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ifosfamide, mitoxantrone and etoposide for refractory lymphomas
Annals of Oncology 6: 609-611, 1995. O 1995 Kluwer Academic Publishers. Printed in the Netherlands.
Short report A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas M. A. Rodriguez, F. C. Cabanillas, F. B. Hagemeister, P. McLaughlin, J. E. Romaguera, F. Swan & W. Velasquez Department of Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, U.S.A.
in 8 patients and intermediate in 40 patients. In the latter group, 12 were transformed from low grade. Background: We have previously reported that combination Results: Overall, 48% of the patients responded, with 21% chemotherapy based on the drugs cytarabine/platinum is having a complete response (CR), and 27% having a partial effective in recurring lymphomas. In this phase II study, we response (PR). The median survival time was 9 months, and prospectively studied a combination regimen of mesna/ifos- the median follow-up of survivors is 51 months at this writfamide, mitoxantrone and etoposide (MINE) in patients with ing. Median time to treatment failure was 12 months for recurring lymphoma who had already received cytarabine/ patients with complete responses, and 5 months for patients platinum but did not respond to the treatment. with partial responses. The most serious complication was Patients and methods: 48 patients received MINE at the myelosuppression, with 2 deaths resulting from neutropenic following doses: mesna 1.33 g/m2 IV daily x 3 , and 500 mg infection. p.o. daily 4 hours after each IV dose; ifosfamide 1.33 g/m2 Conclusion: The MINE regimen induced responses in a IV daily, given concurrently with mesna, x 3 d; mitoxan- moderate fraction of patients after their prior exposure to trone 8 mg/m2 IV on day 1; and etoposide 65 mg/m2 IV cytarabine/platinum salvage therapy, indicating there is no daily x3. Treatment cycles were 21-28 days apart, depend- absolute cross resistance between these drug regimens. ing on patients' blood counts, with a maximum number of 6 cycles in responding patients. The histologic grade of the lymphomas according to the Working Formulation was low Key words: ifosfamide, salvage therapy, lymphoma Summary
Introduction
Patients and methods
Relapse of lymphoma, particularly if it is of intermediate or high grade, is generally associated with short survival times. A small fraction of patients, however, can gain more time by treatment with standard dose chemotherapies [1]. Newer strategies of dose intensification with hematopoetic stem cell rescue may increase the fraction of successful long term patient survival. This approach, however, is not currently accepted therapy for patients over 60 years of age, and its greatest benefit is for patients whose disease shows chemosensitivity to standard treatment strategies [2]. We previously reported the efficacy of cytarabine/platinum-based combination chemotherapy regimens in patients with relapsed lymphoma [3,4]. In this study, we treated patients whose disease did not respond or became refractory to cytarabine/platinum (Ara-C/Plat) therapy with a combination chemotherapy regimen containing mesna/ifosfamide, mitoxantrone, and etoposide (MINE).
Patients who had a histologically proven diagnosis of any grade of lymphoma (graded according to the Working Formulation) were eligible for the study [5]. All patients had a history of prior treatment with a regimen containing anthracycline. Also, all patients had had either no response, or a response of <6 months duration, to one of the following regimens: DHAP (dexamethasone, high-dose cytarabine, platinum); ESHAP (etoposide, methylprednisolone, high-dose cytarabine, platinum); or ASHAP (doxorubicin, methylprednisolone, high-dose cytarabine, platinum) [3, 4, 6). The physiologic and clinical selection criteria were: a Zubrod performance status <4; creatinine <1.5 mg/dl; total bilirubin <1.5 mg/dL; granulocytes >1200 cells/mm3 and a platelet count > 100,000 cells/mm3 unless patients had disease in their bone marrow, and left ventricular ejection fraction >50% by MUGA scan. There were no limitations related to patient age. Informed consent was obtained from all patients in accordance with our Institutiona] Review Board guidelines. The doses of agents in MINE were as follows: mesna 4 gm/m2, divided over 3 days and administered IV over 1 h. (1.33 gm/m2 daily x 3) mixed in the same intravenous solution with ifosfamide 4 gm/ m2 divided over 3 days and administered IV over 1 h. Four hours after ifosfamide therapy, patients received an additional dose of mesna, 500 mg diluted in water or juice and taken by mouth. This
610 approach allowed us to give treatment on an outpatient basis. Mitoxantrone 8 mg/m2 was administered as a short FV infusion on day 1. Etoposide 65 mg/m2 daily was infused over 1 h on days 1-3. Responses to treatment was defined as complete (CR) if patients showed no evidence of disease for at least 2 months and partial (PR) if all measurable lesions shrank at least 50% in two different diameter measurements for at least a month. Severity of toxic effects was graded according to the World Health Organization guidelines [7]. Survival, time to treatment failure, and disease-free survival were determined from the date of registration on the study [8). Curves relating these parameters were constructed by the method of Kaplan and Meier [9].
