Case Report Plasma Cell Leukemia 3 Months After Autologous Blood Cell Transplantation for Multiple Myeloma

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Case report Plasma cell leukemia 3 months after autologous blood cell transplantation for multiple myeloma

K Koskela1,2, T-T Pelliniemi3, T Lakkala4 and K Remes1

Departments of 1Medicine, 3Hematological Laboratory and 4Medical Genetics, Turku University Central Hospital; and 2MediCity Research Center, Turku, Finland

Summary: cally identified plasma cells in the peripheral blood. The patient was examined further and the diagnosis of multiple We describe a patient with multiple myeloma who was myeloma was established in November 1995. The parapro- treated with intensive therapy and autologous blood cell tein was IgG-kappa (31.5 g/l). Bone marrow aspiration transplantation as her first-line treatment. The disease showed 90% infiltration with plasma cells with atypical relapsed 3 months after the transplant as plasma cell morphology. There were several osteolytic bone lesions in leukemia and the patient succumbed in 4 weeks. We the thoracic spine and ribs. The concentrations of serum suggest that an aggressive plasma cell clone may be calcium and creatinine were normal. The disease was selected during the course of intensive treatment. Com- staged III A because of the anemia and bone lesions. plex karyotypic findings are also presented. The patient was treated with three cycles of VAD Keywords: multiple myeloma; intensive therapy; auto- (vincristine + adriamycin + dexamethasone) chemotherapy logous stem cell transplantation; autologous blood cell and oral clodronate. Her myeloma responded well to ther- transplantation; karyotypic analysis apy. Stem cell mobilization with cyclophosphamide 1.2 g/m2 followed by filgrastim 300 ␮g s.c. daily resulted in successful stem cell harvest (5.8 × 106/kg CD34+ cells) 3 months after the diagnosis. Intensified first-line treatment with autologous stem cell After an additional VAD course the patient was found rescue has been shown to improve survival in multiple to be in clinical remission: less than 5% plasma cells in 1 myeloma in comparison to conventional chemotherapy. bone marrow, and serum IgG concentration 8.6 g/l. She However, until now no patient has been reported to be underwent a high-dose treatment with melphalan cured of his/her disease and relapses occur after a median 140 mg/m2 and 12 Gy total body irradiation in five frac- 2 of 2.5 years post-transplant. Some patients may relapse tions. Stem cells were reinfused in March 1996. She reco- quite soon after the intensive treatment which raises the vered well, blood neutrophils reached a level Ͼ1 × 109/l on question about a possible survival and proliferative advan- day +11 and platelets Ͼ20 × 109/l on day +10, and she was tage of the most aggressive myeloma cell clone. Supporting discharged on day +13 post-transplant. this view we report a patient with multiple myeloma who In July 1996, 3 months after ABCT, the patient was underwent intensive therapy with autologous blood cell examined because of nausea, general malaise and leg pains. transplantation (ABCT) as her first-line therapy and who Blood Hb concentration was 124 g/l, platelets 23 × 109/l relapsed in plasma cell leukemic phase 3 months post-trans- and WBC 14.6 × 109/l of which 35% were plasma cells. plant. Serum creatinine concentration was 198 ␮mol/l (normal Ͻ100 ␮mol/l), serum total calcium concentration 4.61 mmol/l (Ͻ2.47), and ionized calcium 2.52 mmol/l (Ͻ1.32). Case report Serum lactate dehydrogenase was 5085 U/l (Ͻ450), IgG Ͻ ␤ Ͻ 25.6 g/l ( 15), 2-microglobulin 8.8 mg/l ( 2.4), and urate The patient was a 42-year-old female, previously in good 886 ␮mol/l (Ͻ340). Serum C-reactive protein was normal physical health. She had a prolonged respiratory tract infec- (Ͻ10 mg/l). There was progression in osteolytic bone tion and myalgias in autumn 1995. Routine laboratory tests lesions. Ultrasonography showed liver infiltrate, and para- revealed anemia, blood hemoglobin (Hb) concentration was aortic lymph node enlargement was seen by nuclear mag- 88 g/l, and erythrocyte sedimentation rate was raised to netic imaging. More than 95% of bone marrow was infil- × 9 140 mm/h. White blood cell count (WBC) was 9.6 10 /l trated by anaplastic pleomorphic plasma cells. Bone mar- with normal differential count and without any morphologi- row and peripheral blood cell immunophenotyping showed 81% and 72% B-B4+, and 91% and 22% CD38bright+ cells, Correspondence: Dr K Koskela, Turku University Central Hospital, Dept respectively, which is consistent with plasma cell mor- of Medicine, Kiinamyllynkatu 4-8, FIN- 20520 Turku, Finland phology. Flow cytometric DNA analysis revealed two Received 3 June 1997; accepted 25 August 1997 aneuploid peaks, one hypodiploid (DNA index 0.92) and Plasma cell leukemia after ABCT K Koskela et al 306 one hyperdiploid (DNA index 1.57) in bone marrow and remissions, but in general myeloma is still an incurable dis- peripheral blood. ease.3,4 The high relapse rate most evidently reflects the Chromosome analysis of bone marrow showed only unsuccessful long-term eradication of the disease with high- abnormal cells. Two different clones were seen; one was dose treatment. Further, myeloma cell contamination of hypodiploid with 42 chromosomes and the other hypertri- stem cell grafts, even when harvested from blood, may be ploid with 71 chromosomes. The karyotype of the a contributing factor.5 To reduce the risk of reinfusion of hypodiploid clone was: 42,X,−X,add(1)(p32),der(1;19) myeloma cells, purification of the blood grafts with stem (q10;p10), add(2)(p21),−4, add(4)(qter), del(6)(q23), der(9) cell (CD34 cell) selection has been introduced.6 t(1;9) (q21; p24), del(12) (p13), ins (13;?) (q21?), +?del(13) Our patient relapsed exceptionally early after intensive (q?14q?32),−14,−15,−21. Complete karyotype of the hyper- treatment with ABCT rescue. In the retrospective series of triploid clone is shown in Figure 1. the EBMT, the median duration of relapse-free survival for The patient was treated with the VAD regimen but no patients in complete remission post-transplant was 29 response was achieved. She had severe infection and gen- months.2 In some patients, response duration was very short eralized hemorrhagic diathesis and died 30 days after diag- which has raised the possibility that high-dose treatment nosis in relapse. In autopsy massive gastrointestinal bleed- selects a resistant cell clone with high proliferative capacity ing was detected. Microscopic analysis showed plasma cell and unopposed growth pattern. In our case, this clone had infiltrates in lymph capillaries, kidneys, liver, spleen, bone the characteristics of plasma cell leukemia. marrow and dura mater. Lymph node enlargement was The modal chromosome numbers seen in the two clones not seen. are in agreement with the flow cytometric DNA analysis. In vitro culture of mononuclear cells from the relapsed Abnormalities of chromosome 1, and deletions of chromo- marrow was undertaken. At present, spontaneous in vitro somes 6 and 13 are frequent findings in multiple myeloma growth of clonal lymphoblastoid cells has been continuing but no chromosome abnormality has been demonstrated to for more than 10 months. be specific or consistent in plasma cell disorders or plasma cell leukemia.7 Discussion Plasma cells have low proliferative capacity, and previously human myeloma cell lines could only be estab- Intensive treatment of multiple myeloma with allogeneic or lished from cells originating in extramedullary plasma- autologous stem cell rescue has introduced a few durable cytomas, pleural fluid or plasma cell leukemias.8 Also, in

