Secondary acute promyelocytic leukemia in a patient with antecedent chemotherapy for breast carcinoma and multiple myeloma – case report

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), accounting for 10-15% of total AML cases⁽¹⁾. Genetically, over 95% of APL patients carry a balanced translocation that involves the long arms of chromosomes 15 and 17 – t(15;17)(q24;q21)⁽¹⁾. Accordingly, a fusion between the promyelocytic leukemia gene (PML) and the retinoic acid receptor alpha gene (RARA) is generated at molecular level, that displays high sensitivity to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)⁽²⁾. Acute promyelocytic leukemia predominantly occurs de novo; however, cases of secondary APL developing after therapy for other malignancies have been previously reported⁽³⁾. Due to the imminent risk of life-threatening bleeding, acute promyelocytic leukemia is considered a hematologic emergency, requiring immediate diagnosis and initiation of specific therapy⁽²⁾.

This report describes the case of a 66-year-old female with a history of type 2 diabetes, grade II essential hypertension, ischemic heart disease, chronic hepatitis C, glaucoma, poorly differentiated invasive breast carcinoma (pT2pN0) treated with five cycles of chemotherapy (finalized in February 2016), and IgA Kappa stage II B multiple myeloma (MM). For multiple myeloma, she underwent three therapeutic lines with bortezomib, the last one consisting of CyBorD (cyclophosphamide, bortezomib and dexamethasone) protocol completed in March 2017, which resulted in a complete response with negative immunofixation in both serum and urine. In April 2019, the patient experienced an asymptomatic relapse of multiple myeloma and was monitored periodically.

In July 2021, the patient presented with fatigue and weakness. The automated complete blood count showed normal hemoglobin (Hb) levels (12.4 g/dL), moderate leukopenia and neutropenia (2.24x10⁹/L and 1.17x10⁹/L, respectively), and mild thrombocytopenia (112x10⁹/L), without atypical cells on peripheral blood smear. Bone marrow aspirate revealed markedly decreased cellularity with 10-15% atypical promyelocytes containing multiple Auer rods, and 4% myelomatous plasma cells. Flow cytometry analysis identified 17% myeloid precursor cells with an immunophenotype compatible with atypical promyelocytes. The fluorescence in situ hybridization (FISH) test confirmed the presence of PML::RARA fusion, leading to the diagnosis of secondary APL (non-high risk) related to previous chemotherapy for breast carcinoma and concurrent multiple myeloma.

Timely induction therapy for APL was initiated, based on combination of ATRA 90 mg/day and ATO 12.5 mg/day. Hematologic remission was achieved, with no atypical promyelocytes in the bone marrow aspirate, although moderate anemia persisted (Hb 8.8 g/dL). In September 2021, the molecular remission was confirmed by quantitative real-time PCR. However, due to neuropsychiatric complications, including speech disorder and pyramidal syndrome, consolidation therapy with ATO was deemed unsuitable. Maintenance therapy was initiated in November 2021, consisting of oral ATRA (90 mg for 15 days, every three months), methotrexate (30 mg/week), and mercaptopurine (50 mg/m²/day).

In February 2022, the patient was admitted with severe anemia (Hb 6.3 g/dL), severe neutropenia (0.42x10⁹/L), and low vitamin B12 levels (127 pg/mL). Bone marrow examination indicated megaloblastic changes of the erythroid precursors without atypical promyelocytes, consistent with bone marrow toxicity induced by methotrexate and vitamin B12 deficiency. After leucovorin administration and vitamin B12 substitution treatment, the anemia was corrected. The hematologic remission of APL was maintained, despite dose reduction of methotrexate (25-50%) and ATRA (50%) imposed by hepatotoxicity. Also, no progression of multiple myeloma (monoclonal component stable at 0.4 g/dL) was observed.

In November 2023, bone marrow cytology showed a normal cellularity, with 12% plasma cells and no atypical promyelocytes, together with undetectable PML::RARA fusion at molecular testing. The patient remains under hematologic surveillance every three months, with no signs of APL relapse or need for further specific treatment.

Breast cancer is the most common malignancy in wo­men, with a high cure rate due to early diagnosis and intensive chemotherapy regimens, including an­thra­cy­cline-alkylating agents⁽⁴⁾. However, these treatments are associated with long-term toxicities, potentially lea­ding to secondary AML⁽⁴⁾. Cases of therapy-related APL have been rarely described in the literature, especially in breast cancer patients treated with topoisomerase II inhibitors (anthracyclines) or alkylating agents^(3,5). No differences in terms of outcome between patients with secondary acute promyelocytic leukemia and those with the de novo APL was noticed⁽³⁾. The occurrence of therapy-related APL in multiple myeloma is infrequent, being reported in association with melphalan treatment⁽⁶⁾.

The reported case refers to an unusual occurrence of APL as a third cancer in a patient previously treated for breast carcinoma and multiple myeloma, suggesting the existence of a possible genetic background predisposing for multiple neoplasms. Acute promyelocytic leukemia was considered as a secondary event to chemotherapy received for breast cancer and, possibly, for multiple mye­loma. The achievement of APL remission demonstrates the efficacy of targeted therapy, despite the presence of a complex oncologic and hematologic background in this patient. 

Autori pentru corespondenţă: Cristina Mambet E-mail: cristina.mambet@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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