1. Waldenström macroglobulinemia Stephen Ansell, MD, PhD Mayo Clinic

2. Topics to be covered - What is Waldenström macroglobulinemia? Who needs treatment? Standard treatment options – Newly diagnosed patients Relapsed patients Questions

3. What is Waldenström macroglobulinemia?

4. Waldenström macroglobulinemia “A disease with two problems” Gertz et al. The Oncologist 2000;5:63-67 Lymphoplasmacytic infiltrate Monoclonal IgM protein

5. –Lymphoplasmacytic infiltrate (usually intertrabecular) –Immunophenotype - surface IgM+, CD19+, CD20+, CD79a+ and PAX5+. CD5−, CD10−, CD23−. –exclude CLL and mantle cell lymphoma –del(6)(q21) is the most common genetic abnormality seen Waldenström macroglobulinemia Morphology and Immunophenotype

6. Waldenström macroglobulinemia Monoclonal IgM Symptoms related to the monoclonal IgM protein are attributable to - –its characteristics in the circulation, –its interaction with various body tissues when deposited, –and its autoantibody activity.

7. MYD88 Mutations in Waldenström macroglobulinemia

8. Waldenström 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 (23%), –Bleeding (23%) –Neurological symptoms (22%) García-Sanz et al. Brit J Haematol. 115: 575-582, 2001

9. Hyperviscosity due to Waldenström macroglobulinemia

10. IgM deposition due to Waldenström macroglobulinemia

11. Autoimmune hemolysis secondary to Waldenström macroglobulinemia

12. Diagnostic Criteria for Waldenström macroglobulinemia Kyle et al. Leukemia. 2009 Jan;23(1):3-9.

13. 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 Waldenström's macroglobulinemia (201 patients) groups Time to evolutionOverall survival

14. 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.

15. Survival of 587 symptomatic patients with Waldenström macroglobulinemia Morel P et al. Blood 2009;113:4163-4170

16. Who needs treatment?

17. 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 biopsy – 20% involvement by lymphoplasmacytic lymphoma CT scan – no lymph nodes

18. 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 Monoclonal 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

19. Many treatment options Watch and wait Single agent rituximab Chemoimmunotherapy combinations Plasmapheresis Clinical trials with new agents Stem cell transplantation Which approach is best?

20. Does everyone need treatment at diagnosis?

21. García-Sanz et al. Brit J Haematol. 115: 575-582, 2001 Watch and wait in Patients with Waldenström's macroglobulinemia Half of the patients who had no symptoms had not yet been treated at 3 years after their diagnosis 10% of the patients had not yet been treated at 10 years

22. 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. Complications 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

23. Before starting therapy – Does the patient have hyperviscosity and do they need plasmapheresis?

24. Plasmapheresis for Waldenström's patients with hyperviscosity Symptoms of hyperviscosity – –Visual deterioration –Neurological symptoms –Bleeding Rarely seen with IgM <4g/dL

25. Before plasmapheresis - optic disc edema (arrowheads), central retinal hemorrhages (bold arrows), and venous “sausaging” (thin arrows). Menke et al. Invest Ophthalmol Vis Sci. 2008Mar;49(3):1157-60. Efficacy of Plasmapheresis for Waldenström's patients with hyperviscosity

26. Initial treatment for untreated symptomatic WM patients

27. Common Treatments used as initial therapy for WM Purine analogue based combinations – –FCR/FR Alkylating agent based combinations – –R-CHOP –DRC –R-Bendamustine Bortezomib based combinations – –BDR Rituximab alone

28. Purine analogue based combinations – FCR/FR Fludarabine, cyclophosphamide, rituximab (FCR) – 43 untreated, symptomatic WM patients ORR 79% - 12% CRs, 21% PRs EFS – 50.1 months 44% had prolonged neutropenia Tedeschi et al, Cancer. 2011 Jul 5. Fludarabine, rituximab (FR) – 43 symptomatic WM patients ORR- 95% - 5% CRs, 81% PRs PFS – 51.2 months 63% had ≥ grade 3 neutropenia, thrombocytopenia or infection. Treon et al. Blood. 2009 Apr 16;113(16):3673-8.

29. Leleu X et al. JCO 2009;27:250-255 Increased incidence of transformation and myelodysplasia in WM patients treated with nucleoside analogs. 193 – nucleoside analogue therapy 136 – other therapy 110 – no therapy 5% transformation and 2% MDS in NA group 0.4% transformation in other groups

30. Alkylating agent based combinations – R-CHOP Prospective randomized trial of CHOP compared to R-CHOP in WM patients. 64 patients with untreated LPL/WM R-CHOP – 34 patients, CHOP – 30 patients Higher 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. 2009 Jan;23(1):153-61.

31. Alkylating agent based combinations – DRC 72 patients with untreated symptomatic WM received Dex 20 mg IV, rituximab 375 mg/m 2 IV on day 1 and cyclophosphamide 100 mg/m 2 orally bid on days 1 to 5 (total dose, 1,000 mg/m2). Repeated every 21 days for 6 months. ORR – 83% (95% CI, 73%-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.

32. Comparative outcomes following CP-R, CVP-R, and CHOP-R in Waldenström's macroglobulinemia. Retrospective single 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 et al. Clin Lymphoma Myeloma. 2009 Mar;9(1):62-6.

33. 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 cycles 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.

34. Bendamustine plus rituximab compared with R-CHOP in WM patients 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.

35. Bortezomib based combinations – BDR/BR Bortezomib, dexamethasone, rituximab (BDR) – 23 untreated, symptomatic WM patients ORR 96% - 3 CRs, 5 VGPRs, 11 PRs Short follow up - PFS – not reached 61% had peripheral neuropathy Treon et al, J Clin Oncol. 2009 Aug 10;27(23):3830-5. Bortezomib, rituximab (BR) – 26 untreated, symptomatic WM patients ORR- 88% - 1 CR, 1 VGPR, 15 PRs PFS – not reached 12% had ≥ grade 3 neutropenia, no grade 3 or 4 neuropathy. Ghobrial et al. Am J Hematol. 2010 Sep;85(9):670-4.

36. Rituximab alone for Waldenström's macroglobulinemia 69 symptomatic WM patients – rituximab x 4 doses ORR 52% - 27% PR, 25% MR Median duration of response – 27 months Gertz et al, Leuk Lymphoma. 2004 Oct;45(10):2047-55. Same study – evaluated IgM levels for “flare” 54% had an increase in IgM 27% still elevated at 4 months No factors predicting an increase in IgM levels could be identified. Ghobrial et al. Cancer. 2004 Dec 1;101(11):2593-8.

37. Mayo Clinic (mSMART) consensus for management of newly diagnosed Waldenström macroglobulinemia Ansell et al. Mayo Clin Proc. 2010;85:824-833 #Bendamustine + rituximab is an alternative #

38. Subsequent treatment in relapsed WM patients

39. 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 - Obatoclax New HDAC inhibitors - LBH589 New proteosome inhibitors – MLN9708 New Imids - Pomalidomide (CC-4047) Other agents – Enzastaurin, Perifosine, Gleevec, Simvastatin, sildenafil citrate

40. Mayo Clinic (mSMART) consensus for management of relapsed Waldenström macroglobulinemia. Ansell et al. Mayo Clin Proc. 2010;85:824-833

41. Transplantation in relapsed Waldenström macroglobulinemia. Autologous transplant – 158 WM patients Non-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.

42. Questions?