We read with great interest the article on comparison of single-dose and escalating dose regimens of donor lymphocyte infusions for relapse after allografting for chronic myeloid leukemia.1 The observation that graft-versus-host disease can be minimized by staggering lymphocyte infusions, even with a similar final number of cells, is of extreme importance.
Two important aspects of the methodology however are missing. The first is age of the patients and whether age is balanced equally in the 2 groups. Since younger patients have a better prognosis for overall survival and a lower rate of graft-versus-host disease following allogeneic bone marrow transplantation, this information is critical.
Another important aspect of the methodology that should be clarified is whether donors received mobilization therapy or not. Since the bulk dose regimen was done during an earlier time period (August 1990 through November 1995) than the escalating dose regimen (December 1995 through January 1998), it is possible but not stated that preparation of the donor may have varied. In many centers including our own, early protocols involved donor lymphocyte infusions obtained without special preparation of the donor. These early studies were associated with a high incidence of graft-versus-host disease and pancytopenia. Subsequently, in our center and others, donor lymphocyte infusions have been obtained using cells mobilized with G-CSF or with other regimens.2-4
We2 and others3,4 have found that use of G-CSF mobilized harvests contain a large number of lymphocytes, at least equal to those of lymphocyte harvests alone. Mobilization with G-CSF, however, results in other benefits that may improve overall efficacy. First, G-CSF mobilization recruits stem cells that can help to avoid pancytopenia, one of the most common and severe complications of donor lymphocyte infusions when used alone. Second, G-CSF mobilization recruits additional effector cells (cytokine producing cells, antigen presenting cells, and others) transferred with the T-lymphocytes, which could possibly further improve the antileukemia effect. Third, G-CSF polarizes lymphocytes from Th1 to Th2 phenotype, resulting in less cytokine reaction and less graft-versus-host disease.5Finally, G-CSF mobilization may maintain graft-versus-leukemia effect while preventing graft-versus-host disease through a perforin-dependent pathway, a particularly attractive way to use donor cells. Whether these theoretical benefits of G-CSF mobilization are achievable on a practical level is not yet clear as only small studies have been reported,3,4 and results have varied from favorable3 to equivocal.4
Clarification of these points will help in the interpretation of the study and could provide important information for subsequent studies.
Neither age nor mobilization likely to have effect
Imperial College School of Medicine at Hammersmith Hospital
London, United Kingdom
Imperial College School of Medicine at Hammersmith Hospital
London, United Kingdom
Imperial College School of Medicine at Hammersmith Hospital
London, United Kingdom
Dr Mehta raises 2 important points. The first relates to the ages of the patients who received DLI in our study by escalating dose regimen (ESC) or bulk dose regimen (BDR) respectively. There was no significant difference between the 2 groups [BDR n = 28, mean age 40.8 (19.5 to 57.6), EDR n = 20, mean age 36.9 (23.9 to 52.8),P = .13]. The slightly higher age in the BDR group can be accounted for by the fact that the ratio of sibling recipients to unrelated donor recipients was higher in the BDR than in the EDR group. Since patient age is indeed a major factor predictive of GVHD after transplant, especially when using unrelated donors,1-1 the higher proportion of recipients of unrelated donor transplants in the EDR group actually strengthens the evidence that it is the regimen of administration that is responsible for the reduced incidence of GVHD.
The second point regards the use of G-CSF mobilized lymphocytes. None of our patients received mobilized peripheral blood mononuclear cells; so the low incidence of GVHD in the EDR group cannot be attributed to the use of this technique. We would like to make some comments to this point. First, the possibility that G-CSF mobilized PBMC may reduce the incidence of pancytopenia remains to be demonstrated. In fact, a preliminary report from the Seattle transplant group showed that the administration of G-CSF mobilized lymphocytes does not prevent the DLI-induced aplasia.1-2 Nevertheless, pancytopenia was not a major problem in our cohort of patients; when it did occur, it resolved spontaneously or after the infusion of the donor stem cells.1-3 The second aspect regards the effect of G-CSF on donor lymphocytes. Although the suggestions provided by Dr Metha may be of value, there is no clear evidence that G-CSF can commit the donor T cells toward a leukemia-specific immune response. The ability of G-CSF to potentiate the immune effectors also remains controversial.1-4 In summary, we feel that the approach we have been using to administer DLI on an escalating dose regimen is effective and is associated with little toxicity, and thus we do not consider any change to be justified.
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