Japanese Journal of Clinical Oncology

Division of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei, and National Yang-Ming University School of Medicine, Taipei, Taiwan

High-dose cytarabine alone or in combination with mitoxantrone has been shown to be active against refractory non-Hodgkin's lymphoma in therapeutic trials. We administered these two drugs to 16 patients with advanced and refractory non-Hodgkin's lymphoma. Cytarabine was administered at 3 g/m² as a 2-h intravenous infusion every 12 h on days 1-4 (8 doses) and mitoxantrone at 6 mg/m²/day as a 1-h intravenous infusion on days 1-5. The clinical efficacy and toxicity were assessed according to the WHO criteria. Five patients (31%, 95% CI: 8-54%) attained complete remission and two had partial remission. In three of the five complete remission patients, the remission lasted for >4 months. The remaining two patients had complete remission for only 1.3 months. Myelosuppression with subsequent infection was the major toxicity of this regimen. Severe leukopenia (WBC <1000/[mu]l) lasted for an average of 20 days and thrombocytopenia (<25 000/[mu]l) 18 days. Five patients (31%) died of treatment-related complications: neutropenia-associated sepsis in three, pneumonia in one and electrolyte imbalance in one. Nonmyeloid toxicities included alopecia in 100% (19% Gr.2, 75% Gr.3), stomatitis in 88% (13% Gr.2, 31% Gr.3), hepatotoxicity in 38% (6% Gr.2, 6% Gr.3), dermatitis in 31% (19% Gr.2), CNS toxicity in 25% (6% Gr.2, 6% Gr.3), infection in 38% (13% Gr.3, 19% Gr.4) and chemical conjunctivitis in 6% (Gr.2). We conclude that a proportion of refractory non-Hodgkin's lymphoma cases will respond to high-dose cytarabine + mitoxantrone, but that the treatment seems too toxic to be acceptable as salvage therapy for refractory non-Hodgkin's lymphoma.

Key words: high-dose ara-C- mitoxantrone - refractory non-Hodgkin's lymphoma

INTRODUCTION

Although the treatment of advanced diffuse non-Hodgkin's lymphoma (NHL) has improved considerably, long-term patient survival using the current therapies still remains less than 50% (1 ). Despite a high initial response rate to therapy, relapse of lymphoma is usually associated with a poor prognosis (2 ). Salvage chemotherapy for such patients is indicated. Since it seems feasible to administer either new drugs or regimens with old agents, the use of larger doses of conventional drugs has been suggested as an approach to overcoming the problem of resistance (3 ).

Cytarabine (ara-C), generally administered at a dose of 100-200 mg/m²/day, is effective for treatment of acute leukemia and malignant lymphoma (4 ). Its clinical efficacy, especially at high dose, against malignant lymphoma resistant to conventional treatment has been demonstrated by Rudnick et al. (5 ). Several phase-II studies have confirmed the activity of mitoxantrone against refractory or relapsed NHL (6 ,7 ). An active combination of high-dose ara-C and mitoxantrone in the treatment of refractory NHL without excessive toxicity has also been reported (8 ). Therefore we were interested to determine whether this regimen would be effective and tolerable for Chinese patients. Here we report preliminary data on the efficacy and toxicity of high-dose ara-C + mitoxantrone in 16 Chinese patients with refractory NHL.

MATERIALS AND METHODS

Between October 1993 and September 1994, 16 patients with advanced NHL refractory to conventional treatment were considered eligible for this study. All had records of measurable biopsy-confirmed NHL, normal serum transaminase and creatinine levels and no active infection. The classification of disease was based on the Working Formulation. All patients gave their written informed consent. Their characteristics are shown in Table 1 .

