Impact of Three Courses of Intensified CHOP Prior to High-Dose Sequential Therapy Followed by Autologous Stem-Cell Transplantation As First-
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《临床肿瘤学》
the Department of Hematology, University Medical Center Groningen
Department of Pathology, Groningen University Hospital
Groningen
Data Center and Department of Internal Medicine, Erasmus MC, Rotterdam
Department of Internal Medicine, University Medical Center Nijmegen St Radboud, Nijmegen
Department of Internal Medicine, Leyenburg Hospital, The Hague
Department of Hematology, VU Medical Center, Amsterdam
Department of Internal Medicine, University Hospital Maastricht, Maastricht
Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands
ABSTRACT
PURPOSE: Timing, appropriate amount, and composition of treatment before high-dose therapy and autologous stem-cell transplantation (ASCT) in patients with poor-risk, aggressive non-Hodgkin's lymphoma (NHL) are still unknown. We conducted two consecutive multicenter phase II trials with up-front, high-dose, sequential chemotherapy and ASCT in poor-risk, aggressive NHL. Both trials had identical inclusion criteria and only differed in amount and duration of induction treatment before ASCT.
PATIENTS AND METHODS: Between 1994 and 2001, 147 newly diagnosed, poor-risk, aggressive NHL patients, age 65 years with stage III to IV and lactate dehydrogenase (LDH) more than 1.5x upper limit of normal (ULN), entered the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) -27 and HOVON-40 trials. Treatment in HOVON-27 consisted of two up-front, high-dose induction courses followed by carmustine, etoposide, cytarabine, and melphalan plus ASCT in responding patients. In HOVON-40, the same treatment was preceded by three intensified courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).
RESULTS: Patient characteristics in both trials were comparable: 80% had diffuse large B-cell lymphoma, 77% had stage IV disease, and median LDH levels were 3.1x ULN. Complete remission (CR) in both trials was 45% to 51%. Before ASCT, CR was 14% in HOVON-27 versus 28% in HOVON-40 (P = .03). Treatment failure was similar (27%). Four-year survival estimates in HOVON-27 compared with HOVON-40 were overall survival, 21% v 50% (P = .007); event-free survival, 15% v 49% (P = .0001); and disease-free survival, 34% v 74% (P = .008). This different outcome favoring HOVON-40 remained highly significant when correcting for competing risk factors in multivariate analysis.
CONCLUSION: In patients with poor-risk, aggressive NHL, addition of intensified CHOP before up-front, high-dose, sequential therapy and ASCT significantly improved the duration of response and survival.
INTRODUCTION
Treatment of patients with poor-risk, aggressive non-Hodgkin's lymphoma (NHL) requires improvement. Patients with a high-risk score according to the International Prognostic Index (IPI),1 who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) -like chemotherapy,2 have a 44% probability of reaching a complete remission (CR), and only 26% will be alive at 5 years from diagnosis.1
Approximately 40% of young patients who experience relapse more than 1 year after first-line treatment can still be rescued by high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT), provided the disease is chemotherapy sensitive.3,4 Consequently, high-dose chemotherapy followed by ASCT has been explored as first-line treatment in young patients with poor-risk, aggressive lymphoma. On the basis of promising results of ASCT in first remission,5–8 the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) started a multicenter phase II study in 1994 (HOVON-27) to investigate a strategy of intensive, high-dose, sequential chemotherapy delivered within a relatively short timeframe, and subsequent ASCT in adults with newly diagnosed, poor-risk, aggressive lymphoma. At the time of closure of this study in January 1999, conflicting results about the efficacy, timing, and optimal treatment schedule of up-front ASCT became apparent.9
Subgroup analysis of study LNH87-2, a randomized trial conducted by the French Groupe d'Etude des Lymphomes de l'Adulte (GELA) group, indicated that ASCT as consolidation in poor-risk patients in first CR after full-length CHOP-like induction treatment was more effective than standard treatment alone.10 In addition, an Italian study showed that short, high-dose, sequential chemotherapy followed by ASCT was better than standard therapy in poor-risk patients without bone marrow (BM) involvement.11 In contrast, preliminary data of a subsequent GELA trial, LNH93-3, yielded conflicting results: standard chemotherapy was better than short, high-dose, sequential chemotherapy and ASCT in poor-risk patients.12
These data, combined with disappointing preliminary results of our HOVON-27 study, suggested no improvement in outcome of short, high-dose, sequential therapy before up-front ASCT. Therefore, we questioned whether extension of induction treatment aimed at additional reduction of tumor load before ASCT might be more efficacious. To that end, we added three dose-dense intensified CHOP (iCHOP) courses before the original HOVON-27 protocol, now referred to as the HOVON-40 study. Because patients were included according to identical entry criteria and both trials were conducted consecutively by the same HOVON centers, we present both studies combined to show the remarkable improvement in outcome by the addition of three courses of iCHOP before high-dose, sequential treatment followed by ASCT.
PATIENTS AND METHODS
Between 1994 and 2001, we conducted two consecutive phase II studies for patients with poor-risk, advanced, aggressive NHL: HOVON-27 (December 1994 to January 1999) and HOVON-40 (February 1999 to November 2001). Figure 1 shows an outline of the studies.
Patients
Eligible patients were age 18 to 65 years and had newly diagnosed, untreated, aggressive NHL according to either the Working Formulation (groups D, E, F, G, H; HOVON-27) or Revised European-American Lymphoma classification (diffuse large B-cell lymphoma, follicular lymphoma grade 3, anaplastic large-cell lymphoma, and peripheral T-cell lymphoma; HOVON-40). All lymphomas were centrally reviewed by P.M.K. and reclassified according to the WHO classification.13 Patients were fully staged, including computed tomography scanning of thorax and abdomen, and BM biopsy. They were required to have high-risk disease according to a HOVON risk score (ie, both Ann Arbor stage III or IV and serum lactate dehydrogenase [LDH] > 1.5x the upper limit of normal of the participating institution). On the basis of the treatment outcome of patients with this combination of risk factors enrolled onto a previous HOVON study,14 they were expected to have survival of only 23% at 5 years when treated with CHOP. Patients were not eligible if they were HIV seropositive, or had a WHO-performance score 3 or 4, CNS lymphoma, concomitant disease, prior malignancy, or major organ dysfunction not directly related to lymphoma infiltration or obstruction.
All patients gave informed consent for study participation according to the regulations of the Dutch health authorities. The study was performed and evaluated by HOVON according to the Helsinki agreement. The participating HOVON institutions and investigators are listed in the Appendix.
