|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 12 (June 15), 2004: pp. 2419-2423 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.092 Nonmyeloablative Allogeneic Hematopoietic Transplantation: A Promising Salvage Therapy for Patients With Non-Hodgkin's Lymphoma Whose Disease Has Failed a Prior Autologous TransplantationFrom the Departments of Blood and Marrow Transplantation and Lymphoma, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Issa F. Khouri, MD, Department of Blood and Marrow Transplantation, Box 423, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ikhouri{at}mdanderson.org
PURPOSE: Allogeneic transplantation for patients with lymphoma who experience a recurrence after an autologous transplantation has been considered a hazardous therapeutic choice. We investigated the safety and efficacy of nonmyeloablative stem-cell transplantation in these patients. PATIENTS AND METHODS: Patients were required to have chemosensitive or stable disease. Twenty consecutive patients were treated in two sequential trials. Fifteen patients underwent a preparative regimen of fludarabine (30 mg/m2 daily for 3 days), intravenous cyclophosphamide (750 mg/m2 daily for 3 days), and rituximab. For the remaining five patients, the conditioning regimen consisted of cisplatin (25 mg/m2 continuous infusion daily for 4 days), fludarabine (30 mg/m2 daily for 2 days), and cytarabine (1,000 mg/m2 daily for 2 days). Tacrolimus and methotrexate were used for graft-versus-host disease prophylaxis. RESULTS: All patients experienced engraftment of donor cells. One patient (5%) experienced grade 2 acute graft-versus-host disease, and no patients experienced a higher grade. One patient experienced disease progression at 115 days post-transplantation and responded to donor lymphocyte infusion. The remaining patients remained disease-free. One patient died at 10.5 months from a fungal infection. With a median follow-up time of 25 months, the estimated 3-year current progression-free survival rate was 95%. CONCLUSION: These data suggest that nonmyeloablative allogeneic stem-cell transplantation is an effective option in lymphoma patients with chemosensitive or stable disease who experience disease recurrence following autologous transplantation.
High-dose chemotherapy and autologous stem-cell transplantation (SCT) is an effective treatment for patients with chemotherapy-sensitive recurrences of aggressive lymphomas.1,2 However, despite substantial improvements in the overall outcome for these patients, disease progression after transplantation remains the major cause of treatment failure. When disease recurs after autologous SCT, treatment options are limited, and the prognosis is poor.3 Although high-dose myeloablative therapy with allogeneic transplantation offers the potential for a graft-versus-lymphoma (GVL) effect,4 the benefits are offset by a treatment-related mortality rate of up to 40%. A higher treatment-related mortality rate of 50% to 80% has been reported in patients who have been previously exposed to high-dose myeloablative therapy.5-7 Given the potential efficacy of GVL's effects against many lymphoid malignancies, we evaluated an alternative strategy of using less toxic, nonmyeloablative preparative regimens with allogeneic transplantation.8 We recently demonstrated a reduced rate of treatment related mortality and graft-versus-host disease (GVHD) in patients with indolent lymphomas that have relapsed after conventional chemotherapy.9 We report the outcome of this strategy in 20 patients with lymphoma, including those with aggressive histologies, after failure of a prior high-dose myeloablative autologous SCT.
Patient Eligibility Our study included 20 consecutive patients with non-Hodgkin's lymphoma (NHL) whose disease had recurred after autologous SCT. To be eligible, patients had to be 70 years of age or younger, have a Zubrod performance status score of 2 or less, and have no uncontrolled active infection or symptomatic organ dysfunction. Patients were required to have chemosensitive or stable disease. Patients with progressive disease were excluded from protocol entry. A signed informed consent form was obtained from all patients. The treatment was reviewed and approved by the institutional review board of The University of Texas M.D. Anderson Cancer Center.
