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Myeloma DCEP (Dexamethasone, Cyclophosphamide, Etoposide, and Cisplatin) Is an Effective Regimen for Peripheral Blood Stem Cell Collection in Multiple Myeloma

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Myeloma DCEP (Dexamethasone, Cyclophosphamide, Etoposide, and Cisplatin) Is an Effective Regimen for Peripheral Blood Stem Cell Collection in Multiple Myeloma Bone Marrow Transplantation (2001) 28, 835–839 2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Myeloma DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) is an effective regimen for peripheral blood stem cell collection in multiple myeloma M Lazzarino1, A Corso1, L Barbarano2, EP Alessandrino1, R Cairoli2, G Pinotti3, G Ucci4, L Uziel5, F Rodeghiero6, S Fava7, D Ferrari8, M Fiumano`9, G Frigerio10, L Isa11, A Luraschi12, S Montanara12, S Morandi13, D Perego14, A Santagostino15, M Savare`16, A Vismara17 and E Morra2 1Division of Hematology, IRCCS Policlinico S Matteo, University of Pavia, Italy; 2Division of Hematology, Ospedale Niguarda, Milano, Italy; 3Division of Oncology, Varese, Italy; 4Division of Oncology, Lecco, Italy; 5Division of Oncology, Milano S Paolo, Italy; 6Division of Hematology, Vicenza, Italy; 7Division of Internal Medicine 2, Legnano, Italy; 8Division of Internal Medicine, Abbiategrasso, Italy; 9Division of Oncology, Sondrio, Italy; 10Division of Internal Medicine, Como, Valduce, Italy; 11Division of Oncology, Gorgonzola, Italy; 12Division of Oncology, Verbania, Italy; 13Division of Hematology, Cremona, Italy; 14Division of Internal Medicine, Desio, Italy; 15Division of Oncology, Vercelli, Italy; 16Division of Internal Medicine, Magenta, Italy; and 17Division of Internal Medicine 2, Rho, Italy Summary: grams for multiple myeloma. Bone Marrow Transplan- tation (2001) 28, 835–839. DCEP (dexamethasone, cyclophosphamide, etoposide, Keywords: peripheral stem cell; mobilization; myeloma; and cisplatin) has proved to be an effective salvage ther- chemotherapy; purging in vivo apy for refractory-relapsed MM patients. Little is known, however, about its potential as mobilizing ther- apy. The aim of this study was to evaluate the efficacy of DCEP in mobilizing PBSC and to define its toxicity. Peripheral blood stem cell (PBSC) transplantation follow- Fifty-five MM patients received DCEP followed by G- ing high-dose chemotherapy represents an integral part of CSF as part of high-dose programs including autolog- front-line therapy in patients with multiple myeloma.1,2 ous transplantation. At the time of mobilization, 40 Many studies have tried to define the optimal number of patients had previously received VAD only, and 15 CD34+ stem cells for rapid hematopoietic reconstitution alkylating agents. Mobilization was successful after PBSC transplantation. A number ranging between 2.0 minimum number of CD34+ cells 2 ؋ 106/kg) in 48/55 and 5.0 ϫ 106/kg has been reported to be sufficient for) patients (87%), and 41/55 patients (75%) collected Ͼ4 engraftment.3–5 Unfortunately, not all patients mobilize an ؋ 106/kg CD34+ cells. Of the seven patients who did adequate number of PBSC to receive intensive conditioning not mobilize stem cells, five (71%) had been previously regimens safely. The combination of high-dose cyclophos- exposed to alkylating agents. The median number of phamide (HDCTX) with hematopoietic growth factors is -CD34+ cells harvested was 5.8 ؋ 106/kg (range 2.1–22.4). considered the standard mobilizing protocol to collect per There was no treatment-related mortality. The side- ipheral blood stem cells.6–8 HDCTX, however, is associated effects of DCEP were always tolerable. No neutropenia with several side–effects such as nausea, emesis, neutro- Ͻ1000/␮l nor thrombocytopenia Ͻ50000/␮l were penic fever, sepsis, cardiac dysfunction, and hemorrhagic observed. No patient required transfusion as a conse- cystitis, with mortality rates of 1% to 2%.7,8 In addition, quence of therapy, or hospitalization for septic HDCTX has limited activity against the myeloma clone complications. In conclusion, DCEP, in addition to its with little improvement of response after three or four demonstrated anti-tumor activity, is an effective regi- cycles of VAD in newly diagnosed patients.2 men for mobilizing peripheral blood progenitor cells in Tumor contamination of the graft is another crucial prob- myeloma patients, with little or no side-effects. These lem. As collection and reinfusion of monoclonal plasma properties render DCEP a useful regimen for the cells might be associated with a shorter disease-free sur- debulking and mobilization phase of high-dose pro- vival, a reduction of tumor contamination of the autograft through positive selection of CD34+ cells has been pro- posed.9–12 Whether the CD34 antigen is present on MM progenitor cells is still debated and, so far, there is no con- Correspondence: Prof M. Lazzarino, Division of Hematology, IRCCS clusive evidence that purging of graft reduces the risk of Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy relapse or progression in multiple myeloma patients. On the Received 7 June 2001; accepted 13 August 2001 other hand, it is known that in vitro purging techniques DCEP in multiple myeloma M Lazzarino