Robert S. Mocharnuk, MD
Instructor, Clinical Medicine
USC/Norris Comprehensive Cancer Center and Hospital
Los Angeles, CA

Alexandra M. Levine, MD
Professor of Medicine
Chief, Division of Hematology
University of Southern California
Medical Director,
USC/Norris Comprehensive Cancer Center and Hospital
Los Angeles, CA

This article includes discussion of investigational and/or unlabeled uses of drugs, including the use of cisplatin and pixantrone in non-Hodgkin’s lymphoma.

Pixantrone, a Novel Anthracycline
Pixantrone (BBR 2778), an aza-anthracenedione DNA intercalator (Figure 1), appears to function like mitoxantrone, another well-known anthracenedione DNA intercalator. By inserting into replicating DNA, these agents stimulate topoisomerase II–mediated DNA cleavage. Unlike mitoxantrone, pixantrone is devoid of 5,8-dihydroxy substitution groups thought to be responsible for the cardiac toxicity associated with these drugs. Preclinical data from mouse models confirm an absence of acute or delayed cardiac toxicity, while maintaining cytotoxic activity superior to doxorubicin or mitoxantrone.1 Pixantrone is currently being studied in a variety of malignant tumors. As a single agent or in combination with other cytotoxic drugs, it has shown particularly promising activity in phase I and II trials for patients with non-Hodgkin’s lymphoma (NHL). In phase I trials, bluish discoloration of the skin and urine occurred but was not serious.2,3

Treatment Issues in Non-Hodgkin’s Lymphoma
In spite of the progress made over the past 3 decades, most patients with aggressive NHL who respond to standard treatments will eventually relapse, while a smaller number will never respond to initial therapy. For the latter, complete remissions (CRs) with additional lines of therapy remain rare, even when non–cross-resistant treatment regimens are employed. Patients with chemosensitive disease can achieve second remissions with standard second-line chemotherapy but rarely maintain these remissions outside the context of high-dose chemotherapy and stem cell support regimens.4 Among patients who experience late relapses (24 months and beyond), retreatment with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone)–like regimens rarely prove effective, and cardiotoxicity remains the dose-limiting toxicity (DLT). A causal link between cumulative doses of doxorubicin and development of congestive heart failure has been delineated5 (Table 1).

For this reason, physicians often forego a second course of CHOP or another anthracycline-containing regimen. As a result, patients are exposed to the potential side effects of platinum-based regimens such as ESHAP (etoposide/methylprednisolone/high-dose cytarabine/cisplatin) or ICE (ifosfamide/carboplatin/etoposide) regimens. Clearly, there is a need for agents as effective as doxorubicin, without its well-known association with cardiac toxicity. Pixantrone might be such an agent.

Single-Agent Activity of Pixantrone in Refractory/Relapsed Non-Hodgkin’s Lymphoma and Solid Tumors

With encouraging preclinical data in hand, investigators launched a series of phase I studies to determine dosage and toxicity of single-agent pixantrone. 2,3,6 Two of these studies enrolled patients with solid tumors,2,3 while a third study focused on patients with aggressive NHL.6 In the first phase I study, pixantrone was administered weekly in graduated dose escalations to 30 French patients with advanced solid tumors.2 Responses were observed among patients with breast and small-cell lung cancers with an ORR of 10% and the DLT was neutropenia. The maximum tolerated dose for weekly pixantrone was 150 mg/m2. Another of these studies was conducted in the United Kingdom and enrolled 24 patients with a variety of solid tumors.3 Participants received a 1-hour infusion of pixantrone every 3 weeks. One patient experienced a significant decline in left ventricular ejection fraction (LVEF) without clinical manifestations, and neutropenia was identified as the DLT. In the third study reported by Dr. Borchmann and colleagues from Germany, 26 patients with relapsed or refractory advanced NHL were treated with escalating doses of weekly pixantrone.6 There were 3 CRs and 2 partial remissions (PRs), for an ORR of 19%. As seen in the other 2 studies, neutropenia was the DLT.