Table 1 . Patients' characteristics and treatment responses

No.	Age/sex	Histology	Stage	Prior treat.	Resp.	Durat. (mo)	OS (mo)
1	45/M	Immunoblastic	III	CHOP * 9	-	-	0.6
2	52/M	Follicular large	III	CHOP * 6	CR	1.3	1.3
				MBACOD * 4
3	32/M	Diffuse mixed	III	COPBLAM * 6	PR	21	23
4	70/M	Immunoblastic	IV	CHOP * 6	-	-	0.3
				MBACOD * 1
5	33/F	Diffuse large	III	CHOP * 6	NR	-	3
6	44/M	Diffuse mixed	IV	MBACOD * 5	NR	-	2.6
7	22/M	Lymphoblastic	IV	CHOP * 1	CR	1.3	1.3
				L-OPD * 2
8	44/M	Diffuse large	IV	CHOP * 3	PR	4	5
				MBACOD * 1
9	38/M	Diffuse mixed	III	COPBLAM * 5	CR	4	4
10	68/M	Diffuse mixed	IV	CHOP * 6	-	-	0.4
				MBACOD * 5
11	35/F	Diffuse large	IV	CHOP * 3	-	-	0.4
12	45/M	Diffuse mixed	IV	CHOP * 1	NR	-	1.9
				MBACOD * 2
13	26/F	Immunoblastic	IV	CHOP * 2	-	-	0.9
14	44/M	Diffuse large	III	MBACOD * 6	CR	>11	>11
15	39/M	Diffuse mixed	IV	CHOP * 6	CR	>9	>9
16	47/F	Diffuse large	III	CHOP * 4	NR	-	2.5
				MBACOD * 2

M, male; F, female; CR, complete remission; PR, partial remission; NR, non-responders; CHOP, cyclophosphamide, adriamycin, oncovin, prednisolone; MBACOD, methotrexate, bleomycin, adriamycin, cyclophosphamide, oncovin, dexamethasone; COPBLAM, cyclophosphamide, oncovin, prednisolone, bleomycin, adriamycin, procabazine; L-OPD, leunase, oncovin, prednisolone, daunorubicin; HD-MTX, high-dose methotrexate; Resp., response; Durat., duration; OS, overall survival.

Ara-C was administered at a dose of 3 g/m² every 12 h by 2-h intravenous infusion on days 1-4 (8 doses) and mitoxantrone at a dose of 6 mg/m²/day on days 1-5 (5 doses). Granulocyte colony-stimulating factor (G-CSF) was administered at a dose of 300 [mu]g/day by subcutaneous injection when patients' WBC was <1000/[mu]l for three consecutive days. Response was evaluated after the first course of treatment and toxicities were evaluated after each course. Complete remission (CR) was defined as complete disappearance of all measurable disease for at least 4 weeks. Partial remission (PR) was defined as >50% reduction in the sum, over all measurable lesions, of the product of the two orthogonal diameters of each lesion, again for at least 4 weeks. Non-responders (NR) were patients with grossly residual or progressive disease. Treatment-related death was considered to have occurred when patients died within 4 weeks after the start of therapy.

Toxicities were assessed on the basis of the WHO criteria and graded from 0-4. Time of recovery from myelosuppression was defined as the duration from the first day of treatment to the day when the white blood cell count exceeded 1000/[mu]l and the platelet count exceeded 25 000/[mu]l without platelet transfusion.

RESULTS

The results of treatment are shown in Table 1 . Among the 16 patients, five who died of treatment-related toxicities were not evaluated for response. Only 11 patients survived for >4 weeks and were evaluated for response. Five patients (31%, 95% CI: 8 to 54%) attained CR for >4 weeks, two had PR and the remaining four were NR.

Treatment-related myelosuppression was found in all patients. Grade 4 neutropenia (neutrophils <500/[mu]l), grade 4 leukopenia (WBC <1000/[mu]l) and thrombocytopenia (platelets <25000/[mu]l) were found in all patients. The median time for leukocyte recovery to >1000/[mu]l was 20 days (range 16-24 days) and that for platelet recovery to >25 000/[mu]l was 18 days (range 13-23 days). Five patients died of treatment-related complications: neutropenia- associated sepsis in three, pneumonia in one and electrolyte imbalance in one.

Non-myeloid toxicities including nausea, vomiting, mucositis, alopecia, skin rashes, chemical conjunctivitis, central nervous system toxicity and elevation of serum transaminase and creatinine levels are shown in Table 2 . Severe mucositis (grade 3 or 4) was found in six patients. Mild to moderate skin rash was found in five patients. Elevation of the serum transaminase level was noted in six patients, including one grade 3 and one grade 4. Elevation of the serum creatinine level was noted in one patient, grade 2. Alopecia was found in all patients, grade 3 being seen in the majority. Infection was found in six patients, two with grade 3 and three with grade 4. Only one patient had transient chemical conjunctivitis, grade 2. No significant cardiac toxicity was found.

