Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma

Citation: Blood Cancer Journal (2015) 5, e362; doi:http://dx.doi.org/10.1038/bcj.2015.86

Web End =10.1038/bcj.2015.86

http://www.nature.com/bcj

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LETTER TO THE EDITOR

Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma

Blood Cancer Journal (2015) 5, e362; doi:http://dx.doi.org/10.1038/bcj.2015.86

Web End =10.1038/bcj.2015.86 ; published online 23 October 2015

Although bendamustine with or without rituximab has demonstrated remarkable efcacy in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) and mantle cell lymphoma (MCL),13 previous reports showed that the incidence of lymphocytopenia was higher in patients receiving bendamustine with or without rituximab than in those receiving other conventional cytotoxic chemotherapies such as R-CHOP regimen,47 which triggers opportunistic infections including cytomegalovirus (CMV) reactivation, hepatitis B virus reactivation, varicella zoster virus (VZV) infections and Pneumocystis jirovecii pneumonia (PCP).812 However, the duration until recovery of the decreased lymphocytes and CD4-positive T cells to the baseline upon bendamustine treatment is still unclear.6

We retrospectively analyzed 56 consecutive patients with relapsed or refractory indolent B-NHL and MCL who received bendamustine (Treakisym) with or without rituximab at our institution between 2011 and 2014. The dose of bendamustine in combination with or without rituximab was 90 mg/m2/day or 120 mg/m2/day on days 1 and 2, respectively. Treatment was given every 28 days for up to six treatment cycles, depending on the response and toxicity. No rituximab maintenance was given. We analyzed their peripheral blood lymphocytes and CD4-positive T-cell counts before, during and after bendamustine treatment, the details of infectious events and their correlations. The study protocol was approved by the institutional review board of the National Cancer Center, Tokyo, Japan.

Thirty-one patients (55%) were male, with a median age of 63 years (range: 3686). Twenty patients (35%) had follicular lymphoma, 14 (25%) MCL, 9 (16%) transformed lymphoma, 5 (9%) extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, 4 (7%) small lymphocytic lymphoma, 2 (4%) nodal marginal zone lymphoma and 1 (2%) each had lymphoplasmacytic lymphoma and low-grade B-NHL, unclassiable. The median number of prior regimens administered was 2 (range: 19). Twenty-three (41%) of the 56 patients received rituximab in combination with bendamustine. The median number of bend-amustine cycles was 4 (range: 16) and the median cumulative dose of bendamustine was 720 mg/m2 (range: 601440 mg/m2). The median follow-up period was 9 months (range: 033 months).

Before starting bendamustine treatment (that is, at baseline), median lymphocyte and CD4-positive T-cell counts were 1025/l (range: 2703420/l) and 282/l (range: 83645/l), respectively. After the rst cycle, they immediately decreased to 545/l (range: 602900/l) and 190/l (range: 116635/l), respectively. During the period between the completion of bendamustine and starting the next treatment (that is, during observation), the median lymphocyte and CD4-positive T-cell count nadirs were 365/l (range: 201310/l) and 93/l (range: 7178/l), respectively. Signicantly decreased lymphocyte counts were detected in 23 patients who received bendamustine with rituximab compared with 33 patients who received bendamustine alone (median: 260 vs 410/l, P = 0.03). Recovery of lymphocyte and CD4-positive T-cell counts to those at the start of treatment was observed in patients who did not receive the next treatment at 79 months after the completion of bendamustine with or without rituximab, and median lymphocyte and CD4-positive T-cell counts were

Figure 1. Lymphocyte counts and CD4-positive T-cell counts. Box plots of lymphocyte counts (a) and CD4-positive T-cell counts (b) among patients who were treated with bendamustine with or without rituximab from baseline to 79 months after the completion of bendamustine.

Letter to the Editor

2

Table 1. Infectious complications between after starting bendamustine and the last follow-up

Patients affected, n (%)

During bendamustine

CONFLICT OF INTEREST

DM received Lectures fee from Honoraria from Eisai Co., Ltd. YK received research funding from Boehringer, Otsuka and Ariad. KT received research funding from Eisai, Symbio, Zenyaku Kogyo and Chugai Pharmaceutical. The other authors declare no conict of interest.

During observation

During subsequent treatments

Total follow-up

ACKNOWLEDGEMENTS

This work was supported in part by the National Cancer Center Research and Development Fund (26-A-4) and a grant for cancer research (Practical Research for Innovative Cancer Control) from the Japan Agency for Medical Research and Development.

H Saito1, D Maruyama1, AM Maeshima2, S Makita1, H Kitahara1, K Miyamoto1, S Fukuhara1, W Munakata1, T Suzuki1, Y Kobayashi1,

H Taniguchi2 and K Tobinai1

1Department of Hematology, National Cancer Center Hospital, Tokyo, Japan and

2Department of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan

E-mail: mailto:[email protected]

Web End [email protected]

This paper was presented in part as a poster presentation at the 56th

Annual Meeting of the American Society of Hematology, San Francisco, CA, USA in December 2014, and this poster presentation received the Abstract Achievement Award in 2014.

REFERENCES

1 Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D et al.

