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Annals of Clinical & Laboratory Science, vol. 38, no. 4, 2008
Case Report and Literature Review: A Rare Patient with Chronic Myeloid Leukemia and Chronic Lymphocytic Leukemia
Sharathkumar Bhagavathi,1 Vidal Borromeo,2 Harsha Desai,1 and Domnita Crisan1 Departments of 1Clinical Pathology and 2Hematology/Oncology, William Beaumont Hospital, Royal Oak, Michigan Abstract. Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common leukemias of the elderly. However, the sequential occurrence of CML followed by CLL in the same patient is extremely rare. In the present report, a 71-yr-old man was diagnosed with Philadelphia (Ph) chromosome positive CML and treated with imatinib mesylate. He went into morphologic, cytogenetic, and molecular remission. Seven years after the diagnosis of CML, he developed CLL. We describe the morphologic, immunophenotypic, cytogenetic, and molecular findings in this patient. Keywords: chronic lymphocytic leukemia, chronic myeloid leukemia, coexistant leukemias Introduction
Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in the western world. Chronic myeloid leukemia (CML), the most common myeloproliferative disorder, has a characteristic t(9;22)(q34;q11) cytogenetic abnormality that involves fusion of the BCR gene on chromosome 22 with the ABL gene on chromosome 9. The BCR/ABL fusion results in constitutive activation of tyrosine kinase, which leads to uncontrolled proliferation of myeloid cells. Concurrence of chronic myeloid and chronic lymphocytic leukemias in the same patient is rare. Most cases reported in the literature are patients who had CLL and CML simultaneously [1-6] or who developed CML several years after treatment of CLL with chemo- or radio-therapy [7-15] (Table 1). Until now, only two patients have been reported in whom CLL developed after the diagnosis of CML [16,17]. In the present study we report an additional patient who developed CLL several years after the diagnosis of CML.
The patient is a 71-yr-old man who presented in 2000 with angina. He had a positive stress echocardiogram and underwent coronary bypass surgery. In 2001, a CBC test gave the following results: hemoglobin 13.1 g/dl, leukocyte (WBC) count 55.5 x 109/L (neutrophils, 27.5 x 109/L; lymphocytes, 3.8 x109/L; monocytes, 3.05 x 109/L; eosinophils, 0.8 x 109/L; basophils, 1.9 x 109/L; metamyelocytes, 4.7 x 109/L; myelocytes, 9.7 x 109/L); and platelet count 534 x 109/L (Fig. 1A). Chronic myeloproliferative disorder was considered in the differential diagnosis and bone marrow (aspiration and biopsy) studies revealed hypercellular marrow with marked granulocytic and megakaryocytic hyperplasia (Fig 1, B-D). The reverse-transcription polymerase chain reaction (RT-PCR) test for BCR/ABL was positive. The patient was diagnosed as CML in chronic phase and was treated with imatinib mesylate. Subsequent BCR/ABL analyses from 2003 until April 2007 were negative. In May 2007, a CBC showed a normal WBC count with absolute lymphocytosis (4.7 x 109/L) (Fig. 1E). Bone marrow studies were performed to evaluate the patient’s CML status and the absolute
Address correspondence to Dr Sharathkumar Bhagavathi, Dept of Clinical Pathology, William Beaumont Hospital, West 13 Mile Road, Royal Oak, MI 48073, USA; tel 248 898 1714; fax 248 898 1257; e-mail [email protected]
0091-7370/08/0400-0405. $1.75. © 2008 by the Association of Clinical Scientists, Inc.
406 Annals of Clinical & Laboratory Science, vol. 38, no. 4, 2008
Fig. 1: Morphology of peripheral blood, bone marrow biopsy and aspirate of CML and CLL. (A): Peripheral blood smear showing leukocytosis with basophilia and thrombocytosis (Wright stain, x200). (B): Bone marrow biopsy showing hypercellular marrow with myeloid and erythroid hyperplasia (H&E x100). (C & D): Bone marrow aspirate showing myeloid and megakaryocytic hyperplasia, and full myeloid maturation (Wright stain, x100, x200). (E): Peripheral blood smear showing mature lymphocytes and a smudge cell (Wright stain, x200). (F): Bone marrow aspirate showing predominantly mature lymphocytes and few myeloid cells (Wright stain, x100). (G & H): Bone marrow biopsy showing involvement of bone marrow by chronic lymphoid leukemia (CLL) in a nodular and interstitial pattern (H&E, x100, x200).
A patient with chronic myelogenous and chronic lymphocytic leukemias 407 Table 1. Reports of patients with chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL). Authors Age (yr) Gender Interval Simultaneous CML and CLL Leoni F, et al  55 M Simultaneous Maher VE, et al  69 M Simultaneous Crescenzi B, et al  64 M Simultaneous Vilpo JA, et al  58 M Simultaneous Esteve J et al  71 F Simultaneous Mansat-De Mas F  68 M Simultaneous CML after the diagnosis of CLL Khojasteh A, et al  55 M 61 mo Faguet GB, et al  83 M 2 mo Teichmann JV, et al  47 M 72 mo Whang-Peng J, et al  62 M 36 mo Whang-Peng J, et al  74 M 24 mo Schreiber ZA, et al  55 M 84 mo Hashimi L, et al  82 F 60 mo 43 M 73 mo Nanjangud GJ, et al  Mossafa C, et al  76 F 12 mo Ramanarayanan J, et al  52 F 29 mo CLL after the diagnosis of CML 54 F 36 mo Salim R, et al  Gargallo P, et al  88 F 20 mo Present case 71 M 74 mo
Chl, Hu Hu Hu Hu, IFN-alpha, Chl Bus, Chl Chl, Vin, Bleo Chl, None Chl None TBI None Fludarabine Hu, IFN-alpha, IM Chl, Hu IM
Abbreviations: Chl: chlorambucil; Hu: hydroxyurea; IFN: interferon; Bus: busulfan; Vin: vincristine; Bleo; bleomycin; TBI: total body irradiation; IM: imatinib mesylate.
