Therapy for Myelodysplastic Syndromes Beyond the Front Line in 2024 in Canada

Authors

  • Rena Buckstein, MD, FRCPC Odette Cancer Center, Sunnybrook Health Sciences Dept of Medicine University of Toronto Head, Hematology Clinical Trials Chair, MDS-CAN

DOI:

https://doi.org/10.58931/cht.2024.3252

Abstract

Management of anemia and/or transfusion dependence (TD) after failure of erythropoietic-stimulating agents (ESA) and therapeutic options after hypomethylating agent (HMA) failures remain the biggest challenges for physicians treating lower and higher-risk myelodysplastic syndromes (MDS), respectively. Fortunately, new therapies are available (or soon to be approved), and innovations in prognostic refinement using next-generation sequencing may also facilitate more precision medicine. This review highlights commercially available (or soon to be) options for the amelioration of anemia and transfusion dependence when ESA’s fail and the management of higher-risk MDS when hypomethylating agents fail or cease working. While not all of these agents are currently funded or approved in Canada, some are available for off-label access or purchase. 

Author Biography

Rena Buckstein, MD, FRCPC, Odette Cancer Center, Sunnybrook Health Sciences Dept of Medicine University of Toronto Head, Hematology Clinical Trials Chair, MDS-CAN

Rena Buckstein is a clinician investigator at the Odette Cancer Centre, Sunnybrook Health Sciences who specializes in malignant hematology. She is an associate professor in the department of medicine at University of Toronto. She completed her medical school training at Boston University and Internal Medicine/Hematology specialty and subspecialty training in Toronto, followed by a fellowship in lymphoma and high dose therapy at Sunnybrook Hospital. She also completed a diploma in clinical epidemiology. She chaired the hematology site group for 15 years and currently leads the hematology clinical trials program at the Odette Cancer Center. Dr. Buckstein founded and chairs a national registry for myelodysplastic syndromes (MDS-CAN) of more than 1400 patients and is an affiliate scientist of Sunnybrook Research Institute. She is a member of the International MDS Foundation scientific advisory board, the Canadian Cancer Society hematology clinical trials sub-committee, a co-chair of an international MDS Guidelines panel for MDS-RIGHT and has chaired national clinical trials in lymphoma and MDS. She has authored and co-authored 144 publications and holds peer reviewed grants from Canadian Cancer Society Research Institute (CCSRI), Canadian Institute of Health Research (CIHR), Ontario Institute for Cancer Research (OICR), and the Leukemia Lymphoma Society of Canada (LLSC) that fund investigator-initiated research in MDS and lymphoma. She is a recipient of the LLSC/UFCW award for leukemia research in Canada. She enjoys teaching and mentoring undergraduate and graduate students. Her interventional research focuses on novel targeted biologic and immunologic therapies for hematologic malignancies focusing on myelodysplastic syndromes and acute myelogenous leukemia and improving the transfusion experience for MDS patients. Her non-interventional research focuses on documenting QOL longitudinally and its predictors and the impact of patient-related factors like frailty and disability on quality of life, and clinical outcomes independent of disease-related prognostic factors. She collaborates on health services research pertaining to ‘real-life’ experience of approved therapies in MDS and the cost/predictors of health care resource utilization. Currently, she is evaluating the impact of age-related clonal hematopoiesis (ARCH) on chemotherapy outcomes in older adults with lymphoid cancers, the association of specific mutations with occult coronary artery disease in MDS patients. 

References

Park S, Grabar S, Kelaidi C, et al. Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood. Jan 15 2008;111(2):574-82. DOI: https://doi.org/10.1182/blood-2007-06-096370

Park S, Hamel JF, Toma A, et al. Outcome of Lower-Risk Patients With Myelodysplastic Syndromes Without 5q Deletion After Failure of Erythropoiesis-Stimulating Agents. J Clin Oncol. May 10 2017;35(14):1591-1597. doi:10.1200/JCO.2016.71.3271 DOI: https://doi.org/10.1016/S0145-2126(17)30162-5

Caballero JC, Dávila J, López-Pavía M, et al. Outcomes and effect of somatic mutations after erythropoiesis stimulating agents in patients with lower-risk myelodysplastic syndromes. Therapeutic Advances in Hematology. 2024;15:20406207231218157. doi:10.1177/20406207231218157 DOI: https://doi.org/10.1177/20406207231218157

Fenaux P, Giagounidis A, Selleslag D, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. Oct 6 2011;118(14):3765-76. doi:10.1182/blood-2011-01-330126 DOI: https://doi.org/10.1182/blood-2011-01-330126

