440Congresso Nazionale Verona, 20-23 ottobre 2013

AUTOIMMUNE HEMOLYTIC ANEMIAS

A. Zanella Ematologia, Fondazione IRCSS Ca’ Granda Ospedale Maggiore Policlinico, Milano

ü  es#mated  incidence  1-‐3  per  105/year,    prevalence  17:100,000,  mortality  rate  11%  [Rose  1998].    

ü  can   be   either   primary   or   secondary   to   lymphoprolifera#ve   diseases,  infec#ons,  immunodeficiency,  and  tumors  

 ü  are  classified  as    “warm”,  “cold”   (which   include  CHD  and  PCH)  and  “mixed”  

according   to   the   thermal   range  of   the  autoan#body.   “Atypical”   cases     (DAT  nega#ve  AIHA,  warm  IgM  AIHA)  are  reported  with  increasing  frequency  

ü  may  develop  gradually,  with  concomitant  physiologic  compensa#on,  or  may  have  a  fulminant  presenta#on  with  rapid    onset  of  profound,  life-‐threatening  anemia  

ü  clinical   manifesta#ons   are   determined   by   the   presence/absence     of  underlying   diseases,   and   by   the   rate   and   type   of   hemolysis   which   mainly  depend  on  the  autoan#body’s  characteris#cs  

AUTOIMMUNE  HEMOLYTIC  ANEMIAS  (AIHA)  

Factors  influencing  the  autoan#body  pathogenicity  and  the  extent  of  anemia  

SEROLOGIC:    Ig  class,  subclass,  thermal  amplitude,  specificity,  affinity,  C  ac#va#ng    efficiency,  ability  to  react  with  macrophages,  quan#ty  and  type  of  cell-‐bound  C/igG,  characteris#c  of  target  an#gen   Op#mal  reac#on  T  (range)    37°C  (0  -‐  40°C)      4°C  (4  -‐  34°C)    

             Ig  class  (C  fixa#on)      IgG  (rare)      IgM  (common)    

         Direct  An#globulin  Test    posi#ve  IgG  (+C3)    posi#ve  C3  Auto-‐abs  specificity      an#-‐Rh      an#-‐I/i        In  vivo  haemolysis      extravascular    intra  and  extra  RBC  sequestra#on  site    spleen      liver  (spleen)      Hemolysis  rate          Extravascular  H.      Intravascular    H.  

       17.5  mL  RBCs/hr      200  mL  RBCs/hr      OTHER:          ac#vity  of  the  re#culoendothelial  system              

         efficacy  of  the  erythroblas#c  response        

Reticulocytopenia in autoimmune hemolytic anemia

In  a  survey  of  cases  of  AIHA  from  the  files  of  Armed  Forces  Ins#tute  of  Pathology  it  was  noted  that  a  number  of  pa#ents  exibited,  at  one  #me  or  another,  a  definite  re#culocytopenia  in  the  presence  of  severe  hemoly#c  anemia  with  a  bone  marrow  that  presented  a  picture  of  intense  erythroid  prolifera#on.  The  phenomenon    appears  to  have  a  sinister  significance.  

Crosby & Rappaport, Blood 1956

Autoimmune   hemoly#c   anemia   with  re#culocytopenia.A  Medical   emergency    Conley  et  al,  JAMA  1980  

Case Age/Sex Hct Retics Duration RBC units Outcome (%) (days)) (n)

1 52/F 10 0.5 10 19 CR 2 78/F 9 0.5 14 12 CR

3 53/F 10 2.0 90 53 PR

4 35/M 9 0.2 5 5 PR

5 49/F 8 3.0 160 84 PR

Zanella, umpublished data

Variability of the erythrocyte response in autoimmune hemolytic anemias: analysis of 109 cases. JL Liesveld, JM Rowe,M A Lichtman. Blood 1987;69:820-6

Twenty per cent of 109 adult AIHA cases are associated with reticulocytopenia and marrow erythroid hyperplasia suggesting that reticulocytopenia was due to ineffective erythropoiesis in most cases

Erythropoietin may improve anemia in patients with AIHA associated with reticulocytopenia. Arbach et al. Transf Med Hemother 2012; 39:221-3

Apoptosis may contribute to the mechanism of reticulocytopenia in AIHA

Excessive apoptosis of marrow erythroblasts in a patient with autoimmune haemolytic anaemia with reticulocytopenia. A van de Loosdrecht et al, Br J Haematol 2000;108:313-5

“The administration of EPO should be considered in pts with therapy-refractory AIHA, particularly in the presence of reticulocytopenia”

New insights into childhood autoimmune hemolytic anemia: a Frenh national ob-servational study of 265 children. Aladjidi N et al, Haematologica 2011; 96:655-63

Thirty nine per cent of children with AIHA had reticulocytopenia of variable duration

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40-49

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60-69

70-79 80

caldifreddimisti

Age (yrs)

Sokol et al., J Clin Pathol 1992 Warm (IgG) Cold (IgM) Mixed

•  cases with Hb

Author          Warm      CHD                  PCH                            Mixed                  Total      Göesche    (1990)  *                38                    7    22  (33%)                          0      67        Sokol                (1992)              16            17    13  (27%)    2      48      Vaglio              (2007)              64*                                                    26                                              6  (6%)  **                      4                              100                                

*5/64(8%)  DAT-‐  nega#ve                **  5/6    (83%)  DAT-‐nega#ve  

AIHA  in  infancy  and  adolescence  (age  <  16  yrs)   02

4

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60-69

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caldifreddimisti

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Sokol et al., J Clin Pathol 1992 Warm (IgG) Cold (IgM) Mixed

*  “During  the  last  4  years,  we  have  studied  a  total  of  531  adults  and  68  children  with  clinically  and  serologically  well-‐  defined  forms  of  immune  hemoly#c  anemias.  Among  these,  Donath-‐Landsteiner  (DL)  hemolysis  was  the  underlying  disease  in  22  of  the  68  children  (32.4%),  but  was  not  observed  in  adults”.    

Clinical  presenta#on:          Fever  (1  m.  before  onset)      60%          Collapse,  coma,  ARF                      3%          Jaundice  not  constant          Splenomegaly                                                31%          Hepatomegaly                                              19%                      Re#culocytopenia  39%                    (median  6  d.  range  1-‐70)    

Immunologic    53%  Post-‐infec#ous      10%  Primary      37%    AIHA  +  ITP  (ES)      37%    

New  insights  into  childhood  autoimmune  hemoly#c  anemia:  a  French  na#onal  observa#onal  study  of    265  children.  Aladjidi  N  et  al,  Haematologica  2011;96:655-‐63  

.  Aladjidi  N  et  al,  Haematologica  2011;96:655-‐63    

10%    mortality    in    the  AIHA/ES  subset  

CR  at    one  month:  58%  

     Direct  an#globulin  test  (DAT)        An#body  screening  &  iden#fica#on  (serum  &  eluate)        Complete  erythrocyte  phenotyping          Addi#onal  serological  inves#ga#ons  

                   DAT  +              AIHA                                                Allo-‐IHA            DRUG-‐induced                    Auto                        Auto+Allo                                                    

                         496                                          385                                        69                                              37                        5  

AIHA  -‐  DIAGNOSTIC  ASPECTS    

•  Posi#ve  DAT  not  specific  for  AIHA      

•  Atypical  cases    (DAT-‐Neg  AIHA  /  Warm  IgM  AIHA)    

DAT negative AIHA

•  Represent 11% of AIHA according to Petz e Garratty (Immune

hemolytic anemias. New York: Churchill Livingstone, 2004)

Causes of false Possible negative results solutions

IgA auto Abs low-affinity IgG Abs

low sensitivity of the tests employed

Use on monospecyfic anti-IgA antisera

test with cold washed RBC test con low-ionic solutions (LISS) polybrene or PEG

More sensitive techniques

§  RBCs  washed  with  Lo-‐ion  §   RBCs  wash  with  LISS  saline  or  saline  at  4°C  §   Polybrene  §   PEG  §   Microcolumn  agglu#na#on  technique  (CAT)  §   Solid  phase  agglu#na#on  technique  (Yamada,  Transfusion  2008)    §   Immunoenzyma#c  assay  (Bencomo  et  al,  Immunohematology  2003)      §   Flow  cytometry  (Lin  et  al,  Transfusion  2009)  §   Mytogen-‐s#mulated  (MS)-‐DAT  (Barcellini  et  al,  Int  J  Hematol  2010)  

DAT  -‐  More  sen#ve  techniques  

Mitogen-stimulated DAT (MS-DAT)

Binding of Auto-Ab to autologous RBC

Mytogenic and/or cytokine stimulation

Auto-Ab in culture

cytokines

ng/ml OD mean OD 1 OD 2 OD 3 ng/ml log OD log2000 636 648 632 629 3,301030 2,8036851000 739 721 746 750 3,000000 2,868644600 800 795 801 805 2,778151 2,903271300 876 845 850 933 2,477121 2,942504150 927 932 948 901 2,176091 2,96708075 1027 1065 1056 961 1,875061 3,011711438 1077 1062 1069 1100 1,574031 3,0322160 1089 1098 1120 1050

y = -0,1284x + 3,248R2 = 0,9753

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functional test quantitative test  

“In   the   last   10   years  we  collected   16   cases   of  DAT(tube,   microcolumn  a n d   s o l i d   p h a s e ) -‐nega#ve   AIHA   in   which  the   diagnosis   was   made  on   the   basis     of   a  posi#ve   MS-‐DAT.   These  cases   represent   roughly  10%   o f   to ta l   A IHA    observed   in   the   same  period”.   W.   Barcellini   et   al,  Int  J  Hematol  2010;91:762-‐9

Br J Haematol 2000;111:452-60

• Shirey RS et al. Fatal immune hemolytic anemia and hepatic failure associated with a warm-reacting IgM autoantibody. Vox Sang 1987; 52:210-22. •  McCann EL et al. IgM autoagglutinins in warm AIHA: a poor prognostic feature. Acta Hematol 1992;82:120-5. •  Garratty G et al. Severe AIHA associated with IgM warm autoantibodies directed against determinants on or associated with glycophorin A. Vox Sang 1997;72:124-30. •  Friedman AM et al. Fatal AIHA in a child due to warm-reactive immunoglobulin M antibody. J Pediatr Hematol Oncol 1998;20:502-5. •  Nowak-Wegrzyn A et al. Fatal warm AIHA resulting from IgM autoagglutinins. J Pediatr Hematol Oncol 2001;23:250-2. •  Arndt PA, Leger RM, Garratty G.Serologic findings in autoimmune hemolytic anemias associated with immunoglobulin M warm autoantibodies. Transfusion 2009;49: 235-42.

SEVERE AND LETHAL AIHA CAUSED BY “WARM” IgM AUTOANTIBODIES

“...AIHAs associated with IgM warm auto Abs are often severe with more fatalities than other types of AIHA….” (Garratty et al, Vox Sang. 1997,72:124-30).

•     Spontaneous  RBCs  agglu#na#on  due  to  crosslinking  of  IgM  autoabs    •       Can  appear  to  have  only  C3    on  RBCs  by  rou#ne  DAT  •       IgG  may  be  present  also  •       Can  appear  to  be  DAT–    by  rou#ne  DAT  

The  hemolysis  remained  refractory  to  treatment  with  prednisolone  and  also  prednisolone  plus  azathioprine,  but  gradually  improved  aser  treatment  with  prednisolone  plus  cyclophosphamide.    CONCLUSION:  Weak  or  nonagglu#na#ng  RBC-‐bound  IgM  warm  an#bodies  can  be  iden#fied  by    DDAT  

T. Bartolmas and A. Swalama Transfusion. 2010 May;50(5):1131-4. Epub 2009 Dec 10

no Cause of hemolysis

identified?

