Haematology+Oncology_News

H aematology & O ncology N ews • Vol. 9 • No. 1 • 2016 14 CONFERENCE COVERAGE

Genes tag increased risk for avascular necrosis in ALL patients under age 10

RBC folate at any time point during therapy. In the study reported by Dr Karol, the researchers studied a discovery cohort of 82 cases of osteonecrosis and 287 controls treated on the Children’s Oncology Group (COG) NCI standard risk ALL protocol and tested for replication in 817 children less than 10 treated on the COG high risk ALL protocol. Both discovery and replication genome-wide association studies adjusted for demographic and therapy variables known to modify the risk of os- teonecrosis. Genes associatedwith the identified single nucleotide polymorphisms were evaluated for enrichment in biologically relevant pathways. Within the discovery cohort and replication cohorts, top ranked variants were located near bone morphogenic protein 7 (BMP7) and PROX1-antisense RNA1. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene, and the genotyping of this variant was verified in the whole exome sequencing data. Pathway analysis of genes linked to top SNPs demonstrated enrichment in glutamate receptor signalling and adipogenesis pathways. “Patients with osteonecrosis are 8-15 times more likely to possesses genetic variants near a gene important to bone development (BMP7) and between 3–6 times more likely to have variants near a gene important to fat levels in the blood (PROX1),” Dr Karol reported.

a complete remission and received post- induction therapy; about 10% of patients experienced avascular necrosis and 22% had at least 1 fracture. Both morbidities were significantly more common in patients aged 10 and older; 23% had avascular necrosis and 31% had a fracture. In younger children, 5.5% had avascular necrosis and 19% had fractures. Of 626 patients tested, about 21% were homozygous for the 2R polymorphism in thy- midylate synthase. In children less than age 10, this 2R/2R genotype was associated with nearly three times the rate of 5-year estimated incidence of avascular necrosis, almost 12%, as compared to the 4% rate seen in children with 2R/3R or 3R/3R genotypes. Among children over age 10, this polymor- phism was associated with an increased risk of bony fracture (multivariable HR 2.13; 95% CI 1.13–3.99; P=0.019). Bony morbidity was not associated with the other tested polymorphisms previously linked to risk of avascular necrosis, including PAI-1 (rs6092), ABCB1 (rs1045642), and the vitamin D receptor Fok1 restriction site (rs228570). No significant association was observed between thymidylate synthase genotype and serum or

over age 10 with ALL, and related to exposure to crucial components of leukaemia therapy including corticosteroids, asparaginase, and methotrexate. Therapy-induced osteonecrosis has become a limiting toxicity in the inten- sification of treatment for paediatric acute lymphoblastic leukaemia (ALL), particularly among patients 10–20 years old. However, children under 10 make up 75% of new paediatric ALL diagnoses, Dr Karol said. So even though osteonecrosis occurs in just 3%-10% of children under age 10, those patients make up 40% of the cases. In Dr Cole’s study, research focused on 19 common genetic polymorphisms in peripheral blood or bone marrow collected at remission from 637 children treated for ALL. The research targeted common variants within genes related to glucocorticoid metabo- lism, oxidative damage, and folate physiology. Children above and below the age of 10 years were evaluated separately. Multivariable models for bony morbidity included sex, WBC at diag- nosis, race, final risk group, and asparaginase randomisation. Blood was collected during treatment for analysis of serum and RBC folate. Of the 637 patients tested, 627 achieved

BY MARY JO DALES Frontline Medical News

V ariants in mesenchymal stem cell genes that are important to bone and fat differ- entiation were associated with the risk of developing osteonecrosis in children under age 10 with acute lymphocytic leukaemia, Dr Seth E. Karol, of St. Jude Children’s Research Hos- pital inMemphis, reported at the annual meet- ing of the American Society of Haematology. In a second study of children with ALL, Dr Peter D. Cole, of Montefiore Medical Centre, Albert Einstein College of Medicine, Bronx, New York, reported that patients under age 10 and homozygous for the 2R polymorphism in thymidylate synthase were at increased risk for avascular necrosis. For children over age 10 with ALL, homozygosity for the 2R polymorphism was linked with an increased risk of fracture. The pathophysiology of bony morbidity differs depending on the patient’s age, Dr Cole noted. “This is the first report identifying a genetic risk factor for avascular necrosis specifically among children younger than 10 years, a group where AVN is significantly less frequent.” Bony morbidity is more common in children

Dr Cole and Dr Karol had no relevant financial disclosures.

