Development of acute myeloid leukemia (AML) in two breast cancer patients undergoing treatment with long-term palbociclib: a dual case report

Introduction

Secondary acute myeloid leukemia (AML) may arise from a previous hematologic disorder such as myelodysplastic syndromes (MDS) or myeloproliferative neoplasms, or from exposure to a previous cytotoxic chemotherapy or radiation therapy that was given for another disease (cancer or autoimmune disease) (1,2).

The development of AML after agent exposure, referred to as therapy-related AML (t-AML), is associated with two classes of drugs: alkylating agents and topoisomerase II (TOP2) inhibitors (1). Breast cancer is one of the most frequently associated malignancies with the development of t-AML (1), and several studies have reported an increased risk of AML after breast cancer treatment (2). Prognosis is generally less favorable for patients with secondary AML than those with de novo AML (1-3).

Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that targets pathways that are essential for progression through the cell cycle, thereby interrupting the proliferation of malignant cells (4). CDK4/6 inhibitors in combination with endocrine therapy are considered standard of care treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Neutropenia is the most frequent adverse event associated with this line of therapy (5).

While t-AML after treatment with alkylating agents or TOP2 inhibitors is well documented, the development of hematologic malignancies concurrent with palbociclib therapy has not frequently been reported. We present two distinct cases of patients who developed AML while on treatment for metastatic breast cancer under the combination of palbociclib and letrozole. We present this article in accordance with the CARE reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-72/rc).

Case presentation

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 Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Case 1

A female patient was diagnosed with breast cancer at the age of 63 years after presenting for a self-referred mammogram in January 2010. The patient was married, had 2 pregnancies and one birth. She did not breastfeed. She had a hysterectomy at age 29 years and was on hormonal replacement therapy for a short undetermined period and had a history of hypothyroidism and osteopenia.

The mammogram found a lobulated and slightly spiculated mass in the upper inner quadrant of her right breast. A breast ultrasound confirmed a 1.4 cm ill-defined hypoechoic lesion that was biopsied, and the pathology revealed a stage 1 grade 2/3 infiltrating ductal carcinoma with positive estrogen (ER) and progesterone (PR) receptors and negative for HER2. She underwent a lumpectomy and right axillary node dissection in February 2010. The patient started on letrozole after completing radiation in July 2010, and completed letrozole therapy in 2016.

In 2019 while undergoing cataract surgery of her left eye, a choroidal mass was found in her right eye and further workup showed liver and bone metastases. In May 2019 she had a liver biopsy from one of the lesions that showed metastatic carcinoma consistent with breast primary, ER and PR receptors strongly positive (Allred 5+3=8). Next-generation sequencing (NGS) showed no actionable mutations with the PIK3CA reported negative.

She then had radiation to the right eye and left tibial lesion in August 2019. In September 2019 the patient was to start on palbociclib, letrozole, and zoledronic acid, however, treatment initiation was delayed after she was admitted to the hospital for the management of acute renal failure when her serum creatinine increased suddenly from 70 µmol/L on August 29, 2019, to 255 µmol/L on September 10, 2019, and reaching a peak of 424 µmol/L on September 13, 2019. Palbociclib (125 mg once daily taken for 21 days out of a 28-day cycle) and letrozole therapy was started in October 2019 after being reviewed by a nephrologist and discharged from hospital. At the time of therapy initiation, leukocyte and neutrophil counts were within normal limits.

