3/31/2014 new directions inaplastic objectives ... anemia...and oncology research cleveland, ohio...

3/31/2014

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Ramon V. Tiu, MDCleveland Clinic Taussig Cancer

InstituteDept. of Translational Hematology

and Oncology ResearchCleveland, 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 2014

April 5, 2014

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

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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


Deferasirox


Baseline Ferritin (ng/ml)

Change in ferritin level post- Tx (ng/ml)

% Change from baseline

P value

Partial ResponderN=11

6693 ±7014

- 3948 ± 4998 - 45.7 % .0029

No ResponseN=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 GVHDRV 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

CD2FcγIII

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

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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

plet

e bl

ood

cell

coun

t

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

02.5

57.510

12.515

17.5

2022.5

2527.5

3032.5

35

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


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

plet

e bl

ood

cell

coun

t

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.

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

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 diagnosedo 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

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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

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Importance of Telomeres in Aplastic Anemia

Telomeres

.

Young N S Hematology 2010;2010:30-35


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

.


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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

.


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

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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

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STAT3 mutations in Aplastic Anemia And MDS

.

Epling-Burnette PK et al. ASH Website.


.

Jerez A et al. Blood 2013;122:2453-2459

Frequency of STAT3 mutations in AA and MDS


.

Jerez A et al. Blood 2013;122:2453-2459

Impact of STAT3 mutations on survival outcomes in AA and MDS

Conclusions

• 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.

3/31/2014 new directions inaplastic objectives ... anemia...and oncology research cleveland, ohio...

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