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Waldenström´s makroglobulinemi Eva Kimby M.D. Ph.D Professor Karolinska Institute Center of Hematology Karolinska University Hospital Stockholm, Sweden.

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Presentation on theme: "Waldenström´s makroglobulinemi Eva Kimby M.D. Ph.D Professor Karolinska Institute Center of Hematology Karolinska University Hospital Stockholm, Sweden."— Presentation transcript:

1 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

2 Fortbildningsdagarna 2-4 oktober 2013 Sundsvall Disclosures Eva Kimby Advisory board : Celgene, Pharmacyclics, Gilead, Jansen, Teva Föreläsararvode: Roche, Mundipharma, Jansen Forskningsstöd: Pfizer, Roche

3 Professor Jan Waldenström Acta Med Scand 1944

4 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

5 Sjukdomssymptom Sjukdomssymptom Anemi/trombocytopeni Anemi/trombocytopeni Relativ anemi (hög plasmavolum ) Relativ anemi (hög plasmavolum ) Lymfadenopati Lymfadenopati B-symptom B-symptom Hyperviskositet Hyperviskositet Kryoglobulinemi Kryoglobulinemi Cold agglutinin disease (CAD) Cold agglutinin disease (CAD) Neuropati Amyloidos

6 WM – diagnos kriterier WM – diagnos kriterier I nternationaI 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”

7 WM – diagnos kriterier Benmärgsinfiltration Benmärgsinfiltration – Små lymfoplasmacytiska lymfocyter – Intertrabekulär växt – Typisk immunfenotyp Biopsi med immunfärgning (IHC) Aspiration och flödescytometri

8 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 Jan;28(1): Multiparameter flow cytometry for the identification of the WM's clone in IgM-MGUS and WM: new criteria for differential diagnosis and risk stratification.

9 May have prognostic significance more aggressive clinical features FISH: 6q deletion (gen: BLIMP-1) 6q21 deletion -10% Konventionell cytogenetics 34% med FISH

10 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%)

11 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 my eloid d ifferentiation 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;

12 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

13 IgM MGUSAsymtomatic WMSymtomatic 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% 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”

14 C-X-C chemokine receptor typ 4 (CXCR4) Hunter Z et al, Blood 2014 Hunter Z et al, Blood 2014 Somatisk ”WHIM-syndrome like” mutation av CXCR4 hos 27% av WM patienter

15 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 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: % of WM cases, thus not a diagnostic marker C-X-C chemokine receptor type 4 (CXCR4)

16 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

17 MGUS: risk factors for evolution NIsotypeRisk Factors Cesana, ,014All BM infiltration, BJ, High ESR, Polyclonal Ig Reduction Gregersen, ,247All BM infiltration, BJ, Polyclonal Ig Reduction, MC size Kyle, IgM MC Size, Serum Albumin Rakjumar, ,384All Abnormal Free Light Chain Ratio, MC size, IgA-IgM isotype Baldini, IgM MC Size, Hemoglobin, Male sex

18 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

19 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

20 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 misst ä nkt Waldenstr ö ms makroglobulinemi

21 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?

22 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)

23 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)

24 När ska behandling inledas? Watch and wait Serum IgM i sig är inte en behandlingsindikation Anaemia/trombocytopenia Adenopati/organomegaly Hyperviskositet Kryoglobulinaemi Köld agglutinin Neuropati Amyloidos Transformation

25 The International prognostic Scoring System for WM (ISSWM) Risk groupAdverse covariates*5-year survival Low 1 (except age) 87% Intermediate 2 Or only age > 65 years 68% High> 236% *Adverse covariates: IgM > 70 g/l Age > 65 years β 2 M > 3mg/l Hb ≤ 11.5 g/dl Plts ≤ 100 x10 9 /l Morel P, et al. Blood 2009; 113:4163–4170.

26 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?

27 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.

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

29 Plasmapheresis for removal of IgM Hyperviscosity-related symptoms Hyperviscosity-related symptoms Prevention Prevention Reduce IgM before rituximab Reduce IgM before rituximab Reversing (rapid effect needed) Reversing (rapid effect needed) Headache, breathlesness Headache, breathlesness Retinopathy Retinopathy Venous dilatation Venous dilatation Bleeding Bleeding Anemia Anemia

30 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 ;31(3): Leblond V et al. J Clin Oncol ;31(3):301-7.

