Bendamustine can severely impair T-cell immunity against cytomegalovirus

Abstract

Bendamustine has rapidly become one of the key drugs for patients with indolent lymphoma because of its safety, tolerability and eff ectiveness. However, two of the 11 patients we have administered the drug developed severe immunosuppression against cytomegalovirus (CMV). Bendamustine potentially hampers immune function and should be used more cautiously.Case 1 A 51-year-old man was diagnosed with follicular lymphoma with massive bone marrow infi ltration in 2006. He received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy that resulted in complete remission, but underwent a few relapses, requiring a R-FND (rituximab, fl udarabine, mitoxantrone and dexamethasone) salvage regimen. At the fi fth relapse in 2011, the regimen was switched to cycles of 120 mg/m 2 /day bendamustine (days 1 -2) every 28 days. During the third cycle, the patient developed severe diarrhea, and lost more than 10 kg in weight. His white blood cell (WBC) count was 2.8 ϫ 10 9 /L with 93% neutrophils and 2.5% lymphocytes. Other relevant laboratory results were aspartate aminotransferase (AST) level, 111 U/L; alanine aminotransferase (ALT) level, 110 U/L; and immunoglobulin G (IgG) level, 339 mg/dL. Th e CD4 count was 21/ μ L with a CD4/8 ratio of 0.16. A positive result for CMV pp65 antigen C10/11 (603/689) and the presence of retinitis strongly suggested that the patient had an active CMV infection. Although the patient ' s serum briefl y became negative for the CMV pp65 antigen after intensive treatment with ganciclovir or foscarnet, a repeat of CMV-associated symptoms and a recurrence of CMV serum positivity were noted on discontinuation of anti-CMV therapy for more than 1 year. Furthermore, CMV-specifi c CD8 ϩ cytotoxic T lymphocytes (CTLs) were persistently undetectable in four samples taken every month using tetramer-based quantifi cation [1], indicating a profound and protracted immune defi ciency against CMV. Reduced intensity hematopoietic stem cell transplant from an unrelated donor was performed to reconstruct cellular immunity against CMV as well as to eradicate residual follicular lymphoma cells. On day 15, the patient suff ered acute renal failure, followed by sudden cardiac arrest. He was emergently resuscitated once, but fi nally died because of multi-organ failure presumably due to CMV-associated hemophagocytic syndrome on day 59 after transplant.Case 2 An 89-year-old woman was diagnosed with diff use large B-cell lymphoma. Despite the administration of two cycles of R-COP (rituximab, cyclophosphamide, vincristine and prednisolone) chemotherapy, only a small response was observed. She then received two cycles of bendamustine at the same dose as the patient in Case 1, because she appeared too frail to be treated by a doxorubicin-containing regimen such as CHOP chemotherapy. She developed nausea and appetite loss 10 days after the last administration of bendamustine. Her WBC count was 4.8 ϫ 10 9 /L with 89% neutrophils and 4.0% lymphocytes. Other relevant laboratory fi ndings were AST...

Cytomegalovirus reactivation with bendamustine in patients with low-grade B-cell lymphoma

“…Although studies have shown the risk of severe infection following treatment with bendamustine to be relatively low compared with that of conventional chemotherapeutic regimens [6], opportunistic infections, including cytomegalovirus reactivation, have been reported in some studies [7][8][9]. The rate of development of CMV reactivation was at least 20 % in the present study, as we did not measure this finding for every patient.…”

Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant

“…These studies strongly suggest that an impaired T‐cell immunity function, determined by Alemtuzumab, may represent a high risk factor for CMV infection/reactivation and that patients treated with this drug should be prospectively and carefully monitored. Furthermore, a large amount of clinical cases of life‐threatening CMV reactivation in hematologic malignancies as well as limited single‐centre experiences have been reported in the last few years, all suggesting a possible role of previous treatment with Rituximab, Bendamustine, and Bortezomib as predisposing factors for CMV infection/reactivation . Unfortunately, due to the heterogeneity of these data, gathered from a variety of different clinical settings, it is difficult to identify other concomitant risk factors for CMV reactivation with some reliability.…”

Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL

“…Some studies found no increase of atypical infections, 7,8,17,18 whereas others noted conflicting data, 16,19 particularly with regard to cytomegalovirus infections. 19 …”

“…7,8,16–19 Specifically, a significant decrease in CD4+ and CD8+ T-lymphocyte counts was observed for up to six months after the end of BR therapy although the impact of lymphopenia on the rate of infections has been controversial. Some studies found no increase of atypical infections, 7,8,17,18 whereas others noted conflicting data, 16,19 particularly with regard to cytomegalovirus infections. 19 …”