Table 2. Non-myeloid toxicities (WHO criteria, graded)

Toxicities	Grade 1	Grade 2	Grade 3	Grade 4
Nausea/Vomiting	6	5	2	-
Mucositis	6	2	5	1
Alopecia	1	3	12	-
Skin	2	3	-	-
Cardiac	0	0	0	0
Hepatic	3	1	1	1
Renal	-	1	-	-
CNS	2	1	1	-
Infection	0	1	2	3
Conjunctivitis	0	1	0	0

DISCUSSION

Ara-C, a pyrimidine analogue and S-phase specific DNA polymerase inhibitor, is the mainstay of treatment for acute non-lymphocytic leukemia (9 ). Repeated therapy with ara-C may lead to development of resistance, which can be overcome by increasing the drug dose (10 ,11 ). Between 1983 and 1993, a number of studies used high-dose ara-C for the treatment of refractory NHL, giving a CR rate of 0-33% (Table 3 ). The majority reported a CR rate of about 25% (12 -16 ).

A larger series conducted by Ho et al. included 31 patients with relapsed NHL who were treated with ara-C 3 g/m²/day for 2 days and mitoxantrone 10 mg/m²/day also for 2 days. CR was obtained in seven patients (23%, 95% CI: 8-37%) for a median of 7 months with tolerable toxicities (8 ). Although a higher dose of ara-C has been found to be associated with a better response, it should not exceed 12 g/m², as this is not tolerated by patients with lymphoma (16 ). However, in a study conducted by Hiddemann et al. (17 ), ara-C was administered at a dose of 3 g/m² every 12 h on days 1-4 (total 24 g/m²) and mitoxantrone was given at a dose of 10-12 mg/m² for 3-5 consecutive days (total 36-50 mg/m²), in response to which 40 patients with refractory acute myeloid leukemia achieved a CR rate of 53% with tolerable toxicity. In our study, all 16 patients received ara-C to a total of 24 g/m² plus mitoxantrone 30 mg/m², different from the regimen reported by Ho et al. but similar to that reported by Hiddemann et al. We used these doses because they were tolerable to patients with refractory leukemia, and it was of interest to determine whether an escalated dose would be associated with a higher response in patients with refractory lymphoma. In our study, five patients (31%, 95% CI 8-54%) achieved CR, including three in whom the response lasted for >4 months (median 5.3 months). Two patients had PR, and the overall response rate was 44% (95% CI 20-68%).

Therapeutic toxicities were similar to those in other reported series (12 ,18 ), but a higher rate of toxicity-related death was found in our study. Five patients (31%) died within 4 weeks due to treatment-related complications, including three who died of profound myelosuppression with sepsis, one who died of pneumonia and one who died of electrolyte imbalance. Non-myeloid toxicities due to high-dose ara-C, including chemical conjunctivitis, dermatitis, diarrhea, impaired liver function, cardiac toxicity, central nervous system toxicity and drug-induced fever (19 ,20 ) did not occur often in our series (Table 2 ).

An additional advantage of high-dose ara-C is its ability to penetrate the CNS (central nervous system) (21 ). However, CNS toxicities have been noted as a result of high-dose ara-C treatment. Lazarus et al. reported that eight of 49 patients receiving high-dose ara-C developed CNS toxicities, including six with grade 2-4 cerebellar dysfunction and two with grade 2-4 cerebral dysfunction (22 ). In our study only one patient developed grade 3 CNS toxicity, with the clinical manifestation of drowsiness. No cerebellar dysfunction was found.

The major complication of high-dose ara-C in this study was myelosuppression. All 16 patients experienced grade 4 leukopenia and thrombocytopenia. Ho et al. reported that rhGM-CSF (recombinant human granulocyte and macrophage colony-stimulating factor) can be applied safely to patients who receive high-dose ara-C, shortening the period of severe cytopenia and causing no adverse effects (23 ). In our study, all patients received G-CSF to reduce the period of severe leukopenia. However, grade 4 leukopenia (WBC < 1000/[mu]l) still lasted for an average of 20 days, and three patients died of leukopenia-associated sepsis. The incorporation of hematopoietic stimulating factors in this high-dose regimen to reduce treatment-related morbidity and mortality warrants further study.

