Independent Prognostic Significance of Monosomy 17 and Impact of Karyotype Complexity in Monosomal Karyotype/Complex Karyotype Acute Myeloid Leukemia: Results from Four ECOG-ACRIN Prospective Therapeutic Trials.

The presence of a monosomal karyotype (MK+) and/or a complex karyotype (CK+) identifies subcategories of AML with poor prognosis. The prognostic significance of the most common monosomies (monosomy 5, monosomy 7, and monosomy 17) within MK+/CK+AML is not well defined. We analyzed data from 1,592 AML patients age 17-93 years enrolled on ECOG-ACRIN therapeutic trials. The majority of MK+ patients (182/195; 93%) were MK+/CK+ with 87% (158/182) having ≥5 clonal abnormalities (CK≥5). MK+ patients with karyotype complexity ≤4 had a median overall survival (OS) of 0.4y compared to 1.0y for MK- with complexity ≤4 (p<0.001), whereas no OS difference was seen in MK+vs. MK- patients with CK≥5 (p=0.82). Monosomy 5 (93%; 50/54) typically occurred within a highly complex karyotype and had no impact on OS (0.4y; p=0.95). Monosomy 7 demonstrated no impact on OS in patients with CK≥5 (p=0.39) or CK≤4 (p=0.44). Monosomy 17 appeared in 43% (68/158) of CK≥5 patients and demonstrated statistically significant worse OS (0.4y) compared to CK≥5 patients without monosomy 17 (0.5y; p=0.012). Our data suggest that the prognostic impact of MK+is limited to those with less complex karyotypes and that monosomy 17 may independently predict for worse survival in patients with AML.

Pediatric acute lymphoblastic leukemia with a t(8;14)(q11.2;q32): B-cell disease with a high proportion of Down syndrome: a Children's Oncology Group study.

The rare translocation t(8;14)(q11.2;q32) has been described in patients with B-cell acute lymphoblastic leukemia (ALL), particularly patients with Down syndrome (DS). We describe patients with the t(8;14)(q11.2;q32) who were identified by the Children's Oncology Group (COG) ALL cytogenetics database, expanding our previous report of 10 patients with this translocation. Twenty-two such patients were treated with COG protocols. All patients had B-cell ALL, and seven (31.8%) had DS. None of the children with DS had an event; thus, these patients had a superior estimated 5-year event-free survival (EFS) compared to non-DS patients (100% vs. 50.1 ± 17.7%; P = 0.04). Only one patient (4.5%) had a concomitant Philadelphia chromosome t(9;22)(q34;q11.2). The cytogenetics data of two additional patients, who were not eligible for COG protocols, are also included in this report. In conclusion, ALL patients with the recurring translocation t(8;14)(q11.2;q32) have the B-cell phenotype and a high percentage have DS. Children with DS and the t(8;14)(q11.2;q34) have improved EFS using standard COG therapy compared to non-DS patients. We did not find an increased number of patients with a concomitant Philadelphia chromosome in this population.

Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. METHODS: We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. RESULTS: We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67). CONCLUSIONS: We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).

Nonsteroidal anti-inflammatory drug and acetaminophen use and risk of adult myeloid leukemia.

