Geriatric Hematology Puzzle: Myelodysplastic Syndromes

The Geriatric Hematology Puzzle: Myelodysplastic Syndromes (MDS)

Dr Neeraj Manikath , claude.ai

Introduction

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral cytopenias, morphologic dysplasia, and an inherent risk of transformation to acute myeloid leukemia (AML). With a median age at diagnosis of 70-75 years, MDS presents unique challenges in the critical care setting, where elderly patients often present with life-threatening cytopenias, infections, or bleeding complications.[1,2] The intensivist must navigate the delicate balance between aggressive supportive care and the understanding that MDS represents a chronic, often incurable condition in the geriatric population.

The incidence of MDS is approximately 4-5 per 100,000 population annually, rising dramatically to >30 per 100,000 in individuals over 70 years.[3] As our population ages, critical care physicians will increasingly encounter MDS patients during acute decompensations or when cytopenias complicate other critical illnesses. Understanding the molecular landscape, prognostic scoring systems, and therapeutic options is essential for informed decision-making and goal-concordant care.

Pearl #1: In any elderly patient presenting with unexplained, refractory cytopenias—particularly macrocytic anemia unresponsive to B12/folate supplementation—think MDS until proven otherwise.

The IPSS-R Score: Stratifying Risk from Indolent to Urgent

The Revised International Prognostic Scoring System (IPSS-R), published in 2012, revolutionized MDS risk stratification by incorporating five independent prognostic variables: bone marrow blast percentage, cytogenetics, hemoglobin level, platelet count, and absolute neutrophil count.[4] The IPSS-R classifies patients into five distinct risk categories: very low, low, intermediate, high, and very high risk, with median survivals ranging from 8.8 years to 0.8 years, respectively.

Understanding the IPSS-R Components:

The cytogenetic abnormalities are divided into five prognostic subgroups: very good (−Y, del(11q)), good (normal karyotype, del(5q), del(12p), del(20q), double anomalies including del(5q)), intermediate (del(7q), +8, +19, i(17q), any other single or double independent clones), poor (−7, inv(3)/t(3q)/del(3q), double including −7/del(7q), complex: 3 abnormalities), and very poor (complex: >3 abnormalities).[4]

The bone marrow blast percentage carries significant weight: <2% (0 points), 2-<5% (1 point), 5-10% (2 points), >10% (3 points). For cytopenias, hemoglobin ≥10 g/dL (0 points), 8-<10 g/dL (1 point), <8 g/dL (1.5 points); platelets ≥100×10⁹/L (0 points), 50-<100×10⁹/L (0.5 points), <50×10⁹/L (1 point); ANC ≥0.8×10⁹/L (0 points), <0.8×10⁹/L (0.5 points).[4]

Critical Care Implications:

In the ICU, the IPSS-R score helps frame prognostic discussions with patients and families. A patient with very low or low-risk MDS (combined scores ≤3) admitted with sepsis secondary to neutropenia may warrant full aggressive care, as their underlying disease may allow years of reasonable quality life. Conversely, a patient with very high-risk MDS (score >6) presenting with multi-organ failure may benefit from early palliative care consultation and goals-of-care discussions.

Pearl #2: The IPSS-R should be calculated for every MDS patient in the ICU. It provides a rational framework for intensity of care decisions and helps avoid both nihilism in low-risk disease and futile care in high-risk disease with multiple organ failures.

Oyster #1: The IPSS-R was developed from diagnosis. In ICU patients with previously treated MDS or those post-hypomethylating agent (HMA) failure, the score may underestimate mortality risk. Consider this when counseling families.

More recently, the IPSS-Molecular (IPSS-M) incorporates molecular mutations and has shown superior prognostic discrimination, but requires next-generation sequencing and may not be readily available in acute settings.[5]

Cytogenetics in MDS: The Prognostic Significance of del(5q) and Complex Karyotypes

Cytogenetic abnormalities are detected in approximately 50% of primary MDS cases and up to 80% of therapy-related MDS.[6] The cytogenetic profile is arguably the most important prognostic factor in MDS, reflecting the underlying biological behavior of the disease.

The del(5q) Anomaly: A Favorable Exception

Isolated deletion of the long arm of chromosome 5 [del(5q)] defines a distinct MDS subtype with unique clinical characteristics. Patients typically present with macrocytic anemia, normal or elevated platelet counts, and <5% bone marrow blasts. The del(5q) syndrome occurs predominantly in women (2:1 ratio) and has a favorable prognosis with median survival exceeding 5 years.[7]

The molecular basis involves haploinsufficiency of ribosomal protein genes (RPS14) and the miR-145/miR-146a cluster on chromosome 5q. This syndrome demonstrates exquisite sensitivity to lenalidomide, an immunomodulatory agent, with erythroid response rates of 67% and cytogenetic complete remission in 45% of patients.[8]

Hack #1: In ICU patients with del(5q) MDS presenting with symptomatic anemia, consider urgent hematology consultation for lenalidomide initiation even during the acute illness if the patient is hemodynamically stable. The response can be dramatic and may reduce transfusion burden within 4-8 weeks.