Treatment
In HOVON-27, initial treatment consisted of two consecutive high-dose chemotherapy combinations, induction (course) I and induction (course) II. Induction I consisted of cyclophosphamide 1,000 mg/m2 every 12 hours on days 1 and 2 (total dose, 4,000 mg/m2), doxorubicin 35 mg/m2 on days 1 and 2 (total dose, 70 mg/m2), and prednisone 100 mg on days 1 through 5. Mesna (Uromitexan, Baxter International Inc, Halle, Germany) 200 mg/m2 was infused every 4 hours starting 10 minutes before and ending 8 hours after the last cyclophosphamide infusion. As soon as hematologic recovery was observed, induction II was administered, which consisted of etoposide 250 mg/m2 every 12 hours on days 1 to 4 (total dose 2,000 mg/m2), mitoxantrone 30 mg/m2 on day 1, and prednisone 100 mg on days 1 through 5. Hematologic recovery was defined as an increasing platelet (PLT) and neutrophil count more than 100 x 109/L and more than 1.0 x 109/L, respectively. After each induction course, patients received 5 μg/kg granulocyte colony-stimulating factor (Filgrastim; Amgen, Thousand Oaks, CA) subcutaneously daily from day 5 until the neutrophil count reached at least 0.5 x 109/L for 2 consecutive days.
Peripheral-blood stem cells were collected and cryopreserved, preferably after induction I or otherwise after induction II according to standard institutional procedures, provided the BM no longer contained lymphoma on histologic examination. No CD34+ selection or purging was performed.
Patients attaining at least a partial response (PR) after induction II, with a collection of at least 2.5 x 106 CD34+ cells/kg, subsequently received high-dose therapy and ASCT. High-dose chemotherapy consisted of carmustine 300 mg/m2 on day –6, etoposide 100 mg/m2 and cytarabine 100 mg/m2 every 12 hours on days –5 through –2, and melphalan 140 mg/m2 on day –1 (BEAM). Stem cells were reinfused on day 0. Patients received hematologic supportive care, including vigorous hydration, allopurinol, irradiated PLT and RBC transfusions, prophylactic oral antibacterial and antifungal treatment, and immediate treatment with intravenous broad-spectrum antibiotics and/or intravenous antifungal treatment if fever and/or documented or suspected infection occurred, according to guidelines of the participating institution. Patients with bulky disease at presentation could be treated with involved-field radiotherapy on PR sites after recovery from ASCT at the discretion of each center. No additional maintenance therapy was administered.
In study HOVON-40, patients were first treated with three courses of iCHOP, before treatment as described for the HOVON-27 trial. iCHOP consisted of cyclophosphamide 1,000 mg/m2, doxorubicin 70 mg/m2, and vincristine 2 mg on day 1; and prednisone 100 mg for 5 consecutive days. Granulocyte colony-stimulating factor 5 μg/kg was administered on days 2 through 11 of each cycle of iCHOP. Cycles were administered every 2 weeks. The first iCHOP course was administered at 100% dose, irrespective of blood cell counts. If WBC counts and/or PLT counts on day 15 after the preceding iCHOP course were less than 3 x 109/L and/or 100 x 109/L, respectively, the following iCHOP course was delayed for 1 week and the subsequent dose of cyclophosphamide and doxorubicin was attenuated based on the actual counts as follows: WBC more than 3 x 109/L and PLT more than 100 x 109/L, 100% dose; WBC 2 to 3 x 109/L and PLT more than 100 x 109/L, 75% dose; WBC 1 to 2 x 109/L or PLT 50 to 100 x 109/L, 50% dose; WBC less than 1 x 109/L or PLT less than 50 x 109/L, 0% dose. Dose modifications for vincristine were made if neurotoxicity occurred at the discretion of the treating physician. Stem cells were collected from the peripheral blood during iCHOP treatment as soon as possible, provided the BM was free of lymphoma, as confirmed by histologic examination. Only patients with a documented response of at least 25% after three courses of iCHOP continued with high-dose sequential treatment as described for the HOVON-27 trial. Patients attaining at least a PR after induction II, with a collection of at least 2.5 x 106 CD34+ cells/kg, continued with BEAM and ASCT.
Response to Treatment and Toxicity
Tumor response was assessed after three iCHOP (HOVON-40) courses, induction II, ASCT, and additional radiotherapy (if administered) according to staging procedures described at diagnosis. Responses were classified as CR (including unconfirmed CR), PR, stable disease, or progressive disease according to the International Workshop Criteria.15 In addition, a minimal response after three iCHOP courses, which qualified the patient for continuation of protocol treatment (HOVON-40), was arbitrarily defined as a regression in size of all measurable lesions of at least 25% in the absence of new lesions. Patients attaining less than a minimal response after three iCHOP courses or less than PR after induction II discontinued protocol treatment and were considered to have experienced treatment failure.
All toxicity, except nausea and hair loss, was graded according to the National Cancer Institute Common Toxicity Criteria grading system. Hematologic toxicity after high-dose treatment and ASCT was assessed separately.
Statistical Analysis
The data were analyzed as of August 2004. Patient characteristics were compared between the two treatment protocols using the Pearson 2 or the Fisher's exact test, whichever was appropriate for discrete variables, or the Wilcoxon rank sum test for continuous variables. Study end points were CR rate, response rate (CR + PR), event-free survival (EFS), disease-free survival (DFS), and overall survival (OS). EFS was defined as the time from start of treatment to progression, relapse, or death as a result of any cause, whichever came first; patients without progression or relapse who were still alive were censored at the date of last contact. DFS was defined as the time from documented first CR on protocol until relapse. OS was defined as the time from the start of treatment to death as a result of any cause; patients still alive were censored at the date of last contact.15
The Kaplan-Meier method was used to estimate EFS, DFS, and OS, and 95% CIs were calculated. The log-rank test was used to compare survival curves between both trials.
The proportions of patients achieving CR on protocol in both trials were compared using logistic regression. Univariate logistic regression was used to analyze differences in CR rate between subgroups according to patient characteristics at diagnosis.
Explorative univariate and multivariate survival analyses with Cox regression were performed to investigate differences in survival between subgroups including the following variables in univariate analysis: sex, age (continuous as well as 60 v > 60 years), WHO performance status ( 1 v > 1), "B" symptoms, Ann Arbor stage (III v IV), bulky disease (> 10 cm diameter), BM involvement, number of extranodal sites (0 to 1 v 2), and age-adjusted IPI (high-intermediate v high). Treatment protocol (HOVON-27 v HOVON-40), age (continuous), WHO performance status, Ann Arbor stage, and number of extranodal sites were also included in the multivariate analysis.
All reported P values are two sided and a significance level = .05 was used.
RESULTS
Patient Characteristics
Between December 1994 and January 1999, we enrolled 66 patients onto HOVON-27, and between February 1999 and October 2001, we enrolled 81 patients onto HOVON-40.
Except for small differences in performance status and number of extranodal sites, there were no significant differences in clinical or pathologic characteristics between both patient groups (Table 1). Central pathology was completed in 93% of patients; the great majority were diffuse large B-cell lymphoma. Median age was 50 years (range, 15 to 65 years) with a minority (11%) older than 60 years. In accordance with the entry criteria, LDH levels were strongly elevated, with a median of 3.1x the upper limit of normal. Extranodal involvement occurred in 77%; BM involvement occurred in 34%. Poor performance status (WHO > 1) was observed in 35% in HOVON-27 versus 20% in HOVON-40 (P = .04). This also accounts for the slightly higher percentage of age-adjusted (aa) -IPI grade 3 in HOVON-27 (33%) compared with HOVON-40 (20%; P = .06). All patients had an aa-IPI risk score of at least 2.
