TY - JOUR
T1 - Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease
AU - Koreth, John
AU - Kim, Haesook T.
AU - Jones, Kyle T.
AU - Lange, Paulina B.
AU - Reynolds, Carol G.
AU - Chammas, Marie J.
AU - Dusenbury, Katherine
AU - Whangbo, Jennifer
AU - Nikiforow, Sarah
AU - Alyea, Edwin P.
AU - Armand, Philippe
AU - Cutler, Corey S.
AU - Ho, Vincent T.
AU - Chen, Yi Bin
AU - Avigan, David
AU - Blazar, Bruce R.
AU - Antin, Joseph H.
AU - Ritz, Jerome
AU - Soiffer, Robert J.
N1 - Publisher Copyright:
© 2016 by The American Society of Hematology..
PY - 2016/7/7
Y1 - 2016/7/7
N2 - Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD41CD251FOXP31 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 adultswith steroid-refractory cGVHDreceived daily IL-2(13106 IU/m2) for12weeks.MediantimefromtransplantationandcGVHDonsetwas616 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 5 =.005; 249 vs 461 days after cGVHD onset; P 5 .03). Treg:Tcon ratios ‡0.07 at baseline and ‡0.2 at week 1 also predicted clinical response (P 5 =.003; P 5 =.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. Lowdose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated. (Blood.
AB - Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD41CD251FOXP31 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 adultswith steroid-refractory cGVHDreceived daily IL-2(13106 IU/m2) for12weeks.MediantimefromtransplantationandcGVHDonsetwas616 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 5 =.005; 249 vs 461 days after cGVHD onset; P 5 .03). Treg:Tcon ratios ‡0.07 at baseline and ‡0.2 at week 1 also predicted clinical response (P 5 =.003; P 5 =.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. Lowdose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated. (Blood.
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U2 - 10.1182/blood-2016-02-702852
DO - 10.1182/blood-2016-02-702852
M3 - Article
C2 - 27073224
AN - SCOPUS:84977609937
SN - 0006-4971
VL - 128
SP - 130
EP - 137
JO - Blood
JF - Blood
IS - 1
ER -
