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Clinical Trial Evaluation

STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2

ORCID Icon, , , , , , , & show all
Pages 631-642 | Received 08 Dec 2022, Accepted 06 Mar 2023, Published online: 21 Apr 2023

References

  • Cogle CR . Incidence and burden of the myelodysplastic syndromes. Curr. Hematol. Malig. Rep.10(3), 272–281 (2015).
  • Fenaux P , HaaseD, SanzGF, SantiniV, BuskeC. Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol.25(Suppl. 3), iii57–69 (2014).
  • Greenberg PL , TuechlerH, SchanzJet al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood120(12), 2454–2465 (2012).
  • Itzykson R , FenauxP, BowenDet al. Diagnosis and treatment of chronic myelomonocytic leukemias in adults: recommendations from the European Hematology Association and the European LeukemiaNet. Hemasphere2(6), e150 (2018).
  • Steensma DP . Myelodysplastic syndromes: diagnosis and treatment. Mayo Clin. Proc.90(7), 969–983 (2015).
  • Fenaux P , MuftiGJ, Hellstrom-LindbergEet 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.10(3), 223–232 (2009).
  • Xu R , LiM, WuPet al. Hypomethylating agents in the treatment of chronic myelomonocytic leukemia: a meta-analysis and systematic review. Hematology26(1), 312–320 (2021).
  • Jabbour E , Garcia-ManeroG, BattyNet al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer116(16), 3830–3834 (2010).
  • Prébet T , GoreSD, EsterniBet al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J. Clin. Oncol.29(24), 3322–3327 (2011).
  • National Comprehensive Cancer Network . National Comprehensive Cancer Network: Myelodysplastic Syndromes (Version 1.2022) (2021). https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf
  • Pfeilstöcker M , TuechlerH, SanzGet al. Time-dependent changes in mortality and transformation risk in MDS. Blood128(7), 902–910 (2016).
  • Arber DA , OraziA, HasserjianRet al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood127(20), 2391–2405 (2016).
  • Bell JA , GalaznikA, BlazerMet al. Transfusion-free interval is associated with improved survival in patients with higher-risk myelodysplastic syndromes engaged in routine care. Leuk. Lymphoma60(1), 49–59 (2019).
  • Chan LSA , ShapiroR, BucksteinRet al. Initial transfusion intensity predicts survival in myelodysplastic syndrome. Leuk. Lymphoma55(10), 2296–2300 (2014).
  • Escalante CP , ChisolmS, SongJet al. Fatigue, symptom burden, and health-related quality of life in patients with myelodysplastic syndrome, aplastic anemia, and paroxysmal nocturnal hemoglobinuria. Cancer Med.8(2), 543–553 (2019).
  • Coston T , PophaliP, VallapureddyRet al. Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients. Am. J. Hematol.94(7), 767–779 (2019).
  • Lachowiez C , CookRJ, Hayes-LattinBet al. Allogeneic transplantation outcomes amongst a contemporary cohort of high-risk myelodysplastic syndrome and acute myeloid leukemia patients aged ≥70 years. Hematol. Oncol. Stem Cell Ther.12(2), 105–109 (2019).
  • Niscola P , PalombiM, TrawinskaMMet al. Managing myelodysplastic syndromes in very old patients: a teaching case report. Clin. Interv. Aging8, 391–394 (2013).
  • Santini V , AllioneB, ZiniGet al. A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia. Leukemia32(2), 413–418 (2018).
  • Zeidan AM , StahlM, SekeresMA, SteensmaDP, KomrokjiRS, GoreSD. A call for action: increasing enrollment of untreated patients with higher-risk myelodysplastic syndromes in first-line clinical trials. Cancer123(19), 3662–3672 (2017).
  • Dinmohamed AG , Van NordenY, VisserOet al. Effectiveness of azacitidine for the treatment of higher-risk myelodysplastic syndromes in daily practice: results from the Dutch population-based PHAROS MDS registry. Leukemia29(12), 2449–2451 (2015).
  • Daver N , BodduP, Garcia-ManeroGet al. Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia32(5), 1094–1105 (2018).
  • Garcia JS , WeiAH, BorateUet al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study. Presented at: American Society of Hematology Virtual Congress.5–8 December 2020 ( Abstract 656).
  • Chandhok NS , LewisR, PrebetT. Hypomethylating agent based combinations in higher risk myelodysplastic syndrome. Leuk. Lymphoma61(5), 1012–1027 (2020).
  • Kaminskas E , FarrellAT, WangYC, SridharaR, PazdurR. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist10(3), 176–182 (2005).
  • Acharya N , Sabatos-PeytonC, AndersonAC. Tim-3 finds its place in the cancer immunotherapy landscape. J. Immunother. Cancer8(1), e000911 (2020).
  • Schwartz S , PatelN, LongmireTet al. Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor. Immunotherapy Advances2, ltac019 (2022).
  • Wolf Y , AndersonAC, KuchrooVK. TIM3 comes of age as an inhibitory receptor. Nat. Rev. Immunol.20(3), 173–185 (2020).
  • Asayama T , TamuraH, IshibashiMet al. Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes. Oncotarget8(51), 88904–88917 (2017).
  • Haubner S , PernaF, KöhnkeTet al. Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML. Leukemia33(1), 64–74 (2019).
