Anamnese: Blanco voorgeschiedenis, geen medicatie, sinds 4 weken progressieve vermoeidheid, dyspneu d effort.

Transcriptie

1 Man, 38 jaar Anamnese: Blanco voorgeschiedenis, geen medicatie, sinds 4 weken progressieve vermoeidheid, dyspneu d effort. Lichamelijk onderzoek: Geen afwijkingen hart/longen, geen hepato/splenomegalie, geen lymfadenopathie, geen hematomen. Laboratorium onderzoek: Hb 2.4 mmol/l, Trombocyten 19 x 10 9 /L, Leukocyten 2.7 x 10 9 /L Granulocyten 0.23 x 10 9 /L, Bilirubine 10, haptoglobine <0.1, LDH 508, Reticulocyten 10 * 10e9/L PNH onderzoek in bloed: Glycosylphosphatidylinositol (GPI)-deficiënte cellen: 41% van de granulocyten, 52% van de monocyten, 5% van de erytrocyten Diagnose? A) Verworven Aplastische Anemie B) PNH C) Anders

2 Laboratorium onderzoek: Hb 2.4 mmol/l, Trombocyten 19 x 10 9 /L, Leukocyten 2.7 x 10 9 /L Granulocyten 0.23 x 10 9 /L, Bilirubine 10, haptoglobine <0.1, LDH 508, Reticulocyten 10 * 10e9/L PNH onderzoek in bloed: Glycosylphosphatidylinositol (GPI)-deficiënte cellen: 41% van de granulocyten, 52% van de monocyten, 5% van de erytrocyten Beenmerg analyse: Crista biopsie: aplasie (celrijkdom < 1%) Beenmerg aspiraat: celarm, geen myelodysplastische afwijkingen, geen cytogenetische afwijkingen Mitomycine gevoeligheid test: Geen verhoogde chromosomale gevoeligheid voor mitomycine

3 Dus mengbeeld AA/PNH bij 38 jarige man Gezien het verlaagde aantal reticulocyten en aplasie van het beenmerg is het beenmergfalen nu de behandel indicatie en daarom behandeling gericht op AA 1 gezonde zus Wat zou u doen? 1. HLA typering zus afwachten 2. Onverwante search inzetten 3. Zo snel mogelijk starten met ATG 4. Anders

4 Dutch guidelines 2013

5 ATG behandeling: Welk ATG? 2013: The NVvH guideline on aplastic anemia advises horse-atg as the preferable type of ATG in first-line treatment. ATGAM* 40 mg/kg/day i.v. day 1-4 Ciclosporine** 5 mg/kg/dag p.o day Prednisolone 1 mg/kg/day i.v. day 1-4 Prednisolone 1 mg/kg/day p.o * Horse derived ATG (Pfizer) ** Dosage based on serumlevels ( ng/ml) day 5-14, after that tapered down to stop in 14 days However, the only available horse-atg is ATGAM which has no registration in Europe This means that there is no reimbursement for ATGAM

6 Vervolg: 2 maanden na diagnose: start behandeling met paard-atg en ciclosporine 6 maanden na start behandeling complete remissie, start afbouwen ciclosporine 2 jaar na start behandeling hb 9.1, neutrofielen 2.0, trombocyten 158 met 2dd 25 mg ciclosporine.

7 January 2014: the NVvH started a national registry for aplastic anemia for registration of base-line characteristics and follow up after treatment Study purpose: evaluation of efficacy and safety of horse-atg in Dutch aplastic anemia patients (non-registered drug) Patients: 18 yrs, treated with h-atg (ATGAM) as first-line treatment. Consecutive enrollment of all patients in the LUMC, UMCG, AMC, UMCU, VU-MC, Erasmus-MC, Medisch Spectrum Twente and Antonius Ziekenhuis Nieuwegein Based on manufacturer s data this cohort comprises >80% of all adult aplastic anemia patients treated with ATGAM as firstline treatment in the Netherlands

8 Baseline characteristics (n = 48) Age (years; median, range) 53 (18-77) Follow-up (months; median, range) 13 (1-45) Disease severity*: Non-severe Severe Very severe 16 (33%) 19 (40%) 13 (27%) *Disease severity: Non-severe aplastic anemia (NSAA): BM cellularity <25% Blood values below normal, not meeting criteria for SAA Severe aplastic anemia (SAA): BM cellularity <25% and 2 of the following: - Neutrophils <0.5 x 10*9/L - Platelets or reticulocytes <20 x 10*9/L Very severe aplastic anemia (VSAA): As for SAA with neutrophils <0.2 x 10*9/L Indication for ATG treatment: (V)SAA or NSAA with transfusion dependency