In December 2019 palbociclib was held due to fatigue and dysgeusia and a dose reduction from 125 to 100 mg occurred in January 2020. Zoledronic acid was changed to denosumab to avoid renal toxicity. She responded well to the treatment with good tolerance after the dose modification of palbociclib. Blood counts were monitored prior to every cycle, and leukocytes and neutrophils remained normal or below normal throughout treatment. The patient was noted to be on chronic antibiotic therapy at this time due to recurrent urinary tract infections. In preparation for knee surgery, palbociclib was held beginning in February 2024. In May 2024 she underwent a left knee replacement and was later admitted to the hospital with knee pain, an elevated white blood cell (WBC) of 24.45×10⁹/L, absolute neutrophil count (ANC) of 16.97×10⁹/L, and C-reactive protein (CRP) of 329.51 mg/L. A prosthetic infection was suspected, however a complete infectious workup was negative. Hematology was consulted with WBC having increased to 57.77×10⁹/L and ANC to 40.21×10⁹/L, with blast cells noted at 1%. An inflammatory or infectious cause was suspected given the elevated CRP, rapid progression of leukocytosis and neutrophilia, and stability of blast cells. BCR-ABL was ordered to rule out chronic myeloid leukemia and came back negative, and CRP was monitored showing a downward trend; neutrophilia was determined to be reactive to inflammatory syndrome.

In September 2024 she experienced anemia [hemoglobin (Hgb) 71×10⁹/L], ANC 17.59×10⁹/L and WBC 51.43×10⁹/L, with circulating blasts of 20%. Bone marrow biopsy showed hypercellular marrow for age, at 50% cellularity, due to increased blasts of 42%, with myeloid phenotype, with positive CD34, CD117, myeloperoxidase (MPO), and decreased trilineage hematopoiesis (Figures 1,2). The patient was diagnosed with AML and started azacitidine and venetoclax. A repeat bone marrow biopsy was performed prior to cycle two which showed AML in morphological remission with blasts of 2%, however disease stopped responding after 5 cycles and treatment was discontinued. Contemporaneously, a computed tomography (CT) scan revealed new liver lesions and the patient started fulvestrant in November 2024. The patient had a prolonged hospital stay complicated by recurrent infections and mobility issues and expired in March 2025 due to severe septic shock post-operative removal of infected knee prosthesis. A summary of the timeline is presented in Figure 3.

Figure 1 Flow cytometry used for the diagnosis of AML for Case 1. Initial gating was performed using FSC and SSC to isolate target cells, with larger size and greater structural complexity typically demonstrating higher values in both parameters. A dominant cell population was identified on the FSC/SSC plot as the initial gate, which in primary specimens often encompasses lymphocytes, monocytes, granulocytes, blasts, atypical cells, or combinations thereof, depending on sample composition. AML, acute myeloid leukemia; FSC, forward scatter; SSC, side scatter.

Figure 2 Bone marrow biopsy slides for Case 1 scanned at 40× magnification taken from AML diagnosis in September 2024. (A) Positive H&E staining; (B) positive CD117 staining; (C) positive CD34 staining; (D) positive MPO staining. AML, acute myeloid leukemia; H&E, hematoxylin and eosin; MPO, myeloperoxidase.

Figure 3 Clinical timeline summary for Case 1. AML, acute myeloid leukemia.

Cytogenetic and molecular results at the time of AML diagnosis: FLT3 ITD mutation, NRAS p. (G12D), RUNX1 p. (Y281Vfs*316), SF3B1 p. (K666N), WT1 p. (R385Gfs*5); 47,XX,+8[4]/46,XX[16].

Case 2

A female patient was diagnosed with stage 2 breast cancer in 1993 at the age of 44 years. The patient was married and had three children and breast fed them for 3–6 months. Her last menstrual period was in 1994. She had a history of osteoporosis, asthma, hemorrhoidectomy, and thyroidectomy. A radical mastectomy was performed with 1/3 lymph nodes positive for malignancy. ER and PR receptors were negative, and the patient underwent adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF), followed by radiation to the chest wall.

In March 2005 at the age of 55 years, two nodules were detected in the right mastectomy scar and removed. The pathology came back as recurrent grade 1 infiltrating lobular carcinoma with positive ER and PR receptors, and negative for HER2. She started letrozole and radiation treatment and completed letrozole therapy in January 2013.

