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a The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; b Auxilio Muto Cancer Center, San Juan, Puerto Rico; c Weill Medical College of Cornell University, New York, New York, USA; d Rush University Medical Center, Chicago, Illinois, USA; e University of Bologna, Bologna, Italy
Correspondence: Fredrick Hagemeister, M.D., The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. Telephone: 713-792-2860; Fax: 713-794-5656; e-mail: fhagemei{at}mdanderson.org
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LEARNING OBJECTIVES
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Learning Objectives
Abstract
Introduction
Indolent Lymphomas: Single-Agent...
Mitoxantrone-Containing...
Conclusions and Future...
References
After completing this course, the reader will be able to:
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ABSTRACT |
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TopLearning ObjectivesAbstractIntroductionIndolent Lymphomas: Single-Agent...Mitoxantrone-Containing...Conclusions and Future...References |
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Key Words. Mitoxantrone • Indolent lymphoma • Combination therapy • Rituximab • Progression-free survival
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INTRODUCTION |
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TopLearning ObjectivesAbstractIntroductionIndolent Lymphomas: Single-Agent...Mitoxantrone-Containing...Conclusions and Future...References |
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Historically, the course of indolent lymphoma is characterized by initial responsiveness to a variety of treatment approaches, with good response rates, but frequent relapses. Most patients with indolent lymphomas appear to have diseases that progress so slowly that delayed treatment is a management option, justifying a "watch and wait" approach to the initial treatment. However, over time, clinical progression occurs in almost all patients, and median survival rates with standard regimens such as cyclophosphamide, doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH, http://www.bedfordlabs.com), vincristine (Oncovin®; Eli Lilly and Company; Indianapolis, IN, http://www.lilly.com), and prednisone (Deltasone®; Pfizer Pharmaceuticals; New York, http://www.pfizer.com), CHOP, range from 5–10 years in large series [1, 2, 5, 6]. More recently, with the introduction of newer therapeutic approaches, improved 10-year survival rates (37%–60%) have been reported in some studies [7]. A recent trial using combination therapy with fludarabine (Fludara®; Berlex Laboratories; Wayne, NJ, http://www.berlex.com), mitoxantrone (Novantrone®; Serono, Inc.; Rockland, MA, http://www.seronousa.com), and dexamethasone (Decadron®; Merck and Co., Inc.; Whitehouse Station, NJ, http://www.merck.com), FND, plus rituximab (Rituxan®; Genentech, Inc.; South San Francisco, CA, http://www.gene.com) demonstrated a 3-year overall survival (OS) rate of 95% and a 5-year failure-free survival (FFS) rate of 70% [8, 9]. Additional studies are required to confirm these findings.
Current National Comprehensive Cancer Network (NCCN)-recommended regimens for the first-line treatment of follicular lymphoma include: single-agent therapy with rituximab, chlorambucil (Leukeran®; GlaxoSmithKline; Philadelphia, PA, http://www.gsk.com), or cyclophosphamide; single-agent fludarabine with or without rituximab; combination treatment with cyclophosphamide, vincristine (Oncovin®; Eli Lilly and Company), and prednisone (Deltasone®; Pfizer Pharmaceuticals), CVP, or CHOP with or without rituximab; and combination treatment with FND with or without rituximab. Because the choice of initial therapy is influenced by multiple factors, such as age, patient comorbidities, and future treatment possibilities (e.g., autologous stem cell transplant), treatment selection may be individualized. Recommendations for second-line treatment include: radioimmunotherapy, for patients who have had no prior stem cell transplant and have adequate bone marrow reserve; autologous or allogeneic stem cell transplant; and chemoimmunotherapy regimens, as described for initial therapy (Table 1
) [10].
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In this report, we review recent data on the use of mitoxantrone-containing regimens in the treatment of indolent NHL.
