Biclonal (CD34+ CD42b+) Myeloblastic and Megakaryoblastic Transformation of Chronic Myeloproliferative/Myelodysplastic Disorders
Authors: Ford Jessica , Behrens Arleen , Vaughan Mary , Wetzler Meir , Barcos Maurice , Wang Eunice S. 
Published: April 2020

Despite the widespread use of molecular and genetic assays (i.e. JAK2V617F, FLT-3, bcr-abl, PML-RARalpha) for diagnoses of myeloid neoplasms, some disease entities remain difficult to define. For instance, distinguishing between blastic phase of bcr-abl negative chronic myeloproliferative disease, unclassifiable (CMPD-U), transformed myelodysplastic/myeloproliferative disease-unclassifiable (MDS/MPD-U), acute megakaryocytic leukemia (AML FAB-M7), and idiopathic myelofibrosis (IMF) per the 2001 WHO classification system remains challenging. Common to all of these diagnoses are marrow dysplasia, presence of immature myelocytic and megakaryocytic cells, and reticulin myelofibrosis. Here we describe our institute experience with 11 patients (pts) who presented between 2004–2008 with acute myeloid neoplasms characterized by prominent myeloblastic and megakaryoblastic cell populations with myelofibrosis. Morphological diagnoses were: MDS-refractory anemia with excess blasts (n=1), blastic phase of MPD/MDS with myelofibrosis (n=5), atypical or mixed acute myelocytic and megakaryoblastic leukemia (n=4), and acute megakaryoblastic leukemia (n=1). Median age at diagnosis was 69 years (range 20–89). Six pts were male (55%) and five female. The majority presented with pancytopenia with a median white blood cell count of 2.55 × 109/l (range&lt;0.01–237.5), median hemoglobin of 9.6gm/dl (range 5.6–10.6), and median platelet count of 57 × 109/l (range 14–296). The median percentage of peripheral blood blasts was 7% (range 0–52%) with a median of 28.5% (range 18.5–73%) blasts in the bone marrow. Organomegaly was present in 4/11 pts (1 hepatomegaly, 3 splenomegaly) at diagnosis. Only two pts reported a known antecedent MDS diagnosis (7 and 9 months prior to AML). One pt had relapsed disease with a prior diagnosis of AML FAB M1. Bcr-abl was negative in all cases; FLT-3 TKD/ITD was negative in all 9/9 cases tested (2 not available). 10/11 marrows underwent correlative cytogenetic tests showing normal karyotype in 2 pts and complex in 4 pts. Four pts had chromosome 7 aberrations (−7/del (7), t(7;17), der (7). One AML had inv(3)(q21q26). Dual immunohistochemical staining for CD34 and CD42b expression confirmed the presence of separate abnormal myeloblastic (CD34+) and megakaryoblastic cells (CD42b+) in all samples with a minority of cells expressing both antigens. All patients underwent therapy for AML/MDS: 8 received cytarabine/anthracyclines/etoposide (ADE) or Hidac-based induction regimens, 1 received subcutaneous cytarabine, 1 received Zarnestra therapy, and 1 Vidaza only. 7/11 pts were refractory to or died during chemotherapy. Three patients achieved complete remission, and two underwent allogeneic stem cell transplantation with overall survival (OS) of 18 and 8.5 months. One relapsed prior to autologous transplant. Median OS for 10 pts was 6.2months (range 0.5–18.5 months) with one pt lost to follow up.

Conclusions: Acute bcr-abl negative myeloid disorders displaying biclonal CD34+ myeloblastic and CD42b+ megakaryoblastic cell populations with myelofibrosis most likely represent leukemic evolution from prior chronic (undiagnosed) MPD or MDS/MPD. Dual immunohistochemical staining for CD34/CD42b is invaluable in distinguishing between the two immature blastic populations with coexpression of both markers on some cells suggestive of a common leukemia stem cell origin. Clinical outcomes of these patients are poor, and allogeneic stem cell transplantation remains the best long-term treatment option if remission can be achieved.