NCCN Continuing Education
Target Audience: This journal article is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-25-010-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until March 10, 2026. PAs should only claim credit commensurate with the extent of their participation.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/Mar2025; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.
Release date: March 10, 2025; Expiration date: March 10, 2026
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN Guidelines for Myelodysplastic Syndromes
• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Myelodysplastic Syndromes
Disclosure of Relevant Financial Relationships
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
Emily Kovach, Guidelines Layout Specialist, NCCN
Jamie Nguyen, PharmD, Associate Scientist/Medical Writer, NCCN
Cindy Hochstetler, PhD, Oncology Scientist/Senior Medical Writer, NCCN
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
Peter L. Greenberg, MD, Panel Chair, has disclosed receiving a consulting fee from Hemavant.
To view disclosures of external relationships for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca, Coherus BioSciences, Geron, Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC, Novartis, SpringWorks Therapeutics, Inc., and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Rigel Pharmaceuticals, Inc.
Overview
Myelodysplastic syndromes (MDS) represent myeloid clonal hemopathies with a relatively heterogeneous spectrum of presentation. Diagnosis and disease stratification are based on multiple factors, including clinical data, peripheral blood and bone marrow morphology, fluorescence in situ hybridization, cytogenetics, flow cytometry, and next-generation sequencing myeloid mutation panels. The major clinical morbidities associated with these disorders are cytopenia-associated complications and the potential for MDS to evolve into acute myeloid leukemia (AML). In addition, chronic transfusions, treatment toxicity, and, in some cases, secondary phenomena such as systemic inflammatory conditions can increase the complexity of care for patients with MDS.1 The incidence of MDS in the general population is approximately 4.5 per 100,000 people per year.2 It is rare among children/adolescents and young adults. Individuals aged <40 years account for 1.6% of MDS cases, with an incidence of 0.1 per 100,000 people per year. In contrast, the incidence increases to 26.9 per 100,000 among individuals aged 70 and 79 years, and further increases to 55.4 per 100,000 in individuals aged ≥80 years.2 The management of MDS is complicated by the generally advanced age of the patients (median age, 77 years),3 the presence of nonhematologic comorbidities commonly seen in this cohort, and the relative inability of older patients to tolerate certain intensive forms of therapy. In addition, when the illness progresses into AML, these patients experience lower response rates to standard therapy than those with de novo AML.4
Drugs approved by the FDA for treating specific patients with MDS include lenalidomide for patients with del(5q) cytogenetic abnormalities; azacitidine (AzaC), decitabine, or the oral combination of decitabine and cedazuridine for treating higher-risk MDS or MDS that is nonresponsive; deferasirox and deferoxamine for iron chelation in the treatment of iron overload; luspatercept-aamt for treating MDS with ring sideroblasts (RS) in patients with no response to prior erythropoiesis-stimulating agent (ESA) treatment or for treating lower-risk MDS; imetelstat for treating lower-risk MDS in patients with no response or loss of response to ESAs or those who are ineligible for ESAs; and ivosidenib for patients with relapsed or refractory mutant IDH1 (mIDH1) MDS.
Management of Lower-Risk MDS
Treatment of Clinically Significant Cytopenias
For patients without symptomatic anemia who have clinically relevant thrombocytopenia or neutropenia, recommended treatment options include a clinical trial, AzaC, decitabine, oral decitabine and cedazuridine, or immunosuppressive therapy (IST), with or without eltrombopag (useful in certain circumstances) for select patients. IST is recommended for patients generally aged ≤60 years and with ≤5% marrow blasts, or those with hypocellular marrows, PNH clone positivity, or STAT-3 mutant cytotoxic T-cell clones. IST includes equine antithymocyte globulin (ATG), with or without cyclosporin A. Additionally, for severe thrombocytopenia, eltrombopag alone could be considered. Some studies have shown clinical benefit with low doses of AzaC or decitabine.5 If there is disease progression, no response following initial treatment, or relapse, the NCCN panel recommends reevaluation with bone marrow and/or molecular testing. Additionally, hypomethylating agents (HMAs) should be considered if not previously used. Following a panel vote, ivosidenib or olutasidenib were added as category 2B treatment options for mIDH1 MDS (see Figure 1). Eltrombopag or romiplostim can be considered for patients with severe or refractory thrombocytopenia.6–8 Subsequent treatment options include ivosidenib or olutasidenib (category 2B) for mIDH1 MDS if an IDH1 inhibitor was not previously used. In the absence of mIDH1, a clinical trial as well as consideration of allogeneic HCT in select patients with lower-risk MDS (International Prognostic Scoring System [IPSS] intermediate-1 [int-1], IPSS-R intermediate, and WHO-Based Prognostic Scoring System [WPSS] intermediate) with severe cytopenias are recommended.