Phase II Trial With Single-Agent Pixantrone Shows Activity in Non-Hodgkin’s Lymphoma

Based upon the promising results of their phase I study, Dr. Borchmann and colleagues launched a multicenter phase II trial, enrolling 33 patients with relapsed aggressive NHL.7 Eligibility criteria did not exclude patients on the basis of age (the median age was 66 years) or chemosensitivity. Further, LVEF requirements were quite liberal, with a LVEF of ≥ 30% allowed for study entry. Additionally, patients had received a median of 2 prior treatment regimens, with a median time since last chemotherapy of 4 months. Participants were treated with pixantrone 85 mg/m2/week for 3 weeks, followed by additional cycles beginning on day 29. An intent-to-treat ORR of 27% was observed, with 5 CRs and 4 PRs, with most responses occurring among the 24 patients with diffuse large B-cell histology. Of particular note, 1 CR was observed out of 7 patients with mantle cell lymphoma, while 5 other mantle cell patients experienced partial but transitory responses. Grade 4 neutropenia occurred in 39% of the patients treated, leading to dose reductions in 5 patients. Median duration of response was approximately 11+ months, although several patients have had no disease progression at ≥ 11 months of follow-up. Three elderly patients (9%) experienced decreases in LVEF > 10%; all had been pretreated with anthracyclines, and 2 had abnormal cardiac function (LVEF < 50%) at study entry.

Combination Regimens With Pixantrone in the Treatment of Relapsed/Refractory Non-Hodgkin’s Lymphoma

Multidrug regimens have become the mainstay of lymphoma treatment for decades, so it is no surprise to learn that pixantrone has been studied in combination with other cytotoxic agents. One combination phase I/II trial substituted pixantrone for etoposide in ESHAP (BSHAP),8 while Dr. Borchmann and colleagues replaced doxorubicin with pixantrone in CHOP.9

Substitution of Pixantrone for Etoposide in the ESHAP Regimen
Dr. Camboni and colleagues reported a multicenter phase I/II study in which 21 patients with confirmed relapsed or refractory aggressive NHL, including diffuse large B-cell, follicular large cell grade 3, peripheral T-cell, transformed lymphoma, and unclassified aggressive subtypes were enrolled.8 Two patients never received treatment and were considered nonevaluable. Inclusion criteria required at least 1 prior treatment regimen for curative intent, as well as adequate cardiac function, defined as ≥ 50% LVEF on multiple-gated acquisition scan. Patients were excluded if prior anthracycline doses exceeded 450 mg/m2, if radiation therapy or chemotherapy had been administered within 4 weeks of study treatment, or if a cardiac event had occurred within the previous 6 months (including myocardial infarction, severe arrhythmia, or uncontrolled hypertension). BSHAP was given primarily on an outpatient basis every 21 days for up to 8 cycles, or 2 cycles beyond CR, or until disease progression, with fixed doses of cytarabine, methylprednisolone, and cisplatin. Pixantrone infusions started at 80 mg/m2, and successive cohorts of 3 patients were to receive doses of 120 mg/m2, 150 mg/m 2, and 180 mg/m2. Two patients did not receive treatment. One patient withdrew consent, while the other was deemed ineligible due to an LVEF of 31%.

Two DLTs (1 grade 3 infection, 1 grade 3 febrile neutropenia) were observed among 6 patients who received pixantrone 80 mg/m2. Therefore, the combination regimen dose of pixantrone was capped at 80 mg/m2 and an additional 13 patients were treated at this level. No clinically significant cardiac toxicity was observed among 19 patients after a total of 70 cycles (median 4, range 1-6) were given. Grade 3 and 4 thrombocytopenia occurred in 10 and 8 patients, while grade 3 and 4 neutropenia was observed in 3 and 13 patients, respectively (Table 2). Febrile neutropenia occurred in 5 patients. Nonhematologic toxicities were mild, with occasional episodes of hyperglycemia, deep vein thrombosis, diarrhea, dehydration, anorexia, and fatigue.

The ORR was 58%, with 7 CRs (37%), 4 PRs (21%), and a median duration of response of 4.8 months (Table 2). Disease stabilization occurred in an additional 33% of the patients. The median overall survival time was 14.7 months. Among 14 patients refractory to the immediately prior regimen, there was a 29% ORR. Six patients (55%) were able to undergo subsequent high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). This is particularly important because disease sensitivity at the time of ASCT remains the most significant predictor of favorable treatment outcome. Furthermore, it was concluded that patients ineligible for ASCT because of age, comorbid conditions, or other impediments, might benefit from a well-tolerated outpatient salvage regimen like BSHAP, with response rates (RRs) clearly comparable or superior to other standard combination therapies.