Santini V, Giagounidis A, Pelligra CG, et al. Impact of Lenalidomide Treatment on Overall Survival in Patients With Lower-Risk, Transfusion-Dependent Myelodysplastic Syndromes. Clin Lymphoma Myeloma Leuk. Sep 2022;22(9):e874-e883. doi:10.1016/j.clml.2022.05.001 DOI: https://doi.org/10.1016/j.clml.2022.05.001

Prebet T, Cluzeau T, Park S, et al. Outcome of patients treated for myelodysplastic syndromes with 5q deletion after failure of lenalidomide therapy. Oncotarget. Oct 10 2017;8(47):81926-81935. doi:10.18632/oncotarget.18477 DOI: https://doi.org/10.18632/oncotarget.18477

López Cadenas F, Lumbreras E, González T, et al. 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. Blood. 2022;140(Supplement 1):1109-1111. doi:10.1182/blood-2022-168718 DOI: https://doi.org/10.1182/blood-2022-168718

Jädersten M, Saft L, Smith A, et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. May 20 2011;29(15):1971-9. doi:10.1200/jco.2010.31.8576 DOI: https://doi.org/10.1200/JCO.2010.31.8576

Santini V, Almeida A, Giagounidis A, et al. Randomized Phase III Study of Lenalidomide Versus Placebo in RBC Transfusion-Dependent Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes and Ineligible for or Refractory to Erythropoiesis-Stimulating Agents. J Clin Oncol. 09 01 2016;34(25):2988-96. doi:10.1200/JCO.2015.66.0118 DOI: https://doi.org/10.1200/JCO.2015.66.0118

Santini V, Almeida A, Giagounidis A, et al. The Effect of Lenalidomide on Health-Related Quality of Life in Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes: Results From the MDS-005 Study. Clin Lymphoma Myeloma Leuk. Feb 2018;18(2):136-144.e7. doi:10.1016/j.clml.2017.12.004 DOI: https://doi.org/10.1016/j.clml.2017.12.004

Santini V, Fenaux P, Giagounidis A, et al. Impact of somatic mutations on response to lenalidomide in lower-risk non-del(5q) myelodysplastic syndromes patients. Leukemia. Mar 2021;35(3):897-900. doi:10.1038/s41375-020-0961-3 DOI: https://doi.org/10.1038/s41375-020-0961-3

Hellström-Lindberg E. Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Br J Haematol. Jan 1995;89(1):67-71. doi:10.1111/j.1365-2141.1995.tb08909.x DOI: https://doi.org/10.1111/j.1365-2141.1995.tb08909.x

Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. Apr 2014;20(4):408-14. doi:10.1038/nm.3512 DOI: https://doi.org/10.1038/nm.3512

Platzbecker U, Götze KS, Kiewe P, et al. Long-Term Efficacy and Safety of Luspatercept for Anemia Treatment in Patients With Lower-Risk Myelodysplastic Syndromes: The Phase II PACE-MDS Study. J Clin Oncol. Aug 23 2022:JCO2102476. doi:10.1200/JCO.21.02476 DOI: https://doi.org/10.1200/JCO.21.02476

Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 01 09 2020;382(2):140-151. doi:10.1056/NEJMoa1908892 DOI: https://doi.org/10.1056/NEJMoa1908892

Komrokji RS, Aguirre LE, Al Ali N, et al. Synergistic Activity of Luspatercept and Erythroid Stimulating Agents Combination for Treatment of Anemia in Lower-Risk Myelodysplastic Syndromes. Blood. 2022;140(Supplement 1):6917-6919. doi:10.1182/blood-2022-169560 DOI: https://doi.org/10.1182/blood-2022-169560

Wang X, Hu CS, Petersen B, et al. Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells. Blood Adv. Sep 25 2018;2(18):2378-2388. doi:10.1182/bloodadvances.2018022012 DOI: https://doi.org/10.1182/bloodadvances.2018022012

Asai A, Oshima Y, Yamamoto Y, et al. A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res. Jul 15 2003;63(14):3931-9.

Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Jan 20 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5 DOI: https://doi.org/10.1016/S0140-6736(23)01724-5

Garcia-Manero G, McCloskey JK, Griffiths EA, et al. Oral Decitabine/Cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: A Longer-Term Follow-up of from the Ascertain Study. Blood. 2021;138(Supplement 1):66-66. doi:10.1182/blood-2021-144648 DOI: https://doi.org/10.1182/blood-2021-144648

Jabbour E, Short NJ, Montalban-Bravo G, et al. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood. 09 28 2017;130(13):1514-1522. doi:10.1182/blood-2017-06-788497 DOI: https://doi.org/10.1182/blood-2017-06-788497

Jabbour EJ, Garcia-Manero G, Strati P, et al. Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS Clinical Research Consortium. Cancer. Mar 15 2015;121(6):876-82. doi:10.1002/cncr.29145 DOI: https://doi.org/10.1002/cncr.29145

Adès L, Girshova L, Doronin VA, et al. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML. Blood Adv. Sep 13 2022;6(17):5132-5145. doi:10.1182/bloodadvances.2022007334 DOI: https://doi.org/10.1182/bloodadvances.2022007334

Prébet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. Aug 20 2011;29(24):3322-7. doi:10.1200/JCO.2011.35.8135 DOI: https://doi.org/10.1200/JCO.2011.35.8135

Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. Aug 15 2010;116(16):3830-4. doi:10.1002/cncr.25247 DOI: https://doi.org/10.1002/cncr.25247

Prebet T, Fenaux P, Vey N, Myelodysplasies GFd. Predicting outcome of patients with myelodysplastic syndromes after failure of azacitidine: validation of the North American MDS consortium scoring system. Haematologica. Oct 2016;101(10):e427-e428. doi:10.3324/haematol.2016.150714 DOI: https://doi.org/10.3324/haematol.2016.150714

Santini V. How I treat MDS after hypomethylating agent failure. Blood. Feb 07 2019;133(6):521-529. doi:10.1182/blood-2018-03-785915 DOI: https://doi.org/10.1182/blood-2018-03-785915

Zeidan AM, Platzbecker U, Bewersdorf JP, et al. Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes. Blood. Apr 27 2023;141(17):2047-2061. doi:10.1182/blood.2022018604 DOI: https://doi.org/10.1182/blood.2022018604

Ball B, Komrokji RS, Adès L, et al. Evaluation of induction chemotherapies after hypomethylating agent failure in myelodysplastic syndromes and acute myeloid leukemia. Blood Adv. Aug 28 2018;2(16):2063-2071. doi:10.1182/bloodadvances.2018015529 DOI: https://doi.org/10.1182/bloodadvances.2018015529

Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol. Sep 10 2018;36(26):2684-2692. doi:10.1200/JCO.2017.77.6112 DOI: https://doi.org/10.1200/JCO.2017.77.6112

Bogenberger JM, Kornblau SM, Pierceall WE, et al. BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia. Aug 2014;28(8):1657-65. doi:10.1038/leu.2014.44 DOI: https://doi.org/10.1038/leu.2014.44

Zeidan AM, Borate U, Pollyea DA, et al. A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Am J Hematol. Feb 2023;98(2):272-281. doi:10.1002/ajh.26771 DOI: https://doi.org/10.1002/ajh.26771

Sallman DA, Foran JM, Watts JM, et al. Ivosidenib in patients with IDH1-mutant relapsed/refractory myelodysplastic syndrome (R/R MDS): Updated enrollment and results of a phase 1 dose-escalation and expansion substudy. Journal of Clinical Oncology. 2022;40(16_suppl):7053-7053. doi:10.1200/JCO.2022.40.16_suppl.7053 DOI: https://doi.org/10.1200/JCO.2022.40.16_suppl.7053

Sebert M, Cluzeau T, Beyne Rauzy O, et al. Ivosidenib Monotherapy Is Effective in Patients with IDH1 Mutated Myelodysplastic Syndrome (MDS): The Idiome Phase 2 Study By the GFM Group. Blood. 2021;138(Supplement 1):62-62. doi:10.1182/blood-2021-146932 DOI: https://doi.org/10.1182/blood-2021-146932

DiNardo CD, Venugopal S, Lachowiez C, et al. Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome. Blood Adv. Jun 13 2023;7(11):2378-2387. doi:10.1182/bloodadvances.2022008378 DOI: https://doi.org/10.1182/bloodadvances.2022008378

Vishwasrao P, Li G, Boucher JC, Smith DL, Hui SK. Emerging CAR T Cell Strategies for the Treatment of AML. Cancers (Basel). Feb 27 2022;14(5)doi:10.3390/cancers14051241 DOI: https://doi.org/10.3390/cancers14051241

Chua CC, Cheok KPL. Taking a step forward in CAR T-cell therapy for acute myeloid leukaemia and myelodysplastic syndrome. Lancet Haematol. Mar 2023;10(3):e161-e162. doi:10.1016/S2352-3026(23)00002-9 DOI: https://doi.org/10.1016/S2352-3026(23)00002-9

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Published

2024-06-27

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1.
Buckstein R. Therapy for Myelodysplastic Syndromes Beyond the Front Line in 2024 in Canada. Can Hematol Today [Internet]. 2024 Jun. 27 [cited 2024 Dec. 21];3(2):22–29. Available from: https://canadianhematologytoday.com/article/view/3-2-buckstein

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