Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease

被引：156

作者：

Koreth, John ^{[1
,2
]}

Kim, Haesook T. ^{[2
,3
]}

Jones, Kyle T. ^{[1
,2
]}

Lange, Paulina B. ^{[1
,2
]}

Reynolds, Carol G. ^{[1
,2
]}

Chammas, Marie J. ^{[1
,2
]}

Dusenbury, Katherine ^{[1
,2
]}

Whangbo, Jennifer ^{[1
,2
]}

Nikiforow, Sarah ^{[1
,2
]}

Alyea, Edwin P., III ^{[1
,2
]}

Armand, Philippe ^{[1
,2
]}

Cutler, Corey S. ^{[1
,2
]}

Ho, Vincent T. ^{[1
,2
]}

Chen, Yi-Bin ^{[2
,4
]}

Avigan, David ^{[2
,5
]}

Blazar, Bruce R. ^{[6
,7
]}

Antin, Joseph H. ^{[1
,2
]}

Ritz, Jerome ^{[1
,2
]}

Soiffer, Robert J. ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Div Hematol Malignancies, D2029,450 Brookline Ave, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston, MA USA

[3] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA

[4] Massachusetts Gen Hosp, Hematol Oncol Div, Boston, MA 02114 USA

[5] Beth Israel Deaconess Med Ctr, Hematol Oncol, Boston, MA 02215 USA

[6] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA

[7] Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN USA

来源：

BLOOD | 2016年 / 128卷 / 01期

基金：

美国国家卫生研究院;

关键词：

REGULATORY T-CELLS; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; BONE-MARROW-TRANSPLANTATION; CLINICAL-TRIALS; CHRONIC GVHD; CRITERIA; TOLERANCE; IL-2; VALIDATION;

D O I：

10.1182/blood-2016-02-702852

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 x 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.

引用

页码：130 / 137

页数：8

共 42 条

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