New Consecutive High-Dose Chemotherapy Modality with Fractionated Blood Stem Cell Support in the Treatment of High-Risk Pediatric Solid Tumors: a Feasibility Study
Total Page：16
File Type：pdf, Size：1020Kb
Bone Marrow Transplantation, (1998) 21, 147–151 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 New consecutive high-dose chemotherapy modality with fractionated blood stem cell support in the treatment of high-risk pediatric solid tumors: a feasibility study T Kajiume1,2, Y Kawano1, Y Takaue1, T Abe1, T Watanabe1, Y Okamoto1, A Makimoto1, K Suenaga1, H Suzuya1, J Sato1, A Yokobayashi2, T Hashimoto3, K Yoshida3, H Ishibashi3, H Takehara3, S Tashiro3 and Y Kuroda1 Departments of 1Pediatrics and 3Surgery I, University of Tokushima, Kuramoto-cho, Tokushima; and 2Department of Pediatrics, Kawasaki Medical School, Kurashiki, Japan Summary: Keywords: solid tumor; children; transplantation; CD34+ cells For the treatment of childhood solid tumors, we perfor- med a pilot feasibility study of consecutive high-dose therapies, in which each course was followed by trans- plantation with granulocyte colony-stimulating factor- Despite the fact that childhood solid tumors are generally mobilized peripheral blood cells which had been separ- chemosensitive and that multimodality therapy has signifi- ated into CD34-positive and -negative fractions by an cantly improved the outcome, subgroups continue to do Isolex system (Baxter). Positive selection of CD341 cells poorly. Poor prognostic features include metastasis and a has been associated with inevitable cell loss. To over- bulky primary tumor. Long-term survival is extremely rare come this loss, CD341 cells that had migrated into the for patients who have primary refractory or relapsed dis- negative fraction were saved and used for the first trans- ease. These problems may be solved through the use of plant, which was followed by a second transplant after high-dose chemotherapy, especially in patients with chemo- a 3- to 5-month interval. In this phase I feasibility study, sensitive tumors, since the effectiveness of anticancer ther- the results in six children were evaluated for safety and apy depends on both the dose intensity of chemotherapy engraftment. Multi-drug cytoreductive regimens using and the timing of drug administration.1 Dose intensity can ranimustine (MCNU), melphalan, thiotepa, carboplatin, be improved either by increasing the dosage of the drug cyclophosphamide or VP-16 were comparable between given at the same intervals, by reducing the delay between the two transplant procedures in terms of their inten- each cycle, or by using stem cell transplantation support. sity. The number of CD341 cells in the ‘CD34(1) frac- At present, the efficacy of autologous bone marrow trans- tion’ was 3.31 × 106/kg (0.63–4.3 × 106/kg), while this plantation (ABMT) is unresolved for most pediatric number in the ‘CD34(2) fraction’ could not be evalu- tumors,2 although its superiority over regular chemotherapy ated correctly due their scarcity (,0.1%). The median has been suggested in some patient subgroups.3 Autologous numbers of infused MNC and CFU-GM were, respect- transplants are associated with the inherent disadvantage ively, 4.2 3 106/kg and 1.75 3 105/kg in the CD34(1) of cancer cell contamination in the graft. To improve the fraction, and 4.8 3 108/kg and 3.35 3 105/kg in the therapeutic efficacy by removing contaminating cancer CD34(2) fraction. The number of days required to achi- cells from autografts, positive selection of blood CD34+ eve an ANC .0.5 3 109/l and a platelet count cells has been widely used. However, major drawbacks of .20 3 109/l and .50 3 109/l were, respectively, 14.5, this strategy include a variable period of cytopenia due to 15.0 and 19.5 in the first transplant with CD342 cells, inevitable cell loss and a high cost. and 13.5, 18.0 and 25.0 in the second transplant with To improve the outcome in children with solid tumors CD341 cells, with no essential difference between the associated with poor prognostic factors with intensifying two treatments. Although the small number of patients, chemotherapy, we initiated a strategy of administering mul- the variation in clinical status and treatment, and the tiple ‘mini-transplants’ given in rapid succession, each with short follow-up invalidate any evaluation of the thera- the support of peripheral blood stem cells (PBSC). peutic benefit of this strategy, the encouraging results In particular, we evaluated a new consecutive-autograft support the feasibility of this strategy, which enables an concept, in which cells that had been recovered in the escalation of dose intensity with an improved CD34-negative fraction are used in the initial transplant. cost/benefit ratio. The basic idea for this study was that the intensity of treat- ment can be increased by the use of cells in the CD34- negative fraction, which still contains a large number