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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. Disclosures Thomas M. Habermann, M.D. NCI/NIH Grants: ECOG U10 Grant PI: 1993-present R01: Co-PI

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Autoimmunity in Chronic Lymphocytic Leukemia

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  1. 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

  2. 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

  3. 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?

  4. RBC Haptoglobin Hgb Albumin Hgb Hgb Methemalbumin Hgb-HPcomplex Hemosiderin Hgb

  5. Antihuman IgG Antihuman Complement, C3 Human IgG or C3red cell antibody Red cell

  6. Paraneoplastic Pemphigus

  7. Paraneoplastic Pemphigus

  8. Cold Agglutinin Rouleaux Peripheral blood, Wright-Giemsa, 800x

  9. AAntigenic presentation Loss of tolerance Macrophage Dendritic cell Autoimmune hemolytic anemia BCytokine secretion and cell-cell contact IL-6 IL-10 Polyclonal IgG T cell TNF TGF- Paraneoplastic pemphigus B cells FAS-L CLL cell Cross-reactive monoclonal antibodies Rh or B3 T cell Erythrocyte Cold agglutinin disease Anti-li IgM Polyreactive BCR CAutoantibody secretion Auto-antigens DAntigenic drive Mechanisms of Autoimmune Disease in Chronic Lymphocytic Leukemia Hodgson K, Ferrer G, Montserrat E, et al. Haematologica. 2011;96: 752-761.

  10. Germinal Center CXCL12 CXCR4  + G + GCR NFB c-Jun c-Fos NFB Post-inflammatory Genes BurgerJA, Motserrat E. Blood . 2013;121:1501-1509.

  11. T Cells CCL3 CCL4 CD40L CD40 VCAM-1, FN + Survival & proliferation Homing & retention CD49d (VLA-4) BCR CLL Syk PI3Ks Btk CXCL12 G Btk PI3Ks Antigen Syk CD79 a,b CXCR4, CXCR5 CXCL12, CXCL13 NLC MSC Burger JA, Montserrat E. Blood. 2013;121, 1501-1509.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Chronic Lymphocytic LeukemiaAutoimmunity: Why Important? BM FailureAIDp= 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.

  17. Survival from Diagnosis of Cytopenia

  18. Chronic Lymphocytic Leukemia:Positive DAT (Coombs’ test) • Incidence: 2.3%-7% • AIHA associated with: • advanced stage • Active CLL • Older patients independent of stage or duration Mauro 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.

  19. 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.

  20. Chronic Lymphocytic Leukemia:Positive DAT After Treatment • CCL4 trial: Treatment+DATAIHAp< • 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 greater Dearden 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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

  25. 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.

  26. 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.

  27. 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.

  28. 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.

  29. Chronic Lymphocytic Leukemia:No Cases of • Acquired hemophilia • Acquired von Willebrand disease

  30. 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 AIHA Landgren 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

  31. 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.

  32. 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.

  33. Chronic Lymphocytic Leukemia:Not Autoimmune Associations • Acquired angio-edema • Renal disease (direct damage): • Membranoproliferative GN, cryoglobulinemic GN, mebranous GN

  34. Chronic Lymphocytic Leukemia:Conclusions • AIHA and ITP are strongly associated with CLL • Management of these require careful clinical considerations

  35. Thank 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

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