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The Role of Mitoxantrone in Non-Hodgkin’s Lymphoma

The Role of Mitoxantrone in Non-Hodgkin’s Lymphoma

ABSTRACT: The development of doxorubicin was an important advance in the treatment of patients with non-Hodgkin’s lymphoma (NHL). Alternatives to doxorubicin, such as mitoxantrone (Novantrone), have less nonhematologic toxicity and could offer a therapeutic advantage in some situations if similar antilymphoma activity exists. Several combination regimens that include mitoxantrone have been shown to be active. These include mitoxantrone/ifosfamide (Ifex) and mitoxantrone/etoposide combinations as salvage therapy for aggressive lymphomas. Mitoxantrone in combination with fludarabine (Fludara) for the treatment of newly diagnosed follicular lymphomas and in combination with fludarabine and dexamethasone for relapsed/refractory follicular lymphomas has produced high complete response rates. Other evolving uses of mitoxantrone include combination therapy with cladribine (Leustatin) or rituximab (Rituxan), and as part of conditioning regimens for hematopoietic stem cell transplantation. In diffuse aggressive lymphoma, mitoxantrone, 10 mg/m², substituted for doxorubicin, 50 mg/m², results in a poorer response when CNOP (cyclophosphamide [Cytoxan, Neosar], mitoxantrone [Novantrone], vincristine [Oncovin], prednisone) is compared to CHOP (cyclophosphamide, doxorubicin HCl, vincristine, prednisone); however, increasing the mitoxantrone dose to 12 mg/m² in either the CNOP or CMP-BOP (cyclophosphamide, mitoxantrone, procarbazine [Matulane], bleomycin [Blenoxane], vincristine, prednisone) regimens yields results comparable to those achieved with the doxorubicin-containing regimen. Comparable results have also been observed when 10 mg/m² of mitoxantrone was substituted for 45 mg/m² of doxorubicin in the m-BACOD (methorexate, bleomycin, doxorubicin [Adriamycin], cyclophosphamide, vincristine, dexamethasone) regimen. Mitoxantrone is active in NHL, and combinations including mitoxantrone can be used effectively and may provide an advantage in the elderly. [ONCOLOGY 16:490-514, 2002]

The treatment of non-Hodgkin’s lymphoma
(NHL) continues to be imperfect. With incidence increasing and the chance of
cure at less than 50%, an improved understanding of NHL is needed, including
which patients will benefit most from various treatments.[1] The American Cancer
Society estimates that 53,900 new cases of NHL will be diagnosed in 2002, and
24,400 related deaths will occur. Both the incidence and mortality of NHL have
been rising since the 1970s. Overall, survival rates are suboptimal, with 1-year
survivals of 70% and 5-year survivals of only 51%.[2,3]

The ongoing effort to better understand NHL is reflected by the
multiple modifications made to NHL classification systems over the past
2 decades. The World Health Organization (WHO) classification system is the
most recently developed and is in line to replace the existing Working
Formulation and Kiel classification systems.[4,5] The WHO classification
reflects improvements in the understanding of the immune system, and is based on
several factors, including histology, immune phenotype, genetic abnormalities,
and clinical features.[6]

Mitoxantrone (Novantrone) is a cytotoxic anthracenedione,
similar in structure to anthracyclines such as doxorubicin.[6] It inhibits
topoisomerase II,
interferes with RNA, and intercalates with DNA (resulting in strand breaks and
cross-links)—all of which lead to cell death. Mitoxantrone is not cell-cycle
specific.[6,7] It was developed in the 1970s as a more tolerable alternative to
anthracyclines.[8] Early research established its activity alone and in
combination with other chemotherapy agents against breast cancer, leukemia, and
lymphoma. More recent studies have demonstrated its activity in the treatment of
prostate cancer and in slowing the progression of multiple sclerosis.[7,8]

Specifically, the activity of mitoxantrone has been established
against both follicular lymphomas and aggressive lymphomas, including diffuse
large-cell lymphomas. In preliminary studies of follicular lymphoma,
mitoxantrone at 14 to 18 mg/m² every 3 to 4 weeks yielded responses in
previously treated patients (including those who had received doxorubicin), with
complete response rates ranging from 6% to 16% and partial response rates from
38% to 56%.[9-11] Previously untreated patients with follicular lymphoma had
slightly higher response rates, with a complete response rate of 29% and a
partial response rate of 67%.[12]

Patients with relapsed or refractory aggressive lymphoma
responded to lower doses of mitoxantrone (12 to 14 mg/m² every 3 to 4 weeks).
The complete response rate ranged from 0% to 30% and the partial response rate,
from 12% to 63%. Some of these patients had received previous treatment with
doxorubicin.[9,10,13-16] This review will evaluate the current use of
mitoxantrone in NHL, paying special attention to dose as it relates to outcome.