Complex Karyotypes: The High-Risk Fingerprint

Complex karyotypes, defined as ≥3 chromosomal abnormalities, represent the opposite end of the prognostic spectrum. These occur in approximately 10-15% of MDS cases and are associated with aggressive disease, high rates of AML transformation (>60% at 2 years), and dismal survival (median 9-12 months).[9]

The monosomal karyotype (MK), defined as two or more autosomal monosomies or a single monosomy with additional structural abnormalities, represents an even worse prognostic subset with median survival of approximately 6 months.[10] Common adverse abnormalities include −7/del(7q), −5/del(5q) when not isolated, inv(3)/t(3q), and abnormalities of chromosome 17 (i(17q) or −17).

Critical Care Decision-Making:

For ICU patients with complex karyotype MDS presenting with severe sepsis or respiratory failure, the intensivist must balance aggressive resuscitation against the stark reality of underlying disease biology. These patients rarely achieve long-term remission with conventional therapies outside of allogeneic stem cell transplantation—an option rarely feasible in critically ill elderly patients.

Pearl #3: Monosomy 7 (−7) is particularly ominous in MDS, associated with poor response to therapy and rapid AML transformation. In critically ill patients with −7, consider time-limited trials of ICU therapies with frequent reassessment.

Oyster #2: Not all complex karyotypes are created equal. A complex karyotype that includes del(5q) may respond better to therapy than one dominated by monosomy 7 or chromosome 3 abnormalities. Review the complete cytogenetic report, not just the "complex karyotype" designation.

The Paradox of Cytopenias in a Hypercellular Bone Marrow

One of the most intellectually fascinating aspects of MDS is the apparent contradiction: patients develop profound cytopenias despite having a normocellular or hypercellular bone marrow packed with hematopoietic precursors. This paradox is the hallmark of ineffective hematopoiesis—the pathophysiologic cornerstone of MDS.[11]

Mechanisms of Ineffective Hematopoiesis:

1. Increased Intramedullary Apoptosis: Dysplastic hematopoietic precursors undergo premature apoptosis within the bone marrow before reaching maturation. Studies demonstrate up to 3-fold increased apoptosis rates in MDS marrow compared to healthy controls.[12] Pro-apoptotic signals including TNF-α, Fas ligand, and TRAIL are upregulated in the MDS bone marrow microenvironment.

2. Defective Maturation: Morphologic dysplasia reflects fundamental defects in cellular maturation pathways. Erythroid precursors may show nuclear budding, binucleation, or megaloblastic features. Myeloid precursors demonstrate hypogranulation, nuclear hyposegmentation (pseudo-Pelger-Huët anomaly), or abnormal granulation. Megakaryocytes may be hypolobulated or demonstrate micromegakaryocyte morphology.

3. Aberrant Cellular Trafficking: Even cells that escape apoptosis may fail to egress appropriately from the bone marrow to peripheral blood due to abnormalities in chemokine signaling (particularly CXCR4/CXCL12 axis) and adhesion molecule expression.[13]

4. Peripheral Destruction: While primarily a disorder of ineffective production, some MDS patients have concurrent immune-mediated peripheral destruction of blood cells, creating a "double hit" phenomenon. This is particularly relevant in hypoplastic MDS subtypes.

Clinical Recognition:

In the ICU, the key clinical clue is persistent or worsening cytopenias despite aggressive supportive care (transfusions, growth factors) in a patient with a non-hypoplastic bone marrow biopsy. The peripheral blood smear may show macrocytic red cells, circulating dysplastic neutrophils with hypogranulation or bilobed nuclei, and variable platelet counts—sometimes with circulating micromegakaryocytes or megakaryocyte fragments.

Hack #2: When evaluating an ICU patient with suspected MDS, always review the peripheral smear personally or with a hematologist. The presence of pseudo-Pelger-Huët cells (neutrophils with bilobed "pince-nez" nuclei) or circulating micromegakaryocytes can clinch the diagnosis even before bone marrow results are available.

Pearl #4: The reticulocyte count is inappropriately low for the degree of anemia in MDS. An absolute reticulocyte count <60,000/μL in a patient with Hgb <8 g/dL suggests ineffective erythropoiesis. Calculate the reticulocyte production index (RPI) = (reticulocyte % × patient Hct)/(45 × maturation time). An RPI <2 indicates inadequate marrow response.

Differentiating MDS from Aplastic Anemia and Other Causes of Cytopenias

The differential diagnosis of cytopenias in the geriatric ICU patient is broad, and distinguishing MDS from other etiologies is critical for appropriate management. The two most important considerations are aplastic anemia (AA) and nutritional/toxic cytopenias.

