

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

AL amyloidosis associated with IgM monoclonal protein: a distinct clinical

entity

6% of AL amyloidosis

4% have AA amyloidosis

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

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

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

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