Treatment The patients were treated in one of two sequential trials for nonmyeloablative allogeneic transplantation. All 20 patients had NHL that had relapsed after a prior autologous hematopoietic transplantation and had achieved complete or partial remission to salvage chemotherapy, or low-bulk stable disease. Transplantation was performed on day 0. In the first trial,10 five patients were treated with cisplatin 25 mg/m2, administered by continuous intravenous infusion on days –6 to –3 and fludarabine, 30 mg/m2, and cytarabine, 1g/m2, on days –4 and –3. To avoid the potential nephrotoxicity associated with cisplatin, the next 15 patients were treated in a second trial with fludarabine, 30 mg/m2, followed 4 hours later by cyclophosphamide 750 mg/m2, with each drug administered intravenously daily on days –5 to –3.9 Rituximab (IDEC Pharmaceuticals, San Diego, CA) was administered intravenously on day –13 (375 mg/m2) and on days –6, +1 and +8 (1,000 mg/m2). Eighteen of the 20 patients received unfractionated peripheral blood progenitor cells from HLA-matched sibling donors. In two patients, bone marrow from a matched unrelated donor was the source of the graft. Patients with a transplant from an unrelated donor were treated with 15 mg/kg of equine antithymocyte globulin intravenously on days –5 to –3 to reduce the risk of rejection. Prophylaxis for GVHD consisted of a combination of tacrolimus (adjusted to maintain a trough level of 5 to 15 ng/mL) and methotrexate (5 mg/m2) administered on days +1, +3, and +6. The same dose was also administered on day +11 to patients with an unrelated donor. The dose of tacrolimus was tapered by day 60+ to 90+ if there were signs of residual disease or a decreased level of chimerism; otherwise, it was maintained for 6 months. Supportive care was provided as previously described.9
Assessment of Outcome Responses were scored by standard criteria used for lymphoma.12 Patients were followed up for intervals of 1, 3, 6, and 12 months after transplantation and every 6 months thereafter. At the follow-up visits, patients underwent physical examinations; blood counts; computed tomography of the chest, abdomen, and pelvis; and gallium scanning if indicated. Bone marrow aspirates and biopsies were also obtained for dual-color flow cytometry. Patients with persistent or progressive disease 2 to 3 months after transplantation were eligible for a donor lymphocyte infusion if there was no evidence of acute or clinically extensive chronic GVHD after discontinuing their immunosuppression regimen. The first donor lymphocyte infusion included 1 x 107 CD3+ cells/kg, and the second (if indicated) 1 x 108 CD3+ cells/kg. Actuarial estimates of time to GVHD, relapse, or death were calculated according to the Kaplan-Meier (KM) method13 from the date of allogeneic stem cell or bone marrow infusion. Current progression-free survival accounting for salvage post donor lymphocyte infusion was estimated using a linear combination of KM estimates, as proposed by Klein et al.14
Patient Characteristics A total of 20 consecutive patients with recurrent NHL after autologous SCT were treated between March 1997 and December 2000. Underlying histologies included diffuse large cell lymphoma (n = 10), mantle-cell lymphoma (MCL; n = 5), follicular grade 3 (n = 2), follicular grade 2 (n = 1), and follicular grade 1 (n = 2). Patient characteristics are listed in Table 1. The median age of patients at the time of the second transplantation was 51 years (range, 21 to 61 years). The median number of previous chemotherapy regimens administered to each patient was four (range, two to eight). Salvage treatment with variable conventional chemotherapy before nonmyeloablative transplantation resulted in complete remission (CR) in 10 patients, partial remission in eight patients, and stable disease in the remaining two patients. Nineteen patients had disease that recurred after one autologous transplantation, and one patient had disease that recurred after two previous transplantations. The median time of progression after the autologous transplantation was 15.5 months (range, 1 to 70 months), and the median time from autologous transplantation to the nonmyeloablative allogeneic transplantation was 24 months (range, 6 to 117 months).
Eighteen patients had an HLA-identical sibling donor, and two had an HLA-matched unrelated donor. The median dose of CD34+ cells infused was 4.7 x 106/kg (range, 3.8 to 6.9 x 106/kg).