In June 2017 she developed pain and a bone scan detected metastases to the left scapula, right pubic ramus, acetabulum, and left femur. Biopsy confirmed metastatic carcinoma, ER and PR positive, and negative for HER2. Patient started letrozole and palbociclib (125 mg once daily taken for 21 days out of a 28-day cycle) in June 2017. Prior to therapy initiation, lab values for WBC, red blood cell (RBC), neutrophils, and platelets were within normal limits. A dose reduction from 125 to 100 mg occurred at cycle 2 due to neutropenia/leukopenia, and the patient subsequently had good tolerance and response to this treatment remaining on it for many years. Blood counts were monitored prior to each cycle and WBC, RBC, and neutrophil counts remained almost exclusively below the lower limit of normal while on palbociclib therapy.

In January 2025, palbociclib was held and she was assessed by hematology for progressive pancytopenia with Hgb 99 g/L, platelet count 27×10⁹/L, ANC 0.57×10⁹/L, and circulating blasts up to 25%. Significant macrocytosis [high mean corpuscular volume (MCV)] preceding the cytopenias, in conjunction with the prior exposure history, raised concern for an underlying MDS and a bone marrow biopsy was expedited. The results concluded hypercellular marrow for age, at 55% cellularity, due to increased blasts of 50%, with myeloid phenotype, with positive CD117, MPO (Figures 4,5). The patient was diagnosed with AML and started treatment with azacitidine and venetoclax. Pancytopenia persisted on treatment and patient was given antifungal and antibacterial prophylaxis. Bone marrow biopsy performed after cycle 2 showed AML in morphological remission. After six cycles, new cytopenias were noted and a repeat biopsy showed relapse of disease with 33% blasts. All treatment was discontinued, and the decision was made for palliative care with antimicrobials and transfusions as indicated. The patient expired in hospital in December 2025. A summary of the timeline is presented in Figure 6.

Figure 4 Flow cytometry used for the diagnosis of AML for Case 2. Initial gating was performed using FSC and SSC to isolate target cells, with larger size and greater structural complexity typically demonstrating higher values in both parameters. A dominant cell population was identified on the FSC/SSC plot as the initial gate, which in primary specimens often encompasses lymphocytes, monocytes, granulocytes, blasts, atypical cells, or combinations thereof, depending on sample composition. AML, acute myeloid leukemia; FSC, forward scatter; SSC, side scatter.

Figure 5 Bone marrow biopsy slides for Case 2 scanned at 40× magnification taken from AML diagnosis in January 2025. (A) Positive H&E staining; (B) positive CD117 staining; (C) positive MPO staining. AML, acute myeloid leukemia; H&E, hematoxylin and eosin; MPO, myeloperoxidase.

Figure 6 Clinical timeline summary for Case 2. AML, acute myeloid leukemia.

Cytogenetic and molecular results at the time of AML diagnosis: KMT2A::MLLT1 fusion, TP53 p. (P278L), U2AF1 p. (S34T); 46,XX,t2;15(q21;q15),t(11;19(q23;p13.3)[9]/46,XX[10].

Discussion

The presented cases documenting the development of AML in two breast cancer patients undergoing prolonged treatment (4.3 and 7.5 years) with the combination of palbociclib and letrozole are unique and represent a subject that remains poorly characterized in the literature. The patients discussed in this report were both diagnosed with hormone receptor-positive metastatic breast cancer that was treated with palbociclib and letrozole. Historically, both patients also received prior letrozole therapy for early-stage breast cancer, and one patient also received the alkylating agent cyclophosphamide more than 30 years prior to AML diagnosis. Both patients presented with hematological abnormalities including circulating blasts that prompted bone marrow biopsy confirming AML.

