- Email: [email protected]
Outpatient regimen rituximab plus ifosfamide, carboplatin and etoposide (R-ICE) for relapsed non-Hodgkin’s lymphoma
Annals of Oncology 14 (Supplement 1): i17–i20, 2003 DOI: 10.1093/annonc/mdg704
Symposium article
Outpatient regimen rituximab plus ifosfamide, carboplatin and etoposide (R-ICE) for relapsed non-Hodgkin’s lymphoma J. Vose1* & V. Sneller2 1
University of Nebraska Medical Center, Omaha, NE, USA; 2Baxter Oncology GmbH, Frankfurt, Germany
Introduction
*Correspondence to: Dr Julie Vose, 987680 University of Nebraska Medical Center, Omaha, NE 68198-7680, USA. Tel: +1-402-559-3848; Fax: +1-402-559-6520; E-mail: [email protected] © 2003 European Society for Medical Oncology
Patients and methods Twenty-eight patients with histologically confirmed recurrent or refractory CD20+ B cell NHL were included in the study. Twelve patients had diffuse large B cell lymphoma, six transformed follicular lymphoma, two Burkitt’s, one mantle cell, one small lymphocytic and six composite aggressive lymphomas. The median age was 59 years (range 33–75). The male to female ratio was 18:10. All 28 patients had previously received one doxorubicin-containing regimen, with or without local radiotherapy. At the time of entry into the study, these patients had progression of disease requiring treatment that occurred either after an initial partial response (PR; seven patients), a CR that lasted <1 year (four patients) or a CR that lasted >1 year (nine patients). Seven patients were primary refractory, and for one patient the data were not available at the time of analysis. Additional criteria for study entry included an Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 or a Karnofsky performance status >70, and evidence of adequate cardiac, pulmonary, hepatic and renal function. No prior bone marrow or peripheral blood stem cell transplantation was allowed, nor concurrent radiotherapy. Transplant protocols were approved by the Institutional Review Boards at each institution. Informed consent was provided according to the Declaration of Helsinki. Patients received rituximab 375 mg/m2 i.v. on days 1, 7 and 14, and ifosfamide 2 g/m2 i.v. over 1 h on days 2–4, etoposide 75 mg/m2 i.v. over 2 h on days 2–4, and carboplatin i.v. [area under the curve (AUC) = 5, maximum 350 mg/m2] on days 2–4 (Table 1). Mesna dose was 60% of ifosfamide dose on the days of treatment with ifosfamide. After the end of ifosfamide infusion two additional doses of mesna (40% of ifosfamide dose) were given orally at 2 and 6 h. The regimen was repeated every 21 days for at least two courses in the absence of disease progression or unacceptable toxicity. Growth factors
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Approximately 1.5 million people worldwide are living with various forms of lymphoma, and it is estimated that 300 000 people will die each year. In terms of incidence and mortality, non-Hodgkin’s lymphoma (NHL) is the second fastest growing cancer in the USA and the third fastest growing in the rest of the world. Each year ∼60 000 people in the USA will be diagnosed with NHL. More than half of the patients with aggressive lymphoma are either primary refractory or, more often, relapse after their initial treatment. It has been shown that high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) does improve survival in patients treated in the first relapse [1]. Second-line chemotherapy regimens for relapsing patients with lymphoma generally include drugs not used during first-line therapy in order to avoid cross-resistant associations and cumulative toxicity. At the University of Nebraska Medical Center (UNMC), the ifosfamide, carboplatin and etoposide (ICE) regimen has been used for patients with relapsed aggressive NHL who are candidates for transplantation. As previously reported by Moskowitz et al. [2], this regimen has advantages of being effective for cytoreduction, results in minimal non-hematological toxicity, is not stem cell toxic and effectively mobilizes stem cells into peripheral blood. Hamlin et al. [3] showed that relapsed patients with diffuse large B cell lymphoma (DLBCL) and good risk disease [second-line age-adjusted international prognostic index (sAAIPI) I/II] are highly curable with ICE-based chemotherapy followed by high-dose chemotherapy and stem cell transplantation. Those patients may have a favorable long-term outcome and therefore need not be exposed to the risk of excessive toxicity of more intensive therapy. On the other hand, poor prognosis patients are candidates for more intensive therapies. Pilot trials using rituximab and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) have suggested an efficacy advantage in both indolent and aggressive B cell NHL, with no significant impact on toxicity. A more recently published randomized trial performed by the Groupe d’Étude des Lymphomes de l’Adulte (GELA) has shown that the addition of rituximab to the CHOP regimen increases the complete response (CR) rate and prolongs event-free survival (EFS) and overall survival
(OS) in untreated elderly patients with diffuse large B cell lymphoma when compared with CHOP alone [4]. Preliminary results from Memorial Sloan–Kettering Cancer Center with rituximab plus ifosfamide, carboplatin and etoposide (R-ICE) in relapsed patients are promising, but the regimen requires inpatient treatment [5]. In some centers in the USA, there is a great need for the development of an outpatient regimen that is effective, tolerable and easy to deliver. With the aim of further improving the clinical response and prolonging EFS and OS of patients with relapsed and refractory aggressive NHL, R-ICE was investigated at the UNMC as an outpatient protocol. The objectives of the study were to determine the chemosensitivity rate in patients with recurrent or refractory NHL treated with ICE in combination with rituximab (R-ICE) and to determine whether rituximab changes the toxicity profile of ICE chemotherapy regimen in these patients.
