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April 14, 2016

MDS: Update on Treatment and Side Effects Management

Azra Raza, MDProfessor of MedicineDirector, MDS CenterColumbia University Medical CenterMilstein Hospital BuildingNew York, NY

Antonietta de los Reyes, MSN, OCN®, FNP-CMDS CenterColumbia University Medical CenterHerbert Irving PavilionNew York, NY

Welcome and Introductions

CLL: Update on Treatment andSide Effects Management

MDS: Update on Treatment and Side Effects Management

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Disclosures

Azra Raza, MD does not have any relevant financial

relationships with any commercial interests to disclose.

Antonietta de los Reyes, MSN, OCN®, FNP-C does not have

any relevant financial relationships with any commercial

interests to disclose.

MDS: Update on Treatment and Side Effects Management

Azra Raza, MDProfessor of Medicine

Director, MDS Center

Columbia University

New York

Myelodysplastic Syndromes: Treatment and Side Effects Management

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WHAT IS MDS?

Divide Mature

Blood formation

Hea

lth

y A

du

lt

Blood

RBC

WBC

Platelets

Divide Mature and Die

MD

S A

du

lt

AnemiaNeutropenia

Thrombocytopenia

Trillion cells every 24 h.

Divide Do not mature

AM

L A

du

lt

AML

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IPSS for Risk Stratification

Greenberg P et al. Blood. 1997;89:2079-2088.

Score Value

Prognostic variable 0 0.5 1.0 1.5 2.0

Bone marrow blasts < 5% 5% to 10% -- 11% to 20% 21% to 30%

Karyotype* Good Intermediate Poor -- --

Cytopenias† 0/1 2/3 -- -- --

Accurately predicts prognosis in ~39% patients

A Prognostic Nightmare

YEARS

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IPSS-R -- 2012

Greenberg P L et al. Blood 2012;120:2454-2465

A case

• A 62-year-old man was discovered to have

borderline cytopenias:

– Hgb 11 g/dL

– WBC 3.6

– Platelet count 162,000

– BM did not meet the minimal criteria for MDS (<10%

dysplastic cells)

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Idiopathic Cytopenia(s) of Undetermined (Uncertain)

Significance (ICUS)

1) Meaningful cytopenias

2) Does not meet minimal diagnostic criteria for MDS

• > 10% dysplastic cells, or

• 5%-19% blasts, or

• Abnormal karyotype typical for MDS

ICUS

Valent P, et al. Leuk Res. 2007;31(6):727-736; Valent P and Horny HP. Eur J Clin Invest. 2009;39(7):548-553.

ICUS Natural History

Hanson C and Steensma D. Abstract presented at: MDS Symposium; May 2009; Patras, Greece.

2,899 marrow exams for cytopeniasat Mayo Clinic over 13 years

1,716: MDS535: non-MDS

neoplasmsMDS-U579: ?

59% 18% 20% 2%

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Case Continued…

• Genetic profiling shows a mutation in TET2

• ICUS to CHIP

CHIP as a precursor state for hematological neoplasms.

David P. Steensma et al. Blood 2015;126:9-16

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Morphologic Subtypes

Cytogenetics

Genetic Mutations

Response to Therapy

Personalization: selection of homogenous groups

MDS Treatment Options

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•Stem cell transplantCurative

RIC Allo-transplant in MDS between 60-70 years

1. Koreth J, Pidala J, Perez WS, et al. J Clin Oncol. 2013;31(21):2662-2270. 2. Cutler CS, Lee S, Greenberg P, et al. Blood. 2004;104(2):579-585.3. Malcovati L, Porta MG, Pascutto C, et al. J Clin Oncol. 2005;23(30):7594-7603. 4. Garcia-Manero G, Shan J, Faderl S, et al. Leukemia. 2008;22(3):538-543.

IPSS Low/Int-1 IPSS Int-2/High

1.0

0.8

0.6

0.4

0.2

0 20 40 60 80 100 120 140

Time (months)

Overa

ll S

urv

ival (p

rob

ab

ility

)

P<.001

Nontransplant therapy

RIC transplant

1.0

0.8

0.6

0.4

0.2

0 20 40 60 80 100 120 140

Time (months)

Overa

ll S

urv

ival (p

rob

ab

ility

)

P<.001

Nontransplant therapy

RIC transplant

RIC, reduced intensity conditioning.

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• ESA

• Lenalidomide

• Hypomethylatingagents

Palliative

Algorithm for treating lower risk MDS

Low and Int-1

5q- deletion± other cytogenetic

alterations?

Yes Lenalidomide

No

SerumEPO ≤500 mU/mL?

