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© 2000 American Society for Clinical Oncology Autografting Followed by Nonmyeloablative Immunosuppressive Chemotherapy and Allogeneic Peripheral-Blood Hematopoietic Stem-Cell Transplantation as Treatment of Resistant Hodgkin’s Disease and Non-Hodgkin’s LymphomaFrom the Hematology and Autologous Stem Cell Transplantation Unit, Department of Hematology, Azienda Ospedale San Martino; Istituto Medicina Legale, Università di Genova, Genova; Centro Trasfusionale, Ospedale San Martino, Genova; Oncologia Medica, Ospedale San Carlo, Milano; Oncologia Medica, Ospedale Circolo di Varese, Varese; and Divisione Medicina, Ospedale Pietrasanta, Italy. Address reprint requests to Angelo Michele Carella, Hematology and Stem Cell Transplant, Department of Hematology, Azienda Ospedaliera e Cliniche, Universitarie Convenzionate, Ospedale San Martino, Via Acerbi 10/22, 16148 Genoa, Italy; email amcarella@ smartino.ge.it.
PURPOSE: To investigate the use of a nonmyeloablative fludarabine-based immunosuppressive regimen to allow engraftment of HLA-sibling donors’ mobilized stem cells and induction of a graft-versus-lymphoma effect for patients with advanced resistant Hodgkin’s disease and non-Hodgkin’s lymphoma. PATIENTS AND METHODS: Fifteen patients with Hodgkin’s disease (n = 10) and non-Hodgkin’s lymphoma (n = 5) were studied. All patients received cyclophosphamide and granulocyte colony-stimulating factor to mobilize autologous hematopoietic stem cells (HSCs). Subsequently, they received high-dose therapy with carmustine, etoposide, cytarabine, and melphalan and reinfusion of HSCs. At a median of 61 days after engraftment, patients were given fludarabine 30 mg/m2 with cyclophosphamide 300 mg/m2 daily for 3 days. Donor-mobilized HSC collections were prepared for fresh infusion and were not T-cell depleted. Methotrexate and cyclosporine were used to prevent graft rejection and as graft-versus-host disease (GVHD) prophylaxis.
RESULTS: Combined treatment was well tolerated. After mini-allografting, hematologic recovery was prompt. Thirteen patients had 100% donor cell engraftment. Eleven patients achieved complete remission (CR) after the combined procedure. Nine patients, who were in partial remission after autografting, achieved CR after mini-allografting. Seven patients developed CONCLUSION: Fludarabine/cyclophosphamide was well tolerated and allowed consistent engraftment in lymphoma allografted patients. Response rates were high in this group of refractory and heavily pretreated patients. This dual procedure seems to be most promising in patients with end-stage malignant lymphomas.
THE CURABILITY OF Hodgkin’s disease and non-Hodgkin’s lymphoma by allogeneic transplantation has been limited by conditioning-related toxicity and patient age. In Hodgkin’s disease, the results have been disappointing because mortality rates have been surprisingly high.1-4 In non-Hodgkin’s lymphoma, allogeneic transplantation has generally yielded excellent relapse-free survival superior to that of autologous transplantations5-10; however, the adverse effects of graft-versus-host disease have often negated this advantage so that overall survival is comparable. The greater potential benefit of allogeneic transplantation could be exploited if conditioning mortality is decreased and tumor burden is minimized. One method would be to use conventional salvage chemotherapy (cisplatinum-containing regimens) or high-dose chemotherapy and autologous transplantation to debulk lymphoma, followed by an allogeneic transplantation using a nonmyeloablative conditioning regimen. The recent observation that nonmyeloablative regimens based on fludarabine or low-dose total-body irradiation have resulted in engraftment of allogeneic cells in hematologic malignancies raises the possibility that such conditionings might even be useful in achieving a graft-versus-lymphoma effect.11-17 The main objective of this pilot study was to determine the feasibility of a dual transplantation approach—autografting followed by mini-allograft—in a very high-risk cohort of patients with Hodgkin’s disease and non-Hodgkin’s lymphomas.