Table 3. Previous reports of high-dose ara-C in refractory lymphoma

Ref.	Cases	Dose	CR (%)	OR (%)	Durat. (mo)	TRD	OS (mo)
(13)	14	2 g/m2 * 12	3 (21)	3 (21)	3	6	-
(14)	28	2 g/m2 * 2-4	0	8 (29)	2.5	2	4.6
(15)	15	3 g/m2 * 2-4	3 (20)	6 (40)	4	0	-
(16)	12	3 g/m2 * 12	4 (33)	6 (50)	4	6	-
(8)	31	3 g/m2 * 2 + mitoxantrone 10 mg/m2 * 2	7 (23)	14 (45)	7	2	6
This study	16	3 g/m2 * 8 + mitoxantrone 6 mg/m2 * 5	5 (31)	7 (44)	5.3	5	4.2

CR, complete remission; OR, overall response; Durat., duration of response; TRD, number of treatment-related death(s); OS, overall survival; -, not described.

Many clinical studies have applied high-dose ara-C and other chemotherapeutic drugs to patients with refractory lymphoma and shown considerable efficacy. In a 90-case study conducted by Velasquez et al. (24 ), high-dose ara-C was combined with dexamethasone and cisplatin for treatment of refractory lymphoma (the DHAP protocol), yielding a CR rate of 31%, PR rate of 26%, and 8% treatment-related mortality. Ezzat et al. (25 ) applied high-dose ara-C with etoposide, methyl prednisolone and cisplatin to 26 patients with relapsed lymphoma (the E-SHAP protocal) and achieved 27% CR and 42% PR with acceptable toxicity. In their study, there was no treatment-related mortality. Wilson et al. (26 ) studied a regimen containing no ara-C and demonstrated a considerable response with tolerable toxicity. They used EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin) in 74 patients with relapsed lymphoma and obtained a CR rate of 27% and a PR rate of 60%. In their study, the incidence of febrile neutropenia was only 17%. Comparing data from these regimens, our regimen produced a similar CR rate in these poor-risk patients, but it seemed too toxic (31% treatment-related death) to be acceptable as a salvage therapy for refractory non-Hodgkin's lymphoma.

Our findings suggest that a proportion of patients with refractory NHL will respond to high-dose ara-C + mitoxantrone, but the treatment is too toxic to be acceptable as a salvage therapy. Further studies are required to determine optimal regimens for treatment of patients with refractory non-Hodgkin's lymphoma.

Acknowledgements

This work was kindly supported by a grant from the Yen Tjing-Ling Medical Foundation.

References

1. Armitage JO. Treatment of non-Hodgkin's lymphoma. N Engl J Med 1993;328:1023-30. MEDLINE Abstract

2. Cabanillas F, Hagemeister FB, Bodey GP, Freireich EJ. IMVP-16: an effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy. Blood 1982;60:693-7. MEDLINE Abstract

3. Frei E, Canellos GP. Dose: a critical factor in cancer chemotherapy. Am J Med 1980;69:585-94. MEDLINE Abstract

4. Kremer WB. Cytarabine. Ann Intern Med 1975;82:684-8. MEDLINE Abstract

5. Rudnick SA, Cadman EC, Capizzi RL, Skell RT, Bertino JR, Mclntosh S. High dose cytosine arabinoside (HDARAC) in refractory acute leukemia. Cancer 1979;44:1189-93. MEDLINE Abstract

6. Gams RA, Steinberg J, Posner L. Mitoxantrone in malignant lymphoma. Semin Oncol 1984;1(suppl 1):47-9.

7. Shenkenberg TD, von Hoff DD. Mitoxantrone: a new anticancer drug with significant clinical activity. Ann Intern Med 1986;105:67-81. MEDLINE Abstract

8. Ho AD, Valle FD, Ruckle H, Schwammborn J, Schlimok G, Hiddemann W et al. Mitoxantrone and high-dose cytarabine as salvage therapy for refractory non-Hodgkin's lymphoma. Cancer 1989;64:1388-92. MEDLINE Abstract

9. Chabner BA, Myers CE, Coleman N, Johns DG. The clinical pharmacology of antineoplastic agents (second of two parts). N Engl J Med 1975;292:1159-68. MEDLINE Abstract

10. Early AP, Preisler HD, Slocum H, Rustum YM. A pilot study of high-dose 1-beta-D-arabinofuransylcytosine for acute leukemia and refractory lymphoma. Clinical response and pharmacology. Cancer Res 1982;42:1587-94. MEDLINE Abstract

