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© 2000 American Society for Clinical Oncology Filgrastim as an Alternative to Donor Leukocyte Infusion for Relapse After Allogeneic Stem-Cell TransplantationFrom the Section of Oncology/Hematology, Department of Internal Medicine and Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE. Address reprint requests to Michael R. Bishop, MD, National Cancer Institute, Building 10, Room 12N226, 10 Center Dr, MSC 1906, Bethesda, MD 20892-1906; email mbishop{at}mail.NIH.gov
PURPOSE: Donor leukocyte infusion (DLI) effectively treats relapse after allogeneic stem-cell transplantation (alloSCT), but the response may require several months and may be associated with significant toxicity. Filgrastim has also been observed to effectively treat leukemic relapse after alloSCT. A retrospective analysis was performed to determine the effectiveness of filgrastim in treating relapses after alloSCT. PATIENTS AND METHODS: Fourteen patients with hematologic malignancies were treated with filgrastim at relapse after alloSCT. Filgrastim was given at 5 mcg/kg/d subcutaneously for 21 consecutive days. Response was evaluated at 7 days after completion of filgrastim. Immunosuppressants, if present, were rapidly tapered to complete discontinuation at the time of relapse. RESULTS: Three patients were not assessable for response because additional therapy was necessary before completion of filgrastim. Six patients (43%) achieved a complete response on an intent-to-treat basis. When response was evaluated based on relapse type, three of four cytogenetic relapses, two of three morphologic relapses, and one of four hematologic relapses achieved a complete remission. Two responses were observed in patients who were completely off of any immunosuppression at the time of relapse. Six patients developed chronic graft-versus-host disease. The event-free and overall survival rates for all 14 patients are 43% and 73%, respectively. CONCLUSION: The use of filgrastim with rapid discontinuation of immunosuppression results in response rates that are similar to results using DLI. Filgrastim could be considered as an alternative or an adjunct to DLI for relapses after alloSCT.
RELAPSE OF DISEASE remains one of the most serious problems after treatment with allogeneic stem-cell transplantation (alloSCT).1 Attempts to perform a second alloSCT have been successful in a minority of patients, primarily children, but these transplants have been associated with an extremely high treatment-related mortality.2 More recently, relapses after alloSCT have been successfully treated with donor leukocyte infusions (DLIs).3-5 DLI has been associated with relatively high response rates in patients with chronic myelogenous leukemia (CML) in chronic phase, but it has been less effective for patients with more advanced CML and other hematologic malignancies.5 In addition, the response to DLI can take several months, and DLI may be associated with severe marrow aplasia and a high incidence of chronic graft-versus-host disease (GVHD). Giralt et al6 have previously reported that the administration of filgrastim (granulocyte colony-stimulating factor) may be effective in treating leukemic relapses after alloSCT in selected cases. These observations were made in patients with both chronic and acute leukemias who received filgrastim to treat cytopenias that had occurred with relapse. The observed responses were rapid and sustained. Based on these observations, it became standard practice at our institution to initially treat leukemic relapses after alloSCT with filgrastim. A retrospective analysis was performed to determine the effectiveness of filgrastim administration in treating leukemic relapses after alloSCT.
Patients Between January 1995 and August 1998, 19 patients relapsed after having undergone alloSCT at the University of Nebraska Medical Center. Two patients received a DLI, two died during preparation for a planned DLI, two were not under the care of University of Nebraska Medical Center physicians at the time of relapse, one had a relapse in the CNS, and, for one patient, the treatment for relapse is unknown. Fourteen patients (median age, 37 years; range, 26 to 60 years) were treated with filgrastim at relapse after alloSCT (Table 1). One of these 14 patients had relapsed after a previous DLI. Patient diagnoses included acute myelogenous leukemia (AML; n = 6), CML (n = 5), myelodysplastic syndrome (n = 2), and chronic lymphocytic leukemia (CLL; n = 1). Two of the CML patients were in chronic phase at the time of transplant or DLI, two were in accelerated phase, and one was in blast crisis. Eleven patients had received an alloSCT from a six-of-six-antigen HLA-matched related donor. Two patients had received an alloSCT from a six-of-six-antigen HLA-matched unrelated donor, and one had received an alloSCT from a five-of-six-antigen HLA-matched unrelated donor. Three patients had normal cytogenetics and a same sex donor. Relapses were documented at 29 days to 1 year after transplant. Ten patients were receiving cyclosporine and/or steroids at the time of relapse. The majority of patients (60%) still receiving immunosuppression at relapse were on cyclosporine alone. Cyclosporine doses at the time of relapse varied from 25 to 200 mg by mouth twice a day.