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Diagnos#c  flow-‐chart  for  suspected    AIHA  in  children  

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Negative pharmacologic anamnesis

Test drug dependant and independant antibodies

Positive pharmacologic anamnesis

Anti-IgA antisera washing at 4°C LISS washing PEG ELISA -IRMA cytometry

Other MS-DAT

DDAT

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Standard DAT (polyspecific antisera)

Raccomandazioni  per  la  ges#one  del  bambino  con  AIHA      AIEOP  (oeobre  2013)  

+ DAT with monospecyfic antisera (anti-IgG and anti C)

+

Test for antibodies in serum (IAT)

+

Auto Ab identification

+ eluate

Intravasc Hemol.

DL biphasic hemolysin

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THERAPY  OF  IDIOPATIC  (w)AIHA  

azathioprine,  CTX,  VCR  

danazol  i.v.  immunoglobulins  plasmapheresis  blood  transfusion  erythropoie#n  

Rituximab  Alemtuzumab  Other  BMT  

cyclosporine  mycophenolate  

steroids  

splenectomy  

K.  Lechner  et  al:  How  I  treat  autoimmune  hemoly=c  anemias  in  adult.  Blood,  2010;16:1831-‐38  In   the   era   of   evidence-‐based  medicine   it   is   surprising   and   regreeable   that   the   treatment   of  AIHA  is  s#ll  not  evidence-‐based.  There  are  no  randomized  studies  and  only  a  few  prospec#ve  phase   2   trials.   Otherwise,   only   retrospec#ve   studies,   smal   series   of   (probably   selected)  pa#ents  or  single  cases  have  been  reported  (evidence  level  5).  There  is  no  formal  consensus  on  the  defini#on  of  CR  or  PR  hematologic  remission  and  refractoriness.  

THERAPY OF IDIOPATHIC (w)AIHA

20-30% no response or need of pred > 0.1-0.2 mg/kg/die to maintain adequate Hb levels

- Rapid response - No predictors of efficacy - Surgical risk - Infective risk

- Delayed response-. side effects

splenectomy cytotoxic-immunesuppressors Cyclophosphamide Azathioprine Cyclosporine Other (Vincristine, 6-MP, 6-TG)

Prednisone (1-1.5 mg/kg/die o 40-60mg/m2 p.o.) for 3-4 weeks, then tapering 5-10 mg/week in 6-12 months

MoAbs: rituximab, alemtuzumab, eculizumab MFM, bortezomib, bendamustin,C1-esterase inhibitor

2008

ü  Low  levels  of  evidence  ü Clinically  heterogeneous  pa#ents  ü Response  to  treatment    not  univocally  defined  

ü  Effec#ve  in  primary  and  secondary  AIHA,    median  OR  60%  (40-‐100%),    In            two  recent  studies  on  larger  cohorts    median  OR  77  and  93%,    median  TTR  3            and  6  w  (1-‐16)  ,  DFS  72%    at  1  yr,  56%  at  2  yr  (Bussone  et  al  2009Penalver  et  al  

2010)      

ü  Effec#ve  in  warm  AIHA  (OR    83-‐87%,  CR  54-‐60%),  and    in  CHD  (OR  58,  CR  4.5%)  (Berentsen  et  al  2006;  Schollkopf  et  a,  2006)  

   

