Results of the phase II NCRN CLL207 trial: alemtuzumab consolidation of MRD-positive patients after conventional chemotherapy results in an improvement in outcome

On 29^th December 2016, the results of the phase II, multicenter, single-arm CLL207 trial were published in the British Journal of Haematology by A.M. Varghese of Leeds Teaching Hospitals NHS Trust, UK, and colleagues.

The study assessed the safety and efficacy of alemtuzumab consolidation in CLL patients with low levels of MRD. At study entry, MRD status was assessed; MRD-positive patients took part in the Main Study and were administered consolidation therapy, MRD-negative patients were followed- up for relapse and were only treated if they became MRD-positive.

Patients were administered 30mg subcutaneous alemtuzumab three times a week for 6 weeks. Patients who were responding but remained MRD-positive were then administered with another 6 weeks of alemtuzumab and reassessed for MRD. If patients became MRD-positive after staying MRD-negative for ≥6 months, they were then eligible for re-treatment.

Key Highlights:

• Main Study:
  • Forty-seven patients (median age 58yrs [40–77], 75% male) were treated
  • Six pts (12.8%) did not receive the full 6 cycles; 12 pts (25.5%) were treated for the further 6 weeks although 4 of these did not receive the full 12 cycles
  • Dose delay or modification for ≥1 week of treatment occurred in 20 pts (42.6%)
  • ORR (CR or PR) = 91.5%; 5-year PFS = 53.2%; 5-year OS = 72.2%
  • Median time to progression = 70 months; median OS = not reached
  • Thirty-nine pts became MRD-negative following treatment; 5-yr survival for MRD relapse, progression or death = 11.2%
  • Median duration of MRD-negativity = 6.7 months (95% CI, 5.6–25.0)
  • 21/39 MRD-negative patients (53.8%) became MRD-positive within 6 months of completing therapy
  • PFS and OS were significantly better in MRD-negative pts at 6 months compared to MRD-positive pts (P-values, 010 and 0.029, respectively)
  • As of August 2015, 15 pts (31.9%) have died, one death thought directly related to alemtuzumab treatment (parainfluenza pneumonitis)
  • A total of 414 AEs reported, 339 suspected to be alemtuzumab related, the most common being rash and cytopenia (both 13%), fatigue and non-specific respiratory symptoms (both 8%), and fever (5%)
• Monitoring Investigation:
  • Fifteen pts were MRD-negative at registration; 4 became MRD-positive and treated
  • Eleven pts followed-up for relapse; median follow-up from previous treatment = 7 yrs
  • One clinical progression and 2 deaths at 6 yrs and 5 yrs after treatment, respectively
  • 10/15 MRD-negative pts at registration became MRD-positive or died
  • Median duration of MRD-negativity = 59.4 months (95% CI, 24.7–not reached)

The authors conclude that alemtuzumab consolidation of MRD-positive patients after conventional chemotherapy results in an improved outcome. It was also noted that after treatment, participants who remained MRD-negative for longer than 6 months had a greater chance of sustained MRD-negativity. Additionally, the authors conducted a subgroup analysis, which found no advantage to extending alemtuzumab therapy beyond 6 weeks. Lastly, the authors state that alemtuzumab treatment carries high toxicity and so, based on the promising rates of MRD-negative remission obtained with alemtuzumab, they have begun a randomized phase III trial (NCRI GALACTIC; ISRCTN64035629) with obinutuzumab. They hope similar MRD-negative remissions can be obtained without the same toxicity.

Abstract:

With immunochemotherapy, remission duration and survival in patients with chronic lymphocytic leukaemia is dependent on the level of minimal residual disease (MRD) after treatment. This phase II trial assessed alemtuzumab consolidation post-chemotherapy in patients who responded with persistent low levels of detectable disease. Blood was screened for MRD using multi-parameter flow cytometry, 6-24 months post-chemotherapy. MRD-positive participants received alemtuzumab 30 mg subcutaneously 3 times weekly for 6 weeks. Following a marrow assessment, MRD-negative participants or non-responders stopped therapy and MRD-positive participants with 1 + log reduction had 6 more weeks of alemtuzumab. Alemtuzumab consolidation was received by 47 participants. One death and 19 of 22 serious adverse events reported from 17 (36%) participants were alemtuzumab-related. MRD eradication from blood and bone marrow was achieved in 39 (83%) participants at the end of consolidation, with 18 (38%) remaining MRD-negative in the blood 6 months later. Of the 18 participants who were MRD-negative at 6 months, the median time to MRD relapse was 46 months, which was similar to patients who were MRD-negative at baseline and were followed up. The 5-year progression-free survival (PFS) and overall survival (OS) of participants who were MRD-negative at 6 months was significantly better than MRD-positive participants [PFS: 78% vs. 39% (P = 0·010), OS: 89% vs. 64% (P = 0·029)].