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© 2002 American Society for Clinical Oncology Role of Nonmyeloablative Allogeneic Stem-Cell Transplantation After Failure of Autologous Transplantation in Patients With Lymphoproliferative MalignanciesByFrom the CR (UK) Department of Medical Oncology, Christie Hospital, Manchester; Department of Hematology, University College, London Hospital, Department of Hematology, Guy’s Hospital, and Department of Hematology, St George’s Hospital, London; Department of Hematology, Glasgow Royal Infirmary, Glasgow; Department of Hematology, University Hospital; and Department of Hematology, Heartlands Hospital, Birmingham, United Kingdom. Address reprint requests to Rajesh Chopra, MD, CR (UK) Department of Medical Oncology, Christie Hospital, Wilmslow Rd, Manchester M20 4BX, United Kingdom; email: rchopra{at}picr.man.ac.uk
PURPOSE: Conventional allogeneic stem-cell transplantation (SCT) after a prior failed autograft is associated with a transplant-related mortality rate of 50% to 80%. The aim of the current study was to evaluate the safety and efficacy of sibling, HLA-matched, nonmyeloablative allogeneic SCT with donor lymphocyte infusion (DLI) in patients with lymphoid malignancy after failure of autologous SCT. PATIENTS AND METHODS: A total of 38 patients with refractory, progressive, or relapsed disease after autologous SCT were entered onto this study. The conditioning regimen consisted of the humanized monoclonal antibody CAMPATH-1H, fludarabine, and melphalan. Fifteen of 35 assessable patients received DLI after SCT. RESULTS: Sustained neutrophil engraftment was achieved in 37 recipients, and platelet engraftment was achieved in 35 patients. The estimated transplant-related mortality was 7.9% at day 100 and 20% at 14 months, the median duration of follow-up. Eight patients experienced grade I/II acute graft-versus-host disease (GVHD) after transplantation, but no grade III/IV GVHD was observed in this setting. However, grade III/IV GVHD occurred in seven patients who received DLI. The actuarial overall survival at 14 months was 53%, with a progression-free survival of 50%. DLI produced a further response in three of 15 recipients. CONCLUSION: Nonmyeloablative allogeneic SCT after CAMPATH-1H–containing conditioning is a relatively safe option compared with conventional allogeneic transplantation for patients who have failed previous autologous SCT. The low incidence of early GVHD enabled the subsequent administration of DLI to improve further clinical responses in this poor-risk group of lymphoma and myeloma patients.
HIGH-DOSE CHEMOTHERAPY with autologous stem-cell transplantation (SCT) is effective in the management of patients with relapsed and resistant lymphoid malignancies.1-4 However, a significant number of patients relapse despite high-dose therapy,5-7 with recurrence commonly attributed to residual disease.1,8-10 Gene-marking studies have indicated that malignant cells contaminating the infused graft can also contribute to relapse.11,12 The outcome in patients who relapse after autologous SCT is generally poor.13-15 A further remission may be attained with conventional-dose chemotherapy, but is rarely durable, particularly if the time interval between transplantation and subsequent relapse is shorter than 12 months.6,13,16 Alternatively, a second transplantation may be considered. Allogeneic SCT offers a theoretical advantage compared with autologous SCT, because of the alloreactivity of donor immune cells against host malignant cells (graft-versus-malignancy [GVM] effect),17-19 but is associated with a treatment-related mortality rate of up to 50% to 80%.20-22 A second autologous SCT procedure is associated with reduced treatment-related mortality but increased relapse compared with allogeneic SCT.21,23 Autologous SCT may be further compromised by limited availability of stem cells.24 Low-intensity transplantation may enable the safer application of an allogeneic SCT procedure25,26 and act as a platform for donor lymphocyte infusion (DLI) to exploit further a GVM effect.27,28 Preliminary reports of nonmyeloablative transplantation have demonstrated high rates of alloengraftment, with significantly reduced toxicity compared with conventional allogeneic SCT.29,30 We report our experience of allogeneic SCT with a conditioning regimen incorporating the humanized monoclonal antibody CAMPATH-1H, fludarabine, and melphalan in patients with recurrent or residual lymphoid malignancy. Our results indicate that in this high-risk setting, nonmyeloablative allogeneic SCT yields durable clinical responses, with or without the additional use of DLI, and substantially reduced transplant-related mortality compared with that commonly reported for conventional allogeneic SCT.
