Autoimmunity in Chronic Lymphocytic Leukemia
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Autoimmunity in Chronic Lymphocytic Leukemia
Autoimmunity in Chronic Lymphocytic Leukemia
Thomas M. Habermann, M.D.
Professor of Medicine
Mayo Clinic College of Medicine
Rochester, MN
October 25, 2013
New York, New York
Thomas M. Habermann, M.D.
Professor of Medicine
Mayo Clinic College of Medicine
Rochester, MN
October 25, 2013
New York, New York
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DisclosuresThomas M. Habermann, M.D.
DisclosuresThomas M. Habermann, M.D.
• NCI/NIH Grants:• ECOG U10 Grant PI: 1993-present• R01: Co-PI
• SNPs in lymphoma: 2002-present• Cancer Control: 2002-2012
• Lymphoma SPORE: co-investigator: 2002-present
• Foundation: Lymphoma Research Foundation: Mantle Cell Lymphoma
• NCI/NIH Grants:• ECOG U10 Grant PI: 1993-present• R01: Co-PI
• SNPs in lymphoma: 2002-present• Cancer Control: 2002-2012
• Lymphoma SPORE: co-investigator: 2002-present
• Foundation: Lymphoma Research Foundation: Mantle Cell Lymphoma
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Four Questions Four Questions
• What are the clinical manifestations of autoimmunity in CLL?
• What are the associations of autoimmunity in CLL?
• What is the biology?
• What are the treatment approaches?
• What are the clinical manifestations of autoimmunity in CLL?
• What are the associations of autoimmunity in CLL?
• What is the biology?
• What are the treatment approaches?
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RBCRBCHaptoglobinHaptoglobin
AlbuminAlbumin
HgbHgbHemosiderinHemosiderin
HgbHgbHgbHgb
HgbHgb
Hgb-HPcomplexHgb-HPcomplex
MethemalbuminMethemalbumin
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Antihuman IgGAntihuman IgG
Antihuman Complement, Antihuman Complement, C3C3
Antihuman IgGAntihuman IgG
Antihuman Complement, Antihuman Complement, C3C3
Human IgG or C3Human IgG or C3red cell antibodyred cell antibodyHuman IgG or C3Human IgG or C3red cell antibodyred cell antibody
Red cellRed cell
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Paraneoplastic PemphigusParaneoplastic Pemphigus
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Paraneoplastic PemphigusParaneoplastic Pemphigus
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Cold Agglutinin Cold Agglutinin
Rouleaux
Peripheral blood, Wright-Giemsa, 800x
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Hodgson K, Ferrer G, Montserrat E, et al. Haematologica. 2011;96: 752-761.
Mechanisms of Autoimmune Disease in Chronic Lymphocytic LeukemiaMechanisms of Autoimmune Disease in Chronic Lymphocytic Leukemia
AA Antigenic presentationAntigenic presentation
DD Antigenic driveAntigenic drive CC Autoantibody secretionAutoantibody secretion
BB Cytokine secretionCytokine secretion and cell-cell contact and cell-cell contact
Loss of toleranceLoss of tolerance
AutoimmuneAutoimmunehemolytic anemiahemolytic anemia
Cold agglutininCold agglutinindiseasedisease
Paraneoplastic pemphigusParaneoplastic pemphigus
Dendritic cellDendritic cellMacrophageMacrophage
IL-6IL-6IL-10IL-10
TGF-TGF- TNFTNF
FAS-LFAS-L
T cellT cell
ErythrocyteErythrocyte
B cellsB cells
Polyclonal Polyclonal IgGIgG
Rh or B3Rh or B3
T cellT cell
CLL cell
Polyreactive BCRPolyreactive BCR
Auto-antigensAuto-antigens
Cross-reactiveCross-reactivemonoclonal monoclonal antibodiesantibodies
Anti-li IgMAnti-li IgM
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NFBc-
Jun
c-Fos
NFB
++
++
CXCL12CXCL12
CXCR4 CXCR4
GCR
Germinal CenterGerminal Center
G
Post-inflammatoryGenes
BurgerJA, Motserrat E. Blood . 2013;121:1501-1509.
