A Prospective Randomized Study Comparing Rituximab and Dexamethasone Vs Dexamethasone Alone in ITP: Results of Final Analysis and Long Term Follow up
Authors: Zaja Francesco , Baccarani Michele , Mazza Patrizio , Vianelli Nicola , Bocchia Monica , Gugliotta Luigi , Defina Marzia , Tieghi Alessia , Amadori Sergio , Campagna Selenia , Ferrara Felicetto , De Simone Maria Carla , Zaccaria Alfonso , Molinari Anna Lia , Angelucci Emanuele , Usala Emilio , Cantoni Silvia , Fornaro Antonella , Visani Giuseppe , Rizzi Rita , De Stefano Valerio , Casulli Francesco , Battista Marta Lisa , Isola Miriam , Soldano Franca , Regazzi Mario , Gamba Enrica , Fanin Renato 
Published: April 2020

Abstract
Introduction. Previous uncontrolled studies have highlighted the activity of rituximab in patients with idiopathic thrombocytopenic purpura (ITP) relapsed or refractory to standard treatments. To better address this effect, a prospective randomized (1:1), multicenter, phase III study comparing treatment with dexamethasone alone (arm A) vs dexamethasone plus rituximab (arm B) was conducted from July 2005 through June 2007 for adult patients with previously untreated ITP and a platelet (PLT) count ≤20 × 109/L.
Material and methods. Patients randomized to arm A received a single course of oral dexamethasone 40 mg on days +1, +2, +3, +4, while patients randomized to arm B received dexamethasone (as in arm A) in association with rituximab 375 mg/m2 iv on days +7, +14, +21, +28. Patients in arm A who failed to achieve a sustained response and had a platelet count ≤20 × 109/L (from day +30 up to the end of 6 months) could receive salvage treatment with the experimental arm (dexamethasone plus rituximab). The primary objective of the study was to compare the sustained response (SR), i.e. PLT count 50 × 109/L at month + 6 of treatment. Secondary objectives were: evaluation of the safety, the initial response (PLT count 50 × 109/L) by day 30 after the initiation of treatment, the activity of salvage therapy with dexamethasone plus rituximab in patients non responding to dexamethasone monotherapy, the definition of clinical and laboratory factors predictive of response and to explore the pharmacokinetics parameters of rituximab and their potential relation with response. Results were analyzed by an intention to treat (ITT) and by a per-protocol (PP) analysis.
Results. One-hundred-one patients (52 for arm A and 49 for arm B) and 64 patients (38 for arm A and 26 for arm B) represented the ITT and PP population, respectively. Demographic baseline data were in accordance to what expected for a population of ITP patients. No significant differences among the two groups of randomization were present. There was a female prevalence and the mean age was 47 and 49 years in arm A and B, respectively. Table 1 summarizes the ITT and PP efficacy results considering 3 different levels of response (i.e. PLT count 50 × 109/L, 100 × 109/L and 150 × 109/L). A significant advantage for arm B patients was documented.
Table 1 Initial response Initial response Sustained response Sustained response Analysis Intention-to Treat Per-Protocol Intention-to Treat Per-Protocol Treatment Arm A Arm B P value Arm A Arm B P value Arm A Arm B P value Arm A Arm B P value Valuable patients 44 25 32 13 52 49 38 26 PLT 3 50×109/L 27% 68% .001 31% 69% .009 36% 63% .004 39% 85% &lt;.001 PLT 3 100×109/L 23% 48% .015 28% 46% .122 33% 53% .019 37% 77% &lt;.001 PLT 3 150×109/L 18% 36% .178 22% 38% .127 25% 43% .029 29% 65% .002
Twenty-seven patients initially allocated to arm A and who failed to achieve initial response or SR received salvage treatment with the dexamethasone plus rituximab. In this group, ITT and PP SR rate were 56% and 59%, respectively. No clinical or laboratory factors predictive of SR were identified. In arm B patients the serum concentrations of rituximab levels did not correlate with the rate of response. Twelve SR patients of arm A, 27 of arm B and 19 of salvage therapy group were systematically followed up beyond month 6 for a median period of observation of 18 months (range 10–34 months). The rate of SR loss (platelets &lt; 50 × 109/L) in these three groups was 25 % (3/12), 11% (3/27) and 10.5% (2/19). The safety profile was good with no substantial difference between the two arms of randomization. No patient died during the study period.
Conclusion. The results of this study indicate that the association of dexamethasone plus rituximab improves patients outcome without worsening of the safety profile. This effect is characterized by prolongation of SR and reduction in relapse rate. The long period of relapse free survival registered in some patients suggests a possible curative effect. This treatment can be offered as an option before splenectomy, particularly in those patients where the surgical option is not well accepted or have higher risk of complications.