A. Muñoz

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.

Megatherapy in children with high-risk Ewing's sarcoma in first complete remission

To improve the prognosis of patients with metastatic or high-risk localized sarcoma in first CR, we explored the role of consolidation therapy with megatherapy and hematopoietic rescue. From 1986 to 1995, of 72 patients with Ewing’s sarcoma from three pediatric departments, 30 were diagnosed as high-risk patients. Of these 30 patients, six did not achieve complete remission and four refused megatherapy and received multimodal treatment (chemotherapy + surgery and/or radio- therapy). The remaining 20 patients received megatherapy. There were 15 males and five females with a median age of 10.8 years (range 2–18 years). Five patients had metastatic disease at initial diagnosis, nine patients had primary tumor in the pelvis and 13 had a tumor volume greater than 100 ml. Overall disease-free survival was 62.7u2009±u200911%; 40u2009±u200921.9% for those with metastatic disease, 76.2u2009±u200912.2% for those with tumor volume greater than 100 ml and 64.8u2009±u200916.5% for those with tumor in pelvic bones. In conclusion, megatherapy has improved the outcome of this group of patients relative to that expected following conventional therapy.

Autologous bone marrow transplantation with monoclonal antibody purged marrow for children with acute lymphoblastic leukemia in second remission

The purpose of this study was to evaluate the outcome of children with acute lymphoid leukemia (ALL) in second remission who have undergone high-dose chemotherapy and radiotherapy and autologous bone marrow transplantation (ABMT) with monoclonal antibody purged marrow, and to determine the main prognostic factors. From 1987 to 1992, 55 children with ALL in second remission underwent ABMT. The conditioning regimen consisted of total body irradiation (TBI) plus cyclophosphamide in 21 patients and TBI plus cyclophosphamide plus cytarabine or VP-16 in 28 patients; the remaining six patients were treated with chemotherapy alone (cyclophosphamide and busulfan, and/or VP-16). The marrow was purged using monoclonal antibodies and complement or magnetic microspheres in all cases. All patients engrafted. Three patients (5%) died early post transplant from infections. Twenty-six patients (47%) relapsed (median 150 days); 26 patients (47%) are alive and in complete remission (CR) at a median of 36 months. The Kaplan–Meier estimation showed a probability of event-free survival (EFS) of 46u2009±u20090.007%. In the univariate analysis, first CR length and conditioning with TBI plus two or more cytotoxic drugs were found to be the most significant predictors of EFS. ABMT with purged marrow is a treatment modality which offers a chance of cure in children with ALL after relapse, including children who relapse early.

Autologous stem cell transplantation for advanced Hodgkin's disease in children

This study evaluates the outcome of myeloablative chemo-radiotherapy and autologous stem cell transplantation (ASCT) in children with Hodgkins disease (HD). Twenty children aged 5 to 18 years (median 10.8 years) at diagnosis, with relapsed, refractory or very poor prognosis HD, underwent ASCT in eight hospitals of our country. Status at transplant was: second complete remission (CR2): nu2009=u200912; further cr (cru2009>2): nu2009=u20093, partial remission (PR): nu2009=u20092, relapse: nu2009=u20092 and first CR (CR1): nu2009=u20091. Eighteen patients received chemotherapy-based conditioning regimens: cyclophosphamide, carmustine and etoposide (CBV): 11 (55%), carmustine, etoposide, cytarabine and melphalan (BEAM): 5, other: 2; and two patients were conditioned with TBI/Cy. Peripheral blood (PB) was the source of progenitor cells in 12 patients, BM in seven, and BM plus PB, in one. All patients engrafted. One patient died of sepsis and multiorgan failure at day 28 after transplantation. All four patients with measurable disease (PR or relapse) at transplantation attained complete remission. Five patients relapsed 5–34 months after transplant (median: 11 months). Eighteen children remain alive with a median survival time of 40 months. The projected 5-year overall survival and event-free survival (EFS) rates were 0.95 and 0.62. High-dose therapy with stem cell rescue can lead to durable remissions in children with advanced HD. Bone Marrow Transplantation (2000) 25, 31–34.

Long-term outcome of allogeneic or autologous haemopoietic cell transplantation for acute lymphoblastic leukaemia in second remission in children. GETMON experience 1983–1998

Summary:We present a retrospective study of long-term outcome and predictive factors of survival and relapse in 219 paediatric patients with acute lymphoblastic leukaemia (ALL) in second remission. They received allogeneic (allo) or autologous (auto) haemopoietic cell transplantation (HCT) depending on the availability of a matched sibling donor. The probability of event-free survival (EFS) for the total patient group was 0.35+0.03 at 14 years. No significant differences were observed for EFS between allo- and auto-HCT: 0.39+0.05 vs 0.32+0.04 (P=0.43). A better EFS was seen in patients with a late relapse (LR) (P=0.06 and 0.02, for allogeneic and autologous respectively). Significantly better EFS was observed in allo-HCT patients under 10 years of age and in auto-HCT patients with leukocytes at diagnosis below 25 × 109/l and late relapse. Predictive factors of failure in both groups were early relapse (ER), medullary relapse and age over 10 years. The probability of relapse (RP) for the total group of patients was 0.57+0.03, and it was significantly higher in auto-HCT patients: 0.65+0.04 vs 0.42+0.06 (P=0.002). Factors predictive for relapse were medullary and early relapse, auto-HCT and WBC >25 × 109/l at diagnosis.

ALLOGENEIC HEMOPOIETIC STEM CELL TRANSPLANTATION FOR CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IN SECOND COMPLETE REMISSION—Similar Outcomes After Matched Related and Unrelated Donor Transplant: A Study of the Spanish Working Party for Blood and Marrow Transplantation in Children (Getmon)

The authors report the results of 58 children with ALL in 2CR after related (n = 31) or unrelated (n = 27) AHSCT. Characteristics at diagnosis and initial and after relapse antileukemic treatment were similar in the related donor (RD) and the unrelated donor (UD) groups. Conditioning consisted of TBI/CY ± VP-16 for patients ≥3 years old (n = 43) and Bu/CY for the rest. Median recipient age was 8 years (range 1–17) in the RD and 9 years (range 3–14) in the UD group. Median follow-up was 54 months (range 24–80) and 52 months (range 22–85) in the RD and the UD groups repectively.The 5-year EFS probability was 43 ± 9% for the RD group and 36 ± 9% in the UD group (p =. 25). The transplant-related mortality was 16% in the RD and 37% in the UD group (p =. 016). In the RD group 36.7% of patients relapsed versus 18.6% in the UD group (p =. 05). GvHD associated with organ failure or infection caused most of the transplant-related deaths in both groups. Survivor quality of life for both groups was good (Lansky score ≤ 90).

ALLOGENEIC HEMOPOIETIC STEM CELL TRANSPLANTATION (HSCT) FOR WISKOTT-ALDRICH SYNDROME: A Report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON)

Allogeneic stem cell transplantation is the only curative treatment for Wiskott-Aldrich syndrome. The authors retrospectively analyzed the outcome with this procedure in 13 patients with severe Wiskott-Aldrich syndrome transplanted in 5 Spanish centers from 1989 to 2006. A patient was transplanted twice from the same donor due to a late engraftment failure. Age at transplant ranged from 7 to 192 months (median 30 months). There were 10 matched donors (3 related and 7 unrelated), 2 mismatched unrelated, and 1 haploidentical. Conditioning regimen consisted of busulfan and cyclophosphamide (BuCy) in 11 cases and fludarabine and melfalan (1) or BuCy (1). ATG was added in transplants from non-genetically matched donors. GvHD prophylaxis consisted of cyclosporine and methotrexate in most patients plus T-cell depletion in the haploidentical HSCT. Nine of the 13 transplanted patients are alive with complete clinical, immunologic, and hematologic recovery 8–204 months (median 101 months) after HSCT. Eight surviving patients had been transplanted from matched donors (3 related and 5 unrelated) and 1 from a haploidentical donor. Four patients died, 2 transplanted from matched donors (1 from acute GvHD and organ failure, 1 from a lymphoproliferative disorder after a second transplant), and 2 transplanted from mismatched unrelated donors (1 from acute GvHD and organ failure, 1 from graft failure and infection). Allogeneic hemopoietic stem cell transplantation must be utilized in all patients with severe Wisckott-Aldrich syndrome, using the most suitable graft variant for each patient.

LONG-TERM RESULTS OF HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS STEM CELL RESCUE FOR HIGH-RISK NEUROBLASTOMA PATIENTS: A Report of the Spanish Working Party for BMT in Children (GETMON)

The authors retrospectively analyzed the long-term outcome of 67 patients over 1 year of age at diagnosis with high-risk neuroblastoma (stage 4 or stage 3 with N-myc amplification) who were treated with megatherapy and stem cell rescue from 1984 to 1998. Median age at transplant was 4 years (range 1.6–15 years). The source of cells was peripheral stem cells in 29 and bone marrow in 38 patients. In 12 patients, an in vitro purging of bone marrow harvest was performed. Most patients were conditioned with melphalan, BCNU, and VM-26. After transplant 19 patients received complementary treatment with IL-2 (16) or 13-cis-retinoic acid (3). Six patients (8%) died from transplant-related toxicity and 39 from disease progression. Three patients were alive with active disease at the time of analysis. Nineteen patients are alive and disease-free at a median follow-up of 104 months. Five-year event-free survival is 0.30. Survival of patients who received a purged graft was not significantly better than the rest. Post-transplant complementary treatment significantly improved overall and event-free survival (p =. 01 and p =. 04, respectively).

Matched-pair analysis comparing allogeneic PBPCT and BMT from HLA-identical relatives in childhood acute lymphoblastic leukemia

This multicenter study was designed to evaluate whether allo-PBPCT provides some advantages, if any, over BMT in terms of engraftment kinetics, acute and chronic GVHD incidence, TRM, relapse incidence and survival in acute lymphoblastic leukemia patients (ALL). From January 1995 to December 1999, 67 ALL patients (34 in the PBPCT group and 33 in the BMT group) were included in this study. Median age for both groups was 8 years (range, 1–18). There were 24 patients in first or second CR in the PBPCT group and 28 such patients in the BMT group. Preparatory regimens were TBI-based in 26/34 in the PBPC group and 25/33 in the BMT group. GVHD prophylaxis was CsA alone in 38 patients (18 PBPCT vs 20 BMT) and CsA plus short Mtx in 29 (16 PBPCT vs 13 BMT). Engraftment was achieved in all cases. Median days to neutrophil recovery was 10 (range, 7–18) after PBPCT vs 14 (range, 9–21) after BMT (P < 0.0001). platelet engraftment (>50 × 109/l) was also faster for PBPCT patients (median 13 days, range, 9–40 vs 23 days, range, 15–165) (P < 0.0001). Acute GVHD grade II–IV incidence was similar in both groups (46.4 ± 8.8% vs 42.7 ± 8.6%) (P = 0.45). Probability of chronic GVHD was 50.6 ± 12.2% after PBPCT vs 27.8 ± 9.2% after BMT (P = 0.1). Probability of relapse was similar (28.7 ± 9.2% for PBPCT vs 27.1 ± 8.2% for BMT) (P = 0.89). There were eight patients who died from transplant-related complications after PBPCT vs 5 after BMT (P, NS). With a median follow-up of 25 months the event-free survival probability was 53 ± 8.9% for PBPCT vs 54.9 ± 9.7% for BMT (P = 0.54). Using PBPC for allogeneic transplantation in childhood ALL results in faster hematopoietic recovery compared to BM, with a similar incidence of aGVHD, TRM, relapse and disease-free survival. However, the issue of cGVHD remains unresolved.

Landscape of early clinical trials for childhood and adolescence cancer in Spain.

PurposeDespite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain.MethodsAll members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center.Results22 phase I and II trials were open as of May 2015: 15 for solid tumors (68xa0%) and 7 for hematological malignancies (32xa0%). Fourteen (64xa0%) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5xa0years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits.ConclusionsClinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer.