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Oxaliplatin-based chemotherapy (dexamethasone, high-dose cytarabine, and oxaliplatin) ± rituximab is an effective salvage regimen in patients with relapsed or refractory lymphoma
Version of Record online: 19 AUG 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 19, pages 4573–4579, 1 October 2010
How to Cite
Rigacci, L., Fabbri, A., Puccini, B., Chitarrelli, I., Chiappella, A., Vitolo, U., Levis, A., Lauria, F. and Bosi, A. (2010), Oxaliplatin-based chemotherapy (dexamethasone, high-dose cytarabine, and oxaliplatin) ± rituximab is an effective salvage regimen in patients with relapsed or refractory lymphoma. Cancer, 116: 4573–4579. doi: 10.1002/cncr.25216
- Issue online: 22 JUN 2010
- Version of Record online: 19 AUG 2010
- Manuscript Accepted: 8 DEC 2009
- Manuscript Revised: 26 NOV 2009
- Manuscript Received: 13 AUG 2009
Patients affected by relapsed or primary refractory lymphomas currently have a poor prognosis and no standard salvage treatment options. This study was carried out to assess the efficacy and safety of a dexamethasone, high-dose cytarabine, and oxaliplatin as salvage therapy in those patients, replacing cisplatin with oxaliplatin in the standard dexamethasone, cytarabine, and cisplatin scheme.
Seventy patients with relapsed or refractory aggressive non-Hodgkin or Hodgkin lymphoma were treated from September 2001 to September 2007. The median age of patients was 51 years (range, 19-75 years). Histological subtypes were: diffuse large B-cell lymphoma (n = 47) and Hodgkin lymphoma (n = 23). The overall response rate was 73% (51 of 70), with 30 (43%) complete remissions and 21 (30%) partial remissions. Fifty-two patients were treated with dexamethasone, high-dose cytarabine, and oxaliplatin as second-line chemotherapy. Forty-eight patients were enrolled in an autologous stem cell transplantation program; forty (83%) finally proceeded to high-dose consolidation and autografting.
No grade 3 or 4 nonhematological toxicity was demonstrated; in particular, no renal or neurotoxicity was reported. After a median follow-up period of 21 months (range, 2-87 months), 22 (31%) patients had died. Probabilities of 2-year progression-free survival (PFS) and overall survival (OS) were 44% and 71%, respectively. In the chemosensitive patients, the PFS and OS were 52% and 83%, respectively. The only factor that significantly correlated with better OS was the response to therapy.
This study confirms that dexamethasone, high-dose cytarabine, and oxaliplatin ± rituximab is an effective and feasible outpatient regimen for salvage therapy in patients affected by relapsed or refractory lymphoma. Moreover, the feasibility and efficacy of this scheme as an in vivo chemosensitive test in patients in autotransplantation programs was confirmed. Cancer 2010. © 2010 American Cancer Society.
About 40% to 60% of patients affected by aggressive non-Hodgkin lymphoma (NHL) fail to achieve complete remission (CR) after an anthracycline-based first-line chemotherapy or relapse after obtaining CR.1 The majority of patients with Hodgkin lymphoma (HL) can be cured with initial treatment, but at least 15% to 20% of them experience early relapse or have refractory disease.2 All these patients are generally characterized by a poor prognosis and will thus need a salvage chemotherapy. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the most successful approach for chemosensitive patients, although advanced age or comorbidity can prevent the patient from being put forward for a bone marrow transplantation. It is absolutely necessary to offer an effective, well-tolerated, and possibly mobilizing salvage chemotherapy with lower toxicities. The most widely accepted salvage regimens are platinum-containing (such as dexamethasone, cytarabine, and cisplatin; etoposide, Solu-Medrol, high-dose cytarabine, and platinum; adriamycin (ADR), solumedrol, cytarabine (ARA-C), cisplatin (CDPP) (ASHAP); ifosfamide, carboplatin, and etoposide) or ifosfamide-based (mesna, ifosfamide, mitoxantrone, etoposide; methylprednisolone, cytarabine, cisplatin [MINE-ESHAP], ifosfamide, methotrexate VP16 [IMVP16]).3-8 Dexamethasone, cytarabine, and cisplatin has been previously demonstrated in a long-term follow-up study to have a response rate of 43%, with a median survival of 6 months.9 This regimen has also been used in patients with indolent NHL and as a salvage regimen in refractory or relapsed HL. In a paper by Olivieri et al,10 the sequence dexamethasone, cytarabine, and cisplatin debulking mobilization followed by autologous stem cell transplantation demonstrated that it was feasible and effective in a high percentage of patients with high-grade NHL and HL. The addition of rituximab to the dexamethasone, cytarabine, and cisplatin regimen in patients with relapsed or refractory diffuse large B-cell lymphoma has proven to be more effective, leading to a higher percentage of complete remission and similar overall remission compared with dexamethasone, cytarabine, and cisplatin alone.11
Oxaliplatin is a third-generation platinum compound with a different spectrum of cytotoxicity than cisplatin or carboplatin. It has be proven to be effective in solid tumors, such as cisplatin-refractory ovarian carcinoma, colorectal carcinoma, and small cell lung cancer. Compared with cisplatin, oxaliplatin has a minor renal or auditory toxicity. The first report of oxaliplatin activity in refractory or recurrent NHL is by Germann et al.12 Of 22 pretreated patients affected by refractory or relapsed B-cell lymphoma, oxaliplatin at a dose of 100 mg/m2 or 130 mg/m2 has shown a 40% overall response rate in the different histological subgroups. Its safety and efficacy thus represent a good option for salvage regimen in heavily pretreated patients.13, 14
In the present study, we modified the dexamethasone, cytarabine, and cisplatin regimen, replacing cisplatin with oxaliplatin and administering cytarabine on Days 2 and 3 to evaluate efficacy and safety in 70 refractory or relapsed patients affected by aggressive NHL or by HL, who were treated as outpatients.
