ASH News Daily - Monday, December 12, 2011 - (Page A-6)

Page A–6 ® AML Find Cancer Early – Really Early By Michael roSenzweiG, Md T he progressive development of malignancy involves the clonal evolution from a normal cell to a malignant one. The sequential acquisition of genetic mutations has been well described in some solid tumors including colon cancer. Our understanding of AML genomics has also progressed significantly in recent years. While the majority of patients have a normal karyotype among this group, patients with internal tandem duplications in the FLT3 tyrosine kinase (FLT3-ITD) have a worse prognosis, whereas pa- MDS «« From Page A-1 mutations in patients with RARS. They identified 62 point mutations in eight patients, with a predominance of transitions. In six out of eight patients they found recurrent somatic mutations in the SF3B1 gene, a gene encoding a core component of RNA splicing machinery. In order to evaluate the frequency of SF3B1 mutations in various myeloid malignancies and other neoplasms, they went on to perform targeted re-sequencing of the gene. They were able to show that mutations are present with higher frequency in patients with MDS (28.1%) when compared with patients with myelodysplastic/myeloproliferative neoplasms (19.3%) and patients with acute myeloid leukemia (5.3%). The gene was found to be mutated in lower percentage (1-5%) in other tumor types. There was a significant relation- ship between SF3B1 mutation status and/or mutant allele burden and the presence and proportion of bone marrow ring sideroblasts — nearly 100 percent. Patients carrying an SF3B1 muta- tion showed a significantly better overall survival and had a lower risk of progression to AML; this better prognosis was retained in multivariate analysis. Dr. Malcovati suggested that, based on these findings, we may have a better understanding of the underlying mechanisms of this disease, and we may be able to “implicate abnormalities in RNA splicing in the pathogenesis of myelodysplastic syndromes.” The MDS puzzle is still nowhere near being completed, but we have just seen another piece added. Dr. Pro indicated no relevant conflicts of interest. ASH NEWS DAILY Monday, December 12, 2011 tients with mutations in NPM1 fare better. Identification of these genomic features in patients with active AML help us to prognosticate and guide our treatment approaches. On the other hand, our understanding of the genomics behind leukemogenesis is less developed, and founding mutations for the development of leukemia from a non-leukemic stem cell are largely unknown. In the Plenary Scientific abstract, “Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia,” Dr. Ravindra Majeti from Stanford University described work done that will help us better understand the nature of mutations in pre-leukemic stem cells through comparative, genomic analysis of de novo AML cells with patient-matched residual nonleukemic hematopoietic stem cells (HSCs). Through this elegant work, Dr. Majeti separated residual hematopoetic stem cells from patients with AML. He then identified specific mutations within the AML cells and then went back to the HSCs to search for those same mutations. While the majority of mutations present in leukemic cells were absent in the HSCs, Dr. Vavindra Majeti presents during plenary scientific session. specific mutations including SKP2 and TET2 mutations were sometimes present in these presumed to be normal cells. These so-called “early” mutations separate normal HSCs from pre-leukemic stem cells and may prove to be founder mutations that later evolve through sequential acquisition of further mutations into AML genomes. The clinical significance of this finding is yet to be seen; however, if a pre-leukemic HSC clone can be found within a pool of residual HSCs, targeting that reservoir may lead to specific anti-leukemic treatment options and more durable remissions. The ability to separate re- sidual HSCs from pre-leukemia stem cells is exciting and provides context for a targeted approach to prevent the most common cause of mortality in our treatment for AML, relapsed disease. In addition, identification of the pre-leukemic stem cell raises the possibility of new, effective treatments including purged autologous hematopoietic cell transplants as part of AML therapy. In summary, this provocative work by Dr. Majeti may identify leukemic cells earlier in their development and provide better, less toxic treatment options. Dr. Rosenzweig indicated no relevant conflicts of interest. Highlights from Sunday’s Sickle Cell Disease Press Briefing By aManda Brandow, do, MS D uring yesterday’s sickle cell disease (SCD) press briefing moderated by Dr. Susan Shurin, acting director of the National Heart, Lung, and Blood Institute, three investigators presented results of recently completed SCD clinical trials that have addressed important clinical questions regarding the care of children with SCD. Dr. Zora Rogers presented results of the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) and followup trial that showed significant clinical benefit of hydroxyurea in young infants nine to 18 months of age. Hydroxyurea decreased pain events, episodes of chest syndrome, hospitalizations, and episodic transfusions. Dr. Patrick McGann also dis- cussed data from the BABY HUG trial that supported the low risk of genotoxicity of hydroxyurea in infants, providing further support and encouragement that hydroxyurea is safe. Dr. Jo Howard concluded the briefing by discussing data from the Transfusion Alternatives Preoperatively in Sickle Cell Disease Trial (TAPS) conducted in the Panelists Drs. Zora R. Rogers, left, Patrick T. McGann, and Jo Howard answer questions during the press briefing “Assessing Therapeutic Strategies and Improving Quality of Life for Patients with Sickle Cell Disease.” United Kingdom, Netherlands, and Canada that evaluated the need for pre-operative transfusion in patients with HbSS/HbSβ0 thalassemia un- dergoing low- to medium-risk surgeries. Children were randomized to either receive or not receive a routine preoperative transfusion, and the trial was closed early because of a significant increase in serious adverse events, including marked increase in acute chest syndrome, in the nontransfused arm. “This trial shows a significant increase in significant complications in those not transfused before surgery and affirms that children with homozygous SCD should be given a transfusion before surgery,” Dr. Howard stated. Additional findings of these studies were presented in oral presentations on Sunday.

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ASH News Daily - Monday, December 12, 2011

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