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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1508-1509
CORRESPONDENCE
To the editor:
Nonmyeloablative transplantation challenged by experimentation
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.4
Treatment-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.
Marlies E. H. M. Van Hoef
Correspondence: Transplant Creations, 260 S Reynolds Street, Ste
506, Alexandria, VA, 22304; e-mail: mvanhoef{at}mindspring.com
References
1.
Chakraverty R, Peggs K, Chopra R, et al.
Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a non-myeloablative conditioning regimen.
Blood.
2002;99:1071-1078[Abstract/Free Full Text].
2.
Giralt S, Thall PF, Khouri I, et al.
Melphalan and purine analog-containing preparative regimens: reduced intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation.
Blood.
2001;97:631-637[Abstract/Free Full Text].
3.
Slavin S, Nagler A, Naparstek E, et al.
Non-myeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases.
Blood.
1998;91:756-763[Abstract/Free Full Text].
4.
Childs R, Clave E, Contentin N, et al.
Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses.
Blood.
1999;94:3234-3241[Abstract/Free Full Text].
5.
Kottaridis PD, Milligan RC, Chakraverty RK, et al.
In vivo Campath-1H prevents graft-versus-host-disease following nonmyeloablative stem cell transplantation.
Blood.
2000;96:2419-2425[Abstract/Free Full Text].
6.
Small TN, Papadopoulos EB, Boulad F, et al.
Comparison of immune reconstitution after unrelated and related T-cell depleted bone marrow transplantation: effect of patient age and donor leukocyte infusion.
Blood.
1999;93:467-480[Abstract/Free Full Text].
Response:
Alemtuzumab and reduced intensity conditioning
We did indeed cite the results from Giralt el
al.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 al2) 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.
Stephen Mackinnon
Correspondence: Stephen Mackinnon, Department of
Haematology, Royal Free and University College London School of
Medicine, 98 Chenies Mews, London, WC1E 6HX, United Kingdom; e-mail:
s.mackinnon{at}ucl.ac.uk.
References
1.
Giralt S, Thall PF, Khouri I, et al.
Melphalan and purine analog-containing preparative regimens: reduced intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation.
Blood.
2001;97:631-637[Abstract/Free Full Text].
2.
Kottaridis PD, Milligan RC, Chakraverty RK, et al.
In vivo Campath-1H prevents graft-versus-host-disease following nonmyeloablative stem cell transplantation.
Blood.
2000;96:2419-2425[Abstract/Free Full Text].
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Related Article in Blood Online:
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Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen
- Ronjon Chakraverty, Karl Peggs, Rajesh Chopra, Donald W. Milligan, Panagiotis D. Kottaridis, Stephanie Verfuerth, Johanne Geary, Dharsha Thuraisundaram, Kate Branson, Suparno Chakrabarti, Premini Mahendra, Charles Craddock, Anne Parker, Ann Hunter, Geoff Hale, Herman Waldmann, Catherine D. Williams, Kwee Yong, David C. Linch, Anthony H. Goldstone, and Stephen Mackinnon
Blood 2002 99: 1071-1078.
[Abstract]
[Full Text]
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