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prednisolone at 100 mg/m2 on days 3-7were administered, followed by a 2-week period of no treatment. Toxicitiesare acceptable, and both patientsachieved complete remission after sixand five courses respectively.

INTRODUCTIONAmong the non-Hodgkin’s lymphomas(NHL), low-grade B-cell lymphomasrefer to small lymphocytic lymphoma,follicular lymphoma, marginal-zone B-cell lymphoma, and lymphoplasmacyticlymphoma. In Europe and the UnitedStates, low-grade B-cell lymphomasaccount for 25 to 40% of NHL. Recentstudies of Japanese patients with lym-phoma have reported that low-grade B-cell lymphomas, follicular lymphomas,and marginal-zone B-cell lymphomasaccount for 15 to 25%, 7 of 15%, and 10of 12% of the total NHL, respectively.1,2

The main characteristics of low-

Two Retroperitoneal Low-GradeB-Cell Lymphoma SuccessfullyTreated With a Combination ofChimeric Anti-CD20 MonoclonalAntibody and CHOPChemotherapyYoichi Kitamura, MDKazuhiko Hayashi, MDKazumi Uchida, MDTsuyoshi Sasagawa, MDHidetoshi Oguma, MDKen Takasaki, MD

Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo,Japan

KEY WORDS: malignant lymphoma,CHOP, rituximab

ABSTRACTAdvanced low-grade B-cell lymphomashave been treated by various modalitiessuch as alkylating-agent monotherapy,combination chemotherapy with anthra-cycline and other drugs. However, thesemodalities of therapy have not beenreflected in survival, and no standardtherapy has been established.

Recently, chimeric anti-CD20 IgG1monoclonal antibody (rituximab) hasfound clinical application, and we per-formed CHOP-rituximab combinationtherapy for 2 patients with advancedretroperitoneal low-grade B-cell lym-phoma. Rituximab at 375 mg/m2 on day1, cyclophosphamide at 750 mg/m2 onday 3, adriamycin at 50 mg/m2 on day 3,vincristine at 1.4 mg/m2 on day 3, and

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grade B-cell lymphomas at the time ofdiagnosis are that they relatively fre-quently affect a middle-aged group(median age 55-60 years), and are oftenadvanced. In American whites, 75 to90% of patients were found to be inadvanced Ann Arbor clinical stage (CS)III-IV, with a high frequency of bonemarrow invasion.3 Follicular lymphomasaccount for the majority of advancedlow-grade B-cell lymphomas.

To date, CS III and IV advancedlow-grade B-cell lymphomas have beentreated by various modalities such asalkylating-agent monotherapy, combina-tion chemotherapy with anthracyclineand other drugs, chemotherapy in com-bination with interferon-a, and massivechemotherapy in combination withautologous or allogeneic hematopoieticstem-cell transplantation. However,these modalities of therapy have notbeen reflected in survival, and no stan-dard therapy has been established.

Recently, chimeric anti-CD20 IgG1monoclonal antibody (rituximab) hasfound clinical application. It has anaction mechanism different from thoseof conventional chemotherapeuticagents, and adverse reactions or mecha-nisms of resistance to it do not overlapwith those to chemotherapeutic agents.4,5

Therefore, the clinical introduction ofrituximab has expanded the potentialfor combination use with otherchemotherapeutic agents, and holdspromise for not only increasing theresponse rate but also prolonging sur-vival.

In this study, we performed CHOP-rituximab combination therapy for 2advanced retroperitoneal low-grade B-cell lymphomas, and achieved completeresponse in 2 patients.

CASE REPORTSCase 1Patient: 65-year-old man.Chief complaint: Sensation of abdominalfullness and back pain.Present illness: He had a sensation ofabdominal fullness and left back pain inMarch 2003, and visited a local clinic,where an intraperitoneal, child-head-sized tumor and cervical and inguinallymphadenopathies were pointed out,and he was referred to our hospital.Laboratory studies, including hemogramand liver and kidney function tests, wereall within normal limits. CT scansshowed ascites and a solid, irregulartumor, 18 × 12 cm in size, invading theceliac and superior mesenteric arteries(Figure 1).

The cytology of chylous ascites wasclass 2. Inguinal lymph node biopsy ledto a histologic diagnosis of non-Hodgkin’s lymphoma, follicular mixedB-cell type according to the WHO clas-sification, and immunostaining showedthe lesion to be CD20-positive (Figure2).Treatment and clinical course: Six cours-es of CHOP-rituximab combinationtherapy (rituximab at 375 mg/m2 on day

Figure 1. CT imaging of case 1 during thetreatment.

Figure 2. Histopathological finding.

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1, cyclophosphamide at 750 mg/m2 onday 3, adriamycin at 50 mg/m2 on day 3,vincristine at 1.4 mg/m2 on day 3, pred-nisolone at 100 mg/m2 on days 3-7) wereadministered. Grade 3 neutropenea wasobserved in every course, but using 2g/kg of G-CSF (colony stimulating fac-tor; lenograstim) the treatment was welltolerated. The 6 courses of this therapycaused a complete reduction of theabdominal tumor and the ascites. Theswelling of the cervical and inguinallymph nodes also disappeared (Figure1). This patient is still alive with no evi-dence of disease after 8 cycles of thetreatment.

Case 2Patient: 57-year-old woman.Chief complaint: General fatigue.Present illness: She had general fatiguein September 2003, and visited a localclinic. Intraperitoneal and inguinal lym-phadenopathies were pointed out, andshe was referred to our hospital.Laboratory studies, including hemogramand liver and kidney function tests, wereall within normal limits. CT scansshowed multiple enlarged lymph nodesaround the abdominal aorta, one ofwhich measured 6.0 cm in diameter,causing hydronephrosis (Figure 3).Inguinal lymph node biopsy led to a his-tological diagnosis of non-Hodgkin’slymphoma, follicular mixed B-cell typeaccording to the WHO classification,and immunostaining showed the lesionto be CD20-positive.

