Durable Responses in Fit Elderly Patients with Chronic Lymphocytic Leukemia (CLL) in a Randomised, Fludarabine-Based, Immunochemotherapy Dose De-Escalation Study - Long-Term Follow-up By Treatment Arm and Mutational Status

BACKGROUND
Immunochemotherapy (ICT) with fludarabine (F), cyclophosphamide (C) and rituximab (R) provides prolonged progression free (PFS) and overall survival (OS) in fit younger patients with CLL. The Australasian Leukaemia and Lymphoma Group (ALLG) CLL5 study previously showed FCR based therapy was safe, tolerable and effective in fit older CLL patients. We now assess the PFS and OS status by treatment arm and mutational status after a minimum of 5 years following final recruitment.

METHODS
Previously untreated patients with progressive CLL aged ≥65 were randomised to one of three treatment regimens FR5, FCR3 and FCR5 (= full dose) as follows: (i) F 24mg/m2 po D1-5 + R (375mg/m2 C1, 500mg/m2 C2-6) iv D1 (FR5), (ii) F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 (FCR3) or (iii) F 24mg/m2 po+ C 150mg/m2 po D1-5 + R iv D1 (FCR5), all given at 4 weekly intervals for an intended 6 cycles. Early cessation of therapy was mandated for grade 3+ toxicity that delayed the next cycle >2 weeks on >2 occasions.

RESULTS
The ITT population comprised 119 patients: 40 female and 79 male. Mean age was 71.6 years (range 64-83). The distribution by treatment arm was even with 38 patients on FR5, 41 on FCR3, and 40 on FCR5. As previously presented (ASH 2014), the overall response rate (ORR) was comparable at 95%, 95% and 97%, and the bone marrow confirmed complete remission (CR) rates 27%, 44% and 44% respectively. ORR and CR were not statistically significant. Toxicity was tolerable, and mainly hematological with neutropenia and thrombocytopenia. Early stopping due to toxicity occurred in 5.6%, 2.4% and 34% respectively, mainly hematological toxicity without complications.

After a minimum of 5 years follow-up, no significant difference by OS (p=0.48) or PFS (p=0.93) (figure 1) was seen by treatment arm. Overall 51 patients (of 117 - 43.6%) died, hence the survival rate was 56.4%. Causes of death by treatment arm for FR5, FCR3 and FCR5 respectively were disease progression 4, 4, 1; Richter transformation 2, 0, 0; infection 2, 0, 7; and second malignancy 2, 4, 4.

Of the 119 patients, 61 (51%) had data on immunoglobulin variable gene (IGHV) mutational status. In 33 (54%), IGHV were mutated (M-CLL) and 28 (46%) had unmutated IGHV (UM-CLL). The distribution by mutation status by treatment arm was even, with 10 each in FR5 and FCR3 and 13 in FCR5. Patients with M-CLL had a 61% lower risk of death and a significantly better PFS (p=0.0079; HR 0.39 [95% CL, 0.19 to 0.80]) than UM-CLL (M-CLL median PFS 110 months vs UM-CLL median PFS 48 months) (figure 2).

CONCLUSIONS: Oral F(C)R therapy is generally safe and well tolerated in CLL patients aged ≥65 years requiring first-line treatment, when early stopping is utilized if prolonged toxicity is encountered; one third on full dose FCR5 stopped early with this rule, mainly with neutropenia. Response rates were high with ORR of 96% and CR rate of 56%. After a minimum of 5 years follow-up, OS and PFS outcomes by the treatment arms FR5 (full dose F, no C), FCR3 (40% FC dose reduction) and FCR5 (full-dose FCR) are essentially identical in this randomized dose de-escalation study. The median PFS overall was 53 months. CLL patients with M-CLL had a significantly superior PFS compared to UM-CLL.