An unusual case of Chronic Lymphocytic Leukemia with trisomy 12
presenting with prolymphocytic transformation and new translocation
8;21.
First Author:
Mishi Bhushan, MD, MPH
Pathology observer, Hematopathology
Medical City Dallas | Medical City Children’s Hospital
7777 Forest Lane, Suite C400
Dallas, TX 75230
Bhushanm0214@gmail.com
P: 469-835-9354
Corresponding and Senior Author:
Kirthi R. Kumar MD., PhD
Medical Director, Hematopathology
Forward Pathology Solutions
Medical City Dallas | Medical City Children’s Hospital
7777 Forest Lane, Suite C400
Dallas, TX 75230
Kirthi.kumar@medicalcityhealth.com
P: 972-566-3843
C: 469-939-5172
F: 972-566-3479
Keywords: CLL, translocation 8;21, AML, RUNX1-RUNX1TX,
prolymphocytic leukemia
Key Clinical Message: First report of translocation 8;21 in a
patient with CLL. RUNX1-RUNX1T1 fusion gene resulting from the
translocation may have played a role in the prolymphocytic
transformation.
An 81-year old male with a history of chronic lymphoid leukemia
(CLL)/small lymphocytic lymphoma (SLL) for over two decades presented
with low back pain, left flank pain, and generalized weakness. Patient’s
initial diagnostic bone marrow performed in 2005 showed chronic
lymphocytic leukemia with trisomy 12 confirmed by routine cytogenetics
analysis. Patient had received multiple lines of chemotherapy including
ibrutinib for the past three years. Patient’s WBC count on this
admission was 60.2 x109 cells/L with hemoglobin 13.2
g/dL and platelet count of 95 x109 cells/L. Imaging
studies revealed generalized adenopathy with massive splenomegaly.
Peripheral blood smear showed numerous prolymphocytes (Figure 1A). Bone
marrow morphology and flow cytometry studies confirmed a prolymphocytic
transformation of CLL (Figure 1B). Interestingly, cytogenetics analysis
showed an abnormal male karyotype with six out of twenty metaphases
showing a translocation between chromosomes 8 and 21 in addition to
trisomy 12 (Figure 2A). Two metaphases showed a deletion of the long arm
of chromosome 13. Remaining metaphases showed normal karyotype (Figure
2B). Patient was started on chemotherapy with R-EPOCH (rituximab,
etoposide, cisplatin, vincristine, cyclophosphamide and prednisone)
regimen with clinical response but opted against further therapy after
his first cycle of chemotherapy.
CLL/SLL is an indolent lymphoproliferative disorder that can transform
into a more aggressive hematolymphoid malignancy in about 5-10% of
patients 1,2. The histologic transformation can
involve an increased number of prolymphocytic cells, referred to as
prolymphocytic transformation or into diffuse large cell lymphoma with
immunoblastic features, also known as Richter’s syndrome (RS) or
transformation (RT) 3,4. RT was first defined in 1928
by Maurice Richter as the transformation of CLL to an aggressive
lymphoma such as high-grade non-Hodgkin lymphoma or Hodgkin’s
lymphoma5–7. Transformation into aggressive
malignancy clinically presents as new or worsening symptoms such as
fevers, night sweats, weight loss, organ failure, and rapidly enlarging
lymphadenopathy. It has a highly unfavorable prognosis8–10 . While transformation to prolymphocytic
leukemia has been well documented, there are no known cases to date of
transformation to prolymphocytic leukemia with 8;21 translocation. The
t(8;21) (q22;q22) translocation is observed in acute myeloid leukemia
(AML) M2 subtype 11,12. The t(8;21) translocation
results in a fusion oncoprotein between RUNX1 and
ETO13. The finding of t(8;21)(q22;q22.1);RUNX1-RUNX1T1
in the setting of high grade transformation of CLL/SLL is rather unusual
with no literature citations of this abnormality.
RUNX1-RUNX1T1 fusion leads to disruption of normal function of the
core-binding factor in the regulation of hematopoietic differentiation
and maturation. There are associated cooperating mutations in theKIT, FLT3 and possibly JAK2 , resulting in activation of
oncogenes and signaling pathways in leukemogenesis of AML. The fusion
gene also interacts with micro-RNAs in leukemogenesis. RUNX1 is critical
for maturation of a wide range of hematopoietic stem cells including
myeloid, B cells and T cells and has been implicated in pathogenesis of
several myeloid and lymphoid malignancies14,15,16. We
postulate that the new translocation 8; 21 had a role to play in the
prolymphocytic transformation of CLL in this
patient12, but the long interval between the patient’s
initial karyotyping and at the time of transformation makes this
association less definitive.