Phase II trial of lenalidomide and dexamethasone combination in naïve CLL patients

On 2 October 2018, Christine Chen from the Princess Margaret Cancer Center, Ontario, CN, and colleagues, published in Leukemia & Lymphoma results of a single-arm, phase II clinical trial (NCT01133743), evaluating lenalidomide and dexamethasone combination for the treatment of naïve chronic lymphocytic leukemia (CLL) patients.

Lenalidomide monotherapy has shown very promising results in the treatment of CLL. However, due to the risk of tumor lysis syndrome (TLS), low starting doses and slow dose escalation strategies. In this study, the investigators hypothesized that the addition of dexamethasone could decrease lenalidomide-mediated toxicity, thus allowing for higher dosing plans and leading to more durable responses. The primary endpoint of the study was objective response to lenalidomide and dexamethasone combination treatment (complete response [CR] and partial response [PR]. Secondary endpoints included, toxicity, response duration, progression-free survival (PFS), and overall survival (OS).

Study design

• N = 31 eligible participants with previously untreated B-cell CLL patients were enrolled
• Lenalidomide dosing: initial dose of 5 mg daily, which was escalated every four weeks by 5 mg (as tolerated) to a daily target dose of 25 mg for a median of 18 cycles (28-day cycle)
• Dexamethasone dosing: 12 mg orally on Days 1–7, 14, and 21 of each cycle for a median of 18 cycles (28-day cycle)
• TLS prophylaxis was achieved with allopurinol and weekly laboratory testing for eight weeks during the dose escalation phase
• Responses and progressive disease (PD) were evaluated with the 2008 International Workshop Group on CLL (iwCLL) Response Criteria and CR was further confirmed by biopsy and bone marrow aspirate

Key findings

• A total of n = 19 patients completed the full treatment plan
• Median daily lenalidomide dose reached (range) = 20 mg (2.5–25 mg) with n = 17 (55%) patients reaching the maximum daily dose of 25 mg
• At a median follow-up = 27 months:
  • Overall response rate was 74.2%, of those n = 20 (64.5%) achieved PR, n = 3 (9.7%) achieved CR, n = 8 (25.8%) patients achieved SD, and n =21 patients had PD
• Median time to best response was longer than 5.0 months (range, 0.8−7)
• Median duration of response (range) = 20.7 (14.9−2) months with n = 11 (48% of responders) patients achieving durable responses at ≥ 24.0 months
• Median PFS = 27 months (95% CI, 20.7−9)
• Estimated two-year PFS = 60.3% (95% CI, 44.4−81.7)
• Estimated two-year OS = 92.6% (95% CI, 83.2−100)

Toxicity

• The main reasons for treatment discontinuation in the n = 12 patients were:
  • Drug-related toxicity (n = 5; 16%) [prolonged cytopenia, recurrent infections, and rash]
  • Patient withdrawal (n = 5; 16%)
  • PD (n =1; 3.2%)
  • Treatment unrelated death from exacerbation of chronic obstructive pulmonary disease (n = 1; 3.2%)
• Lenalidomide dose reduction occurred in n = 14 patients (45%), mainly due to Grade 3−4 cytopenia
• Only one patient required dose reduction of dexamethasone alone
• Lenalidomide dose delay occurred in n = 21 patients (68%) and in 70 of 434 cycles
• Dexamethasone dose delay occurred in n = 21 patients (68%) and in 68 cycles (15% of all cycles)
• Tumor flare (TF) presenting with painful and/or enlarging lymph node(s) occurred in n = 9 (29%) patients, no specific treatment management was required for TF
• No patient developed TLS

The reduction of TS and TLS from the combination of lenalidomide and dexamethasone in previously-untreated CLL patients enabled a higher and quicker lenalidomide dose escalation. This subsequently led to earlier responses and faster time to best response, as compared to the investigators’ previous study on lenalidomide monotherapy in CLL. Nevertheless, deep responses were not reached with only 9.7% of patients achieving CR, and no obvious improvement in PFS.