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Aplastic Anemia: Current

Thinking on the Disease, Diagnosis, and Non-Transplant

Treatment

David A. Margolis, MDdmargolis@mcw.edu

Objectives

• Review Current Thinking regarding differential diagnosis and physiology

for a patient with bone marrow failure.

• Review Current Treatment Options.

• Discuss Current Treatment Algorithm

• Answer Questions as Best as Possible

What is Aplastic Anemia

• Acquired Aplastic Anemia is a disease caused by too few hematopoietic

progenitor cells leading to too few red

blood cells, white blood cells, and

platelets.

• Acquired Aplastic Anemia needs to be differentiated from inherited bone

marrow failure syndromes.

APLASTIC BONE MARROW

HEALTHY BONE MARROW

CAMITTA CRITERIA for

SEVERITY of APLASTIC ANEMIA

• SEVERE AA (SAA)

PERIPHERAL BLOOD (2 of 3):

PMN < 500/ul

PLATELETS < 20,000/ul

RETICULOCYTES < 20,000/ul (< 1%)

MARROW: hypocellular

• VERY SEVERE AA (VSAA): PMN < 200

• MILD AA: LESS AFFECTED THAN SAA

When Should I think of Aplastic Anemia?

• Clues to the diagnosis:

–Reasonably well appearing

–More than one cell line affected

–No significant lymphadenopathy or hepatosplenomegaly

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When Should I think of Aplastic Anemia?

• Diagnostic Procedures:– CBC with manual differential/retic count

– Bone Marrow Aspirate and Biopsy

– Chromosomes/Flow Cytometry to look for malignancy and MDS

– CD59 expression to look for evidence of paroxysmal nocturnal hemoglobinuria

The Bone Marrow is

Aplastic: Is it Acquired

Aplastic Anemia?

• Important to discriminate between an inherited bone marrow failure

syndrome and acquired aplastic

anemia.

• Proper treatment is based on the

correct diagnosis.

• www.marrowfailure.cancer.gov

Inherited Bone Marrow Failure

Syndromes

• Fanconi Anemia-40% without physical stigmata so must do diagnostic/functional DEB test to look for chromosome breakage. – If DEB test abnormal, genetic testing to classify

defect.

• Dyskeratosis Congenita-Classic telomere biology disease. – Nail dystrophy, leukoplakia, lung and liver disease

significant. – Telomere length analysis is becoming a standard

test (stay tuned). – Genetic testing commercially available.

Inherited Bone Marrow Failure

Syndromes

• Schwachman-Diamond Syndrome-SBDS gene defect. Exocrine pancreatic deficiency and neutropenia. – Isoamylase and Trypsinogen are easy

screening tests.

– Genetic Testing commercially available.

• Congenital Amegakaryocytic Thrombocytopenia-MPL gene defect. Profound thrombocytopenia even at birth. – Genetic testing commercially available.

My patient has acquired

SAA: What was the trigger?

• Inciting event leads to an immune mediated destruction of blood progenitor cells– Young et al. Blood, 15 October 2006, Vol. 108, No. 8, pp.

2509-2519

• Trigger is usually not identified

• Check for CMV, EBV, HHV-6, Parvovirus, Hepatitis viruses

• History of jaundice

• Medication history

• Exposures

Pathophysiology of acquired aplastic anemia.

Neal S. Young et al. Blood 2006;108:2509-2519

©2006 by American Society of Hematology

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Somatic mutations in lymphocytes might drive an aberrant immune response.

Neal S. Young Hematology 2013;2013:76-81

©2013 by American Society of Hematology

It’s not just the Immune

System!

• In addition to the role of the immune system, we do believe that in many

patients, there is an interplay between

the immune system and chromosome

machinery called “telomeres”.

• We are in the Telomere Era of Aplastic Anemia in my opinion!

Telomeres 101

• Telomeres are repeat sequences at the ends of chromosomes, which are protective chromosomal material.

• Molecular mechanisms have evolved to maintain telomere length and protective function.

• Mutations in the genes that maintain and protect telomeres cause human disease including marrow failure, liver fibrosis and lung fibrosis.

• Dyskeratosis Congenita is the classic disease of telomere biology.

• Townsley, Bumitru and Young “Bone Marrow Failure and the telomeropathies”– Prepublished 9/18/2014

– DOI http://dx.doi.org/10.1182/blood-2014-05-526285

Mechanisms of telomere attrition.

