Waldenström macroglobulinemia

Stephen Ansell, MD, PhDMayo Clinic

Topics to be covered -

• What is Waldenström macroglobulinemia?

• Who needs treatment?• Standard treatment options –

• Newly diagnosed patients• Relapsed patients

• Questions

What is Waldenström macroglobulinemia?

Waldenström macroglobulinemia“A disease with two problems”

Gertz et al. The Oncologist 2000;5:63-67

Lymphoplasmacytic infiltrate

Monoclonal IgM protein

– Lymphoplasmacytic infiltrate (usually intertrabecular)

– Immunophenotype - surface IgM+, CD19+, CD20+, CD79a+ and PAX5+. CD5−, CD10−, CD23−.

– exclude CLL and mantle cell lymphoma

– del(6)(q21) is the most common genetic abnormality seen

Waldenström macroglobulinemiaMorphology and Immunophenotype

Waldenström macroglobulinemia

Monoclonal IgM

• Symptoms related to the monoclonal IgM protein are attributable to - – its characteristics in the

circulation, – its interaction with

various body tissues when deposited,

– and its autoantibody activity.

MYD88 Mutations in Waldenström macroglobulinemia

Waldenström macroglobulinemia – presenting

symptoms• 217 patients with serum monoclonal

IgM protein ≥ 3 g/dl and > 20% bone marrow involvement - – Asymptomatic (27%)– Anemia (38%), – Hyperviscosity (31%), – B symptoms (23%), – Bleeding (23%) – Neurological symptoms (22%)

García-Sanz et al. Brit J Haematol. 115: 575-582, 2001

Hyperviscosity due to Waldenström

macroglobulinemia

IgM deposition due to Waldenström

macroglobulinemia

Autoimmune hemolysis secondary to Waldenström

macroglobulinemia

Diagnostic Criteria for Waldenström macroglobulinemia

Kyle et al. Leukemia. 2009 Jan;23(1):3-9.

Time to developing WM and Survival in patients with Indolent WM or IgM

MGUS

Baldini L et al. JCO 2005;23:4662-4668

(— MGUS; ···IWM)MGUS (217 patients) and indolent Waldenström's macroglobulinemia (201 patients) groups

Time to evolution Overall survival

Risk of progression from IgM MGUS to WM or another B-cell malignancy

Kyle R A et al. Blood 2003;102:3759-3764

The overall average risk for progression is approximately 1.5% per year.

Survival of 587 symptomatic patients with Waldenström macroglobulinemia

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

Who needs treatment?

Patient 1• 66 year old man• Went for an executive physical – in good health

with no symptoms• Found to be mildly anemic (Hgb 12.8g/dl). Other

blood counts – normal• Also noted to have increased total protein with an

increased gammaglobulin level.• Monoclonal IgM – 1.4 g/dl• Bone marrow biopsy – 20% involvement by

lymphoplasmacytic lymphoma• CT scan – no lymph nodes

Patient 2

• 67 year old man• Severe fatigue, nausea, visual

difficulties, increasing confusion and sleepiness, gums bleed easily.

• Anemic (Hgb 8.8g/dl). Platelets decreased to 96,000.

• Ulcers have developed on his ankles• Monoclonal IgM – 6.6 g/dl. Viscosity –

5.8• Bone marrow biopsy – 85% involvement

by lymphoplasmacytic lymphoma• CT scan – enlarged liver and spleen and

multiple bulky lymph nodes in the abdomen

Many treatment options

• Watch and wait• Single agent rituximab• Chemoimmunotherapy combinations• Plasmapheresis• Clinical trials with new agents• Stem cell transplantation

• Which approach is best?

Does everyone need treatment at diagnosis?

García-Sanz et al. Brit J Haematol. 115: 575-582, 2001

Watch and wait in Patients with Waldenström's macroglobulinemia

Half of the patients who had no symptoms had not yet been treated at 3 years after their diagnosis

10% of the patients had not yet been treated at 10 years

What clinical findings suggest that treatment should be

started?• Fever, night sweats, or weight loss. • Lymphadenopathy or splenomegaly.• Hemoglobin ≤ 10 g/dL or a platelet count

< 100 x 10(9)/L due to marrow infiltration. • Complications such as hyperviscosity

syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia.

Kyle et al. Semin Oncol. 2003 Apr;30(2):116-20

Before starting therapy –

Does the patient have hyperviscosity and do they

need plasmapheresis?

Plasmapheresis for Waldenström's patients with hyperviscosity

• Symptoms of hyperviscosity – – Visual deterioration– Neurological symptoms– Bleeding

• Rarely seen with IgM <4g/dL

Before plasmapheresis - optic disc edema (arrowheads), central retinal hemorrhages (bold arrows), and venous “sausaging” (thin arrows).

Menke et al. Invest Ophthalmol Vis Sci. 2008Mar;49(3):1157-60.

Efficacy of Plasmapheresis for Waldenström's patients with

hyperviscosity

Initial treatment for untreated symptomatic WM

patients

Common Treatments used as initial therapy for WM

• Purine analogue based combinations – – FCR/FR

• Alkylating agent based combinations – – R-CHOP– DRC– R-Bendamustine

• Bortezomib based combinations –– BDR

• Rituximab alone

Purine analogue based combinations –

FCR/FRFludarabine, cyclophosphamide, rituximab (FCR) –

43 untreated, symptomatic WM patientsORR 79% - 12% CRs, 21% PRsEFS – 50.1 months44% had prolonged neutropenia

Tedeschi et al, Cancer. 2011 Jul 5.

Fludarabine, rituximab (FR) – 43 symptomatic WM patientsORR- 95% - 5% CRs, 81% PRsPFS – 51.2 months63% had ≥ grade 3 neutropenia,

thrombocytopenia or infection.Treon et al. Blood. 2009 Apr

16;113(16):3673-8.

