• Open Access

Rituximab monotherapy with eight weekly infusions for relapsed or refractory patients with indolent B cell non-Hodgkin lymphoma mostly pretreated with rituximab: A multicenter phase II study

Authors

  • Kensei Tobinai,

    Corresponding author
    1. Department of Hematology, and Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo
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  • Tadahiko Igarashi,

    1. Hematology/Oncology Division, Gunma Prefectural Cancer Center, Gunma
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  • Kuniaki Itoh,

    1. Department of Breast Oncology and Hematology/Medical Oncology, National Cancer Center Hospital East, Chiba
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  • Mitsutoshi Kurosawa,

    1. Department of Hematology, National Hospital Organization Hokkaido Cancer Center, Sapporo
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  • Hirokazu Nagai,

    1. Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya
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  • Akira Hiraoka,

    1. Department of Hematology and Chemotherapy, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka
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    • Present address: Kenporen Osaka Central Hospital, Osaka, Japan.

  • Tomohiro Kinoshita,

    1. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya
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    • Present address: Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan.

  • Naokuni Uike,

    1. Hematology/Oncology Division, National Hospital Organization Kyushu Cancer Center, Fukuoka
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  • Michinori Ogura,

    1. Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya
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    • Present address: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.

  • Shigeru Nawano,

    1. Department of Radiology, International University of Health and Welfare Mita Hospital, Tokyo
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  • Shigeo Mori,

    1. Department of Pathology, Teikyo University School of Medicine, Tokyo
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  • Yasuo Ohashi,

    1. Biostatistics Sciences, School of Health Science and Nursing Biostatistics, University of Tokyo, Tokyo, Japan
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  • the IDEC-C2B8 Study Group

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    • The participating institutions and principal investigators of the IDEC-C2B8 Study Group are: Hokkaido Cancer Center (M. Kurosawa and K. Aikawa), Sapporo Hokuyu Hospital (M. Kasai and Y. Kiyama), Tochigi Cancer Center (T. Izumi and Y. Kano), Gunma Cancer Center (T. Igarashi and K. Murayama), National Cancer Center Hospital East (K. Itoh), National Cancer Center Hospital (K. Tobinai, Y. Kobayashi, and T. Watanabe), Tokai University School of Medicine (T. Hotta and K. Ando), Aichi Cancer Center Hospital (Y. Morishima, M. Ogura, and K. Yamamoto), Nagoya University School of Medicine (T. Kinoshita, T. Murate, and H. Nagai), Nagoya Medical Center (H. Nagai and H. Ohashi), Kyoto Prefectural University of Medicine (M. Taniwaki), Center for Cardiovascular Diseases and Cancer, Osaka (A. Hiraoka and T. Karasuno), Hiroshima University School of Medicine (A. Sakai), National Kyushu Cancer Center (N. Uike).


To whom correspondence should be addressed.
E-mail: ktobinai@ncc.go.jp

Abstract

Information regarding rituximab monotherapy with eight weekly infusions for relapsed or refractory indolent B cell non-Hodgkin lymphoma (B-NHL), in particular for patients pretreated with rituximab, is limited. To evaluate the efficacy and safety of eight doses of rituximab monotherapy, 52 patients with relapsed or refractory indolent B-NHL were enrolled in the present study. Forty of 45 eligible patients (89%) had follicular lymphoma and 24 (53%) were at intermediate or high risk group according to the Follicular Lymphoma International Prognostic Index. The median number of prior chemotherapy regimens was 1 (range 1–7). At the median follow-up of 12.2 months, the overall response rate (ORR), complete response rate (%CR), and median progression-free survival (PFS) were 69% (95% confidence interval [CI] 53%–82%), 47% (95% CI 32%–62%), and 15.6 months (95% CI 10.6– months), respectively. In the 33 patients pretreated with rituximab, the ORR, %CR, and median PFS were inferior compared with values for the 12 patients who had not received rituximab previously (64%vs 83% for ORR; 39%vs 67% for %CR; and 13.8 vs 17.5 months for median PFS, respectively). All mild-to-moderate infusion-related toxicities were reversible. Grade 3/4 non-hematologic adverse events occurred in six of the 52 patients. Two patients developed Grade 4 late-onset neutropenia and a decrease (>50%) in serum immunoglobulin was observed in six patients. In conclusion, rituximab monotherapy with eight weekly infusions is effective in relapsed patients with indolent B-NHL, with acceptable toxicities, including in patients pretreated with rituximab; however, careful monitoring is recommended for infections associated with late-onset neutropenia and hypogammaglobulinemia. (University Hospital Medical Information Network no. UMIN000002974.) (Cancer Sci 2011; 102: 1698–1705)

Since the introduction of rituximab, a chimeric anti-CD20 mAb, into clinical trials and practice, it has been routinely used for the treatment of indolent and aggressive B cell non-Hodgkin lymphoma (B-NHL) in combination with chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), based on several Phase II and III studies.(1–5) However, in the treatment of indolent B-NHL, of which the most representative histopathologic subtype is follicular lymphoma, rituximab monotherapy has been regarded as a reasonable treatment option, especially for elderly patients with a low tumor burden, partly because indolent B-NHL is slow growing and is difficult to cure even with intensive chemotherapies.(3,6–8) In addition, rituximab monotherapy has often been applied to previously treated and untreated patients with indolent B-NHL(9–11) or as maintenance therapy after achieving remission.(12–16)

Rituximab monotherapy at doses of 375 mg/m2 or slightly higher has been evaluated in Phase II studies with four weekly infusions for relapsed indolent B-NHL(9,10) and with eight weekly infusions for relapsed aggressive B-NHL;(17,18) however, information regarding rituximab monotherapy with eight weekly infusions for relapsed or refractory indolent B-NHL is limited to one previous report of a Phase II study in 37 patients who had not been pretreated with rituximab, in which a tendency for superior efficacy was found (overall response rate [ORR] 57% and median time to progression [TTP] in responders 19.4+ months)(19) compared with the four weekly infusion treatment regimen.(9,10)

In current clinical practice, retreatment with rituximab monotherapy with four weekly infusions is frequently used in patients with relapsed indolent B-NHL pretreated with rituximab.(20,21) However, there are no reports of rituximab retreatment with eight weekly infusions in this patient population. The aim of the present Phase II study was to investigate the outcome of eight weekly infusions of rituximab in patients with relapsed or refractory indolent B-NHL, mostly pretreated with rituximab. Our findings indicate that rituximab monotherapy with eight weekly infusions is safe and effective in this patient population.

Methods

Study design and endpoints.  The present study was a single agent, multicenter, Phase II study. The primary endpoint was the ORR in all eligible patients. Secondary endpoints included progression-free survival (PFS) in all eligible and evaluable patients. The expected ORR (P1) was set at 50% based on the preceding Phase II study for relapsed indolent B-NHL,(9,10) whereas the threshold ORR (P0) was set at 30%. The number of patients required for the study was calculated as 44 (α = 0.05 and 1 –β = 0.8) according to Fleming’s(22) two-stage testing procedure. Assuming that up to 15% of enrolled patients would be ineligible, we planned to enroll 52 patients. All patients were followed-up either until disease progression or for 24 months from the first infusion of rituximab as a protocol treatment.

Patient eligibility criteria.  Patients with CD20-positive indolent B-NHL who had relapsed or were refractory to conventional chemotherapy with or without rituximab were eligible for inclusion in the study. The histopathology of the lymphoma was consistent with small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B cell lymphoma or follicular lymphoma (Grades 1, 2, and 3), according to the World Health Organization (WHO) Classification, 3rd edition.(23) Transformed lymphomas from indolent B-NHL were excluded. Eligible patients had at least one measurable lesion exceeding 1.5 cm in largest diameter. The last chemotherapy cycle had to be completed at least 4 weeks prior to study entry. Previous rituximab administration had to be eight or fewer infusions. In patients who had received rituximab monotherapy or rituximab-containing chemotherapy as prior therapy, objective responses had to have been achieved. Patients were between 20 and 79 years of age and had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.(24) Patients had no other malignancies or serious infection, and had adequate organ function.

Patients meeting any one of the following criteria were excluded from the study: (i) a history of treatment with any mAb other than rituximab; (ii) a history of treatment with rituximab within 1 year prior to study entry; (iii) >5000/μL lymphoma cells in peripheral blood; (iv) symptomatic central nervous system (CNS) involvement or a history of CNS involvement of lymphoma; (v) seropositivity for hepatitis B virus surface antigen, hepatitis C virus antibody, human immunodeficiency virus, or human anti-chimeric antibody (HACA); and (vi) pregnancy or potential pregnancy. Patients who had received hematopoietic growth factors within 1 week prior to enrollment were also excluded from the study.

