Untreated Chronic Lymphocytic Leukemia ...

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Olivia Chan, MD, and Karen L. Chang, MD. Key Words: Untreated ... 109/L]) in peripheral blood, or (2) persistent lymphocy- ..... In: Henderson. ES, Lister TA, eds.
Hematopathology / UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA COEXISTINO WITH ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME

Untreated Chronic Lymphocytic Leukemia Concurrent With or Followed by Acute Myelogenous Leukemia or Myelodysplastic Syndrome A Report of Five Cases and Review of the Literature RaymondLai,

M D , PhD, Daniel A. Arber,

M D , RussellK.

Brynes,

MD,

Olivia C h a n , M D , and Karen L. Chang, M D Key Words: Untreated chronic lymphocytic leukemia; Acute myelogenous leukemia; AML; Myelodysplastic syndrome; MDS; Flow cytometry; Immunohistochemistry

Although it has been known that patients with chronic lymphocytic leukemia (CLL) have a higher frequency of second malignant neoplasms, the development of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in these patients is extremely rare. Most reported cases have been therapyrelated. In this article, we report the clinical and immunophenotypic features of 5 cases of untreated CLL concurrent with or followed by the development of AML or MDS. All 5 patients were men, with ages ranging from 57 to 87 years (mean, 73.8 years). Four patients had AML and 1 patient had refractory anemia with ringed sideroblasts. In the 4 cases of AML and CLL, 2 distinct cell populations (ie, myeloblasts and lymphocytes) were identified morphologically and/or immunophenotypically. Ourfindings support that this rare concurrence of AML or MDS and untreated CLL may represent 2 separate disease processes.

The incidence of blastic transformation of chronic lymphocytic leukemia (CLL) has been reported to be less than 2%) Most of the transformed cases have been reported to be acute lymphoblastic leukemia, usually the FrenchAmerican-British (FAB) L2 or L3 subtype. The occurrence of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in patients with CLL is extremely low. Most reported cases have been therapy-related.2-5 Rarely, cases of AML or MDS occurring in untreated patients with CLL have been described. Most of these cases were reported before the widespread use of immunohistochemistry or flow cytometry technology.6_9 In this article, we report the clinical and immunophenotypic features of 5 cases of untreated CLL concurrent with or followed by the development of AML or MDS.

Materials and Methods Patient Selection The files of the Department of Anatomic Pathology at the City of Hope National Medical Center, Duarte, Calif, were searched for patients with CLL who were given a concurrent or subsequent diagnosis of AML or MDS. The total incidence of CLL cases is not representative of the incidence in the general population because almost all cases were derived from our consultation service. For March 1989 through November 1997, a total of 5 cases were found. Material for morphologic and immunophenotypic

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Abstract

Lai et al / UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA COEXISTING WI ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME

study was available for all cases. Cytogenetic data also were available for 1 case. We specifically excluded cases of AML arising in patients who received chemotherapy for an antecedent CLL. The diagnostic criteria for CLL we used were adapted from those proposed by Bennett et al10: (1) persistent lymphocytosis (>10,000/uL [>10.0 x 109/L]) in peripheral blood, or (2) persistent lymphocytosis (>5,000->10,0007uL [>5.0->10.0 x 109/L]) in peripheral blood and appropriate cell marker studies. In the present study, we used aberrant coexpression of CD5 or CD43 on B cells, monotypic immunoglobulin light chain expression, or both as evidence of an abnormal immunophenotype. Immunohistochemical Studies

Flow Cytometry Studies For 4 cases, material was available for flow cytometry analysis. In all 4 cases, blasts and lymphoid cells from pretreatment bone marrow samples, peripheral blood samples, or both were enriched by density gradient separation, and assays were performed on fresh cells. Threecolor flow cytometric analysis was performed using the CD45 PerCP antibody (Becton-Dickinson) to costain with the following pairs of antibodies: (1) for the myeloblasts, CD14/CD45, CD19/CD10, CD20/HLA-DR, CD33/CD34, CD13/CD15, CD117/CD61, glycoprotein A/CD36, CD56/CD3, and CDllc/CD5; (2) for the lymphoid cells, CD2/CD7, CD4/CD8, CD19/Ig K, CD19/Ig Aa, CD19/IgD, CD19/IgM, CD19/IgA, CD19/IgG, CD19/CD10, and CD20/CD5. All antibodies were purchased from Becton Dickinson. Flow cytometric positivity was defined as more than 20% of cells labeled at intensity higher than the negative controls.13 Cytochemistry For the purpose of subclassifying the AMLs according to the FAB classification system, cytochemical studies 374

