powerpoint presentation slides...11/7/2017 2 winship cancer institute | emory university 7 about mds...

11/7/2017

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Myelodysplastic Syndromes (MDS)Understanding Your Diagnosis and Treatments Options

Martha Arellano, MDWinship Cancer Institute of Emory University School of Medicine

2Winship Cancer Institute | Emory University

Learning Objectives

● Understand what myelodysplastic syndromes (MDS) are

and how they are related to AML, CMML, and MPNs

● Review signs and symptoms, and how MDS is diagnosed

● Review the subtypes and classification of MDS

● Summarize tools to define prognostic of MDS

● Review standard treatment options for MDS

● Introduce emerging treatments for MDS

● Discuss life with MDS


About Bone Marrow and Blood Cells…

The Bone Marrow is the “blood factory”

Blood cells

● White blood cell (fights infection)

● Red blood cell (carries oxygen)

● Platelet (helps blood to clot)


Myelodysplastic Syndrome- What is it?

• A group of diseases that start as a result of damaged blood stem cells in the bone marrow.

• MDS causes the bone marrow to produce abnormal blood cells.• not enough cells • bizarre-looking cells (dysplastic) • Immature cells (blasts)

• In about a quarter of patients with MDS, the MDS can turn into a more aggressive form, which is called acute myeloid (or myelogenous) leukemia (AML).

Dysplastic (bizarre) neutrophils

Normal neutrophil


The Bone Marrow and MDS


Relationship among bone marrow failure

syndromes, MDS, and leukemia

Adapted from N. Young, R. Calado, and P. Scheinber. Blood.2006;108:2509-2519

MPN

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About MDS

● In MDS, there is damage to the stem cells in the bone marrow.

● Sometimes the stem cells don’t mature into normal blood cells (immature cells are “blasts”).

● MDS Blasts block normal blood cell production. This results in:

● Anemia (low number of red cells to carry hemoglobin and provide energy)

● Neutropenia (low number of white cells to fight infection)

● Thrombocytopenia (low number of platelets to clot the blood)

● Pancytopenia (low number of all 3 types of blood cells)

● Blasts can also overgrow in the marrow and spill into the blood.

● When blasts in the blood or marrow reach 20% or more, it is acute myeloid leukemia (AML).


Causes/Risk Factors

• Older age

• Genetics (rarely hereditary)

• Environmental exposures - Benzene is the best reported

• Prior exposure to chemotherapy and/or radiation therapy (therapy-related MDS)


The Risk of MDS Increases with Age

Patient Age


How Common is MDS?

• ~10,000 new cases per year in US and approximately 300-400,000 new cases worldwide

• 10-20% of cases due to chemotherapy/radiation exposure

• ~75% of patients > 60 yrs of age

• Several effective treatments, but…

• The only potentially curative therapy for MDS is allogeneic (donor) stem cell transplantation.


Signs and Symptoms

● Some people have no symptoms.

● Others may experience:

● Fatigue

● Shortness of breath during activity

● Pale skin

● Excessive bruises

● Dizziness

● Increased risk of bleeding

● Infection

● Auto-immune manisfestations12Winship Cancer Institute | Emory University

● Physical Exam

● Blood Tests:

○ Complete Blood Count (CBC)

○ Additional testing to rule out other causes of low blood counts

● Bone marrow tests:

○ Bone marrow aspiration and biopsy to determine:

○ How the cells look. Is there “dysplasia”?

○ Chromosome analysis (are they normal or abnormal?)

○ Genetic testing for specific gene mutations (may be done in blood)

How is MDS diagnosed?

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An MDS diagnosis is made when at least one of the following is found in the bone marrow:

● Blast cells making up more than 5% of the bone marrow cells

● Changes to the structure or form of the bone marrow

● Chromosome abnormalities

○ About half of MDS patients have abnormal bone marrow chromosomes

○ Those chromosome abnormalities (too few, too many, missing parts, extra parts)

can help with the diagnosis and predicting the prognosis of the MDS.

How is MDS diagnosed? (cont’d)


More about Chromosomes and How Cells Divide

It’s a boy! 46,XY???!! 50,XXXYYY


MDS Classification

• Historically, doctors classified MDS subtypes based on the appearance of the patient’s marrow

and blood cell counts.

• The French-American-British (FAB) classification consists of the following main subtypes:

• Refractory anemia (RA)

• Refractory anemia with excess blasts (RAEB)

• Refractory anemia with excess blasts in transformation (RAEB-T)

• Chronic myelomonocytic leukemia (CMML)

• The World Health Organization (WHO) classification is used more often now and is more detailed.

It takes into account the chromosome abnormalities and gene mutations found in the blood or

bone marrow.


Disease Peripheral Blood findings Bone Marrow findings

RCUD, RA, RN, RT uni or bicytopenia, blasts <1% *unilineage dysplasia, ≥ 10% of the cells, < 5% blasts, < 15% RS

RARS anemia, no blasts > 15% RS, <5% blasts, erythroid dysplasia only

RCMD cytopenia(s), blasts < 1%, no auer rods, monocytes <1 × 109/L

dysplasia, > 10% cells of > 2 lineages, <5% blasts, no auer rods, +/- 15% RS

RAEB-1 cytopenia(s), blasts < 5%, no auer rods, monocytes <1 × 109/L

uni or multilineage dysplasia, 5-9% blasts, no auer rods

RAEB-2 cytopenia(s), blasts 5-19%, auer rods ±, monocytes < 1 × 109/L

uni or multilineage dysplasia, 10-19% blasts, +/- auer rods

MDS-U Cytopenias, < 1% blasts dysplasia in <10% cells, accompanied by cytogenetic evidence of MDS, < 5% blasts

MDS withisolated del (5q)

Anemia, platelets normal or increased, blasts < 1%

normal to ↑ megas with hypolobated nuclei, <5% blasts, no Auer rods, Isolated del5q

2008 WHO Classification of MDS

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (Eds): Lyon 2008.


WHO Classification of MDS

MDS with single lineage dysplasia

MDS with ring sideroblasts (MDS-RS)

MDS-RS and single lineage dysplasia

MDS-RS and multilineage dysplasia

MDS with multilineage dysplasia

MDS with excess blasts

MDS with isolated del(5q)

MDS, unclassifiable

Myeloid neoplasms with germ line predisposition

Provisional entity: Refractory cytopenia of childhood

Daniel A. Arber, Attilio Orazi, Robert Hasserjian, et al. Blood 2016 , Swerdlow SH, Campo E, Harris NL, Jaffe ES, et al. Lyon 2008. 18Winship Cancer Institute | Emory University

What Determines Prognosis in MDS?

• The International Prognostic Scoring System (IPSS) and the Revised International Prognostic Scoring

System (IPSS-R) are the most commonly used tools used to predict the course of the MDS.

• Both systems use the following to come up with a number (the prognostic score):

• The percentage of blast cells in the bone marrow

• The chromosomes in the bone marrow cells (some abnormalities are favorable, some unfavorable)

• The types of cells in the blood that are decreased (white cells, hemoglobin in the red cells,

platelets), and how low the numbers are.

• The IPSS-R score can help the doctor to estimate the patient’s prognosis; meaning, the patient’s

probability of surviving and the probability of progressing to AML.

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The Revised International Prognostic Scoring System (IPSS-R)


Outcomes Based on IPSS-R Category

Survival AML-free Survival

Greenberg, et al. Blood 2012. 120: 2454-2465


Gene Mutations in MDS

R. Bejar et al. N Engl J Med 2011.22Winship Cancer Institute | Emory University

Survival According to IPSS and Gene Mutation Status

R. Bejar et al. N Engl J Med 2011.


What are the goals of treatment in MDS?

• Stop or slow down the progression of MDS to AML

• Improve the blood counts

• Suppress the abnormal cells

• Maintain or improve patient’s quality of life


MDS Treatment

In deciding on a treatment, the hematologist/oncologist will consider:

• Who is the patient? (other medical problems, overall health)

• What is the major problem for the patient? (anemia, thrombocytopenia, etc)

• Type and prognostic (risk) score of the MDS (low risk vs. high risk?)

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MDS Treatment, cont.

Goals for lower risk patients:

• Decrease the number of blood transfusions needed

• Decrease the number of platelet transfusions needed

• Lower the risk of infection

• Increase the number of good-quality years of life

Goals for higher risk patients:

• Same as low risk patients

• Increase life expectancy, which is much shorter than those with low-risk MDS

• Some patients can be cured with a donor bone marrow transplant


Treatment Approaches for MDS

The most common treatments for MDS include

● Observation of blood cell counts (watch and wait)

● Transfusions of blood (red cells) or platelets

● Iron chelation therapy- to prevent iron build up from red cell transfusions.