MDS-4. NCCN Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2025.0013
Treatment of Symptomatic Anemia
For patients with del(5q) chromosomal abnormalities alone or with one other cytogenetic abnormality, except those involving chromosome 7, and symptomatic anemia, lenalidomide is a category 1 preferred option if the serum erythropoietin (sEPO) level is >500 mU/mL. If sEPO is ≤500 mU/mL, lenalidomide is a preferred regimen and epoetin alfa and darbepoetin alfa are other recommended regimens. An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MDS. If there is no response to lenalidomide or ESAs, or in cases of relapse (recurrence of symptomatic anemia or transfusion requirements), patients should follow treatment options (with the exception of imetelstat) for patients without the del(5q) abnormality, with RS <15% (or RS <5% with an SF3B1 mutation) and sEPO levels >500 mU/mL. Reevaluation with bone marrow and/or molecular testing is generally recommended in cases of no response, intolerance, or relapse.
In 2024, the panel voted on the preference stratification for multiple newly added regimens and previously unstratified existing ones incorporating the results into the updated guidelines (see Figures 2–4). During the 2024 annual NCCN Guidelines update meeting for MDS, the panel also considered including olutasidenib, an IDH1 inhibitor, as a treatment option. The panel acknowledged that olutasidenib is FDA-approved only for relapsed/refractory AML and noted that available data for MDS primarily involve patients with higher-risk disease. Ultimately, they voted to add olutasidenib as an alternative to ivosidenib in multiple settings, as described in these NCCN Guidelines Insights (see Figures 1–4).
MDS-5. NCCN Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2025.0013
MDS-6. NCCN Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2025.0013
MDS-7. NCCN Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2025.0013
The panel evaluated and discussed the data for imetelstat. In the phase III IMerge study, patients with IPSS low or [int-1] risk MDS with disease that relapsed or was refractory to ESAs, or who were ineligible for ESAs (ie, sEPO level >500 mU/mL) were randomized 2:1 to receive imetelstat or placebo.9 A higher percentage of patients treated with imetelstat achieved the primary endpoint of red blood cell transfusion independence (RBC-TI) for ≥8 weeks (40% vs 15% with placebo; P=.0008) and the secondary endpoint of RBC-TI for ≥24 weeks (28% vs 3% with placebo; P=.0001). Among those who achieved the primary endpoint, the median RBC-TI duration was 51.6 weeks with imetelstat and 13.3 weeks with placebo. Hematologic improvement-erythroid was observed in 64% of patients in the imetelstat arm (vs 52% in the placebo arm) when assessed by the IWG 2006 response criteria. Hematologic improvement-erythroid was 42% in the imetelstat arm and 13% in the placebo arm when assessed by the IWG 2018 response criteria. The results of a subgroup analysis showed that among patients with sEPO >500 mU/mL, 26.9% (vs 9.1% for placebo; P=.107) and 15.4% (vs 0.0% for placebo; P=.050) achieved TI with imetelstat at 8 and 24 weeks, respectively. Ninety-one percent of patients treated with imetelstat experienced grade 3–4 treatment-emergent adverse events (TEAEs), compared with 47% of patients receiving placebo, with neutropenia (68% vs 3% in the placebo arm) and thrombocytopenia (62% vs 8% in the placebo arm) reported as the most frequent events. The panel voted to add imetelstat as a treatment option in multiple settings, as described in this article (see Figures 2 and 3). The panel also added a footnote for imetelstat, noting that the initial dosing is 7.1 mg/kg administered intravenously monthly, with potential dose decrements since frequent transient thrombocytopenia and neutropenia may occur. Starting platelet and neutrophil levels should be ≥75,000 and ≥1,500, respectively. Following the FDA approval of imetelstat, an interim version of the guidelines that included recommendations for imetelstat was published.
