Concurrent Administration of High-Dose Rituximab Before and After Autologous Stem-Cell Transplantation for Relapsed Aggressive B-Cell Non-Ho
http://www.100md.com
《临床肿瘤学》
the Departments of Blood and Marrow Transplantation, Lymphoma, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
ABSTRACT
PURPOSE: We investigated the efficacy and safety of administering high-dose rituximab (HD-R) in combination with high-dose carmustine, cytarabine, etoposide, and melphalan chemotherapy and autologous stem-cell transplantation (SCT) in patients with recurrent B-cell aggressive non-Hodgkin’s lymphoma (NHL).
PATIENTS AND METHODS: Sixty-seven consecutive patients were treated. Rituximab was administered during stem-cell mobilization (1 day before chemotherapy at 375 mg/m2 and 7 days after chemotherapy at 1,000 mg/m2), together with granulocyte colony-stimulating factor 10 μg/kg and granulocyte-macrophage colony-stimulating factor 250 μg/m2 administered subcutaneously daily. HD-R of 1,000 mg/m2 was administered again days 1 and 8 after transplantation. The results of this treatment were retrospectively compared with those of a historical control group receiving the same preparative regimen without rituximab.
RESULTS: With a median follow-up time for the study group of 20 months, the overall survival rate at 2-years was 80% (95% CI, 65% to 89%) for the study group and 53% (95% CI, 34% to 69%) for the control group (P = .002). Disease-free survival was 67% (95% CI, 51% to 79%) for the study group and 43% (95% CI, 26% to 60%) for the control group (P = .004). The median time to recovery of absolute neutrophil count to 500 cells/μL was 11 days (range, 8 to 37 days) for the rituximab group and 10 days (range, 8 to 17 days) for the matched control group (P = .001). However, infections were not significantly increased in patients treated with rituximab.
CONCLUSION: The results of this study suggest that using HD-R and autologous SCT is a feasible and promising treatment for patients with B-cell aggressive NHL.
INTRODUCTION
Recurrent non-Hodgkin’s lymphoma (NHL) has a poor prognosis with conventional chemotherapy.1 Despite intensive research with novel chemotherapy regimens, patients with recurrent disease typically have only a transient response to salvage therapies and ultimately succumb to their disease. The incidence of NHL has been increasing in the United States over the past 30 years, and NHL is currently the fifth leading cause of cancer-related death in men in the United States.2
High-dose chemotherapy followed by autologous stem-cell transplantation (SCT) has been frequently used for patients with relapsed, aggressive, chemosensitive NHL. In patients with histologically aggressive diseases, overall survival (OS) and progression-free survival rates of approximately 60% and 40%, respectively, have been reported.3-8 Most treatment failures after transplantation can be ascribed to disease relapse, which usually occurs within 1 to 2 years of transplantation. New strategies designed to reduce the incidence of relapse after autologous SCT must take into consideration patients’ limited hematopoietic reserve during the early posttransplantation period.
Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA) is an anti-CD20 human-mouse chimeric monoclonal antibody indicated for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL. The use of rituximab as a single agent results in impressive response rates and durations of response in patients with indolent NHL and improves efficacy when used in combination with chemotherapy for both indolent and aggressive NHL.9-13 Responses to rituximab treatment vary by the histologic subtype of NHL. In patients with low-grade follicular lymphoma, response rates are approximately 70% to 75% with first-line treatment and 50% to 60% in relapsed follicular lymphoma. In contrast, in patients with diffuse B-cell large-cell lymphoma (DBLCL), single-agent rituximab response rates of 30% to 40% have been reported. Rituximab significantly increases response rates when used in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone.14,15
Recent studies have suggested that higher doses16 or more doses17,18 of rituximab may increase the response rate. CD20 is not expressed by hematopoietic stem cells, and therefore, we hypothesized that rituximab treatment would not inhibit engraftment produced by these early progenitors. Treatment with high-dose rituximab (HD-R) may successfully eliminate minimal residual disease, further delaying or preventing disease relapse and potentially extending the duration of survival after autologous SCT. Therefore, the objectives of the current study were to evaluate the impact of rituximab on toxicity, disease-free survival (DFS), and OS when added before and after high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) chemotherapy and autologous SCT in patients with aggressive NHL.
PATIENTS AND METHODS
Patients
Patients with aggressive large-cell, follicular or diffuse, B-cell CD20-positive lymphoma whose disease had relapsed after conventional chemotherapy were eligible for enrollment. Other inclusion criteria were age 65 years, a Zubrod performance status score of 2, and less than 10% bone marrow involvement on gross pathologic examination after cytoreduction with conventional chemotherapy.
Exclusion criteria were HIV or human T-cell leukemia virus type 1 seropositivity, pregnancy, left ventricular ejection fraction less than 50%, active CNS involvement, serum creatinine more than 1.6 mg/dL or serum bilirubin more than 1.5 mg/dL (unless a result of NHL), absolute neutrophil count less than 1,000 cells/μL and platelets less than 100,000/μL (unless secondary to tumor), diffusing capacity of the lung for carbon monoxide less than 50% of the predicted value, and severe concomitant medical or psychiatric illness.
