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Graft Purging in Autologous Bone Marrow Transplantation: A Promise Not Quite Fulfilled

Graft Purging in Autologous Bone Marrow Transplantation: A Promise Not Quite Fulfilled

The rationale for graft purging- that infusion of malignant cells contained within the hematopoietic progenitor cells (HPC) infused back to patients who have received high-dose therapy will contribute to relapse-seems very sound. Who would willingly be infused with cancer cells, and who would ever suggest that infusion of such cancer cells could ever be thought of as a good idea? Nonetheless, Alvarnas and Forman are correct in their conclusion that purging has never been demonstrated to lead to improved outcome in randomized trials. The evidence for the presence of tumor cells in HPC collections is overwhelming, as outlined in the accompanying review. Numerous studies in a variety of disease settings have demonstrated that both bone marrow and peripheral blood collections are often contaminated with tumor cells. Even in the absence of clinical trial data demonstrating the need for purging, this might provide some rationale for therapy designed to minimize tumor involvement, particularly now that this can be accomplished more simply by in vivo administration of monoclonal antibody therapy. Benefit of Purging Unsupported
The most convincing evidence that purging is not required comes from two pieces of information. First, patients who relapse after autologous stem cell transplant tend to do so at sites of previous disease, suggesting that endogenous disease (rather than infused tumor cells) is the major cause of relapse, and this is almost certainly the case. However, gene-marking studies have demonstrated that such infused cells are capable of homing back to sites of previous disease, and it is therefore likely that infused tumor cells can at least contribute to relapse at these sites.[1] Second, and more convincingly, randomized trials have not shown any clinical benefit for purging. This could be explained by three possibilities: (1) Purging might be successfully performed and still be irrelevant to outcome. This is certainly the case in patients destined to relapse when high-dose therapy does not lead to eradication of the endogenous tumor. (2) The trials performed have not been sufficiently large or had sufficient follow-up to demonstrate any potential benefit of purging. (3) The clinical trials could have been performed using purging strategies that are not successful in their stated aim, ie, to eradicate residual tumor cells. The Dana-Farber studies did not demonstrate an advantage for patients who underwent transplantation with purged grafts over those who did not; indeed, all patients in this phase II trial received purged grafts. The outcome was improved for patients in whom purging led to successful eradication of the detectable tumor cells.[2] Therefore, purging attempts that are unsuccessful are highly unlikely to lead to demonstrable improvements in outcome. The published randomized trials do not help delineate which of these three possibilities is most likely. In particular, the CUP (Chemotherapy, Unpurged, or Purged stem cell transplantation) trial, which has now been published in peer-reviewed format, contained only a small number of patients per arm and does not comment on the success of the purging strategy.[3] The use of CD34 selection alone, which was used in the randomized trial in multiple myeloma,[4] rarely led to complete eradication of tumor cells in preclinical studies performed in my laboratory (unpublished information). It is hard to argue with the findings of the American Society for Blood and Marrow Transplantation expert panel, which concluded that the use of purged HPC grafts was "not an effective treatment."[5] However, a better conclusion would be that the use of the purging strategy as studied in trials to date has not been effective. Ex Vivo vs In Vivo Purging
Ex vivo purging has most likely had its day. Increased regulatory controls, high cost, and lack of demonstrated efficacy in clinical trials makes further use of this strategy difficult to justify. However, increased availability of multiple monoclonal antibodies for clinical use should allow exploration of the potential benefit of in vivo purging. This approach has a great advantage over ex vivo purging, in that it can be used at the time of stem cell collection to decrease tumor cell contamination, but can also be used- posttransplant, which would serve the dual purpose of clearing residual tumor cells infused back to the patient while eradicating any remaining endogenous tumor cells. Hopefully, as a community, we will do a better job evaluating these therapies than we did assessing the ex vivo purging strategies used in the past.

Disclosures

Dr. Gribben receives grant support from Berlex Oncology.

References

1. Rill DR, Santana VM, Roberts WM, et al: Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells. Blood 84:380-383, 1994.
2. Gribben JG, Freedman AS, Neuberg D, et al: Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 325:1525-1533, 1991.
3. Schouten HC, Qian W, Kvaloy S, et al: High-dose therapy improves progression-free survival and survival in relapsed follicular non- Hodgkin’s lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918-3927, 2003.
4. Stewart AK, Vescio R, Schiller G, et al: Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: Results of a multicenter randomized controlled trial. J Clin Oncol 19:3771-3779, 2001.
5. Hahn T, Wingard JR, Anderson KC, et al: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: An evidence-based review. Biol Blood Marrow Transplant 9:4-37, 2003.
 
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