Chronic myeloid leukemia (CML) is an indolent neoplasm which is known for its invariable progression from a chronic to blastic phase. However, CML primarily presenting with megakaryocytic blast crisis (MKBC) in a young male without any preceding chronic phase is of extremely rare occurrence. We report an unusual case of a 22-year-old man who presented for the first time with splenomegaly and presence of blasts in the peripheral blood and bone marrow, clinically masquerading as acute leukemia. This case report highlights the uncommon manifestation of MKBC in a previously undiagnosed CML. The case also reveals the importance of a careful bone marrow examination and an appropriate immunophenotyping as well as role of cytogenetics in differentiating this rare entity from other closely mimicking myeloproliferative neoplasms.
CML in transformation carries a dismal prognosis and imposes a major therapeutic challenge. Accumulations of certain mutations and chromosomal aberrations derive a case of CML from a relatively benign chronic phase to blast phase which is characterized by presence of >20% blasts in the peripheral blood or bone marrow or an extramedullary accumulation of blast cells, or large foci or clusters of blasts in the bone marrow biopsy (WHO, 2016). These criteria must be supported by the presence of Philadelphia (Ph) chromosome resulting from reciprocal translocation of chromosomes 9 and 22.1,2 Phenotype most commonly seen in blast crisis is of the myeloid lineage followed by lymphoid and erythroid. MKBC is extremely uncommon, comprising of 90% Ph-positive cells. An overall final diagnosis of CML in MKBC was rendered. Patient was subsequently put on a 7+3 regimen of cytarabine and doxorubicin in combination with Dasatinib 140mg daily. A hemogram repeated after two months showed a striking response to therapy with a WBC count of 2400/µL and a differential count of neutrophil 43%, lymphocyte 55%, eosinophil 1% and monocyte 1%, thereby suggestive of hematological remission. Patient was then advised to continue dasatinib and to remain on clinico-hematological follow-up. Till now there are no features of either residual disease or progression of the disease.
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CML in blast crisis may show magakaryoblastic phenotype which poses a diagnostic challenge in differentiating it from de novo Acute Megakaryoblastic Leukemia (AMKL) which is also a rare diagnosis. The two entities are difficult to differentiate morphologically alone especially when no prior history of CML is available. Contrary to the usual occurrence of CML in the fourth decade in the Indian population, our case involved a young patient. Splenomegaly, leukocytosis and basophilia, which are consistent features of CML were also present in our patient. Persistence or increase in any of these signifies disease progression. In contrast, none of the three features are seen in de novo AMKL. The megakaryoblasts are usually medium to large in size (12-18 µm) with a round to indented nucleus, fine reticular chromatin, one to three nucleoli and basophilic cytoplasm which may show distinct blebs or pseudopod formation. Circulating micromegakaryocytes were not seen but megakaryocytic fragments, dysplastic large platelets and hypogranular neutrophils which are a feature of M7 leukemia, were conspicuous in the present case. The dysplastic features seen in the neutrophils as well as the erythroid precursors on BMA in our case can also be seen in AML with myelodysplasia-related changes (AML-MDC), however dysplasia in AML-MDC must be present in minimum 50% of the cells in at least 2 lineages, supplemented by the signature cytogenetic abnormalities. Hence AML-MDC was excluded in this case.
BMA of our patient yielded a diluted marrow probably due to myelofibrosis which is a frequent finding in both AML-M7 and MKBC. Besides fibrosis, bone marrow biopsy in both conditions shows varying proportions of blasts and maturing dysplastic megakaryocytes. Confirmation of megakaryocytes and megakaryoblasts requires expression of platelet-specific antigens such as CD41, CD42, CD61 or Factor VIII on IHC or FCM. Megakaryoblasts are often negative for CD34 and MPO, however markers like CD13 or CD33 may be positive, as in our case. A leukoerythroblastic blood picture along with presence of >20% blasts, myelofibrosis and presence of clusters of abnormal megakaryocytes in the BMB implicate consideration of AML-M7, acute panmyelosis with myelofibrosis, and primary myelofibrosis in blast transformation as the possible differentials besides a diagnosis of CML with blast crisis. Features such as leukocyte count, splenomegaly, basophilia and CD34 positive blasts in the marrow provide a valuable clue in differentiating between these close mimicking entities. However, demonstration of BCR-ABL fusion protein or Ph chromosome proves pivotal in arriving at a diagnosis as in our case. Here, another neoplasm namely, Ph-positive AML (WHO, 2016) needs to be addressed. Literature states that presence of left shifted myeloid maturation, splenomegaly and basophilia in the peripheral blood favour a diagnosis of CML in blast crisis rather than Ph-positive AML9.
CML-MKBC carries a poor prognosis with usually low expected survival rate. Combination of chemotherapy and tyrosine kinase inhibitors (TKI) has proven beneficial in improving the disease outcome to the extent of achieving a haematological remission as in our patient.
Conclusion
Megakaryocytic blast crisis has a characteristically low incidence and may prove to be a diagnostic challenge for the clinicians and the pathologists especially in previously undetected CML cases. The case report highlights the importance of differentiating blast transformation of CML from other close differentials with the use of an appropriate IHC panel and cytogenetic studies, as there are therapeutic implications.
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