Abstract
Background: The effects of a novel salvage regimen, IDEA (ifosfamide, cytosine arabinoside, etoposide and dexamethasone), which does not include anthracycline or platinum, in patients with non-Hodgkin's lymphoma (NHL) were examined. Patients and Methods: Thirty-four patients with refractory or relapsed NHL were treated with IDEA. Results: The overall remission and complete remission rates were 67.6% and 35.3%, respectively. The toxicity of IDEA was tolerable. With a median follow-up of 14 months, one-year overall survival (OS) and progression-free survival rates were 75.1% and 43.7%, respectively. Adequate numbers of CD34+ cells were obtained in 77.8% of the patients assigned to receive autologous peripheral blood stem cell (PBSC) transplantation. High-dose chemotherapy with autologous PBSC transplantation was carried out in 14 patients; their 3-year OS was 75.0%, with a median follow-up of 38 months. Conclusion: IDEA is an effective second-line chemotherapy regimen for NHL patients and has an excellent PBSC-mobilizing effect.
CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) or CHOP-like regimens are primarily administered as first-line chemotherapy for patients with newly diagnosed non-Hodgkin's lymphoma (NHL) (1) and the complete remission (CR) rate achieved with CHOP is approximately 65% . However, relapsed or refractory patients after first-line chemotherapy have a poor prognosis (2, 3) and more effective salvage regimens with acceptable toxicity are needed.
A novel salvage chemotherapy has been designed without anthracyclines or platinum in order to avoid cardiac and renal toxicities, consisting of ifosfamide, cytosine arabinoside, etoposide and dexamethasone, named “IDEA.” After its approval for clinical use in Japan, rituximab was added to the IDEA regimen for patients with CD20-positive B-cell NHL. A pilot study of the IDEA regimen was conducted in 34 patients with refractory or relapsed NHL, which demonstrated the feasibility, efficacy in response and efficacy in mobilization of PBSC.
Patients and Methods
Patients and staging. A retrospective analysis of 34 patients (13 women, 21 men) with pathologically diagnosed refractory or relapsed non-Hodgkin's lymphoma, treated between June 1998 and September 2005 at Okayama University Hospital was performed. The study was approved by the Internal Review Board of the hospital. Inclusion criteria were age 20-80 years and the presence of at least one area of measurable disease. All patients had previously received at least one chemotherapy regimen and had either refractory or recurrent disease. Patients were ineligible if they had positive serological tests for human immunodeficiency virus (HIV) antibodies, hepatitis B virus antigens (HBsAg) or antibodies to hepatitis C virus (HCV-Ab), or severe illness unrelated to lymphoma.
The International Prognostic Index (IPI) was determined at the time of the refractory or relapsed status in patients with diffuse large B-cell lymphoma (DLBCL) (4).
Treatment. The IDEA protocol is shown in Figure 1. Patients received 1300 mg/m2 ifosfamide intravenously (i.v.) on days 1 to 3, 150 mg/m2 etoposide i.v. on days 1 to 3, 750 mg/m2 cytosine arabinoside i.v. over 3 h every 12 h on days 2 and 3, and 40 mg/body dexamethasone i.v. on days 1 to 4. Chemotherapy doses were based on a dose-finding study of IDEA in nine patients (data not shown). Granulocyte-colony stimulating factor (G-CSF) was administered subcutaneously (filgrastim 50 μg/m2 or lenograstim 2 μg/kg) when neutrophil counts were below 500/mm3 after chemotherapy. Rituximab 375 mg/m2 was given on the day preceding IDEA therapy for nine patients with CD20-positive B-cell lymphomas.