Myelodysplastic Syndrome vs. Aplastic Anemia:

Aplastic anemia represents immune-mediated destruction of hematopoietic stem cells, resulting in a hypocellular bone marrow with fatty replacement. While both conditions present with cytopenias, their pathophysiology, treatment, and prognosis differ fundamentally.

Feature	MDS	Aplastic Anemia
Age	Median 70-75 years	Bimodal: 15-25 and >60 years
Bone marrow cellularity	Normo/hypercellular (90%)	Hypocellular (<25%)
Dysplasia	Present (defining feature)	Absent
Cytogenetics	Abnormal (50%)	Normal (>95%)
PNH clone	Rare (<5%)	Common (40-50%)
Macrocytosis	Prominent	Mild or absent
Response to immunosuppression	Poor (<20%)	Good (60-70%)

Hypoplastic MDS—The Diagnostic Quandary:

Approximately 10-15% of MDS cases present with hypocellular bone marrow (<30% cellularity in patients <60 years, <20% in patients >60 years), creating diagnostic confusion with AA.[14] These cases represent a unique challenge:

• May have morphologic dysplasia that is subtle or hard to appreciate in a hypocellular aspirate
• Often demonstrate cytogenetic abnormalities (30-50%), which essentially exclude pure AA
• May have concurrent features of both MDS and immune-mediated marrow failure
• Some may respond to immunosuppressive therapy (anti-thymocyte globulin, cyclosporine), though less predictably than AA

Diagnostic Approach:

1. Flow Cytometry for PNH Clone: The presence of a glycosylphosphatidylinositol (GPI)-anchored protein-deficient clone (PNH clone) >1% strongly suggests aplastic anemia or AA/MDS overlap. High-sensitivity flow cytometry should be performed on all patients with unexplained cytopenias.[15]

2. Cytogenetic Analysis: Clonal cytogenetic abnormalities essentially confirm MDS. However, normal cytogenetics do not exclude MDS, particularly in hypoplastic variants.

3. Next-Generation Sequencing: Somatic mutations in myeloid-related genes (SF3B1, SRSF2, TET2, ASXL1, DNMT3A) support MDS diagnosis. ASXL1 and U2AF1 mutations are particularly specific for MDS, while DNMT3A and TET2 can occur in clonal hematopoiesis of indeterminate potential (CHIP) in elderly individuals without MDS.[16]

4. Bone Marrow Morphology: The WHO classification requires dysplasia in ≥10% of cells in at least one lineage for MDS diagnosis. An experienced hematopathologist should review all cases of suspected hypoplastic MDS.

Other Differential Diagnoses:

• Vitamin B12/Folate Deficiency: Produces macrocytosis and ineffective hematopoiesis with megaloblastic changes that can mimic MDS. Always check B12 (with methylmalonic acid/homocysteine if borderline) and folate. Responds rapidly to supplementation.

• Copper Deficiency: Seen with gastric bypass, excessive zinc supplementation, or malabsorption. Causes anemia, neutropenia, and myelodysplastic features. Check serum copper and ceruloplasmin.

• HIV Infection: Can cause cytopenias with dysplastic features. All patients should have HIV testing.

• Alcohol/Medication Toxicity: Chronic alcohol causes macrocytosis and cytopenias. Medications (methotrexate, valproic acid, mycophenolate) can cause reversible dysplasia.

• Copper and Arsenic Toxicity: Important to exclude, particularly in patients with environmental exposures.

Hack #3: In the ICU, if you're uncertain whether cytopenias represent MDS or another etiology, institute a "diagnostic trial." Replace B12/folate, discontinue potentially myelosuppressive medications, optimize nutrition, and reassess in 2 weeks. True MDS will not respond to these interventions.

Pearl #5: Ring sideroblasts (erythroid precursors with iron-laden mitochondria forming a perinuclear ring covering >1/3 of the nucleus) are highly suggestive of MDS, particularly when >15% of erythroid precursors are affected. The presence of ring sideroblasts defines MDS-RS (MDS with ring sideroblasts), often associated with SF3B1 mutations and relatively favorable prognosis.

Oyster #3: Dysplasia is a morphologic diagnosis that can be somewhat subjective. A single dysplastic feature noted by a pathologist does not automatically equal MDS—particularly in critically ill patients with recent intensive chemotherapy, growth factor use, or severe infections that can cause transient dysplastic changes. Seek expert hematopathology review.

Therapeutic Ladder: From Supportive Care (ESAs) to Hypomethylating Agents to Transplant

The treatment of MDS is risk-adapted, with therapeutic intensity matched to disease severity and patient fitness. For the critical care physician, understanding the treatment landscape is essential for prognostic discussions and recognizing complications of MDS therapies.