EPO ± G-CSFSupportive care

Clinical trial

LenalidomideAzacitidineDecitabine

ATG ± cyclosporineSupportive care

Clinical trial

Yes No

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Epo Improves Anemia in a Subset of Patients With MDS

• According to a meta-analysis, mean response rates range from 15% to 20%1

• Predictors for good response include serum Epolevel and transfusion need1

– <500 U/L and limited prior need for transfusion1

• Most responses to ESA occur within 8 weeks of treatment, some patients respond after 12 weeks2,3

1. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. Br J Haematol. 2003;120(6):1037-1046. 2. Ludwig H. Semin Oncol. 2002;29(3 suppl 8):45-54. 3. Casadevall N, Durieux P, Dubois S, et al. Blood. 2004;104(2):321-327.

15%-20%

8 weeks

ESA, erythropoiesis-stimulating agent.

LENALIDOMIDE

Transfusion-dependent anemia due to low- or Int-1–risk MDS associated with del(5q) with or without additional abnormalities

221. Revlimid [prescribing information]. Summit, NJ: Celgene Corp; 2013. 2. List A, Dewald G, Bennett J, et al. N Engl J Med. 2006;355(14):1456-1465. 3. Raza A, Reeves JA, Feldman EJ, et al. Blood. 2008;111(1):86-93.

Responders Nonresponders

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Lenalidomide Toxicity

• Allergic reactions

– Scalp itching

– Rash

– Controlled mostly by Benadryl® (diphenhydramine), occasional steroid use

• Diarrhea

– Lomotil® (diphenoxylate and atropine)

• Myelosuppression

N Engl J Med. 2006;355(14):1456-1465.Blood. 2008;111(1):86-93.

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Dose Modification

• Reserved for patients experiencing a 50% or greater decline in ANC or platelet count

• Treatment with Lenalidomide should be held until toxicity resolves and then resumed as follows

– 5mg/day for patients at 10mg/day

– 5 mg/every other day

– 5 mg twice weekly dose as long as there are no signs of disease progression

N Engl J Med. 2006;355(14):1456-1465.Blood. 2008;111(1):86-93.

HMAs in Lower Risk MDS

• Limited data

– In transfusion-dependent, lower-risk MDS resistant to ESA, HMA therapy results in approximately 17% transfusion independence

1. Vidaza [prescribing information]. Summit, NJ: Celgene Corp; 2012. 2. Dacogen [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; 2010.3. Kantarjian H, Issa JP, Rosenfeld CS, et al. Cancer. 2006;106(8):1794-803. 4. Fenaux P, Adès L. Blood. 2013;121(21):4280-4286.

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Algorithm for treating higher risk MDS

Is a donor available

for

bone marrow

transplantation?

Yes

No

Bone marrow

transplantation

High/

Int-2

patient

Is the patient fit for

transplantation?Yes

No

Hypomethylating agents

Adapted from NCCN Guidelines on Myelodysplastic Syndromes V.1.2009.

ResponseExperimental

Drugs

Azacitidine (VIDAZA®) Efficacy: CALGB 9221

• Clinical Benefit

• 40% of patients treated with VIDAZA experienced clinical benefit

• 16% responded (CR + PR) and 24% improved

*Per the Study 9221 response criteria.†Patients who had positive changes in peripheral counts but did not meet criteria for CR or PR were considered improved.

VIDAZA full prescribing information.

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VIDAZA®: Most Commonly Occurring Adverse Reactions

(All Grades) in CALGB Studies 9221 and 8921 (SC Route)

Preferred Term(CALGB Criteria)

Observation n = 92 (%)

All VIDAZA (SC) n = 220 (%)

Nausea 16 (17.4) 155 (70.5)

Anemia 59 (64.1) 153 (69.5)

Thrombocytopenia 42 (45.7) 144 (65.5)

Vomiting 5 (5.4) 119 (54.1)

Pyrexia 28 (30.4) 114 (51.8)

Leukopenia 27 (29.3) 106 (48.2)

Diarrhea 13 (14.1) 80 (36.4)

Injection site erythema 0 77 (35.0)

Constipation 6 (6.5) 74 (33.6)

Neutropenia 10 (10.9) 71 (32.3)

Ecchymosis 14 (15.2) 67 (30.5)

VIDAZA full prescribing information.

Study 9221: Maximizing Response With VIDAZA®

• Achievement of PR was initially reported between the 2nd and 19th treatment cycles*

• Achievement of CR was between the 8th and 15th treatment cycles†

• Continue therapy beyond the initial benefit to achieve full benefit for patients

Celgene Corporation, Data on File.