Each patient provided informed consent at the time of study entry. The study was approved by the institutional review board of each participating institution and was conducted in compliance with the Declaration of Helsinki.

Central pathology review.  Unstained microscope slides of lymphoma tissues at initial diagnosis and/or at relapse were collected from each institution. In addition to H&E staining, immunohistochemical analyses were conducted using mAb, including an anti-CD20 mAb (L26), anti-CD3 mAb, anti-CD5 mAb, anti-CD10 mAb, anti-bcl-2 mAb, and anti-cyclin D1 mAb, as described previously.(25) Preparations were examined microscopically by a central pathology review committee composed of three hematopathologists.

Rituximab administration and premedication.  Rituximab (IDEC-C2B8), manufactured by Genentech (South San Francisco, CA, USA), was supplied by Zenyaku Kogyo (Tokyo, Japan). The dosing schedule involved eight consecutive weekly infusions of 375 mg/m2 rituximab. Patients were premedicated with 2 mg d-chlorpheniramine maleate and 400 mg acetaminophen 30 min prior to each infusion of rituximab. The rate of infusion was increased from 25 to 100 mg/h and then to 200 mg/h at 1 h intervals, based on the results of the preceding Phase I and II studies of rituximab monotherapy in Japan.(10,26)

Adverse events and adverse drug reactions.  All adverse events (AE) associated with rituximab, or those for which the relationship with rituximab was unknown, were regarded as adverse drug reactions (ADR). The ADR were graded according to the toxicity criteria of the Japan Clinical Oncology Group,(27) an expanded version of the National Cancer Institute–Common Toxicity Criteria (version 2.0, http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf, accessed Jun 21, 2011).

Serum rituximab and HACA levels.  Serum concentrations of HACA were monitored before and after rituximab infusion using an ELISA, as described previously.(9,10,18,26) Serum rituximab concentrations were determined in 18 patients who signed another informed consent form for this pharmacokinetic (PK) study.(10,18,26) The PK parameters were calculated using WinNolin professional software (version 5.0.1; Pharsight, Mountain View, CA, USA).

Tumor response and PFS.  Tumor lesions were observed by weekly physical examination during rituximab administration and using computed tomography (CT) scans approximately every 3 months thereafter. Response was assessed according to the International Workshop NHL Response Criteria.(28) In the present study, a CR was defined as the complete disappearance of all lesions and radiological or biological abnormalities and the absence of any new lesions. The term “CR unconfirmed” (CRu) was used to describe patients who met the criteria for a CR but who had an indeterminate bone marrow (BM) assessment or a >75% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of all measurable lesions but with a residual mass. A partial response (PR) was defined as a >50% decrease from baseline in the SPD of all measured lesions, no increase in the size of any other lesions, and no new lesions. Stable disease (SD) was defined as neither a 50% decrease nor a 50% increase in the SPD of measured lesions; progressive disease (PD) was defined as the appearance of any new lesion or a >50% increase in the SPD from the nadir. In addition to efficacy evaluation at each participating institute, an independent third-party panel of three radiologists performed central evaluation using the CT films collected. The primary efficacy variable was the best ORR (the relative frequency of responders showing CR, CRu, or PR). Secondary efficacy variables included the CR rate (%CR) and PFS (defined as the time from the date of enrollment to the date of PD assessment or the date of death from any cause).

Statistical analyses.  Response rates and 95% confidence intervals (CI) were calculated using Fisher’s exact test. The median PFS (and 95% CI) was estimated using the Kaplan–Meier method(29) with the log-rank test.(30) In addition, pretreatment factors affecting ORR and PFS were analyzed. Factors selected for multivariate analyses included sex, age, Ann Arbor clinical stage,(31) Follicular Lymphoma International Prognostic Index (FLIPI),(32) pathology, lactate dehydrogenase (LDH), extranodal disease, BM involvement, tumor size, prior chemotherapy regimens, prior rituximab treatment, and duration of lymphoma. In multivariate analyses, a stepwise logistic regression model was used for factors affecting ORR and Cox’s stepwise regression model was used for PFS. The relationship between PK parameters and response was analyzed using Student’s t-test. All statistical analyses were performed with SAS version 9.1 (SAS Institute, Cary, NC, USA).