● Growth factors (red cell growth factors, rarely, white cell growth factors)

● Drug therapy

● Chemotherapy

● Clinical trials

● Stem cell or bone marrow transplantation


The 1st

Question

• Is the patient a candidate for consideration of allogeneic SCT?

• How?

• When?

• General considerations• Age up to 70-75

• General health

• Physical activity/performance status—can the patient walk a mile?


Who is a transplant candidate?


Deciding Who Is a Transplant Candidate

Hematopoietic Cell Transplant Comorbidity Index (HCT-CI)

ML Sorror et al. Blood 106: 2912 (2005) 30Winship Cancer Institute | Emory University

What is a transplant?

• Most powerful and most dangerous treatment for blood cancers

• Chemotherapy +/- radiation to destroy the marrow and immune system

followed by

• Infusion of donor cells to reconstitute the marrow and immune system• Long term immune suppression is necessary

• Risk is related to:

• donor immune attack on patient tissues—graft vs host disease

• infection

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Changes that made transplant an option for more patients…

• Better general medical management for heart disease

• Use of less intensive pre-transplant chemotherapy regimens—”mini-transplant”

• Better immune suppressive medications

• Better supportive care


But what about everyone else…?


Treatment Approaches for MDS

The most common treatments for MDS include

● Observation of blood cell counts (watch and wait)

● Transfusions of blood (red cells) or platelets

● Iron chelation therapy- to prevent iron build up from red cell transfusions.

● Growth factors (red cell growth factors, rarely, white cell growth factors)

● Drug therapy

● Chemotherapy

● Clinical trials

● Stem cell or bone marrow transplantation


Observation of Blood Cell Counts (Watch and Wait)

● A “watch and wait” approach can be the best

option for low risk patients.

● A watch and wait approach allows doctors to

monitor a patient’s condition and blood counts

without starting treatment until it is needed.

● The advantage of “watch and wait” is that

patients can avoid the potential side effects of

therapy until their MDS progresses.

Patients on “watch and wait” should:

● continue to see their doctor● have regular tests and exams● tell their doctor about any

new symptoms● remember that treatment

may be needed if there are signs of disease progression.


Transfusions

Red blood cells transfusions may:

● Improve red blood cell counts (and hemoglobin)

● Relieves symptoms of anemia such as:

● shortness of breath

● dizziness

● fatigue

● chest pain

Platelet transfusions treat

● Low platelet counts

● Unusual bleeding

● Excessive bruising


Iron Chelation Therapy

● Uses medicine (iron chelators) to remove excess iron

○ Deferasirox (Exjade®, Jadenu®)

○ Deferiprone (Ferriprox®)

○ Deferoxamine mesylate (DFO; Desferal®)

● May be appropriate for anemic patients who depend on transfusions

● Most appropriate for low risk patients

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Iron Chelation in Lower Risk MDS

chelated

not chelated not chelated

weaklychelated

Adequatelychelated

M. Delforge, et al. Leukemia Research 38 2014 38Winship Cancer Institute | Emory University

Growth Factors

Red blood cell growth factors (Erythropoiesis-Stimulating Agents or “ESAs”)

● Epoetin alfa (Procrit®)

● Darbepoetin alfa (Aranesp®)

White blood cell growth factors

● Granulocyte-colony stimulating factor (G-CSF)

● Granulocyte macrophage-colony stimulating factor (GM-CSF)

Platelet growth factors (in clinical trials)

● Romiplostim (Nplate®)

● Eltrombopag (Promacta®)


Drug Therapy

Some single-drug approaches that have been FDA approved for MDS are:

● Hypomethylating agents (HMA): Azacitidine (Vidaza®) or Decitabine (Dacogen®)

○ For low- and high-risk patients

○ Improves bone marrow function

○ Kills unhealthy cells

○ Given intravenously (IV) or subcutaneously (SC) one week/month

○ Oral azacitidine in clinical trials


Drug Therapy (cont’d)

● Lenalidomide (Revlimid®)

○ Preferred therapy for patients with transfusion-dependent anemia due to low- or

intermediate-1-risk MDS

○ Works best for those with deletion 5q

○ Can be combined with other therapies

● Imatinib mesylate (Gleevec®)

○ FDA-approved for patients with MDS associated with platelet-derived growth factor

receptor (PDGFR) gene rearrangements


What about Combination therapy in MDS?

• Most patients treated with azacitidine or decitabine (HMA) who achieve a response, will lose their response over time.