i18 Table 1. Rituximab plus ifosfamide, carboplatin and etoposide chemotherapy
Table 2. Toxicities in patients treated with rituximab plus ifosfamide, carboplatin and etoposide
Day 1 Rituximab 375 mg/m2 Ifosfamide 2 g/m2 + mesna Etoposide 75 mg/m
2
Carboplatin AUC 5 (maximum 350 mg/m2)
Toxicities 2
3
4
+
Cycles with grade 3–4 toxicities (%)
7
14
Fever
+
+
Neutropenia
75 (grade 4 in 57)
4
+
+
+
Anemia
18
+
+
+
Thrombocytopenia
49 (grade 4 in 12)
+
+
+
Nausea
2
+
+
+
Elevated creatinine
2
Repeat on day 21 if ANC >1500/µl and platelets >100 000/µl. ANC, absolute neutrophil count; AUC, area under the curve.
At the completion of two cycles of R-ICE, patients in CR or PR underwent stem cell collection followed by HDT/ASCT. All patients received the BCNU (bis-chloro-ethylnitrosourea), etoposide, cytarabine and melphalan (BEAM) high-dose consolidation regimen. Four patients received radiation post-transplant. Patients who were not eligible for ASCT received up to four cycles of R-ICE. Patients were transplanted at the University of Nebraska or at one of two other institutions. Staging evaluations were performed before transplantation, ∼100 days after transplantation and then at yearly intervals. Responses were assessed by full computerized tomography staging. Evaluation of responses was done using Cheson criteria. A sensitive relapse was defined as at least 50% reduction in the bidimensional measurements of the disease with the use of conventional salvage chemotherapy. A resistant relapse was defined as a <50% reduction in the size of the tumor mass with the use of conventional salvage chemotherapy following relapse from an initial complete remission. National Cancer Institute Common Toxicity Criteria (NCI CTC) were used to define toxicities. Transplant outcome was analyzed with respect to EFS and OS. Survival time was calculated from the date of the first rituximab dose until death from any cause or until last follow-up evaluation for patients who were still alive. EFS was calculated from the first rituximab dose until appearance of an event. An event was defined as death from any cause, progression or relapse after response. The survival distributions were calculated using the Kaplan–Meier product-limit estimate.
Results From September 2000 to September 2002, 28 patients with relapsed and refractory B cell NHL were enrolled in the study. In all 28 patients, R-ICE was administered as an outpatient therapy. After two cycles of R-ICE, seven patients (25%) achieved a CR and 13 patients achieved a PR (46%), for an overall response rate of 71%. Nineteen patients (68%) proceeded to stem cell transplantation, one patient after a single cycle of R-ICE and the others after two cycles of R-ICE. Twenty-two patients had chemosensitive disease and six had chemoresistant disease. Stem cell product and engraftment data are unavailable for three patients, one patient was transplanted at UNMC on September 2002 and two patients transplanted at other institutions. The
median number of CD34+ stem cells infused among evaluable transplanted patients (n = 16) was 4.4 × 106 CD34+ cells/kg body wt (range 1.2–37.6). Median time for platelets to reach 20 000/µl was 12 days. Median time for the absolute neutrophil count (ANC) to reach 500/µl was 11 days. All patients achieved ANC >500/µl and platelet transfusion independence. Median time to reach red blood cell (RBC) independence was 10 days. Four patients remained RBC transfusion dependent, all other patients achieved RBC transfusion independence. The toxicities associated with the regimen were mild to moderate and consisted mostly of hematological toxicities (Table 2). Neutropenia and thrombocytopenia were the only reported grade 4 toxicities. Eight patients required admission to hospital. Four were hospitalized because of neutropenic fever and two because of progressive disease and the need for pain control. One patient was admitted to hospital for acute renal failure, which was likely related to the use of CT contrast media, previous treatment with cisplatin and hydronephrosis. One patient was hospitalized because of an attempted suicide. One patient developed mild neurotoxicity that resolved quickly after discontinuation of ifosfamide and administration of methylene blue. Median follow-up of surviving patients was 15 months (range 3–24) from the start of R-ICE chemotherapy. Eleven patients progressed and nine died (all from progressive disease). Twelve of 28 patients experienced an event at a median of 16 months after the first rituximab dose. The estimated 1-year EFS rate among all patients is 60%. Nine of 28 patients have died, but median OS has not been reached. The estimated 1-year survival rate among all patients is 72%. Among the 19 patients who proceeded to transplant, six experienced an event. The median EFS has not been reached and the estimated 1-year EFS among transplanted patients is 70%. Four of 19 transplanted patients have died. The median OS has not been reached and the estimated 1-year OS rate is 82% (for a summary of the survival data, see also Table 3).
