March 1, 2007

The Future Of Allogeneic Hematopoietic Stem Cell Transplantation For Metastatic Renal Cell Carcinoma In The Era Of Target-Specific Therapy - Allogeneic hematopoietic stem cell transplantation (BMT) for metastatic renal cell carcinoma (RCC) was first reported by Childs in 1999. In that report, patients received a conditioning regimen of fludarabine/cyclophosphamide, prior to BMT. The incidence of acute graft versus host disease (GVHD, thought to be linked to tumor response) was 53% and chronic GVHD was 21%. Overall response rate was 53%, with 3 complete and 7 partial responses, although treatment related mortality was 11%.

Subsequently, 16 other studies examining the role of BMT in RCC have been published, involving 167 patients. In summary, these studies report an acute GVHD rate of 50%, a chronic GVHD rate of 30%, a treatment related mortality rate of 14%, and a significantly lower response rate of 22%. It should be noted that these patients, for the most part, had failed other prior therapies, had progressive disease, and had large tumor burdens. One limitation of this therapy is the need for a matched donor of stem cells, which can be identified only 20-30% of the time. More recent studies have examined the role of stem cells isolated from unrelated umbilical cord blood, which may circumvent the need for a matched donor.

In contrast, targeted therapies (sunitinib, sorafenib, bevacizumab, etc.) have demonstrated significant delays in time to progression, improved survival, but few, if any, clinically significant responses. For the most part, patients demonstrate minor responses or prolonged stabilization of disease, but no durable complete responses as those seen with immunotherapy such as interferon, interleukin 2, and BMT. Targeted therapy is rapidly becoming front line therapy for metastatic RCC due to the ease of administration and management of toxicity, thus raising the question as to whether there remains a role for immunotherapeutic approaches such as BMT in the future.

The authors conclude that there is, indeed, a role for BMT in the treatment of patients with metastatic RCC, but further refinements in the technology are required to improve efficacy, decrease toxicity, and minimize treatment related mortality before more widespread acceptance will occur. These include:

-- Identification of tumor specific antigens that can be targeted to minimize or eliminate the toxicity of GVHD.

-- Need to identify optimal standard conditioning regimen.

-- Need to identify sources of stem cells that will allow more widespread application of this treatment modality (such as umbilical cord blood).

-- Need for improved patient selection. Treatment related responses can take months to ensue after engraftment. Patients with rapidly progressive disease, large tumor burdens, or those that have failed multiple prior regimens demonstrate a biology that is not conducive to enduring this delay in time to treatment effect. To utilize this therapy, there is a 2-3 month window of preparative time prior to treatment, and therefore this modality should be considered early rather than late in the course of a patient's disease.

With these advances, the authors argue that BMT (and other immunotherapy approaches) remains a viable and attractive therapy for patients with metastatic RCC, due in large part to the higher incidence of durable responses when compared to the newer targeted therapies.

Ueno NT and Cheng YC
Bone Marrow Transplantation 38: 711-714, 2006.

Reviewed by Contributing Editor Christopher G. Wood, MD, FACS

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