Treatment and Response
Treatment including ASCT was completed by two thirds of the patients (Table 2). Additional radiotherapy was administered to a minority of the patients (22%).
The CR rates were 45% (HOVON-27) and 51% (HOVON-40; Table 2). Although the difference in response to overall protocol treatment between both trials was not significant, the fraction of patients with CR before starting ASCT was twice as large in HOVON-40 (28%) compared with HOVON-27 (14%; P = .03). Treatment failure was the major reason for discontinuing protocol treatment, and occurred in 27% (HOVON-27) and 26% (HOVON-40) of patients (Table 3).
Stem-Cell Collection
Stem cells were collected in 54 (82%; HOVON-27) and 65 patients (80%; HOVON-40). In HOVON-27, stem cells were collected in one procedure after induction I in 34 (63%) or after induction II in 20 patients (37%), yielding a median of 8.5 x 106 (range, 0.1 to 86.7 x 106) CD34+ cells/kg; in HOVON-40, stem cells were collected during iCHOP in 28 (43%), after induction I in 35 (54%), or after induction II in two patients (3%), yielding a median of 4.7 x 106 (range, 0.4 to 45.6 x 106) CD34+ cells/kg in one procedure. Additional peripheral blood or BM stem cells were collected in six patients (three in each trial). In one patient only BM stem cells were collected.
Toxicity
iCHOP treatment was well tolerated and could be administered on schedule on an outpatient basis. As expected, substantial hematologic and nonhematologic toxicities were observed after induction I, II, and BEAM. No significant differences were observed between the two trials. Substantial mucositis, often necessitating parenteral nutrition, was the most frequent nonhematologic toxicity during intensive treatment. Pooled results for all reported nonhematologic toxicities grade 3 to 4 (Table 4), and hematologic toxicity and transfusions are presented (Table 5).
Six patients (9%) in HOVON-27 and five patients (6%) in HOVON-40 died as a result of treatment-related causes.
Survival
With a median follow-up of patients still alive in HOVON-27 of 83 months (range, 50 to 112 months) and in HOVON-40 of 34 months (range, 13 to 59 months), 53 (80%) and 40 (49%) patients, respectively, have died; NHL was the cause in 85% and 80% of the deaths, respectively. Highly significant differences in the estimated OS, EFS, and DFS rates were observed. The 4-year actuarial estimates for patients in HOVON-27 compared with HOVON-40 were OS, 21% (95% CI, 12% to 32%) versus 50% (95% CI, 37% to 61%; log-rank P = .007); EFS, 15% (95% CI, 8% to 25%) versus 49% (95% CI, 38% to 59%; P = .0001); and DFS, 34% (95% CI, 17% to 51%) versus 74% (95% CI, 58% to 85%; P = .008). The corresponding Kaplan-Meier curves are depicted in Figure 2.
Prognostic Factors
In univariate analysis, WHO performance status more than 1 was the only factor associated with a lower CR rate (odds ratio, 0.45; 95% CI, 0.21 to 0.97; P = .043), but this was no longer significant in multivariate analysis.
In univariate Cox regression analysis, treatment according to protocol HOVON-40 was associated with better outcome for all survival end points as described in the previous section. Increased age and BM involvement were associated with shorter OS. WHO performance status more than 1 and BM involvement were adverse prognostic factors for EFS; higher age and bone marrow involvement were adverse prognostic factors for DFS.
In multivariate analysis, HOVON-40 remained a statistically significant strong prognostic factor for EFS, DFS, and OS (Table 6).
DISCUSSION
These consecutive studies highlight the importance of a robust induction treatment before up-front ASCT in patients with poor-prognosis, aggressive NHL. Addition of three courses of iCHOP to sequential high-dose induction therapy before ASCT in our HOVON-40 protocol resulted in a higher fraction of patients in CR before ASCT and, more importantly, in a highly significant improvement of all survival end points.
Although this study was not a controlled, randomized trial, characteristics of patients in trials HOVON-27 and HOVON-40 were highly comparable, and both trials were conducted consecutively in the same HOVON centers. The only difference was the addition of three courses of iCHOP as preinduction treatment in HOVON-40. Thus, short of randomization and duration of follow-up, these studies were well qualified for comparison of treatment outcome, and results remained independently affected by treatment when corrected for risk factors and observation time in multivariate analysis.
Outcome in trial HOVON-27, consisting of only two courses of high-dose therapy before BEAM and ASCT, was clearly disappointing. Although one could ask whether these results could be even worse than what might be expected of standard CHOP treatment, the outcome of patients in HOVON-27 was identical to a cohort of 52 patients with similar risk factors in a previous HOVON-3 study.14
The failure to improve on standard CHOP treatment in trial HOVON-27 might be related to (or be a combination of) a relatively high percentage of patients with intrinsically chemotherapy-resistant disease reflected by 27% primary treatment failures; a rather late tumor response reflected by a CR fraction of only 14% after induction versus 39% after ASCT; and a poor quality of CR, with a 4-year DFS of only 34%.
The rationale of high-dose sequential treatment in poor-risk, aggressive NHL is to overcome chemotherapy resistance by rotating a succession of drugs administered at high dosages, in a tight schedule, as shortly after one another as possible. A sequential high-dose regimen followed by ASCT as designed by Gianni et al,11 showing superior results to standard-dose methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin, seemed proof of principle of this concept. However, neither the GELA12 nor this study (HOVON-27) could confirm these results with a similar strategy.
The distinction between high-dose sequential therapy and standard therapy as an induction regimen before ablative therapy and ASCT, as well as the relative merits of these strategies, are still not clear. Full-length standard CHOP-like therapy followed by ASCT was not superior to standard CHOP-like therapy for unselected patients with aggressive NHL in randomized trials conducted by GELA,16 the Italian Non-Hodgkin's Lymphoma Group,17 and the European Organization for Research and Treatment of Cancer.18 Retrospective subgroup analysis of both the LNH87-2 GELA trial and the Italian study, however, indicated a benefit of ASCT for patients with aa-IPI 2 to 3 who completed standard induction therapy,17,19 but this could not be confirmed in the European Organization for Research and Treatment of Cancer study.18 Abbreviated standard chemotherapy followed by ASCT is not superior to full-length standard therapy,14,20,21 whereas abbreviated high-dose chemotherapy yielded even inferior results to standard treatment in aa-IPI 2 to 3 patients.12 In contrast, the Groupe Ouest-Est des Leucemies et des Autres Maladies du Sang reported an improved EFS for high-dose therapy with ASCT compared with standard CHOP in patients with aa-IPI 0 to 2, but improved survival was restricted to aa-IPI 2 patients only.22 Of note, the induction treatment in the ASCT arm of this trial consisted of only two dose-dense courses of a CHOP-like regimen cyclophosphamide, epirubicin, vindesine, prednisone. Given the good results, the relatively low dose of cyclophosphamide and the absence of high-dose etoposide in the GOELAMS study is remarkable compared with the dosage of these drugs in the Milan11 and HOVON protocols.
