Dear Editor:
Bendamustine produces long-lasting objective responses in patients with indolent non-Hodgkin lymphoma, including follicular lymphoma (FL) [1]. However, lymphopenia, especially a reduced number of CD4-positive T cells, was reported to potentially lead to lethal infections after bendamustine therapy [2]. Employing bendamustine at cumulative doses ≥ 1080 mg/m2 might induce delayed CD4-positive T cell recovery [3]. We investigated the effects of bendamustine exposure at cumulative doses < 1080 versus 1080 mg/m2 on the reduction of CD4-positive T cell counts following bendamustine therapy in patients with FL. This was a retrospective analysis of data from 59 patients with FL who received bendamustine therapy from January 2011 to December 2018 in our institution. The study protocol was approved by the Kyushu Medical Center review board. According to the total dose and number of treatment cycles of bendamustine, we divided the patients into three groups: < 1080 mg/m2 bendamustine for 4 cycles (group 1, n = 29), < 1080 mg/m2 bendamustine for 6 cycles (group 2, n = 8), and 1080 mg/m2 bendamustine for 6 cycles (group 3, n = 22). As presented in Table 1, the mean age was higher in group 2 (p = 0.043), and the number of prior chemotherapy regimens was higher in group 1 (p = 0.039). Although the number of patients with CD4-positive T cell counts < 200/μl at baseline tended to be lowest in group 2 (p = 0.067), which was associated with age < 70 years (vs. ≥ 70; odds ratio [OR] = 8.520, 95% confidence interval [CI] = 2.030–35.80, p = 0.034) and 0–1 prior chemotherapy regimens (vs. > 1; OR = 5.160, 95% CI = 1.320–20.10, p = 0.018) using multivariate logistic regression analysis, the number of patients with CD4-positive T cell counts < 200/μl after 3 months of bendamustine treatment also tended to be lowest in group 2, and this finding was not associated with any patient characteristics (Table 1). Coronavirus disease 2019 (COVID-19) raises specific concerns in terms of morbidity and mortality for patients with FL because of their immunocompromised status induced by the disease or recent exposure to cytotoxic chemotherapy, especially bendamustine and anti-CD20 immunotherapy. Bendamustine appeared to be associated with death, but most patients treated with bendamustine had relapsed/refractory lymphoma [4]. Anti-CD20 treatment within 1 year was not associated with death. Further studies are merited to explore the impact of bendamustine on the evolution of COVID-19. Because the standard dose of bendamustine therapy may be associated with a high mortality risk, our data suggest that for elderly patients receiving bendamustine-based therapy, a reduced initial bendamustine dose (70 mg/m2) such as that used in the GREEN study for unfit patients with chronic lymphocytic leukemia at the investigator’s discretion [5], opposed reduced numbers of chemoimmunotherapy cycles, might explain the decreased risk of serious infections in this population. This study had several limitations, including its single-institute nature and small sample size. Further evaluations for FL are warranted to identify the best dose of bendamustine, notably a reduced initial bendamustine dose, and suitable patients to define the best-tailored treatment at diagnosis.
Table 1.
