Type of post‐grafting immunosuppression after non‐myeloablative blood cell transplantation may influence risk of delayed haemolysis due to minor abo incompatibility

We read with interest the recent report by Bolan et al (2001) which summarized the experience at the National Institutes of Health with regard to haemolytic complications from minor ABO incompatibility after human leucocyte antigen (HLA)-matched sibling, non-myeloablative peripheral blood stem cell (PBSC) transplantation. The authors reported two severe cases of delayed immune haemolysis owing to a Ôpassenger lymphocyte syndromeÕ in nine consecutive patients given non-myeloablative transplants. One of the patients died on post-transplant d 16 owing to multiorgan failure resulting from severe haemolysis; the other required multiple red blood cell transfusions but eventually recovered with complete resolution of haemolysis. Haemolysis developed on post-transplant d 7 and 10 respectively. Both patients received cyclophosphamide and ̄udarabine as their preparative non-myeloablative regimen, and cyclosporine (CSA) alone was given for post-grafting immunosuppression. This relatively high incidence of a passenger leucocyte syndrome with associated fatal haemolysis is concerning. Minor ABO mismatches constitute approximately 30% of all conventional haematopoietic stem cell transplants, and clinically detectable haemolysis has been reported in 10±30% of patients (Gajewski et al, 1992). Two types of haemolysis owing to minor ABO incompatibility can be distinguished. ÔEarlyÕ haemolysis is caused by haemagglutinins (HA) present in the plasma of marrow or PBSC products. In contrast, ÔdelayedÕ haemolysis is owing to active antibody production by transplanted donor lymphocytes. Although delayed haemolysis is usually mild and selflimited, it has been associated with severe haemolytic episodes (Sniecinski & O'Donnell, 1999). Non-myeloablative haematopoietic cell transplantation is a relatively novel treatment approach (McSweeney & Storb, 1999; Carella et al, 2000). It entails preparative regimens and post-grafting immunosuppression aimed at preventing graft rejection and clinically intolerable graftversus-host disease while relying on graft-versus-tumour effects for disease eradication. At our institution, the nonmyeloablative preparative regimen consists of ̄udarabine, 30 mg ¤ m, given on d )4, )3 and )2, and total body irradiation (200 cGy) administered on d 0, which is followed by infusion of unmodi®ed PBSC. CSA (6á25 mg ¤ kg p.o. b.i.d.) and mycophenolate mofetil (MMF) (15 mg ¤ kg p.o. b.i.d.) given for post-grafting immunosuppression are started on d )3 and d +1 respectively. The advantage of this approach is a considerable reduction in early regimen-related toxicities compared with myeloablative transplantation. Whether non-myeloablative regimens confer a greater risk for developing delayed haemolytic complications is currently unknown. Based on our institutional experience, this complication has only been seen in 2 out of 40 (5%) HLA-matched non-myeloablative PBSC transplants (23 with related donors; 17 with unrelated donors) in which minor ABO incompatibility was present. Our ®rst patient who developed this complication was a 52-year-old woman with chronic myelogenous leukaemia who showed severe haemolysis 10 d after transplant from a major and minor ABO-mismatched, HLA-matched unrelated female donor (unpublished observations). She fully recovered from this complication and is alive and well more than 5 months later. The second patient, a 38-year-old male with chronic myelogenous leukaemia, developed hyperacute graftversus-host disease of the skin and haemolysis on d 7 following a transplant from a minor ABO-mismatched, HLA-matched unrelated male donor. He experienced an initial 10% decline in his haematocrit over a 24-h period and has ongoing mild haemolysis owing to destruction of host red blood cells (RBCs) by donor HAs. He is currently 3 weeks post transplant and otherwise doing well. Graftversus-host disease is under control after initiation of methylprednisolone therapy on post-transplant d 12. The higher incidence of a passenger leucocyte syndrome reported by Bolan et al (2001) than in our series (22% versus 5%) may be owing to differences in the kind of postgrafting immunosuppression used. Under steady-state conditions, B cells producing naturally occurring HAs are under T-cell control. However, after transplantation of PBSC into ABO-mismatched hosts, HA-producing B cells might escape T-cell control when T-cell activation is blocked by CSA given for post-grafting immunosuppression. Accordingly, one report described that the use of CSA alone was associated with a relatively high incidence of severe delayed haemolysis in myeloablative haematopoietic cell transplantation (Gajewski et al, 1992). Bolan et al (2001) used CSA only whereas in our series CSA was given in combination with the antimetabolite MMF (Niederwieser et al, 2000). In vitro and in vivo data suggest that MMF is a potent suppressor of both Tand B-cell activity (Allison & Eugui, 1996). Delayed haemolysis has rarely been described in patients given the antimetabolite methotrexate (MTX) either alone or in combination with T-cell activation blockers CSA or FK 506. Presumably, British Journal of Haematology, 2002, 116, 500±501