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© 2003 American Society for Clinical Oncology Nonablative Allogeneic Stem-Cell Transplantation for Advanced/Recurrent Mantle-Cell Lymphoma
From the Departments of Blood and Marrow Transplantation, Laboratory Medicine, Lymphoma, and Pathology, 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, Unit 423, the University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ikhouri{at}mdanderson.org.
Purpose: Patients with relapsed mantle-cell lymphoma have poor prognosis and short survival. Our aim was to determine the efficacy of nonablative allogeneic stem-cell transplantation in patients with relapsed mantle-cell lymphoma. Patients and Methods: Eighteen patients were treated in one of two consecutive trials. Thirteen patients underwent a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and high-dose rituximab. For the remaining five patients, the conditioning regimen consisted of cisplatin (25 mg/m2 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: The median age was 56.5 years. Patients underwent a median of three prior chemotherapy regimens. Prior autologous transplantation failed in five (28%) patients and 16 (89%) had chemosensitive disease. Donor cell engraftment occurred in all patients. Eight patients (44%) required no platelet or RBC transfusion, and acute graft-versus-host disease of greater than grade 2 did not develop in any patient. The day-100 mortality was 0%. Complete remission (CR) occurred in 17 patients. Three patients progressed, and one was reinduced into continuous CR with donor lymphocyte infusion. With a median follow-up period of 26 months, the actuarial probability of current-event-free-survival at 3 years was 82% (95% CI, 65% to 99%). Conclusion:Our data suggest that nonablative allogeneic transplantation is a safe and potentially effective strategy for patients with relapsed and chemosensitive mantle-cell lymphoma.
MANTLE-CELL LYMPHOMA (MCL) is an aggressive cancer that often presents in advanced stages in association with poor prognostic features.1–5 Although patients initially respond to combination chemotherapy, the disease typically reoccurs within 1 year of therapy. The median survival in patients from the time of the initial diagnosis is approximately 3 years, and 1 year following relapse.2–5 High-dose therapy with allogeneic hematopoietic transplantation has been shown to induce durable remissions in some patients with refractory lymphomas and relapsed MCL.6–10 Responses have also been observed from donor lymphocyte infusion (DLI) for MCL. These findings suggest the presence of a potent graft-versus-lymphoma effect against this malignancy. However, high-dose therapy and allogeneic transplantation has been associated with a high rate of treatment-related mortality of approximately 40%. Because the median age of patients with MCL is 60 to 65 years, more than half of the patients would not be considered for this strategy. Recently, nonablative preparative regimens have been developed to reduce the toxicity of allogeneic transplantation and allow development of graft-versus-malignancy effects as primary treatment of malignancy. We recently demonstrated an 8% treatment-related mortality rate using a nonablative allogeneic transplantation for treatment of low-grade lymphoma.11 We therefore investigated the use of a nonablative conditioning regimen with allogeneic stem-cell transplantation for MCL. The goal was to utilize a lower-dose, well-tolerated, preparative regimen to achieve engraftment and initial disease control, allowing development of the graft-versus-lymphoma effect to eradicate the malignancy.
