Current Treatment Options for Waldenstrom’s Macroglobulinemia

2019 IMWF Educational ForumJune 7, 2019

Edward A. Stadtmauer, MDChief, Hematologic Malignancies SectionProfessor of MedicineAbramson Cancer CenterUniversity of PennsylvaniaPhiladelphia, Pa

Diagnostic criteria(First described by Jan Gosta Waldenström in 1944)

1. Lymphoplasmacyticlymphoma in the bone marrow

2. IgM monoclonal protein inserum protein electrophoresis

3. MYD88 L265P gene mutation

WHO Classification 2018

Manifestations of WM

Lymphadenopathy≤20% at diagnosis;50-60% at relapse.

↓HB>>> ↓PLT> ↓WBC

Hyperviscosity Syndrome:Epistaxis, Headaches

Impaired vision>6,000 mg/dL or >4.0 CP

Cold Agglutinemia (5%)Cryoglobulinemia (10%)IgM Neuropathy (20%)Amyloidosis (5-10%)

Hepcidin (protein regulator of iron)↓Fe-> Anemia

Bone Marrow

Bing NeelSyndrome, rare CNS

infiltration with lymphoma

Constitutional symptoms: fevers, night sweats, weight loss, fatigue, itch

IgG IgA IgM κ λ

A C

B D

Differential diagnosis

IgM myeloma• Plasma cells with

lymphoplasmacyticmorphology

• Can be CD20+ • No B-cell component• Cyclin D1 expression• FISH: t(11;14)• No MYD88 L265P• Tends to have bone

lesions

Marginal zone lymphoma• No mast cells• MYD88 L265P in 5-8%• Nodal/extranodal with

minimal BM involvementIgM MGUS• No evidence of myeloma

or lymphoma in the marrow

Castillo et al. Am J Hematol 2017

ISSWM: International Staging System for WM

Factors Associated with Prognosis in the IWMSS• Age >65• Hemoglobin <11.5 gr/dL• Platelet count <100k/ml• B2-microglobulin >3 mg/dL• Monoclonal IgM concentration >7 gr/dL

Risk Category Factors Median survival (months)

Low 0 or 1 (except age) 142.5

Intermediate Age>65 or 2 98.6

High >2 43.5

Morel P et al. Blood 2009;113(18):4163-4170

Morel P et al. Blood 2009;113(18):4163-4170

IWMSS: International WM Staging System

Number at riskYears

Survival Time in Years

Prop

ortio

n su

rvivin

g

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

0.0

0.2

0.4

0.6

0.8

1.0

(p=

0 )

Number of patients at risk:

3692031487395136170203High

1423325079106126143174194216Inte

25334351648796110133152155Low

Why not treat everybody at diagnosis?

• WM patients enjoy decades of life

• WM is unlikely to be cured with available treatments

• Treatment may promote resistance

Guidelines for Initiation of Therapy• Hemoglobin ≤10 g/dL on basis of disease• Platelet <100,000 mm3 on basis of disease• Symptomatic hyperviscosity• Moderate/severe peripheral neuropathy• Symptomatic extramedullary disease (e.g.

lymphadenopathy, hepatosplenomegaly, renal involvement, pleural effusions, Bing-Neel syndrome, etc.)

• Symptomatic cryoglobulins, cold agglutinins, autoimmune-related events, amyloidosis.

• Significant symptomatic disease

Kyle et al. Semin Oncol 2003Anderson et al JNCCN 2016

Alkylating agentsThis class of chemotherapy drugs includes chlorambucil, cyclophosphamide, melphalan and bendamustine.

THE GOOD: A trial comparing bendamustine with Rituxan against R-CHOP showed superior progression-free survival for the WM patients being treated with bendamustineand Rituxan.

THE BAD: These drugs directly damage the DNA of cells. People who are candidates for stem cell transplantation should not be treated with alkylating agents prior to stem cell collection-except cyclophosphamide—because these drugs are likely to decrease production of functioning red cells, white cells and platelets.

Biological therapy (monoclonal antibodies)

Rituximab (Rituxan) targets a protein called “CD20” that is found on the surface of B cells, including WM cells

Rituxan is FDA approved for use alone or in combination with other medications to treat certain types of NHL. Rituxan is also avery effective choice for treating patients with IgM-related neuropathies.

Alemtuzumab targets a different protein, called “CD52,” on the membrane of lymphoma cells. Campath is FDA approved to treat CLL, but it has also been found to help some patients with WM and is currently being studied in clinical trials. Can increase infection risk.

Corticosteroids and Immunomodulatory Agents

Steroids such as dexamethasone and prednisone as well as other glucocorticoids can be useful in the treatment of WM, especially in patients with severely low blood cell counts who are not candidates for treatments with drugs that affect normal blood cellproduction. Corticosteroids also help decrease the nauseaand vomiting that other chemotherapy agents may cause.

THE BAD: Fluid retention, weight gain, infection risk, difficulty sleeping, mood swings

Thalidomide is a drug approved in the treatment of myeloma andhas been shown to be effective in some patients withWM. The best results with thalidomide in WM patients haveoccurred when it was used in combination with otherdrugs, such as Rituxan or dexamethasone.

Purine nucleoside analogues

This category of drugs pentostatin, fludarabine and cladribine. Very active in lymphoma.

THE BAD: Patients who are candidates for stem cell transplantation should not be treated with fludarabine or cladribineuntil an adequate number of stem cells have been collected due to bone marrow suppression.

Can also cause significant bone marrow suppression and lymphopenia that can be prolonged and lead to increased infections.

May be associated with an increased risk of disease transformation or myelodysplastic syndrome.

