Acute myeloblastic leukemia secondary to breast cancer treatment: a case report

¹Hematology Laboratory, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy of Oujda, Mohammed First University, Oujda, Morocco, ²Internal Medicine Department, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy of Oujda, Mohammed First University, Oujda, Morocco

^&Corresponding author
Loubna Yacoubi, Hematology Laboratory, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy of Oujda, Mohammed First University, Oujda, Morocco

Introduction    

According to the World Health Organization's 2022 classification, post-cytotoxic therapy myeloid tumors are a distinct category that includes cases of acute myeloid leukemia (AML), myelodysplastic syndromes and treatment-related myelodysplastic/myeloproliferative neoplasms, which occur following cytotoxic therapy for an unrelated condition [1]. Therapy-related acute myeloid leukemia (t-AML) is associated with a high probability of unfavorable cytogenetics and shorter survival than de novo AML [2]. Breast cancer is the most common primary tumor preceding t-AML, followed by non-Hodgkin's lymphoma [2]. Increased incidence of t-AML due to advances in cancer treatment, reflected in longer life expectancy and improved patient survival [3].

Patient and observation     

Patient information: this is a 66-year-old female patient followed at the oncology center since 26/08/2020 for infiltrating ductal carcinoma of the breast treated with neoadjuvant chemotherapy from September 2020 to February 2021, protocol: 4AC60 + 4 Paclitaxel triweekly (Epirubicine 188 mg + Cyclophosphamide 940 mg/each 3 weeks for 4 cycles, then Paclitaxel 330 mg/each 3 weeks for 4 cycles), last treatment received on 09/02/2021; then put on tamoxifen-type hormone therapy (1 x 20 mg tablet daily) since 26/02/2021. She then underwent a mastectomy+homolateral axillary skimming on 09/04/2021, followed by adjuvant radiotherapy to the left chest wall and left supraclavicular area at a total dose of 42Gy in 15 fractions, spread out from 21/06/2021 to 09/07/2022, then put on Tamoxifen, with good breast control at the date of her last consultation in early 2023.

Clinical findings: clinical examination revealed a conscious patient, hemodynamically and respiratorily stable, with mucocutaneous pallor and no tumor syndrome. The patient suffered from anorexia, asthenia, and weight loss.

Timeline of the current episode: the history of the disease dates back to 3 months after her last consultation, with the onset of an anemic syndrome accompanied by increasing deterioration in the general condition.

Diagnostic assessment: a complete blood count showed normocytic normochromic anemia (hemoglobin 10.3 g/dl) (reticulocytes: 89.8G/L), thrombocytopenia (87 G/L), and leukocytosis (white blood cells 13740/ul). In addition, the biochemical workup revealed high levels of LDH (425 IU/L), uric acid (67.6mg /L). A peripheral blood smear revealed 10% blasts characterized by their large size, with high nucleocytoplasmic ratio, cytoplasmic basophilia, fine and nucleolated chromatin, Auer bodies were not observed (Figure 1). Bone marrow examination revealed 48% myeloid blasts, 25% neutrophil lineage, 23% monocytes, 03% erythroblasts and 01% lymphocytes. The Myeloperoxidase (MPO) reaction was negative in 100% of blasts, with numerous signs of dysplasia in the neutrophil granular lineage (hypogranulation, hypolobulation) (Figure 2). Immunophenotypic analysis revealed an estimated 76% myeloid blast population expressing HLA-DR, TdT, CD33, CD13, CD64, CD4, CD14 and CD56, but absent CD34 expression. The karyotype was not performed due to the patient's lack of resources.

Diagnosis: the diagnosis of t-LAM was based on cytological and immunophenotypic criteria for AML and on the patient's history of breast cancer treatment.

Therapeutic interventions: the patient was placed on an age-appropriate aracytin-idarubicin protocol.

Follow-up and outcome of interventions: the patient died.

Informed consent: the patient has expressed her consent to the publication of this report.

Discussion     

The most frequent consequences of chemotherapy-treated breast cancer are acute leukemia and myelodysplastic syndrome; indeed, most acute leukemias are myeloid, but treatment-related acute lymphocytic leukemia is estimated to account for 10% to 12% of all leukemias. Other hematological malignancies, such as multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma, may also be of concern to breast cancer patients [4]. The type, duration, and cumulative dose of chemotherapy are determining factors in the development of t-AML: Alkylating agents and topoisomerase II inhibitors are well-known factors associated with an increased risk of developing t-AML [5]. In six trials conducted by the National Surgical Adjuvant Breast and Bowel Project, the incidence of t-AML was markedly elevated in patients receiving intensified doses of cyclophosphamide and doxorubicin who required granulocyte-colony stimulating factor (G-CSF) support. Granulocyte-colony stimulating factor may promote the proliferation of damaged cells, leading to the development of leukemia [6].