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Burger JA, Montserrat E. Blood. 2013;121, 1501-1509.
PI3Ks
Btk
Syk
Syk
Btk
PI3KsG
Homing &retention
Survival &proliferation
CXCL12CXCL12
CXCR4,CXCR4,CXCR5CXCR5
T CellsT Cells
CCL3CCL3CCL4CCL4
BCRBCR
AntigenAntigenCD79CD79a,ba,b
CD49dCD49d(VLA-4)(VLA-4)
MSCMSC
CLL
VCAM-1, FNVCAM-1, FN
NLC
CXCL12,CXCL13
CD40LCD40LCD40CD40
++
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Chronic Lymphocytic Leukemia:Biology
Chronic Lymphocytic Leukemia:Biology
• Acquired T-cell defects:• Numerical increase in T-cells• Inversion of the CD4:CD8 ratio
• Production of CLL cells of the inhibitory cytokines IL-6, Il-10, TNF, and TGF-beta
• Alterations in T-cell cytoskeleton formation and vesicle transportation
Görgün G, Holderried TAW, Zahrieh D, et al. J Clin Invest 2005;115:1797-1805.
Ramsay AG, Gribben J. Haematologica 2009;94:11198-1202.
• Acquired T-cell defects:• Numerical increase in T-cells• Inversion of the CD4:CD8 ratio
• Production of CLL cells of the inhibitory cytokines IL-6, Il-10, TNF, and TGF-beta
• Alterations in T-cell cytoskeleton formation and vesicle transportation
Görgün G, Holderried TAW, Zahrieh D, et al. J Clin Invest 2005;115:1797-1805.
Ramsay AG, Gribben J. Haematologica 2009;94:11198-1202.
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Chronic Lymphocytic LeukemiaBiology ITP and AIHA Associations
Chronic Lymphocytic LeukemiaBiology ITP and AIHA Associations
• Unmutated IGHV gene
• High ZAP70 expression
• Increased serum beta-2 microglobulin
Zent CS, Ding W, Schwager SM, et al. Br J Haematol. 2008;141:615- 621.
Moreno C, Hodgson K, Ferrer G, et al. Blood. 2010116:4771-4776.
Visco C, Giaretta I, Ruggeri M, et al. Leukemia. 2007;21:1092-1093.
• Unmutated IGHV gene
• High ZAP70 expression
• Increased serum beta-2 microglobulin
Zent CS, Ding W, Schwager SM, et al. Br J Haematol. 2008;141:615- 621.
Moreno C, Hodgson K, Ferrer G, et al. Blood. 2010116:4771-4776.
Visco C, Giaretta I, Ruggeri M, et al. Leukemia. 2007;21:1092-1093.
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Chronic Lymphocytic Leukemia:Biology
Chronic Lymphocytic Leukemia:Biology
• CLL is associated with impairment of the innate immune system
Schlesinger M, Broman I, Lugassy G. Leukemia 1996;10:1509-1513.
Maki G, Hayes GM, Naji A, et al. Leukemia 2008;22:998-1006.
• CLL is associated with impairment of the innate immune system
Schlesinger M, Broman I, Lugassy G. Leukemia 1996;10:1509-1513.
Maki G, Hayes GM, Naji A, et al. Leukemia 2008;22:998-1006.
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Chronic Lymphocytic LeukemiaAutoimmunity: Why Else Important?
Chronic Lymphocytic LeukemiaAutoimmunity: Why Else Important?
• Is this is important in how a patient might be managed? A Rai stage III or IV or Binet stage C patient could be “down-staged” to a I or II or A.
• Patients with active AIHA and ITP are still excluded from randomized clinical trials
• “AID cytopenia occurred in all stages of CLL, patients responded well to treatment, AID did not alter OS, and AID contributed to death in only 6 (12%) of patients.”
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
• Is this is important in how a patient might be managed? A Rai stage III or IV or Binet stage C patient could be “down-staged” to a I or II or A.
• Patients with active AIHA and ITP are still excluded from randomized clinical trials
• “AID cytopenia occurred in all stages of CLL, patients responded well to treatment, AID did not alter OS, and AID contributed to death in only 6 (12%) of patients.”