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Results Patient 1 A 57-year-old man with leukocytosis (WBC count, 172,000/LIL [172.0 x 109/L]) with 74% (0.74) lymphocytes was given a diagnosis of CLL. No treatment was given. Ten months later, the CBC count revealed the following: hemoglobin, 6.8 g/dL (68 g/L); platelet count, 38 x 103/uL (38 x 109/L); WBC count, 24,000/LIL (24.0 x 109/L). The peripheral blood smears showed 30% blasts with folded nuclei, fine chromatin, multiple nucleoli, and scant to moderate amounts of agranular cytoplasm. A subset of lymphocytes also was noted. Dysplastic features were not seen. The bone marrow trephine biopsy sections showed partially infarcted bone marrow. The viable portion was composed of 80% blasts and 20% lymphocytes. Flow cytometric analysis of the bone marrow aspirate specimen was performed, and the results are given in liable II. Cytochemical studies revealed the blasts to be positive for myeloperoxidase and Sudan black B. The final diagnosis was AML (FAB-MI) arising in a patient with CLL. Patient 2 A 78-year-old man sought care because of a 6-month history of weight loss, easy fatigability, and pain in the left side of the abdomen. He had a 4-year history of CLL, for which no therapy was administered. The CBC count showed a WBC count of 50,370/uX [50.4 x 109/L]. The peripheral blood smear revealed 24% blasts, 50% (0.50) small lymphocytes, and 26% (0.26) neutrophils. The blasts had large nuclei with smooth regular contours, delicate chromatin, and prominent nucleoli. The cytoplasm was scant and agranular. Dysplastic features were not seen. The blasts were negative for myeloperoxidase, Sudan black B, and a-naphthyl-butyrate-esterase by cytochemistry. Flow cytometric analysis of the peripheral blood mononuclear cells and immunohistochemical studies of the bone marrow clot biopsy specimen were performed, and the results are given in Table 1. The final diagnosis was AML (FAB-MO) with preexisting CLL. Patient 3 An 87-year-old man sought care because of recent anorexia and weight loss. The physical examination revealed a palpable spleen. The CBC count showed the following: WBC count, 47,100/uL (47.1 x 109/L); hemoglobin, 12.1 g/dL (121 g/L); and and platelet count, 132 x 103/uL (132 x 109/L). The WBC population contained 44% (0.44) small

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For 2 cases, material was available for paraffin immunohistochemical study. Immunohistochemical studies were performed using an automated instrument (Techmate 1000, Ventana, Tucson, Ariz) with formalin- or B5-fixed, paraffin-embedded tissue sections, using previously published methods, including heat-induced epitope retrieval modification.11,12 Antibodies against the following antigens were used: CD20 (clone L26, 1:100, DAKO, Carpinteria, Calif), immunoglobulin K light chain (clone A8B5, 1:300, DAKO), immunoglobulin X light chain (clone R10-21-F3, 1:300, DAKO), CD43 (Leu 22, 1:10, Becton Dickinson, San Jose, Calif), terminal deoxynucleotidyl transferase (1:20 dilution, Supertech, Bethesda, Md), and myeloperoxidase (1:100, DAKO).

including a-naphthyl-butyrate-esterase, Sudan black B, and myeloperoxidase were performed in 3 of 4 cases of AML.

Hematopathology / ORIGINAL ARTICLE

•Table II Cytochemical Findings and Immunophenotypic Analysis by Flow Cytometry or Immunohistochemistry Immunophenotype of AML Blasts (Test)

Immunophenotype of CLL Cells (Test) Positive

Negative

CD5, CD19, HLA-DR,

Myeloid markers (FC)

Patient No. 1

K(FC)

2

CD5, CD19, CD23, IgM, K(FC)

CD10, X, IgD, IgA, IgG, myeloid markers (FC)

3

CD11c, CD19, CD20, K, IgG (FC)

CD5, CD10, \, IgD, IgM, IgA (FC)

4 5

CD20, CD43 (IH) CD20, CD43 (IH); CD5, CD19, CD20(FC)

CD3, MPO (IH) CD10(FC)

Positive CD13, CD15, CD33 (FC); MPO, Sudan black B (CC) CD34, CD45, CD117, HLA-DR (FC);CD43(IH)

CD11c, CD13, CD33, CD34, CD45, c-kit, HLA-DR (FC); ANBE, >80% blasts positive (CC) MPO(IH) NA

Negative Lymphoid markers (FC) CD2, CD4, CD7, CD8, CD10, CD33, Tdt (FC); CD20, Tdt (IH); MPO, Sudan black B, ANBE (CC) CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD19, CD20, CD56, CD61 (FC) CD3, CD20, CD43 (IH) NA

CLL = chronic lymphocytic leukemia; AML = acute myelogenous leukemia; FC = flow cytometry: CC = cytochemistry; IH = immunohistochemistry; Tdt = terminal deoxynucleolidyl transferase; ANBE = cx-naphthyl-butyrate-esterase; NA = not applicable. Downloaded from http://ajcp.oxfordjournals.org/ by guest on April 10, 2016

lymphocytes and 12% blasts. Basophilia (8% [0.08]) also was found. The blasts had round nuclei, fine chromatin, prominent nucleoli, and abundant pale blue cytoplasm. Only occasional azurophilic granules were seen in a small percentage of blasts. Auer rods were absent. No dysplastic features were seen. Flow cytometric analysis of the peripheral blood mononuclear cells was performed to further characterize the lymphoid and blast populations, and the results are given in Table 1. The blasts were positive for a-naphthyl-butyrate-esterase (>80%) and focally positive for myeloperoxidase and Sudan black B. Examination of the subsequent bone marrow specimens supported a diagnosis of AML (FAB-M5) with concurrent CLL. Cytogenetic studies showed a normal male karyotype. Patient 4 An 80-year-old man was known to have a long history of CLL for which he received no treatment. A routine follow-up CBC count revealed the following: hemoglobin, 9.1 g/dL (91 g/L); platelet count, 40 x 103/|iL (40 x 109/L); and WBC count, 9,000/uX (9.0 x 109/L). The peripheral blood smears revealed 45% (0.45) lymphocytes, 19% blasts, 4% metamyelocytes, 30% (0.30) segmented neutrophils, and 2% (0.02) monocytes. The bone marrow aspirate smears contained 39% blasts and 28% lymphocytes llmage II. The blasts were medium to large and contained irregular nuclear contours and occasional nucleoli. The cytoplasm was moderate in amount and contained cytoplasmic azurophilic granules. Trilineage dysplastic features also were noted. The bone marrow clot sections were normocellular (50%) and showed multiple CLL nodules llmage 21 admixed with clusters of myeloblasts llmage 31. Immunologic characterization by immunohistochemistry was done, and the results are

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llmage I I Bone marrow aspirate smears from case 4 showing 2 different populations of cells, chronic lymphocytic leukemia cells and blasts (Wright-Giemsa, x600).

given in Table 1. The final diagnosis was AML (FAB-M2) with preexisting CLL. Patient 5 Examination of a 67-year-old man who had no previous hematologic disease revealed lymphadenopathy (right cervical and right axillary lymph nodes), splenomegaly, and persistent anemia. A CBC count showed: hemoglobin, 10.9 g/dL (109 g/L); platelet count, 163 x 10-VLIL (163 x 109/L); WBC count, 9,600/u.L (9.6 x 109/L) with 37% (0.37) lymphocytes and 58% (0.58) segmented neutrophils. The RBCs were macrocytic. The bone marrow Am J Clin Pathol 1999.111:373-378 3 7 5

Lai et al / UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA COEXISTING WITH ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME

•Image 3J Bone marrow trephine biopsy section from the same area as shown in Image 2 highlighting the presence of myeloblasts (right) (myeloperoxidase stain, x400).

