Annals of Oncology Advance Access originally published online on November 1, 2006
Annals of Oncology 2007 18(2):364-369; doi:10.1093/annonc/mdl393
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© 2006 European Society for Medical Oncology
hematologic malignancies |
A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: a single-institution study
1 Department of Hematology and Oncology
2 Department of Transfusion Medicine and Immunohematology, Graduate School of Medicine, University of Tokyo
3 Department of Pathology, Toranomon Hospital
4 Department of Pathology, Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan
* Correspondence to: Prof M. Kurokawa, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81-3-5800-6527; Fax: +81-3-3815-8350; E-mail: kurokawa-tky{at}umin.ac.jp
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: Late-onset neutropenia (LON) has been reported following rituximab-containing chemotherapy. Its incidence and risk factors, however, have not been extensively studied.
Patients and methods: We retrospectively reviewed the medical records of 107 patients treated with rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphomas and identified cases with LON as defined by the neutrophil count of 
1.0 x 109/l without an apparent cause after the recovery of neutrophil count following completion of the intended chemotherapy.
Results: With a median follow-up of 411 days, 23 patients developed LON out of the 107 at a median of 106 days after the last chemotherapy. Cumulative incidence of LON among the total patients was 24.9%. The median neutrophil count nadir was 0.61 x 109/l. The LON episodes were generally self-limited, and filgrastim was administered in one patient. Including this patient, there were no serious infectious episodes in the cases with LON. In multivariate analysis, intensive chemotherapy regimens including high-dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) and high-dose methotrexate-containing regimens without ASCT were a risk factor for LON.
Conclusion: This study suggests that LON is a frequent complication of rituximab-containing intensive chemotherapy.
Key words: late-onset neutropenia, lymphoma, neutropenia, rituximab
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Rituximab, a chimeric monoclonal antibody against human CD20, is widely used as a single agent or in combination with chemotherapy for various types of CD20-positive B-cell malignancies [1–5]. This agent adds little toxicity when combined with chemotherapy regimens aside from mild to moderate infusion-related reaction, which is frequently encountered with the first dose [1, 2]. Late-onset neutropenia (LON) is a newly recognized late complication of rituximab-combining chemotherapy. The cause of LON has been attributed to rituximab, but the mechanism for developing LON remains undetermined [6–9]. According to previous reports, LON is usually considered to be an uncommon event with standard-dose chemotherapy, while a higher incidence has been reported after high-dose therapy followed by stem cell transplantation [10, 11]. The incidence and the clinical course of LON, however, are unclear, especially among patients who receive rituximab-containing regimen as the first-line chemotherapy. For instance, the incidence of LON after the combination therapy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), the most common first-line regimen for B-cell lymphomas, has not been reported. Such a late complication may be elusive unless it leads to infection in large-scale prospective studies. Thus, we investigated the incidence and the clinical course of LON in clinical practice at our department.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patient population
We retrospectively reviewed the medical charts of consecutive patients who had completed the intended primary treatment of CD20-positive lymphomas at our department from March 1996 through May 2006. Patients who had achieved complete response or complete response undetermined according to the International Workshop criteria and with a follow-up period of at least 1 month after the last chemotherapy cycle were analyzed. Two patients with indolent lymphomas who had previously received involved field radiotherapy as an initial treatment followed by the rituximab-containing regimen for the progressive disease were included. Characteristics of patients and primary treatments are shown in Table 1. After the primary treatment, the interval of follow-up visits and blood tests were at physicians' discretion. Generally, complete blood count with differential and reticulocyte counts was carried out every 2–8 weeks during first 2 years of follow-up.
