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Waldenström´s makroglobulinemi

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.

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Waldenström´s makroglobulinemi

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  1. Waldenström´smakroglobulinemi Eva Kimby M.D. Ph.D Professor Karolinska Institute Center of HematologyKarolinska University Hospital Stockholm, Sweden Fortbildningsdagarnaihematologi Linköping 2 oktober 2014

  2. 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. Incipientmyelomatosisor essentialhyperglobulinemiawith fibrinogenopenia • Oronasal bleeding • Lymphadenopathy/enlargedlymphnodes • Anemia and thrombocytopenia • Hyperviscosity • Elevatederythrocyte sedimentation rate (SR) • Lymphoid cells and mast-cells in bone marrow Waldenström J. Acta Med Scand 1944

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

  6. InternationaI Workshop on WM Athens 2002* Paris 2004 Stockholm 2008 Venice 2010 Newport 2012 London 2014 *Owen RG, et al. Clinicopathologicaldefinition of WM SeminOncol. 2003Athens 2002 Enl WHO-klassifikationen 2008: “WM is a lymphoplasmacytic lymphoma” WM – diagnoskriterier

  7. Benmärgsinfiltration • Smålymfoplasmacytiskalymfocyter • Intertrabekulärväxt • Typiskimmunfenotyp • Biopsi med immunfärgning (IHC) • Aspiration och flödescytometri WM – diagnoskriterier

  8. Positivitetför Light chain restricted IgM CD19, CD22, (dim), CD25, CD27 ochCD52 CD5 positiviteti5-20% av fallen Negativitetför CD10, CD23, CD103 ochCD138 Ensubklon, främstplasmaceller , är CD20-negativ och CD138-positiv WM immunofenotyp Paiva B, et al. Leukemia. 2014 Jan;28(1):166-73. Multiparameter flowcytometry for the identificationof the WM'sclone in IgM-MGUS and WM: new criteria for differential diagnosis and risk stratification.

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

  10. M-spike in serum required for WM IrrespectiveofIgMconcentration Splenomegaly+IgM spike • MYD88mutations status • till hjälp vid differentiering från • Marginal zons lymfom (7-10%) • IgM- myeloma • KLL med plasmacytiskdifferentiering (4%) Differential diagnosis:Spleniskmarginal zons lymfom CD22+ and CD11c+

  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 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

  12. Metod för MYD88 L265P • Allele-specific PCR iblod: • Circulating WM-cells – • High concordance BM-blood • if CD19+ selected cells are used for allele-specific PCR • patient-friendly, but not specific

  13. Diagnostic criteria (Mayo): *B-symtom, anemia, hyperviscosity, lymphadenopathy/hepatosplenomegaly MYD88 L265P vid IgM MGUS: 10-87% Vid förekomstav mutation större risk för “malignant evolution”

  14. Hunter Z et al, Blood2014 Somatisk”WHIM-syndrome like” mutation av CXCR4 hos 27% avWM patienter C-X-C chemokine receptor typ 4 (CXCR4)

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

  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

  18. AsymptomatiskWaldenström: • 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 faktorerförevolution: Hbnivåoch serum MC Uppföljning: Var4-6 månad : Kliniskundersökning Hboch serum Ig M OBS! Tänkpåsekundära problem; neuropati, amyloidos

  20. Utredning vid misstänkt Waldenströms makroglobulinemi

  21. Fler prover: • DAT = direkt antiglobulin test • evprov 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 M-komponent • Huvudvärk, synrubbningar, blödningar, dyspné, • pgahyperviskositet • Njursvikt, Raynaudfenomen, hudutslag, led- muskel-smärta, • neuropati(pgaKryoglobulinemi typ I och II) • Hemolytiskanemi pga autoantikroppar (I-antigen) • Trombocytopenipga autoantikroppar • Perifer neuropatipga autoantikroppar • mot MAG (myelin-associerad glycoprotein) eller GM1 (ganglioside M1)

  23. När ska behandling inledas? Serum IgM i sig är inte en behandlingsindikation Watchand wait • Anaemia/trombocytopenia • Adenopati/organomegaly • Hyperviskositet • Kryoglobulinaemi • Köldagglutinin • Neuropati • Amyloidos • Transformation

  24. The International prognostic Scoring System for WM (ISSWM) *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 .

  25. MYD88 L265P as a prognostic marker? WM-cellsharboring the L265P mutation, exhibit constitutive signaling leading to the hyperactivationof NF-κB WM patients without the mutation have worse prognosis? Level of mutation of importance? Quantitative PCR?

  26. 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 options for WM Treatment recommendations by the 4th International Workshop on WMDimopoulos MA, et al.J Clin Oncol 2009; 27:120–126 Updated at last International Workshop on WM, Newport 2012, in manuscript .