MATERIALS AND METHODS
Seventy patients affected by relapsed or refractory aggressive B-cell NHL and HL were followed from 2001 to 2007 at the Departments of Hematology of Alessandria, Florence, Siena, and Turin Hospitals and were evaluated in a multicenter retrospective analysis. Inclusion criteria were: histological proven diagnosis of aggressive high-grade NHL or HL according to the World Health Organization (WHO) classification, documented relapse after previous chemotherapy or disease resistant to chemotherapy, older than 18 years, and no previous platinum-containing chemotherapy.
Oxaliplatin was delivered as a 2-hour intravenous infusion at a dose of 130 mg/m2 on Day 1. Cytarabine was given on Days 2 and 3 at a dose of 2 g/m2 intravenously (first dose: 3-hour infusion on Day 2 at 3:00 PM and second dose: 3-hour infusion on Day 3 at 8:00 AM), and dexamethasone 40 mg was administered orally from Days 1 to 4. Rituximab was administered on Day 0 at a dose of 375 mg/m2 in patients with NHL. (This began in 2003 when the Italian health authorities allowed the use of the monoclonal antibody, anti-CD20, in diffuse large B-cell lymphoma.) The cycle was repeated every 3 weeks for a total of 2 to 6 cycles.
Peripheral blood stem cell (PBSC) mobilization and PBSC harvest were planned after the second cycle of dexamethasone, high-dose cytarabine, and oxaliplatin in patients who were candidates to receive a high-dose therapy with ASCT. All patients who were candidates for mobilization had to have a negative bone marrow histology before the apheresis.
Granulocyte colony-stimulating factor was routinely administered from Day 7 to Day 12. As supportive care, patients received allopurinol 300 mg daily, and cotrimoxazole and sulfamethoxazole 960 mg twice a week for Pneumocystis carinii pneumonia prophylaxis.
Patients had blood samples taken on Day 7 or Day 10 and before starting the next cycle. In case of persistent hematological toxicity grade 3 on the day of treatment, all drug treatments were delayed until the blood count recovered; whereas in case of grade 3 nonhematological toxicity, treatment was stopped. CR was defined as the complete disappearance of any radiological or biological lesions present at diagnosis and the absence of new lesions. Partial remission (PR) was defined as regression by >50% of the measurable lesions and the absence of new lesions. Stable disease was defined as the regression by <50% of all measurable lesions without the appearance of any new lesions. Progressive disease was defined as the appearance of new lesions or the growth of any initial lesion by >50%. Nonresponders (NRs) were those patients who obtained less than PR or discontinued treatment because of adverse effects and those who died.15
Overall survival (OS) was calculated from the start date of salvage treatment until death from any cause or until last patient contact, whereas disease-free survival (DFS) was taken from the date of CR (for relapsed patients we used the date of second complete remission) to the date of relapse or of last contact, and the curves were measured only using patients in CR after induction therapy. Progression-free survival (PFS) was calculated from start of salvage treatment until progression, relapse, death, or last follow-up. Toxicity was defined according to the WHO toxicity grading scale.