Figure 1 Karyotype of the hypertriploid bone marrow cell from a patient with plasma cell leukemia. The abnormal clone is: 71,XX,−X, der (1;19)(q10;p10), +der(1;19)(q10;p10), add(2)(p21), add(2)(p21), −4, del(6)(q23), +del(6)(q23),+7,+8, der(9)t(1;9)(q21;p24), der(9)t(1;9) (q21;p24),+11, del(12)(p13), del(12)(p13), ins(13;?)(q21;?), +?del(13)(q?14q?32), +?del(13)(q?14?32), −14,−15, −18, add(20)(p12), +add(20) (p12),−21, −21,+22. The changes common for both hypodiploid and hyper-triploid clones are shown in bold. Plasma cell leukemia after ABCT K Koskela et al ¨ 307 our case, an in vitro cell line was established indicating a 2 Bjorkstrand B, Goldstone AH, Ljungman P et al. Prognostic major growth potential of these highly malignant cells. factors in autologous stem cell transplantation for multiple The treatment of post-transplant relapse may be a thera- myeloma: an EBMT registry study. Leuk Lymphoma 1994; 15: peutic dilemma because of the apparent resistance of the 265–272. malignant clone. In a recent analysis of 94 such relapses, 3 Gahrton G. Allogeneic bone marrow transplantation in multiple myeloma. Br J Haematol 1996; 92: 251–254. however, further salvage treatment was beneﬁcial for most ¨ Ͼ 4 Bjorkstrand B, Ljungman P, Svensson H et al. Allogeneic of the patients; a late relapse ( 12 months) after the pre- bone marrow transplantation vs autologous stem cell trans- 9 ceding autotransplant was a favorable prognostic factor. In plantation in multiple myeloma: a retrospective case-matched agreement with the poor treatment outcome of our patient, study from the European Group for Blood and Marrow Trans- the treatment results of primary or secondary plasma cell plantation. Blood 1996; 88: 4711–4718. leukemia have been reported to be dismal with median sur- 5 Mariette X, Fermand J-P, Brouet J-C. Myeloma cell contami- vivals of only few months.10 nation of peripheral blood stem cell grafts in patients with We conclude that on some occasions an aggressive, multiple myeloma treated by high-dose therapy. Bone Marrow highly resistant myeloma cell clone may be spared by inten- Transplant 1994; 14: 47–50. sive therapy and stem cell rescue. Plasma cell leukemia 6 Schiller G, Vescio R, Freytes C et al. Transplantation of CD34+ peripheral blood progenitor cells after high-dose represents an extreme of these cases with disappointing chemotherapy for patients with advanced multiple myeloma. treatment outcome. The incidence of rapidly progressive Blood 1995; 86: 390–397. disease post-transplant remains to be evaluated in both mul- 7 Zandecki M, Lai J-L, Facon T. Multiple myeloma: almost all tiple myeloma and also other disease entities receiving patients are cytogenetically abnormal. Br J Haematol 1996; high-dose therapies. 94: 217–227. 8 Klein B. Cytokine, cytokine receptors, transduction signals, and oncogenes in human multiple myeloma. Semin Hematol References 1995; 32: 4–19. 9 Tricot G, Jagannath S, Vesole DH et al. Relapse of multiple 1 Attal M, Harousseau J-L, Stoppa A-M et al. A prospective, myeloma after autologous transplantation: survival after sal- randomized trial of autologous bone marrow transplantation vage therapy. Bone Marrow Transplant 1995; 16: 7–11. and chemotherapy in multiple myeloma. New Engl J Med 10 Kosmo MA, Gale RP. Plasma cell leukemia. Semin Hematol 1996; 335: 91–97. 1987; 24: 202–208.