Introduction

Lenalidomide is an immunomodulatory agent directly targeting of myelodysplastic syndromes (MDS) clones, immunomodulation, erythropoiesis restoration, and angiogenesis inhibition.

Aim

To assess the efficacy and safety of lenalidomide in RBC transfusion-dependent patients with International Prognostic Scoring System (IPSS) Low-/ Intermediate-1-risk del5q MDS.

Patient Profile

• Patients 18 years of age or older with investigator-documented IPSS Low or Intermediate-1-risk MDS with del5q31,
• With or without additional cytogenetic abnormalities, and
• RBC transfusion-dependent anemia (no 8 consecutive weeks without RBC transfusions within the 16 weeks before randomization)

Methods

• Phase 3, randomized, double-blind study
• 205 patients were randomized in 1:1:1 ratio to receive:
  • lenalidomide 10 mg/day on days 1 to 21(n=69)
  • lenalidomide 5 mg/day on days 1 to 28, (n=69)
  • placebo on days 1 to 28 (all 28-day cycles) (n=67)
• Crossover to lenalidomide or higher dose was allowed after 16 weeks

Study Endpoints

• The primary endpoint was RBC-TI for ≥26 consecutive weeks
• Secondary endpoints included erythroid response, duration of RBC-TI, cytogenetic response, OS, AML progression, safety, and health-related QoL (HRQoL)
• Changes in hemoglobin levels were determined from baseline

Results

• More patients in the lenalidomide 10- and 5-mg groups achieved significant RBC-transfusion independence (TI) for ≥26 weeks (primary > endpoint) versus placebo (P < .001)

  Figure 1: Erythroid response, as assessed by RBC-TI for >26 weeks

  

• Among patients who achieved RBC-TI for >26 weeks with lenalidomide (dose groups combined), onset of response occurred in 48.8% of patients during cycle 1, 37.2% during cycle 2, 9.3% in cycle 3, and 4.7% in cycle
• Subgroup analysis

• RBC-TI for >26-week rates favoured lenalidomide 10 mg over 5 mg for most subgroups
• In patients treated with lenalidomide (n=45) with elevated baseline erythropoietin (EPO) levels (>500 mIU/mL) a significant better erythroid response rate was observed with lenalidomide 10 mg than 5 mg (76.2% vs 33.3%; P =.004)

• Predictors of erythroid response
  • Factors significantly predictive of RBC-TI for >26 weeks were
    • lenalidomide treatment (P=.0001 for lenalidomide10 mg vs placebo; P=.0004 for lenalidomide 5 mg vs placebo)
    • higher baseline platelet count >150x10⁹/L; P=.003)
    • longer time since MDS diagnosis (>2 years; P=.05)
• Changes in hemoglobin levels
  • Median maximum hemoglobin increases in patients responding to lenalidomide therapy (RBC-TI ≥8 weeks) for 10 mg was 6.3 g/dL and for 5 mg 5.2 g/dL
• Cytogenetic responses
  • Cytogenetic response rates (CR + PR) with lenalidomide 10 mg on days 1 to 21 was 50.0% and lenalidomide 5 mg on days 1 to 28 was 25.0%.
  • Median time to cytogenetic response in 10 mg and 5 mg groups were 93 days and 85 days respectively
• HRQoL
  • Treatment with lenalidomide improved HRQoL (FACT-An); improvements were apparent at week 12 and were significantly greater with lenalidomide (both groups) than placebo
• Disease Progression
  • Overall, AML progression was reported in 30.4% of patients who were randomized to placebo but crossed over to lenalidomide and 23.2% and 21.7% of patients who received lenalidomide 5 mg and 10 mg, respectively.
  • Median time to AML progression was 30.9 months in placebo group, 31.8 months in lenalidomide 5 mg group and 36.1 months in lenalidomide 10 mg group
• Survival
  • Median OS rates were 42.4 months, ≥35.5 months and 44.5 months in placebo, lenalidomide 5 mg and lenalidomide 10 mg groups respectively
  • For the lenalidomide groups combined, 3-year overall survival were 56.5%

AML-free survival and OS: 6-month landmark analysis

• Patients achieving RBC-TI for >8 weeks showed 42% reduction in the relative risk of AML progression or death (P=.048) and a 47% reduction in the relative risk of death (P=.021)
• Risk of AML progression or death significantly increased with higher baseline ferritin levels, older age, and higher transfusion burden

Safety

• The incidence of AEs was similar for both lenalidomide doses.
• The most common drug-related AEs were neutropenia and thrombocytopenia, which generally occurred within the first 2 cycles and decreased thereafter.
• Lenalidomide dose reductions (per protocol) were required because of AEs in 38 patients (55.1%) and 36 patients (52.2%) in the lenalidomide 10 mg and 5 mg groups, respectively.
• The most common reasons for lenalidomide dose reductions were neutropenia (10 mg, 33.3%; 5 mg, 27.5%) and thrombocytopenia (10 mg, 21.7%; 5 mg, 11.6%).
• Dose interruption was reported in 32 patients (46.4%) and 20 patients (29.0%), respectively.
• The most common reasons for dose interruptions were neutropenia (10 mg,
• 23.2%; 5 mg, 11.6%) and thrombocytopenia (10 mg, 13.0%; 5 mg, 11.6%).
• Discontinuation from treatment because of AEs was reported in 6 patients (8.7%) in the lenalidomide 10 mg group, 12 patients (17.4%) in the 5 mg group, and 3 patients (4.5%) in the placebo group.

Table 1: Grade 3 or 4 AEs reported in 5% of patients (double-blind > phase; safety population)

Grade 3 or 4 AEs, * n (%)	Placebo (n =67)	Lenalidomide 5 mg (n =69)	Lenalidomide 10 mg (n =69)
Patients with >1 AE	43.3	89.9	94.2
Neutropenia	14.9	73.9	75.4
Thrombocytopenia	1.5	33.3	40.6
Leukopenia	0	13.0	8.7
Anemia	9.0	5.8	2.9
DVT	1.5	1.4	5.8

*Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0.

• Treatment was discontinued because of AEs in 8.7% of patients in the lenalidomide 10 mg group, 17.4% in the 5 mg group, and 4.5% in the placebo group.

Conclusion

• Both lenalidomide doses (5 mg and 10 mg) demonstrated significant RBC-TI and cytogenetic responses and were generally well tolerated with a manageable safety profile in patients with IPSS Low- or Intermediate-1-risk MDS with del5q31
• RBC-TI was durable and was associated with improvements in hemoglobin levels and HRQoL and reduced risk of death
• These findings support the use of a starting dose of 10 mg inLow- or Intermediate-1-risk MDS with del5q31 with subsequent dose reductions or interruptions if needed

Reference

Blood. 2011;118(14):3765-3776