Etoposide, ifosfamide, and methotrexate with or without bleomycin in refractory or recurrent lymphomas

Annals of Oncology, Supplement 1 to Volume 2: 25-30, 1991. © 1991 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Etoposide, ifosfamide, and methotrexate with or without bleomycin in refractory or recurrent lymphomas Mohammad R. Nowrousian, Christof H. Anders, Norbert Niederle, Marianne Nagel-Hiemke, Thomas Moritz, Siegfried Seeber & Carl G. Schmidt West German Tumor Center, Department of Internal Medicine (Cancer Research), University of Essen, Essen, FRG

Key words: combination chemotherapy, refractory lymphomas, recurrent lymphomas The majority of therapeutic regimens prescribed for refractory or recurrent lymphoma have been ineffective, with complete remission (CR) achieved only rarely and briefly. To improve the rate and duration of response, new regimens containing etoposide and ifosfamide or either drug in combination with other agents were introduced. A combination of etoposide/cisplatin/prednisone produced a partial remission (PR) or minor response in 34% of patients, and patients treated with an etoposide/ifosfamide combination achieved a 70% PR or minor response rate [1,2]. Etoposide in combination with vindesine/prednisolone, carmustine/bleomycin/methotrexate, or ifosfamide/hydroxyurea resulted in 40%, 27%, and 5% CR and 20%, 13%, and 47% PR, respectively [3-5]. The most encouraging results were observed in a study using IMVP-16 (ifosfamide/methotrexate/etoposide) [6], in which an overall response rate of 81% and a CR rate of 37% were achieved. Median duration of CR was 12 months, and 42% of those achieving CR were predicted to be alive at 36 months. Such responses might be due in part to the dose and schedule of drugs used in this regimen, but a possible synergistic effect between etoposide and methotrexate might also play a role [7].

IMVP-16 appeared to be valuable for our patients with refractory or recurrent lymphoma because in general, prior therapy had not included etoposide and ifosfamide. Additionally, cross resistance between the drugs used in IMVP-16 and those used in prior therapy was apparently lacking. On the other hand, IMVP-16 is reported to be associated with considerable myelotoxicity [6]. Therefore, we used a modification of this drug combination and added bleomycin to the regimens of patients who had not received it before [8]. Bleomycin is known to be effective against malignant lymphomas, has the advantage of being nonmyelosuppressive [9], and can be given in full doses together with other agents. Results obtained with the VIM ± B regimen (etoposide/ifosfamide plus mesna/methotrexate/with or without bleomycin) are reported here, Patients and therapy Since 1984, we have used VIM + B to treat 47 patients (32 men, 15 women), ranging in age from 17 to 66 years (median 45). Of the 47,15 had relapsed following CR after first-line chemotherapy, 28 had failed to

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Summary. The prognosis of patients with refractory or relapsed malignant lymphoma is poor. To improve the outcome of such patients, a therapeutic regimen of VIM + B (etoposide/ifosfamide plus mesna/methotrexate/ with or without bleomycin) was administered. Of 47 patients treated, 15 had relapsed following complete remission (CR) after first-line chemotherapy, 28 had failed to achieve CR with first-line therapy, and four failed to respond to multiple salvage regimens. All patients had received extensive prior chemotherapy, and 36 had received combinations containing doxorubicin. Eight patients had low-grade non-Hodgkin's lymphoma (NHL), 28 had high-grade NHL, and 11 patients had Hodgkin's disease. Overall response rate was 87%, with 45% CR and 42% partial remission (PR). Median relapse-free interval was 8 months in patients with CR and 6 months in those with PR. Of patients with CR, 43% were predicted to be without relapse at 2 years and 31% at 5 years. Median survival time for all patients treated was 14 months-22 months for those with CR and 10 months for those with PR. Probability of survival at 2 years was 30% in all patients, 50% in patients with CR, and 15% in those with PR. VIM ± B appears to be effective against refractory or recurrent lymphoma, resulting in response in a large number of patients and long-term survival and possible cure in a small but significant number. Results indicate that VIM ± B is particularly effective in patients with high-grade NHL who have responded suboptimally to primary therapy.

