Waldenstrom s Macroglobulinemia (WM) Treatment Options for Recurrent WM- What Are My Choices?

Transcription

1 Waldenstrom s Macroglobulinemia (WM) Treatment Options for Recurrent WM- What Are My Choices? IWMF Patient Education Forum June, 2016 Jeffrey V. Matous, MD

2 Very Important Points The nature of WM is that is probably not curable Therefore, in virtually every patient who needs to be treated a first time, it eventually recurs Remember: Not every recurrence means that treatment must be restarted We do not just treat the numbers (IgM), the same reasons for treating WM patients initially apply to WM patients with relapsed/recurrent disease

3 More Important Points Usually when WM relapses it has the same behavior or nature as when it first was causing symptoms BUT NOT ALWAYS WM can transform to more aggressive kinds of non-hodgkin lymphoma More times relapsing = more resistance to chemotherapy treatments and therefore more life-threatening

4 What is a relapse? A relapse assumes that a patient required prior treatment for WM That treatment resulted in a remission of some kind (partial, near complete, complete) There is evidence of the WM worsening This may or may not be associated with symptoms

5 How do we define and recognize a relapse? Common: the IgM and M spike go up repeatedly over multiple readings Or lymph node enlargement occurs by physical exam or CT scan Without any symptoms or health problems: laboratory or biochemical relapse For clinical trials normally the M spike must rise by at least 0.5 g/dl over the lowest value following the previous treatment

6 We do not treat the IgM only Same rules apply as for newly diagnosed WM

7 Manifestations of WM Disease HCT, PLT, WBC Adenopathy, splenomegaly 20% Fatigue, Sweats Cytokinemia? Hyperviscosity Syndrome: Epistaxis, HA, Impaired vision >4.0 CP IgM Neuropathy (22%) Cryoglobulinemia (10%) Cold Agglutinemia (5%) Treon and Merlini, Williams Hematology 2011

8 Consensus Recommendations for Initiation of Therapy in WM Hgb 10 g/dl on basis of disease Platelets <100,000 mm 3 on basis of disease Symptomatic hyperviscosity (>4.0 cp) Moderate/severe peripheral neuropathy Symptomatic cryoglobulins, cold agglutinins, autoimmune-related events, amyloid. Kyle RA, et al. Semin Oncol. 2003;30(2):

9 Approach to treatment from a doc s perspective Does my patient really require treatment right now? Is the WM behaving similarly to before when I last treated it or has it changed? Is there any evidence of transformation to aggressive non-hodgkin lymphoma What is the pace of the relapse? Is it fast or slow? What are the symptoms or WM problems which we hope to improve? What treatment(s) have we used before? Burned any bridges? Neuropathy? Bad reactions to the antibodies?

10 How WM docs decide on treatment Are there any clinical trials? How aggressive can and should we be? What can my patient tolerate? What are the goals of treatment?

11 WM docs learn from famous statesman

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14 Define the Goal of Retreatment Is it to achieve the deepest remission possible? OR Is it to control symptoms or manage the disease? This absolutely affects the treatment decision

15 OK So Which Chemo? Go back to the well Can do for most chemos but only IF: It worked really well previously It was well tolerated It produced a long lasting remission Without lingering side effects Examples: bortezomib, rituximab, ibrutinib Usually not: CHOP, perhaps Bendamustine

16 Guide to the primary therapy of WM. Steven P. Treon Blood 2015;126: by American Society of Hematology

17 Guide to therapy of previously treated WM. Steven P. Treon Blood 2015;126: by American Society of Hematology

18 OK Let s Talk About the Antibodies We mean: rituximab & ofatumumab

19 Rituxan side effects flare infusional reactions (patients often say allergic )

20 IgM (mg/dl) IgM flare occurs following Rituximab therapy including combination therapy in patients with Waldenstrom s Macroglobulinemia * IgM flare rates reported with Rituximab therapy * Time (weeks) * * * * * Denotes patient underwent plasmapheresis at this time point for hyperviscosity. Monotherapy (40-60%) Fludarabine/Rituximab (40%) Cyclophosphamide/Prednisone/Rituximab (25-30%) Thalidomide/Rituximab (50%) Lenalidomide/Rituximab (75%) Bortezomib/Dexamethasone/Rituximab (9%) Donnelly et al, ASH 2001; Dimopoulos et al, JCO 2002; Treon et al, Ann Oncol 2004; Ghobrial et al, Leuk Lymph 2004.

