Japanese Journal of Clinical Oncology Advance Access originally published online on May 30, 2007
Japanese Journal of Clinical Oncology 2007 37(5):382-384; doi:10.1093/jjco/hym037
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© 2007 Foundation for Promotion of Cancer Research
Combination Chemotherapy with Bortezomib, Cyclophosphamide and Dexamethasone may be Effective for Plasma Cell Leukemia
1 Division of Hematology and Oncology, Department of Internal Medicine
2 Department of Laboratory Medicine
3 Department of Diagnostic Radiology, Korea University Medical Center, Seoul, Korea
For reprints and all correspondence: Byung Soo Kim, Division of Oncology and Hematology, Department of Internal Medicine, Korea University Medical Center, 126-1, Anamdong 5-ga, Seongbuk-ku, Seoul, 136-705, Korea. E-mail: kbs0309{at}korea.ac.kr
Received November 10, 2006; accepted December 23, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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Plasma cell leukemia is a rare malignant plasma cell disorder characterized by proliferation of plasma cells in blood and the bone marrow, the outcome of which is poor with conventional therapy. More effective treatment strategies are therefore needed for this disorder. Here, we report a case of secondary plasma cell leukemia from Immunoglobulin D multiple myeloma refractory to doxorubicin-containing chemotherapy and thalidomide. The patient achieved complete remission with bortezomib-containing chemotherapy as follows: bortezomib 1.3 mg/m2 intravenous infusion on days 1, 4, 8 and 11; cyclophosphamide 750 mg/m2 intravenous infusion on days 1 and 3; dexamethasone 40 mg/m2 intravenous infusion on days 1–4. Complete remission was maintained until the fourth course of the treatment, and we then performed autologous peripheral blood stem cell transplantation. Our experience suggests that combination chemotherapy with bortezomib, cyclophosphamide and dexamethasone may be an effective induction treatment for plasma cell leukemia.
Key Words: bortezomib • cyclophosphamide • plasma cell leukemia • multiple myeloma
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INTRODUCTION |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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Plasma cell leukemia (PCL) is a rare, aggressive leukemic form of multiple myeloma characterized by rapid progression and poor prognosis. The diagnosis is based on a circulating absolute plasma cell count above 2000/mm3 and a plasmacytosis of more than 20% of the total leukocyte count. There are two clinical types: either primary or secondary. Primary PCL is de novo plasma cell leukemia without pre-existence of multiple myeloma, and accounts for about 60% of PCL cases; secondary PCL occurs as a terminal event in late-stage multiple myeloma accounting for the remaining 40% of cases (1). PCL is generally characterized by an aggressive clinical course and refractoriness to chemotherapy; thus it usually shows a very poor prognosis with a median survival of 6–8 months compared to multiple myeloma (2). The poor outcome is likely related to the biologically aggressive nature of this disease, which is generally resistant to conventional chemotherapy (3). This is especially the case for secondary PCL. Therefore, a more effective treatment approach to patients with this disorder is needed. Bortezomib is a proteasome inhibitor, which has been successfully used for the treatment of multiple myeloma (4). Recently, the efficacy of bortezomib was also observed in a series of patients with newly diagnosed or relapsed PCL (5). Thus, bortezomib-based chemotherapy may be an effective treatment for PCL. In this report, we describe a patient with secondary PCL who achieved a complete remission after combination chemotherapy with bortezomib, cyclophosphamide and dexamethasone.
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CASE REPORT |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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A 33-year-old male patient was diagnosed with multiple myeloma on the basis of a pathologically confirmed plasmacytoma in the thoraco-lumbar spine, plasmacytosis (10.1%) in bone marrow aspirates and monoclonal IgD and lambda gammopathy. The serum creatinine level was within normal range: 0.8 mg/dl. A chromosome study of the bone marrow aspirate showed complex abnormalities: 47, X, –Y, +1, addition (1)(p13), translocation (1;3)(p13;q21), addition (4)(q21), translocation (7;13)(q11.2;p11.2), deletion (10)(p11.2) and +19. Thus, we started combination chemotherapy with vincristine, adriamycin, dexamethasone (VAD) every 3 weeks: vincristine 0.4 mg continuous iv infusion per day for 4 days, adriamycin 9 mg/m2 continuous iv infusion per day for 4 days and dexamethasone 40 mg iv or PO from day 1 to 4, and day 9 to 12. After the second course of the chemotherapy, the serum M-protein decreased to 19.1% of total protein levels. However, the patient developed right upper abdominal pain after the fourth course. Computed tomography (CT) showed a right chest wall mass and hepatomegaly (Fig. 1A). Follow-up bone marrow study showed 26.2% plasma cells. At that time, his complete blood count (CBC) was as follows: leukocyte 4200/mm3 (neutrophil 53%, lymphocyte 40%, monocyte 5%, basophil 2%), hemoglobin 11.1 g/dl, platelet 213 000/mm3. Thus, we started the second-line treatment with thalidomide and dexamethasone (thalidomide 200 mg/m2 PO D1–14, dexamethasone 40 mg PO D1–4). However, the patient's condition rapidly deteriorated, and the right chest wall mass increased. On day 16 after the commencement of thalidomide and dexamethasone treatment, his CBC results were as follows: leukocyte 14 200/mm3 (plasma cell 20%, 2840/mm3), Hgb 6.3 g/dl and platelet count 230 000/mm3. The peripheral blood smear showed plasmacytosis and the bone marrow aspirate showed more than 80% plasma cells that had CD38 and lambda light chain positive expression. Serum LDH and beta-2 microglobulin were also increased, 1231 IU/l and 4.07 mg/l, respectively.
