Megakaryocytic Blast Phase (M-BP) of Chronic Myelogenous Leukemia (CML).
Authors: Quintás-Cardama Alfonso , Kantarjian Hagop , Cortes Jorge 
Published: October 2019

Abstract
Approximately 65% of patients with CMP BP exhibit a myeloid phenotype, 30% a lymphoid, and 5% of cases have and undifferentiated or mixed phenotype. Only anecdotal cases of BP with megakaryocytic differentiation (M-BP) have been reported. To evaluate the incidence and outcome of M-BP, we reviewed 410 patients with CML who underwent transformation to BP at M.D. Anderson Cancer Center between January 1999 and April 2007. Three cases (2 female) were diagnosed as having M-BP (incidence 0.7%). The median age was 50 years (range, 49–74). Two patients were initially diagnosed with chronic phase (CP) CML while 1 presented initially with M-BP. The median time from CML diagnosis to M-BP transformation was 76 months (range, 0–101). At the time of transformation, 2 patients presented with >20% bone marrow (BM) blasts whereas 1 other had only 2% blasts but developed extensive subcutaneous granulocytic sarcomas. The median white blood cell count at the time of transformation was 41.4x109/L (range, 39–44.7), hemoglobin 10.6 g/dL (range, 9.6–10.9), platelet count 270x109/L (range, 22–383), peripheral blood (PB) blast percentage 9% (range, 1–20), BM blast percentage 32% (range, 2–65). Flow cytometry analysis in BM blasts demonstrated positivity for markers of myeloid lineage (CD11c, CD13, CD33) as well as CD41 in all 3 patients. All patients expressed p210 BCR-ABL1 transcripts (b3a2 in 2 cases, b2a2 in 1). Initial therapy for M-BP in 1 patients consisted of troxacitabine (with no response), followed by imatinib 400 mg/d, which rendered a complete cytogenetic response (CCyR) for 35 months. The patient then received nilotinib at 600 mg twice daily with no response and died 7 months later. A second patient received imatinib 600 mg/d, ara-C 10 mg/d subcutaneous, and idarubicin 12 mg/m2 intravenous every 14 days, achieving a CCyR for 28 months. The patient relapsed in accelerated phase based on clonal evolution (i(17), −7,−18, and double Philadelphia chromosome). Therapy with dasatinib 140 mg/d was started, resulting in a brief CCyR (4 months) but prolonged (20 months) complete hematologic response (CHR), during which a F317L mutation was detected that resulted in loss of CHR. This patient is currently on hydroxyurea 59 months after diagnosis of M-BP. The third patient, who presented with a subcutaneous granulocytic sarcoma, achieved a brief CHR on dasatinib 50 mg twice daily. Dasatinib therapy was interrupted due to pericardial tamponade. While off therapy, the patient developed wide-spread granulocytic sarcomas of the skin, subcutaneous tissue, and right orbit, as well as 30% blasts in BM. DNA expansion of specific clones followed by DNA sequencing detected the dasatinib-resistant mutation V299L in 30% of clones. Therapy with dasatinib was ineffective and the patient died after 14 months in M-BP. In conclusion, M-BP is an extremely rare subtype of BP CML and exhibits resistance to conventional BCR-ABL kinase inhibitor therapy. Although prolonged responses can be achieved with these agents, more effective therapies are warranted.