Volume 13, Issue 1 , Pages 31-33, January 2007
What’s Past Is Prologue: Lessons Learned and the Need for Further Development of Allogeneic Hematopoietic Stem Cell Transplantation for Renal Cell Carcinoma
Article Outline
Rini and colleagues [1] recently reported the results of a multi-institutional study by the Cancer and Leukemia Group B (CALGB) investigating nonmyeloablative hematopoietic cell transplantation in patients with advanced renal cell carcinoma (RCC). Twenty-two patients received conditioning with cyclophosphamide and fludarabine followed by a granulocyte colony-stimulating factor mobilized peripheral blood stem cell transplant from an HLA-matched sibling. Patients were eligible to receive donor lymphocyte infusions and/or interferon-α to treat disease progression. Sustained engraftment was observed in 21 patients, with 17 patients achieving >90% donor T cell chimerism by day 120. Progression-free survival (3 months) and overall survival (5.5 months) were extremely short. Despite the presence of grade II-IV acute and chronic graft-versus-host disease (GVHD; 32% and 23% of patients, respectively), no objective disease responses were observed. This report brings to mind prior early experiences of allogeneic transplantation for hematologic diseases and highlights the need for further research of allogeneic transplantation for metastatic RCC.
Several decades ago, when the use of allogeneic transplantation for chronic myelogenous leukemia (CML) was first reported by Thomas et al [2], the results were exciting and disappointing; exciting in the sense that a proportion of patients was cured, but disappointing in terms of poor overall efficacy and substantial toxicity. As time went on, it became clear that the limited efficacy of the approach was largely related to selecting patients with advanced CML (blast crisis) and that a substantial proportion of the morbidity and mortality of the procedure occurred as a consequence of ineffective supportive care. By the end of the 20th century, with better patient selection criteria and the advent of more effective supportive care measures, approximately 80% of patients with chronic phase CML could be expected to be cured after allogeneic hematopoietic cell transplantation [2]. Although the suitability of solid tumors as targets for allogeneic immunotherapy remains under investigation, this report from the CALGB makes us ask whether history may be repeating itself, this time for metastatic RCC.
Several analogies can be drawn from the experience of Thomas et al. First, a graft-versus-tumor (GVT) effect can be evoked against RCC; proof of concept was established in 2000 and ≥9 small case series since that time have reported delayed tumor regression after transplantation consistent with a GVT effect, with long-term and occasionally complete responses being observed in some patients with widely metastatic disease (Table 1) [3]. Although current transplantation strategies enrolling patients with advanced tumors and short anticipated survival may considerably limit the efficacy of this approach, proof of concept and the observation of durable complete responses provide a foundation on which to further develop more effective transplantation approaches. Second, it has been clear from the first report of a delayed GVT effect against RCC that a number of factors can limit a successful transplantation outcome. Unfortunately, patients are often referred for consideration of an allogeneic transplant too late in the course of their disease, as a “last ditch effort,” when all other therapeutic options have failed. RCC is intrinsically resistant to chemotherapeutic agents, even after they have been dose intensified. Because the conditioning regimen offers no direct tumor cytoreductive effect and because GVT effects against RCC appear delayed compared with hematologic malignancies, patients often succumb to tumor progression before a donor immune-mediated GVT effect can occur. This delay makes careful selection of patients for the procedure obligatory. Exclusion of patients with survival so short that a GVT effect is unlikely to occur, including those with rapid tumor growth, unfavorable histologies, hypercalcemia, and other factors predictive of short survival, is necessary given this limitation. From the initial report of GVT effects in RCC, delays in responses and responses being restricted to tumors of clear cell histology were reported [3]. The extremely short survival in the patient cohort reported in this study and the failure to restrict enrollment to those with clear cell histology suggest that investigators in this trial may not have adapted sufficiently stringent inclusion criteria appropriate for this type of procedure. Although earlier reports had clearly identified this limitation, this trial was initiated before some of those reports were published. As such, this study provides additional evidence highlighting the critical importance of being selective in choosing patients with metastatic RCC who undergo transplantation. Collectively, these factors likely played a role in the lack of a response and the short overall survival observed in the patients presented in the CALGB study.