Selection of Patients Our study included 18 patients with diffuse MCL who failed to achieve remission or recurred after either conventional chemotherapy or autologous stem-cell transplantation. Patients generally received induction therapy with the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) alternating with high-dose methotrexate, cytarabine, and rituximab regimen to achieve a minimal disease state before transplantation. To be eligible for the study, 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 cardiac or pulmonary disease. Patients also had to have stable or chemosensitive disease. Informed consent 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 Prophylaxis for graft-versus-host disease (GVHD) consisted of a combination of tacrolimus, adjusted to maintain a trough level of 5 to 15 ng/mL) and methotrexate (5 mg/m2) given on days 1, 3, and 6 after transplantation. The same dose was also given on day 11 to patients with a mismatched or unrelated donor. The dose of tacrolimus was tapered by day 60 to 90 if there were signs of residual disease; otherwise, it was maintained for 6 months. Prophylactic therapies against Pneumocystis carinii, Candida, herpes simplex virus, and cytomegalovirus infections were administered as previously described.11
Quantitative Chimerism Analysis PCR was performed on the pretransplant, donor, and post-transplant samples for 35 cycles. One µl of each of the PCR products was mixed with 0.4 µL of the Gene Scan ROX 500 molecular weight standard (Applied Biosystems, Foster City, CA) and 20 µL of deionized formamide; this was followed by denaturation at 95°C for 5 minutes and then rapid cooling to 4°C. The samples were then loaded on to an ABI3700 Genetic Analyzer (Applied Biosystems, Foster City, CA) for capillary electrophoresis and automated size fractionation using ABI DNA Genescan Analysis Software (Version 3.0, Applied Biosystems, Foster City, CA). The patterns of the pretransplantation, donor, and posttransplantantation samples were compared to determine the engraftment status. In the case that a mixed chimera pattern was identified in a posttransplantation sample, the mixed chimera status was quantified. The chimerism status was also assessed and quantified in the T cell subpopulations, which were harvested by a RosetteSep T-cell enrichment kit according to the manufacturer’s recommendations (Stem Cell Technology Inc, Vancouver, BC, Canada).
Evaluations Acute and chronic GVHD were graded according to the consensus criteria.12 Actuarial estimates of time to GVHD, relapse, or death were calculated according to the method of Kaplan and Meier.13 Current progression-free survival accounting for salvage post donor lymphocyte infusion was estimated using a linear combination of Kaplan and Meier estimates, as proposed by Klein et al.14 Disease stage and responses were scored by standard criteria used in patients with lymphoma.15 Patients were followed up 1, 3, 6, and 12 months after transplantation and every 6 months thereafter. Patients were clinically assessed more frequently at the discretion of the primary physician. At the follow-up visits, patients had 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 chromosomal analysis and dual-color flow cytometry. Patients with gastrointestinal symptoms underwent screening endoscopy to look for possible lymphomatous involvement. Patients with persistent disease 2 to 3 months after transplantation were eligible to a DLI if there was no evidence of acute or clinically extensive chronic GVHD after discontinuation of their immunosuppression regimen. The first DLI included 1 x 107 CD3+ cells/kg and the second (if indicated) 1 x 108 CD3+ cells/kg. To assess for residual disease, PCR was performed to look for the bcl-1 gene rearrangement and/or the allele-specific third complementary-determining region, as previously described, if a lymph node was accessible for a biopsy.11 In addition, a two-color fusion fluorescence in situ hybridization assay was performed to directly detect t(11;14)(q13:q32). The high sensitivity of this test which can detect 91% of cases of MCL, was previously described by Gu et al.16
Patients Eighteen patients were included in the analysis. All cases were reviewed by an expert hematopathologist for diagnostic confirmation with immunophenotypic studies and by characteristic cyclin D1 expression. The patients ranged in age from 46 to 64 years (median, 56.5 years). There were 15 males and three female patients. The median time from diagnosis was 40 months (range, 9 to 121 months). The number of prior chemotherapy regimens received by each patient ranged from one to 10 (median, three). Autologous stem-cell transplantation had failed in five patients. On evaluation at their relapse, 13 patients (72%) had stage IV disease, eight (44%) had gastrointestinal, and one had lung involvement; three (17%) had involvement of peripheral blood, and one (patient 16) had blastic features. The International Prognostic Index15 level was greater than 1 in nine of the 15 patients (60%) for whom the level was available. Salvage therapy was given to 17 patients before transplantation for cytoreduction purposes. This resulted in complete remission (CR) in eight patients, partial remission in eight patients, and two patients had stable disease (Table 1  ). The duration of remission could not be determined because all patients underwent transplantation within four weeks of the conclusion of chemotherapy. One patient could not receive cytoreductive therapy because of cytopenia.