The treatment was reviewed and approved by the Institutional Review Board of The University of Texas M.D. Anderson Cancer Center. Written informed consent was obtained from all patients.
Clinical Evaluation
Disease stage was evaluated using Ann Arbor criteria and assigned an International Prognostic Index (IPI) score.19 All cases were reviewed by an experienced hematopathologist for diagnostic confirmation. All patients underwent the following staging procedures: physical examination, CBC with differential count, serum chemistry panel, serum beta2-microglobulin measurement, chest radiography, computed tomography of the abdomen and pelvis, gallium scanning, and bilateral bone marrow aspiration and biopsies. Patients were evaluated after 1, 3, 6, and 12 months and every 6 months thereafter. Patients were assessed more frequently at the discretion of their primary physician.
Clinical assessments after SCT included time to hematopoietic recovery, posttransplantation response rate, OS, DFS, and adverse events. Time to neutrophil count recovery was defined as the first of 3 consecutive days when the absolute neutrophil count was 500 cells/μL, and platelet count recovery was defined as the first day after transplantation when the platelet count was 20,000/μL (independent of platelet transfusions). Responses were scored using the standard criteria for patients with lymphoma as described by Cheson et al.20
Autologous Stem-Cell Collection
Rituximab (375 mg/m2) was infused 1 day before chemotherapy. Stem cells were then mobilized with either cyclophosphamide (4 to 7 g/m2) in 34 patients or ifosfamide (3.33 g/m2 daily for 3 days) plus etoposide (150 mg/m2 twice a day [bid] for 3 days) in 33 patients. After chemotherapy, patients were treated daily with granulocyte colony-stimulating factor (G-CSF; 10 μg/kg subcutaneously) and granulocyte-macrophage colony-stimulating factor (GM-CSF; 250 μg/m2 subcutaneously), and rituximab was again administered 7 days after chemotherapy at 1,000 mg/m2. Stem cells were then collected from peripheral blood according to standard techniques.
Preparative Regimen for SCT
The preparative regimen for SCT was standard BEAM therapy (carmustine 300 mg/m2 by 1-hour intravenous [IV] infusion on day –6, cytarabine 200 mg/m2 IV bid on days –5 through –2 for a total of eight doses, etoposide 200 mg/m2 IV bid on days –5 through –2 for a total of eight doses, and melphalan 140 mg/m2 IV on day –1). Rituximab (1,000 mg/m2) was administered to all patients in the rituximab study group 1 and 8 days after SCT. Patients received GM-CSF 250 μg/m2 subcutaneously daily, beginning on day 0 until hematologic recovery.
Historic Control Group
Patient data and treatment results were retrospectively compared with those of 30 consecutive patients treated at M.D. Anderson Cancer Center for aggressive large-cell, follicular or diffuse, B-cell NHL with autologous SCT under a protocol that immediately preceded our study. Patients in the control group were treated between June 1994 and November 1996 and were previously reported.21 Patients with T-cell phenotyping were excluded. This group had received similar initial and salvage chemotherapy as the study group but had not received rituximab. They had their stem cells mobilized with ifosfamide plus etoposide, with the same schedule and dosages as in the study group, and G-CSF. They then received the same BEAM regimen with G-CSF but did not receive rituximab or GM-CSF.
Statistical Methods
Patient characteristics in the study and control groups were compared using 2 and Fisher’s exact tests for categoric variables and the Mann-Whitney rank sum test for continuous variables. Actuarial rates of survival, disease progression, and DFS were estimated from the day of SCT using the Kaplan-Meier method and compared with the rates of patients in the control group using the log-rank test. A comprehensive multivariate analysis to evaluate the effect of adding HD-R to the preparative regimen independently of patient and disease characteristics was not possible in this study because of the small sample size. The Cox proportional hazards model was used to evaluate prognostic factors for disease progression in the study group. Statistical significance was defined as P .05. The statistical analysis was performed using STATA 7.0 software (Stata Corp, College Station, TX).
RESULTS
Patients
Between June 2000 and July 2003, 67 consecutive patients at M.D. Anderson Cancer Center were treated with the study regimen; these patients are referred to as the rituximab study group. Patient demographics and baseline disease characteristics of the study and control groups are listed in Table 1.
Patients in the study group ranged in age from 20 to 65 years (median, 51 years). Most patients (55%) were men. Forty-one patients had de novo DBLCL, and 26 patients had aggressive lymphomas that had a follicular component (discordant, transformed, or follicular large). All patients had undergone salvage therapy for chemosensitive disease before stem-cell mobilization. In 59 patients (88%), rituximab was combined with salvage chemotherapy. The last dose of rituximab was administered a median of 38 days (range, 19 to 374 days) before study entry.
