aplasticanemiawhatsonthehorizon tiu.pptx [read-only]...transfusion-dependent iron overload • how...

5/28/2013

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Ramon V. Tiu, MD

Cleveland Clinic Taussig Cancer Institute

Dept. of Translational Hematology and Oncology Research

Cleveland, Ohio USA

New Directions in Aplastic

Anemia Treatment: What’s on the

Horizon?

AA&MDS International Foundation Living with Aplastic Anemia, MDS, or PNH Patient and Family

Conferences in 2013

June 22, 2013

Objectives

• To provide new information on emerging therapies in aplastic

anemia (AA)

• To provide updates in the development of biomarkers that impact survival, clonal evolution and relapse in AA

• To provide new developments on molecular genetics in AA

Emerging Therapies (Iron Chelators)

Deferasirox

• Rationale: – Too much iron can lead to suppressive effects on immature RBC precursors

– Evaluation of Patient’s Chelation with Exjade (EPIC) Trial .

• Phase IIIb, one-year, open-label, single-arm study in patients diagnosed with transfusion-dependent iron overload

• How does the drug work?

JW Lee et al. Haematologica. April 2013Hartmann J et al. Leuk Res. Mar 2013


Definition of Response

JW Lee et al. Haematologica. April 2013

† TI- at least , a one 8 week period without transfusions


Clinical Responses


• Total AA Patient in the study: 116

• No Complete Responders

• Median time to response: 85 days (range 1-277)

•One patient had a platelet response

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Deferasirox


Baseline Ferritin

(ng/ml)

Change in ferritin level post- Tx

(ng/ml)

% Change from baseline

P value

Partial Responder

N=11

6693 ±7014

- 3948 ± 4998 - 45.7 % .0029

No Response

N=13

4365 ±3063

- 2021 ± 3242 - 27.6% .0171

Emerging Therapies (Novel T cell Therapies)

Alefacept

• Rationale: – Novel immunosuppressive therapies with

less toxicities are needed for AA patients

• How does the drug work?

Alefacept

• Humanized recombinant dimeric fusion protein composed of LFA3 and Fc

portion of human IgG

• FDA approved for the treatment of chronic plaque psoriasis

• Have been found to be of use in GVHD

RV Tiu. AA and MDS International YIA Grant Report. 2012

Mechanism of Action of Alefacept

Activated T cell

Activated T cell

Naive T cell Naive

T cell

Naive T cell

LFA-3

CD2

CD2

CD2 CD2

CD2

CD2

FcγIII

ApoptoticActivated T cell

Naive T cell

Hematopoietic Stem Cell

APC APC

APC

Amevive

I II III

LFA-3

LFA-3

Amevive

Amevive

Amevive

NK cell


Clinical Response

Patient Dose Response Type of Hematologic

Response†

Side effects

1 7.5 mg/ week for 12 weeks

PR N cough, sore throat, and nasal

congestion

2 7.5 mg/ weekfor 12 weeks

NR - Mild muscle aches

3 7.5 mg/ weekfor 12 weeks

PR H/ N/ P None

4 10 mg/ weekfor 12 weeks

PR H/ N/ P None

†: H- Hemoglobin; N: Neutrophils; P: Platelets RV Tiu. AA and MDS International YIA Grant Report. 2012


Patient #3

Com

ple

te b

lood

cell

count

1 2 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5

Pre(mos)

Post(mos)

During (week)

Abs Retic (108/uL)

ANC (104/uL)

Hgb (g/dL)

Platelets (103/uL)

Treatment

0

2.5

5

7.5

10

12.5

15

17.5

20

22.5

25

27.5

30

32.5

35



02.5

57.510

12.515

17.520

22.525

27.530

32.535

1 2 3 4 1 2 3 4 5 6 7 8 9 101112 1 2 3 4

Abs Retic (108/uL)

ANC (104/uL)

Hgb (g/dL)

Platelets (103/uL)

Pre(mos)

Post(mos)

During(week)

Treatment

Com

ple

te b

lood

cell

count

Patient #4

Unfortunately:In December 2011, Astellas Pharma US announced that the company has

voluntarily discontinued the promotion, manufacturing, distribution and sales of alefacept because of business needs but not related to safety issues.