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
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Chronic Lymphocytic LeukemiaAutoimmunity: Why Important?Chronic Lymphocytic LeukemiaAutoimmunity: Why Important?
BM Failure AID p=
Total 228 (75%) 75 (25%)
Median OS 4.4 yrs 9.1 yrs <0.001
CLL dx 1 yr 9.3 yrs =0.881
♂/♀ 160/68 =0.05
Vs . OS
Without (yrs) 12.4/9.7 =.045
Zent CS, Ding W, Schwager SM, et al. Br J Haematol 2008;141:615-621.
BM Failure AID p=
Total 228 (75%) 75 (25%)
Median OS 4.4 yrs 9.1 yrs <0.001
CLL dx 1 yr 9.3 yrs =0.881
♂/♀ 160/68 =0.05
Vs . OS
Without (yrs) 12.4/9.7 =.045
Zent CS, Ding W, Schwager SM, et al. Br J Haematol 2008;141:615-621.
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AID 75 47 29 15 8 4
228 123 66 33 11 4
Survival from Diagnosis of Cytopenia
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Chronic Lymphocytic Leukemia:Positive DAT (Coombs’ test)
Chronic Lymphocytic Leukemia:Positive DAT (Coombs’ test)
• Incidence: 2.3%-7%
• AIHA associated with:• advanced stage• Active CLL• Older patients independent of stage or
durationMauro FR, Foa R, Cerretti R, et al. Blood 2000;95:2786-2792.
Moreno C, Hodgson K, Ferrer G, et al. Blood 2010;116:4771-4776.
Barcellini W, Capalbo S, Agostinelli RM, et al. Haematologica 2006;91:1689-1692.
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
• Incidence: 2.3%-7%
• AIHA associated with:• advanced stage• Active CLL• Older patients independent of stage or
durationMauro FR, Foa R, Cerretti R, et al. Blood 2000;95:2786-2792.
Moreno C, Hodgson K, Ferrer G, et al. Blood 2010;116:4771-4776.
Barcellini W, Capalbo S, Agostinelli RM, et al. Haematologica 2006;91:1689-1692.
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
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Chronic Lymphocytic Leukemia:Positive DAT: prognosis
Chronic Lymphocytic Leukemia:Positive DAT: prognosis
Series # Prognosis
Mauro 1203 active disease, no OS influence
Zent 1750 Immune cytopenia superior OS
Moreno 961 Immune cytopenia superior OS
Dearden 783 + DAT poorer response to Rx
Mauro FR, Foa R, Cerretti R, et al. Blood 2000;95:2786-2792.
Zent C, Ding W, Schwager SM, et al. Br J Haematol 2008;141:615-621.
Moreno C, Hodgson K, Ferrer G, et al. Blood 2010;116:4771-4776.
Dearden C, Wase R, Else M, et al. Blood 2008;111:1820-1826.
Series # Prognosis
Mauro 1203 active disease, no OS influence
Zent 1750 Immune cytopenia superior OS
Moreno 961 Immune cytopenia superior OS
Dearden 783 + DAT poorer response to Rx
Mauro FR, Foa R, Cerretti R, et al. Blood 2000;95:2786-2792.
Zent C, Ding W, Schwager SM, et al. Br J Haematol 2008;141:615-621.
Moreno C, Hodgson K, Ferrer G, et al. Blood 2010;116:4771-4776.
Dearden C, Wase R, Else M, et al. Blood 2008;111:1820-1826.
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Chronic Lymphocytic Leukemia:Positive DAT After Treatment
Chronic Lymphocytic Leukemia:Positive DAT After Treatment
• CCL4 trial:
Treatment +DAT AIHA p< • Chlorambucil 14% 12%• Fludarabine (F): 13% 11%• Fludarabine 10% 5% .01 + cyclophosphamide
• German CLL 8 trial FC +/-R AIHA risk: 1%
• Conclusion: Risk after purine analog no greaterDearden C, Wade R, Else M, et al. Blood 2008;111:1820-1826.
