Chakraverty et al1 recently reported short-term follow-up results of unrelated donor nonmyeloablative transplantations (NMTs) using alemtuzumab (Campath-1H) as in vivo T-cell depletion method. Conditioning consisted of alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis with cyclosporine was administered during 3 months prior to transplantation. Only 3 of 44 evaluable patients developed grade III-IV GVHD. Deaths were not associated with GVHD but with severe infections. Upon treatment for relapse with donor lymphocyte infusions (DLIs), 50% of patients developed GVHD. The authors referenced several articles2-5 and selected the paper with most negative results for comparison.2 In that report nonmyeloablative conditioning consisted of either fludarabine or cladribine and melphalan.2 Tacrolimus (FK506), an experimental drug, and short-course methotrexate were used as GVHD prophylaxis in the majority of patients and administered for either 3 or 6 months. The cladribine cohort was closed early due to high treatment-related mortality (87.5%). The risk of grade III-IV GVHD in unrelated and related donor transplantations was 39% and 16%, respectively; of 86 patients, 16 died of GVHD and 12, of infections, several of which might have been induced by nonlethal GVHD. In 2 other referenced papers of NMTs in related transplantations, alemtuzumab was also not included in the conditioning regimen.3,4 In these reports cyclosporin GVHD prophylaxis was either given until engraftment and then tapered3 or administered for 30 or 60 days respectively in mixed and full chimeras and then tapered.4Treatment-related mortality due to GVHD was 15.6% and 0%, respectively; there was only 1 death in the second report (6.6%) due to infection.3,4 In the other referenced report of NMTs in mainly related donor transplantations,5 the same conditioning regimen was used as that reported by Chakraverty et al.1 In this report, remarkably, of the 8 deaths, 3 occurred due to bacterial infections and 1, due to GVHD after DLI.5 Patient populations in various reports differ from low to high risk and disease status at transplant from first complete remission to very advanced disease; the effect of T-cell depletion on risk of relapse can therefore not be addressed, although notable relapse or disease progression occurred in reports using alemtuzumab.1,5
Promotion of alemtuzumab for use in NMTs should not blindly occur based on these reports. FK506 has shown lack of efficacy and has not been registered, which may explain the high rate of GVHD2. Experimentation with the duration of cyclosporine administration makes interpretation of GVHD and associated mortality unreliable for comparison.3,4 Delayed immune recovery, increased risk of infection, and increased incidence of relapse are associated with T-cell depletion and compromise efficacy when DLIs with associated risk of GVHD are subsequently to be given to support immune recovery or treat relapse.1,5,6 Recommendation of T-cell depletion in NMTs for reduction of GVHD should not occur based on the authors' presented information, as benefits and risks have not been considered weighted nor has comparison with standard NMTs occurred.
Alemtuzumab and reduced intensity conditioning
We did indeed cite the results from Giralt el al.1-1 This was not only because their conditioning regimen used in all but 8 of the 86 patients used both fludarabine and melphalan in doses similar or identical to our series, but also because this was the only report (apart from our initial publication, Kottaridis et al1-2) to include data using unrelated donors.
Tacrolimus (FK506) in combination with methotrexate has been shown to be at least as effective at preventing GVHD as the combination of cyclosporine A plus methotrexate in randomized trials. We believe that our data convincingly show that the combination of pretransplantation in vivo alemtuzumab (Campath-1H) and posttransplantation cyclosporine A is more effective at preventing GVHD than conventional immunosuppression, especially when using unrelated donors.
The use of alemtuzumab or any other maneuver that effectively results in T-cell depletion of the graft may have adverse effects, including slow immune reconstitution resulting in an increased risk of viral infection and stable mixed chimerism that could abrogate the graft-versus-leukemia (GVL) effect of the allograft and lead to relapse of the underlying malignancy. Longer-term follow-up will be required to assess whether these potential disadvantages will outweigh the lower GVHD-related morbidity and mortality.
Lastly, we do not “blindly” advocate the use of alemtuzumab in reduced-intensity conditioning regimens but would encourage Dr Van Hoef and others to enter patients into clinical trials that will seek to answer some of the many unresolved questions relating to this novel approach to allogeneic transplantation. We believe that it is important to promote an evidence-based evolutionary approach, rather than a creationist approach, to transplantation research.
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