Although rare, t-AML can also occur after treatment with immunosuppressive agents in patients without a history of cancer [5]. Therapy-related acute myeloid leukemia are thought to result from mutations in hematopoietic stem cells and/or the bone marrow microenvironment induced by cytotoxic therapy [7]. The fact that only some patients treated with identical protocols develop acute leukemia suggests that some individuals may have a genetic predisposition due to mutations in DNA damage detection or repair genes (e.g. BRCA1/2 or TP53) [7]. However, in most cases, the underlying pathogenesis remains unknown. Several features distinguish t-AML from de novo AML. Patients with t-AML have a higher incidence of TP53 mutations and chromosome 5 or 7 abnormalities. They also have complex cytogenetic mapping and respond less well to chemotherapy [7]. In 20-30% of cases, the first manifestation of treatment-related myeloid neoplasia is acute leukemia without a myelodysplastic phase, in which case they are associated with prior treatment with topoisomerase II inhibitors and generally present balanced translocations involving rearrangements of 11q23, notably t(9;11)(p21. 3;q23.3) and t(11;19) (q23.3;p13.1 ); 21 q22.1, as well as t(8;21) (q22;q22.1) and t(3;21)(q26.2;q22.1), and other abnormalities, such as t(15;1 7) (q24.1;q21.1) and inv(16) (p13.1q22). These balanced translocations may involve the MLL gene in chromosome band 11q23, or the PML/RARA genes in treatment-related acute promyelocytic leukemia. Therapy-related acute myeloid leukemia is rapidly progressive: the latency period is shorter, up to 12 months in some cases [8].

Around 70% of patients have a previous myelodysplastic phase or t-AML with myelodysplastic features with a long latency period (5-7 years), which is associated with alkylating agent and/or radiation therapy, and usually present with unbalanced chromosomal aberrations, most commonly partial loss of 5q, loss of chromosome 7 or deletion of 7q. Loss of 5q is often associated with one or more additional chromosomal abnormalities in a complex karyotype, such as de (13q), del(20q), del(11q), del(3p), loss of 17p or chromosome 17, loss of chromosome 18 or 21, or gain of chromosome 8 [8]. Studies investigating the development of t-AML after any malignancy and chemotherapy reveal that TP53 was mutated in 20% - 50% of t-AML patients, which is significantly higher than de novo AML patients, while FLT3 mutations were observed in 15% - 18% [9]. A small proportion of NM-t patients have an apparently normal karyotype. As a rule, diagnosis involves meeting the criteria for acute myeloid leukemia in addition to a documented history of chemotherapy or wide-field radiotherapy for an unrelated neoplasm [8].

The appearance of unexplained cytopenias in a person with prior exposure to cytotoxic drugs warrants investigation of possible therapy-related myeloid neoplasm(t-NM) [8]. The clinical and immunophenotypic presentation of t-NM is similar to that of de novo AML [8]. In our case, the myelogram was initially difficult to read because of the atypical morphology of the blasts with signs of dysplasia. Immunophenotyping confirmed the blastic nature of the blasts. Patients with t-AML have a poor prognosis, with a median survival of eight to 10 months after diagnosis [10]. Treatment of t-AML is tailored to the patient's age, comorbidities, performance status, and cytogenetic characteristics [10]. The only curative treatment is allogeneic bone marrow transplantation after daunorubicin-cytarabine (CPX-351) induction chemotherapy [10].

Conclusion     

Our case adds to the body of literature affirming the relationship of chemotherapy for breast cancer to the development of t-AML. Further investigation of this association is warranted, given its widespread use in the treatment of breast cancer. In the future, it will be important to identify effective therapies without these adverse effects, without sacrificing therapeutic gain.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

All authors have read and approved the final of this manuscript.

Figures     

Figure 1: morphology of blast from our case on a blood smear stained with May-Grünwald Giemsa (x100)

Figure 2: blasts morphology on examination of bone marrow stained with May-Grünwald Giemsa (x100)

References