11. Capizzi RL, Poole M, Copper MR, Richards F, Stuart JJ, Jackson DV et al. Treatment of poor risk acute leukemia with sequential high-dose ara-C and asparaginase. Blood 1984;63:694-700. MEDLINE Abstract

12. Breithaupt H, Pralle H, Eckhardt T, von Hattingberg M, Schick J, Loeffler H. Clinical results and pharmacokinetics of high dose cytosine arabinoside (HD ara-C). Cancer 1982;50:1248-57. MEDLINE Abstract

13. Rohatiner AZS, Slevin ML, Dhaliwal HS, Malpas JS, Lister TA. High-dose cytosine arabinoside: response to therapy in acute leukemia and non-Hodgkin's lymphoma. Cancer Chemother Pharmacol 1984;12:90-3.

14. Kantarjian H, Barlogie B, Plunkett W, Velasquez W, McLaughlin P, Riggs S et al. High-dose arabinoside in non-Hodgkin's lymphoma. J Clin Oncol 1983;1:689-94. MEDLINE Abstract

15. Shipp MA, Takvorian RC, Canellos GP. High-dose cytosine arabinoside: active agent in treatment of non-Hodgkin's lymphoma. Am J Med 1984;77:845-50. MEDLINE Abstract

16. Adelstein DJ, Lazarus HM, Hines JD, Herzig RH. High-dose cytosine arabinoside in previously treated patients with poor prognosis non-Hodgkin's lymphoma. Cancer 1985;56:1493-6. MEDLINE Abstract

17. Hiddemann W, Kreutzmann H, Straif K, Ludwig WD, Mertelsmann R, Donhuijsen-Ant R et al. High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia. Blood 1987;69:744-9. MEDLINE Abstract

18. Hines JD, Oken MM, Mazza JJ, Keller AM, Streeter RR, Glick JM. High-dose cytosine arabinoside and m-AMSA is effective therapy in relapsed acute nonlymphocytic lukemia. J Clin Oncol 1984;2:545-9. MEDLINE Abstract

19. Bensinger TA, Fahey JL, Kellon DB, Beutler E. Febrile reaction response to cytarabine. JAMA 1974;229:1578. MEDLINE Abstract

20. Slavin RE, Dias MA, Saral R. Cytosine arabinoside induced gastro-intestinal toxic alterations in sequential chemotherapeutic protocols. A clinical-pathologic study of 33 patients. Cancer 1978;42:1747-59. MEDLINE Abstract

21. Frick J, Ritch PS, Hansen RM, Anderson T. Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside. J Clin Oncol 1984;2:365-8. MEDLINE Abstract

22. Lazarus HM, Herzig RH, Herzig GP, Phillips GL, Roessmann U, Fishman DJ. Central nervous system toxicity of high-dose systemic cytosine arabinoside. Cancer 1981;48:2577-82. MEDLINE Abstract

23. Ho AD, Valle FD, Engelhard M, Hiddemann W, Ruckle H, Schlimok G et al. Mitoxantrone/high-dose ara-C and recombinant human GM-CSF in the treatment of refractory non-Hodgkin's lymphoma. Cancer 1990;66:423-30. MEDLINE Abstract

24. Velasquez WS, Cabanillas F, Salvador P, McLaughlin P, Fridrik M, Tucker S et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose ara-C and dexamethasone (DHAP). Blood 1988;71:117-22. MEDLINE Abstract

25. Ezzat AA, Khalifa F, Berry J, Khan B, Raja MA, Abdel-Warith A. E-SHAP: an effective treatment in selected patients with relapsed non-Hodgkin's lymphoma. Ann Oncol 1994;5:453-6. MEDLINE Abstract

26. Wilson WH, Bryant G, Bates S, Fojo A, Wittes RE, Steinberg SM et al. EPOCH chempotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J Clin Oncol 1993;11:1573-82. MEDLINE Abstract

Received October 21, 1996; accepted January 13, 1997
For reprints and all correspondence: Wei-Shu Wang, Division of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei, 201, Section 2, Shih-Pai Road, Taipei, Taiwan 11217
Abbreviations: ara-C, cytarabine; NHL, non-Hodgkin's lymphoma; G-CSF, Granulocyte colony-stimulating factor; CR, complete remission; PR, partial remission; NR, non-responders

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