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INDOLENT LYMPHOMAS: SINGLE-AGENT THERAPIES |
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TopLearning ObjectivesAbstractIntroductionIndolent Lymphomas: Single-Agent...Mitoxantrone-Containing...Conclusions and Future...References |
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Mitoxantrone
Mitoxantrone, an anthracenedione compound, has a spectrum of clinical activity similar to that of the anthracyclines. It lacks the amino sugar of doxorubicin and the characteristic ring structure of classical anthracyclines. On the basis of these modifications, it was predicted that mitoxantrone would retain the antineoplastic activity of the anthracycline class with less potential for cardiotoxicity [12, 13]. Preclinical studies demonstrated that mitoxantrone inhibits topoisomerase II, interferes with RNA synthesis, and intercalates with DNA, resulting in strand breaks and crosslinking [12, 14]. Mitoxantrone also has demonstrated potent activity in preclinical lymphoma models and appears clinically active against both aggressive and follicular lymphomas [15–17].
Mitoxantrone is clinically associated with a much lower cardiotoxic risk than is doxorubicin. Although the mechanism of mitoxantrone-induced cardiotoxicity is not certain, anthracycline-associated cardiotoxicity appears to be caused by activated oxygen-free radicals; in vitro, mitoxantrone has been shown to generate free radicals to a much lesser degree than doxorubicin [18]. In a comparative trial of patients with advanced breast cancer treated with either cyclophosphamide, doxorubicin, and fluorouracil (CAF) or cyclophosphamide, mitoxantrone, and fluorouracil (CNF), investigators observed significantly less cardiotoxicity in the group receiving CNF [13].
Fludarabine
Fludarabine, one of the purine analogues, is an antimetabolite with significant activity against chronic lymphocytic leukemia and indolent lymphomas. Phase I and phase II trials of fludarabine in patients with relapsed and refractory follicular lymphomas demonstrated response rates of 30%–60% [19–21]. When combined in vitro, fludarabine and mitoxantrone exert synergistic effects [22]. In a study of patients with relapsed or refractory indolent lymphomas who received fludarabine, mitoxantrone, and dexamethasone, complete response (CR) and partial response (PR) rates were 47% and 47%, respectively. Acute nonhematologic toxicities, such as nausea and vomiting, were modest. The major adverse effect was myelosuppression. Opportunistic infections with Pneumocystis carinii and Herpes zoster were seen. On the basis of these promising results, investigators began clinical trials of FND in previously untreated patients with indolent lymphomas [23].
Rituximab
Rituximab, a chimeric mouse/human antibody directed against CD20, is an important therapeutic option for patients with B-cell lymphomas. In preclinical studies, rituximab lysed CD20+ cells via human-complement or antibody-dependent cell-mediated cytotoxicity and induced apoptosis in the presence of either goat antimouse IgG or Fc receptor–expressing cells [24]. Many investigators have demonstrated that single-agent rituximab has significant clinical activity in pretreated patients with follicular lymphomas. In one study, patients with follicular lymphomas who received first-line single-agent rituximab had a clinical response rate of 73% and a molecular response rate of 62% at 1 year [24]. Rituximab has now been combined with many different chemotherapy regimens. When this antibody was combined with CHOP, CRs were seen in 50%–60% of patients and PRs were seen in 30%–40% [25–28]. Similar synergy was observed when rituximab was combined with fludarabine both in vitro and in vivo [27]. These regimens, and others, appear to result in longer disease-free survival times for patients with indolent lymphomas when compared with patients who receive chemotherapy alone. However, no study has unequivocally demonstrated superior survival rates using the combination of rituximab and chemotherapy. Toxicities following rituximab chemotherapy combinations were generally similar to those occurring with these regimens when administered without rituximab, indicating an absence of overlapping toxicities.
