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Blood | 2009

The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes

James W. Vardiman; Juergen Thiele; Daniel A. Arber; Richard D. Brunning; Michael J. Borowitz; Anna Porwit; Nancy Lee Harris; Michelle M. Le Beau; Eva Hellström-Lindberg; Ayalew Tefferi; Clara D. Bloomfield

Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.


Blood | 2016

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia

Daniel A. Arber; Attilio Orazi; Robert P. Hasserjian; Jürgen Thiele; Michael J. Borowitz; Michelle M. Le Beau; Clara D. Bloomfield; Mario Cazzola; James W. Vardiman

The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here.


The New England Journal of Medicine | 2009

Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia

Charles G. Mullighan; Xiaoping Su; Jinghui Zhang; Ina Radtke; Letha A. Phillips; Christopher B. Miller; Jing Ma; Wei Liu; Cheng Cheng; Brenda A. Schulman; Richard C. Harvey; I. Ming Chen; Robert J. Clifford; William L. Carroll; Gregory H. Reaman; W. Paul Bowman; Meenakshi Devidas; Daniela S. Gerhard; Wenjian Yang; Mary V. Relling; D. Pharm; Sheila A. Shurtleff; Dario Campana; Michael J. Borowitz; Ching-Hon Pui; Malcolm A. Smith; Stephen P. Hunger; Cheryl L. Willman; James R. Downing

BACKGROUND Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. METHODS We studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL. RESULTS More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. CONCLUSIONS Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL.


Blood | 2008

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study.

Michael J. Borowitz; Meenakshi Devidas; Stephen P. Hunger; W. Paul Bowman; Andrew J. Carroll; William L. Carroll; Stephen B. Linda; Paul L. Martin; D. Jeanette Pullen; David S. Viswanatha; Cheryl L. Willman; Naomi J. Winick; Bruce M. Camitta

Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Childrens Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Institute high-risk (NCI HR) patients who were MRD(+). The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.


Journal of Clinical Oncology | 2009

Improved Early Event-Free Survival With Imatinib in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: A Children's Oncology Group Study

Kirk R. Schultz; W. Paul Bowman; Alexander Aledo; William B. Slayton; Harland N. Sather; Meenakshi Devidas; Chenguang Wang; Stella M. Davies; Paul S. Gaynon; Michael E. Trigg; Robert Rutledge; Laura Burden; Dean Jorstad; Andrew J. Carroll; Nyla A. Heerema; Naomi J. Winick; Michael J. Borowitz; Stephen P. Hunger; William L. Carroll; Bruce M. Camitta

PURPOSE Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups. PATIENTS AND METHODS We evaluated whether imatinib (340 mg/m(2)/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph- ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) -identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT. RESULTS Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% +/- 11% (95% CI, 64% to 90%), more than twice historical controls (35% +/- 4%; P < .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% +/- 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% +/- 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction. CONCLUSION Imatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.


Nature Genetics | 2013

The genomic landscape of hypodiploid acute lymphoblastic leukemia

Linda Holmfeldt; Lei Wei; Ernesto Diaz-Flores; Michael D. Walsh; Jinghui Zhang; Li Ding; Debbie Payne-Turner; Michelle L. Churchman; Anna Andersson; Shann Ching Chen; Kelly McCastlain; Jared Becksfort; Jing Ma; Gang Wu; Samir N. Patel; Susan L. Heatley; Letha A. Phillips; Guangchun Song; John Easton; Matthew Parker; Xiang Chen; Michael Rusch; Kristy Boggs; Bhavin Vadodaria; Erin Hedlund; Christina D. Drenberg; Sharyn D. Baker; Deqing Pei; Cheng Cheng; Robert Huether

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32–39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.


Blood | 2010

Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome

Richard C. Harvey; Charles G. Mullighan; Xuefei Wang; Kevin K. Dobbin; George S. Davidson; Edward J. Bedrick; I-Ming Chen; Susan R. Atlas; Huining Kang; Kerem Ar; Carla S. Wilson; Walker Wharton; Maurice H. Murphy; Meenakshi Devidas; Andrew J. Carroll; Michael J. Borowitz; W. Paul Bowman; James R. Downing; Mary V. Relling; Jun Yang; Deepa Bhojwani; William L. Carroll; Bruce M. Camitta; Gregory H. Reaman; Malcolm A. Smith; Stephen P. Hunger; Cheryl L. Willman

To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these high-risk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ± 5.1%, compared with 63.5% ± 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapse-free survival (21.0% ± 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.


JAMA | 2009

Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia.

