Chronic myeloid leukemia in a patient treated with palbociclib and exemestane: a case report

Introduction

Breast cancer is the most common type of cancer in women, both in terms of incidence and mortality (1). Hormone receptor-positive (HR⁺), human epidermal growth factor receptor 2-negative (HER2⁻) breast cancer represents the predominant subtype, accounting for approximately 70% of all breast cancers (2). Cyclin-dependent kinase (CDK) 4/6 inhibitors, such as palbociclib, ribociclib, dalpiciclib, and abemaciclib, have been introduced as a treatment option for patients with HR⁺/HER2⁻ advanced breast cancer. Of note, these inhibitors are primarily used as first-line therapy in combination with an aromatase inhibitor (3-5). CDK4/6 inhibitors selectively block CDK4/6, resulting in the suppression of the CDK-retinoblastoma (RB)-E2F signaling pathway. This blockade prevents cells from transitioning from the G1 phase to the S phase, thereby inhibiting the uncontrolled proliferation of tumor cells (6).

Leukopenia and neutropenia are the most common adverse effects of endocrine therapy (ET) with palbociclib (7). Nevertheless, reports of hematological malignancies associated with palbociclib treatment are rare. Herein, we present a case of a patient who was treated with palbociclib for breast cancer and subsequently diagnosed with chronic myeloid leukemia (CML). We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-224/rc).

Case presentation

A 71-year-old woman was diagnosed with breast cancer in the left breast 12 years ago and underwent a modified radical mastectomy. The pathological analysis revealed pT1cN0M0, stage IA breast cancer. Immunohistochemistry revealed invasive ductal carcinoma with the following markers: estrogen receptor (ER) 95% (2+), progesterone receptor (PR) 20% (2+), human epidermal growth factor receptor 2 (HER2, c-erbB-2) (2+), and Ki-67 40% (+). Fluorescence in situ hybridization (FISH) was negative. She received adjuvant chemotherapy with six cycles of docetaxel (75 mg/m²), epirubicin (75 mg/m²), and cyclophosphamide (500 mg/m²), followed by six years of ET with anastrozole.

In 2017, the patient underwent surgical resection due to the presence of enlarged nodules in the left lung (Figure 1A,1B). Postoperative pathological biopsy revealed lung metastasis of breast cancer. Immunohistochemical analysis showed: thyroid transcription factor-1 (−), cytokeratin 7 (+), P63 protein individually weak (+), Ki-67 approximately 40% (+), ER (+), PR (+), and HER2 (1+). ET was switched to tamoxifen (20 mg/day). Two years later, the patient underwent surgical resection again due to the enlargement of a nodule in the right lower lung (Figure 2A,2B). Postoperative pathological biopsy again confirmed lung metastasis of breast cancer. Immunohistochemical results showed: thyroid transcription factor-1 (−), cytokeratin 7 (+), mammaglobin (+), gross cystic disease fluid protein-15 (+), GATA binding protein 3 (+), ER (+), PR (−), and Ki-67 30% (+). Following surgery, the patient was administered ET with exemestane in November 2019.

Figure 1 The image illustrates a progressive mass in the left lung, observed in April and September 2017 (indicated by the circle) (A,B).

Figure 2 The images depicting the progressive enlargement of the patient’s right lung mass over a two-year period, spanning from 2017 to 2019 (indicated by the circle) (A,B).

Since palbociclib became available in China in July 2018, the patient was initiated on a combination regimen of exemestane 25 mg and palbociclib 125 mg in November 2020. During the treatment, the patient developed grade III neutropenia, leading to a dose reduction of palbociclib to 100 mg. Despite intermittent follow-up due to coronavirus disease 2019 (COVID-19) quarantine protocols, the patient’s condition remained well-controlled, with no newly identified lesions.

In December 2022, the patient was admitted to the hospital with symptoms of a newly diagnosed COVID-19 infection and chest pain lasting for 2 hours. Blood tests showed leukocytes at 35.04×10⁹/L, platelets at 331×10⁹/L, hemoglobin at 127 g/L, and neutrophils at 21.37×10⁹/L. A repeat blood test revealed leukocytes at 52.09×10⁹/L, platelets at 319×10⁹/L, hemoglobin at 130 g/L, and an absolute neutrophil count of 29.69×10⁹/L (Figure 3A). Subsequent bone marrow aspiration smear revealed highly active myeloproliferative activity with 85% granulopoiesis. The proliferation of the granulocytic system was aberrant and highly active, with easily identifiable cells at each stage (Figure 3B,3C), and the blood smear indicated significant granulocytosis, characterized by increased middle and late juvenile granulocytes. Bone marrow biopsy revealed extremely active proliferation of nucleated bone marrow cells with minimal adipose tissue. Granulopoiesis was markedly increased, while other forms of hyperplasia were suppressed. Based on the above examination, the patient considered the possibility of CML and ruled out other causes of leukocytosis or other myelomonocytic disorders, such as chronic myelomonocytic leukemia, polycythemia vera, and primary myelofibrosis. Subsequent FISH studies showed positive for the BCR::ABL1 fusion gene, further confirming the patient’s CML. Then, the patient began treatment with imatinib mesylate at 400 mg daily. Palbociclib was discontinued, and the patient transitioned to exemestane monotherapy for breast cancer therapy. After 3 months of imatinib treatment, the CML was effectively controlled, and palbociclib was reintroduced at a reduced dosage of 75 mg.