There were 30 patients in the control group. Seventeen patients had de novo DBLCL, and 13 patients had aggressive lymphoma that had a follicular component. Patient and disease characteristics were comparable in the study and control groups, with the exception of disease status at transplantation, IPI score at transplantation, and serum lactate dehydrogenase (LDH) level at transplantation favoring the control group. Most patients in the control group (80%) had sensitive disease in first relapse or second complete remission compared with 51% of patients in the rituximab group (P = .01). Twenty four patients (36%) in the study group were in primary induction failure, and 10 (42%) of these patients received three or more chemotherapy regimens before study entry. All patients in the control group had an IPI score 1, whereas 18% of patients who underwent HD-R treatment had a score of more than 1 (P < .01). In addition, only four patients (13%) in the control group had an elevated LDH level compared with 14 patients (21%) in the study group (P = .3; Table 1).
Engraftment
Peripheral-blood progenitors cells were the source of the autologous grafts in all patients in the study and control groups. Six patients in the study group received both blood and marrow cells. The inadequate stem-cell mobilization in these six patients was the underlying cause of changing the chemotherapy used for stem-cell mobilization in the study group from cyclophosphamide to the ifosfamide plus etoposide regimen used in all of the controls.
We intentionally infused a lesser amount of stem cells in our recent protocols. Therefore, the median number of CD34-positive cells infused was more than 2.5-fold higher in the control group than in the rituximab study group (Table 2). The median time to recovery of absolute neutrophil count to 500 cells/μL was 11 days (range, 8 to 37 days) for the rituximab group and 10 days (range, 8 to 17 days) for the matched control group, which was a significant difference (P = .001).
The median time to complete lymphocyte recovery ( 500/μL) did not differ significantly between the rituximab study group and the control group (median, 20 days; range, 10 to 164 days in the study group v median, 17 days; range, 9 to 109 days in the control group; P = .3). However, the median time to platelet recovery to 20,000/μL was 11 days (range, 6 to 100 days) for patients who received HD-R; this was significantly longer than the median of 9 days (range, 6 to 16 days) for matched controls (P = .05).
The engraftment analysis included five patients who had prolonged cytopenia after SCT. Three cases were attributed to poor mobilization of blood stem cells, one was associated with cytomegalovirus infection, and one was attributed to the use of trimethoprim and sulfamethoxazole. Two other patients had a transient neutropenia that lasted for 3 days (at 4 months after SCT in one patient and 7 months after SCT in the other patient). Both cases were related to infections, and a prompt response to G-CSF was observed in both patients.
Efficacy
Sixty-one patients (91%) in the rituximab study group experienced a complete response, and five patients (8%) achieved a partial response after SCT. One patient (1%) had stable disease. The median follow-up time of all patients was 20 months (range, 2 to 42 months) in the study group and 30 months (range, 2 to 99 months) in the control group. Comparison of outcomes was conducted at 2 years after SCT to ensure comparable follow-up times.
Disease progression was the major cause of treatment failure for both groups, but significantly fewer patients treated with rituximab experienced progression after transplantation compared with controls. The progression rate at 2 years was 33% (95% CI, 21% to 48%) for the study group and 52% (95% CI, 35% to 71%) for the control group (P = .02). Only one treatment failure occurred after 2 years in the study group, and it was related to myelodysplasia. The actuarial DFS rate at 2 years was 67% (95% CI, 51% to 79%) for the study group and 43% (95% CI, 26% to 60%) for the control group (P = .004; Fig 1). The actuarial survival rate was 80% (95% CI, 65% to 89%) for the rituximab study group and 53% (95% CI, 34% to 69%) for the control group (P = .002; Fig 2).
Prognostic Factors
On univariate analysis, an elevated LDH level (> 618 U/L) was the only significant prognostic factor for disease progression (hazard ratio [HR] = 3.3; 95% CI, 1.3 to 8.9) and survival (HR = 4.1; 95% CI, 1.3 to 12.6; Table 3). The remaining IPI components did not add further prognostic value. We observed no significant effects for age, sex, disease status at transplantation, number of prior chemotherapy regimens, histology (de novo or transformed DBLCL), beta2-microglobulin level, the number of extranodal sites, or time to recovery of lymphocytes to 300 or 500/μL (categorized at the median of 16 and 20 days, respectively, or as quartiles).
Because LDH level at transplantation was the only significant prognostic factor for both disease progression and mortality in the study group, we compared the rate of progression separately for patients with high and low LDH in the study group to the rate in the control group (Fig 3). Patients with elevated LDH levels in the study group had a rate of progression comparable to all patients in the control group (HR = 0.9; P = .9), whereas patients with low LDH levels had a significantly lower rate of progression (HR = 0.3; P = .005). The HRs were similar when we excluded the four patients with high LDH levels from the control group.
Safety
Overall, safety and tolerability were similar for the HD-R and control groups, with no significant differences between groups in infections or toxicity. All patients had hematopoietic recovery, and there was no treatment-related mortality in either group. Overall, 25 episodes of bacterial infections occurred in the 67 patients comprising the rituximab group versus 14 infections in the 30 control patients (P = .4). Five patients in the study group and none of the controls (P = .3) developed a reactivation of cytomegalovirus infection; all of the patients responded to therapy, and no patient had cytomegalovirus disease.
