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.
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?
6
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 |
8
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)
9
Risk stratification
10
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
11
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)
19
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
22
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
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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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