Discussion The results of treatment of aggressive NHL are still not satisfactory for relapsed high-risk patients, primary refractory patients and patients who fail to achieve remission, independent of type of
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were not used prophylactically. Stem cells were collected using granulocyte colony-stimulating factor (filgrastim) at a dose of 10 µg/kg, starting from day +4 after the second chemotherapy cycle.
i19 Table 3. One-year EFS and OS in patients treated with rituximab plus ifosfamide, carboplatin and etoposide 1-year EFS
1-year OS
All patients (n = 28)
60%
72%
Transplanted patients (n = 19)
70%
82%
EFS, event-free survival; OS, overall survival.
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regimen used. Patients with poor risk disease (sAAIPI III/IV), would benefit from more aggressive innovative therapy and should be included in clinical trials in order to improve their outcome. New alternative regimens include the addition of monoclonal antibodies such as rituximab, radioimmunotherapy, the use of novel chemotherapeutic agents or modifications in the administration of agents which may improve the response rates and the ability of patients to go on transplantation. With an aim to increase response rates, the monoclonal antibody rituximab was added to the ICE regimen in CD20+ relapsed and refractory NHL. In this study R-ICE was found to be a highly effective regimen for cytoreduction and mobilization, especially when considering that more than half of the patients in this series had unfavorable lymphoma subtypes (mantle cell, transformed lymphoma, composite aggressive lymphoma and Burkitt’s lymphoma) or unfavorable disease characteristics. The UNMC strategy is to proceed with the transplant as soon as responses, either complete or partial, have been achieved. In this study the overall response rate of 70% was achieved by using only two cycles of R-ICE, including one patient who proceeded to transplantation after only one cycle. The rapid response induction and high overall response rate suggest that rituximab may enhance the activity of ICE. With the addition of rituximab to ICE in a population that is less responsive to traditional salvage regimens, we have been able to achieve response rates comparable with those usually seen in populations that respond well. It is difficult to compare outpatient R-ICE with other rituximab-containing salvage regimens for relapsed lymphomas, because different patient groups were included in small series. Some limited comparison is possible with the study reported by Jost et al. [6], since patients in both studies have similar clinical characteristics. The CR and PR rates with rituximab plus etoposide, prednisolone, vincristine, doxorubicin and cyclophosphamide (R-EPOCH) were 23% and 69%, respectively. Kewalramani et al. [5] reported an overall response rate of 80% when using an inpatient R-ICE regimen for the treatment of relapsed and refractory DLBCL. Ifosfamide 5 g/m2 was been administered in 24-h continuous infusion. The results suggested that the addition of rituximab to ICE (R-ICE) may double the CR rate achieved by using ICE alone, with no significant additive toxicity or impairment of stem cell collection. The overall response rate in relapsed patients was 96%, with 70% CRs, and in refractory patients 46% and 31%, respectively. Furthermore, whereas the second-line international prognostic index (sIPI) predicts response to ICE, the adverse features of the sIPI appear to be overcome by R-ICE. The difference in responses observed by using two similar R-ICE regimens may be due to the fact that this study involved a heterogeneous population with less than
half of the patients having DLBCL and the fact that patients in this study received less cycles of chemotherapy before transplantation. The R-ICE regimen as reported by Kewalramani et al. [5] was tested in DLBCL patients only. A CR rate of 60% achieved with the paclitaxel plus topotecan and rituximab (TTR) combination in relapsed patients and of 25% in those with primary refractory aggressive lymphomas were reported by Younes et al. [7]. The TTR regimen, although effective for cytoreduction, has not been used for mobilization. After two cycles of TTR, patients must receive one or two additional cycles of ifosfamide/etoposide regimen for mobilization purposes and transplantation is delayed for a few weeks. Compared with outpatient R-ICE, the TTR regimen with growth factor support is likely to be more toxic, more expensive, requires additional cycles of mobilization regimen for stem cell