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One hundred and seven patients were treated with a rituximab-containing chemotherapy regimen. Ninety-four patients underwent rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP), with patients followed by consolidative high-dose chemotherapy with autologous hematopoietic stem cell transplantation (ASCT) in five, and followed by radiotherapy in 23. Among them, 25 patients were treated with four cycles of chemotherapy or less (abbreviated chemotherapy) mainly because it was combined with involved field radiotherapy for localized diffuse large B-cell lymphoma (DLBCL) (n = 20). Three patients underwent rituximab combined with cyclophosphamide, vincristine, and prednisolone (R-CVP). In this study, we defined R-CHOP followed by consolidative ASCT (n = 5, as described above) and high-dose methotrexate-containing regimens: fractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone alternating with high-dose methotrexate–cytarabine (R-hyperCVAD/MA) (n = 5), the Cancer and Leukemia Group B 9251 regimen for Burkitt's lymphoma (BL regimen) (n = 3), and other high-dose methotrexate-containing regimens (n = 2), as intensive regimens. Among them, three patients underwent ASCT as a consolidation after completing R-hyperCVAD/MA, and two patients with the BL regimen received radiotherapy. These intensive regimens were carried out according to the protocol in our department for high-risk DLBCL according to the age-adjusted international prognostic index, mantle cell lymphoma, DLBCL of intravascular variant, Burkitt's lymphoma, and DLBCL with involvement of the central nervous system or the testis. All of these patients received six cycles of chemotherapy or more according to the protocol. Thus, the chemotherapy duration as defined by the time from the start of chemotherapy through completion, including high-dose therapy, was longer in the patients who had intensive regimens than those with R-CHOP or R-CVP (median 166 days, range 96–206 days, versus 112 days, range 22–214 days, the Mann–Whitney U-test, P < 0.0001). For rituximab-containing chemotherapy, one dose of rituximab 375 mg/m2 was administered with each chemotherapy cycle in general. There was no patient who had been treated with maintenance rituximab therapy. Twenty-five patients received involved field radiotherapy after the completion of chemotherapy.
As a control, we reviewed the charts of 52 consecutive patients who underwent chemotherapy without rituximab as a primary treatment of CD20-positive lymphomas at our department (Table 1). Proportions of patients who had intensive regimens (14.0% versus 9.6%, P = 0.432), abbreviated chemotherapy (23.4% versus 19.2%, P = 0.555), consolidative ASCT (7.5% versus 5.8%, P = 0.691), and radiotherapy (23.4% versus 36.5%, P = 0.082) were comparable between the rituximab-containing chemotherapy-treated group and the control group. Rituximab was included in the standard protocol for indolent lymphomas in 2001 and for aggressive lymphomas in 2003. Therefore, treatment periods of the control group predated those of the studied patients. Otherwise, patients in the both groups were followed in the same manner and there were no changes in supportive treatments.
definition of LON
Various definitions of LON have been used in previous reports [6–8, 12]. In this study, we defined LON as neutropenia of 1.0 x 109/l [grade 3 according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC)] without an apparent cause after the recovery of neutrophil count following completion of the intended chemotherapy and before progression of lymphoma and/or additional chemotherapy. Severe LON was defined as neutropenia of 0.5 x 109/l (grade 4 according to the NCI-CTC). Neutropenia that was observed after the recovery from the first episode of LON was defined as the second episode of LON as far as the patient had not had progressive lymphoma and/or been treated with additional chemotherapy. One patient had interferon and lamivudine because of exacerbation of chronic hepatitis B. This patient was censored at the start of interferon. For patients with LON, we had not defined a protocol for work-up or indication for the use of granulocyte colony-stimulating factor.
statistical analysis
Univariate and multivariate analyses for time-to-event covariates were carried out using the log-rank test and proportional-hazard modeling, respectively. Factors associated with at least borderline significance (P < 0.10) in univariate analyses were subjected to a multivariate analysis and deleted stepwise from the model. The cumulative incidence of LON was evaluated using Gray's method considering progression of lymphoma before LON as a competing risk [13].
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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incidence and risk factors of LON
With a median follow-up of 411 days, 23 (21.5%) patients developed LON out of the 107 patients who received rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphomas. The cumulative incidence of LON was 24.9% (Figure 1A). Severe LON was observed in 10 (9.3%) patients, and its cumulative incidence was 15.4%. In contrast, no episodes of LON were observed in the control group (52 patients).
