Extramedullary sudden blast crisis in chronic-phase chronic myeloid leukemia during first-line treatment with nilotinib

The natural course of chronic myelogenous leukemia (CML) has changed dramatically since the introduction of tyrosine kinase inhibitors (TKIs) with 490% of the patients achieving long-term disease control. Development of resistance with progression to accelerated phase/blastic crisis (AP/BC) is observed in a limited percentage of patients and is mainly documented in those who do not respond ‘optimally’ according to cytogenetic and molecular response criteria at given intervals. Rare reports of an abrupt blastic transformation defined as sudden blast crisis (SBC) have been described in chronic-phase (CP) CML patients, who had already achieved optimal response, that is, complete cytogenetic (cCgR) or even deep molecular response (MR or better). Herein, we present an extremely rare case of unpredictable blastic transformation in a patient receiving nilotinib. A 53-year-old Caucasian female patient was diagnosed with CP CML. At diagnosis, the spleen was palpable 1 cm below left costal margin, hemoglobin was 11.3 g/dl, platelet counts were normal and white blood cell counts were 105× 10/l with a left shift, 12% basophils and 5% blasts. Nested reverse transcriptase PCR from peripheral blood (PB) revealed the presence of the chimeric bcr-abl1 (β3α2 transcript), whereas bone marrow (BM) cytogenetics confirmed the presence of t(9;22)(q34;q11) translocation in all metaphases. According to Sokal index and Hasford score, the patient was classified as high risk (1.20 and 1759, respectively). However, based on the newer European Treatment and Outcome Study risk score, her disease was stratified as low risk (score o87). She was started on nilotinib 300 mg bid and complete hematologic response (cHR) was documented within 30 days after the initiation of nilotinib. At 3 months on nilotinib treatment, she achieved a cCgR, whereas quantitative real-time PCR (RQ-PCR) revealed a bcr-abl/abl ratio of 0.07%. At her following reevaluation (6 months after nilotinib), the patient remained in cHR and cCgR with a bcr-abl/abl ratio of 0.05%. Thus, our patient was considered as an optimal responder, according to the current European Leukemia Net (ELN) recommendations for CML. Seven months after diagnosis and 1 month after the documentation of optimal response, while receiving nilotinib, the patient complained of right lower quadrant pain, loss of appetite and weight, without significant findings on clinical examination. An abdominal computed tomography scan revealed right iliac lymphadenopathy of 4 cm in maximal diameter. Shortly, thereafter, she developed right inguinal lymphadenopathy. A lymph node biopsy was performed and lymph node cells were also isolated. Lymph node imprints showed immature blast cells, whereas fluorescence in situ hybridization analysis showed the presence of the bcr-abl1 fusion gene in 81% of 200 interphase nuclei. The histologic examination of the lymph node demonstrated infiltration by an immature cell population, with fineshaped nuclear chromatin and prominent nucleoli with a high mitotic and apoptotic rate (Figure 1). Immunochemistry was positive for MPO (diffuse), c-kit, CD34, CD56 and CD61 and negative for neuroendocrine markers. Cytogenetic analysis of the lymph node cells showed 100% positivity for Ph chromosome with an additional tetrasomy of chromosome 19; 48,XX,t(9;22)(q34; q11),+19,+19[25]. The bcr-abl/abl ratio in the lymph node cells was 24%. Mutation analysis by direct sequencing showed the presence of the T315I. At the same time, the patient remained in cHR, while trephine biopsy and BM cytogenetics were normal and bcr-abl/abl ratio in peripheral blood was 0.06%. Thus, the patient still met the criteria of optimal response according to the ELN guidelines when peripheral blood was examined, but the presence of extramedullary blastic transformation, classifies her as a CML case with blastic transformation. Nilotinib was stopped, and induction chemotherapy for acute myeloid leukemia with the ‘7+3’cytarabine-idarubicin regimen was administered. Ponatinib was not available at that time and her siblings were not histocompatibility leukocyte antigen-compatible