Results of a Phase I/II Trial of Pixantrone in Combination with Fludarabine, Dexamethasone, and Rituximab in the Treatment of Patients with Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma (NHL).

Background: Pixantrone (P) is a novel aza-anthracenedione that has substantially less delayed cardiotoxicity than either doxorubicin or mitoxantrone in animal models, with greater efficacy than either against murine lymphoma and leukemia in in vivo models. In patients (pts) with relapsed or refractory indolent NHL, P + rituximab (R) delayed the time to tumor progression compared with single agent R (395 vs. 245 days, log rank p-value <0.001). In addition, the overall response rate was higher in the P+R arm (75%, CR 35%) compared with single agent R-treated pts (ORR 33% and CR 11%). Fludarabine (F)-mitoxantrone (N)-dexamethasone (D)-rituximab (FND-R) is an alternative active combination in indolent B-cell lymphoma pts. The current study substituted P for N in the combination therapy (FPD-R), with the objective of determining the recommended dose (RD) of P and the safety and efficacy of FPD-R in pts with relapsed or refractory indolent NHL.

Methods: Pts received P (day 2) with F (25 mg/m²/day, days 2–4), D (20 mg/day, days 1–5), and R (375 mg/m²/day, day 1) in a 28 day regimen. This was a dose escalation study; once the RD was determined, the next cohort of pts was to be treated at that dose.

Results: Three pts were treated with P at 80 mg/m² and 25 pts at 120 mg/m², which was the RD determined in the Phase I portion of the study. The median age was 63 (range 32–78); all pts had WHO performance status 0–1. All pts had received at least one prior chemotherapy regimen (median 1, range 1–4). The median number of cycles received was 5 (range 1–8). The overall response rate (response of any duration) was 89% for 27 evaluable pts, with 17 (63%) complete responses (CR), 2 (7%) unconfirmed complete responses (CRu), and 5 (19%) partial responses (PR). Seventy percent of pts experienced a CR/CRu/PR that lasted at least 8 weeks, with a median duration of response of 25 months, (range 2.4 to 43). Grade 3/4 hematologic toxicities were neutropenia 23 (82%), thrombocytopenia 6 (21%), febrile neutropenia 3 (11%), and anemia 1 (4%). Non-hematologic adverse events were primarily grade 1 or 2 in severity. A total of 7 of 28 (25%) pts evaluable for safety had a decline in LVEF ≥ 10% to ≤ 20%. No pt had a decline in LVEF > 20 %. In 4 pts the decline in LVEF was transient and returned toward baseline with continued follow-up. Five of the 7 pts with a decline in LVEF were asymptomatic. Two pts reported transient shortness of breath with spontaneous resolution without treatment. No episodes of CHF were reported.

Conclusions: The RD of pixantrone in the FPD-R regimen is 120 mg/m². The primary toxicity is hematologic; no serious cardiotoxicity was observed. This treatment is highly active and is associated with major, durable responses. The regimen can be given on an outpatient basis and is well tolerated in relapsed and refractory indolent NHL pts.