Danielle M. Townsley et al. Blood 2014;124:2775-2783

©2014 by American Society of Hematology

Diagnostic algorithm for germline telomere diseases.

Danielle M. Townsley et al. Blood 2014;124:2775-2783

©2014 by American Society of Hematology

Telomere Biology may explain the observation that androgen’s have helped some with marrow failure (From Townsley

et al Blood 2014)……• Patients with telomeropathies may be particularly responsive

to male hormones.

• The mechanism of action of male hormones is likely direct

modulation of TERT gene expression to increase telomerase, as inferred from tissue culture experiments and mouse models.

• Male hormones might help to slow the rate of telomere attrition, enhance cell regeneration, and improve not only

hematopoiesis but also other organ dysfunction resulting from

telomere attrition.

• In a prospective research trial at the National Institutes of

Health that has enrolled >24 patients (clinicaltrials.govidentifier: #NCT0144137), danazol appears effective in

improving blood counts and reversing telomere attrition.

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Case 1

• 25 year old Caucasian female presents with a chief complaint of a heavy menstrual period.

• Current period is now at 4-5 days and she is changing a pad every 1-2 hours instead of a few times a day.

• In retrospect, has had “red dots” for a week or so.

• No fevers. Has had fatigue and has felt light headed for last day or two.

Immune Suppression

Therapy

• Multiple approaches.• NHLBI and EBMT set the benchmarks.

• NHLBI “gold standard” is ATG/CSA/Prednisone (Rosenfeld 1995, Young 2003, Scheinberg 2008)

• http://patientrecruitment.nhlbi.nih.gov/AplasticAnemia.aspx

-Alemtuzumab for refractory or relapsed SAA

-Fludarabine/CY for refractory SAA-Eltrombopag in Aplastic Anemia Patients

-Randomized trial of Alemtuzumab versus r-ATG/CSA

What is the data re: IST and how

does that affect decision

making regarding BMT?

• Data from NIH

– JAMA 2003

– Journal of Pediatrics 2008

Rosenfeld, S. et al. JAMA 2003;289:1130-1135.

ALL PATIENTS-60% survival

RESPONSE AT THREE MONTHS

Copyright restrictions may apply.

Late Events After Immunosuppressive Therapy

RELAPSE-up to 40% CLONAL EVOLUTION:

MDS/MONOSOMY 7

10-15%

ATG experience in Kids from NIH

(Scheinberg et al. J of Peds 2008;

Vol 153 page 814)

• N=77 treated from 1989-2006

• The overall response rate in children at 6 months was 74% (57/77); 35% had a CR and 65% had a PR. All of the children achieved transfusion independence.

• The cumulative incidence of relapse at 10 years was 33%: the median time to relapse was 558 days

– No difference in the incidence of relapse was seen between those with CR and those with PR.

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Take Home Message

• When a patient with acquired SAA does not have a matched sibling, the recommendation is to proceed with intensive immune suppression following Rosenfeld et al, 1995 with EQUINE ATG/Cyclosporine/prednisone.

• Other options include high dose Cyclophosphamide at Hopkins.

• Always consider a clinical trial.

• Clinical trials are starting to focus on not only the immune system but on the stem cell compartment as well (stay tuned).

• Eltrombopag is a thrombopoietin agonist.

• Dr. Cynthia Dunbar gets credit for

thinking it may help with SAA.

• Initial study was for SAA patients without platelet recovery….

What is eltrombopag and why might

it help a patient with Aplastic

Anemia?

Original Article

Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia

Matthew J. Olnes, M.D., Ph.D., Phillip Scheinberg, M.D., Katherine R. Calvo, M.D., Ronan Desmond, M.D., Yong Tang, M.D., Ph.D., Bogdan

Dumitriu, M.D., Ankur R. Parikh, M.D., Susan Soto, B.S.N., Angelique Biancotto, Ph.D., Xingmin Feng, M.D., Ph.D., Jay Lozier, M.D., Ph.D., Colin

O. Wu, Ph.D., Neal S. Young, M.D., and Cynthia E. Dunbar, M.D.

N Engl J MedVolume 367(1):11-19

July 5, 2012

Olnes MJ et al. N Engl J Med 2012;367:11-19.

Lineage Characteristics of Responses to Eltrombopag.

Olnes MJ et al. N Engl J Med 2012;367:11-19

Bone Marrow Cellularity at Baseline and at 8 Months or Longer in Four Patients with Trilineage Responses to Eltrombopag.

