Prognostic value of measurable residual disease detection after a fixed-duration chemotherapy-free treatment: a prospective analysis of the CLL14 trial

The prognostic value of measurable residual disease (MRD) in chemotherapy-free treatments in the first-line setting is not well known. At the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition, Kirsten Fischer, University of Cologne, Cologne, DE, presented a prospective analysis of the CLL14 trial with a focus on the prognostic value of MRD detection after a fixed-duration chemotherapy-free treatment of venetoclax plus obinutuzumab (VenG) vs chlorambucil plus obinutuzumab (ClbG), in previously untreated patients with chronic lymphocytic leukemia (CLL) and coexisting conditions.

Efficacy and safety data from this trial have already been presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.

Study design

• N= 432 previously untreated patients with CLL and comorbidities, with a cumulative illness rating scale (CIRS) score >6 and/or an estimated creatinine clearance (CrCl) <70 mL/min were randomized 1:1 to receive six cycles of VenG or ClbG (216 patients per treatment group; intention to treat population [ITT]) with six additional cycles of venetoclax or chlorambucil, respectively
• The primary endpoint was progression-free survival (PFS)
• Key secondary endpoints were: response rates, MRD, and overall survival (OS)
• Peripheral blood (PB) samples for MRD were taken at Cycle 7, 9, and 12, and then every three months
• MRD in the bone marrow (BM) was assessed at Cycle 9 and three months after the end of treatment in patients who had a response to treatment
• Outcome was analyzed according to known MRD risk groups, i.e. detectable (≥10^-4) and undetectable (<10^-4) as well as to known clinical and biological risk factors
• Patients characteristics have been previously reported here

Results

PFS and OS

At the data cut-off (August 2019), all patients had completed treatment. The median follow-up was 39.6 months

• PFS was significantly higher in the VenG arm than in the ClbG arm (hazard ratio [HR]= 0.31; 95% confidence interval [CI], 0.22─0.44; p< 0.0001)
• Median PFS was not reached in the VenG arm vs 36 months in the ClbG arm
• Three-year estimated PFS was 82% in the VenG arm vs 50% in the ClbG arm
• The PFS benefit with VenG was observed in subgroups:
  • Both patients with mutated or unmutated IGVH in the VenG arm showed a better PFS (median, not reached) vs patients in the ClbG arm with mutated (median, 43 months) or unmutated (median, 26 months) IGVH; a benefit was also observed in patients with TP53 deletions and/or mutations in the VenG arm vs the ClbG arm
• Regarding the OS, no differences were observed between the two groups (HR= 1.03; 95% CI, 0.60─1.75; p= 0.92)

MRD

• Three months after completion of therapy, in the ITT population, VenG achieved higher rates of undetectable MRD (assessed by allele-specific oligonucleotide polymerase chain reaction [ASO-PCR]) compared with ClbG:
  • PB 76% vs 35% (p< 0.001)
  • BM 57% vs 17% (p< 0.001)
• These results were confirmed by next generation sequencing in PB, with 42% patients in the VenG arm vs 7% in the ClbG arm reaching undetectable MRD (<10^-6)
• The duration of undetectable MRD (uMRD) was longer in the VenG arm (not reached) in comparison with the ClbG arm (median duration, 10 months)

Correlation of MRD and PFS

• uMRD correlated with favorable PFS rates at 24 months. Patients, in both treatment groups, who achieved uMRD had a longer duration of PFS in comparison with patients who had detectable MRD
• In the VenG arm, the uMRD translated in an improved PFS, regardless of the clinical response status at the end of treatment

Conclusions

• VenG fixed-duration treatment:
  • Showed good efficacy, with a significantly higher PFS across all relevant subgroups in comparison with the ClbG treatment
  • Achieved high and sustainable rates of uMRD in patients with previously untreated CLL and coexisting conditions
• uMRD at the end of treatment translated in an improved PFS, confirming the prognostic value of MRD assessment for this chemotherapy-free treatment