collection and delays the HDT for several weeks. By using ICE at a median follow-up of 12 months, EFS and OS for all patients enrolled in the study was 30% and 55%, respectively [2]. By using outpatient R-ICE the estimated 1-year EFS and OS therefore appears to be much better than by using ICE alone. This should be interpreted with caution, however, since this is not a randomized comparison. Wilson et al. [8] reported that by using R-EPOCH fever and neutropenia occurred in 20% of cycles, despite the concomitant use of growth factors in all patients. A high rate of neutropenia grade 4 (42%) has been observed for TTR resulting in 16% febrile episodes [7]. Again, all patients received growth factors prophylactically. Outpatient R-ICE had a comparable rate of grade 4 neutropenia, but the rate of febrile episodes was only 4%. Despite the observed rate of neutropenia, the R-ICE regimen can easily be given on an outpatient basis with the concomitant use of growth factors only when indicated. There were two treatment-related deaths reported for R-EPOCH [6]. In contrast, no treatment-related deaths have been reported so far for outpatient or inpatient R-ICE. The other non-hematological toxicities reported for outpatient R-ICE were remarkably mild. Bociek et al. [9] studied the relationship between ease of mobilization of peripheral blood progenitor cells and outcome after transplantation. The data suggested that patients with NHL who experience rapid mobilization (defined as >4 × 106 CD34+ cells/kg in a single collection) appeared to have a reduced risk of significant infection within 100 days after transplantation. As shown previously, the combined use of rituximab to chemotherapy may slightly deplete the number of CD34+ cells harvested, but numbers achieved in this study by using R-ICE are still high and resulted in excellent engraftment. Most of the above listed salvage regimens, including the R-ICE regimen developed by Kewalramani et al. [5], require hospitalization. Most of the drugs in the R-EPOCH regimen were given in a 96-h continuous infusion, which required at least 3 days of hospitalization. R-ICE as described in this study can be easily and safely given on an outpatient basis, which reduces the cost of the procedure. In conclusion, R-ICE is effective and well tolerated and can be administered in an outpatient setting. Two-thirds of patients can proceed with the transplantation after two cycles of R-ICE.
i20 The regimen allows collection of high-quality peripheral blood progenitor cells upon recovery for HDT and transplantation with excellent engraftment.
4. 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 2002; 346: 235–242.
Disclosure
5. Kewalramani T, Zelenetz A, Bertino J et al. Rituximab significantly increases the complete response rate in patients with relapsed or primary refractory DLBCL receiving ICE as second-line therapy (SLT). Abstract 1459, American Society of Hematology 43rd Annual Meeting, December 7–11, 2001, Orlando, FL.
Dr Vose reports no financial relationships with companies whose products are mentioned in the text. V.S. is an employee of Baxter Oncology GmbH.
References
7. Younes A, McLaughlin P, Hagemeister FB et al. High response rate and complete remission rate achieved by adding rituximab to taxol plus topotecan (TTR) with G-CSF support for the treatment of patients with relapsed/refractory aggressive B-cell lymphoma. Abstract 1456, American Society of Hematology 43rd Annual Meeting, December 7–11, 2001, Orlando, FL. 8. Wilson WH, Gutierrez M, O’Connor P et al. The role of rituximab and chemotherapy in aggressive B-cell lymphoma: a preliminary report of dose-adjusted EPOCH-R. Semin Oncol 2002; 29 (1 Suppl 2): 41–47. 9. Bociek RG, Lynch JC, Yee GC et al. Outcome and factors associated with slow mobilization of peripheral blood progenitor cells (PBPC) in patients undergoing autologous transplantation for non-Hodgkin’s lymphoma. Abstract 3575, American Society of Hematology 43rd Annual Meeting, December 7–11, 2001, Orlando, FL.
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1. 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 1995; 333: 1540–1545. 2. Moskowitz CH, Bertino JR, Glassman JR et al. Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin’s lymphoma. J Clin Oncol 1999; 17: 3776–3785. 3. Hamlin PA, Zelenetz AS, Nimer SD et al. The age-adjusted international prognostic index (AAIPI) predicts outcome following autologous stem cell transplantation (ASCT) in patients (PTS) with relapsed and primary refractory diffuse large B-cell lymphoma (DLBCL). Ann Oncol 2002; 13 (Suppl 2): 75 (Abstr 250).