Jun Yang; Cheng Cheng; Wenjian Yang; Deqing Pei; Xueyuan Cao; Yiping Fan; Stanley Pounds; Geoffrey Neale; Lisa R. Treviño; Deborah L. French; Dario Campana; James R. Downing; William E. Evans; Ching-Hon Pui; Meenakshi Devidas; W P Bowman; Bruce M. Camitta; Cheryl L. Willman; Stella M. Davies; Michael J. Borowitz; William L. Carroll; Stephen P. Hunger; Mary V. Relling

CONTEXT Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. OBJECTIVES To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. DESIGN, SETTING, AND PATIENTS Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Childrens Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. MAIN OUTCOME MEASURES Minimal residual disease at the end of induction therapy, measured by flow cytometry. RESULTS There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. CONCLUSION Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.


Nature Genetics | 2011

Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia

Jun Yang; Cheng Cheng; Meenakshi Devidas; Xueyuan Cao; Yiping Fan; Dario Campana; Wenjian Yang; Geoff Neale; Nancy J. Cox; Paul Scheet; Michael J. Borowitz; Naomi J. Winick; Paul L. Martin; Cheryl L. Willman; W. Paul Bowman; Bruce M. Camitta; Andrew J. Carroll; Gregory H. Reaman; William L. Carroll; Mignon L. Loh; Stephen P. Hunger; Ching-Hon Pui; William E. Evans; Mary V. Relling

Although five-year survival rates for childhood acute lymphoblastic leukemia (ALL) are now over 80% in most industrialized countries, not all children have benefited equally from this progress. Ethnic differences in survival after childhood ALL have been reported in many clinical studies, with poorer survival observed among African Americans or those with Hispanic ethnicity when compared with European Americans or Asians. The causes of ethnic differences remain uncertain, although both genetic and non-genetic factors are likely important. Interrogating genome-wide germline SNP genotypes in an unselected large cohort of children with ALL, we observed that the component of genomic variation that co-segregated with Native American ancestry was associated with risk of relapse (P = 0.0029) even after adjusting for known prognostic factors (P = 0.017). Ancestry-related differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy, indicating that modifications to therapy can mitigate the ancestry-related risk of relapse.


The American Journal of Surgical Pathology | 1997

Blastic natural killer cell leukemia/lymphoma: A clinicopathologic study

Joseph A. DiGiuseppe; Diane C. Louie; James E. Williams; David T. Miller; Constance A. Griffin; Risa B. Mann; Michael J. Borowitz

The classification of natural killer (NK)-cell and NK-like T-cell malignancies has undergone significant evolution in recent years. Although examples of NK-cell tumors resembling acute leukemia have been described anecdotally as blastic, blastoid, or monomorphic NK-cell leukemia/lymphoma (NKL/L), the clinical and pathologic features of these tumors have not been systematically defined. We report four patients with blastic NKL/L and describe the clinical, pathologic, and immunophenotypic findings in these cases. All patients were elderly (58-82 years) and presented with cutaneous plaques. Two patients also had adenopathy, and three patients had marrow involvement at presentation. Biopsy of cutaneous lesions showed atypical superficial and deep dermal lymphoid infiltrates. Involved lymph nodes were architecturally effaced by an interfollicular infiltrate with blastic cytologic features. In Wright-Giemsa-stained blood or marrow smears, tumor cells had finely distributed nuclear chromatin, many with nucleoli, and variable amounts of cytoplasm. In contrast to many NK and NK-like T-cell disorders, azurophilic cytoplasmic granules were absent or inconspicuous. The tumor cells were immunophenotypically distinctive. They expressed intermediate density CD45, as is characteristic of blasts; in addition, the cells were positive for HLA-DR, CD2, CD4, and the NK-associated antigen CD56. Surface CD3, cytoplasmic CD3, and CD5 were negative in all cases tested, whereas CD7 was expressed in two cases. In formalin-fixed tissue, tumor cells marked with antibodies to CD43, but not with other T- or B-lineage-related antibodies. All three cases studied for Epstein-Barr viral RNA by in situ hybridization were negative. Although treatments varied, all three patients with clinical follow-up died within months of the diagnosis. The clinical course in two patients culminated in an overtly leukemic phase. These findings suggest that blastic NKL/L represents a distinct clinicopathologic entity, characterized by cutaneous, nodal, and marrow involvement by blastic cells with immunophenotypic characteristics of true NK cells. The disease afflicts elderly patients, pursues an aggressive course, and may culminate in overt leukemia.

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Stephen P. Hunger

University of Pennsylvania

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Naomi J. Winick

University of Texas Southwestern Medical Center

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Andrew J. Carroll

University of Alabama at Birmingham

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Brent L. Wood

University of Washington

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Mignon L. Loh

University of California

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Julie M. Gastier-Foster

Nationwide Children's Hospital

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