Treatment Options for Recurrent WM- What Are My Choices? · 2016-06-19 · Adenopathy, splenomegaly ≤20% ... Approach to treatment from a doc’s perspective Does my patient really

Waldenstrom’s Macroglobulinemia (WM)

Treatment Options for Recurrent WM-

What Are My Choices?

IWMF Patient Education Forum

June, 2016

Jeffrey V. Matous, MD

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

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

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

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

We do not treat the IgM only

Same rules apply as for newly diagnosed

WM

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

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.

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?

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?

WM docs learn from famous

statesman

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

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

Guide to the primary therapy of WM.

Steven P. Treon Blood 2015;126:721-732

©2015 by American Society of Hematology

Guide to therapy of previously treated WM.

Steven P. Treon Blood 2015;126:721-732

©2015 by American Society of Hematology

OK Let’s Talk About the

Antibodies

We mean: rituximab & ofatumumab

Rituxan side effects

“flare”

“infusional reactions” (patients often say “allergic”)

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

“Rituxumab Flare”

Ghobrial et al. Cancer 2004; 101: 2593–2598

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

Velcade and Rituxan to treat WM

Ghobrial I M et al. JCO 2010;28:1422-1428

©2010 by American Society of Clinical Oncology

(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

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

Ixazomib

Presented By Steven Treon at 2016 ASCO Annual Meeting

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

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

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

Slide 18


Serum IgM and Hb Levels Following Ibrutinib


Slide 20


Progression-free and overall survival for 63 previously WM patients treated with ibrutinib


Slide 22


Responses to ibrutinib are impacted by <br />MYD88 (L265P and non-L265P) and CXCR4 mutations


Slide 24


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

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)

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

Remember: Treatment

decisions are fluid You can always audible with your doctor

Treatment Options for Recurrent WM- What Are My Choices? · 2016-06-19 · Adenopathy, splenomegaly ≤20% ... Approach to treatment from a doc’s perspective Does my patient really

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