43(5): ,2002. Division of Hematology, Department of Medicine, Zagreb University Hospital Center and School of Medicine, Zagreb, Croatia

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1 43(5):55-554,22 CLINICAL SCIENCES Combination of Ifosfamide, Methotrexate, and Etoposide (IMVP) as a Salvage Therapy for Relapsed and Refractory Aggressive Non-Hodgkin Lymphoma: Retrospective Study Igor Aurer, Nadira Durakoviæ, Ivo Radman, Damir Nemet, Silva Zupanèiæ-Šalek, Jasminka Kovaèeviæ-Metelko, Vinko Bogdaniæ, Dubravka Sertiæ, Mirando Mrsiæ, Mirta Mikuliæ, Boris Labar Division of Hematology, Department of Medicine, Zagreb University Hospital Center and School of Medicine, Zagreb, Croatia Aim. There are contradictory reports on the outcomes of IMVP (ifosfamide, methotrexate, and etoposide) treatment in patients with aggressive non-hodgkin s lymphomas. Our aim was to evaluate retrospectively the results of this treatment in our institution. Methods. Twenty eight patients with refractory or relapsed aggressive non-hodgkin s lymphomas received IMVP between April 997 and June 2. Median follow-up of the survivors was 24 months. There were 5 women and 3 men, aged 5-68 years. Twelve patients were refractory to primary treatment. The number of previous treatment lines varied between one and five. The overall response rate to IMVP treatment was 39%, with 6 patients achieving complete and 5 partial response/remission. Eleven patients received a subsequent hematopoietic stem cell transplant after IMVP therapy. Results. Median duration of the survival for all patients was 6 months, and the response duration for responders 6 months. Nine patients had grade 3 hematologic toxicity or higher, 5 developed significant infectious complications, and one developed the tumor lysis syndrome. There was one treatment-related death due to infection. The patients with a low or low-intermediate international prognostic index at the start of IMVP had a significantly better survival and progression-free survival rates than those with high or high-intermediate score. Seven patients with hematopoietic stem cell transplant were alive in December 2. Conclusion. IMVP is an active regimen with acceptable level of toxicity in patients with relapsed or refractory aggressive non-hodgkin s lymphoma. However, outcomes of this treatment are unsatisfactory and better treatment is still needed. Key words: etoposide; ifosfamide; lymphoma, B-cell; lymphoma, diffuse; lymphoma follicular; lymphoma, high-grade; lymphoma, intermediate-grade; lymphoma, large-cell; lymphoma, non-hodgkin; lymphoma, T-cell; methotrexate Currently available first-line combination therapy regimens are an effective treatment for aggressive non-hodgkin s lymphoma, especially in patients with low-risk features (-5). The gold standard is a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which results in 6% of patients achieving complete remission (). Even so, about 4% of the patients who achieve complete remission relapse. Such patients, as well as those not responding to first-line therapy, need second-line therapy. Several salvage chemotherapy regimens have been introduced, based either on a platinum compound (e.g., combination of dexamethasone, cytarabine, and cisplatin DHAP) or ifosfamide (e.g., combination of ifosfamide, methotrexate, and etoposide IMVP; or combination of ifosfamide, carboplatin, and etoposide ICE) (5-7). None of them is uniformly effective and all are associated with significant toxicity and poor long-term survival. A randomized comparison of these regimens has never been done. The only therapy improving the long-term survival is high-dose chemotherapy followed by autologous bone marrow or blood stem cell rescue, but it is efficacious only in patients with a chemosensitive relapse (8,9). We have been using IMVP routinely as a second-line treatment regimen in patients with aggressive non-hodgkin s lymphoma for more than 4 years. Since only two studies have been published on the efficacy of this regimen in relapsed and refractory non- Hodgkin s lymphoma cases, with contradictory results (,), we decided to perform a retrospective analysis of our patients treated with IMVP at our institution. 55

2 Patients and Methods Patients Between April 997 and June 2, 28 consecutive patients with aggressive non-hodgkin s lymphoma were treated with IMVP combination therapy. The median age of patients was 47 years (range 5-68). Histologic type of lymphoma, stage, and international prognostic index (IPI) (2) had been determined in all patients before IMVP was introduced (Table ). All patients had been treated for their illness prior to IMVP, receiving between and 5 lines of therapy (median 2), with at least one containing anthracyclines. There were 6 patients who relapsed after having achieved complete (2 patients) or partial remission (4 patients), and 2 who were refractory to previous therapy. Three patients had been previously autografted. Twelve patients were in the first and 4 in second relapse. Median duration of illness from diagnosis to IMVP therapy was 2.5 months (range 3-6). Before IMVP therapy was started, all patients were routinely restaged: 8 patients had stage IV disease, 4 had stage III, 5 had stage II, and one had stage I according to Ann Arbor classification (3). Twenty-two patients had B symptoms (unexplained fever, unexplained weight loss, drenching night sweats, or severe pruritus). Eleven patients had a low or low-intermediate