Autoimmunity in CLL. Anne Silva, MD Hematology Fellows Conference

Transcription

1 Autoimmunity in CLL Anne Silva, MD Hematology Fellows Conference

2 Case Presentation Mr. M is a 62 year old male with multiple medical problems including pulmonary sarcoidosis on steroids, was incidentally diagnosed of CLL/SLL in 2004 during an admission for cryptogenic organizing pneumonia. Noted to have bulky cervical adenopathy on exam and splenomegaly (19 cm) on CT. CBC showed anemia with Hct in mid 20 s, normalplatelet and WBCcount and normal differential. Biopsyof of left cervicallymphnode lymph confirmed dx of CLL/SLL flow was CD19 (+), CD23 (+), CD5 (+), CD20 (+), lambda light chain restricted, low ZAP 70 and CD38. BM bx with 7.8% 8%CLLinvolvement involvement, normal hematopoiesis Cytogenetics and FISH normal

3 Anemia: Thought to be due to inflammatory block rather than CLL (BM with normal hematopoiesis and normal iron stores) Low EPO in setting of renal insufficiency Negative work up for a hemolytic process and DAT ( ) 2009 Patient noted to be progressively thrombocytopenic Restaging of CLL showed BM now with 13% CLL by flow and 25% morphologicaly, with low ZAP 70 and CD38 CTwithworsening worsening splenomegaly of27cm Patient treated with Fludarabine/Rituxan developed Fludarabine associated hemolytic anemia after 1 st cycle with ( )DAT. FR discontinued Anemia responded ddto a course of steroids

4 Completed 6 cycles of Cytoxan/Rituxan ending 7/2009 Noted to have delayed BM recovery with treatment In 1/2010 pt developed significant anemia (Hct low 20 s) and thrombocytopenia (plt as low as 17k) and dx with Evans syndrome (AIHA and ITP) Work up revealed hemolytic anemia with (+) DAT for warm IgG Minimal evidence of CLL on restaging CT and BM with 0.006% CLL cells by flow Spleen 30 cm on CT AIHA did not well respond to steroids, IVIG or Rituxan

5 Underwentsplenectomy withsomeimprovement improvement inhis anemia and thrombocytopenia Continued to have evidence of hemolytic anemia with (+) DAT 4/2010 Pt developed hypoxic respiratory failure and pneumonitis and ultimately ventilator dependent.

6 Autoimmune Manifestations in CLL Predominantly directed against cells of hematopoietic origin. Autoimmune Hemolytic Anemia (10 25%) Immune Thrombocytopenia (1 5%) Pure Red Cell Aplasia (rare) Autoimmune Neutropenia (rare) Non hemic autoimmunity in CLL are very rare. Glomerulonephritis Paraneoplastic Pemphigus

7 Mechanisms of Autoimmunity in CLL Initial assumption Possibility of neoplastic CLL cells responsible for autoantibody production. Malignant B CLL cells express very small amounts of low affinity, polyreactive, monoclonal immunoglobulin's (usually IgM or IgD, and rarely IgG or IgA) In majority of cases, however, autoimmune manifestations in CLL are due to warm reactive, polyclonal IgG antibodies. Current model Polyclonal autoantibodies are produced by autoreactive normal B cells in a T cell dependent manner, and not by CLL clones, in an environment of T reg dysregulation.

8 Current Model of Mechanisms of Autoimmunity i in CLL B CLL malignant clone as an aberrant APC, and activation of autoreactivet helper (Th) cells. Studies on patients with AIHA in CLL Found to have activated Th cells specific for Rh protein. B CLL cell are found to specifically bind and internalize certain erythrocyte proteins, such as Rh group and erythrocyte protein band 3, and serve as an APC to Th cells. Leukemic cells in splenic stroma readily encounter degradation products ofrbcand platelets and likelya major site of Th activation.

9 B CLL Cells as Aberrant APC s Caligaris-Cappio F, Hamblin T J JCO 1999;17:399

10 Autoimmune Cytopenia in CLL; Prevalence, Clinical Associations, and Prognostic Significance. Moreno et. al. Blood. 2010; 116(23): Analysis of a total of 960unselected patients diagnosed with Analysis of a total of 960 unselected patients diagnosed with CLL in Barcelona from

11 Prevalence of autoimmune cytopenia. 70/960 patients had autoimune cytopenia (7%) 49/70 had AIHA (42 DAT+, 7 DAT ) 20/70 had ITP 1/70 had both AIHA and ITP (Evans syndrome) Presentation of autoimmune cytopenia. 19 were dt detected tdat diagnosis i (12 AIHA, 7 ITP) 3 before diagnosis (1 AIHA, 2 ITP) 48 during the course of the disease (36 AIHA, 11 ITP, 1 Evans syndrome) 35 patients developed either ITP or AIHA during or after therapy with median time of 6 months. Moreno et. al. Blood, 2010; 116(23)

12 Clinical and biological characteristics of patients with/without autoimmune cytopenia. Moreno et. al. Blood, 2010; 116(23)

