Case Presentation:
A 9-year-old male presented with lymphadenopathy, leukocytosis with
white blood cell count (WBC) 277 x109/L, Hemoglobin
6.1g/dL, and circulating blasts in peripheral blood. The flow cytometry
analysis of peripheral blood confirmed 85% blasts expressing CD34,
CD13, CD117, CD15, HLA-DR partial, CD7 and CD2. Most blasts were
negative for MPO but equivocally express cytoplasmic CD3 (with an
intensity lower than background T cells). In addition, a small
population of discrete blast population (less than 5%) were positive
for MPO. These flow cytometry findings raised differential diagnoses of
MPAL, early T precursor (ETP)-ALL or AML with aberrant T cell antigen
expression. A bone marrow biopsy was performed, and the flow cytometry
analysis of bone marrow revealed dim cytoplasmic CD3 on blasts with the
intensity equal to background T-cells. There was a discrete population
of blasts (5-10%) with positive MPO expression. The findings supported
a T/My MPAL diagnosis based on the current WHO diagnostic criteria. The
immunostains of CD3 and MPO on bone marrow core biopsy also supported
the diagnosis. The genetic and cytogenetic karyotype studies on bone
marrow aspirate revealed a BCL11B copy gain (rearrangement not
detected) and FLT3-ITD. The patient was treated on COGAALL1732 protocol
and while leukocytosis responded to initial treatment, on day three of
treatment, the patient was found on CT to have a large intraparenchymal
hemorrhage and died the following day.
We report a unique case demonstrating the diagnostic and treatment
challenge of MPAL with BCL11B copy gain. MPAL comprises less than
5% of pediatric acute leukemia.13 The current
diagnostic criteria of MPAL relies on flow cytometry,
immunohistochemistry or less frequently by cytochemical stain to
determine the blast lineage.7 However, it is
subjective regarding the percentage and intensity of antigen expression
when assigning the lineage. For instance, the peripheral blasts in our
patient revealed very dim expression of cytoplasmic CD3 and less than
5% MPO+ blasts, which together created a diagnostic
challenge.14
Because of the rarity of MPAL, there are frequently diagnostic
challenges that could lead to delay in treatment initiation as well as a
lack of prospective trial data to guide
therapy.11,12,15 BCL11B rearrangement is known
to associate with a distinct subgroup of acute leukemias with a broadly
variable phenotype, including AML, ETP-ALL, and
MPAL.5,6,8,13,16 The functional consequence ofBCL11B rearrangement is overexpression ofBCL11B .8 Our patient had a BCL11B copy
gain without known rearrangement, which might be an alternative
mechanism of BCL11B overexpression. Moreover, the leukemias withBCL11B aberrations frequently contain FLT3-ITD and other high
risk mutations.8 An ex vivo drug-sensitivity profile
study revealed that FLT3 tyrosine kinase inhibitors are effective on
these leukemias with BCL11B rearrangement and
FLT3-ITD,8 which may provide a novel therapy strategy
for MPAL with BCL11B rearrangement in the future.
In summary, MPAL is a rare leukemia which presents diagnostic
challenges. We report a patient with an identified BCL11B copy
gain without rearrangement present in T/myeloid MPAL. Identification of
this BCL11B aberration may contribute to the current molecular
knowledge of MPAL, and ideally additional prospective studies of
patients with MPAL will more clearly define diagnostic criteria and
appropriate therapy.