sponse rates were correlated with histologic grade or a specific prior ara-C/Plat regimen. The median survival time was 9 months, and the median time to treatment failure was 3 months (Fig. 1). Given that the overall response rate was <50%, we expected that, in general, the time to treatment failure would be short. Therefore, we also analyzed time to treatment failure according to response. The median time to treatment failure was 12 months for patients with CR, and 5 months for patients with PR.
Results 1
Clinical features
TIME TO TREATMENT FAILURE AND SURVIVAL
0.9
The clinical features of the 48 patients, are shown in Table 1. The majority of the patients had intermediate grade histology: 21 patients had diffuse large cell lymphoma; 3 had follicular large cell lymphoma; 2 had diffuse mixed cell lymphoma; 1 had diffuse small cleaved cell lymphoma; and 12 had transformed from a low grade histology at diagnosis to intermediate grade at relapse. One patient with lymphoblastic lymphoma of high grade histology was analyzed with the intermediate grade cohort Eight patients had low grade histology: 4 had follicular small cleaved cell lymphoma; 2 had follicular mixed cell lymphoma; and 2 had diffuse small lymphocytic lymphoma.
-m-
TTF
-*-
SURV
03 07 *
03
— • -
—• 23
30 SS UONTHS
Fig. 1. Time to treatment failure and survival for the 48 patients treated with MINE, after prior anthracycline and ara-C/Platinum based combination chemotherapies.
Response Overall, 48% of the patients responded to treatment, and 21% achieved CR. The median follow-up time for survivors is 51 months. No significant differences in reTable 1. Patient characteristics. Median (range) Age (years) Prior regimens LDH (IU/L) B2M (mg/dl)
54 (24-78) 2 (2-5) 758 (155-8367) 4.0(1.4-11) Number of patients
Male/female Histology grade Low Intermediate Transformed Response to primary therapy No response Partial response Complete response <12 months duration > 12 months duration Unknown
30/18 8 28 12 4 18 15 91 2
" Two follicular small cleaved cell, two diffuse large cell, five transformed.
Toxic effects
In the 176 cycles of chemotherapy that were given, the most significant toxic effect we saw in patients was myelosuppression. Among the patients with myelosuppression, the mean absolute granulocyte count was 700 cells/mm3 (± 1,200 SD), the mean platelet count was 92,000 cells/mm3 (± 72,000 SD), and the mean hemoglobin was 8.8 gm/dL (± 1.7 SD). There were 25 episodes of neutropenic fever. Two patients died of sepsis. Three patients experienced bleeding associated with thrombocytopenia: one had hematuria; one had guaiac positive stools (the patient was tested in response to a complaint of abdominal pain); and one had 'coffee grounds' emesis. All patients developed alopecia. Other significant non-hematologic toxicities included neurological and renal dysfunction. Of most clinical significance, the creatinine levels of 6 patients rose to 2.0 gm/dL, and 10 had reversible neurologic symptoms of confusion or somnolence related to ifosfamide. One patient with grade 4 neurotoxicity had reversible coma. One patient had a seizure, and underlying central nervous system involvement by lymphoma was discovered. In one patient an asymptomatic drop in LVEF (below normal) occurred and in a second patient congestive heart failure developed.
611 Discussion
References
The lymphomas of the patient population treated on this protocol had shown clinically aggressive courses with either poor responses to frontline treatment and/ or progression on second line therapy. All the lymphomas had been treated previously with anthracycline based regimens and Ara-C/Plat regimens. Thus, the responses to the MINE regimen noted in the study are of interest, indicating that ifosfamide in combination with etoposide and mitoxantrone may act against some tumors despite resistance mechanisms to the other drugs employed. The median time to treatment failure was 12 months for patients with complete responses and 5 months for patients who had partial responses. These numbers are comparable with the results seen in patients who received the MIME and ESHAP regimens [1,4]. The most serious toxic effect of MINE seen in this population was myelosuppression, which was surprisingly severe given the modest doses of each of the drugs used in the regimen. The degree of myelosuppression was much lower in another cohort of patients treated with MINE at the same doses, but who specifically had not had prior exposure to Ara-C/Plat [10]. This was also true of nephrotoxicity and neurotoxicity. It is possible that, despite having normal creatinine levels, the patients with prior platinum exposure have a decreased clearance of ifosfamide metabolites or that their bone marrow, kidneys, and CNS are sensitized to ifosfamide toxicity by prior platinum therapy. We conclude that the MINE regimen has moderate activity in patients who have been exposed to Ara-C/ Plat combinations, indicating total cross resistance between these drug combinations does not occur. The median time to treatment failure for complete responses was a year, thus the best use of this regimen could be in a strategy that includes prompt consolidation of response with intense chemotherapy with or without hematopoetic stem cell rescue.
