This month in the European Journal of Haematology, Othman Al-Sawafand Kirsten Fischer( Department I of Internal Medicineand Center for Integrated Oncology Cologne-Bonn, University of Cologne, Germany) et al.published the results of an open-label, multicenter, phase I/II trialaiming to determine the Maximal Tolerable Dose (MTD) of alemtuzumab consolidation and to evaluate safety and efficacy in CLL patients who responded to second-line fludarabine-based treatment.
The trial took place between 2003 and 2008 at six different centers across Germany and was carried out by the German CLL Study Group(GCLLSG).
A total of 13 patients were enrolled with a median age of 68 years (range, 55–74) in recent second remission (CR = 2; PR = 11) after treatment with F/FCR/B/BR. Initially, two patient cohorts were outlined receiving alemtuzumab either by IV (cohort A) or SC (cohort B). Alemtuzumab consolidation had to be started at the earliest of 90 days and latest of 150 days after the last dose of chemotherapy.
Key Highlights:
Dosing and toxicity
- In cohort A, MTD defined as dose level 1 = 10mg
- Of three pts at dose level 2 (20mg), two DLTs reported: one Fever of Unknown Origin (FUO) and one skin infection (erythema multiforme), both requiring IV antibiotics
- No DLTs reported in pts receiving 10mg
- Three pts successfully treated at 10mg in cohort B with no DLTs; SC cohort was suspended due to poor enrolment
Efficacy
- Pts who were in CR remained in CR after consolidation
- Of pts who were in PR, 5/11 converted to CR after consolidation
- Four pts in PR had residual splenomegaly; 1 pt also exhibited residual lymphadenopathy
- MRD negative (<1x10 -4) = 4/13 (30.8%); 3 entered consolidation with MRD negativity
- Overall, 10 pts showed an MRD response
- After a median observation time of 71.5 months: PD = 8/13 pts
- Three deaths due to PD and subsequent malaise/infections
- Median PFS:
- Overall = 28.5 months
- In pts who achieved CR = 30.1 months
- In pts who achieved PR = 9.6 months
- In cohort A pts at dose level 2 (20mg) = 5.3 months
- In cohort A pts at dose level 1 (10mg) = 18.2 months
- In cohort B pts at dose level 1 (10mg) = 23.5 months
- At last observation (90 months), median OS = not reached
- OS at 4-yrs at dose level 1 (10mg) inc. cohorts A and B pts = 66.7%; in dose level 2 (20mg) IV pts = 75.0%
The authors concluded by stating that alemtuzumab consolidation therapy at low doses can be an effective option in CLL patients in second remission. The marketing authorization for alemtuzumab (MabCampath) was withdrawnby the European Medicines Agency (EMA) on 8 thAugust 2012 and so “routine use of alemtuzumab is not possible nowadays.” The authors hypothesize that, seeing as consolidation has shown benefit in CLL patients, different approaches with other available agents such as anti-CD20 antibodies may offer an alternative consolidation strategy for CLL.
Abstract:
OBJECTIVE: Despite high rates of long-lasting remissions in patients with chronic lymphocytic leukaemia (CLL) treated with chemoimmunotherapy, none of the current therapeutic approaches is curative with the exception of allogeneic transplantation. One strategy to extend progression-free survival and long-term survival might be the establishment of consolidation therapies.
METHODS: In this trial, patients with complete or partial second remission after fludarabine-based treatment received consolidation therapy with alemtuzumab. The aim of this phase I/II trial was to determine the maximal tolerable dose (MTD) of alemtuzumab consolidation and to evaluate safety and efficacy in patients who responded to second-line fludarabine-based treatment. Thirteen patients in complete (CR) or partial remission (PR) received alemtuzumab dose escalation starting with 10 mg intravenously (iv) once weekly for 8 wk and increasing in 10-mg intervals per dose level.
RESULTS: The main dose-limiting toxicities (DLTs) were infectious complications, and the MTD was determined at 10 mg. After alemtuzumab consolidation, seven of 13 patients (53%) were in CR, and four of these patients (30.7%) achieved minimal residual disease (MRD) negativity (<1 × 10E-4). At a median follow-up of 71.5 months, four patients were progression-free, with a median progression-free survival (PFS) of 28.5 months after the end of second-line treatment.
CONCLUSION: The results provide a safe and efficient schedule with weekly intravenous application of 10 mg of alemtuzumab as a consolidation regime in patients with CLL.