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Annals of Oncology 12: 1493-1494. 2001. Letters to the editor Prolonged neutropenia following anti CD20 therapy in a patient with relapsed follicular non-Hodgkin's lymphoma and corrected with IVIG Mabthera or rituxan, a chimeric monoclonal antibody (mAb) directed against the B-cell receptor, the CD20 antigen, is rapidly emerging as a first or second line therapy for management of low-grade lymphomas (NHL) [1-3]. It acts by depleting both malignant and normal pre-B and mature lymphocytes by a variety of mechanisms, such as complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and induction of apoptosis, after binding to the CD20 antigen expressed on their surfaces. It is a reasonably safe agent and long-term complications have been reported to be rare. However, these are early days and we are bound to come across some relatively rare but significant complications of this agent. The incidence of neutropenia and thrombocytopenia has been reported to be very low and have been transitory. We have recently treated a patient with follicular lymphoma who relapsed after multiple chemotherapy regimens. The patient continued to have persistent neutropenia even six months after antiCD20 therapy. G.F., a 54-year-old male was diagnosed to have follicular, small and large cells type NHL, stage IVB with marrow involvement in 1995. Following six cycles of the standard CHOP chemotherapy the response was reported to be complete. Subsequently, he was given six cycles of fludarabine in a dose of 25 mg/sq.m/d x 5 when a relapse was noted. The disease showed partial response. He returned to us for unremitting fever in March 1999. CBC showed Hb - 8.29 g/dl,WBC-2.54x 10 9 /l,ANC-1.29x 109/l, platelet-47.6 x 109/l. He had evidence of intra-abdominal NHL with splenomegaly and retroperitoneal lymphadenopathy. Consent for marrow examination could not be obtained. He was put on oral chlorambucil and prednisolone. This combination immediately produced results with remission of fever and improvement in blood counts. After three cycles of oral chlorambucil and prednisolone, followed by CEPP regimen of cyclophosphamide, etoposide, procarbazine and prednisolone x 3 cycles. Due to progression of the disease by the time he completed CEPP x 3, he was informed about the role of mabthera in relapsed low-grade NHLs. He gave consent to use the drug. He received Mabthera in a dose of 375 mg/sq.m/week x 4 (dose rounded off to 700 mg for each dose) during the month of February 2000. The following events were noted subsequent to administration of mabthera. In the second week of April he came febrile. A complete blood count showed severe neutropenia of 0.235 x 109/l, with hemoglobin of 11.9 g/dl and platelet counts of 208 x 109/l. A bone marrow aspirate showed hypocelluar marrow with about 40% mature lymphocytes. There was no evidence of myelodysplasia. A trephine biopsy of the bone marrow would have been more informative, but the patient did not consent. Ultrasound examination of the abdomen showed only subcentimeter lymph nodes in the retroperitoneum, suggesting favorable response to mabthera. He required multiple admissions for treatment of his oro-pharyngeal and esophageal ulcers and febrile episodes. He received multiple antimicrobials, parenteral nutrition, blood components and hematopoietic growth factors GM-CSF and G-CSF. Growth factors have been able to improve the neutrophil counts only temporarily. We diagnosed his case to be chronic neutropenia with clinical manifestations of oral ulcers and epidermolysis. Serum immunoglobulin levels showed marked lowering of immunoglobulins: IgG - 280 mg/dl (normal value 700-1500 mg), IgA - 68 mg/dl (90-450 mg) and IgM - 84 mg/dl (60-250 mg). This apparently resulted from severe suppression of B lymphocytes. He was treated with intravenous immunoglobulins (IVIG), 30 G every week for three weeks. Four weeks post IVIG, the CBC had normalized and the oral and skin ulcers completely healed. Figure I shows the details of treatment and hematologic pictures from the time of administration of rituxan to date. The serum Ig levels also returned to normal. The disease and hematology continue to be normal to date. There is very little doubt that monoclonal antibody therapy with antiCD20 molecule has found a niche in the treatment of low-grade NHL. The agent can be safely administered in the majority of patients without significant side effects. Development of severe neutropenia in this case was noted a few weeks after antiCD20 therapy. Hence, it appears to be related to the drug. Whether the agent itself or the pre-existent extensive marrow involvement is responsible for prolonged neutropenia, remains unknown. The etiology of cytopenia following mabthera treatment needs to determined. This could be an immune phenomenon resulting from impact of the agent on hematopoietic stem cells or one of the committed lineages. One recent case report implicated parvovirus B19 in development of pure cell aplasia following treatment for NHL with chemotherapy and concomitant rituximab [4]. The patient's hemoglobin level improved following three doses of 30 g per week of intravenous immunoglobulin (IVIG). As the authors did not report the values of peripheral blood white cells and platelets, we presume these were within the normal limit. It has been reported that depleted B-lymphocytes following mabthera treatment may take a very long time to recover [5]. This renders the patient immunocompromised. Our patient received a therapeutic trial of IVIG. This case has highlighted the possible VVA1 V**2 W a s V*»6 W » 8 VMJ*12 «6*16 Vftd.17 WA2D VMJ*21 V\tO<2 Vt«k23 VW<31 » Figure I. Hematological parameters following rituxan and IVIG. I 1494 complications of prolonged neutropenia following antiCD20 monoclonal antibody therapy. This might be particularly applicable to the patients who have received extensive prior chemotherapy and remain cytopenic at the time of initiation of monoclonal antibody treatment. T. K.. Saikia,* H. Menon & S. H. Advani Department of Medical Oncology, Tata Memorial Hospital, Pare/, Mumbcii, India; * Author for correspondence (e-mail: saikias{a) vsnl.com) References 1. Mclaughlin P, Grillo-Lopez AJ. Link BK et al. Rituximub chimeric anh-CD20 monoclonal antibody therapy for relapsed indolent lymphoma Half of patients respond to a four-dose treatment program J Clin Oncol 1998: 16. 