DISCUSSION
Our results suggest that high dosages of rituximab administered to patients with aggressive B-cell NHL before and after autologous SCT can significantly increase OS and DFS rates compared with traditional high-dose conditioning regimens without rituximab. This improvement occurred without increasing the risk of infection or toxicity, and the treatment-related mortality rate was 0% in both groups of patients. The small number of patients in the control group did not allow evaluation of the independent effect of the regimen in a multivariate analysis; yet patient characteristics were comparable in the two groups, with the exception of the IPI score, LDH level, and disease status at SCT, which favored the control group.
One difference between the study and historical control groups was the use of rituximab during salvage chemotherapy in the rituximab study patients; the use of rituximab before stem-cell collection and transplantation may also have contributed to the favorable outcome in the study group. However, in a recent study,22 the outcome after autologous transplantation was not statistically significant from controls when the addition of rituximab was limited to salvage chemotherapy used in preparation for transplantation and was not administered after the transplantation itself.
The results of several trials of rituximab administered before stem-cell collection and after SCT indicate that this approach is safe in terms of mobilization and engraftment.23-29 Tumor-cell contamination in the stem-cell product can be reduced with rituximab, and an increase in molecular remission after transplantation has been suggested. However, most of these trials involved patients with follicular or mantle-cell lymphoma. Thus, our report may represent the first study suggesting that the addition of rituximab before and after conventional SCT is associated with superior results in patients with aggressive B-cell NHL.
The standard dosage of rituximab is 375 mg/m2 once a week for 4 weeks. However, in what is considered the pivotal trial of rituximab in patients with indolent NHL,9 median serum antibody levels were higher in responding patients than in nonresponders (502.8 and 412.4 mg/μL, respectively; P = .001). Therefore, several investigators have evaluated modifications to the dosing schedule. Alternative approaches included higher doses16 or a greater number of doses.17,18 Higher response rates have been observed with these strategies. Piro et al18 conducted a phase II trial in which eight weekly infusions of rituximab were evaluated in patients with refractory or relapsed indolent NHL. Among 35 assessable patients, 14% experienced a complete response, and 46% experienced a partial response. Patients with bulky disease also experienced disease response, including 25% of patients with lesions larger than 7 cm. This initiated our use of a higher dose of rituximab in our study. The effectiveness of HD-R was indirectly shown by Magni et al,23 who used rituximab for in vivo purging of autologous stem-cell collection before SCT for follicular and mantle-cell lymphoma. In that study, 33% of the collected stem cells had no clonal cells detected by polymerase chain reaction assay after one course of in vivo treatment with rituximab. After the second course of treatment, 93% of cells were lymphoma free compared with 40% of cells in the control group treated with chemotherapy alone for mobilization. However, controlled studies with pharmacokinetics are needed to determine the optimal dosage and schedule of rituximab in patients who undergo autologous SCT.
Benekli et al29 reported a significantly higher bacterial infection rate in rituximab-treated patients than in patients who did not receive rituximab. Other researchers have demonstrated that the immunosuppressive effects of rituximab slightly delay immune recovery; however, these delays do not result in an increased incidence of posttransplantation infection.26 The increased rate of posttransplantation infections seen in our study was not statistically significant, despite the use of HD-R. The delayed recovery of peripheral-blood counts in the rituximab-treated group may be confounded by the higher number of stem cells infused in the control group and the different supportive growth factors used after transplantation.
The improvement in outcome observed with the addition of rituximab before and after SCT seems to be related mostly to a significant decrease in the rate of disease progression that usually occurs within 1 to 2 years of transplantation. Brugger et al27 demonstrated that additional clinical and molecular responses were noted for several months after the discontinuation of rituximab. In their study, 31 patients with follicular or mantle-cell lymphoma were treated with 375 mg/m2 of rituximab once a week for 4 weeks at a median of 63 days after autologous SCT. At a median follow-up of 24 months, 29 patients remained in clinical remission. In that study, there were no detectable clonal cells in 22% of patients before they underwent high-dose chemotherapy. This number increased to 53% after the conditioning regimen, to 72% 4 weeks after rituximab, and to 100% 6 months after SCT. However, it remains to be seen whether the improvement in response seen with rituximab in the setting of autologous SCT indicates an improvement in disease eradication or simply a delay in time to relapse for some patients. Longer follow-up is needed to be able to answer this question.
In our study, we identified serum LDH as the only prognostic factor for OS or progression. Patients with de novo or transformed histologies of DBLCL had a comparable outcome (Table 3). It has been suggested by Mounier et al30 that rituximab is able to prevent failure of cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with DBLCL with bcl-2 protein overexpression but not in patients who tested negative for bcl-2. In our study, we were not able to address the impact of bcl-2 and outcome after autologous SCT with rituximab because of insufficient information about bcl-2 expression in both the study and control groups at the time this analysis was undertaken.
In conclusion, HD-R in conjunction with standard high-dose chemotherapy and autologous SCT was efficacious and generally well tolerated by patients with relapsed or refractory NHL and led to improved OS and DFS rates compared with control patients who did not receive rituximab. Further follow-up is needed to confirm the effects of this therapy on long-term survival. These encouraging results provide the rationale for conducting prospective, randomized trials of rituximab and rituximab dosing in patients who undergo autologous SCT for CD20-positive lymphomas.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by a research grant from Berlex (Seattle, WA).