Patient Eligibility and Characteristics A total of 38 consecutive patients with lymphoid malignancy treated at seven centers in the United Kingdom between January 1998 and December 2000 were included in the analysis. Thirteen patients had been included in a previous study,31 but were reported in this series with extended follow-up. Informed consent was obtained from all patients and donors before treatment initiation. Treatment protocols were approved by the ethics committee at each center. All patients underwent prior autologous SCT and were enrolled on the current study as a result of refractory, progressive, or relapsed disease. Interim treatment with conventional chemotherapy before consolidation resulted in partial remission (PR) in 22 patients and complete remission (CR) in seven patients, with progressive or refractory disease reported in the remaining nine patients. Underlying diseases included Hodgkin’s disease (HD) (n = 12), high-grade non-Hodgkin’s lymphoma (NHL) (n = 10), low-grade NHL (n = 1), multiple myeloma (MM) (n = 12), chronic lymphocytic leukemia (n = 1), and mantle-cell lymphoma (MCL) (n = 2). The median age of the patients at the time of the second transplantation was 44 years (range, 25 to 64 years). The median time between first and second transplantation was 26 months (range, 5 to 96 months). The minimum follow-up was 4 months (median, 14 months). Patient characteristics are listed in Table 1.
All donors were siblings and fully matched for HLA-A and HLA-B antigens using serology, with molecular typing for HLA-C, HLA-DRB1, and HLA-DQB1 (n = 6), or by full molecular typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 (n = 32). There were no mismatches at any of the alleles.
Conditioning Regimen
Stem-Cell Harvesting and Dose
Graft-Versus-Host Disease Prophylaxis
Supportive Care
Chimerism Assessment
Donor Lymphocyte Infusion
Statistical Analysis
Toxicity Transplant-related mortality. The estimated transplant-related mortality at day +100 and at 14 months (the median duration of follow-up) was 7.9% and 20%, respectively (Fig 1). Of the six toxic deaths, three were recorded during the first 100 days after transplantation and were attributed to gram-negative septicemia, multiorgan failure, and an infection of the basal ganglia (days +21, +23, and +68, respectively) (Table 2). Of the three late deaths, one was attributed to renal failure (day +158, in a patient in CR with pre-existing renal impairment) and two were infective in origin (day +226, gastrointestinal CMV infection; day +255, pulmonary aspergillosis).
CMV infection. CMV reactivation occurred in 18 of 24 patients (75%) who were CMV-seropositive or had seropositive donors, but CMV viremia was not observed in the 14 seronegative recipients with seronegative donors. Of the 18 patients with CMV reactivation, only one developed clinical CMV disease. Incidence of GVHD after transplantation. Only eight patients developed acute GVHD (grade I/II). A total of 33 patients survived beyond 100 days; of these, five (15%) developed chronic GVHD. Notably, all patients with chronic GVHD had received DLI (see below).
Hematopoietic Recovery
Chimerism
Response to Transplantation
Disease progression. At a median follow-up of 14 months (range, 4 to 37 months), 10 patients are in CR (five with HD, two with NHL, two with MCL, and one with MM), and 10 patients have nonprogressive disease (four with HD, two with NHL, and four with MM). A total of 12 patients have had documented progressive disease; of these, 10 have died. Toxic deaths were recorded for the remaining six patients (Table 3). The actuarial overall and PFS rates at 14 months were 53% and 50%, respectively (Figs 2 and 3). Univariate analysis of factors including age, sex, disease type, interval between transplantations, disease status at transplantation, and cell dose failed to identify statistically significant prognostic factors for overall survival. However, there was a trend toward improved overall survival in patients with HD compared with other lymphoid malignancies (83% at 14 months, P = .077), although longer follow-up in a greater number of patients is required to confirm this preliminary observation.