Level 1: Supportive Care and Erythropoiesis-Stimulating Agents (ESAs)

Transfusion Support:

Red blood cell transfusions remain the cornerstone of supportive care for symptomatic anemia in MDS. The transfusion trigger should be individualized, but generally Hgb <7-8 g/dL warrants transfusion in stable patients, with higher thresholds (8-9 g/dL) for patients with cardiovascular disease or active bleeding.[17]

Major concern: Chronic transfusions lead to iron overload, with cardiac and hepatic siderosis developing after approximately 20-25 units. Serum ferritin >1000-2500 ng/mL warrants iron chelation therapy (deferasirox, deferiprone, or deferoxamine) in lower-risk MDS patients expected to survive >1 year.[18]

Platelet transfusions are indicated for bleeding or platelet counts <10,000/μL (prophylactic). Some guidelines recommend prophylactic transfusion at <20,000/μL in patients with fever, infection, or coagulopathy.

Erythropoiesis-Stimulating Agents (ESAs):

Recombinant erythropoietin (EPO) or darbepoetin can reduce transfusion requirements in 40-60% of lower-risk MDS patients, particularly those with baseline EPO levels <500 mU/mL and low transfusion burden (<2 units/month).[19]

Predictors of ESA response:

• Serum EPO <500 mU/mL: 74% response rate
• Serum EPO >500 mU/mL: 7% response rate
• Low transfusion burden (<2 units/month): Better response
• IPSS low/intermediate-1: Better response

Dosing: Epoetin alfa 40,000-60,000 units SC weekly or darbepoetin 300-500 μg SC every 2-3 weeks. Response is typically seen within 8-12 weeks if it occurs at all. Addition of G-CSF may improve response rates.

Hack #4: In ICU patients with lower-risk MDS and anemia, consider starting ESAs during the hospitalization if the expected ICU stay is >2 weeks and the patient is likely to benefit from reduced transfusion burden. While response takes weeks, early initiation may provide benefit during prolonged critical illness recovery.

Level 2: Immunomodulatory Therapy (Lenalidomide)

Lenalidomide is specifically indicated for transfusion-dependent anemia in patients with deletion 5q MDS, where it achieves transfusion independence in 67% of patients and cytogenetic complete remission in 45%.[8] The mechanism involves selective inhibition of clones with del(5q) through haploinsufficiency of casein kinase 1A1 (CSNK1A1).

Dosing: 10 mg daily for 21 days of 28-day cycle, with dose reductions for cytopenias.

Major toxicities: Severe neutropenia and thrombocytopenia (requiring dose holds/reductions), increased risk of thrombosis (consider aspirin prophylaxis), rash, and diarrhea.

Pearl #6: Lenalidomide causes an initial paradoxical worsening of cytopenias in the first 4-8 weeks before response. Patients require close monitoring with weekly CBC initially and often need growth factor support (G-CSF) to navigate through this period.

Level 3: Hypomethylating Agents (HMAs)

Azacitidine and decitabine are pyrimidine nucleoside analogs that inhibit DNA methyltransferases, leading to DNA hypomethylation and reactivation of silenced tumor suppressor genes. These agents represent the standard of care for higher-risk MDS (IPSS intermediate-2 or high risk).

Azacitidine:

The pivotal AZA-001 trial demonstrated improved overall survival compared to conventional care (24.5 vs 15 months) in higher-risk MDS.[20] Azacitidine delays AML transformation and improves quality of life.

Dosing: 75 mg/m² SC or IV daily for 7 days every 28 days. Critical point: Minimum of 4-6 cycles are required to assess response, as initial responses may be delayed. Median time to response is 2-3 cycles.

Decitabine:

Similar efficacy to azacitidine with different dosing schedule: 20 mg/m² IV daily for 5 days every 28 days or 20 mg/m² IV daily for 3 days every 28 days (European schedule).

Response rates: Overall response rates (CR + partial response + hematologic improvement) of 40-60%, with complete remission in 15-20% of higher-risk MDS patients.

Toxicities: Cytopenias (particularly during first 2 cycles), infection risk, injection site reactions (azacitidine), nausea, fatigue. Most cytopenias recover before the next cycle.

Critical Care Considerations:

ICU admission during HMA therapy most commonly occurs due to:

1. Febrile neutropenia/sepsis: Neutrophil nadirs occur days 14-21 of cycle. Treat aggressively with broad-spectrum antibiotics.
2. Bleeding: Thrombocytopenia may be profound. Transfuse to maintain platelets >10,000-20,000/μL.
3. Tumor lysis syndrome: Rare but reported, particularly with high blast counts.

Hack #5: If a patient on HMA therapy presents to ICU with neutropenic fever in week 2-3 of their cycle, discuss with oncology about SKIPPING the next cycle to allow hematologic recovery. Dose delays or modifications may be necessary, but do not abandon therapy entirely unless there are multiple cycles of persistent severe cytopenias despite dose reductions.

