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Waldenstrom’s Macroglobulinemia (WM)
Treatment Options for Recurrent WM-
What Are My Choices?
IWMF Patient Education Forum
June, 2016
Jeffrey V. Matous, MD
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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
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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
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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
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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
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We do not treat the IgM only
Same rules apply as for newly diagnosed
WM
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Manifestations of WM Disease
Adenopathy,
splenomegaly
≤20%
HCT, PLT, WBC
Hyperviscosity
Syndrome:
Epistaxis, HA,
Impaired vision
>4.0 CP
IgM Neuropathy (22%)
Cryoglobulinemia (10%)
Cold Agglutinemia (5%) Fatigue, Sweats
Cytokinemia?
Treon and Merlini, Williams Hematology 2011
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Consensus Recommendations for Initiation of Therapy in WM
Hgb ≤10 g/dL on basis of disease
Platelets <100,000 mm3 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):116-120.
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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?
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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?
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WM docs learn from famous
statesman
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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
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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
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Guide to the primary therapy of WM.
Steven P. Treon Blood 2015;126:721-732
©2015 by American Society of Hematology
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Guide to therapy of previously treated WM.
Steven P. Treon Blood 2015;126:721-732
©2015 by American Society of Hematology
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OK Let’s Talk About the
Antibodies
We mean: rituximab & ofatumumab
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Rituxan side effects
“flare”
“infusional reactions” (patients often say “allergic”)
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IgM flare occurs following Rituximab therapy including
combination therapy in patients with Waldenstrom’s
Macroglobulinemia.
1 2 3 4 5 6 7 8 9
0
2000
4000
6000
8000
10000
12000
IgM
(m
g/d
L)
Time (weeks)
*
*
*
*
**
* Denotes patient
underwent
plasmapheresis at
this time point for
hyperviscosity.
Donnelly et al, ASH 2001; Dimopoulos et al, JCO 2002; Treon et al, Ann Oncol 2004; Ghobrial et al, Leuk Lymph 2004.
Monotherapy (40-60%)
Fludarabine/Rituximab (40%)
Cyclophosphamide/Prednisone/Rituximab (25-
30%)
Thalidomide/Rituximab (50%)
Lenalidomide/Rituximab (75%)
Bortezomib/Dexamethasone/Rituximab (9%)
IgM flare rates reported with
Rituximab therapy
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“Rituxumab Flare”
Ghobrial et al. Cancer 2004; 101: 2593–2598
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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
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Velcade and Rituxan to treat WM
Ghobrial I M et al. JCO 2010;28:1422-1428
©2010 by American Society of Clinical Oncology
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(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;28:1422-1428
©2010 by American Society of Clinical Oncology
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Everolimus (RAD001) also effective
in WM
Treon et al Submitted to Blood 2016
Everolimus as Primary Therapy in WM (WMCTG 09-214)
• 33 untreated patients
• About 75% of patients responded
• More lung irritation
• Not really used upfront
• Some patients had very long lasting remissions however
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Ixazomib
Presented By Steven Treon at 2016 ASCO Annual Meeting
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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):826-833; 2012
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Study Overview Methods. Whole genome sequencing n=30pts (paired normal-tissue and tumor-
tissue sequencing in 10 patients) Sanger sequencing, n=54 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 38182641 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 !
MYD88-Directed NF-κB Signaling. Treon SP et al. N Engl J Med
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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
29
Phase II Study of Ibrutinib in Relapsed/Refractory WM
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Slide 18
Presented By Steven Treon at 2016 ASCO Annual Meeting
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Serum IgM and Hb Levels Following Ibrutinib
Presented By Steven Treon at 2016 ASCO Annual Meeting
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Slide 20
Presented By Steven Treon at 2016 ASCO Annual Meeting
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Progression-free and overall survival for 63 previously WM patients treated with ibrutinib
Presented By Steven Treon at 2016 ASCO Annual Meeting
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Slide 22
Presented By Steven Treon at 2016 ASCO Annual Meeting
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Responses to ibrutinib are impacted by <br />MYD88 (L265P and non-L265P) and CXCR4 mutations
Presented By Steven Treon at 2016 ASCO Annual Meeting
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Slide 24
Presented By Steven Treon at 2016 ASCO Annual Meeting
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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.
Should MYD88 and CXCR4 be tested in all WM patients?
Treon S P et al. Blood 2014;123:2791-2796
Courtesy X LeLeu
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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)
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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
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Remember: Treatment
decisions are fluid You can always audible with your doctor