Unique Familial MLL(KMT2A)-Rearranged Precursor B-Cell Infant Acute Lymphoblastic Leukemia in Non-twin Siblings.

BACKGROUND: Infant acute lymphoblastic leukemia (ALL) has never occurred in families except for the ∼100% concordant cases in monozygous twins attributed to twin-to-twin metastases. We report the first kindred with infant ALL in non-twin siblings. The siblings were diagnosed with MLL-rearranged (MLL-R) ALL 26 months apart. The second affected sibling had an unaffected dichorionic monozygous co-twin. Both had fatal outcomes. PROCEDURES: Translocations were characterized by karyotype, FISH, multiplex FISH, and MLL breakpoint cluster region (bcr) Southern blot analysis. Breakpoint junctions and fusion transcripts were cloned by PCR. TP53 mutation and NADPH quinone oxidorecuctase 1 (NQO1) C609T analyses were performed, and pedigree history and parental occupations were ascertained. The likelihood of chance occurrence of infant ALL in non-twin siblings was computed based on a binomial distribution. Zygosity was determined by single nucleotide polymorphism (SNP) array. RESULTS: The translocations were not related or vertically transmitted. The complex karyotype of the proband's ALL had chromosome 2, 3, 4, and 11 abnormalities causing a 5'-MLL-AFF1-3' fusion and a non-productive rearrangement of 3'MLL with a chromosome 3q intergenic region. The affected twin's ALL exhibited a simple t(4;11). The complex karyotype of the proband's ALL suggested a genotoxic insult, but no exposure was identified. There was no germline TP53 mutation. The NQO1 C609T risk allele was absent. The likelihood of infant ALL occurring in non-twin siblings by chance alone is one in 1.198 × 10(9) families. CONCLUSIONS: Whether because of a deleterious transplacental exposure, novel predisposition syndrome, or exceedingly rare chance occurrence, MLL-R infant ALL can occur in non-twin siblings. The discordant occurrence of infant ALL in the monozygous twins was likely because they were dichorionic.

Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors.

BACKGROUND: Survival of pediatric patients with malignant germ cell tumors has improved dramatically with the use of cisplatin-based chemotherapy, though patients are at high risk of significant long-term complications. In a prospective study, carboplatin was substituted for cisplatin in an attempt to minimize nephro- and oto-toxicities, while achieving excellent disease-free survival. PROCEDURE: All consecutive patients with malignant germ cell tumors at The Children's Hospital of Philadelphia were treated between 1989 and 1998. After pathologic confirmation of disease and pretreatment evaluation of pulmonary, renal, and otologic function, patients received etoposide 150 mg/m(2) days 1, 2, 3; carboplatin 600 mg/m(2) day 2; and bleomycin 10 mg/m(2) day 3 for at least four courses. RESULTS: Twenty-three patients were entered for study, and were available for evaluation. All patients achieved either a complete or partial remission following therapy with surgery and chemotherapy. With a median of 58 months of follow-up, overall survival is 91% and event-free survival is 87%. Therapy was given as an outpatient, and well tolerated, with 20 admissions for fever and neutropenia. Ototoxicity and nephrotoxicity, when evaluated, have been extremely limited. Three patients, all with stage III disease, have relapsed; one of these remains alive and disease free. CONCLUSIONS: Carboplatin can successfully substitute for cisplatin during the treatment of pediatric germ cell tumors without sacrificing response or survival. Long-term effects, especially nephrotoxicity and ototoxicity, were rare or mild among the small number of patients evaluated. Carboplatin appears to be a safe and efficacious alternative in the treatment of germ cell tumors, and should be considered as primary therapy for pediatric patients.