Pearl #7: HMA failure (lack of response after 4-6 cycles or relapse after initial response) portends a grave prognosis with median survival of 4-6 months. Novel agents (venetoclax combinations, clinical trials) should be considered, but goals of care discussions are essential.

Oyster #4: Do not start HMAs in critically ill patients with multi-organ failure or those unlikely to survive >3 months. These agents require 4-6 months to demonstrate efficacy, and initial cytopenias may worsen clinical status. HMAs are for patients well enough to survive the treatment course.

Level 4: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Allogeneic HSCT remains the only curative therapy for MDS, with 3-year overall survival rates of 35-50% depending on risk stratification and patient age.[21] However, transplant-related mortality remains substantial (15-40%), particularly in elderly patients.

Indications:

• Higher-risk MDS (IPSS intermediate-2, high, or very high)
• Lower-risk MDS with poor-risk cytogenetics or high transfusion burden
• Young patients (<60-65 years) with adequate performance status
• Availability of matched sibling or unrelated donor

Reduced-Intensity Conditioning (RIC):

RIC regimens have extended the feasibility of transplant to patients up to age 70-75 with acceptable comorbidity indices (HCT-CI score). These regimens rely more on graft-versus-leukemia effect than myeloablation, with lower acute toxicity but similar long-term survival compared to myeloablative conditioning in older patients.[22]

Critical Care and Transplant:

ICU admission post-transplant occurs in 25-40% of patients, most commonly for:

1. Acute respiratory failure: Multifactorial (infection, pulmonary edema, diffuse alveolar hemorrhage, ARDS)
2. Septic shock: Particularly during neutropenic period (days 0-14)
3. Acute GVHD complications: Gastrointestinal GVHD with diarrhea/bleeding, hepatic GVHD
4. Sinusoidal obstruction syndrome (SOS/VOD): Presents with jaundice, hepatomegaly, ascites, weight gain
5. Thrombotic microangiopathy (TMA): Presents with hemolysis, thrombocytopenia, renal failure

Hack #6: The presence of GVHD substantially changes ICU management. Patients with GVHD on high-dose steroids/immunosuppression are profoundly immunocompromised. Maintain low threshold for bronchoalveolar lavage (BAL) in any respiratory symptoms, as opportunistic infections (CMV, Pneumocystis, Aspergillus, HHV-6) are common and require specific therapy.

Pearl #8: Post-transplant ICU mortality is heavily influenced by the number of organ failures. Single organ failure (e.g., isolated respiratory failure requiring mechanical ventilation) has ~50% ICU mortality. Three or more organ failures (requiring ventilation, vasopressors, and renal replacement) has >90% mortality. These data should inform goals-of-care discussions.[23]

Novel and Emerging Therapies

Several new agents show promise in MDS:

1. Luspatercept: Approved for anemia in lower-risk MDS with ring sideroblasts or SF3B1 mutation. Acts on the transforming growth factor-β pathway to promote late-stage erythropoiesis. Reduces transfusion burden in ESA-refractory patients.[24]

2. Venetoclax Combinations: The BCL-2 inhibitor combined with HMAs shows activity in HMA-naive and HMA-failure patients, with ORR of 50-75% in early studies.[25]

3. IDH Inhibitors: Ivosidenib (IDH1) and enasidenib (IDH2) target specific mutations present in 10-20% of MDS/AML patients.

4. Magrolimab: Anti-CD47 antibody showing promising early results in TP53-mutated MDS, a historically treatment-refractory subset.

Conclusion: Integrating MDS Care in the ICU

Caring for MDS patients in the ICU requires understanding the biological heterogeneity of the disease, accurate prognostic assessment, and realistic discussions about treatment limitations. Key principles include:

1. Risk stratify using IPSS-R to frame prognostic discussions
2. Recognize that lower-risk MDS patients can have prolonged survival and warrant full supportive care
3. Understand that higher-risk MDS, particularly with complex karyotypes or post-HMA failure, has dismal prognosis
4. Avoid starting disease-modifying therapy (HMAs, lenalidomide) in critically ill patients with multi-organ failure
5. Support patients through expected cytopenias from MDS therapy with transfusions and growth factors
6. Engage palliative care early for symptom management and goals-of-care discussions

The geriatric hematology puzzle of MDS challenges us to balance hope with realism, therapeutic intervention with compassionate limitation, and cure-directed therapy with quality of life. By mastering the prognostic tools, understanding the cytogenetic landscape, recognizing the paradox of ineffective hematopoiesis, and navigating the therapeutic ladder, critical care physicians can provide optimal care for this complex patient population.

References

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2. Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood. 2014;123(6):829-836.

3. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109(8):1536-1542.

4. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465.

5. Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid. 2022;1(7):EVIDoa2200008.

6. Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241-247.

7. Giagounidis AA, Germing U, Aul C. Biological and prognostic significance of chromosome 5q deletions in myeloid malignancies. Clin Cancer Res. 2006;12(1):5-10.

8. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355(14):1456-1465.

9. Schanz J, Tüchler H, Solé F, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30(8):820-829.

10. Breems DA, Van Putten WL, De Greef GE, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26(29):4791-4797.

11. Parker JE, Mufti GJ. Ineffective haemopoiesis and apoptosis in myelodysplastic syndromes. Br J Haematol. 1998;101(2):220-230.

12. Tehranchi R, Woll PS, Anderson K, et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N Engl J Med. 2010;363(11):1025-1037.

13. Schmitz B, Thiele J, Witte OW, Kaufmann R. Proliferative activity and cell death in myelodysplastic syndromes. Int J Oncol. 1998;13(5):1099-1104.

14. Huang TC, Ko BS, Tang JL, et al. Comparison of hypoplastic myelodysplastic syndrome (MDS) with normo-/hypercellular MDS by International Prognostic Scoring System, cytogenetic and genetic studies. Leukemia. 2008;22(3):544-550.

15. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009;144(2):206-216.

16. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373(1):35-47.

17. Carson JL, Guyatt G, Heddle NM, et al. Clinical Practice Guidelines from the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA. 2016;316(19):2025-2035.

18. Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol. 2008;88(1):24-29.

19. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003;120(6):1037-1046.

20. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Efficacy

 of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232.

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22. McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010;28(11):1878-1887.

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Additional Clinical Pearls and Oysters Summary

Pearl #9: Always assess the "MDS-Comorbidity Index" in ICU patients. The presence of cardiac disease (EF <50%), liver disease (bilirubin >1.5× ULN), or renal impairment (Cr >2 mg/dL) significantly impacts transplant eligibility and overall prognosis beyond the IPSS-R score alone.

Pearl #10: In MDS patients with profound neutropenia (<200/μL) and sepsis, consider empiric antifungal coverage earlier than typical neutropenic fever protocols. MDS patients often have prolonged neutropenia and functional neutrophil defects, increasing invasive fungal infection risk.

Oyster #5: Beware the "blast crisis" presentation. Some patients with previously undiagnosed MDS present to the ICU with rapid AML transformation (>20% blasts). These patients have particularly poor outcomes—median survival 4-6 months even with therapy—and often have preceding complex karyotypes. Check old CBCs if available; the MDS may have been smoldering unrecognized.

Oyster #6: Not all pancytopenias in elderly patients are MDS. Autoimmune conditions (lupus, rheumatoid arthritis with Felty's syndrome, large granular lymphocyte leukemia) can mimic MDS. Check ANA, rheumatoid factor, and flow cytometry for LGL expansion (CD3+/CD57+ T cells or CD3-/CD16+CD56+ NK cells).

Hack #7: For MDS patients with refractory thrombocytopenia and bleeding, consider trying a thrombopoietin receptor agonist (romiplostim, eltrombopag) off-label. While not FDA-approved for MDS, case series show 40-60% platelet response rates in carefully selected lower-risk patients. Coordinate with hematology, as there's theoretical concern about increasing blast counts.

Hack #8: In del(5q) MDS patients with severe thrombocytopenia paradoxically coexisting with anemia, hold off on lenalidomide until platelets improve. Lenalidomide will worsen thrombocytopenia initially. Consider ESA therapy first, or if transfusion-independent, watchful waiting with close monitoring.

Pearl #11: SF3B1 mutations define a distinct MDS subtype characterized by ring sideroblasts, relative thrombocytosis, and favorable prognosis (median survival >5 years). These patients respond well to luspatercept. If you see ring sideroblasts on bone marrow, specifically ask pathology to test for SF3B1—it changes management.

Pearl #12: TP53 mutations occur in 10-15% of MDS, particularly in therapy-related MDS and complex karyotype disease. These mutations confer extremely poor prognosis (median survival 9-12 months) and predict resistance to HMAs, lenalidomide, and most conventional therapies. Novel agents (magrolimab, eprenetapopt) or clinical trials are the best options. TP53-mutated MDS warrants early palliative care involvement.

Oyster #7: Some medications can cause reversible "pseudo-MDS" with dysplastic changes: high-dose valproic acid, ganciclovir, mycophenolate mofetil, and chronic arsenic or lead exposure. Always review medications and environmental exposures. Stopping the offending agent and reassessing in 4-6 weeks can clarify the diagnosis.

Hack #9: For ICU patients with MDS and severe anemia requiring frequent transfusions but unable to tolerate ESAs or other therapy, consider a trial of danazol (synthetic androgen) 200 mg PO TID. Response rates are modest (15-30%), but in lower-risk patients, it may reduce transfusion requirements. Main side effect is virilization/hepatotoxicity—check LFTs monthly.