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
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ABSTRACT
PURPOSE: We investigated the efficacy and safety of administering high-dose rituximab (HD-R) in combination with high-dose carmustine, cytarabine, etoposide, and melphalan chemotherapy and autologous stem-cell transplantation (SCT) in patients with recurrent B-cell aggressive non-Hodgkin’s lymphoma (NHL).
PATIENTS AND METHODS: Sixty-seven consecutive patients were treated. Rituximab was administered during stem-cell mobilization (1 day before chemotherapy at 375 mg/m2 and 7 days after chemotherapy at 1,000 mg/m2), together with granulocyte colony-stimulating factor 10 μg/kg and granulocyte-macrophage colony-stimulating factor 250 μg/m2 administered subcutaneously daily. HD-R of 1,000 mg/m2 was administered again days 1 and 8 after transplantation. The results of this treatment were retrospectively compared with those of a historical control group receiving the same preparative regimen without rituximab.
RESULTS: With a median follow-up time for the study group of 20 months, the overall survival rate at 2-years was 80% (95% CI, 65% to 89%) for the study group and 53% (95% CI, 34% to 69%) for the control group (P = .002). Disease-free survival was 67% (95% CI, 51% to 79%) for the study group and 43% (95% CI, 26% to 60%) for the control group (P = .004). The median time to recovery of absolute neutrophil count to 500 cells/μL was 11 days (range, 8 to 37 days) for the rituximab group and 10 days (range, 8 to 17 days) for the matched control group (P = .001). However, infections were not significantly increased in patients treated with rituximab.
CONCLUSION: The results of this study suggest that using HD-R and autologous SCT is a feasible and promising treatment for patients with B-cell aggressive NHL.
INTRODUCTION
Recurrent non-Hodgkin’s lymphoma (NHL) has a poor prognosis with conventional chemotherapy.1 Despite intensive research with novel chemotherapy regimens, patients with recurrent disease typically have only a transient response to salvage therapies and ultimately succumb to their disease. The incidence of NHL has been increasing in the United States over the past 30 years, and NHL is currently the fifth leading cause of cancer-related death in men in the United States.2
High-dose chemotherapy followed by autologous stem-cell transplantation (SCT) has been frequently used for patients with relapsed, aggressive, chemosensitive NHL. In patients with histologically aggressive diseases, overall survival (OS) and progression-free survival rates of approximately 60% and 40%, respectively, have been reported.3-8 Most treatment failures after transplantation can be ascribed to disease relapse, which usually occurs within 1 to 2 years of transplantation. New strategies designed to reduce the incidence of relapse after autologous SCT must take into consideration patients’ limited hematopoietic reserve during the early posttransplantation period.
Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA) is an anti-CD20 human-mouse chimeric monoclonal antibody indicated for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL. The use of rituximab as a single agent results in impressive response rates and durations of response in patients with indolent NHL and improves efficacy when used in combination with chemotherapy for both indolent and aggressive NHL.9-13 Responses to rituximab treatment vary by the histologic subtype of NHL. In patients with low-grade follicular lymphoma, response rates are approximately 70% to 75% with first-line treatment and 50% to 60% in relapsed follicular lymphoma. In contrast, in patients with diffuse B-cell large-cell lymphoma (DBLCL), single-agent rituximab response rates of 30% to 40% have been reported. Rituximab significantly increases response rates when used in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone.14,15
Recent studies have suggested that higher doses16 or more doses17,18 of rituximab may increase the response rate. CD20 is not expressed by hematopoietic stem cells, and therefore, we hypothesized that rituximab treatment would not inhibit engraftment produced by these early progenitors. Treatment with high-dose rituximab (HD-R) may successfully eliminate minimal residual disease, further delaying or preventing disease relapse and potentially extending the duration of survival after autologous SCT. Therefore, the objectives of the current study were to evaluate the impact of rituximab on toxicity, disease-free survival (DFS), and OS when added before and after high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) chemotherapy and autologous SCT in patients with aggressive NHL.
PATIENTS AND METHODS
Patients
Patients with aggressive large-cell, follicular or diffuse, B-cell CD20-positive lymphoma whose disease had relapsed after conventional chemotherapy were eligible for enrollment. Other inclusion criteria were age 65 years, a Zubrod performance status score of 2, and less than 10% bone marrow involvement on gross pathologic examination after cytoreduction with conventional chemotherapy.
Exclusion criteria were HIV or human T-cell leukemia virus type 1 seropositivity, pregnancy, left ventricular ejection fraction less than 50%, active CNS involvement, serum creatinine more than 1.6 mg/dL or serum bilirubin more than 1.5 mg/dL (unless a result of NHL), absolute neutrophil count less than 1,000 cells/μL and platelets less than 100,000/μL (unless secondary to tumor), diffusing capacity of the lung for carbon monoxide less than 50% of the predicted value, and severe concomitant medical or psychiatric illness.
The treatment was reviewed and approved by the Institutional Review Board of The University of Texas M.D. Anderson Cancer Center. Written informed consent was obtained from all patients.