Methods Patients were prospectively monitored for relapse at +1, +3, +6, +9, +12, +15, +18, and +24 months after transplantation with bone marrow aspirations and biopsies with cytogenetics and, when appropriate (eg, Philadelphia chromosome), with fluorescent in situ hybridization (FISH). Polymerase chain reaction was not available for analysis on these patients. Relapses were classified as described by Kolb.3 Briefly, patients were classified as having a cytogenetic relapse if there was only evidence of relapse by cytogenetics and/or FISH. Patients were classified as having a morphologic relapse if they had morphologic evidence of relapse in the bone marrow but no evidence of circulating leukemic cells. Patients were classified as having a hematologic relapse if they were found to have circulating leukemic cells supported by bone marrow, cytogenetics, and/or flow cytometry. Patients who were found to have a hematologic relapse in between bone marrow monitoring and whose donor was immediately available, defined as less than 1 to 2 weeks, were considered for DLI on a case by case basis. At the time of relapse, filgrastim (Neupogen; Amgen, Thousand Oaks, CA) was given at 5 mcg/kg by subcutaneous administration daily for 21 consecutive days. If the patient was on any immunosuppressive agents at the time of relapse, these were rapidly tapered within 2 weeks for complete discontinuation during filgrastim administration. Response was re-evaluated by repeat bone marrow biopsy with cytogenetics ± FISH at 7 days after completion of filgrastim. In the one patient with CLL, lymphadenopathy also was monitored by computed axial tomography scans at the same frequency as bone marrow examination. Response was defined as a complete hematologic, morphologic, and cytogenetic remission. Responding patients were subsequently monitored monthly for 2 consecutive months and then every 3 months thereafter.
At the time of relapse, seven patients were classified as having a hematologic relapse, three as having a morphologic relapse, and four as having a cytogenetic relapse (Table 1). Three patients experienced progression of disease necessitating additional therapy before completion of filgrastim. All three of these patients had either AML or myelodysplastic syndrome, with hematologic relapses within 100 days of transplant. Eleven patients completed their assigned therapy. There was no significant toxicity noted with filgrastim administration. Maximal WBC counts were all noted to be less than 50,000/mL. Six of the 11 patients who completed filgrastim therapy achieved a complete hematologic, morphologic, and cytogenetic response. Four of the six complete responses were observed on the day-28 evaluation after completion of filgrastim. The other two patients both had nearly complete responses at day 28 of filgrastim treatment and complete responses by day 100 after filgrastim treatment. On an intent-to-treat basis, the overall complete remission rate was 43% for all 14 patients. When response was evaluated based on relapse classification, three of four patients with a cytogenetic relapse, two of three patients with a morphologic relapse, and one of four patients with a hematologic relapse achieved a complete response. Four of six responders had CML; three of these had a cytogenetic relapse. Of the other two responders, one had AML with a morphologic relapse, and one had CLL with hematologic relapse. Two of the responding patients had not received any immunosuppressive agents in excess of 3 months before the initiation of filgrastim. At the time of evaluation for response, all assessable patients’ bone marrows had cellularities in excess of 10%. Most patients were observed to have an increase or stabilization marrow cellularity. Subsequent monitoring failed to demonstrate any evidence of marrow aplasia. Nine of 13 assessable patients developed either acute or chronic GVHD. Two patients had chronic GVHD before filgrastim administration. Six patients subsequently developed chronic GVHD within 1 to 6 months after filgrastim administration. Three patients developed limited chronic GVHD, and three developed extensive chronic GVHD. Chronic GVHD was observed in five of the six responders. Extensive chronic GVHD was generally limited to the skin with sclerodermatous changes. One patient had extensive chronic GVHD involving the mouth and tongue. This latter patient received a transplant from a five-of-six-antigen HLA-matched unrelated donor. The development of chronic GVHD was noted after the determination of response in all five patients. At the time of this analysis, three of the six responders had relapsed after an initial response to filgrastim. The duration of their responses was greater than 12 months in all three patients. Two of these relapses were chloromas, one in the breasts and one in the left flank. The chloromas were not present at the time of their original relapse. The third relapse was in the patient with CLL, who had an isolated recurrence in an axillary lymph node. All three of these patients’ bone marrows were normal with all cells of donor origin. At a median follow-up of 14.5 months, the estimated event-free survival was 43% (Fig 1). The estimated overall survival was 73%; the median survival has not yet been reached.
