Tratamiento de macroglobulinemia de Waldenström - Dr. Jorge Julio Castillo

How I treat Waldenstrรถm Macroglobulinemia in 2016

Jorge J. Castillo, MD Assistant Professor of Medicine Harvard Medical School Jorgej_castillo@dfci.harvard.edu

Disclosures Consulting • Otsuka Pharmaceuticals • Biogen IDEC • Alexion Pharmaceuticals

Research Funding • Millennium Pharmaceuticals • Gilead Sciences • Pharmacyclics Inc. • Abbvie Inc.

Waldenström’s Macroglobulinemia – first described by Jan Gosta Waldenström in 1944.

Lymphoplasmacytic Lymphoma • Cellular Morphology: lymphocytes, lymphoplasmacytic cells, plasma cells • BM Pattern: interstitial with diffuse or nodular infiltrates with excess mast cells associated with lymphoid aggregates.

• LN/SP: diffuse pattern

BM

BM

LN

1.00

0.00

0.00

Overall survival probability 0.25 0.50 0.75

Overall survival probability 0.25 0.50 0.75

1.00

Improved survival in patients with Waldenstrom macroglobulinemia

0 0

5

10 Years from diagnosis 1981-1990 2001-2010

15 1991-2000

20

5

10 Years from diagnosis 20-49 years 60-69 years 80+ years

15 50-59 years 70-79 years

Age at diagnosis is the most important prognostic factor Castillo et al. Br J Haematol 2015

20

Manifestations of Waldenstrom macroglobulinemia ↓HCT, ↓PLT, ↓WBC

Hyperviscosity Syndrome: Nosebleeds, headache, Impaired vision >4.0 CP Adenopathy, splenomegaly ≤20% (at Dx) Treon, Hematol Oncol 2013

Hepcidin ↓Fe Anemia

IgM Neuropathy (22%) Cryoglobulinemia (10%) Cold Agglutinemia (5%)

Guidelines for Initiation of Therapy • • • • •

Hemoglobin ≤10 g/dL on basis of disease Platelet <100,000 mm3 on basis of disease Symptomatic hyperviscosity (>4.0 cp) 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.

Kyle, Semin Oncol 2003; Anderson, JNCCN 2016.

TREATMENT OPTIONS

Bendamustine and rituximab Subset analysis RCT • Bendamustine-R (N=22) vs.

CHOP-R (N=19) • Good option for patients with lympadenopathy or enlarged liver/spleen • ORR 80%; CR 20% • PFS 69 months Rummel, Lancet 2013 Treon Clin Lymphoma Myeloma Leuk 2011

Adverse events Potential stem cell toxicity Cytopenias Infusion reactions 0.5-1% risk of secondary leukemia

Cyclophosphamide-based therapy Phase II studies • Combined with rituximab and dexamethasone (CDR) • Widely available • Well tolerated • ORR 83%; CR 7% • Median PFS 3 years when given upfront Dimopoulos, J Clin Oncol 2007 Buske, Leukemia 2009 Kastritis Blood 2015

Adverse events • Alopecia • Cytopenias • 1% risk of secondary leukemia

Bortezomib-based therapy Advantages • Combined with rituximab and dexamethasone (BDR) • ORR 80-90% • CR 10-20% • Median TTR: 4-8 weeks • No risk of secondary malignancies Treon, J Clin Oncol 2009 Ghobrial, Am J Hematol 2010 Dimopoulos, Blood 2013.

Disadvantages • Peripheral neuropathy – less with weekly or SQ • Thrombocytopenia • Steroids and zoster prophylaxis

Carfilzomib-based therapy Advantages • Combined with rituximab and dexamethasone (CARD) • ORR 87% • CR 3%; VGPR 35% • Less neuropathy (<5%)

Treon, Blood 2014

Disadvantages • Increases glucose and cholesterol • Hypogammaglobulinemia • Heart problems: HTN, CAD • Steroids and zoster prophylaxis

Nucleoside analogues Advantages • Randomized study showed fludarabine better than chlorambucil • ORR: 48% vs. 39% • Median PFS: 36 vs. 27 months • ORR 80% when rituximab added Dimopoulos, J Clin Oncol 2009 Leleu, J Clin Oncol 2009 Leblond J Clin Oncol 2013

Disadvantages • Risk of MDS/AML is 5-10% • Avoid in ASCT candidates • Lower doses for older patients

Rituximab single agent Advantages • Well tolerated • ORR: 30-40% • Median TTR 3-4 months • Most commonly used regimen for Waldenström in the US.

Treon Clin Cancer Res 2001 Castillo Br J Haematol 2016 Olszewski Oncologist 2016

Disadvantages • Delayed responses • Infusion reactions • Avoid if IgM >4,000 mg/dL or HV • IgM flare: 40% of patients • Rituximab Intolerance (7%) – Consider Ofatumumab.

To Maintain or Not to Maintain?

