The Role of Mitoxantrone in Non-Hodgkin’s Lymphoma

Dr. Armitage is an experiencedinvestigator in both lymphoma research and marrow/stem cell transplantation. Assuch, 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 cardiotoxicpotential of these agents, as well as the literature that defines the doses ofdoxorubicin and mitoxantrone that have equivalent myelosuppressive toxicity.

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

Mitoxantrone Combinations

Dr. Armitage’s review is comprehensive. Therefore, in lieu ofproviding additional breadth or depth, I will offer a perspective about the useof mitoxantrone at one institution, which parallels the overview that the authorhas 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 agentfor patients with lymphoma. At the time, we were focusing on another promisinganthracycline analog, bisantrene, which has been abandoned largely because ofone nonhematologic toxicity, namely phlebitis.[1] In the "beautycontest" by which comparable agents are judged,[2] one blemish can bedamning.

After others described the single-agent efficacy ofmitoxantrone, trials at MDACC were designed to explore its potential incombination chemotherapy regimens for patients with malignant lymphoma andHodgkin’s disease.[3-7] For patients with recurrent lymphoma, mitoxantrone fitnicely 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 withrecurrent aggressive lymphoma.

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

The FND Regimen

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

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

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

In our experience with lymphoma patients, the addition ofprophylaxis for Pneumocystis carinii has largely abrogated the problem ofopportunistic infections associated with the FND regimen. Thus, we havecontinued to incorporate dexamethasone into both salvage and front-line FNDregimens. With either FND or FN, it is the impressive efficacy results that aremost compelling.

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

Conclusions

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

*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: Activityof 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 phaseII trial of mesna/ifosfamide, mitoxantrone and etoposide for refractorylymphomas. Ann Oncol 6:609-611, 1995.

4. Rodriguez MA, Cabanillas FC, Velasquez W, et al: Results of asalvage 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 studyof the combination of fludarabine, mitoxantrone, and dexamethasone in low-gradelymphoma. 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 forindolent lymphoma. J Clin Oncol 14:1262-1268, 1996.

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

8. Cabanillas F, Hagemeister FB, Bodey GP, et al: IMVP-16: Aneffective regimen for patients with lymphoma who have relapsed after initialcombination chemotherapy. Blood 60:693-697, 1982.

9. Cabanillas F, Hagemeister FB, McLaughlin P, et al: Results ofMIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol5:407-412, 1987.

10. Cabanillas F, Rodriguez MA, Swan F Jr: Recent trends in themanagement of lymphomas at M. D. Anderson Cancer Center. Semin Oncol 17(suppl10):28-33, 1990.

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

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

13. Tsimberidou AM, McLaughlin P, Younes A, et al: Randomizedcomparison 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 andmitoxantrone plus rituximab vs CHOP plus rituximab as first-line treatment inpatients with follicular lymphoma (abstract). Blood 98(suppl 1):842a, 2001.

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

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

17. White EL, Shaddix SC, Brockman RW, et al: Comparison of theactions of 9-b-D-arabinofuranosyl-2-fluoroadenine and9-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 biologicalactivity of 9-b-D-arabinofuranosyl-2-fluoroadenine and the biochemical actionsof its triphosphate on DNA polymerases and ribonucleotide reductase from HeLacells. Mol Pharmacol 21:474-477, 1982.

19. Parker WB, Bapat AR, Shen J-X, et al: Interaction of2-halogenated dATP analogs (F, CI, and Br) with human DNA polymerases, DNAprimase, and ribonucleotide reductase. Mol Pharmacol 34:485-491, 1988.

20. Parker WB, Shaddix SC, Chang CH, et al: Effects of2-chloro-9-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)adenine on K562 cellularmetabolism and the inhibition of human ribonucleotide reductase and DNApolymerases by its 5´-triphosphate. Cancer Res 51:2386-2394, 1991.

21. Sancar A: Excision repair in mammalian cells. J Biol Chem270:15915-15918, 1995.

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