MDS

Question 1

Abnormalities of which chromosome are the most common abnormality in MDS?

Answer 1

Abnormalities of which chromosome are the most common abnormality in MDS? 5

Question 2

Which mutation in MDS has been associated with a more favorable diagnosis?

Answer 2

SF3B1

Question 3

Previous exposure to what agents increases the risk of MDS?

Answer 3

• Alkylating agents
• Topoisomerase II inhibitors
• Ionizing radiation

Question 4

Alkylating agent-related MDS characteristically causes mutations of chromosome(s) ____ with a median onset of ____ after therapy.

Answer 4

• chromosomes 5 and 7
• 5-7 years after therapy

Question 5

Topoisomerase inhibitor-related MDS typically causes mutations of chromosome(s) ____ with a median onset of ____ after therapy.

Answer 5

• chromosome 11q23
• 2-3 years after therapy

Question 6

There is risk for developing ____ from antecedent MDS.

Answer 6

Secondary AML

Question 7

MDS is classified as AML if ____.

Answer 7

Presence of any of the following muations (regardless of blasts or other features):
* t(15:17)
* t(8:21)
* inv16

or greater than 20% blasts

Question 8

Current therapy recommendations for MDS are based on what stratification categories?

Answer 8

Current therapy recommendations divide patients into lower-risk and higher-risk groups.

Question 9

____ is the only curative therapy forMDS.

Answer 9

Allogeneic hematopoietic cell transplantation (HCT)

Question 10

Patients with lower-risk MDS may benefit from ____.

Answer 10

• Hematopoietic growth factors (ie: ESA and luspatercept)
• DNA hypomethylating agents
• Immunosuppressive therapy
• Immunomodulating agents (ie: lenalidomide)

Question 11

Patients with higher-risk MDS are more likely to progress to AML and may benefit from ____.

Answer 11

• DNA hypomethylating agents
• Intensive chemotherapy
• Allogeneic HCT

Question 12

When do you decide to treat or deploy therapy in lower-risk MDS?

Answer 12

When the patient becomes transfusion dependent. Patients that are transfusion independent are typically just observed until then.

Question 13

Describe the role of hematopoietic growth factors in the treatement of MDS.

Answer 13

Haven’t been shown to change the natural history of the disease and, in contrast to some solid tumors, have not been reported to have detrimental effects on
overall survival or progression.

Question 14

When do you use ESA in MDS?

Answer 14

• Lower-risk disease
• Transfusion dependent but low pretreatment RBC requirement (<2 units per month).
• EPO level <500 units/L

Question 15

How is ESA dosed in MDS?

Answer 15

Common dose is epoetin alpha (or epoetin alfa-epbx) 300 units/kg subQ 3x/week - titrate to achieve a hemoglobin level of 10-12 g/dL.

Question 16

Describe the role of thrombopoiesis stimulating agents in MDS.

Answer 16

• Not fully known at this time.
• Concern regarding complications related to disease transformation and marrow fibrosis.
• Can consider eltrombopag or romiplostim in patients with severe or refractory thrombocytopenia.

Question 17

Chemotherapy options in MDS include ____.

Answer 17

• Hypomethylating agents (Azacitadine, Decitabine, or the comination Decitabine/Cedazuridine)
• Intensive therapy with regimens used for induction therapy in AML.

Question 18

Which hypomethylating agent is preferred in MDS and why?

Answer 18

Azacitadine because it has shown to improve overall survival especially in patients with progressing or high-risk disease

Question 19

Describe the role of hypomethylating agents in MDS

Answer 19

• Primarily used in higher-risk disease as they have shown to decrease risk of leukemic transformation in these patients. Considered the standard of care in this subgroup.
• Less utility in lower-risk MDS as they have not shown to modify the natural history of disease in these patients but they are an appropriate option for lower-risk patients with symptomatic anemia and elevated epoetin levels who are not expected to respond to other treatment options.
• Indicators for use are:
  1. Higher-risk MDS
  2. Not a candidate for high-intensity therapy
  3. Potential candidate for allogeneic HCT, but in which a delay is anticipated. These agents may be used as “bridging therapy” prior to transplant.
  4. Relapse after allogeneic HCT.

Question 20

Describe the role of lenalidomide in MDS

Answer 20

This is an immunomodulating agent with demonstrated activity in lower-risk MDS - particularly beneficial in patients with del(5q) as the sole chromosomal abnormality. This subtype confers a favorable prognosis.

Question 21

Describe the role of luspatercept in MDS

Answer 21

• Luspatercept – is a first in class recombinant fusion protein that inhibits the transforming growth factor dependent stages of erythroid maturation.
• Luspatercept can be used without regard to EPO levels unlike ESAs or lenalidomide in non-del-5q).
• Luspatercept does not provide disease modifying effects, thus is unlikely to reduce the risk of progression to AML (importantly it also does not lead to an increased risk of progression to AML).
• The primary indictor for use are lower-risk MDS with ring sideroblasts.

Question 22

How is luspatercept dosed in MDS?

Answer 22

1 mg/kg subQ q3weeks - titrate based on hemoglobin levels.

Question 23

Describe the role of immunosuppressive therapy in MDS

Answer 23

Immunosuppression with anti-thymocyte globulin (ATG), steroids, cyclosporine, and can be used to treat the cytopenias associated with lower-risk MDS. The following pretreatment characteristics are predictive of response to immunosuppressive therapy:
* Younger age (≤60 years old)
* Shorter duration of red cell transfusion dependence (RCTD)
* Overrepresentation of the class II histocompatibility antigen DR15 (HLA-DR15)
* Bone marrow hypoplasia (<5% blasts)
* Normal cytogenetics

Question 24

Describe the overall treatment principles/draw the treatment algorithm for lower-risk MDS.

Question 25

What is the minimum number of courses needed prior to considering the treatment of MDS with a hypomethylating agent a failure?

Answer 25

A minimum of 4-6 courses.

Question 26

Describe the role of intensive chemotherapy in MDS

Answer 26

* Regimens that are used for induction therapy in AML may be considered in **higher-risk** patients with good performance status and few co-morbidities who are awaiting allogeneic HCT and require a reduction in disease burden. * Remission rates of 40-60% have been reported, but treatment-related mortality approaches 40%. Given the advanced age and potential medical comorbidities of this population, there is high risk of morbidity and mortality from AML-like intensive remission induction therapy with cytotoxic chemotherapy. * The most important prognostic factor of response to AML-like therapy is karyotype. Patients with unfavorable karyotype [***complex karyotype or del(7q)***] have a low response rate and short response duration.

Question 27

Describe the role of iron-chelating therapy in MDS

Answer 27

* Therapy for MSD may alleviate the patient’s RBC transfusion needs, but a substantial proportion of patients may not respond to treatment and may develop iron overload increasing the risk of hepatic, cardiac, and endocrine damage. ICT was associated with a greater median survival time than non-use of ICT, **especially in lower-risk MDS** patients. * If > 20 RBC transfusions have been received and serum ferritin > 2500 ng/mL, consider daily ICT to decrease iron overload (to a ferritin level less than 1,000 ng/mL), particularly for those with >1-year expected lifespan (factoring in co-morbid conditions) and good prognosis (IPSS Low-risk and Intermediate-1 and for potential allogeneic HCT candidates). * Current guidelines suggest that ICT can be achieved with either deferoxamine or deferasirox. ***Deferasirox is contraindicated in patients with high-risk MDS**** due to the possibility of liver or kidney impairment and gastrointestinal bleeding. Deferiprone therapy remains a controversial.