A comparative study of reduced dose alemtuzumab in matched unrelated donor and related donor reduced intensity transplants

Abstract

In vivo T cell depletion with 100 mg alemtuzumab prevents graft-versus-host disease (GVHD) in reduced intensity conditioned transplants but is associated with delayed immune reconstitution, a higher risk of infection and relapse. De-escalation studies have shown that a reduced dose of 30 mg is as effective as 100 mg in preventing GVHD in matched related donor (MRD) transplants. Dose reduction in matched unrelated donor (MUD) transplants is feasible but the comparative efficacy of alemtuzumab in this setting is not known and opinions vary widely concerning the optimal level of GVHD prophylaxis that should be achieved. Through retrospective analysis we made an objective comparison of MUD transplants receiving an empirically reduced dose of 60 mg, with MRD transplants receiving a 30 mg dose. We observed proportionate levels of alemtuzumab according to dose but an inverse relationship with body surface area particularly in MRD transplants. MUD transplants experienced more acute and chronic GVHD, higher T cell chimerism, more sustained use of ciclosporin and less need for donor lymphocyte infusion than MRD transplants. Thus, doubling the dose of alemtuzumab to 60 mg did not provide equivalent prevention of GVHD after MUD transplant although there was no difference in non-relapse mortality or survival compared with MRD transplants.

Keywords: T cell depletion; bone marrow transplantation; graft-versus-host disease.

Figure 1

Consort diagram summarising patients included in the study. FMA: fludarabine, melphalan, alemtuzumab (dose in mg); FLAMSA: fludarabine, cytarabine, amsacrine (with cyclophosphamide and total body irradiation transplant); MUD, matched unrelated donor; MMUD, mismatched unrelated donor (<9/10 antigen‐mismatched MUD).

Figure 2

(A) Comparison of mean serum alemtuzumab level on day +1 in matched related donor (MRD) recipients of 30 mg and matched unrelated donor (MUD) recipients of 60 mg **P = 0·0002. (B) Comparison of mean serum alemtuzumab level on day +3–4 in MRD recipients of 30 mg, MUD recipients of 60 mg and historical controls receiving 100 mg alemtuzumab **P = 0·0028. (C) Correlation between body surface area and serum alemtuzumab in MRD recipients of 30 mg; open symbols indicate bone marrow (BM); closed symbols indicate peripheral blood stem cell (PBSC) grafts. (D) Correlation between body surface area (Dubois) and serum alemtuzumab in MUD recipients of 60 mg. Open symbols indicate BM; closed symbols indicate PBSC grafts.

Figure 3

(A) Comparison of median peripheral blood T cell chimerism at day 100 in matched unrelated donor (MRD) recipients of 30 mg and matched unrelated donor (MUD) recipients of 60 mg alemtuzumab **P = 0·0002. (B) Incidence and severity of acute graft‐versus‐host disease (GVHD) in MRD recipients of 30 mg and MUD recipients of 60 mg alemtuzumab; **P < 0·0001. (C) Incidence and severity of chronic GVHD in MRD recipients of 30 mg and MUD recipients of 60 mg alemtuzumab; **P < 0·0001.

Figure 4

(A) Comparison of mean (± SEM) ciclosporin levels in matched related donor (MRD) patients receiving 30 mg (dotted line) versus matched unrelated donor (MUD) patients receiving 60 mg alemtuzumab. Significant differences between means after Bonferroni correction; **P = 0·0007 at day +84 and P = 0·0028 at day +98. (B) Incidence of cytomegalovirus reactivation in seropositive recipients of 30 mg (MRD) and 60 mg (MUD) alemtuzumab, **P < 0·0001.

Figure 5

(A) Cumulative incidence of non‐relapse mortality. (B) Cumulative incidence of relapse. (C) Kaplan Meier curves of overall survival. Grey lines show matched related donor (MRD) recipients of 30 mg alemtuzumab; black lines show matched unrelated donor (MUD) recipients of 60 mg alemtuzumab. HR, Hazard ratio.