Hallek M, Fischer K, Fingerle-Rowson G, et al. Lancet 2010;376:1164-1174.
• CCL4 trial:
Treatment +DAT AIHA p< • Chlorambucil 14% 12%• Fludarabine (F): 13% 11%• Fludarabine 10% 5% .01 + cyclophosphamide
• German CLL 8 trial FC +/-R AIHA risk: 1%
• Conclusion: Risk after purine analog no greaterDearden C, Wade R, Else M, et al. Blood 2008;111:1820-1826.
Hallek M, Fischer K, Fingerle-Rowson G, et al. Lancet 2010;376:1164-1174.
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Chronic Lymphocytic Leukemia:Positive DAT (Coombs’ test)
Chronic Lymphocytic Leukemia:Positive DAT (Coombs’ test)
• Treatment:• 34/37 treatment directed specifically at AIHA• 86% corticosteroids• 13 (35%) achieved a CR and 14 (38%) PR with
a median duration of response of 0.62 years
Zent CS, Ding W, Schwager SM, et al. 2008;141:615-621.
Other refrerences:
Moreno C, Hodgson K, Ferrer G, et al. Blood 2010;116:4771-4776.
Visco C, GiarettaI, Ruggeri M, et al. Leukemia 2008:222:998-1006.
• Treatment:• 34/37 treatment directed specifically at AIHA• 86% corticosteroids• 13 (35%) achieved a CR and 14 (38%) PR with
a median duration of response of 0.62 years
Zent CS, Ding W, Schwager SM, et al. 2008;141:615-621.
Other refrerences:
Moreno C, Hodgson K, Ferrer G, et al. Blood 2010;116:4771-4776.
Visco C, GiarettaI, Ruggeri M, et al. Leukemia 2008:222:998-1006.
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Chronic Lymphocytic Leukemia:Immune Thrombocytopenia
Chronic Lymphocytic Leukemia:Immune Thrombocytopenia
• Incidence: <1%-5.0%
• The diagnosis is a clinical one • Sudden drop in platelet count (> 50% or <100
X 10(9)/L)• Absence of splenomegaly, infection, or
chemotherapy• Increased megakaryocytes
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
• Incidence: <1%-5.0%
• The diagnosis is a clinical one • Sudden drop in platelet count (> 50% or <100
X 10(9)/L)• Absence of splenomegaly, infection, or
chemotherapy• Increased megakaryocytes
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
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Chronic Lymphocytic LeukemiaImmune Thrombocytopenia
Chronic Lymphocytic LeukemiaImmune Thrombocytopenia
• + DAT in 47% of patients with ITP
• 31 (89%) were treated• 27 (87%) received corticosteroids and only
treatment in 11 (35%)• 9 (29%) CR and 11 (35%) PR with a median
duration of response of 1.9 years
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
• + DAT in 47% of patients with ITP
• 31 (89%) were treated• 27 (87%) received corticosteroids and only
treatment in 11 (35%)• 9 (29%) CR and 11 (35%) PR with a median
duration of response of 1.9 years
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
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Chronic Lymphocytic LeukemiaImmune Thrombocytopenia
Chronic Lymphocytic LeukemiaImmune Thrombocytopenia
• Treatment:• If CLL quiescent, then treat as ITP only:
• Corticosteroids, splenectomy• Alternative immunosuppression• Rituximab• IV immunoglobulin• Thrombopoietin receptor agonists
• If active disease, then treat the underlying disease
• Treatment:• If CLL quiescent, then treat as ITP only:
• Corticosteroids, splenectomy• Alternative immunosuppression• Rituximab• IV immunoglobulin• Thrombopoietin receptor agonists
• If active disease, then treat the underlying disease
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Chronic Lymphocytic Leukemia and AIHA and ITP
Chronic Lymphocytic Leukemia and AIHA and ITP
• Purine analogs should be avoided in patients with a history of autoimmune cytopenias, particularly if related to purine-analog therapy
• R-CVP : 14/20 CR; 5/20 PR; median TTT 27.7 mos Bastion Y Coiffier B, Dumontet C, et al. Ann Oncol 1992;3:171-172.