Results

Patient characteristics.  Fifty-two patients were enrolled in the study between October 2004 and March 2008 from 15 institutions across Japan. All 52 patients were confirmed to be CD20 positive, but the intensity of CD20 expression was not quantified by immunohistochemical staining. The major characteristics of all 52 patients and the 45 eligible patients at the time of enrollment are summarized in Table 1. One patient was ineligible for inclusion in the study because his lesion was judged non-malignant by the central pathology review. Another six patients were also deemed ineligible for inclusion in the study by the extramural review committee: two patients did not have any tumor lesions >1.5 cm; in one patient, the tumor had been measured by ultrasonography and not a CT scan at the time of enrollment; one patient had been treated with more than eight infusions of rituximab prior to study enrollment; one patient had not responded to previous chemotherapy containing rituximab; and one patient had a Grade 3 abnormality in serum potassium levels at the time of enrollment. Thus, 45 patients were judged eligible for inclusion in the study and their characteristics were similar to those of all 52 patients (Table 1). Thirty-three of the 45 eligible patients (73%) had been pretreated with rituximab monotherapy or in combination with chemotherapy.

Table 1.   Patient characteristics
 EnrolledEligible
  1. †Diagnoses were made by the central pathology review committee. WHO, World Health Organization; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase.

No. patients5245
No. women/men27/2523/22
Median (range) age (years)60 (32–79)62 (32–79)
Histopathology† (WHO)
 Follicular
  Grade 1 (n)1614
  Grade 2 (n)2522
  Grade 3a (n) 4 3
  Grade 3b (n) 1 1
 Nodal marginal zone (n) 4 4
 Extranodal marginal zone (n) 1 1
 Not evaluated (n) 1 0
Clinical stage at restaging (Ann Arbor) I–II/III–IV (n)20/3218/27
ECOG performance status 0–1/>1 (n)52/045/0
B-symptoms absent/present (n)51/144/1
No. nodal sites <4/>439/1333/12
Bulky disease (>5 cm)1616
Extra nodal site absent/present (n)40/1235/10
Positive/negative BM involvement (n) 7/45 5/40
Serum LDH normal/elevated (n)40/1233/12
Follicular Lymphoma International Prognostic Index
 Low2621
 Intermediate1715
 High 9 9
Median (range) interval from the onset of symptoms (years) 4.7 (1.3–22.3) 4.8 (1.3–22.3)
Median (range) interval from the last therapy (years) 2.5 (0.1–13.8) 2.8 (0.1–13.8)
Prior therapy
 Surgery (n) 5 4
 Radiotherapy (n)1211
 Chemotherapy (n)5245
  Median no. prior chemotherapy regimens (range) 1 (1–7) 1 (1–7)
 Rituximab therapy (n)3833
  Rituximab monotherapy (n) 7 5
  Rituximab with chemotherapy (n)3128
  Median no. (range) rituximab administrations 4 (3–12) 4 (3–8)
 Median no. (range) relapses 1 (0–3) 1 (0–3)
Response to prior therapy
 Relapse/resistant46/639/6

Early termination of rituximab treatment.  Two patients discontinued rituximab treatment early before completion of the planned eight infusions. One patient withdrew consent after the sixth infusion of rituximab because of the occurrence of Grade 3 bronchospasm accompanied by dyspnea. Another patient was removed from the study by her investigator because her pre-existing Grade 3 hypokalemia had worsened to Grade 4 after the third infusion of rituximab.

Efficacy.  Efficacy was evaluated in all 45 eligible patients as per the protocol.

ORR, complete response rate (%CR) and PFS.  As indicated in Table 2, the ORR was 69% (31/45 patients; 95% CI 53%–82%), including a %CR of 47% (21/45 patients; 95% CI 32%–62%). Median PFS was 15.6 months at the median follow-up of 12.2 months (Fig. 1a).

Table 2.   Response and progression-free survival (= 45)
 All eligible patientsPrior therapy
With rituximabWithout rituximab
  1. The overall response rate (*P = 0.287, Fisher’s exact test), complete response rate (†P = 0.176, Fisher’s exact test) and progression-free survival (‡P = 0.372, log-rank test) were compared with those in patients who had not been treated with rituximab. Responses were evaluated according to the International Workshop NHL Response Criteria(28) and show the number of patients in each group with the percentage given in parentheses. The complete response rate consisted of the complete response rate plus the complete response unconfirmed rate. CI, confidence interval.

