Ofatumumab and Bendamustine in Previously Treated CLL and SLL

Despite response rates of 85–95% with fludarabine and rituximab (R)-based therapies in multicenter trials, patients (pts) with CLL invariably relapse. Ofatumumab (O) and Bendamustine (B) have each shown efficacy in relapsed/refractory CLL with ORRs of 68–78% and 44–58%, respectively. While excellent responses have been seen with BR in CLL (77-91%), the combination of O and B has yet to be investigated. In this phase II study, we are combining O and B in previously treated CLL and SLL in order to investigate the efficacy and tolerability of this regimen. We report our experience with the first 5 pts here.

Pts with relapsed/refractory CLL/SLL with adequate performance status and organ function were eligible as long as they had not received B previously. Pts received O 300 mg IV on D −7, followed by O 1000 mg IV on D1 and B 70 mg/m² on D1, 2 of each cycle (C). Premedications included acetaminophen 650 mg PO, diphenhydramine 50 mg PO, and hydrocortisone 100 mg IV prior to O and Ondansetron 8 mg IV prior to B. Pts received 6 cycles of OB as long as tolerated or until disease progression. The target enrollment is 40 pts.

Of the 5 pts on study, the median age was 62 years, 4 were male, and 3 were Rai Stage III/IV. One pt had sole del 13q, 3 had del 11q, and 1 had del 17p cytogenetics. Pts received a mean of 2 prior therapies (range, 1–4).

The first 3 pts developed Grade 2 infusion-related reactions with O during C1. Thus, the protocol was amended to increase acetaminophen to 1000 mg and hydrocortisone to 200 mg for O premedication.

Three patients developed > Grade 3 neutropenia which delayed C2 treatment in 2 pts. Two pts experienced > Grade 3 anemia requiring transfusion. In addition, multiple infections arose on study. Pt 1 had a Grade 1 URI requiring hospitalization during C1. Pt 2 had a Grade 2 pneumonia with Grade 3 NTP during C1 and a Grade 2 UTI during C2. Pt 4 developed a Grade 3 pneumonia, Grade 3 hepatosplenic fungal infection, and Grade 3 bacteremia after C1. Pt 5 had a Grade 2 URI during C1 and Grade 2 sinusitis during C3. The protocol was amended so that pegfilgrastim was to be given with each cycle.

After C1, Pts 1 and 4 developed a systemic neurotoxicity, characterized by blunted affect, weakness, fatigue, and failure to thrive requiring hospitalization. Complete infectious, metabolic, psychological, and neurologic evaluation was negative for Pt 1. Due to his ongoing weakness, he was removed from study after C2 and discharged to rehab. At 3 months he was only able to walk 3 blocks and his affect remained blunted. Pt 4 was found to have pneumonia on admission. With antibiotics, his functional status improved, but his affect remained mildly altered. Proposed etiologies for this neurotoxicity included infection such as viral reactivation or cytokine release storm. The protocol was amended to exclude pts with history of neurologic deficit and to perform a thorough neurologic evaluation including brain MRI, lumbar puncture, and serum and CSF viral serologies and cytokines levels at onset of concerning symptoms.

Pts received a median of 2 cycles of therapy (range, 1–6). All showed evidence of response after C1. Pt 1 achieved a clinical CR with C1 but was removed from study after C2 and had recurrent disease at 5 months. Pt 2 achieved a CR after C3 and remains progression-free 5 months after completing C6. Pts 3 and 4 initially showed a response after C1 but developed Richter’s transformation during C2. Pt 5 had a response after C1 and is currently in C4. The most common reasons for stopping therapy were toxicity and Richter’s transformation.

OB has significant efficacy in pts with multiply-relapsed and highly-refractory CLL/SLL. However, toxicity is considerable, particularly in terms of infection. In addition, despite an initial response, Richter’s transformation has been reported in two patients. As this is a small cohort with multiple confounding factors, further evaluation is needed.

Broome:Alexion: Honoraria, Speakers Bureau. Cheson:Cephalon: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding.