The European Survey on Evans syndrome:

1
The European Survey on Evans syndrome an update
Marc MICHEL M.D, Department of Internal
Medicine, Henri Mondor University Hospital,
Créteil (France)
2
Evans syndrome background

• Rare condition ( 0.8 to 3.7 of AIHA/ITP)
• Combination of ITP and AIHA (Evans 1951)
• Both conditions can occur simultaneously or
  sequentially
• Can be isolated ( idiopathic ) or associated
  with various conditions SLE, PI, NHLs
• Little is known about prognosis (higher risk of
  bleeding ?), outcome and management (small
  series, pediatric)
• J Ped Hem Onc 199719433-37

3
Study design

• Retrospective survey, multicentric (France,
  Italy)
• Inclusion criteria
• Age gt15 years
• AIHA
• Hb level lt 10 g/dL
• Hemolysis
• Positive DAT (or if - exclusion of any other
  cause of hemolysis)
• ITP
• Usual criteria (ASH) and platelet count lt 100 x
  109/L
• Normal marrow

4
Treatment response criteria

• AIHA
• CR Hb level 12g/dl and no signs of hemolysis
• PR 10 Hb lt 12 g/dl with an increase of at
  least 2g in Hb level from baseline
• ITP
• CR platelet count gt 150 x 109/L
• PR plt count gt 50 x 109/L with an increase of
  at least twofold the initial count

5
Results patients

• N 54 patients
• 20 men (37) / 34 women (63)
• Mean age 60 19 years
• Mean age at ITP onset 54.7 21y
• Mean age at AHAI onset 54.6 22y

6
Results delay ITP/AIHA
19
57
24

• Mean delay beetween the 2 conditions 37
  months35

7
Results baseline characteristics

• Mean Hb at AHAI diagnosis 7.7 .02 g/dl,
  median 8.0 g/dl 2.6-11
• Lowest Hb level, mean 6g/dl 1.93
• Mean plt count at ITP diagnosis 33 x 109/L,
• median 25 x 109/L 1 100 x 109/L

8
Results Clinical presentation

• Bleeding symptoms in 28/54 (52) patients at ITP
  onset
• 5/28 had life-threatening haemorrhage, with 2
  cases of non-fatal ICH (3.7)
• 25/54 patients (46) required at least one
  transfusion (2 to 10 RPC) at AHAI onset
• AHAI lead to a cardiac complication in 6/28
  patients (21) aged of 60 or above (including MI
  in 2 cases and ACS in 4), all of whom required
  transfusion, one stroke at AHAI onset.

9
Results underlying diseases

• Idiopathic ES in 33/54 cases (61)
• Associated conditions
• SLE (aged from 15 to 55 years) n 6
•  Lupus like syndrome  n 4
• CVI n 3
• NHL
  n 2
• Others PAPS, Sjogren synd, MGUS, n 6
  HCV, congenital asplenia, uterus cancer
  
• 
  Total n 21

10
Results underlying diseases

• Among the patients with an initial diagnosis of
   idiopathic  ES, after a median follow-up of
  3.5 years
• - A B-cell NHL occured in 2 patients
• (aged 73 and 83)
• A MDS was diagnosed in 2 others
• (aged 73 and 80)

11
ResultsDAT specificity
n 4 (2)
46
46
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Resultsmarkers of hemolysis

• Haptoglobin in 49/50 cases (98)
• LDH in 42/49 cases (85)
• Bilirubin in 33/45 (73)
• Reticulocytosis (gt 120x109/L) in 37/47 (78)
• Blood smear 10/49 cases (20), presence of
  schizocytes ( to ) spherocytes

13
ResultsAntiplatelet Abs

• Result available in only 18/54 cases
• PFIT and/or MAIPA
• 13/18 positive (72) IIbIIa in 5/5

