April D. Sorrell

Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971

Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution. Later development of acute myeloid leukemia (AML) occurs in some. Prospective enrollment (n = 135) elucidated the natural history in Down syndrome (DS) patients diagnosed with TMD via the use of uniform monitoring and intervention guidelines. Prevalent at diagnosis were leukocytosis, peripheral blast exceeding marrow blast percentage, and hepatomegaly. Among those with life-threatening symptoms, most (n = 29/38; 76%) received intervention therapy until symptoms abated and then were monitored similarly. Organomegaly with cardiopulmonary compromise most frequently led to intervention (43%). Death occurred in 21% but only 10% were attributable to TMD (intervention vs observation patients: 13/14 vs 1/15 because of TMD). Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively. On the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms, 3 groups were identified with differing survival: low risk with neither finding (38%), intermediate risk with hepatomegaly alone (40%), and high risk with both (21%; overall survival: 92% ± 8%, 77% ± 12%, and 51% ± 19%, respectively; P ≤ .001). Among all, AML subsequently occurred in 16% at a median of 441 days (range, 118-1085 days). The trial is registered at http://www.clinicaltrials.gov as NCT00003593.

Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial

The Childrens Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (+/- 1.8%) and to MP was 79.0% (+/- 2.1%; P = .004 log rank), although overall survival was 91.9% (+/- 1.4%) and 91.2% (+/- 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m(2) per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m(2) (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.

Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: a report from the Children's Oncology Group.

Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent outcomes while avoiding toxicity, the Childrens Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard‐timing regimen of dexamethasone, cytarabine, 6‐thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Childrens Cancer Group [CCG] 2891).

Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes

As with most genetic cancer predisposition syndromes, inherited susceptibility to myelodysplastic syndrome (MDS) and acute leukemia (AL) is likely to be more common than previously appreciated. As next-generation sequencing technologies become integrated into clinical practice, we anticipate that the number of cases of familial MDS/AL identified will increase. Although the existence of syndromes predisposing to MDS/AL has been known for some time, clinical guidelines for the screening and management of suspected or confirmed cases do not exist. Based on our collective experience caring for families with these syndromes, we propose recommendations for genetic counseling, testing, and clinical management. We welcome discussion about these proposals and hope that they will catalyze an ongoing dialog leading to optimal medical and psychosocial care for these patients.

Tumor Protein p53 (TP53) Testing and Li-Fraumeni Syndrome

Prevalent as an acquired abnormality in cancer, the role of tumor protein p53 (TP53) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53-targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.

Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome : current status of clinical applications and future directions.

Prevalent as an acquired abnormality in cancer, the role of tumor protein p53 (TP53) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53-targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.

Bioavailability and Pharmacokinetic Features of Etoposide in Childhood Acute Lymphoblastic Leukemia Patients

The bioavailability and pharmacokinetic characteristics of etoposide were studied in 12 relapsed B-lineage acute lymphoblastic leukemia (ALL) patients after both intravenous (i.v.) infusion and oral administration. Following a 1 hour i.v. infusion of SO mg/m2 etoposide, the elimination half-life ranged from 49.8 min to 509.4 min (mean ± SD = 218.6 ± 134.7 min), the MRT ranged from 71.8 to 734.9 min (mean ± SD = 315.4 ± 194.3 min) and the systemic clearance of etoposide ranged from 15.7 to 38.0 ml/min/m2 (mean ± SD = 24.1 ± 7.0 ml/min/m2). The AUC ranged from 2234.9 to 5427.0 μM±min) (mean ± SD = 3827.8 ± 1069.5 μM±min) and Vc ranged from 2026.9 to 13505.2 rnl/m2 (mean ± SD = 6825.4 ± 3278.5 ml/m2). The maximum plasma etoposide levels ranged from 6.0 to 28.4 μM (mean ± SD = 13.6 ± 6.3 μM). The bioavailability of oral etoposide was determined by comparing the AUC following i.v. infusion to the AUC following oral administration in the same patient. The overall bioavailability (mean ± SD) was 60.6 ± 22.4% (ranged from 17.6% to 91.2%). The elimination half-life following oral administration (mean ± SD) was 209.8 ± 196.3 min (ranged from 51.0 to 794.2 min). The time required to reach the maximum plasma etoposide concentration was 145.4 ± 118.7 min (ranged from 23.7 to 396.9 min). To our knowledge, this is the first report concerning the bioavailability of etoposide in pediatric leukemia patients. All of the other pharmacokinetic properties of etoposide in pediatric B-lineage ALL leukemia patients reported here were similar to those described previously.

Hereditary Leukemia Due to Rare RUNX1c Splice Variant (L472X) Presents with Eczematous Phenotype

Deleterious mutations in the RUNX1 gene cause hereditary leukemia due to a rare syndrome called Familial platelet Disorder with Associated Myeloid Malignancy (FPDMM). We describe the characteristics of a family with FPDMM due to a novel RUNX1 mutation (L472X), located in the most 3-prime end of the gene reported to date. Our 36-year old proband presented with incidentally detected thrombocytopenia and a family history suggestive of FPDMM. Contrary to previously described families, affected members of our kindred express an eczematous phenotype, reportedly most severe in members who develop leukemia. Pedigree analysis shows that the L472X mutation tracks with thrombocytopenia, acute leukemia, and eczema. The L472X mutation produces a stably expressed RUNX1 protein product with a corresponding decrease in wild type RUNX1 expression. Our data supports the inclusion of eczema in the FPDMM phenotype and suggests the possibility that the RUNX1 L472X mutant causes the type of dominant negative affect that is associated with an elevated risk of leukemia in FPDMM families.

Clinical and functional properties of novel VHL mutation (X214L) consistent with Type 2A phenotype and low risk of renal cell carcinoma.

Sorrell AD, Lee S, Stolle C, Ellenhorn J, Grix A, Kaelin Jr WG, Weitzel JN. Clinical and functional properties of novel VHL mutation (X214L) consistent with Type 2A phenotype and low risk of renal cell carcinoma.

T-Cell Lymphoblastic Leukemia/Lymphoma Syndrome With Eosinophilia and Acute Myeloid Leukemia

This case represents an example of an unusual T‐cell lymphoblastic leukemia/lymphoma syndrome associated with eosinophilia and myeloid malignancy in a young boy. This case is one of only five reported “leukemic” variants of the disease and demonstrates the importance of considering this poor prognostic diagnosis in pediatric acute lymphoblastic leukemia. This case also illustrates the importance of an interactive multidisciplinary approach to the laboratory evaluation of a leukemia patient.