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In univariate analysis, advanced stages (Ann Arbor stages III and IV), intensive primary treatment regimens, consolidative high-dose therapy followed by ASCT, and absence of radiotherapy as a primary treatment were associated with a higher incidence of LON (Table 2). There was a trend for a higher incidence of LON in patients who were 65 years old or younger. In this study, sex, histology, bone marrow involvement at diagnosis, or adopting abbreviated chemotherapy was not a risk factor for LON. In the multivariate analysis, the use of primary treatment regimens with higher intensity than that of R-CHOP or R-CVP was an independent risk factor for LON (Figure 1B, Table 2). Although, by definition, patients who had consolidative ASCT were included in the group of intensive primary treatment regimens, a high incidence of LON (50.3%) was also observed when only the patients without ASCT were analyzed. Even for the patients who received R-CHOP or R-CVP without consolidative ASCT, the incidence of LON was 20.4%.
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clinical courses of LON
Clinical courses of the patients with LON are summarized in Table 3. The first LON episode in each patient developed at a median of 106 (range 46–384) days after the last chemotherapy and at a median of 124 (range 46–384) days after the last administration of rituximab. Neutrophil count nadir during LON episodes in each patient ranged from 0.008 x 109 to 0.96 x 109/l (median 0.6 x 109/l). The recovery from neutropenia was observed at a median of 28 (range 5–84) days. In most cases, neutropenia was observed at only one visit. Sustained neutropenia lasting at least >3 weeks was, however, observed in six episodes (range 22–81 days). Including these cases, there was no concurrent drop in platelet or reticulocyte count in the patients with LON. Bone marrow examination was carried out in two patients. In one patient (case 11-1), the result was unremarkable, while in the other (case 23-1), maturation arrest of myeloid series was seen. Filgrastim was administered in one patient for LON, and neutrophil count recovered promptly after one dose. Otherwise, all LON episodes recovered spontaneously without administering hematopoietic factors. All LON cases were detected in blood tests at routine follow-up, and no serious complications with LON were observed aside from one patient with mild tonsillitis. Three patients (cases 11-2, 13-2, and 23-2) developed the second episode of LON at 49, 53, and 56 days after the recovery from the first episode of LON, respectively. Time to the recovery from the second episodes of LON was 28, 42, and 63 days, respectively. Progression of lymphoma was observed in five patients out of 23 patients who had LON. The median progression-free survival was 28.4 months after completion of primary therapy which was comparable to that of the patients without LON (data not shown).
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One patient (case 11-1) developed neutropenia immediately after the stem cell mobilization with filgrastim alone 3 months after completion of R-hyperCVAD/MA. In this case, upon consecutive administration of 600 µg of filgrastim per day for 4 days, there was only a slight increase in white blood cell count (3.6 x 109 to 6.7 x 109/l) and we could collect only 0.084 x 106/kg CD34-positive cells, which were not enough for transplantation. The neutrophil count on the day of stem cell collection was 5.2 x 109/l, and after cessation of filgrastim, it decreased steadily to 0.55 x 109/l on the fifth day. LON in this case lasted for 1 week, and there was no sign of infection during this period.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Rituximab has changed the treatment paradigm of CD20-positive B-cell malignancies. This agent is used as a single agent or in combination with chemotherapy. Improvement in complete response rates and in long-term prognosis has been shown by adding rituximab to the original chemotherapy regimen in several B-cell malignancies including DLBCL and follicular lymphoma [1, 2, 4, 5]. The toxicity of rituximab is generally mild, if any, and a major concern is restricted to infusion-related toxicity at the first administration of rituximab [2]. With its increased use, however, uncommon adverse events attributed to rituximab have been recognized [6, 14]. LON is one of such events and we also attribute LON to the use of rituximab because it was never seen in the patients treated with chemotherapy alone as described in the literature [7, 8], although clinical characteristics of the studied group and the control group were not comparable because of the retrospective design of this study (Table 1).
