How should marrow suppression secondary to myelodysplastic syndrome be managed in an older adult with pancytopenia?

Management of Marrow Suppression Secondary to MDS

The management of marrow suppression in MDS depends critically on risk stratification using IPSS-R, with lower-risk patients receiving supportive care and targeted therapies for cytopenias (erythropoiesis-stimulating agents for anemia, lenalidomide for del(5q)), while higher-risk patients require hypomethylating agents (azacitidine or decitabine) as first-line therapy, with allogeneic stem cell transplantation being the only potentially curative option for eligible patients. 1, 2, 3

Initial Risk Stratification

• Calculate the IPSS-R score immediately using three key parameters: bone marrow blast percentage, number and severity of cytopenias, and cytogenetic abnormalities—this score determines the entire treatment algorithm. 1, 2, 3

• Patients are classified as lower-risk (very low, low, intermediate) or higher-risk (intermediate, high, very high) based on IPSS-R, which fundamentally dictates treatment goals and approach. 1, 4

• Consider molecular mutations (particularly TP53, ASXL1, RUNX1, SF3B1) for additional prognostic refinement, as these can modify risk assessment and influence treatment decisions. 1, 3, 5

Management of Lower-Risk MDS

Treatment Goals and Approach

• The primary goal in lower-risk MDS is to reduce transfusion dependency, improve cytopenias, and enhance quality of life—not necessarily to prolong survival, as approximately half of elderly patients die of causes unrelated to MDS. 1, 2

Anemia Management (Most Common Cytopenia)

• First-line therapy for anemia without del(5q): Erythropoiesis-stimulating agents (ESAs) such as recombinant erythropoietin (30,000-80,000 units weekly) or darbepoetin (150-300 mcg weekly), which achieve 40-60% erythroid response rates when baseline EPO level is <200-500 U/L and transfusion requirement is low or absent. 1, 4

• ESAs represent an independent favorable prognostic factor for survival and have no impact on progression to AML. 1

• For patients with del(5q): Lenalidomide is the preferred first-line therapy rather than ESAs, as it specifically targets this cytogenetic abnormality. 1, 3

Transfusion Support

• RBC transfusions serve as appropriate sole treatment for anemia in lower-risk MDS when ESAs fail or are contraindicated, though they lead to iron overload requiring monitoring. 1

• Monitor ferritin levels in transfusion-dependent patients and consider iron chelation therapy, particularly if allogeneic transplant is being considered, as elevated labile plasma iron predicts increased infection-related mortality post-transplant. 1

Management of Higher-Risk MDS

First-Line Therapy

• Hypomethylating agents (HMAs) are the standard first-line therapy for higher-risk MDS, with azacitidine 75 mg/m² daily for 7 days every 28 days being the category 1 recommendation. 1, 2, 6, 3

• Decitabine (15 mg/m² IV every 8 hours for 3 days every 6 weeks, or alternative dosing schedules) can be used as an alternative to azacitidine. 2, 6, 4

• Oral decitabine/cedazuridine combination was approved in 2020 as an alternative to IV decitabine, offering equivalent efficacy with improved convenience. 3

Critical Monitoring for HMA Therapy

• Myelosuppression is the most frequent cause of HMA dose reduction, delay, and discontinuation—neutropenia of any grade occurs in 90% of patients (grade 3-4 in 87%), thrombocytopenia in 89% (grade 3-4 in 85%), and anemia in 82%. 6

• Perform complete blood count with platelets at baseline, prior to each cycle, and as needed to monitor response and toxicity. 6

• Critical caveat: Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and do not necessarily indicate progression of underlying MDS—this is expected toxicity, not treatment failure. 6

Dose Modifications for HMA Toxicity

• For hematologic toxicity (ANC <1000/μL, platelets <50,000/μL, or any grade 3-4 non-hematologic toxicity): delay dose up to 2 weeks, then reduce to 11 mg/m² every 8 hours (33 mg/m²/day) upon restarting if using decitabine. 6

• For non-hematologic toxicity (serum creatinine ≥2 mg/dL, SGPT/bilirubin ≥2× ULN, active infection): delay treatment until toxicities resolve. 6

• Continue HMAs until disease progression if tolerated, as they can serve as a bridge to transplant. 2

Allogeneic Stem Cell Transplantation

• Allogeneic SCT remains the only potentially curative treatment for MDS and should be evaluated at diagnosis for all higher-risk patients up to age 70 years (occasionally fit patients >70 years can be considered). 1, 3, 4

• HLA-identical siblings or matched unrelated donors are preferred, though haploidentical donors and cord blood are now viable alternatives with comparable outcomes. 1

• For patients aged <55 years without comorbidities, myeloablative conditioning should be offered as relapse risk is higher with reduced-intensity conditioning. 1

• Consider cytoreduction with HMAs or AML-like chemotherapy when marrow blasts are >10%, especially before non-myeloablative transplant. 1

• Iron chelation should be provided to eligible patients until conditioning begins, as iron overload predicts increased infection-related mortality post-transplant. 1

Special Populations and Considerations

• Elderly patients (≥75 years) with good performance status can still benefit from azacitidine treatment—age alone should not exclude patients from HMA therapy. 2

• Patients with TP53 mutations have particularly poor outcomes with standard therapies and may require more aggressive approaches or clinical trial enrollment. 2, 3, 5

• For patients with intermediate IPSS-R scores, consider treatments typically applied to higher-risk MDS if other biological characteristics (somatic mutations) or resistance to first-line treatment suggests poorer prognosis. 1

Common Pitfalls to Avoid

• Do not delay treatment in higher-risk patients until progression to overt AML—once disease progression is documented (increasing cytopenia or marrow blasts), cytotoxic treatment is indicated. 7

• Do not interpret early myelosuppression during HMA cycles 1-2 as treatment failure or disease progression—this is expected toxicity requiring supportive care, not treatment discontinuation. 6

• Do not use RBC transfusion requirements alone as reason to start cytotoxic therapy in lower-risk patients without documented disease progression. 7

• Ensure comprehensive diagnostic workup (bone marrow aspirate/biopsy, cytogenetics, flow cytometry) is completed before initiating therapy, as accurate risk stratification is essential for appropriate treatment selection. 1, 8, 2