Myelodysplastic Syndromes Treatment Protocols

Treatment recommendations for myelodysplastic syndromes (MDS) are based on a patient’s prognostic grouping. This can be determined using the Revised International Prognostic Scoring System (IPSS-R) in addition to evaluation of a patient’s performance status, symptoms, care goals, cytopenias, and molecular genetic testing (eg, for 5q31 deletion or SF3B1 mutations). ^[1] Alternatively, if an appropriately broad next-generation sequencing platform is performed, molecular scoring systems such as the International Prognostic Scoring System–Molecular ^[29] (IPSS-M) may be used to assign prognosis and select therapy. 

Currently, a handful of US Food and Drug Administration (FDA)–approved therapies for MDS are available, including lenalidomide, the erythroid maturation agent luspatercept, hypomethylating agents such as azacitidine and decitabine, and iron chelators such as deferasirox. ^{[2, 3]} Special considerations and supportive care are also described below. ^[4]

See Myelodysplastic Syndromes: Classification, Features, Diagnosis, and Treatment Options, a Critical Images slideshow, to help identify, classify, work up, and treat these disorders.

IPSS-R very-low-, low-, or intermediate-risk patients

These patients should receive supportive care. Selected patients who have not required transfusion and have modest, asymptomatic cytopenias may be observed initially.

Treatment in patients with symptomatic anemia; < 2 units (U) of red blood cell (RBC) transfusion required per month; and 5q31 deletion, with or without other cytogenetic abnormalities, is as follows:

• Lenalidomide 10 mg PO daily, either continuous dosing or on days 1-21 every 28 d
• If no response or intolerance, treat as for patients without del5q

Patients with symptomatic anemia, 2 units (U) of RBC transfusion required per month, and low (≤500 mU/mL) serum erythropoietin levels may be treated with single-agent erythropoiesis stimulating agents (ESAs), as follows:

• Epoetin alfa 40,000-60,000 U SC 1-3 times weekly, or

• Darbepoetin alfa 150-300 µg SC weekly ^{[5, 6]}

Patients with symptomatic anemia, < 2 units (U) of RBC transfusion required per month, and low (≤500 mU/mL) serum erythropoietin levels may be treated with combined ESAs and granulocyte colony-stimulating factor (G-CSF), as follows:

• Epoetin alfa 40,000-60,000 U SC 1-3 times weekly, or

• Darbepoetin alfa 150-300 µg SC weekly ^{[5, 6]}  plus

• Filgrastim 300 µg SC 3 times weekly, doses adjusted to hemoglobin (Hb) level of 11-13 g/dL, and total white blood cell (WBC) count ≤10 × 10⁹/L ^[7]

Patients with symptomatic anemia, < 2 units (U) of RBC transfusion required per month, and serum erythropoietin levels > 500 mU/mL, without 5q31 deletion, but with myelodysplastic syndromes with ring sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), or  patients without 5q31 deletion, but with MDS-RS or MDS/MPN-RS-T treated with ESAs with or without G-CSF who have not had hematologic improvement or who lost hematologic improvement after initial response (note that patients with MDS-RS and MDS/MPN-RS-T often harbor mutaitons in SF3B1, and patients with > 5% ring sideroblasts and mutated SF3B1 may also respond to luspatercept) ^{[31, 32, 34]} :

• Luspatercept starting at 1 mg/kg SC every 3 weeks; the patient is still transfusion dependent after 6 weeks (2 consecutive doses), dose may be increased to 1.33 mg/kg SC every 3 weeks, and again after another 6 weeks to 1.75 mg/kg SC every 3 weeks if still transfusion dependent.

Treatment should be paused if hemoglobin is >11.5 g/dL in absence of transfusions and restarted when hemoglobin is < 11 g/dL. If the hemoglobin concentraiton rises >2 g/dL within 3 weeks in the absence of transfusions, reduce dose as follows:

• Current dose 1.75 mg/kg: Reduce dose to 1.33 mg/kg once every 3 weeks
• Current dose 1.33 mg/kg: Reduce dose to 1 mg/kg once every 3 weeks
• Current dose 1 mg/kg: Reduce dose to 0.8 mg/kg once every 3 weeks
• Current dose 0.8 mg/kg: Reduce dose to 0.6 mg/kg once every 3 weeks
• Current dose  0.6 mg/kg: Discontinue luspatercept

In patients with symptomatic anemia, < 2 units (U) of RBC transfusion required per month, and serum erythropoietin levels > 500 mU/mL, without 5q31 deletion, and without MDS-RS or MDS/MPN-RS-T, or patients without 5q31 deletion, and without MDS-RS or MDS/MPN-RS-T, treated with ESAs with or without G-CSF who have not had hematologic improvement or who lost hematologic improvement after initial response, management is as follows:

• Evaluate likelihood of response to immunosuppressive therapy

• Patients who are < 60y and have ≤5% marrow blasts or those with hypocellular marrows, are human leukocyte antigen (HLA)–DR15 positive, paroxysmal nocturnal hemoglobinuria (PNH) clone positive, or have STAT-3 mutant cytotoxic T cell clones are likely to respond to equine antithymocyte globulin (ATG) 40 mg/kg/day IV over 4-6h for 4d plus cyclosporine starting at 5-12 mg/kg/day IV beginning on day 14, dosed to maintain therapeutic levels of 200-400 ng/mL. ^[8]

Patients without those characteristics are unlikely to respond to immunosuppressive therapy and should be considered for azacitidine/decitabine or lenalidomide. ^[8]

• Recommended azacitidine dosage is 75 mg/m² SC or IV on days 1-7; every 28 d ^{[9, 10, 11]}  or