1. Cabanillas F, Hagemeister FB, McLaughlin P et al. Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 1987; 5:407-12. 2. Wheeler C, Strawderman M, Ayash L et al. Prognostic factors for treatment outcome in auto-transplantation of intermediategrade and high-grade non-Hodgkin's lymphoma with cyclophosphamide, carmustine, and etoposide. J Clin Oncol 1993; 11:1085-91. 3. Velasquez WS, CabaniUas F, Salvador P et al. Effective salvage therapy for lymphoma with cisplatin in combination with high dose Ara-C and dexamethasone (DHAP). Blood 1988; 71: 117-22. 4. Velasquez WS, McLaughlin P, Tucker S et al. ESHAP - an effective chemotherapy regimen in refractory and relapsing lymphoma; A 4-year follow-up study. J Clin Oncol 1994; 12: 1169-76. 5. Non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classification of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. Cancer 1982; 49: 2112-35. 6. CabaniUas F, McLaughlin P, Hagemeister FB et al. Improvement in survival and disease free survival of intermediate grade (IGL) and immunoblastic lymphomas (IBL) treated with the novel ATT regimen. Proc Am Soc Clin Oncol 1994; 13: 338 (Abstr). 7. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment Cancer 1981; 47: 207-14. 8. Dixon DO, McLaughlin P, Hagemeister GB et al. Reporting outcomes in Hodgkin's disease and lymphoma. J Clin Oncol 1987; 5:1670-2. 9. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 10. Rodriguez MA, CabaniUas F, Hagemeister F et al. MINEESAP: A novel and effective salvage combination for lymphoma. Proc Am Soc Clin Oncol 1992; 11: 327 (Abstr 1114). Received 14 February 1995; accepted 2 May 1995. Correspondence to: M. Alma Rodriguez, M.D. U.T. M.D. Anderson Cancer Center 1515 Holcombe Blvd., Box 68 Houston, TX 77030 USA.
Short report A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas M. A. Rodriguez, F. C. Cabanillas, F. B. Hagemeister, P. McLaughlin, J. E. Romaguera, F. Swan & W. Velasquez Department of Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, U.S.A.
in 8 patients and intermediate in 40 patients. In the latter group, 12 were transformed from low grade. Background: We have previously reported that combination Results: Overall, 48% of the patients responded, with 21% chemotherapy based on the drugs cytarabine/platinum is having a complete response (CR), and 27% having a partial effective in recurring lymphomas. In this phase II study, we response (PR). The median survival time was 9 months, and prospectively studied a combination regimen of mesna/ifos- the median follow-up of survivors is 51 months at this writfamide, mitoxantrone and etoposide (MINE) in patients with ing. Median time to treatment failure was 12 months for recurring lymphoma who had already received cytarabine/ patients with complete responses, and 5 months for patients platinum but did not respond to the treatment. with partial responses. The most serious complication was Patients and methods: 48 patients received MINE at the myelosuppression, with 2 deaths resulting from neutropenic following doses: mesna 1.33 g/m2 IV daily x 3 , and 500 mg infection. p.o. daily 4 hours after each IV dose; ifosfamide 1.33 g/m2 Conclusion: The MINE regimen induced responses in a IV daily, given concurrently with mesna, x 3 d; mitoxan- moderate fraction of patients after their prior exposure to trone 8 mg/m2 IV on day 1; and etoposide 65 mg/m2 IV cytarabine/platinum salvage therapy, indicating there is no daily x3. Treatment cycles were 21-28 days apart, depend- absolute cross resistance between these drug regimens. ing on patients' blood counts, with a maximum number of 6 cycles in responding patients. The histologic grade of the lymphomas according to the Working Formulation was low Key words: ifosfamide, salvage therapy, lymphoma Summary
Introduction
Patients and methods
Relapse of lymphoma, particularly if it is of intermediate or high grade, is generally associated with short survival times. A small fraction of patients, however, can gain more time by treatment with standard dose chemotherapies [1]. Newer strategies of dose intensification with hematopoetic stem cell rescue may increase the fraction of successful long term patient survival. This approach, however, is not currently accepted therapy for patients over 60 years of age, and its greatest benefit is for patients whose disease shows chemosensitivity to standard treatment strategies [2]. We previously reported the efficacy of cytarabine/platinum-based combination chemotherapy regimens in patients with relapsed lymphoma [3,4]. In this study, we treated patients whose disease did not respond or became refractory to cytarabine/platinum (Ara-C/Plat) therapy with a combination chemotherapy regimen containing mesna/ifosfamide, mitoxantrone, and etoposide (MINE).
