Miguel Ángel Ruiz Díaz

Comparison of peripheral blood progenitor cell mobilization in patients with multiple myeloma : high-dose cyclophosphamide plus GM-CSF vs G-CSF alone

The best method for peripheral blood progenitor cell (PBPC) mobilization in patients with multiple myeloma (MM) remains controversial. We report the results of two different methods of PBPC collection for autologous transplantation in 40 patients with stage II or III MM. In group I (n = 18), HD-CY, 4 g/m2 i.v., was administered followed by GM-CSF, 8 μ g/kg/day s.c., until the end of collection, starting the leukaphereses after hematological recovery (>1 × 109/l WBC). In group II (n = 22), G-CSF, 10 μ g/kg/day s.c., was used alone until the last day of collection, starting consecutive aphereses on the 5th day. A minimum of two aphereses were performed to collect at least 2 × 106/kg CD34+ cells. Both patient groups were comparable for age, sex and clinical prognostic features as well as previous therapies. In group I, the median yields per pheresis were: MNC 1.47 (1.38–2.32) × 108/kg, CFU-GM 0.82 (0.18–13.2) × 104/kg and CD34+ cells 1.98 (0.96–6.96) × 106/kg. In group II these results were: MNC 2.44 (2.06–3.6 × 108/kg) (P = 0.03), CFU-GM 0.75 (0.16–7.8) × 104/kg and CD34+ 1.05 (0.32–3.4) × 106/kg (P = 0.02). The median number of aphereses performed in each group was 5 (4–12) with a median of 5.24 ± 2.51 in group I and 3 (2–6) with a median of 3.1 (±0.91) in group II (P = NS). Hospitalization for PBPC mobilization was required in all patients in group I and the treatment-related toxicity was greater in this group: 12 patients (66%) developed fever requiring antibiotics during the neutropenic period after HD-CY and six (33%) patients required transfusion support. After receiving busulfan 12 mg/kg p.o. and melphalan 140 mg/m2 i.v., as the conditioning regimen, the median periods to reach granulocytes (>0.5 × 109/l) and platelet (>20 × 109/l) engraftment were 12 and 11 days respectively (ranges 8–20 and 10–16) in group I (HD-CY plus GM-CSF group), and 11 and 13 days respectively (ranges 7–42 and 10–38) in group II (G-CSF group) (P = NS). In conclusion, these data suggest that although HD-CY plus GM-CSF is superior to G-CSF alone based on mean CD34+ cell yield per pheresis, adequate CD34+ cell collections can be achieved with G-CSF alone in most MM patients with less toxicity and with simplification of the procedure.

Analysis of factors associated with low peripheral blood progenitor cell collection in normal donors

BACKGROUND: Predictive factors of the response to rHuG–CSF in normal donors have not been extensively studied.

High-dose chemotherapy with autologous stem cell rescue for children with high risk and recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors

Current treatment for high risk and recurrent medulloblastoma (MB) and supratentorial primitive neuroectodermal tumors (stPNET) has a very poor prognosis in children. High dose chemotherapy (HDCT) and autologous stem cell rescue have improved survival rates. We present 19 patients (thirteen classified in the high risk group and six patients with recurrent disease) that received HDCT and autologous stem cell rescue.In the high risk group [Med Pediatr Oncol 38 (2002) 83], all patients underwent neurosurgical debulking. Standard chemotherapy was prescribed in 10 patients. Radiotherapy was given to 4 patients (all older than 4 years old). In the recurrence disease group [Childs Nerv Syst 15 (1999) 498], five patients underwent surgery. Radiotherapy was given to those who were not previously irradiated. The HDCT in twelve patients consisted of busulfan 4 mg/kg/day, orally over 4 days in 6-hourly divided doses and melphalan at a dose of 140 mg/m2/day by intravenous infusion over 5 min on day −1. Three patients additionally received thiotepa 250 mg/m2/day intravenously over 2 days and four patients additionally received topotecan 2 mg/m2/day over 5 days by intravenous infusion over 30 min. The other seven patients received busulfan and thiotepa at the same doses.Patient’s stem cells were mobilized with granulocyte colony-stimulating factor at a dose of 12 μg/kg twice daily subcutaneously for four consecutive days. Cryopreserved peripheral blood progenitor cells were re-infused 48 h after completion of chemotherapy. With a median follow-up of 34 months (range 5–93) eight complete responses and one partial response were observed. Three patients died of treatment-related toxicities (15%). The 2 year event-free survival was 37.67 ± 14% in all patients and 57 ± 15% for the high risk group.Therefore we conclude that HDCT may improve survival rates in patients with high risk/recurrent MB and stPNET despite treatment toxicity.

