T‐lymphoid or T/myeloid blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy: a report of 14 cases

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the BCR-ABL1 fusion gene resulting from t(9;22)(q34;q11.2), its variant translocations, or rarely, cytogenetically cryptic chromosomal rearrangements, and by a natural course of three distinct stages: chronic phase (CP), accelerated phase, and blast phase (BP) [1]. With tyrosine kinase inhibitors (TKIs) becoming standard front-line therapy, progression of CML from CP to BP has dramatically decreased, and the long-term cumulative probability of progression is only about 5% [2]. When BP does occur, in approximately 70% of patients the blasts are of myeloid lineage and in 20–30% of cases, lymphoid lineage [3]. While lymphoid BP is of B-cell lineage in almost all patients, rarely Tlymphoid BP can occur. To our knowledge, very few cases of CML with T-lymphoid or T/myeloid BP have been reported in the era of tyrosine kinase inhibitor therapy [4–9]. During a review of 2520 adult patients with CML diagnosed at The University of Texas MD Anderson Cancer Center since 1998, when TKI therapy was implemented in our hospital, to the year of 2016, we identified 449 patients with documented BP confirmed by histopathology. Of these 449 patients, 296 (65.9%) had myeloid BP, including 15 patients with extramedullary myeloid sarcoma as the sole presentation of blast transformation, 139 (31.0%) had lymphoid BP, and 14 (3.1%) had mixed phenotype BP. Of the 139 patients with lymphoid BP, 133 (95.7%) had B-lymphoid BP and six (4.3%) had T-lymphoid BP. Of the 14 patients with mixed phenotype BP, four (28.6%) had T/myeloid BP and 10 (71.4%) had B/myeloid BP. Of all cases of CMLBP, the incidence of T-lymphoid BP was 1.3% and the incidence of combined T-lymphoid and T/myeloid BP was 2.2%. The ratio of T-lymphoid vs. B-lymphoid BP was 1 : 22, and the ratio of combined T-lymphoid and T/myeloid vs. combined B-lymphoid and B/myeloid BP was 1 : 14. Four additional cases of CML-BP (three T-lymphoid and one T/myeloid) were collected from other institutions, forming a study group of 14 patients: nine with Tlymphoid and five with T/myeloid BP. The diagnosis of T/myeloid BP was made when both CD3 and myeloperoxidase were identified using cytochemistry, flow cytometry, and/or immunohistochemistry according to the WHO criteria for mixed phenotype acute leukemia. The clinicopathological data, including age, gender, medical history, imaging, molecular and cytogenetic studies, were reviewed and are shown in Table 1. To the best of our knowledge, this is the largest case series of T-lymphoid or T/myeloid BP of CML to date. There were eight men and six women. The median age at time of diagnosis of CML-BP was 53 years old. Four patients (#4, 8, 10, and 11) had an established history of CML-CP, and three of them had available date of diagnosis of CML-CP. The interval time from initial diagnosis of CML-CP to blastic transformation was 19.1, 73.2, and 8.3 months for patients #4, 10, and 11, respectively. Another four patients initially presented with BCR-ABL1positive T-lymphoblastic lymphoma, but had CML-CP in the concurrent bone marrow, and the remaining six patients had CML-BP in the bone marrow initially. By imaging, 10 patients had extramedullary involvement, including lymphadenopathy (8/10) and splenomegaly (2/ 10). By conventional karyotyping, additional cytogenetic abnormalities other than t(9;22)(q34;q11.2) were found in nine patients: including an extra copy of der(22) (n = 4), +8 (n = 2), +19 (n = 2), and others. Molecular data were available for 12 patients: six had the p210 and six had p190 subtype of BCR-ABL1 transcripts. Of four patients (#4, 8, 10, and 11) with a history of CML-CP, three of them had available treatment information. Patient #4 received interferon alpha and ara-C and subsequent allogeneic stem cell transplantation (alloSCT) due to inadequate response to interferon, and patients #10 and 11 received TKI therapy before blastic transformation. Overall, 13 patients had available treatment information for BP. Nine patients received TKIs, 11 received hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) chemotherapy, and