In HOVON-40, we prolonged the induction phase and incorporated a higher cumulative dose of cyclophosphamide and doxorubicin; we expected better outcome by increasing the CR rate before ASCT and improving the quality of CR. The addition of three iCHOP courses not only doubled the fraction of patients in CR before ASCT, but also improved the quality of CR as reflected by an increased 4-year DFS from 34% in HOVON-27 to 74% in HOVON-40. Although this study does not answer the question whether treatment with up-front ASCT is necessary in high-risk patients, these results strongly support the notion that up-front ASCT is probably more successful in patients having reached a CR after an adequate amount of induction therapy.
However, one in every fourth patient had primary refractory disease, and this apparently could not be overcome by increasing the dose or shortening the time interval of chemotherapy because these results were not different between HOVON-40 (26%) and HOVON-27 (27%). Chemotherapy refractoriness is probably inherent to the selection of patients with advanced-stage, aggressive NHL, and strongly elevated LDH levels in our studies, and remains an important issue to address in the development of new treatment strategies for these poor-risk patients. Anti-CD20 monoclonal antibodies (rituximab) administered in combination with CHOP significantly reduce the risk of treatment failure in elderly patients with diffuse large B-cell lymphoma.23 Similar results have been observed in the North-American Intergroup study,24 and also in the recently reported Mint trial in young patients.25 These observations, and the absence of clinically significant toxicity, make rituximab an obvious candidate for combination with high-dose treatment such as the HOVON-40 protocol. Future clinical trials comparing full-length rituximab plus CHOP-like therapy to an HOVON-40-like high-dose scheme with rituximab are needed to analyze the additional contribution of up-front ASCT after optimal intensive induction therapy in poor-risk diffuse large B-cell lymphoma patients.
Appendix
The following Dutch (NL) and Belgian (B) hospitals (physicians) participated in HOVON trials 27 and 40: NL-Zwolle-Isala Clinics, location Sophia (M. van Marwijk Kooy), NL-Nieuwegein-Sint Antonius Hospital (D.H. Biesma), NL-Maastricht-University Hospital Maastricht (H.C. Schouten), NL-Den Haag-Leyenburg Hospital (P.W. Wijermans), NL-Amsterdam-Slotervaart Hospital (M. Soesan), NL-Sittard-Maasland Hospital (F.L.G. Erdkamp), NL-Enschede-Medical Spectrum Twente (M.R. Schaafsma), NL-Amersfoort-Meander Medical Center (M.H.H. Kramer), NL-Amsterdam-Antoni van Leeuwenhoek Hospital (J.W. Baars), NL-Rotterdam-Erasmus MC-DDHK (M.B. van't Veer), NL-Groningen-Groningen University Hospital (G.W. van Imhoff), NL-Nijmegen-University Medical Center Nijmegen St. Radboud (M.A. MacKenzie), NL-Utrecht-University Medical Center Utrecht (L.F. Verdonck), NL-Amsterdam-VU Medical Center (G.J. Ossekoppele), NL-Amsterdam-Amsterdam Medical Center (J. van der Lelie), NL-Leiden-Leiden University Medical Center (R. Willemze), NL-Rotterdam-Erasmus MC (P. Sonneveld), B-Leuven-University Hospital Leuven Gasthuisberg (L. Vandenberghe), NL-Amstelveen-Amstelveen Hospital (G.J. Timmers).
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank E.G. Boerma for excellent help with the pathology review.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329:987-994, 1993
Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328:1002-1006, 1993
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
Guglielmi C, Gomez F, Philip T, et al: Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16:3264-3269, 1998
Gulati SC, Shank B, Black P, et al: Autologous bone marrow transplantation for patients with poor-prognosis lymphoma. J Clin Oncol 6:1303-1313, 1988
Nademanee A, Schmidt GM, O'Donnell MR, et al: High-dose chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy during first complete remission in adult patients with poor-risk aggressive lymphoma: A pilot study. Blood 80:1130-1134, 1992
Freedman AS, Takvorian T, Neuberg D, et al: Autologous bone marrow transplantation in poor-prognosis intermediate- grade and high-grade B-cell non-Hodgkin's lymphoma in first remission: A pilot study. J Clin Oncol 11:931-936, 1993
Sierra J, Conde E, Montserrat E: Autologous bone marrow transplantation for non-Hodgkin's lymphoma in first remission. Blood 81:1968-1969, 1993
Shipp MA, Abeloff MD, Antman KH, et al: International Consensus Conference on High-Dose Therapy With Hematopoietic Stem Cell Transplantation in Aggressive Non-Hodgkin's Lymphomas: Report of the jury. J Clin Oncol 17:423-429, 1999
Haioun C, Lepage E, Gisselbrecht C, et al: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: Updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15:1131-1137, 1997
Gianni AM, Bregni M, Siena S, et al: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336:1290-1297, 1997
Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20:2472-2479, 2002
Jaffe ES, Harris NL, Stein H, et al (eds): WHO Classification of Tumours: Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2001
Verdonck LF, van Putten WLJ, Hagenbeek A, et al: Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma. N Engl J Med 332:1045-1051, 1995
Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI Sponsored International Working Group. J Clin Oncol 17:1244-1253, 1999
Haioun C, Lepage E, Gisselbrecht C, et al: Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin's lymphoma in first complete remission: A study of 464 patients—Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 12:2543-2551, 1994
Santini G, Salvagno L, Leoni P, et al: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: Results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16:2796-2802, 1998
Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al: Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: Randomized phase III EORTC study. J Natl Cancer Inst 93:22-30, 2001
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
Kaiser U, Uebelacker I, Abel U, et al: Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. J Clin Oncol 20:4413-4419, 2002
Martelli M, Gherlinzoni F, De Renzo A, et al: 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. J Clin Oncol 21:1255, 2003
Milpied N, Deconinck E, Gaillard F, et al: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350:1287-1295, 2004
Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002
Habermann TM, Weller E, Morrison VA, et al: Rituximab-CHOP versus CHOP with or without maintenance rituximab in patients 60 years of age or older with diffuse large B-cell lymphoma (DLBCL): An update. Blood 104:11, 2004 (abstr 127)
Pfreundschuh MG, Trumper L, Gill D, et al: First analysis of the completed Mabthera International (MInT) trial in young patients with low-risk diffuse large B-cell lymphoma (DLBCL): Addition of rituximab to a CHOP-like regimen significantly improves outcome of all patients with the identification of a very favorable subgroup with IPI=0 and no bulky disease. Blood 104:11, 2004 (abstr 157)(Gustaaf W. van Imhoff, Br)
Department of Pathology, Groningen University Hospital
Groningen
Data Center and Department of Internal Medicine, Erasmus MC, Rotterdam
Department of Internal Medicine, University Medical Center Nijmegen St Radboud, Nijmegen
Department of Internal Medicine, Leyenburg Hospital, The Hague
Department of Hematology, VU Medical Center, Amsterdam
Department of Internal Medicine, University Hospital Maastricht, Maastricht
Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands
ABSTRACT
PURPOSE: Timing, appropriate amount, and composition of treatment before high-dose therapy and autologous stem-cell transplantation (ASCT) in patients with poor-risk, aggressive non-Hodgkin's lymphoma (NHL) are still unknown. We conducted two consecutive multicenter phase II trials with up-front, high-dose, sequential chemotherapy and ASCT in poor-risk, aggressive NHL. Both trials had identical inclusion criteria and only differed in amount and duration of induction treatment before ASCT.