Role of DLI Fourteen of 35 assessable patients received DLI for progressive disease (n = 9), relapse from CR after transplantation (n = 3), or residual disease after transplantation (n = 2). An additional patient in CR received DLI with the aim of converting mixed chimerism to full donor chimerism. Details of the timing, dosage, and number of lymphocyte infusions are listed in Table 4.
DLI was associated with a response in six of the 12 patients (50%) with progressive or relapsed disease. Three patients (two with HD and one with MCL) achieved CR, with two maintaining CR 10 and 11 months after DLI administration, respectively, and relapse occurring at 17 months after DLI in the third patient. However, it should be noted that both patients with HD received additional chemotherapy because of high tumor burden. Two patients (one with HD and one with MM) remained progression-free at 9 and 12 months after DLI treatment, and one patient with MM achieved PR but died 7 months after DLI as a result of gastrointestinal CMV infection and grade III GVHD. Of the six patients who failed to respond to DLI, five have since died from progressive disease. Administration of DLI to the two patients with PR had a positive outcome, with CR maintained in one patient (MM) for 21 months, and PFS of 8 months’ duration in the second (HD). The patient in CR treated with DLI for conversion of mixed chimerism converted to 100% donor hematopoiesis and remains in CR. Overall, therefore, DLI was solely responsible for responses in three of the 15 patients (patients 31, 33, and 37 in Table 4). Acute GVHD occurred in 10 of the DLI recipients (three grade I/II and seven grade III/IV) and five developed chronic GVHD, with four patients experiencing both chronic and acute GVHD. One patient could not be assessed for GVHD because of rapid disease progression. Notably, the five patients who experienced chronic GVHD remain in CR or with nonprogressive disease. The prior administration of DLI was significantly associated with the development of GVHD, particularly chronic GVHD (P = .008). There was no correlation between age, cell dose, time between diagnosis and transplantation, or time between transplantation and DLI, and the incidence of acute or chronic GVHD. Chimerism data were available on 13 of the patients who received DLI; mixed and donor chimerism were documented in nine patients and four patients, respectively. Mixed chimerism did not confer protection from GVHD after DLI, with grade III/IV GVHD observed in five of the nine patients demonstrating mixed chimerism. Seven patients with mixed chimerism converted to 100% donor hematopoiesis after administration of DLI (four in CR, two in PR, and one with disease progression), and the remaining two patients died from disease before further chimerism assessment.