Cyclophosphamide
Cyclophosphamide, the most frequently used alkylating agent in the treatment of lymphomas, was first described as therapy for diffuse large-cell lymphoma in 1975 [29]. The CHOP regimen subsequently became standard treatment for patients with aggressive lymphomas and is also frequently used by clinicians to treat indolent lymphomas [5]. However, the standard CHOP regimen has not been proven to be capable of eradicating MRD in patients with follicular lymphomas, as documented by the persistence of cells bearing the bcl-2 gene rearrangement in blood and marrow. This observation has encouraged the investigation of cyclophosphamide in combination with newer agents, such as rituximab, fludarabine, and mitoxantrone, in patients with relapsed disease [26, 30].
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MITOXANTRONE-CONTAINING COMBINATION REGIMENS |
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TopLearning ObjectivesAbstractIntroductionIndolent Lymphomas: Single-Agent...Mitoxantrone-Containing...Conclusions and Future...References |
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). In one, FM was administered alone [6], whereas the other three trials used concomitant or sequential administration of rituximab. Of these latter three, one included a randomized comparison of FM and CHOP followed by rituximab in selected patients in both arms [31]. In the remaining two trials, FM was also combined with either dexamethasone (FND) or cyclophosphamide (FCM) [8, 30].
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Seventy-eight eligible patients were enrolled in the study. Forty-four percent attained CRs and 50% had PRs. The median PFS was 32 months, and the estimated 4-year PFS rate was 38%. The median overall survival time had not been reached with 88% of the patients alive at 4 years. Molecular response rates were not studied. The FM regimen was generally well tolerated, with infrequent mild gastrointestinal toxicities being the predominant nonhematologic side effects. Reversible myelosuppression was the major toxicity, with grades 3 and 4 neutropenic episodes occurring in 27 patients. Although 10 patients had documented infections, including three episodes of Herpes zoster in patients who received 4–8 cycles of chemotherapy, no life-threatening or fatal opportunistic infections occurred.
Overall, the SWOG trial indicated that FM is an effective, well-tolerated regimen for the treatment of patients with advanced indolent lymphomas. Although cross-trial comparisons can be misleading, the PFS with this regimen was similar to those reported with prior anthracycline-based SWOG regimens. Because this trial did not include dexamethasone, it is not possible to determine whether the efficacy of the FND regimen is equivalent to that of the CHOP regimen. The estimated 4-year OS rate in this trial was somewhat better than those reported from previous SWOG trials, but this result could possibly be attributed to an effect of better salvage therapy.
FM with or without Rituximab Versus CHOP with or without Rituximab as Front-Line Therapy for Patients with Advanced Follicular Lymphomas
Italian investigators performed a study to compare the efficacies of the FM and CHOP chemotherapy regimens, as measured by clinical and molecular response rates [31]. In that study, selected patients received rituximab following chemotherapy in both arms. The choice of whether to administer rituximab was based on clinical and molecular restaging: patients who achieved both clinical and molecular CRs did not receive rituximab; patients who achieved a clinical CR without a molecular CR or a PR with or without a molecular CR were treated with sequential rituximab immunotherapy; nonresponding patients went off study. Patients received either FM or CHOP at conventional doses, but with cycles repeated every 21 days (Fig. 1). Patients did not receive prophylaxis for Pneumocystis carinii infection. The primary study end points were the clinical CR rates with each regimen; secondary end points included molecular response, comparison of outcomes with and without rituximab, and OS, relapse-free survival, and PFS rates [31].
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FND and Concurrent Rituximab Versus FND Followed by Sequential Rituximab as Initial Therapy for Indolent Lymphomas
In a randomized trial, investigators studied the FND regimen, with rituximab given concurrently (concurrent FND+R) or sequentially (sequential FND+R), as initial therapy in patients with stage IV small lymphocytic or follicular lymphomas. All patients who responded after completing chemotherapy received maintenance interferon-
2b for 1 year. FND was administered for eight courses, given every 28 days. The primary end point was molecular remission at 12 months. Secondary end points included FFS and OS rates, tolerability, and safety [8].
