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Lower-Risk MDS
beau hilton, 2023-03-31
Case presentation
81M w CKD (b/l Cr 1.8), HFpEF (admitted 2x last year), AF (on apixaban), p/w hgb 10.1, MCV 99.
Feels fine overall, some DoE that is longstanding, doing well since last admission and diuresis.
No frequent infections.
Doesn’t have dentures, no OTC supps.
current
Case presentation
81M w CKD (b/l Cr 1.8), HFpEF (admitted 2x last year), AF (on apixaban), p/w hgb 10.1, MCV 99.
Feels fine overall, some DoE that is longstanding, doing well since last admission and diuresis.
No frequent infections.
Doesn’t have dentures, no OTC supps.
next
No notes.
Lower-Risk MDS
beau hilton, 2023-03-31
1
Case presentation
81M w CKD (b/l Cr 1.8), HFpEF (admitted 2x last year), AF (on apixaban), p/w hgb 10.1, MCV 99.
Feels fine overall, some DoE that is longstanding, doing well since last admission and diuresis.
No frequent infections.
Doesn’t have dentures, no OTC supps.
2
Case presentation
Labs
hgb 10.1, MCV 99
plt 132
WBC 5.3, normal diff
folate, B12 replete
TSAT 19%
3
Case presentation
Given 1g IV iron, seen back in 10wks, BMBx scheduled prophylactically
hgb 9.6, MCV 97
other counts unchanged
4
Case presentation
BMBx
- 35% cellularity
- blasts 1%
- dysplasia in 15% of erythroid precursors (megaloblastic erythroblasts, basophilic stippling, cytoplasmic vacuolation)
- no ringed sideroblasts
- del(5q)
- NGS pending
5
Questions
- How common is MDS?
- What do people present with?
- How do we risk-stratify MDS?
- What are the relative incidences of the risk strata?
- When do we intervene in lower-risk disease?
- What tools do we have?
- How do we sequence therapies?
- Can we impact prognosis?
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Epidemiology
- yearly incidence: 4/100,0001
- incidence increases with age:2
- <40yo: 0.1/100,000
- >65yo: 25/100,000
- 70-79yo: 30/100,000
- >80yo: 60/100,000
- underreported: yearly incidence >65yo may be as high as 75/100,0003
- median age of dx: 70-75
- male predominance
- 5.4/100,000 vs 2.9/100,000 in women
- del(5q) more common in women (7:3)
- 75% are LR-MDS
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S/sx prevalence (%)1
| Fatigue | 55 |
| Hgb <10 g/dL | 52 |
| Plt <100 x 109/L | 40 |
| ANC <800 x 109/L | 18 |
| Fever/infection | 15 |
| Bleeding | 8 |
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Diagnosis
- ≥1 cytopenias
- hgb <10, ANC <1800, plt <100k
- ≥10% dysplastic cells in ≥1 lineage*
- <20% blasts
- presence of certain cytogenetic/molecular findings
- absence of AML-defining (cyto)genetics (e.g. t(8;21), CBFB-MYH11)
* if certain cytogenetic changes**, can dx MDS w/o dysplasia (<10% of cases)
** monosomy 5, 7, or 13; 5q, 7q, and 13q deletions; i(17p) and t(17p); 11q deletion; 9q or 12p deletion; or t(12p), idic (X)(q13)
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Risk stratification
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Risk stratification (IPSS)
| Variable | Score | ||||
| 0 | 0.5 | 1 | 1.5 | 2 | |
| Bone marrow blasts (percent) | <5 | 5-10 | - | 11-20 | 21-30 |
| Karyotype | Good | Intermediate | Poor | - | - |
| Cytopenias | 0-1 | 2-3 | - | - | - |
- Karyotype stratification:
- Good: Normal, -Y, del(5q), del(20q)
- Intermediate: not good nor poor
- Poor: ≥3 abnl, chromosome 7 abnl
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Risk stratification (IPSS)
| Risk group | IPSS score |
| Low | 0 |
| Intermediate-1 | 0.5 to 1 |
| Intermediate-2 | 1.5 to 2 |
| High | 2.5 to 3.5 |
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Risk stratification (IPSS-R)
| 0 | 0.5 | 1.0 | 1.5 | 2.0 | 3.0 | 4.0 | |
| blast % | ≤2 | >2 - <5 | 5 - 10 | >10 | |||
| hgb | ≥10 | 8 - <10 | <8 | ||||
| plt | ≥100 | 50 - 100 | <50 | ||||
| ANC | ≥0.8 | <0.8 | |||||
