Showing papers by "Martin S. Tallman published in 2017"
University of Ulm1, Fred Hutchinson Cancer Research Center2, King's College London3, University of Rome Tor Vergata4, University of Münster5, Brigham and Women's Hospital6, University of Chicago7, Memorial Sloan Kettering Cancer Center8, Leipzig University9, VU University Amsterdam10, University of Valencia11, National Taiwan University12, Monash University13, Alfred Hospital14, Erasmus University Medical Center15, Ohio State University16
TL;DR: An international panel to provide updated evidence- and expert opinion-based recommendations for diagnosis and management of acute myeloid leukemia in adults includes a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.
4,066 citations
Harvard University1, Mayo Clinic2, Duke University3, Ohio State University4, Hannover Medical School5, Monash University6, Autonomous University of Barcelona7, Radboud University Nijmegen8, Fred Hutchinson Cancer Research Center9, Stanford University10, Memorial Sloan Kettering Cancer Center11, University of Chicago12, University Health Network13, Leipzig University14, University of Ulm15, Goethe University Frankfurt16, Dresden University of Technology17, University of Rome Tor Vergata18
TL;DR: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event‐free survival among patients with AML and a FLT3 mutation.
Abstract: BackgroundPatients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin — an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation — to standard chemotherapy would prolong overall survival in this population. MethodsWe screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of muta...
1,474 citations
Cornell University1, Memorial Sloan Kettering Cancer Center2, University of Texas MD Anderson Cancer Center3, University of Colorado Denver4, Harvard University5, NewYork–Presbyterian Hospital6, Northwestern University7, Sarah Cannon Research Institute8, University of Texas Southwestern Medical Center9, City of Hope National Medical Center10, Cleveland Clinic11, University of Miami12, Stanford University13, Institut Gustave Roussy14, Université Paris-Saclay15, University of Oxford16, Celgene17, Agios Pharmaceuticals18
TL;DR: Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib, a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes.
1,084 citations
TL;DR: Deep-coverage, targeted, next-generation sequencing data of paired tumor and blood samples from 8,810 individuals suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology.
528 citations
City of Hope National Medical Center1, Memorial Sloan Kettering Cancer Center2, Washington University in St. Louis3, Northwestern University4, Seattle Cancer Care Alliance5, Stanford University6, University of Michigan7, Ohio State University8, Case Western Reserve University9, Harvard University10, University of California, San Diego11, Mayo Clinic12, Yale Cancer Center13, University of Wisconsin-Madison14, Fox Chase Cancer Center15, University of South Florida16, University of Tennessee Health Science Center17, Duke University18, University of California, San Francisco19, University of Alabama at Birmingham20, University of Colorado Boulder21, Johns Hopkins University22, University of Texas MD Anderson Cancer Center23, University of Utah24, Brigham and Women's Hospital25, Vanderbilt University26, Roswell Park Cancer Institute27, National Comprehensive Cancer Network28
TL;DR: This portion of the NCCN Guidelines for AML focuses on management and provides recommendations on the workup, diagnostic evaluation, and treatment options for younger and older adult patients.
Abstract: Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.
497 citations
TL;DR: Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome, and trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph- like ALL.
Abstract: Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.
293 citations
TL;DR: In this article, the authors measured 2-HG, mIDH2 allele burden, and cooccurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response.
280 citations
Ohio State University1, Memorial Sloan Kettering Cancer Center2, University of Manitoba3, Hofstra University4, Mayo Clinic5, Institute of Cancer Research6, Semmelweis University7, National Institute for Health Research8, Heidelberg University9, Lund University10, Laboratory of Molecular Biology11, University of Alberta12, University of Barcelona13, Hebrew University of Jerusalem14, University Health Network15, University of Texas MD Anderson Cancer Center16, Medical University of Łódź17, Scripps Health18, Peter MacCallum Cancer Centre19, Rappaport Faculty of Medicine20, University of Rochester Medical Center21, German Cancer Research Center22, University of Bologna23
TL;DR: The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients, and organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research.
171 citations
TL;DR: A multigene NGS approach to measuring residual disease in AML provides additional information on differential clearance of disease alleles and can assess clonal architecture before transplantation.
102 citations
TL;DR: Deep targeted mutational and copy number analysis of classical hairy cell leukemia and de novo vemurafenib-resistant cHCL identified a novel gain-of-function mutation in IRS1 and losses of NF1 and NF2, each of which contributed to resistance.
73 citations
TL;DR: SYNCRIP is identified as a new RBP that controls the myeloid leukemia stem cell program and it is proposed that targeting these RBP complexes might provide a novel therapeutic strategy in leukemia.
