Angelo M. Carella @
Department of Hematology/Oncology, IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy.
@ Angelo M. Carella, M.D., IRCCS Casa Sollievo della Sofferenza,
71013 San Giovanni Rotondo (FG), Italy
Fax: +39-0882-410258; e-mail: amcarella@operapadrepio.it
High-dose chemotherapy followed by autologous peripheral-blood stem cell transplantation has resulted in long-term disease-free survival of 30%-60% in selected patients with refractory and relapsed Hodgkin's disease. In addition, a significant reduction in early transplant-related mortality in more recent studies has led to the widespread acceptance of autografting. Comparatively few studies of allografting for Hodgkin's disease have been performed. Although no prospective randomized trials have been performed, historical results suggest a significantly lower relapse rate when allografting results are compared to autografting results. These results suggest that a graft-versus-Hodgkin's disease effect may exist. Unfortunatey, the lower relapse rate following allografting is offset by higher transplant-related mortality. The use of low-intensity non-myeloablative regimens for allografting may harness a graft-versus-Hodgkin's disease effect with less morbidity than that observed following conventional allografting.
Hodgkin's disease is the most common malignancy in people 10-30 years of age, with an incidence of 3 per 100,000 [1-3]. In this disease, as in other hematological malignancies, strong evidence in favor of a dose-response relationship between antineoplastic treament and therapeutic outcome has been found. Use of cyclic combination chemotherapy (mechlorethamine/vincristine/procarbazine/predisone [MOPP]) in patients with advanced-stage disease has allowed more than 80% of patients to achieve complete remission and more than 50% of those remitters to maintain complete remission permanently [4]. Susequently, MOPP has gradually been replaced with doxorubicin/bleomycin/vinblastine/dacarbazine [ABVD]), which currently is regarded as the gold standard in treatment due to a more favorable toxicity profile [5]. Although Hodgkin's disease represents a relative success story for modern hemato-oncology, many critical management decisions, such as the exact role of autologous and allogenic peripheral-blood stem cell [PBSC] transplantation, still remain unclear.
Autologous Stem Cell Transplantation:
...
Autologous Stem Cell Transplantation in Relapsed Patients:
...
Autologous Stem Cell Transplantation as Part of Initial
Therapy:
...
Therapy After Relapse Following Autografting:
...
Allogeneic Stem Cell Transplantation:
...
A new enthusiasm for allografting in malignant lymphomas has arisen
from the use of less intensive preparative regimens that provide sufficient
immunosuppresion for allogeneic engraftment; this means less toxicirty
than standard high-dose preparative regimens [68-76].
These non-myeloablative transplants are expected to allow the development
of graft-versus-lymphoma reactions with less morbidity than conventional
allografting. Several reports have demonstrated favorable outcomes in small
cohorts of lymphoma patients [68, 69,
74-76].
Some investigators have tested non-myeloablative allograft as consolidation
therapy after autografting [76] or for relapse after
autografting [75]. In fact, the greater potential benefit
of allografting could be exploited if conditioning mortality is decreased
and tumor burden is minimized with autografting before mini-allografting,
mainly in patients with primarily resistant disease, disease < 1 year
from complete remission, or multiple relapses. The recent observations
that fludarabine-containing regimens have resulted in engraftment of allogeneic
cells (with or without early cyclosporine withdrawal and/or donor lymphocyte
infusion) with reduced morbidity and procedure-related deaths raise the
possibility that less intensive conditioning regimens might also be useful
in patients with an indication for allografting but who are too old to
receive the conventional procedure.
Autografting Followed by Mini-Allografting:
In Genoa, a strategy of autografting followed by allografting has
recently been designed to take advantage of both the anti-neoplastic and
immunosuppresive effects of high-dose therapy to allow succesful allogeneic
cell therapy in patients with advanced lymphomas [76].
Thirteen
patients with Hodgkin's disease were treated. All patients received
high-dose therapy with BEAM (carmustine/etoposide/cytosine arabinoside/melphalan)
protocol and autologous PBSC infusion followed by autografting. The conditioning
regimen for allografting consisted of fludarabine 30 mg/m2 daily
with cyclophosphamide 300 mg/m2 for 3 days followed by donor-mobilized
PBSC collections. These cells were prepared for fresh infusion and were
not T-cell depleted. Methotrexate and cyclosporine were used to prevent
graft rejection and as GVHD prophylaxis. Combined therapy was well tolerated.
Ten
patients had 100% donor cell engraftment. Eight patients achieved
a complete remission after the combined procedure. Six patients,
who were in partial remission after autografting, achieved a complete remission
after mini-allografting. Six patients developed grade 2 or more
acute GVHD, and 1 developed extensive chronic GVHD. Two
of 3 patients who received the highest number of donor lymphocytes
developed grade 3 acute GVHD. Ten patients are currently alive,
and 5 of these are in continuous complete remission 412-767 days
(median: 627 days) after allografting (Figure 5). Three patients
died (1 of progressive disease, 1 of progressive disease
combined with extensive chronic GVHD, and 1 of infection).
The fludarabine/cyclophosphamide conditioning regimen
was well tolerated and allowed consistent engraftment. The response
rates were high in this group of refractory and heavily pretreated
patients. However, more data are required to assess the value of
this treatment.
Late Effects of Transplantation:
...
Conclusion and Future Directions:
High-dose therapy followed by PBSC rescue has been accepted
for several situations affecting patients with Hodgkin's disease. Although
no randomized trial has clearly demonstrated overall survival advantages
with high-dose therapy, there is wide agreement that this procedure is
better than conventional salvage chemotherapy in patients who fail to achieve
complete remission or who relapse within 1 year from remission [22].
At the moment, the value of early autografting in patients who relapse
after a longer initial remission remains controversial, and only ongoing
randomized trials can give us a definitive answer.
Early mortality rates after high-dose therapy are less
than 5%, and the biggest risk for these patients is relapse. Consequently,
it is hoped that new technologies can be developed to improve the results
of high-dose therapy. In this context, the value of double autografting
[33] or autografting followed by mini-allografting
[76] in patients who have an HLA-identical sibling should
be further explored. Continued monitoring for detection of late events
is mandatory; reports of successful pregnancies following high-dose therapy
are gratifying.
This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC 2000).
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...
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