Patients who had a histologically proven diagnosis of any grade of lymphoma (graded according to the Working Formulation) were eligible for the study [5]. All patients had a history of prior treatment with a regimen containing anthracycline. Also, all patients had had either no response, or a response of <6 months duration, to one of the following regimens: DHAP (dexamethasone, high-dose cytarabine, platinum); ESHAP (etoposide, methylprednisolone, high-dose cytarabine, platinum); or ASHAP (doxorubicin, methylprednisolone, high-dose cytarabine, platinum) [3, 4, 6). The physiologic and clinical selection criteria were: a Zubrod performance status <4; creatinine <1.5 mg/dl; total bilirubin <1.5 mg/dL; granulocytes >1200 cells/mm3 and a platelet count > 100,000 cells/mm3 unless patients had disease in their bone marrow, and left ventricular ejection fraction >50% by MUGA scan. There were no limitations related to patient age. Informed consent was obtained from all patients in accordance with our Institutiona] Review Board guidelines. The doses of agents in MINE were as follows: mesna 4 gm/m2, divided over 3 days and administered IV over 1 h. (1.33 gm/m2 daily x 3) mixed in the same intravenous solution with ifosfamide 4 gm/ m2 divided over 3 days and administered IV over 1 h. Four hours after ifosfamide therapy, patients received an additional dose of mesna, 500 mg diluted in water or juice and taken by mouth. This
610 approach allowed us to give treatment on an outpatient basis. Mitoxantrone 8 mg/m2 was administered as a short FV infusion on day 1. Etoposide 65 mg/m2 daily was infused over 1 h on days 1-3. Responses to treatment was defined as complete (CR) if patients showed no evidence of disease for at least 2 months and partial (PR) if all measurable lesions shrank at least 50% in two different diameter measurements for at least a month. Severity of toxic effects was graded according to the World Health Organization guidelines [7]. Survival, time to treatment failure, and disease-free survival were determined from the date of registration on the study [8). Curves relating these parameters were constructed by the method of Kaplan and Meier [9].
sponse rates were correlated with histologic grade or a specific prior ara-C/Plat regimen. The median survival time was 9 months, and the median time to treatment failure was 3 months (Fig. 1). Given that the overall response rate was <50%, we expected that, in general, the time to treatment failure would be short. Therefore, we also analyzed time to treatment failure according to response. The median time to treatment failure was 12 months for patients with CR, and 5 months for patients with PR.
Results 1
Clinical features
TIME TO TREATMENT FAILURE AND SURVIVAL
0.9
The clinical features of the 48 patients, are shown in Table 1. The majority of the patients had intermediate grade histology: 21 patients had diffuse large cell lymphoma; 3 had follicular large cell lymphoma; 2 had diffuse mixed cell lymphoma; 1 had diffuse small cleaved cell lymphoma; and 12 had transformed from a low grade histology at diagnosis to intermediate grade at relapse. One patient with lymphoblastic lymphoma of high grade histology was analyzed with the intermediate grade cohort Eight patients had low grade histology: 4 had follicular small cleaved cell lymphoma; 2 had follicular mixed cell lymphoma; and 2 had diffuse small lymphocytic lymphoma.
-m-
TTF
-*-
SURV
03 07 *
03
— • -
—• 23
30 SS UONTHS
Fig. 1. Time to treatment failure and survival for the 48 patients treated with MINE, after prior anthracycline and ara-C/Platinum based combination chemotherapies.
Response Overall, 48% of the patients responded to treatment, and 21% achieved CR. The median follow-up time for survivors is 51 months. No significant differences in reTable 1. Patient characteristics. Median (range) Age (years) Prior regimens LDH (IU/L) B2M (mg/dl)
54 (24-78) 2 (2-5) 758 (155-8367) 4.0(1.4-11) Number of patients
Male/female Histology grade Low Intermediate Transformed Response to primary therapy No response Partial response Complete response <12 months duration > 12 months duration Unknown
30/18 8 28 12 4 18 15 91 2
" Two follicular small cleaved cell, two diffuse large cell, five transformed.
