Reversible Macrocytosis with Cyclin Dependent Kinase Inhibitors
Authors: Kamboj Jasmine , Chalhoub Elie , Friedell Peter E. 
Published: October 2019

Abstract
Introduction
Cyclin-dependant kinases (CDKs) are a family of serine threonine kinases regulating cell cycle progression. The interaction of cyclin D (encoded by CCND1) with CDK4/6 helps in hyper-phosphorylation of the retinoblastoma (Rb) gene product, which further facilitates in progression through G1 to S phase of the cell cycle. Oncogenic signals in Hormone Receptor(HR)-positive breast cancer facilitate CCND1 amplification and overexpression of CDK4/6 to drive breast cancer proliferation and are associated with endocrine resistance in breast cancer.
CDK4/6 inhibitors selectively inhibit CDK4 and CDK6, resulting in loss of RB1 phosphorylation, henceforth blocking cell cycle progression and causing G1 phase arrest. These agents have profound activity in hormone receptor positive breast cancer cell lines and work synergistically with endocrine therapies to combat endocrine resistance in breast cancer.
Neutropenia is a known side effect of CDK4/6 inhibitors, with an incidence as high as 70%. Anemia as a side effect has been reported with low incidence. We report macrocytosis in patients receiving CDK4/6 inhibitors.
Methods
Retrospective analysis was performed at Sanford Health Bemidji. IRB approval was sought prior to initiation of the review. All patients who received CDK4/6 inhibitor in combination with hormonal therapy from 1/2016-2/2018 were included. Dates for initiating CDK4/6 inhibitor, onset of macrocytosis, maximum mean corpuscular volume (MCV-max) achieved, correlation of time with rising MCV (MCV-t) and normalization of MCV in the absence of CDK4/6 inhibitor (reversibility of macrocytosis) was documented. Complete Blood Count (CBC) was reviewed. Work up for elevated MCV was performed in each patient. Bone marrow biopsies were not performed.
Results
Table.
All patients (n=6) had rising MCV, within 4-6 weeks of initiation of the CDK4/6 inhibitor. Time to achieve MCV more than 100, varied from 3 to 7 months, this timing did not correlate well with baseline MCV. Progressively rising MCV with the duration of use of CDK4/6 inhibitor was seen. Reversibility of MCV was seen in 3 patients (Case B, C and D) who had interruption of CDK4/6 inhibitor for health related issues. Normalization of MCV on discontinuation of CDK4/6 inhibitor and rise in MCV on resumption of CDK4/6 inhibitor was seen. Hemoglobin drop from the baseline was not seen in any of the patients. Apart from neutropenia and macrocytosis, no other abnormality was seen on CBC. Stability of disease was documented in all patients on first set of scans done at 3 months and radiologic complete remission was documented in approximately 6-9 months of being on CDK4/6 inhibition. Macrocytosis workup was performed in all patients, including vitamin B12, folic acid, TSH, reticulocyte count, peripheral smear reviews and liver function tests. Vitamin B12 was low normal in case D, and was supplemented, without any changes seen on MCV.
Conclusions
CDK4/6 inhibition has become extremely prevalent in the recent times for hormone receptor positive breast cancer. We hypothesize that CDK4/6 inhibition produces reversible macrocytic anemia of unknown clinical significance. Given all patients had elevation in MCV along with complete radiologic remission, there is a possible causal relationship of elevated MCV and treatment response. The long-term clinical significance of observed macrocytosis and possible dysplasia, are important questions that need to be answered in large clinical trials.

Disclosures
No relevant conflicts of interest to declare.