Between June 1997 and February 1999, 15 patients who had HLA-sibling donors were enrolled in this protocol in the Department of Hematology of San Martino Hospital in Genoa, Italy. Details of each patient are listed in Table 1. Ten patients (ages 19 to 37 years) had Hodgkin’s disease (six with stage IVB disease, one with IIIA, one with IIIB, and two with IIA) at a median of 31 months (range, 7 to 126 months) after diagnosis. Four patients had primary refractory disease after two to three conventional chemotherapy regimens, one patient was in first relapse, two were in second relapse, two were in fourth relapse, and one was in partial remission. Five patients (ages 24 to 60 years) had non-Hodgkin’s lymphoma, stage IV according to the International Working Formulation classification of non-Hodgkin’s lymphoma: small lymphocytic (one patient), predominantly small-cleaved cell (one patient), diffuse small-cleaved cell (one patient), and large-cell immunoblastic (two patients) at a median of 25 months (range, 8 to 121 months) from diagnosis. Two were primary refractory, and one each was in first, third, and fourth relapse.
All 15 patients were considered to have a poor prognosis: the median number of prior chemotherapy regimens was two (including radiation in 10 patients), 13 of the 15 had mediastinal and/or retroperitoneal bulky disease, and two patients relapsed even after autografting. Informed consent was obtained from each patient and donor before initiation of the protocol, which was approved by the Ethics Committee of San Martino Hospital. All patients were treated with cyclophosphamide (3 g/m2) and granulocyte colony-stimulating factor (G-CSF; 5 µg/kg subcutaneously each day [SC qd]) to mobilize hematopoietic stem cells. CD34+ cells were obtained by leukapheresis and cryopreserved. The preparative regimen for autografting involved carmustine 300 mg/m2 on day 1, etoposide 200 mg/m2 on days 2 through 5, cytarabine 200 mg/m2 bid on days 2 through 5, and melphalan 140 mg/m2 on day 6.6 Two or 3 days after the end of chemotherapy, autologous hematopoietic stem cells were reinfused into the patients. G-CSF 5 mg/kg SC qd was given until neutrophil count reached more than 1 x 109/L for 3 consecutive days. All patients received intravenous prophylactic third-generation cephalosporins, aminoglycosides, and amphotericin B when neutrophils were less than 1 x 109/L. After recovery from the autologous procedure, the patients were discharged from the hospital and evaluation of response was carried out with radiographs, computed tomography scans, gallium scanning, and bone marrow histology. When clinically stable, patients were readmitted for allogeneic transplantation at a median of 61 days (range, 33 to 1,194 days) after autografting (Table 1). The preparative regimen consisted of fludarabine 30 mg/m2 followed by cyclophosphamide 300 mg/m2 on days -4, -3, and -2 before infusion of donor cells. Donors received G-CSF 10 µg/kg SC qd for 3 to 4 days; after that, mobilized hematopoietic stem cells were collected by leukapheresis on 1 or more days, if necessary, to achieve a possible dose of more than 2 x 106 CD34+ cells/kg of recipient weight. Donor collections were prepared for fresh infusion and were not T-cell depleted, but in cases of major or minor ABO incompatibility between donor and recipient, were subjected to standard procedures for erythrocyte or plasma removal, respectively. On day 0 (and on day +1, if required) unmanipulated hematopoietic stem cells were transfused to the recipients. Methotrexate 8 mg/m2 on day +1, +3, +5 and cyclosporine (CSA) were used to prevent graft rejection and as an acute graft-versus-host disease (aGVHD) prophylaxis. CSA was given from day -1 as an intravenous daily continuous infusion of 1 mg/kg, which was later changed to 5 mg/kg orally. Patients showing 100% donor complete chimerism by minisatellite analysis on day +60 continued CSA until day +180; thereafter, CSA was tapered by 25% to 30% every 7 to 10 days and discontinued by day +180 if no sign of aGVHD developed. In patients with mixed chimerism on day +60, CSA was tapered off over 7 to 10 days and chimerism analysis was repeated after 2 weeks. Patients not evolving to 100% donor chimerism after CSA withdrawal received monthly escalating doses of donor lymphocyte infusion (DLI; 1 x 106/kg, 1 x 107/kg, 5 x 107/kg), with frequent evaluation of chimerism until 100% donor stem chimerism, GVHD, disease regression, or graft rejection occurred. Patients with symptomatic aGVHD were treated with CSA and methylprednisolone. Complete remission was defined as the disappearance of all disease and symptoms for at least 1 month. Partial remission was defined as 50% reduction in the sum of products of the two greatest perpendicular diameters of measurable lesions and 50% reduction in marrow involvement. All other outcomes were considered treatment failure. Overall survival was measured from allografting until death from any cause. Hematopoietic chimerism was assessed by marrow cytogenetic analysis in male/female donor-recipient combinations to evaluate the actual proportions of host and donor hematopoietic cells in mitosis. In all patients, serial samples of bone marrow were analyzed for degree of donor-recipient chimerism using polymerase chain reaction of informative minisatellite regions, which identified differences between recipient and donor (based on polymorphisms found in pretransplantation recipient/donor samples).18,19 Chimerism was evaluated on days 10, 20, 30, 45, 60, 90, 120, 150, and 180 posttransplantation.
