Waldenström´s makroglobulinemi Eva Kimby M.D. Ph.D Professor Karolinska Institute Center of Hematology Karolinska University Hospital Stockholm, Sweden Fortbildningsdagarna i hematologi Linköping 2 oktober 2014

Disclosures Eva Kimby Advisory board : Celgene, Pharmacyclics, Gilead, Jansen, Teva Föreläsararvode: Roche, Mundipharma, Jansen Forskningsstöd: Pfizer, Roche

Professor Jan Waldenström Acta 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 Lymfadenopati B-symptom Relativ anemi (hög plasmavolum) Lymfadenopati B-symptom Hyperviskositet Kryoglobulinemi Cold agglutinin disease (CAD) Neuropati Amyloidos

WM – diagnos kriterier InternationaI 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 Negativitet 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 in IgM-MGUS and WM: new criteria for differential diagnosis and risk stratification.

FISH: 6q deletion (gen: BLIMP-1) -10% Konventionell cytogenetics 34% med FISH May have prognostic significance more aggressive clinical features

M-spike in serum required for WM Irrespective of IgM concentration Splenomegaly+IgM spike MYD88 mutations status till hjälp vid differentiering från Marginal zons lymfom (7-10%) IgM- myeloma KLL med plasmacytisk differentiering (4%) Differential diagnosis: Splenisk marginal zons lymfom CD22+ and CD11c+

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

Metod för MYD88 L265P 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

Diagnostic criteria (Mayo): IgM MGUS Asymtomatic WM Symtomatic WM M-component, type IgM < 30g/L, and/or ≥30g/L, and/or M-component, type IgM ≥30g/L, and/or LPL in BM <10% LPL in BM ≥10% No WM related symtom* No WM related symtom WM relaterad symtom or end-organ -failure* *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) Somatisk ”WHIM-syndrome like” mutation av CXCR4 hos 27% av WM patienter Hunter Z et al, Blood 2014

C-X-C chemokine receptor type 4 (CXCR4) Somatic ”WHIM-syndrome like” CXCR4 C1013G mutation: 20-30 % of WM cases, thus not a diagnostic marker 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?

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 disorders Higher risk of progression than IgG-IgA MGUS

MGUS: risk factors for evolution Isotype Risk Factors Cesana, 2001 1,014 All BM infiltration, BJ, High ESR, Polyclonal Ig Reduction Gregersen, 2001 1,247 BM infiltration, BJ, Polyclonal Ig Reduction, MC size Kyle, 2003 213 IgM MC Size, Serum Albumin Rakjumar, 2005 1,384 Abnormal Free Light Chain Ratio, MC size, IgA-IgM isotype Baldini, 2005 217 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

Utredning vid misstänkt Waldenströms makroglobulinemi • 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)

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 M-komponent 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? Serum IgM i sig är inte en behandlingsindikation Watch and wait 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 Low 1 (except age) 87% Intermediate 2 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 agents Rituximab (standard or extended schedule) Cladribine/fludarabine Chlorambucil Bortezomib Rituximab-based combinations R + fludarabine/cladribine/pentostatin +cyclophosphamide R + bendamustine R + cyclophosphamide + dexamethasone (DRC) R+ bortezomib Treatment recommendations by the 4th International Workshop on WM Dimopoulos MA, et al. J Clin Oncol 2009; 27:120–126 Updated at last International Workshop on WM, Newport 2012, in manuscript .

Single-agent therapy Single-agent rituximab Plasmapheresis Low Ig M and cytopenias Plasmapheresis High Ig M - risk of “flare” Single-agent chlorambucil Old age and slow progression .

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. 30

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 20 40 60 80 100 0.0 0.2 0.4 0.6 0.8 1.0 Months PFS FAMP CHB N Median (Months) Fludarabine 207 36.3 Chlorambucil 27.1 Factors influencing PFS Negatively: Clb, albumin<35g/l, ptls<100, age>70y P=0.01 Median follow up is 32.5 months. 32

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

FC and FCR good efficacy Fludarabine/combinations FC and FCR good efficacy Hematologic toxicities Grade 3/4 Neutropenia Thrombocytopenia Infections Transformation MDS/AML Purinanalogues No indication in younger patients if autologous ASCT is a later alternative

Other less toxic combinations Dexamethasone + 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):62-6 3. Rummel MJ. Lancet. 2013 Apr 6;381(9873):1203-10.

Dimopoulos et al. J Clin Oncol 2007; 25: 3344-9 DRC regimen (n=72) CR = 7% PR = 67% MR = 9% SD = 8% PD = 8% Dexamethasone 20 mg IV day 1 Rituximab 375 mg/m2 IV day 1 Cyclophosphamide 100 mg/m2 PO BID days 1–5 courses repeated every 21 days X6 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) Dimopoulos et al. J Clin Oncol 2007; 25: 3344-9

R-Benda vs R-CHOP: Progression free survival Rummel MJ et al.: Blood 2009.114: 168 (abs#405). Lancet. 2013 Apr 6;381(9873):1203-10 2 2

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) Bortezomib Multicenter protocol (BDR) Reference CR PR MR SD PD ORR Dimopoulos et al Blood 2009; 114: 2886a 3% 52% 16% 13% 71% Dimopoulos et al. * Blood. 2013 Nov 7;122(19):3276-82 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 .. 40

WM therapy Single-agent rituximab High Ig M ....risk of “flare” DRC Low Ig M and cytopenias DRC Bortezomib Plasmapheresis High Ig M ....risk of “flare” Single-agent chlorambucil Old age and slow progression .

Proposed European trial: DRC versus DRC+ bortezomib sc

Treon et al, ASH 2013, abstract 251 Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib in patients with relapsed/refractory WM 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

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

Gopal G, Salles G, et al 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

Timepoint for response evaluation is crucial WM Consensus Panel : Recommendations on Response Criteria   Weber D et al. Semin Oncol. 2003;30:127-31. Updates Kimby 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

Bing Neel syndrome Definition Infiltration of malignant lymphoplasmacytoid/WM cells in the central nervous system. Meninges (dura & arachnoid) Intracerebral tumour Cerebrospinal fluid Involved?

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 BNS K. 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

CNS penetrating chemotherapy 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

Use of fludarabin in 4 BNS patients 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

Giampaolo Merlini gmerlini@unipv.it 8th International Workshop on Waldenström’s Macroglobulinemia August 14-16, 2014 London, United Kingdom Diagnosis and workup of the patient with Ig M monoconal gammopathy - amyloidosis Giampaolo Merlini gmerlini@unipv.it

AL amyloidosis associated with IgM monoclonal protein: a distinct clinical entity  6% of AL amyloidosis 4% have AA amyloidosis

Survival of patients with IgM-related AL according to NT-proBNP and albumin: a distinct staging system Palladini & Merlini Clin Lymphoma Myeloma Leuk. 2013;13:244-6 Terrier et al, Medicine, 2008;87:99-109

Treatment and outcome of 263 patients with IgM-related AL amyloidosis Impact of bortezomib based regime on overall survival * 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 Roussel et al, ASH 2012 Annual Meeting Abstract 4074 *Palladini et al, Clin Lymphoma Myeloma Leuk. 2011 ;11:143-5.

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