Approach

Treatment for MDS is guided by risk assessment, disease type/characteristics (e.g., cytogenetic abnormalities, ring sideroblasts), symptoms/severity of cytopenias, and erythropoietin levels (in patients with anemia).[12][15]​​​ Other important treatment considerations include patient age, performance status, comorbidities, and patient preference/goals.

Risk assessment informs treatment. The revised International Prognostic Scoring System (IPSS-R) is used to determine whether patients have lower-risk disease or higher-risk disease. See Criteria.

All patients should be encouraged to enroll in a clinical trial (if available and eligible), particularly those with higher-risk disease and those unresponsive to treatment.[12][15]​​

Supportive care

Supportive care is central to management of MDS. All symptomatic patients (lower- or higher-risk) should receive supportive care as appropriate, which includes: red blood cell (RBC) transfusions with iron chelation support (for anemia); platelet transfusions (for thrombocytopenia and bleeding); and anti-infective therapy (e.g., antibiotics).[12][15]

Transfusions

RBC transfusion (with iron chelation therapy support if needed) is recommended for symptomatic anemia.[15] Patients should be transfused with the minimum number of units necessary to relieve symptoms of anemia or to return the patient to a safe hemoglobin level.

RBC transfusions are usually warranted if hemoglobin falls below 7 g/dL or 8 g/dL.[12][70]​ However, RBC transfusions should be individualized because symptomatic anemia may occur at higher hemoglobin levels.

Platelet transfusions are recommended for thrombocytopenic bleeding.[15] Platelet transfusions should not be used routinely in patients with thrombocytopenia in the absence of bleeding unless platelet count is <10,000/microliter.[15] Avoiding unnecessary platelet transfusions can improve quality of life and may reduce the risk of repeated suboptimal response to transfusion (platelet refractoriness).

All transfused blood products should be irradiated before use in patients who are potential candidates for allogeneic stem cell transplantation (SCT).[15]

Anti-infective therapy

​Antibiotics are recommended for bacterial infections and prophylaxis may be considered when starting patients on therapy; consult local guidance.[15]

Patients who have undergone allogeneic SCT should receive antibiotic prophylaxis alongside post-transplant immunosuppressive regimens used to manage graft-versus-host diseasse.[15]

Allogeneic stem cell transplantation (SCT)

Allogeneic SCT is the only potentially curative therapy for MDS.[71]

​Allogeneic SCT is recommended for patients with high-risk disease, if eligible.[15] It may be considered for select patients with lower-risk disease (e.g., intermediate risk according to IPSS-R with severe cytopenias; see Criteria).

Patients should be assessed for suitability for allogeneic SCT and referred for transplant evaluation as early as possible following diagnosis.[12][15][71]​ Many patients are unsuitable for allogeneic SCT because of advanced age, lack of a compatible donor (although becoming less common with use of haploidentical transplant), poor performance status, or comorbidities.

A matched sibling donor, unrelated donor, haploidentical donor, or cord blood donor can be used for allogeneic SCT.[71]​ Standard or reduced-intensity conditioning regimens may be considered.[71]

Lower-risk disease: asymptomatic

Lower-risk disease (e.g., very-low, low, or intermediate risk according to IPSS-R) is associated with a relatively low risk of progression to acute myeloid leukemia (AML) or death.

Treatment for lower-risk disease is focused on improving quality of life by reducing symptoms, reducing transfusion need, and preventing complications associated with cytopenias.

Patients with lower-risk disease who are asymptomatic can be monitored without treatment until symptoms, complications of cytopenias, or disease progression occur, or are likely to occur.[16]

Lower-risk disease: symptomatic anemia

For treatment of symptomatic anemia in lower-risk patients, the National Comprehensive Cancer Network (NCCN) recommends stratifying patients based on erythropoietin levels and the following disease type/characteristics:[15]

  • MDS-5q, i.e., MDS with del(5q), with or without one other cytogenetic abnormality except those involving chromosome 7

  • MDS-SF3B1, i.e., MDS with no del(5q), with or without other cytogenetic abnormalities, with ring sideroblasts ≥15% (or ≥5% with an SF3B1 mutation)

  • MDS with no del(5q), with or without other cytogenetic abnormalities, with ring sideroblasts <15% (or <5% with an SF3B1 mutation). See Classification.