No. patients evaluated453312
Response
 Complete response13 (29%)9 (27%)4 (33%)
 Complete response unconfirmed8 (18%)4 (12%)4 (33%)
 Partial response10 (22%)8 (24%)2 (17%)
 Stable disease12 (27%)10 (30%)2 (17%)
 Progression disease1 (2%)1 (3%)0
 Not evaluable1 (2%)1 (3%)0
Overall response rate 31 (69%) 21 (64%) 10 (83%)
 95% CI53–82%45–80%52–98%
Progression-free survival
 Median (months)15.613.817.5
 95% CI10.6–9.7–9.6–
Figure 1.

 Progression-free survival (PFS) curves for (a) all eligible patients at a median follow-up time of 12.2 months (median PFS 15.6 months; 95% confidence interval [CI] 10.6–; = 45) and (b) patient groups who had either received prior rituximab therapy (––––; = 33; median PFS 13.8 months, 95% CI 9.7–) or not (- - - - -; = 12; median PFS 17.5 months, 95% CI 9.6–). (○), censored.

Efficacy in patients with a prior history of rituximab treatment.  Of the 45 eligible patients, 33 (73%) had a history of rituximab treatment at the time of study enrollment. Five had been pretreated with rituximab monotherapy and the remaining 28 had been pretreated with rituximab-containing chemotherapy. The median number of prior rituximab infusions was 4 (range 3–8). As indicated in Table 2 and Figure 1(b), the ORR, %CR, and PFS of patients who had been pretreated with rituximab exhibited a tendency towards inferior efficacy compared with those patients who had not been pretreated with rituximab, although the differences failed to reach statistical significance.

Factors affecting ORR and PFS.  Univariate analysis revealed that PFS was significantly associated with FLIPI (Fig. 2a; = 0.004, log-rank test). The median PFS of the low-risk FLIPI group was longer than that of the intermediate- and high-risk groups. Multivariate analysis of the 45 eligible patients indicated that advanced stage (III–IV) was an independent, unfavorable factor affecting ORR (odds ratio 6.623; 95% CI 1.021–43.478), whereas age (<60 years) and being in a higher risk FLIPI group (i.e. intermediate and high risk) were factors unfavorably affecting PFS (hazard ratio [HR] 4.651, 95% CI 1.218–17.857 for age; HR 7.684, 95% CI 1.992–29.647 for intermediate- and high-risk FLIPI groups).

Figure 2.

 Progression-free survival (PFS) curves for (a) patients categorized according to the Follicular Lymphoma International Prognostic Index as low risk (––––; = 21; median PFS not reached, 95% CI 10.6–), intermediate risk (–·–·–·–; = 15; median PFS 15.8 months, 95% CI 9.7–17.5), and high risk (··········; = 9; median PFS 8 months, 95% CI 3.8–13.8), and (b) patient groups showing higher (maximum drug concentration [Cmax] >450 μg/mL; ––––; = 21; median PFS not reached, 95% CI 12.1–) and lower (Cmax≤450 μg/mL; - - - - -; = 6; median PFS 10.9 months, 95% CI 7.6–13.8) serum rituximab levels. (○), censored.

Safety.  Safety was evaluated in all 52 patients who received at least one infusion of rituximab. Grade 2 or greater toxicities relating to rituximab are listed in Table 3.