The current options for patients who relapse after an alloSCT include a second transplant, removal of immunosuppression, interferon in selected cases of CML, or a DLI.7,8 DLI has been successfully used in both children and adults.5 However, DLI has severe limitations, including a decreased activity in patients with acute leukemias or bulky disease (eg, non-Hodgkin’s lymphoma), a delayed response (weeks to months), and potentially severe toxicity in the form of GVHD, which is observed in more than 50% of patients.5,9,10 Reports of the use of filgrastim for relapse have been anecdotal with the exception of the report by Giralt et al.6,7,11 Filgrastim for relapse offers potential advantages over DLI. First, it is well tolerated; the primary acute side effects being those typically associated with filgrastim administration, including mild arthralgias and low-grade fevers. It may, however, be associated with the development of GVHD, both acute and chronic, which was observed in approximately 54% of patients in this analysis. Second, the response is relatively rapid; by a week after the completion of therapy (ie, 28 days), responses could be reasonably assessed. This may provide adequate time to make arrangements to secure donor leukocytes in the event that the donor is not readily available. Most importantly, marrow aplasia, which is observed in a significant number of patients receiving DLI, was not observed with filgrastim.5,8 Similar to results with DLI, filgrastim administration had limited efficacy in patients with overt hematologic relapse of their acute leukemias. In this situation, cytoreduction of the leukemia may be necessary, either with conventional chemotherapy or a nonmyeloablative preparative regimen, which seems to have success in patients with sensitive disease.10 The primary question is why would this therapy work at all? There are several potential explanations. The first is that filgrastim had little or no effect, and the observed responses were a result of the removal of immunosuppression, permitting a graft-versus-leukemia effect.8 This may not provide an adequate explanation, however, because two of the observed responses occurred in patients receiving no immunosuppression at the time of their relapse. This clinical situation is not significantly different than for DLI where immunosuppression is also routinely withdrawn.4,11 A second possible explanation is that the filgrastim provides a competitive advantage for normal hematopoiesis, potentially increasing the numbers of effector cells.12 Another related explanation is that the increased hematopoiesis after filgrastim dilutes the leukemic cells present in the marrow, and the observed results were actually a false-positive. This seems highly unlikely given the high sensitivity of FISH and the continued maintenance of response long after the acute effects of filgrastim had subsided. A last possible explanation for the efficacy of filgrastim is a direct effect on the immune system. The administration of filgrastim is known to cause a shift of T cells from Type 1 to Type 2 cytokine pattern and a reduction of cytotoxic T-cell activity.13 These effects would seem contradictory to an enhanced antileukemic response; however, it has been demonstrated that cytotoxic T-cell activity is preserved through a perforin-dependent pathway after filgrastim exposure.14 Still, the overall effects of filgrastim on the immune system are not well known. Regardless of the mechanism of action, these data suggest that the administration of filgrastim, either alone or in conjunction with discontinuation of immunosuppression if present, can result in rapid, complete cytogenetic remissions for patients who relapse after alloSCT. Further studies are required to substantiate these results and to provide further understanding of this treatment. However, given the ease of administration, minimal related complications, and the relatively rapid assessment of response, it seems reasonable to consider filgrastim as an initial treatment option for relapse after alloSCT. It should be considered as an adjunct and not a replacement to other treatments, particularly DLI. A practical strategy could include the use of filgrastim as initial management for relapse, permitting time to make arrangements for donor leukocyte collection. In the event there was no response to filgrastim, DLI could then be used with little predicted loss in efficacy. A more interesting alternative would be a direct comparison of filgrastim administration with DLI. The administration of filgrastim seems to be a practical and effective option for cytogenetic or molecular leukemic relapses after alloSCT.
1. Armitage JO: Bone marrow transplantation. N Engl J Med 330:827-838, 1994 2. Mrsic M, Horowitz MM, Atkinson K, et al: Second HLA-identical sibling transplants for leukemia recurrence. Bone Marrow Transplant 9:269-275, 1991
3.
Kolb HJ, Mittermüller J, Clemm C, et al: Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462-2465, 1990
4.
Porter DL, Roth MS, McGarigle C, et al: Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med 330:100-106, 1994
5.
Collins RH Jr, Shpilberg O, Drobyski WR, et al: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 15:433-444, 1997
6.
Giralt S, Escudier S, Kantarjian H, et al: Preliminary results of treatment with filgrastim for relapse of leukemia and myelodysplasia after allogeneic bone marrow transplantation. N Engl J Med 329:757-761, 1993
7.
Giralt SA, Champlin RE: Leukemia relapse after allogeneic bone marrow transplantation: A review. Blood 84:3603-3612, 1994 8. Collins RH, Rogers RR, Bennett M, et al: Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation: Apparent graft-versus-leukemia effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplant 10:391-395, 1992[Medline]
9.
Mackinnon S, Papadopoulos EB, Carabasi MH, et al: Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: Separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 86:1261-1268, 1995
10.
Slavin S, Naparstek E, Nagler A, et al: Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation. Blood 87:2195-2204, 1996 11. Carral A, Sanz GF, Sanz MA: Filgrastim for the treatment of leukemic relapse after bone marrow transplantation. Bone Marrow Transplant 18:817-819, 1996[Medline]
12.
Elmaagacli AH, Beelen DW, Opalka B, et al: The risk of residual molecular and cytogenetic disease in patients with Philadelphia chromosome positive first chronic phase chronic myelogenous leukemia is reduced after transplantation after transplantation of allogeneic peripheral blood stem cells compared with bone marrow. Blood 94:384-389, 1999
13.
Pan L, Delmonte J Jr, Jalonen CK, et al: Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward Type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood 86:4422-4429, 1995
14.
Pan L, Teshima T, Hill GR, et al: Granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation maintains graft-versus-leukemia effects through a perforin-dependent pathway while preventing graft-versus-host disease. Blood 93:4071-4078, 1999. Submitted August 17, 1999; accepted February 15, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