• A phase 2 study showed a 44% response rate with eltrombopag, an oral thrombopoietin mimetic, among 25 patients with refractory aplastic anemia.

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Conclusions

• Treatment with eltrombopag was associated with multilineage clinical responses in some patients with refractory severe aplastic anemia.

Eltrombopag FDA Approval

• In August 2014, eltrombopag was approved by the FDA for use in

patients with SAA who have had an

inadequate response to immune

suppression therapy.

– Personal communication: “…for those

who do not have a good transplant

option…”

Follow Up Study

• Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug

• Blood 2014 (March 20)• Ronan Desmond1,

• Danielle M. Townsley1,

• Bogdan Dumitriu1,

• Matthew J. Olnes2,

• Phillip Scheinberg3, • Margaret Bevans4,

• Ankur R. Parikh1,

• Kinneret Broder1,

• Katherine R. Calvo5,

• Colin O. Wu6, • Neal S. Young1, and

• Cynthia E. Dunbar1

Methods

• N=44 (25 were in NEJM study)• We modified the protocol in August 2012 to include

tapering of eltrombopag and discontinuation in patients with platelets >50 × 103/μL, hemoglobin >10 g/dL, and neutrophils >1 × 103/μL for more than 8 weeks, without transfusions.

• Five patients fulfilled these criteria, and eltrombopag was tapered and then discontinued after a median of 28.5 months (range, 9-37 months).

• All 5 patients have maintained stable counts with a median follow-up off drug of 13 months

• Their bone marrows have remained normocellular

Responses to eltrombopag by lineage.

Ronan Desmond et al. Blood 2014;123:1818-1825

©2014 by American Society of Hematology

Bone marrow cellularity in patients 1 and 2.

Ronan Desmond et al. Blood 2014;123:1818-1825

©2014 by American Society of Hematology

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Clonal Evolution

• 43 patients received eltrombopag

• Eight patients developed clonal cytogenetic abnormalities during eltrombopag administration. • Seven had a normal karyotype confirmed within 3 months of starting drug, assessed by

conventional cytogenetics. • One patient (#42) had insufficient metaphases on his sample prior to entering the study but a

normal karyotype 9 months prior to entering the study.• Only 2 of 8 patients had dysplastic changes when new cytogenetic abnormalities appeared,

but some samples were severely hypocellular, making assessment of morphology difficult. • None had increased myeloblasts. • Clonal evolution events occurred in 6 of 8 nonresponding patients, and the new cytogenetic

changes were detected on the marrow performed at response assessment. • Two responding patients evolved. One responder (#26), whose counts had been gradually

increasing while on the extension arm, was noted to have falling counts at 13 months, and the marrow showed mild dyserythropoeisis and 13q deletion.

• A second responder (#32) had stable blood counts and on routine evaluation marrow at 10 months had also developed del 13q, but no dysplastic features were seen. Chromosome 7 abnormalities developed in 5 of 8 evolvers. Because many of these evolvers proceeded immediately to transplant, sequential cytogenetics were available on only 4, who showed no significant change in clone size 1 to 9 months later.

My (DAM)Conclusions

• NHLBI group has taught us that eltrombopag has a role in patients with SAA.

• We are still learning what that role is.

• Patients who have responded to eltrombopag can come off the medication and have sustained response.

• Clonal Evolution is risk that needs to be factored into decision making in individual cases.

What’s the next logical

question?

• Moving forward, can we integrate immune suppression and stem cell

numbers?

Stem cells as limiting in the response to immunosuppressive therapy.

Neal S. Young Hematology 2013;2013:76-81

©2013 by American Society of Hematology

Take Home Message

• When a patient with acquired SAA does not

have a matched sibling, the

recommendation at this time is to proceed

with intensive immune suppression following

Rosenfeld et al, 1995 with EQUINE

ATG/Cyclosporine/prednisone.

• Other options include high dose

Cyclophosphamide at Hopkins.

• Always consider a clinical trial.

Treatment Algorithm for SAA

(Korthof et al for the EBMT. BMT

2013)

• A. Matched Sibling BMT

– First Line Therapy

• B. Immune Suppression

– If no matched sibling, then IST is first line.

• C. Unrelated Donor BMT

– No response to IST or relapse after IST

• D. Haploidentical BMT

– Rescue from primary graft failure

– Urgent need due to neutrophil counts

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Take Home Message-Now

in Question

• The previous take home message in general

is rooted in the risk/benefit analysis utilizing

older data of alterative donor transplants.