14
Treatment AIHA

• Steroids were given in 52/54 cases (96) as
  first-line therapy 1-2 mg/kg/d HDMP, IVIG in 1
  case (failure). Duration highly variable (3-18
  months)
• Short-term response
• - CR 21/52 (40)
• - PR 22/52 (42)
• - failure 8/52 (15)
• - not available 2

15
Treatment AIHA

• Other treatments (for refractory AIHA or as
  steroid sparing strategy)
• - Danazol n 4 (3 CR/PR)
• Iv or oral cyclophosphamide n 4
• Imuran n 4 (3 PR)
• Cyclosporin n 3 (2 CR/PR)
• Mmf n 1
• Plasmapheresis n 1 (transient PR)

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Treatment ITP

• 41/53 (77) of the patients were treated with
  steroids for ITP gt initial response
• 20/41 CR (49)
• 12/41 PR (29)
• 8/41 failure (19.5), 1 NA
• 26/54 (48) got IVIG (1-2 g/kg)
• 10/26 CR (38)
• 6/26 PR (23)
• 10/26 (38)

17
Treatment ITP

• Danazol (400-600 mg/j) n 9 gt 6 CR/PR, 3
  failures (stop for hepatitis in 2 cases)
• Vinca alkaloids (vincristine / vinblastine) n
  5
• 2CR/PR, 3 failures, 2 cases of neuropathy
• Dapsone n 3 (2 CR/PR, 1 failure)
• Iv cyclophosph. n 1 (CR)

18
Splenectomy (n 14)

• N 8 for AIHA gt 6 CR (75), 1 PR, 1 failure
• N 5 for corticodependent ITP gt 2 CR (1
  transient), 1 transient PR, 2 failures
• N 2 for corticodependent ES gt 2 CR (one
  transient)
• Overall 8/14 long-term CR (57)
• 2/14 (14) patients died from a septic skock
  post-splenectomy (on day 4 and 18)

19
Rituximab (n 3)

• Mainly for refractory ITP
• All 3 underwent previous splenectomy
• CR in all 3 cases
• Mean follow-up 9 months

20
Outcome

• Median follow-up after AIHA 36 months
• Median follow-up after ITP 42 months
• ITP was chronic (gt 6 months) in 40/49 cases (81)
• At time of analysis
• - 28 patients (52) were in CR/PR on treatment
  (prednisone IS)
• - 20 patients (37 ) were in treatment-free
  CR/PR of both ITP and AIHA
• 6 patients were not in remission
• 12 patients (22) had died

21
Causes of deaths (n12)

• Sepsis post-chemotherapy for NHL n 3 cases
• Septic shock post-splenectomy n 2
• MDS n 2
• MI n 1
• Oesophagus cancer n 1
• Uterus cancer 1
• Stroke 1
• Unknown 1

22
Conclusions

• While Evans syndrome is mainly associated with
  SLE/LLD in young adults, it may precede the onset
  of NHL or MDS in elderly patients
• In elderly patients, the risk of cardiac
  complications related to AIHA seems to be higher
  than the risk of bleeding related to ITP
• The therapeutic strategy is heterogeneous and
  needs further evaluation. The risk of infections
  must be taken into consideration (risk/benefit
  ratio)

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Questions

• Which initial laboratory workup ?
• Systematic search for ANA (tested in 77), Acl,
  Ig levels?
• Which tests to look for an underlying NHL ?
• Total body CT-scan ?
• Is marrow biopsy or apsirate mandatory ?
• What is the best therapeutic strategy ?
• - Duration of initial therapy with steroids
• - When splenectomy / rituximab should be
  considerered
• France cannot live without Europe !
• gt collaborative prospective
  studies

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Acknowledgements

• F. Rodeghiero, Vicenza (Italy)
• M. Ruggeri, Vicenza (Italy)
• G. Emilia, Modena (Italy)
• L. Cirasino, Milano (Italy)
• F. Zaja, Udine (Italy)
• V. Chanet, Clermont-Ferrand (France)
• B. Godeau