Characteristics, outcomes, WBC counts, lymphocyte counts, and immune status in patients with follicular lymphoma treated with bendamustine
| Characteristics | Bendamustine exposure | P | ||
|---|---|---|---|---|
| < 1080 mg/m2 | 1080 mg/m2 | |||
| Cycle | ||||
| 4 (n = 29) | 6 (n = 8) | 6 (n = 22) | ||
| Age, median (range) years | 68 (53–88) | 81 (59–84) | 67 (51–81) | 0.039 |
| > 70 years old, n (%) | 13 (45) | 7 (88) | 10 (45) | 0.100 |
| Sex, n (%) | ||||
| Male | 12 (41) | 2 (25) | 9 (41) | 0.688 |
| Female | 17 (59) | 6 (75) | 13 (59) | |
| Number of prior chemotherapy regimens, median (range) | 2 (1–4) | 1 (0–3) | 1 (0–3) | 0.043 |
| > 1 regimen, n (%) | 16 (55) | 1 (13) | 7 (32) | 0.053 |
| Total bendamustine exposure, median (range) (mg/m2) | 720 (480–960) | 780 (720–900) | 1080 | |
| Rituximab, n (%) | 23 (79) | 6 (75) | 19 (86) | 0.724 |
| Rituximab maintenance, n (%) | 2 (7) | 2 (25) | 3 (14) | 0.273 |
| Median (range) follow-up (month) | 105 (96–114) | 96 (46–104) | 42 (19–66) | < 0.001 |
| Baseline | ||||
| WBC (/μl), median (range) | 4600 (1900–8100) | 5550 (3000–8600) | 4650 (2700–8800) | 0.738 |
| Lymphocyte (/μl), median (range) | 1050 (387–2436) | 1353 (792–3440) | 1071 (429–2964) | 0.522 |
| CD4-positive T cell (/μl), median (range) | 255 (76–730) | 436 (189–1032) | 304 (94–1188) | 0.051 |
| CD4-positive T cell < 200/μl, n (%) | 13 (44) | 1 (12) | 4 (18) | 0.067 |
| IgG (mg/dl), median (range) | 933 (167–1626) | 1126 (700–1780) | 862 (433–1436) | 0.126 |
| After 3 months of bendamustine exposure | ||||
| WBC (/μl), median (range) | 3210 (1300–7500) | 4400 (2400–5600) | 3250 (1700–7700) | 0.424 |
| Lymphocyte (/μl), median (range) | 558 (100–2829) | 1131 (295–3080) | 598 (177–2000) | 0.133 |
| CD4-positive T cell (/μl), median (range) | 73 (10–282) | 126 (29–1170) | 59 (18–360) | 0.227 |
| CD4-positive T cell < 200/μl, n (%) | 27 (93) | 5 (62) | 20 (90) | 0.081 |
| IgG (mg/dl), median (range) | 717 (128–1729) | 850 (575–1390) | 755 (263–1846) | 0.424 |
| After 1 year of bendamustine exposure | ||||
| WBC (/μl), median (range) | 3800 (2400–7300) | 4150 (2400–5900) | 3400 (1900–7100) | 0.657 |
| Lymphocyte (/μl), median (range) | 975 (96–1776) | 1022 (465–1813) | 860 (240–1846) | 0.585 |
| CD4-positive T cell (/μl), median (range) | 180 (23–532) | 238 (79–715) | 186 (28–577) | 0.425 |
| CD4-positive T cell < 200/μl, n (%) | 17 (58) | 3 (37) | 12 (54) | 0.631 |
| IgG (mg/dl), median (range) | 715 (143–1630) | 850 (500–1552) | 810 (250–1380) | 0.924 |
WBC, white blood cell; CD, cluster of differentiation; IgG, immunoglobulin G
Continuous variables were expressed as the median and range, and differences between groups were assessed using the Mann-Whitney U test. Intergroup differences in categorical variables were expressed as numbers and percentages, and differences between groups were assessed using the chi-squared test
Acknowledgments
We thank the patients and clinical staff for their participation in the study. We also acknowledge the Clinical Research Institute, Kyushu Medical Hospital, for editorial support. We thank Joe Barber Jr., PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.
Author contributions
S. Y. designed the study, analyzed the data, and prepared the manuscript. T. M., M. M., M. K., K. T., and H. I. prepared and reviewed the manuscript. All named authors met the International Committee of Medical Journal Editors criteria for authorship of this article and take responsibility for the integrity of the work as a whole, and all authors have given their approval for this version to be published.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Ethics approval
This was a retrospective study with no experimental interventions. The study was approved by the Institutional Review Board of the Kyushu Medical Center in Japan.
Footnotes
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