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The Role of Mitoxantrone in Non-Hodgkin’s Lymphoma

The Role of Mitoxantrone in Non-Hodgkin’s Lymphoma

Dr. Armitage is an experienced investigator in both lymphoma research and marrow/stem cell transplantation. As such, he is ideally suited to comment on the attributes of mitoxantrone (Novantrone) in the treatment of malignant lymphoma.

Inevitably, mitoxantrone must be compared with doxorubicin, which remains the standard against which anthracycline analogs are evaluated. Dr. Armitage reviews the pertinent literature concerning the cardiotoxic potential of these agents, as well as the literature that defines the doses of doxorubicin and mitoxantrone that have equivalent myelosuppressive toxicity.

For an agent to be dose-escalated in a preparative regimen for stem cell transplantation, its nonhematologic toxicity profile should be favorable. Mitoxantrone clearly fulfills this criterion; it has been successfully incorporated into preparative regimens at doses that are five to six times those that can be administered without stem cell support.

Mitoxantrone Combinations

Dr. Armitage’s review is comprehensive. Therefore, in lieu of providing additional breadth or depth, I will offer a perspective about the use of mitoxantrone at one institution, which parallels the overview that the author has provided. At the University of Texas M. D. Anderson Cancer Center (MDACC), we did not play a key role in the development of mitoxantrone as a single agent for patients with lymphoma. At the time, we were focusing on another promising anthracycline analog, bisantrene, which has been abandoned largely because of one nonhematologic toxicity, namely phlebitis.[1] In the "beauty contest" by which comparable agents are judged,[2] one blemish can be damning.

After others described the single-agent efficacy of mitoxantrone, trials at MDACC were designed to explore its potential in combination chemotherapy regimens for patients with malignant lymphoma and Hodgkin’s disease.[3-7] For patients with recurrent lymphoma, mitoxantrone fit nicely into an evolving series of ifosfamide(Ifex)/etoposide regimens,[8,9,3] culminating in the MINE-ESHAP* strategy cited by Dr. Armitage.[4] MINE-ESHAP remains a highly successful salvage regimen for patients with recurrent aggressive lymphoma.

The MINE regimen subsequently became a link in a three-phase alternating triple therapy scheme for patients with previously untreated aggressive lymphoma.[10] In our experience, this alternating triple therapy strategy has been most beneficial to patients with high-risk prognostic features.[11] For patients with favorable prognostic features, it appears that a simpler CHOP-based strategy (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) is preferable to the more complex alternating triple therapy strategy.

The FND Regimen

In 1988, mitoxantrone was integrated into a 10-drug front-line program for indolent lymphoma that was also called alternating triple therapy,[12] although it differs from the aggressive lymphoma alternating triple-therapy program. Parallel to that front-line strategy, the simpler FND regimen (fludarabine [Fludara], mitoxantrone, dexamethasone) was devised for patients with relapsed indolent lymphoma.[5,6] The latter regimen has been fairly widely accepted, first and foremost because of its efficacy, but also because of its tolerability.

In a subsequent front-line comparative trial, the alternating triple therapy regimen appeared to be superior to FND in some situations.[13] But the overall simplicity of the FND regimen, its efficacy, and the substantial encouraging confirmatory data from other institutions have made the fludarabine/mitoxantrone (FN) combination (with or without steroids) an appealing option for patients with indolent lymphoma. A notable recent study of FN without steroids, reported in preliminary fashion at the 2001 meeting of the American Society of Hematology, showed this regimen to be equivalent to CHOP in many respects, and possibly superior to CHOP in terms of complete remission and molecular remission rates.[14]

Regarding FND, Dr. Armitage correctly draws attention to concerns about opportunistic infections and the issue of whether steroids might be a problematic part of the regimen. These concerns do not relate to mitoxantrone, but rather to fludarabine, when it is used with steroids. Such considerations are largely based on observations made in sequential chronic lymphocytic leukemia (CLL) trials at MDACC, which found that prednisone added little to the efficacy of fludarabine compared to the previous experience with fludarabine alone.[15] This is the key report that raised the concern about the concurrent use of nucleoside analogs and steroids. It should be noted that the rate of opportunisitic infections was low (< 1% of all courses) with fludarabine plus prednisone in this report, and that the historical control group of 113 patients treated with fludarabine alone had no opportunistic infections,[15] despite the known risk of such infections with the nucleoside analogs.[16]

In our experience with lymphoma patients, the addition of prophylaxis for Pneumocystis carinii has largely abrogated the problem of opportunistic infections associated with the FND regimen. Thus, we have continued to incorporate dexamethasone into both salvage and front-line FND regimens. With either FND or FN, it is the impressive efficacy results that are most compelling.

Dr. Armitage cites in vitro evidence that provides insight into the clinical synergism between fludarabine and mitoxantrone. Underlying this synergy, most likely, is the effect of fludarabine on the DNA repair process.[17-22] Fludarabine inhibits key DNA repair enzymes; thus, the efficacy of DNA-damaging agents such as alkylators or intercalators can be enhanced when used concurrently with fludarabine.

