Biologic Assignment Trial of Reduced-Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients 50-75 Years of Age With Advanced Myelodysplastic Syndrome

Abstract

Purpose: Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined.

Methods: We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration.

Results: The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm (P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined.

Conclusion: We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.

Trial registration: ClinicalTrials.gov NCT02016781.

Conflict of interest statement

Ryotaro NakamuraConsulting or Advisory Role: Viracor Eurofins, Magenta Therapeutics, Kadmon, Napajen PharmaResearch Funding: Helocyte, Miyarisan PharmaceuticalTravel, Accommodations, Expenses: Kyowa Hakko Kirin, Alexion Pharmaceuticals Bart ScottHonoraria: Bristol Myers SquibbConsulting or Advisory Role: Celgene, Acceleron Pharma, Astex Pharmaceuticals, NovartisSpeakers' Bureau: Alexion Pharmaceuticals, Celgene, Jazz Pharmaceuticals, NovartisResearch Funding: Celgene Betul OranResearch Funding: AROG Phamarceuticals, Astex Pharmaceuticals Asmita MishraResearch Funding: Novartis Richard T. MaziarzHonoraria: Novartis, Omeros, PACT PharmaceuticalsConsulting or Advisory Role: Novartis, Incyte, Kite, a Gilead company, Bristol Myers Squibb, Intellia Therapeutics, ArtivaPatents, Royalties, Other Intellectual Property: Athersys Inc shared patent re: use of mesenchymal stromal cells for treatment of GVHDTravel, Accommodations, Expenses: Novartis, Incyte, Kite, a Gilead company Joseph McGuirkHonoraria: Kite, a Gilead company, AlloVir, Juno Therapeutics, Magenta TherapeuticsConsulting or Advisory Role: Kite, a Gilead company, Juno Therapeutics, AlloVir, Magenta Therapeutics, EcoR1 CapitalSpeakers' Bureau: Kite/GileadResearch Funding: Novartis, Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, Pluristem Therapeutics, Kite, a Gilead company, AlloVirTravel, Accommodations, Expenses: Kite, a Gilead company Peter WesterveltConsulting or Advisory Role: Pfizer Sumithira VasuConsulting or Advisory Role: Omeros, Johnson & JohnsonPatents, Royalties, Other Intellectual Property: The Ohio State University has entered into an exclusive licensing agreement with Kiadis Inc Mrinal PatnaikHonoraria: Kura OncologyConsulting or Advisory Role: Kura OncologyResearch Funding: Stemline Therapeutics Stephen J. FormanStock and Other Ownership Interests: MustangBio, Lixte BiotechnologyConsulting or Advisory Role: Alimera Sciences, Lixte Biotechnology, MustangBioResearch Funding: MustangBioPatents, Royalties, Other Intellectual Property: MustangBio Mikkael A. SekeresConsulting or Advisory Role: Celgene, Millennium, Pfizer, NovartisResearch Funding: Takeda, Pfizer, Bristol Myers Squibb Frederick AppelbaumStock and Other Ownership Interests: Jasper Therapeutics Brent LoganConsulting or Advisory Role: Daiichi Sankyo, Enlivex Therapeutics Ltd, Gamida Cell Mary HorowitzConsulting or Advisory Role: Magenta Therapeutics, Janssen Research & Development, MedacResearch Funding: Biovitrum, Jazz Pharmaceuticals, Magenta Therapeutics, Novartis, Kite/Gilead, Actinium Pharmaceuticals, Amgen, Amneal Pharmaceuticals, Anthem, Bluebird Bio, Bristol Myers Squibb, Chimerix, CSL Behring, Cyto-Sen Therapeutics, Daiichi Sankyo, Gamida Cell, GlaxoSmithKline, Mesoblast, Miltenyi Biotec, Neovii, Oncoimmune, Pfizer, Pharmacyclics, Regeneron, Sanofi, Seattle Genetics, Shire Corey CutlerStock and Other Ownership Interests: Bluebird Bio, Idera, Verastem, Northwest Biotherapeutics, Actinium PharmaceuticalsHonoraria: Omeros, PfizerConsulting or Advisory Role: Incyte, Jazz Pharmaceuticals, CareDX, Mesoblast, Syndax, MedsenicNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram for BMT CTN 1102. Two hundred sixty (67.7%) of the enrolled subjects were biologically assigned to the Donor arm and 124 (32.3%) assigned to the No-Donor arm. On the Donor arm, 187 (71.9%) of the participants have completed the 3-year follow-up period, with 62 surviving until 3 years and 125 dying. Of the No-Donor arm participants, 100 (80.6%) have completed the follow-up period, 14 surviving until the 3 years and 86 dying. Three subjects withdrew from study, two on the Donor arm and one on the Non-Donor arm, each declining to participate further in completing study visits and quality-of-life assessments. The remaining 71 subjects on the Donor arm and 23 on the Non-Donor arm are still being followed until the 3-year mark.

FIG 2.

(A) Estimates of OS after registration. OS curves are adjusted for age, race or ethnicity, performance status, IPSS score, duration of disease, and response to HMA in an intention-to-treat analysis. (B) Forest plot of subgroup analyses for OS. The forest plot shows the OR of OS at 3 years for Donor versus No-Donor arm subjects in subgroups determined by age, race or ethnicity, performance status, IPSS score, duration of disease, and response to HMA. NOTE. x-axis has a logarithmic scale. (C) Estimates of LFS after registration. LFS curves are adjusted for age, race or ethnicity, performance status, IPSS score, duration of disease, and response to HMA in an intention-to-treat analysis. (D) Forest plot of subgroup analyses for LFS. The forest plot shows the OR for LFS at 3 years after consent for Donor versus No-Donor arm subjects in subgroups determined by age, race or ethnicity, performance status, IPSS score, duration of disease, and response to HMA. NOTE. x-axis has a logarithmic scale. HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; IPSS-R, Revised International Prognostic Scoring System; LFS, leukemia-free survival; MDS, myelodysplastic syndromes; OR, odds ratio; OS, overall survival.

FIG 3.

(A) Estimates of OS after registration, as-treated analysis. OS curves are adjusted for age, race or ethnicity, performance status, IPSS score, duration of disease, and response to HMA in an as-treated analysis. (B) Estimates of LFS after registration, as-treated analysis. LFS curves are adjusted for age, race or ethnicity, performance status, IPSS score, duration of disease, and response to HMA in an as-treated analysis. HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; LFS, leukemia-free survival; OS, overall survival.