Macrocytosis and dysplastic anemia is associated with the cyclin-dependent kinase 4/6 inhibitor palbociclib in metastatic breast cancer

Abstract

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...

The relevance of macrocytosis induction during neoadjuvant dose-dense chemotherapy in breast cancer patients

“…Macrocytosis (elevation of MCV above upper normal limit) has developed in 31 out of 82 patients (38%) treated with AC-T dose-dense chemotherapy. This was less than expected in comparison to previously published results with chemotherapy in metastatic breast cancer (47-61%), as well as in our investigation of macrocytosis induction in ovarian cancer patients (67%) [12,14,15]. Similar to other reports, MCV elevation was accompanied by only mild drop in hemoglobin levels during treatment, which did not differ significantly between macrocytosis and no macrocytosis group [16].…”

Cyclin-Dependent Kinase 4/6 Inhibitor (Palbociclib) Induced Aplastic Anemia in a Patient with Metastatic Breast Cancer

“…An additional cohort study showed development of macrocytosis and red cell dysplasia in 34 patients treated with palbociclib, typically after 4 cycles. The dysplastic changes were reversible on discontinuation of palbociclib [16]. Although our patient developed worsening anemia with mildly elevated MCV, dysplastic changes were not seen in the bone marrow aspirate.…”

“…MDS, with reversible macrocytic anemia, attributed to palbociclib has been reported recently. Three cases of reversible MDS were observed and reported by Anampa et al [16]. These patients had dysplastic changes in their peripheral blood, and they all had bone marrow aspirates/biopsies which also showed dysplastic changes in erythroid precursors and megakaryocytes with bone marrow cellularity of about 10%.…”

Inducible deletion of CDK4 and CDK6 – deciphering CDK4/6 inhibitor effects in the hematopoietic system

“…Patients treated with CDK4/6 inhibitors frequently develop anemia. 28 , 38 In order to understand the contribution of CDK4 or CDK6 in this process, we studied erythroid development in Cdk4 D/D and Cdk6 D/D mice and their littermate controls. Cdk4 D/D and Cdk6 D/D mice displayed significantly reduced numbers of RBC in peripheral blood.…”

“…CDK4/6 inhibitor-associated side effects manifest primarily in the hematopoietic system and include anemia, neutropenia and lymphopenia. 28 , 29 , 38 As attempts are ongoing to develop CDK inhibitors that will more specifically target individual CDK it is important to attribute side effects to either CDK4 or CDK6. We analyzed novel mouse models harboring floxed Cdk4 or Cdk6 alleles and deleted CDK4 or CDK6 in adult hematopoiesis.…”