| cytogenetics | very good -Y, del(11q) | good normal, del(12p), del(20q), del(5q), double w del(5q) | intermediate single NOS, del(7q), +8, +19, i(17q), double w/o del(5q) or -7/del(7q) | poor -7, double w -7/del(7q), inv(3)/t(3q)/del(3q), 3 abnl | very poor >3 abnl | ||
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Risk stratification (IPSS-R)
| Risk group | IPSS-R score | ||
| very low | ≤1.5 | ||
| low | >1.5 to 3.0 | ||
| intermediate | >3 to 4.5 | ||
| high | >4.5 to 6 | ||
| very high | >6 |
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Risk stratification (IPSS-many)
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Management
Goals of management
No interventions have been shown conclusively to improve OS in LR-MDS.1
- reduce sx
- reduce tfx dependence
- minimize morbidity
- balance tox of tx vs tox of dz
- 1there is now a suggestion that early EPO may improve OS (Garelius 2022, abstract at the EHA Annual Congress)
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Management - anemia
EPO
- relatively high dose, e.g. 60,000u EPO q7d, 500 μg darbepoetin alfa q21d
- meta-analysis: ~40% response rate overall (hgb up 1-1.5g, reduction in tfx)
- 2017 RCT: 15% RR at 24wk (0% in placebo)
- Open-label 48wk f/u: 35% RR
- response rate is higher if lower baseline EPO (e.g.<200 IU/L)
- if high tfx dependence (≥1 tfx/14d) and EPO >200, RR <10%
- mean duration of response: 8-23mo
- fever in 10%
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Management - anemia
luspatercept
- TGF-b superfamily, promotes late-stage erythropoeisis
- MDS-RS (usu SF3B1-mutant)
- tfx independence in ~40% (~10% in placebo)1
- median duration of response ~30wks
- diarrhea, nausea, back pain, dizziness in 20%
- 1Fenaux et al 2020, NEJM (MEDALIST trial)
lenalidomide
- del(5q) (sometimes non-del(5q) if used in combo w epoeitin alfa)
- 21/28d cycles
- 2011 RCT: tfx independence in 40-60%
- median duration of response >2y
- G3-4 neutropenia 70%, thrombocytopenia in ~33%
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Management - anemia - new stuff
imetelstat
- telomerase inhibitor
- IV, 2h infusion q4wks
- "IMerge" trial (phase 2 complete, phase 3 finished recruiting)
- R/R tfx burden (≥4 pRBC/8wks)
- primary endpoint: transfusion independence ≥8wk
- 37% reached primary endpoint
- 42% >8wks, 32% >24wks, 29% >52wks
- possibly disease-modifying (clonal burden decreased in some)
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Management - anemia - new stuff
roxadustat
- HIF inhibitor (approved in China for CKD, not approved in US d/t c/f thrombosis, CV events)
- oral, 3x/wk
- phase 3, LR-MDS, <5% blasts, low tfx burden
- ~50% reduction in tfx
- EPO level doesn’t seem to matter, but sample size is small
H3B-8800
- spliceosome modulator (e.g. SF3B1, SRSF2, U2AF1)
- oral
- 42 pts w HR or LR-MDS, 88% w spliceosome mutations
- 14% had reduced pRBC or plt tfx dependence
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Management - thrombocytopenia
romiplostim1
- plt <20k: 1250 vs 1800 plt tfx per 100 pt-years
- plt >20k: 80 vs 225 bleeding events per 100 pt-years
eltrombopag1
- baseline plt <30k
- improved plt count in 50% (3% in placebo)
- 1TPO possibly yield higher risk of AML transformation, particularly in MDS-EB, but longer f/u studies failed to show an association (e.g. Kantarjian 2018)
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Management - multipenia/neutropenia
- HMA
- may be able to use 3d cycles, rather than 5/7
- 29% CR or PR (12% w best supportive care)
- oral azacitidine
- CC-486, "Onureg"
- RBC-TI 31% (placebo 11%)1
- this study used IPSS: ~30% would have been upstaged w IPSS-R
- ATG
- 1Garcia-Manero et al 2021, JCO
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Management
MDS-hypoplastic
- LR-MDS w <25% cellularity appears to somewhat overlap w aplastic anemia
- so -> ATG, cyclosporine, etc.