Engraftment Chimerism data were available for all patients. The median percentage of donor cells at 30 days was 99% (range, 49% to 100%). One patient had early withdrawal of tacrolimus because of a percentage of donor chimerism that decreased from 99% to 70%. The median percentage of donor cells at 100 days for all patients was 100% (range, 50% to 100%).
Response The median follow-up period was 25 months (range, 12 to 52 months). The estimated 3-year current progression-free survival rate was 95% (95% CI, 69% to 99%; Fig 1).
There were eight documented episodes of bacterial infection, four of which were catheter-related. Eight patients had reactivation of cytomegalovirus infection. Four other patients had a fungal infection. One pulmonary Aspergillus infection was the cause of the only death that occurred in this study. That patient had undergone two prior autologous transplants and was disease-free at the time of death, 10.5 months postallogeneic transplantation. One patient experienced grade 2 acute GVHD (cumulative incidence of 5%; 95% CI, 1% to 32%). Grade 3 or 4 acute GVHD did not occur. The KM incidence of extensive and limited chronic GVHD was 50% (95% CI, 31% to 73%). The sites involved with chronic GVHD included the skin (10 patients), mouth (seven patients), liver (three patients), eyes (three patients) and lungs (one patient). Three patients continue to require therapy with immunosuppressive agents. The Zubrod performance status score of patients who remain alive was 0 in 16 patients and 1 in the remaining three patients.
The results of our trial of nonmyeloablative transplantation in patients with NHL whose disease recurred after a previous treatment with high-dose myeloablative therapy and autologous transplantation are very encouraging. The patients were heavily pretreated and included aggressive histologic types of disease. Most patients had responded to prior salvage chemotherapy before the allogeneic transplant. At a median follow-up of 25 months, only one patient experienced relapse. In contrast, the median time to disease relapse for these patients after their prior autologous transplantation was 15.5 months. GVL activity is suggested by the durable responses after a nonmyeloablative regimen with only moderate intrinsic antilymphoma activity and by the response observed in one patient to donor lymphocyte infusion. This outcome compares favorably with studies using high-dose myeloablative transplants or alternative forms of therapy. Subgroup analysis demonstrated a surprisingly low mortality rate and lack of relapse in the 12 patients with diffuse large cell lymphoma or follicular grade 3 lymphoma. Patients with these histologic types have been hitherto described as the least sensitive to the GVL effect among all patients with NHL.15Although the number of patients in the study is small, these results suggest a promising role for nonmyeloablative SCT in patients with these lymphoid histologic types. Branson et al16 treated 38 patients with various lymphoproliferative disorders whose disease recurred after a previous autologous SCT with a nonmyeloablative transplantation from an HLA-matched sibling transplantation. The median time of 26 months (range, 5 to 96 months) between first and second transplantation, was comparable to time interval described in our study. The conditioning regimen consisted of CAMPATH-1H 20 mg intravenously on days –8 to –4 and a combination of fludarabine and melphalan. The median age of patients was 44 years, and only nine were older than 50 years. Actuarial overall survival at 14 months was 53%, with a progression-free survival rate of 50%. In that study, 10 patients had high-grade NHL, and two had MCL. Four (30%) of those 12 patients experienced a CR. Our study differed in that we did not employ CAMPATH-1H, which produces in vivo T-cell depletion; this agent effectively prevents GVHD but may also impair immune antilymphoma effects. The apparent efficacy of our treatment may also be potentially attributed to several other factors. The preparative regimens were truly nonmyeloablative, in which hematopoietic recovery would be expected to occur in less than 28 days, even in the absence of transplantation. The 100% engraftment of donor cells and the lack of a secondary graft failure likely reflected effective immunosuppression from both the transplantation regimens and the preceding treatment. In addition, the strategy of maintaining full immunosuppression for 6 months unless there was disease progression or a decrease of donor chimerism resulted in a 5% incidence of acute grade 2 GVHD, with no patients experiencing grade 3 or 4 acute GVHD. The final interpretation of the results reported must be tempered, however, by the fact that the patients treated in this report were selected to have recurrent lymphoma, responsive to chemotherapy before autologous SCT, and that continue to be chemosensitive or low bulk stable disease at the time of relapse. This chemosensitivity at study entry allowed tumor control early after nonmyeloablative transplantation to allow time for the GVL effect to become established. Nevertheless, the apparent efficacy and limited toxicity of this strategy offers an attractive alternative to conventional chemotherapy or myeloablative transplantation. The approach to patients with chemoresistant disease remains challenging. These patients are more likely to have early failures after the nonmyeloablative strategy, and patients not responding to salvage were not considered appropriate candidates for this approach. Our ongoing strategy is attempting to improve the results in these patients by adding radioimmunotherapy to the conditioning regimen in order to have a better tumor control early after transplantation. In conclusion, this nonmyeloablative strategy can be safely extended to patients with chemosensitive or stable lymphoma whose disease has recurred after high-dose myeloablative therapy and autologous hematopoietic transplantation. GVL effects appear to be operative in patients with aggressive lymphoid malignancies in this setting. Prior autografting should not exclude these patients from nonmyeloablative transplantation.
