Thalidomide Administration for the Treatment of Resistant Plasma Cell Leukemia

Plasma cell leukemia (PCL) is a rare plasma cell dyscrasia which may arise de novo or during the course of multiple myeloma (MM) and is then referred to as secondary PCL. Primary and secondary PCL occur in 1.6% of all MM cases. Both types of PCL are resistant to various treatment options similar to those administered to MM patients.Given the low incidence of the disease, only few references are found in the literature and the number of patients enrolled is usually small. In spite of the use of intensive regimens, the survival rates do not exceed 6–8 months [1].Thalidomide, a derivative of glutamic acid, was introduced in therapeutics as a sedative agent with antivomiting action in the late 60s. Because of its teratogenic effects in pregnant women it was soon removed.Recently, it has been again used to treat patients with MM, refractory to other treatments and with limited options for further chemotherapy. The rationale for the administration of thalidomide is its antiangiogenetic and immunomodulatory activity against neoplasias with neovascularization; an additional activity of thalidomide, i.e. induction of apoptosis of newly formed vessels in experimental animal models is being investigated now [2, 3, 4].We describe the results of thalidomide administration to two women with secondary PCL resistant to chemotherapy.A 74-year-old woman with IgGĸ MM, in complete remission since 5 years, was admitted to the hospital because of low back pain and dyspnea. On clinical examination she was pale, she had sinus tachycardia, petechiae and echymoses, while there was no lymphadenopathy or hepatosplenomegaly. She received only monthly cycles of 90 mg pamidronate. Laboratory data on admission were: Hb 7.3 g/dl, Ht 22.5%, WBC 21.5 × 109/l, plasma cells in the peripheral blood smear 38%, platelets 25 × 109/l, creatinine 2.1 mg/dl, urea 87 mg/dl, LDH 825 U/l, β2-M: 6,725 mg/l, Ca2+ 10.8 mg/dl, total protein 11.5 g/l. albumin: 3.8 g/l. Immunoelectrophoresis of serum proteins revealed monoclonal paraprotein IgGĸ. IgG level was 4.5 g/l. A bone marrow aspirate and biopsy revealed 67% infiltration by plasma cells. Six cycles of the chemotherapeutic VAD regimen containing vincristine, Adriamycin and dexamethasone were administered to the patient without any response. During this period, the patient also received recombinant human erythropoietin 10,000 U three times/week and continued monthly infusions of pamidronate. Following the last cycle of VAD, in an attempt to improve hematological parameters and performance status, we administered thalidomide 200 mg daily, orally. Six weeks after the initiation of treatment, her anemia and thrombocytopenia improved while bone marrow infiltration by plasma cells was 20% and the IgGĸ monoclonal component in the serum was 2.1g/l. Eight weeks after the initial administration of thalidomide, her hematological values were: Ht 35%, Hb 11.2 g/dl, WBC 6.7 × 109/l, without evidence of plasma cell infiltration in the peripheral smear and platelets were 125 × 109/l.She remained alive, in good condition with partial response, 14 months after the initiation of thalidomide treatment, and died of sepsis due to Pseudomonas aeruginosa infection. Thalidomide administration was well tolerated except for constipation and sedation.A 46-year-old woman was diagnosed to have nonsecretory MM 6 years ago. She received 18 cycles of the combination regimen melphalan-prednisone and 6 cycles of the VAD regimen containing vincristine, Adriamycin or liposomal doxorubicin and dexamethasone, followed by autologous bone marrow transplantation. After a 19-month disease-free period, she lost weight and presented with fatigue and low grade fever. Her hematological parameters were: Hb 8.7 g/dl, Ht 27.2%, platelets 215 × 109/l, WBC 9.5 × 109/l with 32% plasma cells in the peripheral blood smear. Biochemical parameters were within the normal range except for slightly elevated β2-M levels (4,100 µg/dl), while LDH was 610 U/l. There was no evidence of monoclonal paraprotein in the serum or urine. A bone marrow aspiration and biopsy revealed 95% plasma cell infiltration of the bone marrow. She received four cycles of a chemotherapeutic regimen containing vincristine, liposomal doxorubicin and dexamethasone, without improvement. Treatment with thalidomide 200 mg daily was initiated. Hematological evaluation 6 weeks after the initiation of thalidomide was: Ht 33.5%, platelets 238 × 109/l, WBC: 7.8 × 109/l without evidence of plasma cells in the peripheral smear. Bone marrow aspiration and biopsy revealed plasma cell infiltration 28%. Values of β2-M and LDH returned to normal.No severe toxicity due to thalidomide administration was observed; the only side effects were mild sedation and sensory neuropathy, but without influence in the quality of life and daily activities. She remains in partial response 19 months after the initiation of thalidomide administration while she continues treatment.PCL is a rare plasma cell dyscrasia which arises de novo or during the course of MM. Survival rates are low, because the disease has an aggressive course; the maximum survival is 8–10 months; there is no effective and generally accepted treatment for the disease. Since PCL is a rare disease and the series of patients small, current knowledge about treatment comes from studies concerning aggressive forms of MM.Beneficial effects have been described with the administration of high-dose melphalan and the VAD regimen [1, 5]. Recently, promising results have been described following thalidomide administration to patients with melphalan- and doxorubicin-resistant MM [5, 6].As indicated in a recent publication by Hideshima et al. [7], thalidomide acts by inducing apoptosis, or arresting G1 growth phase. Thalidomide also inhibits tumor necrosis factor-α (TNFα), which in turn inhibits (vascular endothelial growth factor (VEGF). VEGF as well as endothelial growth factor (EGF) cause proliferation and enhance migration of MM cells as well as PCL cell lines. VEGF seems also to play a significant role in the progression of MM to PCL because it induces more than 100-fold PCL cell migration, while it induces only a 2-fold activation of MM cells. Another antitumor activity of thalidomide consists of increasing IL-10 production, modulation and enhancement of cell-mediated immunity by direct stimulation of cytotoxic T cells [5, 6, 8, 9].These references indicate that there is a different mechanism of action of thalidomide against PCL cells. The absence of severe myelosuppression and other side effects related to high doses of chemotherapy administered to PCL patients suggest that thalidomide may be an ideal drug for patients with PCL in whom other therapeutic options have failed.The adverse effects of thalidomide, such as sedation, dizziness constipation or neuropathy, appear minor compared with its beneficial effects, i.e. induction of partial remission with a good quality of life for the two patients with chemotherapy resistant PCL.