Table 3.   Adverse drug reactions (≥Grade 2) in all 52 patients
 No. patientsTotal ≥Grade2 (%)
Grade 2Grade 3Grade 4
  1. Fevers were axillary temperatures. The table includes all adverse drug reactions (ADR) that were probably or possibly related to rituximab. The ADR were graded according to the Japan Clinical Oncology Group (JCOG) Toxicity Criteria,(27) an expanded version of the NCI Common Toxicity Criteria (version 2.0).The ADR were documented at the highest grade throughout the study period. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Hematologic toxicity
 Leukopenia132116 (31)
 Neutropenia4127 (13)
 Thrombocytopenia1102 (4)
 Hemoglobin decreased1001 (2)
Non-hematologic toxicity
 Rash5005 (10)
 Pruritus5005 (10)
 Fever (pyrexia)4004 (8)
 Urticaria4004 (8)
 Diarrhea3003 (6)
 Dizziness2002 (4)
 Erythema2002 (4)
 Weight loss2002 (4)
 Abdominal pain1001 (2)
 Acute pancreatitis0101 (2)
 Anorexia1001 (2)
 Bronchospasm0101 (2)
 Chills1001 (2)
 Constipation1001 (2)
 Dyspnea0101 (2)
 Dyspepsia1001 (2)
 Eczema1001 (2)
 Edema, eyelid1001 (2)
 Febrile neutropenia0101 (2)
 Hepatic cirrhosis1001 (2)
 Nasal drainage1001 (2)
 Oropharyngeal discomfort1001 (2)
 Oropharyngeal pain1001 (2)
 Phonation disorder1001 (2)
 Rectosigmoid cancer0011 (2)
 Stomatitis1001 (2)
 Scrotal swelling1001 (2)
 Tenderness1001 (2)
 Vomiting1001 (2)
Abnormal laboratory findings
 Occult blood in urine1102 (4)
 ALT increased0011 (2)
 AST increased0011 (2)
 Hyperbilirubinemia0011 (2)
 Hyperkalemia1001 (2)
 Hypoalbuminemia1001 (2)
 Hypokalemia0101 (2)
Infections
 Bronchopneumonia1001 (2)
 Hepatitis B0011 (2)
 Herpes virus infection1001 (2)
 Herpes zoster1001 (2)
 Nasopharyngitis1001 (2)
 Otitis media1001 (2)
 Pneumonia0101 (2)
 Viral enteritis0101 (2)

Hematologic toxicities.  Of all 52 patients, 34 (65%) developed hematologic toxicities relating to rituximab. Leukopenia and neutropenia were observed in 27 (52%) and 20 patients (38%), respectively; however, cytopenias exceeding Grade 2 were not frequent, as indicated in Table 3. The neutropenia in 10 of the 20 patients occurred after completion of rituximab treatment. The median time from the last rituximab infusion to the documentation of neutropenia was 3.2 months (range 1.6–8.4 months).

Two patients developed Grade 4 neutropenia at 2.5 and 3.0 months after completion of rituximab therapy. These two patients recovered to the normal range or baseline without support by hematopoietic growth factors. One patient developed Grade 3 febrile neutropenia concomitant with Grade 4 viral enteritis 6.6 months after completion of the treatment protocol. Her neutrophil count recovered to the normal range 11 days after the initiation of supportive care.

Non-hematologic toxicities.  Forty-nine of the 52 patients (94%) enrolled in the present study developed non-hematologic toxicities related to rituximab treatment, which were mostly infusion-related symptoms such as fever, chills, a burning sensation, headache, asthenia, pain, throat discomfort, perspiration, and pruritus and most of which did not exceed Grade 2. These symptoms generally appeared during the first infusion, decreased at subsequent infusions, and were effectively controlled within 24 h by prophylactic or supportive care with antihistamines and antipyretics.

Abnormal laboratory findings.  Most laboratory abnormalities were of Grade 1, with Grade 2 or greater abnormalities rare (Table 3). Grade 4 elevation of liver enzymes (alanine aminotransferase, aspartate aminotransferase) was observed in one patient who developed viral hepatitis B (Table 4).

Table 4.   Grade 3/4 non-hematologic adverse events
Patient no./toxicityGradeOnset
  1. The table includes all Grade 3/4 non-hematologic adverse events (AE) that were probably or possibly related to rituximab. The AE were graded according to the Japan Clinical Oncology Group (JCOG) Toxicity Criteria,(27) an expanded version of the NCI Common Toxicity Criteria (version 2.0). The AE were documented at the highest grade throughout the study periods. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Patient 2
 Pneumonia3Cycle 1 (Day 7)
Patient 3
 Bronchospasm3Cycle 6 (during infusion)
 Dyspnea3 
Patient 13
 Febrile neutropenia3Day 201 after completion of Cycle 8
 Viral enteritis3 
Patient 21
 Acute pancreatitis3Day 197 after completion of Cycle 8
Patient 43
 Rectosigmoid cancer4Day 287 after completion of Cycle 8
Patient 44
 Hepatitis B accompanied by Grade 4 increases in AST and ALT4Day 193 after completion of Cycle 8

Infections.  Eighteen episodes of infection were observed during the study period. Grade 2 or greater infections are listed in Table 3. Although one patient developed Grade 3 pneumonia after the first rituximab infusion, the planned eight rituximab infusions were completed after recovery with supportive care. Two patients developed Grade 4 viral hepatitis B and Grade 3 viral enteritis at 6.3 and 6.6 months after the completion of eight rituximab infusions, respectively. Other infections were of Grade 1/2.

