Muromonab-CD3 (Orthoclone OKT3®), methylprednisolone and cyclosporine for acute graft-versus-host disease prophylaxis in allogeneic bone marrow transplantation

Abstract

We report the results of a prospective non-randomized phase II study of Muromonab-CD3 (Orthoclone OKT3 s ), an anti-CD3 monoclonal antibody, with methylprednisolone (MP) and cyclosporine (CSA) for acute GVHD (aGVHD) prophylaxis in 22 hematologic malignancy patients. OKT3 was given at 0.1 mg/kg/day with a maximum dose of 5 mg/day. Initial MP dose was 1000 mg before OKT3, with subsequent doses at 1 mg/kg/ day before each OKT3 infusion with a planned taper beginning at day þ 28. CSA (3 mg/kg/day) was given as a continuous infusion at day À1 and adjusted to maintain serum levels between 250 and 399 ng/ml. Allogeneic BMT donors were HLA-matched siblings (n ¼ 17), single HLAmismatched-related (n ¼ 1) and HLA-matched unrelated (n ¼ 4). All patients achieved neutrophil engraftment at a median 11 days (range, 8-25 days). By intent-to-treat, the cumulative incidence of grade II-IV aGVHD was 33% (95% CI 13-53%) at a median 26 days post-BMT (range, 14-84 days). Chronic GVHD developed in 11/12 evaluable patients. Eight patients (36%) developed OKT3 first dose reactions; no cases of post-transplant lymphoproliferative disorder were observed. OKT3 depleted peripheral CD3 þ cells in vivo as measured by flow cytometry. OKT3 þ MP þ CSA combination is moderately effective aGVHD prophylaxis, however, it is unlikely to be superior to CSA þ MTX.

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc− mouse model

“…Interestingly, the pattern of cytokine inhibition induced by IVIG was different from one observed with CsA or OKT3. As expected, given their mechanisms of action, 36,[46][47][48][49][50][51][60][61][62] CsA and OKT3 inhibited most cytokines and particularly pro-inflammatory Th1 (IFN-g and IL-2). Of all the cytokines tested, secretion of IFN-g was the highest recorded in PBS-treated mice suggesting that the reduction of GvHD in CSA and OKT3 mice was related to its inhibition.…”

“…CsA is a calcineurin inhibitor that inhibits T-cell activation and proliferation 46 by preventing or blocking the synthesis of many cytokines, including IL-2 and IFN-g. [47][48][49][50] OKT3 is a MoAb that directly reacts with the e-chain of the CD3 receptor on the TCR, initiating its clearance from the membrane surface, which leads to the silencing of T-cell allo-reactivity by inducing apoptosis. 36,51 We showed that OKT3 and CsA reduced the incidence of GvHD by up to 60% and also decreased related mortality in NSG mice. These results are relevant from a clinical perspective as OKT3 is usually used for refractory GvHD.…”

“…Indeed CsA inhibits T-cell activation and proliferation [46][47][48][49][50] whereas OKT3 induces T-cell apoptosis. 36,51 Unlike OKT3 and CsA, IVIG did not inhibit the proliferation of human T-cells. As inhibition of T-cell proliferation is one of the caveats of immunosuppression because it leads to the inhibition of the graft vs leukemia, this finding could have an impact on clinical practice.…”

“…These results are relevant from a clinical perspective as OKT3 is usually used for refractory GvHD. [31][32][33][34][35][36] and despite first-line prophylaxis usually consisting of CsA and MTX, GvHD still occurs in 10-50% of patients depending on the HLA disparity between host and donor. 29,52 Although CsA is considered a cornerstone in GvHD prophylaxis, we showed that its reduction of GvHD-related mortality was comparable to that observed by IVIG in our model.…”

“…CsA is a key drug used in GvHD prophylaxis in humans [27][28][29][30] and OKT3 is used for steroid-refractory GvHD. [31][32][33][34][35][36] We showed that OKT3 and CsA significantly prevented GvHD-related mortality ( Figure 1), with a greater efficacy for OKT3. CsA was not significantly better than IVIG in preventing mortality (P ¼ 0.681), although as expected, there was evidence of superior efficacy of OKT3 over IVIG (P ¼ 0.009).…”