Final Diagnosis -- Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia

FINAL DIAGNOSIS:

DISCUSSION:

On admission to the UPMC, the patient was treated with leukopheresis and hydroxyurea to lower the WBC. His respiratory status remained unstable with continued dyspnea, and his O2 status was closely monitored. He developed petechiae on his arms; a subsequent DIC screen revealed active DIC, and he was started on low molecular weight heparin. The patient's respiratory status improved somewhat, but on the day he was to start induction chemotherapy, he was found pulseless in bed. Resuscitation efforts could not revive him.

The morphologic and immunophenotypic data support the presence of two hematologic malignancies: chronic lymphocytic leukemia, T-cell type and acute myeloid leukemia. In this case, the presence of a marked leukocytosis of small lymphocytes with irregular nuclei, inconspicuous nucleoli and mature CD4+ T cell phenotype without antigen loss are characteristic of T-CLL.

Although some controversy exists as to its precise classification, some agree that it is indeed a separate entity with features distinct from other T-cell chronic lymphoproliferative disorders. Bona fide T-CLL is very rare and probably accounts for less than 1% of all CLL. Unlike patients with B-CLL, these patients do poorly, with only minimal responses to chemotherapy in a minority of patients. (1,2,3) Although this patient's HTLV-1 status was not known, this virus has been only rarely associated with T-cell CLL. (13,14) T-CLL should be differentiated from other chronic T-cell lymphoproliferative disorders. In T-cell prolymphocytic leukemia the prolymphocytes are larger with a prominent nucleolus, and a lower nuclear:cytoplasmic ratio with a similar immunophenotype to T-CLL. Mycosis fungoides/Sezary syndrome would typically have antigen loss immunopenotypically. Sezary cells in the peripheral blood of patients with mycosis fungoides demonstrate deeply indented convoluted or "cerebriform" nuclei without marrow involvement. Most cases are CD7 negative. In adult T-cell lymphoma/leukemia the cells demonstrate a hyperlobated or "cloverleaf" nucleus and most are CD4+ and CD7+. HTLV-1 genomes are found in all cases. Large granular lymphocytic leukemias are commonly CD4 and CD7 negative, with CD8+, CD16+, and CD57+/-. Natural killer cell large granular lymphocytic leukemias do not demonstrate T-cell receptor gene rearrangements, are CD3-, CD8+/-, CD16+, CD56+/- and CD57+/-. The lack of positivity for B cell associated antigens, monoclonal light chains, and coexpression of CD19+/CD5+ would rule out B-CLL. In this case, the morphologic, immunophenotypic and clinical features were most consistent with T-CLL. The identification of a T-cell receptor gene rearrangement supported the clonal nature of the T-cells and was of benefit in distinguishing the T-cells from a reactive process.

Immunophenotypically, the myeloblasts were positive for CD13, CD33, CD14, CD15, and myeloperoxidase. Tdt and CD34 were negative. The blasts strongly expressed non-specific esterase and peroxidase, the latter finding not characteristic but can be seen in acute monoblastic leukemia. These findings, together with the morphology and flow cytometric immunophenotypic studies favored a diagnosis of AML-FABM5a.

The incidence of secondary cancers in B-CLL patients is increased, with higher rates of lung carcinoma, melanoma, and Hodgkin's disease, presumably due to impaired immune surveillance mechanisms. (4) Others have noted an increase in diffuse large cell lymphomas in this same patient population. (5) Although the incidence of acute leukemia in patients with B-cell CLL varies from 0-6.9%, recent studies indicate that it may be much less frequent than previously thought. (5) Most often acute leukemias associated with B-CLL are therapy related (5,6) but acute leukemias representing blastic transformation of existing B-CLL (8), and simultaneous coexistent acute myeloid leukemia with B-CLL (9,11) including AML developing in untreated B-CLL have also been reported. (7,10) The prognosis of AML developing in patients with B-CLL appears to be similar to AML in other patients. The current case may represent a therapy related AML, as the patient was treated with alkylating agents including Fludarabine, which has well documented leukemogenic potential. (12)

Cytogenetic findings demonstrated an 8;22 translocation, which has been reported in AML FAB type M4 or M5. The presence of a subclone with 2;22 translocation would suggest progression of disease. Typical cytogenetic findings for T-CLL involve abnormalities of chromosome 14, which were not present in this case. Whether this abnormal karyotype was derived from the T-cells or the myeloid blasts could not be determined.

This case was unusual for the presence of a T-CLL, and it may represent the first case of a therapy related AML in a patient with T cell CLL.

REFERENCES

  1. Hoyer, JD et al. True T-cell chronic lymphocytic leukemia: A morphologic and immunophenotypic study. Blood 1995;86 1163-1169.
  2. Wong KF et al. T- cell form of chronic lymphocytic leukemia: a reaffirmation of its existence. British Journal of Hematology 1996; 93:157-159.
  3. Kingreen D and Siegert W. Chronic lymphatic leukemias of T and NK type. Leukemia 1997; 11: (supp) 2, S46-49.
  4. Travis, Louis B et al. Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst 1992; 84:1422-1427.
  5. Robertson LE et al. Therapy related leukemia and myelodysplastic syndrome in chronic lymphocytic leukemia. Leukemia 1994; 8:2047-2051.
  6. McPhedran, Peter and Heath, Clark W. Acute leukemia occurring during chronic lymphocytic leukemia. Blood 1970; 35:7-11, .
  7. Wallis, JP and Joyner, MV. Acute myeloid leukemia developing in a patient with longstanding untreated chronic lymphocytyic leukemia. Acta Heamat. 1986; 75:229-231.
  8. Zarrabi, Mohammad H et al. Chronic lymphocytic leukemia terminating in acute leukemia. Arch Intern Med. 1977; 137:1059-1064.
  9. Conlan, Muareen G and Mosher, Deanne F. Concomittent chronic lymphocytic, acute myeloid leukemia and thrombosis with a protien C defficiency. Cancer 1989; 63:1398-1401.
  10. Stern N et al. Chronic lymphatic leukemia terminating in acute myeloid leukemia. Cancer 1981; 47:1849-1851.
  11. Monharan A et al. Simultaneous occurrence of lympho- and myeloproliferative disorders: a report of 4 cases. British Jounal of Hematology 1981;48:111-116.
  12. Frewin RJ et al. Myelodysplasia occurring after fludarabine treatment for chronic lymphocytic leukemia. Clinical and Laboratory Hematology 1997; 19:151-152.
  13. Mori, Naoki et al. An HTLV-1 carrier who developed CD4+ T-CLL expressed the IL-2 receptor B chain alone without expressing the alpha chain. British Journal of Hematology 1993; 85:185-7.
  14. Pawson R et al. The human T cell lymphotropic viruses types I/II are not involved in T prolymphocytic leukemia and large granular lymphocytic leukemia. Leukemia 1997; 11:1305-11.

Contributed by Peter Christakos, MD and Lydia Contis, MD

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