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The final diagnosis for this patient being PCL; salvage chemotherapy was started with bortezomib, cyclophosphamide and dexamethasone: bortezomib 1.3 mg/m2 iv infusion over 3–5 s on days 1, 4, 8 and 11; cyclophosphamide 750 mg/m2 iv on days 1 and 3; dexamethasone 40 mg/m2 iv on days 1–4. After the first course of chemotherapy, the size of the right chest wall mass was significantly reduced and the general health status of the patient was improved. The treatment was repeated every 4 weeks. A follow-up bone marrow study after the second course of chemotherapy showed an absence of plasma cells and the serum immunofixation electrophoresis indicated a disappearance of the monoclonal gammopathy. The chest CT scan revealed complete remission of the chest wall mass (Fig. 1B). The major toxicity was hematologic. A grade III neutropenia and thrombocytopenia were observed around days 10–14. However, they were manageable with granulocyte colony stimulating factor (G-CSF) support and additional dosage modification was not required. Non-hematologic toxicity included gastrointestinal toxicity (grade 1–II nausea) and sensory neuropathy (grade II). The chemotherapy was repeated until the fourth cycle and then the patient received autologous peripheral blood stem cell transplantation (PBSCT) because there was no sibling match or unrelated donor. The conditioning regimen was as follows: bortezomib 1.0 mg/m2 on days 4 and 1, melphalan 50 mg/m2 iv on day 4, melphalan 150 mg/m2 iv on day 1. Peripheral blood stem cells were mobilized by infusion of G-CSF 10 µg/kg for 6 days and the total infused CD34+ cell count was 3.51 x 106/kg and the engraftment was observed at post-transplant day + 23 (absolute neutrophil count > 0.5 x 109/l, platelet count > 20 x 109/l). However, around post-transplant day +90, the disease relapsed again, and the patient eventually died with multi-organ failure as a result of disease progression 2 months later.
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DISCUSSION |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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In this case, PCL developed from an initially diagnosed multiple myeloma during treatment with VAD combination chemotherapy. Thus, this case could be categorized as a secondary PCL. However, because secondary PCL generally occurs as a terminal event, from long-lasting multiple myeloma, this development of PCL, during treatment for multiple myeloma, is an unusual presentation of PCL. It is possible that this form of multiple myeloma might represent a more aggressive intrinsic disease compared to other more common cases of multiple myeloma. At diagnosis of the IgD myeloma, the chromosomal abnormalities found in the bone marrow aspirate were complex; the same chromosomal findings were observed with the development of PCL. In previous reports, the incidence of diploid or hypodiploid karyotypes were higher in PCL than in multiple myeloma; the findings of t(11;14), t(14;16) and monosomy 13 have been found more frequently in PCL (6,7). Although these complex chromosomal abnormalities are not specific findings for PCL development, these chromosomal abnormalities might be related to the development of PCL and the aggressive clinical course of this case. Initially, the type of M protein in our case was IgD; IgD myeloma is a rare subtype of multiple myeloma accounting for 2% of all myeloma subtypes (2). This subtype has a poorer prognosis than other subtypes. Although most reported cases of PCL have shown IgG type M protein, IgD has also been reported in patients with PCL (7). Considering the more aggressive clinical course of IgD myeloma, IgD myeloma might have also influenced our patient's clinical course.
When PCL developed, we performed combination chemotherapy consisting of bortezomib, cyclophosphamide and dexamethasone. We used bortezomib because of its favorable results in patients with refractory multiple myeloma (8). In addition, we added cyclophosphamide to the combination of bortezomib and dexamethasone because cyclophosphamide-based treatment has been reported to show better treatment outcomes in patients with PCL (9,10). We found a rapid and effective response with the commencement of this treatment, and a complete remission was documented after the second course of treatment. The major toxicity observed was neutropenia and thrombocytopenia, which were managed by G-CSF support. Although it is uncertain whether these responses were mainly owing to bortezomib or other agents including cyclophosphamide, our experience suggests that aggressive treatment consisting of bortezomib and cyclophosphamide may be a feasible treatment for PCL. This approach is supported by recent reports demonstrating the efficacy of bortezomib for the treatment of refractory IgD myeloma and PCL (11,12). The combination of bortezomib, cyclophosphamide and dexamethasone similar to our regimen was also recently reported as a well tolerated regimen producing high response rate compared to bortezomib alone and bortezomib plus dexamethasone (13). Therefore, if an appropriate consolidation or maintenance treatment were to follow a successful achievement of remission, it might be possible to prolong the complete remission of PCL, which currently has a dismal prognosis. In summary, we present a rare case of secondary PCL in which combination chemotherapy of bortezomib, cyclophosphamide and dexamethasone led to complete remission. This is the first report about the experience with bortezomib, cyclophosphamide, and dexamethasone in PCL.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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