How to treat Aplastic anemia. How to deal with PNH clones in Aplastic Anemia

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1 How to treat Aplastic anemia How to deal with PNH clones in Aplastic Anemia Stijn Halkes Sacha Zeerleder Anneke Brand No conflicts of interest

2 Program Introduction Aquired Aplastic Anemia (AA) SHA Introduction Paroxysmal Nocturnal Hemobloginuria (PNH) ABR Clinical Case AA/PNH All Issues on AA/PNH All Discussion: Second line treatment for AA How to transplant AA patients What we do not know: Issues for updated Guidelines 2016 AA???

3 Aplastic anemia Pancytopenia Persistent, unexplained marrow aplasia Lymphocyte infiltration

4 Aplastic anemia Incidence 2-3/million a year First peak incidence in adolescence Second peak incidence > 60 year Incidence per million per year in different age categories (Maluf, Haematologica 2009)

5 Aplastic anemia: congenital versus acquired Congenital aplastic anemia Acquired aplastic amemia Part of well described syndromes Including skeletal and skin abnormalities Fanconi anemia (chromosomal instability) Dyskeratosis congenita (short telomeres)

6 Pathogenesis of acquired aplastic anemia Bone marrow exhaustion due to accelerated loss of self-renewal capacity Immune mediated destruction of HPCs and/or their niche

7 Pathogenesis of acquired aplastic anemia Bone marrow exhaustion due to accelerated loss of self-renewal capacity Pre treatment leukocyte short telomere length is associated with risk of relapse, clonal evolution, and overall survival in AA. (Scheinberg, JAMA 2010) TERC and TERT gene mutations causing reduced telomerase activity and accelerated telomere attrition are found in adult AA patients (Townsed, Blood 2014) Immune mediated destruction of HPCs and/or their niche Increased numbers of Th17 cells in blood of AA patients (Peffault de Latour, Blood 2010) Decreased numbers of regulatory T cells in blood of AA patients (Kordasti, Blood 2012) Oligoclonal T-cell expansion of CD8 T cells is quantitatively related to disease activity in AA patients (Risitano, Lancet 2004) Over-representation of HLA DR2 in AA patients (Song Human Immunology 2010) Beneficial effect of immune suppressive treatment in AA patients

8 1970 Immune suppressive treatment in AA Mathé (Presse Med 1970): Antilymphocytic serum for Bone Marrow Failure Immunoglobulins were prepared from horses immunized against human lymphocytes from the blood of healthy volunteers This anti lymphocytic serum was used in the conditioning regimen for allogeneic stem cell transplantation in patients with bone marrow aplasia In some patients without engraftment, autologous recovery was seen during weeks/months after treatment It was hypothesized that infusion of anti lymphocytic serum had lead to recovery of patient hematopoiesis by lysis of auto-reactive T cells Development of Anti Thymocyte Globuline (ATG) as treatment for AA

9 1980 Development of horse derived ATG Brand Cells for immunisation Animal Dose ATGAM Human Thymocytes Horse 40 mg/kg/day for 4 days Lymphoglobulin Human Thymocytes Horse 15 mg/kg/day for 5 days Prepared by immunizing horses with Ficoll based selected cells derived from fragments of human thymus glands. IgG purification, other unknown purifications? Polyclonal preparation containing 10-20% human specific antibodies.

10 One RCT with ATGAM: response rate 60% Randomized study , 42 patients, mean age 32 ATGAM 20 mg/kg for 8 days If no response after 3 months in control group: cross-over ATGAM Control Antithymocyte globulin treatment in patients with aplastic anemia. A prospective randomized trial. Champlin, N Engl J Med 1983: 308( ) (Maluf, Haematologica 2009)

11 1990 Combination horse-atg and Cyclosporin In severe AA (granulocytes < 0.5*10 6 /ml) the combination of horse-atg and Cyclosporin (CsA) is better than horse-atg alone Frickhofen (Blood 2003) ATG: Lysis CsA: Suppression Autoreactive T cells

12 2000 Development of a stronger ATG Brand Cells for immunisation Animal Dose ATGAM Human Thymocytes Horse 40 mg/kg/day for 4 days Lymphoglobulin Human Thymocytes Horse 15 mg/kg/day for 5 days Thymoglobulin Human Thymocytes Rabbit 3.75 mg/kg/day for 5 days

13 2000 Development of a stronger ATG 2011: Randomized study comparing rabbit-atg and horse-atg ATGAM) in AA After rabbit-atg longer T cell depletion Scheinberg NEJM 2011

14 Inferiority of rabbit ATG compared to ATGAM 2011: Randomized study comparing rabbit-atg and horse-atg in AA After horse-atg higher response rate Scheinberg NEJM 2011

15 Inferiority of rabbit ATG compared to Lymphoglobulin Cohort analysis LUMC (higher dose rabbit-atg) : horse-atg Response rate 69% : rabbit-atg Response rate 33% Halkes NEJM 2011

16 Inferiority of rabbit ATG compared to horse ATG Despite inferior T cell depletion after horse-atg, higher response rate compared to rabbit-atg in aplastic anemia. Horse-ATG compounds other than anti T cell antibodies may be responsible for this effect. Antibodies to specific subsets of T cells? Antibodies to B cells? Antibodies to endothelial cells? No clear mechanism of action for horse-atg in AA

17 Curative options in AA: ATG or allogeneic SCT ATG SCT Readily available Response after 3 weeks >90% Limited acute toxicity Response after 3-6 months 60-70% Relapses Clonal evolution MDS/AML PNH Time for donor search Transplant related mortality Acute GVHD Chronic GVHD

18 No RCT in AA for ATG versus allosct Retrospective analysis of overall survival in patients with acquired AA Locasciulli Haematologica 2007

19 Hoe nu te behandelen? Dutch guidelines 2013

20 Dutch guidelines 2013

21 How to deal with PNH clones in Aplastic Anemia In 40% of AA patients PNH cells are found at diagnosis They have the AA/PNH overlap sydrome AA PNH