Pearl #13: Acute coronary syndrome or severe arrhythmias in MDS patients may be related to iron overload cardiomyopathy from chronic transfusions, NOT just atherosclerotic disease. Check cardiac MRI with T2 sequences if available. Ferritin >2500 ng/mL and >100 units transfused should raise suspicion. These patients may benefit from aggressive iron chelation.*

Hack #10: If an MDS patient in the ICU develops sudden deterioration with fever, back pain, and respiratory distress 15-60 minutes post-red cell transfusion, consider hemolytic transfusion reaction. MDS patients with multiple transfusions develop alloantibodies. Stop transfusion immediately, send pink plasma and urine for hemolysis labs, support with IVF, and notify blood bank urgently for investigation.

Special Populations and ICU-Specific Considerations

Therapy-Related MDS (t-MDS)

Approximately 10-15% of MDS cases are therapy-related, occurring after exposure to chemotherapy (particularly alkylating agents, topoisomerase II inhibitors) or radiation therapy for prior malignancies. Therapy-related MDS has distinctive features:

• Shorter latency period (median 2-5 years post-exposure)
• Higher frequency of adverse cytogenetics (60-70%): complex karyotypes, monosomy 7, del(5q) without favorable features
• TP53 mutations in up to 40% of cases
• Poor response to standard therapies
• Median survival 8-12 months

Critical Care Implication: When a patient with t-MDS presents to the ICU, their prognosis is substantially worse than de novo MDS with similar IPSS-R scores. Factor this into intensity of care discussions and consider early goals-of-care conversations.

MDS-Associated Autoimmune Phenomena

Up to 10-30% of MDS patients develop autoimmune or inflammatory conditions, including:

• Vasculitis (cutaneous and systemic)
• Relapsing polychondritis
• Inflammatory arthritis
• Sweet syndrome (acute febrile neutrophilic dermatosis)
• Autoimmune hemolytic anemia or ITP

These phenomena may respond to corticosteroids or immunosuppression, but must be distinguished from infection—a critical diagnostic challenge in the ICU setting.

Pearl #14: Sweet syndrome presents with painful erythematous plaques/nodules, fever, and neutrophilic infiltration on biopsy. It occurs in 5-10% of MDS patients. Treat with systemic corticosteroids (prednisone 0.5-1 mg/kg/day), NOT antibiotics. Skin biopsy is diagnostic and should be performed early if suspected.

Clonal Hematopoiesis of Indeterminate Potential (CHIP)

CHIP refers to the presence of somatic mutations in myeloid-associated genes (particularly DNMT3A, TET2, ASXL1) in individuals without cytopenias or morphologic dysplasia. CHIP increases with age: 10% prevalence at age 70, 20% at age 90.

Distinguishing CHIP from MDS:

• CHIP: No cytopenias, no dysplasia, often single mutation with VAF <10%
• MDS: Cytopenias present, dysplasia present, often multiple mutations with higher VAF

Why ICU physicians should care: CHIP is associated with increased cardiovascular mortality, particularly inflammatory conditions like heart failure and coronary disease. Patients with CHIP may be at higher risk of severe inflammatory responses in critical illness. Recent data suggest CHIP may increase mortality in sepsis through dysregulated inflammatory signaling.

The Challenge of MDS in the Post-COVID Era

COVID-19 infection in MDS patients carries significant mortality risk (20-30% in published series), particularly in higher-risk disease and those with severe cytopenias. Management considerations:

1. Vaccination response: Reduced in MDS patients, particularly those on HMAs. Consider antibody testing post-vaccination.

2. Continued HMA during COVID: Data suggest continuing azacitidine/decitabine during mild-moderate COVID may not worsen outcomes and prevents disease progression.

3. Monoclonal antibody therapy: Should be offered to MDS patients with COVID-19 if available, given their immunocompromised state.

4. Long COVID: May exacerbate baseline fatigue and cytopenias in MDS patients, complicating assessment of disease status.

Goals-of-Care Framework for MDS in the ICU

Appropriate goals-of-care discussions are essential for MDS patients in the ICU. Consider the following framework:

Favorable Prognosis (Consider Full ICU Support):

• IPSS-R very low or low risk
• Isolated del(5q) or normal cytogenetics
• Age <70 with good performance status
• Treatment-naive or responding to therapy
• Single organ failure

Intermediate Prognosis (Consider Time-Limited Trial):

• IPSS-R intermediate risk
• Age 70-80 with reasonable performance status
• On active therapy with stable disease
• Two organ failures

Poor Prognosis (Consider Comfort-Focused Care):

• IPSS-R high or very high risk with complex karyotype/monosomy 7
• TP53-mutated disease
• Post-HMA failure
• Transformed to AML (>20% blasts)
• Age >80 with multiple comorbidities
• Three or more organ failures
• Post-transplant with refractory GVHD and multiple organ failures

Hack #11: Use the "Surprise Question": "Would I be surprised if this patient died in the next 6-12 months?" If the answer is "No," initiate palliative care consultation early in the ICU course. For high/very high-risk MDS, the answer is almost always "No."