21 Rituxumab Flare Ghobrial et al. Cancer 2004; 101:

22 WM patients more frequently do not tolerate Rituxan Rituxan can produce allergic reactions while infusing Premedications are always given- usually benadryl & tylenol Non WM: rare it cannot be given successfully 1/6 WM patients no matter what we do just cannot tolerate it Tricks of the trade: more aggressive premedication (steroids), longer infusions, break up the dose Can try ofatumumab

23 Velcade and Rituxan to treat WM Ghobrial I M et al. JCO 2010;28: by American Society of Clinical Oncology

24 (A) The maximum percent decrease in immunoglobulin M (IgM) over all cycles in response to therapy per patient in responding patients. Ghobrial I M et al. JCO 2010;28: by American Society of Clinical Oncology

25 Everolimus (RAD001) also effective in WM Treon et al Submitted to Blood 2016 Everolimus as Primary Therapy in WM (WMCTG ) 33 untreated patients About 75% of patients responded More lung irritation Not really used upfront Some patients had very long lasting remissions however

26 Ixazomib Presented By Steven Treon at 2016 ASCO Annual Meeting

27 MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia Steven P. Treon, M.D., Ph.D., Lian Xu, M.S., Guang Yang, Ph.D., Yangsheng Zhou, M.D., Ph.D., Xia Liu, M.D., Yang Cao, M.D., Patricia Sheehy, N.P., Robert J. Manning, B.S., Christopher J. Patterson, M.A., Christina Tripsas, M.A., Luca Arcaini, M.D., Geraldine S. Pinkus, M.D., Scott J. Rodig, M.D., Ph.D., Aliyah R. Sohani, M.D., Nancy Lee Harris, M.D., Jason M. Laramie, Ph.D., Donald A. Skifter, Ph.D., Stephen E. Lincoln, Ph.D., and Zachary R. Hunter, M.A. N Engl J Med, 367(9): ; 2012

28 Treon SP et al. N Engl J Med Study Overview Methods. Whole genome sequencing n=30pts (paired normal-tissue and tumortissue sequencing in 10 patients) Sanger sequencing, n=54 MYD88-Directed NF-κB Signaling. Key findings. Genetic analysis has revealed a common somatic mutation in exon 5 of MYD88 (Myeloid differentiation factor 88) in more than 90% of patients with WM. A somatic variant (T C) in LPL cells was identified at position at 3p22.2. This variant predicted an amino acid change (L265P) in MYD88. MYD88 L265P was absent in paired normal tissue samples from Waldenström's macroglobulinemia or non-igm LPL and in B cells from healthy donors. MYD88 L265P was absent or rarely expressed in patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Conclusion. MYD88 L265P is the most frequent recurring mutation in patients with Waldenström's macroglobulinemia = a molecular signature!

29 Phase II Study of Ibrutinib in Relapsed/Refractory WM Screening Informed Consent and Registration Ibrutinib 420 mg po daily Progressive Disease or Unacceptable Toxicity SD or Response Continue x 26 cycles Stop Ibrutinib Event Monitoring Event Monitoring Opened May 2012

30 Slide 18 Presented By Steven Treon at 2016 ASCO Annual Meeting

31 Serum IgM and Hb Levels Following Ibrutinib Presented By Steven Treon at 2016 ASCO Annual Meeting

32 Slide 20 Presented By Steven Treon at 2016 ASCO Annual Meeting

33 Progression-free and overall survival for 63 previously WM patients treated with ibrutinib Presented By Steven Treon at 2016 ASCO Annual Meeting

34 Slide 22 Presented By Steven Treon at 2016 ASCO Annual Meeting

35 Responses to ibrutinib are impacted by <br />MYD88 (L265P and non-l265p) and CXCR4 mutations Presented By Steven Treon at 2016 ASCO Annual Meeting

36 Slide 24 Presented By Steven Treon at 2016 ASCO Annual Meeting

37 Should MYD88 and CXCR4 be tested in all WM patients? Somatic mutations in MYD88 and CXCR4 are Important determinants of clinical presentation Impact overall survival in WM. Targeted therapies directed against MYD88 and/or CXCR4 signaling may provide a personalized treatment approach to WM. Treon S P et al. Blood 2014;123: Courtesy X LeLeu

38 How to be involved in your treatment Know your medications Report any possible side effects track your WM by carefully following your blood tests (IgM, M spike, red blood cell count)

39 Summary Initial treatment must be tailored to the individual ALWAYS a great idea to consider a clinical trial Many great choices for care No room for dogma

40 Remember: Treatment decisions are fluid You can always audible with your doctor