Grade 3/4 non-hematologic AE.  The Grade 3/4 non-hematologic AE in six patients are given in Table 4. Three patients developed pneumonia, viral enteritis, and hepatitis B infections. Although one other patient developed Grade 3 bronchospasm with dyspnea after the sixth rituximab infusion, it was manageable with supportive care. Another patient developed Grade 3 acute pancreatitis at 6.5 months after completion of rituximab treatment. The patient recovered 12 days later. In addition, one patient developed rectosigmoid cancer 9.4 months after completion of rituximab treatment, which was managed by surgical resection. This patient showed neither clinical signs nor radiographic abnormalities suggestive of malignancy in the lower abdomen at the time of study entry. Nine months after the last rituximab infusion, the patient was found to have an intestinal obstruction suggestive of colon cancer and was hospitalized for a colectomy. Histopathological examination revealed tubular adenocarcinoma in the rectosigmoid junction. The relationship between the development of this rectosigmoid carcinoma and rituximab is unknown.

Other pharmacological findings.

T and B cell counts in peripheral blood.  All patients exhibited a marked decrease in CD19+ and CD20+ cells after the first rituximab infusion. The decrease lasted for 3 months and recovered gradually from 6 months or later, except in one patient. None of the patients was found to have HACA.

Serum immunoglobulins.  A decrease in serum immunoglobulins (IgA, IgM, or IgG) to ≤50% than baseline was observed in six patients. The time course of changes in serum immunoglobulin levels is given in Table 5.

Table 5.   Serum immunoglobulin levels
Patient no.No. prior rituximab administrationsResponseTreatment period (weeks)
 Baseline12–2324–3536–4748–7172–96
  1. Normal ranges are: 870–1700 mg/dL for IgG; 46–260 and 33–190 mg/dL for IgM in women and men, respectively; and 110–410 mg/dL for IgA. The table includes values that markedly decreased (>50%) compared with the baseline. CR, complete response; CRu, complete response unconfirmed; NE, not evaluable.

5 (male)6PRIgG (mg/dL)380358325283207152
% Decrease from baseline614264660
IgM (mg/dL)226≤5≤5≤5≤5
% Decrease from baseline73≤77≤77≤77≤77
IgA (mg/dL)1289490766549
% Decrease from baseline2730414962
13 (female)0NEIgM (mg/dL)4725212530
% Decrease from baseline47554736
IgA (mg/dL)9763494647
% Decrease from baseline35495352
16 (male)4NEIgM (mg/dL)2312141018
% Decrease from baseline48395722
22 (male)0CRuIgM (mg/dL)92281714
% Decrease from baseline708285
23 (male)8CRIgM (mg/dL)46281918
% Decrease from baseline395961
25 (male)4CRIgM (mg/dL)85413435
% Decrease from baseline526059

Serum rituximab levels and correlation with PFS.  Serum rituximab levels in 15 patients who received eight infusions increased cumulatively, but did not reach a steady state. There were no significant differences in serum rituximab levels between responders and non-responders, and no correlations between PK parameters and ORR. However, PFS in patients showing a higher maximum drug concentration (Cmax) of rituximab (>450 μg/mL) was longer than that in patients with a lower Cmax (Fig. 2b; = 0.018, log-rank test).

Discussion

The present Phase II study revealed that rituximab monotherapy with eight weekly infusions is safe and effective in patients with relapsed indolent B-NHL, including those who have been pretreated with rituximab. An analogous eight-dose rituximab Phase II study was conducted in relapsed patients with indolent B-NHL who had not been pretreated with rituximab by Piro et al. in the US.(19) The ORR in the present study was comparable to that reported in the US study (69%vs 60%), whereas the %CR in the present study was higher than that in the US study (47%vs 14%). These differences may be explained, in part, by differences in the response criteria and patient characteristics, including histopathologic subtypes, such as SLL. Regarding Grade 2 or greater AE, there were no clinically relevant differences between the two studies, except for slightly more frequent skin reactions (rash, pruritus, and urticaria) in the present study. Previously, we have conducted three rituximab monotherapy studies in Japan.(10,18,21) There appear to be no differences between the Japanese studies and those from Western countries in terms of efficacy and safety,(9,10,33,34) suggesting no ethnic-related differences in responses to rituximab monotherapy.

