Immunosuppressive treatment in acquired aplastic anemia. André Tichelli Hematology, University Hospital Basel

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1 Immunosuppressive treatment in acquired aplastic anemia André Tichelli Hematology, University Hospital Basel

2 Why is immunosuppressive treatment a choice for acquired aplastic anemia? Hematopoietic stem cell T cells Hematopoietic stem cell transplantation (HSCT) Immunosuppressive treatment (IS)

3 Some questions that we try to answer today Standard immunosuppressive treatment Alternative non-transplant treatment modalities ATG administration, toxicity, type of hematopoietic reconstitution Relapse, refractory disease, and clonal evolution Immunosuppressive treatment in the elderly Pregnancy after successful immunosuppression What should not be done Scheinberg P and Young N. Blood, 2012; 120: Marsh J et la. BJHmatol. 2010; 150:

4 Improvement of survival of AA treated with immunosuppression n= 3711 Survival period pts OS S at 5 years > % % % % p=0,6681 p=0,0000 p=0, Days since Immunosuppression SAA-EBMT registry, update July 2012

5 Horse ATG and Cyclosporine is the gold standard immunosuppressive treatment for SAA Overall response rates with hatg + CSA is 60 to 70% P = 0.04 Event free survival 1,0,8,6,4,2 0, ATG & CsA; 39% ATG; 24% Years since Immunosuppression For economical reasons, unique course of IS applied (China) Frickhofen N et al. Blood. 2003; 101: Yizhou Zheng et al, Exp. Hematol. 2006; 34:

6 Meta-analysis comparing ATG alone versus ATG combined with CSA Favors ATG&CSA Favors ATG ATG & CSA significantly reduces all-cause mortality by 50% at 3 months, 1 and 5 years non-response No difference for risk of relapse and clonal evolution Anat Gafter-Gvili et al. Acta Haematol. 2008; 120:

7 Influence of the age at first-line immunosuppressive treatment Tichelli A. et al. Blood 2011;117:

8 Severity of the disease is significant for patients treated with immunosuppression but not with BMT Immunosuppression Transplantation Tichelli A. et al. Blood 2011;117: SAA-EBMT registry, update July 2012

9 Can we improve immunosuppressive treatment in treatment-naive patients? Type Response ATG + CSA + G-CSF * No difference in response or survival ATG + CSA + GM-CSF and EPO No difference in response or survival ATG + CSA + Mycophenolate No difference in response or survival ATG + CSA + Sirolimus No difference in response or survival Alemtuzumab alone# Low response rate (19%); increase in early deaths; study has to be discontinued *Tichelli et al. Blood 2011 Teramura et al. Blood 2005 Glukcmann et al. BJH 2002 #Scheinberg P.et al. Blood. 2012;119:

10 Androgens as an adjunct to immunosuppressive treatment Historical results Remission in 9/17 children treated with androgens and corticosteroids Prospective EBMT study ATG + Androgens ATG randomization - ATG ± oxymetholone - n = 134 Response rate at 4 months - 56% (with androgens); - 40% without androgens - P= Main effect in female patients with neutrophils < 0.5 x10 9 /l ATG and androgens Retrospective study, 87 AA patients Double dose of ATG OS 78% at 5 years Low toxicity in women Bacigalupo A. Br J Haematol. 1993; (83) Leleu X. Ann Hematol. 2006;85:

11 Can high-dose of Cyclophosphamide (Cy) replace ATG and CSA in the treatment of aplastic anemia? 10 patients with aplastic anemia treated with Cy ± cyclosporine Results (2001) - 7/10 complete remissions - follow-up 10.8 years - No clonal transformation Results 2010 (n=44 newly SAA) - OS 88%; response rate 71%; EFS 58% - No relapse, MDS, clinical PNH Comments Severe fungal infections are of concern Maybe, maybe not We will never have a large randomized study Randomized NIH study Cy ATG P n=15 n=16 Hospitalization (days) Iv antibiotics (days) Fungal infections PMN <0.2 x10 9 /l (days) Deaths Follow-up NIH study Cy ATG Overall response 8 (53%) 13 (81%) Relapse 2 (13%) 3 (18%) PNH 4 (27%) 5 (31%) Cytogenetic evolution 1/12 (8%) 2/14 (14%) Brodsky R. Blood. 1996; (87) Brodsky et al. Blood 2010;115: Socié G: Blood : Tisdale J. Blood. 2002; (100); Tisdale J. Lancet. 2000; (356)