257 AIHA (173 W, 75 C, 9 nd), of whom 56 children

. Br  J  Haematol  2008;14:149-‐69. Eur  J  Intern  Med  2011;22:220-‐9  

ü  Effec#ve  in  refractory  pediatric  AIHA,  including    Evans  S.  (56  cases,  OR  84  -‐100%,  CR  67-‐100%)(Quar#er  2001;  Zecca    et      al  2003;  Bader-‐Meunier  2007;  Rao  et  al  2008)  

ü  Response  independent  from  prior  treatment,  including  splenectomy  (Berentsen  et  al  2004;  Narat  et  al  2005;  Berentsen  et  al  2006;  Schollkopf  et  al  2006;  Barcellini  &  Zanella  2011),  

ü  Retreatment  effec#ve,  even    If  repeated    (  Rao  et  al  2008;  Narat  et  al    2005;  Trapé  et  al    2005,  Barcellini  &  Zanella  2013  )  

ü  Well  tolerated  also  in  children  (Garvey  2008).  Data  on  long  term  safety  needed    (few  cases  of  progressive  mul#focal  leukoencephalopathy  )  (Gea-‐Banacloche    2010)  

ü  Median  dose  in  adults  and  children    375  mg/m2/w  x    4  w(range  2-‐12)      

2008 . Br  J  Haematol  2008;14:149-‐69.

Complete  and  par#al  responses  (CR  and  PR)  were  defined  as  Hb  >  12  g/dL  and  >  10  g/dL  at  month  +2;  Sustained  response  (SR)  was  defined  as  Hb  >  10  g/dL  at  month  +6,  and  +12  in  the  absence  of  any  treatment.  

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ü  LD  rituximab  100  mg  fixed  dose  weekly  on  days  7,  14,  21,  28  along  with  standard  oral  PDN  (1  mg/kg/die  day  +1  to  +  30,  followed  by  quick  tapering)  

ü  OR  82.6%  at  month  +2,  and  subsequently  stabilized  ~90%  at  month  +6  and  +12  

ü  response  was  beqer  in  14  WAIHA  (OR  100%  at  all  #me-‐points)  than  in  9  CHD  (on  average  60%)  

ü  the  relapse  free  survival  (RFS)  was  100%  for  WAIHA  at  +6  and  +12  months  versus  89%  and  59%  in  CHD  

ü  The  risk  of  relapse  was  higher  in  CHD  and  in  pa#ents  with  longer  interval  between  diagnosis  and  enrolment.    

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ü  Treatment  was  well  tolerated  and  no  adverse  events  or  infec#ons  were  recorded  

ü   Re-‐treatment  was  also  effec#ve  ü  Steroid  administra#on  was  reduced  both  as  cumula#ve  

dose  (~50%)  and  dura#on  compared  with  the  pa#ent's  past  history.    

The  overall  response  was  90%,  100%,  100%,  and  89%  and  the  relapse-‐free  survival  87%,  79%,  68%,  and  68%  at  6,  12,  24,  and  36  months,  respec#vely.    Response  rates  were  slightly  beeer  in  WAIHA  than  in  CHD,  and  relapse  risk  was  greater  in  cold  than  warm  forms  (HR  2.1,95%  CI  0.6–7.9).    Four  pa#ents  were  retreated  (one  pa#ent  twice),  all  achieving  a  response,  las#ng  a  median  of  18  months  (range  9–30).    Treatment  was  well  tolerated  without  adverse  events  or  infec#ons.  

EXPERT  OPINIONS    Lechner  K  &  Jager  U:  How  I  treat  autoimmune  hemoly=c  anemias  in  adults.  Blood  2010;  16:1831-‐8.    «It  is  no  doubt  that  the  short-‐term  benefit/risk  ra#o  for  rituximab  is    high  and  that  rituximab  is  certainly  the  best  op#on  for  pa#ents  who  are  not  eligible  for  or  who    refuse  splenectomy.»      «…In  our  opinion  the  sequence  of    second-‐line  treatment  in  primary    warm  AIHA  should  be  splenectomy,  rituximab,  and  thereawer  any  of  the  immunosuppressive  drugs».  «Alemtuzumab    considered  as  a  «Treatment  of  last  resort  (severe  anemia  nd        none  of  the  known  drugs  have  worked)».  

