BACKGROUND Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR–ABL1–positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6–NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.)

Pulmonary fibrosis develops in Hermansky-Pudlak syndrome (HPS) types 1 and 4. Limited information is available about lung disease in HPS type 2 (HPS-2), which is characterized by abnormal function of the adaptor protein-3 (AP-3) complex. To define lung disease in HPS-2, one child and two adults with HPS-2 were evaluated at the National Institutes of Health on at least two visits, and another child was evaluated at the University of Texas Health Science Center San Antonio. All four subjects with HPS-2 had findings of interstitial lung disease (ILD) on a high-resolution computed tomography scan of the chest. The predominant feature was ground glass opacification. Subject 1, a 14-year-old male, and subject 4, a 4-year-old male, had severe ILD, pulmonary fibrosis, secondary pulmonary hypertension and recurrent lung infections. Lung biopsy performed at 20 months of age in subject 1 revealed interstitial fibrosis and prominent type II pneumocyte hyperplasia without lamellar body enlargement. Subject 2, a 27-year-old male smoker, had mild ILD. Subject 3, a 22-year-old male nonsmoker and brother of subject 2, had minimal ILD. Severe impairment of gas exchange was found in subjects 1 and 4 and not in subjects 2 or 3. Plasma concentrations of transforming growth factor-β1 and interleukin-17A correlated with severity of HPS-2 ILD. These data show that children and young adults with HPS-2 and functional defects of the AP-3 complex are at risk for ILD and pulmonary fibrosis.

Key Points Hermansky-Pudlak syndrome type 2 confers a moderate risk for hemophagocytic lymphohistiocytosis.

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Suboptimal pain relief after 1 dose of IV morphine was associated with admission from the ED. Further investigation of pain relief, using validated pain assessment scales, as an outcome in VOE management is warranted.