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a separate trial of LCZ696 in patients with heart failure and a preserved ejection fraction, there was no relationship between the blood-pressure effect and the natriuretic peptide level.8 PARADIGM-HF may well represent a new threshold of hope for patients with heart failure. Efforts to design novel pharmacotherapies that exploit our growing knowledge of pathophysiological pathways are increasingly coming to the clinical arena. The dual (or more) action of such drugs may translate into even greater long-term survival for patients (Fig. 1).9,10 The beneficial results seen in PARADIGM-HF may apply to a wide spectrum of patients, even those who are currently receiving the best possible therapy. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Perelman School of Medicine, University of Pennsyl­ vania, Philadelphia. This article was published on August 30, 2014, at NEJM.org. 1. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosor-

bide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-57. [Erratum, N Engl J Med 2005; 352:1276.] 2. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–nepri-

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lysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004. 3. Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21. 4. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-38. 5. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebocontrolled study. Lancet 2010;376:875-85. [Erratum, Lancet 2010; 376:1988.] 6. von Lueder TG, Sangaralingham SJ, Wang BH, et al. Reninangiotensin blockade combined with natriuretic peptide system augmentation: novel therapeutic concepts to combat heart failure. Circ Heart Fail 2013;6:594-605. 7. Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, Lef kowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet 2010;375:1255-66. 8. Jhund PS, Claggett B, Packer M, et al. Independence of the blood pressure lowering effect and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart failure with preserved ejection fraction: an analysis of the ­PARAMOUNT trial. Eur J Heart Fail 2014;16:671-7. 9. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302. 10. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-55. DOI: 10.1056/NEJMe1409898 Copyright © 2014 Massachusetts Medical Society.

A Call to Action for Acute Lymphoblastic Leukemia Timothy A. Graubert, M.D. The cure rates for precursor B-cell acute lymphoblastic leukemia (ALL) among children have improved, but the prognosis for older patients and children with relapsed disease remains poor. Risk stratification based on clinical features and disease characteristics can improve outcomes by enabling physicians to reduce the toxicity of therapy for patients with lower-risk disease and intensify therapy for patients with higher-risk disease. The negative prognosis associated with the t(9;22) translocation, which results in expression of the BCR–ABL1 activated kinase fusion protein, is attenuated by treatment that includes tyrosine kinase inhibitors, providing a paradigm for molecularly guided therapy in patients with precursor B-cell ALL. Several years ago, a subtype of precursor B-cell ALL was identified that shares a gene-expression profile with Ph-positive ALL (the term commonly used to describe ALL associated with the Philadelphia chromosome, which results from the t[9;22] trans1064

location).1,2 The pattern of gene expression in patients with Ph-like ALL prompted the hypothesis that other oncogenic drivers could substitute for BCR–ABL1, triggering a similar signaling cascade. Indeed, previous studies have identified rearrangements and mutations that activate cytokine receptor signaling in some cases of Ph-like ALL.3,4 In this issue of the Journal, Roberts et al.5 define the frequency and genomic landscape of Ph-like ALL in a cohort of 1725 children and young adults with precursor B-cell ALL. They observed a marked rise in the proportion of Ph-like cases with age, from 12% among children to 27% among young adults (Fig. 1A). Nearly half (49.4%) of the young adults had either Ph-positive or Ph-like disease. The Ph-like cases were frequently found to be associated with IKZF1 alterations (in 68% of patients with Ph-like ALL) and high CRLF2 expression (in 47%), with the latter caused by genomic rearrangement in all

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editorials

A

Children (1–15 years of age)

Adolescents (16–20 years of age)

Young Adults (21–39 years of age)

Ph-like BCR–ABL1

11.9%

4.2%

33.0%

20.6%

ETV6–RUNX1

23.2%

27.4%

Hyperdiploid

38.0%

TCF3–PBX1

5.9%

14.6%

3.7%

ERG

15.5% 1.5%

4.1% 8.2%

10.7%

15.1% 4.5%

7.3%

1.3%

10.2%

5.1%

MLL

22.0%

5.4%

Hypodiploid Other

1.8% 3.0% 1.8%

B

TSLPR (CRLF2)

Kinase Interleukin-7 receptor

Cell membrane

Cytoplasm

JAK2 EPOR

JAK2

Ruxolitinib

CRLF2

JAK2

Primary human leukemia cell

STAT5 P P STAT5

Inhibitor

ABL1 ABL2

Dasatinib

CSF1R PDGFRB

Nucleus P STAT5 STAT5 P

NTRK3

Crizotinib

Figure 1. Actionable Genetic Lesions in Philadelphia Chromosome–like (Ph-like) Precursor B-Cell Acute Lymphoblastic Leukemia (ALL). Panel A shows the distribution of major molecular subtypes of precursor B-cell ALL. The proportion of cases associated with an unfavorable prognosis (e.g., Ph-positive [BCR–ABL1] or Ph-like ALL) increases from childhood (1 to 15 years of age) to adolescence (16 to 20 years of age) and young adulthood (21 to 39 years of age), and the proportion of cases with a more favorable prognosis (e.g., hyperdiploidy or ETV6–RUNX1) decreases with age. Percentages may not sum to 100 because of rounding. Panel B shows the heterodimeric thymic stromal lymphopoietin receptor (TSLPR) complex that signals through the JAK–STAT pathway to regulate B-cell lymphopoiesis, among other functions. Kinase-activating mutations in this and other cytokine signaling pathways are frequent in precursor B-cell ALL and represent potential therapeutic targets of kinase inhibitors. P denotes a phosphate group.

