Waldenstrom

1
Waldenstroms Macroglobulinemia

• Jonathan L. Kaufman, MD
• Assistant Professor
• Hematology Oncology
• Winship Cancer Institute, Emory University

2
WHO Classification of Lymphomas

• B-cell neoplasms
• Peripheral B-cell neoplasms
• Follicular lymphoma
• B-cell CLL/small lymphocytic lymphoma
• Lymphoplasmacytic lymphoma/immunocytoma
• Extranodal marginal zone B-cell lymphoma of
  mucosa-associated lymphoid tissue (MALT) type
• Nodal marginal zone lymphoma (with or without
  monocytoid B-cells)
• Splenic marginal zone lymphoma (with or without
  villous lymphocytes)
• Hairy cell leukemia
• Plasmacytoma/plasma cell myeloma
• Mantle cell lymphoma
• B-cell prolymphocytic leukemia
• Diffuse large B-cell lymphoma
• Burkitt lymphoma
• Precursor B-cell neoplasms
• Precursor B-cell acute lymphoblastic leukemia (B
  ALL)

Indolent Low Grade
Other
Aggressive High Grade
3
Distribution of Indolent Lymphomas
Lymphoma Type Distribution,
Follicular
Grade 1 9.5
Grade 2 6.2
Grade 3 6.4
Small lymphocytic 6.7
Lymphoplasmacytic 1.2
Marginal zone
Nodal 1.8
Exranodal 7.6
Splenic lt 1
Blood . 1997893909-3918.
4
Cellular Origin of B-Cell Lymphomas
Most B-Cell Lymphomas Are Derived From the
Germinal Center
Hairy cell leukemiaProlymphocytic leukemia
B-CLL
Splenic marginal-zone lymphoma
MALT lymphoma
Multiple myeloma
Plasmacell
Lymphoplasmacytic lymphoma/Waldenströms
macroglobulinemiaPrimary effusion lymphoma
B-CLL(unmutated V gene)
Classical Hodgkins lymphoma
Posttransplantlymphomas
Küppers R. Nat Rev Cancer. 20055251-262.
5
Antigen Expression in B-Cell Lineage
CLL, PLL
HCL
WM
MM
FL, DLBCL
MCL, Burkitts
ALL
Pre-B
Early B
Stem cell
Mature B
Plasmacytoid B
Plasma
Activated B
Germinal center
CD5 CD19 CD20 CD22 CD52
Jaffe. In Non-Hodgkins Lymphoma. 1997.
6
Lymphoplasmacytic Lymphoma
Cells Lymphocytes, lymphoplasmacytoid cells, plasma cells excess mast cells in association with lymphoid aggregates
BM Interstitial pattern diffuse or nodular infiltrates excess mast cells in association with lymphoid aggregates
LN/SP Diffuse pattern

LN
BM
BM
7
Lack of Relationship Between Serum IgM Levels and
BM Involvement in WM
14,000
IgM (mg/dL)
12,000
10,000
8000
6000
4000
2000
0
0
20
40
60
80
100
BM Involvement ()

• Treon SP. Blood. 20091142375-2385.

8
Clinicopathological Manifestations of WM
? HCT, ? PLT, ? WBC
Hyperviscosity syndrome epistaxis, HA, impaired
vision gt 4.0 CP
Adenopathy, splenomegaly 15
IgM neuropathy ( 20) Cryoglobulinemia (lt
5) Cold agglutinemia (lt 10)
Fatigue, constitutional Sxs cytokinemia?
Treon SP, et al. Cancer Treat Res.
2008142211-242.
9
Funduscopic Exam in a WM Patient With
Hyperviscosity
10
IgM Related Neuropathies in WM

• Observed in 20 of WM patients
• IgM can often be found to react with specific
  neural antigens these autoantibodies define very
  specific clinical syndromes
• Myelin-associated glycoprotein (MAG)
• Ganglioside M1 (GM1)
• Sulfatide

MAG antibody staining
Courtesy of Todd Levine, MD
11
Cryoglobulinemia in a Patient With WM
Prepheresis
Postpheresis
12
Anemia in Waldenströms Macroglobulinemia

• Bone marrow replacement
• Hemodilution (high IgM levels)
• Hemolysis (cold agglutinin warm antibody)
• Iron deficiency (hepcidin)
• Therapeutic injury (nucleoside analoguemediated
  hemolysis MDS)

13
Summary

• WM is an IgM-producing lymphoplasmacytic lymphoma
  characterized by the presence of a BM infiltrate
  irrespective of serum IgM level
• Familial inheritance is common
• Molecular testing is revealing gene targets that
  can delineate patients at risk for familial
  disease as well as genes involved in the
  pathogenesis of WM
• Mast cells support the growth of WM cells though
  CD40L, which is induced by WM cell secreted
  sCD27, and represents a novel target of WM therapy

14
Treatment Approaches for Waldenströms
Macroglobulinemia
15
Consensus Panel Recommendations for Initiation of
Therapy in WM

• Hb 10 g/dL on basis of disease
• PLT lt 100,000 mm3 on basis of disease
• Symptomatic hyperviscosity (gt 4.0 cp)
• Moderate to severe peripheral neuropathy
• Symptomatic cryoglobulinemia, cold agglutinemia,
  amyloidosis, or symptomatic autoimmune related
  events on the basis of disease

Kyle RA, et al. Semin Oncol. 200330116-120.
16
International Prognostic Scoring System for WM

• Adverse prognostic factors
• Age gt 65 yrs
• Hb 11.5 g/dL
• Platelets 100 x 109 cells/L
• ß2M gt 3 mg/L
• IgM gt 7 g/dL

Number of Prognostic Factors 5-Year Survival,
0-1 87
2 68
3-5 36

• Excluding age.
• Or age gt 65 years.