6. Jost LM, Jermann M, Stahel RA et al. Rituximab–EPOCH: an effective salvage regime for relapsed, refractory, or transformed B-cell lymphoma. Results of a phase II study. Proc Am Soc Clin Oncol 2001; 20; 290 (Abstr 1157).
Symposium article
Outpatient regimen rituximab plus ifosfamide, carboplatin and etoposide (R-ICE) for relapsed non-Hodgkin’s lymphoma J. Vose1* & V. Sneller2 1
University of Nebraska Medical Center, Omaha, NE, USA; 2Baxter Oncology GmbH, Frankfurt, Germany
Introduction
*Correspondence to: Dr Julie Vose, 987680 University of Nebraska Medical Center, Omaha, NE 68198-7680, USA. Tel: +1-402-559-3848; Fax: +1-402-559-6520; E-mail: [email protected] © 2003 European Society for Medical Oncology
Patients and methods Twenty-eight patients with histologically confirmed recurrent or refractory CD20+ B cell NHL were included in the study. Twelve patients had diffuse large B cell lymphoma, six transformed follicular lymphoma, two Burkitt’s, one mantle cell, one small lymphocytic and six composite aggressive lymphomas. The median age was 59 years (range 33–75). The male to female ratio was 18:10. All 28 patients had previously received one doxorubicin-containing regimen, with or without local radiotherapy. At the time of entry into the study, these patients had progression of disease requiring treatment that occurred either after an initial partial response (PR; seven patients), a CR that lasted <1 year (four patients) or a CR that lasted >1 year (nine patients). Seven patients were primary refractory, and for one patient the data were not available at the time of analysis. Additional criteria for study entry included an Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 or a Karnofsky performance status >70, and evidence of adequate cardiac, pulmonary, hepatic and renal function. No prior bone marrow or peripheral blood stem cell transplantation was allowed, nor concurrent radiotherapy. Transplant protocols were approved by the Institutional Review Boards at each institution. Informed consent was provided according to the Declaration of Helsinki. Patients received rituximab 375 mg/m2 i.v. on days 1, 7 and 14, and ifosfamide 2 g/m2 i.v. over 1 h on days 2–4, etoposide 75 mg/m2 i.v. over 2 h on days 2–4, and carboplatin i.v. [area under the curve (AUC) = 5, maximum 350 mg/m2] on days 2–4 (Table 1). Mesna dose was 60% of ifosfamide dose on the days of treatment with ifosfamide. After the end of ifosfamide infusion two additional doses of mesna (40% of ifosfamide dose) were given orally at 2 and 6 h. The regimen was repeated every 21 days for at least two courses in the absence of disease progression or unacceptable toxicity. Growth factors
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Approximately 1.5 million people worldwide are living with various forms of lymphoma, and it is estimated that 300 000 people will die each year. In terms of incidence and mortality, non-Hodgkin’s lymphoma (NHL) is the second fastest growing cancer in the USA and the third fastest growing in the rest of the world. Each year ∼60 000 people in the USA will be diagnosed with NHL. More than half of the patients with aggressive lymphoma are either primary refractory or, more often, relapse after their initial treatment. It has been shown that high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) does improve survival in patients treated in the first relapse [1]. Second-line chemotherapy regimens for relapsing patients with lymphoma generally include drugs not used during first-line therapy in order to avoid cross-resistant associations and cumulative toxicity. At the University of Nebraska Medical Center (UNMC), the ifosfamide, carboplatin and etoposide (ICE) regimen has been used for patients with relapsed aggressive NHL who are candidates for transplantation. As previously reported by Moskowitz et al. [2], this regimen has advantages of being effective for cytoreduction, results in minimal non-hematological toxicity, is not stem cell toxic and effectively mobilizes stem cells into peripheral blood. Hamlin et al. [3] showed that relapsed patients with diffuse large B cell lymphoma (DLBCL) and good risk disease [second-line age-adjusted international prognostic index (sAAIPI) I/II] are highly curable with ICE-based chemotherapy followed by high-dose chemotherapy and stem cell transplantation. Those patients may have a favorable long-term outcome and therefore need not be exposed to the risk of excessive toxicity of more intensive therapy. On the other hand, poor prognosis patients are candidates for more intensive therapies. Pilot trials using rituximab and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) have suggested an efficacy advantage in both indolent and aggressive B cell NHL, with no significant impact on toxicity. A more recently published randomized trial performed by the Groupe d’Étude des Lymphomes de l’Adulte (GELA) has shown that the addition of rituximab to the CHOP regimen increases the complete response (CR) rate and prolongs event-free survival (EFS) and overall survival
(OS) in untreated elderly patients with diffuse large B cell lymphoma when compared with CHOP alone [4]. Preliminary results from Memorial Sloan–Kettering Cancer Center with rituximab plus ifosfamide, carboplatin and etoposide (R-ICE) in relapsed patients are promising, but the regimen requires inpatient treatment [5]. In some centers in the USA, there is a great need for the development of an outpatient regimen that is effective, tolerable and easy to deliver. With the aim of further improving the clinical response and prolonging EFS and OS of patients with relapsed and refractory aggressive NHL, R-ICE was investigated at the UNMC as an outpatient protocol. The objectives of the study were to determine the chemosensitivity rate in patients with recurrent or refractory NHL treated with ICE in combination with rituximab (R-ICE) and to determine whether rituximab changes the toxicity profile of ICE chemotherapy regimen in these patients.
