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© 2003 American Society for Clinical Oncology Early Autologous Stem-Cell Transplantation Versus Conventional Chemotherapy as Front-Line Therapy in High-Risk, Aggressive Non-Hodgkin’s Lymphoma: An Italian Multicenter Randomized Trial
From the Departments of Cellular Biotechnology and Hematology and Experimental Medicine and Pathology, University "La Sapienza" of Rome, Hematology University "Tor Vergata" Rome, and Division of Hematology "La Cattolica" University of Rome, Rome; Institute of Hematology and Medical Oncology, University of Bologna, Bologna; Division of Hematology, University of Napoli, Napoli; Hematology University of Perugia, Perugia; Division of Hematology, Ravenna Hospital, Ravenna; Division of Hematology, Pesaro Hospital, Pesaro; Division of Internal Medicine, University of Bari, Bari; Division of Hematology, Taranto Hospital, Taranto; and Division of Hematology, Cesena Hospital, Cesena; Italy. Address reprint requests to Maurizio Martelli, MD, Dipartimento Biotecnologie Cellulari ed Ematologia, University "La Sapienza" via Benevento, 6 00161 Roma, Italy; email: martelli{at}bce.med.uniroma1.it.
Purpose: To evaluate the role of early intensification with high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) as front-line chemotherapy for patients with high-risk, histologically aggressive non-Hodgkin’s lymphoma (NHL). Patients and Methods: We planned a multicenter, randomized trial to compare a conventional chemotherapy regimen of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; arm A) with an abbreviated regimen of MACOP-B (8 weeks) followed by HDT and ASCT (arm B) for intermediate-high-risk/high-risk patients (according to the age-adjusted International Prognostic Index). From September 1994 to April 1998, 150 patients with aggressive lymphoma were enrolled onto the trial. Seventy-five patients were randomly assigned to arm A and 75 patients were randomly assigned to arm B. In both arms, involved-field radiation therapy (36 Gy) was delivered to the site of bulky disease. Results: The rate of complete response was 68% in arm A and 76% in arm B (P = not significant [NS]). Three toxic deaths (4%) occurred in arm B and one (1%) occurred in arm A (P = NS). In arm B, 30 patients (40%) did not undergo HDT and ASCT. According to the intention-to-treat analysis at a median follow-up of 24 months, 5-year overall survival probability in arms A and B was 65% and 64% (P = .95), 5-year progression-free survival was 49% and 61% (P = .21), and 5-year relapse-free survival was 65% and 77% (P = .22), respectively. Conclusion: Abbreviated chemotherapy followed by intensification with HDT-ASCT is not superior to conventional chemotherapy in patients with high-risk, aggressive NHL. Additional randomized trials will clarify whether HDT-ASCT as front-line therapy after a complete course of conventional chemotherapy improves survival in this group of patients.
DIFFUSE LARGE-CELL lymphomas are highly chemotherapy-sensitive malignancies. Treatment with conventional combination chemotherapy produces complete remission (CR) rates of 50% to 70% and disease-free survival rates of approximately 50%.1–4 More intensive third-generation regimens, despite their promising initial results, did not prove to be better than the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone.5,6 It may be crucial to identify at diagnosis which patients are at high risk of failure to respond or of relapse. Many prognostic models have been proposed7,8; recently, the International Prognostic Index (IPI) was shown to be a simple and widely accepted prognostic classification.9 In this model, patients considered to have poor prognosis, defined as intermediate-high risk or high risk, have a probability of long-term survival of 46% and 32%, respectively. For such patients, new therapeutic approaches are warranted. At present, high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is the treatment of choice for patients with relapsed aggressive non-Hodgkin’s lymphoma (NHL) that are still responding to salvage chemotherapy.10–12 Whether autologous transplantation has a role as front-line therapy in high-risk patients is still a matter of debate.13 A previous multicenter randomized study from our group in patients with partial response after abbreviated conventional first-line chemotherapy failed to demonstrate the superiority of HDT followed by ASCT as compared with cisplatin, cytarabine, and dexamethasone.14 Another multicenter study in the same setting of patients yielded the same conclusions.15 A few phase III randomized studies have been published on the use of HDT followed by ASCT as consolidation treatment in patients with aggressive NHL in first CR after conventional front-line chemotherapy16,17 or as up-front chemotherapy.18 These studies showed that the use of HDT plus ASCT is beneficial in terms of freedom from progression only in high-risk patients, thus supporting this approach only in this subset of patients. Other prospective randomized trials in which an abbreviated conventional chemotherapy regimen followed by early HDT-ASCT was compared with standard front-line chemotherapy produced contrasting results.19,20 Given the above-described findings, we conducted a prospective, multicenter, randomized trial in histologically aggressive NHL with the aim of comparing a shorter program of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; 8 weeks) followed by carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC) high-dose chemotherapy plus ASCT versus a standard MACOP-B regimen (12 weeks). The main end point of this study was to assess the role of early intensification with HDT and ASCT as front-line chemotherapy in patients with at least two risk factors according to the age-adjusted IPI.