Toxic effects
In the 176 cycles of chemotherapy that were given, the most significant toxic effect we saw in patients was myelosuppression. Among the patients with myelosuppression, the mean absolute granulocyte count was 700 cells/mm3 (± 1,200 SD), the mean platelet count was 92,000 cells/mm3 (± 72,000 SD), and the mean hemoglobin was 8.8 gm/dL (± 1.7 SD). There were 25 episodes of neutropenic fever. Two patients died of sepsis. Three patients experienced bleeding associated with thrombocytopenia: one had hematuria; one had guaiac positive stools (the patient was tested in response to a complaint of abdominal pain); and one had 'coffee grounds' emesis. All patients developed alopecia. Other significant non-hematologic toxicities included neurological and renal dysfunction. Of most clinical significance, the creatinine levels of 6 patients rose to 2.0 gm/dL, and 10 had reversible neurologic symptoms of confusion or somnolence related to ifosfamide. One patient with grade 4 neurotoxicity had reversible coma. One patient had a seizure, and underlying central nervous system involvement by lymphoma was discovered. In one patient an asymptomatic drop in LVEF (below normal) occurred and in a second patient congestive heart failure developed.
611 Discussion
References
The lymphomas of the patient population treated on this protocol had shown clinically aggressive courses with either poor responses to frontline treatment and/ or progression on second line therapy. All the lymphomas had been treated previously with anthracycline based regimens and Ara-C/Plat regimens. Thus, the responses to the MINE regimen noted in the study are of interest, indicating that ifosfamide in combination with etoposide and mitoxantrone may act against some tumors despite resistance mechanisms to the other drugs employed. The median time to treatment failure was 12 months for patients with complete responses and 5 months for patients who had partial responses. These numbers are comparable with the results seen in patients who received the MIME and ESHAP regimens [1,4]. The most serious toxic effect of MINE seen in this population was myelosuppression, which was surprisingly severe given the modest doses of each of the drugs used in the regimen. The degree of myelosuppression was much lower in another cohort of patients treated with MINE at the same doses, but who specifically had not had prior exposure to Ara-C/Plat [10]. This was also true of nephrotoxicity and neurotoxicity. It is possible that, despite having normal creatinine levels, the patients with prior platinum exposure have a decreased clearance of ifosfamide metabolites or that their bone marrow, kidneys, and CNS are sensitized to ifosfamide toxicity by prior platinum therapy. We conclude that the MINE regimen has moderate activity in patients who have been exposed to Ara-C/ Plat combinations, indicating total cross resistance between these drug combinations does not occur. The median time to treatment failure for complete responses was a year, thus the best use of this regimen could be in a strategy that includes prompt consolidation of response with intense chemotherapy with or without hematopoetic stem cell rescue.
1. Cabanillas F, Hagemeister FB, McLaughlin P et al. Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 1987; 5:407-12. 2. Wheeler C, Strawderman M, Ayash L et al. Prognostic factors for treatment outcome in auto-transplantation of intermediategrade and high-grade non-Hodgkin's lymphoma with cyclophosphamide, carmustine, and etoposide. J Clin Oncol 1993; 11:1085-91. 3. Velasquez WS, CabaniUas F, Salvador P et al. Effective salvage therapy for lymphoma with cisplatin in combination with high dose Ara-C and dexamethasone (DHAP). Blood 1988; 71: 117-22. 4. Velasquez WS, McLaughlin P, Tucker S et al. ESHAP - an effective chemotherapy regimen in refractory and relapsing lymphoma; A 4-year follow-up study. J Clin Oncol 1994; 12: 1169-76. 5. Non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classification of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. Cancer 1982; 49: 2112-35. 6. CabaniUas F, McLaughlin P, Hagemeister FB et al. Improvement in survival and disease free survival of intermediate grade (IGL) and immunoblastic lymphomas (IBL) treated with the novel ATT regimen. Proc Am Soc Clin Oncol 1994; 13: 338 (Abstr). 7. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment Cancer 1981; 47: 207-14. 8. Dixon DO, McLaughlin P, Hagemeister GB et al. Reporting outcomes in Hodgkin's disease and lymphoma. J Clin Oncol 1987; 5:1670-2. 9. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 10. Rodriguez MA, CabaniUas F, Hagemeister F et al. MINEESAP: A novel and effective salvage combination for lymphoma. Proc Am Soc Clin Oncol 1992; 11: 327 (Abstr 1114). Received 14 February 1995; accepted 2 May 1995. Correspondence to: M. Alma Rodriguez, M.D. U.T. M.D. Anderson Cancer Center 1515 Holcombe Blvd., Box 68 Houston, TX 77030 USA.