Abstract: The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis. Gene expression profiling of SYNCRIP-depleted cells demonstrated a loss of the MLL and HOXA9 leukemia stem cell program. SYNCRIP and MSI2 interact indirectly though shared mRNA targets. SYNCRIP maintains HOXA9 translation, and MSI2 or HOXA9 overexpression rescued the effects of SYNCRIP depletion. Altogether, our data identify SYNCRIP as a new RBP that controls the myeloid leukemia stem cell program. We propose that targeting these RBP complexes might provide a novel therapeutic strategy in leukemia.
TL;DR: To the editor: Over the past 4 decades, outcomes have improved dramatically among pediatric patients with acute lymphoblastic leukemia (ALL), with observed cure rates now >80% in developed countries.
TL;DR: The utility of developing PDX banks for modeling human leukemia is demonstrated, and the importance of genomic profiling of PDX and patient samples to ensure concordance is emphasized before performing mechanistic or therapeutic studies.
Abstract: Genomic studies have identified recurrent somatic mutations in acute leukemias. However, current murine models do not sufficiently encompass the genomic complexity of human leukemias. To develop preclinical models, we transplanted 160 samples from patients with acute leukemia (acute myeloid leukemia, mixed lineage leukemia, B-cell acute lymphoblastic leukemia, T-cell ALL) into immunodeficient mice. Of these, 119 engrafted with expected immunophenotype. Targeted sequencing of 374 genes and 265 frequently rearranged RNAs detected recurrent and novel genetic lesions in 48 paired primary tumor (PT) and patient-derived xenotransplant (PDX) samples. Overall, the frequencies of 274 somatic variant alleles correlated between PT and PDX samples, although the data were highly variable for variant alleles present at 0-10%. Seventeen percent of variant alleles were detected in either PT or PDX samples only. Based on variant allele frequency changes, 24 PT-PDX pairs were classified as concordant while the other 24 pairs showed various degree of clonal discordance. There was no correlation of clonal concordance with clinical parameters of diseases. Significantly more bone marrow samples than peripheral blood samples engrafted discordantly. These data demonstrate the utility of developing PDX banks for modeling human leukemia, and emphasize the importance of genomic profiling of PDX and patient samples to ensure concordance before performing mechanistic or therapeutic studies.
TL;DR: In this article, an expression-based virtual screening was performed to identify highly active antileukemic drugs that synergize with Notch1 inhibition in T-cell acute lymphoblastic leukemia (T-ALL).
Abstract: The Notch1 gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo. Mechanistically, network perturbation analyses showed eIF2A-phosphorylation–mediated inhibition of protein translation as a critical mediator of the antileukemic effects of withaferin A and its interaction with NOTCH1 inhibition. Overall, these results support a role for anti-NOTCH1 therapies and protein translation inhibitor combinations in the treatment of T-ALL.
University of Chicago1, Mayo Clinic2, Duke University3, University of South Florida4, Ohio State University5, Dresden University of Technology6, City of Hope National Medical Center7, University of Rome Tor Vergata8, Alfred Hospital9, University of Barcelona10, University of Alberta11, Radboud University Nijmegen12, Leipzig University13, Stanford University14, Memorial Sloan Kettering Cancer Center15, University of Ulm16, Hannover Medical School17, Goethe University Frankfurt18, Harvard University19
TL;DR: This randomized, double-blinded phase III trial demonstrated a statistically significant overall survival benefit when M was added to induction and consolidation chemotherapy followed by one year of maintenance compared to standard chemotherapy in patients (pts) with activating FLT3 mutations.
TL;DR: In patients aged ≤ 60 yrs with FLT3 mutated AML, induction treatment with cytarabine/anthracycline/crenolanib resulted in a CR in 24/29 patients, suggesting that adding crenolanIB, a potent FLT 3 inhibitor, to standard induction chemotherapy in younger patients withFLT3-mutated AML may be associated with a low relapse rate, especially if HSCT is routinely used.
TL;DR: In this article, the authors evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK525762 in relapsed and refractory acute myeloid leukemia (AML) patients.
German Cancer Research Center1, Mayo Clinic2, Johns Hopkins University3, Memorial Sloan Kettering Cancer Center4, Cardiff University5, University of Maryland, College Park6, Masaryk University7, Charles University in Prague8, Palacký University, Olomouc9, King's College London10, Nottingham University Hospitals NHS Trust11, Fred Hutchinson Cancer Research Center12, University of Washington13, Charité14, Dresden University of Technology15, University Hospital Heidelberg16
TL;DR: ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX /ATRA in t-APL.
Abstract: Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80-93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.