Conclusions

In conclusion, mitoxantrone has earned its place in the armamentarium of agents that are effective in patients with non-Hodgkin’s lymphoma. The 104 references cited by Dr. Armitage represent an impressive body of literature that attests to the drug’s efficacy. An interesting footnote is that, despite this compelling information, lymphoma remains an off-label use for mitoxantrone, putting it in good company with etoposide, cytarabine, cisplatin, and numerous other agents that are used widely in patients with malignant lymphoma.

*MINE-ESHAP = mesna (Mesnex), ifosfamide, mitoxantrone (Novantrone), etoposide; etoposide, methylprednisolone (Solumedrol), high-dose cytarabine (Ara-C), cisplatin (Platinol).

References

1. McLaughlin P, Cabanillas F, Hagemeister FB, et al: Activity of bisantrene in refractory lymphoma. Cancer Treat Rep 71:631-633, 1987.

2. Cheson BD: The purine analogs—a therapeutic beauty contest. J Clin Oncol 10:868-871, 1992.

3. Rodriguez MA, Cabanillas FC, Hagemeister FB, et al: A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas. Ann Oncol 6:609-611, 1995.

4. Rodriguez MA, Cabanillas FC, Velasquez W, et al: Results of a salvage treatment program for relapsing lymphoma—MINE consolidated with ESHAP. J Clin Oncol 13:1734-1741, 1995.

5. McLaughlin P, Hagemeister FB, Swan F Jr, et al: Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma. J Clin Oncol 12:575-573, 1994.

6. McLaughlin P, Hagemeister FB, Romaguera JE, et al: Fludarabine, mitoxantrone, and dexamethasone (FND): An effective new regimen for indolent lymphoma. J Clin Oncol 14:1262-1268, 1996.

7. Hagemeister FB, Cabanillas F, Velasquez WS, et al: NOVP: A novel chemotherapeutic regimen with minimal toxicity for treatment of Hodgkin’s disease. Semin Oncol 17(suppl 10):34-38, 1990.

8. 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 60:693-697, 1982.

9. Cabanillas F, Hagemeister FB, McLaughlin P, et al: Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 5:407-412, 1987.

10. Cabanillas F, Rodriguez MA, Swan F Jr: Recent trends in the management of lymphomas at M. D. Anderson Cancer Center. Semin Oncol 17(suppl 10):28-33, 1990.

11. Cabanillas F, Rodriguez-Diaz Pavón J, Hagemeister FB, et al: Alternating triple therapy for treatment of intermediate grade and immunoblastic lymphoma. Ann Oncol 9:511-518, 1998.

12. McLaughlin P, Hagemeister FB, Swan F, et al: Intensive conventional dose chemotherapy for stage IV low-grade lymphoma: High remission rates and reversion to negative of peripheral blood bcl-2 rearrangement. Ann Oncol 5(suppl 2):73-74, 1994.

13. Tsimberidou AM, McLaughlin P, Younes A, et al: Randomized comparison of fludarabine, novantrone, dexamethasone (FND) vs CHOD-BLEO/ESHAP/NOPP (alternating triple therapy; ATT) in patients with stage IV indolent lymphoma (abstract). Blood 96(suppl 1): 508a, 2000.

14. Zinzani PL: A randomized trial of fludarabine and mitoxantrone plus rituximab vs CHOP plus rituximab as first-line treatment in patients with follicular lymphoma (abstract). Blood 98(suppl 1):842a, 2001.

15. O’Brien S, Kantarjian H, Beran M, et al: Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 82:1695-1700, 1993.

16. Cheson BD: Infectious and immunosuppressive complications of purine analog therapy. J Clin Oncol 13:2431-2448, 1995.

17. White EL, Shaddix SC, Brockman RW, et al: Comparison of the actions of 9-b-D-arabinofuranosyl-2-fluoroadenine and 9-beta-D-arabinofuranosyladenine on target enzymes from mouse tumor cells. Cancer Res 42:2260-2264, 1982.

18. Tseng W-C, Derse D, Cheng Y-C, et al: In vitro biological activity of 9-b-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. Mol Pharmacol 21:474-477, 1982.

19. Parker WB, Bapat AR, Shen J-X, et al: Interaction of 2-halogenated dATP analogs (F, CI, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase. Mol Pharmacol 34:485-491, 1988.

20. Parker WB, Shaddix SC, Chang CH, et al: Effects of 2-chloro-9-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5´-triphosphate. Cancer Res 51:2386-2394, 1991.

21. Sancar A: Excision repair in mammalian cells. J Biol Chem 270:15915-15918, 1995.

22. Koehl U, Li L, Nowak B, et al: Fludarabine and cyclophosphamide: Synergistic cytotoxicity associated with inhibition of interstrand cross-link removal (abstract). Proc Am Assoc Cancer Res 38:2, 1997.

 
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