Eligibility Criteria This study was a prospective, randomized, phase III, multicenter trial involving 18 centers in Italy. The protocol was approved by the institutional board for human investigation at each participating center. Study eligibility criteria included the following: (1) age 15 to 60 years; (2) biopsy-proven diagnosis of aggressive NHL according to the Revised European-American Lymphoma classification21 of diffuse large B-cell, peripheral T-cell, or anaplastic NHL (all biopsies and histologic specimens underwent histologic review by expert hematopathologists: S.A.P. at the University of Bologna, B.F. at the University of Perugia, and E.P. at the University of Rome); (3) stage II through IV disease or stage I disease with bulky mediastinal presentation according to the Ann Arbor staging system; (4) IPI-adjusted score defined as intermediate/high or high risk; (5) normal renal, pulmonary, cardiac, and hepatic function; (6) negative serology for human immunodeficiency virus or hepatitis B or C; and (7) written informed consent.
Staging Procedures
Study Design and Patient Characteristics
Pretreatment patient characteristics are listed in Table 1  . There were no significant differences in any parameter considered between the two arms, with the exception of anaplastic large-cell histology, which was significantly more frequent among patients in arm B.
Arm A. Patients who achieved CR, complete response unconfirmed (CRu), or partial response (PR) at the end of the treatment underwent follow-up evaluation. If bulky disease was present at diagnosis or a residual mass was present at the end of chemotherapy, a course of radiation therapy on the involved field was allowed. Patients with minor response (MR) were considered nonresponders (NRs), and for them, the subsequent treatment was left to the discretion of the investigator. Arm B. Patients who obtained CR, CRu, PR, or MR after 8 weeks of MACOP-B proceeded to HDT-ASCT; after completion of the treatment plan, patients with bulky or residual mass could receive IFRT. The stem-cell source could be either peripheral blood or bone marrow. Bone marrow collection started when the marrow was repopulated after the last course of MACOP-B. Collection and cryopreservation of bone marrow were performed according to standard procedures;22 at least 1.5 x 108 nucleated cells/kg of body weight were collected. Peripheral-blood stem cell (PBSC) mobilization and collection had to be performed by administering granulocyte colony-stimulating factor (G-CSF) 24 hours after week 8 of MACOP-B therapy or by administering G-CSF alone 2 weeks after the completion of week 8 of chemotherapy. Different mobilizing procedures were not allowed. Patients with bone marrow involvement at diagnosis could use PBSCs exclusively. From September 1996, all eligible patients underwent only PBSC transplantation. The absence of marrow involvement by lymphoma cells was rechecked at the time of stem-cell collection by histology and flow cytometry. It was recommended that the interval between the end of chemotherapy and stem-cell collection and transplantation should not be longer than 4 weeks. Patients assigned to HDT-ASCT underwent a 5-day period of a four-drug chemotherapy regimen according to the BEAC schedule consisting of carmustine 300 mg/m2 on day -7 and etoposide 200 mg/m2, cytarabine 200 mg/m2, and cyclophosphamide 35 mg/kg on days -6 through -3, followed by reinfusion of autologous stem cells after 48 hours, nominally day 0 of the transplantation procedure. During the ASCT procedure, patients were housed in a clean room without an air filter system. Prophylaxis with sulfamethoxazole and trimethoprim 1,600 mg twice daily three times per week was administered from the beginning of front-line chemotherapy to day -7 of the preparative regimen and was reinstituted at the time of discharge and continued for 6 months after transplantation. Oral amphotericin B as prophylaxis was given from day +1 and continued until granulocyte recovery. All patients received acyclovir intravenously 15 mg/kg/d beginning on day +1 for prevention of herpes virus infection. Empiric broad-spectrum antibiotics and parenteral nutrition were used as clinically indicated. Platelet transfusions from single donors were given for platelet counts of less than 10 x 109/L. Leukocyte-free erythrocyte concentrates were administered when the hemoglobin level decreased to less than 8 g/dL. All blood products were irradiated during the ASCT procedures (20 Gy); central venous lines were used in all patients. All patients received G-CSF at the dose of 5 mg/kg/d given subcutaneously beginning on day +1 after ASCT.
