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The Role of Mitoxantrone in Non-Hodgkin’s Lymphoma

The Role of Mitoxantrone in Non-Hodgkin’s Lymphoma

Dr. Armitage presents a succinct and thorough review of the role of mitoxantrone (Novantrone) in patients with non-Hodgkin’s lymphoma (NHL). He begins by emphasizing the importance of accurate diagnosis as described in the World Health Organization classification which evolved from the Revised European American Lymphoma classification. Both of these present day classifications are based on the immunologic principles separating lymphomas into B- and T-cell disorders developed in the 1970s by Lennert, Lukes, and Collins.[1,2] His review addresses multiple issues in mitoxantrone therapy, including dose intensity, cardiotoxicity, combination therapy with nucleoside analogs in low-grade lymphomas, the impact of rituximab (Rituxan), therapy for acquired immunodeficiency syndrome (AIDS)-related lymphoma, and the role of high-dose mitoxantrone as part of a preparative regimen for autologous transplants.

Dose intensity and dose equivalency have always been issues in the treatment of NHL. In retrospect, the results of the Intergroup study indicating that the new "intensive" regimens—MACOP-B (methotrexate, leucovorin, doxorubicin [Adriamycin], cyclophosphamide [Cytoxan, Neosar], vincristine [Oncovin], prednisone, bleomycin [Blenoxane]), m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone), and ProMACE/CytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, vincristine, methotrexate)—produced results equivalent to those achieved with CHOP (cyclophosphamide, doxorubicin HCl, vincristine, prednisone) should not be a surprise, because the doses of the most active agents (cyclophosphamide and doxorubicin) were equivalent or higher in CHOP compared to the newer regimens.[3]

Although CHOP has been shown to be superior to CNOP (cyclophosphamide, mitoxantrone [Novantrone], vincristine, prednisone) in a randomized trial in elderly patients,[4] Dr. Armitage argues that the study’s conclusion is based on the assumption that the doses of doxorubicin and mitoxantrone were equivalent. He maintains that the inferior results of CNOP could be due to a lower dose of one drug (mitoxantrone) being compared to a higher dose of another drug (doxorubicin)—ie, the study did not compare equivalent doses. He indicates that even a small increase in the dose of mitoxantrone could lead to similar response rates between CNOP and CHOP.

Progress in Therapy

Mitoxantrone is an effective agent in NHL, and Dr. Armitage addresses its strengths. When compared to doxorubicin, mitoxantrone produces less alopecia, mucositis, nausea, vomiting, and cardiotoxicity. It has been best studied as part of salvage regimens, particularly the MINE regimen (mesna [Mesnex], ifosfamide [Ifex], mitoxantrone, etoposide) and in combination with nucleoside analogs plus steroids for low-grade NHL. As Dr. Armitage points out, omitting the steroids for the latter regimen decreases the risk of opportunistic infections without sacrificing efficacy.

Progress in the therapy of NHL has involved the development of monoclonal antibodies, better antiretroviral therapy for AIDS, and autologous transplant as salvage. Combination chemotherapy with rituximab is becoming standard therapy for many B-cell lymphomas, particularly diffuse large B-cell NHL, as evidenced by the results of the randomized European trial in elderly patients, which favored CHOP plus rituximab over CHOP alone.[5] Highly active antiretroviral therapy (HAART) has improved the prognosis of AIDS patients, and combination chemotherapy can be administered to selected patients with AIDS-related lymphoma, often in conjunction with HAART and growth factor support.

The Parma trial established autologous transplant as standard therapy for chemosensitive aggressive lymphomas[6]; however, there is little consensus about the best preparative regimens. Although mitoxantrone can be used in the preparative therapy, the potential for cardiotoxicity exists due to the fact that most of these patients have already received anthracyclines.

Conclusions

Dr. Armitage reviews the strengths of mitoxantrone, but the agent is likely to remain a backup to anthracyclines unless randomized trials can demonstrate its superiority. Better diagnostic and prognostic models will predict which patients are more likely to be responsive to a specific therapy. Genomic profiling of large B-cell lymphoma can identify favorable and unfavorable prognostic groups that are not recognized by clinical factors.[7] Chemosensitivity assays may enable the identification of patients who would be better treated with an "inferior" drug earlier in the course of the disease.[8] Dr. Armitage’s article provides a state-of-the-art review of mitoxantrone in lymphoma, but the drug’s optimal use needs to be investigated further.

References

1. Lukes, RJ, Collins RD: Immunologic characterization of human malignant lymphomas. Cancer 34:1488-1503, 1974.

2. Lennert K, Stein H, Kaiserling E: Cytological and functional criteria for the classification of malignant lymphomata. Br J Cancer 31 (suppl):29-43, 1975.

3. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993.

4. Sonneveld P, de Ridder M, van der Lelie H, et al: Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP vs CNOP chemotherapy. J Clin Oncol 13:2530-2539, 1995.

5. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002.

6. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540-1545, 1995.

7. Shipp MA, Ross KN, Tamayo P, et al: Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 8:68-74, 2002.

8. Kravtsov VD, Greer JP, Whitlock JA, et al: Use of the microculture kinetic assay of apoptosis to determine chemosensitivities of leukemias. Blood 92:968-980, 1998.

 
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