Relapse after autologous SCT for lymphoid malignancy is associated with a poor prognosis, with median survivals of 10.5 and 3 months reported for patients with HD and NHL, respectively.13 Patients with MM also have a poor outlook in this setting.5,15 There may, however, be a group of patients with a good performance status who warrant consideration for further salvage therapy. The main treatment options in this setting are generally considered to be conventional chemotherapy, the results of which have been largely disappointing,6,13,16 or a second transplantation. There have been few studies evaluating the role of a second autologous SCT procedure in relapsed lymphoproliferative malignancies. Vandenberghe et al37 reported a series of 34 patients with HD or NHL who underwent a second autologous SCT (n = 31) or conventional allogeneic SCT (n = 3) procedure. In this study, 20 patients had experienced relapse after prior autologous SCT, and the remaining patients underwent a second transplantation for treatment of refractory or residual disease or as an elective procedure for poor-risk disease. The overall transplant-related mortality was 18%, with an overall survival of 48% and PFS of 42% at 2 years. However, the survival curves had not reached a plateau. Autologous SCT in this setting may be compromised by limited availability of stem cells24,38 or tumor-cell contamination of the infused graft.39-41 Studies in lymphoma and myeloma have demonstrated that allogeneic SCT is associated with a significantly lower relapse rate compared with autologous SCT, supporting the concept of a GVM effect.17,42-46 The observation that DLI could reinduce remission in patients whose disease had relapsed after allogeneic SCT lends further support to this GVM effect.19,47-49 However, issues relating to tolerability may preclude the use of allogeneic SCT in this setting; a number of studies have reported transplant-related mortality rates extending up to 50% to 80%,13,20,22,23,50,51 and in a direct comparative study in 84 patients with MM and relapsed or refractory disease after autologous SCT, allogeneic SCT was associated with a markedly lower rate of disease progression (31% v 72%) but reduced overall survival (29% v 54%) compared with autologous SCT.21 The use of nonmyeloablative conditioning is associated with sustained donor-cell engraftment, reduced toxicity, and the potential to maintain a GVM effect.26,52 In addition, the induction of mixed chimerism may serve as a platform for DLI, to further eradicate malignant cells and convert mixed chimerism to full donor hematopoiesis.27,53 This approach may also reduce the incidence of acute GVHD, which is, at least in part, a consequence of a cytokine storm induced by high-intensity conditioning regimens.54 Studies using nonmyeloablative conditioning regimens in heterogeneous patient populations have demonstrated encouraging results, with low treatment-related mortality.29,31,55-57 However, there are few data reporting nonmyeloablative allogeneic SCT after prior autologous SCT in poor-risk patients with lymphoid malignancy. After Anderlini et al58 and Nagler et al59 established the feasibility of nonmyeloablative transplantation after autologous SCT, further series were reported.60-62 Although day-100 transplant-related mortality rates were low (0% to 20%), the small patient numbers, heterogeneous conditioning regimens, and variable use of DLI preclude definitive conclusions regarding efficacy. However, these reports consistently demonstrated a high incidence of acute GVHD after transplantation (46% to 80%), which limited the use of further DLI. GVHD was severe (grade III/IV) in over half of the affected patients, and contributed to substantial transplant-related mortality. More promising results were reported in a larger study by Carella et al,63 in which 15 poor-risk patients with HD or NHL were selected to receive autologous SCT followed by elective low-intensity allogeneic SCT as consolidation. The initial autologous SCT resulted in PR or CR in all 15 patients. The low-intensity allogeneic SCT conditioning regimen consisted of fludarabine 30 mg/m2 followed by cyclophosphamide 300 mg/m2 for 3 days before donor-cell infusion. Response to the double-transplantation procedure was favorable, with only two toxic deaths and with 10 patients remaining alive (seven CRs), at a median follow-up of 11 months. Notably, in the current study, all 38 patients had progressive or relapsed disease after autologous SCT and therefore represent a very-poor-risk cohort. The low early transplant-related mortality of 7.9% compares favorably with that seen in conventional allogeneic SCT,20,22,50,51 and is partly attributable to the low incidence of acute GVHD after transplantation. As the use of CsA GVHD prophylaxis was similar to that reported in previous studies,60-62 the reduced frequency of acute GVHD is probably because of CAMPATH-1H–mediated in vivo donor T-cell depletion.31 Indeed, in a nonrandomized comparative analysis of CAMPATH-1H/CsA versus methotrexate/CsA after nonmyeloablative allogeneic SCT, patients receiving CAMPATH-1H experienced a significantly lower incidence