The investigators have reported results of therapy for 149 evaluable patients who had more than 12 months of follow-up. At a median follow-up of 30 months, 92% of the patients receiving concurrent treatment and 85% of the patients receiving sequential treatment achieved a clinical CR (p = 0.17). The molecular response rate at 1 year was high in both arms of the study, but significantly better for those who received concurrent FND+R (89% versus 68% for sequential FND+R; p = .01). The 3-year FFS times were 77 months for concurrent and 64 months for sequential therapy (p = 0.11); the 3-year OS rate was 95% in both groups. Both treatment schedules were well tolerated. Although there was a slightly higher incidence of grade 3–4 neutropenia with concurrent FND+R, there was no higher incidence of infection.
The results of that trial, conducted at the MD Anderson Cancer Center, suggest that concurrent FND+R results in a slightly higher 3-year FFS rate than sequential FND+R, although the difference was not statistically significant. However, for the subset of patients with follicular lymphomas, the 3-year FFS rate was significantly better for the concurrent FND+R arm than for the sequential FND+R arm (84% versus 59%; p = .01). Longer follow-up is needed to assess these results more fully, especially with regard to OS rates. Sample sizes were relatively small in this single-institution study, which was not powered to detect differences in FFS or OS. In addition, the effect of interferon and its schedule on results in both arms is unknown.
FCM and FCM with Rituximab for Recurrent Indolent Lymphomas
The German Low Grade Lymphoma Study Group performed a randomized trial comparing FCM plus rituximab (FCM+R) with FCM alone in the treatment of patients with relapsed or refractory follicular, lymphoplasmacytic, or mantle cell lymphomas. Since most patients had received CHOP chemotherapy as initial treatment, a fludarabine-containing regimen was chosen for salvage therapy. One hundred forty-seven patients received treatment, randomized to either FCM alone for four courses given every 28 days or FCM+R on day 1 of each cycle. Of the 126 evaluable patients, 52% had follicular lymphomas and 38% had mantle cell histology [30].
Sixty-one percent of patients receiving FCM alone achieved CRs (14%) or PRs (47%), compared with 82% (37% CR rate and 46% PR rate) for patients receiving FCM+R (p < .007). The PFS (p < .028) and OS (p < .002) rates were also significantly better for patients receiving FCM+R. While only a little more than one-third of the patients treated with the combined therapy achieved CRs, these results reflect the adverse prognostic impact of having failed combination chemotherapy and the inclusion of mantle cell histology. Although requiring confirmation in additional studies with larger numbers of patients, this was the first prospective randomized trial to demonstrate that combined immunochemotherapy in patients with relapsed follicular and mantle cell lymphomas is superior to chemotherapy alone, both in terms of response and survival rates.
Thiotepa, Vincristine, Prednisone, and Mitoxantrone plus Rituximab for Marginal Zone Lymphoma
Marginal zone lymphoma (MZL) is a small cell subtype of indolent lymphoma for which no standard therapy has been established. As previously discussed, mitoxantrone is associated with less cardiotoxicity and alopecia than doxorubicin. Thiotepa, likewise, does not induce alopecia and is not associated with the immunosuppressive properties of fludarabine. The combination of thiotepa, vincristine, prednisone, and mitoxantrone (TOP-M) has been shown to be useful in elderly patients with diffuse large cell lymphoma [32]. The TOP-M regimen, consisting of thiotepa (7.5 mg/m2), mitoxantrone (7.5 mg/m2), vincristine, and prednisone as per the CHOP regimen, and rituximab (375 mg/m2), all given on day 1 of a 21–28 day cycle (in accordance with resolution of cytopenias), was administered to 12 patients with disseminated MZL [33]. Four patients received TOP-M alone and eight received TOP-M plus rituximab. The doses of thiotepa and mitoxantrone were escalated by a total of 2.5 mg to a maximum of 20 mg/m2 based on nadir blood counts. Four patients had stage III disease, eight had stage IV disease, four had B symptoms, and four had elevated lactate dehydrogenase levels. Treatment was well tolerated, with only two episodes of hospitalization for fever. There was no cardiac toxicity. Eleven of 12 patients (92%) had clinical responses, with nine (75%) confirmed and unconfirmed CRs (CR/CRu) and two (17%) PRs. The median duration of response had not been reached with a range of 11–40 months of follow-up. Based on these preliminary findings, TOP-M with rituximab appears to be a well-tolerated and active regimen for disseminated MZL and may have utility for the treatment of other indolent lymphomas.
