Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.

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The landscape of genomic alterations across childhood cancers

BackgroundThe prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. MethodsIn 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data...

/pdf/germline-mutations-in-predisposition-genes-in-pediatric-3jgn97c2y2.pdf

Germline Mutations in Predisposition Genes in Pediatric Cancer

We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.

/pdf/the-molecular-landscape-of-pediatric-acute-myeloid-leukemia-4bmdg5abpa.pdf

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance.

https://www.cell.com/cancer-cell/pdf/S1535-6108(12)00438-2.pdf

An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.

Background: FEDR is an oral, selective Janus kinase 2 (JAK2) inhibitor approved for treatment (Tx) of patients (pts) with MF, including those previously treated with RUX. In the single-arm, phase 2 JAKARTA2 trial in pts with MF resistant/intolerant to prior RUX, the most common adverse events (AEs) during FEDR Tx were gastrointestinal (GI) events. JAKARTA2 ended in 2013, when a temporary clinical hold was placed on FEDR due to suspected cases of Wernicke’s encephalopathy (WE). The safety and efficacy of FEDR in pts with MF previously treated with RUX are being further evaluated in the ongoing, single-arm, phase 3b FREEDOM trial (NCT03755518), which includes prospective strategies for preventing or mitigating GI AEs, thiamine decreases, and potential WE. Aims: To assess the safety of FEDR and the effectiveness of AE mitigation strategies in the FREEDOM trial. Methods: Eligible pts had intermediate- or high-risk MF, platelets ≥50×109/L, and spleen volume ≥450cm3 by MRI/CT or palpable spleen ≥5 cm below the left costal margin. Pts must have received prior RUX for ≥3 mo, or for ≥28 d with development of red blood cell transfusion requirement (≥2 units/mo for 2 mo) or grade ≥3 thrombocytopenia, anemia, hematoma, or hemorrhage. All pts received FEDR 400 mg/d in continuous 28-d cycles. AE mitigation strategies include prophylactic and symptomatic use of anti-nausea/vomiting and anti-diarrheal Tx, thiamine supplementation, FEDR dosing modifications, and administration of FEDR with food. Results: In all, 34 pts were enrolled and 16 pts continued to receive FEDR at data cutoff (April 9, 2021). Reasons for FEDR discontinuation (D/C) in >1 pt were lack of efficacy (n=5), AEs (n=4), disease progression (n=2), pt decision (n=2), and to undergo transplant (n=2). Median FEDR Tx duration at cutoff was 28.3 (range, 1.6–101.3) wk; 14 (41%) pts had completed >12 cycles. At baseline (BL), median (range) age was 68.5 (49–82) y, time from MF diagnosis was 3.4 (0.1–17.4) y, and spleen size was 15 (3–31) cm. Most pts (62%) had primary MF, and all pts had received ≥3 mo of prior RUX; the most common reason for RUX D/C was loss of response/Tx failure (41%). During FEDR Tx, 22 (65%) pts received ondansetron and 11 (32%) pts received loperamide. GI AEs in >10% of pts were constipation (47%), diarrhea (35%), nausea (26%), abdominal pain (24%), and vomiting (18%). Nausea, vomiting, and diarrhea decreased as Tx continued. Most GI AEs were grade (G) 1/2 (including nausea, vomiting, and diarrhea) and there were no Tx-related G3/4 GI AEs. No pt required FEDR reduction, interruption, or D/C due to a Tx-related GI AE. Tx-related G3/4 AEs were reported in 11 (32%) pts, including anemia in 7 (21%) pts, and neutropenia, thrombocytopenia, and hyperkalemia in 2 (6%) pts each. At BL, 1 pt had thiamine below the 70 nmol/L lower limit of normal (LLN), which normalized before the pt received FEDR. During FEDR Tx, thiamine levels dropped below the LLN for 4 pts between cycles 2 and 3 (and for 1 pt at end of Tx); for these pts, levels returned to normal with thiamine supplementation and no FEDR interruption or reduction was required (Figure). Five other pts received prophylactic thiamine supplementation. There were no cases of WE. Image:Summary/Conclusion: FEDR was generally well tolerated in pts with MF previously treated with RUX. The frequency and severity of GI AEs were substantially lower in FREEDOM than in previous FEDR clinical trials, likely due to early implementation of GI prophylaxis. Thiamine decreases were uncommon and easily managed with routine monitoring and oral supplementation as needed. 

P1042: safety and tolerability results from the phase 3b freedom trial of fedratinib (fedr), an oral, selective jak2 inhibitor, in patients with myelofibrosis (mf) previously treated with ruxolitinib (rux)

Vedant Gupta

Papers

An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.

P1042: safety and tolerability results from the phase 3b freedom trial of fedratinib (fedr), an oral, selective jak2 inhibitor, in patients with myelofibrosis (mf) previously treated with ruxolitinib (rux)