1、Waldenstrm macroglobulinemia,Stephen Ansell, MD, PhD Mayo Clinic,Topics to be covered -,What is Waldenstrm macroglobulinemia? Who needs treatment? Standard treatment options Newly diagnosed patients Relapsed patients Questions,What is Waldenstrm macroglobulinemia?,Waldenstrm macroglobulinemia “A dis
2、ease with two problems”,Gertz et al. The Oncologist 2000;5:63-67,Lymphoplasmacytic infiltrate,Monoclonal IgM protein,Lymphoplasmacytic infiltrate (usually intertrabecular) Immunophenotype - surface IgM+, CD19+, CD20+, CD79a+ and PAX5+. CD5, CD10, CD23. exclude CLL and mantle cell lymphoma del(6)(q21
3、) is the most common genetic abnormality seen,Waldenstrm macroglobulinemia Morphology and Immunophenotype,Waldenstrm macroglobulinemia Monoclonal IgM,Symptoms related to the monoclonal IgM protein are attributable to - its characteristics in the circulation, its interaction with various body tissues
4、 when deposited, and its autoantibody activity.,MYD88 Mutations in Waldenstrm macroglobulinemia,Waldenstrm macroglobulinemia presenting symptoms,217 patients with serum monoclonal IgM protein 3 g/dl and 20% bone marrow involvement - Asymptomatic (27%) Anemia (38%), Hyperviscosity (31%), B symptoms (
5、23%), Bleeding (23%) Neurological symptoms (22%),Garca-Sanz et al. Brit J Haematol. 115: 575-582, 2001,Hyperviscosity due to Waldenstrm macroglobulinemia,IgM deposition due to Waldenstrm macroglobulinemia,Autoimmune hemolysis secondary to Waldenstrm macroglobulinemia,Diagnostic Criteria for Waldenst
6、rm macroglobulinemia,Kyle et al. Leukemia. 2009 Jan;23(1):3-9.,Time to developing WM and Survival in patients with Indolent WM or IgM MGUS,Baldini L et al. JCO 2005;23:4662-4668,( MGUS; IWM) MGUS (217 patients) and indolent Waldenstrms macroglobulinemia (201 patients) groups,Time to evolution,Overal
7、l survival,Risk of progression from IgM MGUS to WM or another B-cell malignancy,Kyle R A et al. Blood 2003;102:3759-3764,The overall average risk for progression is approximately 1.5% per year.,Survival of 587 symptomatic patients with Waldenstrm macroglobulinemia,Morel P et al. Blood 2009;113:4163-
8、4170,Who needs treatment?,Patient 1,66 year old man Went for an executive physical in good health with no symptoms Found to be mildly anemic (Hgb 12.8g/dl). Other blood counts normal Also noted to have increased total protein with an increased gammaglobulin level. Monoclonal IgM 1.4 g/dl Bone marrow
9、 biopsy 20% involvement by lymphoplasmacytic lymphoma CT scan no lymph nodes,Patient 2,67 year old man Severe fatigue, nausea, visual difficulties, increasing confusion and sleepiness, gums bleed easily. Anemic (Hgb 8.8g/dl). Platelets decreased to 96,000. Ulcers have developed on his ankles Monoclo
10、nal IgM 6.6 g/dl. Viscosity 5.8 Bone marrow biopsy 85% involvement by lymphoplasmacytic lymphoma CT scan enlarged liver and spleen and multiple bulky lymph nodes in the abdomen,Many treatment options,Watch and wait Single agent rituximab Chemoimmunotherapy combinations Plasmapheresis Clinical trials
11、 with new agents Stem cell transplantationWhich approach is best?,Does everyone need treatment at diagnosis?,Garca-Sanz et al. Brit J Haematol. 115: 575-582, 2001,Watch and wait in Patients with Waldenstrms macroglobulinemia,Half of the patients who had no symptoms had not yet been treated at 3 year
12、s after their diagnosis,10% of the patients had not yet been treated at 10 years,What clinical findings suggest that treatment should be started?,Fever, night sweats, or weight loss. Lymphadenopathy or splenomegaly. Hemoglobin 10 g/dL or a platelet count 100 x 10(9)/L due to marrow infiltration. Com
13、plications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia.,Kyle et al. Semin Oncol. 2003 Apr;30(2):116-20,Before starting therapy Does the patient have hyperviscosity and do they need plasmap
14、heresis?,Plasmapheresis for Waldenstrms patients with hyperviscosity,Symptoms of hyperviscosity Visual deterioration Neurological symptoms BleedingRarely seen with IgM 4g/dL,Before plasmapheresis - optic disc edema (arrowheads), central retinal hemorrhages (bold arrows), and venous “sausaging” (thin
15、 arrows).,Menke et al. Invest Ophthalmol Vis Sci. 2008Mar;49(3):1157-60.,Efficacy of Plasmapheresis for Waldenstrms patients with hyperviscosity,Initial treatment for untreated symptomatic WM patients,Common Treatments used as initial therapy for WM,Purine analogue based combinations FCR/FR Alkylati
16、ng agent based combinations R-CHOP DRC R-Bendamustine Bortezomib based combinations BDR Rituximab alone,Purine analogue based combinations FCR/FR,Fludarabine, cyclophosphamide, rituximab (FCR) 43 untreated, symptomatic WM patientsORR 79% - 12% CRs, 21% PRsEFS 50.1 months44% had prolonged neutropenia