Protocol design for IDEA therapy. Patients received 1300 mg/m2 ifosfamide intravenously (i.v.) on days 1 to 3, 150 mg/m2 etoposide i.v. on days 1 to 3, 750 mg/m2 cytosine arabinoside i.v. over 3 h every 12 h on days 2 and 3, and 40 mg/kg body weight dexamethasone i.v. on days 1 to 4. *G-CSF was administered subcutaneously (filgrastim 50 μg/m2 or lenograstim 2 μg/kg) when the neutrophil count was less than 500/mm3. #Rituximab 375 mg/m2 was given on the day preceding G-IDEA therapy for patients with CD20-positive B-cell lymphomas.
One to five cycles (median, 3) of the IDEA regimen were administered every 3 weeks. The second or later course of chemotherapy was started after hematological recovery (neutrophils over 1000/μL and platelet count over 50000/μL) following the previous course and doses were adjusted in accordance with the severity of myelosuppression and complications.
PBSC collection. PBSC collection was performed to allow autologous PBSC transplantation (auto-PBSCT), regardless of the disease status or type of lymphoma. After the second cycle of IDEA therapy, an increased dose of G-CSF (filgrastim 200 μg/m2 or lenograstim 5 μg/kg) was given subcutaneously (s.c.) on the day of the nadir or when the neutrophil count was <1000/μL and was then continued to the day of PBSC harvest. Harvest was initiated when the white blood cell count recovered from the nadir to >5000/μL. Patients from whom fewer than 2×106 CD34+ cells/kg were collected were considered cases of poor mobilization.
Criteria for response and toxicity evaluation. The response was assessed on day 14-28 of the second cycle of IDEA treatment. CR and partial remission (PR) in response to IDEA were assessed using the International Working Group criteria (5). Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (6).
Auto-PBSCT. Patients undergoing auto-PBSCT were required to have a cardiac ejection fraction >50% and normal pulmonary and renal function, and collection of more than 2×106 CD34+ cells/kg. Fourteen patients received high-dose chemotherapy, consisting of 200 mg/m2 ranimustine on days -8 and -3, 300 mg/m2 carboplatin on days -7 to -4, 500 mg/m2 etoposide on days -6 to -4, 50 mg/kg cyclophosphamide on days -3 and -2, and then supported with auto-PBSCT. G-CSF (filgrastim 200 μg/m2 or lenograstim 5 μg/kg) was administered intravenously from day +1 to the day on which the white blood cell count was >5000/μL.
Patient characteristics.
Statistical analysis. Point estimates and their 95% confidence intervals (95% CIs) for OS and progression-free survival (PFS) were calculated based on the Kaplan-Meier product limit method (7). The initial date of OS and PFS was defined as day 1 of IDEA therapy. The final date of OS and PFS was defined as the last date of follow-up and the date on which a patient was confirmed to have progressive disease, respectively. Stat View 5.0 (SAS Institute, Cary, NC, USA) was used for statistical analyses.
Results
Patient characteristics. The characteristics of the 34 patients are shown in Table I. The median age of the subjects was 60 years (range: 24-80), and performance status (PS), as defined by the Eastern Cooperative Oncology Group (ECOG), was 0 to 1 in 23 patients and 2 or more in 11 patients (8). The median cumulative dose of doxorubicin was 300 mg/m2 (range 50-500 mg/m2). Twenty-eight patients (82.4%) were in disease stage III/IV. Nineteen patients (55.9%) had DLBCL. In terms of the prognostic risk factors of the patients with DLBCL, they were evaluated according to IPI for disease recurrence or a refractory state. Three patients (15.8%) had 0 or 1 risk factors and 16 patients (84.2%) had 2 or more risk factors.
Overall survival and progression-free survival of patients treated with IDEA.
Chemotherapeutic effect.
Responses and survival. A total of 92 chemotherapy cycles of IDEA were given to the 34 patients (median 3 cycles). Twelve (35.3%) and 11 patients (32.4%) achieved CR and PR, respectively. Thus, the overall remission rate (ORR, complete plus partial remission) was 67.6% (95% CI 49.4-82.6%). Of 19 patients with DLBCL, nine (47.4%) attained CR and six (31.6%) achieved PR; the ORR was 78.9% (95% CI 54.4-93.9%).