During the annual meeting, the panel debated whether ESAs should be recommended as a first-line treatment option for patients with lower-risk MDS without del(5q), with or without other cytogenetic abnormalities, and with RS ≥15% (or RS ≥5% with an SF3B1 mutation). The panel discussed the data from the COMMANDS trial at length and noted that there was limited benefit to luspatercept compared with ESAs in patients with RS-negative disease (27% of the patients).10,11 Panel members also noted that patients with transfusion-independent MDS may have disease that responds to ESAs if sEPO levels are low.12 As such, the panel added a footnote to consider epoetin alfa or darbepoetin alfa if sEPO ≤200 mU/mL (see Figure 5). The category of preference for luspatercept-aamt was revised from other recommended to preferred for patients with symptomatic anemia without del(5q), with or without other cytogenetic abnormalities, and with RS <15% (or RS <5% with an SF3B1 mutation) and sEPO ≤500 mU/mL. The phase III randomized COMMANDS trial evaluated the use of luspatercept in patients without del(5q) and with IPSS-R very-low risk, low-risk, or intermediate-risk MDS (73% of whom had RS); no prior ESA treatment; sEPO <500 mU/mL; and RBC transfusion requirements.10 Data from the primary analysis revealed that 60% of patients receiving luspatercept achieved the primary endpoint of RBC transfusion independence for ≥12 weeks, with a concurrent mean hemoglobin increase of ≥1.5 g/dL, compared with 35% of patients receiving epoetin alfa (P<.0001). In patients with RS-positive disease, response rates for the primary endpoint were 65% with luspatercept versus 29% with epoetin alfa, but in those with RS-negative disease, response rates were similar: 47% with luspatercept versus 50% for epoetin alfa. However, of note, the mean duration of response in these patients was 126.6 weeks with luspatercept and 89.7 weeks with epoetin alfa. In a subgroup analysis, in patients with sEPO ≤200 mU/mL, the response rate for the primary endpoint was 66% in the luspatercept arm versus 41% in the epoetin arm. Overall, the most common grade 3–4 TEAEs in the luspatercept arm included hypertension and anemia (10% each). For epoetin alfa, anemia and pneumonia (8% each) were the most common grade 3–4 TEAEs.
MDS-6A. NCCN Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2025.0013
Patients without the del(5q) abnormality, alone or with other cytogenetic abnormalities and with symptomatic anemia, are categorized based on RS percentage and sEPO levels. In patients without del(5q), with or without other cytogenetic abnormalities, with RS ≥15%, or with RS ≥5% with an SF3B1 mutation, luspatercept-aamt (category 1; preferred) and imetelstat (if sEPO >500 mU/mL [ineligible for ESAs]; other recommended) are first-line options (see Figure 2). Epoetin alfa and darbepoetin alfa may be considered if sEPO ≤200 mU/mL. If there is no response by 3 to 6 months of treatment with luspatercept-aamt or relapse, and the sEPO level is ≤500 mU/mL, imetelstat (category 1; preferred), as well as epoetin alfa with or without granulocyte colony-stimulating factor (G-CSF) (other recommended), or darbepoetin alfa with or without G-CSF (other recommended), are recommended options. If there is no response after 3 to 6 months of treatment with luspatercept-aamt or relapse occurs, and the sEPO level is >500 mU/mL, or if there is no response to first-line treatment with imetelstat or relapse occurs, imetelstat (if not previously used) and luspatercept-aamt (if not previously used) (category 1) are preferred treatment options. Consideration of lenalidomide use is another recommended option. Based on data from the MEDALIST trial, luspatercept-aamt, if not previously used, was added as a category 1 recommendation (see Figure 2).13 If there is no response after 6 to 8 weeks of treatment with ESAs (with or without G-CSF) or after 3 to 6 months of treatment with imetelstat, luspatercept-aamt, or lenalidomide, or if relapse occurs, enrollment in a clinical trial or treatment with one of the following is recommended: AzaC (preferred), ivosidenib if mIDH1 (other recommended), olutasidenib if mIDH1 (category 2B; other