Myint H, Copplestone JA, Orchard J, et al. Br J Haematol 1995;91:341-344.
Bowen DA, Call TG, Shanafelt TD, et al. Leuk & Ly 2010;51:620-627.
• Purine analogs should be avoided in patients with a history of autoimmune cytopenias, particularly if related to purine-analog therapy
• R-CVP : 14/20 CR; 5/20 PR; median TTT 27.7 mos Bastion Y Coiffier B, Dumontet C, et al. Ann Oncol 1992;3:171-172.
Myint H, Copplestone JA, Orchard J, et al. Br J Haematol 1995;91:341-344.
Bowen DA, Call TG, Shanafelt TD, et al. Leuk & Ly 2010;51:620-627.
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Chronic Lymphocytic LeukemiaImmune Thrombocytopenia
Chronic Lymphocytic LeukemiaImmune Thrombocytopenia
• A study of 1,278 patients demonstrated that acute ITP at diagnosis or at any time in the disease was associated with an inferior outcome compared to those who never had ITP
• This was probably related to the association of ITP with an unmutated IGVH gene
Visco C, GiarettaI, Ruggeri M, et al. Leukemia 2007;21:1092-1093.
Visco C, Ruggeri M, Evangelista LM, et al. Blood 2008;111:1110-1116.
• A study of 1,278 patients demonstrated that acute ITP at diagnosis or at any time in the disease was associated with an inferior outcome compared to those who never had ITP
• This was probably related to the association of ITP with an unmutated IGVH gene
Visco C, GiarettaI, Ruggeri M, et al. Leukemia 2007;21:1092-1093.
Visco C, Ruggeri M, Evangelista LM, et al. Blood 2008;111:1110-1116.
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Chronic Lymphocytic LeukemiaPure Red Cell Aplasia
Chronic Lymphocytic LeukemiaPure Red Cell Aplasia
• Incidence: 0.5%-2%
• Parvovirus IgM serology was positive in 3/6 patients
• 9/9 treatment; corticosteroids 7/9 and in 5 this was the only treatment
• Median duration of initial response was 0.24 years
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
• Incidence: 0.5%-2%
• Parvovirus IgM serology was positive in 3/6 patients
• 9/9 treatment; corticosteroids 7/9 and in 5 this was the only treatment
• Median duration of initial response was 0.24 years
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
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Chronic Lymphocytic LeukemiaAutoimmune Neutropenia
Chronic Lymphocytic LeukemiaAutoimmune Neutropenia
• Incidence: <1%-2%
• Presentation: serious neutropenic infections
• No responders in Mayo Clinic experience
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
• Incidence: <1%-2%
• Presentation: serious neutropenic infections
• No responders in Mayo Clinic experience
Zent CS, Ding W, Reinalda MS, et al. Leuk & Lymph 2009;50:1261-1268.
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Chronic Lymphocytic Leukemia:No Cases of
Chronic Lymphocytic Leukemia:No Cases of
• Acquired hemophilia
• Acquired von Willebrand disease
• Acquired hemophilia
• Acquired von Willebrand disease
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Chronic Lymphocytic Leukemia:Is AID a risk for developing CLL?Chronic Lymphocytic Leukemia:Is AID a risk for developing CLL?
• Nordic case-control study: risk of CLL was much higher in patients with a positive personal or family history of CLL
• Individuals who developed CLL had a much higher incidence of AIHA: AIHA carried a 3.86-fold risk of developing CLL
• Positive OR (6.7) for AIHALandgren O, Engels EA, Caporaso NE, et al. Blood 2006;108:292-296
Landgren O, Gridley G, Check D, et al. Br J Haematol 2007;139:791-798.
Söderberg KC, Jonsson F, Winqvist O, et al. Eur J Cancer 2006;42:3028-3033
• Nordic case-control study: risk of CLL was much higher in patients with a positive personal or family history of CLL
• Individuals who developed CLL had a much higher incidence of AIHA: AIHA carried a 3.86-fold risk of developing CLL
• Positive OR (6.7) for AIHALandgren O, Engels EA, Caporaso NE, et al. Blood 2006;108:292-296
Landgren O, Gridley G, Check D, et al. Br J Haematol 2007;139:791-798.