The authors indicated no potential conflicts of interest.
Supported in part by research grants from The G & P Foundation for Cancer Research. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333:1540–1545, 1995
2. Haioun C, Lepage E, Gisselbrecht C, et al: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: Final analysis of the prospective LNH87-2 protocol—A Groupe d'Etude des Lymphomes de l'Adulte Study. J Clin Oncol 18:3025–3030, 2000
3. Vose JM, Bierman PJ, Anderson JR, et al: Progressive disease after high-dose therapy and autologous transplantation for lymphoid malignancy: Clinical course and patient follow-up. Blood 80:2142–2148, 1992 4. Van Besien KW, De Lima M, Giralt SA, et al: Management of lymphoma recurrence after allogeneic transplantation: The relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 19:977–982, 1997[CrossRef][Medline] 5. de Lima M, van Besien KW, Giralt SA, et al: Bone marrow transplantation after failure of autologous transplant for non-Hodgkin's lymphoma. Bone Marrow Transplant 19:121–127, 1997[CrossRef][Medline] 6. Tsai T, Goodman S, Saez R, et al: Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation. Bone Marrow Transplant 20:859–863, 1997[CrossRef][Medline] 7. Radich J, Gooley T, Sanders JE, et al: Second allogeneic transplantation after failure of first autologous transplantation. Biol Blood Marrow Transplant 6:272–279, 2000[CrossRef][Medline] 8. Khouri IF, Champlin, RE: Non-myeloablative stem cell transplantation for lymphoma. Semin Oncol 31:22–26, 2004
9. Khouri IF, Saliba RM, Giralt S, et al: Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 98:3595–3599, 2001 10. Khouri IF, Saliba RM, Giralt S, et al: Long term remission and low mortality with cisplatin, fludarabine, cytarabine nonablative preparative regimen and allogeneic stem cell transplantation (AST) for histologically aggressive non-Hodgkin's lymphoma (NHL). Blood 98:190a, 2001 (abstr 795) 11. Przepriorka D, Weisdorf D, Martin P, et al: Consensus conference on acute GVHD grading. Bone Marrow Transplant 15:825–828, 1995[Medline]
12. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphoma. J Clin Oncol 17:1244–1253, 1999 13. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 14. Klein JP, Keiding N, Shu Y, et al: Summary curves for patients transplanted for chronic myeloid leukemia salvaged by a donor lymphocyte infusion: The current leukemia-free survival curve. Br J Haematol 109:148–152, 2000[CrossRef][Medline] 15. Van Besien KW, Mehra RC, Giralt SC, et al: Allogeneic bone marrow transplantation for poor-prognosis lymphoma: Response, toxicity and survival depend on disease histology. Am J Med 100:299–307, 1996[CrossRef][Medline]
16. Branson K, Chopra R, Kottaridis P, et al: Role of non-myeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies. J Clin Oncol 20:4022–4031, 2002 Submitted September 16, 2003; accepted March 19, 2004. This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