recommended), decitabine (other recommended), imetelstat if not previously used (other recommended), oral decitabine and cedazuridine (other recommended), consideration of lenalidomide (useful in certain circumstances), or ATG with cyclosporin A with or without eltrombopag (ATG may be omitted when clinically indicated). If there is no response to ATG with cyclosporin A with or without eltrombopag within 3 to 6 months or intolerance or relapse, patients should follow the treatment pathway for serum EPO >500 mU/mL (poor probability to respond to IST). If there is no response within 6 cycles of AzaC, or 4 cycles of decitabine or oral decitabine and cedazuridine, no response to imetelstat or lenalidomide, or if intolerance or relapse occurs following treatment with these regimens, ivosidenib or olutasidenib (category 2B) are recommended for mIDH1 MDS if an IDH1 inhibitor was not previously used. A clinical trial or consideration of hematopoietic cell transplant (HCT) is recommended for select patients without mIDH1.
Epoetin alfa, darbepoetin alfa, and luspatercept-aamt are preferred options for patients without del(5q), with or without other cytogenetic abnormalities, with RS <15% (or RS <5% with an SF3B1 mutation), and with sEPO ≤500 mU/mL (see Figure 3). Patients with normal cytogenetics, RS <15%, and sEPO levels of ≤500 mU/mL may respond to epoetin alfa if relatively high doses are administered.14–16 Iron repletion needs to be verified before instituting epoetin alfa or darbepoetin alfa therapy. If no response occurs after 6 to 8 weeks with ESAs alone (despite adequate iron stores) or after 3 to 6 months with luspatercept-aamt, or if relapse occurs, treatment with imetelstat (category 1; preferred), luspatercept-aamt if not previously used (preferred), epoetin alfa with or without G-CSF or lenalidomide (other recommended), or darbepoetin alfa with or without G-CSF or lenalidomide (other recommended) are recommended. If no response occurs following subsequent treatment with ESAs, with or without lenalidomide or G-CSF, within 6 to 8 weeks of treatment, or following subsequent treatment with imetelstat or luspatercept-aamt within 3 to 6 months of treatment, or if relapse occurs, treatment should be discontinued. Patients should follow treatment options for those without the del(5q) abnormality, with sEPO >500 mU/mL, and with poor probability to respond to IST. Imetelstat (if not previously used) (category 1; preferred), ivosidenib if mIDH1 (useful in certain circumstances), and olutasidenib (if mIDH1) (category 2B; useful in certain circumstances) are also options.
Patients with symptomatic anemia, without del(5q), with or without other cytogenetic abnormalities, with RS <15% (or RS <5% with an SF3B1 mutation), and with sEPO levels >500 mU/mL should be evaluated to determine whether they would be good candidates for IST (generally aged ≤60 years and with ≤5% marrow blasts, or with hypocellular marrows, PNH clone positivity, or STAT3-mutant cytotoxic T-cell clones) (see Figure 3). For patients with disease that has a good probability to respond to IST, treatment with ATG plus cyclosporin A, with or without eltrombopag, is recommended. ATG may be omitted when clinically indicated. If there is no response within 3 to 6 months or if intolerance or relapse occurs, or if the patients have disease that has a poor probability to respond to IST, enrollment in a clinical trial or treatment with AzaC (preferred), decitabine (other recommended), imetelstat if not previously used (other recommended), oral decitabine and cedazuridine (other recommended), or consideration of lenalidomide (useful in certain circumstances), is recommended. Oral decitabine and cedazuridine could be a substitution for intravenous decitabine in patients with IPSS int-1 and above.17 If there is no response within 6 cycles of AzaC or 4 cycles of decitabine or oral decitabine and cedazuridine or no response to imetelstat or lenalidomide, or intolerance or relapse occurs, ivosidenib or olutasidenib (category 2B) is recommended for mIDH1 MDS if an IDH1 inhibitor was not previously used. A clinical trial or consideration of HCT for select patients is recommended for patients without mIDH1.