Response Assessment
Statistical Methods
Analysis was based on status of disease in June 2001 with a minimum of at least 1 year of follow-up. Our main objective was to compare overall survival (OS); secondary objectives were to compare response rates, progression-free survival (PFS), relapse-free survival (RFS), and toxicity. Results of all randomized patients in the two treatment arms were analyzed on an intention-to-treat basis. All survival data were censored at the closing date or the date of last contact when this preceded the closing date. The actuarial curves were estimated according to the Kaplan and Meier method and compared by the log-rank test.24,25 The actuarial OS in both groups was calculated from the date of diagnosis (starting time) until last contact or death for any cause (event). Actuarial RFS was calculated for patients who achieved a CR after first-line therapy from the date of first CR to the date of last contact, if alive and nonrelapsed, or to relapse or death (events), whichever came first. PFS includes all patients and was calculated from the beginning of treatment to the date of relapse, progression of disease, death, or to the date of last contact. Univariate analysis was performed by the log-rank test or Cox proportional hazards regression model,26 as appropriate. Multivariate analysis was performed by a Cox model using a stepwise selection method. Statistical tests for comparison of main objectives were regarded as significant if the two-sided P value was less than .05. The
Arm A After MACOP-B therapy, 46 (61%) and 21 patients (28%) achieved CR and PR, respectively; seven patients (10%) were considered NRs. One patient (1%) died as a result of toxicity during MACOP-B chemotherapy. Twenty-two of 34 patients with bulky disease and one patient without bulky disease but with residual mass after chemotherapy received IFRT. After IFRT, five patients in PR obtained CR and one NR patient achieved a PR. Thus, at the end of the chemoradiotherapy, 51 patients (68%) were considered to have achieved CR, 17 patients (23%) achieved stable PR, and six patients (8%) were classified as NRs. The remaining 12 patients with bulky disease did not receive the programmed IFRT for the following reasons: one patient died as a result of chemotherapy toxicity, six patients experienced early relapse/progression, and five patients were in CR after chemotherapy and a medical decision was made to not administer IFRT. After a median time of 8 months (range, 1 to 34 months), 18 (35%) of 51 patients experienced relapse and nine (53%) of 17 patients progressed from PR (Table 2 ). All 27 patients who experienced relapse or disease progression were assigned to salvage treatment with HDT-ASCT, and 12 of these patients (44%) achieved a second CR. Twenty-one patients (28%) died of early or late progression of NHL, and one patient (1%) died of chemotherapy toxicity. Currently, 53 (70%) of 75 patients are still alive, of whom 33 are in first continuous CR, eight are in stable PR, and 12 were successfully treated with salvage therapy (HDT-ASCT).
During MACOP-B therapy, hematologic toxicity (World Health Organization grade 3/4) with granulocytopenia was observed in 24 (32%) of 75 patients, and anemia was observed in 15 (20%) of 75 patients. Mucositis (grade 3/4) was observed in 51 (68%) of 75 patients, and infections or neutropenic fever were observed in 12 (16%) of 75 patients.
