Haematologica 2002; 87:(01)ELT04
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Sustained complete remission following a combination of very low intensity chemotherapy with rituximab in an elderly patient with Burkitt's lymphoma
Yossi Cohen,* Gail Amir,° Eliezer A. Rachmilewitz,* Aaron Polliack*
*Departments of Hematology and °Pathology, Hadassah University Hospital, Jerusalem, Israel.

Correspondence: Professor Aaron Polliack, MD, Head of Lymphoma-Leukemia Unit, Department of Hematology, Jerusalem, Hadassah University Hospital, Israel 91120. Fax 972-3-5749717. Email: rakefet1@012.net.il
Rituximab, an anti-CD20 monoclonal antibody has an additive effect when given with chemotherapy in indolent as well as some aggressive B-cell lymphoproliferative disorders. Its role in Burkitt's lymphoma (BL) has not been established until now but the strong expression of CD20 makes this lymphoma subtype a reasonable candidate for combination therapy with rituximab. Here we describe an elderly, 78-year old patient with low compliance who was treated successfully for extranodal BL with 4-cycles of rituximab, combined with vincristine and low-dose oral etoposide followed by monthly cycles of oral etoposide and rituximab as maintenance therapy. She achieved a sustained ongoing complete remission of over 18 months and is currently disease-free. As a combination of chemotherapy with immunotherapy is probably synergistic in BL, low intensity chemotherapy combined with immunotherapy may be used in the treatment of elderly patients who cannot tolerate the conventional intensive chemotherapy used in BL.

Rituximab, an anti CD20 monoclonal antibody is already being used effectively for the treatment of primary and relapsed indolent C20+ follicular lymphoma.1-3 Rituximab basically has a favorable toxicity profile and is indeed less toxic to the normal hematopoietic system than chemotherapy. Furthermore, it appears to be more effective when used together with chemotherapy than as a single agent.4 Benefit in other indolent lymphoproliferative disorders, including lymphoplasmacytic lymphoma5-7 and chronic lymphocytic leukemia8,9 has also been recorded. In addition, complete molecular remissions have also been attained in these patients with follicular lymphoma10 and there appears to be continued tumor regression even after therapy has been discontinued. From recent and ongoing studies, it appears that rituximab is also effective in the treatment of advanced aggressive large B-cell lymphoma in the elderly,11 however longer follow-up may still be required in order to assess the durability of response in these patients. Rituximab also appears to be a safe and relatively efficient therapy for post-transplant B-lymphoproliferative disorders (PTLD) as primary therapy12 and for relapsed lymphoma after transplant.13 Most recently, it has also been used as part of the treatment for minimal residual disease in CD20+ acute lymphoblastic leukemia (ALL)14 and in combination with cytoreductive regimens as in vivo purging in peripheral blood stem-cell transplantation for aggressive and indolent B-cell lymphomas.15,16 Further multicenter trials are also in progress in an attempt to define the role of these agents in mantle-cell and diffuse large B-cell lymphomas.17

At present, very limited data are available on the role of rituximab in Burkitt's lymphoma (BL).18,19 It could indeed be expected to be effective in this disorder because BL cells strongly express CD20. Here, we describe a 78-year old patient with relapsed localized extranodal BL and low compliance who was treated successfully as an out-patient with a regimen containing rituximab, vincristine and low-dose oral etoposide. The patient has achieved sustained complete remission (CR) lasting over 18 months and is currently still disease free.
In 1998, a 78-year old lady presented with a rapidly growing left periorbital mass shown on biopsy to have the typical histopathology of Burkitt's lymphoma. Staining for CD20 was strongly positive. While initial staging, after imaging techniques and bone marrow biopsy, was compatible with stage 1A disease, an incidental small mass in her left breast was also found and shown to be intraductal carcinoma. She was first treated with 4-cycles of CHOP at standard dose and achieved CR. Thereafter, she underwent left lumpectomy with ipsilateral adjuvant axillary lymph-node irradiation (64 Gy) as treatment for the breast carcinoma. She then received additional adjuvant radiotherapy (34 Gy) to the periorbital region so as to complete the appropriate therapy for stage 1A extranodal lymphoma. Both CT and gallium scans now confirmed complete remission. Twelve months after initial diagnosis, two new masses appeared in her right breast and in the right axilla. These were biopsied and shown to be relapsed Burkitt's lymphoma. Because of concern about her age, general condition and compliance to high dose salvage chemotherapy, she was treated less aggressively as an outpatient with 4-biweekly cycles of rituximab (375 mg/m2) combined with oral etoposide (day 2, 100 mg/m2; days 2-6, 50 mg/m2) and vincristine (1.4 mg/m2) on day 2. The rituximab was given on day 1 of the cycle and she achieved CR as documented by whole body CT-scan, PET-scan and mammography. She continued to receive monthly maintenance therapy with oral etoposide and rituximab at the same dosages for four more months and has remained disease-free for the past 18 months. Her last CT-scan was performed in October 2001 and she remains in CR.
Here we report a case of relapsed extranodal Burkitt's lymphoma successfully managed on an outpatient basis with 8-cycles of rituximab combined with very low intensity chemotherapy which included vincristine and low-dose oral etoposide. After 18 months she remains in complete remission and repeated normal CT, gallium and PET scans are all normal. Indeed, in indolent2,4 and aggressive B-cell lymphoma,11,17 a bimodal therapeutic approach with chemoimmunotherapy (CHOP+ rituximab) proved to be effective in achieving remission. However, the cell turnover in BL is so rapid that some concern may indeed arise regarding its safety as frontline therapy in BL, particularly since rituximab cytotoxicity is unrelated to the cell-cycle and as a result, massive tumor lysis could possibly occur during therapy. Suboptimal efficacy is also of concern, for immune-mediated cytotoxicity (ADCC) may lag behind the rapid cell turnover rate seen in BL. Until now, only a few abstracts have been documented on the use of Rituximab in the very aggressive lymphoproliferative disorders, BL18,19 and ALL.15,16 The present case experience supports the assumption that combining rituximab in therapeutic regimens for BL may well be as effective as in indolent and large B-cell lymphoma, with acceptable side effects. However, our patient did not have bulky disease and attention must still be paid to the safety profile of rituximab when used as primary therapy in these patients. On the other hand, it could prove useful in the eradication of minimal residual disease and it can be combined with low intensity chemotherapy in elderly patients with BL who cannot tolerate intensive chemotherapy.

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