i18 Table 1. Rituximab plus ifosfamide, carboplatin and etoposide chemotherapy
Table 2. Toxicities in patients treated with rituximab plus ifosfamide, carboplatin and etoposide
Day 1 Rituximab 375 mg/m2 Ifosfamide 2 g/m2 + mesna Etoposide 75 mg/m
2
Carboplatin AUC 5 (maximum 350 mg/m2)
Toxicities 2
3
4
+
Cycles with grade 3–4 toxicities (%)
7
14
Fever
+
+
Neutropenia
75 (grade 4 in 57)
4
+
+
+
Anemia
18
+
+
+
Thrombocytopenia
49 (grade 4 in 12)
+
+
+
Nausea
2
+
+
+
Elevated creatinine
2
Repeat on day 21 if ANC >1500/µl and platelets >100 000/µl. ANC, absolute neutrophil count; AUC, area under the curve.
At the completion of two cycles of R-ICE, patients in CR or PR underwent stem cell collection followed by HDT/ASCT. All patients received the BCNU (bis-chloro-ethylnitrosourea), etoposide, cytarabine and melphalan (BEAM) high-dose consolidation regimen. Four patients received radiation post-transplant. Patients who were not eligible for ASCT received up to four cycles of R-ICE. Patients were transplanted at the University of Nebraska or at one of two other institutions. Staging evaluations were performed before transplantation, ∼100 days after transplantation and then at yearly intervals. Responses were assessed by full computerized tomography staging. Evaluation of responses was done using Cheson criteria. A sensitive relapse was defined as at least 50% reduction in the bidimensional measurements of the disease with the use of conventional salvage chemotherapy. A resistant relapse was defined as a <50% reduction in the size of the tumor mass with the use of conventional salvage chemotherapy following relapse from an initial complete remission. National Cancer Institute Common Toxicity Criteria (NCI CTC) were used to define toxicities. Transplant outcome was analyzed with respect to EFS and OS. Survival time was calculated from the date of the first rituximab dose until death from any cause or until last follow-up evaluation for patients who were still alive. EFS was calculated from the first rituximab dose until appearance of an event. An event was defined as death from any cause, progression or relapse after response. The survival distributions were calculated using the Kaplan–Meier product-limit estimate.
Results From September 2000 to September 2002, 28 patients with relapsed and refractory B cell NHL were enrolled in the study. In all 28 patients, R-ICE was administered as an outpatient therapy. After two cycles of R-ICE, seven patients (25%) achieved a CR and 13 patients achieved a PR (46%), for an overall response rate of 71%. Nineteen patients (68%) proceeded to stem cell transplantation, one patient after a single cycle of R-ICE and the others after two cycles of R-ICE. Twenty-two patients had chemosensitive disease and six had chemoresistant disease. Stem cell product and engraftment data are unavailable for three patients, one patient was transplanted at UNMC on September 2002 and two patients transplanted at other institutions. The
median number of CD34+ stem cells infused among evaluable transplanted patients (n = 16) was 4.4 × 106 CD34+ cells/kg body wt (range 1.2–37.6). Median time for platelets to reach 20 000/µl was 12 days. Median time for the absolute neutrophil count (ANC) to reach 500/µl was 11 days. All patients achieved ANC >500/µl and platelet transfusion independence. Median time to reach red blood cell (RBC) independence was 10 days. Four patients remained RBC transfusion dependent, all other patients achieved RBC transfusion independence. The toxicities associated with the regimen were mild to moderate and consisted mostly of hematological toxicities (Table 2). Neutropenia and thrombocytopenia were the only reported grade 4 toxicities. Eight patients required admission to hospital. Four were hospitalized because of neutropenic fever and two because of progressive disease and the need for pain control. One patient was admitted to hospital for acute renal failure, which was likely related to the use of CT contrast media, previous treatment with cisplatin and hydronephrosis. One patient was hospitalized because of an attempted suicide. One patient developed mild neurotoxicity that resolved quickly after discontinuation of ifosfamide and administration of methylene blue. Median follow-up of surviving patients was 15 months (range 3–24) from the start of R-ICE chemotherapy. Eleven patients progressed and nine died (all from progressive disease). Twelve of 28 patients experienced an event at a median of 16 months after the first rituximab dose. The estimated 1-year EFS rate among all patients is 60%. Nine of 28 patients have died, but median OS has not been reached. The estimated 1-year survival rate among all patients is 72%. Among the 19 patients who proceeded to transplant, six experienced an event. The median EFS has not been reached and the estimated 1-year EFS among transplanted patients is 70%. Four of 19 transplanted patients have died. The median OS has not been reached and the estimated 1-year OS rate is 82% (for a summary of the survival data, see also Table 3).