PATIENTS AND METHODS: Between 1994 and 2001, 147 newly diagnosed, poor-risk, aggressive NHL patients, age 65 years with stage III to IV and lactate dehydrogenase (LDH) more than 1.5x upper limit of normal (ULN), entered the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) -27 and HOVON-40 trials. Treatment in HOVON-27 consisted of two up-front, high-dose induction courses followed by carmustine, etoposide, cytarabine, and melphalan plus ASCT in responding patients. In HOVON-40, the same treatment was preceded by three intensified courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).
RESULTS: Patient characteristics in both trials were comparable: 80% had diffuse large B-cell lymphoma, 77% had stage IV disease, and median LDH levels were 3.1x ULN. Complete remission (CR) in both trials was 45% to 51%. Before ASCT, CR was 14% in HOVON-27 versus 28% in HOVON-40 (P = .03). Treatment failure was similar (27%). Four-year survival estimates in HOVON-27 compared with HOVON-40 were overall survival, 21% v 50% (P = .007); event-free survival, 15% v 49% (P = .0001); and disease-free survival, 34% v 74% (P = .008). This different outcome favoring HOVON-40 remained highly significant when correcting for competing risk factors in multivariate analysis.
CONCLUSION: In patients with poor-risk, aggressive NHL, addition of intensified CHOP before up-front, high-dose, sequential therapy and ASCT significantly improved the duration of response and survival.
INTRODUCTION
Treatment of patients with poor-risk, aggressive non-Hodgkin's lymphoma (NHL) requires improvement. Patients with a high-risk score according to the International Prognostic Index (IPI),1 who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) -like chemotherapy,2 have a 44% probability of reaching a complete remission (CR), and only 26% will be alive at 5 years from diagnosis.1
Approximately 40% of young patients who experience relapse more than 1 year after first-line treatment can still be rescued by high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT), provided the disease is chemotherapy sensitive.3,4 Consequently, high-dose chemotherapy followed by ASCT has been explored as first-line treatment in young patients with poor-risk, aggressive lymphoma. On the basis of promising results of ASCT in first remission,5–8 the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) started a multicenter phase II study in 1994 (HOVON-27) to investigate a strategy of intensive, high-dose, sequential chemotherapy delivered within a relatively short timeframe, and subsequent ASCT in adults with newly diagnosed, poor-risk, aggressive lymphoma. At the time of closure of this study in January 1999, conflicting results about the efficacy, timing, and optimal treatment schedule of up-front ASCT became apparent.9
Subgroup analysis of study LNH87-2, a randomized trial conducted by the French Groupe d'Etude des Lymphomes de l'Adulte (GELA) group, indicated that ASCT as consolidation in poor-risk patients in first CR after full-length CHOP-like induction treatment was more effective than standard treatment alone.10 In addition, an Italian study showed that short, high-dose, sequential chemotherapy followed by ASCT was better than standard therapy in poor-risk patients without bone marrow (BM) involvement.11 In contrast, preliminary data of a subsequent GELA trial, LNH93-3, yielded conflicting results: standard chemotherapy was better than short, high-dose, sequential chemotherapy and ASCT in poor-risk patients.12
These data, combined with disappointing preliminary results of our HOVON-27 study, suggested no improvement in outcome of short, high-dose, sequential therapy before up-front ASCT. Therefore, we questioned whether extension of induction treatment aimed at additional reduction of tumor load before ASCT might be more efficacious. To that end, we added three dose-dense intensified CHOP (iCHOP) courses before the original HOVON-27 protocol, now referred to as the HOVON-40 study. Because patients were included according to identical entry criteria and both trials were conducted consecutively by the same HOVON centers, we present both studies combined to show the remarkable improvement in outcome by the addition of three courses of iCHOP before high-dose, sequential treatment followed by ASCT.
PATIENTS AND METHODS
Between 1994 and 2001, we conducted two consecutive phase II studies for patients with poor-risk, advanced, aggressive NHL: HOVON-27 (December 1994 to January 1999) and HOVON-40 (February 1999 to November 2001). Figure 1 shows an outline of the studies.
Patients
Eligible patients were age 18 to 65 years and had newly diagnosed, untreated, aggressive NHL according to either the Working Formulation (groups D, E, F, G, H; HOVON-27) or Revised European-American Lymphoma classification (diffuse large B-cell lymphoma, follicular lymphoma grade 3, anaplastic large-cell lymphoma, and peripheral T-cell lymphoma; HOVON-40). All lymphomas were centrally reviewed by P.M.K. and reclassified according to the WHO classification.13 Patients were fully staged, including computed tomography scanning of thorax and abdomen, and BM biopsy. They were required to have high-risk disease according to a HOVON risk score (ie, both Ann Arbor stage III or IV and serum lactate dehydrogenase [LDH] > 1.5x the upper limit of normal of the participating institution). On the basis of the treatment outcome of patients with this combination of risk factors enrolled onto a previous HOVON study,14 they were expected to have survival of only 23% at 5 years when treated with CHOP. Patients were not eligible if they were HIV seropositive, or had a WHO-performance score 3 or 4, CNS lymphoma, concomitant disease, prior malignancy, or major organ dysfunction not directly related to lymphoma infiltration or obstruction.
All patients gave informed consent for study participation according to the regulations of the Dutch health authorities. The study was performed and evaluated by HOVON according to the Helsinki agreement. The participating HOVON institutions and investigators are listed in the Appendix.