of GVHD, without an adverse effect on overall survival. Patients receiving CAMPATH-1H, however, had a significantly higher incidence of CMV reactivation.64 It should be pointed out that although there was a 75% reactivation rate in this study, only one patient developed fatal CMV disease. This highlights the success of using PCR-based assays and the early use of ganciclovir or foscarnet. The response rates reported in our study are promising, with an overall survival and PFS of 53% and 50%, respectively, at the median time of follow-up (14 months). However, there was a notable number of postprocedure relapses, and the PFS curve does not reach a plateau, so longer follow-up will be necessary to ascertain long-term efficacy. These results are in accordance with those of Dey et al,28 who reported 2-year overall survival and PFS rates of 45% and 37.5%, respectively, with nonmyeloablative allogeneic SCT after conditioning with cyclophosphamide, antithymocyte globulin, and thymic irradiation in 13 patients with relapsed lymphoid malignancy. In this study, seven patients received DLI after transplantation, and of these, four demonstrated a response. The transplant-related mortality rate was 7%. In the current study, subgroup analysis identified the most favorable response in patients with HD (14-month overall survival > 80%). Notably, of nine patients with HD demonstrating a response, only two had achieved CR before allogeneic SCT. Although the number of patients on the study is too small to show a statistically significant difference, these results suggest a promising role for nonmyeloablative allogeneic SCT in HD, and lend support to preliminary evidence of a graft-versus-Hodgkin’s effect.45,65 In addition, six of 13 patients with NHL responded (four CRs). Of note, CR was observed in the two patients with MCL, a condition with poor documented response to conventional chemotherapy and autologous SCT.66-68 Less favorable results were observed in heavily pretreated patients with MM, with nonprogressive disease currently documented in only five of 12 patients. These results contrast with a recently published series, which included 31 patients with MM and reported a CR rate of 39% at a median follow-up of 6 months.69 In this study, the conditioning regimen consisted of melphalan 100 mg/m2 for 25 patients receiving grafts from HLA-matched siblings, with the addition of 2.5 Gy of total-body irradiation and fludarabine 30 mg/m2 for 2 days, for six recipients of matched-unrelated grafts. Eighteen patients received DLI, of whom six were treated with additional chemotherapy. Transplant-related mortality was comparable to that observed in the current study, with three early and six late toxic deaths. However, it remains to be seen whether this response is sustained with longer follow-up, as the actuarial overall survival fell to 31% at 2 years. There is a paucity of data regarding the administration of DLI after nonmyeloablative allogeneic SCT. In the current study, the incidence of GVHD after transplantation was low, permitting DLI administration in 15 patients. However, it has proved difficult to evaluate the precise role of DLI, because of concomitant administration of chemotherapy in four patients. DLI produced a further improvement in disease status in three (20%) of the patients who received DLI, but it is possible that response was attributable solely to the transplantation procedure, as it is recognized that patients with lymphoid malignancies can show a delayed response to transplantation. Two thirds of patients developed GVHD after DLI, with the majority experiencing grade III/IV disease. The increased incidence of GVHD after DLI compared with the immediate post–allogeneic SCT period provides an additional indication that CAMPATH-1H was responsible for providing protection from early acute GVHD. Strategies such as depletion of donor T-cell subsets before lymphocyte infusion could therefore potentially confer protection against GVHD while maintaining a GVM effect. Allogeneic SCT for patients with relapsed/refractory lymphoid malignancy after autologous SCT has hitherto been recognized as a hazardous therapeutic choice. This study in a heavily pretreated patient cohort demonstrates that nonmyeloablative SCT results in sustained engraftment, with low transplant-related toxicity. Although the results presented in this study are encouraging, we would urge caution because of possible selection bias and lack of a plateau in the PFS curve. Longer follow-up in a larger group of patients is necessary to substantiate these findings. It should also be pointed out that conventional allogeneic transplantation is associated with a plateau in survival despite a higher mortality rate.18 This report nonetheless provides a basis for the development of studies comparing nonmyeloablative allogeneic SCT and subsequent DLI with alternative approaches, such as a second autologous SCT, in patients with relapsed and refractory hematologic disease.
Rajesh Chopra is supported by the CR (UK) and Christie Hospital Leukaemia Research Funds.
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ABSTRACT
INTRODUCTION