13 Prognostic significance of autoimmune cytopenia No significant difference observed in terms of overall survival in patients with or without autoimmune cytopenia. No difference in outcome observed according to time at which cytopenia was detected. Moreno et. al. Blood, 2010; 116(23)

14 The prognostic significance of positive DAT test in CLL: a beneficial effect of the combination of fludarabine and cyclophosphomide p on the incidence of hemolytic anemia. Dearden et. al. Blood. 2008; 111(11): A prospective multicenter randomized controlled trial (LRF CLL4) conducted in UK. 777 patients with CLL randomized to receive either Chlorambucil or Fludarabine alone or Fludarabine/Cytoxan (FC) as first line treatment ratio 2:1:1

15 DAT Results and incidence of AIHA Incidence of (+)DAT pre treatment was 14% (89/637 pt s tested) Incidence of AIHA during treatment was 10% (77/759 pt s). 12% receiving Chlorambucil 11% receiving Fludarabine 5% receiving FC DAT correctly predicted for development of AIHA after therapy in 83% of cases, however, only 28% of DAT (+) patients developed daiha, while 8% DAT ( ). Positive predictive value of DAT test in predicting AIHA 28%; p p g Negative predictive value of DAT test was 93%.

16 DAT results of 299 patients with results available both at entry and after treatment Patient s treated with single agent Fludarabine was most likely to remain DAT(+), and to change from negative to positive. Dearden et. al. Blood. 2008; 111(11):

17 The predictive value of AIHA for survival and PFS Dearden et. al. Blood. 2008; 111(11):

18 The predictive value of DAT positivity for survival and PFS Dearden et. al. Blood. 2008; 111(11):

19 Survival and PFS: Differences in event rates by DAT results within ihi AIHA subgroups No AIHA, ( )DAT hd had better survival Dearden et. al. Blood. 2008; 111(11):

20 Treatment Related AIHA LRF CLL4 trial noted that patient s receiving Chlorambucil or Fludarabine monotherapy are 3 times likely to develop AIHA than those receiving FC. Fludarabine therapy was not found to be associated with higher risk of developing AIHA compared to Chlorambucil. FC noted to have a beneficial effect on both the expression of DAT and development of AIHA. Possible mechanism Profound depletion of T cell subsets, particularly Treg, with treatment (such as purine analogs) leading to failure of control of autoreactive T cells.

21 Immune anemia's in patients with CLL treated with FCR incidence and predictors. Borthakur et al. BJH 2007; 136: Retrospective analysis of 300 patients with CLL, enrolled prospectively to receive FCR as first line therapy at M. D. Anderson. Incidence, outcomes and predictors of AIHA and pure red cell aplasia (PRCA) were analyzed. f h l d df 9 of 300 pt s with AIHA prior to treatment were excluded from final analysis.

22 IA in CLL patients treated with FCR 6.5% developed IA (5.8% AIHA and 0.7% PRCA) on or after treatmentwith FCR not significantlydifferent from FC data. Most patients (82.4%) with AIHA had a ( ) DAT.? of FCR therapy masking DAT positivity below the threshold of detection Other causes of DAT ( ) AIHA include IgM and IgA antibody mediated hemolysis, low affinity Ab s, destruction of IgG sensitized RBC by ADCC. Of the 9 pt s with AIHA prior to treatment; 2 had resolution of AIHA with FCR alone, 4 more responded to additional immune manipulation (i.e. cyclosporine, steroids) 1 pt had worsening of AIHA with FCR, but promptly p responded to oral steroids and discontinuation of FCR

23 Fludarabine associated AIHA in CLL The two most evident risk factors for developing Fludarabine associated AIHA : (+) DAT Prior history of Fludarabine associated AIHA LRF CLL4 trial showed that CLL pt s treated with Fludarabine monotherapy has increased risk of developing AIHA and more likely to remain DAT (+) or convert to DAT positivity compared to FC. Therapy with FC or FCR should be considered in pt s with increased risk. Fl d bi h ldb id d i ih i hi f Fludarabine should be avoided in pt s with prior history of Fludarabine associated AIHA.

24 Conclusion Autoimmune manifestations in CLL are primarily directed against cells of hematopoietic origin. The autoantibodies responsible for autoimmune manifestations in CLL are not produced by the leukemic clone and is polyclonal. B CLL leukemic cells act as aberrant APC in activating autoreactive Th cells, thus, initiating production of autoantibodies throughbystander normal B cells.

25 Conclusion DAT status at time of initiation of therapy with/without AIHA provides a prognostic indicator for both OS and PFS. AIHA was noted to be an independent prognostic factor for OS, but not for PFS. The risk of pt s developing AIHA with a (+) DAT was 1 in 3 (PPV 28%). DAT ( ) was noted to be a strong predictor (>90%) for not developing AIHA.

26 Conclusion FC combination was noted to have less incidence of AIHA as well as FCR therapy front line compared to Fludarabine or Chlorambucil alone. FC or FCR can be considered for patients with high risk for developing AIHA such as pt s with (+) () DAT pre treatment. Fludarabine should be avoided in pt s with prior history of Fludarabine induced AIHA.