INTRODUCTION
Chronic myeloid leukemia (CML) is a myeloproliferative bone marrow disease. It presents granulocyte proliferation and a potential rise in the blast count of the bone marrow. This neoplasm occurs because of BCR-ABL fusion. Imatinib, the BCR-ABL tyrosine kinase inhibitor, has been successfully used as a first-line treatment for CML during the last 25 years. Unfortunately, imatinib resistance has been described and has been the main topic in CML research. BCR-ABL domain mutations are the main cause of resistance and are detected in the majority of cases [1]. In addition to these mutations, many other factors play a key role in imatinib resistance, such as the biology of malignant cells, genetic background, gene amplifications, and pharmacologic aspects. In this case report, we described a patient who was resistant to imatinib without any imatinib-resistant mutations.
CASE PRESENTATION
A 47-year-old male with complaints of sore throat and rapid weight loss was diagnosed with CML-chronic phase and intermediate risk group in September 2019. Imatinib has been prescribed as a first-line treatment.
At the onset of the disease, blood smear showed leukocytosis (269.18×109/L), anemia (9.5 g/dL), and normal platelet count (389×109/L). Ultrasound screening revealed splenomegaly + 7 ms. The bone marrow aspirate smears showed 2% blasts, 15% erythroid cells, 23% immature granulocytes, 39% mature granulocytes, 11% mature lymphocytes, 4% immature eosinophils, 3% basophils, 3% mature eosinophils. Trephine biopsy showed hypercellular marrow with sheets of immature cells, elevated megakaryocytes, and reticulin grade I.
Interphase fluorescence in situ hybridization showed BCR-ABL1 translocation in 100% of the cells. The reverse transcription-polymerase chain reaction (RT- PCR) for the BCR-ABL1 fusion transcript p210 was detected at 56.322% international scale (IS).
In February 2021, he presented with persistent thrombocytopenia and anemia. RT- PCR for the BCR-ABL1 fusion transcript p210 was detected at 16.359% IS. At the end of the first year, the patient did not achieve a major molecular response (MMR), although next-generation sequencing using a 54 myeloid-targeted gene panel was negative for ABL1 L248V, G250E, Y253H, E255K, F311L, T315I, F317L, F311I, M351T, and other point mutations (Figure 1). Nilotinib is prescribed as a second-line treatment. Within a month, he achieved significant clinical and hematological improvement. At the end of the second year, the patient achieved MMR.
DISCUSSION
Many patients with chronic phase CML [2] and accelerated phase [3] achieve major cytogenetic and molecular responses with imatinib. However, many patients develop resistance against imatinib, which is often associated with point mutations in BCR-ABL [4]. The prognosis is not favorable for such patients. In addition to molecular resistance against imatinib, other mechanisms such as intrinsic resistance of CML stem cells [5,6], bioavailability of imatinib [7], clonal progression, BCR-ABL-independent signaling pathway involvement, and poor accumulation of imatinib in the central nervous [8,9] have also been described.
Imatinib resistance is a crucial issue in CML treatment. In the future, new, more successful BCR-ABL inhibitors, combination therapy, and molecules that enter the blood-brain barrier may improve the outcomes of CML therapy. This approach can also prevent imatinib resistance in the early phase of CML.
Ethics
Informed Consent: Patient freely and voluntarily gave consent and signed a Informed Consent Form.
Financial Disclosure: The author declared that this study received no financial support.