Page 165 - Haematologica Vol. 107 - September 2022

ARTICLE - Immune deficiency during RM after transplantation L. Bouard et al.
infection incidence,6,7,8 but no additional infection-related deaths.9 It has been shown that prolonged rituximab ad- ministration induces hypogammaglobulinemia,10 while some authors have also reported rituximab-induced neu- tropenia episodes.11,12,13 Rituximab, when combined with chemotherapy, was also associated with increased inci- dence of opportunistic infections such as Pneumocystis jiroveci pneumonia14 and progressive multifocal leukoen- cephalopathy due to JC virus.15 The common condition for these infections might be T CD4 lymphopenia and ab- sence of prophylaxis for Pneumocystis infections.
RM is the cornerstone of MCL treatment, but there is li- mited reporting on its infectious and immune con- sequences on a homogeneous population undergoing a myeloablative procedure. Therefore, we conducted a pre- planned ancillary study including patients from the LyMa trial, a phase III prospective trial in which patients were randomized between RM and observation. The primary objective was to investigate infectious and immune con- sequences of RM after ASCT. Secondary objectives were to describe infection sites reported, use of γ globulin sub- stitution as well as to analyze the impact of RM-induced immunodeficiency on patients’ outcome.
Methods
Patient selection
All patients included, transplanted and randomized in the LyMa trial (clinicaltrials gov. Identifier: NCT 00921414) were considered eligible (n=240). All patients provided informed consent in writing. The trial’s final results have been pub- lished. In brief, 299 patients were included in LyMa trial. Two hundred and seventy-nine patients completed all four courses of R-DHAP (rituximab, dexamethasone, cy- tarabine and platinum derivative) induction, among whom 20 received four additional courses of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and predniso- lone) because of an insufficient response to R-DHAP. Only those patients considered as in response, i.e., complete response (certain or uncertain) or partial response with a minimum of 75% decrease in tumor burden, were eligible for ASCT. Two hundred and fifty-seven patients received intensification with R-BEAM (rituximab, carmustine, eto- poside, cytarabine and melphalan). A total of 240 were randomized between observation arm (Obs arm) and ri- tuximab arm (RM arm). Each treatment arm included 120 patients. There was no difference in patients’ character- istics, and EFS, PFS and OS were statistically better in the RM arm.3 Patients in the RM arm were planned to receive an injection of rituximab every 2 months for 3 years, for a total of 18 injections.
This study is a preplanned ancillary study of the random- ized phase III trial LyMa (clinicaltrials gov. Identifier: NCT
00921414), which was approved by a formally constituted Ethics Review Board.
Monitoring and end points
Clinical examination was performed by local investigators every 2 months, before rituximab injection or during medical consultation. The following data collected pros- pectively were analyzed: occurrence of febrile event (de- fined as body temperature above 38°C), occurrence of clinically documented infection (possibly non-exclusive with febrile event), hospitalization for infectious reason and Ig substitution. Occurrences of neutropenia <0.5x109/L, T CD4 lymphopenia <0.2x109/L and hypogam- maglobulinemia <6 g/L and <4 g/L were measured at points in time as defined by the protocol: neutrophils counts and Ig rates were collected every 2 months from month (M) 2 to M36. CD4 lymphocytes rates were measured at M2, M4, M8, M12, M24 and M36. In order to evaluate the respective impacts of ASCT and RM on in- fectious risk and/or impaired immune restoration, follow- up periods were prospectively divided into four: from randomization to 6 months (period 1), from 6 to 12 months (period 2), from 12 to 24 months (period 3) and from 24 months to 36 months (period 4). The division was pre- planned before analysis.
Statistical analysis
The number of patients with clinical or biological events in the two arms were compared with a chi-square test or Fischer test if numbers were inferior to five. These tests are bilateral with a significance threshold of 5%. For each period, the number of patients affected was compared to the number of patients not excluded from the trial (Online Sup- plementary Table S2). Survival data were analyzed according to the occurrence of the five following events: infectious episode, neutropenia <0.5x109/L, hypogammaglobulinemia <6 g/L and <4 g/L and CD4 lymphopenia <0.2x109/L. A Ka- plan Meier survival analysis and log-rank test were con- ducted. Patients were set as « yes » for the occurrence of an event if it had occurred at least once at the time of analysis. Treatment-effect was estimated by hazard ratio and the confidence interval were obtained by Cox regres- sion model. Correlation analysis and substitution by γ glo- bulins were compared by using the Wilcoxon test for paired data. In order to identify patients with an increased infectious risk and/or delayed immune restoration, we conducted univariate and multivariate analysis of the fol- lowing variables (defined as occurrence of biological event: PNN <0.5x109/L; Ig levels <6 g/L or 4 g/L and T CD4 lymphopenia <0.2x109/L). We selected epidemiologic and disease diagnostic characteristics such as sex, age, per- formance status, Ann Arbor stage, mantle cell lymphoma international prognostic index (MIPI) score, morphologic variant or bone marrow involvement. Morphologic, meta-
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