Replacement of Doxorubicin by Pixantrone in the CHOP Regimen
Pixantrone was substituted for doxorubicin in the CHOP regimen and was administered to 23 patients with relapsed aggressive lymphoma in a phase I trial reported by Dr. Borchmann.9 There were 13 CRs and 4 PRs, for an ORR of 74%, while an additional 4 patients achieved disease stabilization (Table 2). Most responses occurred at the 120-mg/m2/week dose level, and only 1 case of grade 4 dose-limiting neutropenia was observed at this level.

Conclusion

Investigators continue to experiment with monoclonal antibodies, radioimmunotherapy, and multiple novel chemotherapeutic agents in order to improve upon RRs, duration of responses, and toxicity profiles in salvage NHL regimens. Based on the information presented above, pixantrone might offer significant advantages over existing therapies and warrants further study in combination with some of the newer targeted therapies. Among patients with cardiovascular disease, pixantrone might offer a powerful alternative to the anthracycline therapy that has otherwise been indicated for a wide variety of tumor types. In July 2004, pixantrone received fast-track designation from the US Food and Drug Administration to begin a randomized phase III trial for third-line or subsequent treatment of relapsed aggressive NHL, which is life-threatening. The trial is ongoing, and results are awaited with interest.

Two randomized phase III trials are accruing patients, one in indolent, and the other in aggressive NHL. The AZA III 02 trial is comparing pixantrone/rituximab to rituximab alone in 800 patients in the United States, Europe, and Israel with relapsed/refractory indolent NHL.10 Time to progression is the primary endpoint. Based on the data reported by Dr. Borchmann and colleagues,7 the PIX301 study is being conducted to compare single-agent pixantrone to selected single agents, including vinorelbine, oxaliplatin, ifosfamide, etoposide, and mitoxantrone as third-line treatment for patients with relapsed aggressive NHL.11 The trial has an expected accrual of 320 patients.

References

1. Beggiolin G, Crippa L, Menta E, et al. Bbr 2778, an aza-anthracenedione endowed with preclinical anticancer activity and lack of delayed cardiotoxicity. Tumori 2001; 87:407-16.
2. Faivre S, Raymond E, Boige V, et al. A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies.Clin Cancer Res 2001; 7:43-50.
3. Dawson LK, Jodrell DI, Bowman A, et al. A clinical phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly.Eur J Cancer 2000; 36:2353-9.
4. Singer CR, Goldstone AH. Clinical studies of ABMT in non-Hodgkin’s lymphoma. Clin Haematol 1986; 15:105-50.
5. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003; 97:2869-79.
6. Borchmann P, Schnell R, Knippertz R, et al. Phase I study of BBR 2778, a new aza-anthracenedione, in advanced or refractory non-Hodgkin’s lymphoma. Ann Oncol 2001; 12:661-7.
7. Borchmann P, Morschhauser F, Parry A, et al. Phase-II study of the new aza-anthracenedione, BBR 2778, in patients with relapsed aggressive non-Hodgkin’s lymphomas. Haematologica 2003; 88:888-94.
8. Camboni G, Fayad L, Tulpule A, et al. A phase I/II trial of BBR-2778 (pixantrone), methylprednisolone, cisplatin, and cytosine arabinoside (BSHAP) in relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL). Proc Am Soc Clin Oncol 2004; 23:578 (abstract 6590).
9. Borchmann P, Schnell R, Morschhauser F, et al. A phase I study of pixantrone (BBR 2778) in combination with cyclophosphamide, vincristine and prednisone in patients with relapsed aggressive non-Hodgkin’s lymphoma. Blood 2003; 102:642a (abstract 2369).
10. Comparative trial for pixantrone in combination with rituximab in indolent non-Hodgkin’s lymphoma. National Institutes of Health [Web site]. Available at: http://www.clinicaltrials.gov/ct/ show/NCT00060671?order=3. Accessed: October 20, 2004.
11. Phase 3 BBR 2778 for relapsed, aggressive non-Hodgkin’s lymphoma (NHL). National Institutes of Health [Web site]. Available at: http://www.clinicaltrials.gov/ct/show/NCT00088530?order=6. Accessed: October 20, 2004.