26 Results An overall response rate of 87% was achieved, with a CR rate of 45% and a PR rate of 42%. The median relapse-free interval according to type of response was 8 months in patients with CR and 6 months in those with PR (Fig. 1). All patients with PR relapsed during a 15-month period. In CR patients, relapses that did occur also appeared during this time period, but 43% of CR patients were predicted to be relapse-free at 2 years and 31% at 5 years. The median survival time for all patients was 14 months, 22 months for those with CR, and 10 months for those with PR. The probability of survival at 2 years was 30% for all patients, 50% for patients with CR, and 15% for those with PR. Thirty-nine percent of patients with refractory lymphoma and 56% of those with relapsing disease achieved CR. The PR rates in the two groups were 48% and 31%, respectively. Relapse-free intervals and the survival rates according to disease status at beginning of therapy are shown in Fig. 2. Patients with refractory lymphoma who responded to VIM ± B had a median

24

36

48

60

72

Months

Fig. I. Relapse-free interval and survival by response type CR = complete remission; PR = partial remission.

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achieve CR with first-line chemotherapy, and four had failed to respond to multiple salvage regimens after relapse. The latter two patient groups were considered to have refractory lymphomas. All patients had received extensive prior chemotherapy, and 36 of the 47 had received combinations containing doxorubicin. Eleven patients had Hodgkin's disease, and 36 nonHodgkin's lymphoma (NHL). Low-grade NHL according to the Kiel classification [10] was present in eight patients (three centroblastic-centrocytic, three centrocytic, and two lymphoplasmocytoid), and high-grade NHL in 28 patients (11 centroblastic, two immunoblastic, three lymphoblastic, one immunoblastic-centroblastic, nine undifferentiated large cell, two pleomorphic T cell). Two percent of the 47 patients had stage I, 13% stage II, 9% stage in, and 76% stage IV disease. Physical examination, complete hematogram, and biochemical profile were performed regularly at the beginning of treatment with VIM ± B, as were plain radiograph and/or axial computed tomography (CT) of the chest; CT and/or sonography of the abdomen and pelvis; and bone scan and marrow aspirate and biopsy. All patients had measurable disease and were evaluated before each cycle of therapy for tumor response. Tumor regressions lasting at least 2 months were regarded as responses. CR was defined as the disappearance of all measurable disease and all disease-related symptoms, and PR as a reduction of more than 50% of the tumor mass. A reduction less than PR, tumor regression with regrowth between the therapy cycles, or stable disease were considered no change. VIM±B consisted of etoposide 90 mg/m2/d in a two-hour infusion, days 1, 3, 5; ifosfamide 1,200 mg/ mVd in a one-hour infusion, days 1 to 5 plus mesna 10 mg/kg intravenously (IV) immediately and four and eight hours after each ifosfamide dose; methotrexate 30 mg/mVd IV, days 1, 5; and bleomycin 15 mg/d, subcutaneously, days 1, 5, 12. In four patients with CNS involvement, one third of each methotrexate dose was given intrathecally. Bleomycin was given only to patients who had not received it previously. Treatment was repeated every 3 weeks if the peripheral neutrophil and platelet counts were above 1.5 x 10 9 /L and 100 X 109/L, respectively. The doses of etoposide and methotrexate were reduced by 30% of the initial calculated doses if granulocyte nadirs were less than 0.5 x 109/L and platelet nadirs less than 40 x 10VL. In patients with CR, two to three additional cycles of VIM ± B were given after CR was achieved. In patients with PR, VIM ± B was continued until disease progression. Each patient was considered to be evaluable for statistical analysis from the start of treatment. Duration of relapse-free interval was calculated from the achievement of response to relapse, and duration of survival from the beginning of therapy to death. Patients lost to follow-up were considered to have relapsed or died. The Kaplan-Meier method was used to plot survival curves.

27 100

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Fig. 2. Relapse-free interval and survival by disease status at initiation of therapy with etoposide/ifosfamide plus mesna/methotrexate/with or without bleomycin (VIM ± B). CR = complete remission; PR = partial remission.