In this study, the cumulative incidence of LON was 24.9% with higher incidence (54.4%) in patients receiving intensive primary treatment compared with patients who received conventional treatment with R-CHOP or R-CVP (20.4%). A high incidence of LON has been reported in patients treated with rituximab before and/or after ASCT [10–12]. A French group reported six patients with LON (neutrophil count of <0.5 x 109/l) out of 39 patients (15%) treated with the same protocol using rituximab and consolidative ASCT [10]. Consistent with this, we observed a high incidence of LON (57.1%) in patients who underwent consolidative ASCT. Furthermore, the current study revealed that patients who primarily received rituximab in combination with intensive regimens incorporating high-dose methotrexate without consolidative ASCT also had a high incidence (50.3%) of LON. It is possible that factors associated with the diseases on their own, which necessitated these intensive regimens, may have directly contributed to the development of LON, although all of these patients were free of progression for >1 year after the episode of LON.
In the present study, patients having radiotherapy as a primary treatment had lower incidence of LON (Table 2). Among these 25 patients, 20 were treated with a combination of abbreviated chemotherapy plus involved field radiation. The other five patients had radiotherapy after completing six cycles of chemotherapy for initial bulky lesion and so on. Thus, it would be very convincing that it is not absence of radiotherapy as a primary treatment, but the amount of chemotherapy that is a risk factor for LON, and this is in line with another finding that the use of intensive regimens was a risk factor for LON. In this study, however, the use of abbreviated chemotherapy itself was not associated with lower incidence of LON. Although there may be some unknown confounding factor, we have no account of this at the moment.
We also found a high incidence (20.4%) of LON even in patients treated with R-CHOP and R-CVP, which are the most commonly used regimens for CD20-positive lymphomas. We assume that this result could be applied widely to patients who are treated with these regimens. The manufacturer of rituximab reported the calculated post-marketing reporting rate of LON of <0.02% [15]. These facts suggest the possibility that many cases with rituximab-associated LON are unrecognized in clinical practice. The report from Australia described eight episodes of severe LON among 53 patients (15%) who were treated with rituximab [7]. That study, however, included mainly patients with relapsed follicular lymphoma, and patients treated with rituximab alone were analyzed together, which makes it difficult to estimate the incidence of LON in a primary treatment setting. The cumulative incidence of severe LON of 9.3% in the current study is consistent with the previous report from NCI of the USA in which the incidence was reported to be 8% out of 76 patients treated with dose-adjusted EPOCH with rituximab as a frontline treatment of DLBCL, AIDS-related lymphomas, and mantle cell lymphoma [8]. We believe that less severe LON is more commonly seen than is generally thought. Because episodes of LON can be short and rarely complicated with severe infection, as shown in this study, it can elude recognition by physicians. As this retrospective study was carried out based on routine clinical practice, some LON episodes may have eluded recognition as they developed and subsided between blood tests. Thus, the actual incidence of LON might be even higher than revealed by this study.
The median time to LON in this study was similar to that observed in the previous studies [6, 7]. Although B-cell count was not followed serially in this study, the onset of LON coincided with or preceded the timing of normal B-cell recovery described in the literature [3], supporting the hypotheses that etiology of LON is related with the recovery of nonmalignant B-cell population after administration of rituximab. Production of anti-neutrophil autoantibody by repopulating B cells has been implicated [6]. Recently, another hypothesis has been reported in which perturbation of stromal-derived factor-1 during B-cell recovery inhibits the egression of neutrophil from the bone marrow [8]. B-cell recovery-associated mechanism may not be the only cause of LON, however, because it has rarely been reported in patients who were treated with rituximab alone [3], and the incidence of it might be associated with chemotherapy regimen used along with rituximab, as shown in this study.
In conclusion, we found a high incidence of LON in the series of patients who underwent rituximab-containing primary chemotherapy for CD20-positive B-cell lymphoma. The use of intensive primary chemotherapy regimen was a risk factor for LON. It was generally self-limited and not associated with severe infections. We should, however, be aware of it especially when applying intensive chemotherapy regimens along with rituximab.
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Footnotes |
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These authors contributed equally to this work. 
Received for publication August 1, 2006. Revision received September 12, 2006. Accepted for publication September 14, 2006.
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