The outcome in 15 patients undergoing autografting followed by nonmyeloablative allografting is listed in Table 2.
Autografting No serious complication other than mucositis occurred after chemotherapy with carmustine, etoposide, cytarabine, and melphalan. The median dose of CD34+ cells obtained and infused was 3.6 x 106 cells/kg (range, 0.9 to 17 x 106 cells/kg). All patients recovered neutrophils more than 1 x 109/L in 3 to 23 days (median, 10 days), and 10 patients were platelet transfusion–independent in 10 to 27 days (median, 15 days) after autografting; five patients had prolonged thrombocytopenia. All five patients with non-Hodgkin’s lymphoma obtained a partial remission of lymphoma on computed tomography scan. In particular, mediastinal and/or retroperitoneal involvement was decreased by 50% in all patients, and a reduction of approximately 50% bone marrow or parenchymal localizations was also demonstrated. Among the 10 patients with Hodgkin’s disease, three achieved complete remission, with disappearance of Hodgkin’s disease in bone marrow, mediastinal, and lung, and seven patients achieved partial remission.
Allografting Nine patients who were in partial remission after autografting achieved a complete remission after allografting. Subsequently, two patients experienced relapse and are now alive in fourth and second relapse at 700 and 630 days after transplantation, respectively; two patients died of brain hemorrhage after aspergillus infection (day 120) and extensive chronic GVHD (cGVHD; day 260). To date, five patients maintain the complete remission 210 to 340 days (median, 270 days) after allografting ± DLI. It is of interest that three patients (two with Hodgkin’s disease and one with non-Hodgkin’s lymphoma) with disease primarily refractory to first- and second-line intensive conventional chemotherapy, who achieved partial debulking of the disease after autografting, were able to obtain for the first time complete remission after mini-allografting and without DLI (Table 3). Two patients maintain remission at 210 and 335 days after allografting, whereas the third patient experienced relapse and is now alive at 630 days in second relapse despite DLI. The Kaplan-Meier survival and event-free survival plots are shown in Figs 1 and 2.
Chimerism Analysis All patients had evidence of donor cell engraftment. The percentage of donor cells increased progressively, and six patients achieved full chimerism without DLI 90 to 210 days (median, 133 days) after donor hematopoietic stem-cell infusion. In seven patients with mixed chimerism, CSA was withdrawn without success in terms of chimerism modification. After DLI, full chimerism was achieved in all patients at a median of 210 days (range, 90 to 420 days).
Toxicity
To date, 10 patients are alive between 210 and 700 days (median, 337 days) after transplantation. Five patients died: two patients as a result of progressive disease (one with Hodgkin’s disease at day 66 and the other with non-Hodgkin’s lymphoma at day 172), one patient as a result of progressive Hodgkin’s disease combined with extensive cGVHD (day 460), and two patients as a result of brain hemorrhage after aspergillus infection (day 120) and extensive cGVHD (day 260) during their remissions achieved with mini-allografting. The three patients who received the maximum dose of DLI developed greater than grade 2 aGVHD (two patients) or extensive cGVHD (one patient) (Tables 4 and 5).