Memorial Sloan Kettering Cancer Center1, University of Texas MD Anderson Cancer Center2, Ohio State University3, Vanderbilt University4, Johns Hopkins University5, City of Hope National Medical Center6, Harvard University7, University of Colorado Boulder8, University of Colorado Denver9, University of Chicago10, Erasmus University Rotterdam11, University of California, Los Angeles12, Celgene13, Agios Pharmaceuticals14
TL;DR: Ivosidenib or enasidenib combined with induction chemotherapy was generally well tolerated and one dose-limiting toxicity was observed.
St. Jude Children's Research Hospital1, Sapienza University of Rome2, Carlos III Health Institute3, Hannover Medical School4, Boston Children's Hospital5, Aarhus University Hospital6, Children's Hospital at Westmead7, Memorial Sloan Kettering Cancer Center8, University of Pavia9, University of Valencia10
TL;DR: Initial high WBC counts and obesity are likely predictors of TH-ED in childhood APL, and the efficacy of novel drugs for APL-associated coagulopathy or of frontline arsenic trioxide and ATRA combination regimens in reducing ED rates remains to be established.
Abstract: Clinical trials on childhood acute promyelocytic leukemia (APL) report early death (ED) rates of 3-8%, but predictors of thrombohemorrhagic (TH)-ED are not well understood. In a retrospective study, we aimed to determine the incidence and predictors of TH-ED in childhood APL. Data were analyzed from children and adolescents with t(15;17)-positive APL (n = 683) who started treatment with all-trans retinoic acid (ATRA) and chemotherapy in different international studies. Demographic data; initial white blood cell (WBC), peripheral blood (PB) blast, and platelet counts; hemoglobin value; coagulation parameters; morphologic variant (M3 or M3v); and induction details were analyzed. Early death was defined as death occurring within 30 days of presentation. The incidence of ED was 4.7% (32 of 683 patients). Predictors of TH-ED were identified by univariable and multivariable Cox proportional hazard regression analyses (n = 25). In univariable analysis, high WBC (>10 × 109/L) (P 30 × 109/L) (P < 0.001), M3v (P < 0.01), and black ethnicity (P < 0.001) were independent predictors of TH-ED. In multivariable analysis, high WBC count (P < 0.01) and obesity (i.e., body mass index ≥95th percentile for age) (P = 0.03) were predictors of TH-ED. Initial high WBC counts and obesity are likely predictors of TH-ED in childhood APL. The efficacy of novel drugs for APL-associated coagulopathy or of frontline arsenic trioxide and ATRA combination regimens in reducing ED rates in childhood APL remains to be established.
University of Texas MD Anderson Cancer Center1, Institut Gustave Roussy2, Memorial Sloan Kettering Cancer Center3, Cornell University4, Ohio State University5, University of Colorado Denver6, University of Colorado Boulder7, University of Miami8, Northwestern University9, University of Texas Southwestern Medical Center10, University of California, San Francisco11, Washington University in St. Louis12, Sarah Cannon Research Institute13, Harvard University14, City of Hope National Medical Center15, University of Alabama16, Johns Hopkins University17, Mayo Clinic18, Oregon Health & Science University19, Medical University of South Carolina20, Emory University21, Cleveland Clinic22, Agios Pharmaceuticals23
Harvard University1, Mayo Clinic2, Duke University3, Ohio State University4, Dresden University of Technology5, Alfred Hospital6, University of Barcelona7, Radboud University Nijmegen8, Leipzig University9, Fred Hutchinson Cancer Research Center10, Stanford University11, Memorial Sloan Kettering Cancer Center12, University of Ulm13, Hannover Medical School14, Goethe University Frankfurt15, University of Chicago16
TL;DR: This global randomized, double-blinded placebo-controlled phase III trial demonstrated a statistically significant overall survival benefit when M was added to induction and consolidation chemotherapy followed by maintenance compared to standard chemotherapy in patients (pts) with activating FLT3 muts.
TL;DR: It is highlighted that transplantation for MDS remains underutilized, particularly for candidates over the age of 65, and factors associated with a lower likelihood of undergoing transplantation included age ≥65 (P < .001), age ≥ 65 (P = .001), and <5% blasts at diagnosis (overall P = .031).
TL;DR: It is suggested that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage.
Abstract: The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy (E2997). High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage.
TL;DR: Assessment of the efficacy of combining venetoclax with either HMA or LDAC in patients with relapsed or refractory (R/R) myeloid malignancies found 6 out of 21 patients achieved PR or better on venetClax regimens with ORR of 28.6%, based on landmark analysis.