*The median number of cycles needed to achieve a PR was 7†The median number of cycles needed to achieve a CR was 8

21 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21Treatment

Cycles

Achievement of PR

Achievement of CR

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Azacitidine Treatment Prolongs Overall Survival in Higher-Risk MDS Patients

Compared with Conventional Care Regimens: Results of the

AZA-001 Phase III Study

P Fenaux, MD, GJ Mufti, MD, V Santini, MD, C Finelli, MD, A Giagounidis, MD, R Schoch, MD,A List, MD, S Gore, MD, J Seymour, MD, E Hellstrom-Lindberg, MD, J Bennett, MD,

J Byrd, MD, J Backstrom, MD, L Zimmerman, BSN, D McKenzie, MS, CL Beach, PharmD and L Silverman, MD

on behalf of the International Vidaza High-Risk MDS Survival Study Group

Overall Survival: Azacitidine vs CCR ITT Population

Log-Rank p=0.0001

Time (months) from Randomization

Pro

port

ion

Su

rviv

ing

CCR

AZA

Difference: 9.4 months

24.4 months

15 months

50.8%

26.2%

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Meaningful responses to both drugs generally short-lived in small subsets of patients

Bo

ne

M

arro

w

Time

MDS Stem Cell

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Genomics in Cancer Care

What is genomics? Genomics is the study of the entire genome

Genomics

Genomics in Cancer Care

What is genomics? Genomics is the study of the entire genome

“PANOMICS”

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Will this cure MDS?

Convert MDS into a chronic disease that patients can live with and not die from

More Than One Way to Build Bridges!Proud to partner in the MOONSHOT 2020

VIEW FROM MY OFFICE AT COLUMBIA UNIVERSITY MEDICAL CENTER

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Managing Treatment Side Effects of MDS

Antonietta De Los Reyes, MSN, OCN, FNP-CSMDS Center

Columbia University Medical CenterHerbert Irving Pavilion

New York, NY

Common Side Effects of Treatments

A. Erythropoietin Stimulating Agents (ESA):

• Procrit® (epoetin alfa) or Aranesp® (darbepoetin alfa) – SQ (weekly or bi-weekly) Hgb < 10 gms

• S/E:

– Headaches

– Body aches

• Management:

– Acetaminophen

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B. Lenalidomide – 10 mg podaily x 28 days every month

• S/E:̶ Myelosuppression̶ Allergic reactions- rash/scalp

itching̶ Diarrhea

• Management:̶ Weekly blood counts̶ Dose modifications̶ Growth factors̶ Transfusions̶ Antibiotics̶ Antihistamine/Steroids̶ Anti-diarrhea

C. Hypomethylathing Agents:Azacitidine and Decitabine – IV or SQ for 5 or 7 days every 4 weeks

• S/E:– Nausea – Cytopenias– Constipation – Infection

• Management:– Antiemetics (e.g. Kytril®/Zofran®)– Transfusions– Growth factors– Stool softener/laxatives (e.g. Colace®/Miralax®)– Antibiotics– Dose modifications – dose delay and dose reduction

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D. Iron Chelating Agents:

Deferasirox (Exjade® or Jadenu®) – oral once daily

• S/E:– Abdominal pain

– Diarrhea

– Nausea and vomiting

– Rash

• Management:– Antidiarrheals (e.g. Imodium®, Lomotil)

– Antiemetics (e.g. Kytril, Zofran)

– Antihistamines (e.g. Benadryl)

– Steroids – Topical or Medrol® dose pack

– Dose modifications

Patient Assistance:www.oncologyaccessnow.com/index.jsp - Novartiswww.revlimid.com/mm-patient/affording-revlimid/financial-assistance - Celgenewww.panfoundation.org - Patient Access Network Foundationwww.LLS.org/copay - The Leukemia & Lymphoma Society

MDS Resources:www.LLS.org/MDSwww.LLS.org/educationvideoswww.mdsbeacon.com/links/support-groupswww.mds-foundation.org/global-patient-support-groupswww.mdscenterfornurses.com/nurse-and-patient-resourceswww.aamds.org

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References:

Cancer. Net (2015). MDS: Coping with Side Effects. Retrieved from www.cancer.net/cancer-types/myelodysplastic-syndromes-mds/coping-side-effects

Chemocare. Retrieved from www.chemocare.com/chemotherapy/side-effects/default.aspx

Besa E. & Krishnan K, et al. Myelosdysplastic Syndrome Treatment & Management (12/6/2015) retrieved from

emedicine.medscape.com/article/207347-treatment

MDS: Update on Treatment and Side Effects Management

Question & Answer SessionThe speakers’ slides are available for download at

www.LLS.org/CE

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MDS: Update on Treatment and Side Effects Management

The Leukemia & Lymphoma Society (LLS) offers:

•Live, Online Chats provide a friendly forum for patients to share experiences:

www.LLS.org/chat

•What to ask: Lists of suggested questions for patients to ask the healthcare team.

Share question guides with your patients: www.LLS.org/whattoask

•LLS Online Social Network for HCPs and patients to seek answers and share

information: www.CommunityView.LLS.org

Information Resource Center:

Speak one-on-one with an Information Specialist who can assist

patients and healthcare professionals through cancer treatment,

including clinical trial searches, financial and social challenges.

EMAIL: infocenter@LLS.org

TOLL-FREE PHONE: (800) 955-4572

MDS: Update on Treatment and Side Effects Management

The Leukemia & Lymphoma Society (LLS) offers:

Free education materials:

www.LLS.org/publications

Continuing education programs and

videos: www.LLS.org/professionaled