12 Rabbit ATG provides stronger immunosuppression than horse ATG. Is rabbit ATG better for the treatment of SAA? Cause of death (11/35) Horse ATG Rabbid ATG Response at 6 months 68% 37% Overall survival at 3 years 96% 76% deaths 4 14 Cause of death (11/35) Time to death Scheinberg P.et al. NEJM. 2011; 365: Sepsis (5) 9,210,243,326, 370 Pneumonie (2) 207; 209 Sepsis &multiorgan failure Sepsis & cardiac arrest 148 Intracranial hemorrhage 288 Post-SCT fungal infection Marsh J et al. Blood. 119:

13 Thrombopoietin receptor agonist for aplastic anemia Non-randomized study on 25 SAA patients, refractory to immunosuppression, and transfusion dependent for platelets 11/25 had hematological response, 9/11 became transfusion-independent for platelets Multi-lineage lineage hematological responses to eltrombopag Potential role for eltrombopag to augment responsiveness to ATG/CSA Olnes MJ et al NEJM. 2012; 367:11-9

14 Can we use CSA alone as an immunosuppressive treatment (in an outpatient setting)? Parameter CSA N=61 ATG+CSA N=54 p Response 28 (46%) 40 (74%).02 Hemoglobin 9.7 ( ) 11.8 ( ).03 Neutrophils Platelets Second ATG 15 (25%) 3 (6%) EFS 41 (67%) 49 (90%).001 Comments Effective treatment, not necessitating hospitalization Provided no immediate risk A proportion of patients will need a second course with ATG + CSA Marsh J et al. Blood 1999; 93:

15 Administration and toxicity of Immunosuppression Preparation of ATG administration Central line platelet counts 20 G/L Filtration/irradiation of blood products Patients need not be free of infection before initiating ATG Withhold -blockers Prednisone, continued for 2 weeks as a prophylaxis of serum sickness Acute toxicity of ATG Fever, rigors Hemodynamic and respiratory compromise Increase of liver enzymes Anaphylaxis (rare) Toxicity of CSA Decrease of renal function Hypertension Gingival hyperplasia worse in combination of calcium channel blockers Serum sickness Begins 5 to 10 days after first dose More when prolonged regimen is applied Clinical presentation - Fever - Rash - Arthralgia and myalgia - Abdominal and neurologic complaints - Myocarditis, pericarditis, pleurisies Scheinberg P and Neal Y. Blood 2012;120:

16 How we follow SAA patients treated with Immunosuppression Response to immunosuppression delayed 50% at 3 months 75% at 6 months incomplete persistent reduced in vitro proliferation capacity and morphological abnormalities Frickhofen N. Blood 2003 (101) Nissen. Br J Haematol. 1993; (83)

17 Relapses after immunosuppression are frequent and independent of the type of immunosuppression used Rosenfeld S. JAMA 2003 (289:

18 Some of the patients are cyclosporine dependent over years 11/43 (26%) needed CsA >6 months 6 patients on continuous CSA for 9-12 years Frickhofen N. Sem Hematol (37) Frickhofen N. Blood (101)

19 Relapses after immunosuppression are treatable and have a good outcome 1. course 2. course P Immediate side effects 26% 30% ns Serum sickness 63% 57% ns Appearance (median day) Treatment for relapsed SAA Increase or restart CSA Second ATG+CSA Experimental immunosuppression? Unrelated HSCT? Tichelli A. Br J Haematol (100) Scheinberg. P. Br J Haematol. 2006; 133:

20 Patients with refractory SAA have worse outcomes Retreatment with rabbit ATG Relapse Refract. Overall response 66% 27% Third course of ATG (n=17) Event free survival OS at 1000 days 90% 65% Deaths 3 6 Death after alternative HSCT 1 2 Survival Scheinberg P. et al Br J Haematol. 2006; 133: Gupta V. et al. Br J Haematol. 2005, 129;

21 Prediction of response (non-response) to immunosuppressive treatment Predictors for response Neutrophil count at day 30 are predictive for OS in patients receiving G-CSF Predictors for response Blood counts at 3 months Reticulocyte counts or platelet count > 50 x10 9 /L Survival at 5 years 90% Versus 42% when less Rosenfeld S. JAMA 2003 (289: Tichelli A. et al. Blood 2011;117:

22 William Dameshek. Blood, 1967; 30:

23 Secondary MDS / AML in aplastic anemia patients treated with immunosuppression Tichelli A. Br J Haematol. 1988; (69) Kojima S. Blood. 2002;100):

24 Risk factors for secondary MDS / AML in aplastic anemia patients treated with immunosuppression Risk factors HR p MDS Age > 45yr AML MDS/A ML Age > 45yr G-CSF Age > 45yr G-CSF Risk factors Repeated immunosuppression Splenectomy Non-responsive to immunosuppression Long-term use G-CSF Socié G. et al Blood. 2007;109: Ohara A. Blood. 2002;100: Socié G. NEJM. 1993; 329:

25 Clonal karyotype evolution in aplastic anemia Karyotyp anomaly /-13q -Y others No patients % of total 23% 40% 13% 7% 16% Outcome Monosomy 7 of bad prognosis Trisomy 8 / del(13q) or monosomy 13 of good prognosis - Rare evolution into MDS/AML - Good response to IS Transient chromosomal abnormalities are rare Maciejewski JP. Blood. 2002;99: Scheinberg Ph. JAMA. 2010;304:

26 Telomere length correlates with relapse, clonal evolution and survival, but not with response Scheinberg P. JAMA. 2010; 304: ; 133:

27 Clonality in aplastic anemia represents an escape mechanism from the immune pressure Afable M.G. ASH educational 2011

28 Androgens, telomere length and risk of clonal evolution ATG and androgens Retrospective study on 87 AA patients Double dose of ATG OS 78% at 5 years Cumulative incidence at ten years of MDS/AML 3.1% Low toxicity in women Androgens and clonal evolution Lower risk Positive effect of androgens on telomere length Addition of androgens to immunosuppression Relative risk o.28; p=0.02 Leleu X. Ann Hematol. 2006;85: Socié G. NEJM. 1993; 329:

29 PNH clones in SAA treated with ATG and cyclosporine PNH clones present in about 40-50% of patients with aplastic anemia Median pretreatment PNH clone size 9.7% (interquartile range ) Good correlation between GPIcells and LDH In majority of patients no specific intervention required Clinical symptoms and signs in patients with a clone of >50% (7/30) - significant hemolysis (4) - thrombosis (3) Scheinberg P. Haematologica. 2010;95:

30 Biologic parameters in AA/PNH patients Parameter PNH clone P Small 0.01%-2% (n=16) Intermediate 2%-20% (n=5) Large >20% (n=8) Ferritin [ng/ml] 800 ( ) 898 ( ) 181 (92-503) LDH [U/L] 800 ( ) 133 ( ) 1464 ( ) Bilirubin [μmol/l] 10 (5-54) 8 (5-14) 21 (11-40) Reticulocyte [x10 9 /L] 51 (25-122) 73 (50-85) 82 (52-124) Unpublished data from Hematology Basel