Vanderbilt University1, Harvard University2, Mayo Clinic3, Stanford University4, Indiana University5, Abbott Northwestern Hospital6, University Hospitals of Cleveland7, University of Pennsylvania8, Albert Einstein College of Medicine9, Shaare Zedek Medical Center10, National Foundation for Cancer Research11, Memorial Sloan Kettering Cancer Center12
TL;DR: The presence of a monosomal karyotype (MK+) and/or a complex karyotypic (CK+) identifies subcategories of AML patients with poor prognosis.
TL;DR: It is suggested that many patients may not need traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT.
Abstract: The introduction of the tyrosine kinase inhibitors (TKI) into the treatment of patients with Ph or BCR-ABL1-positive acute lymphoblastic leukemia has revolutionized the treatment of this poor prognosis acute leukemia. The combination of TKI with chemotherapy has improved response rates and allowed more patients to proceed to allogeneic hematopoietic cell transplant (alloHCT). Older patients have excellent responses to TKI and corticosteroids or in combination with minimal chemotherapy. This raises the question as to whether patients require full-intensity chemotherapy with TKI to achieve molecular remissions. The pediatricians have proposed that cure is achievable without alloHCT in children. These results have suggested that many patients may not require traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT. The data in support of these questions is presented here and a suggested future clinical trial design based on these data is proposed.
TL;DR: Reducing the APL related ED rate in centers with limited resources is feasible provided early initiation of ATRA administration and early correction of coagulopathy in high-risk patients in addition to prompt treatment of DS.
Abstract: Although acute promyelocytic leukemia (APL) is a curable hematologic malignancy, early death (ED) remains a significant cause of treatment failure especially in developing countries. In a retrospective data analysis of 67 adult APL patients diagnosed in United Arab Emirates we report an ED rate of 11.9% which is comparable to that reported from more developed countries. We identified the following parameters at presentation as significant predictor of increased ED: Age >40 years (P = 0.015), fever (P = 0.030), WBC count >20 × 109/L (P = 0.010), the breakpoints other than bcr1 (P = 0.043) and fibrinogen level 10 × 109/L and expression of HLA-DR (P = 0.018) or CD2 (P = 0.017) were significant predictors for differentiation syndrome (DS) which was found to be a predictor of ED (P = 0.002). Reducing the APL related ED rate in centers with limited resources is feasible provided early initiation of ATRA administration and early correction of coagulopathy in high-risk patients in addition to prompt treatment of DS. To our knowledge this is the first report from the Arabian Gulf describing ED in APL.
University of Colorado Denver1, Memorial Sloan Kettering Cancer Center2, Cornell University3, Institut Gustave Roussy4, Université Paris-Saclay5, University of Texas MD Anderson Cancer Center6, University of Texas Southwestern Medical Center7, City of Hope National Medical Center8, Celgene9, Agios Pharmaceuticals10
TL;DR: Clinical outcomes for older patients with previously untreated m IDH 2 AML who received enasidenib monotherapy are reported, with the only serious treatment-related TEAEs reported for more than 1 patient being fatigue, nausea, and decreased appetite.
TL;DR: The clinical utility of CGP is reported to characterize these previously undescribed activating fusion genes, in conjunction with childhood B- or T-ALL, and describe responses to TKIs.
Abstract: Acute lymphoblastic leukemia (ALL) is among the most curable childhood cancers with a 90% overall survival in the good-risk category.1 Though the remission and cure rates among newly diagnosed patients have improved, the prognosis for those with relapsed disease remains poor. Better risk stratification integrating cytogenetics and genomics has enabled improvements in therapy and prediction of relapse. Recently the clinical utility of comprehensive genomic profiling (CGP) has been recognized, in particular, for risk stratification of about 25–30% of childhood ALL patients who do not appear to harbor any of the established chromosomal abnormalities (Supplementary Information).2 By way of illustration, a novel subgroup of BCR-ABL1-like ALL has been described, in which patients lack the BCR-ABL1 fusion but exhibit a gene expression profile similar to that of BCR-ABL1-positive ALL.3 Furthermore, some of these patients have been demonstrated to harbor tyrosine kinase-activating fusion genes, notably including PDGFRB and JAK2 fusions. The EBF1-PDGFRB gene fusion has been well studied and found to be responsive to the ABL1 tyrosine kinase inhibitor (TKI), imatinib mesylate.4, 5, 6 Here, we have identified three novel PDGFRB fusions (PDGFRB fused to each of SATB1, AGGF1 and DOCK2) in children with either precursor B-cell (B-ALL) or T-cell ALL (T-ALL). We report the clinical utility of CGP to characterize these previously undescribed activating fusion genes, in conjunction with childhood B- or T-ALL, and describe responses to TKIs.