  • Zeidan AM , Al-KaliA, BorateUet al. P787: sabatolimab (MBG453) combination therapy regimen for patients with higher-risk myelodysplastic syndromes: the myelodysplastic syndromes studies in the STIMULUS immuno-myeloid clinical trial program. HemaSphere6, 682–683 (2022).
  • Zeidan AM , AndoK, RauzyOet al. Primary Results of STIMULUS-MDS1: a randomized, double-blind, placebo-controlled phase II study of TIM-3 inhibition with sabatolimab added to hypomethylating agents (HMAs) in adult patients with higher-risk myelodysplastic syndromes (MDS) [oral]. Presented at: 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.New Orleans, LA, USA12 December 2022 ( Abstract 853).
  • Bencomo-Alvarez AE , RubioAJ, GonzalezMA, EiringAM. Energy metabolism and drug response in myeloid leukaemic stem cells. Br. J. Haematol.186(4), 524–537 (2019).
  • Riether C , SchürchCM, OchsenbeinAF. Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death Differ22(2), 187–198 (2015).
  • Kikushige Y , MiyamotoT, YudaJet al. A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemic progression. Cell Stem Cell17(3), 341–352 (2015).
  • Ding L , LeyTJ, LarsonDEet al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature481(7382), 506–510 (2012).
  • Curigliano G , GelderblomH, MachNet al. Phase I/Ib clinical trial of sabatolimab, an anti-TIM-3 antibody, alone and in combination with spartalizumab, an anti-PD-1 antibody, in advanced solid tumors. Clin. Cancer Res.27(13), 3620–3629 (2021).
  • Brunner AM , EsteveJ, PorkkaKet al. Efficacy and safety of sabatolimab in combination with hypomethylating agents in patients with very high/high-risk myelodysplastic syndrome and acute myeloid leukemia: final analysis from a phase Ib study. Presented at: 2021 American Society of Hematology (ASH) Annual Meeting and Exposition.Atlanta, GA, USA, 10–14 December 2021.
  • Wei AH , EsteveJ, PorkkaKet al. Sabatolimab (MBG453) dose selection and dose-response analysis in myelodysplastic syndrome/acute myeloid leukemia: population pharmacokinetics modeling and evaluation of clinical efficacy/safety by dose.. Presented at: 2020 American Society of Hematology Virtual Congress.5–8 December 2020.
  • Yellen SB , CellaDF, WebsterK, BlendowskiC, KaplanE. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J. Pain Symptom Manage.13(2), 63–74 (1997).
  • Aaronson NK , AhmedzaiS, BergmanBet al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J. Natl Cancer Inst.85(5), 365–376 (1993).
  • Herdman M , GudexC, LloydAet al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual. Life Res.20(10), 1727–1736 (2011).
  • Sekeres MA , SteensmaDP. Rethinking clinical trial endpoints in myelodysplastic syndromes. Leukemia33(3), 570–575 (2019).
  • Thota S , OganesianA, AzabM, GriffithsEA. Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia. Future Oncol.17(16), 2077–2087 (2021).
  • Wei A , GarciaJ, BorateUet al. Updated safety and efficacy of venetoclax in combination with azacitidine for the treatment of patients with treatment-naive higher-risk myelodysplastic syndromes: phase Ib results. Presented at: European Hematology Association Virtual Congress.9–17 June 2021 ( Abstract EP917).
  • Uy N , SinghA, GoreSD, PrebetT. Hypomethylating agents (HMA) treatment for myelodysplastic syndromes: alternatives in the frontline and relapse settings. Expert Opin Pharmacother18(12), 1213–1224 (2017).
  • Sallman D , MalkiMA, AschAet al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in MDS patients: phase 1b results. Presented at: European Hematology Association Virtual Congress.11–14 June 2020 ( Abstract S187).
  • Sallman DA , AlMalki MM, AschASet al. Magrolimab in combination with azacitidine for patients with untreated higher-risk myelodysplastic syndromes (HR MDS): 5F9005 phase 1B study results. Presented at: European Hematology Association Annual Congress.Vienna, Austria, 9–12 June 2022 ( Abstract S166).
  • Gilead Sciences Inc . Gilead Sciences Inc: FDA lifts partial clinical hold on MDS and AML magrolimab studies (2022). https://www.gilead.com/news-and-press/press-room/press-releases/2022/4/fda-lifts-partial-clinical-hold-on-mds-and-aml-magrolimab-studies
  • Garcia-Manero G , WinerES, DeangeloDJet al. S129: TAKEAIM LEUKEMIA- a phase 1/2A study of the IRAK4 inhibitor emavusertib (CA-4948) as monotherapy or in combination with azacitidine or venetoclax in relapsed/refractory AML or MDS. HemaSphere6, 30–31 (2022).
  • Santini V . How I treat MDS after hypomethylating agent failure. Blood133(6), 521–529 (2019).
  • Ades L , GirshovaL, DoroninVAet al. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast percentage AML. Blood Adv.6(17), 5132–5145 (2022).
  • Khoury JD , SolaryE, AblaOet al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia36(7), 1703–1719 (2022).
  • Dohner H , WeiAH, AppelbaumFRet al. Diagnosis and Management of AML in Adults: 2022 ELN Recommendations from an International Expert Panel. Blood140(12), 1345–1377 (2022).
  • Arber DA , OraziA, HasserjianRPet al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemia: Integrating Morphological, Clinical, and Genomic Data. Blood (2022).
  • Bernard E , TuechlerH, GreenbergPLet al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evidence1(7), EVIDoa2200008 (2022).