Therapy-related AML results from mutational events or changes to the chromosome that are brought about by exposure to certain cytotoxic therapies. Under the pressure of chemotherapy and radiotherapy, normal hematopoietic stem cells are depleted and mutant clones that are more resistant to DNA damage gain proliferative advantage. Further DNA damage in the form of additional mutations or abnormalities is incurred via cytotoxic therapy, resulting in the emergence of fully leukemic cells and changes in the bone marrow microenvironment that may interfere with normal function (6). Most cases of t-AML after alkylating agents or radiation develop 5–6 years after the exposure—with some documented up to 16 years later—and commonly present as an MDS (7). A case series investigating t-AML noted one case with a latency period of 20 years (8), but this finding was isolated and not reproduced in the literature. It is common for cytogenetic abnormalities to present in patients with t-AML, however this most frequently involves chromosomes 5 and/or 7 (7). Although we cannot exclude cyclophosphamide exposure in patient two as a possible contributor, we consider this to be less likely given the 30-year time span and lack of precursor MDS or expected chromosomal abnormalities.

While patient one did not show any translocations at chromosomes 5 or 7, cytogenetic studies did reveal an abnormal karyotype with a gain of chromosome 8 detected. Trisomy 8 is a cytogenetic aberration that can be seen in 10% to 15% of patients with AML and is associated with an intermediate prognosis (9). We know that genetic predisposition may influence the development of t-AML. The European LeukemiaNet recommendations in 2022 have removed therapy-related AML as a category, and instead apply previous therapy as a diagnostic qualifier (1). The molecular basis of t-AML has been divided into different subtypes including (I) secondary-type mutations (SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2); (II) TP53 mutations; and (III) “de-novo”- or pan-AML-type mutations [including but not limited to NPM1, KMT2A (MLL) rearrangements, FLT3, NRAS, KRAS, IDH1, IDH2, WT1] (6). Both presented patients exhibited pathogenic mutations associated with AML, suggesting an underlying vulnerability to its development. Patient 1 presented with FLT3-ITD, NRAS, and WT1 mutations, along with mutations in RUNX1 and SF3B1 which are associated with adverse risk and can confer poor prognosis. Patient 2 carried a KMT2A::MLLT1 fusion as well as TP53 and U2AF1 mutations which are also associated with adverse risk and poor prognosis (6). Pre-existing clonal hematopoiesis of indeterminate potential (CHIP) cannot be excluded, although this predominantly affects DNMT3A, TET2, and ASXL1, for which mutations were absent in these two patients (10). However, mutations in DNA damage response and repair genes are expected in t-AML and were observed in the patient who received prior alkylating therapy with a TP53 mutation. The possibility must be considered that prolonged neutropenia resulting from palbociclib therapy may have masked developing CHIP-associated cytopenias.

We were not able to find any studies linking palbociclib to leukemogenesis, and currently only case reports have raised concern regarding hematological malignancies in patients on long-term treatment with CDK4/6 inhibitors, although causation remains speculative. CDK4/6 inhibitors such as palbociclib inhibit phosphorylation of retinoblastoma (Rb) resulting in cell cycle arrest in the G1 phase, thereby disrupting cell proliferation. While this is effective in treating hormone receptor-positive breast cancer, this can inadvertently cause DNA damage (11).

Development of acute lymphoblastic leukemia (ALL) has been reported in one case of a patient on palbociclib, where it was hypothesized that cell cycle arrest and apoptosis caused by a CDK4/6 inhibitor could lead to the proliferation of leukemic cells (12). In another case report documenting development of AML while on treatment with palbociclib, the patient had also received various other therapies therefore it was difficult to establish a link; however raised suspicion that known side effects of palbociclib such as pancytopenia, as well as long term exposure to the drug, may contribute to the development of AML (13).

It is imperative to note that these case reports serve to highlight an observation, and many other factors may have contributed to the development of AML in these patients, including prior agent exposure, comorbidities such as chronic infections, or genetic predisposition. In practice, practitioners should consider any pre-existing risk factor while monitoring patients on long-term palbociclib. While cytopenias are expected to occur as a side effect, lack of count recovery between cycles may warrant investigation into an underlying hematological pathology. Close monitoring for pattern changes in blood counts over time may also reveal early trends and serve as a flag for further investigation. Significant macrocytosis that is otherwise unexplained can be an early sign of MDS, that can in turn progress to AML. Paying close attention to the WBC differential for the presence of blast cells can be especially important in patients at increased risk. Awareness of CHIP-associated mutations is also important as NGS panels are more commonly performed.