High-dose busulfan/melphalan as conditioning for autologous PBPC transplantation in pediatric patients with solid tumors

We conducted a prospective pilot study to assess the feasibility and safety of high-dose busulfan/melphalan as conditioning therapy prior to autologous PBPC transplantation in pediatric patients with high-risk solid tumors. From January 1995 to January 1999, 30 patients aged 2–21 years (median 8) were entered into the study. There were 14 females and 16 males. Diagnoses included neuroblastoma in 10 patients; Ewing’s sarcoma and peripheral neuroectodermal tumor (PNET) in 15 patients and rhabdomyosarcoma in five patients. Treatment consisted of busulfan 16 mg/kg, orally over 4 days (from days −5 to −2) in 6 hourly divided doses, and melphalan at a dose of 140 mg/m2 given by intravenous infusion over 5 min on day −1. G-CSF mobilized PBPC were used as autologous stem-cell rescue. One patient developed a single generalized convulsion during busulfan therapy. The most relevant non-hematologic toxicity was gastrointestinal, manifesting as grade 2–3 mucositis and diarrhea in 12 patients. Two patients died of procedure-related complications, one from veno-occlusive disease of liver and multiorgan failure and the other from adult respiratory distress syndrome. Probability of treatment-related mortality was 6.6 ± 4.5%. With a median follow-up of 18 months (range, 1–48), 19 patients are alive and disease-free, the actuarial EFS at 4 years being 55 ± 12% for the whole group. We conclude that high-dose busulfan/melphalan for autologous transplantation in children with solid tumors is feasible even in small patients. It is well-tolerated, with an acceptable transplant-related mortality and has proven antitumor activity.

Donor age-related differences in PBPC mobilization with rHuG–CSF

BACKGROUND: Data on the administration of rHuG–CSF to normal donors <18 years old are very limited.

Administration of recombinant human granulocyte colony-stimulating factor to normal donors: results of the Spanish National Donor Registry. Spanish Group of Allo-PBT.

A Spanish National PBPC Donor Registry has recently been established for short- and long-term safety data collection in normal donors receiving rhG-CSF. To date, 466 donors have been included in the Registry. Median (range) dose and duration of rhG-CSF administration was 10 μg/kg/day (4–20) and 5 days (4–8), respectively. Donors underwent a median of two aphereses (range, 1–5). Adverse effects consisted mainly of bone pain (90.2%), headache (16.9%) and fever (6.1%), but no donor discontinued rhG-CSF prematurely due to toxicity. Side-effects were more frequent in donors receiving >10 μg/kg/day than in those with lower doses (82.8% vs 61.8%; P = 0.004). A significant decrease between baseline and post-apheresis platelet counts was the most important analytical finding (229 × 109/l vs 140 × 109/l; P < 0.0001), with a progressive reduction in platelet count with each apheresis procedure. one donor developed pneumothorax that required hospitalization due to central venous line placement. the mean cd34+ cell dose collected was 6.9 × 106/kg (range, 1.3–36), with only 14 donors (2.9%) not achieving a minimum target of CD34+ cells of 2 × 106/kg. No definitive information about potential long-term side effects is yet available. However, we hope this National Registry will serve as a useful basis for better monitoring of the efficiency and side-effects of cytokine administration in healthy people.

Follow-up of healthy donors receiving granulocyte colony-stimulating factor for peripheral blood progenitor cell mobilization and collection. Results of the Spanish Donor Registry

Information about the long-term follow-up and safety of granulocyte colony-stimulating factor administration to healthy donors is limited. Findings of this study indicate that clinical side effects are generally mild, and that development of secondary hematologic malignancy is unlikely. Background Information about the long-term follow-up and safety of granulocyte colony-stimulating factor administration to healthy donors is limited. The aims of this study were to analyze the side effects of granulocyte colony-stimulating factor administration in donors included in a Spanish Registry of hematopoietic stem cell donors and to determine the long-term outcome of these donors. Design and Methods The Spanish National Donor Registry was developed to record the short- and long-term results of granulocyte colony-stimulating factor administration to mobilize peripheral blood progenitor cells in normal donors. To date, 1436 donors (771 males, 665 females) with a median age of 37 years (range, 1 to 74 years) have been registered. Granulocyte colony-stimulating factor was the only cytokine administered. A baseline investigation was performed in every donor before granulocyte colony-stimulating factor administration and follow-up investigations (controls) were planned at 4 weeks and annually thereafter for up to 5 years after the mobilization. Results At least one of the scheduled controls was performed in 736 donors, while 320 donors have been followed for 2 years or more. The peripheral white blood cell count decreased significantly from 6.8×109/L at baseline to 5.9×109/L at 4 weeks after leukapheresis (p<0.0001) and remained at values lower than those observed premobilization until 2 years after mobilization. In contrast, hemoglobin concentration and platelet count returned to normal values within 1 year after mobilization. Bone pain (90%) and headache (33%) were the most frequently reported granulocyte colony-stimulating factor-related side effects. Five patients (0.68%) were diagnosed as having solid tumors (lung cancer in two patients and thyroid carcinoma, choroid melanoma, and colon carcinoma in one patient each) between 10 and 64 months after administration of granulocyte colony-stimulating factor. No hematologic malignancies have been reported. Conclusions The clinical side effects of granulocyte colony-stimulating factor administration in healthy donors are generally mild. Changes in blood counts were minimal and mainly affected white blood cell counts, which returned to normal values within 2 years after granulocyte-colony stimulating factor administration. No patient developed a hematologic malignancy. A larger number of donors and longer follow-up are needed to determine the safety of granulocyte colony-stimulating factor administration definitively.

