Dose De-Escalation of Alemtuzumab in Matched Unrelated Donor Hematopoietic Stem Cell Transplantation: A Single Centre Retrospective Study
Authors: Madkhali Maymoon Mohammed , Mitchell Alex , Wright Callum , Pearce Kim , Pagan Sarah , Duncan Louise , Macdonald Jamie , Lam Jason , Milne Paul , Publicover Amy , Hurst Erin , Bigley Venetia , Hale Geoff , Collin Matthew 
Published: December 2024

Alemtuzumab is a humanized anti-CD52 antibody that efficiently reduces the incidences of acute and chronic graft versus host disease (GVHD) in reduced intensity allogeneic hematopoietic stem cell transplantation. While used for more than 20 years, the optimal dosing of alemtuzumab in matched unrelated donor (MUD) transplants has not been formally evaluated. This retrospective single-center study examined alemtuzumab dose de-escalation from 60mg to 30mg in fludarabine and melphalan conditioned MUD transplants.

The opportunity to compare these cohorts arose from a policy change in the dose of alemtuzumab for fludarabine and melphalan conditioned transplants, beginning January 2019. Published cohort studies had suggested that as little as 10mg alemtuzumab given on day -1 provided effective prophylaxis against graft versus host disease in unrelated donor transplants (1). A case-controlled study also showed comparable overall survival between patients with and without alemtuzumab in combination with fludarabine and melphalan (2).

All patients were conditioned with 5 doses of fludarabine 30mg/m2 (daily on days -7 to -3) and melphalan 140 mg/m2 (on day -2 or -1). From 2015 to 2018, 47 patients received 60mg of alemtuzumab (30mg on days -4 and -2) and from 2019 to 2021, 42 patients received 30mg (on day -1). A minimum dose of 4x106/kg CD34+ stem cells was infused. Pre-emptive donor lymphocyte infusions were given to all patients with mixed T cell chimerism in the absence of GVHD starting at 6 months post-transplant with a dose of 3 x 105 CD3+ cells/kg and continued every 3 months in half-log increments until full donor chimerism or the occurrence of GVHD. Both cohorts were similar in age, transplant indication, stem cell source, human leukocyte antigen (HLA) matching and cytomegalovirus (CMV) serostatus. All patients gave consent for clinical follow-up and blood sampling according to the research protocol ‘Improving HSCT Outcome’ (IRAS 129780; Northumberland and North Tyneside Research Ethics Committee, United Kingdom).

Serum samples were available from 21 patients in the 60mg group and 19 patients in the 30mg group at days 0, +7, and +14. Alemtuzumab levels were measured by ELISA utilizing an affinity-purified human polyclonal anti-idiotype antibody derived from a patient who had developed anti-alemtuzumab immunity during the development of alemtuzumab as a treatment for lymphoproliferative disorders. The re-expression of CD52 was monitored at serial time points after transplant as a surrogate for the effective level of alemtuzumab in vivo.

The mean level (SD) of alemtuzumab at transplantation was 3.63 (1.33) µg/ml with 30mg compared with 6.55 (1.66) µg/ml with 60mg of alemtuzumab (p = &lt;0.0001). Alemtuzumab remained detectable at +7 and +14 days and was significantly different between the two cohorts, declining to 0.49 (0.52) µg/ml with 30mg and 1.12 (0.84) µg/ml with 60mg on day +14 (p = 0.0264). Re-expression of CD52 by multiple lineages was observed by 21 days post-transplant.

There was no increase in the incidence or severity of acute GVHD which occurred in 52% and 55% of recipients of 60mg and 30mg alemtuzumab, respectively. The one-year incidence of chronic GVHD was also similar between 60mg and 30mg cohorts, occurring in 61% and 41%, respectively. Two-year overall survival was 69% with 30mg and 68% in with 60mg with no detectable differences in relapse or non-relapse mortality. Greater freedom from CMV reactivation was observed with 30mg (43% compared with 78%; p = 0.012). No differences were detected in lymphocyte reconstitution, donor T cell chimerism, nor use of donor lymphocyte infusion.

This retrospective data concurs with previously published series in adults that the empiric dose of alemtuzumab may be safely reduced in matched unrelated donor transplants. We found that 30mg in day -1 provides comparable mitigation of GVHD risk and a small benefit in immune reconstitution compared to 60mg (day -4, -2), in MUD transplants. With late scheduling of infusion (day -1 versus day -7 to -4), further dose reduction may be possible without increasing the risk of GVHD. As it is not possible to perform a clinical trial with an off-label drug, this may only be achieved by a process of retrospective audit, as described here.

Note: the use of alemtuzumab in conditioning for transplantation is off-label

1. Bertz, H. (2009) Biol Blood Marrow Transplant, 15, 1563-1570.

2. Perez-Simon, J. A. (2002). Blood, 100, 3121-3127