• What is the current data (post 2005) for

alternative donor transplants for children

and young adults with SAA?

Alternative Donor Transplant

• Historically, the

major barriers

to survival have

been rejection

and GVHD.

0

20

40

60

80

100

0 0.5 1 1.5 2 2.5 3 3.5 4

DEEG

NMDP SERIES

BBMT 5:243, 1999

Su

rviv

al %

Years

1 OSTEOSARCOMA

1 HODGKINS

DISEASE

The Milwaukee Experience-Updated

0 36 72 108 144 180 216 252 2880

10

20

30

40

50

60

70

80

90

100Survival

Event-Free Survival

Months

Event= Death orCancer

Margolis et al. BJH 1996

1987-2003

N=41

Median age 10 y (1-24 y)

Median F/U is 10.5 years (2y-17y)

Deaths due to rejection, regimen related toxicity

THE DELICATE BALANCE-Revisited

TBIT

DEPLETION

HLA

=HLA

=

REJECTION GVHD

BC/

DM

Well Matched UNR donor BMT

in the Current Era (2005)

• Significant improvements in outcomes in the last 10-15 years reproduced in North America, Europe, and Asia.– Deeg (BBMT 2001)

– Bacigalupo (BMT 2005, Haematologica 2010)– Samarasinghe (BJH 2012)

– Marsh (BMT 2014)• Common themes include the use of Fludarabine

and Cyclophosphamide in the conditioning regimen and bone marrow as the HPC source

• TBI dose eliminated or low (200 cGy=2Gy)

(A) Effect of age in patients receiving FCA (left panel), stratified by the median age of 13 years.

Bacigalupo A et al. Haematologica 2010;95:976-982

©2010 by Ferrata Storti Foundation

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Landmark Paper!

• Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia

• Blood 2011• Judith C. Marsh1, • Vikas Gupta2, • ZiYi Lim1, • Aloysius Y. Ho1, • Robin M. Ireland1, • Janet Hayden1, • Victoria Potter1, • Mickey B. Koh3, • M. Serajul Islam3, • Nigel Russell4, • David I. Marks5, • Ghulam J. Mufti1,*, and • Antonio Pagliuca1,*

Methods

• Conditioning with Fludarabine, Alemtuzumab, low dose

cyclosphosphamide.

• NO TBI for matched donors (related or

Unrelated)

• N=21 matched sibling donors

• N=29 UNR donor

• Median Age=35 (8-62) (12 over 50)

Judith C. Marsh et al. Blood 2011;118:2351-2357

©2011 by American Society of Hematology

Overall survival (OS) curves for the study Excellent outcome of matched unrelated donor

transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy:

a United Kingdom multicentre retrospective

experience• Samarasinghe et al.

• BJH 2012

• N=44 for transplant with this package

– Also evaluated those receiving IST first with rabbit ATG/CSA

– All donors matched at A,B,C,DRB1,DQB1

• Fludarabine 150 mg/m2

• Cyclophosphamide

– 11: CY 200; 33: CY120

• Alemtuzumab (Campath)

– 14: 0.3 mg/kg/day x3

– 30: 0.2 mg/kg/day x5

Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following

failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience

British Journal of Haematologypages n/a-n/a, 29 FEB 2012 DOI: 10.1111/j.1365-2141.2012.09066.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2012.09066.x/full#bjh9066-fig-0001

(A)Children with Idiopathic SAA who received Rabbit ATG/Ciclosporin as first line therapy. The 5-year estimated failure-free survival (FFS) following immunosuppressive therapy was 13·3% (95% CI 4·0 to 27·8) and overall survival (OS) was 94·2% (95% CI 78·7 to 98·6). (n = 43).

(B)OS and FFS following matched unrelated donor-haematopoietic stem cell transplantation with the FCC (fludarabine, cyclophosphamide, alemtuzumab) regimen. The estimated 5-year OS/FFS following HSCT was 95·01% (95% CI 81·38 to 98·74). (n = 44)

Take Home Message

• Well matched unrelated donor bone marrow

transplants have excellent survival with conditioning regimens that should limit late effects.

– Mismatching and age are risk factors for rejection.

• Don’t be afraid to transplant in the current era.

• Continued refinement of the conditioning regimen to prevent rejection and GVHD prevention

strategies to minimize late effects especially cGVHD.