Table 1. Nonmyeloablative Allogeneic Stem Cell Transplantation for Metastatic Renal Cell Carcinoma: Series Published up to 2006
| Study | Patients, n | Conditioning Agents | GVHD Prophylaxis | aGVHD (II-IV) | cGVHD | TRM | Response (PR or CR) |
|---|---|---|---|---|---|---|---|
| Childs et al [5] | 19 | Flu + Cy | CSA | 53% | 21% | 11% | 53% |
| Rini et al/Artz et al | 18 | Flu + Cy | Tacro + MMF | 22% | 39% | 14% | 22% |
| Bregni et al | 7 | Flu + TT | CSA + MTX | 86% | 71% | 0% | 57% |
| Pedrazzoli et al | 7 | Flu + Cy | CSA + MTX | 0% | N/A | 29% | 0% |
| Blaise et al | 25 | Flu + Bu + ATG | CSA | 42% | 60% | 9% | 8% |
| Nakagawa et al | 9 | Flu/Cla + Bu + ATG | CSA | 44% | 44% | 0% | 11% |
| Ueno et al [4] | 15 | Flu + Mel | Tacro + MTX | 47% | 27% | 33% | 20% |
| Hentschke et al | 10 | Flu + TBI ± ATG | CSA + MMF | 50% | 30% | 40% | 0%⁎ |
| Massenkeil et al | 7 | Flu + Cy + ATG | CSA ± MMF | 29% | 57% | 14% | 29% |
| Tykodi et al | 8 | Flu + TBI | CSA + MMF | 50% | 50% | 13% | 13% |
| Barkholt et al | 124 | V | CSA ± MMF or MTX | 40% | 33% | 16% | 32% |
| Rini et al | 22 | Flu + Cy | Tacro + MTX | 32% | 23% | 9% | 0% |
⁎mixed response observed. |
Although transplantation may not be advisable for those with rapidly advancing disease or poor prognostic factors (eg, high lactate dehydrogenase levels, poor performance status, high calcium or hemoglobin concentrations), results for other patients can be quite good, including partial and complete responses associated with a prolongation in survival compared with nonresponders [4, 5, 6, 7]. As such, adopting necessary selection criteria should not be considered “extreme” but rather “appropriate” given the limitations of current nonmyeloablative transplantation approaches. Studies of transplantation for hematologic malignancies in the late 1970s and early 1980s likewise adapted appropriate methods to select patients who were most likely to benefit from the procedure, with a net improvement in outcome compared with early transplantation results. Another important consideration is the learning curve that comes with performing allogeneic transplantation on patients with solid tumors. As pointed out by the investigators in the CALGB trial, transplantation for solid tumors is unique from hematologic malignancies because it requires coordination between the solid tumor “specialist” who may not otherwise have transplantation expertise and the transplantation physician who may not routinely care for patients with RCC. Centers performing such transplantations need to have not only expertise in performing and managing complications associated with allogeneic transplantation but also a comprehensive team approach in which medical, radiation, and surgical oncologists are available to assist in the selection of appropriate transplant candidates and to manage complications associated with tumor progression. Further, because GVT effects can be closely linked to GVHD, using a transplantation strategy that seeks to induce rather than avoid alloreactivity through aggressive immunosuppression withdrawal, donor lymphocyte infusions, and post-transplantation interferon use, all of which increase the risk of acute and chronic GVHD, is a reasonable goal. In the CALGB trial, only 2 of 22 patients went on to receive donor lymphocyte infusions or interferon-α therapy, despite progression occurring in most. Thus, it is important that physicians who investigate allogeneic transplantation for solid tumors be well versed in the nuances of the disease and use appropriate and aggressive treatments to manage disease progression occurring in the early post-transplantation window before a GVT effect has occurred. As an example, for mild skin GVHD, the use of topical rather than more globally immunosuppressive systemic steroids may be preferred. Further, incorporating a strategy of “permissive GVHD” in which immunosuppression tapering occurs in the setting of mild non-life-threatening acute and chronic GVHD may also be used to optimize a GVT effect against the tumor (a strategy not typically used for hematologic malignancies). A greater understanding of the importance and effectiveness of these types of unconventional maneuvers seems necessary before such strategies can be incorporated globally into transplantation protocols used in the cooperative group setting.