et al 836 cause stem cell loss and depletion of T and B lymphocytes Becton Dickinson, San Jose, CA, USA) for 15 min at 20°C, from the graft, with consequent delayed immune recovery then lysed with a lyse-no-wash standard assay and finally and increased infectious complications in transplanted incubated for 10 min at 4°C. Cells were processed with patients.9,13,14 To reduce tumor contamination of the graft, FACSort analyzer (Becton Dickinson). Data acquisition an alternative is to improve in vivo debulking using more was performed with Cellquest software (Becton intensive chemotherapy programs during the mobilizing Dickinson). phase.15 We used a combination of dexamethasone, cyclo- phosphamide, etoposide and cisplatin (DCEP) with the aim Cryopreservation of treating myeloma and at the same time mobilizing PBSC. The rationale was: (1) DCEP has proved to be an Cells, diluted in dimethylsulfoxide (DMSO) solution at a effective and well tolerated regimen for refractory MM final DMSO concentration of 10%, were frozen to −160°C patients; (2) the side-effects of this combination are accept- by means of a KRYO II Series freezer (Planer R203) at able even in the fragile setting of refractory patients; (3) a controlled rate and then stored in the liquid phase of schemes including cisplatin, in association with G-CSF, nitrogen. have been reported as good mobilizing protocols in cancer patients. To our knowledge, this is the first study on DCEP Statistical analysis as a mobilizing regimen in multiple myeloma patients. The aim of this study was to evaluate its efficacy in mobilizing Continuous variables are reported as median and range, and stem cells and to define its toxicity. categorical variables as count and relative frequency. For each dichotomized clinical parameter, analysis of variance (ANOVA) techniques were used to test for a difference in Materials and methods the mean numbers of collected CD34+ cells between the two groups of patients defined according to the clinical Patients parameter. Because of the small sample size, no multivari- Between January 2000 and February 2001, 55 patients (30 ate analysis was carried out. Fisher’s exact test was used males and 25 females) with myeloma received DCEP to assess the association between dichotomous clinical + (dexamethasone, cyclophosphamide, etoposide, and parameters and a yield of CD34 cells below the threshold cisplatin) in 4-day infusions followed by G-CSF as part of of 4 ϫ 106/kg. The dichotomous parameters significantly + high-dose programs including autologous transplantation. associated with a yield of CD34 cells below the threshold + The median age was 54 years (range 30–68). Of 55 patients, were then considered as risk factors for a low CD34 col- 40 had previously received VAD only, and 15 alkylating lection. Finally, the number of risk factors present in each agents. Patients were restaged at the start of DCEP. The patient was used to build a scoring system to predict an + stages by Durie and Salmon criteria were as follows: 36 inadequate yield of CD34 cells. All tests were two-tailed, patients stage I; six stage II; 13 stage III. With the aim of with a significance level P р 0.05. identifying factors correlated with the number of CD34+ cells mobilized, the therapeutic history of the patients and the following clinical and laboratory parameters at the start Results of DCEP were evaluated: stage, interval from first treatment to DCEP, previous exposure to alkylating agents, type of M The clinical and laboratory characteristics of patients and component, Bence–Jones proteinuria, skeletal involvement, prior chemotherapy history are reported in Table 1. Of the age, WBC and platelet counts, hemoglobin level, bone mar- 55 patients, 15 (27%) had been previously exposed to row plasmacytosis, creatinine, urea. WBC and platelet counts, hemoglobin level, creatinine, and urea were evalu- ated as categorical variables with respect to the normal Table 1 Characteristics of patients at the start of DCEP ranges. We used a cut-off of 50% for bone marrow plasma- cytosis, and of 6 months as interval from first treatment Number of patients 55 to DCEP. Male/Female 30/25 Age 54 (30–68) Patients received DCEP (dexamethasone 40 mg for 4 Type of MC days, and 4-day continuous infusion of daily doses of IgG 38 cyclophosphamide 400 mg/m2, etoposide 40 mg/m2, cispla- IgA 10 tin 10 mg/m2) as mobilizing therapy, followed by hemopo- BJ 6 ␮ NS 1 ietic growth factor (G-CSF 5 g/kg/day) starting 48 h after Hb g/dl 11.6 ± 1.75 the end of chemotherapy. PBSC were collected with a con- WBC/109/l 6.2 ± 2.7 tinuous-flow blood cell separator (Spectra, COBE BCT, Platelets/109/l (mean ± s.d.) 251 ± 94.8 Lakewood, CO, USA), processing a total volume per Bone marrow involvement Ͼ50% 15 (27%) leukapheresis of two to three blood mass volumes. Prior exposure to alkylating agents 15 (27%) Disease stage at the start of DCEP I 36 (65%) Flow cytometry II 6 (11%) III 13 (24%) Aliquots of the leukapheresis products were incubated with Months from first treatment to DCEP 4 (2–54) phycoerythrin-conjugated monoclonal anti-CD34 (HPCA2, Bone Marrow Transplantation DCEP in multiple myeloma M Lazzarino et al 837 alkylating agents.
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