17、Tedeschi et al, Cancer. 2011 Jul 5. Fludarabine, rituximab (FR) 43 symptomatic WM patientsORR- 95% - 5% CRs, 81% PRsPFS 51.2 months63% had grade 3 neutropenia, thrombocytopenia or infection.Treon et al. Blood. 2009 Apr 16;113(16):3673-8.,Leleu X et al. JCO 2009;27:250-255,Increased incidence of tran
18、sformation and myelodysplasia in WM patients treated with nucleoside analogs.,193 nucleoside analogue therapy 136 other therapy 110 no therapy5% transformation and 2% MDS in NA group 0.4% transformation in other groups,Alkylating agent based combinations R-CHOP,Prospective randomized trial of CHOP c
19、ompared to R-CHOP in WM patients. 64 patients with untreated LPL/WM R-CHOP 34 patients, CHOP 30 patientsHigher ORR for R-CHOP (94 vs 67%, p=0.0085) Longer TTF - median of 63 months for R-CHOP vs 22 months for CHOP (p=0.0033) No major differences in treatment-associated toxicity,Buske et al. Leukemia
20、. 2009 Jan;23(1):153-61.,Alkylating agent based combinations DRC,72 patients with untreated symptomatic WM received Dex 20 mg IV, rituximab 375 mg/m2 IV on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5 (total dose, 1,000 mg/m2). Repeated every 21 days for 6 months.ORR 83% (95% CI, 7
21、3%-91%), including 7% CR, 67% PR, and 9% minor responses. 2-year PFS for all patients was 67% 9% of patients - grade 3 or 4 neutropenia,Dimopoulos et al. J Clin Oncol. 2007 Aug 1;25(22):3344-9.,Comparative outcomes following CP-R, CVP-R, and CHOP-R in Waldenstrms macroglobulinemia.,Retrospective sin
22、gle institution study CHOP-R (n = 23), CVP-R (n = 16), or CP-R (n = 19)ORR and CR rates : CHOP-R (ORR, 96%; CR, 17%); CVP-R (ORR 88%; CR 12%); CP-R (ORR, 95%; CR, 0%); p= NS. More treatment-related neuropathy and febrile neutropenia in patients treated with CVP-R and CHOP-R versus CP-R.,Ioakimidis e
23、t al. Clin Lymphoma Myeloma. 2009 Mar;9(1):62-6.,Alkylating agent based combinations R-Bendamustine,30 patients with WM bendamustine 90 mg/m2 I.V. on days 1, 2 and rituximab 375 mg/m2 I.V. on day 1. 6 patients received bendamustine with ofatumumab 1000 mg I.V. on day 1. Median number of treatment cy
24、cles was 5. ORR - 83.3%, with 5 VGPR and 20 PR. Median PFS was 13.2 months. Prolonged myelosuppression was more common in patients who received prior nucleoside analogues,Treon et al. Clin Lymphoma Myeloma Leuk. 2011 Feb 1;11(1):133-5.,Bendamustine plus rituximab compared with R-CHOP in WM patients,
25、A subset analysis in the prospective randomized STIL trial - bendamustine plus rituximab (BR) compared with R-CHOP,Rummel MJ, et al. Lancet. 2013 Apr 6;381(9873):1203-10.,Bortezomib based combinations BDR/BR,Bortezomib, dexamethasone, rituximab (BDR) 23 untreated, symptomatic WM patientsORR 96% - 3
26、CRs, 5 VGPRs, 11 PRsShort follow up - PFS not reached61% had peripheral neuropathyTreon et al, J Clin Oncol. 2009 Aug 10;27(23):3830-5. Bortezomib, rituximab (BR) 26 untreated, symptomatic WM patientsORR- 88% - 1 CR, 1 VGPR, 15 PRsPFS not reached12% had grade 3 neutropenia, no grade 3 or 4 neuropath
27、y.Ghobrial et al. Am J Hematol. 2010 Sep;85(9):670-4.,Rituximab alone for Waldenstrms macroglobulinemia,69 symptomatic WM patients rituximab x 4 dosesORR 52% - 27% PR, 25% MRMedian duration of response 27 monthsGertz et al, Leuk Lymphoma. 2004 Oct;45(10):2047-55.Same study evaluated IgM levels for “
28、flare”54% had an increase in IgM27% still elevated at 4 monthsNo factors predicting an increase in IgM levels could be identified.Ghobrial et al. Cancer. 2004 Dec 1;101(11):2593-8.,Mayo Clinic (mSMART) consensus for management of newly diagnosed Waldenstrm macroglobulinemia,Ansell et al. Mayo Clin P
29、roc. 2010;85:824-833,#Bendamustine + rituximab is an alternative,#,Subsequent treatment in relapsed WM patients,New drugs with promise Dr Ghobrial clinical trials and new agents,Bendamustine mTOR inhibitors - RAD001 (Everolimus) New anti-CD20 antibodies BTK inhibitors - ibrutinib Anti-bcl2 agents -
30、Obatoclax New HDAC inhibitors - LBH589 New proteosome inhibitors MLN9708 New Imids - Pomalidomide (CC-4047) Other agents Enzastaurin, Perifosine, Gleevec, Simvastatin, sildenafil citrate,Mayo Clinic (mSMART) consensus for management of relapsed Waldenstrm macroglobulinemia.,Ansell et al. Mayo Clin P
31、roc. 2010;85:824-833,Transplantation in relapsed Waldenstrm macroglobulinemia.,Autologous transplant 158 WM patientsNon-relapse mortality 3.8%5-year PFS 40%5-year OS 68%Kyriakou et al, J Clin Oncol. 2010 May 1;28(13):2227-32. Allogeneic transplant 86 WM patients (37 MAC and 49 RIC)Non-relapse mortality 33%(MAC), 23% (RIC)5-year PFS 56%5-year OS 62%Kyriakou et al. J Clin Oncol. 2010 Nov 20;28(33):4926-34.,Questions?,
