Efficacy and Tolerability Of Frontline Oral Fludarabine and Cyclophosphamide Combination Therapy For Elderly Patients With Chronic B-Cell Lymphocytic Leukaemia and Low Grade Non Hodgkin Lymphoma
Authors: Bergamaschi Micaela , Mitscheunig Laura , Guolo Fabio , Ghiso Anna , Galaverna Federica , Miglino Maurizio , Clavio Marino , Ballerini Filippo , Canepa Letizia , Lemoli Roberto , Gobbi Marco , Pierri Ivana 
Published: October 2019

Abstract

Background
Treatment of elderly patients needs to be considered in view of patients’ physical condition and social environment in addition to diagnosis, staging and risk factors.
Fludarabine was the first purine analogue with an oral formulation available for clinical use. The oral formulation offers equivalent efficacy and improved tolerability profile compared to the intravenous (IV) formulation. IV fludarabine requires several administrations that may expose patients to the risk of clinical side effects and potential logistic problems.

Aims
To assess whether frontline oral fludarabine and cyclophosphamide (FC) combination therapy for elderly or clinical unfit patients with B-cell chronic lymphocytic leukemia (B-CLL) and low grade non Hodgkin lymphoma (NHL), is well tolerated, effective and cost-saving.

Methods
Between April 2005 and March 2013, 10 elderly untreated patients (mean age 75, range 68-86) with B-CLL requiring treatment, according to ESMO guidelines, and 21 stage ≥3 indolent NHL (mean age 73, range 47 -89) received therapy with low dose oral fludarabine (25mg/mq/die) and cyclophosphamide (150mg/mq/die) from day 1 to 3. Study design consisted of 6 cycles repeated at 4 weeks intervals in the outpatient clinic. Patients received antibiotic prophylaxis with trimethoprim/sulphamethoxazole (160/800 mg once a day, 3 times a week) and allopurinole (300 mg once a day from days 0 to 4). Four follicular NHL, 6 small lymphocytic NHL, 7 marginal zone NHL, 2 indolent mantle cell NHL and 2 lymphoplasmacytic NHL were treated. Performance status was WHO £ 2 in all patients. Comorbidities, which included diabetes, hypertension and chronic heart disease, were present in 12 patients (grade ≤ 2). The median number of cycles was 4 (range 2-6). No patients reduced either the dose or the number of cycles because of hematologic and extra-hematologic toxicities. Specifically, only 2 patients experienced grade III neutropenia, treated with G-CSF.

Results
Definition of response was reported according to the updated IWCLL-NCI 2008 international general practice criteria, valuated after 3 and 6 cycles. Twenty seven of 31 patients (87%) obtained a clinical response (14 CR and 13 PR). Only 1 responding patient (90 years old) died after 24 months from therapy because of aplastic anemia. In particular, the response rate was 4/4 for follicular NHL (1RP, 3RC), 5/6 for small lymphocytic NHL (2 RC, 3 RP), 7/7 for marginal zone NHL (3 RC, 4RP),1/2 for lymphoplasmacytic and 2/2 mantle cell NHL (PR), 8/10 for B-CLL (3 RC, 5 RP).
We consider as Event Free Survival (EFS) time to progression, adverse event with a grade >3 (CTCAE) during treatment, relapse or death. Overall survival (OS) was defined as the time from the start of treatment to death or last follow-up. Survival distributions were calculated using the method of Kaplan and Meier. With a median follow-up of 67 months (range 16-187), we observed a median EFS about 38 months and median OS has not been reached.
We used Genzyme-sponsored Excel program to compare direct hospital cost of oral to IV FC (both 3 days regimen). IV treatment required 18 day service admissions with a total cost of € 7.527 while the oral therapy required 6 ambulatory visits with total cost of € 1.642 (costs including: pharmacy, nurses and physicians costs). In this analysis we did not consider social and psychological cost such as transportation, care giver loss of working hours, trauma of repeated venipunctures.

Conclusions
These results suggest that oral FC could be effective and well tolerated for elderly patients unfit for more aggressive treatments. The efficacy of our therapeutic regimen is comparable to intravenous FC (20 mg/m2 and 600 mg/m2) regimen used by Flinn et al. (Blood 2000) with an ORR about 90 %. Hovewer, in that study 17/60 patients experienced a grade 3 or 4 neutropenia with 1 death due to sepsis. In conclusion, most of our patients did not experience severe toxic side effects or required hospitalizations, enjoing a good quality of life.

Disclosures:
No relevant conflicts of interest to declare.