Nine patients with CD20-positive B-cell lymphoma were treated with IDEA plus rituximab. Seven had DLBCL, and the other two had follicular lymphomas. Three patients had already been treated with rituximab as a first-line therapy. Five patients (55.6%) obtained CR and two patients (22.2%) obtained PR; the ORR was 77.8% (95% CI 50.6-104.9%). Response rates are summarized in Table II. OS and PFS curves are shown in Figure 2. With a median follow-up of 14 months, one-year OS and PFS were 75.1% (95% CI 60.2-90.1%) and 43.7% (95% CI 27.0-60.5%), respectively.
Overall survival of IDEA-treated patients who underwent autologous transplantation.
Hematological toxicity.
High-dose chemotherapy with auto-PBSCT was carried out in 14 patients (DLBCL 9, others 5). The median age was 58 years (range 24-68). Nine patients (64.3%) had DLBCL and three had aggressive T-cell lymphomas. With a median follow-up of 38 months, 3-year OS was 75.0% (95% CI 50.5-99.5%). The OS curve is shown in Figure 3.
Hematological toxicity. All 34 patients could be assessed for toxicity after 92 cycles of IDEA therapy (Table III). Grade 4 neutropenia occurred in almost all cycles (96.7%), but the duration of neutropenia was very short, with a median of 4 days (range 0-11) and the nadir was on day 11.5 (median). Thrombocytopenia (platelet count <20000/μL) occurred in 71.7% and the nadir was on day 13 (median, range 10-18). Median duration with <50000/μL was 3.5 days. Platelet transfusions were carried out in 78.3% of the courses, but the frequency of platelet transfusion in each course was typically once or twice (86%). Anemia was comparatively moderate and grade 4 anemia occurred in 19.6% of cases. In 44.6% of the cycles, red blood cell transfusions were necessary. In IDEA plus rituximab therapy, grade 4 neutropenia occurred in 100%, thrombocytopenia in 89.7% and grade 3 to 4 anemia in 58.6% of cases. These results indicated that the hematological toxicities were almost the same as without rituximab.
Non-hematological toxicity.
Non-hematological toxicity. Non-hematological toxicities are shown in Table IV. None of the patients developed grade 4 toxicity. Febrile neutropenia occurred in 23.9% of all cycles, but all patients recovered quickly. None of the patients died of infection and sepsis occurred in only one case with Klebsiella pneumoniae. Mild AST/ALT elevation (grade 1 or 2) was observed in 46.7% of cases. Grade 3 hypersensitivity was observed in three cases. Grade 3 hypotension occurred in two patients. Cardiac ultrasonography indicated normal cardiac function in these cases; thus, laboratory findings suggested that the hypotension may have been due to adrenal gland dysfunction. Grade 3 left ventricular dysfunction occurred in one case, a 69-year-old woman with angioimmunoblastic T cell lymphoma who received CHOP and developed complete atrioventricular block. A temporary pacemaker improved her cardiac function. Grade 1 elevation of serum creatinine level occurred in only two cycles and was reversible. Rituximab added to the IDEA therapy did not exacerbate non-hematological toxicity compared with the toxicity of IDEA alone (data not shown).
Peripheral blood stem cell mobilization. The results of cell harvesting and purification are presented in Table V. Peripheral blood stem cells were harvested after IDEA therapy in 18 patients. Of these, 11 had relapsed and 7 were refractory to the first-line therapy. The median number of harvested CD34+ cells was 3.05×106 cells/kg (range 0.18 to 48.1×106) per patient, and the mean number of harvested CD34+ cells per apheresis was 2.59×106/kg. The number of apheresis procedures ranged from 1 to 4 (median once) and in 14 of 18 patients (77.8%, 95% CI 58.6-97.0%) more than 2.0×106 cells/kg CD34+ cells were obtained. The day of harvest, from the beginning of IDEA therapy, was day 15 (median, range 13 to 21, SD: 1.19).