31 Natural history of PNH clones in patients presenting as aplastic anemia Influence of PNH clone size Small initial size PNH clone (<15%) - less likely to develop hemolysis No PNH clone at diagnosis - Unlikely to develop during follow-up PNH clone size over time - Overall progressive decrease - Clone size increase in 30%-40% Specific intervention - Oral anticoagulation if clone >50% and platelets >50x109/L - Eculizumab if significant symptoms or history of thrombosis Scheinberg P. et al Haematologica. 2010; 95: Pu JJ et al Eur J Haematol. 2011; 87:37-45

32 Overall survival is not the only relevant outcome in aplastic anemia Overall survival Event free survival Event free survival Death Non-response Relapse Clonal evolution Tichelli A. et al. Blood 2011;117:

33 Quality-adjusted time without symptoms and toxicity (Q-TWiST) defines periods spend in various health states ATG treated patients spent more time with treatment related toxicity needing transfusions and drugs in partial remission (abnormal blood counts) at higher risk of clonal disorder BMT patients spent more time in CR without drugs without symptoms or toxicity with chronic GVHD Viollier R. et al Ann Hematol. 2006; 84: 47-55

34 Age and outcome of immunosuppressive treatment in patients with SAA Decrease of survival with advanced age No age difference for Response Relapse rate Higher death rate in older age <20 years Age Survival 5 years <20 years 82±4% years 78±4% years 60±8% >70 years 33±16% Tichelli A. et a. Ann Int Med Update SAA WP 2010

35 Most of the deaths in the elderly are due to early infections Causes < 60 years 60 years p Total number Number deaths 20 (15%) 24 (41%) Infections 9 (45%) 15 (63%) Non response/ relapse 6 (30%) 2 (8%) n.s. Malignancies 1 (5%) 2 (8%) n.s. Cardiovascula r disease 1 (5%) 3 (12%) TRM 3 (15%) 1 (4%) n.s. unknown 0 1 (4%) n.s. Based on data from the G-CSF study (Tichelli A. et al. Blood 2011;117: )

36 Should we give attenuated Immunosuppression in the elderly? Small retrospective single center study (Canada) - 24 patients - Median age, 70 years (61-78) - 50% dose reduction of ATG Immunosuppressive treatment - Normal ATG+CSA (n=7) - Reduced dose of ATG+CSA (n=13) - CSA alone (n=4) Response - Similar to what is expected - No difference with attenuated IS - 4 cardiac events 14 patients with aplastic anemia - 12 were evaluable - Median age 71 years (62-74) Treatment - One third of the standard ATG dose, without CSA Results - Good tolerance of the treatment - 2 deaths of infection - 1 response at 6 months Discrepancy between both studies due to additional CSA treatment or different reduced ATG dose? Kao SY. Et al. Br J Heamtol. 2008; 142: Killick S.B. et al. Leuk Research. 2006; 30:

37 Treatment strategy in patients older than 60 years with newly diagnosed aplastic anemia Treatment decision and the type of immunosuppression should be based Severity of the disease and infectious complications The presence of co-morbidity The willingness of the patient and his family members to be treated Tichelli A and Marsh J. BJH. 2013; 48:

38 Patients with aplastic anemia Eligible for IS Comorbidities Willingness of patient yes no Best supportive care SAA/vSAA with severe neutropenia and/or severe infection Moderate AA with neutrophils >0.5 x10 9 /L without severe infection Patients with a syngeneic donor ATG + CSA CSA ± androgens Syngeneic BMT Non-responders still eligible for IS Tichelli A and Marsh J. BMT. in Press

39 Outcome of pregnancy & disease among women with aplastic anemia treated with immunosuppression Relationship between aplastic anemia and pregnancy remains controversial Aplastic anemia may develop during pregnancy And recover spontaneously after delivery The outcome of pregnancy and the disease after successful immunosuppression 47 pregnancies in 36 women - 1 pregnancy (n=27) - 2 pregnancies (n=8) - 4 pregnancies (n=1) Status of SAA at pregnancy - CR in 13 - PR in 30 - PNH in 4 General outcome - Spontaneous abortion 2 - Elective abortion 1 - Twins 1 - Uncomplicated course 22 - Complicated course 14 o Death 2 o Eclampsia 2 o Relapse of AA 7 - Premature birth 5 Tichelli A. et al. Ann I Med. 2002; (137)