Treatment
In HOVON-27, initial treatment consisted of two consecutive high-dose chemotherapy combinations, induction (course) I and induction (course) II. Induction I consisted of cyclophosphamide 1,000 mg/m2 every 12 hours on days 1 and 2 (total dose, 4,000 mg/m2), doxorubicin 35 mg/m2 on days 1 and 2 (total dose, 70 mg/m2), and prednisone 100 mg on days 1 through 5. Mesna (Uromitexan, Baxter International Inc, Halle, Germany) 200 mg/m2 was infused every 4 hours starting 10 minutes before and ending 8 hours after the last cyclophosphamide infusion. As soon as hematologic recovery was observed, induction II was administered, which consisted of etoposide 250 mg/m2 every 12 hours on days 1 to 4 (total dose 2,000 mg/m2), mitoxantrone 30 mg/m2 on day 1, and prednisone 100 mg on days 1 through 5. Hematologic recovery was defined as an increasing platelet (PLT) and neutrophil count more than 100 x 109/L and more than 1.0 x 109/L, respectively. After each induction course, patients received 5 μg/kg granulocyte colony-stimulating factor (Filgrastim; Amgen, Thousand Oaks, CA) subcutaneously daily from day 5 until the neutrophil count reached at least 0.5 x 109/L for 2 consecutive days.
Peripheral-blood stem cells were collected and cryopreserved, preferably after induction I or otherwise after induction II according to standard institutional procedures, provided the BM no longer contained lymphoma on histologic examination. No CD34+ selection or purging was performed.
Patients attaining at least a partial response (PR) after induction II, with a collection of at least 2.5 x 106 CD34+ cells/kg, subsequently received high-dose therapy and ASCT. High-dose chemotherapy consisted of carmustine 300 mg/m2 on day –6, etoposide 100 mg/m2 and cytarabine 100 mg/m2 every 12 hours on days –5 through –2, and melphalan 140 mg/m2 on day –1 (BEAM). Stem cells were reinfused on day 0. Patients received hematologic supportive care, including vigorous hydration, allopurinol, irradiated PLT and RBC transfusions, prophylactic oral antibacterial and antifungal treatment, and immediate treatment with intravenous broad-spectrum antibiotics and/or intravenous antifungal treatment if fever and/or documented or suspected infection occurred, according to guidelines of the participating institution. Patients with bulky disease at presentation could be treated with involved-field radiotherapy on PR sites after recovery from ASCT at the discretion of each center. No additional maintenance therapy was administered.
In study HOVON-40, patients were first treated with three courses of iCHOP, before treatment as described for the HOVON-27 trial. iCHOP consisted of cyclophosphamide 1,000 mg/m2, doxorubicin 70 mg/m2, and vincristine 2 mg on day 1; and prednisone 100 mg for 5 consecutive days. Granulocyte colony-stimulating factor 5 μg/kg was administered on days 2 through 11 of each cycle of iCHOP. Cycles were administered every 2 weeks. The first iCHOP course was administered at 100% dose, irrespective of blood cell counts. If WBC counts and/or PLT counts on day 15 after the preceding iCHOP course were less than 3 x 109/L and/or 100 x 109/L, respectively, the following iCHOP course was delayed for 1 week and the subsequent dose of cyclophosphamide and doxorubicin was attenuated based on the actual counts as follows: WBC more than 3 x 109/L and PLT more than 100 x 109/L, 100% dose; WBC 2 to 3 x 109/L and PLT more than 100 x 109/L, 75% dose; WBC 1 to 2 x 109/L or PLT 50 to 100 x 109/L, 50% dose; WBC less than 1 x 109/L or PLT less than 50 x 109/L, 0% dose. Dose modifications for vincristine were made if neurotoxicity occurred at the discretion of the treating physician. Stem cells were collected from the peripheral blood during iCHOP treatment as soon as possible, provided the BM was free of lymphoma, as confirmed by histologic examination. Only patients with a documented response of at least 25% after three courses of iCHOP continued with high-dose sequential treatment as described for the HOVON-27 trial. Patients attaining at least a PR after induction II, with a collection of at least 2.5 x 106 CD34+ cells/kg, continued with BEAM and ASCT.
Response to Treatment and Toxicity
Tumor response was assessed after three iCHOP (HOVON-40) courses, induction II, ASCT, and additional radiotherapy (if administered) according to staging procedures described at diagnosis. Responses were classified as CR (including unconfirmed CR), PR, stable disease, or progressive disease according to the International Workshop Criteria.15 In addition, a minimal response after three iCHOP courses, which qualified the patient for continuation of protocol treatment (HOVON-40), was arbitrarily defined as a regression in size of all measurable lesions of at least 25% in the absence of new lesions. Patients attaining less than a minimal response after three iCHOP courses or less than PR after induction II discontinued protocol treatment and were considered to have experienced treatment failure.
All toxicity, except nausea and hair loss, was graded according to the National Cancer Institute Common Toxicity Criteria grading system. Hematologic toxicity after high-dose treatment and ASCT was assessed separately.
Statistical Analysis
The data were analyzed as of August 2004. Patient characteristics were compared between the two treatment protocols using the Pearson 2 or the Fisher's exact test, whichever was appropriate for discrete variables, or the Wilcoxon rank sum test for continuous variables. Study end points were CR rate, response rate (CR + PR), event-free survival (EFS), disease-free survival (DFS), and overall survival (OS). EFS was defined as the time from start of treatment to progression, relapse, or death as a result of any cause, whichever came first; patients without progression or relapse who were still alive were censored at the date of last contact. DFS was defined as the time from documented first CR on protocol until relapse. OS was defined as the time from the start of treatment to death as a result of any cause; patients still alive were censored at the date of last contact.15
The Kaplan-Meier method was used to estimate EFS, DFS, and OS, and 95% CIs were calculated. The log-rank test was used to compare survival curves between both trials.
The proportions of patients achieving CR on protocol in both trials were compared using logistic regression. Univariate logistic regression was used to analyze differences in CR rate between subgroups according to patient characteristics at diagnosis.
Explorative univariate and multivariate survival analyses with Cox regression were performed to investigate differences in survival between subgroups including the following variables in univariate analysis: sex, age (continuous as well as 60 v > 60 years), WHO performance status ( 1 v > 1), "B" symptoms, Ann Arbor stage (III v IV), bulky disease (> 10 cm diameter), BM involvement, number of extranodal sites (0 to 1 v 2), and age-adjusted IPI (high-intermediate v high). Treatment protocol (HOVON-27 v HOVON-40), age (continuous), WHO performance status, Ann Arbor stage, and number of extranodal sites were also included in the multivariate analysis.
All reported P values are two sided and a significance level = .05 was used.
RESULTS
Patient Characteristics
Between December 1994 and January 1999, we enrolled 66 patients onto HOVON-27, and between February 1999 and October 2001, we enrolled 81 patients onto HOVON-40.
Except for small differences in performance status and number of extranodal sites, there were no significant differences in clinical or pathologic characteristics between both patient groups (Table 1). Central pathology was completed in 93% of patients; the great majority were diffuse large B-cell lymphoma. Median age was 50 years (range, 15 to 65 years) with a minority (11%) older than 60 years. In accordance with the entry criteria, LDH levels were strongly elevated, with a median of 3.1x the upper limit of normal. Extranodal involvement occurred in 77%; BM involvement occurred in 34%. Poor performance status (WHO > 1) was observed in 35% in HOVON-27 versus 20% in HOVON-40 (P = .04). This also accounts for the slightly higher percentage of age-adjusted (aa) -IPI grade 3 in HOVON-27 (33%) compared with HOVON-40 (20%; P = .06). All patients had an aa-IPI risk score of at least 2.