In the present study, the efficacy of rituximab monotherapy in patients who had been pretreated with rituximab tended to be inferior compared with efficacy in patients without a history of rituximab treatment, as evidenced by ORR, %CR, and PFS, although these differences failed to reach statistical significance. It has been reported previously that prior rituximab treatment is an unfavorable prognostic factor in patients with diffuse large B cell lymphoma who receive salvage chemotherapy at relapse.(35,36) In addition, a maintenance study involving follicular lymphoma found that the improvements in the OS and PFS of a patient group whose remission was induced with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP) were both less than those of a patient group whose remission was induced with CHOP.(13,37) Nevertheless, the efficacy results of rituximab monotherapy with eight weekly infusions in patients pretreated with rituximab (ORR 64%, %CR 39%, and median PFS 13.8 moths) still compared favorably with efficacy in patients that had not been pretreated(9,10) and in patients pretreated with four weekly rituximab infusions.(20,21) Although the exact reasons for the relatively high efficacy in patients pretreated with rituximab in the present study are unknown, they may be explained, in part, by the extended eight weekly rituximab infusions. Considering these results, rituximab monotherapy with eight weekly infusions is a reasonable therapeutic option for this patient population.

The frequency and severity of the AE observed in the present study appeared to be slightly higher than in our previous on relapsed indolent B-NHL,(10) which consisted of only four rituximab infusions rather than the eight used in the present study, and were almost equivalent to those in aggressive B-NHL.(18) In addition to the extension of rituximab dosing, shorter monitoring intervals may be responsible for the higher frequency and severity of AE in the present study. One of the notable findings of the present study is the relatively frequent observation of late-onset neutropenia and hypogammaglobulinemia. Of the 20 patients who developed neutropenia, half (= 10) developed it after completion of the treatment protocol (onset 1.6–8.4 months after completion of treatment). Although Grade 4 neutropenia was observed in two of the 10 patients, these two patients did not suffer from severe infections. In six patients, serum immunoglobulin levels were decreased to <50% of each baseline level. In particular, there was a marked decrease in IgM and this decrease was seen in all six patients. One of the six patients who concomitantly developed Grade 3 febrile late-onset neutropenia also developed Grade 4 viral enteritis, whereas no infectious episode was observed in the remaining five patients. Such a marked decrease in serum immunoglobulin levels was not observed in our previous four-dosing monotherapy study of relapsed indolent B-NHL,(10) whereas similar tendencies were observed in a previous eight-dosing rituximab monotherapy study in aggressive B-NHL.(18) Although rituximab monotherapy is a reasonable treatment option for patients with untreated or treated indolent B-NHL, especially for elderly patients with a low tumor burden, careful monitoring for infections and secondary malignancy is required.

In conclusion, rituximab monotherapy with eight weekly infusions is safe and effective in patients with relapsed or refractory indolent B-NHL, including those who have been pretreated with rituximab, suggesting that this therapy is a reasonable option for this patient population. However, careful monitoring is recommended for infections associated with late-onset neutropenia and hypogammaglobulinemia.

Acknowledgments

This study was supported by Zenyaku Kogyo (Tokyo, Japan). The authors thank the patients and their families and all the investigators, including the physicians, nurses, and laboratory technicians in the participating institutions of this multicenter trial. The authors are grateful to Drs N. Horikoshi (Juntendo University School of Medicine, Tokyo, Japan), K. Oshimi (Juntendo University School of Medicine), S. Shirakawa (Mie University, Tsu, Japan), and K. Toyama (Tokyo Medical College, Tokyo, Japan) for their critical review of the clinical data as members of the Independent Data and Safety Monitoring Committee. The authors are also grateful to Drs T. Terauchi (National Cancer Center, Tokyo, Japan) and M. Matsusako (St Luke’s International Hospital, Tokyo, Japan) for their central radiological review as members of the CT Review Committee, and Y. Matsuno (Hokkaido University Hospital, Sapporo, Japan) and S. Nakamura (Nagoya University School of Medicine, Nagoya, Japan) for their histopathological review as members of the Central Pathology Review Committee. The authors also acknowledge Y. Arita, T. Uesugi, M. Tachikawa, S. Fukuda, Y. Ikematsu, T. Itoh, K. Inatomi, I. Okugaito, and T. Kayo (Zenyaku Kogyo) for their help with data collection and statistical analysis.

Disclosure Statement

Tomohiro Kinoshita received research funding from Zenyaku Kogyo (Tokyo, Japan). The remaining authors have no conflicts of interest.

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