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© 2002 American Society for Clinical Oncology Allogeneic Stem-Cell Transplantation of Renal Cell Cancer After Nonmyeloablative Chemotherapy: Feasibility, Engraftment, and Clinical ResultsByFrom the University of California San Francisco, Comprehensive Cancer Center, San Francisco, CA; Section of Hematology/Oncology, The University of Chicago Hospitals and University of Chicago Cancer Research Center, Chicago, IL. Address reprint requests to Brian I. Rini, MD, UCSF Comprehensive Cancer Center, 1600 Divisadero, 3rd Floor, San Francisco, CA 94115; email: brini{at}medicine.ucsf.edu
PURPOSE: To evaluate the feasibility and safety of nonmyeloablative allogeneic stem-cell transplantation in patients with metastatic renal cell cancer (RCC) and to evaluate efficacy with respect to engraftment and tumor regression. PATIENTS AND METHODS: Between February 1999 and June 2001, patients with refractory, metastatic RCC were screened for enrollment. A fludarabine and cyclophosphamide–based conditioning regimen was used. Patients received granulocyte-macrophage colony-stimulating factor–mobilized, unmanipulated stem cells from a 6/6 HLA-matched sibling donor. Prophylaxis against graft rejection and graft-versus-host disease (GVHD) included tacrolimus and mycophenolate mofetil. RESULTS: A total of 284 patients with metastatic RCC were seen during this time period. Eighty-four patients who had siblings available for HLA typing were actively screened for enrollment, and 15 patients have undergone treatment. Durable donor engraftment was achieved in one of the first four patients treated. Patients no. 5 through 15 received a more immunosuppressive conditioning regimen, and all have achieved sustained donor engraftment. In the 12 patients with at least 180 days of follow-up, acute GVHD has occurred in two patients and chronic GVHD in six patients, with four transplant-related mortalities. Four partial responses have been observed (response rate, 33% in all patients; 44% in the nine patients with sustained donor engraftment). CONCLUSION: Nonmyeloablative allogeneic stem-cell transplantation is feasible for a minority of patients with metastatic RCC. Adequately immunosuppressive conditioning is required for sustained donor engraftment, which is required for an antitumor response. Acute and chronic GVHD are the major causes of substantial morbidity and mortality. Metastatic RCC is susceptible to a graft-versus-tumor effect promoted by allogeneic stem-cell transplantation.
METASTATIC RENAL cell carcinoma (RCC) remains a model of a treatment-resistant yet immunologically influenced malignancy. Interleukin-2 and interferon-alpha, for example, lead to objective tumor response in 10% to 15% of patients, in part via proliferation and activation of T lymphocytes and natural killer cells. As well, case reports of spontaneous regression in RCC patients further implicate patient immune response in controlling tumor growth. A more thorough understanding of cancer immunology through basic and clinical research has fueled immunotherapeutic approaches for this and other diseases. In RCC, however, cytokine dose modification, combination therapy, or coadministration of tumor-infiltrating lymphocytes or lymphokine-activated killer cells has failed to have a significant impact on overall survival.1-3 Novel immunologic treatment approaches are therefore necessary for patients with cytokine-refractory disease. One approach that has been used in the treatment of hematologic malignancies is transplantation of allogeneic stem cells preceded by immunosuppressive chemotherapy. This procedure allows for engraftment of allogeneic stem cells in the patient and recognition of the primary disease as foreign by the engrafted immune cells. These immunologic effects were first recognized by Weiden et al,4 who noted that patients who developed moderate or severe graft-versus-host-disease (GVHD) after standard myeloablative allogeneic bone marrow transplantation had a 2.5 times lower relapse rate than patients who developed minimal or no GVHD (P < .01). These initial observations were subsequently confirmed by analyzing transplants in which T-cells were removed from the donor bone marrow before transplantation. Although patients who received T-cell–depleted transplantations developed much less acute and chronic GVHD, the leukemia relapse rate was 2.75 times higher (P < .01).5 These findings were also observed in a large retrospective analysis from the International Bone Marrow Transplant Registry.6 Last, complete remissions can be induced by donor lymphocyte infusion (DLI) in chronic myelogenous leukemia that has relapsed after allogeneic transplantation.7 Collectively, these data support T lymphocytes as the effector cells in the graft-versus-tumor effect of allogeneic transplantation. RCC may be susceptible to a graft-versus-tumor effect as T lymphocytes have been shown to be an important component of the antitumor immunologic response. In addition to the known effects of cytokines in this disease, it