Treatment and Response
Treatment including ASCT was completed by two thirds of the patients (Table 2). Additional radiotherapy was administered to a minority of the patients (22%).
The CR rates were 45% (HOVON-27) and 51% (HOVON-40; Table 2). Although the difference in response to overall protocol treatment between both trials was not significant, the fraction of patients with CR before starting ASCT was twice as large in HOVON-40 (28%) compared with HOVON-27 (14%; P = .03). Treatment failure was the major reason for discontinuing protocol treatment, and occurred in 27% (HOVON-27) and 26% (HOVON-40) of patients (Table 3).
Stem-Cell Collection
Stem cells were collected in 54 (82%; HOVON-27) and 65 patients (80%; HOVON-40). In HOVON-27, stem cells were collected in one procedure after induction I in 34 (63%) or after induction II in 20 patients (37%), yielding a median of 8.5 x 106 (range, 0.1 to 86.7 x 106) CD34+ cells/kg; in HOVON-40, stem cells were collected during iCHOP in 28 (43%), after induction I in 35 (54%), or after induction II in two patients (3%), yielding a median of 4.7 x 106 (range, 0.4 to 45.6 x 106) CD34+ cells/kg in one procedure. Additional peripheral blood or BM stem cells were collected in six patients (three in each trial). In one patient only BM stem cells were collected.
Toxicity
iCHOP treatment was well tolerated and could be administered on schedule on an outpatient basis. As expected, substantial hematologic and nonhematologic toxicities were observed after induction I, II, and BEAM. No significant differences were observed between the two trials. Substantial mucositis, often necessitating parenteral nutrition, was the most frequent nonhematologic toxicity during intensive treatment. Pooled results for all reported nonhematologic toxicities grade 3 to 4 (Table 4), and hematologic toxicity and transfusions are presented (Table 5).
Six patients (9%) in HOVON-27 and five patients (6%) in HOVON-40 died as a result of treatment-related causes.
Survival
With a median follow-up of patients still alive in HOVON-27 of 83 months (range, 50 to 112 months) and in HOVON-40 of 34 months (range, 13 to 59 months), 53 (80%) and 40 (49%) patients, respectively, have died; NHL was the cause in 85% and 80% of the deaths, respectively. Highly significant differences in the estimated OS, EFS, and DFS rates were observed. The 4-year actuarial estimates for patients in HOVON-27 compared with HOVON-40 were OS, 21% (95% CI, 12% to 32%) versus 50% (95% CI, 37% to 61%; log-rank P = .007); EFS, 15% (95% CI, 8% to 25%) versus 49% (95% CI, 38% to 59%; P = .0001); and DFS, 34% (95% CI, 17% to 51%) versus 74% (95% CI, 58% to 85%; P = .008). The corresponding Kaplan-Meier curves are depicted in Figure 2.
Prognostic Factors
In univariate analysis, WHO performance status more than 1 was the only factor associated with a lower CR rate (odds ratio, 0.45; 95% CI, 0.21 to 0.97; P = .043), but this was no longer significant in multivariate analysis.
In univariate Cox regression analysis, treatment according to protocol HOVON-40 was associated with better outcome for all survival end points as described in the previous section. Increased age and BM involvement were associated with shorter OS. WHO performance status more than 1 and BM involvement were adverse prognostic factors for EFS; higher age and bone marrow involvement were adverse prognostic factors for DFS.
In multivariate analysis, HOVON-40 remained a statistically significant strong prognostic factor for EFS, DFS, and OS (Table 6).
DISCUSSION
These consecutive studies highlight the importance of a robust induction treatment before up-front ASCT in patients with poor-prognosis, aggressive NHL. Addition of three courses of iCHOP to sequential high-dose induction therapy before ASCT in our HOVON-40 protocol resulted in a higher fraction of patients in CR before ASCT and, more importantly, in a highly significant improvement of all survival end points.
Although this study was not a controlled, randomized trial, characteristics of patients in trials HOVON-27 and HOVON-40 were highly comparable, and both trials were conducted consecutively in the same HOVON centers. The only difference was the addition of three courses of iCHOP as preinduction treatment in HOVON-40. Thus, short of randomization and duration of follow-up, these studies were well qualified for comparison of treatment outcome, and results remained independently affected by treatment when corrected for risk factors and observation time in multivariate analysis.
Outcome in trial HOVON-27, consisting of only two courses of high-dose therapy before BEAM and ASCT, was clearly disappointing. Although one could ask whether these results could be even worse than what might be expected of standard CHOP treatment, the outcome of patients in HOVON-27 was identical to a cohort of 52 patients with similar risk factors in a previous HOVON-3 study.14
The failure to improve on standard CHOP treatment in trial HOVON-27 might be related to (or be a combination of) a relatively high percentage of patients with intrinsically chemotherapy-resistant disease reflected by 27% primary treatment failures; a rather late tumor response reflected by a CR fraction of only 14% after induction versus 39% after ASCT; and a poor quality of CR, with a 4-year DFS of only 34%.
The rationale of high-dose sequential treatment in poor-risk, aggressive NHL is to overcome chemotherapy resistance by rotating a succession of drugs administered at high dosages, in a tight schedule, as shortly after one another as possible. A sequential high-dose regimen followed by ASCT as designed by Gianni et al,11 showing superior results to standard-dose methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin, seemed proof of principle of this concept. However, neither the GELA12 nor this study (HOVON-27) could confirm these results with a similar strategy.
The distinction between high-dose sequential therapy and standard therapy as an induction regimen before ablative therapy and ASCT, as well as the relative merits of these strategies, are still not clear. Full-length standard CHOP-like therapy followed by ASCT was not superior to standard CHOP-like therapy for unselected patients with aggressive NHL in randomized trials conducted by GELA,16 the Italian Non-Hodgkin's Lymphoma Group,17 and the European Organization for Research and Treatment of Cancer.18 Retrospective subgroup analysis of both the LNH87-2 GELA trial and the Italian study, however, indicated a benefit of ASCT for patients with aa-IPI 2 to 3 who completed standard induction therapy,17,19 but this could not be confirmed in the European Organization for Research and Treatment of Cancer study.18 Abbreviated standard chemotherapy followed by ASCT is not superior to full-length standard therapy,14,20,21 whereas abbreviated high-dose chemotherapy yielded even inferior results to standard treatment in aa-IPI 2 to 3 patients.12 In contrast, the Groupe Ouest-Est des Leucemies et des Autres Maladies du Sang reported an improved EFS for high-dose therapy with ASCT compared with standard CHOP in patients with aa-IPI 0 to 2, but improved survival was restricted to aa-IPI 2 patients only.22 Of note, the induction treatment in the ASCT arm of this trial consisted of only two dose-dense courses of a CHOP-like regimen cyclophosphamide, epirubicin, vindesine, prednisone. Given the good results, the relatively low dose of cyclophosphamide and the absence of high-dose etoposide in the GOELAMS study is remarkable compared with the dosage of these drugs in the Milan11 and HOVON protocols.