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

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

  29. 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 ClinOncol. 2013. 20;31(3):301-7.

  30. 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 % WM 1- prospective randomized trial 07/01-12/09 (n=414)

  31. WM1 progression-free survival 1.0 0.8 0.6 PFS 0.4 0.2 FAMP CHB 0.0 0 20 40 60 80 100 Months Factors influencing PFS Negatively: Clb, albumin<35g/l, ptls<100, age>70y P=0.01

  32. OS 5 years • Chlorambucil: 61.4% [52.9;71.3] • Fludarabine: 70.3% [62.7-78.8] (p=0.04) Survival

  33. The addition of R to front-line therapy with CHOP in Lymphoplasmacyticlymphoma (including WM) • A higher response rate • Longer time to treatment failure Buske C, et al. Leukemia. 2009;23:153-61 CD20 + tumor cells Rituximabofvalue?

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

  35. Dexamethasone + rituximab + cyclophosphamide (DRC)1 Cyclophosphamide+prednisone+rituximab (CP-R)2 Bendamustine + rituximab3 Other less toxic combinations 1. Dimopoulos MA, et al. J ClinOncol 2007; 25:3344–3349. 2.Ioakomidis L et al, ClinLymphomaMyeloma. 2009 Mar;9(1):62-6 3. Rummel MJ. Lancet. 2013 Apr 6;381(9873):1203-10.

  36. 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 Cyclophosphamide100 mg/m2 PO BID days1–5 courses repeated every 21 days X6 ORR = 83% Mediantime to 50% IgMreduction: 4.1 mo(range0.7–14) IgM flare: 32% (>25%IgMincrease in 11%of patients) Dimopoulos et al. J Clin Oncol 2007; 25: 3344-9

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

  38. Proteosominhibitors= bortezomib carfilzomib • Everolimus decreasein serum IgM level, but increase in BM involvement • Lenalidomideunclear 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 Other drugs

  39. BortezomibMulticenter protocol (BDR) Cycle 1 (21-days): bortezomib1.3 mg/m2 on days 1, 4, 8, 11 Cycles 2-5 (35-days): bortezomib1.6 mg/m2 d 1,8,15, 22 Rituximab 375 mg/m2 + Dexa 40 days 1, 8, 15, 22 (8 infusions R) * Progression-free survival: 42 months Peripheral neuropathy in 46% (grade ≥3 in 7%) 8% discontinued bortezomib due to neuropathy ..

  40. WM therapy Single-agentchlorambucil Single-agentrituximab Low Ig M and cytopenias DRC Bortezomib Plasmapheresis High Ig M ....risk of “flare” Old age and slow progression .

  41. DRC versus DRC+ bortezomibsc Proposed European trial:

  42. Bruton’sTyrosine Kinase (BTK) Inhibitor Ibrutinib in patients with relapsed/refractory WM • MYD 88 L265P - trigger NFκB signaling by direct interaction with BTK in WM cells • Ibrutinib420mg/dag under 2 år, eller tills progress ellertoxicitet • MutationsMYD88 L265P hos 49/43 (93%) WHIM-like CXCR4 hos 10/40 (25%) MYD88 Treon et al, ASH 2013, abstract 251

  43. Ibrutinib in relapsed/refractoryWM Response impacted by mutations in CXCR4 but notin MYD88 Major response rate: 77% for patients with wild-type CXCR4 vs 30% in those with WHIM-like CXCR4 mutations (p=0.018) Decreasesin serum IgMM-spike (p=0.012) and improvementsin hemoglobin (p=0.058) greater in patients with wild-type CXCR4 Treon et al ASH 2013, abstract 251

  44. PI3K inhibitors • GS1101/idelalisibinhibits 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

  45. PI3K-Delta Inhibitor Idelalisibin Patients With Double RefractoryIndolent B-CellLymphoma • 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

  46. Randomiserad, double-blind, placebo-controllerad Fas 3 Studier • Idelalisibi kombination med • Bendamustin och rituximab(BR) (GileadStudy 125) • eller med • Rituximabalone (GileadStudy 124) • Patienter som ej är aktuella för högdos kemoterapi/SCT Relapse-studier hos oss: Indolent lymphoma

  47. WM Consensus Panel : Recommendations on Response Criteria Weber Det al. Semin Oncol. 2003;30:127-31. Updates Kimby E, et al. ClinLymphomaMyeloma. 2006:6:380-3. Owen RG, et al. Br J Haematol. 2013;160:171-6 Timepointfor response evaluation is crucial

  48. Conversion from PR to CR PR CR Delayed response

  49. 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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