Japanese Journal of Clinical Oncology Advance Access originally published online on September 19, 2005
Japanese Journal of Clinical Oncology 2005 35(10):622-625; doi:10.1093/jjco/hyi153
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© 2005 Foundation for Promotion of Cancer Research
Case Report |
Myelodysplastic Syndrome with Complex Karyotypic Abnormality in a Patient with Waldenström's Macroglobulinemia after Sequential Treatment with Chlorambucil and Fludarabine
1 Division of Oncology-Hematology, Department of Internal Medicine and 2 Department of Laboratory Medicine, Yeungnam University College of Medicine, Daegu, Korea
For reprints and all correspondence: Myung Soo Hyun, Division of Oncology-Hematology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea. E-mail: hms{at}med.yu.ac.kr
Received March 30, 2005; accepted August 8, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONCASE REPORTDISCUSSIONReferences |
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A therapy-related myelodysplastic syndrome (t-MDS) during the course of Waldenström's macroglobulinemia (WM) has been observed in rare patients. In most of them, the condition developed after treatment with alkylating agents. We experienced a 65-year-old male patient who was diagnosed as WM. He was treated with intermittent oral chlorambucil for 12 months and three cycles of fludarabine, and complete response was achieved after fludarabine treatment. During routine outpatient follow-up, severe anemia occurred. His bone marrow aspirate showed dysplastic hemopoiesis with ringed sideroblasts and siderocytes, which is consistent with MDS (refractory anemia with ringed sideroblasts). Cytogenetic analysis showed complex chromosomal abnormalities including 5q deletion, 12p deletion and monosomy 18. When decision is made to treat WM with chlorambucil and/or fludarabine, a potential risk for t-MDS or therapy-related acute myeloid leukemia should be considered and a close hematologic monitoring is needed.
Key Words: Waldenström's macroglobulinemia • myelodysplastic syndrome • chlorambucil • fludarabine
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INTRODUCTION |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONReferences |
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Waldenström's macroglobulinemia (WM) is a very rare disease (1), especially in Asian countries. Historically, treatment options have been limited. Because of the rarity of the disease and the lack of formally established protocol, physicians around the world have utilized different therapies for WM patients. Several regimens have been applied alone or in combination in the hope that synergistic response would be found to be effective. Typically, three classes of drugs have been used against WM, including alkylating agents (2,3), nucleoside analogs, such as fludarabine (4,5) and cladribine (2-CdA) (6); and more recently, monoclonal antibodies, such as Rituxan (rituximab) (7).
The standard therapy for patients with symptomatic WM has been the administration of oral alkylating agents such as chlorambucil and cyclophosphamide. Treatment-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/t-AML) is an uncommon but crucial late complication in patients who received alkylating agents or topoisomerase II inhibitors.
Here, we report a very rare case of t-MDS in a patient with chlorambucil resistant WM after treatment with fludarabine.
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CASE REPORT |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONReferences |
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A 65-year-old male patient was admitted with complaints of cough and dyspnea. At physical examination, his blood pressure was 130/85 mmHg, pulse rate 80/min, respiratory rate 20/min and body temperature 36.5°C. His respiratory sound was decreased in left lower lung field.
The initial laboratory findings were: white blood cell count (WBC) 7.6 x 109/l (seg 42%, lymphocyte 38% and monocyte 14%), hemoglobin (Hb) 7.7 g/dl and platelet count 307 x 109/l on complete blood cell count (CBC), blood urea nitrogen 14 mg/dl, creatinine 1.6 mg/dl, protein 9.5 g/dl, albumin 3.3 g/dl, erythrocyte sedimentation rate 95 mm/h, lactate dehydrogenase 269 IU/l, aspartate aminotransferase 20 IU/l, alanine aminotransferase 9 IU/l on blood chemistry. Pleural effusion in left lung field was found on chest radiography. The patient had an exudative pleural effusion with lymphocyte dominance. Pleural biopsy revealed diffuse plasmacytoid lymphocytes of positive reaction with CD19, CD20, CD22 and CD79, but no reaction with CD10 and CD23. The pathologic diagnosis in pleural biopsy was lymphoplasmacytic lymphoma according to the World Health Organization classification. Computed axial tomography scan of abdomen revealed massive enlargements of peripancreatic and para-aortic lymph nodes, and mild intrahepatic duct dilatation without demonstrable obstruction or space occupying lesion in liver. The IgM level was 3150 mg/dl in the serum. Protein excretion of 1530 mg was noted in 24 h without urinary Bence Jones' protein. The serum protein electrophoresis characterized M-spike and immunoelectrophoresis revealed IgM and lambda light chain. Bone marrow was hypercellular and extensively infiltrated with lymphocytes and a few plasmacytoid lymphocytes (Fig. 1). Chromosomal study showed no abnormalities.