– Campath, Fludarabine (Marsh data)

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Current State “Areas of

Controversy”

• Timing, Timing, Timing

• Preceding therapy

– No courses of IST-Can we just move to upfront

MUD UNR donor BMT for certain age and ethnic groups based on published data?

– Is a study required?

– Fortunately, the question is being asked!

56th ASH Annual Meeting

Similar Outcome of Upfront Unrelated and Matched Sibling donor

HSCT in idiopathic AA of Childhood and Adolescence.

A study by UK Pediatric BMT WP, PDWP and SAAWP of the EBMT

Carlo Dufour, MD

Background and Rationale

• Classical treatment algorythm of SAA forsees IST (ATG and CsA) as first-line option,

if a MFD is not available.

• IST: very good survival rate but high rate of failures.

Background and Rationale

• Faulty hematopoiesis limits quality of life of children & adolescents.

• HSCT from MUD as front-line treatment with no prior failed IST, never investigated

so far in a comparative way.

• We compared the outcome of a UK cohort with historical matched controls from

EBMT data base.

UD vs MFD HSCT CASE CONTROL STUDY

1 UD HSCT vs 3 MFD HSCT

Matches: gender

source of cells

age at trasplant

Interval Dx-HSCT

Interval Dx- neutrophil recovery

UD MFD

0.39 yrs 0.31 yrs p= 0.93

UD 96%

MFD 91%

P=0.30

UD 92%

MFD 87%

P=0.32

Events: deaths

rejection

UD vs IST front-line

1 UD HSCT vs 2 IST front-line (Horse ATG- Lymphoglobulin)

Matches: gender

age at treatment

UD 96%

IST 94%

P=0.64

UD 92%

IST 40%

P=0.0001

Events: death

relapse

no response

need for transplant

clonal evolution

Response 3 months after h ATG 46% (~ 3/4partial)

6 months after h ATG 61% (~ 2/3 partial)

Jeong et al, Haematologica 14

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MUD vs MUD post-failed IST

1 MUD upfront vs 1 MUD post-failed IST

Matches: gender

age at trasplant

source of cells

MUD upfront 95%

MUD post IST 74%

P=0.02

MUD upfront 95%

MUD post IST 74%

P=0.02

What do these findings say

• UD HSCT fares: similar to MFD with no significantly longer interval Dx-neutr engraft

better than IST front-line

better than MUD post failed IST

Limitations

• Retrospective

• Different conditioning and serotherapy (Alentuzumab vs ATG)

• Caucasian patients higher chanches to find a donor

Take Home Message

• MUD HSCT is a good front-line option in children & adolescents with SAA

• Caveats:

Start donor search at diagnosis

Evaluate likelihood of MUD HSCT feasibility in 3-4 months since diagnosis

Careful discussion with family/patient of MUD vs IST

•Need for care in specialized AA haematology centres

Treatment Algorithm for SAA

(Korthof et al for the EBMT. BMT

2013)

• A. Matched Sibling BMT

– First Line Therapy

• B. Immune Suppression

– If no matched sibling, then IST is first line.

• C. Unrelated Donor BMT

– No response to IST or relapse after IST

• D. Haploidentical BMT

– Rescue from primary graft failure

– Urgent need due to neutrophil counts

Treatment Algorithm for SAA 2014:

The Hard Cases

• No response to IST or relapse after IST…….

• Well matched (10/10 or 12/12) UNR donor go to BMT with data based confidence.

– Very important to have doctor/patient relationship

because survival is not 100% across the board.

• No well matched donor are the hard cases now.

– Eltrombopag

– Alternative, Alternative donor BMT

• Post CY Haplo vs. Haplo+Cord vs. Double Cord

– Other immune suppression such as Alemtuzumab

Objectives

• Review Current Thinking regarding differential diagnosis and physiology

for a patient with bone marrow failure.

• Review Current Treatment Options.

• Discuss Current Treatment Algorithm

• Answer Questions as Best as Possible

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THANK

YOU!•Aplastic Anemia and MDS

International Foundation/Staff

•My mentors Drs. Camitta and Casper.

•Our team at the MACC Fund Center

for Cancer and Blood Disorders in MKE

•Our patients

•Dr. Young and his incredible team for

teaching us and running wonderful

studies.

•Dr. Dumitriu

•Dr. Townsley

•Dr. Scheinberg

•Dr. Dunbar