31 WM 1- prospective randomized trial 07/01-12/09 (n=414) WM 1- prospective randomized trial 07/01-12/09 (n=414) Chlorambucil : 8 mg/m2 x10 days/28 days Chlorambucil : 8 mg/m2 x10 days/28 days (max 12 cycles) (max 12 cycles) CR+PR: 38.6% Oral Fludara : 40 mg/m2 orally x5 days/28 days (max 6 cycles) Oral Fludara : 40 mg/m2 orally x5 days/28 days (max 6 cycles) CR+PR: 47.8 % CR+PR: 47.8 %

32 WM1 progression-free survival WM1 progression-free survival Months PFS FAMP CHB NMedian (Months) Fludarabine Chlorambucil P=0.01 Factors influencing PFS Negatively: Clb, albumin 70y

33 Survival Survival OS 5 years Chlorambucil: 61.4% [52.9;71.3] Chlorambucil: 61.4% [52.9;71.3] Fludarabine: 70.3% [ ] Fludarabine: 70.3% [ ] (p=0.04) (p=0.04)

34 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 A higher response rate Longer time to treatment failure Longer time to treatment failure Buske C, et al. Leukemia. 2009;23:153-61

35 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

36 Other less toxic combinations Dexamethasone + rituximab + cyclophosphamide (DRC) 1 Cyclophosphamide+prednisone+rituximab (CP-R) 2 Bendamustine + rituximab 3 1. Dimopoulos MA, et al. J Clin Oncol 2007; 25:3344– Ioakomidis L et al, Clin Lymphoma Myeloma Mar;9(1): Rummel MJ. Lancet Apr 6;381(9873):

37 Dimopoulos et al. J Clin Oncol 2007; 25: Dimopoulos et al. J Clin Oncol 2007; 25: CR = 7% CR = 7% PR = 67% PR = 67% MR = 9% MR = 9% SD = 8% SD = 8% PD = 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 1 Rituximab 375 mg/m2 IV day 1 Cyclophosphamide 100 mg/m2 PO BID days 1–5 courses repeated every 21 days X6

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

39 Other drugs Other drugs Proteosominhibitors = bortezomib Proteosominhibitors = bortezomib carfilzomib carfilzomib Everolimus d ecrease in serum IgM level, but increase in BM involvement Everolimus d ecrease in serum IgM level, but increase in BM involvement Lenalidomide unclear anemia Lenalidomide unclear anemia Carfilzomib, Rituximab and Dexamethasone (CaRD) Carfilzomib, Rituximab and Dexamethasone (CaRD) Highly active neuropathy sparing approach for proteasome-inhibitor based therapy in WM proteasome-inhibitor based therapy in WM Treon et al, ASH 2013, abstract 757

40 Bortezomib Multicenter protocol (BDR) 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).. Referenc e CRPRMRSDPDORR Dimopoulos et al Blood 2009; 114: 2886a 3%52%16%13%16% 71% Dimopoulos et al. * Blood Nov 7;122(19): %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

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

42 Proposed European trial: Proposed European trial: DRC versus DRC+ bortezomib sc DRC versus DRC+ bortezomib sc

43 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

44 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

45 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

46 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

47 Relapse-studier hos oss: Indolent lymphoma 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

48 Recommendations on Response Criteria WM Consensus Panel : Weber D et al. Semin Oncol. 2003;30: Updates Kimby E, et al. Clin Lymphoma Myeloma. 2006:6: Owen RG, et al. Br J Haematol. 2013;160:171-6 Timepoint for response evaluation is crucial

49 Delayed response Delayed response Conversion from PR to CR PR CR

50 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

51 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

52 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

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

54 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

55 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

56 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 Sep;30(3):255-9.

57 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

58 Methotrexate  3 g/m 2 Cytarabine Intermediate to high dosing  2 g/m 2 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

59 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

60 { Giampaolo Merlini 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

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

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

63 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 ;11: * 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 Jul 15

64 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

65 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 Eva Kimby, Stockholm


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