40 Complications during pregnancy, delivery and post-delivery in women with SAA treated with IS No of pregnancies 36 With complications 14 Pregnancy thrombocytopenia n=5 relapse n=7 uneventful n=2 Delivery transfusions (n=4) bleeding (n=1) eclampsia (n=1) transfusions (5) bleeding (1) eclampsia (n=1) uneventful (n=1) Post-pregnancy return to prepregnancy values n=5 refractory to ATG death in aplastic anemia spontaneous remission (n=3) remission with retreatment (n=3) Recovery cerebral thrombosis death Tichelli A. et al. Ann I Med. 2002; (137)

41 Deviation in % of blood values compared to pre-pregnancy values Successful pregnancy is possible for females in remission of SAA after immunosuppression Relapse during second and third trimester may occur - Spontaneous remission or retreatable patients Hemoglobin and thrombocytes significantly decrease during pregnancy - but tend to normalize after delivery Severe complications may occur

42 Failure free survival at 5 years (%) according to severity and age of the patient Marsh J. Blood Review. 2005

43 What not to do in case of newly diagnosed SAA? What not to do Watchful waiting in symptomatic patients and patients with SAA Start with growth factors and/or erythropoietin Cyclosporine alone Corticosteroids Androgens alone Treatment in inexperienced centers Reasons Risk of infections (bacterial and/or fungal) Ineffective, costly, loss of precious time Except for moderate cases and some elderly Not efficient and risk of fungal infections Not efficient, loss of precious time SAA do behave differently as malignant diseases Scheinberg P and Young N. Blood, 2012; 120:

44 Take home messages In patients with SAA of any age without a matched sibling donor, immunosuppressive therapy should be started immediately Combination of ATG and cyclosporine is the immunosuppression of choice Horse ATG provides better outcome than rabbit ATG Relapses are treatable but refractory aplastic anemia have a poor prognosis Immunosuppressive therapy has no upper age limit Immunosuppression is not a curative treatment: risk of late events with relapse, transformation into MDS/AML, persistence/evolution of PNH may occur

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46 Danazol as first line therapy for aplastic anemia? Danazol in absence of ATG- CSA (Mexico) Danazol n= males Age 51 (6-85) Median daily dose 400mg during 12 months Response rate 47% Median time to response 90 days (30-720) Jaime-Pérez J.C. et al. Ann Hematol. 2011; 90:

47 When and whom to treat Stable and moderate aplastic anemia Observation is adequate as long as no transfusion are required and no recurrent infections SAA and patients who progress to SAA Immediate treatment Definitive treatment Choice of the definitive treatment depends on Age of the patient Availability of a donor Severity of the disease Immediate measures 1.Transfusions for symptoms related to anemia and thrombocytopenia No prophylactic transfusions for asymptomatic thrombocytopenia Many centers use irradiated products and single donor platelets 2.Broad spectrum antibiotics for fever or documented infection in the presence of neutrophils < 0.5 x10 9 /l Fungal infection increase with prolonged severe neutropenia 3.Immediate family HLA typing for patients <40 years Scheinberg P and Young N. Blood, 2012; 120: Marsh J et la. BJHmatol. 2010; 150:

48 Treatment strategy in patients older than 60 years with newly diagnosed aplastic anemia Treatment decision and the type of immunosuppression should be based Severity of the disease and infectious complications The presence of co-morbidity The willingness of the patient and his family members to be treated Patients not at risk for or without infections Start with CSA alone as outpatient (+TPO recept. agonist?) If no response at 6 months or progression of AA Evaluate treatment with ATG/CSA Patients with infection or with SAA Evaluate frontline treatment with ATG/CSA Tichelli A and Marsh J. BJH. 2013; 48: