Maurizio Miano

Haematopoietic stem cell transplantation trends in children over the last three decades : a survey by the paediatric diseases working party of the European Group for Blood and Marrow Transplantation

This paper describes the trends in haematopoietic stem cell transplantation (HSCT) activity for children in Europe over the last three decades. We analysed 31 713 consecutive paediatric HSCTs reported by the European Group for Blood and Marrow Transplantation (EBMT) centres between 1970 and 2002. Data were taken from the EBMT registry and were compared according to period and centre category (paediatric or combined). Since 1996, there has been a significant increase in the number of HSCTs performed exclusively by paediatric centres, as well as in the number of alternative donor HSCTs, and in the use of peripheral blood stem cells (P<0.0001). The number of allogeneic HSCTs (allo-HSCTs) for acute lymphoblastic leukaemia, acute myeloblastic leukaemia and chronic myeloid leukaemia remained stable, whereas it increased for myelodysplastic syndromes and lymphomas, and decreased significantly for non-malignant diseases (P<0.0001). Multivariate analysis showed that younger age, human leukocyte antigen genoidentical donors, HSCT performed after 1996 and transplant centres performing more than 10 allo-HSCT/year were all associated with decreased transplant-related mortality (TRM) (P<0.0001). The number of autologus HSCTs (auto-HSCTs) for acute leukaemia decreased significantly, whereas it increased for solid tumours (P<0.0001). Multivariate analysis showed that both auto-HSCT performed before 1996 and paediatric solid tumours (P<0.0001) had higher TRM. Indications for paediatric HSCT have changed considerably during the last seven years. These changes provide tools for decision making in health-care planning and counselling.

Stem cell transplantation from HLA-matched related donor for Fanconi's anaemia: a retrospective review of the multicentric Italian experience on behalf of Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)–Gruppo Italiano Trapianto di Midollo Osseo (GITMO)

Twenty‐seven consecutive Italian patients with Fanconis anaemia (FA) underwent stem cell transplantation (SCT) from an HLA‐matched related donor in 10 Italian centres of the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP), Gruppo Italiano di Trapianto di Midollo Osseo (GITMO). Twenty‐two patients (81·5%) were conditioned with low‐dose (median 20 mg/kg) cyclophosphamide (Cy) and thoraco‐abdominal or total body irradiation (median dose 500 cGy), five patients (18·5%) with high‐dose Cy (median 120 mg/kg). Graft‐vs.‐host disease (GVHD) prophylaxis was carried out with cyclosporin A in 26 cases; methotrexate (MTX) was added in eight cases. One patient received MTX alone. The median follow‐up was 36 months. Ninety‐two percent of patients (25 out of 27) engrafted, grade II and III acute GVHD occurred in 28% and 8% of patients, respectively, with chronic GVHD in 12·5%. Conditioning‐related toxicity was mild: 4% of patients had grade III mucositis, 7·4% had grade II haemorrhagic cystitis, 14·8% had grade III liver toxicity and 11·1% had grade III renal toxicity. Transplant‐related mortality at 12 months was 19·2%, survival at 36 months was 81·5%, with a median Karnofsky score of 100%. No late tumours occurred after a mean follow‐up of the survivors of 5 years. None of the studied variables significantly affected the survival, including conditioning regimen, acute GVHD and clinical non‐haematological phenotype. Among the studied variables, only conditioning regimens containing high‐dose Cy and the presence of genital abnormalities were significantly (P < 0·05) associated with an increased rate of acute GVHD. Our study demonstrates that the Italian FA patients undergoing SCT from an HLA‐matched related donor have a very good outcome. These patients, when compared with others of different ethnic origin who underwent allogeneic bone marrow transplantation, showed a less severe non‐haematological phenotype, raising the possibility that this milder phenotype may have, at least in part, contributed to the outcome. Our data may provide a useful tool for further studies aiming to correlate genotype with phenotype.

Four year follow-up of a case of fucosidosis treated with unrelated donor bone marrow transplantation

Fucosidosis is a rare autosomal recessive lysosomal disorder caused by α-fucosidase deficiency. We report a child with fucosidosis, second daughter of non-consanguineous parents, for whom biochemical diagnosis followed clinical evidence of the disease in her older sister. Based on previous experiences, the indication to transplant was considered. Since she lacked a matched sibling, an unrelated marrow donor was found. At pre-hematopoietic stem cell transplantation evaluation, first signs of neurological involvement were clinically detectable. MRI showed diffuse hypomyelination and auditory brainstem responses and somatic-sensorial evoked potentials were altered. Visual evoked potentials were normal, tortuosity in the retinal veins and peripapillary hemorrhages were detected. Bone marrow transplantation conditioning was with a regimen of busulphan, thiotepa and cyclophosphamide; in vivo Campath 1G, cyclosporin A and short course methotrexate were given to prevent graft-versus-host disease. The patient engrafted rapidly and her post-transplant course was complicated by moderate graft-versus-host disease, transient episodes of idiopathic thrombocytopenic purpura, repeated septic complications and recurrent episodes of Sweets syndrome. Sequential short tandem repeat polymorphisms on peripheral blood and bone marrow cells documented the persistence of donor engraftment. Follow-up showed a progressive rise of enzymatic levels. Psychomotor development improved, as confirmed by evaluation of evoked potentials and by MRI scanning. Bone Marrow Transplantation (2001) 27, 747–751.

Megatherapy combining I131 metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma

Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has very poor prognosis which is estimated at 25%. Metabolic radiotherapy with I131 MIBG appears a feasible option to enhance the effects of chemotherapy. Seventeen patients having MIBG-positive residual disease received 4.1–11.1 mCi/kg of I131 MIBG 7–10 days before initiating the high-dose chemotherapy cycle consisting of busulphan 16 mg/kg and melphalan 140 mg/m2 followed by PBSC infusion. We compared the toxicity in these patients to that seen in 15 control subjects with neuroblastoma who underwent a PBSC transplant without MIBG therapy. We observed greater toxic involvement of the gastrointestinal system in children treated with I131 MIBG: grade 2 or 3 mucositis developed in 13/17 patients treated with I131 MIBG and in 9/15 treated without it. Grade 1–2 gastrointestinal toxicity occurred in 12/17 children given MIBG and in 5/15 of the controls. One child receiving I131 MIBG developed transient interstitial pneumonia. Another child who also received I131 MIBG after PBSC rescue developed fatal pneumonia after the third course of metabolic radiotherapy. Our experience indicates that MIBG can be included in the high-dose chemotherapy regimens followed by PBSC rescue for children with residual neuroblastoma taking up MIBG. Attention should be paid to avoiding lung complications. Prospective studies are needed to demonstrate the real efficacy of this treatment. Bone Marrow Transplantation (2001) 27, 571–574.

Risk of complications during hematopoietic stem cell collection in pediatric sibling donors: a prospective European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party study.

We investigated prospectively factors influencing the safety of hematopoietic stem cell (HSC) collection in 453 pediatric donors. The children in the study donated either BM or peripheral blood stem cells (PBSCs) according to center policy. A large variability in approach to donor issues was observed between the participating centers. Significant differences were observed between BM and PBSC donors regarding pain, blood allotransfusion, duration of hospital stay, and iron supplementation; however, differences between the groups undergoing BM vs PBSC donation preclude direct risk comparisons between the 2 procedures. The most common adverse event was pain, reported mainly by older children after BM harvest, but also observed after central venous catheter (CVC) placement for PBSC collection. With regard to severe adverse events, one patient (0.7%) developed a pneumothorax with hydrothorax after CVC placement for PBSC collection. The risk of allotransfusion after BM harvest was associated with a donor age of < 4 years and a BM harvest volume of > 20 mL/kg. Children < 4 years were at higher risk than older children for allotransfusion after BM harvest and there was a higher risk of complications from CVC placement before apheresis. We conclude that PBSC and BM collection are safe procedures in children.

Early complications following haematopoietic SCT in children

Early complications can be defined as those occurring within 100 days after transplant. Both epithelial and endothelial damage represent the pathogenetic basis for the onset of the most frequent complications. Clinical features related to endothelial damage depend on the involved district or on the grade and type of general distribution. Veno-occlusive disease (VOD) most often occurs within the first 20 days of haematopoietic SCT (HSCT) and is characterized by the obstruction of small intrahepatic venules and is caused by an initial injury of the sinusoid endothelial cells. The incidence in children ranges between 27 and 40%, and symptoms include hepatomegaly, portal hypertension and ascites. Early intervention with defibrotide (DF) proved to be effective for the treatment; however, overall mortality ranges between 20 and 50%. Thrombotic microangiopathy (TAM) incidence is 4–13%. It is often associated with the use of CYA or tacrolimus, and symptoms include haemolytic anaemia, thrombocytopenia and renal and/or central nervous system impairment. Treatment includes plasmapheresis and supportive care. The promising role of DF needs to be confirmed. The onset of engraftment syndrome may occur 1 or 2 days before the neutrophil count in peripheral blood increases. Clinical symptoms include fever not related to infection, respiratory involvement with pulmonary infiltrates or hypoxia and skin rash. Treatment consists of steroid administration for a few days. Haemorrhagic cystitis (HC) may occur early or later following transplant. Early-onset HC is related to mucosal damage caused by the catabolites of chemotherapy drugs, and late-onset HC is mostly caused by viral infections. The incidence ranges between 1 and 25%. Clinical symptoms include haematuria and dysuria without infections. Treatment includes hyperhydration and platelet support. In case of vescical clots, bladder irrigation is indicated. In advanced cases, hyperbaric oxygen administration or surgery may be useful. The use of cidofovir for BK virus-related HC seems encouraging, but further studies are needed to confirm its real efficacy.

Diagnostic potential of hepcidin testing in pediatrics

Hepcidin, a peptide hormone released by hepatocytes into circulation is the main regulator of dietary iron absorption and cellular iron release. Although commercial tests are available, assay harmonization for hepcidin has not been yet reached, making reference intervals and consequent clinical decisions still elusive for each assay and specific population. The aim of this study is to set up hepcidin measurement in pediatric age and to investigate its potential usefulness in the diagnosis and management of iron disorders in children.

Daclizumab as useful treatment in refractory acute GVHD: a paediatric experience

GVHD remains a serious complication after allogeneic SCT. We describe 13 paediatric patients treated with daclizumab for refractory acute GVHD (aGVHD). After 30 days of daclizumab administration, all patients with cutaneous aGVHD reached complete response. Among patients with gastrointestinal disease, 50 and 30% had complete and partial response, respectively, whereas 11 and 55% of patients with hepatic aGVHD achieved CR and PR, respectively. Overall, complete (46%) and partial (46%) responses were demonstrated in 92% of our patients, whereas the remaining patients (8%) were nonresponders. No life-threatening infectious episodes were recorded within 100 days from transplant in this selected group of paediatric patients. Overall 46% of patients were alive at a median of 461 days from SCT, but 50% of them developed chronic GVHD. In our experience, daclizumab proved to be a useful and safe treatment for refractory and steroid-resistant/dependent aGVHD, in particular for cutaneous and low-moderate intestinal involvement.

How I manage Evans Syndrome and AIHA cases in children.

The management of Evans Syndrome in children is challenging due to the lack of evidence‐based data on treatment. Steroids, the first‐choice therapy, are successful in about 80% of cases. For children who are resistant, relapse or become steroid‐dependent, rituximab is considered a valid second‐line treatment, with the exception of those with an underlying diagnosis of autoimmune lymphoproliferative syndrome who may benefit from other options such as mycophenolate mofetil and sirolimus. Better knowledge of the immunological mechanisms underlying cytopenias and the availability of new immunosuppressive drugs can be helpful in the choice of more targeted therapies that would enable the reduction of the use of long‐term steroid administration or other more aggressive options, such as splenectomy or stem cell transplantation. This manuscript provides an overview of the pathogenic background of the disease, and suggests a clinical approach to diagnosis and treatment with a particular focus on the management of relapsing/resistant disease.

Clofarabine, cyclophosphamide and etoposide for the treatment of relapsed or resistant acute leukemia in pediatric patients

Abstract Clofarabine is a promising new chemotherapeutic agent that is active in the treatment of pediatric acute leukemia. Forty children (16 with acute myeloid leukemia [AML], 24 with acute lymphoblastic leukemia [ALL]), aged 1–20 years (median 7.6 years) with relapsed or refractory ALL or AML were treated because of resistance to first-line treatment (n =5), or for first (n =22), second (n =11) or third relapse (n =2). They received clofarabine (40 mg/m2/day) associated with etoposide (100 mg/m2/day) and cyclophosphamide (440 mg/m2/day) administered as one or two induction cycles (5 days of chemotherapy) in an attempt to reach complete remission (CR) or CR without platelet recovery (CRp). This was followed by 1–3 consolidation cycles (4 days of chemotherapy) for a maximum of four cycles. Seven (44%) out of 16 and 10 (42%) out of 24 evaluable children with AML and ALL, respectively, responded to treatment. The most common adverse events were infections and gastrointestinal and hepatic toxicity. Thirteen (76%) out of 17 responders underwent hematopoietic stem cell transplant. The 24-month overall survival was 25%, while it was 59% among patients who responded to the first induction cycle. Our study suggests that this drug regimen is well tolerated and can be effective in heavily pretreated pediatric patients with relapsed or refractory acute leukemia.