Long term follow-up of chlorambucil, mitoxantrone and dexamethasone vs fludarabine, mitoxantrone and dexamethasone in patients with FL

Some patients with follicular lymphoma (FL) do not experience symptoms for long periods of time while others require treatment to control symptoms of this indolent disease. One of the treatment options is immunochemotherapy. However, it is important to identify patients that are most likely to respond to those regimens. Previous studies have demonstrated that measurable residual disease (MRD) status correlates with progression-free (PFS), while the progression of disease within 24 months (POD24) has been shown to negatively impact on patient survival. Baseline total metabolic tumor volume (TMTV) and a complete metabolic response (CMR) after induction immunochemotherapy have been demonstrated to be associated with both PFS and overall survival (OS).

Mark J. Bishton and colleagues compared chlorambucil, mitoxantrone and dexamethasone (CMD) vs fludarabine, mitoxantrone and dexamethasone (FMD), and assessed molecular responses and their impact on outcomes in patients with untreated advanced, symptomatic FL. The study did not incorporate rituximab-based therapy as either induction or maintenance because rituximab in combination with chemotherapy was not approved in the UK at the time patients were recruited onto the study. The long-term follow-up of the study was recently published in the British Journal of Haematology and is summarized below.¹

Methods

• A prospective, open label, multicenter phase III study in adult patients with previously untreated advanced stage III/IV FL
• Patients were randomized and stratified using the International Prognostic Index (IPI) score to receive up to eight 28-day cycles
  • The CMD group – chlorambucil 10 mg orally on Days 1–10, mitoxantrone 12 mg/m² intravenously (IV) on Day 1, and dexamethasone 20 mg orally on Days 1–5
  • The FMD group – fludarabine 25 mg/m² IV on Days 1–3 with mitoxantrone, and dexamethasone as above
• Computerized tomography (CT) imaging was used for staging and response assessment after 4 cycles of therapy
  • Patients with no response or progressive disease (PD) were withdrawn, while patients with response continued until a maximum of 8 cycles
• Diagnostic peripheral blood (PB) and bone marrow (BM) samples were screened for t(14;18) and if negative, also for other breakpoints within the BCL-2 locus
  • The presence of the BCL-2 rearrangement was reassessed in BM/PB samples to evaluate molecular response
• Endpoints included:
  • Primary: PFS
  • Secondary: OS, time to treatment failure (TTF), remission rates, molecular response rates, and the impact of molecular responses on both PFS and OS

Results

Patient characteristics

• In total, 400 patients were randomized between May 2000 and April 2006
  • 11 patients in the CMD and 9 in the FMD group were found to be ineligible and were excluded from the analysis
  • 185 in the CMD group and 186 patients in the FMD group received treatment, with 160 and 145 of patients, respectively, continuing the treatment after 4 cycles
  • 111 patients completed 8 cycles of in CMD while 88 patients completed 8 cycles of FMD
• Patient baseline characteristics are presented in Table 1

Table 1. Patient baseline characteristics

Efficacy

• The overall response rates (ORR) were similar between study groups (94.2% vs 90.9% in CMD and FMD groups, respectively; p = 0.25). The best overall responses are presented in Table 2
• The median follow-up period was 11.4 years
• The median PFS for the CMD and FMD groups was 3.6 and 3.0 years, respectively
• The median OS was 14.6 vs 15.7 years for the CMD and FMD groups, respectively
  • Median OS in patients with POD24 was 3.9 years vs 13.7 years in non-POD24 patients, with restricted mean survival time (RMST) difference of -4.15 years (-5.32 to -2.99; p < 0.001)
  • RMST difference in survival for POD24 patients between treatment groups was not significantly different, although there was a trend for those patients with POD24 FMD to have the poorest outcomes (p = 0.09)
    • in the CMD group: −3.10 years (−4.73 to −1.46) over 13.2 years compared with patients without POD24 (p < 0.001)
    • in the FMD group: -5.17 years (-6.76 to -3.58) over 13.7 years (p <0.001) compared with patients without POD24

• • There was no difference between the treatment in the OS from the time of progression, with a median OS of 9.5 vs 8.7 years for the CMD and FMD groups, respectively
• Time to treatment failure (TTF) was superior in the CMD arm compared with FMD (2.9 vs 1.6 years; HR 0.78; 95% CI, 0. 60–1.01; p = 0.06)
• Over time, PFS and OS changed from favorable in the CMD to the FMD group, with no single factor found to be contributing to the change

 Table 2. Best overall responses

Molecular analysis

• In total, molecular response assessment was carried out in samples from 47 patients in the CMD group and 45 patients in the FMD group, but one in the CMD group and four in the FMD group were found to ineligible and subsequently excluded
• 25 out of 46 (54.3%) patients in the CMD group and 20 out of 41 (48.8%) of patients in the FMD group achieved molecular remission (p = 0.6)
• Molecular negativity compared to molecular positive result was associated with a higher median PFS (5.6 years vs 2.3 years; p < 0.001) and median OS (not reached vs 12.5 years; p < 0.01)
• There was no correlation between molecular response and treatment on PFS
• In the FMD group but not the CMD group, MRD positivity compared with MRD negative status was associated with lower survival
• MRD positivity was also associated with POD24 (p = 0.001)
• The single-round multiplex polymerase chain reaction (PCR) techniques on BM samples was as predictive of PFS, as nested PCR

Safety

• Both treatment regimens were associated with manageable safety profile (Table 3)
• Incidence of Grade 3/4 adverse events was low and similar between treatment groups, except for infections (14.1% of patients and 11.3% of patients in the CMD and FMD groups, respectively)
• In total, 71 deaths occurred in the CMD group and 66 in the FMD group, including 13 deaths considered to be treatment-related (five in the CMD and eight in the FMD group)

Table 3. Grade 3–4 adverse events ≥1% of patients

Conclusion

Although the initial report after follow-up of 31 months suggested superior efficacy of CMD regimen over FMD in terms of PFS, the longer follow-up showed an opposite result from eight years onwards. The authors attributed the reverse of the trend to fewer patients with late progression on FMD treatment.

Although there was no difference in outcomes between arms, the results demonstrated significant improvement in OS in patients who achieved MRD negativity, a first such observation in a prospective study. The initiation of the study pre-dated FL IPI score as a prognostic marker for newly diagnosed FL and the incorporation of positron emission tomography into response assessment. However, the results were concordant with previous findings on the use of POD24 as a prognostic factor for OS after chemotherapy induction. The authors believe that future clinical trials in FL should include CMR, MRD status, and POD24 rates as standard endpoints.