Results of the phase III CLL1 trial – risk adapted therapy of fludarabine or watch and wait in patients with early stage CLL

In a Letter to the Editor of Leukemia, Manuela A. Hoechstetter from Klinikum Schwabing, Munich, Germany, et al. reported findings from the CLL1 trial conducted by the German CLL study group (NCT00262782).

The CLL1 trial aimed to investigate risk-adapted therapy in patients with early stage (0–II) Chronic Lymphocytic Leukemia (CLL). The trial’s protocol was designed in 1997 and identified High-Risk (HR) patients who may progress and receive subsequent treatment ≤2 years after diagnosis either by Lymphocyte Doubling Time (LDT) of less than 12 months or Bone Marrow Infiltration Pattern (BMIP). HR patients were randomly assigned, at a ratio of 1:1, to either early fludarabine (HR-F: 25mg/m2 IV, days 1–5, q28 x 6 cycles) or watch and wait (HR-W&W).

CLL1 was carried out in 123 centers in Germany and Austria and the primary endpoint was PFS. Secondary measures included OS and Time-To-First-Treatment (TTFT).

Key Highlights:

Patients and treatment:

• In total, 189 HR pts included: HR-F = 93 pts; HR-W&W = 96 pts
• Completed ≥1 course = 70 pts; one patient discontinued after 2 days due to intolerance
• Not treated = 22 (drop-out rate = 24.7%); these were followed with W&W without further information
• Total course administered = 388 (median = 6)
• Courses administered at planned doses = 373 (96%); dose reduction by >50% = 9 courses (2.3%); dose reduction by >25% = 6 courses (2.1%)
• Full 6 courses administered to 57/70 HR-F pts (80.3%)

Efficacy:

• ORR = 91.4%; CR = 27 pts (38.6%); PR = 37 pts (52.9%); SD = 5 pts (7.1%); PD = 1 patient (1.4%)
• Median follow-up = 8.5 years (range, 0–13.9)
• In all pts:
  • Median PFS = 59.4 months (95% CI, 47.2–71.6)
  • Median TTFT = 110.2 months (95% CI, 95.9–124.6)
  • Median OS = not reached (74.7% alive at 10 years)
• HR versus Low-Risk (LR) pts:
  • Median PFS = 2.1 months (95% CI, 14.6–28.1) versus 1 months (95% CI, 61.4–74.8); P < 0.001
  • Median TTFT = 53.8 months (95% CI, 42.3–65.4) versus not reached; P < 0.001
  • Median OS = 130.2 months (95% CI, 116.1–144.3) versus not reached; P < 0.001
• HR-F versus HR-W&W pts:
  • Median PFS = 30.1 months (95% CI, 21.7–38.5) versus 9 months (95% CI, 8.9–16.9); P < 0.001
  • Median TTFT = 74.2 months (95% CI, 54.7–93.8) versus 1 months (95% CI, 29.1–53.1); P = 0.04
  • Median OS = 126.8 months (95% CI, 110.9–142.7) versus not reached; P = 0.75 (not significant)

Toxicity:

• AEs observed in 248 courses (63.9%); hematologic toxicities were most common
• Most frequent non-hematological AEs = infections, allergic reactions, and liver enzyme elevation
• No treatment related deaths reported
• Overall, 148 deaths (20.8%) occurred; HR-F = 38 (40.9%); HR-W&W = 35 (36.5%); LR = 75 (14.4%)
• Most pts died from CLL (n=59, 39.9%)
• Death due to Secondary Primary Malignancy (SPM) reported in 23 pts (15.5%); the most common malignancies were lung and gastrointestinal cancers
• Richter’s Transformation, including one Hodgkin Lymphoma, resulted in the death of 5 pts (one HR patient, 4 LR pts)
• Other reasons caused the deaths of 36 pts (24.3%) primarily infections (44.4%) and coronary heart disease (19.4%)

The authors stated that their findings support watch and wait as the current standard of care for early stage CLL. The group, based on their results, also caution not to treat too early. Lastly, they emphasize that novel agents require “rigorous testing in randomized trials before being approved or generally used in early stage CLL.”

Abstract:

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