Cyclophosphamide Pulse Therapy in Severe Refractory Crohn's Disease: A Retrospective Multicenter Case Series

Abstract

Background and aims: In Crohn's disease (CD) patients still remain refractory to current regimens, including biologicals. Previous data from small single-center studies indicated cyclophosphamide pulse therapy (CPT) to be effective for induction of remission at least in steroid-refractory cases. The aim of the present study was to study the efficacy and safety of CPT in mainly tumor necrosis factor (TNF)-refractory complicated CD patients.

Methods: Patients with refractory CD undergoing CPT were identified in 13 centers of the German IBD Study Group and retrospectively registered. In total, 41 patients (12 male, 29 female, median age 36 years, range 18-72 years) were included for analysis. Seventy-eight percent of these had previously been treated with thiopurines and 90% had previously received anti-TNF antibodies. Former steroid treatment was found throughout the cohort.

Results: Patients received a median number of 5 (1-13) pulses every 28 (13-54) days in a period of 120 (12-411) days. A median dose of 766 (600-1,200) mg and a median cumulative dose of 4,500 (750-9,750) mg was given. A clinical response (reduction in the Harvey-Bradshaw Index [HBI] ≥2 points) was found in 68% of the patients and clinical remission (HBI <5 points) in 32%. Steroids could be reduced from 31 to 12 mg per day over all patients. Side effects were recorded in 71% (n = 29) of the patients. Three patients terminated CPT due to side effects. No patient died.

Conclusion: Our data point to CPT as a therapeutic alternative for induction of remission in patients with severe refractory courses of CD including TNF antagonists. CPT might serve as bridging for maintenance treatment.

Keywords: Cyclophosphamide; Pulse therapy; Refractory Crohn's disease; Retrospective multicenter case series.

Fig. 1

Clinical activity before and after cyclophosphamide pulse therapy (CPT) expressed by the Harvey-Bradshaw index (HBI). The median HBI at week 0 was 10 points. It dropped to a median of 5 points at the individual end of CPT. This reduction of the median HBI by 5 points was statistically significant (p < 0.018) as indicated by the asterisk.

Fig. 2

Assessment of the efficacy of cyclophosphamide pulse therapy (CPT) by the individual treating physician. Clinical efficacy was assessed at the end of the cyclophosphamide period for each patient. The treatment was terminated due to efficacy in 28% of the patients, while CPT was finally considered ineffective in 65% of the subjects. In 8% intolerable side effects were recorded.

Fig. 3

Reduction of concomitant systemic steroid treatment under cyclophosphamide pulse therapy (CPT). The median steroid dose at the beginning and after CPT in our cohort is presented. The median steroid dose was 31 mg prednisolone/day at week 0 and dropped to 12 mg prednisolone/day at the individual end of CPT. This reduction by 19 mg prednisolone/day was statistically significant (p < 0.0005) as indicated by the asterisk.