has been shown that clonally expanded cytotoxic T lymphocytes (CTL) are present in primary and metastatic RCC specimens and demonstrate HLA-restricted cytotoxicity against RCC cell lines.8 These antigen-specific CTL have also been shown to persist in vivo.9 As the antigenic targets of these CTL have yet to be precisely defined, allogeneic CTL that could recognize as-yet-undefined tumor antigens and exert a cytotoxic, antitumor effect may be useful in the treatment of RCC. Infusion of allogeneic cells has been attempted for solid tumors. Porter et al10 administered up to 5 million U/m2/d of interferon alpha-2b x 4 weeks followed by four semiweekly infusions of allogeneic, HLA-matched mononuclear cells to a total cumulative median dose of 3.0 x 108 cells/kg. No postinfusion immunosuppression was given. In three patients with RCC, no durable donor chimerism was achieved, no GVHD was observed, and clinical responses were not seen. These results demonstrate the importance of a sufficiently immunosuppressive conditioning regimen to allow durable donor cell engraftment, without which an antitumor effect is not possible. More pertinent, Childs et al11,12 reported on the use of nonmyeloablative stem-cell transplantation in patients with cytokine-refractory, metastatic RCC. Nineteen patients with treatment-refractory metastatic RCC were given cyclophosphamide 60 mg/kg x 2 days and fludarabine 25 mg/m2 x 5 days, followed by infusion of peripheral blood progenitor cells from a 5/6 or 6/6 HLA-matched sibling. One hundred percent donor chimerism was achieved via tapering of posttransplantation cyclosporine and/or DLI given in escalating doses. Of the 19 patients, three durable complete responses (CRs) and seven partial responses (PRs) were seen. Ten patients experienced acute GVHD, leading to one transplant-related mortality from acute GVHD of the gastrointestinal tract. Disease response was seen only after 100% donor T-cell chimerism was achieved. This seminal report established the potential graft-versus-tumor effect of allogeneic T cells in metastatic RCC. We thus conducted a phase II trial of nonmyeloablative allogeneic stem-cell transplantation in cytokine-refractory metastatic RCC. The primary end point of this study was to determine the feasibility and safety of this approach. Engraftment and tumor regression were recorded.
Patient Eligibility Patients were included in the trial if they had histologically confirmed, progressive, measurable metastatic RCC. Patients must have been 18 to 65 years of age with a donor who was a healthy, HLA-identical (6/6) or a one locus mismatched (5/6) sibling. To be considered measurable, a lesion must have been clearly defined by x-ray or physical examination in at least two dimensions (0.5 x 0.5 cm for radiologically demonstrated and 2.0 x 2.0 cm for physical examination demonstrated lesions). If a patient had a single measurable or assessable lesion, it must not have been within the portal of previous irradiation. In addition, an Eastern Cooperative Oncology Group performance status of 0 or 1 and at least 4 weeks from previous surgery, radiation, chemotherapy, or immunotherapy was required. Women of childbearing potential must have had a negative urine pregnancy test and must have taken adequate precautions to prevent pregnancy during treatment. All patients signed a written, informed consent approved by the institutional review board. Patients were excluded if they had active infection, including hepatitis or human immunodeficiency virus, or total bilirubin > 2 g/dL. Patients with central nervous system (CNS) metastatic disease must have undergone appropriate treatment (radiation and/or surgery) and be off steroids without clinical symptoms for 8 weeks to be eligible. Patients with a history of CNS metastatic disease and those experiencing neurologic signs or symptoms underwent a computed tomographic (CT) scan of the brain with contrast before enrolling. There were no restrictions on the basis of histologic subtype or previous therapy. In addition, those with a known hypersensitivity to Escherichia coli–derived products (because of Neupogen [Amgen, Thousand Oaks, CA] use) were also excluded.
Pheresis of Allogeneic Donors
Treatment Plan
Posttransplantation Immunosuppression
Management of Posttransplantation Progression or Recurrence
Response Assessment
Engraftment
Infection Prophylaxis
Statistical Considerations
Screening Between February 1999 and June 2001, 284 patients with metastatic RCC presented to the University of Chicago Genitourinary Oncology Clinic (Fig 1). Of these, 84 patients had progressive, metastatic RCC and at least one sibling who were screened further. Thirty-seven patients did not have an HLA-matched sibling, 23 patients were ineligible because of rapidly progressive disease, four patients refused treatment, three patients received a transplant at another center, and two patients are awaiting insurance approval. A total of 15 patients have undergone treatment, and results from the first 12 patients with at least 180 days of follow-up are reported here.