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CONCLUSIONS AND FUTURE DIRECTIONS |
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TopLearning ObjectivesAbstractIntroductionIndolent Lymphomas: Single-Agent...Mitoxantrone-Containing...Conclusions and Future...References |
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Mitoxantrone is associated with few significant grade 3–4 nonhematologic side effects. Because mitoxantrone has a lower cardiotoxic potential than doxorubicin, it may be advantageous to initially use mitoxantrone in the treatment of patients with indolent NHL, reserving doxorubicin for later use. However, this hypothesis has yet to be clinically tested. Mitoxantrone-based regimens can also be offered to patients who are concerned about anthracycline-associated alopecia. Central venous access is not required for the administration of mitoxantrone in any combination, since extravasation of this drug does not produce significant tissue injury or necrosis. Mitoxantrone also appears to be associated with less gastrointestinal toxicities than CHOP, including nausea and vomiting, abdominal pain, and constipation, making it an attractive drug to use in combination with fludarabine as therapy for older patients.
Because FM-based regimens use only 3 days of treatment with fludarabine, in contrast to 5 days with other fludarabine-containing regimens, FM may also be a preferable choice for patients who subsequently undergo autologous or allogeneic stem cell transplants. The primary toxicity of fludarabine is myelosuppression, which may be prolonged in some patients, especially in those receiving higher doses or prolonged therapy [19–21]. Given the greater potential for serious myelotoxicity associated with greater fludarabine exposure, a shorter 3-day course may be a safer alternative when given in combination with mitoxantrone.
A potential new approach is the sequential combination of chemotherapy with radioimmunotherapeutic agents, such as the anti-CD20 radioimmunoconjugates 131I-tositumomab and 90Yttrium-ibritumomab-tiuxetan. Both agents have demonstrated activity in patients with follicular lymphomas refractory to both prior chemotherapy and rituximab [34–37]. New studies combining mitoxantrone-containing regimens with radioimmunoconjugates are planned and may add to our knowledge of the benefit of these drugs.
Despite therapeutic progress, cure remains the ultimate goal for patients with indolent lymphomas. Whether this can be achieved now is conjectural; however, prolongation of life, enhanced quality of life with PFS, and minimizing toxicity are goals equally important and hopefully achievable.
Brief Patient Case
A 56-year-old female executive of a high fashion magazine fortuitously noticed a 2.5-cm left supraclavicular node while dressing. Her history includes rheumatic fever and murmur as a child as well as smoking 1–2 packs of cigarettes per day for 30 years. A computed axial tomography (CAT) scan disclosed hilar lymphadenopathy but clear lung fields and she was asymptomatic. A node biopsy established the diagnosis of follicular, grade one lymphoma. Work-up revealed 1–2 cm nodes in the inguinal area, but all laboratory data were otherwise unrevealing. The patient emphasized that she must maintain her appearance and hectic pace for the next several years and was managed with observation. After 1.5 years, she presented with a history of rapidly growing peripheral nodes and weight loss. Evaluation disclosed no evidence of transformation; however, a CAT scan showed significant abdominal lymphadenopathy with some impingement on the ureters and moderate bilateral hydronephrosis. There was also a 20-cm enlarged spleen with some pressure effects on the stomach. Cardiac evaluation showed a multigated acquisition (MUGA) scan ejection fraction of 55%. Creatinine clearance was 55 ml/minute. The patient was treated with FM+R in order to achieve a rapid response. She had an excellent response, remained in response for 20 months, and was able to maintain her current lifestyle during and after treatment.
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ACKNOWLEDGMENT |
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REFERENCES |
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