9 Response at 6 months (N=43) Two patients died before reaching 6 months follow up (1 at 1 month due to hemorrhagic stroke, 1 at 3 months due to concomitant DLBCL) Overall survival up to 6 months is 96% (95% CI %) N(%) 95% confidence interval Response* 24 (56%) 41-71% PR 21 (49%) CR 3 (7%) No response NR 19 (44%) 29-59% * Definition of response: CR = normalization of blood values, PR = neutrophil count > 0.5 x 10 9 /L and transfusion independent

10 Second line treatment if NR (n = 19) Supportive care* 9 HSCT 6 Rabbit-ATG 3 Sirolimus, epoeitine, androgens 1 * 3 patients became transfusion independent at respectively 8, 10 and 18 months after start of ATGAM

11 Overall survival after 6 months (N=40) Response at 6 months (CR+PR) 1 death due to subarachnoidal bleeding at 8 months 1 death due to complications of HSCT at 10 months (relapse at 7 months) No response at 6 months 2 deaths due to complications of HSCT at 7 and 12 months respectively 1 death due to multi-organfailure at 15 months (second line treatment a.o sirolimus, erytropoeitine, androgens) 1 death due to secondary AML at 44 months (also treated with r- ATG)

12 Conclusion At 6 months, overall survival of adults with aplastic anemia after treatment with ATGAM is 96% (95% CI %) Transfusion-independence is reached in 56% of the patients within 6 months (95% CI 41-71%) which is comparable to previously published data Based on this analysis, ATGAM (horse-atg) is confirmed as the recommended first-line immune-suppressive therapy in adults with acquired aplastic anemia 12

13 NVvH Registry In collaboration with: S. Sypkens Smit L. de Wreede (statistics) C. Halkes F. Falkenburg J. Schreurs M. de Groot S. Zeerleder M. Raaijmakers E. Meijer T. Snijders R. Raymakers R. Fijnheer Supported by: N. Schaap H. Koene

14 Casus: en de PNH clone? percentage X 10 9 /L granulocyten GPI deficient monocyten GPI deficient trombocyten Hematological improvement and decrease in PNH clone size

15 Issues in AA/PNH Why this combination of rare disease? If a patient has both PNH and aplastic anemia, which should you treat? Should all aplastic anemia patients be tested for PNH? If so, how often?

16 PNH: a stem cell disease characterized by PIGA mutation Mutation in the PIGA gen is associated to loss of Glycosylphosphatidylinositol (GPI)-anchor but is not sufficient to induce PNH: Healthy subjects: circulating PNH PMNs (10 in 10 6 cells) Permissive environment for PNH clone expansion Mutation in PIGA gen is quite common-in the presence of a normal bone marrow no chance to expand for PNH cells Araten et al. 1999; Hu et al. 2005; Hertenstein et al. 1995; Rosti et al. 1997; Keller et al. 2001; Jasinski et al. 2001; Maciejewski et al. 1997; Rosse et al. 1966; Rotoli et al. 1984; van der Schoot et al. 1990; Endo et al. 1996; Risitano et al. 2007

17 PNH: Escape or relative advantage theory Healthy individual External conditions permissive for PNHclone expansion PIGA-gene mutation: common phenomenon No biological consequencesno expansion in the presence of otherwise healthy cells Antigen-driven immune response against BM-tissue antigens (e.g. epitopes on GPI?) GPI+ GPI- Rotoli &Luzzato 1989; Dunn et al 2000; Karadimitris et al. 2000; Plasilova et al. 2004; Chen et al. 2000; Chen et al. 2005; Nagakura et al. 2002; Murakami et al. 2002; Nachbur et al. 2006; Risitano et al. 2007

18 Development of AA or PNH AA PNH 18

19 Development of AA or PNH AA Aplastic Bone marrow Low reticulocyte count Hemolysis -/+ Very low platelet and neutrophil counts PNH Increased reticulocyte count Hemolysis

20 Hypothesis: AA is caused by an auto-immune reaction to the normal hematopoiesis PNH cells can escape from this In patients responding to Immune suppressive treatment the PNH clone size will decrease