Discussion The results of treatment of aggressive NHL are still not satisfactory for relapsed high-risk patients, primary refractory patients and patients who fail to achieve remission, independent of type of
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were not used prophylactically. Stem cells were collected using granulocyte colony-stimulating factor (filgrastim) at a dose of 10 µg/kg, starting from day +4 after the second chemotherapy cycle.
i19 Table 3. One-year EFS and OS in patients treated with rituximab plus ifosfamide, carboplatin and etoposide 1-year EFS
1-year OS
All patients (n = 28)
60%
72%
Transplanted patients (n = 19)
70%
82%
EFS, event-free survival; OS, overall survival.
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regimen used. Patients with poor risk disease (sAAIPI III/IV), would benefit from more aggressive innovative therapy and should be included in clinical trials in order to improve their outcome. New alternative regimens include the addition of monoclonal antibodies such as rituximab, radioimmunotherapy, the use of novel chemotherapeutic agents or modifications in the administration of agents which may improve the response rates and the ability of patients to go on transplantation. With an aim to increase response rates, the monoclonal antibody rituximab was added to the ICE regimen in CD20+ relapsed and refractory NHL. In this study R-ICE was found to be a highly effective regimen for cytoreduction and mobilization, especially when considering that more than half of the patients in this series had unfavorable lymphoma subtypes (mantle cell, transformed lymphoma, composite aggressive lymphoma and Burkitt’s lymphoma) or unfavorable disease characteristics. The UNMC strategy is to proceed with the transplant as soon as responses, either complete or partial, have been achieved. In this study the overall response rate of 70% was achieved by using only two cycles of R-ICE, including one patient who proceeded to transplantation after only one cycle. The rapid response induction and high overall response rate suggest that rituximab may enhance the activity of ICE. With the addition of rituximab to ICE in a population that is less responsive to traditional salvage regimens, we have been able to achieve response rates comparable with those usually seen in populations that respond well. It is difficult to compare outpatient R-ICE with other rituximab-containing salvage regimens for relapsed lymphomas, because different patient groups were included in small series. Some limited comparison is possible with the study reported by Jost et al. [6], since patients in both studies have similar clinical characteristics. The CR and PR rates with rituximab plus etoposide, prednisolone, vincristine, doxorubicin and cyclophosphamide (R-EPOCH) were 23% and 69%, respectively. Kewalramani et al. [5] reported an overall response rate of 80% when using an inpatient R-ICE regimen for the treatment of relapsed and refractory DLBCL. Ifosfamide 5 g/m2 was been administered in 24-h continuous infusion. The results suggested that the addition of rituximab to ICE (R-ICE) may double the CR rate achieved by using ICE alone, with no significant additive toxicity or impairment of stem cell collection. The overall response rate in relapsed patients was 96%, with 70% CRs, and in refractory patients 46% and 31%, respectively. Furthermore, whereas the second-line international prognostic index (sIPI) predicts response to ICE, the adverse features of the sIPI appear to be overcome by R-ICE. The difference in responses observed by using two similar R-ICE regimens may be due to the fact that this study involved a heterogeneous population with less than
half of the patients having DLBCL and the fact that patients in this study received less cycles of chemotherapy before transplantation. The R-ICE regimen as reported by Kewalramani et al. [5] was tested in DLBCL patients only. A CR rate of 60% achieved with the paclitaxel plus topotecan and rituximab (TTR) combination in relapsed patients and of 25% in those with primary refractory aggressive lymphomas were reported by Younes et al. [7]. The TTR regimen, although effective for cytoreduction, has not been used for mobilization. After two cycles of TTR, patients must receive one or two additional cycles of ifosfamide/etoposide regimen for mobilization purposes and transplantation is delayed for a few weeks. Compared with outpatient R-ICE, the TTR regimen with growth factor support is likely to be more toxic, more expensive, requires additional cycles of mobilization regimen for stem cell collection and delays the HDT for several weeks. By using ICE at a median follow-up of 12 months, EFS and OS for