Long-term follow up of phase II GELCAB trial: first-line fludarabine, cyclophosphamide and mitoxantrone in patients with advanced FL

On 18^th January 2017, Laura Magnano from the Hospital Clínic de Barcelona, Barcelona, Spain, and colleagues published results of their 12 year follow up¹ of a phase II GELCAB trial in the Annals of Hematology.

The phase II trial, previously reported in Haematologica in 2008 by Silvia Montoto et al., investigated fludarabine, mitoxantrone, and cyclophosphamide (FCM) to treat previously untreated FL patients with advanced stage disease.² The current follow up report focuses on FCM’s effect on survival, relapse, and late toxicities.

Key Highlights:

• The phase 2 GELCAB trial
  • Fludarabine 25mg/m² IV on D1–3; cyclophosphamide 200mg/m² IV on D1–3; mitoxantrone 6mg/m² IV on D1; administered on an outpatient basis every 4 weeks
  • Pts who achieved CR or PR as assessed by CT after third cycle continued treatment up to six cycles; pts who did not respond were excluded from the study
  • Enrolled 120 patients from Jan 2000–Dec 2003 (median age 52; range, 24–65yrs)
  • Stage IV disease in 96 pts (80%), bone marrow involvement in 94 pts (78%), intermediate/high risk FLIPI in 78/99 evaluable pts (78%)
  • At end of treatment: CR = 83% (99 pts); PR = 11% (13 pts); treatment failure = 6% (disease progression in 5 pts, and early death in 2 pts due to aspiration pneumonia and progressive multifocal leukoencephalopathy)
• After median follow up of 12.5yrs (range, 1.6–15)
  • Relapse/progression in 45% (54 pts; 24 pts <2yrs into follow up); 26 pts died during follow up
  • 5-yr PFS = 62% (95% CI, 55–69%); 10-yr PFS = 46% (95% CI, 36–56%)
  • 5-yr OS = 88% (95% CI, 82–94%); 10-yr OS = 83% (95% CI, 76–90%)
  • 5-yr OS from relapse/progression = 61% (95% CI, 41–81%) for early relapse (<2yrs) and 88% (95% CI, 76–100%) for late relapses (≥2yrs; P = 0.009)
  • Histological Transformation to DLBCL occurred in 10 pts (8%); median Time to Transformation = 8.2yrs (range, 1–11.3yrs)
  • Risk of transformation at 5yrs = 2% (95% CI, 0–4%); at 10yrs = 9% (95% CI, 3–15%)
  • Secondary malignancies = 10 pts (8%), median time from FL diagnosis to second cancer diagnosis = 7.6yrs (range, 1.1–11.6yrs)
  • Risk of second neoplasms (solid or hematologic) at 5-yrs= 3% (95% CI, 0–6%); at 10-yrs = 8% (95% CI, 2–14%)
  • Age >45 years at time of FCM therapy associated with development of second neoplasm (12% vs 0% for >45yrs and ≤45yrs, respectively; P = 0.01)
  • Therapy-related MDS/AML occurred in 3 pts at 7, 8, and 9.5yrs post-FCM therapy
  • Solid cancers occurred in 7 pts (6%): squamous lung cancer (n = 3), larynx squamous cell carcinoma, uterus, bladder, and colon (n = 1 each)
  • Median time between diagnosis of FL and solid cancer = 5yrs (range, 1.08–11.6)

Based on this long follow up data, the authors stated that FCM regimen allows high rates of overall response (93%) and demonstrates prolonged PFS. They also stated that the regimen had a high molecular response rate. Currently, there are concerns with using fludarabine containing regimens for treatment of lymphoma, mainly due to concerns relating to late toxicities. The authors of the follow up reported that the most common causes of death were disease progression (62%) and secondary malignancies (19%). This low, but not unimportant, incidence of secondary malignancies indicates that it is paramount that patients in prolonged remission stay in care and complete appropriate testing for secondary malignancies.

Abstract:

Fludarabine combinations are very affective in follicular lymphoma (FL) with high rates of complete response and prolonged survival. However, late toxicities could be a concern. The aim of the present study was to analyze the long-term impact on survival, relapse and late toxicities of a trial of treatment with fludarabine, mitoxantrone and cyclophosphamide (FCM regimen) for untreated patients with advanced stage FL. One hundred and twenty patients enrolled in a phase 2 trial of treatment with FCM regimen between 2000 and 2003 were evaluated. After a median follow-up of 12 years, 52 patients eventually relapsed/progressed with 10 year progression-free survival (PFS) of 46 %. Ten patients showed histological transformation to aggressive lymphoma with a risk of transformation of 2 and 9 % at 5 and 10 years, respectively. Three patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and seven solid neoplasms with an overall risk of 3 and 8 % at 5 and 10 years, respectively. Twenty-six patients eventually died during the follow-up. Overall survival at 10 years was 83 %. In conclusion, FCM regimen allows excellent long-lasting response in previously untreated patients with FL. The incidence of late events including histological transformation and secondary neoplasia is low but not negligible.