MDS-5q with erythropoietin levels ≤500 IU/L

  • Lenalidomide (preferred) or an erythropoiesis-stimulating agent (ESA; e.g., epoetin alfa, darbepoetin alfa) is recommended for initial treatment of symptomatic anemia in lower-risk patients with MDS-5q and erythropoietin levels ≤500 IU/L.[15] Patients who fail to respond (i.e., no improvement in hemoglobin or no reduction in RBC transfusion requirement) to an ESA prescribed first-line can be considered for lenalidomide therapy, if absolute neutrophil count is >500/microliter and platelet count is >50,000/microliter.[15]

  • If there is no response to initial treatment with lenalidomide or an ESA, a clinical trial or treatment with a hypomethylating agent (azacitidine [preferred]; decitabine; or decitabine/cedazuridine) is recommended.[15]

  • If there is no response to (or there is intolerance of) treatment with hypomethylating agents, patients can be treated with ivosidenib if they have IDH1 mutations, or considered for a clinical trial or allogeneic SCT if they do not have IDH1 mutations.[15]

MDS-5q with erythropoietin levels >500 IU/L

  • Lenalidomide is recommended for initial treatment of symptomatic anemia in lower-risk patients with MDS-5q and erythropoietin levels >500 IU/L.[15] Patients with erythropoietin levels >500 IU/L are unlikely to benefit from treatment with ESAs.[72]

  • If there is no response to initial treatment, a clinical trial or treatment with a hypomethylating agent is recommended.[15]

  • If there is no response to (or there is intolerance of) treatment with hypomethylating agents, these patients can be treated with ivosidenib if they have IDH1 mutations, or considered for a clinical trial or allogeneic SCT if they do not have IDH1 mutations.[15]

MDS-SF3B1 with erythropoietin levels ≤500 IU/L

  • Luspatercept is recommended for initial treatment of symptomatic anemia in lower-risk patients with MDS-SF3B1 and erythropoietin levels ≤500 IU/L.[15][73]

  • If there is no response to initial treatment, imetelstat or an ESA is recommended.[15] Granulocyte colony-stimulating factor (G-CSF; e.g., filgrastim) may be combined with an ESA to treat anemia. Evidence suggests that G-CSF may improve the erythroid response rate of ESAs.[74]​ A validated decision model has been developed for predicting erythroid responses to ESAs plus G-CSF based on erythropoietin level and number of previous RBC transfusions.[75]

  • If there is no response to treatment with imetelstat or ESAs (with or without G-CSF), patients can be considered for a clinical trial (if available and eligible) or treatment with a hypomethylating agent.[15]

  • Patients who do not respond to (or are intolerant of) treatment with hypomethylating agents can be treated with ivosidenib if they have IDH1 mutations, or considered for a clinical trial or allogeneic SCT if they do not have IDH1 mutations.[15] Patients who do not respond to ivosidenib can be considered for a clinical trial or allogeneic SCT.[15]

MDS-SF3B1 with erythropoietin levels >500 IU/L

  • Luspatercept or imetelstat is recommended for initial treatment of symptomatic anemia in lower-risk patients with MDS-SF3B1 and erythropoietin levels >500 IU/L.[15][73]

  • Lenalidomide can be considered if there is no response to initial treatment with luspatercept or imetelstat.[15]

  • If there is no response to treatment with lenalidomide, patients should be considered for a clinical trial or treatment with a hypomethylating agent.[15]

  • Patients who do not respond to (or are intolerant of) treatment with hypomethylating agents can be treated with ivosidenib if they have IDH1 mutations, or considered for a clinical trial or allogeneic SCT if they do not have IDH1 mutations.[15] Patients who do not respond to ivosidenib can be considered for a clinical trial or allogeneic SCT.[15]

MDS with no del(5q) with ring sideroblasts <15% with erythropoietin levels ≤500 IU/L

  • An ESA alone or luspatercept is recommended for initial treatment of symptomatic anemia in lower-risk patients with no del(5q) and ring sideroblasts <15% (or <5% with an SF3B1 mutation) and erythropoietin levels ≤500 IU/L.[15][76]​ Patients who fail to respond (i.e., no improvement in hemoglobin or no reduction in RBC transfusion requirement) to an ESA prescribed first-line can be considered for luspatercept therapy.[15]

  • G-CSF or lenalidomide may be combined with an ESA if there is no response to initial treatment with an ESA alone or luspatercept.[15][74][75]​ Imetelstat or lenalidomide alone can also be considered if there is no response to initial treatment in these patients.

