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Rafael Bejar MD, PhD

Aplastic Anemia & MDS International Foundation

Regional Patient and Family Conference

September 17th, 2016

Síndromes Mielodisplásicos: SMD de alto riesgo y los avances en el

tratamiento

Overview

• Pronóstico y refinación de "alto" riesgo

• Nuevos tratamientos

• Avances en el trasplante de células madre

• Ejemplos del laboratorio

Refinación del Pronóstico

Low Blood CountsHombre de 71 años de edad con glóbulos rojos grandes y recuentos bajos de sangre que se desarrollaron durante los últimos 6 meses.

RangoNormal

1.9 7.9

45

Low Blood Counts

Way too many cells in the bone marrow4% blasts in aspirate

Dysplasia in all three cell types

Normal Karyotype (chromosomes ok)

RangoNormal

1.9 7.945

Hombre de 71 años de edad con glóbulos rojos grandes y recuentosbajos de sangre que se desarrollaron durante los últimos 6 meses.

Greenberg et al. Blood. 1997;89:2079-88; Greenberg et al. Blood. 2012:120:2454-65.

International Prognostic Scoring System

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MDA Lower Risk ModelPrognostic

Category

LR-PSS Prognostic Score Value

1 2

Cytogenetics Not normal or del(5q)

Age, years ≥ 60

Hemoglobin, g/dL < 10

Platelets, × 109/L 50-200 < 50

BM blasts, % ≥ 4%

Garcia-Manero G, et al. Leukemia. 2008;22:538-543.

Risk

Category

Risk

Score

1 0-2

2 3-4

3 ≥ 5

Survival, months from referral

Pa

tie

nts

, %

0 2412 4836 60 8472 960

20

40

60

80

100

25%-33% of patients are in Category 3

The survival of Category 3 patients is similar to that of Intermediate-2 riskpatients using the IPSS!

IPSS-Revised (IPSS-R)

Greenberg et al. Blood. 2012:120:2454-65.

ipss-r.com

Terapias Aprobadas

Directrices para SMD de alto riesgo

Objetivo: mejorar la duración de la vida

Inhibitors of DNA methyl transferases:

Both incorporate into DNA and cause hypomethylation (DEC > AZA)

AZA preferentially causes DNA damage and induces apoptosis

Hypomethylating Agents

AZA-001 Phase III: AZA vs. ld-ARA-C vs. supportive care

OS benefit: + 9.5 mos

Time to AML: 17.8 vs. 11.5 mos

TI: 45% vs. 11%

Azacitidine Response:

ORR: ~50%

CR: ~17%

Median time to response: 3 cycles (81% by cycle 6)

Azacitidine

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Decitabine Phase III Trial ADOPT Trial and 3-Schedule Trial

Dosed q8h x 3 days per 28 days Dosed q24h x 5 days per 28 days

CR: 17% CR: 17%

CR+PR: 30% CR+PR: 32%

ORR: 52% (+ heme response)

Best response: 50% at 2 cycles

Major Toxicity:Neutropenia: 31% (FN 11%)

Thrombocytopenia: 18%

Decitabine Guidelines for Higher Risk MDS

Special Considerations:

Refer for Transplant Early- Even patients in their 70’s can benefit from RIC transplant

AZA > DEC (for now)- AZA has been shown to have a survival advantage, DEC has not (yet)

Don’t forget Quality of Life- Consider treatment palliative and weigh against patient needs

Look for Clinical Trials- Few option after AZA are available and none are approved

Objetivo: mejorar la duración de la vida

Outcomes After Azacitidine

Comparison to decitabine failures @ MDACC: median survival 4.3 months, n=87

Prébet T et al, J Clin Oncol 2011; Aug 20;29(24):3322-7. Epub 2011 Jul 25.Jabbour E et al, Cancer 2010; 116:3830–3834.

