Blasts in context:the impact of the immune environment on acute myeloid leukemia prognosis and treatment

Acute myeloid leukemia (AML) is a cancer that originates from the bone marrow (BM). Under physiological conditions, the bone marrow supports the homeostasis of immune cells and hosts memory lymphoid cells. In this review, we summarize our present understanding of the role of the immune microenvironment on healthy bone marrow and on the development of AML, with a focus on T cells and other lymphoid cells. The types and function of different immune cells involved in the AML microenvironment as well as their putative role in the onset of disease and response to treatment are presented. We also describe how the immune context predicts the response to immunotherapy in AML and how these therapies modulate the immune status of the bone marrow. Finally, we focus on allogeneic stem cell transplantation and summarize the current understanding of the immune environment in the post-transplant bone marrow, the factors associated with immune escape and relevant strategies to prevent and treat relapse.</p

Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients With CML-CP: The ENRICH Study

AbstractBackgroundMany patients with chronic myeloid leukemia in chronic phase experience chronic treatment-related adverse events (AEs) during imatinib therapy. These AEs can impair quality of life and lead to reduced treatment adherence, which is associated with poor clinical outcomes.Patients and MethodsIn the phase II ENRICH (Exploring Nilotinib to Reduce Imatinib Related Chronic Adverse Events) study (N = 52), the effect of switching patients with imatinib-related chronic low-grade nonhematologic AEs from imatinib to nilotinib was evaluated.ResultsThree months after switching to nilotinib, 84.6% of the patients had overall improvement in imatinib-related AEs (primary endpoint). Of 210 imatinib-related AEs identified at baseline, 62.9% had resolved within 3 months of switching to nilotinib. Of evaluable patients, most had improvements in overall quality of life after switching to nilotinib. At screening, 65.4% of evaluable patients had a major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale). After switching to nilotinib, the rate of the major molecular response was 76.1% at 3 months and 87.8% at 12 months. Treatment-emergent AEs reported with nilotinib were typically grade 1 or 2; however, some patients developed more serious AEs, and 8 patients discontinued nilotinib because of new or worsening AEs.ConclusionOverall, results from the ENRICH study demonstrated that switching to nilotinib can mitigate imatinib-related chronic low-grade nonhematologic AEs in patients with chronic myeloid leukemia in chronic phase, in conjunction with acceptable safety and achievement of molecular responses. This trial was registered at www.clinicaltrials.gov as NCT00980018

Prediction of Graft-Versus-Host Disease in Humans by Donor Gene-Expression Profiling

BACKGROUND: Graft-versus-host disease (GVHD) results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantation (AHCT). Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be “stronger alloresponders” than others, and consequently more likely to elicit GVHD. METHODS AND FINDINGS: To this end, we measured the gene-expression profiles of CD4(+) and CD8(+) T cells from 50 AHCT donors with microarrays. We report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD or not. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, we found that for chronic GVHD the “dangerous donor” trait (occurrence of GVHD in the recipient) is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-β signaling and cell proliferation. CONCLUSIONS: These findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient. The ability to discriminate strong and weak alloresponders using gene-expression profiling could pave the way to personalized transplantation medicine

Risk of progression in chronic phase-chronic myeloid leukemia patients eligible for tyrosine kinase inhibitor discontinuation: Final analysis of the TFR-PRO study

Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP-CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD-eligible patients, we conducted TFR-PRO, a cohort retro-prospective study: 870 CP-CML patients eligible for TD formed a discontinuation cohort (505 patients) and a reference one (365 patients). The primary objective was the time adjusted rate (TAR) of progression in relation to TD. Secondary endpoints included the TAR of molecular relapse, that is, loss of major molecular response (MMR). With a median follow up of 5.5 years and 5188.2 person-years available, no events occurred in the TD cohort. One event of progression was registered 55 months after the end of TD, when the patient was contributing to the reference cohort. The TAR of progression was 0.019/100 person-years (95% CI [0.003-0.138]) in the overall group; 0.0 (95% CI [0-0.163]) in the discontinuation cohort; and 0.030 (95% CI [0.004-0.215]) in the reference cohort. These differences are not statistically significant. Molecular relapses occurred in 172/505 (34.1%) patients after TD, and in 64/365 (17.5%) patients in the reference cohort, p &lt; .0001. Similar rates were observed in TD patients in first, second or third line of treatment. CML progression in patients eligible for TD is rare and not related to TD. Fears about the risk of disease progression among patients attempting TD should be dissipated

Psychological Profiles in the Prediction of Leukocyte Telomere Length in Healthy Individuals

<div><p>Background</p><p>Shorter telomere length (TL) may signal premature cellular aging and increased risk for disease. While depression and psychosocial stress have been associated with shorter telomeres, other psychological risk factors for cardiovascular disease have received less attention.</p><p>Purpose</p><p>To evaluate the association between TL and psychological risk factors (symptoms of anxiety and depression, hostility and defensiveness traits) for heart disease, and to examine whether chronological age and sex moderate the associations observed.</p><p>Methods</p><p>132 healthy men and women (M_age = 45.34 years) completed the Marlowe-Crowne Social Desirability Scale, the Beck Depression Inventory II, The Beck Anxiety Inventory and the Cook-Medley Hostility Scale. Relative TL was measured by quantitative polymerase chain reaction (PCR) of total genomic DNA samples. A series of hierarchical linear regressions were performed controlling for pertinent covariates.</p><p>Results</p><p>Shorter TL was observed among individuals high in defensiveness (β = -.221) and depressive symptoms (β = -.213), as well as in those with less hostility (β =.256) and anxiety (β =.220)(all Ps<.05). Psychological variables explained 19% of the variance over and above that explained by covariates (age, sex, exercise, alcohol consumption, systemic inflammation, and 24-hr mean arterial pressure). Age moderated the relation between TL and defensiveness (β =.179, p =.03). Sex did not influence any of the relations.</p><p>Conclusions</p><p>Telomere length is associated with psychological burden though the direction of effect differs depending on the psychological variables under study. Further research is needed to determine the reasons for and implications of these seemingly contradictory findings.</p></div

Detailed summary of concurrent associations between individual psychological factors and TL.

<p>Detailed summary of concurrent associations between individual psychological factors and TL.</p