Traditional Therapies for Waldenstrom s Macroglobulinemia. Christine Chen Princess Margaret Cancer Centre Toronto, Canada May 2014

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1 Traditional Therapies for Waldenstrom s Macroglobulinemia Christine Chen Princess Margaret Cancer Centre Toronto, Canada May 2014

2 Jeff Atlin ( )

3 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

4 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)

5 Chlorambucil PROS: - Oral drug - Convenient and cheap - Well-tolerated - Lots of experience CONS: - Slow onset - Requires prolonged therapy - Risk of cancers or MDS Still used commonly worldwide but usually reserved for elderly or debilitated

6 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 fludarabine Major Responses: % (CR <10%) Rapid onset (<2 mos) Response durations up to 5 years

7 Nucleoside analogue side-effects 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

8 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

9 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

10 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: Dimopoulos et al J Clin Oncol 2002;20: Treon et al Ann Oncol 2005;16:132-8

11 IgM flare with Rituximab Treon, S. P. et al. Ann Oncol : % with rituximab monotherapy Higher risk if baseline IgM 6000mg/dL or M-spike >4000mg/dL Typically occurs at 1 month, resolving by 4 months

12 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)

13 Bortezomib (Velcade) Proteasome inhibitor proteasome Regimen: Traditionally given IV twice weekly once weekly subcutaneous dosing now used Post- Glutamyl Site Tryptic Site Major responses: 78-85% as a single agent Rapid onset (often within 6 wks) Does not damage stem cells Bortezomib Chymotryptic Site proteasome cross-section Side effects: neuropathy (74%), low platelets, risk of shingles (herpes zoster)

14 Bortezomib PROS: Generally welltolerated 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

15 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

16 Bendamustine PROS: Generally welltolerated 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)

17 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

18 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 Doubled over CVP Marcus et al Blood 2005;105:1417

19 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

20 CDR Regimen: Cyclophosphamide orally twice daily (days 1-5) Dexamethasone IV Day 1 only 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 Dimopoulos J Clin Oncol 2007;25:3344

21 Nucleoside Analogue Combinations Ref Regimen Major Resp % CR % Median Response Duration 1 FR (Fludarabine + Rituximab) TTP 51.2 mos 2 CR (Cladribine + Rituximab) TTTF 60.3 mos 3 CCR (Cladribine, cyclophosphamide + rituximab) Duration of response 58.6 mos 4 FCR EFS >77 mos 5 FCM (FC + mitoxantrone) TTF >50 mos Durable responses! But toxicities are significant low counts (prolonged), infections 1. Treon et al. Blood 2009;113: Laszlo et al. JCO 2010;28: Thomas et al. Haematologica 2007;92:PO Tedeschi et al. Cancer 2012;118: Federico et al. JCO 2013;31:1506

22 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 Progression-free survival in WM subgroup Rummel et al. Lancet 2013;381:1203

23 Progression-free rate Rituximab maintenance significantly reduces the risk of progression by 50% Patients at risk stratified HR= % CI 0.39; 0.64 p< Time (months) 82% 66% Rituximab maintenance N=505 Observation N=513 Salles et al PRIMA study ASCO 2010

24 Maintenance Rituximab Schedules End of chemo years months 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

25 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

26 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

27 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)

28 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)

29 General First-line Approach Older, debilitated Younger and fit Chlorambucil (Rituximab alone) 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

30 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

31 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?

32 Myeloma and WM Group at Princess Margaret Cancer Centre Donna Reece (head) Christine Chen Suzanne Trudel Rodger Tiedemann Vishal Kukreti Anca Prica