Crowther  M.  et  al.  Evidence-‐based  focused  review  of  the  treatment  of  idiopathic  warm  immune  hemoly=c  anemia  in  adults.  Blood  2011;118:4036-‐40.  «We  suggest   for   the   treatment  of   relapsed  or   refractory  AIHA  that  Rituximab   (375  mg/m2  weekly  for  4  weeks)  or  splenectomy  should  be  considered  over  alternate  therapies  (Grade  2C).   Furthermore,   although   there   are   no   head-‐to-‐head   comparison   of   rituximab   and  splenectomy,   published   evidence   suppor#ng   the   use   of   rituximab   is  more   extensive   than  splenectomy   (ungraded   recommenda#on).   The   choice   of   second-‐line   therapies   should  depend   on   pa#ents,   values   and   preferences   and   local   circumstances».   «There   is   some  evidence   for   the   use   of   alemtuzumab,   high-‐dose   cyclophosphamide,   mycophenolate  mofe#l,   and  vincris#ne-‐labeled  platelets,  but   the   small  number  of   reported   cases  and   the  poten#al  side  effects  prevent  us  from  making  a  recommenda#on  

   

Rituximab375 mg/mq/sett x 4 sett

Endoxan10 mg/kg/die x 10 gg

O50 mg/kg/die x 4gg

Splenectomia

Altre terapie:Alemtuzumab, TCSE

Aggiungere immunosoppressoreal fine di ridurre o sospendere PDN

MMF (300-600 mg/mq/2v/die)

AZA (25-200 mg/die)

CYA (2-10 mg/kg/die)

NR

RP

RP

RP

NR

NR

NR

RC

RC

RC

Non risposta a terapiaprima linea

Dipendenza da steroide(>0.1-0.2 mg/kg/die PDN)

Off therapy

Off therapy

Off therapyRP

Continuare (vedi testo)

RC

Off therapy

Raccomandazioni  per  la  ges#one  del  bambino  con  AIHA      AIEOP  (oeobre  2013)  

CONCLUSIONS  -‐  TAKE  HOME  MESSAGES  

ü  AIHA may be clinically heterogeneous, 1/3 of cases with a severe onset (Hb

FINE

Alemtuzumab  therapy  in  idiopathic  AIHA    

Willis    et  al    J.,    Bri=sh  Journal  of  Haematology    2001;  114:  891,    Alemtuzumab  10  mg/d/iv  in:    4  refractory  idiopa#c  AIHA  (adults)  (2  warm,  1  cold,  1  mixed):  1CR,  2PR,  1NR)          (median  follow  up  10  m)      3    Evans  (  1  child,  2  adul#).:  2  RC    Cheung  WW  et  al,  Haematologica  2006,  91  (1)  42-‐3.    1  warm  AIHA    refractory  to  rituximab:  CR    awer  a  cumula#ve  dose  of    883    mg        CMV  reac#va#on.    Gomez-‐Almaquer  et  al    Blood  2010;176:4783-‐5  Alemtuzumab  10  mg  s.c      +      100  mg  rituximab    in  8    idiopathic  warm  AIHA:    OR  8/8,  CR  6/8        Time  to  response  1-‐31  w      Median  dura#on  of  response    46  w  (22-‐89)  Grade  1  toxicity  at  first  dose.    30%  infec#ons.    