What Doses of Mitoxantrone and Anthracyclines Are Comparable?

Determining the optimal dose of mitoxantrone in NHL leads to a
related question: What is the comparable dose of mitoxantrone and doxorubicin
for use in NHL? The relevance of the question stems from the widespread use of
doxorubicin in combination therapy for NHL, the high level of activity of both
doxorubicin and mitoxantrone in NHL, and the fact that mitoxantrone is closely
related to the anthracyclines pharmacologically.

Posner et al reported that in early comparative trials of
mitoxantrone and doxorubicin in breast cancer, a 5:1 ratio of doxorubicin to
mitoxantrone was chosen based on data suggesting that this ratio would yield
equally myelosuppressive doses of the drugs. Thus, when comparing CNF
(cyclophosphamide [Cytoxan, Neosar], mitoxantrone [Novantrone], fluorouracil
[5-FU]) to CAF (cyclophosphamide, doxorubicin [Adriamycin], 5-FU) in breast
cancer, 10 mg/m² of mitoxantrone was compared to 50 mg/m² of doxorubicin.
Single-agent comparisons used 12 to 14 mg/m² of mitoxantrone and 60 to 75 mg/m²
of doxorubicin administered every 3 to 4 weeks.[17]

As described later in this review, the doses of mitoxantrone in
combination therapy for NHL have ranged from 10 to 12 mg/m². Given that 12 mg/m²
represents a 20% increase in dose intensity over the lower dose, an increase of
2 mg/m² could be an extremely important difference if there is a significant
dose-response curve at this dose range.

Moderate reductions in the dose intensity of doxorubicin have
produced a striking decrease in treatment outcome for breast cancer
patients.[18] In the treatment of aggressive NHL, two studies found that 50 mg/m² of doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin HCl,
vincristine, prednisone) was superior to 10 mg/m² of mitoxantrone in CNOP
(cyclophosphamide, mitoxantrone, vincristine, prednisone),[19,20] and one study
found the two regimens to be comparable.[21]

In a fourth trial, CNOP was found to be comparable to CHOP when
the dose of mitoxantrone was increased to 12 mg/m² and compared to 50 mg/m²
doxorubicin.[22] Similar results were observed in other regimens that
substituted mitoxantrone, 12 mg/m², for doxorubicin, 50 mg/m²,[23] or
mitoxantrone, 10 mg/m², for doxorubicin, 45 mg/m².[24,25] Therefore,
the CNOP regimen should include mitoxantrone at 12 mg/m² if the goal is to
achieve a therapeutic outcome comparable to that of CHOP with doxorubicin at 50
mg/m².

Are There Differences in Toxicity Between Mitoxantrone and
Anthracyclines?

Patients receiving mitoxantrone experience less nonhematologic
toxicity (alopecia, nausea, vomiting) than those receiving doxorubicin. This
advantage may be particularly beneficial to patients such as the elderly, who
may not tolerate full-dose doxorubicin therapy.

In early trials comparing mitoxantrone to doxorubicin (or CAF to
CNF) in breast cancer, significantly lower rates of alopecia, nausea, vomiting,
and stomatitis were reported in the mitoxantrone arm.[17] In later trials in
lymphoma patients, in which a mitoxantrone-containing regimen was compared to a
doxorubicin-containing regimen, the severity of alopecia was significantly
reduced in many studies[19,20,22-26] or reported to occur less
frequently.[21,27] Similarly, nausea and vomiting were significantly reduced in
trials comparing a mitoxantrone regimen to a doxorubicin regimen,[19,20] with
one trial reporting significantly less mucositis in the mitoxantrone arm.[19]

Studies have shown that the cardiotoxicity associated with
mitoxantrone is qualitatively similar to that associated with the anthracyclines,
and is more likely to appear after cumulative mitoxantrone doses of 160 mg/m²,
or 100 mg/m² if the patient has received previous anthracycline
therapy.[28] Although mitoxantrone may be less cardiotoxic than doxorubicin at
comparable cumulative doses, caution is necessary because cardiotoxicity can
also occur at low doses of mitoxantrone. Patients who have previously received
doxorubicin or mediastinal irradiation, or who have underlying cardiac disease,
will be at greater risk for mitoxantrone-associated cardiotoxicity.[6,7]

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