Patient Characteristics Table 1 lists the characteristics of the patients who underwent transplantation. The median age of patients was 54 years (range, 47 to 61 years), with 11 men and one woman. Clear cell was the predominant histology in 11 patients, and one patient had a pure papillary tumor. The median number of metastatic sites was two (range, one to three sites), predominantly lung and lymph node. Eleven patients (92%) had previous nephrectomy, and the median number of previous systemic treatments was two (range, one to four treatments). Eleven patients had failed previous cytokine therapy. Patient 10 had failed previous metastasectomy and chemotherapy and had refused cytokine treatment.
Engraftment Patients received a mean of 4.35 CD34+ cells/kg (range, 2.40 to 8.33 CD34+ cells/kg) infused fresh daily over a median of 2 days (range, 1 to 3 days). CD3+ cell dose was not recorded. Donor engraftment was measured by VNTR or FISH after infusion of stem cells. Table 2 lists the chimerism results for patients at the designated time points. T-cell chimerism is reported when measured. Sustained donor engraftment was not achieved for three of the first four patients using the initial conditioning regimen. The first patient achieved 100% donor chimerism after removal of immunosuppression. Patient no. 2 had a declining percentage of donor cells, and DLI administered at day 191 did not lead to sustained engraftment. Patient no. 3 also had low initial donor chimerism and lost his graft by day 180. No DLI was administered. Patient no. 4 had PD on day 30 CT scans and, therefore, had his immunosuppression tapered at that time. Day 100 VNTR analysis revealed 35% donor T-cells, and the patient received DLI secondary to further PD. Chimerism testing 30 days after DLI revealed no donor cells. Patient nos. 2 to 4, who failed to achieve sustained donor engraftment, regained adequate host hematopoiesis and are alive with PD.
On the basis of this initial experience, it was believed that the conditioning regimen was insufficiently immunosuppressive to allow adequate, durable donor cell engraftment. Thus, the conditioning regimen was changed to fludarabine 30 mg/m2/d from day -8 through day -4 and cyclophosphamide 2 g/m2/d on day -3 and day -2. As seen in Table 2, all patients who were treated with this conditioning regimen and had assessment of chimerism demonstrated sustained donor engraftment. Notably, patient no. 4 underwent a second transplant with a different sibling donor using the more immunosuppressive conditioning regimen and achieved 100% donor chimerism at day 100. Comparison of the absolute total lymphocyte and lymphocyte subset (CD4, CD8) counts on day 0, day 15, day 30, and day 100 between patients on the different conditioning regimens or between patients who engrafted versus those who did not revealed no significant differences (data not shown). Of note, the only patient who engrafted after receiving the first conditioning regimen had finished treatment with an oral alkylating agent (temozolomide) 5 months before transplantation. The three patients who lost their graft after receiving the first conditioning regimen had finished systemic therapy 16 months (chemotherapy), 18 months (antiangiogenic agent), and 27 months (high-dose interleukin-2) before transplantation.
Response to Treatment
Toxicity A summary of transplantation-related toxicity is presented in Table 3. Four patients (33%) experienced SAEs while on the study, leading to four transplantation-related mortalities. Patient no. 6 was a 60-year-old man who had extensive mediastinal and hilar lymphadenopathy. He had stable disease by CT scans and 70% donor T-cells at day 30. He developed progressive respiratory failure approximately 2 months after transplantation and was found to have culture-negative pneumonia unresponsive to intubation and intravenous antibiotics. He died on day 66. There was no evidence of GVHD at the time of death. No autopsy was performed. Patient no. 7 was a 60-year-old man who had extensive lung and thoracic lymph node metastases and developed grade 4 acute GVHD of the gastrointestinal tract requiring hospitalization and high-dose steroids. He died on day 106 from refractory gastrointestinal GVHD and pulmonary aspergillosis. No autopsy was performed. Patient no. 9 was a 52-year-old woman who had lung and lymph node metastases and developed grade 3 gastrointestinal GVHD requiring high-dose steroids and antithymocyte globulin. She recovered from this GVHD and developed PD. She died on day 183 from a bleeding event into a new CNS metastasis. Platelet count at the time of bleed was 18,000 K/µL. No autopsy was performed. Patient no. 11 was a 57-year-old man who had lung and lymph node metastases and developed confusion and ataxia on day 9. An emergent CT scan of the brain revealed extensive cerebellar hemorrhage with herniation precluding spontaneous respiration. A decision for comfort care only was made by the family, the patient was taken off mechanical ventilation, and he died shortly thereafter. An autopsy revealed extensive systemic metastases including hemorrhage within a solitary right cerebellar metastasis with herniation and brain stem compression. The platelet count was 42,000 K/µL on the day of hemorrhage. Pretransplant CT did not reveal evidence of CNS disease. A pretransplant magnetic resonance imaging scan of the CNS was not performed.
Two patients developed acute GVHD of the gastrointestinal tract. As noted above, both required hospitalization and steroids. One patient died from this acute GVHD, and the other recovered with steroids and antithymocyte globulin. Extensive chronic GVHD developed in six patients, including three of the patients who had a PR. To date, this has been successfully treated in all six patients with reinstatement of tacrolimus and steroids.
On the basis of the importance of T lymphocytes in effective RCC therapy and in the antitumor effect of allogeneic transplantation, we investigated nonmyeloablative allogeneic transplantation for refractory, metastatic RCC. The initial reports of this procedure have generated excitement among patients and physicians.11,12 It is important, however, to define the applicability of this procedure to the metastatic RCC population at large as well as to define principles on which to base future applications of this approach in RCC and other solid tumors. Patients who had refractory, metastatic RCC and presented to the University of Chicago Genitourinary Oncology Clinic were considered. Only patients who were 65 years of age or younger and had siblings available for HLA typing were actively screened for enrollment. In addition, patients who had rapidly progressing disease and/or poor performance status at presentation generally were not screened because of the many inherent time delays in performing this procedure. Eligibility testing (approximately a 1-month delay), insurance approval (approximately a 2-month delay), and the potential antitumor effects of an allogeneic graft (approximately a 4- to 6-month delay) significantly limit the eligible patient population. Thus, it is a minority of metastatic RCC patients who are eligible for this procedure. A large metastatic RCC patient base, in addition to expertise in both renal cancer and allogeneic transplantation, is required. A phase II intergroup trial of nonmyeloablative allogeneic stem-cell transplantation in RCC led by the Cancer and Leukemia Group B is ongoing and will allow for access to qualified centers. Experience with the initial conditioning regimen suggested that immunosuppression was inadequate to allow sustained donor engraftment. Likewise, two patients who were given DLI after inadequate conditioning did not achieve engraftment or demonstrate clinical benefit. The recent alkylator therapy of the first patient may have allowed for engraftment in that case. Higher cumulative doses of chemotherapy (presumably resulting in greater immunosuppression) administered with the second conditioning regimen led to sustained engraftment in all subsequent patients. Adequately immunosuppressive conditioning regimens are thus required for sustained donor engraftment, and such engraftment is necessary for a graft-versus-tumor effect. Many different conditioning regimens are currently being investigated, and the resultant variable engraftment profiles may have an impact on response time, incidence of GVHD, myelosuppression, and overall efficacy. The optimal regimen remains to be determined. Four PRs among 12 patients were observed, consistent with a graft-versus-tumor effect and thus confirming the susceptibility of RCC to allogeneic immune attack. Importantly, the antitumor effect was observed only after 100% donor T-cell chimerism and 6 months after transplantation in all four patients. Our reported and ongoing experience suggests that younger, otherwise healthy patients with low-volume, slow-growing disease are the best candidates for allogeneic transplantation. Not surprising, these characteristics define metastatic RCC patients who respond best to any from of immunotherapy. Given the limitations of a small sample size, no conclusions regarding response duration or impact of therapy on disease-free or overall survival can yet be made. Toxicity of nonmyeloablative stem-cell transplantation was significant. Four transplantation-related mortalities resulted from the four SAEs that occurred in those patients. Two patients experienced acute GVHD, and six patients experienced chronic GVHD. Thus, as after standard allogeneic transplantation, GVHD is the major cause of morbidity and mortality. We observed more chronic but less acute GVHD than reported by Childs et al12 (17% v 53% acute GVHD and 50% v 21% chronic GVHD, respectively). The overall incidence of GVHD was similar (67% v 74%). Our approach differs slightly with an additional immunosuppressive agent and a longer duration of immunosuppression after transplantation. Whether this has an impact on clinical response rates or affects ultimate GVHD incidence is unknown. Additional investigation into preservation of a graft-versus-tumor effect while minimizing GVHD is required if this procedure is to be applied more safely to a broader patient population. The Cancer and Leukemia Group B trial will use tacrolimus and