Leleu X et al. JCO 2009;27:250-255

Increased incidence of transformation and myelodysplasia

in WM patients treated with nucleoside analogs.

193 – nucleoside analogue therapy136 – other therapy110 – no therapy

5% transformation and 2% MDS in NA group0.4% transformation in other groups

Alkylating agent based combinations – R-CHOP

Prospective randomized trial of CHOP compared to R-CHOP in WM patients.64 patients with untreated LPL/WMR-CHOP – 34 patients, CHOP – 30 patients

Higher ORR for R-CHOP (94 vs 67%, p=0.0085)Longer TTF - median of 63 months for R-CHOP vs 22 months for CHOP (p=0.0033)No major differences in treatment-associated toxicity

Buske et al. Leukemia. 2009 Jan;23(1):153-61.

Alkylating agent based combinations – DRC

72 patients with untreated symptomatic WM received Dex 20 mg IV, rituximab 375 mg/m2 IV on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5 (total dose, 1,000 mg/m2). Repeated every 21 days for 6 months.

ORR – 83% (95% CI, 73%-91%), including 7% CR, 67% PR, and 9% minor responses. 2-year PFS for all patients was 67%9% of patients - grade 3 or 4 neutropenia

Dimopoulos et al. J Clin Oncol. 2007 Aug 1;25(22):3344-9.

Comparative outcomes following CP-R, CVP-R, and CHOP-R in

Waldenström's macroglobulinemia.

Retrospective single institution study – CHOP-R (n = 23), CVP-R (n = 16), or CP-R (n = 19)

ORR and CR rates : CHOP-R (ORR, 96%; CR, 17%); CVP-R (ORR 88%; CR 12%); CP-R (ORR, 95%; CR, 0%); p= NS.

More treatment-related neuropathy and febrile neutropenia in patients treated with CVP-R and CHOP-R versus CP-R.

Ioakimidis et al. Clin Lymphoma Myeloma. 2009 Mar;9(1):62-6.

Alkylating agent based combinations – R-Bendamustine

30 patients with WM – bendamustine 90 mg/m2 I.V. on days 1, 2 and rituximab 375 mg/m2 I.V. on day 1. 6 patients received bendamustine with ofatumumab 1000 mg I.V. on day 1. Median number of treatment cycles was 5. ORR - 83.3%, with 5 VGPR and 20 PR. Median PFS was 13.2 months. Prolonged myelosuppression was more common in patients who received prior nucleoside analogues

Treon et al. Clin Lymphoma Myeloma Leuk. 2011 Feb 1;11(1):133-5.

Bendamustine plus rituximab compared with R-CHOP in WM

patients• A subset analysis in the prospective

randomized STIL trial - bendamustine plus rituximab (BR) compared with R-CHOP

Rummel MJ, et al. Lancet. 2013 Apr 6;381(9873):1203-10.

Bortezomib based combinations –

BDR/BRBortezomib, dexamethasone, rituximab (BDR) –23 untreated, symptomatic WM patientsORR 96% - 3 CRs, 5 VGPRs, 11 PRsShort follow up - PFS – not reached61% had peripheral neuropathy

Treon et al, J Clin Oncol. 2009 Aug 10;27(23):3830-5.

Bortezomib, rituximab (BR) – 26 untreated, symptomatic WM patientsORR- 88% - 1 CR, 1 VGPR, 15 PRsPFS – not reached12% had ≥ grade 3 neutropenia, no grade

3 or 4 neuropathy.Ghobrial et al. Am J Hematol. 2010 Sep;85(9):670-4.

Rituximab alone for Waldenström's

macroglobulinemia69 symptomatic WM patients – rituximab x 4 doses

ORR 52% - 27% PR, 25% MRMedian duration of response – 27 months

Gertz et al, Leuk Lymphoma. 2004 Oct;45(10):2047-55.

Same study – evaluated IgM levels for “flare”

54% had an increase in IgM27% still elevated at 4 monthsNo factors predicting an increase in IgM

levels could be identified.Ghobrial et al. Cancer. 2004 Dec 1;101(11):2593-8.

Mayo Clinic (mSMART) consensus for management of newly diagnosed Waldenström macroglobulinemia

Ansell et al. Mayo Clin Proc. 2010;85:824-833#Bendamustine + rituximab is an alternative

#

Subsequent treatment in relapsed WM patients

New drugs with promiseDr Ghobrial – clinical trials and new agents

• Bendamustine• mTOR inhibitors - RAD001 (Everolimus)• New anti-CD20 antibodies• BTK inhibitors - ibrutinib• Anti-bcl2 agents - Obatoclax• New HDAC inhibitors - LBH589• New proteosome inhibitors – MLN9708• New Imids - Pomalidomide (CC-4047)• Other agents – Enzastaurin, Perifosine,

Gleevec, Simvastatin, sildenafil citrate

Mayo Clinic (mSMART) consensus for management of relapsed Waldenström

macroglobulinemia.

Ansell et al. Mayo Clin Proc. 2010;85:824-833

Transplantation in relapsed Waldenström macroglobulinemia.

Autologous transplant –158 WM patientsNon-relapse mortality – 3.8%5-year PFS – 40%5-year OS – 68%

Kyriakou et al, J Clin Oncol. 2010 May 1;28(13):2227-32.

Allogeneic transplant – 86 WM patients (37 MAC and 49 RIC)Non-relapse mortality – 33%(MAC), 23%

(RIC)5-year PFS – 56%5-year OS – 62%

Kyriakou et al. J Clin Oncol. 2010 Nov 20;28(33):4926-34.

Questions?