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The patient was diagnosed as WM with evidence of pleural and bone marrow infiltration by lymphoplasmacytic lymphocytes and immunophenotypic studies. He was treated with chlorambucil 0.2 mg/kg with prednisolone 1 mg/kg for days 1–5 every 28 days (CP regimen) for 12 months. One month after 12 cycles of CP regimen, his CBC showed WBC 4.3 x 109/l, Hb 8.5 g/dl and platelet 203 x 109/l and his IgM levels, which had initially declined after the first two cycles of chemotherapy, elevated to the 4230 mg/dl.
He underwent for a total of three cycles of fludarabine 25 mg/m2 on days 1–5 every 28 days with a complete response and normalization of his IgM levels. Thirty-four months after the chemotherapy, his CBC showed progressive anemia. His bone marrow aspirate showed dysplastic hemopoiesis (Fig. 2) with ringed sideroblasts and siderocytes, which is consistent with MDS [refractory anemia with ringed sideroblasts (RARS)] (Fig. 3). He was diagnosed as t-MDS (RARS) according to the French–American–British (FAB) classification. In this case, chromosomal study showed complex chromosomal abnormalities including 5q deletion, 12p deletion and monosomy 18 (Fig. 4).
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The patient wished to receive supportive care and died 1 month later.
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DISCUSSION |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONReferences |
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After alkylating agents became a mainstay of therapy for WM for many years, the development of myelodysplasia or acute leukemia has occasionally been reported (2). Although it might be expected that oral chlorambucil therapy in WM could induce t-MDS, the reported incidence was relatively low. A review of the literature (Medline, January 1966–February 2005) disclosed 21 cases of WM evolving into t-MDS/t-AML. All subtypes of AML according to the FAB classification, except M3 and M5, have been reported. Available cytogenetic abnormalities were monosomy 7 and an extra Y chromosome in two and one cases, respectively. The simultaneous existence of MDS and AML in four MDS cases was reported in only two cases. Most of them received chlorambucil and/or melphalan.
New treatment modalities with purine analogs such as fludarabine or 2-CdA have been proposed for alkylating agents-resistant WM patients or even as first-line treatment. Recent published experiences with first-line use in WM are limited because neither higher response rates nor survival benefits and toxicities was attained (8). AML and myelodysplasia occurring in chronic lymphocytic leukemia (CLL) patients who received initial therapy with fludarabine have been reported (9). In another study of 31 chlorambucil-treated patients with low-grade lymphoproliferative disorders including CLL who subsequently received fludarabine, significant marrow dysplastic changes were shown in five patients (10).
MDS was also developed in four cases of 43 patients with indolent non-Hodgkin's lymphoma after completion of the 2-CdA treatment (11), as have three cases, two of whom had no or minimal alkylator exposure, presenting after 2-CdA therapy to 27 patients with WM (12).
The use of alkylating agents is associated with a dose-dependent increase in the incidence of t-MDS/t-AML (13,14).
The leukemogenicity of the alkylating agents, such as cyclophosphamide, melphalan, busulfan and chlorambucil, is not fully understood (15). Although they form covalent intrastrand and interstrand DNA cross-linking, and may induce leukemia through such mechanisms as point mutations, deletions and inappropriate recombination, because of the enhanced and aberrant DNA repair (16,17), the possible etiololgy of the non-treated cases remains controversial (18). In t-AML/t-MDS after alkylating agents, cytogenetic studies have shown unbalanced chromosomal aberrations, a total loss or a deletion of the long arm of either chromosome 5 or 7 (19,20).
Fludarabine inihibits the DNA repair process and has the synergism combined with an agent like cyclophosphamide (21). There could be increased DNA damage. Fludarabine is also an immunosuppressive agent, and loss of immunosurveillance may play additional role in leukemogeneis (22).
The synergistic effect of fludarabine-alkylator combination is likely to be related to the occurrence of alkylator-induced DNA damage and inhibition of subsequent DNA repairs by fludarabine (22).
In conclusion, we report a very rare case of t-MDS associated with sequential chlorambucil/fludarabine treatment for WM. Both chlorambucil and fludarabine have a potential risk for t-MDS/t-AML and adverse effects would be augmented by combination or sequential treatment. When decision is made to treat the WM patients with chlorambucil and/or fludarabine, close hematologic monitoring would be needed during the treatment, because the prognosis for patients with t-MDS/t-AML remains very poor.
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References |
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