Monitoring Response to MDS Therapy

Understanding response criteria helps ICU physicians interpret hematology consultant notes and anticipate clinical trajectory:

IWG 2006 Response Criteria:

• Complete Remission (CR): Marrow <5% blasts, Hgb >11 g/dL, ANC >1000/μL, platelets >100,000/μL
• Partial Remission (PR): 50% decrease in blasts, improvement in cytopenias
• Marrow CR (mCR): Marrow <5% blasts without peripheral blood count recovery
• Hematologic Improvement (HI): Defined improvements in RBCs (Hgb increase >1.5 g/dL), platelets (increase >30,000/μL or 50% from baseline), or ANC (increase >500/μL)
• Stable Disease (SD): No improvement, no progression
• Progressive Disease (PD): Worsening cytopenias, increasing blasts, new cytogenetic abnormalities

Pearl #15: Achieving CR with HMA therapy takes time—median 4-6 months. Early cycles often show worsening cytopenias before improvement. Do not declare treatment failure before at least 4-6 cycles unless there is clear disease progression (rapidly increasing blasts, new extramedullary disease).

Emerging Biomarkers and Future Directions

The landscape of MDS is rapidly evolving with integration of molecular diagnostics:

Next-Generation Sequencing (NGS) Panels routinely test for mutations in:

• Splicing factors: SF3B1 (favorable), SRSF2, U2AF1, ZRSR2
• Epigenetic modifiers: TET2, DNMT3A, ASXL1, IDH1/2, EZH2
• Transcription factors: RUNX1, ETV6
• Signaling: FLT3, JAK2, NRAS/KRAS, CBL
• Tumor suppressors: TP53 (very poor prognosis)
• Cohesin complex: STAG2

Clinical Utility:

• SF3B1 mutations predict response to luspatercept
• TP53 mutations predict HMA resistance and need for novel agents
• IDH1/2 mutations may respond to specific IDH inhibitors
• Multiple mutations in high molecular risk genes (TP53, ASXL1, RUNX1, EZH2) predict poor outcomes

Oyster #8: The presence of multiple mutations does not automatically equal poor prognosis. The IDENTITY matters. A patient with SF3B1 + TET2 mutations has favorable prognosis, while TP53 + ASXL1 + RUNX1 portends dismal outcomes. Discuss with hematology to interpret molecular data in context.

Conclusion

Myelodysplastic syndromes represent one of the most complex diagnostic and therapeutic challenges in geriatric hematology. For the critical care physician, understanding MDS requires fluency in prognostic scoring systems, cytogenetic interpretation, the paradox of ineffective hematopoiesis, and the therapeutic ladder from supportive care through transplantation.

Key takeaways for the intensivist:

1. Use IPSS-R to risk-stratify every MDS patient and frame prognostic discussions
2. Cytogenetics matter immensely: del(5q) = good, complex karyotype = bad, monosomy 7 = very bad
3. Understand ineffective hematopoiesis: cytopenias with normocellular/hypercellular marrow is the MDS signature
4. Differentiate carefully from aplastic anemia, nutritional deficiencies, and drug toxicities
5. Match therapy intensity to disease risk and patient fitness
6. Recognize HMA and transplant complications requiring ICU care
7. Engage palliative care early for high-risk disease, post-HMA failure, and TP53-mutated MDS
8. Remember: Not all elderly patients with cytopenias need bone marrow biopsies in the ICU, but those with unexplained, persistent cytopenias despite treatment of reversible causes warrant hematology evaluation

The geriatric hematology puzzle of MDS challenges us to integrate molecular diagnostics, clinical acumen, and compassionate prognostication. As our population ages and targeted therapies evolve, the intensivist's role in caring for these complex patients will only grow in importance. By mastering these concepts, we can provide expert, evidence-based care that honors both the science of hematology and the art of critical care medicine.

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Final Pearl #16: When in doubt, call your hematologist. MDS is nuanced, and expert guidance on prognosis, therapy, and transfusion thresholds can significantly impact patient outcomes and quality of ICU care. Hematology-critical care collaboration is essential for optimal MDS management.

Final Oyster #9: Don't let the diagnosis of MDS lead to therapeutic nihilism. Lower-risk MDS patients can live for years with good quality of life. Match your ICU intensity to their disease risk, not just to the intimidating diagnosis label. Every MDS patient deserves individualized assessment, not a blanket poor prognosis.