Régis Peffault de Latour - MaRIH

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E-MaRIH - Grenoble

Régis Peffault de Latour French reference center for aplastic anemia & PNH

French network for rare immunological & hematological disorders (MaRIH) Hôpital Saint-Louis, Paris, France

Monday April 23rd, 2018

http://www.aplasiemedullaire.com/

• Pathophysiology

– Idiopathic aplastic anemia (and PNH)

• Diagnosis

• Management in 2018

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Idiopathic aplastic anemia Agenda


Idiopathic aplastic anemia Physiopathology – immune actors

+ Tc1

TNF

Treg

Th1 immune response

IFN

Bone marrow

Solomou et al, Blood 2006; Bettelli et al, Nature 2008;

Feng X et al, Haematologica 2010; Peffault de Latour et al, Blood 2010

1) Th1 immune mediated response

3) Th17 implication

2) Tregs

quantitative

deficit


Idiopathic aplastic anemia Lanscape

DKC

SDS

FA

Inherited Acquired Clonal evolution

Bone marrow failures disorders (BMF)


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Idiopathic aplastic anemia Diagnosis

- Pancytopenia (+/- PNH)

• Macrocytosis is common

• Lymphocytes count is usually preserved

• Isolated cytopenia at early stage (thrombocytopenia)








- Bone marrow aspiration

• No abnormal cells










- Bone marrow biopsy (diagnosis)

• Cellularity <30%

• Dyserythropoiesis (usual)

• Mast cells, lymphoid hyperplasia, plasma cells, macrophages










- Bone marrow biopsy (diagnosis)

• Cellularity <30%

• Dyserythropoiesis (usual)

• Mast cells, lymphoid hyperplasia, plasma cells, macrophages

- Negative screening for Fanconi Anemia & Telomeropathy

Camitta BM et al. Blood 1976;48:63–70 SAA, severe AA; VSAA, very severe AA

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SAA

Hypocellularity (<30%) and at

least 2/3 criteria:

PNN <0.5x109/L

Platelets <20x109/L

Reticulocytes <20x109/L

VSAA

PNN <0.2x109/L

Moderate Not all criteria for SAA

PNN >0.5x109/L

Transfusions?

Yes No

Treatment Follow-up

Idiopathic aplastic anemia Management

Idiopathic aplastic anemia needed to be treated

HLA-identical sibling donor and age < 40

HSCT

Marrow/Cy + ATG/CSA MTX

No sibling donor or age 40 or more

hATG + CSA

Refractory/relapse

10/10 (8/8 matched UD*) Young (<30 years)

First year

YES: Unrelated matched BMT

Treatment (guidelines)

NO: Eltrombopag Repeated IST Alternative

(mismatch BMT)




HSCT



hATG + CSA

Refractory/relapse


First year



Same algorythm in the presence of a AA/PNH syndrom

(without significant hemolysis) NO: Eltrombopag Repeated IST Alternative

(mismatch BMT)



HSCT



hATG + CSA

Refractory/relapse


First year





(mismatch BMT)


Sibling transplantation

Long-term

Event

No of

Events 6yr-CI (%)

Secondary Cancer 1 2 (0-9)

Osteonecrosis 10 21 (10-36)

Cardiovascular

complications

1 2 (0-9)

Endocrine

dysfunctions

7 19 (9-31)

Saint Louis experience. Haematologica. 2012.

61 53 38 35 33 30 28

N. At risk

87,5 % (CI 95%, 78-97)

Surv

ival

Pro

bab

ility

Time (months)

0 12 24 36 48 60 72

0.0

0.2

0.4

0.6

0.8

1.0

Marrow / Cy-ATG / CSA + MTX (standard) As soon as possible (<100 days)

61 patients Median follow-up 77 months



HSCT



hATG + CSA

Refractory/relapse


First year





(mismatch BMT)


Horse ATG + Cyclosporine

The French experience – overall survival

Peffault de Latour et al, American Journal of Hematology 2018 in press

N=465, 2011-2017 - First line, n=379 - Relapse, n=33 - Refractory, n=26



The French experience – overall survival


N=465, 2011-2017 - First line, n=379 - Relapse, n=33 - Refractory, n=26

n=140 n=133 n=84

First line, Disease severity



The French experience – response characteristics

Response characteristics

– Responders

• 40% at months 3 & 60% at months 6


Time to response Cum incidence (overall)




– Responders


• Better & quicker response for patients with moderate aplastic anemia



Time to response Cum incidence (Severity)




– Responders



– Complete response is exceptional (!)







– Responders



– Complete response is exceptional (!)

– Refractory patients (about 30-40%)




Refractory patients


HSCT



hATG + CSA

Refractory/relapse

10/10 (8/8 matched UD) Young (<30 years)

First year




Unrelated transplantation?


(mismatch BMT)


Marrow as source of stem cells In the first year after diagnosis for refractory patients

Flu Cy ATG Low dose TBI (EBMT / BMT CTN / Japan)

Ove

rall

Surv

ival

Eapen M et al, Blood 2011; Bacigalupo,et al, Haematologica 2010; Devillier R et al, Haematologica 2016;

Bacigalupo, Blood 2016 In press; Anderlini P et al, Lancet Hematology 2015; Marsh J et al, Blood 2011

Time (day)

<10 years (85%)

11-30 years (77%)

30-40 years (66%)

>40 years (49%)

Unrelated transplantation

Guidelines & role of age


3 Risk factors - Age (30)

- MUD versus mismatch UD - BMT in the first year post AA versus after

Bacigalupo, Blood 2016; Devillier et al, Haematologica 2016

French cohort (n=131)

Validation cohort (EBMT) (n=751)

Years post BMT

Unrelated transplantation

Decision making process



HSCT



hATG + CSA

Refractory/relapse


First year





(mismatch BMT)


27


HSCT



hATG + CSA

Refractory/relapse


First year



(mismatch BMT)




Adapted from Olnes M et al. N Engl J Med 2012;367:11; Desmond R et al. Blood 2014;123:1818

47 patients screened

26 patients enrolled (cohort 1)

25 patients received eltrombopag

Four patients discontinued treatment

Response rate = 44% (11/25)

18 patients (cohort 2) received treatment

An additional six patients met the hematological response criteria = 40%

(17/43)

Overall response rate = 40% (17/43)

Successful taper off eltrombopag and sustained multilineage response

in five patients

TPO receptor agonist and refractory aplastic anemia

Response rate








(17/43)



in five patients


Response rate

Olnes et al NEJM 2012









(17/43)



in five patients


Response rate

Olnes et al NEJM 2012

Desmond et al Blood 2014


Subject (age)

Response Baseline Abnormality Time on

Eltrombopag (Months)

Dysplasia Outcome

7 (60) NR 46XY[20] Monosomy 7 3 N Died of progressive

cytopenias

8 (18) NR 46XX[6] Trisomy 8 3 N HSCT

19 (20) NR 46XY[20] Monosomy 7 3 N HSCT

26 (67) R 46XY[20] del(13q) 13 Yes (mild) HSCT

31 (41) NR 46XY[20] Trisomy 21

Monosomy 7

3

6 Yes (mild) Awaiting HSCT

32 (66) R 46XY[20] del(13q) 9 N Under observation

36 (23) NR 46XY[20] Monosomy 7 3 N HSCT

42 (17) NR No

metaphases Chromosome 7 3 N HSCT

HSCT, hematopoietic stem cell transplant; NR, nonresponder; R, responder; TPO-R, TPO, thrombopoietin receptor Desmond R et al. Blood 2014;123:1818–1825; Olnes MJ et al. N Engl J Med 2012;367:11–19

Eight patients (19%) developed cytogenetic abnormalities during eltrombopag treatment

Advise serial bone marrow biopsies

Clonal evolution


• ATG-naïve patients (Cohort A, n=11)

• Refractory patients (Cohort B, n=35)

• Disease characteristics:

French experience - patients characteristics

Lengliné et al, Haematologica 2017



• Safety

– 1 SAE (liver toxicity)

– Clonal evolution (lack of follow-up …)

French experience - main messages




• Safety



• Response rate = 40%

• 3 months for refractory patients

• 6 months for 1st line

• Multi-lineage response = 30% among responders





• Safety



• Response rate = 40%

• 3 months for refractory patients

• 6 months for 1st line

• Multi-lineage response = 30% among responders

• Of note

– 20% of non responders responded at a higher dose (225 mg)

– Second IST including ATG (Revolade-ATG-CSA) lead to

excellent results in refractory patients (response rate = 100%

but n=8)





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HSCT



hATG + CSA

Refractory/relapse


First year



(mismatch BMT)




Conclusions

• Diagnosis

– Inherited versus idiopathic aplastic anemia

• First line treatment in 2018

– Sibling transplantation: patients < 40 years

– Horse ATG + Cyclosporine for the others

• Refractory patients (6 months)

– Matched unrelated transplantation: patients < 30 years

– Experimental transplantation: patients < 20 years (?)

– Eltrombopag (+/- second course of ATG) for the others

Perspectives – Eltrombopag first line

• Phase II study

– Horse ATG + Cyclosporine + Revolade

– Responders 86%; Complete response 37% (6 months)

Patients naïfs clinicaltrials.gov NCT01623167

April 2017

Patients naïfs clinicaltrials.gov NCT02099747

Perspectives – Eltrombopag first line

Accrual 120/200

Thank you!

The French Reference Center for aplastic anemia and PNH in Paris

Saint-Louis Hospital Robert Debré Hospital Institute of Hematology, IUH St-Louis

F Sicre, T Leblanc, A Baruchel, G Socié (clinic)

N Vasquez, W. Cuccuini, J Soulier (Fanconi Team),

C Kannengiesser, E Lainey, L Da Costa (Telomeres team)


Régis Peffault de Latour - MaRIH

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