Clinical Evaluation
Disease stage was evaluated using Ann Arbor criteria and assigned an International Prognostic Index (IPI) score.19 All cases were reviewed by an experienced hematopathologist for diagnostic confirmation. All patients underwent the following staging procedures: physical examination, CBC with differential count, serum chemistry panel, serum beta2-microglobulin measurement, chest radiography, computed tomography of the abdomen and pelvis, gallium scanning, and bilateral bone marrow aspiration and biopsies. Patients were evaluated after 1, 3, 6, and 12 months and every 6 months thereafter. Patients were assessed more frequently at the discretion of their primary physician.
Clinical assessments after SCT included time to hematopoietic recovery, posttransplantation response rate, OS, DFS, and adverse events. Time to neutrophil count recovery was defined as the first of 3 consecutive days when the absolute neutrophil count was 500 cells/μL, and platelet count recovery was defined as the first day after transplantation when the platelet count was 20,000/μL (independent of platelet transfusions). Responses were scored using the standard criteria for patients with lymphoma as described by Cheson et al.20
Autologous Stem-Cell Collection
Rituximab (375 mg/m2) was infused 1 day before chemotherapy. Stem cells were then mobilized with either cyclophosphamide (4 to 7 g/m2) in 34 patients or ifosfamide (3.33 g/m2 daily for 3 days) plus etoposide (150 mg/m2 twice a day [bid] for 3 days) in 33 patients. After chemotherapy, patients were treated daily with granulocyte colony-stimulating factor (G-CSF; 10 μg/kg subcutaneously) and granulocyte-macrophage colony-stimulating factor (GM-CSF; 250 μg/m2 subcutaneously), and rituximab was again administered 7 days after chemotherapy at 1,000 mg/m2. Stem cells were then collected from peripheral blood according to standard techniques.
Preparative Regimen for SCT
The preparative regimen for SCT was standard BEAM therapy (carmustine 300 mg/m2 by 1-hour intravenous [IV] infusion on day –6, cytarabine 200 mg/m2 IV bid on days –5 through –2 for a total of eight doses, etoposide 200 mg/m2 IV bid on days –5 through –2 for a total of eight doses, and melphalan 140 mg/m2 IV on day –1). Rituximab (1,000 mg/m2) was administered to all patients in the rituximab study group 1 and 8 days after SCT. Patients received GM-CSF 250 μg/m2 subcutaneously daily, beginning on day 0 until hematologic recovery.
Historic Control Group
Patient data and treatment results were retrospectively compared with those of 30 consecutive patients treated at M.D. Anderson Cancer Center for aggressive large-cell, follicular or diffuse, B-cell NHL with autologous SCT under a protocol that immediately preceded our study. Patients in the control group were treated between June 1994 and November 1996 and were previously reported.21 Patients with T-cell phenotyping were excluded. This group had received similar initial and salvage chemotherapy as the study group but had not received rituximab. They had their stem cells mobilized with ifosfamide plus etoposide, with the same schedule and dosages as in the study group, and G-CSF. They then received the same BEAM regimen with G-CSF but did not receive rituximab or GM-CSF.
Statistical Methods
Patient characteristics in the study and control groups were compared using 2 and Fisher’s exact tests for categoric variables and the Mann-Whitney rank sum test for continuous variables. Actuarial rates of survival, disease progression, and DFS were estimated from the day of SCT using the Kaplan-Meier method and compared with the rates of patients in the control group using the log-rank test. A comprehensive multivariate analysis to evaluate the effect of adding HD-R to the preparative regimen independently of patient and disease characteristics was not possible in this study because of the small sample size. The Cox proportional hazards model was used to evaluate prognostic factors for disease progression in the study group. Statistical significance was defined as P .05. The statistical analysis was performed using STATA 7.0 software (Stata Corp, College Station, TX).
RESULTS
Patients
Between June 2000 and July 2003, 67 consecutive patients at M.D. Anderson Cancer Center were treated with the study regimen; these patients are referred to as the rituximab study group. Patient demographics and baseline disease characteristics of the study and control groups are listed in Table 1.
Patients in the study group ranged in age from 20 to 65 years (median, 51 years). Most patients (55%) were men. Forty-one patients had de novo DBLCL, and 26 patients had aggressive lymphomas that had a follicular component (discordant, transformed, or follicular large). All patients had undergone salvage therapy for chemosensitive disease before stem-cell mobilization. In 59 patients (88%), rituximab was combined with salvage chemotherapy. The last dose of rituximab was administered a median of 38 days (range, 19 to 374 days) before study entry.
There were 30 patients in the control group. Seventeen patients had de novo DBLCL, and 13 patients had aggressive lymphoma that had a follicular component. Patient and disease characteristics were comparable in the study and control groups, with the exception of disease status at transplantation, IPI score at transplantation, and serum lactate dehydrogenase (LDH) level at transplantation favoring the control group. Most patients in the control group (80%) had sensitive disease in first relapse or second complete remission compared with 51% of patients in the rituximab group (P = .01). Twenty four patients (36%) in the study group were in primary induction failure, and 10 (42%) of these patients received three or more chemotherapy regimens before study entry. All patients in the control group had an IPI score 1, whereas 18% of patients who underwent HD-R treatment had a score of more than 1 (P < .01). In addition, only four patients (13%) in the control group had an elevated LDH level compared with 14 patients (21%) in the study group (P = .3; Table 1).
