Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of - (n = 46) or - (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of (- or -) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (, ,) identified in 63 patients (50.8% of those with rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (, ,, and ) in 14.1%, rearrangements or fusions in 8.8%, alterations activating other JAK-STAT signaling genes (, ,) in 6.3% or other kinases (, ,) in 4.6%, and mutations involving the Ras pathway (, ,, ) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.

Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is a newly identified high-risk (HR) B-lineage ALL subtype, accounting for ∼15% of children with National Cancer Institute–defined HR B-ALL. It occurs more frequently in adolescents and adults, having been reported in as much as 27% of young adults with ALL between 21 and 39 years of age. It exhibits adverse clinical features, confers a poor prognosis, and harbors a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, making it amenable to treatment with tyrosine kinase inhibitor (TKI) therapy. Multiple groups are currently conducting clinical trials to prospectively screen patients with Ph-like ALL and incorporate the relevant TKI for those harboring ABL-class gene rearrangements or those with JAK-STAT pathway alterations. The success of combinatorial treatment of TKI with chemotherapy in the setting of Ph-positive ALL suggests that this approach may similarly improve outcomes for patients with Ph-like ALL. Hence, Ph-like ALL illustrates the modern treatment paradigm of precision medicine and presents unique opportunities for harnessing international collaborations to further improve outcomes for patients with ALL.

Introduction Studies suggest that patients with cancer are more likely to experience severe outcomes from COVID-19. Therefore, cancer centers have undertaken efforts to care for patients with cancer in COVID-free units. Nevertheless, the frequency and relevance of nosocomial transmission of COVID-19 in patients with cancer remain unknown. The goal of this study was to determine the incidence and impact of hospital-acquired COVID-19 in this population and identify predictive factors for COVID-19 severity in patients with cancer. Methods Patients with cancer and a laboratory-confirmed diagnosis of COVID-19 were prospectively identified using provincial registries and hospital databases between March 3 rd and May 23 rd , 2020 in the provinces of Quebec and British Columbia in Canada. Patient’s baseline characteristics including age, sex, comorbidities, cancer type, and type of anti-cancer treatment were collected. The exposure of interest was incidence of hospital-acquired infection defined by diagnosis of SARS-CoV-2 ≥ 5 days after hospital admission for COVID-unrelated cause. Co-primary outcomes were death or composite outcomes of severe illness from COVID-19 such as hospitalization, supplemental oxygen, intensive-care unit (ICU) admission and/or mechanical ventilation. Results A total of 252 patients (N=249 adult, and N=3 pediatric) with COVID-19 and cancer were identified, and the majority were residents of Quebec (N=233). One-hundred-and-six patients (42.1%) received active anti-cancer treatment in the last 3 months prior to COVID-19 diagnosis. During a median follow-up of 25 days, 33 (13.1%) required admission to the ICU, and 71 (28.2%) died. Forty-seven (19.1%) had a diagnosis of hospital-acquired COVID-19. Median overall survival was shorter in those with hospital-acquired infection, compared to a contemporary community-acquired population (27 days vs unreached, HR 2.3, 95% CI 1.2-4.4, p=0.0006). Multivariate analysis demonstrated that hospital-acquired COVID-19, age, ECOG status, and advanced stage of cancer were independently associated with death. Interpretation Our study demonstrates a high rate of nosocomial transmission of COVID-19, associated with increased mortality in both univariate and multivariate analysis in the cancer population, reinforcing the importance of treating patients with cancer in COVID-free units. We also validated that age and advanced cancer were negative predictive factors for COVID-19 severity in patients with cancer.

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IMPORTANCE Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-totreat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases. OBJECTIVE To assess the feasibility of identifying potentially actionable mutations using nextgeneration sequencing-based assays in a clinically relevant time frame. DESIGN, SETTING, AND PARTICIPANTS This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Québec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board. MAIN OUTCOMES AND MEASURES Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies. RESULTS A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken. CONCLUSIONS AND RELEVANCE Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, (continued) Key Points Question Can genome sequencing facilitate the molecular profiling of the patient's tumor to identify actionable and targetable alterations? Findings In this diagnostic study of 62 consecutive pediatric patients with hard-to-treat cancer who were enrolled in the TRICEPS study, incorporating multimodal genomic sequencing, including RNA sequencing, into the management of refractory or relapsed childhood and adolescent cancers identified potentially actionable alterations in 54 (87%)...

Survival of children with cancers has dramatically improved over the past several decades. This success has been achieved through improvement of combined modalities in treatment approaches, intensification of cytotoxic chemotherapy for those with high-risk disease, and refinement of risk stratification incorporating novel biologic markers in addition to traditional clinical and histologic features. Advances in cancer genomics have shed important mechanistic insights on disease biology and have identified "driver" genomic alterations, aberrant activation of signaling pathways, and epigenetic modifiers that can be targeted by novel agents. Thus, the recently described genomic and epigenetic landscapes of many childhood cancers have expanded the paradigm of precision medicine in the hopes of improving outcomes while minimizing toxicities. In this review, we will discuss the biologic rationale for molecularly targeted therapies in genomically defined subsets of pediatric leukemias, solid tumors, and brain tumors. .