9% didn’t tolerate AZA (69% were not responding, 31% had an initial response)

55% primary failure (progression in 60% , stable disease without response in 40%)

36% secondary failure after initial response (best response: CR 20% , PR 7%, HI 73%)

Reasons for “failure” in azacitidine failure study

Outcomes after failure

Median overall survival for whole cohort post-AZA: 5.6 months

2 year survival: 15%

Favorable factors: female, younger (<60), better risk karyotype, <10% blasts, some response to azacitidine

Slide borrowed from Dr. David Steensma

• Data available on 435 pts – from AZA001, J9950, J0443, French compassionate program

• Overall median survival after azacitidine failure: 5.6 months

Prébet T et al J Clin Oncol 2011; 29:3322-7Jabbour E et al Cancer 2010;116(16):3830-4

Subsequent therapy Number of patients (%) Median survival

Allogeneic transplant 37 (9%) 19.5 months

Investigational therapy (e.g. IMiD, HDACi, other)

44 (10%) 13.2 months

Intensive cytotoxic therapy (e.g., 3&7)

35 (8%) 8.9 months

Low-dose chemotherapy (e.g. LDAC, 6-MP)

32 (7%) 7.3 months

Palliative / supportive care 122 (28%) 4.1 months

Subsequent therapy unknown 165 (38%) 3.6 months

Slide borrowed from Dr. David Steensma

Outcomes After Azacitidine

Tratamiento del SMD de alto Riesgo

Necesitamos terapias MEJORES!

Necesitamos MÁS terapias!Mejores Formulaciones

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Oral Azacitidine

2011 – Oral AZA given 7 days out of 28 is safe and appears effective

2012 – Treating for 14 or 21 days enhances biologic activityand is effective – 34% ORR and 40% transfusion independent

2013 – Phase III Clinical Trial of Lower Risk Transfusion Dependence

PROSOral drug that can be taken at home

CONSGastrointestinal side effectsMay take 6-8 cycles to reach maximum response

SGI-110

Resistant to degradation

Longer half-life

May allow less frequent dosing

- 5 days vs. once weekly

Yoo C B et al. Cancer Res 2007;67:6400-8.

Phase 2 study of SGI-110 in 102 patients with Intermediate or

High Risk MDS or CMML

Biologically Effective Dose 60 mg/m2 daily x 5

Highest Well Tolerated Dose 90 mg/m2 daily x 5

RANDOMI Z A T I ON

IWG 2006 MDS

Response Criteria

Treatment continued until unacceptable toxicity, disease progression

Major Eligibility

Previously Treated MDS/CMML

or

Treatment Naïve MDS/CMML

• IPSS Int-1,2 and HR

• ECOG PS 0-2 • Adequate

hepato-renal function

Phase 2 study of SGI-110 in 102 patients with Intermediate or

High Risk MDS or CMML

ResponseCategory

60 mg/m2 (n=53) 90 mg/m2 (n=49)

CR+mCR 10 (18.8) 11 (22.4)

ORR 14 (26%) 17 (35%)

ResponseCategory

Prev Treated(n=53)

Tx Naïve (n=49)

CR+mCR 11 (20.8) 10 (20.4)

ORR 12 (23%) 19 (39%)

60 mg/m2 (n=53) 90 mg/m2 (n=49)

8-week RBCs TransfusionIndependent n (%)

7/27 (26%) 5/24 (21%)

8-week Platelet Transfusion Independent n (%)

4/13 (31%) 5/15 (33%)

Take Home Message: SGI-110 may be useful after AZA failure

Nuevas Indicaciones

Combination Therapy

Example: Many clinic trials in development combine:

Azacitidine + Experimental Therapies

Approach: Improve upon existing therapies

Advantage: backbone is already FDA approved

Positive results can quickly change practice!

