The Addition Of Interleukin-6 Inhibition To Standard Gvhd Prophylaxis Prevents Acute Gvhd: Interim Results Of a Phase I/II Clinical Study

• Published in: Blood 2013-11, Vol.122 (21), p.908-908
• Main Authors: Kennedy, Glen A, Varelias, Antiopi, Vuckovic, Slavica, Zhang, Ping, MacDonald, Kelli PA, Leach, Justine, Sturgeon, Elise, Avery, Judy, Olver, Stuart D, Lor, Mary, Hutchins, Cheryl J, Morton, James A, Durrant, Simon TS, Misra, Ashish, Subramoniapillai, Elango, Butler, Jason P, Curley, Cameron, Tey, Siok K, Hill, Geoffrey R
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.908.908

We and others have demonstrated the dysregulation of interleukin-6 (IL-6) early after experimental bone marrow transplantation (BMT) and protection from acute GVHD following the administration of an anti-IL-6 receptor (IL-6R) antibody. In these models, where GVHD prophylaxis is not administered, systemic IL-6, IFNγ and TNF levels peak 7 days after BMT before returning to baseline by the third week. We have determined cytokine dysregulation in a large clinical cohort of allogeneic stem cell transplant (SCT) recipients conditioned with myeloablative Cy/TBI (12 Gy, n = 25) or reduced intensity Flu/Mel (120mg/m2, n = 25) receiving standard GVHD prophylaxis with cyclosporine and MTX (d 1 at 15mg/m2, d 3, 6, 11 at 10mg/m2). IL-6 levels rose from pre-transplant levels of 6.4 ± 0.7 pg/ml to a peak of 58.8 ± 8.8 pg/ml at day 7 (P < 0.0001) with a fall at day 14 to 39.0 ± 12.5 pg/ml (P < 0.0001) and return to baseline by day 30 (6.2 ± 0.9 pg/ml), consistent with the preclinical data. IL-6 dysregulation was not different in recipients of matched sibling or unrelated donor grafts but was proportional to the intensity of conditioning (day 7 levels after Cy/TBI vs. Flu/Mel: 83.3 ± 12.2 pg/ml vs. 31.0 ± 10.1 pg/ml, P< 0.0001). In contrast to preclinical mouse data, no systemic increases were seen in any other cytokine including IFNγ, TNF, IL-17, IL-4, IL-13 and IL-10. We thus initiated a phase I/II study whereby a human neutralizing monoclonal antibody (mAb) against the IL-6R was administered on day -1 to patients receiving Cy/TBI or Flu/Mel conditioned allogeneic SCT from HLA (10/10)–matched sibling or unrelated donors with standard cyclosporine/MTX GVHD prophylaxis. There was no T cell depletion. The primary endpoint was the incidence of grade II-IV acute GVHD and the study has achieved its planned enrollment (n = 48). There was no toxicity attributable to IL-6R antibody administration. Pharmacokinetic analysis confirmed high levels of IL-6R Ab at day 3 (mean 64.7 ug/ml) which persisted in all patients 3 weeks after BMT (mean = 9.8 ug/ml) and remained above the level of detection (0.1ug/ml) in 75% of patients at day 30 (mean = 1.9 ug/ml). IL-6 levels were dramatically increased (relative to baseline) in patients receiving antibody due to the inability to excrete the inactive IL-6 – soluble IL-6R antibody complex (peak IL-6 levels at day 7 = 773.6 ± 207.9 pg/ml; P < 0.0001) and remained increased at day 30 (60.9 ± 24.4 pg/ml; P < 0.0001), returning to baseline by day 60