aspirate smears showed an increased number of small lymphoid cells (41%). Granulocytic precursors were mildly left-shifted with mild megaloblastic changes. Iron stain revealed increased iron stores and incorporation; many ringed sideroblasts were identified. The bone marrow trephine biopsy specimen showed multiple lymphoid nodules in a predominantly nonparatrabecular pattern. Immunohistochemical studies were performed on the bone marrow trephine biopsy sections, and the results are given in Table 1. No treatment was given, and a follow-up CBC count showed a WBC count of 9,600/uL (9.6 x 109/L) with 60% (0.60) lymphocytes. The final diagnosis was myelodysplastic syndrome (refractory anemia with ringed sideroblasts) with concurrent CLL.

subtype of AML or MDS are summarized in ITable 21. The ages of the patients with AML ranged from 57 to 87 years. All 5 patients were men.

Discussion

In summary, 4 patients had a diagnosis of AML, and 1 was given a diagnosis of MDS (refractory anemia with ringed sideroblasts). The age and sex of the patients, the duration of CLL before the diagnosis of AML, and the

There have been a small number of reports of untreated CLL manifesting with or followed by AML or MDS. Almost all of these reports have been single-case reports. In addition, most of these cases were reported before the widespread acceptance of the FAB classification and before the widespread use of flow cytometric and immunohistochemical techniques. Only 4 recent reports contain immunophenotypic data,14-17 and their findings are summarized in ITable 31. In the present article, we report an additional 5 cases of untreated CLL concurrent with or followed by AML or MDS. All of the cases were studied

•Table 21 Summary of Patients' Data and Final Diagnosis Patient No.

Sex/Age (y)

First Manifestation

1 2 3 4

M/57 M/78 M/87 M/80

CLL CLL CLL/AML CLL

5

M/67

CLL and MDS

Duration of CLL Before Diagnosis of AML/MDS 10 mo 4y NA Long history but exact duration unknown NA

FAB Subtype of AML/MDS M1 MO M5 M2 Refractory anemia with ringed sideroblasts

CLL = chronic lymphocytic leukemia; AML = acute myelogenous leukemia; MDS = myelodysplastic syndrome; FAB = French-American-British classification; NA = not applicable. 376

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•Image 21 Bone marrow trephine biopsy section from the same case as Image 1 showing a chronic lymphocytic leukemia nodule (left) (H&E, x100).

Hematopathology / ORIGINAL ARTICLE

ITable 31 Case Reports of Untreated CLL Coexisting with AML or MDS Immunophenotypes References

Sex/Age (y) of Patients

Diagnosis

Conlan and Mosher14

M/69

CLL/AML at presentation

Lima et al15

F/66

CLL/AML (M2) at presentation

Sylvester et al 18

F/85

CLL7MDS at presentation

Mateu et al1

M/59

CLL/AML (M1)

Positive

Cytogenetics

NA

NA

Myeloblasts: CD11b, CD14, CD15, CD41a; lymphoid cells: CD22, FMC7, myeloid markers NA

t(3;12),-7,+(12), -13,-15; i(21), der(21;22)

NA

Nonclonal abnormalities: del(7)(q22); t(1;4)(p36;q26); t(6;7)(p23;q26); t(1;9)(q25;p23)

Myeloid, 13q-; lymphoid cells, trisomy 12

CLL = chronic lymphocytic leukemia: AML = acme myelogenous leukemia; MDS = myelodysplaslic syndrome; NA = not applicable.

by using flow cytometric techniques, immunohistochemical techniques, or both. In all 4 cases of CLL associated with AML, the morphologic impression of 2 separate processes was confirmed by flow cytometric data, immunohistochemical data, or both. Two immunologically distinct cell populations were demonstrated in all 4 cases. With the exception of case 3, the small lymphoid cells coexpressed CD20 and CD5/CD43, consistent with chronic lymphocytic leukemia. The lymphoid cells expressed no myeloid markers. Although the B-lineage lymphoid population in case 3 was CD5", it did not express CD 10, and the cells had round regular contours without plasmacytoid differentiation. Combining the clinical, morphologic, and the overall immunophenotypic features, we considered this lymphoid neoplasm most consistent with CLL rather than other low-grade B-cell lymphoproliferative disorders. Approximately 10% of CLL cases have been reported to be CD5".18 In the 3 cases of AML with detailed flow cytometric data available, the blasts expressed typical myeloid markers, such as CD 13 and CD33, and did not express any lymphoid markers, including CD5 and CD20. The results of the present study support the use of a full panel of monoclonal antibodies for immunophenotyping to more readily recognize an unexpected second hematologic malignant neoplasm and to provide important information about the clonality of the 2 morphologically distinct processes. When we combined the data from the cases we studied and those from the previously documented cases,2-4-67-9 a © American Society of Clinical Pathologists

