Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders associated with progression to leukemia and poor survival. Clonal hematopoiesis in people without an MDS diagnosis carries an increased risk of cardiovascular death. Many clonally restricted mutations are shared between patients with MDS and those with non-MDS clonal hematopoiesis; therefore, we evaluated the risk of cardiovascular death among patients with MDS. We evaluated adults with MDS in the Surveillance, Epidemiology, and End Results database of the National Cancer Institute and compared them with the general population living in the same states. We grouped histological subtypes of MDS into lower-, intermediate-, and higher-risk disease. The primary outcomes were overall survival and primary cause of death (COD) as reported to state registries. A total of 21 372 patients with MDS between 2001 and 2011 died during follow-up with a known COD. The rate of death due to cardiovascular disease (CVD) was 4613 per 100 000 person-years, compared with 2091 in the age- and-sex-adjusted US population (standardized mortality ratio, 2.21). At 24 months, the cumulative incidence of death attributed to MDS or leukemia was 23% vs 8% for CVD. Among those alive at 60 months, 27% eventually died of CVD compared with 29% from MDS or leukemia; those with lower-risk disease who survived >60 months had more deaths attributed to cardiovascular causes (30%; 95% confidence interval [CI], 26.7-33.2%) than MDS itself (24%; 95% CI, 21.4-27.5%). Patients with MDS are more likely to die of cardiovascular causes than the general population. Modifying cardiovascular risk factors, especially among those with lower-risk disease, may be warranted for MDS-related clinical care.
Successful intensive induction chemotherapy for acute myeloid leukemia (AML) results in at least a 2 to 4 log10 reduction in the 1 trillion malignant cells that are present at diagnosis, often with recovery of normal platelet and neutrophil levels within a month after treatment initiation — an impressive result for a short course of treatment. More than half of patients with AML achieve remission after intensive induction therapy with an anthracycline and cytarabine, but relapse is common. Predicting the likelihood of relapse for an individual patient can be helpful in tailoring the intensity of postremission treatment.1 Even when a patient . . .
<p>PDF file - 68K, Table summarize results of annotation analyses of aberrantly spliced transcripts detected in AML patients as compared to normal donors.</p>
<div>Abstract<p>Clonal hematopoiesis (CH) is more common in older persons and has been associated with an increased risk of hematological cancers and cardiovascular diseases. The most common CH mutations occur in the <i>DNMT3A</i> and <i>TET2</i> genes and result in increased proinflammatory signaling. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (NCT01327846) evaluated the neutralizing anti-IL1β antibody canakinumab in 10,061 randomized patients with a history of myocardial infarction and persistent inflammation; DNA samples were available from 3,923 patients for targeted genomic sequencing. We examined the incidence of non-hematological malignancy by treatment assignment and CH mutations and estimated the cumulative incidence of malignancy events during trial follow-up. Patients with <i>TET2</i> mutations treated with canakinumab had the lowest incidence of non-hematological malignancy across cancer types. The cumulative incidence of at least one reported malignancy was lower for patients with <i>TET2</i> mutations treated with canakinumab versus those treated with placebo. These findings support a potential role for canakinumab in cancer prevention and provide evidence of IL1β blockade cooperating with CH mutations to modify the disease course.</p><p><b>Prevention Relevance:</b> We reveal that administering canakinumab is associated with a decrease in non-hematological malignancies among patients with clonal hematopoiesis (CH) mutations. These findings underscore canakinumab’s potential in preventing cancer and provide proof of IL1β blockade collaborating with CH mutations to enhance its clinical benefits.</p><p><a href="https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1940-6207.CAPR-24-0234" target="_blank"><i>See related Spotlight, p. 399</i></a></p></div>
<p>Supplementary Figure S2 shows cumulative incidence of lung cancer by treatment in patients without CH mutations, stratified by the canakinumab dose.</p>
The myelodysplastic syndromes (MDS) are frequently associated with clonally restricted cytogenetic abnormalities, but until recently, the molecular pathobiology underlying this diverse group of neoplastic bone marrow disorders has been largely obscure. During the last 10 years, many investigative groups have applied the formidable power of new molecular biology techniques to hunt for recurrent genetic alterations in MDS primary cells. Several genetic abnormalities, including mutations in RUNX1 (AML1), TET2, ASXL1, and TP53, have been discovered in a substantial fraction of MDS cases; genes rearranged or mutated less commonly in MDS include IER3, ATRX, RAS, and FLT3. Furthermore, haploinsufficiency and expression changes in RPS14, miR-145 and miR-146a, CDC25c, PP2A and SPARC in the absence of point mutations have also been implicated in MDS pathobiology. A major challenge will be to determine which of these mutations are causative "drivers" either in the development or progression of MDS, which might be therapeutically important because they predict response to treatment, and which are merely "passengers" along for the ride that alter phenotype but have no effect on the natural history of the disease. While the altered cellular biology of MDS is also increasingly well-understood, many mysteries remain. Abnormalities in iron regulation, microenvironment interactions, regulation of apoptosis, and oxidative damage/DNA repair may all play an important pathobiological role. By gaining a deeper understanding of the mechanisms of these complex and heterogeneous diseases, we will hopefully improve our ability to treat our patients with MDS beyond the therapies with limited effectiveness that are available at present.