Thirteen patients had an HLA-identical sibling donor, one had a mismatched sibling donor, and four had an HLA-matched unrelated donor.
Engraftment PCR analysis showed donor cell engraftment in all patients. The median percentage of donor T-cell chimerism in peripheral blood at 21 days was 55%. This increased to 100% (range, 0% to 100%) at 90 days after transplantation. One patient (patient 3) had a secondary graft failure 45 days after transplantation. This patient had received a mismatched transplant and had poorly tolerated the ATG. As a result, the third dose of ATG within the conditioning regimen was reduced. She recovered autologous hematopoiesis.
Outcome
Of the seventeen patients who achieved CR after transplantation, nine had evidence of minimal residual MCL shown by PCR (Fig 2 ) at the time of transplantation. Six subsequently achieved molecular remission without additional intervention. Three patients remained PCR-positive; one (patient 6) had relapsed.
Three patients developed grade 2 acute GVHD involving skin (three patients) or gastrointestinal tract (one patient); cumulative incidence of 17%; 95% CI, 6% to 48%). Grade 3 or 4 acute GVHD did not occur. The incidence of extensive chronic GVHD was 36% (95% CI, 18% to 63%). Three patients had gastrointestinal involvement, and one had liver involvement. Three deaths occurred. One was related to infection at 19 months, in the setting of GVHD (patient 17) and one patient died of progressive disease (patient 10). The third death that occured was unrelated to therapy. This patient (patient 11) had a history of deep vein thrombosis before transplantation, and died of a pulmonary embolism at an outside hospital 15 months after transplantation while in continuous remission and off all therapy related to this protocol. No patients experienced greater than grade 2 nonhematologic toxicity. Cytomegalovirus antigenemia occurred in nine patients that responded to ganciclovir treatment.
The median follow-up time from transplantation was 26 months (range, 11 to 47 months). The estimated 3-year survival rate and current progression-free survival rate from transplantation are 85.5% (95% CI, 53% to 96%) and 82% (95% CI, 65% to 99%), respectively (Fig 3
This study demonstrates the potential efficacy of nonablative allogeneic hematopoietic transplantation for advanced or relapsed MCL. The results are encouraging in this group of heavily pretreated patients who had already received a median of three prior chemotherapy regimens. In addition, autologous stem cell transplantation had failed in 28% of patients. All patients had at least 11 months of follow-up from transplantation. The current progression-free survival at 3 years was 82%. The apparent efficacy of our treatment may be related to several factors. One is that the conditioning regimens used were minimally toxic. The day-100 mortality was 0%, despite the prior exposure of five patients to high-dose chemotherapy and autologous transplant. This confirms the safety described in the initial reports in low-grade lymphoma.11 The other important factor, may be related to the status of patients at transplant. Sixteen of the 18 patients included had chemosensitive disease. The chemotherapy alone, however, cannot explain the favorable outcome in this analysis. The durable response to donor lymphocyte infusion in a patient who had early progression, and the molecular conversion in a patient from a PCR-positive to a PCR-negative status four months after transplantation, suggest that the efficacy of this nonablative allogeneic strategy is mostly related to an immune graft-versus-lymphoma effect. This is the largest reported series from a single institution of allografting after nonablative conditioning as salvage therapy following failed conventional chemotherapy or autologous stem-cell transplantation. The European Group for Blood and Bone Marrow Transplantation17 recently reported their results with nonablative allogeneic transplantation from various centers in 22 patients with MCL. The median age of the patients was 52 years (range, 44 to 57 years). The median number of prior lines of therapy was two. Seventy-three percent of patients had chemosensitive disease at the time of transplantation. Progression-free survival at 2 years was 0%. The major cause of failure was disease progression. A large number of