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Take Home Message: LEN has activity in non-del(5q) LR MDS

• Transfusion dependent Lower Risk MDS without del(5q) randomized to:

- Lenalidomide 10 mg daily or Placebo

• 26.9% became transfusion independent

• Median response duration of 32.9 weeks

• Being female, prior ESA, and low EPO were factors predictive of response

• Rates of AML progression were similar in both arms

Lenalidomide in non-del(5q)

Nuevos Tratamientos

Pipeline of Completely New Drugs

PD1-PDL1 Inhibitors

BCL2 Inhibitors

TGF-beta Inhibitors

Neddylation Inhibitors

Indolamine Dioxygenase Inhibitors

p53 Modulators

Hedgehog Inhibitors

Aminopeptidase Inhibitors

LSD-1 Inhibitors

Anti-CD33a AntibodiesOpciones

Disease

ON 01910

Gumireddy K, et. al. Cancer Cell 2005; 7: 275.

Rigosertib (ON-01910)

PLK1 & Cdc25C Inhibition

Multikinase Inhibitor

Finished Phase III Trial

3-day continuous infusion

Slide borrowed from Dr. Rami Komrokji

N BM CR (+HI) HI ORR

All patients 32 6 (1) 4 10/32 (31%)

3-day infusions 17 4 (1) 3 7/17 (41%)

3-day pivotal (1800 mg/d) 13 4 (1) 2 6/13 (46%)

0 20 40 60 80

0

20

40

60

80

100

Weeks

Su

rviv

al p

rob

ab

ility

(%

)

BM Blast Response

Not Assessed

Progressive Disease

Stable BM Blast Count

50%+ BM Blast Decrease

OS by Marrow

Blast Response

Median:

68 wks

Raza et al. Blood 2011; 3822

Rigosertib after Azacitidine

Slide borrowed from Dr. Rami Komrokji

Randomized Phase III Study of IV Rigosertib vs. BSC in Higher-risk MDS After HMA Failure

RigosertibN = 199

BSCN = 100

Number (%) of deaths 161 (81%) 81 (81%)

Median follow-up (months) 17.6 19.5

Median survival (months) 8.2 5.9

95% CI 6.0 - 10.1 4.1 - 9.3

Stratified HR (rigosertib/BSC) 0.87

95% CI 0.67 - 1.14

Stratified log-rank p-value 0.33

All Patients

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Randomized Phase III Study of IV Rigosertib vs. BSC in Higher-risk MDS After HMA Failure

RigosertibN = 199

BSCN = 100

Number (%) of deaths 161 (81%) 81 (81%)

Median follow-up (months) 17.6 19.5

Median survival (months) 8.2 5.9

95% CI 6.0 - 10.1 4.1 - 9.3

Stratified HR (rigosertib/BSC) 0.87

95% CI 0.67 - 1.14

Stratified log-rank p-value 0.33

Primary HMAFailure

Randomized Phase III Study of IV Rigosertib vs. BSC in Higher-risk MDS After HMA Failure

Take Home Message: Rigosertib is underwhelming after HMA failure,But we don’t have good alternatives either

Hedgehog Inhibitor – Phase II

Gumireddy K, et. al. Cancer Cell 2005; 7: 275.

Hedgehog Inhibitors

Slide borrowed from Dr. Rami Komrokji

Pathway important for stem cells

Several inhibitors in development

Drug PF-04449913Phase I in AML and MDS had several responders (7/21)

Combination of PF-04449913 and azacitadine is available at UCSD to previously untreated MDS patients.

Luspatercept

TPO mimetics

G-CSF (neupogen)

ESAs

EPO/ESAs

TGF-b

Luspatercept

TPO mimetics

G-CSF (neupogen)

ESAs

EPO/ESAs

TGF-b

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Promoting Red Cell Production

Luspatercept (ACE-536) and Sotatercept (ACE-011)

Promoting Red Cell Production

Luspatercept (ACE-536) and Sotatercept (ACE-011)

Immune Based Therapies

PD1 and PD-L1 Inhibitors

Combination Trial will be opening at UCSD in the Fall

Trasplante de Células Madre

Trends in Transplantation

Goal of Hematopoietic Stem Cell Transplantation:

#1) Replace a dysfunction host hematopoietic system with normal, healthy donor marrow.

#2) Allow the donor immune system to destroy the abnormal, diseased host cells (MDS).

Conditioning

Donor Cells

Engraftment Graft-vs.-MDS

<5% of patients with MDS currently undergo allogeneic SCT

“Only curative therapy”

Survives transplant;MDS cured!

(35-40%)

Survives transplant;MDS recurs/persists

(30-40%)

Patients who go in to RIC allo SCT with <10% blasts appear to have lower relapse

Transplant candidateDonor identified

Dies from complication of transplant

(20-25%)

Optimal timing, pre-transplant therapy, conditioning unclear;usually reserved for IPSS Int-2/High (IBMTR Markov analysis)

Cutler C et al Blood 2004; 104(2):579-85Sekeres M et al JNCI 2008;100(21):1542-51. Slide borrowed from Dr. David Steensma

Allogeneic Stem Cell Transplantation for MDS

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Obstacles to TransplantationGraft Rejection

– need to suppress the host immune system

Toxicity– infection– organ damage– graft versus host disease

Finding a Donor– siblings match only 25% of the time– and are often too old or ill to donate

Overcoming ObstaclesAvoiding Graft Rejection

– better approaches to immune suppression

Less Toxicity– better supportive care– better antigen matching– reduced intensity conditioning

Alternative Sources for Stem Cells– haploidentical – “half” match– umbilical cord blood stem cells

0

20

40

60

80

100

1990-1996 1997-2003 2004-2010 1990-1996 1997-2003 2004-2010

< 50 years

>= 50 years

Trends in Allogeneic Transplantsby Transplant Type and Recipient Age*

1990-2010

* Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma

Tra

nspla

nts

, %

0

20

40

60

80

100

2001-2005 2006-2010 2001-2005 2006-2010

<=20 yrs

21-40 yrs

41-50 yrs

51-60 yrs

>60 yrs

Allogeneic Transplants for Age > 20yrs,Registered with the CIBMTR, 1993-2010

- by Donor Type and Graft Source -

Num

ber

of Tra

nspla

nts

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

10,000

11,000

12,000

13,000

14,000

1993-94 1995-96 1997-98 1999-00 2001-02 2003-04 2005-06 2007-08 2009-10

Related BM/PB

Unrelated BM

Unrelated PB

Unrelated CB

Bejar et al. ASH Meeting 2012. (in submission)

Blasts < 5% (n=42)

Blasts ≥ 5% (n=45)

p = 0.029

Other karyotype (n=59)

Complex karyotype (n=28)

p = 0.005

Overall Survival After Transplant

Genetics and Transplantation

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72 patients with select mutations

TK Pathway = NRAS, KRAS, CBL, CBLB, JAK2, PTPN11, BRAF, MPL, KITBejar et al. ASH Meeting 2012. (in submission)

Genetics and TransplantationNo Complex Karyotype (n=59)

Complex and TP53 Mut Absent (n=12)

Complex and TP53 Mut Present (n=16)

Overall Survival After TransplantNo Adverse Mutation (n=47)

TP53 Mutated (n=18)

TET2 Mutated w/o TP53 mutation (n=10)

DNMT3A Mutated w/o TP53 or TET2 mutation (n=12)

Genetics and Transplantation

Genetic testing can better predict risk of transplantation

Identify patients that are unlikely to do well with standard approaches.

Find those that might do better than expected!

Immune Cell TherapyKiller T-cell

Plasma B-cell

Tumor Cell

Chimeric Antigen Receptor

Immune Cell Therapy

Chimeric Antigen Receptor Modified T-cell

Tumor Cell

Bejar LabAlbert Perez Sigrid Katz

Tiffany Tanaka Brian Reilly

Amaan Abidi Bennett Caughey

Fiona Gowen-Huang

AcknowledgementsMDS Center of Excellence at UCSDElizabeth Broome Huanyou Wang - Hematopathology

Edward Ball Peter Curtin - BMT Group

Matthew Wieduwilt Grace Ku

Carolyn Mulroney Caitlin Costello

Sandford Shattil John Adamson - Hematology Group

Catriona Jamieson Michael Choi

Erin Reid Annette Von Drygalski

Our amazing CLINIC and INFUSION CENTER nurses and staff

And most of – our incredible patients and families!