Morel P, et al. Blood. 20091134163-4170.
17
Treatment Options in WM
ORR, CR,
Alkylator therapy (chlorambucil) 30-50 0-5
Nucleoside analogues 30-70 0-10
Monoclonal antibodies (rituximab, alemtuzumab) 40-50 0-5
Bortezomib 40-60 0-5
Combination therapies
Nucleoside analogues/ rituximab 70-90 5-10
Cyclophosphamide-based therapy/rituximab 70-90 5-15
Thalidomide/rituximab 70 5
Bortezomib/dex/rituximab 90 22
Treon SP, et al. Blood. 20061073442-3446.
Dimopoulos MA, et al. J Clin Oncol.
200927120-126. Treon SP, et al. Blood.
20081124452-4457. Treon SP, et al. J Clin
Oncol. 2009 273830-3835.
18
Response Status Correlates With PFS in WM Pts on
Rituximab-Based Therapy
1.00
P lt .0001
Plt0.0001
0.75
0.50
Without Progression ()
CR
0.25
VGPR
PR
MR
NR
0
0
10
20
30
40
50
60
70
80
90
Mos From Treatment Initiation
Treon SP, et al. Third International Pt Physic
Summit on WM. May 1-3, 2009 Boston, MA.
19
Rituximab-Induced IgM Flare in Pts Receiving
Combination Therapy

• Monotherapy (60)1
• Fludarabine/rituximab (40)2
• Cyclophosphamide/prednisone/rituximab (20 to
  30)3
• Thalidomide/rituximab (50)4
• Lenalidomide/rituximab (75)5
• Bortezomib/dexamethasone/rituximab (9)6

1. Treon SP, et al. Ann Oncol. 2004151481-1483.
2. Nichols G, et al. ASH 2004. Abstract 4612. 3.
Ioakimidis L, et al. Clin Lymphoma Myeloma.
2009962-66. 4. Treon SP, et al. Blood.
2008.1124452- 4457. 5. Treon SP, et al. Clin
Cancer Res. 200915355-360. 6. Treon SP, et al.
J Clin Oncol. 200927 Epub ahead of print.
20
Long-term Follow-up of WM Patients Treated With
Nucleoside Analogues

• N 463 patients with WM
• Long-term outcome of NA-treated patients compared
  with patients treated without an NA or who
  remained on watch and wait
• Incidence of transformation to aggressive
  lymphoma increased by 7-fold and MDS/AML by
  3-fold in NA-treated patients
• OS for transformed patients was not different vs
  nontransformed patients and may reflect effective
  salvage with CHOP-R

Leleu X, et al. J Clin Oncol. 200927250-255.
21
Randomized Clinical Trial of R-CHOP vs CHOP in
Patients With WM
1.0
0.9
0.8
0.7
0.6
Probability
0.5
0.4
0.3
R-CHOP, median 5.2
0.2
CHOP, median 1.8
0.1
P .0241
0.0
2
5
1
3
6
0
4
Yrs After the Start of Induction
Pts at Risk, n
23 18 16
9 7 3
025 14 10
5 1 0
R-CHOPCHOP
Buske C, et al. Leukemia. 200923153-161.
22
Randomized Clinical Trial of R-CHOP vs CHOP in
Patients With WM
Buske C, et al. Leukemia. 200923153-161.
23
StiL NHL 1-2008 Bendamustine-Rituximab (B-R) vs
CHOP-R

• Pts with previously untreated Stage III or IV NHL
  of the following types
• Follicular
• Waldenström
• Marginal zone
• Small lymphocytic
• Mantle cell
• Age 18 years
• WHO PS 0-2

Bendamustine-rituximab
R
CHOP-rituximab
Bendamustine 90 mg/m2 Day 1, 2 R Day 1, max 6
cycles, every 4 weeks. CHOP-R, max 6 cycles,
every 3 weeks.
Rummel MJ, et al. Blood. 2009114 Abstract 405.
24
B-R vs CHOP-R Hematotoxicity Grades 3/4
B-R (n 1450) of Cycles CHOP-R (n 1408) of Cycles P Value
Leukocytopenia 12.1 38.2 lt.0001
Neutropenia 10.7 48.5 lt.0001
G-CSF administered 4.0 20.0 lt.0001
Thrombocytopenia 0.7 1.2
Anemia 1.4 1.9
Rummel MJ, et al. Blood. 2009114 Abstract 405.
25
B-R vs CHOP-R Toxicities (All CTC Grades)
B-R (n 260)? of Patients CHOP-R (n 253)? of Patients P Value
Alopecia - lt.0001
Paresthesias 18 73 lt.0001
Stomatitis 16 47 lt.0001
Skin (erythema) 42 23 .0122
Allergic reaction (skin) 40 15 .0003
Infectious complications 96 127 .0025
Sepsis 1 8 .0190
Rummel MJ, et al. Blood. 2009114 Abstract 405.
26
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27
Maintenance Rituximab in WM

• Retrospective study
• 248 rituximab-naive WM patients who underwent
  treatment with a rituximab-containing regimen
• 86 patients (35) received maintenance rituximab
• Best categorical response, PFS, OS, serum
  immunoglobulins, and blood counts examined

Treon SP, et al. ASH 2009. Abstract 3750.
28
Results PFS
100
75
Rituximab maintenance
No rituximab maintenance
Alive or Without Progression ()
50
25
0
0
10
20
30
40
50
60
70
80
90
100
110
120
Mos From Treatment Initiation
Observation, Mos Maintenance, Mos P Value
Median PFS 28.6 56.3 .0001
Treon SP, et al. ASH 2009. Abstract 3750.