patients examined — findings that are consistent with the results of previous studies.2,3 Patients with high CRLF2 expression frequently had JAK1 or JAK2 mutations (found in 55% of patients with CRLF2 rearrangement), as previously reported,3,4 but the study by Roberts et al. extends these findings considerably. Comprehensive genomic analysis revealed somatic mutations (fusion, deletions, or point mutations) predicted to alter kinase activity in 91% of patients with Ph-like ALL. (The remaining patients did n engl j med 371;11

not have a kinase-altering mutation or had insufficient material available for analysis.) A majority of the mutations affected cytokine receptors (e.g., EPOR, FLT3, or PDGFRB) or their downstream signaling pathways (Fig. 1B). Several of the mutant alleles had functional consequences when ectopically expressed in cell lines (conferring cytokine independence or constitutive STAT5 activation). The growth and aberrant signaling in these cell lines were inhibited in a predictable fashion: fusions involving ABL1,

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ABL2, or CSF1R were sensitive to ABL inhibitors (imatinib or dasatinib), and JAK2 fusions were sensitive to a Janus kinase inhibitor (ruxolitinib). Similarly, the growth of primary human leukemia cells was inhibited in vitro and in mouse xenograft models when the cells were exposed to kinase inhibitors tailored to the genetic profile of the primary tumors. There is a wealth of additional data in the article by Roberts et al.5 that the leukemia community will be mining for some time. Mutations in transcription factors that are important for lymphoid development were found more frequently in patients with Ph-like ALL than in patients with non-Ph-like ALL. This observation, together with the pattern of concurrent mutations affecting cytokine receptor signaling, should inform the design of more accurate mouse models of this disease. In addition, the observation that the prognosis within the subgroup of patients with Ph-like ALL may be further refined by assessment of the status of the JAK2 or EPOR locus requires independent validation. Finally, therapeutic strategies need to be developed and tested for the minority of patients without kinase mutations, as well as for those with only Ras pathway mutations. The study by Roberts et al.5 represents a call to action in several respects. First, the role of tyrosine kinase inhibitors in the management of Ph-like ALL must be tested in prospective clinical trials. The improved outcome after the addition of tyrosine kinase inhibitors to cytotoxic chemotherapy for the treatment of Ph-positive ALL provides the basis for some optimism that a similar approach could be applied to Ph-like ALL. The study by Roberts et al. provides strong preclinical evidence that kinase-altering mutations are biologically relevant drivers in Ph-like ALL. Several anecdotal clinical responses described in their Supplementary Appendix (available at NEJM.org) are encouraging but will require systematic study in well-controlled clinical trials. Second, the frequency of Ph-like ALL among older adults is unknown, but the agedependent rise in the proportion of Ph-like cases in children and young adults raises the possibility that the poor prognosis for adults may be due in part to a higher prevalence of this disease phenotype. Clearly, the genetic features of ALL in adults require additional study, with the

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hope that this will reveal new therapeutic targets for these patients. Third, the potential prognostic and therapeutic significance of the Ph-like subtype mandates development of diagnostic tools that can be widely deployed. Geneexpression profiling remains a research technique that is not practical for routine use in diagnostic laboratories. Low-density gene-expression arrays or flow cytometry–based assays have been proposed as alternative diagnostic strategies,6 but these methods require further refinement and validation. Finally, rapid-turnaround molecular profiling will be needed to identify potentially actionable mutations in patients with Ph-like ALL. Mutational profiling with the use of large gene panels is now widely available in academic centers and commercial laboratories, but many of these platforms do not include a strategy for gene-fusion detection. Improvements in risk stratification and tailored treatment plans for children with precursor B-cell ALL represent major successes in pediatric oncology. The findings of Roberts et al. provide new opportunities for investigation in children and young adults with Ph-like ALL and may well be extended to address the unmet medical needs of older adults with precursor B-cell ALL. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Massachusetts General Hospital Cancer Center, Boston. 1. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al.

A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 2009;10:125-34. 2. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360:470-80. 3. Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 2012;22:153-66. 4. Loh ML, Zhang J, Harvey RC, et al. Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children’s Oncology Group TARGET Project. Blood 2013;121:485-8. 5. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinaseactivating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 2014;371:1005-15. 6. Harvey RC, Kang H, Roberts KG, et al. Development and validation of a highly sensitive and specific gene expression classifier to prospectively screen and identify B-precursor acute lymphoblastic leukemia (ALL) patients with a Philadelphia chromosome-like (“Ph-like” or “BCR-ABL1-Like”) signature for therapeutic targeting and clinical intervention. Blood 2013;122:826. DOI: 10.1056/NEJMe1407477 Copyright © 2014 Massachusetts Medical Society.

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A call to action for acute lymphoblastic leukemia.

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