Management of Higher-Risk MDS
Hypomethylating agent (HMA) therapy is the standard of care for patients with higher-risk MDS (ie, those in Revised IPSS [IPSS-R] intermediate-, high-, or very-high-risk categories), preferably as a bridge to HCT in eligible patients. Because overexpression of the B-cell lymphoma 2 (BCL-2) protein has been linked to disease progression in MDS, studies are ongoing to investigate the efficacy and safety of venetoclax, a BCL-2 inhibitor, in patients with higher-risk MDS, either as first-line treatment or for those with disease that is refractory or resistant to HMAs.18,19 Abstract data from a phase Ib study investigating the combination of venetoclax and AzaC for 14 days in a 28-day cycle in up-front higher-risk MDS resulted in an overall response rate (ORR) of 29.9%, a median overall survival (OS) of 26 months, and a median complete remission duration of 16.6 months; 39.3% of patients subsequently underwent transplantation.18 The most frequent grade ≥3 TEAEs were neutropenia (48.6%), thrombocytopenia (43.0%), febrile neutropenia (42.1%), and anemia (34.6%). Phase I results from a study investigating the combination of venetoclax with AzaC in patients with high-risk MDS or chronic myelomonocytic leukemia revealed ORRs of 82% in the HMA-naïve cohort and 100% in patients with relapsed/refractory disease following HMA treatment.20 Neutropenia (39%), thrombocytopenia (39%), lung infection (30%), and febrile neutropenia (17%) were the most frequent grade 3–4 TEAEs. In another study, treatment with venetoclax in combination with AzaC in patients with relapsed/refractory MDS resulted in a modified ORR of 39% and a median OS of 12.6 months.21 Febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%) were the most frequent grade ≥3 hematologic adverse events. Although panel members acknowledged that the combination of venetoclax with HMA is not yet FDA-approved for MDS, given that many MDS experts use the regimen off-label and based on encouraging available data, the panel recommended adding HMAs in combination with venetoclax as a treatment option for both transplant and nontransplant candidates with higher-risk MDS (see Figure 4). Given the nuances of when the drug would be recommended, the panel added a cautionary footnote stating that the addition of venetoclax is based on patient status and tolerance, considering the drug’s associated neutropenias and thrombocytopenias (see Figure 6). Some emerging data have shown efficacy of novel agents, including venetoclax in combination with HMA with or without ivosidenib to target mIDH1 in patients with myeloid malignancies, including higher-risk MDS.18,22 When used as cytoreduction for MDS in combination with an HMA, venetoclax has been effectively given for 14 days in monthly courses.18 Repeating bone marrow evaluation after 1 to 2 cycles is important to clarify the recovery of hematopoiesis and potential requirement for further therapy.