Fig. 3. Relapse-free interval and survival by response type in patients with refractory lymphoma. CR = complete remission; PR = partial remission.

response duration of 8 months, compared with 5 months for those with recurrent lymphoma. Twentyseven percent of patients with refractory and 8% with recurrent lymphoma were predicted to be without disease progression at 2 years. Median survival time was 17 months for refractory lymphoma patients and 8 months for those with recurrent disease. Probability of survival at 2 years was 40% in the first group and 13% in the second. Sixty-four percent of refractory lymphoma patients with CR were estimated to be without relapse at 5 years, and their probability of survival at 5 years was 69%. In refractory lymphoma patients with PR, there was a median relapse-free interval of 4 months; all of these patients showed disease progression during the first 15 months; and none survived longer than 26 months (Fig. 3). Results according to histologic disease type are summarized in Table 1. Of 11 patients with Hodgkin's disease (eight refractory, three relapsed), three achieved CR (27%) and six PR (55%); of 36 with NHL (23

refractory, 13 relapsed), 18 had a CR (50%) and 14 a PR (39%). The CR rate for 28 patients with high-grade NHL (17 refractory, 11 relapsed) was 50%, and the PR rate was 43%. Median relapse-free interval for patients with Hodgkin's disease who responded to VIM ± B was 8 months compared with 6 months for those with NHL, and probability of relapse-free survival at 2 years was 22% in the first group and 20% in the second. Median survival time and the probability of survival at 2 or 5 years were also comparable for both groups. For patients with high-grade NHL, the largest group of patients studied, the median relapse-free interval was 6 months for both CR and PR cases (Fig. 4). However, 32% of patients with CR were predicted to remain disease-free at 5 years, whereas all patients with PR showed disease progression during the first 15 months. Median survival time was 12 months for all high-grade NHL patients - 16 months for those with CR and 12 months for those with PR. Probability of survival at 5 years was 29% for patients with CR. In contrast, no

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48

28 Table I. Response to VIM ± B according to the histologic type of lymphoma (Kiel classification). Histologic type

No. No. No. No. No. patients CR (%) PR (%) NC (%) F (%)

High-grade NHL Lymphoblastic Immunoblastic Immunoblasticcentroblastic Centroblastic Undifferentiated large cell Pleomorphic T cell Low-grade NHL Centrocytic Centroblasticcentrocytic Lymphoplasmocytoid Hodgkin's disease

28 3 2

2 11

Total

47

NHL (high-grade) CR PR

14(50) 0 0

1 11

0 9

9

4

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1 4(50) 2

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VIM ± B = etoposide/ifosfamide plus mesna/methotrexate/with or without bleomycin; CR = complete remission; PR = partial remission; NC — no change; F = failure; NHL = non-Hodgkin's lymphoma. (n = 14)

patient with PR survived longer than 26 months. Of 18 patients treated with additional bleomycin, six achieved CR (33%) and nine PR (50%). Median duration of response was 7 months for CR and 3 months for PR. Probability of relapse-free survival at 2 and 5 years was 33% for CR patients. In contrast, disease progression occurred in all PR patients during the first 9 months. Of the 29 patients treated without bleomycin, 15 achieved CR (52%) and 11 PR (38%). Median duration of response was 10 months and 8 months for CR and PR patients, respectively. Forty-eight percent of CR patients were estimated to be without relapse at 2 years and 29% at 5 years. All patients with PR, however, relapsed during the first 15 months. VIM ± B toxicities were well tolerated and acceptable. All patients received accompanying antiemetic therapy, which may explain why the majority experienced only mild to moderate nausea and vomiting. Other toxicities, observed in a total of 203 therapy courses, were as follows: moderate fever 4%; moderate to severe stomatitis 2%; minimal microhematuria 9%; and mild reversible liver dysfunction 8%. Severe stomatitis occurred only in patients with CNS involvement who received methotrexate intrathecally. A moderate, bleomycin-induced pneumonitis, a reversible, druginduced hyperbilirubinemia, and an episode of septicemia occurred. No therapy-related death was observed. In 86%, the calculated full drug doses could be given. The median day for the lowest blood cell count was day 14; median lowest leukocyte count was 1.95 x 10VL (range 0.3 to 6.2), and median lowest platelet count was 107 x 10YL (range, 7 to 436).

(n = 28)

24

36

48

60

72

Months

Fig. 4. Relapse-free interval and survival by response type in patients with high-grade non-Hodgkin's lymphoma (NHL). CR = complete remission; PR = partial remission.