Mobilization effects.
Discussion
The novel salvage regimen, IDEA contains ifosfamide, high-dose cytosine arabinoside, etoposide and dexamethasone. Ifosfamide was used as it has relative non-cross resistance with cyclophosphamide used for CHOP therapy (9) and a mobilizing activity as well as optimal CNS penetration, facilitating clearance of occult disease (10). High-dose cytosine arabinoside is reported effective for the treatment of relapsing lymphoma (11) and etoposide has synergistic effect with cytosine arabinoside (12). Both high-dose cytosine arabinoside and etoposide are not usually incorporated into first-line chemotherapy. In this study, the effects of IDEA in patients with relapsed or refractory NHL were examined. The ORR of 66.7% and CR of 35.3% against relapsed or refractory NHL were effective and encouraging, regardless of the histological heterogeneity. In the light of the DLBCL, IDEA showed satisfactory anti-tumor activity with ORR and CR rates of 78.9% and 47.4%, respectively.
High-dose chemotherapy and autologous stem cell transplantation (ASCT) has been demonstrated to be significantly more effective than conventional chemotherapy for patients with relapsed or refractory NHL who respond completely or partially to salvage chemotherapy (13). Thus, salvage chemotherapy needs high anti-tumor activity with preserving cardiac and renal function for high-dose chemotherapy and ASCT. Salvage regimens involving cisplatin such as DHAP (cisplatin, cytarabine and dexamethasone), ESHAP (etoposide, methylprednisolone, cytosine arabinoside and cisplatin) and ICE (ifosfamide, carboplatin and etoposide) have been reported to be effective with CR rates of 25-35% (2, 14, 15). However, irreversible renal injury or dysfunction was sometimes observed in platinum-containing therapy. In this study, the cardiac and renal toxicity of the IDEA regimen was mild and tolerable. Reversible cardiac toxicity occurred in one patient with relatively high risk of cardiac damage from her clinical course. Renal toxicity was fairly mild, with grade 1 elevation of serum creatinine levels in only two cycles. The absence of anthracyclines and platinum in IDEA may contribute to the reduced cardiac and renal toxicities.
Another important finding in this study is that IDEA regimen has sufficient mobilizing effect on PBSC. The median total number of harvested CD34+ cells was 3.05×106 cells/kg and 77.8% of patients obtained adequate CD34+ cells. Fifty percent of patients experienced the aphereses on day 15, thus it was easy to predict the first day of apheresis after the G-IDEA therapy. Three of four patients who failed the mobilization after IDEA regimen had the involvement of lymphoma cells in their bone marrow, suggesting that bone marrow involvement might be a predicting factor for unsuccessful mobilization as reported by Micallef et al. (16). The Parma study showed that high-dose chemotherapy and ASCT increases overall survival in patients with chemotherapy-sensitive NHL in relapse compared with conventional chemotherapy (13). The OS at 5 years was 53% in the transplantation group in the Parma study (13). ICE and R-ICE with ASCT produced OS of 56% and 67% at 2 years, respectively (17). In this study, although patients treated with auto-PBSCT following IDEA were elder in age (median, 58 years) than those of reported regimens (ICE and RICE; median, 48 and 45 years, respectively), 3 years OS was 75.0% (95% CI: 50.5-99.5%) with a median follow-up of 38 months. IDEA plus auto-PBSCT might induce longer survival in chemotherapy-sensitive NHL in relapse even in older patients.
In conclusion, it has been demonstrated that IDEA is an effective second-line chemotherapy regimen for relatively elderly patients with primary refractory or recurrent NHL, without severe toxicities. Moreover, IDEA showed a good PBSC-mobilizing effect and IDEA followed by auto-PBSCT may result in improved responsiveness and survival. There is a plan to evaluate the superiority of IDEA as a salvage therapy in a larger clinical trail in elderly patients.
- Received August 13, 2008.
- Revision received December 17, 2008.
- Accepted February 13, 2009.
- Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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