Proteasome inhibitorsThis class of drug blocks the action of proteasomes (cellular complexes that break down proteins).

THE GOOD: Bortezomib is FDA approved to treat patients with myeloma and patients with mantle cell lymphoma who have received at least one prior therapy. Velcade induces apoptosis (cell death) of primary WM lymphoplasmacytic cells.

THE BAD: Neuropathy is a major concern for the use of Velcadein WM patients, and weekly (instead of twice weekly) administration has been investigated to decrease risk of neuropathy.

Carfilzomib, a proteasome inhibitor which has a lower risk for neuropathy, but higher risk of cardiovascular events active in WM patients in combination with rituximab and dexamethasone.

Regimen N Overallresponse

Majorresponse PFS

BDR 23 88% 65% 66 monthsBDR weekly 59 85% 68% 42 months

BR 71 80% 75% NRCaRD 31 87% 68% 46 months

Proteasome inhibitors

Treon JCO 2009Dimopoulos Blood 2013Ghobrial AJH 2010Treon Blood 2014

Bruton tyrosine kinase (BTK) inhibitor

This class of drugs targets BTK which is activated by theMYD88 L265P mutation. The FDA approved ibrutinib, taken by mouth, for the treatment of symptomatic WM patients. Mutations in the CXCR4 gene may impact response to ibrutinib.

Hem

oglo

bin

(g/d

L)

Seru

m Ig

M (m

g/dL

)

Treon et al. N Engl J Med 2015

Regimen N Overallresponse

Majorresponse PFS

IbrutinibRelapsed 63 91% 73% Not reached

at 5 yearsIbrutinib

R refractory 31 90% 71% 86% at 18 months

IbrutinibPrimary therapy 30 100% 83% 92% at 18

months

BTK inhibitors

Treon NEJM 2015; Treon ASH 2017Dimopoulos Lancet Oncology 2017Treon ASH 2017

Ibrutinib Related Adverse Events in previously treated WM patients

• No impact on IGA and IGG immunoglobulins# of patients with toxicity

★

★10% incidence with larger WM Experience; earlier presentation for those patients with prior Afib history.

Treon et al, NEJM 2015; Gustine et al, AJH 2016

Resistance to ibrutinib• CXCR4 mutations• Slower responses• More superficial

responses• Shorter duration of

response

BTK mutations

• Have been described in CLL and MCL

• Usually in BTK C481S• Only in CXCR4 mutated

patients

Abstract 803. BTKCys481Ser Mutation Drives Ibrutinib Resistance through ERK1/2 Hyperactivation, and Can Confer a Protective Effect on Bystander Waldenström Macroglobulinemia and ABC DLBCL Cells through Paracrine Mediated Pro-Survival Signaling

SCT French Experience

32 1111N=

TRM= 12.5% 36% 27%

EFS= 32 36 NR

Kyriakou, C. et al. J Clin Oncol; 28:2227-2232 2010

Kaplan-Meier plot of progression-free survival (PFS) and overall survival probabilities. ASCT, autologous stem-cell transplantation.

BCWM treatment algorithm

Comparisons of Initial Therapy for Waldenstroms

Regimen Route of Duration of Therapy Benefit LimitationAdministration

Benda/Rituxan (BR) IV 4-6 months +/- 2 yrs High RR Real Chemomonthly Long remission (Nausea

VomitingLow blood counts)

Bortezomib/DEX/Rituxan (BDR) 6 months +/- 2 years High RR NeuropathyIV/Sub Cu Long remission Frequent dosingweekly

Ibrutinib +/- Rituxan Oral/IV limited rituximab High RR Continuous therapycontinuous ibrutinib Long remission MYD88 neg, CRCX4 daily pos may not respond

deeply or long termatrial fibrillationhypertension

Frequently, the best therapy is no therapy!

Acknowledgements

Principle InvestigatorsAdam CohenAlfred GarfallEdward StadtmauerCarl June

Penn Myeloma/BMTDan VoglBrendan WeissPatricia ManganEmilie TilhouColleen ErbMary SanchezTim HoltzKelly KrausKathy Cunningham

Heme/Onc DivisionDavid PorterNoelle FreyLynn SchuchterAlison LorenSteve SchusterJakub Svoboda

ACC TRPKaren DengelNaseem KerrHolly McConnevilleElizabeth VelosoLester LledoAnne ChewTOO NUMEROUS TOPUT ON SLIDE

CCIJos MelenhorstSimon LaceyYolanda MahnkeChris CarlsonNina Luning PrakMartin CarrollMike Malone

CVPFBruce L. LevineZoe ZhengJulio CotteDawn MeierAlexey Bersenev

FundingNovartis, AdaptimmuneLeukemia & Lymphoma SocietyNIH: K12 CA076931 The Parker InstituteACC Pilot funds : Heme Malignancies TCE, GREG WOLF FoundationACC Shared Resources (Human immunology Core, CRU, Biostatistics, etc)

U MarylandAaron RapoportAshraf Z. BadrosSaul YanovichGorgun AkpekSunita PhillipsKelly-Marie BettsPhillip MillerSandra Westphal

AdaptimmuneGwen K Binder-SchollBent K JakobsenDominic P SmethurstHelen K Tayton-MartinJoanna E BrewerAlan D BennettAndrew B GerryNick J PumphreyLilliam Ribeiro

Special Thanks To: THE PATIENTS AND THEIR FAMILIESTHE INPATIENT AND OUTPATIENT

NURSING STAFF, REFERRING MDsTHE MYELOMA AND CELLULAR

IMMUNOTHERAPY COMMUNITY