• Outcome of MDS after HMA failure is poor.

• Therefore, single-agent therapy is inadequate and efforts need to focus on finding active combinations and new therapies.

• Clinical trials of combination therapy may be the best option


Chemotherapy

These drugs may include

● Cytarabine (cytosine arabinoside, ara-C; Cytosar-U®)

● Idarubicin (Idamycin®)

● Daunorubicin (Cerubidine®)

● Mitoxantrone (Novantrone®)

Chemotherapy is not a long-term option for MDS.

*In clinical trials, newer drugs are being investigated

Generally, chemotherapy is reserved for patients who are being prepared for

transplant and/or have progressed toward leukemia

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How do We Try to Improve Treatments for MDS

Champions-shop.gr 44Winship Cancer Institute | Emory University

Genetic Variability MDS, Potential for New Targeted Treatments

Gondek LP, Tiu R, O’Keefe CL, et al. Blood 2008; 111(3): 1534-1542; Kulasekararaj A, Mohamedali A, Mufti G. BJH 2013, 162, 587-605.

SNP Array


What about Clinical Trials?

What is a clinical trial?

● A carefully controlled research study conducted by doctors to

○ improve treatment options

○ increase survival

○ improve quality of life

● Designed to give patients the access to promising therapies, while offering protection against

possible unknown side effects

● A patient can stop participating in a trial at any time, for any reason


More About Clinical Trials

Who should participate?

● Trials are not only for people with the

most advanced disease.

● Patients should not wait for standard

treatment to fail before asking about

trials.

● Trials can be designed to test new treatments

that improve response rates or improve

quality of life of patients with newly

diagnosed or very limited disease as well.

Ask about the phase of the clinical trial:

● Phase I - 1st in human studies, looking for side effects to find the right dose

● Phase II – Looking for efficacy; does the drug work in this disease?

● Phase III – compares the new drug to the standard therapy (if one exists)


Promising Investigational Approaches (clinical trials)

• Immune therapies- alone or in combination with other agents

• Targeted therapies aimed at specific genetic mutations

• Bi-specific antibodies – smart bombs that direct immune cells to the target

• Combination regimens


Advances in Immune Therapy for AML and MDS

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Clinical Implications of Gene Mutations in MDS


A Clinical Trial Can Be the Best Option…


Potential Treatment Side Effects/Complications

Chemotherapy-related side effects

● Low blood counts (anemia, neutropenia, thrombocytopenia)

● Mouth sores

● Hair loss

● Rashes

● Nausea/Vomiting/Diarrhea

Possible signs of infection

● Fever

● Chills

● Cough

● Sore throat

● Pain when urinating

● Diarrhea


Coping with Side Effects (supportive care)

● Antibiotics

● Medication for nausea/vomiting

● Hand-washing to prevent infection

● Keep the patient’s central-line clean

● Practice good dental hygiene


Life with MDS-Being Active

• Being active can help you to stay strong.

• These are things that you can do to help:

• Be active.

• Do as much of your self-care as you can.

• Take daily walks.

• Balance activity with rest.

• If your neutrophils are low, try to stay away

from crowds and dirt.


Life with MDS- Your Diet

• Eat a normal, healthy diet.

• Fresh fruits and vegetables should be washed fully.

• You do not need to avoid foods unless you are already

on a special diet for other reasons.

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Life with MDS-Your Sex Life

• Sex and intimacy are a normal part of life. There are no special limits. Use caution if your platelet count is low.

• Patients (and their partners) of reproductive age, should avoid getting pregnant while taking chemotherapy, because the medications may harm the unborn fetus.

• Tell your doctor or health care team if you are having problems with low sex drive or erectile dysfunction. There may be medications that can help.


Life with MDS-Your Mood

• Feeling depressed can keep you from doing what is most important to you. It can also cause you to have aches, pains, problems sleeping, or feeling anxious.

• Feeling depressed can best be treated by using a counselor or therapist and sometimes, by adding medications.

• Tell your doctor if you feel depressed, so that they can get you the help you need.


Follow-up

● Track each visit and record what was discussed

● Ask your doctor if and why certain tests are

being done and what to expect

● Ask for copies of lab reports

● Discuss test results

● Find out if and when follow-up tests are needed

● Seek medical and psychosocial support for

fatigue, depression and other long-term effects

as needed.

● A second opinion is appropriate, if needed.


Questions & Answers

[email protected]

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