Conclusions

These cases highlighting the rare but serious development of AML while undergoing long-term treatment with palbociclib raise the possibility of a potential association, although definitive causality cannot be established. In the absence of established studies, case reports can serve an important role in supplementing available literature. The frequent occurrence of cytopenia associated with CDK4/6 therapy could potentially play a role (14), particularly when treatment is sustained over long time periods. It is also worth considering the role of CDK4/6 inhibition in cell cycle arrest and the possibility of impaired DNA repair resulting in genetic mutations (11). Given that prior cytotoxic exposure was absent or occurred remotely in these cases, further research and monitoring for potential secondary hematologic malignancies is warranted for long-term palbociclib therapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-72/rc

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-72/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-72/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 Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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/.

References

1. Capelli D, Menotti D, Fiorentini A, et al. Secondary Acute Myeloid Leukemia: Pathogenesis and Treatment. In: Li W, ed. Leukemia. Brisbane (AU): Exon Publications; October 16, 2022.
2. Valentini CG, Fianchi L, Voso MT, et al. Incidence of acute myeloid leukemia after breast cancer. Mediterr J Hematol Infect Dis 2011;3:e2011069. [Crossref] [PubMed]
3. Kayser S, Döhner K, Krauter J, et al. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood 2011;117:2137-45. [Crossref] [PubMed]
4. Braal CL, Jongbloed EM, Wilting SM, et al. Inhibiting CDK4/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences. Drugs 2021;81:317-31. [Crossref] [PubMed]
5. Slamon DJ, Diéras V, Rugo HS, et al. Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer. J Clin Oncol 2024;42:994-1000. [Crossref] [PubMed]
6. Kotsiafti A, Giannakas K, Christoforou P, et al. Progress toward Better Treatment of Therapy-Related AML. Cancers (Basel) 2023;15:1658. [Crossref] [PubMed]
7. Adult Acute Myeloid Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]. Accessed January 8, 2026. Available online: https://www.cancer.gov/types/leukemia/hp/adult-aml-treatment-pdq
8. Yang J, Chen B. Therapy-related acute myeloid leukemia: A case series. Oncol Lett 2022;23:171. [Crossref] [PubMed]
9. Hemsing AL, Hovland R, Tsykunova G, et al. Trisomy 8 in acute myeloid leukemia. Expert Rev Hematol 2019;12:947-58. [Crossref] [PubMed]
10. Mangaonkar AA, Bolton KL, Patnaik MM. Clonal Hematopoiesis of Indeterminate Potential and Clonal Cytopenias of Undetermined Significance: 2026 Update on Clinical Associations and Management Recommendations. Am J Hematol 2026;101:550-65. [Crossref] [PubMed]
11. Crozier L, Foy R, Mouery BL, et al. CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal. EMBO J 2022;41:e108599. [Crossref] [PubMed]
12. Park JH, Park H, Kim KH, et al. Acute Lymphoblastic Leukemia in a Patient Treated with Letrozole and Palbociclib. J Breast Cancer 2020;23:100-6. [Crossref] [PubMed]
13. Dhamsania R, Singh A, Mahmood S, et al. Rare case of therapy-related acute myeloid leukemia from breast carcinoma management with palbociclib. Chest. 2024;166:A4247-A4248.
14. Ren X, Yan C, Tian L, et al. Haematopoietic cytopenia associated with cyclin-dependent kinase 4/6 inhibitors: A real-world study of data from the food and drug administration adverse event reporting system database. Int J Immunopathol Pharmacol 2022;36:3946320221145520. [Crossref] [PubMed]