IPI score (-2), and 7 had a high or high-intermediate score (3-5) (Table ). Median follow-up was 24 months. Table. Histologic type, stage, and international prognostic index (IPI) score of patients with relapsed or refractory aggressive non-hodgkin s lymphoma treated with IMVP a Stage IPI Lymphoma type No. I II III IV low high ALCL Follicular B-LCL Total a Abbreviations: IMVP ifosfamide, methotrexate, and etoposide; ALCL anaplastic large cell lymphoma; B-LCL B-large cell lymphoma. Chemotherapy The treatment regimen was composed of ifosfamide, mg/m 2 on days -5, methotrexate 3 mg/m 2 IV on days 3 and, and etoposide mg/m 2 IV on days -3. Uromitexan (25 mg/m 2 ) was given three times daily for uroprotection during ifosfamide treatment. Cycles were repeated every three to four weeks, and the total number of cycles was determined individually. In case of treatment-associated low blood counts, the treatment was delayed until the recovery of blood counts. Therapy was generally given in an inpatient setting. Occasionally, the patients who lived close to the hospital and could come three times daily to the clinic received the therapy as outpatients. If there were no complications, the patients were discharged after chemotherapy (day 5 or 6). Supportive Care Patients were instructed to take prophylactic antibiotic and antifungal drugs. Those with previous neutropenic fever or infections received granulocyte-colony stimulating factor (G-CSF, 3 ig SC daily) prophylactically, starting on day until neutrophil recovery. Toxicity Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (4). Response Criteria Responses to treatment were analyzed according to the standard criteria (5). Complete remission and complete remission-unconfirmed were considered complete responses. Further Treatment After IMVP therapy, patients who were younger than 6, had never received an autograft, and had performance status -2 were considered candidates for autografting. Those in complete remission received cyclophosphamide and G-CSF, whereas others received mini-beam (combination of carmustine, etoposide, cytarabine, and melfalan) for stem cell mobilization (6). Autografting was performed after conditioning all patients with the BEAM. Eight out of eligible patients received an autograft, whereas 2 had an insufficient number of stem cells for safe grafting. After undergoing treatment with IMVP, 3 patients in relapse after autotransplantation received allografts. They were younger than 45 and had an HLA identical sibling donor. Conditioning was performed with cyclophosphamide and total body irradiation (7). Patients who were in partial remission after IMVP or had bulky disease (>5 cm) before IMVP received involved-field radiotherapy. Lymph node areas with active or previous bulky disease were irradiated with 36 Gy from a cobalt source. Irradiation was performed following hematopoietic recovery after transplantation. Patients in complete remission after IMVP ineligible for transplantation were irradiated as described and received no further treatment until relapse. Data Analysis SPSS for Windows Version. (SPSS Inc. Chicago, IL, USA) was used for statistical evaluation of the data. Survival function and disease-free survival function were estimated with Kaplan & Meier method (8). Log-rank test was used for survival comparison, and Spearman s rho test for group comparison. The level of significance was.5. Results Toxicity Hematologic toxicity of IMVP therapy was frequent (Table 2). In nine out of 28 patients significant hematologic toxicity resulted in treatment postponement. There were a total of 9 episodes of neutropenic fever in 78 cycles, one of them with a lethal outcome. The cause of infection was established in only 3 cases. Hemorrhagic cystitis did not occur in any of the patients. Except for nausea and vomiting, there was only a single episode of severe non-hematologic, non-infectious toxicity. One patient developed a tumor lysis syndrome, with severe hyperkalemia and increased concentrations of uric acid and creatinine (toxicity grade III). Table 2. Hematologic toxicity of IMVP treatment (ifosfamide, methotrexate, and etoposide) in patients with relapsed or refractory aggressive non-hodgkin s lymphoma No. of patients with toxicity grade Parameter I II III IV Hemoglobin Granulocytes 2 4 Platelets Response and Survival The overall response rate to IMVP treatment was 39%. Six out of 28 patients achieved a complete remission, and 5 achieved a partial remission. Median overall survival duration for the whole group was 6 months (range -42). Median progression-free survival for responders was 6 months (range -35) (Fig. ). Eight patients were subsequently autografted and three were allografted. In December 2, seven patients were still alive, six autografted, and one allografted. Three were in a complete remission, one in a partial remission, and three did not respond to IMVP (one of the non-responders was allografted). We analyzed the prognostic significance of different histologic subtypes of lymphoma, IPI score at 55