Arm B
Of the 45 patients who underwent ASCT, 29 patients used PBSCs and 16 patients used bone marrow cells. The mean interval between the end of the short MACOP-B program and ASCT was 8 weeks (range, 4 to 26 weeks); in 23 patients (51%), ASCT was carried out with an interval longer than the scheduled 4 weeks. Considering only the 45 patients who actually underwent ASCT, 17 patients (38%) were in CR, 26 patients (58%) were in PR, and two patients (4%) were in MR after eight courses of MACOP-B; after HDT and ASCT plus IFRT, 39 patients (87%) achieved a CR, four patients (9%) achieved PR, and two patients (4%) died as a result of treatment-related toxicity. In this group, 10 of the 26 patients with bulky disease at diagnosis and who had intended to receive IFRT actually received the treatment after ASCT (six patients in PR, three in CR, and one in MR); 16 patients did not receive IFRT (two patients died during ASCT and the remaining 14 patients were in CR after ASCT and a medical decision was made to not administer IFRT). Two of these 14 patients experienced relapse (one in the previous bulky area). Considering the 30 patients who did not undergo ASCT, 14 had bulky disease at diagnosis and only three received the planned IFRT; the remaining 11 patients were considered not eligible for IFRT for the following reasons: seven patients were in early progression, two patients had inadequate clinical status (one had deep-vein thrombosis with pulmonary embolism and one had right femoral artery occlusion with gangrene), and two patients were considered ineligible by medical decision (these patients were probably considered to be out of protocol). In conclusion, at the end of the programmed therapy for all 75 patients included in arm B according to the intention-to-treat analysis, 57 patients (76%) and 14 patients (19%) achieved CR and PR, respectively, one patient (1%) achieved MR, and three patients (4%) died as a result of therapy-related toxicity. After the median time of 7 months (range, 1 to 39 months), 16 patients (22%) experienced relapse or disease progression after ASCT (12 of 57 patients from CR and four of 14 patients from MR/PR), and all died of lymphoma. Currently, 56 (75%) of 75 patients are still alive, of whom 45 are in first complete continuous remission and 11 are in stable PR (Table 2 The patients submitted to PBSC transplantation received a median of 6.5 x 108/kg of nucleated cells (range, 2.43 to 34). All patients who underwent transplantation had pancytopenia and marrow engraftment occurred in all cases. The median time to reach a granulocyte recovery greater than 0.5 x 109/L was 12 days (range, 10 to 17 days); the median time to platelet recovery greater than 20 x109/L was 13 days (range, 11 to 25 days). All patients experienced nausea (grade 3/4) and mucositis (grade 3/4) and had fever higher than 38.5°C during the aplastic phase, necessitating empiric antibiotic therapy. Treatment-related death occurred in two patients (3%) during ASCT procedures, one as a result of cerebral stroke probably related to hypertensive crisis during thrombocytopenia and one as a result of cardiac failure followed by acute respiratory distress syndrome. At this time, no secondary myelodysplastic syndrome or acute myelogenous leukemia has been noted.
According to the intention-to-treat analysis, the difference in the CR rate for the two groups was not statistically significant (68% in arm A and 76% in arm B; P > .10). After a median follow-up of 24 months, the 5-year OS of all 150 patients was 64% (95% confidence interval [CI], 42% to 51%; Fig 2
HDT with ASCT for aggressive NHL is recommended in various subsets of patients. Although there is consistent evidence for the efficacy of ASCT in patients with chemotherapy-sensitive relapse,12 the role of transplantation as front-line therapy in PR or CR is still uncertain.13–15 In this group of patients, previous randomized studies reported by Santini et al16 and Haioun et al17 suggested that ASCT should be restricted only to intermediate-/high-risk and high-risk groups as defined by the IPI, but that hypothesis had to be confirmed in subsequent prospective randomized trials. Two recent phase II studies reported encouraging survival results with HDT and PBSC transplantation as front-line therapy in high-risk NHL patients when compared with historical results with conventional chemotherapy.28,29 In a prospective study, Gianni et al18 accrued 98 patients with aggressive high-risk NHL without bone marrow involvement and randomly assigned the patients to receive conventional MACOP-B or inductive high-dose sequential therapy followed by ASCT. With a median follow-up of 55 months, high-dose sequential therapy was superior to conventional chemotherapy in terms of CR rate, 7-year PFS, and event-free survival (EFS; 76% and 49%, respectively; P = .004). The results of our prospective randomized study demonstrate that early intensification with HDT and ASCT after an abbreviated induction therapy is not significantly superior to conventional MACOP-B in IPI intermediate-/high- and high-risk patients with aggressive NHL. The MACOP-B regimen with or without IFRT (arm A) as front-line therapy resulted in a 68% rate of CR, and the addition of HDT with ASCT with or without IFRT to a short eight courses of MACOP-B (arm B) gave similar results, with a 76% rate of CR (P = not significant [NS]). According to the intention-to-treat analysis, at a median follow-up of 24 months, the 5-year actuarial curves did not show a significant difference, with a PFS of 49% versus 61% (P = NS), RFS of 65% versus 77% (P = NS), and