Söderberg KC, Jonsson F, Winqvist O, et al. Eur J Cancer 2006;42:3028-3033
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Chronic Lymphocytic Leukemia:Controversies
Chronic Lymphocytic Leukemia:Controversies
• Clinically apparent autoimmune disorders have been retrospectively reported in 2% to 12%
• Positive serum markers, “serologic autoimmunity” have been reported in 8%-41% of patients
• However, case control studies do not suggest an increase in AID in patients with CLL
Barcillini W, Capalbo S, Agostinelli RM, et al. Haematologica 2006;91:1689-1682.
Vanura K, Le T, Estabauer H, et al. Haematologica. 2008;93: 1912-1916.
Hamblin TJ, Osceier DG, Young BJ. J Clin Path 1986;39:713-716.
• Clinically apparent autoimmune disorders have been retrospectively reported in 2% to 12%
• Positive serum markers, “serologic autoimmunity” have been reported in 8%-41% of patients
• However, case control studies do not suggest an increase in AID in patients with CLL
Barcillini W, Capalbo S, Agostinelli RM, et al. Haematologica 2006;91:1689-1682.
Vanura K, Le T, Estabauer H, et al. Haematologica. 2008;93: 1912-1916.
Hamblin TJ, Osceier DG, Young BJ. J Clin Path 1986;39:713-716.
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Chronic Lymphocytic Leukemia:Other Associations
Chronic Lymphocytic Leukemia:Other Associations
• Cold agglutinin disease
• Paraneoplastic pemphigus
• Peripheral neuropathy: anti-myelin-assoicated glycoprotein (anti-MAG)
• Focal cresentric pauci-immune glomerular injury (Antineutrophil cytoplasmic antibodies (ANCAs))
Ruzickova S, Pruss A, Odendahl M, et al. Blood 2002;100:3419-3422.
Taintor AR, Leiferman KM, Hashimoto T, et al. J AM Acad Dermatol 2007;56:S73-6.
Henricksen KJ, Hong RB, Sobrero MI, et al. Am J Kidney Diseases 25 October 2010. http://dx.doi.org/10.1053/j.ajkd.2010.08.011.
• Cold agglutinin disease
• Paraneoplastic pemphigus
• Peripheral neuropathy: anti-myelin-assoicated glycoprotein (anti-MAG)
• Focal cresentric pauci-immune glomerular injury (Antineutrophil cytoplasmic antibodies (ANCAs))
Ruzickova S, Pruss A, Odendahl M, et al. Blood 2002;100:3419-3422.
Taintor AR, Leiferman KM, Hashimoto T, et al. J AM Acad Dermatol 2007;56:S73-6.
Henricksen KJ, Hong RB, Sobrero MI, et al. Am J Kidney Diseases 25 October 2010. http://dx.doi.org/10.1053/j.ajkd.2010.08.011.
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Chronic Lymphocytic Leukemia:Not Autoimmune Associations
Chronic Lymphocytic Leukemia:Not Autoimmune Associations
• Acquired angio-edema
• Renal disease (direct damage):• Membranoproliferative GN, cryoglobulinemic
GN, mebranous GN
• Acquired angio-edema
• Renal disease (direct damage):• Membranoproliferative GN, cryoglobulinemic
GN, mebranous GN
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Chronic Lymphocytic Leukemia:Conclusions
Chronic Lymphocytic Leukemia:Conclusions
• AIHA and ITP are strongly associated with CLL
• Management of these require careful clinical considerations
• AIHA and ITP are strongly associated with CLL
• Management of these require careful clinical considerations
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Thank YouThank You
Organizing Committee: Morton Coleman, MD; Ruben Niesvizky, MD;
Richard R. Furman, MD; John P. Leonard, MD
Imedex
Sandy Campbell, Faculty Liason
Sponsors
Patients
Attendees
Organizing Committee: Morton Coleman, MD; Ruben Niesvizky, MD;
Richard R. Furman, MD; John P. Leonard, MD
Imedex
Sandy Campbell, Faculty Liason
Sponsors
Patients
Attendees