3 2 3 4 Figure. Overall survival and progression-free survival of patients with non-hodgkin s lymphoma treated with IMVP (ifosfamide, methotrexate, and etoposide). Overall survival full line; progression-free survival dashed line. the start of IMVP therapy, and disease status (refractory vs relapsed) for overall survival. Histologic Subtypes Response rate for different histological groups (follicular, B-large cell, and anaplastic large cell lymphoma) was 3 out of 8, 7 out of 4, and out of 6, respectively. Median survival was 3.5, 6.5, and 9 months, respectively. These differences were not significant (Fig. 2) Figure 2. The influence of histologic types on overall survival of patients with non-hodgkin s lymphoma treated with IMVP (ifosfamide, methotrexate, and etoposide). Anaplastic large-cell lymphoma full line; large B-cell lymphoma dotted line; follicular lymphoma dashed line. IPI Score The response rate in patients with a low IPI score (-2) was 36%. Three of them achieved a complete response lasting for a median of 25 months (range 8-35), and one achieved a partial remission. The response rate in 7 patients with a high IPI score (3-5) was 4%. Three of them achieved complete responses of the median duration of 6 months (range 3-24), and 4 had partial responses. Median survival of patients with low IPI scores (-2) was months (range 2-42), and of those with high scores (3-5) was 4 months (range -3). The difference in survival was significant (p<.5, Fig. 3) Figure 3. The influence of international prognostic index scores on overall survival of patients with non-hodgkin s lymphoma treated with IMVP (ifosfamide, methotrexate, and etoposide). IPI -2 full line; IPI 3-5 dashed line. The difference was significant (p=.422, log-rank test). Disease Status The response rate in 6 relapsing patients was 44%. Four achieved a complete response and 3 achieved a partial response. The median survival was 8 months (range 2-42). Out of 2 patients with refractory disease before IMVP, 2 achieved a partial response and 2 had a complete response. The median survival was 3.5 months (range -24). These differences were not significant (Fig. 4) Figure 4. The influence of disease status on overall survival of patients with non-hodgkin s lymphoma treated with IMVP (ifosfamide, methotrexate, and etoposide). Patients in relapse full line; refractory patients dashed line. The difference was not significant (p=.32, log-rank test). 552

4 Discussion The results of ifosfamide-based second-line regimens for the treatment of aggressive non-hodgkin s lymphoma vary substantially, with response rates ranging from 2% to 7%. Unfortunately, there is no proof that these differences result from differences in treatment efficacy rather than from differences in patient selection (7). In our institution, IMVP was a moderately effective second-line therapy with tolerable toxicity. Less than half of patients with relapsed and refractory aggressive non-hodgkin s lymphoma responded to treatment, and the median overall survival was 6 months. The incidence of toxic death was low. These outcomes are comparable with those of the British report (), but different from the MD Anderson Cancer Center study (), probably due to the difference in patient selection. Our results are comparable with most second-line regimens (9-23). Different histological types of aggressive non- Hodgkin s lymphoma have different prognosis, but histology has lower prognostic impact than IPI does (24). Due to the small number of patients in each category, we were unable to show a significant difference in outcomes between patients with follicular, B-large cell, and anaplastic large cell non-hodgkin s lymphoma. The same is true for the disease status. The patients with refractory disease are generally considered to have a worse prognosis than those who are in relapse. Our data followed such a trend, which did not reach statistical significance, probably due to the limited number of patients. In our study, IPI score (2) seemed to be the most powerful prognostic indicator for this group of patients, which is in accordance with other studies (25, 26). It is quite surprising that such a simple index should be of supreme prognostic importance in almost all histological groups of non-hodgkin s lymphoma, irrespective of the disease phase and treatment given. The only long-term survivors are patients who were transplanted after chemotherapy. This emphasizes the need to make every attempt to collect stem cells and transplant them to a patient with aggressive non-hodgkin s lymphoma who failed first-line treatment. Finally, the outcomes of our patients with non- Hodgkin s lymphoma were not satisfactory. Today, the attempts to improve the outcomes of such patients are focusing on more aggressive chemotherapy regimens with high-dose ifosfamide, e.g. ICE (27), and their combination with monoclonal antibodies, like rituximab (28). According to some reports, such regimens have response rates of almost % but are also significantly more toxic. Regarding previous unfavorable experience from the cases where aggressive treatment was adopted as a standard based only on phase II data (), it is very encouraging that a large intergroup phase III trial is being planned to compare RICE (ICE + rituximab) with a standard dose regimen combined with rituximab (R-DHAP). The results of this trial will have an important impact on the treatment of patients with relapsing or refractory aggressive non-hodgkin s lymphoma. Acknowledgment This research was supported in part by grants No. 988 and 833 from the Croatian Ministry of Science. References Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-hodgkin s lymphoma. N Engl J Med 993;328: Kluin-Nelemans HC, Zagonel V, Anastasopoulo A, Bron D, Roozendaal KJ, Noordijk EM, et al. 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