OS of 65% versus 64% (P = NS) in arms A and B, respectively. However, for PFS and RFS, our study was designed to detect a 25% increase of probability of survival at 5 years; thus the trend to better results with HDT-ASCT in a range of 10% increased survival could become significant in a larger cohort of patients. For OS, we must consider that 12 (44%) of 27 patients in arm A (MACOP-B with or without IFRT) who received HDT-ASCT as postrelapse salvage treatment obtained a second CR; this is a confounding factor when we try to evaluate the impact of transplantation procedures in the two original groups. Univariate and multivariate analysis of parameters present at diagnosis failed to show any factor able to accurately predict a poorer outcome. In our experience, HDT and ASCT did not significantly increase toxicity-related deaths, which were similar in both arms (one patient in arm A and three patients in arm B); a major problem in our study was the feasibility of the intensified program in arm B, in which a high number of patients (30 of 75; 40%) did not actually receive the programmed HDT-ASCT. However, a high percentage of patients who did not reach ASCT are reported in other randomized studies, in which HDT-ASCT was compared with a conventional regimen in responding patients after standard front-line induction therapy.12,15,30 In our study, the most common reason for exclusion from ASCT was disease progression before the transplantation procedure, probably owing to the brevity of chemotherapy courses and the delayed time for the ASCT procedure in 23 (51%) of 45 patients (interval to ASCT > 4 weeks). Thus it is possible that a complete 12-week course of MACOP-B and a timed (< 4 weeks) ASCT procedure could prevent the incidence of disease progression before ASCT and consequently could improve significantly the results in the ASCT arm. Recently, other randomized studies in which HDT followed an abbreviated induction phase did not demonstrate a benefit of HDT over conventional treatment in this group of patients. In the LNH93–3 trial, 370 patients with intermediate-/high- and high-risk disease were randomized to receive either full standard induction therapy or a short induction phase including a debulking course and two cycles of standard therapy followed by HDT. With a median follow-up of 30 months, the EFS (63%) and OS (47%) rates for patients receiving standard induction therapy were superior to rates for those who received early HDT (54% and 41%, respectively).19 The German High-Grade Lymphoma Study Group randomly assigned 312 patients with elevated LDH levels and stages II to IV disease to receive either five courses of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide followed by IFRT or three cycles of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide followed by ASCT and IFRT. After 30 months, there was no difference in EFS and OS between the two arms, even for patients with intermediate-/high- or high-risk factors.20 A European Organization for Research and Treatment of Cancer phase III study randomly assigned 194 patients with aggressive NHL to standard chemotherapy (eight cycles) or to four cycles of the same chemotherapy followed by HDT-ASCT. Approximately 140 patients (70%) were IPI low or low/intermediate risk. In this study, no significant difference in terms of 5-year OS (68% v 77%) and PFS (61% v 56%) were found between the ASCT arm and the control arm. A subset analysis on patients with high-risk IPI status, although too small for reliable statistical analysis, yielded similar results.30 When these experiences are compared with those of our study, all have in common the use of HDT-ASCT after an abbreviated chemotherapy induction phase. Conversely, taking into account the favorable results reported by Santini et al16 and Haioun et al,17 where ASCT was performed as consolidation in CR patients after a conventional chemotherapy, we may suppose that HDT-ASCT benefits patients only if they have achieved a prior response to a complete standard induction treatment. In conclusion, our study suggests that an abbreviated induction standard regimen followed by HDT plus ASCT does not significantly improve survival as compared with conventional chemotherapy in patients with high-risk aggressive NHL. The absence of a clear advantage by HDT-ASCT may be due to the abbreviation of the MACOP-B course and to the delay of the procedure, which may cause early progression of disease, thus hindering the intensive consolidation. Several additional ongoing randomized trials will clarify whether patients with IPI high-risk NHL may benefit from a front-line high-dose therapy strategy, either used as sequential induction therapy or as consolidation after complete standard induction chemotherapy.
Other participating institutions include the following: Division of Hematology, Mantova Hospital, Mantova (Enrico Aitini); Division of Hematology, Forlì Hospital, Forli (Patrizia Gentilini); Division of Hematology, University of Genova, Genova (Marco Gobbi); Division of Hematology, Latina Hospital, Latina (Fabrizio Ciccone); Division of Hematology, Avellino Hospital, Avellino (Fioravante Ronconi); and Division of Hematology, Chioggia Hospital, Chioggia (Raffaele Battista), Italy.
We thank Bruno Rotoli, MD, for helpful review of the manuscript.
Supported by Ministero dell’ Università e Ricerca Scientifica (MURST) 40%.
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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
2 test was used whenever appropriate for comparison of subgroups according to the Mantel-Haenszel method.
