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

The rationale for graft purging-that infusion of malignant cellscontained within the hematopoieticprogenitor cells (HPC) infusedback to patients who have receivedhigh-dose therapy will contribute torelapse-seems very sound. Whowould willingly be infused with cancercells, and who would ever suggestthat infusion of such cancer cells couldever be thought of as a good idea?Nonetheless, Alvarnas and Forman arecorrect in their conclusion that purginghas never been demonstrated tolead to improved outcome in randomizedtrials.The evidence for the presence oftumor cells in HPC collections is overwhelming,as outlined in the accompanyingreview. Numerous studies ina variety of disease settings have demonstratedthat both bone marrow andperipheral blood collections are oftencontaminated with tumor cells. Evenin the absence of clinical trial datademonstrating the need for purging,this might provide some rationale fortherapy designed to minimize tumorinvolvement, particularly now that thiscan be accomplished more simply byin vivo administration of monoclonalantibody therapy.Benefit of Purging Unsupported
The most convincing evidence thatpurging is not required comes fromtwo pieces of information. First, patientswho relapse after autologousstem cell transplant tend to do so atsites of previous disease, suggestingthat endogenous disease (rather thaninfused tumor cells) is the major causeof relapse, and this is almost certainlythe case. However, gene-markingstudies have demonstrated that suchinfused cells are capable of homingback to sites of previous disease, andit is therefore likely that infused tumorcells can at least contribute torelapse at these sites.[1]Second, and more convincingly,randomized trials have not shown anyclinical benefit for purging. Thiscould be explained by three possibilities:(1) Purging might be successfullyperformed and still be irrelevantto outcome. This is certainly the casein patients destined to relapse whenhigh-dose therapy does not lead toeradication of the endogenous tumor.(2) The trials performed have not beensufficiently large or had sufficientfollow-up to demonstrate any potentialbenefit of purging. (3) The clinicaltrials could have been performedusing purging strategies that are notsuccessful in their stated aim, ie, toeradicate residual tumor cells. TheDana-Farber studies did not demonstratean advantage for patients whounderwent transplantation withpurged grafts over those who did not;indeed, all patients in this phase IItrial received purged grafts. The outcomewas improved for patients inwhom purging led to successful eradicationof the detectable tumorcells.[2] Therefore, purging attemptsthat are unsuccessful are highly unlikelyto lead to demonstrable improvementsin outcome.The published randomized trialsdo not help delineate which of thesethree possibilities is most likely. Inparticular, the CUP (Chemotherapy,Unpurged, or Purged stem cell transplantation)trial, which has now beenpublished in peer-reviewed format,contained only a small number ofpatients per arm and does not commenton the success of the purgingstrategy.[3] The use of CD34 selectionalone, which was used in the randomizedtrial in multiple myeloma,[4]rarely led to complete eradication oftumor cells in preclinical studies performedin my laboratory (unpublishedinformation).It is hard to argue with the findingsof the American Society for Bloodand Marrow Transplantation expertpanel, which concluded that the useof purged HPC grafts was "not aneffective treatment."[5] However, abetter conclusion would be that theuse of the purging strategy as studiedin trials to date has not been effective.Ex Vivo vs In Vivo Purging
Ex vivo purging has most likelyhad its day. Increased regulatory controls,high cost, and lack of demonstratedefficacy in clinical trials makesfurther use of this strategy difficult tojustify. However, increased availabilityof multiple monoclonal antibodiesfor clinical use should allow explorationof the potential benefit of in vivopurging. This approach has a greatadvantage over ex vivo purging, inthat it can be used at the time of stemcell collection to decrease tumor cellcontamination, but can also be used-posttransplant, which would serve thedual purpose of clearing residual tumorcells infused back to the patientwhile eradicating any remaining endogenoustumor cells. Hopefully, as acommunity, we will do a better jobevaluating these therapies than we didassessing the ex vivo purging strategiesused in the past.

Disclosures:

Dr. Gribben receivesgrant support from Berlex Oncology.

References:

1.

Rill DR, Santana VM, Roberts WM, etal: Direct demonstration that autologous bonemarrow transplantation for solid tumors canreturn a multiplicity of tumorigenic cells. Blood84:380-383, 1994.

2.

Gribben JG, Freedman AS, Neuberg D,et al: Immunologic purging of marrow assessedby PCR before autologous bone marrow transplantationfor B-cell lymphoma. N Engl J Med325:1525-1533, 1991.

3.

Schouten HC, Qian W, Kvaloy S, et al:High-dose therapy improves progression-freesurvival and survival in relapsed follicular non-Hodgkin’s lymphoma: Results from the randomizedEuropean CUP trial. J Clin Oncol21:3918-3927, 2003.

4.

Stewart AK, Vescio R, Schiller G, et al:Purging of autologous peripheral-blood stemcells using CD34 selection does not improveoverall or progression-free survival afterhigh-dose chemotherapy for multiple myeloma:Results of a multicenter randomizedcontrolled trial. J Clin Oncol 19:3771-3779,2001.

5.

Hahn T, Wingard JR, Anderson KC, etal: The role of cytotoxic therapy with hematopoieticstem cell transplantation in the therapyof multiple myeloma: An evidence-based review.Biol Blood Marrow Transplant 9:4-37,2003.