Treatment and clinical course: Five

courses of CHOP-rituximab combina-tion therapy were administered as inCase 1. Grade 3 neutropenea wasobserved in course 1, 2, 4, and 5, butwith the use of 2 g/kg/day of lenogras-tim, the treatment was also well tolerat-ed. The 5 courses of this therapy causeda complete reduction in the periaorticswollen lymph nodes. The swelling of theinguinal lymph nodes also disappeared(Figure 3). This patient is also alive withno evidence of disease after 8 cycles ofthe treatment.

DISCUSSIONLow-grade B-cell lymphomas, as typifiedby follicular lymphoma, are intractablediseases that have a slow course with along median survival of 7 to 10 yearsand, in most patients, undergo histologictransformation to higher-grade histolog-ic types, mainly diffuse large B-cell lym-phoma (DLBCL), and ultimately causeneoplastic death. It has been reportedthat the histologic transformation rate offollicular lymphoma is as high as 40 to70%, and that the median of the periodbetween diagnosis and histologic trans-formation is 4 to 5 and a half years, andthat the median survival after histologictransformation is less than 1 to 2 years.6,7

Since a permanent cure is difficult toachieve, the long-term prognosis is poor-er than that of intermediate- and high-grade lymphomas. Rosenberg et alreported that in the patients at all stagesof disease treated by various modalities,the remission rate was approximately80%, but the relapse late was also highwith a mean remission period of 24months, 5-year survival rate of 60 to80%, 10-year survival rate of 50 to 60%,5-year exacerbation-free survival rate of30 to 40%, and 10-year exacerbation-free survival rate of 25%.8 The 10-yearsurvival rate of low-grade B-cell lym-phomas compared with that of interme-diate- and high-grade NHL is better at60% vs 35%, but the 15-year survival

Figure 3. CT imaging of case 2 during thetreatment.

rate is poorer at 26% vs 33%.8 The diffi-culty?maintaining remission, and theoccurrence of relapse and exacerbationover a long period are due to the factthat low-grade B-cell lymphoma cellsare resistant to chemotherapeutic agentsand thus intractable.

Rituximab is a chimeric anti-CD20IgG1 monoclonal antibody that hasrecently found clinical application. It hasbeen confirmed that rituximab binds tothe human B-cell surface antigen CD20,and selectively exerts a cytotoxic effecton B-cell tumors by antibody-dependentcellular cytotoxicity (ADCC) and com-plement-dependent cytotoxicity (CDC)or by directly acting on cells with bcl-2gene rearrangement (a molecular bio-logical characteristic of CD20-positive Bcells), thereby inducing apoptosis.9,10

Cross-resistance to conventionalchemotherapeutic agents and rituximabdoes not occur, and rituximab has acompletely different mechanism ofaction. It has been reported that theresponse rate and CR rate of rituximabmonotherapy are 48% (80/166) and 6%(10/166), respectively, and that it is safe,with low toxicity as indicated by a rateof toxicity over grade 3 of only 12% inspite of fever (43%), chills (28%), andheadache (14%).11

Rituximab has an action mechanismdifferent from those of conventionalchemotherapeutic agents, and adversereactions or mechanisms of resistance toit do not overlap with those tochemotherapeutic agents.4,5 Therefore,the clinical introduction of rituximab hasbeen expanding the potential for combi-nation use with various chemotherapeu-tic agents.

Although CHOP is a standard ther-apy for intermediate- and high-degreelymphomas, the CR rate for untreatedfollicular lymphomas has been reportedto be 36%.12 In addition, amazingresponse and CR rates of 55% and 95%,respectively, have been reported for

CHOP-rituximab combination therapyfor untreated follicular lymphomas.Thus, this combination therapy hasincreasingly become a powerful candi-date for the standard therapy for low-grade B-cell lymphomas.

Clinical trials of CHOP-rituximabcombination therapy are in progress asan attempt at therapy for low-grade B-cell lymphomas. Six courses of CHOPtherapy in combination with 6 doses ofrituximab (375 mg/m2) achieved anORR of 95% (38/40) and a CR rate of55% (22/40).

Retroperitoneal malignant lym-phoma is relatively rare, and often foundat advanced disease. The key problem iswhether prolonged survival or pro-longed relapse-free survival in patientsin CR will be achieved. In the 2 patientsreported here, CHOP-rituximab combi-nation therapy achieved CR, making fol-low-up evaluation of survival important.

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3. Portlock CS. Management of the low-gradenon-Hodgkin’s lymphomas. Semin Oncol.1990;17:51-59.

4. Kadin ME, Berald CW, Namba K, et al.Lymphoproliferative diseases in Japan andWestern countries. Hum Pathol. 1983;14:745-772.

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11. McLaughlin P, Grillo-Lopez AJ, Link BK, etal. Rituximab chimeric anti-CD20 monoclon-al antibody therapy for relapsed indolentlymphoma: half of patients respond to four-dose treatment program. J Clin Oncol.1998;16:2825-2833.

12. Freedman A, Gribben J, Neuberg D, et al.High-dose therapy and autologous bone mar-row transplantation in patients with follicularlymphoma during first remission. Blood.1996;88:2780-2786.

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8. Rosenberg SA. The low-grade non-Hodgkin’slymphoma: challenges and opportunities. JClin Oncol. 1985;3:299-310.

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