Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Genetic diversity within leukemia-associated immunophenotype-defined subclones in AML.

Acute myeloid leukemia (AML) is a highly heterogeneous disease showing dynamic clonal evolution patterns over time. Various subclones may be present simultaneously and subclones may show a different expansion pattern and respond differently to applied therapies. It is already clear that immunophenotyping and genetic analyses may yield overlapping, but also complementary information. Detailed information on the genetic make-up of immunophenotypically defined subclones is however scarce. We performed error-corrected sequencing for 27 myeloid leukemia driver genes in 86, FACS-sorted immunophenotypically characterized normal and aberrant subfractions in 10 AML patients. We identified three main scenarios. In the first group of patients, the two techniques were equally well characterizing the malignancy. In the second group, most of the isolated populations did not express aberrant immunophenotypes but still harbored several genetic aberrancies, indicating that the information obtained only by immunophenotyping would be incomplete. Vice versa, one patient was identified in which genetic mutations were found only in a small fraction of the immunophenotypically defined malignant populations, indicating that the genetic analysis gave an incomplete picture of the disease. We conclude that currently, characterization of leukemic cells in AML by molecular and immunophenotypic techniques is complementary, and infer that both techniques should be used in parallel in order to obtain the most complete view on the disease.

[Clonal hematopoiesis: a risk factor for leukemia and cardiovascular disease?] / Klonale hematopoëse.

Upon ageing, hematopoietic stem or progenitor cells harboring acquired leukemia-associated mutations may expand clonally and become detectable in peripheral blood. So-called clonal hematopoiesis may be detected in 5-55% of (otherwise healthy) individuals aged ≥ 70 years. Clonal hematopoiesis is associated with a higher risk of developing hematological neoplasms, although most individuals never develop malignant disease. Surprisingly, clonal hematopoiesis is also recognized as a new cardiovascular risk factor. Specific patient categories may be at higher risk for the consequences of clonal hematopoiesis. For future risk stratification, there is a need to distinguish high-risk clonal hematopoiesis from 'physiological' ageing processes. In this article we summarize current knowledge on clonal hematopoiesis and its clinical implications. Given the widespread application of next-generation sequencing in routine diagnostics, multidisciplinary recommendations for clinical management of individuals with detected clonal hematopoiesis should be developed.

IAPs as therapeutic targets in haematological malignancies.

BACKGROUND: Regulation of apoptosis is fundamental to maintain the balance between cell survival and cell death. Disruption of this process may have severe consequences, contributing to carcinogenesis. Therapeutic targeting of the proteins that control apoptosis may therefore be used in the treatment of various types of cancer. OBJECTIVE: We address whether regulators of apoptosis could be suitable targets for the treatment of haematological cancers. METHODS: We focus on the emerging role of inhibitor of apoptosis (IAP) proteins in cancer, their modulators and the possibility of therapeutically targeting these proteins in haematological cancer. RESULTS/CONCLUSION: IAPs have emerged as an important novel class of intracellular proteins that regulate apoptosis. Various compounds have been described that may be used to modulate the activity of IAPs, which opens the way to therapeutically targeting these proteins in cancer.

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Apoptosis is an essential process for the selection and survival of lymphocytes. Resistance to apoptosis can promote malignant transformation of hematopoietic cells. Proteins that regulate apoptosis may therefore be critically involved in the development of hematological cancer. A delicate balance between pro- and antiapoptotic mechanisms determines whether a cell death signal can activate the execution of the apoptotic cell death program. The family of inhibitor of apoptosis (IAP) proteins is a recently identified, novel category of apoptosis-regulatory proteins. IAPs can inhibit the activation of caspases that are the executioners of apoptosis, activated by both the extrinsic and intrinsic pathway. IAPs may thereby set the threshold for apoptosis-activation and play a key role in the regulation of apoptotic cell death. IAPs themselves are also subject to strict regulation through feedback mechanisms. This paper focuses on the role of IAP family proteins in the regulation of apoptosis and discusses implications for their involvement in cancer and possible use for cancer therapy, especially in leukemias and lymphomas.