So what should be done at this juncture? First, the selection of patients for allogeneic transplantation should be subject to strict transplantation-based (rather than disease-based) criteria. These criteria should be further expanded to include known prognostic markers related to survival in patients with metastatic RCC. Rather than viewing selectivity as a bias unfairly affecting the validity of a study, we should take advantage of it to find new prognostic factors that can be used to identify those patients who would derive the most benefit from GVT effects. The recently initiated multi-institutional National Marrow Donor Program study of unrelated-donor transplantation for metastatic RCC incorporates eligibility criteria to select those patients most likely to benefit from this approach including clear cell only histology and other variables associated with survival times sufficient for the induction of a GVT effect (ie, normal calcium, lactate dehydrogenase, and hemoglobin levels).
Second, the fact that GVT effects against RCC appear delayed compared with hematologic malignancies cannot be ignored. Novel, innovative trials that incorporate strategies to control disease until a GVT effect can occur; such as through the use of tumor angiogenesis inhibition in the immediate post-transplantation period, could potentially overcome this limitation.
Third, efforts should be focused on the development of transplantation approaches that capitalize on the induction of beneficial GVT effects and avoid GVHD. The identification of antigens targeted by the donor immune system that are restricted to the tumor could lead to more effective strategies incorporating post-transplantation tumor vaccination or the adoptive infusion of in vitro expanded donor T cells reactive against patient RCC cells. The adoptive infusion of alloreactive donor natural killer cells with enhanced cytotoxicity compared with autologous natural killer cells is another promising area of research [8].
Fourth, recent advances in therapies targeting tyrosine kinases involved in tumor angiogenesis (eg, sunitinib malate [Sutent], sorafenib [Nexavar]) have recently expanded the therapeutic options for patients with metastatic RCC. Although these drugs do not appear to have the potential to cure, they can induce partial responses and disease stabilization, significantly prolonging the time to tumor progression. There exists a theoretical concern that enrolling patients into transplantation trials for whom these agents have failed may further shorten the already brief window of time that these patients have for a GVT effect to be induced. Strategies that incorporate these drugs into the transplantation regimen itself will likely be investigated in the near future.
The apparent lack of effect observed in the CALGB trial may unfortunately spur negative perceptions regarding the potential usefulness of transplantation for metastatic RCC, particularly among those without knowledge of the track record of the successful evolution in efficacy of allogeneic transplantation for other malignant disorders. Although hematologic malignancies may in general be more sensitive to GVT effects, observation of durable complete remissions after allogeneic transplantation for RCC by other groups combined with the failure of this trial to induce GVT effects underscores the need for a continuing commitment to research in this field.
References
- Adoptive immunotherapy by allogeneic stem cell transplantation for metastatic renal cell carcinoma: a CALGB Intergroup Phase II Study. Biol Blood Marrow Transplant. 2006;12:778–785
- . Historical markers in the development of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 1999;5:341–346
- . Nonmyeloablative transplantation: an allogeneic-based immunotherapy for renal cell carcinoma. Clin Cancer Res. 2004;10:6353S–63539S
- Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. Blood. 2003;102:3829–3836
- Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med. 2000;343:750–758
- Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer. Blood. 2002;99:4234–4236
- Allogeneic stem-cell transplantation of renal cell cancer after nonmyeloablative chemotherapy: feasibility, engraftment, and clinical results. J Clin Oncol. 2002;20:2017–2024
- . The second international meeting on Allogeneic Transplantation in Solid Tumors (ATST). Bone Marrow Transplant. 2006;38(8):527–537
PII: S1083-8791(06)00669-0
doi:10.1016/j.bbmt.2006.09.011
© 2007 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 13, Issue 1 , Pages 31-33, January 2007