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Bibliography
Baer, C., Huber, S., Hutter, S., Meggendorfer, M., Nadarajah, N., Walter, W., Platzbecker, U., Götze, K., Kern, W., Haferlach, T., Hoermann, G., & Haferlach, C. (2022). Risk Prediction in MDS: A Validation of the IPSS-M and Comparison to IPSS-R and to Two Other Personalized Prediction Tools. Blood, 140(Supplement 1), 1128–1129. https://doi.org/10.1182/blood-2022-159939
Brunner, A. M., Leitch, H. A., van de Loosdrecht, A. A., & Bonadies, N. (2022). Management of patients with lower-risk myelodysplastic syndromes. Blood Cancer Journal, 12(12), Article 12. https://doi.org/10.1038/s41408-022-00765-8
Cogle, C. R., Craig, B. M., Rollison, D. E., & List, A. F. (2011). Incidence of the myelodysplastic syndromes using a novel claims-based algorithm: High number of uncaptured cases by cancer registries. Blood, 117(26), 7121–7125. https://doi.org/10.1182/blood-2011-02-337964
Diez-Campelo, M. (2022, December 11). Evaluation of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent Low Risk Del(5q) MDS Patients. Final Results of Sintra-REV Phase III International Multicenter Clinical Trial. 64th ASH Annual Meeting and Exposition. https://ash.confex.com/ash/2022/webprogram/Paper168718.html
Garcia-Manero, G., Santini, V., Almeida, A., Platzbecker, U., Jonasova, A., Silverman, L. R., Falantes, J., Reda, G., Buccisano, F., Fenaux, P., Buckstein, R., Diez Campelo, M., Larsen, S., Valcarcel, D., Vyas, P., Giai, V., Olíva, E. N., Shortt, J., Niederwieser, D., … Giagounidis, A. (2021). Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes. Journal of Clinical Oncology, 39(13), 1426–1436. https://doi.org/10.1200/JCO.20.02619
Greenberg, P. L., Tuechler, H., Schanz, J., Sanz, G., Garcia-Manero, G., Solé, F., Bennett, J. M., Bowen, D., Fenaux, P., Dreyfus, F., Kantarjian, H., Kuendgen, A., Levis, A., Malcovati, L., Cazzola, M., Cermak, J., Fonatsch, C., Le Beau, M. M., Slovak, M. L., … Haase, D. (2012). Revised international prognostic scoring system for myelodysplastic syndromes. Blood, 120(12), 2454–2465. https://doi.org/10.1182/blood-2012-03-420489
Meunier, M., & Park, S. (2022). Lower-risk myelodysplastic syndromes: Current treatment options for anemia. EJHaem, 3(4), 1091–1099. https://doi.org/10.1002/jha2.523
Mohty, R., Al Hamed, R., Bazarbachi, A., Brissot, E., Nagler, A., Zeidan, A., & Mohty, M. (2022). Treatment of myelodysplastic syndromes in the era of precision medicine and immunomodulatory drugs: A focus on higher-risk disease. Journal of Hematology & Oncology, 15(1), 124. https://doi.org/10.1186/s13045-022-01346-9
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Bibliography
Sekeres, M. A., & Taylor, J. (2022). Diagnosis and Treatment of Myelodysplastic Syndromes: A Review. JAMA, 328(9), 872. https://doi.org/10.1001/jama.2022.14578
Toprak, S. K. (2022). Past, present and future in low-risk myelodysplastic syndrome. Frontiers in Medicine, 9. https://www.frontiersin.org/articles/10.3389/fmed.2022.967900
Witte, T. de, Malcovati, L., Fenaux, P., Bowen, D., Symeonidis, A., Mittelman, M., Stauder, R., Sanz, G., Čermák, J., Langemeijer, S., Hellström-Lindberg, E., Germing, U., Holm, M. S., Mądry, K., Tatic, A., Almeida, A. M., Savic, A., Rogulj, I. M., Itzykson, R., … Smith, A. (2020). Novel dynamic outcome indicators and clinical endpoints in myelodysplastic syndrome; the European LeukemiaNet MDS Registry and MDS-RIGHT project perspective. Haematologica, 105(11), Article 11. https://doi.org/10.3324/haematol.2020.266817
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