title: Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease.
abstract: Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs). Previous phase 1 studies identified a low daily dose of interleukin-2 (IL-2) that was well tolerated, did not exacerbate alloimmunity, augmented Treg in vivo, and was associated with improvement of active cGVHD. In the current phase 2 study, 35 adults with steroid-refractory cGVHD received daily IL-2 (1 × 10(6) IU/m(2)) for 12 weeks. Median time from transplantation and cGVHD onset was 616 days (range, 270-2145 days) and 317 days (range, 28-1880 days), respectively. Two patients withdrew and 5 required IL-2 dose reductions due to side effects. Twenty of 33 evaluable patients (61%) had clinical responses at multiple cGVHD sites (liver, skin, gastrointestinal tract, lung, joint/muscle/fascia). Three patients (9%) had progressive cGVHD. Compared with pretreatment levels, Treg and natural killer cell counts rose >fivefold (P < .001) and >fourfold (P < .001), respectively, without significant change in conventional CD4 T cells (Tcons) or CD8 T cells. The Treg:Tcon ratio rose >fivefold (P < .001). Clinical responders initiated IL-2 earlier (508 vs 917 days after transplantation, P = .005; 249 vs 461 days after cGVHD onset; P = .03). Treg:Tcon ratios ≥0.07 at baseline and ≥0.2 at week 1 also predicted clinical response (P = .003; P = .0003, respectively). After a 4-week treatment hiatus, clinical responders were eligible to continue IL-2 therapy indefinitely. During 2 years of extended IL-2 therapy, clinical and Treg immune responses persisted, while Tcon count and Treg:Tcon ratio gradually normalized. Low-dose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA;
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Jones
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Paulina B
authors.initials: PB
authors.lastname: Lange
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Carol G
authors.initials: CG
authors.lastname: Reynolds
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Marie J
authors.initials: MJ
authors.lastname: Chammas
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Katherine
authors.initials: K
authors.lastname: Dusenbury
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Whangbo
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Sarah
authors.initials: S
authors.lastname: Nikiforow
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Corey S
authors.initials: CS
authors.lastname: Cutler
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Hematology/Oncology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: Yi-Bin
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and.
authors.forename: David
authors.initials: D
authors.lastname: Avigan
authors.affiliation: University of Minnesota Masonic Cancer Center and Division of Blood and Marrow Transplantation, Department of Pediatrics, Minneapolis, MN.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
mesh_terms: D000328:Adult; D000368:Aged; D002908:Chronic Disease; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage*; D007694:Killer Cells, Natural; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory; D013997:Time Factors
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2