Recurrent deletion of 9q34 in adult normal karyotype precursor B-cell acute lymphoblastic leukemia.

The prognosis of adult normal karyotype (NK) precursor B-cell acute lymphoblastic leukemia (B-ALL) has not improved over the last decade, mainly because separation into distinct molecular subsets has been lacking and no targeted treatments are available. We screened the genome of blasts from 10 adult NK B-ALL patients for novel genomic alterations by array comparative genomic hybridization and verified our results with fluorescent in situ hybridization and gene expression profile with the same probes. The results demonstrate cryptic deletions of 9q34 involving SET, PKN3, NUP188, ABL1, and NUP214 in three of the samples. The smallest deletion resulted in the likely juxtaposition of the SET and NUP214 genes. This aberration has not been described before in adult NK B-ALL. Larger number of samples is warranted to determine the prognostic significance of this cryptic deletion.

Genetic polymorphisms of ATP-binding cassette (ABC) proteins, overall survival and drug toxicity in patients with Acute Myeloid Leukemia.

The overall survival of patients with acute myeloid leukemia (AML) remains poor due to both intrinsic and acquired chemotherapy resistance. Over expression of ATP binding cassette (ABC) proteins in AML cells has been suggested as a putative mechanism of drug resistance. Genetic variation among individuals affecting the expression or function of these proteins may contribute to inter-individual variation in treatment outcomes. DNA from pre-treatment bone marrow or blood samples from 261 patients age 20-85 years, who received cytarabine and anthracycline-based therapy at Roswell Park Cancer Institute between 1994 and 2006, was genotyped for eight non-synonymous single nucleotide polymorphisms in the ABCB1, ABCC1 and ABCG2 drug transporter genes. Heterozygous (AG) or homozygous (AA) variant genotypes for rs2231137 (G34A) in the ABCG2 (BRCP) gene, compared to the wild type (GG) genotype were associated with both significantly improved survival (HR=0.44, 95%CI=0.25-0.79), and increased odds for toxicity (OR=8.41, 95%CI= 1.10-64.28). Thus genetic polymorphisms in the ABCG2 (BRCP) gene may contribute to differential survival outcomes and toxicities in AML patients via a mechanism of decreased drug efflux in both, AML cells and normal progenitors.

Treating octogenarian and nonagenarian acute myeloid leukemia patients--predictive prognostic models.

BACKGROUND: Treating the octogenarian and nonagenarian patients who have acute myeloid leukemia (AML) with intensive chemotherapy is controversial. Several models to predict outcome were proposed, including the use of a comorbidity index. However, it is unclear whether the Charlson comorbidity index (CCI) or the hematopoietic cell transplant comorbidity index (HCTCI) is more sensitive. METHODS: The authors analyzed their experience with 92 patients aged >or=80 years who had AML. Patients' pretreatment characteristics and their treatment outcomes were recorded. RESULTS: All patients were offered intensive treatment; 59 patients (64%) were treated intensively with a variety of regimens, whereas 33 patients (36%) elected to receive supportive care. The CCI and the HCTCI had similar predictive ability for outcome in both groups. A multivariate analyses of prognostic factors identified near-normal albumin (48% of patients; 1-year survival rate, >27%) as a favorable factor for the whole cohort, age <83 years (47% of patients; 1-year survival rate, >25%) and nonmonocytic morphology (75% of patients; 1-year survival rate, >26%) as favorable factors for the intensively treated cohort, and bone marrow blasts <46% (50% of patients; 1-year survival rate, >19%) as a favorable factor for patients who received supportive care. CONCLUSIONS: This retrospective analysis was developed to assist in treatment decisions for octogenarian and nonagenarian patients with AML. The findings will need validation in a prospective study.

Metachronous and synchronous presentation of acute myeloid leukemia and lung cancer.

Smoking is associated with both acute myeloid leukemia (AML) and lung cancer. We therefore searched our database for concomitant presentation of AML and lung cancer. Among 775 AML cases and 5225 lung cancer cases presenting to Roswell Park Cancer Institute between the years January 1992 and May 2008 we found 12 (1.5% of AML cases; 0.23% of lung cancer cases) cases (seven metachronous and five synchronous) with AML and lung cancer. All but one patient were smokers. There were no unique characteristic of either AML or lung cancer in these patients. Nine patients succumbed to AML, one died from an unrelated cause while undergoing treatment for AML, one died of lung cancer and one patient is alive after allogeneic transplantation for AML. In summary, this study supports the need for effective smoking cessation programs.

Thrombotic microangiopathy after allogeneic blood and marrow transplantation is associated with dose-intensive myeloablative conditioning regimens, unrelated donor, and methylprednisolone T-cell depletion.

BACKGROUND: Allogeneic blood and marrow transplantation (BMT)-associated thrombotic microangiopathy (TM) contributes to transplant-related morbidity and mortality. This report examines the incidence of and risk factors for allogeneic BMT-associated TM in two patient cohorts treated before and after changes in myeloablative conditioning regimen intensity (high vs. standard intensity). METHODS: Cohort 1 includes 153 consecutive allogeneic BMT patients who underwent transplantation between April 1994 and October 1997 with an allogeneic BMT-associated TM crude incidence of 12%. Cohort 2 includes 75 consecutive allogeneic BMT patients who underwent transplantation from November 1997 to November 2000 with an allogeneic BMT-associated TM crude incidence of 1%. RESULTS: In cohort 1, matched unrelated donor transplant and methylprednisolone (MP) T-cell depletion (TCD) of donor bone marrow were significantly associated with allogeneic BMT-associated TM by univariate analysis; therefore, a logistic model incorporating these effects was constructed to calculate the expected number of allogeneic BMT-associated TM cases in cohort 2. Seven cases would have been expected, but only one was observed (P = 0.003; bayesian predictive test). The multivariate analysis of both cohorts yielded MP-TCD (P<0.001), high-intensity myeloablative conditioning regimens used in cohort 1 (P = 0.02), and matched unrelated donor (P = 0.03) as significant predictors of time to allogeneic BMT-associated TM. CONCLUSION: Avoidance of high-intensity conditioning regimens may decrease the incidence of allogeneic BMT-associated TM.