methotrexate for GHVD prophylaxis, as there is some evidence that other regimens may have an adverse impact on the incidence of chronic GVHD.14 Two patients died from hemorrhage into CNS metastases. Although the platelet counts at the time of bleed were low, they were above the 10,000 K/µL mark established for prophylactic platelet transfusions. Given the presence in both undetected CNS metastases, several actions are warranted. A pretransplantation magnetic resonance imaging scan would increase detection of clinically silent CNS metastases and exclude such patients. Also, routine brain imaging at the time of other CT scans after transplantation would lead to earlier detection of progressive CNS disease with appropriate intervention. Also, other preparative regimens for nonmyeloablative transplant have used low-dose total-body irradiation with fludarabine instead of cyclophosphamide. This approach may lead to less thrombocytopenia and thus less clinically significant bleeding sequelae. Last, exclusion of patients with any history of CNS metastases, even if adequately treated and stable, may prevent this complication. This series is too small to draw firm conclusions in this regard, but ongoing studies must carefully monitor for this complication so that appropriate guidelines can be developed. Investigation into the effector cells mediating the graft-versus-tumor and graft-versus-host responses is needed to deliver therapy more safely and broaden the applicability of this approach. Ultimately, discovery of RCC-specific tumor antigens and generation of tumor-specific T-cell clones are required. Investigation into alternative stem-cell sources (ie, matched unrelated donors) is also needed. The ongoing intergroup trial will further define the morbidity, mortality, and response rate of nonmyeloablative allogeneic stem-cell transplantation in metastatic RCC.
Supported in part by the University of Chicago Cancer Support Grant no. CA 14599-27; the Fred C. Buffett professorship (N.J.V.); Amgen Inc, Thousand Oaks, CA; the Cancer Treatment Research Foundation, Arlington Heights, IL; and Berlex Laboratories Inc, Montville, NJ. We thank the Protocol and Data Management Office at The University of Chicago and all the physicians, nurses, and data managers involved. Thanks to the Kidney Cancer Association for patient referrals, Richard Childs, MD, for intellectual input, and the patients and families for their support.
1. Bukowski RM: Cytokine therapy for metastatic renal cell carcinoma. Semin Urol Oncol 19: 148-154, 2001[Medline]
2.
Figlin RA, Thompson JA, Bukowski RM, et al: Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 17: 2521-2529, 1999 3. Figlin R, Gitlitz B, Franklin J, et al: Interleukin-2-based immunotherapy for the treatment of metastatic renal cell carcinoma: An analysis of 203 consecutively treated patients. Cancer J Sci Am 3 (suppl 1): S92-S97, 1997 4. Weiden PL, Sullivan KM, Flournoy N, et al: Antileukemic effect of chronic graft-versus-host disease: Contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 304: 1529-1533, 1981[Medline] 5. Marmont AM: Alloimmune effects of bone marrow transplantation for leukaemia on the leukaemic diseases. Bone Marrow Transplant 7: 2-3, 1991 6. Horowitz MM, Bortin MM: Current status of allogeneic bone marrow transplantation. Clin Transpl 41-52, 1990 7. Helg C, Starobinski M, Jeannet M, et al: Donor lymphocyte infusion for the treatment of relapse after allogeneic hematopoietic stem cell transplantation. Leuk Lymphoma 29: 301-13, 1998[Medline] 8. Caignard A, Guillard M, Gaudin C, et al: In situ demonstration of renal-cell-carcinoma-specific T-cell clones. Int J Cancer 66: 564-570, 1996[CrossRef][Medline]
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Jantzer P, Schendel DJ: Human renal cell carcinoma antigen-specific CTLs: Antigen-driven selection and long-term persistence in vivo. Cancer Res 58: 3078-3086, 1998
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Porter DL, Connors JM, Van Deerlin VM, et al: Graft-versus-tumor induction with donor leukocyte infusions as primary therapy for patients with malignancies. J Clin Oncol 17: 1234, 1999
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Childs RW, Clave E, Tisdale J, et al: Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: Evidence for a graft-versus-tumor effect. J Clin Oncol 17: 2044-2049, 1999
12.
Childs R, Chernoff A, Contentin N, et al: Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 343: 750-758, 2000 13. Rini BI, Zimmerman TM, Gajewski TF, et al: Allogeneic peripheral blood stem cell transplantation for metastatic renal cell carcinoma. J Urol 165: 1208-1209, 2001[CrossRef][Medline]
14.
Przepiorka D, Anderlini P, Saliba R, et al: Chronic graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 98: 1695-1700, 2001 Submitted August 7, 2001; accepted December 20, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