  • Patients who do not respond to treatment with an ESA (with or without G-CSF or lenalidomide) or imetelstat can be considered for a clinical trial or treatment with a hypomethylating agent.[15]

  • If there is no response to (or there is intolerance of) treatment with hypomethylating agents, patients can be treated with ivosidenib if they have IDH1 mutations, or considered for a clinical trial or allogeneic SCT if they do not have IDH1 mutations.[15] Patients who do not respond to ivosidenib can be considered for a clinical trial or allogeneic SCT.[15]

MDS with no del(5q) with ring sideroblasts <15% with erythropoietin levels >500 IU/L

  • Patients with MDS who have no del(5q) and ring sideroblasts <15% (or <5% with an SF3B1 mutation) and erythropoietin levels >500 IU/L should be evaluated for suitability for immunosuppressive therapy (IST). Patients who are likely to respond to IST (e.g., those with hypocellular bone marrow) can be treated with IST comprising antithymocyte globulin (ATG) with or without cyclosporine.[15][77]​ Eltrombopag may be combined with IST. A corticosteroid should be given alongside ATG to prevent serum sickness.

  • IST may be effective in patients ages ≤60 years with ≤5% marrow blasts, or in those who have the following features: HLA-DR15 positivity; paroxysmal nocturnal hemoglobinuria (PNH) clone; or STAT-3 mutant T-cell clone. However, the evidence is mixed.[77][78][79][80][81]​​​

  • Patients who are unlikely to respond to IST, or who are unresponsive to initial treatment with IST, can be considered for a clinical trial, or treatment with a hypomethylating agent or imetelstat.[15][77] Lenalidomide may also be considered if absolute neutrophil count is >500/microliter and platelet count is >50,000/microliter.[15]

  • If there is no response to (or there is intolerance of) treatment with hypomethylating agents, imetelstat, or lenalidomide, patients can be treated with ivosidenib if they have IDH1 mutations, or considered for a clinical trial or allogeneic SCT if they do not have IDH1 mutations.[15]

Lower-risk disease: clinically relevant thrombocytopenia or neutropenia (without symptomatic anemia)

A clinical trial or a hypomethylating agent is recommended for initial treatment of patients with lower-risk disease who have clinically relevant thrombocytopenia or neutropenia (without symptomatic anemia).[15]

Patients likely to respond to IST (e.g., those with hypocellular bone marrow) can be considered for initial treatment with ATG plus cyclosporine (with or without eltrombopag).[15][77] Eltrombopag alone can be considered for treatment of severe or life-threatening thrombocytopenia in lower-risk patients.[15]

A hypomethylating agent (if not previously used) or ivosidenib (if patients have IDH1 mutations) can be considered if there is disease progression or no response to initial treatment of clinically relevant thrombocytopenia or neutropenia in lower-risk patients.[15] Romiplostim can be considered for treatment of severe or refractory thrombocytopenia.[15][82]​​ Patients who do not have IDH1 mutations should be considered for a clinical trial or allogeneic SCT.[15]

Higher-risk disease

Patients with higher-risk disease (e.g., intermediate, high, or very high risk according to IPSS-R) have a poor prognosis (relatively increased risk of progression to AML or death).[12][15]

Treatment for higher-risk disease is focused on delaying progression and prolonging survival, reducing symptoms and complications, and improving quality of life.

Higher-risk patients should be promptly referred for allogeneic SCT evaluation.[12][83][84]​ Patients should be encouraged to enroll in a clinical trial (if available and eligible), especially if they have poor prognostic markers (e.g., TP53 mutations).

Higher-risk disease: transplant candidate

Higher-risk patients may undergo immediate allogeneic SCT if suitable (e.g., based on age, performance status, comorbidities, patient preference, and donor availability).[12][15]

Pre-transplant cytoreduction (debulking) using chemotherapy or hypomethylating agents is recommended to reduce marrow blasts to <5% in patients with high tumor burden.[12][15][54]

Ivosidenib can be used for cytoreduction if there is no response to chemotherapy or hypomethylating agents, and the patient has IDH1​ mutations.[15] Cytoreduction may reduce the risk of post-transplant relapse. However, this has not yet been confirmed by prospective clinical trials.

Higher-risk disease: nontransplant candidate

Higher-risk patients who are unsuitable for allogeneic SCT can be considered for a clinical trial or initial treatment with a hypomethylating agent.[12][15][85]​ Azacitidine improves overall survival in higher-risk patients compared with supportive care and chemotherapy.[86]​ A survival benefit with decitabine has not been shown in phase 3 trials, but a US-based registry study suggested similar survival to azacitidine.[87]

Oral decitabine/cedazuridine may be used instead of intravenous decitabine based on patient preference and convenience. In patients with higher-risk disease, treatment with a hypomethylating agent should continue until the patient stops responding or treatment becomes intolerable.

Patients who do not respond to initial treatment with a hypomethylating agent can be treated with ivosidenib if they have IDH1​ mutations, or considered for a clinical trial if they do not have IDH1​ mutations.[15]

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