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.