• Alternative azacitidine schedules, associated with similar response rates: 75 mg/m² SC or IV on days 1-5, 8, and 9; every 28 d ^[12]  or  azacitidine 75 mg/m² SC or IV days 1-3 every 28 days ^[35]

• Decitabine using the initial FDA-approved schedule, which is not frequently adopted due to inconvenience: 15 mg/m ² IV over 3 h every 8 h (or 45 mg/m ²/day) for 3 d; every 6 wk ^[13]   or
• Decitabine on outpatient schedule, now widely adopted: 20 mg/m ² IV over 1 h daily on days 1-5; every 28 d ^{[13, 14, 15]}   or  decitabine 20 mg/m ² IV days 1-3 every 28 days ^[35]
• Lenalidomide , 10 mg PO daily, either continuous dosing or on days 1-21 every 28 d

IPSS-R high-risk or very-high-risk patients

The following applies to IPSS-R high-risk or very-high-risk patients regardless of transfusion frequency or intermediate-risk patients with high transfusion needs (> 2 U RBCs per month), in whom impending transformation to acute myeloid leukemia (AML) is a concern. Good candidates for high-intensity therapy are young patients with few or no comorbidities, 10-20% myeloblasts, good performance status, adequate psychosocial support, and access to a center with dedicated leukemia and transplant programs.

High-intensity therapy is as follows:

• AML-type induction therapy, such as 7+3 (idarubicin 12 mg/m² IV push on days 1-3 plus cytarabine 100-200 mg/m²/day continuous IV infusion on days 1-7) ^[16] or azacitidine or decitabine, as outlined above

• Allogeneic stem cell transplantation (ASCTD) consultation should also be recommended for these select patients; ASCT may be performed as initial therapy or following cytoreduction with any of the other therapies for MDS

Options for patients who are not candidates for high-intensity therapy, or prefer low-intensity therapy, are as follows:

• Azacitidine 75 mg/m² SC or IV on days 1-7; every 28 d; this regimen has been associated with improvements in transfusion dependence, quality of life (QoL) and overall survival (OS) in phase III trials ^{[9, 10, 11]}  or

• Alternative schedule of azacitidine, associated with similar response rates: 75 mg/m² SC or IV on days 1-5, 8, and 9; every 28 d ^[12]  or

• Decitabine using the initial FDA-approved schedule, which is not frequently adopted due to inconvenience: 15 mg/m² IV over 3 h every 8h (or 45 mg/m²/day) for 3 d; every 6 wk ^[13] or

• Decitabine on outpatient schedule, now widely adopted: 20 mg/m² IV over 1 h daily on days 1-5; every 28 d ^{[13, 14, 15]}

• For patients preferring oral therapy: decitabine 35 mg/cedazuridine 100 mg PO daily days 1-5 of 28-day cycles ^[36]

Special considerations

See the list below:

• ASCT is the only potentially curative therapy for MDS.

• Appropriate patients should be referred early for consultation with a transplant specialist, before extensive transfusion support, infectious complications, or transformation to AML.

• Generally, early transplantation is advocated for young patients who are IPSS INT-2–risk and high-risk patients. ^[17]

• Consider referral for clinical trial participation at any stage of therapy.

• The regimens above have been tested in the frontline setting, and there is no standard of care at the inevitable time of frontline therapeutic failure for higher-risk MDS, which carries an extremely poor prognosis. ^[37]

• Clinical trial participation in this situation is highly recommended. Commercially available agents approved for AML, such as the BCL2 inhibitor venetoclax (in combination with hypomethylating agents) ^[38] and inhibitors of mutant IDH1 ^[39] or IDH2 ^[41] have demonstrated activity in this setting, and these agents are under further investigation in patients with MDS.

• When considering the choice of a particular therapeutic regimen, it is important to consider the time to initial and best response; the duration of time to response is also critical in evaluating the success of therapies.

• Therapeutic regimens should generally not be changed in the absence of progression or toxicity unless an adequate trial of the current regimen has been undertaken.

The median time to response for the therapies listed above is as follows:

• ESAs with or without granulocyte-colony stimulating factor (G-CSF): 8-12 wk ^{[18, 14]}
• Lenalidomide: 4.6 wk ^[19]
• ATG plus cyclosporine: 4 mo ^[20]
• Azacitidine or decitabine: 1.7 mo ^[15] to 3 mo ^[21]
• Induction chemotherapy: 4-6 wk

Supportive care

Infection prophylaxis

• Indicated for patients with prolonged, severe neutropenia (< 0.5 × 10⁹/L for ≥ 7 d) due to either disease or therapy, who are at risk for opportunistic infections and febrile neutropenia

• Infection prophylaxis during periods of neutropenia should be considered, using a fluoroquinolone, ^[22] a second-generation azole antifungal, ^[23] and an antiherpetic agent ^[24]

Transfusion support

• RBC transfusions (leuko-reduced) for patients who have symptomatic anemia
• Platelet transfusions for thrombocytopenia-related bleeding
• Irradiated packed RBCs are suggested for transplant candidates

Management of transfusion iron overload

• For patients who survive long enough to receive over 20-30 U of packed RBCs, transfusion iron overload is probable

• End-organ iron deposition may cause cardiac, hepatic, or endocrine dysfunction

• Iron-chelating agents (deferoxamine, deferasirox) are available, but they have not been shown to decrease complications in MDS patients in prospective randomized trials. For this reason, many experts limit the use of these agents to patients likely to survive several years with transfusion dependence (eg, R-IPSS very-low-risk and low-risk patients).

• Each iron-chelating agent has its own drawbacks: Deferoxamine requires inconvenient subcutaneous infusions and is associated with infusion-site reactions and cataracts; deferasirox is an oral agent but it is costly, requires monitoring of vision and kidney and liver function, and is contraindicated in severe thrombocytopenia.