Discussion A number of studies have been performed to improve response in patients with refractory or recurrent lymphomas. Although overall response rates of 34% to 70% have been achieved, CR rates have usually remained low and responses have been brief [1,3-5,11]. The most encouraging results were obtained in a study using the drug combination IMVP-16 [6] in which the overall response rate was 81% and the CR rate 37%. In addition, 42% of patients achieving CR were predicted to be alive at 36 months. The effectiveness of ifosfamide/etoposide combinations in adequate doses has also been shown in other studies [8,12-14]. In one study, methyl-GAG, a nonmyelosuppressive agent, was added to IMVP-16 [13,15], resulting in an overall response rate of 60% with 24% CR. This new combination (MIME [methyl-GAG/ifosfamide/methotrexate/etoposide]) appeared to induce a higher response rate in low-grade follicular lymphomas than had

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1 0 2(25) 2(25)

29 ry therapy. It therefore appears reasonable to evaluate the effectiveness of this regimen as part of front-line therapy in patients with aggressive NHL. Acknowledgment

We wish to thank Mrs. B. Maranca for her excellent assistance in the statistical analysis of the data. References 1. Cavalli F. VP-16 in the treatment of malignant lymphomas: A report from the Swiss Group for Clinical Cancer Research (SAKK). Semin Oncol 1985; 12: 33-36. 2. Scheulen ME, Bremer K, Niederle N et al. Treatment of refractory malignant lymphomas with ifosfamide/etoposide combination chemotherapy. Cancer Treat Rev 1983; 10:137-143. 3. Gasser AB, Steward WP, Wagstaff J et al. Treatment of relapsed non-Hodgkin's lymphoma with a combination of hydroxyurea, ifosfamide, and etoposide. Cancer Treat Rep 1985; 69: 225-226. 4. Hancock BW. Vindesine, etoposide (VP-16), and prednisolone (VEP) in relapsed patients with grade II non-Hodgkin's lymphoma. Semin Oncol 1985; 12: 26-28. 5. Helms SR, Oblon DJ, Braylan RC et al. Etoposide, carmustine, bleomycin, and methotrexate with leucovorin rescue as retreatment for unfavorable non-Hodgkin's lymphoma. Cancer Treat Rep 1985; 69: 783-786. 6. Cabanillas F, Hagemeister FB, Bodey GP et al. IMVP-16: An effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy. Blood 1982; 60:693-697. 7. Yalowich CJ, Fry DW, Goldman ID. Teniposide (VM-26)- and etoposide (VP-16-213)-induced augmentation of methotrexate transport and polyglutamylation in Ehrlich ascites tumor cells in vitro. Cancer Res 1982; 42: 3648-3653. 8. Nowrousian MR, Schoetensack B, Pfeiffer R et al. Combination chemotherapy with etoposide (VP-16), ifosfamide, methotrexate, and bleomycin (VIM(B)) for refractory or recurrent lymphomas. Contrib Oncol 1987; 26: 414-422. 9. Haas CD, Coltman CA, Gottlieb JA et al. Phase II evaluation of bleomycin; A Southwest Oncology Group Study. Cancer 1976; 38: 8-12. 10. Lennert K, Mohri N, Stein H et al. The histopathology of malignant lymphoma. Br J Haematol 1975; 31:193-203. 11. Corder MP, Clamon GH. Salvage therapy of aggressive nonHodgkin's lymphoma with a combination of vinblastine, bleomycin, and cisplatin. Cancer 1984; 54: 202-206. 12. Busch FW, Kriiger HU, Kraft A et al. Combination of ifosfamide, methotrexate, VP-16, and bleomycin (IMV-BLEO) as salvage therapy for non-Hodgkin's lymphoma. Contrib Oncol 1987; 26:425-430. 13. Cabanillas F, Hagemeister FB, McLaughlin P et al. Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 1987; 5:407-412. 14. Heinz R, Dittrich CH, Ludwig H et al. Results of a new drug combination (VP-16 - Ifosfamide - Mitoxantrone - Bleomycin/VIM-BLEO) in advanced non-Hodgkin's lymphomas. Contrib Oncol 1987; 26:438-445. 15. Cabanillas F, Velasquez WS, McLaughlin P et al. Results of recent salvage chemotherapy regimens for lymphoma and Hodgkin's disease. Semin Hematol 1988; 25:47-50. 16. Cabanillas F, Jagannath S, Philip T. Management of recurrent or refractory disease, in Magrath IT (ed): The Non-Hodgkin's Lymphoma. London, Melbourne, Auckland, Edward Arnold, 1990, pp 360-372.

