Myelodysplastic Syndromes Flashcards
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Myelodysplastic Syndromes
Chromosomal Abnormalities
Chromosome 5 - Most common Chromosomal abnormalitiy in MDS
Other Chromosomal abnormalities - Chromosomes 3, 5, 7, 8, 11, 17, 20
Myelodysplastic Syndromes
Gene Mutations associated with Adverse Clinical Features
- Complex Karyotype (TP53)
- Excess Bone Marrow Blast Proportion (RUNX1, NRAS, and TP53)
- Severe Thrombocytopenia (RUNX1, NRAS and TP53)
Myelodysplastic Syndromes
Risk Factors
Previous Exposure:
- Alkylating Agents
- Topoisomerase II Inhibitors
- Ionizing Radiation
Myelodysplastic Syndromes
Mutations and Prognostic Factors
SF3B1 mutation has been associated with a more favorable prognosis
Myelodysplastic Syndromes
Treatment
Goals of Therapy
- Alteration of the natural history of the disease / delaying disease progression
- Reducing number of red blood cell transfusions
- Improving quality of life
- Prolonging survival
Myelodysplastic Syndromes
Treatment
Allogeneic Hematopoietic Stem Cell Transplantation (HCT)
Only Curative therapy
Myelodysplastic Syndromes
Treatment
Recommended Therapies
Lower-Risk Disease
Patients with lower-risk disease may benefit from:
- ** hematopoietic growth factors** (ie: erythropoietin stimulating agents [ESA] and luspatercept)
- hypomethylating agents
- Immunosuppressive therapy
- immunomodulating agents (ie: lenalidomide).
Therapy in this subset of patients is based on transfusion needs. Patients that are transfusion independent are typically observed until they become transfusion dependent.
Myelodysplastic Syndromes
Treatment
Recommended Therapies
Higher-Risk Disease
High-Risk = More likely to progress to AML
May Benefit from:
- Hypomethylating agents
- Intensive Chemotherapy
- Allogeneic HCT
Myelodysplastic Syndromes
Treatment- LOWER-RISK MDS
Recommended Therapies
Hematopoietic Growth Factors
Neither granulocyte/macrophage colony stimulating factor (GCSF/GMCSF), thrombopoietin receptor agonists, luspatercept, nor ESA change the natural history of the disease.
GCSF increases circulating neutrophils and may decrease the risk of infections.
- GCSF not recommended for routine prophylaxis. Consider if recurrent.
ESA increase hematocrit in 30-58% of MDS patients
- Titrate to acheive goal Hgb 10-12 g/dL
- Best response when pts baseline EPO is <500U/L
Myelodysplastic Syndromes
Treatment - LOWER-RISK MDS
Recommended Therapies
Lenalidomide
An immunomodulating agent with demonstrated activity in lower-risk MDS
Particularly beneficial in patients w/ del(5q) as sole chromosomal abnormality
Myelodysplastic Syndromes
Treatment - LOWER-RISK MDS
Recommended Therapies
Luspatercept
First in class recombinant fusion protein that inhibits the transforming growth
factor dependent stages of erythroid maturation
COMMANDS Trial
- Incidence of RBC transfusion independence favored Luspatercept vs Epoetin alfa
- Patients without ringed sideroblasts did not benefit from luspatercept over epoetin alfa
FDA APPROVAL INDICATIONS:
- EPO-naive setting = luspattercept approve regardless of ringed sideroblasts
- EPO-refractory/intolerant = ringed sideroblasts MUST be present
Myelodysplastic Syndromes
Treatment - LOWER-RISK MDS
Recommended Therapies
Luspatercept
Adverse Events
Adverse Reactions
- Thrombocytopenia
- Fatigue
- Peripheral Edema
- Nausea
- Dyspnea
- Hypertension
Myelodysplastic Syndromes
Treatment - LOWER-RISK MDS
Recommended Therapies
Immunosuppressive Therapies
Agents
Can be used to treat the cytopenias associated with MDS
- Equine anti-thymocyte globulin (ATG)
- steroids
- cyclosporine
- eltrombopag
Approximately 30% of MDS patients respond to these agents
Sustained increases in:
- Hemoglobin
- Neutrophils
- Platelet Production
Myelodysplastic Syndromes
Treatment - LOWER-RISK MDS
Recommended Therapies
Immunosuppressive Therapies
Predictive Response Characteristics
- 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
- Evidence of a paroxysmal nocturnal hemoglobinuria (PNH) clone
- STAT-3 mutant cytotoxic T-cell clones
Myelodysplastic Syndromes
Treatment - LOWER-RISK MDS
Recommended Therapies
Hypomethylating Agents
Azacitadine and Decitabine
Lower-Risk MDS:
- Some studies have demonstrated clinical benefit w/ low doses of azacitadine/decitabine
Appropriate option for lower-risk patients w/ symptomatic anemia and elevated epoetin levels who are NOT expected to respond to other treatment options
Myelodysplastic Syndromes
Treatment - HIGHER-RISK DISEASE
Recommended Therapies
- Hypomethylating Agents
- Intensive Chemotherapy (Anthracyclines, Cytarabine, Fludarabine)
- Ivosidenib
Myelodysplastic Syndromes
Treatment - HIGHER-RISK DISEASE
Recommended Therapies
Hypomethylating Agents
Considered standard of care in this subgroup
- Azacitadine/Decitabine = theoretically similar
- Azacitadine preferred by NCCN (proven survival benefit)
- 4-6 cycles of treatment required to determine treatment failure
Myelodysplastic Syndromes
Treatment - HIGHER-RISK DISEASE
Recommended Therapies
Hypomethylating Agents
Regimens used for induction therapy in AML may be considered in patients w/ good performance status and few co-morbidities who are awaiting allogeneic HCT
Most important factor of response to AML-like therapy is karyotype
- unfavorable karyotype (complex karyotpe or del(7q)) have low response rate/short duration of response
Myelodysplastic Syndromes
Treatment - HIGHER-RISK DISEASE
Recommended Therapies
Ivosidenib
FDA Approved for R/R MDS based on 19 patients with R/R MDS
- Small number study and difficult to understand safety or efficacy in this population
Myelodysplastic Syndromes
Sumary of Preferred Treatment Options
HIGHER RISK
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Myelodysplastic Syndromes
Sumary of Preferred Treatment Options
LOWER RISK
Image PAGE 10
Myelodysplastic Syndromes
Iron Chelation Therapy
SUMMARY
- Therapy for MDS may alleviate patient RBC need but substatial proportion of patients may not respond to tx and develop IRON OVERLOAD
- -> Increased risk of Hepatic, Cardiac and Endocrine Damage
- NO studies demonstrating Overall Survival Benefit w/ iron chelation in MDS
Myelodysplastic Syndromes
Iron Chelation Therapy
Treatment
- If > 20 RBC transfusions have been received
AND - Serum Ferritin >2500 ng/mL:
–> Consider daily iron chelation to decrease iron overload
- Deferoxamine or Deferasirox
Deferoxamine AVOID if CrCl <40ml/min
Deferasirox contraindicated in patients with high-risk MDS due to possibility of liver or kidney impairment and GI bleeding
