Quantitation Of Residual Tumor In Patients Undergoing Allo-transplantation

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Abstract

The laboratory continues serial monitoring of BCR-ABL expression in blood leukocytes from all patients undergoing allotransplantation for treatment of chronic myelogenous leukemia at the NIH. The emergence of highly potent tyrosine kinase inhibitors (TKIs) as an therapeutic agent for this disease in recent years has dramatically altered the clinical role of allotransplantation for CML. Whereas transplantation previously was the only curative modality, TKIs prevent disease progression in most patients, and consequently only a small patient subset with refractory disease ultimately require allotransplantation. Despite the higher complexity of the drug resistant patients who ultimately require transplant, our data to date suggests many nonetheless achieve high-grade molecular remissions post transplant. Continued followup using sensitive BCR-ABL detection assays will be necessary before these trends can be unequivocally confirmed. This laboratory uses assays designed to detect short tandem repeat (STR) microsatellite polymorphisms extensively as a tool for monitoring engraftment and donor chimerism in all patients undergoing stem cell allotransplantation at the NIH. These assays also are a useful tool in detecting residual or recurrent (recipient-derived) leukemia, lymphoma, and myelodysplasia in the blood or bone marrow of transplanted patients. Indeed, chimerism assays are essential in distinguishing recurrent primary disease from secondary, donor derived malignancies in this setting. In one notable recent instance, a patient allotransplanted two years earlier for AML was found to have circulating blasts in his peripheral blood morphologically consistent with recurrence. Chimerism analysis however, clearly established the abnormal cells were of donor origin and hence represented a second malignancy of donor origin not recurrent disease. Chimerism assays post stem cell transplant provide valuable information about residual malignancy in many of the patients undergoing experimental allotransplantation at the NIH. Finally, my laboratory has begun exploring the potential of plasma DNA as a source for monitoring minimal residual disease in patients with B cell malignancies. The initial studies in this area have been focused on monitoring specific B cell rearrangements in patients with multiple myeloma. These efforts are particularly pertinent because recent advances in multiple myeloma therapy for the first time make it possible to routinely induce high-grade clinical remissions in this population of patients. The most sensitive assay for monitoring of residual disease currently in use (bone marrow aspirate/biopsy/flow cytometry) is invasive or and in highly vulnerable to sampling errors. In a proof of principle study we are examining whether tumor derived rearranged B cell receptor products released into plasma can be used to monitor tumor cell mass in vivo. To this end, the laboratory has isolated and sequenced clonal B cell products from five multiple myeloma patients and will use patient specific qPCR assays for serial monitoring of responsive patients. The studies which are in the early phases should be able to definitively address the potential usefulness of plasma DNA for this form of minimal residual disease monitoring in multiple myeloma and later in other B cell malignancies.