Clinical Significance and Risk Factors of Delayed-Onset Neutropenia (DON) after Autologous Stem Cell Transplantation (ASCT) for B-Cell Non-Hodgkin Lymphoma: A Single-Institute Analysis.
Authors: Kato Harumi , Matsuo Keitaro , Yamamoto Kazuhito , Oki Yasuhiro , Kondo Chihiro , Kagami Yoshitoyo , Morishima Yasuo 
Published: October 2019

Abstract
Background: DON is known as one of the adverse events after ASCT, for which rituximab usage has been reported to be a risk factor. One of the limitations in previous reports is that confounding by indication for rituximab treatment, and thus it is yet unclear if rituximab is an independent risk factor for DON. To examine the impact of rituximab considering such limitation as well as to explore possible other determinants and clinical significance of DON, we conducted a retrospective cohort study.
Method: Subjects were consecutive 97 patients with B-cell non-Hodgkin lymphoma receiving ASCT between 1991 and 2007 in Aichi cancer center hospital. We defined DON as absolute neutrophil count < 0.1 x 109/L at any point after 30 days post ASCT without apparent cause of neutropenia. We investigated adverse events and risk factors using propensity score (PS), step-wise method and bootstrap resampling method. PS for preference of rituximab treatment was calculated based upon fourteen clinical factors; rituximab usage, age, sex, performance status, clinical stage, B symptom, bulky lesions, no. of extra nodal sites, lactate dehydrogenase level, no. of prior chemothearpy and local radiation, existence of bone marrow involvement, status at ASCT, and types of conditioning regimens (total-body-irradiation (TBI) containging regimens or not). Unconditional logistic regression models adjusted for PS and other potential risk factors were applied to estimates odds ratios (ORs) and their 95% confidence intervals (CIs) for occurrence of DON. Selection of potential risk factors in validation analysis was done by forward step-wise method (p-value for removal=0.10 and that for inclusion=0.05). Finally, we applied bootstrap resampling method for validation of our analyses (repeating 10,000 times with 97 sampling from original cohort).
Results: 56.7% patients were treated with rituximab combined chemotherapy before ASCT, of which 26.3% had prior rituximab exposure. The median number of prior chemotherapy was one (range; one to five), and 47.4% patients received three or more prior regimens before ASCT. 22.7% patients received TBI regimen. With a median follow-up of 3.42 years, DON was observed in 46.7% patients. The lowest neutrophil count was 446 x 106/L (range; 9–992). Of the patients developing DON, 17.2% patients experienced febrile infectious events. Interstitial pneumonia (IP) was observed in 10% of the patients with DON and 5.5% without DON. No patients experienced Grade 4 or 5 events. By step-wise method, selected factors for final validation model were rituximab usage, TBI, female sex, B symptom, and prior radiation therapy. In the validation, usage of rituximab (OR=3.28: 1.07–10.0, p=0.037), and prior radiation before ASCT (1.81: 1.24–2.63, p=0.002) were identified as independent risk factors for DON. Other factors failed to demonstrate significant impact on DON.
Conclusion: DON was associated with febrile infectious events in 17% patients and most of the cases achieved rapid clinical improvement. Our retrospective cohort analysis considering confounding by indication for rituximab confirmed significant impact of usage of rituximab on DON among B-cell lymphoma patients receiving autologous HSCT. Further evaluation of the impact of radiation therapy before HSCT on DON is also warranted.