The recent article by Ballen et al1 offers the opportunity for some considerations. The originality of this study resides in the infusion either of nonmobilized pheresed lymphocytes from HLA-identical siblings or of umbilical cord blood cells with various degrees of HLA mismatches in patients with refractory cancer or hematologic malignancies. The immunosuppression consisted only of 100-cGy total body irradiation. Not surprisingly, given the low level of immunosuppression, all cancer patients rejected the lymphocytes and all cord blood transplants did not engraft. The only patients evaluable for follow-up were the 11 patients who received lymphocytes from their sibling donor. Nine of them had some level of donor chimerism and 6 developed acute graft-versus-host disease (aGVHD). In this context, characterized by the infusion of allogeneic lymphocytes in an immunocompromised host without support of stem cells, the subsequent aGVHD may be compared with the transfusion-associated GVHD (TA-GVHD). TA-GVHD is a dramatic event with the clinical features of classical aGVHD and a later development of pancytopenia, with overwhelming infection as the most common cause of death.2 In the Ballen et al1 study, 6 patients experienced neutropenia, in some cases with Gram-negative sepsis. Unfortunately, Ballen et al do not clarify the correlation between neutropenia and aGVHD. However, it is noteworthy that 2 of the patients who developed GVHD later received an infusion of stem cells from their donors. It is reasonable to assume that, at least in part, the same patients who had aGVHD later developed neutropenia.
In a similar study, Porter et al3 obtained the engraftment of allogeneic lymphocytes in 4 of 16 patients, and the only patient who developed grade 4 aGVHD subsequently had pancytopenia and died of infection. We believe that these findings are convincing enough to reconsider the rationale of clinical trials based on lymphocyte infusion without stem cell support, particularly in this era of “mini-transplants.” Further, the Ballen et al1results highlight the unique susceptibility of hematopoietic tissue to graft-versus-host effect because, in the particular setting of this trial, the bone marrow damage is related only to the graft-versus-host effect. Otherwise, in the context of myeloablative and, at a lesser extent, nonmyeloablative transplantation, the graft-versus-host–induced aplasia is masked by the cytotoxic effect of the conditioning regimen and by the competition between recipient and donor stem cells. The high immunogenicity of hematopoietic tissue can explain, at least in part, the satisfactory clinical results obtained in the treatment of hematologic malignancies with allogeneic stem cell transplantation.4
Low-dose TBI for malignancy: cellular immune therapy
The authors appreciate the communication from Dr Montefusco. However, we do not agree with the assertion that there was no stem cell support. This is not the case and it has been known for decades that nonmobilized peripheral blood contains stem cells. The procedure that we have carried out is perhaps the most “mini” of transplantations with only 100-cGy whole body irradiation and the infusion of relatively small numbers of stem cells with CD3 lymphocytes.1-1 The latter point is critical. We have shown in extensive murine work in syngeneic systems that engraftment is determined by stem cell competition.1-2 In the allogeneic setting either more ablation or some type of additional tolerization is necessary.1-3 It is clear, however, that a major determinant of engraftment and chimerism is stem cell competition. A quite small number of stem cells will repopulate a host if the host has markedly depleted stem cells, as was undoubtedly the case with our patients. It has been shown in murine studies that a single stem cell can accomplish this over time. In addition, it is important to understand that 100 cGy, while not being overtly myeloid toxic (ie, resulting in profound decreases in peripheral blood counts), is profoundly stem cell toxic, with decreases in marrow stem cells persisting for as long as 1 year after irradiation.1-4 Our patients were heavily pretreated and then exposed to 100 cGy. There was also undoubtedly a component of lymphocyte graft-versus-marrow effect.
All of these influences served to produce patients with profound marrow stem cell deficits, who were then repopulated with very low levels of CD34+ cells, as low as 104/kg. Admittedly, CD34+ cells are not stem cells but they do give a possible surrogate marker for the presence of stem cells. The fact that our patients became chimeric and in some cases showed 100% chimerism clearly illustrates the presence of stem cells in our infused product. Therefore, our approach involves a combination of stem cells and lymphocytes.
Clearly, new approaches continue to be necessary in this clinical arena. The mini-transplantations represent a relatively mini-advance with the most promising results seen in the indolent lymphomas. This is shown by the phenomena of mini-transplantation creep, in which the transplants become less and less “mini” and more and more toxic. Investigation of different approaches involving infusion of lymphocyte populations with hematopoietic stem cells, lymphocyte populations alone, or other putative antitumor cell types should be pursued with vigor. The bottom line in our studies is that some very gratifying responses in refractory hematologic malignancies were obtained with relatively little toxicity. Two of these patients remain free of disease at 4 and 2-and-a-half years after transplantation.
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