Bendamustine plus rituximab is effective and has a favorable toxicity prole in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol 2005; 23: 33833389.2 Rummel MJ, Balser C, Kaiser U, Bck HP, Stauch MB, Heider A et al. Bendamustine plus rituximab versus udarabine plus rituximab in patients with relapsed follicular, indolent, or mantle cell lymphomas 8-year follow-up results of the randomized phase III study NHL 2-2003 on behalf of the StiL (Study Group Indolent Lymphomas, Germany) [abstract]. Blood 2014; 124: 145.3 Ohmachi K, Ando K, Ogura M, Uchida T, Itoh K, Kubota N et al. Multicenter phase II study of bendamustine for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Cancer Sci 2010; 101: 20592064.4 Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in rst-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 2014; 123: 29442952.5 Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grnhagen U, Losem C et al. Bendamustine plus rituximab versus CHOP plus rituximab as rst-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013; 381: 12031210.6 Garca Muoz R, Izquierdo-Gil A, Muoz A, Roldan-Galiacho V, Rabasa P, Panizo C. Lymphocyte recovery is impaired in patients with chronic lymphocytic leukemia and indolent non-Hodgkin lymphomas treated with bendamustine plus rituximab. Ann Hematol 2014; 93: 18791887.7 Layman RM, Ruppert AS, Lynn M, Mrozek E, Ramaswamy B, Lustberg MB et al. Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer. Cancer Chemother Pharmacol 2013; 71: 11831190.8 Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N et al. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2013; 31: 21032109.9 Hasegawa T, Aisa Y, Shimazaki K, Nakazato T. Cytomegalovirus reactivation with bendamustine in patients with low-grade B-cell lymphoma. Ann Hematol 2015; 94: 515517.10 Hosoda T, Yokoyama A, Yoneda M, Yamamoto R, Ohashi K, Kagoo T et al. Bendamustine can severely impair T-cell immunity against cytomegalovirus. Leuk Lymphoma 2013; 54: 13271328.11 Tapan U, May SK, Fiore J, Kozyreva O. Reactivation of hepatitis B virus following bendamustine-containing chemotherapy in a patient with multiple myeloma. Leuk Lymphoma 2011; 52: 916918.12 Hashimoto K, Kobayashi Y, Asakura Y, Mori M, Azuma T, Maruyama D et al. Pneumocystis jiroveci pneumonia in relation to CD4+ lymphocyte count in patients with B-cell non-Hodgkin lymphoma treated with chemotherapy. Leuk Lymphoma 2010; 51: 18161821.

Cytomegalovirus antigenemiaAll grades 4 (7) 2 (4) 9 (16) 15 (27) Grade 3 0 (0) 0 (0) 0 (0) 0 (0)

Cytomegalovirus disease (colitis)All grades 0 (0) 0 (0) 1 (2) 1 (2) Grade 3 0 (0) 0 (0) 1 (2) 1 (2)

Pneumocystis pneumoniaAll grades 0 (0) 0 (0) 0 (0) 0 (0) Grade 3 0 (0) 0 (0) 0 (0) 0 (0)

Varicella zoster virusAll grades 0 (0) 0 (0) 2 (4) 2 (4) Grade 3 0 (0) 0 (0) 1 (2) 1 (2)

Hepatitis B virus reactivationAll grades 1 (2) 0 (0) 1 (2) 2 (4) Grade3 0 (0) 0 (0) 0 (0) 0 (0)

Other infectionsAll grades 15 (25) 8 (13) 18 (32) Grade3 3 (6) 0 (0) 3 (6)

1045/l (range: 1702580/l) and 223/l (range: 47709/l), respectively (Figures 1a and b). In comparison between 1 month and 79 months after the completion of bendamustine without rituximab, lymphocyte counts were signicantly increased (median: 565 vs 1125/ l, P = 0.003). On the other hand, with rituximab, lymphocyte counts were not signicantly increased (median: 600 vs 780/l, P = 0.07).

The number of patients who received prophylaxis at the physicians discretion against PCP, VZV infection and fungal infection were 44 (79%), 37 (66%) and 4 (7%), respectively. Infectious events were observed in 32 patients (57%) during the period between the initiation of bendamustine and the last follow-up (that is, total follow-up). CMV antigenemia was detected in 15 patients (27%), VZV infection in 2 (4%), CMV colitis in 1 (2%) and other infectious complications in 18 patients (32%), namely, fever in 15 (27%), febrile neutropenia in 2 (4%), sepsis in 2 (2%), urinary tract infection in 2 (2%) and oral candidiasis in 1 (2%) (Table 1). Although no statistically signicant differences were detected between lymphocytopenia and the incidence of infectious events in this study, mainly because of the small number of patients, all infectious events occurred within 9 months after the completion of bendamustine in patients who received no treatment after bendamustine during follow-up.

In this study, recovery of lymphocyte and CD4-positive T-cell counts to those at baseline was observed at 79 months after the completion of bendamustine with or without rituximab. Although statistical signicance was not identied, some reports have suggested that the absolute lymphocyte count might be relevant to the development of CMV reactivation8,9 and hepatitis B virus reactivation.11 In the patients who received rituximab in combination with bendamustine, it tended to take longer for the lymphocyte counts to recover.

Our analysis revealed that relapsed or refractory patients with indolent B-NHL and MCL showed prolonged lymphocytopenia and low CD4-positive T-cell counts for at least 79 months after the completion of bendamustine with or without rituximab. The prophylaxis against PCP and VZV deserves consideration for at least 79 months after bendamustine treatment. Further investigations are needed to conrm our results.

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