21 PNH clone size after treatment with ATG Scheinberg Haematologica 2010: In 207 AA patients treated with ATGAM in NIH, follow-up of 2 years 60% without PNH clone at diagnosis: 20% had PNH clone at one or more occasions in this period 40% had PNH clone at diagnosis 10% PNH clone had gone after ATG 50% decrease of clone size after ATG 40% increase of clone size after ATG In this cohort, complications of PNH (thrombosis, transfusions needed for hemolysis, hemolytic crises) were only seen if clone size was >50% (9% of total cohort)

22 Issues in AA/PNH Why this combination of rare disease? Hypothesis: PNH clones escape auto-immune attack If a patient has both PNH and aplastic anemia, which should you treat? Look at bone marrow cellularity Look at reticulocyte count Should all aplastic anemia patients be tested for PNH? If so, how often? Yes: at diagnosis, after ATG at a yearly base If PNH clone present at least once per three months

23 Diagnostiek en behandeling ernstige aplastische anemie bij volwassenen Hoe verder met niet-responderende patiënten? Konijn ATG na falen paard ATG (respons 27-77%) Alemtuzumab (respons 37%) AlloSCT Eltrombopag?

24 Diagnostiek en behandeling ernstige aplastische anemie bij volwassenen Hoe verder met niet-responderende patiënten? Konijn ATG na falen paard ATG (respons 27-77%) Alemtuzumab (respons 37%) AlloSCT Eltrombopag?

25 AlloSCT bij AA Bacigalupo Haematol 2012 Socié Hematology

26 AlloSCT: GVHD en late effecten GVHD voorkomen: T cel depletie van het transplantaat Indien mogelijk beenmerg als stamcelbron Post transplantatie maximale immuunsupressie Beperken late effecten (mn secundaire maligniteiten): Zo mogelijk geen total body irradiation in conditionering NB gebasseerd op cohorten met alleen maar of veel kinderen

27 Eltrombopag in AA Eltrombopag = agonist of thrombopoetin receptor Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia. Olnes, N Engl J Med 2012: 367(11-19)

28 Eltrombopag in AA Refractory AA patients: 11 from 25 showed responses (44%) Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia. Olnes, N Engl J Med 2012: 367(11-19)

29 Eltrombopag in AA In part of responding patients eltrombopag can be stopped 20% of patients developed new cytogenetic abnormalities (especially chromosome 7 loss) Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Desmon,Blood 2014: 123( ) Combination ATGAM, CsA and eltrombopag as first line treatment AA: 85-90% responses at 6 months (ASH 2014, Young)

30 Eltrombopag in AA after ATG Registration in the Netherlands (Nov 2015): patients with severe aplastic anemia who are relapsing after or refractory for ATG Procedure for reimbursement has been started in December 2015, answer from ZIN expected in June 2016

31 Eltrombopag in first line? EBMT Race Study First line treatment Open in LUMC (January 2016) Soon in AMC, UMCG, UMCU

32 2016 revisie van Nederlandse richtlijnen Issues: Diagnostiek Welk diagnostisch onderzoek dient te worden gedaan bij verdenking verworven aplastische anemie? Behandeling Algemeen: Wat is de optimale antibiotische profylaxe in patiënten met neutropenie in het kader van ernstige aplastische anemie? Wanneer is er een behandel indicatie? Wanneer dient de behandeling gericht te zijn op PNH en wanneer op AA? Wat is de indicatie voor allogene SCT als eerste lijn behandeling? Wat is een geschikte tweede lijn behandeling indien een patiënt niet respondeert op ATG?

33 Issues: 2016 revisie van Nederlandse richtlijnen Behandeling ATG specifiek: Tot welke leeftijd kan ATG gegeven worden? Hoe lang moet het effect van ATG worden afgewacht alvorens over te gaan op tweede lijn behandeling? Indien er respons op de combinatie ATG en cyclosporine is, hoe moet dan omgegaan worden met de cyclosporine: kan dit meteen gestaakt worden of dient er langzaam afgebouwd te worden? Is het effectief om bij een responderende patiënt die na staken of tijdens afbouwen van cyclosporine een achteruitgang in het bloedbeeld heeft de cyclosporine te hervatten of op te hogen? Hoe is lange termijn follow up van AA patiënten na ATG? Hoe moet worden omgegaan met een zwangerschapswens bij vrouwelijke AA patiënten die geen allogene stam cel transplantatie hebben ondergaan?

34 Issues: 2016 revisie van Nederlandse richtlijnen Behandeling Stamceltransplantatie specifiek: Wat is een geschikt conditionering schema voor AA patiënten boven de 55? Wat is een geschikt conditionering schema voor AA patiënten onder de 55?