The outlook for patients with Hodgkin’s disease and non-Hodgkin’s lymphoma who do not enter a complete remission after first-line combination chemotherapy is poor.20,21 Because conventional salvage chemotherapies have not modified the survival for most of these patients, many are treated with high-dose therapy/autografting. The results of several single-institution studies have suggested a superior outcome for patients who receive autografting in this setting versus conventional therapies.22-31 Five-year actuarial overall and progression-free survival rates of 36% and 32%, respectively, were recently published by the European Bone Marrow Transplantation Group in 175 patients with Hodgkin’s disease who did not enter remissions after induction chemotherapy.32 Similar to several previous series, the extent of therapy before autografting was a significant factor in univariate analysis. Patients who had received more than one prior regimen had a significantly worse outcome when compared with those who received only one course. The results of this study suggest that autografting may be an effective strategy for patients with Hodgkin’s disease who do not respond to induction chemotherapy, whether they have progressive disease or brief remission followed by relapse. Unfortunately, many of these patients will experience disease progression and will ultimately die. In non-Hodgkin’s lymphoma (mainly in low-grade lymphoma) since the limitations of autografting have become more evident, renewed interest in allografting and clinical application of potential graft-versus-lymphoma effects has been generated.3-6,33-35 Although the clinical evidence of graft-versus-lymphoma remains anecdotal, many cases of lymphoma regression in allografting recipients after withdrawal of CSA or after DLI have been described34-36; moreover, the attainment of molecular remission was also demonstrated in follicular lymphoma.37 Whether because of lack of tumor contamination or a graft-versus-lymphoma effect, a large number of studies indicate a lower recurrence rate of lymphoma after allografting when compared with autografting. Only one prospective study comparing allografting with autografting was reported and indicates a significantly decreased recurrence rate after allografting and a trend toward improved disease-free survival.8 Unfortunately, the adverse effects of high-dose therapy and GVHD have often negated the advantage of allografting on autografting and led to an equivalent (non-Hodgkin’s lymphoma) or less than equivalent (Hodgkin’s disease) overall survival in these diseases. If allografting is performed safely, the possibility of a graft-versus-lymphoma effect in Hodgkin’s disease and non-Hodgkin’s lymphoma would make further studies important. The recent observation that fludarabine-containing regimens have resulted in engraftment of allogeneic cells in hematologic and nonhematologic malignancies raises the possibility that such conditioning might even be useful in achieving a graft-versus-lymphoma effect combined with a decisively decreased mortality.11-17 The 15 patients in this study were unlikely to be cured with autografting alone. After autografting, only three patients achieved complete remission and two of them were short-lived, with progression of disease occurring at the time of allografting procedure. Allografting with nonmyeloablative conditioning produced a high number of complete remissions. Complete chimerism was documented in 13 (87%) of these patients, six without DLI and seven after a series of DLI. The fludarabine/cyclophosphamide regimen, originally proposed for the treatment of indolent lymphomas,11,13 was extremely well tolerated. This regimen permitted the engraftment of allogeneic cells, which seem to determine graft-versus-lymphoma effect, in a manner similar to that reported in other hematologic neoplasia at the M.D. Anderson Cancer Center11 and at the Hadassah University12 but without incidence of neutropenia and other important side effects. This low toxicity confirms previous reports of nonmyeloablative transplantation outcome11-13,15-17 and should be viewed in the context of a patient population with a high risk of transplantation-related mortality. Furthermore, the remission achieved after allografting observed in these patients occurred many months after mini-allografting. This delay implies that the extremely low-intensity regimen used and the long period elapsed from autografting cannot explain their activity against these lymphomas. In conclusion, the use of autografting to debulk lymphoma and less toxic nonmyeloablative preparative regimens enabled engraftment and generation of a graft-versus-lymphoma effect that was responsible for much of the benefit of allogeneic hematopoietic stem-cell transplantation in mediating these dramatic lymphoma regressions. Future studies are required to define whether similar good results could be achieved with salvage chemotherapy (such as cisplatin-containing regimens) before nonmyeloablative allogeneic transplantation.
Supported by Associazione Italiana per la Ricerca sul Cancro (AIRC 1999) and Associazione Italiana per le Leucemie (AIL 1999).