Collection and transplantation of peripheral blood progenitor cells mobilized by G-CSF alone in children with malignancies

Results of collection and transplantation of peripheral blood progenitor cells (PBPC) mobilized by G‐CSF in 31 children with different malignancies were analysed. A total of 43 aphereses were performed, following administration of granulocyte colony‐stimulating factor (G‐CSF), using a continuous flow blood cell separator (Cobe Spectra) through a central venous catheter. For patients weighing ≤25 kg the extracorporeal line was primed with red blood cells. The mean blood flow rate was 33.2ml/min (range 12–56ml/min). The mean number of mononuclear cells (MNC), granulocyte‐macrophage colony‐forming units (CFU‐GM) and CD34+ cells collected were 7.22×108/kg body weight (b.w.), 15.9×104/kg and 5.44×106/kg respectively.

Observational prospective study of viral infections in children undergoing allogeneic hematopoietic cell transplantation: a 3-year GETMON experience

We studied surveillance, incidence and outcome of viral infections in children undergoing allogeneic hematopoietic cell transplantation (HCT) in the main pediatric transplant units in Spain. We prospectively collected data from first year post-HCT in every consecutive allogeneic HCT performed during 3 years (N=215): first HCT=188 and second HCT=27; median age=6.6 years (0.1–20.7). Most patients had acute leukemia (N=137) and 135 recipients (63%) were CMV seropositive. A total of 46 patients underwent cord blood transplant, 133 patients underwent HCT from alternative donors (62%) and 101 patients received anti-thymocyte globulin. Observational time was completed in 137 patients, whereas the remaining 78 died after a median survival time of 99 days (3–352). CMV was monitored in all patients; adenovirus (ADV) and human herpesvirus 6 (HHV-6) were monitored in 101 and 33 patients, respectively. We found 145 viral infections in 103 patients: CMV (n=42), ADV (n=32), HHV-6 (n=7), polyomavirus (n=20), EBV (n=6), VZV (n=17) and others (n=8). CMV infection was significantly higher in seropositive patients (25 vs 7%) (P=0.02). Extensive chronic GVHD (cGVHD) was significantly associated with an increased rate of viral infections (12 of 16 patients with cGVHD had infections vs 91 of 199 without GVHD) (P=0.035). In total, 10 patients (4.6%) died of viral infections (CMV=5, ADV=3, respiratory=2). We found a high incidence of viral infection, but mortality was low.

Unrelated cord blood transplantation for severe combined immunodeficiency and other primary immunodeficiencies

HCT is currently the treatment of choice for children with severe primary immunodeficiencies (PIDs). Frequently, these patients lack an HLA-identical sibling donor, and umbilical cord blood (UCB) transplantation may be an option; however, experience in this field remains scant. Fifteen children with PID (SCID 11, X-linked lymphoproliferative syndrome 2, Omenns syndrome 1, Wiskott–Aldrich syndrome 1) received a UCB transplant. The donor was unrelated in 14 cases and related in 1. Median age at transplant was 11.6 months (range, 2.9–68.0) and median weight 7 kg (range, 4–21). Thirteen patients were conditioned with busulphan and cyclophosphamide and 2 with fludarabine and melphalan. Nine patients received antithymocyte globulin. Median NC × 107/kg infused was 7.9 (range, 2.9–25.0) and median CD34 × 105/kg 2.9 (range, 1.0–7.9). All patients engrafted. Median days to >0.5 × 109/l neutrophils was 31. Eight patients developed acute graft-versus-host disease (GvHD) grades II–IV and one chronic GvHD. Viral and fungal infections were frequent. Four patients died: three from GvHD grade IV complicated by infection and one from progressive interstitial lung disease. Five-year survival was 0.73±0.12. All surviving patients presented complete immunologic reconstitution. No patient is intravenous immunoglobulin (IVIg) replacement therapy-dependent. UCB transplantation is a valid option for children with PID who lack an HLA-identical sibling donor.