strong male predominance was noted, with a male/female ratio of approximately 3:1. This disease combination also is confined to the older age group, with a median age of 78 years in the present study. In addition, the more common FAB subtypes of AML, such as FAB-MO, FAB-MI, FABM2, and FAB-M4, all were represented in this series. Neither the cases we studied nor those described in the literature were cases of acute promyelocytic leukemia. The exact nature of the coexistence of untreated CLL and AML or MDS is unknown. Patients with CLL may have decreased immune surveillance of emerging neoplastic clones and a higher frequency of second malignant neoplasms. In fact, the risk of second malignant neoplasms in CLL patients is between 9% and 20%. I9 Lung carcinomas, colon carcinomas, and sarcomas are the most common second neoplasms in this patient population.19 Multiple myeloma is reported to occur at 10 times the expected rate in patients with CLL,19 with some cases hypothesized to arise from the same B-cell clone.'-20-21 Deregulation of normal Bcell function in CLL also may lead to an increased incidence of infection and autoimmune cytopenias in many patients. However, there is no documented increase in the incidence of AML, despite the common use of alkylating agents for treatment of CLL. None of the patients included in the present study had been treated for CLL before the development of AML or MDS. The occurrence of CLL and AML or MDS in the same patient may represent divergent differentiation of the same stem cell clone or, alternatively, 2 separate processes. Am J Clin Pathol 1999; 111:373-378

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Myeloblasts: MY3, MY9; lymphoid cells: Leu 1,T3, B1 Myeloblasts: CD13, CD33, CD34, CD38, CD71; lymphoid cells: CD5. CD19, HLA-DR, IgM, K Lymphoid cells: CD5, CD20, CD23, HLA-DR, IgM, IgD Myeloblasts: CD4, CD13, CD33, CD56, MPO; lymphoid cells: CD5, CD23, CD43, K

Negative

Lai et al / UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA COEXISTING WITH ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME

6. Lawlor E, McCann SR, Whelan A, et al. Acute myeloid leukemia occurring in untreated chronic lymphocytic leukemia. Br J Haematol. 1979;43:369-373. 7. Manoharan A, Catovsky D, Clein P, et al. Simultaneous and spontaneous co-occurrence of lympho- and myeloproliferative disorders: a report of four cases. Br J Haematol. 1981;48:111-116. 8. Wallis JP, Joyner MV. Acute myeloid leukemia developing in a patient with longstanding untreated chronic lymphocytic leukemia. Acta Haematol. 1986;75:229-231. 9. Stern N, Shemesh J, Ramot B. Chronic lymphatic leukemia terminating in acute myeloid leukemia: review of the literature. Cancer. 1981;47:1849-1851. 10. Bennett JM, Catovsky D, Daniel MT. Proposalforthe classification of chronic (mature) B and T lymphoid leukemias. J Clin Pathol. 1989;42:567-584. 11. Sheibani K, Tubbs RR. Enzyme immunohistochemistry: technical aspects. Semin Diagn Pathol. 1984;1:235-250. 12. Gown AM, deWever N, Battifora H. Microwave-based antigenic unmasking: a revolutionary new technique for routine immunohistochemistry. Appl Immunohistochemistry. 1994;1:256-266. 13. Khalidi H, Medeiros LJ, Chang KL, et al. The immunophenotype of adult myeloid leukemia: high frequency of lymphoid antigen expression and comparison of immunophenotype, French-American-British classification, and karyotypic abnormalities. Ami Clin Pathol. 1998;109:211-220. 14. Conlan MG, Mosher DF. Concomitant chronic lymphocytic leukemia, acute myeloid leukemia, and thrombosis with From the Division of Pathology, City of Hope National Medical protein C deficiency: case report and review of the literature. Center, Duarte, California. Cancer. 1989;63:1398-1401. Address reprint requests to Dr Chang: Division of Pathology,15. Lima M, Porto D, Rodrigues M, et al. Cytogenetic findings in City of Hope National Medical Center, 1500 E Duarte Road, a patient presenting simultaneously with chronic lymphocytic Duarte, CA 91010. leukemia and acute myeloid leukemia. Cancer Genet Acknowledgment: We thank Eddie Hu, MD, Los Angeles, Cytogenet. 1996;87:38^0. Calif, and his office stafffor providing clinical follow-up 16. Sylvester LS, Nowell PC, Bonner H, et al. Concurrent information for patient 2. diagnosis of chronic lymphocytic leukemia and myelodysplastic syndrome. Leuk Res. 1997;21:619-621. 17. Mateu R, Bellido M, Sureda A, et al. Concomitant chronic lymphocytic leukemia and acute myeloid leukemia with an uncommon immunophenotype. Am] Hematol. References 1997;56:281-287. 1. Foucar K. B cell chronic lymphocytic and prolymphocytic 18. Keating MJ. Chronic lymphocytic leukemia. In: Henderson leukemia. In: Knowles DM, ed. Neoplastic Hematopathology. ES, Lister TA, eds. Leukemia. 6th ed. Philadelphia, Pa: Baltimore, Md: Williams & Wilkins; 1992:1181-1208. Saunders; 1990:556-586. 2. Roberts PD, Forster PM. Chronic lymphocytic leukemia 19. Silber R, Stahl R. CLL and related disease. In: Williams W], associated with acute myelomonocytic leukemia. Br J Beutler E, Erslev A], et al, eds. Hematology. 4th ed. New York, Hematol. 1973;25:203-206. NY: McGraw-Hill; 1990:1018. 3. Warwick R, Goldstone AH, Janossy G. Chronic lymphocytic 20. Bassan R, Comotti B, Minetti B, et al. Concurrent multiple leukemia uncovered by successful treatment of acute myeloid myeloma and chronic lymphocytic leukemia. Am J Clin leukemia. BMJ. 1976;2:1111-1112. Pathol. 1984;82:624-627. 4. Barcey AW, Maddox A, Immken L, et al. Coexistence of 21. Fernand JP, Herait JP, Brouet JC. Associated chronic myelodysplastic syndrome and untreated chronic lymphocytic lymphocytic leukemia and multiple myeloma: origin from a leukemia with development of acute myeloid leukemia single clone. Blood. 1985;66:291-293. immediately after treatment of chronic lymphocytic leukemia. AmJHemawl. 1989;30:174-180. 5. Robertson LE, Estey E, Kantarjian H, et al. Therapy-related leukemia and myelodysplastic syndrome in chronic lymphocytic leukemia. Leukemia. 1994;12:2047-2051.

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Recently, cytogenetic studies have shed some light on this issue. While some cases have no detectable chromosomal abnormalities (such as the case reported by Conlan et al as well as case 3 in this series), chromosomal aberrations are documented in a small number of cases.4-15-17 In 1 case report, chromosomal aberrations commonly seen in CLL and AML (including trisomy 12 and monosomy 7) were found in the unstimulated peripheral blood mononuclear cells, and it was suggested that these findings support the single-clone hypothesis.15 However, because spontaneous mitosis of CLL cells is extremely unusual in unstimulated 24-hour cultured cells, the cytogenetic alterations detected probably reflect the karyotype of myeloblasts only. In another study, the myeloid and lymphoid clones were found to have different chromosomal abnormalities, with 13q- chromosome found in myeloid cells and trisomy 12 found in lymphoid cells.16 These findings suggest the concurrent development of 2 separate clonal disorders. This view is further supported by the identification of 2 morphologically and immunologically distinct cell populations in the cases we studied, as well as in the other reported cases. Molecular study of any newly observed cases may enhance our understanding of this rare association of CLL with AML or MDS.