BACKGROUND: Little is known about the causes of adult leukemia. A few small studies have reported a reduced risk associated with regular use of nonsteroidal anti-inflammatory drugs (NSAID). METHODS: In a population-based case-control study, we evaluated analgesic use among 670 newly diagnosed myeloid leukemia cases [including 420 acute myeloid leukemias (AML) and 186 chronic myeloid leukemias (CML)] and 701 controls aged 20 to 79 years. Prior use of aspirin, ibuprofen, acetaminophen, other NSAIDs, and COX-2 inhibitors was assessed and included frequency, duration, and quantity. ORs and 95% CIs were calculated using unconditional logistic regression adjusting for potential confounders. RESULTS: Regular/extra strength aspirin use was inversely associated with myeloid leukemia in women (OR = 0.59, 95% CI = 0.37-0.93) but not in men (OR = 0.85, 95% CI = 0.58-1.24). In contrast, acetaminophen use was associated with an increased risk of myeloid leukemia in women only (OR = 1.60, 95% CI = 1.04-2.47). These relationships were stronger with increasing dose and duration. When stratified by leukemia type, aspirin use was inversely associated with AML and CML in women. No significant overall associations were found with ibuprofen or COX-2 inhibitors for either sex; however, a decreased risk was observed with other anti-inflammatory analgesic use for women with AML or CML (OR = 0.47, 95% CI = 0.22-0.99; OR = 0.31, 95% CI = 0.10-0.92, respectively). CONCLUSIONS: Our results provide additional support for the chemopreventive benefits of NSAIDs, at least in women. Because leukemia ranks fifth in person-years of life lost due to malignancy, further investigation is warranted. IMPACT: NSAIDs may reduce, whereas acetaminophen may increase, myeloid leukemia risk in women.

22q13.32 deletion and duplication and inversion in the same family: a rare occurrence.

Chromosome 22q13.3 deletion syndrome is a well-recognized cause of global developmental delay, while duplication of the same chromosome is a rare occurrence. The presence of both abnormalities in the same family has never been reported, to our knowledge. We report a rare occurrence of 22q13.3 duplication and 22q13.3 deletion in siblings, as a consequence of a mother's inversion on her 22nd chromosome (p13;q13.32). A 6 year old male was noted in infancy to have mild global developmental delay without dysmorphic features. His genetic testing revealed he had 22q13.3 duplication to the terminus. His 4 year old brother was noted in early infancy to have severe global developmental delay and dysmorphic features related to 22q13.3 deletion to the terminus. Their mother had a long inversion on her 22nd chromosome. Genetic tests for their father and eldest brother were unremarkable. The mother's inversion may rearrange to form 22q duplication or deletion when passed on to children. The chance of a child born with a chromosome imbalance is as high as 50%.

FLT3 mutations at diagnosis and relapse in acute myeloid leukemia: cytogenetic and pathologic correlations, including cuplike blast morphology.

CONTEXT: Acquired mutations in the fms-like tyrosine kinase 3 gene (FLT3) adversely impact relapse risk after chemotherapy in patients with acute myeloid leukemia (AML). The FLT3 mutation status may differ at diagnosis and relapse, suggesting a potential role in chemoresistance, yet few reports have addressed the cytogenetic and pathologic correlates of FLT3 mutations in relapsed AML. OBJECTIVES: To determine FLT3 mutations at diagnosis and relapse in a cohort of adult patients with chemoresistant AML and to correlate mutation status with multiple variables. DESIGN: We retrospectively determined FLT3 internal tandem duplication (FLT3/ITD) and FLT3 tyrosine kinase domain mutations in 50 diagnosis/relapse pairs. We correlated FLT3 status with karyotype, World Health Organization 2008 subtype, white blood cell count, biopsy cellularity, blast percentage, and the presence of invaginated ("cuplike") blast nuclei. RESULTS: In 11 of 50 patients (22%) the FLT3 mutation status differed at relapse and diagnosis, with a trend toward gain of FLT3/ITD (n = 7) and loss of FLT3 tyrosine kinase domain (n = 5) mutations. FLT3-mutated AMLs correlated with the World Health Organization 2008 subtype, AML, not otherwise specified, hyperproliferative features at diagnosis and relapse, and cytogenetic evolution. FLT3-wild type AMLs correlated with the subtype AML with myelodysplasia-related changes and frequently had adverse presentation karyotypes. Cuplike blast morphology was associated with FLT3/ITD+ status and with high mutation levels. Four of 7 patients with relapse-only FLT3/ITD mutations exhibited cuplike blasts at relapse after being noncuplike at diagnosis. CONCLUSIONS: In addition to well-known correlates in pretreatment specimens, FLT3 mutation status has pathologic and cytogenetic significance at relapse. A shift to cuplike blast morphology at relapse may herald emergence of a previously undetected FLT3/ITD mutation.