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Gajewski JL, Phillips GL, Sobocinski KA, et al: Bone marrow transplants from HLA-identical siblings in advanced Hodgkin’s disease. J Clin Oncol 14: 572-578, 1996 5. Jones RJ, Ambinder RF, Piantadosi S, et al: Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 3: 649-653, 1991 6. Chopra R, Goldstone AH, Pearce R, et al: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin’s lymphoma: A case-controlled analysis of the European Bone Marrow Transplant Group registry data. J Clin Oncol 11: 1690-1695, 1992 7. Van Besien KW, Rakesh CM, 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[Medline]
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Ratanatharothorn V, Uberti J, Karanes C, et al: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin’s lymphoma. Blood 84: 1050-1055, 1994 9. Appelbaum FR: Treatment of aggressive non-Hodgkin’s lymphoma with marrow transplantation. Marrow Transplant Rev 3: 1-16, 1993
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Slavin S, Nagler A, Naparstek E, et al: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91: 756-763, 1998 13. Khouri IF, Keating M, Korbling M, et al: Transplant-like: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16: 2817-2824, 1998[Abstract] 14. Mc Sweeney P, Storb R: Establishing mixed chimerism with immunosuppressive, minimally myelosuppressive conditioning: Preclinical and clinical studies. American Society of Hematology Educational Book, 1999, pp 396-405 15. Sykes M, Preffer F, McAfee S, et al: Mixed lymphohematopoietic chimerism and graft versus lymphoma effect are achievable in adult recipients following non-myeloablative therapy and HLA-mismatched donor bone marrow transplantation. Lancet 353: 1755-1761, 1999[Medline] 16. Carella AM, Champlin R, Slavin S, et al: Mini-allografting: ongoing trials in humans. Bone Marrow Transplant 25: 345-350, 2000[Medline]
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Yahalom J, Gulati SC, Toia M, et al: Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin’s disease. J Clin Oncol 11: 1062-1070, 1993
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Sweetenham JW, Carella AM, Taghipour G, et al: High-dose therapy and autologous stem cell transplantation for adult patients with Hodgkin’s disease who do not enter remission after induction chemotherapy: Results in 175 patients reported to the European Group for Blood and Marrow Transplantation. J Clin Oncol 17: 3101-3109, 1999 33. Van Besien KW, Khouri IF, Giralt SA, et al: Allogeneic bone marrow transplantation for refractory and recurrent low-grade lymphoma: The case for aggressive management. J Clin Oncol 13: 1096-1101, 1995[Abstract] 34. Petersen FB, Appelbaum FR, Bigelow CL, et al: High-dose cytosine arabinoside, total body irradiation and marrow transplantation for advanced malignant lymphoma. Bone Marrow Transplant 4: 483-488, 1989[Medline] 35. Van Biesen KW, de Lima M, Giralt SA, et al: Management of lymphoma recurrence after allogeneic transplantation: The relevance of graft versus lymphoma effects. Bone Marrow Transplant 19: 977-982, 1997[Medline] 36. Rudolphi M, Basara N, Bischoff M, et al: Induction of graft versus lymphoma reaction in stage IVB cell non-Hodgkin’s lymphoma, after allogeneic peripheral blood stem cell transplant: Comparison of laboratory, radiological and clinical findings. Blood 90:4475a, 1997 (abstr) (suppl 1) 37. Mandigers C, Meijerink JP, Raemaekers JM, et al: Graft vs lymphoma effect of donor leukocyte infusion shown by real-time quantitative PCR analysis of t(14;18). Lancet 352: 1522-1523, 1998[Medline] Submitted January 27, 2000; accepted June 28, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
grade 2 acute GVHD (aGVHD) and two developed extensive chronic GVHD (cGVHD). Three patients who received the highest number of donor lymphocyte infusions (DLIs) developed grade 3 GVHD (two patients) and extensive cGVHD (one patient). Ten patients are currently alive, and five are in continuous CR. Seven patients received DLI, with five CRs. Five patients died: one of progressive disease, two of progressive disease combined with aGVHD or cGVHD, one of extensive cGVHD, and one of infection. 
, censored patients. Abbreviation: Cum., cumulative.
, patients who are alive and in remission.