All included patients were considered in the statistical analysis. OS, DFS, and PFS were estimated according to the Kaplan-Meier method. The log-rank test was used to assess the significance of differences for each prognostic factor in the univariate analysis. The Cox proportional hazards regression model and the logistic regression models were used to assess how patients' characteristics predict DFS and OS. Our data were analyzed using the Statistical Package for Social Science.16 The limit of significance for all analyses was defined as P = .05. A 2-tailed test was used in all calculations.
From 2001 to 2007, 70 patients were treated at the hematology departments of Alessandria, Florence, Siena, and Turin hospitals. All patients were evaluated and included in the statistical analysis. Table 1 shows the patients' characteristics. Median age was 51 years (range, 19-75 years); there were 45 men and 25 women; 47 (67%) had diffuse large B-cell lymphoma, and 23 (33%) had HL.
|Characteristics||CR, No. (%)||PR, No. (%)||NR-Prog, No. (%)||Total, No. (%)||P|
|Men||15 (21)||13 (19)||17 (24)||45 (64)|
|Women||15 (21)||8 (12)||2 (3)||25 (36)||NS|
|<65||22 (31)||17 (24)||15 (21)||54 (76)|
|>64||8 (12)||4 (6)||4 (6)||16 (24)||NS|
|Non-Hodgkin lymphoma||18 (26)||16 (23)||13 (18)||47 (67)|
|Hodgkin lymphoma||12 (17)||5 (7)||6 (9)||23 (33)||NS|
|2||23 (33)||14 (20)||15 (21)||52 (74)|
|≥3||7 (10)||7 (10)||4 (6)||18 (26)||NS|
|Yes||18 (26)||11 (16)||13 (19)||42 (60)|
|No||12 (17)||10 (14)||6 (9)||28 (40)||NS|
|Yes||5 (7)||6 (9)||12 (17)||23 (33)|
|No||25 (36)||15 (21)||7 (10)||47 (77)||.004|
|Yes||12 (17)||0||4 (6)||16 (23)|
|No||18 (26)||21 (30)||15 (21)||54 (77)||.001|
At diagnosis, according to the Ann Arbor Classification, 7 (10%) patients were at stage I, 22 (31%) at stage II, 20 (29%) at stage III, and 21 (30%) at stage IV. Twenty (29%) patients had B symptoms, and 22 (31%) had bulky disease. According to the International Prognostic Index, when considering only the NHL patients, there were 18 patients at low, 16 at low/intermediate, 9 at intermediate/high, and 4 at high risk. The overall number of cycles administered was 233, and the median number was 4 (range, 2-6). Thirty-four patients received 2 cycles of chemotherapy; 24 patients received 4 cycles, 2 patients received 5 cycles, and 10 patients received 6 cycles. Fifty-two patients received dexamethasone, high-dose cytarabine, and oxaliplatin as second-line therapy and 18 as third-line (4 after high-dose chemotherapy and ASCT). Twenty-three patients were considered to have primary tumors refractory to induction therapy. In refractory patients, dexamethasone, high-dose cytarabine, and oxaliplatin therapy was used as a chemosensitive test to take patients toward a high-dose therapy and subsequently ASCT. Forty-eight patients were enrolled in an ASCT program; 46 (96%) of the 48 had an adequate peripheral stem cell collection, and 2 patients did not. The ASCT program was finally performed in 40 (83%). Autologous stem cell transplantations were planned in 25 patients with NHL and successfully performed in 19 of them. Six patients did not perform the ASCT, in 2 of them because of lack of PBSC collection and in the other 4 because of disease progression. Among the Hodgkin patients, ASCT was planned in 23 cases and performed in 21 of them; 1 patient refused the procedure, and for the other patient the therapeutic program was modified to a reduced-intensity allogeneic transplantation. No dose reduction was required. Treatment was delayed in 29 (12%) cycles mostly because of hematological toxicity. Eight patients did not complete the planned therapy; the reason for stopping treatment was disease progression. Nineteen (40%) of 47 NHL patients did not receive rituximab.
Response to Treatment
The response rate was evaluated 1 month after completion of therapy. After the induction therapy, the overall response rate was 73% (51 of 70), with 30 complete remissions (43%) and 21 partial remissions (30%); 19 patients were refractory (27%). The only factor that significantly affected obtaining a response to therapy was the time from diagnosis to dexamethasone, high-dose cytarabine, and oxaliplatin therapy. Complete remission was significantly higher in patients treated with salvage therapy >1 year from diagnosis (53%) in comparison with those relapsed within 1 year (34%) (P = .01). According to histological subtypes, the overall response rate was 72% and 74% in NHL and HL, respectively. In NHL patients, we did not find any differences in terms of overall response according to whether rituximab was used or not used (respectively, 78% and 75%). Twenty-three (33%) patients had refractory primary tumors; 5 achieved CR and 6 PR, with an overall response rate of 48%. Eight (73%) of these responding patients performed ASCT, and the remaining 3 did not because of advanced age. Only 4 (33%) out 12 patients who did not respond to dexamethasone, high-dose cytarabine, and oxaliplatin were treated with ASCT. Finally, 40 (83%) of 48 patients proceeded to high-dose consolidation and autografting. Twenty-seven patients were in CR, 9 were in PR, and 4 had active disease at the moment of transplantation. After high-dose therapy and autologous transplantation, 1 more patient achieved CR (28 CRs), 2 patients progressed rapidly and died, and the other 10 were alive but with active disease.