In HOVON-40, we prolonged the induction phase and incorporated a higher cumulative dose of cyclophosphamide and doxorubicin; we expected better outcome by increasing the CR rate before ASCT and improving the quality of CR. The addition of three iCHOP courses not only doubled the fraction of patients in CR before ASCT, but also improved the quality of CR as reflected by an increased 4-year DFS from 34% in HOVON-27 to 74% in HOVON-40. Although this study does not answer the question whether treatment with up-front ASCT is necessary in high-risk patients, these results strongly support the notion that up-front ASCT is probably more successful in patients having reached a CR after an adequate amount of induction therapy.
However, one in every fourth patient had primary refractory disease, and this apparently could not be overcome by increasing the dose or shortening the time interval of chemotherapy because these results were not different between HOVON-40 (26%) and HOVON-27 (27%). Chemotherapy refractoriness is probably inherent to the selection of patients with advanced-stage, aggressive NHL, and strongly elevated LDH levels in our studies, and remains an important issue to address in the development of new treatment strategies for these poor-risk patients. Anti-CD20 monoclonal antibodies (rituximab) administered in combination with CHOP significantly reduce the risk of treatment failure in elderly patients with diffuse large B-cell lymphoma.23 Similar results have been observed in the North-American Intergroup study,24 and also in the recently reported Mint trial in young patients.25 These observations, and the absence of clinically significant toxicity, make rituximab an obvious candidate for combination with high-dose treatment such as the HOVON-40 protocol. Future clinical trials comparing full-length rituximab plus CHOP-like therapy to an HOVON-40-like high-dose scheme with rituximab are needed to analyze the additional contribution of up-front ASCT after optimal intensive induction therapy in poor-risk diffuse large B-cell lymphoma patients.
Appendix
The following Dutch (NL) and Belgian (B) hospitals (physicians) participated in HOVON trials 27 and 40: NL-Zwolle-Isala Clinics, location Sophia (M. van Marwijk Kooy), NL-Nieuwegein-Sint Antonius Hospital (D.H. Biesma), NL-Maastricht-University Hospital Maastricht (H.C. Schouten), NL-Den Haag-Leyenburg Hospital (P.W. Wijermans), NL-Amsterdam-Slotervaart Hospital (M. Soesan), NL-Sittard-Maasland Hospital (F.L.G. Erdkamp), NL-Enschede-Medical Spectrum Twente (M.R. Schaafsma), NL-Amersfoort-Meander Medical Center (M.H.H. Kramer), NL-Amsterdam-Antoni van Leeuwenhoek Hospital (J.W. Baars), NL-Rotterdam-Erasmus MC-DDHK (M.B. van't Veer), NL-Groningen-Groningen University Hospital (G.W. van Imhoff), NL-Nijmegen-University Medical Center Nijmegen St. Radboud (M.A. MacKenzie), NL-Utrecht-University Medical Center Utrecht (L.F. Verdonck), NL-Amsterdam-VU Medical Center (G.J. Ossekoppele), NL-Amsterdam-Amsterdam Medical Center (J. van der Lelie), NL-Leiden-Leiden University Medical Center (R. Willemze), NL-Rotterdam-Erasmus MC (P. Sonneveld), B-Leuven-University Hospital Leuven Gasthuisberg (L. Vandenberghe), NL-Amstelveen-Amstelveen Hospital (G.J. Timmers).
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank E.G. Boerma for excellent help with the pathology review.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329:987-994, 1993
Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328:1002-1006, 1993
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
Guglielmi C, Gomez F, Philip T, et al: Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16:3264-3269, 1998
Gulati SC, Shank B, Black P, et al: Autologous bone marrow transplantation for patients with poor-prognosis lymphoma. J Clin Oncol 6:1303-1313, 1988
Nademanee A, Schmidt GM, O'Donnell MR, et al: High-dose chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy during first complete remission in adult patients with poor-risk aggressive lymphoma: A pilot study. Blood 80:1130-1134, 1992
Freedman AS, Takvorian T, Neuberg D, et al: Autologous bone marrow transplantation in poor-prognosis intermediate- grade and high-grade B-cell non-Hodgkin's lymphoma in first remission: A pilot study. J Clin Oncol 11:931-936, 1993
Sierra J, Conde E, Montserrat E: Autologous bone marrow transplantation for non-Hodgkin's lymphoma in first remission. Blood 81:1968-1969, 1993
Shipp MA, Abeloff MD, Antman KH, et al: International Consensus Conference on High-Dose Therapy With Hematopoietic Stem Cell Transplantation in Aggressive Non-Hodgkin's Lymphomas: Report of the jury. J Clin Oncol 17:423-429, 1999
Haioun C, Lepage E, Gisselbrecht C, et al: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: Updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15:1131-1137, 1997
Gianni AM, Bregni M, Siena S, et al: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336:1290-1297, 1997
Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20:2472-2479, 2002
Jaffe ES, Harris NL, Stein H, et al (eds): WHO Classification of Tumours: Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2001
Verdonck LF, van Putten WLJ, Hagenbeek A, et al: Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma. N Engl J Med 332:1045-1051, 1995
Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI Sponsored International Working Group. J Clin Oncol 17:1244-1253, 1999
Haioun C, Lepage E, Gisselbrecht C, et al: Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin's lymphoma in first complete remission: A study of 464 patients—Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 12:2543-2551, 1994
Santini G, Salvagno L, Leoni P, et al: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: Results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16:2796-2802, 1998
Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al: Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: Randomized phase III EORTC study. J Natl Cancer Inst 93:22-30, 2001
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
Kaiser U, Uebelacker I, Abel U, et al: Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. J Clin Oncol 20:4413-4419, 2002
Martelli M, Gherlinzoni F, De Renzo A, et al: 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. J Clin Oncol 21:1255, 2003
Milpied N, Deconinck E, Gaillard F, et al: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350:1287-1295, 2004
Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002
Habermann TM, Weller E, Morrison VA, et al: Rituximab-CHOP versus CHOP with or without maintenance rituximab in patients 60 years of age or older with diffuse large B-cell lymphoma (DLBCL): An update. Blood 104:11, 2004 (abstr 127)
Pfreundschuh MG, Trumper L, Gill D, et al: First analysis of the completed Mabthera International (MInT) trial in young patients with low-risk diffuse large B-cell lymphoma (DLBCL): Addition of rituximab to a CHOP-like regimen significantly improves outcome of all patients with the identification of a very favorable subgroup with IPI=0 and no bulky disease. Blood 104:11, 2004 (abstr 157)(Gustaaf W. van Imhoff, Br)