of + Correspondence: Dr Y Takaue, Department of Pediatrics, University CD34 cells. To overcome the possible infusion of malig- Hospital of Tokushima, Kuramoto-cho 3, Tokushima 770, Japan nant cells, patients then received a second and final trans- + Received 19 May 1997; accepted 25 August 1997 plant with CD34 cells that had been indirectly depleted of New consecutive high-dose therapy modality T Kajiume et al 148 malignant cells. New methods in cancer therapy should be Collection and isolation of blood cells critically evaluated before they are incorporated into routine practice. In this respect, the end-point of evaluation in this In two patients, aphereses were performed in the recovery pilot feasibility study in six children with high-risk solid phase of consolidation chemotherapy with 50–200 mg/m2 tumors was safety and the recovery of hematopoiesis. We of recombinant human granulocyte colony-stimulating fac- believe that the results of this small study may contribute tor (G-CSF; filgrastim, Kirin Brewery Co, Tokyo, Japan). to the development of strategies for clinical application of The remaining patients were mobilized by G-CSF alone (10 enriched CD34+ cells. mg/kg/day for 5 days). Details of the procedure for col- lecting blood cells have been described elsewhere.4–7 Briefly, a Fenwal CS-3000 Plus cell separator (Baxter Limited, Deerfield, IL, USA) was operated using a small- Materials and methods volume collection chamber (SVCC) and a granulocyte chamber to process 100–350 ml of blood per kg body Patients weight. Cells were recovered in 50-ml suspension. Cells were then isolated with the Isolex 50 system Six patients (one of each with ovarian tumor, testicular (Baxter Limited) according to the manufacturer’s instruc- tumor, retinoblastoma, rhabdomyosarcoma, brain tumor tions. Briefly, cells were incubated with 0.5% human g- and Wilms’ tumor) were enrolled into this study with the globulin (Polyglobin N; Bayer Japan, Tokyo, Japan) con- written consent of the patients or their parents. This study taining PBS for 15 min to block intact Fc-receptors on the was approved by the Institutional Review Board. There cell surface. After incubation, cells were washed with PBS were four males and two females, and the patients ranged containing 1% HSA and incubated with anti-CD34 mono- in age from 1 to 16 years (median, 9.5 years). All of the clonal antibody (9C5; Baxter) at a cell/antibody ratio of patients received surgery, and their characteristics and a 106/0.5 g. After 30 min of incubation at 4°C with gentle detailed history of previous therapy are summarized in rotation (4/min), cells were washed three times with PBS Table 1. Associated poor-prognosis factors included mul- and resuspended in IMDM with 1% HSA at 1–2 × 107/ml. tiple metastases (n = 3), recurrent tumor (n = 3) and wide The anti-CD34 antibody-coated cells were incubated with local invasion (n = 1). All of these patients were considered sheep anti-mouse IgG1-coated microspheres (Dynabeads; to be eligible for this experimental consecutive high-dose Dynal Corporation, Oslo, Norway) for 30 min with rotation, therapy protocol. and cells which were bound to the beads were then col- Table 1 Patient characteristics Case Age/Sex Diagnosis Risk factors/Previous therapy Conditioning regimen Interval (months) No. First transplant Second transplant Dx (recurrence) 1st/2nd with CD34(2) fr with CD34(1) fr to PBSCT transplant 1 10/F Ovarian tumor Recurrent abdominal CBDCA (1.6 g/m2) CBDCA (1.2 g/m2)9 3 (immature teratoma) dissemination, multiple VP-16 (0.6 g/m2) VP-16 (0.6 g/m2) pulmonary metastases/CBDCA, CY (50 mg/kg) L-PAM (70 mg/m2) VP-16, pirarubicin 2 16/M Testicular tumor Stage IV, inoperable wide CBDCA (1.6 g/m2) CBDCA (1.2 g/m2)6 4 (yolk sac tumor) invasion refractory to therapy VP-16 (1.2 g/m2) VP-16 (0.6 g/m2) with VCR, CBDCA and CY (50 mg/kg) L-PAM (140 mg/m2) pirarubicin 3 11/F Bilateral Recurrent metastatic tumor 6 CBDCA (1.6 g/m2) CBDCA (1.2 g/m2)3 3 retinoblastoma years after surgery and VP-16 (1.2 g/m2) VP-16 (0.6 g/m2) radiation therapy CY (50 mg/kg) L-PAM (210 mg/m2) 4 1/M Rhabdomyosarcoma Multiple pulmonary CBDCA (1.2 g/m2) CBDCA (1.2 g/m2)5 5 (shoulder, embryonal metastases/actinomycin-D, VP-16 (0.6 g/m2) VP-16 (0.6 g/m2) type) cisplatinum, VP-16, CY and L-PAM (120 mg/m2) Thiopeta (250 pirarubicin THP-ADR (50 mg/m2) mg/m2) 5 5/M Brain tumor (yolk Recurrent tumor after CBDCA (1.6 g/m2) CBDCA (1.2 g/m2)3 4 sac tumor) surgery/CBDCA and VP-16 VP-16 (1.2 g/m2) VP-16 (1.2 g/m2) IFO (6 g/m2) MCNU (220 mg/m2) 6 9/M Wilms’ tumor Multiple pulmonary and brain L-PAM (210 g/m2) CBDCA (1.2 g/m2)8 5 (nephroblastoma, metastases/actinomycin-D, VP-16 (0.6 g/m2) favorable) VCR, doxorubicin, cisplatinum L-PAM (210 mg/m2) M = male; F = female; Dx = diagnosis; CBDCA = carboplatinum; VP-16 = etoposide; CY = cyclosphosphamide; L-PAM = melphalan; ADR = doxorub- icin; IFO = ifosphamide; MCNU = ranimustine.