Utility of interphase FISH to stratify patients into cytogenetic risk categories at diagnosis of AML in an Eastern Cooperative Oncology Group (ECOG) clinical trial (E1900).

We evaluated the efficacy of FISH to detect chromosome anomalies in the evaluation of young (<60 years) patients with AML. Patients were enrolled in E1900, an ECOG clinical trial for AML. The protocol was designed to collect bone marrow or blood for both cytogenetic and FISH studies at study entry (diagnosis). FISH for each patient was performed and utilized eight probe sets to detect t(8;21), t(9;22), t(11;var), t(15;17), inv(16), +8, -5/5q, and -7/7q. We analyzed 237 specimens with complete cytogenetic and FISH results. Results for each specimen were classified by probe set into one of six categories. The concordance rate between cytogenetic and FISH results ranged from 98 to 100% for all probe sets and kappa analysis for concordance had a p-value of <0.0001. The high level of agreement between cytogenetic and FISH results demonstrate the accuracy of a panel of eight FISH probe sets for the detection of significant abnormalities in AML. Data from this investigation support the use of FISH as an adjunct method to increase the yield of useful cytogenetic results in large cooperative trials and demonstrate the potential of FISH as a follow-up study of minimal residual disease in ECOG trials.

Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial.

Pretreatment cytogenetics is a known predictor of outcome in hematologic malignancies. However, its usefulness in adult acute lymphoblastic leukemia (ALL) is generally limited to the presence of the Philadelphia (Ph) chromosome because of the low incidence of other recurrent abnormalities. We present centrally reviewed cytogenetic data from 1522 adult patients enrolled on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. The incidence and clinical associations for more than 20 specific chromosomal abnormalities are presented. Patients with a Ph chromosome, t(4;11)(q21;q23), t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy (Ho-Tr) all had inferior rates of event-free and overall survival when compared with other patients. In contrast, patients with high hyperdiploidy or a del(9p) had a significantly improved outcome. Multivariate analysis demonstrated that the prognostic relevance of t(8;14), complex karyotype, and Ho-Tr was independent of sex, age, white cell count, and T-cell status among Ph-negative patients. The observation that Ho-Tr and, for the first time, karyotype complexity confer an increased risk of treatment failure demonstrates that cytogenetic subgroups other than the Ph chromosome can and should be used to risk stratify adults with ALL in future trials.

Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic syndrome: an Eastern Cooperative Oncology Group (ECOG) study.

Cytogenetic analysis can be important in determining the prognosis and diagnosis of a number of hematological disorders, including myelodysplastic syndromes (MDS). Here, we compared metaphase chromosomal analyses on bone marrow aspirates from MDS patients with interphase fluorescence in situ hybridization (FISH) using probes specific for chromosomes nos. 5, 7, 8, 11, 13 and 20. Forty-three patients enrolled in ECOG protocol E1996 for low risk MDS and five patients enrolled in ECOG protocol E3996 for high risk MDS were studied by both metaphase chromosomal analysis and interphase FISH. Excluding those with a clonal loss of the Y chromosome, an abnormal clone was detected by cytogenetic analysis in 18 of 48 samples (37.5%). In comparison, our FISH panel detected an abnormal clone in 17 of 48 samples (35.4%). Twenty-nine of 30 samples with apparently normal karyotypes, including those with a missing Y chromosome, were also normal by our FISH panel. One patient had an occult deletion of chromosome 11 that was detected by FISH. These results indicate that around 60% of patients with MDS do not have abnormalities that are detectable by either chromosomal or FISH studies. In addition, it appears that interphase FISH studies are nearly as sensitive as cytogenetic analyses and can be a useful tool in studying bone marrow aspirates where cytogenetic analysis is not possible.