OS and Event-Free Survival
At the time of this analysis, the median follow-up was 21 months (range, 2-87 months), 48 (69%) patients were alive, and 22 (31%) had died, 21 because of disease progression and 1 because of sepsis. Overall survival was 71% at 2 years and 58% at 5 years (Fig. 1). According to the histotype, it was 58% at 2 years and 39% at 5 years in NHL patients and 95% at 2 years and 89% at 5 years in HL patients (P = .001) (Fig. 2). OS was statistically significantly better (P = .0004) in patients with chemosensitive disease in comparison to refractory disease (83% vs 38% at 2 years). Patients who underwent the programmed ASCT showed a significantly better overall survival rate, in comparison with those who did not (P = .01). In univariate analysis, OS was significantly affected by the histotype (Hodgkin vs non-Hodgkin: P = .001), response to salvage therapy (CR vs PR and NR: P = .000), remission status at ASCT (P = .001), and performance of autologous PBSC transplantation (P = .0004). In multivariate analysis, only remission status at ASCT was notable (P = .004).
PFS was 44% at 2 years and 35% at 5 years; according to histotype, it was 35% at 2 years and 23% at 5 years in NHL patients and 64% at 2 years and 50% at 5 years in HL patients (P = .008) (Fig. 3). PFS was statistically better (P = .01) in patients with chemosensitive disease in comparison to the refractory patients (52% vs 28% at 2 years). In the univariate analysis, PFS was significantly affected by response to salvage therapy (CR vs PR and NR: P = .000), remission status at ASCT (P = .000), and performed autologous PBSC transplantation (P = .01). In the multivariate analysis, only the response to salvage therapy was notable (P = .0000).
Stem Cell Mobilizing Capacity of Dexamethasone, High-Dose Cytarabine, and Oxaliplatin
Adequate stem cell mobilization was obtained in 46 of 48 eligible patients. The median peak number of CD34+ progenitors was achieved at Days 11 to 13. The median number of collected CD34+ cells was 6.35 × 106/kg body weight (range, 2-20.1). Forty-two of 46 patients collected CD34, with 1 leukapheresis.
Grade 3 and 4 toxicity was mainly hematological (see Table 2); no severe bleeding complications were reported; and in 11 (16%) patients, prophylactic platelets transfusions were occasionally required. No grade 3 or 4 nonhematological toxicity was demonstrated; in particular no renal or neurological toxicity was reported (see Table 2). No toxic deaths were recorded.
|Toxicities||WHO 0||WHO 1||WHO 2||WHO 3||WHO 4|
|Neutropenia||22 (31)||10 (14)||13 (18)||11 (16)||14 (21)|
|Anemia||51 (73)||7 (10)||8 (11)||4 (6)||0|
|Trombocytopenia||16 (23)||16 (23)||12 (17)||15 (21)||11 (16)|
|Neuropathy||60 (86)||10 (14)||0||0||0|
|Infections||61 (88)||5 (7)||2 (3)||1 (1)||1 (1)|
|Nausea and vomiting||64 (91)||6 (9)||0||0||0|
|Gastroenteric||68 (96)||1 (2)||1 (2)||0||0|
|Hepatic||68 (96)||1 (2)||1 (2)||0||0|
The present study demonstrates that the dexamethasone, high-dose cytarabine, and oxaliplatin regimen effected great activity in 70 patients with relapsed or refractory Hodgkin or NHL and that this regimen also shows a high mobilizing efficacy.