MDS-7A. NCCN Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2025.0013
Several new treatment regimens were added, as described in this article (see Figure 4). Mutations in IDH1 or IDH2 genes occur in approximately 4% to 12% of patients with MDS.23–25 Substudy data from a phase I trial investigating the safety and efficacy of ivosidenib in 18 evaluable patients with relapsed or refractory MDS with mIDH demonstrated an ORR of 83.3% and an approximate median OS of 36 months.26 Additionally, 71.4% and 75.0% of patients with RBC transfusion dependence and platelet transfusion dependence, respectively, achieved transfusion independence. Grade ≥3 TEAEs were fatigue and hyponatremia (5.3% each). Emerging data have also shown the utility of olutasidenib for treatment patients with IDH1 mutations. In one study of patients with intermediate-, high-, or very-high-risk MDS, 33% treated with olutasidenib monotherapy and 69% treated with combination olutasidenib and AzaC achieved an overall response.27 Cytopenias were the most commonly reported grade 3–4 TEAEs. Although not studied in MDS, the combination of ivosidenib and AzaC has shown clinical benefit in patients with newly diagnosed mIDH1 AML who were ineligible for intensive induction chemotherapy.28 In a phase III trial, treatment with ivosidenib plus AzaC resulted in improved event-free survival (hazard ratio [HR], 0.33; P=.002) and median OS (24.0 vs 7.9 months; HR, 0.44; P=.001) compared with treatment with placebo plus AzaC. Other ongoing clinical trials are investigating the efficacy of targeted IDH1/2 inhibitors in patients with MDS (ClinicalTrials.gov identifiers: NCT03503409, NCT03471260, and NCT03744390).22,29,30
Allogeneic HCT (allo-HCT) is recommended for eligible patients with higher-risk MDS (see Figure 4). Treatment with AzaC plus ivosidenib (if mIDH1) (category 2B) or plus olutasidenib (if mIDH1) (category 2B) or enrollment in a clinical trial prior to allogeneic HCT; treatment with HMAs (AzaC, decitabine, or oral decitabine and cedazuridine) with or without venetoclax; and high-intensity chemotherapy are also options. Oral decitabine and cedazuridine could be a substitution for intravenous decitabine in patients with IPSS int-1 and above.17 The addition of venetoclax is based on patient status and tolerance. Single-agent ivosidenib, single-agent olutasidenib (category 2B), or AzaC in combination with olutasidenib (category 2B) followed by allo-HCT may be considered for mIDH1 MDS if there is no response following treatment with HMAs with or without venetoclax or high-intensity chemotherapy. Allo-HCT is recommended if there is no response to HMAs with or without venetoclax or high-intensity chemotherapy and in the absence of mIDH1 or following a response, although most centers require evidence of response to HMAs if blast counts are >10% prior to proceeding to allo-HCT. However, at some centers, failure to achieve <5% blasts with cytoreduction should not preclude patients from proceeding to transplant, as these patients appeared to derive survival benefit from transplant.31,32 The panel recommends reevaluation with bone marrow and/or molecular testing following relapse after allo-HCT or if there is no response. In patients with disease relapse after a prolonged remission following the first transplant or with no response, a second transplant or donor lymphocyte infusion immuno-based therapy may be considered. Enrollment in a clinical trial or treatment with HMAs (AzaC, decitabine, or oral decitabine and cedazuridine) are also options. If there is no response to treatment or the disease relapses, enrollment in a clinical trial or supportive care is recommended.
For patients with higher-risk MDS who are not candidates for intensive therapy or allogeneic HCT, the use of AzaC (category 1) with or without venetoclax, decitabine with or without venetoclax, oral decitabine and cedazuridine with or without venetoclax, ivosidenib (category 2B) with or without AzaC (if mIDH1) (category 2B), or olutasidenib with AzaC (if mIDH1) (category 2B) are recommended. AzaC with or without venetoclax is a preferred regimen, whereas the others are listed as other recommended regimens. Enrollment in a clinical trial is also an option for these patients. The addition of venetoclax is based on patient status and tolerance. If there is no response or intolerance or relapse occurs, reevaluation with bone marrow and/or molecular testing is recommended. Ivosidenib or olutasidenib (category 2B), if an IDH1 inhibitor was not previously used, is recommended for mIDH1 MDS if there is no response within 6 cycles of AzaC or 4 cycles of decitabine or oral decitabine and cedazuridine, or if intolerance or relapse occurs. Enrollment in a clinical trial is recommended if there is no response or relapse following treatment with ivosidenib or olutasidenib within 3 to 6 months or for those without mIDH1.
Conclusions
The NCCN Guidelines for MDS are based on extensive evaluation of the reviewed risk-based data and outline current approaches for the comprehensive care of MDS. The treatment landscape for MDS has evolved in recent years, with several new therapeutic agents receiving FDA approval. However, because a substantial proportion of subsets of patients with MDS either lack or lose effective treatment options for managing their cytopenias or for altering the natural history of the disease, clinical trials with these and other novel therapeutic agents are critical for disease management. Additionally, supportive care measures, including relevant transfusions, antibiotics, psychosocial support, and quality-of-life considerations, should be offered to these patients. The panel will continue to evaluate emerging data to help inform management recommendations for the NCCN Guidelines.
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