Basophilic leukemia in recurrent chronic myelogenous leukemia blast phase

A 31-year-old man with a four-year history of chronic myelogenous leukemia (CML) presents in his second blast phase. The patient’s initial diagnosis was made after routine analysis revealed a white blood cell count (WBC) of 353 10/L. Initial bone marrow biopsy results and cytogenetics were not available for review. The patient responded initially to hydroxyurea followed by imatinib mesylate, at 400 mg daily. A subsequent bone marrow was consistent with morphologic remission; results of cytogenetics and molecular studies were not available. After *3-years, a repeat bone marrow biopsy revealed myeloid blasts comprising 80% of cells consistent with blast phase of CML. Retrospective review of peripheral blood and bone marrow showed only rare (less than 1%) blasts containing granules resembling immature basophils. RT-PCR was positive for BCR-ABL transcript (p210 and p190), and chromosome analysis showed 47, XY, t(2;3)(p23;q29), +8, t(9,22)(q34; q11.2) in 20 of 20 metaphase spreads. Flow cytometric analysis revealed a CD45 positive blast population with moderate side light scatter that strongly expressed CD34, CD117, and CD7 as well as variably expressed CD13, CD33, CD11c, and CD2. Intracellular staining revealed that 1/3 of these cells were myeloperoxidase positive. The imatinib mesylate dose was increased to 800 mg daily but was not tolerated due to nausea. The imatinib mesylate was discontinued, and a second generation ABL kinase inhibitor was initiated. The patient responded to this drug for several months until severe abdominal pain lead to its discontinuation. Less than one week after discontinuation the patient was found to have a WBC of 17 10/L with 30% blasts in peripheral blood, and the tyrosine kinase inhibitor was restarted. Circulating blasts persisted, and the patient underwent induction chemotherapy with an eventual goal of allogeneic transplant. Following this treatment, blasts were no longer detected in peripheral blood, and the patient was thought to be in hematologic remission. After *3-months our patient presented with a WBC of 47 10/L and 76% blasts. These results are consistent with recurrent CML blast phase, though morphologic remission was not established by bone marrow biopsy and persistence of earlier blast crisis remains a possibility. Multiple blast populations were detected morphologically in peripheral blood (Images 1–3), and presence of metachromatic granules after toluidine blue stain indicated a subset (9% of blasts) of basophilic origin (Image 4); maturing basophils were also present (4% of WBC). The patient has since entered a research protocol and had response to a different second generation ABL kinase inhibitor. After 3-weeks of therapy, his WBC has decreased to 1.9 10/L, although occasional blasts (6%) persist. CML is a myeloproliferative disease of bone marrow derived stem cells that contain fusion of BCR on chromosome 22 with c-ABL on chromosome 9 (i.e. Philadelphia chromosome) and which characteristically produces the p210 fusion protein. The initial indolent chronic phase of CML is unstable, and the disease ultimately progresses to accelerated and blast phases. Since the Philadelphia chromosome can be detected in all hematopoietic lineages the blast phase may include neutrophilic, eosinophilic, monocytic, erythroid, megakaryocytic, and basophilic blasts in predominance or in any combination. In about 20–30% of patients the blast phase is due to proliferation of lymphoblasts, and rare patients may have both myeloid and lymphoid blast populations. Acute basophilic leukemia represents <1% of all cases of acute myelogenous leukemia (AML) and must be differentiated from the blast phase of CML, AML with maturation associated with 12p abnormalities or t(6;9), acute eosinophilic leukemia, and acute lymphoblastic leukemia with prominent coarse granules. The persistence of t(9,22), as in the described case, is strong evidence for a predominant basophilic blast population arising from abnormal CML stem cells.