Engraftment
Peripheral-blood progenitors cells were the source of the autologous grafts in all patients in the study and control groups. Six patients in the study group received both blood and marrow cells. The inadequate stem-cell mobilization in these six patients was the underlying cause of changing the chemotherapy used for stem-cell mobilization in the study group from cyclophosphamide to the ifosfamide plus etoposide regimen used in all of the controls.
We intentionally infused a lesser amount of stem cells in our recent protocols. Therefore, the median number of CD34-positive cells infused was more than 2.5-fold higher in the control group than in the rituximab study group (Table 2). The median time to recovery of absolute neutrophil count to 500 cells/μL was 11 days (range, 8 to 37 days) for the rituximab group and 10 days (range, 8 to 17 days) for the matched control group, which was a significant difference (P = .001).
The median time to complete lymphocyte recovery ( 500/μL) did not differ significantly between the rituximab study group and the control group (median, 20 days; range, 10 to 164 days in the study group v median, 17 days; range, 9 to 109 days in the control group; P = .3). However, the median time to platelet recovery to 20,000/μL was 11 days (range, 6 to 100 days) for patients who received HD-R; this was significantly longer than the median of 9 days (range, 6 to 16 days) for matched controls (P = .05).
The engraftment analysis included five patients who had prolonged cytopenia after SCT. Three cases were attributed to poor mobilization of blood stem cells, one was associated with cytomegalovirus infection, and one was attributed to the use of trimethoprim and sulfamethoxazole. Two other patients had a transient neutropenia that lasted for 3 days (at 4 months after SCT in one patient and 7 months after SCT in the other patient). Both cases were related to infections, and a prompt response to G-CSF was observed in both patients.
Efficacy
Sixty-one patients (91%) in the rituximab study group experienced a complete response, and five patients (8%) achieved a partial response after SCT. One patient (1%) had stable disease. The median follow-up time of all patients was 20 months (range, 2 to 42 months) in the study group and 30 months (range, 2 to 99 months) in the control group. Comparison of outcomes was conducted at 2 years after SCT to ensure comparable follow-up times.
Disease progression was the major cause of treatment failure for both groups, but significantly fewer patients treated with rituximab experienced progression after transplantation compared with controls. The progression rate at 2 years was 33% (95% CI, 21% to 48%) for the study group and 52% (95% CI, 35% to 71%) for the control group (P = .02). Only one treatment failure occurred after 2 years in the study group, and it was related to myelodysplasia. The actuarial DFS rate at 2 years was 67% (95% CI, 51% to 79%) for the study group and 43% (95% CI, 26% to 60%) for the control group (P = .004; Fig 1). The actuarial survival rate was 80% (95% CI, 65% to 89%) for the rituximab study group and 53% (95% CI, 34% to 69%) for the control group (P = .002; Fig 2).
Prognostic Factors
On univariate analysis, an elevated LDH level (> 618 U/L) was the only significant prognostic factor for disease progression (hazard ratio [HR] = 3.3; 95% CI, 1.3 to 8.9) and survival (HR = 4.1; 95% CI, 1.3 to 12.6; Table 3). The remaining IPI components did not add further prognostic value. We observed no significant effects for age, sex, disease status at transplantation, number of prior chemotherapy regimens, histology (de novo or transformed DBLCL), beta2-microglobulin level, the number of extranodal sites, or time to recovery of lymphocytes to 300 or 500/μL (categorized at the median of 16 and 20 days, respectively, or as quartiles).
Because LDH level at transplantation was the only significant prognostic factor for both disease progression and mortality in the study group, we compared the rate of progression separately for patients with high and low LDH in the study group to the rate in the control group (Fig 3). Patients with elevated LDH levels in the study group had a rate of progression comparable to all patients in the control group (HR = 0.9; P = .9), whereas patients with low LDH levels had a significantly lower rate of progression (HR = 0.3; P = .005). The HRs were similar when we excluded the four patients with high LDH levels from the control group.
Safety
Overall, safety and tolerability were similar for the HD-R and control groups, with no significant differences between groups in infections or toxicity. All patients had hematopoietic recovery, and there was no treatment-related mortality in either group. Overall, 25 episodes of bacterial infections occurred in the 67 patients comprising the rituximab group versus 14 infections in the 30 control patients (P = .4). Five patients in the study group and none of the controls (P = .3) developed a reactivation of cytomegalovirus infection; all of the patients responded to therapy, and no patient had cytomegalovirus disease.