The results of the PARMA trial17 demonstrated that patients who undergo high-dose therapy followed by ASCT after an adequate response to dexamethasone, cytarabine, and cisplatin chemotherapy have better failure-free survival and OS rates than patients who only received dexamethasone, cytarabine, and cisplatin. After the publication of this trial—the only reported study of patients treated with randomized therapy for relapsed disease—investigators assumed that all regimens were equivalent to dexamethasone, cytarabine, and cisplatin in achieving remission and that any regimen that would induce a response in a patient with relapsed disease would have results as good as those for dexamethasone, cytarabine, and cisplatin followed by stem cell transplantation. Overall response rates ranging from 55% to 67%, including CR rates ranging from 15% to 31%, have been previously reported with dexamethasone, cytarabine, and cisplatin in patients with NHL previously treated with chemotherapy.3, 16, 18, 19 The results of the dexamethasone, high-dose cytarabine, and oxaliplatin regimen was first reported in a paper by Machover et al.20 The overall response rate and complete remission were, respectively, 73% and 53% in a cohort of 15 patients with different histologies. Although experimental data for a synergistic interaction between cytosine arabinoside and oxaliplatin (L-HOP) are not available, the activity observed in this study suggests that synergy might occur. Recently, other studies tested the efficacy and safety of platinum derivative oxaliplatin in polichemotherapy.21-23 The present study confirms that the dexamethasone, high-dose cytarabine, and oxaliplatin regimen has significant activity in patients with NHL or HL who had received prior treatment. Seventy-three percent of the patients responded to therapy, and 43% attained a CR. No differences were observed in different histotypes (73% in NHL and 74% in HL). Forty-eight patients were programmed to receive a stem cell transplantation; in 46 (96%) of the 48 patients, the dexamethasone, high-dose cytarabine, and oxaliplatin regimen proved to be highly effective at mobilizing a sufficient number of stem cells, and 40 (83%) patients of these 48 patients underwent high-dose therapy with BCNU etoposide, aracytin, melphalan (BEAM) and stem cell transplantation. The dexamethasone, high-dose cytarabine, and oxaliplatin regimen proved to be an effective mobilizing regimen; moreover, it helped in preparing a large number of relapsed or refractory patients for stem cell transplantation. Dexamethasone, high-dose cytarabine, and oxaliplatin induced an overall response in 48% of refractory patients, and 8 out 23 patients with primary refractory disease (35%) had the possibility of receiving high-dose therapy and an autologous stem cell transplantation. Dexamethasone, high-dose cytarabine, and oxaliplatin therapy was administered to all patients as outpatients; the use of oxaliplatin reduced the amount of fluid and avoided prehydration, and no renal toxicity was observed. Toxicity was within acceptable limits of tolerance. Neutropenia and thrombocytopenia WHO grade 2 to 4 occurred in 55% and 54% of patients, respectively. However, they were of short duration, did not require hospitalization and did not result in complications. The dose-limiting toxic effect of oxaliplatin is sensory peripheral neuropathy. In our transient, peripheral patients, neuropathy was experienced by 14% of the assessable patients. Neuropathy of grade >2 was not observed in the present study. Our data confirm that the combination of L-HOP with high-dose Aracytine did not change the incidence or characteristics of sensory neuropathy. No other clinically significant extrahematological toxicity was recorded in the study (see Table 2).
The OS and PFS are significantly higher in patients with HL in comparison with NHL because HL patients were treated after first relapse, with the intention to perform high-dose chemotherapy and ASCT. As reported in the multivariate analysis, the pre-ASCT status is the only condition that significantly affects a better OS and PFS, confirming the indispensable role of an effective salvage therapy.
In conclusion, the present study confirms that dexamethasone, high-dose cytarabine, and oxaliplatin therapy is highly active for the treatment of patients with HL or NHL, whether or not they are candidates for high-dose chemotherapy and stem cell transplantation. The regimen was able to mobilize adequate numbers of circulating CD34+ cells, and hematopoietic engraftment occurred within the expected time in patients receiving ASCT. Time to neutrophil (>0.5 × 109/L) and platelet (>20 × 109 L) recovery was, respectively, 11 and 16 days. Moreover, this regimen has toxicity characteristics that compare favorably with those reported in dexamethasone, cytarabine, and cisplatin; that patients can be treated as outpatients is also an advantage. The lack of renal toxicity reported for oxaliplatin-containing regimens means that it can be considered as a treatment for elderly patients. Our large cohort of patients confirms that the dexamethasone, high-dose cytarabine, and oxaliplatin regimen has promising activity, with an acceptable toxicity profile, and could be a favorable treatment option for relapsed or refractory lymphoma patients regardless of whether they are eligible for an autologous transplant.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
- 16SPSS Inc. SPSS for Windows, version 12.0 Chicago, IL: SPSS; 1998.
- 19High-dose chemotherapy followed by autologous bone marrow transplantation vs. dexamethasone, cisplatin and cytarabine in aggressive non-Hodgkin's lymphoma with partial response to front-line chemotherapy: a prospective randomised Italian multicenter study. J Clin Oncol. 1996; 14: 534-542., , , et al.