Observation vs. maintenance rituximab therapy OS

100

100

75

75

50 Rituximab Maintenance

Alive (%)

Alive or without progression (%)

PFS

25

50

Rituximab Maintenance N=246

No Rituximab Maintenance N = 248

25 No Rituximab Maintenance

0

0 0

20

40

60

80

100

Time from treatment initiation (months)

Treon Br J Haematol 2011

120

0

20

40

60

80

100

Time from treatment initiation (months)

Disadvantages Infusion reactions Increased risk of infections Hypogammaglobulinemia

120

New Directions in WM

MYD88 L265P Somatic Mutation C to G at position 38186241 at 3p22.2

• 91% of WM pts • 10% IGM MGUS • No difference sporadic vs. familial pts Treon, New Engl J Med 2012

Acquired UPD at 3p22.

MYD88 L265P in WM/IGM MGUS METHOD

TISSUE

WM

IGM MGUS

Treon

WGS/Sanger

BM CD19+

91%

10%

Xu

AS-PCR

BM CD19+

93%

54%

Gachard

PCR

BM

70%

Varettoni

AS-PCR

BM

100%

Landgren

Sanger

BM

Jiminez

AS-PCR

BM

86%

Poulain

PCR

BM CD19+

80%

Argentou

PCR-RFLP

BM

92%

Willenbacher

Sanger

BM

86%

Mori

AS-PCR/BSiE1

BM

80%

Ondrejka

AS-PCR

BM

100%

Ansell

WES/AS-PCR

BM

97%

Patkar

AS-PCR

BM

85%

47% 54% 87% 1/1 MGUS

TLR

IL1R

L265P

BTK

MYD88

P

P

L265P

MYD88

PI3K

P

P

P

TAK1

MYD88 L265P Signal Pathway

P

TRAF6 P P

NEMO IKKα IKKβ

P P

IκBα

P

p50 P

p65

NFkB

Yang et al, Blood 2013 SURVIVAL

WHIM-like CXCR4 C-tail mutations in WM Warts, Hypogammaglobulinemia, Infection, and Myelokathexis.

B

Hunter Blood 2014

Most common: CXCR4C1013G (S338X )

Somatic WHIM-CXCR4 Mutations were detected in 21/63 patients (34%) on ibrutinib study.

MYD88 and CXCR4 mutations Genomic abnormalities

CXCR4

Treon Blood 2014

MYD88 Mutant

Wild-type

Mutant

30%

------------

Wild-type

60%

10%

Treon N Engl J Med 2015

Ibrutinib in previously treated WM Median

Range

63

44-86

Male/Female

48/15

N/A

Prior therapies

2

1-8

Hemoglobin (mg/dL)

10.5

8.2-13.8

Serum IgM (mg/dL)

3,610

735-8,390

B2M (mg/dL)

3.9

1.3-14.2

BM Involvement (%)

70

3-95

Adenopathy >1.5 cm

37 (58.7%)

N/A

Splenomegaly >15 cm

7 (11.1%)

N/A

Age (yrs)

Treon N Engl J Med 2015

Serial Serum IgM Levels Following Ibrutinib Best IgM Response: 3,610 to 915 mg/dL; p<0.0001 9000

Serum IgM (mg/dL)

8000

Median time to MR=4 weeks

7000 6000 5000 4000 3000 2000 1000 0 Baseline Cycle 2 Cycle 3 Cycle 6 Cycle 9 Cycle 12 Cycle 15 Cycle 18 Cycle 21

Serial Hemoglobin Levels Following Ibrutinib Best Hemoglobin Response: 10.5 to 13.5; p<0.0001 16

Hemoglobin (g/dL)

15 14 13 12 11 10 9 8

Response and survival outcomes

Treon NEJM 2015

FDA News Release FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma First drug approved to treat WaldenstrĂśmâ&#x20AC;&#x2122;s macroglobulinemia For Immediate Release January 29, 2015

Ibrutinib Related Adverse Events Early • Anemia • Neutropenia • Thrombocytopenia • Rash • Nausea • Diarrhea • Arthralgias

Delayed • Increased risk of bleeding • Atrial fibrillation • Hypertension

Novel pathways, novel targets, novel agents • Oral proteasome inhibitors – Ixazomib – Oprozomib – Marizomib

• Anti-CD38 antibodies – Daratumumab

• Anti-CXCR4 therapy – Ulocuplumab

• BTK inhibitors – Acalabrutinib – BGB-3111

• BCL2 antagonists – Venetoclax

• IRAK1/4 inhibitors • MYD88 assembly inhibitors

Summary § Waldenström macroglobulinemia is rare and incurable but patients enjoy prolonged survival. § Most treatment options are highly effective but with toxicity. § MYD88 L265P is present >90% of WM patients and triggers activation of BTK in WM cells. § The oral BTK inhibitor ibrutinib is safe, effective and approved to treat patients with symptomatic WM. § PI3K inhibitors, CXCR4 inhibitors, MYD88 blockers, BCL2 antagonists to enter clinical trials.

How I treat Waldenstrรถm Macroglobulinemia in 2016

Jorge J. Castillo, MD Assistant Professor of Medicine Harvard Medical School jorgej_castillo@dfci.harvard.edu