DISCUSSION
Our results suggest that high dosages of rituximab administered to patients with aggressive B-cell NHL before and after autologous SCT can significantly increase OS and DFS rates compared with traditional high-dose conditioning regimens without rituximab. This improvement occurred without increasing the risk of infection or toxicity, and the treatment-related mortality rate was 0% in both groups of patients. The small number of patients in the control group did not allow evaluation of the independent effect of the regimen in a multivariate analysis; yet patient characteristics were comparable in the two groups, with the exception of the IPI score, LDH level, and disease status at SCT, which favored the control group.
One difference between the study and historical control groups was the use of rituximab during salvage chemotherapy in the rituximab study patients; the use of rituximab before stem-cell collection and transplantation may also have contributed to the favorable outcome in the study group. However, in a recent study,22 the outcome after autologous transplantation was not statistically significant from controls when the addition of rituximab was limited to salvage chemotherapy used in preparation for transplantation and was not administered after the transplantation itself.
The results of several trials of rituximab administered before stem-cell collection and after SCT indicate that this approach is safe in terms of mobilization and engraftment.23-29 Tumor-cell contamination in the stem-cell product can be reduced with rituximab, and an increase in molecular remission after transplantation has been suggested. However, most of these trials involved patients with follicular or mantle-cell lymphoma. Thus, our report may represent the first study suggesting that the addition of rituximab before and after conventional SCT is associated with superior results in patients with aggressive B-cell NHL.
The standard dosage of rituximab is 375 mg/m2 once a week for 4 weeks. However, in what is considered the pivotal trial of rituximab in patients with indolent NHL,9 median serum antibody levels were higher in responding patients than in nonresponders (502.8 and 412.4 mg/μL, respectively; P = .001). Therefore, several investigators have evaluated modifications to the dosing schedule. Alternative approaches included higher doses16 or a greater number of doses.17,18 Higher response rates have been observed with these strategies. Piro et al18 conducted a phase II trial in which eight weekly infusions of rituximab were evaluated in patients with refractory or relapsed indolent NHL. Among 35 assessable patients, 14% experienced a complete response, and 46% experienced a partial response. Patients with bulky disease also experienced disease response, including 25% of patients with lesions larger than 7 cm. This initiated our use of a higher dose of rituximab in our study. The effectiveness of HD-R was indirectly shown by Magni et al,23 who used rituximab for in vivo purging of autologous stem-cell collection before SCT for follicular and mantle-cell lymphoma. In that study, 33% of the collected stem cells had no clonal cells detected by polymerase chain reaction assay after one course of in vivo treatment with rituximab. After the second course of treatment, 93% of cells were lymphoma free compared with 40% of cells in the control group treated with chemotherapy alone for mobilization. However, controlled studies with pharmacokinetics are needed to determine the optimal dosage and schedule of rituximab in patients who undergo autologous SCT.
Benekli et al29 reported a significantly higher bacterial infection rate in rituximab-treated patients than in patients who did not receive rituximab. Other researchers have demonstrated that the immunosuppressive effects of rituximab slightly delay immune recovery; however, these delays do not result in an increased incidence of posttransplantation infection.26 The increased rate of posttransplantation infections seen in our study was not statistically significant, despite the use of HD-R. The delayed recovery of peripheral-blood counts in the rituximab-treated group may be confounded by the higher number of stem cells infused in the control group and the different supportive growth factors used after transplantation.
The improvement in outcome observed with the addition of rituximab before and after SCT seems to be related mostly to a significant decrease in the rate of disease progression that usually occurs within 1 to 2 years of transplantation. Brugger et al27 demonstrated that additional clinical and molecular responses were noted for several months after the discontinuation of rituximab. In their study, 31 patients with follicular or mantle-cell lymphoma were treated with 375 mg/m2 of rituximab once a week for 4 weeks at a median of 63 days after autologous SCT. At a median follow-up of 24 months, 29 patients remained in clinical remission. In that study, there were no detectable clonal cells in 22% of patients before they underwent high-dose chemotherapy. This number increased to 53% after the conditioning regimen, to 72% 4 weeks after rituximab, and to 100% 6 months after SCT. However, it remains to be seen whether the improvement in response seen with rituximab in the setting of autologous SCT indicates an improvement in disease eradication or simply a delay in time to relapse for some patients. Longer follow-up is needed to be able to answer this question.
In our study, we identified serum LDH as the only prognostic factor for OS or progression. Patients with de novo or transformed histologies of DBLCL had a comparable outcome (Table 3). It has been suggested by Mounier et al30 that rituximab is able to prevent failure of cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with DBLCL with bcl-2 protein overexpression but not in patients who tested negative for bcl-2. In our study, we were not able to address the impact of bcl-2 and outcome after autologous SCT with rituximab because of insufficient information about bcl-2 expression in both the study and control groups at the time this analysis was undertaken.
In conclusion, HD-R in conjunction with standard high-dose chemotherapy and autologous SCT was efficacious and generally well tolerated by patients with relapsed or refractory NHL and led to improved OS and DFS rates compared with control patients who did not receive rituximab. Further follow-up is needed to confirm the effects of this therapy on long-term survival. These encouraging results provide the rationale for conducting prospective, randomized trials of rituximab and rituximab dosing in patients who undergo autologous SCT for CD20-positive lymphomas.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by a research grant from Berlex (Seattle, WA).
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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