Full Dose Bendamustine (Treanda ®) Can Be Safely Combined with Rituximab, Etoposide and Carboplatin (TREC): Results of a Phase I Trial in Patients with Relapsed or Refractory Lymphoma

Traditional salvage strategies for relapsed lymphoma are less effective when disease recurs after modern front line therapies (e.g. R-CHOP, BEACOPP). Furthermore, typical multi-agent regimens require inpatient hospitalization and carry the risk of significant non-hematologic toxicity from drugs such as ifosfamide, high-dose cytarabine, and cisplatin. Bendamustine (Treanda ®, T) has both broad spectrum clinical activity in lymphoma and a moderate side effect profile, though limited data exist on the utility of this agent as part of a dose-intense rescue approach. We, thus, hypothesized that bendamustine could safely supplant ifosfamide within the RICE regimen yielding a feasible, effective, outpatient multi-agent salvage strategy (TREC) for patients with relapsed or refractory lymphoma.

Eligibility included: relapsed/refractory lymphoma (untreated T-NHL or MCL was allowed during stage 1), age ≥18 years, performance status of 0–2, measurable disease, no active CNS involvement, ANC ³ 1,500/μL, platelets ³ 100,000/μL, adequate hepatic and renal function, no active arrhythmias, and no known HIV. The primary objective of the study was to define a maximally tolerated dose (MTD) of bendamustine associated with a dose limiting toxicity (DLT) rate of ≤25%. A DLT was defined as any related non-hematologic grade ≥4 adverse event (AE), or inability to complete one full cycle of therapy due to toxicity. Therapy was delivered in the outpatient setting and consisted of bendamustine ranging from 60 mg/m² to 120 mg/m² daily on days 1 and 2 in combination with carboplatin (AUC = 5 on day 1), etoposide (100 mg/m² on days 1 to 3) and rituximab (375 mg/m², for CD20+ disease only on either day 2 or 3) every 21 days for up to 2 cycles with G-CSF support. Single patient dose escalation occurred until a DLT was observed, followed by cohorts of 4 patients up to a maximum dose of 120mg/m² × 2. Response was measured by standard criteria (Cheson 2007). AEs were graded using the CTCAE v4.0

Twenty-four patients were treated, 4 in stage 1, and 20 in stage 2 with no DLTs observed. Baseline features included median age = 58 (range 18 – 72) years, median prior therapies = 1 (range 0 – 2), and refractory to last regimen = 16 (of 22 evaluable, 73%). All B-NHL patients had disease progression following prior rituximab. Histologies included Hodgkin lymphoma (HL, n = 8), diffuse large B-cell (DLBCL, n = 9), mantle cell (n = 2), T-NHL (n = 2), follicular (n = 2), and lymphoplasmacytic lymphoma (n = 1). Twenty-three patients received 2 cycles and one received 1 cycle due to disease progression. All cycles were given in the outpatient settings. Thirteen non-hematologic AEs ≥ grade 3 (SAEs) were observed in 9 patients. The most common related SAEs were dehydration (2), and febrile neutropenia (2). Responses were observed in 16 patients (67%) with 9 CR, and 7 PR. Response rates in HL and DLBCL were 88% (6CR, 1PR), and 56%.

Mobilization of peripheral blood stem cells (PBSC) was successful in all 15 attempts immediately following the second cycle of T(R)EC (median yield: 5.58×10⁶CD34/kg, range 3.96 – 11.68). At the last update with a median follow up of 8 (range 2 – 18) months, 19 (79%) patients are alive, and 13 (54%) are progression free, including 10 of 12 who subsequently underwenttransplant.

This multicenter phase I trial confirms the ability to safely replace ifosfamide with 120mg/m² × 2 of bendamustine, yielding the TREC regimen for patients with relapsed/refractory lymphoma. The outpatient administration, manageable toxicity profile, effective use for PBSC mobilization, and preliminary response data are encouraging. These data support future evaluation of TREC, including our ongoing expansion cohorts further investigating outcomes in patients with DLBCL and HL.

Budde:Teva: Research Funding. Gopal:TEVA: Research Funding.