dysplastic anemia is associated with the Cyclin-Dependent Kinase 4/6 inhibitor palbociclib in metastatic breast cancer. Haematologica. 2017; 102:xxx doi:10.3324/haematol.2017.181941 Publisher's Disclaimer. Hematopoiesis is a dynamic process that relies on active proliferation and differentiation of stem cells into erythrocytes, myelocytes, and platelets; processes that rely on coordinated progression through various phases of the cell-cycle. Neutropenia is a well-recognized adverse effect of palbociclib, and rapidly reversible when the drug is interrupted, but nevertheless occurs in 80% of patients treated with palbociclib, whereas anemia (24%) and thrombocytopenia (16%) are less Figure S2). No other common causes for macrocytosis were observed, including B12/folate deficiency, liver insufficiency, or hypothyroidism (Table S1). Unilateral bone marrow aspirate/biopsy in all 3 cases revealed moderately hypocellular marrow (~ 10% cellularity) with mildly decreased myeloid/erythroid ratio, dysplastic erythroid forms including binucleated forms, nuclear budding, small hypolobated megakaryocytes, and adequate stainable iron sores ( Figure 1F-M and Figure S2). Due to pathological similarities to MDS, cytogenetic/mutational analysis was conducted that did not reveal any pathogenic chromosomal alterations or mutations (GENOPTIX's 40-gene myeloid molecular profile). Flow cytometry did not reveal an increase in leukemic blasts.
E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.To determine the extent of macrocytosis in a larger cohort, we evaluated hematological parameters in 34 patients who had received palbociclib for ER+ MBC between January 1, 2015and March 1, 2017 (n=34). Hematological parameters during palbociclib treatment, maximum MCV and minimum Hb, were compared to baseline values using the Wilcoxon signed-rank test.Significant change in MCV (delta MCV) was defined as Figure S4); however, when delta MCV≥10 was included as time-dependent variable, this difference was not statistically significant (HR 0.59, p=0.4).These data suggest that palbociclib use led to a macrocytic, dysplastic anemia with bone marrow changes that mimic human MDS. Therefore, CDK4 and CDK6 expression by qRT-PCR was evaluated using MDS derived (n=183) and healthy (n=17) CD34+ hematopoietic stem cells (HSCs) obtained from a large cohort of gene expression profiles. CDK6 expression was significantly lower...