Juvenile myelomonocytic leukemia presenting with features of neonatal hemophagocytic lymphohistiocytosis and cutaneous juvenile xanthogranulomata and successfully treated with allogeneic hemopoietic stem cell transplant.

Juvenile xanthogranuloma (JXG) is rarely associated with either hemophagocytic lymphohistiocytosis (HLH) or juvenile myelomonocytic leukemia (JMML) and when in association with the latter there is usually neurofibromatosis type 1. We report a child who presented with JXG and HLH during the neonatal period and who subsequently developed JMML during early infancy in whom there is no evidence of neurofibromatosis type 1. The patient was refractory to standard HLH therapy but he is well and is now 42 months after mismatched unrelated donor hemopoietic stem cell transplant without evidence of HLH or JMML. His JXG lesions show involution, in keeping with the expected natural history of this disorder.

Use of enzyme replacement therapy (Laronidase) before hematopoietic stem cell transplantation for mucopolysaccharidosis I: experience in 18 patients.

We describe the use of enzyme replacement therapy in conjunction with hematopoietic stem cell transplantation in 18 consecutive patients with severe mucopolysaccharidosis type I. The survival and engraftment rate was 89% overall and 93% for the 15 patients who received full-intensity conditioning.

Treosulfan-containing regimens achieve high rates of engraftment associated with low transplant morbidity and mortality in children with non-malignant disease and significant co-morbidities.

Treosulfan is an immuno-suppressive and myeloablative alkylating agent that has been introduced as a conditioning agent in stem cell transplantation (SCT). Most studies have been performed in adult patients with malignancy where a low incidence of regimen-related toxicity has been reported. We report the use of treosulfan in 32 consecutive children undergoing SCT for non-malignant disease. Patients received a total treosulfan dose of 36 or 42 g/m(2)/patient given in three daily, divided doses. A range of other conditioning agents and serotherapy was administered to patients who underwent family donor SCT (n = 11), or unrelated donor SCT (n = 21). One patient (3%) died early. Transplant morbidity was limited and mucositis was only mild. Dermatological toxicity was frequent but mild. Twenty-eight patients (87.5%) established donor cell engraftment. In 25 patients (78%) there was adequate, stable donor engraftment. Four patients have required additional transplant procedures to maintain adequate donor-derived haemopoiesis. Twenty-seven patients (84%) survive with a median follow up of 417 d. There were four late deaths due to progression of the underlying disease, graft-versus-host disease or infection. Treosulfan-based conditioning regimens achieve excellent engraftment with reduced regimen-related toxicity in children with non-malignant disease at high risk for both regimen-related toxicity and graft failure.

Improved outcome from invasive adenovirus infection in pediatric patients after hemopoietic stem cell transplantation using intensive clinical surveillance and early intervention.

Adenovirus is a common cause of morbidity and mortality after hemopoietic stem cell transplantation in children. Recently the incidence, risk factors, and outcome of such infections have been better defined using improved virologic detection methods, in particular polymerase chain reaction. We have introduced intensive virologic surveillance for adenovirus in our institution including at least weekly polymerase chain reaction testing of blood and stool samples. We report on 71 prospectively monitored transplants, including 40 from unrelated donors. In total, there were 8 cases of invasive adenovirus infection, 3 of whom died. Mortality was less than in previous studies as cases were managed with antiviral chemotherapy and reduction of immune suppression. In fatal cases, there was concurrent difficult graft versus host disease making withdrawal of immune suppression therapy impossible. We describe 2 cases of graft failure in association with adenovirus viremia and its treatment that were successfully managed with further donor cell infusion.

A cross-linker-sensitive myeloid leukemia cell line from a 2-year-old boy with severe Fanconi anemia and biallelic FANCD1/BRCA2 mutations.

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital and developmental abnormalities, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), and strong predisposition to acute myeloid leukemia (AML). In this article, we describe clinical and molecular findings in a boy with a severe FA phenotype who developed AML by the age of 2. Although he lacked a strong family history of cancer, he was subsequently shown to carry biallelic mutations in the FANCD1/BRCA2 gene. These included an IVS7 splice-site mutation, which is strongly associated with early AML in homozygous or compound heterozygous carrier status in FA-D1 patients. Myeloid leukemia cells from this patient have been maintained in culture for more than 1 year and have been designated as the SB1690CB cell line. Growth of SB1690CB is dependent on granulocyte macrophage colony stimulating factor or interleukin-3. This cell line has retained its MMC sensitivity and has undergone further spontaneous changes in the spectrum of cytogenetic aberrations compared with the primary leukemia. This is the second AML cell line derived from an FA-D1 patient and the first proof that malignant clones arising in FA patients can retain inherited MMC sensitivity. As FA-derived malignancies are normally not very responsive to treatment, this implies there are important mechanisms of acquiring correction of the cellular FA phenotype that would explain the poor chemoresponsiveness observed in FA-associated malignancies and might also play a role in the initiation and progression of cancer in the general population.

Retrovirally mediated correction of bone marrow-derived mesenchymal stem cells from patients with mucopolysaccharidosis type I.

We have investigated the utility of bone marrow-derived mesenchymal stem cells (MSCs) as targets for gene therapy of the autosomal recessive disorder mucopolysaccharidosis type IH (MPS-IH, Hurler syndrome). Cultures of MSCs were initially exposed to a green fluorescent protein-expressing retrovirus. Green fluorescent protein-positive cells maintained their proliferative and differentiation capacity. Next we used a vector encoding alpha-L-iduronidase (IDUA), the enzyme that is defective in MPS-IH. Following transduction, MPS-IH MSCs expressed high levels of IDUA and secreted supernormal levels of this enzyme into the extracellular medium. Exogenous IDUA expression led to a normalization of glycosaminoglycan storage in MPS-IH cells, as evidenced by a dramatic decrease in the amount of (35)SO(4) sequestered within the heparan sulfate and dermatan sulfate compartments of these cells. Finally, gene-modified MSCs were able to cross-correct the enzyme defect in untransduced MPS-IH fibroblasts via protein transfer.