Traditional Therapies for Waldenstrom’s

Macroglobulinemia

Christine Chen

Princess Margaret Cancer Centre Toronto, Canada

May 2014

Jeff Atlin (1953-2014)

Standard treatment options

Single drug therapies – Chlorambucil (alkylating agents) – Fludarabine and cladribine (nucleoside analogues) – Rituximab (monoclonal antibodies) – Bendamustine – Bortezomib (proteasome inhibitors)

Combination therapies – Alkylator-rituximab – Fludarabine/cladribine-based – Bendamustine-based – Bortezomib-based

Transplantation

Chlorambucil

Alkylating agent (cyclophosphamide, melphalan)

Oral drug used for decades

Many different regimens: – Continuous daily dose

– Intermittent dosing 7-10days every month

Major responses: – First-line 60-70%, response duration 30 mos

– Slow onset (can take up to a year!)

Side effects: – Short term – nausea, hair loss, low blood counts

– Long term – secondary cancers, myelodysplasia (MDS)

Still used commonly worldwide but usually reserved for elderly or debilitated

PROS:

- Oral drug

- Convenient and cheap

- Well-tolerated

- Lots of experience

CONS:

- Slow onset

- Requires prolonged therapy

- Risk of cancers or MDS

Chlorambucil

Fludarabine and cladribine

Nucleoside (NA) analogues

Regimen: – Intravenous (oral is available in

some countries) – Fludarabine daily x 5 days every

month for 4-8 cycles

Major Responses: – 30-100% (CR <10%) – Rapid onset (<2 mos) – Response durations up to 5 years

fludarabine

Short term: – Low blood counts

– Immune suppression unusual pneumonias

(pneumocystis) and viral infections

Long term: – Risk of second cancers

1.6% MDS/AML and 6.2% transformed lymphoma

(Leleu et al J Clin Oncol 2009;27:250-55)

– Stem cell toxic

– Immune suppression late infections even years after therapy

Nucleoside analogue side-effects

Fludarabine and cladribine

PROS: – Rapid onset

– High response rates

– Long response duration (>2 yrs)

– Shorter treatment periods

CONS: – Intravenous

– Side effects Infections

Secondary MDS

– Stem cell toxic

– CR still uncommon

Rituximab

Monoclonal antibody to CD20

3 different mechanisms for killing cancer cells

Used extensively to treat various lymphomas and immune disorders

Taylor et al. Nature Clin Practice Rheum (2007) 3, 86-95

Rituximab

Regimens: – Weekly infusions x 4 when used alone – Also given in combination and as maintenance after chemo

Major responses: – 20-35% responses with short response duration – Up to 58% with extended regimen (Dimopoulos; Treon)

Side effects:

– Mostly related to infusion (shortness of breath, flushing, low BP) typically long infusions (2-6 hrs)

– Risk of hepatitis B flare must check before starting

– IgM flare (54-90%)

Gertz et al Leuk Lymphoma 2004;45:2047-55

Dimopoulos et al J Clin Oncol 2002;20:2327-33

Treon et al Ann Oncol 2005;16:132-8

Treon, S. P. et al. Ann Oncol 2004 15:1481-1483

IgM flare with Rituximab

• 50-60% with rituximab monotherapy

• Higher risk if baseline IgM 6000mg/dL or M-spike >4000mg/dL

• Typically occurs at 1 month, resolving by 4 months

Rituximab

PROS:

– Generally well-tolerated

– Does not cause bone marrow suppression

– Particularly useful for hemolysis (failed steroids) or neuropathy

– No known risk of MDS or second cancers

CONS:

– “Moderately effective” when used alone

– Infusion toxicities

– Expensive ($5000 per dose)

Bortezomib (Velcade)

Chymo-

tryptic

Site

Post-

Glutamyl

Site

Tryptic

Site

Bortezomib

Proteasome inhibitor

Regimen:

– Traditionally given IV twice weekly once weekly subcutaneous dosing now used

Major responses: – 78-85% as a single agent – Rapid onset (often within 6 wks) – Does not damage stem cells

Side effects: – neuropathy (74%), low platelets,

risk of shingles (herpes zoster)

proteasome

proteasome cross-section

Bortezomib

PROS:

– Generally well-tolerated

– Rapid responses

– No known risk of MDS or second cancers

– Not stem cell toxic

– No IgM flare

CONS:

– Injection

– Inconvenient dosing

– Toxicities:

Neuropathy

Herpes zoster

– Expensive ($7500 per cycle)

• Not routinely available for WM in many countries

Bendamustine Structurally similar to

alkylators and nucleoside analogues

Regimen: – Typically given IV for 2

days at the beginning of each 4 week cycle

Major responses: – 80% first-line

Side effects: – low blood counts, rash,

infusion reactions – not known to cause late

cancers

Bendamustine

PROS:

– Generally well-tolerated – does not cause hair loss

– Can be used in patients with kidney dysfunction

– No IgM flare

CONS:

– Intravenous

– Inconvenient dosing

– Toxicities:

Rash

Low blood counts

Long-term effects?

– Expensive ($4000 per cycle)

Combination therapies

Alkylating agents with rituximab – CVP-R/CPR, CHOP-R, CDR, Benda-R

Nucleoside analogue combinations – FC, FR, FCR

– CR, CCR

Bortezomib combinations – BR, BDR

Alkylator-Rituximab Combinations

CVP-R: – Cyclophosphamide (IV) – Vincristine (IV) – Prednisone (oral) – Rituximab (IV) – every 3-4 weeks for 6-8 cycles

Side effects: – Vincristine – neuropathy – Prednisone – insomnia, diabetes, stomach upset

Efficacy in indolent lymphoma: – Overall responses 80% – Time to progression 30 mos

Marcus et al Blood 2005;105:1417

Doubled over CVP

Should we step up CVP-R to CHOP-R?

CHOP-R addition of doxorubicin (H) can cause hair loss, low counts, nausea, skin irritation

CP-R vincristine can cause/worsen neuropathy

Response CHOP-R (23 pts) CVP-R (16 pts) CP-R (19 pts)

Overall responses 22 (96%) 14 (68%) 18 (95%)

Complete responses 4 (17%) 2 (12%) 0

Time to progression 18 mos >35 mos >20 mos

Ioakimidis et al. Clin Lymph Myeloma 2009;9:62

CDR

Regimen: – Cyclophosphamide orally twice daily (days 1-5)

– Dexamethasone IV

– Rituximab IV

– Given every 3 weeks for 6 months

Major responses: 83% but takes 4 mos to response

Side effects: – Well-tolerated

– Minimal drops in blood counts

– 1/3 developed IgM flare

Day 1 only

Dimopoulos J Clin Oncol 2007;25:3344

Nucleoside Analogue Combinations

Ref Regimen Major

Resp %

CR

%

Median Response Duration

1 FR (Fludarabine + Rituximab) 86 4.6 TTP 51.2 mos

2 CR (Cladribine + Rituximab) 89 28 TTTF 60.3 mos

3 CCR (Cladribine, cyclophosphamide + rituximab)

94 17 Duration of response 58.6 mos

4 FCR 79 11.6 EFS >77 mos

5 FCM (FC + mitoxantrone) 91 72 TTF >50 mos

Durable responses!

But toxicities are significant – low counts (prolonged), infections 1. Treon et al. Blood 2009;113:3673 2. Laszlo et al. JCO 2010;28:2233 3. Thomas et al. Haematologica 2007;92:PO-1227 4. Tedeschi et al. Cancer 2012;118:434 5. Federico et al. JCO 2013;31:1506

Bendamustine + rituximab

Responses >90%

Less toxic than CHOP-R – Fewer low blood counts,

infections, neuropathy, and hair loss

Many now prefer Benda-

R as first line therapy

Rummel et al. Lancet 2013;381:1203

Progression-free survival in WM subgroup

Rituximab maintenance significantly

reduces the risk of progression by 50%

stratified HR=0.50

95% CI 0.39; 0.64

p<.0001

Time (months)

Rituximab maintenance

N=505

Observation

N=513

6 0 12 18 24 30 36

Pro

gre

ss

ion

-fre

e r

ate

0.8

0.6

0.4

0.2

0

1.0

82%

66%

Patients at risk

505

513

472 443 336 230 103 18

469 411 289 195 82 15

Salles et al PRIMA study ASCO 2010

Maintenance Rituximab Schedules

Best dosing schedule and duration of maintenance unclear

Salles ASCO 2010 abstract

Van Oers Blood 2006;108:3295

Hainsworth JCO 2005;23:1088

Ghielmini Blood 2004;103:4416

Fortspointner Blood 2006;108:4003

End of

chemo 6 9

2 years 12

months

3

2 4 6 8 10 12

6 9 12 3

Bortezomib combinations

BR (Ghobrial JCO 2010;28:1422; Ghobrial Am J Hematol June 2010 Epub)

– Weekly bortezomib – Responses: first-line 65%, relapse 51% – Only 5% severe neuropathy

BDR (Treon JCO 2009;27:3830)

– Bortezomib twice weekly – Responses: firstline 83% – Time to response (1.1 mos) – Severe neuropathy 30%

Advantages to bortezomib combinations:

– Rapid onset of action – No IgM flare – Non-myelosuppressive, non-stem cell toxic

Autologous stem cell transplant

Used at some institutions for young patients in relapse

Must avoid stem-cell damaging chemo prior (fludarabine)

EBMT review of 158 WM pts: – Half relapse at 5 years – Best results if still sensitive to

chemotherapy and ≤3 prior lines of therapy

(Kyriakou J Clin Oncol 2010;28:2227)

Salvage chemo

The “patient’s stem cells”

are collected with growth

factors ± chemotherapy

High-dose chemotherapy ±

radiation to kill cancer cells

in the bone marrow

Stem cell infusion to regrow

the normal bone marrow

Plasmapheresis (PLEX)

Mechanical removal of proteins from blood One pheresis removes up to 50% IgM and reduces

viscosity by 60% Temporizing measure

Indications

– Hyperviscosity – Peripheral neuropathy – Bleeding related to the IgM protein

Longterm PLEX may be useful (Buskard et al. CMAJ 1977)

How to choose?

Patient considerations: – Age

– Comorbidities (diabetes, pre-existing neuropathy, heart disease, etc)

– Fitness or functional level

– Patient location, access to hospital/clinic

– Patient preference

Disease considerations: – Low blood counts

– Need for rapid disease control (hyperviscosity, severe cytopenias, cryoglobulinememia)

– WM complications (neuropathy, hemolysis, etc)

General First-line Approach

Older, debilitated

Chlorambucil

(Rituximab alone)

Younger and fit

Alkylator-rituximab combinations (Benda-R, CP-R, CDR) followed by maintenance rituximab

Special considerations: - Low blood counts Rituximab alone

- Need rapid response (i.e. hyperviscosity) fludarabine (FR) or bortezomib (BDR) combos avoid rituximab alone

General relapse approach

Additional considerations: – Choice of first-line therapy (duration of response,

tolerance)

– Whether stem cell transplant candidate

Guidelines: – Consider repeat of same chemo if response >2 years

– If <2 years, alternate regimen

– Consider stem cell collection in advance of fludarabine

– Clinical trials

Summary – Traditional Therapies for WM

Many options available must take an individualized approach

Supportive care important

How do new agents like ibrutinib change the use of traditional therapies in WM?

Myeloma and WM Group at Princess Margaret Cancer Centre

– Donna Reece (head) – Christine Chen – Suzanne Trudel – Rodger Tiedemann – Vishal Kukreti – Anca Prica