Figure 3 Leukocyte count in complete blood count analysis and bone marrow aspiration smear. (A) The variations in white blood cell count of the patient, from the initial diagnosis of chronic myeloid leukemia to achieving disease control following treatment. (B) Bone marrow aspiration smear showing an unusually active neutrophilic granulocyte with Wright’s stain, at a magnification of 1,000×. (C) Wright’s stain showing hyperactive myelodysplasia at a magnification of 100×.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

Cancer development is often attributed to the uncontrolled proliferation of cells due to the dysregulation of cell cycle processes. The G1-S transition is a critical checkpoint in normal cell cycle regulation, which becomes disrupted in cancer cells, leading to unchecked cellular growth. CDK4/6 inhibitors suppress cell cycle proteins and mitotic regulators by inhibiting RB protein phosphorylation. This inhibition down-regulates S-phase cell cycle proteins and mitotic regulatory genes, impeding nucleotide biosynthesis and DNA replication, ultimately inducing G1 phase arrest and contributing to tumor regression (8). Palbociclib, a member of the CDK4/6 inhibitor class, was the first to be approved for use in combination with an aromatase inhibitor for the treatment of advanced breast cancer (5). Long-term pooled safety analyses of palbociclib have shown that the most common adverse events when combined with ET are neutropenia and infections, occurring in 80.6% and 54.7% of patients, respectively (9).

CML is a myeloproliferative disorder originating from hematopoietic stem cells (HSCs). It is characterized by the accumulation of leukemia cells at various stages of development, resulting from increased self-renewal, uncontrolled proliferation, impaired differentiation, and reduced apoptosis (10). A study suggested that alterations in the cell cycle can contribute to the survival and sustained growth of stem/progenitor cells in CML (11). The use of CDK4/6 inhibitors is known to induce cell cycle arrest at the G1 phase, with subsequent apoptosis considered a key mechanism of action (12). We hypothesize that CDK4/6 inhibitors prevent the proliferation of tumor cells and in some cases also alter the cell cycle of normal cells, resulting in uncontrolled proliferation of hematopoietic stem cells, leading to the development of CML. A case report from Korea also reported a patient with advanced breast cancer diagnosed with acute lymphoblastic leukemia in the treatment of palbociclib and letrozole (13). The article suggested that the inhibition of CDK 4/6 promoted cell cycle arrest, contributing to the proliferation of leukemic cells in this patient. However, a notable point in our report is that without prior genetic testing, it is challenging to distinguish treatment-related CML from de novo CML based on chromosome disorder, because both can share the same genetic features, particularly the presence of the Philadelphia chromosome (BCR::ABL1) (14).

In addition, we also analyzed therapy-related myeloid neoplasm (t-MN) as a result of cytotoxic treatments. Anthracyclines and alkylating agents, in particular, are known for their leukemogenic potential. A previous study found that the risk of leukemia is higher when two cytostatic drugs—each with low or non-leukemogenic potential—are used in combination. This suggests a possible synergistic effect on leukemogenesis between drugs directly interacting with DNA and those targeting DNA topoisomerase II (15). In this case, the patient received a chemotherapy regimen for six cycles postoperatively. Although epirubicin and cyclophosphamide individually have low leukemogenic potential, their combination increases the risk of leukemia due to their synergistic effects. However concerning the latency period, the risk of patients with previously existing solid tumors being diagnosed with t-MN increased within 9–12 months after treatment, peaked at 2 years, and gradually reduced to baseline within 10–15 years (16). Moreover, the study indicates that leukemia induced by alkylating agents typically has an incubation period of 3–5 years and often involves specific cytogenetic abnormalities on chromosomes 5 and/or 7 (17). Anthracyclines have a shorter incubation period (typically 1–3 years) for leukemia and are often associated with chromosomal abnormalities, particularly on chromosome 11, including translocation at 11q23 and abnormalities at 21q22 (15). In our case, it had been 11 years since the patient was treated with cyclophosphamide and epirubicin, and the two common chromosomal abnormalities associated with these drugs were not detected in the patient. Therefore, we consider that the patient has a low risk of developing CML due to the above chemotherapy drugs. The patient had also received taxanes such as docetaxel, but the main long-term side effect of these drugs was peripheral nerve damage (18). In addition, in endocrine treatment, the main side effects of tamoxifen or aromatase inhibitors such as anastrozole and exemestane were vasomotor symptoms, musculoskeletal disorders, and genitourinary syndrome of menopause, but they were rare in bone marrow (19). Therefore, docetaxel or ET is also less likely to have caused the development of CML in this patient.

Conclusions

This is the first documented case of chronic myeloid leukemia diagnosed following palbociclib treatment. While there is limited literature on the association between CDK4/6 inhibitors and hematological malignancies, the occurrence of CML in this patient may be linked to palbociclib treatment. Considering the risk of developing t-MN and bone marrow inhibition, the hemogram of HR⁺/HER2⁻ breast cancer patients should be carefully monitored during CDK4/6 inhibitor treatment, and based on our findings, it is recommended to perform the blood routine examination every 1–2 weeks. Besides, we recommend genetic screening before using CDK4/6 inhibitors to better distinguish primary or treatment-relevant genetic alterations.

Acknowledgments

The authors would like to thank the patient.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-224/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-224/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-224/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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