                           CR  in  13/16  cases  

                   

 

Alemtuzumab  in  CLL-‐related  AIHA  

Osterborg A, Curr Hematol Malig Rep. 2009

CR  in  11/12  cases

Mycophenolate  mofe#l  therapy  in  AIHA  

Howard,  Br  J  Haematol.  2002;117:712-‐5      4  pts  with  AIHA  and  6  with  ITP  showed  a  CR  or  a  good  PR    Lin  JT,  Ann  Hematol.  2002;  81:723-‐6    1  pts  with  AIHA  secondary  to  MDS  showed  CR      Alba  P,  Lupus.  2003;12:633-‐5  2  pts  with  AIHA  secondary  to  ESL  showed  a  good  PR    Kotb  R,  Eur  J  Hematol  2005;  75:  60-‐4  4  pts  with  AIHA  (1  Evans  S.)  +  9  ITP  showed  100%  and  78%  response    respec#vely    “The  cumula#ve  data  suggest  a  poten#al  place  for  MMF  in  the  treatment  arsenal  of  refractory  cytopenias.”  

CR/good  PR  in  11/11  cases  

66  yrs  old  pa#ent.  In  2001  symptoma#c  CAD  (dispnoea,  fa#gue)  refractory  to  steroids.  Ini#al  response  to    5  doses  of  rituximab.  In  2004  e  2006  ritreatment  with  rituximab:    ineffec#ve.  

Blood  2009;113:3485-‐6  

ü  52  pa#ents  with  ITP,  AIHA  and  Evans'  syndrome  from  50  centres  in  the  EBMT  registry    

ü  Subjected  to  autologous  or  allogeneic  HSCT  up  to  2008  

ü  OS  at  5  years  was  61±5%  

ü  Analysis  of  the  24  children  with  immune  cytopenias  (19  allogeneic  HSCT  and  7  autologous  HSCT)  confirmed  a  60%  PFS  with  allogeneic  HSCT  vs  35%  with  autologous  HSCT,  with  a  TRM  of  20%  overall  

ü  It  remains  unclear  whether  symptoma#c  ‘cytopenia-‐free  survival'  is  best  achieved  with  autologous  or  allogeneic  HSCT  

                 Snowden  JA,  EBMT  guidelines  in  severe  autoimmune  diseases.  Bone  Marrow  Transplant.  2012    

BMT  IN  AIHA  

TAD standardantisiero polispecifico

TAD con antisieri monospecifici

Anti IgG e anti C3d

Ricerca altra causa di emolisi

Sieri monospecifici IgALavaggi a 4°C

Lavaggi con LISSPEG

ELISA-IRMACitofluorimetria

Ricerca anticorpinel siero (IAT)

neg

pos

neg

pos

pos Emolisi Intra vasc

si

pos

Anamnesi per assunzione di farmaci

Ricerca anticorpifarmaco dipendenti efarmaco-indipendenti

Eluato

Altro(MS-DAT)

pos

neg

pos

neg

Anemia emolitica disospetta natura immune

pos

posneg

pos

neg

Identificazoneanticorpi

neg

Stop

Stop

Emolisine bifasiche

DL

Raccomandazioni  per  la  ges#one  del  bambino    con  AIHA,    AIEOP,  oeobre  2013    

Diagnosi di AEA da Ab caldi

PDN per os1-2 mg/kg/die

x 3 sett.

continua PDNx 1 sett.

continua PDNdosaggio pieno

x 2 sett.

Riduzione graduale PDN(almeno 6 mesi)

Continua PDN allaDose minima efficace

Riaumentare PDN a dosaggio precedente

Terapiaseconda linea

Recidiva

RC

RC

RC - RP

NR Riconsiderare diagnosi differenziale

Recidiva

Dipendenza PDN

RP

< 0.1 – 0.2 mg/Kg/die > 0.1 – 0.2 mg/Kg/die

RP

Stoptherapy

Possibili terapie aggiuntive nei casi gravi (v. testo)

M-PDN ad alte dosi e.v.IG e.v.

TrasfusionePlasma exchange

RACCOMANDAZIONI  PER  LA  GESTIONE  DEL  BAMBINO  CON  AIHA-‐  AIEOP  oqobre  2013