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IMVP-16 alone. In large cell lymphomas, however, the effectiveness of the two regimens seemed to be comparable [16]. In our study, an overall response rate of 87% and a CR rate of 45% was achieved with VIM ± B. Furthermore, 43% of CR patients were predicted to be relapse-free at 2 years and 31% at 5 years. These results appear to be similar to those obtained with IMVP-16 or MIME. Considering the frequency of infection and mucositis, however, VIM ± B seems to be more tolerable. Results obtained with IMVP-16, MIME, and VIM + B are also comparable with those of the newly developed regimen DHAP (dexamethasone/high-dose cytarabine/cisplatin [17]. The latter is reportedly associated with considerable myelotoxicity, but is more effective than MIME in low-grade lymphomas, and can be useful in patients who have already received etoposide or ifosfamide [16]. In the present study, patients who were treated with additional bleomycin showed a lower CR rate and shorter median duration of CR or PR than did patients who were not treated with bleomycin. Long-term results, however, were comparable in the two groups of patients. Additional bleomycin was also used in another study [12], in which observed CR rate and duration of remission were almost comparable with those obtained in our study patients treated without bleomycin. In both studies, the majority of patients had high-grade NHL. As in the MIME study, addition of a nonmyelosuppressive agent may not improve results in these patients. However, the therapeutic role of bleomycin added to VIM should be further investigated. Although the CR rate was higher in patients with NHL than in those with Hodgkin's disease, overall response rate and duration of response, as well as probability of long-term survival, were similar in the two groups. VIM ± B appeared to be particularly effective in patients with high-grade NHL. One half of these patients responded with CR, and 32% of those with CR were estimated to be disease-free and possibly cured at 5 years. The majority of these long-term survivors had refractory lymphoma and had failed to achieve a CR with primary therapy. Similar observations were made in another study [12]. These results have encouraged the use of etoposide/ifosfamide/ methotrexate combinations in sequential chemotherapeutic regimens for aggressive lymphomas, which have led to high CR rates and high probabilities of long-term survival [18-22]. On the basis of these results, VIM ± B appears to be an effective, well-tolerated regimen for refractory or recurrent lymphomas both in Hodgkin's disease and NHL. Treatment with VIM ± B leads to a large number of responses and longer remission durations for patients with recurrent lymphomas. In refractory disease patients high CR rates can be achieved. Significant numbers of responders experience long-term survival and possible cure, particularly those with high-grade NHL who have showed suboptimal response to prima-

30 17. Velasquez WS, Cabanillas F, Salvador P et al. Effective salvage therapy for lymphoma with cisplatin in combination with highdose ara-C and dexamethasone (DHAP). Blood 1988; 71: 117-122. 18. Cabanillas F, Burgess MA, Bodey GP et al. Sequential chemotherapy and late intensification for malignant lymphomas of aggressive histologic type. Am J Med 1983; 74: 382-388. 19. Gerhartz HH, Thiel E, Brittinger G et al (NHL Study group). German-Austrian multicenter trial for aggressive non-Hodgkin lymphomas: COP-BLAM/IMVP-16 chemotherapy with randomized adjuvant radiotherapy. Blut 1988; 56:139-142. 20. Herbrecht R, Garcia JJ, Bergerat JP et al. VP-16, ifosfamide, and methotrexate combination chemotherapy for aggressive non-Hodgkin's lymphomas after failure of the LNH 84 regimen. Cancer Chemother Pharmacol 1989; 24: 338-339.

21. Nowrousian MR, Meier CR, Schoetensack B et al. Sequential combination chemotherapy (CA-BOPP/VIM) for the treatment of high-grade malignant non-Hodgkin's lymphoma. Acta Oncol 1989; 28: 495-500. 22. Steinke B, Kriiger HU, Kraft H et al. Response-oriented therapy with CHOP and VIM-Bleo in high-grade malignant nonHodgkin's lymphomas. Blut 1988; 56: 269-271. Correspondence to: Mohammed R. Nowrousian, MD West German Tumor Center University of Essen Department of Internal Medicine (Cancer Research) Hufelandstr. 55 4300 Essen 1, FRG

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