patients in that trial were treated with in vivo T-cell depletion with either the humanized monoclonal antibody alemtuzumab or antithymocyte globulin, which may explain this high relapse rate. The results of this study are encouraging when contrasted with our experience with autologous stem-cell transplantation after cytoreduction with the hyper-CVAD regimen.18 Of those patients who had been previously treated, only 17% were event-free at 3 years. Patients in that group were cytoreduced and 38% were in CR before their transplantation. Their characteristics, including age, stage, and marrow involvement were comparable to the patients included in the present study. Recently, a CD20-specific monoclonal antibody, conjugated with 131I, was administered with high-dose etoposide and cyclophosphamide in an attempt to improve the outcome after autologous transplantation.19 However, the patients were younger than those in our study, with the oldest patient being 59 years of age. In addition, results were probably skewed by the fact that patients with a tumor bulk of more 500 cm3, splenomegaly, or no measurable disease were excluded. The probability of progression-free survival at 3 years was only 61%, with a median follow-up of 19 months. Our data suggest that nonablative allogeneic stem-cell transplantation may improve the outcome in patients with relapsed and chemosensitive MCL. Longer follow-up and controlled trials comparing nonablative allogeneic transplantation with other treatments are needed to confirm the efficacy of this approach.
The authors indicated no potential conflicts of interest.
This study was supported in part by research grants from the G & P Foundation for Cancer Research.
1. Barista I, Romaguera JE, Cabanillas F: Mantle-cell lymphoma. Lancet Oncol 3:141–148, 2001 2. Hiddemann W, Unterhalt M, Hermann R, et al: Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study. J Clin Oncol 16:1922–1930, 1998[Abstract]
3. Velders GA, Kluin-Nelemans JC, De Boer CJ, et al: Mantle-cell lymphoma: a population-based clinical study. J Clin Oncol 14:1269–1274, 1996
4. Fisher RI, Dahlberg S, Nathwani BN, et al: A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. Blood 85:1075–1082, 1995 5. Armitage JO, Weisenberger DD: for the Non-Hodgkin’s Lymphoma Classification Project. New approach to classifying non-Hodgkin’s lymphomas: Clinical features of the major histologic subtypes. J Clin Oncol 16:2780–2795, 1998[Abstract]
6. Przepiorka D, van Besien K, Khouri I, et al: Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma. Ann Oncol 10:527–532, 1999
7. van Besien K, Sobocinski KA, Rowlings PA, et al: Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 92:1832–1836, 1998
8. Hosing C, Saliba RM, McLaughlin P, et al: Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin’s lymphoma. Ann Oncol 14:737–744, 2003 9. van Besien KW, Mehra RC, Giralt SA, 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]
10. Khouri IF, Lee MS, Romaguera J, et al: Allogeneic hematopoietic transplantation for mantle-cell lymphoma: molecular remissions and evidence of graft-versus-malignancy. Ann Oncol 10:1293–1299, 1999
11. Khouri IF, Saliba RM, Giralt SA, 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 12. Przepiorka D, Weisdorf D, Martin P, et al: Report of the 1994 consensus conference on acute GVHD grading. Bone Marrow transplant 15:825–828, 1995[Medline] 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. Shipp MA, Harrington DP, Anderson JR, et al: A predictive model for aggressive NHL: the International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329:987–994, 1993 16. Gu J, Zaidi TM, Shi H, et al: Fluorescence-in-situ-hybridization (FISH) approaches in the detection of t(11, 14)(q13;q32) for mantle cell lymphoma (MCL). Proc Am Assoc Cancer Res 42:1872a, 2001
17. Robinson SP, Goldstone A, Mackinnon S, et al: Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor transplantation: An analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 100:4310–4316, 2002
18. Khouri IF, Romaguera J, Kantarjian H, et al: Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 16:3803–3809, 1998
19. Gopal AK, Rajendran JG, Petersdorf SH, et al: High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood 99:3158–3162, 2002 Submitted May 15, 2003; accepted August 18, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