Genes, induction response identify high risk childhood B-lymphoblastic leukaemia patients with good outcomes

Nilotinib safe, effective as first- line therapy for CML-CP patients age 65 and older BY MARY JO DALES Frontline Medical News A ge did not affect molecular response or the incidence of adverse reactions to nilotinib among patients with chronic myeloid leu- kaemia in chronic phase (CML-CP), based on results from a subanalysis of the ENEST1st study. The analysis of the ENEST1st study, reported by Dr Francis J. Giles, compared outcomes for 1089 newly diagnosed CML-CP patients, 19% were aged 65 years or older and 81% were younger than age 65 years. All patients had typical transcripts and were treated for 3 months or less with nilotinib 300 mg twice daily in the open-label study. For those 65 years and older, Sokal risk scores were low in 4.5%, intermediate in 61.2%, and high in 23.4%, with missing data for 10.9%. For younger patients, Sokal risk scores were low in 42.1%, intermediate in 32%, and high in 16.9%, with missing data for 9. At 18 months, there was an overall 38.4% rate (95% CI, 35.5– 41.3%) of MR 4 grade molecular response, which was defined as BCR-ABL level of 0.01% or less on the International Scale or unde- tectable BCR-ABL in cDNA with at least 10,000 ABL transcripts. The MR 4 rate at 18 months did not significantly vary by age. For patients under age 65, the cumulative incidence of MR 4 by 18 months was 48.8% (95% CI, 45.4–52.1%); among patients aged 65 and older, the incidence of MR 4 was 48.3% (95% CI, 41.4–55.2%). The MR 4.5 rate by 18 months was 32.5% in younger patients and 28.4% in older patients, reported Dr Giles of the Institute for Drug Development, Cancer Therapy and Research Centre, at the University of Texas Health Science Centre at San Antonio, and his colleagues. Based on Sokal score, the MR 4 rate by 18 months in younger patients was 53.6% (low), 45.2% (intermediate), and 35.4% (high), respectively. For older patients, the MR 4 rate by 18 months based on Sokal score was 44.4% (low), 49.6% (intermediate), and 44.7% (high). Six patients (0.6%) progressed to accelerated phase/blast crisis (AP/BC) on study; 13 patients (1.2%) died by 24 months. The most common adverse events were rash (21.4%), pruritus (16.5%), and headache (15.2%).

(29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk clas- sification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29. Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induc- tion. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders. Of the 96% of patients evaluable for post-induction treat- ment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL. Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%. The standard risk and high risk groups were then combined and analysed based on cytogenetic subtype. The favourable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients.

BY MARY JO DALES Frontline Medical News

C ytogenetic profile and response to initial induction ther- apy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukaemia patients who have good outcomes, Dr Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncol- ogy Group (COG). Outcomes were excellent for patients with favourable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr Raetz, of Huntsman Cancer Institute and Primary Children’s Hos- pital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favourable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients. The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects. The COG used clinical, biologic, and early disease re- sponse measures to study 11,144 patients, aged 1–30 years, enrolled on the COG AALL03B1 classification study. Pa- tients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Haematology. After induction therapy, patients were classified into low

In the 21% (1483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively. In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrowminimal residual disease less than 0.01% – the 243 high risk patients who had favourable cytogenetics and no detectable leukaemia cells in their CSF had 5 years EFS of 95% and OS of 98%.

Novartis is the sponsor of the ENEST1st study. Dr Giles consults for and receives honoraria and research funding from Novartis.

Dr Raetz had no relevant financial disclosures.

ASH President David A Williams © 2015 American Society of Hematology.