Safety and Tolerabilityof Subcutaneous Cladribine Therapy in Progressive Multiple Sclerosis

Objective: To evaluate the safety and tolerability of subcutaneous (s.c.) cladribine therapy in patients with chronic progressive multiple sclerosis (CPMS), and to evaluate the effects on lymphocyte subsets. Background: Cladribine, a synthetic antineoplastic agent with immunosuppressive effects, may favourably affect the course of CPMS. However results of a previous reported clinical trial showed significant myelosuppression in some patients. Design/Methods:19 patients with severe (mean extended disability status score [EDSS] = 6.7) CPMS were treated on a compassionate basis with cladribine 0.07 mg/kg/ day s.c. for 5 days per cycle, repeated every 4 weeks for a total of 6 cycles. Patients underwent clinical evaluation, EDSS, and hematologic analysis before, during, and following therapy. Results: The treatment was very well tolerated with no clinically significant side effects observed. Between baseline and the end of cycle 6, mean decreases were noted in absolute lymphocyte count from 1697 to 463 (p = 0.000012), CD4 count from 865 to 187 (p = 0.0000008), CD8 from 418 to 165 (p = 0.005) and CD19 from 197 to 26 (p = 0.000002). Platelet, granulocyte and RBC counts were unaffected. Approximately one year after completion of therapy, some recovery of CD4 and CD8 counts had occurred although both counts remained suppressed compared to baseline (302 and 227 respectively); the CD19 count had recovered essentially to normal by one year. EDSS scores post-therapy revealed some deterioration in 8 patients and stable scores in the remaining 11. Global patient evaluations of the treatment were mixed. Conclusions: Cladribine therapy, at lower doses than previously reported, was remarkably well tolerated in CPMS, with no significant myelosuppression. Profound effects occurred in total lymphocyte count and CD4, CD8 and CD19 subsets. RESUME: Securite et tolerabilite de la cladribine sous-cutanee dans le traitement de la sclerose en plaques progressive. But: D'evaluer la securite et la tolerabilite de la cladribine sous-cutanee (s.c.) chez les patients atteints de sclerose en plaques progressive chronique (SEPPC) et d'evaluer ses effets sur differentes populations lymphocytaires. Introduction: La cladribine, un agent antineoplasique synthetique qui a des proprietes immunosuppressives peut influencer favorablement revolution de la SEPPC. Cependant, les resultats des essais therapeutiques rapportes a date ont montre une myelosuppression significative chez certains patients. Methodes: 19 patients atteints de SEPPC severe (score moyen a l'echelle d'invalidite EDSS = 6.7) ont ete traites sur une base humanitaire avec la cladribine a la dose de 0.07 mg/kg/jour par voie s.c. pendant 5 jours par cycle, a toutes les 4 semaines, pour un total de 6 cycles. Les patients ont subi une evaluation clinique, EDSS, et des analyses hematologiques avant, pendant et apres le traitement. Resultats: Le traitement a ete tres bien tolere, sans effet secondaire cliniquement significatif. Entre la phase pre-traitement et la fin du sixieme cycle, des diminutions moyennes du decompte absolu des lymphocytes de 1697 a 463 (p = 0.000012), du decompte CD4 de 865 a 187 (p = 0.0000008), du decompte CD8 de 418 a 165 (p = 0.005) et CD19 de 197 a 26 (p = 0.000002) ont ete observees. Le decompte des plaquettes, des granulocytes et des globules rouges n'etait pas atteint. Environ un an apres la fin du traitement, une recuperation du decompte CD4 et CD8 Stait evidente, bien que ces deux decomptes demeuraient supprimes en comparaison avec ceux de la phase pr6-traitement (302 et 227 respectivement); le decompte CD19 etait revenu a la normale a un an. Les scores EDSS post-traitement ont montre une deterioration chez 8 patients et des scores stables chez les 11 autres. L'eValuation globale du traitement par les patients etait mixte. Conclusions: La cladribine s.c, a dose plus faible que dans les etudes rapportees anterieurement, a 6te remarquablement bien toleree chez les patients atteints de SEPPC, sans myelosuppression significative. Des effets marques ont ete notes sur le decompte lymphocytaire total et sur les sous-populations CD4, CD8 et CD19. Can. J. Neurol. Sci. 1998; 25: 295-299