all patients enrolled in the study was 30% and 55%, respectively [2]. By using outpatient R-ICE the estimated 1-year EFS and OS therefore appears to be much better than by using ICE alone. This should be interpreted with caution, however, since this is not a randomized comparison. Wilson et al. [8] reported that by using R-EPOCH fever and neutropenia occurred in 20% of cycles, despite the concomitant use of growth factors in all patients. A high rate of neutropenia grade 4 (42%) has been observed for TTR resulting in 16% febrile episodes [7]. Again, all patients received growth factors prophylactically. Outpatient R-ICE had a comparable rate of grade 4 neutropenia, but the rate of febrile episodes was only 4%. Despite the observed rate of neutropenia, the R-ICE regimen can easily be given on an outpatient basis with the concomitant use of growth factors only when indicated. There were two treatment-related deaths reported for R-EPOCH [6]. In contrast, no treatment-related deaths have been reported so far for outpatient or inpatient R-ICE. The other non-hematological toxicities reported for outpatient R-ICE were remarkably mild. Bociek et al. [9] studied the relationship between ease of mobilization of peripheral blood progenitor cells and outcome after transplantation. The data suggested that patients with NHL who experience rapid mobilization (defined as >4 × 106 CD34+ cells/kg in a single collection) appeared to have a reduced risk of significant infection within 100 days after transplantation. As shown previously, the combined use of rituximab to chemotherapy may slightly deplete the number of CD34+ cells harvested, but numbers achieved in this study by using R-ICE are still high and resulted in excellent engraftment. Most of the above listed salvage regimens, including the R-ICE regimen developed by Kewalramani et al. [5], require hospitalization. Most of the drugs in the R-EPOCH regimen were given in a 96-h continuous infusion, which required at least 3 days of hospitalization. R-ICE as described in this study can be easily and safely given on an outpatient basis, which reduces the cost of the procedure. In conclusion, R-ICE is effective and well tolerated and can be administered in an outpatient setting. Two-thirds of patients can proceed with the transplantation after two cycles of R-ICE.
i20 The regimen allows collection of high-quality peripheral blood progenitor cells upon recovery for HDT and transplantation with excellent engraftment.
4. 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 2002; 346: 235–242.
Disclosure
5. Kewalramani T, Zelenetz A, Bertino J et al. Rituximab significantly increases the complete response rate in patients with relapsed or primary refractory DLBCL receiving ICE as second-line therapy (SLT). Abstract 1459, American Society of Hematology 43rd Annual Meeting, December 7–11, 2001, Orlando, FL.
Dr Vose reports no financial relationships with companies whose products are mentioned in the text. V.S. is an employee of Baxter Oncology GmbH.
References
7. Younes A, McLaughlin P, Hagemeister FB et al. High response rate and complete remission rate achieved by adding rituximab to taxol plus topotecan (TTR) with G-CSF support for the treatment of patients with relapsed/refractory aggressive B-cell lymphoma. Abstract 1456, American Society of Hematology 43rd Annual Meeting, December 7–11, 2001, Orlando, FL. 8. Wilson WH, Gutierrez M, O’Connor P et al. The role of rituximab and chemotherapy in aggressive B-cell lymphoma: a preliminary report of dose-adjusted EPOCH-R. Semin Oncol 2002; 29 (1 Suppl 2): 41–47. 9. Bociek RG, Lynch JC, Yee GC et al. Outcome and factors associated with slow mobilization of peripheral blood progenitor cells (PBPC) in patients undergoing autologous transplantation for non-Hodgkin’s lymphoma. Abstract 3575, American Society of Hematology 43rd Annual Meeting, December 7–11, 2001, Orlando, FL.
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1. 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 1995; 333: 1540–1545. 2. Moskowitz CH, Bertino JR, Glassman JR et al. Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin’s lymphoma. J Clin Oncol 1999; 17: 3776–3785. 3. Hamlin PA, Zelenetz AS, Nimer SD et al. The age-adjusted international prognostic index (AAIPI) predicts outcome following autologous stem cell transplantation (ASCT) in patients (PTS) with relapsed and primary refractory diffuse large B-cell lymphoma (DLBCL). Ann Oncol 2002; 13 (Suppl 2): 75 (Abstr 250).
6. Jost LM, Jermann M, Stahel RA et al. Rituximab–EPOCH: an effective salvage regime for relapsed, refractory, or transformed B-cell lymphoma. Results of a phase II study. Proc Am Soc Clin Oncol 2001; 20; 290 (Abstr 1157).