2825-33. 2. Solal-Cehgny P. Brousse N, Eftikhan Pel al. Rituximab as first-line treatment of Ibllicular lymphoma patients with a low tumor burden. Preliminary results of a phase II trial (Abstr). Ann Oncol 1999: 10 (Suppl 3): 130. 3. Hainsworlh JD, Burris III HA. Mornssey LH et al. Rituximab monoclonal antibody as initial therapy for patients with low-grade non-Hodgkin's lymphoma. Blood 2000; 95. 3052-6. 4. Sharma VR. Fleming DR and Slone SP. Pure red cell aplasia due to parvovirus BI9 in a patient treated with rituximab. Blood 2000. 96: 1184-6. 5. Red" ME. Carncr K. Chambers KS et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994. 83: 435 45. Use of gemcitabine (GEM) in advanced myelodysplastic syndromes Myelodysplastic syndromes (MDS) are an heterogeneous group of diseases with an indolent course, but invariable leukemic transformation and poor prognosis due to the resistance of leukemic cells to chemotherapy [I]. Supportive care is the mainstay of therapy in elderly patients, with allogeneic bone-marrow transplantation being the treatment of choice, when available, in the youngest [2]. The aim of our study is to verify the safe use of a new nucleoside analogue with anti-leukemic activity, gemcitabine (GEM), in advanced MDS or secondary acute leukemias (sAL) [3, 4] Ten patients, mean age 71 years (median 71. range 65 to 79) (2 RAEB-t, 1 CMMoL. 7 sAL) were treated following oral informed consent, with GEM 1000 mg/day weekly for a mean of seven doses (median 8, range 2 to 14) in a day-hospital regimen. Antibacterial prophylaxis with cyprofloxacine and transfusional support were given when Hb <8.0 g/dl and platelets <20 x 10y/l. An objective response to the treatment was considered to be a stable increase in peripheral blood cell count and/or a reduction in bone marrow immature cells. The control group was represented by 20 historical patients (mean age 70.5 (median 70.5, range 52 to 85) (9 RAEB. 7 RAEB-t. 4 sAL) treated with low-dose ara-C 15 mg, subcutaneously. twice a day for a mean of eight cycles (median 4, range 1 to 8). The differences between quantitative variables were estimated using the Mann-Whitney test. Observation time, defined as the time from entering the protocol to the death of the patient was analyzed using the method of Kaplan and Meier. In the GEM group, only one patient displayed a transient reduction in bone marrow immature cells. Nine patients received RBC concentrates (a mean of 7 U; median 8, range 5 to 14) and three patients PLT random units (a mean of 4 U). Infectious complications consisted of two bacterial pneumonitis. two sepsis, and one FUO and determined a mean of 2.5 days of hospitalization. Severe toxicity was observed in I patient who discontinued GEM because of WHO grade 3 gastrointestinal toxicity. All patients died due to disease progression after a mean follow-up of 11 months (median 5, range 2 to 34). In the control group, two patients died after one cycle of therapy as a result of cerebral hemorrhage and fungal pneumonia, respectively. Transfusional support consisted of a mean of 8 U of RBC (median 6.5, range I to 19) (P = 0.89) in all patients and of 4.5 U of PLT (median 9, range 5 to 28) in eight patients (P = 0.77). Eleven patients were hospitalized due to infectious complications: two pneumonia, four sepsis and one pulmonary TBC for a mean of 4.5 days (median 2, range 0 to 18) (P = 0.55). All patients had died at a mean follow-up of eight months (median 7, range 1 to 28) (P = 0.92). No statistically significant differences were observed in the survival curves of the two groups of patients. Whereas, response rate seems to be an important endpoint for phase 2 studies of new agents to treat MDS. a relevant goal should be to prolong patient survival while alleviating diseaserelated complications (chronic anemia, hemorrhage, infections) [5]. The safe use of GEM observed in our patients warrants more studies to evaluate the role of GEM in MDS and/or acute leukemias, perhaps in association with other anti-leukemic drugs (i.e. oral idarubicin) or differentiating agents. A possible role in controlling erythropoiesis (as indicated by the increase in highly fluorescent reticulocytes observed in four of our patients) also makes the association of GEM therapy with hemopoietic growth factors intriguing. A. Di Mario,* L. Pagano, L. Mele, V. De Stefano & G. Leone Cattedra di Ematologia, Universitd Catto/ica del Sacro Cuore, Rome, Italy; *Author for correspondence (e-mail: a. dimario @ eudoramail. com) References 1. Heaney ML. Golde DW Myelodysplasia. N Engl J Med 1999: 340: 1649-60. 2. Anderson JE. Appelbaum FR, Fisher LD et al. Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome Blood 1993; 8. 677-81 3. Bergman AM, Pinedo HM. Jongsma APM et al. Decreased resistance to gemcitabine (2'. 2'-difluorodeoxycytidine) or cytosinc arabinoside-resistant myeloblastic murine and rat leukaemia cell lines: Role of altered activity and substrate specificity of deoxycytidine kinase. Biochem Pharmacol 1999: 57: 397-406. 4. Santini V. Bernabei PA. Zozzini A et al. Apoptotic and antiproliferative effects of gemcitabine and gemcitabine plus ara-C on blast cell from patients with blast crisis chronic myeloprolifcrative disorders. Haematologica 1997; 82. 11-5 5. Cheson BD. Bennett JM, Kantarjian H et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000: 96. 3671-4.