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Emerging Therapies (Combination Therapies)

Cyclosporine plus Levamisole

• Rationale: – Developing novel therapies for patients with moderate AA

• Patient Cohort– 118 patients with mAA

o 42 newly diagnosed

o 76 chronic

• Regimen– CsA 3 mg/kg per day in adults plus Levamisole 150 mg per day in adults – CsA 5 mg/kg per day in children plus or 2.5 mg/kg per day in children,

– Either regimen will be continued for 12 more months after achieving maximal hematologic response, followed by a slow taper

X Li et al. Ann Hematol. April 2013

Emerging Therapies (Combination Therapies)

Clinical Response

X Li et al. Ann Hematol. April 2013

Newly dx mAA Chronic mAA P value

Overall Response

Rate

100 % 86.8 %

24 month PFS

95.2 % (95% CI: 85.9-

100)

93.6 % (95% CI: 86.9-

100 %)

0.50

2 year EFS 86.8 (95% CI: 70.4-

100)

57.0 %(95% CI: 43.5-

70.4 %)

.001

Biomarkers

Predictive/ Prognostic Biomarkers (ARC and ALC)

Scheinberg P et al. BJH . 2008

• NIH Study of 316 SAA patients (1989-2005)

• Defining important predictors of response to hATG +CsA therapy at 6 mos of therapy

• Factors looked at includes age, PNH clone, hematological factors like ANC, platelet count, Hgb, Absolute reticulocyte count (ARC), absolute lymphocyte count

• Presence of PNH clone is defined as presence of positive Ham test for samples until yr 2000 and subsequently GPI-(neg) Neutrophils or red cells >1%

• ARC and ALC are predictive

Biomarkers

Predictive/ Prognostic Biomarkers (ARC/ ALC)

Scheinberg P et al. BJH . 2008

Biomarkers

Predictive/ Prognostic Biomarkers (ANC and ARC)

Chang M et al. EJH . 2009

• Korean Study of 62 SAA patients (1994-2007)

• Defining important predictive/ prognostic markers

• Patient got rATG + CsA or hATG + CsA

• Factors looked at includes age, type of ATG clone, baseline hematological factors like ANC, platelet count, Absolute reticulocyte count (ARC), absolute lymphocyte count (ALC), total WBC, sveerity of disease, etiology

• Only predictive factor is ANC >0.3 x109/L

• Prognostic Factors: ARC >10.9 x109/L and response status

Importance of Telomeres in Aplastic Anemia

Telomeres

.

Young N S Hematology 2010;2010:30-35

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Telomerase Complex

.

Young N S Hematology 2010;2010:30-35


Telomere Length and Disease Relapse

.

Scheinberg P et al. JAMA. 2010


Telomeres and Clonal Evolution

.



Telomere Length as a predictor for clonal evolution in AA

.

Calado RT et al. Leukemia. April 2012


More Monosomy 7 and chromosomal

Instability in patients with short telomeres

.

Calado RT et al. Leukemia. April 2012


Telomeres and Survival

.


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Differentiating AA vs hypocellular MDS using SNP-A Karyotyping

SNP-Array Karyotyping

#57 whole genome

Chromosome 7 Chromosome X

Total Copy number

Allele specificcopy number

IdeogramHeterozygous SNP call

Ideogram

Smoothed copynumber

Raw copy number

Allelecall

AAABBB

BM 250K

UPD6p12.1-pter Chr7 monosomyPat#96

B.

A.

2N

1N

3N

2N1N

3N

Afable M et al. Blood. 2011

Differentiating AA vs hypocellular MDS using SNP-A Karyotyping


More chromosomal defects detected by SNP-Array Karyotyping comparedto metaphase cytogenetics in AA and hypocellualr MDS

SNP-A Karyotyping


Early Detection of Clonal Evolution by SNP-Array Karyotyping

Genetic Causes of Inherited AA

Presence of MPL mutations in Inherited cases of AA

.

Walne A J et al. Haematologica 2012;97:524-528

Cytogenetic Defects and Molecular Mutations in Fanconi Anemia

Rare NRAS, RUNX1, Flt-3 and MLL mutations in FA that

transformed to AML

.

Quentin S et al. Blood 2011;117:e161-e170

Absence of Spliceosome MutationsIn Aplastic Anemia

Spliceosome Genes (SF3B1, SRSF2, U2AF1, ZRSR2)

.

Visconte et al. Haematologica. 2013 (Under Review)Visconte et al. Blood. 2012

SF3B1- all WT

SRSF2- all WT

U2AF1- all WT

ZRSR2- all WT

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Conclusion

• Some patients with AA treated with iron chelator, deferasirox achieved transfusion independence but the results will need to be clarified in bigger

studies

• Targeting the CD2-LFA3 pathway is a viable treatment option in AA

• ARC and ALC are important in predicting immunosuppressive response in

AA

• Shorter Telomeres have adverse impact on survival, clonal evolution and

relapse in AA

• SNP-A karyotyping can improve cytogenetic detection in AA

• Molecular genetics can unravel new information on the pathophysiology of AA.

aplasticanemiawhatsonthehorizon tiu.pptx [read-only]...transfusion-dependent iron overload • how...

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