lymphocytosis, and revealed hypercellular marrow with trilineage hematopoiesis and infiltration of small mature lymphocytes (35-40% of cellularity) with hyper-clumped chromatin and scant cytoplasm (Fig. 1, F-H). Immunophenotyping by flow cytometry showed CD5 (+) and CD23 (+) kappa monotypic B cells consistent with CLL. Cytogenetic analysis demonstrated 46, XY, Inv (9) (p12q13) and was negative for t(9;22). Currently the patient continues in morphologic, cytogenetic, and molecular remission of CML. His CLL is in the indolent phase and is being monitored without therapeutic intervention. Discussion This case report describes a rare occurrence of sequential CML and CLL in the same patient. CLL is the most common leukemia of adults in the western world, and constitutes about 25-30% of all leukemias. The incidence of CLL is increasing in
patients >60 years old and occurs at a rate of 20/100,000 per year . CML is a chronic myeloproliferative disease originating in abnormal pluripotent stem cells and resulting in involvement of multiple hematopoietic lineages but predominantly myeloid. Association between chronic lymphocytic leukemia (CLL) and myeloid malignancies (CML, AML, and MDS) is a rare event. Patients with CLL are predisposed to the development of a second malignancy due to impaired immune system or chemotherapy . The second malignancy in the majority of cases is nonhematologic and occurs several years after the diagnosis of CLL . Patients with CML have a natural history of evolution to blast crisis, and are rarely associated with a second malignancy [21,22]. Occurrence of CML and CLL in the same patient is a rare event. In most cases reported in the literature (Table 1), CLL preceded the development of CML [7-15] or the leukemias both developed simultaneously [1-6]. Development of CML and
408 Annals of Clinical & Laboratory Science, vol. 38, no. 4, 2008 CLL in a patient is facilitated by interaction between lymphoid and myeloid lineages. Peters et al  reported that BCR/ABL-transformed cells secrete a variety of cytokines including interleukin3 (IL3). Cytokine IL3 increases the production of B lymphoid cells from human CD 34(+) CD 38(-) immature cells . These mechanisms may contribute to the development of CLL in patients with a diagnosis of CML. Until now, there have been only two reported instances of CLL developing after the diagnosis of CML [16,17]. In both cases, the patients were in the chronic phase of CML, and CLL developed 20 and 36 mo after the onset of CML. In both patients, CML and CLL arose from distinct clones. Whether this signifies a defective stem cell micro-environment that triggers leukemogenesis or whether two distinct events occurred by chance in the same individual needs to be clarified. In the present study we report a patient who developed CLL 7 yr after the diagnosis of CML. The patient was initially diagnosed as CML in chronic phase and was treated with imatinib mesylate. The patient achieved morphologic, cytogenetic, and molecular remission. Seven years after the diagnosis of CML, the patient developed leukocytosis with absolute lymphocytosis. Bone marrow studies were done to evaluate lymphocytosis as well as CML status. The results showed infiltration of small lymphocytes with morphologic and immunophenotypic findings characteristic of CLL. In conclusion, we report a patient who developed CLL 7 yr after the diagnosis of CML. To our knowledge this is the third such case in the literature. References 1. Leoni F, Ferrini PR, Castoldi GL, Pata M, del Prete GF, Tomasi P: Simultaneous occurrence of chronic granulocytic leukemia and chronic lymphocytic leukemia. Haematologica 1987;72:253-256. 2. Maher VE, Gill L, Towners PL, Wallace JE, Savas L, Woda BA, et al. Simultaneous chronic lymphocytic leukemia and chronic myelogenous leukemia: evidence of a separate stem cell origin. Cancer 1993;71:19931997. 3. Cresscenzi B, Sacchi S, Marasca R, Temperani P, La Starza R, Matteucci C, et al. Distinct genomic events in the myeloid and lymphoid lineages in simultaneous
presentation of chronic myeloid leukemia and B-chronic lymphocytic leukemia. Leukemia 2002;16:955-956. 4. Vilpo JA, Klemi P, Lassila O, Schroder J, de la Chapelle A. Transformation in chronic granulocytic leukaemia. Different blast cell clones in different anatomical sites. Acta Haematol 1979;62:247-250. 5. Esteve J, Cervantes F, Rives S, Rozman M, Zarco MA, Montesettat E. Simultaneous occurrence of B cell chronic lymphocytic leukemia and chronic myeloid leukemia with further evolution to lymphoid blast crisis. Hematologica 1997;82:596-599. 6. Mansat-De Mas V, Rigal-Huguet F, Cessar G, Kuhlein E, Laurent G, Dastugue N. Chronic myeloid leukemia associated with B-cell chronic lymphocytic leukemia: evidence of two separate clones as shown by combined cell-sorting and fluorescence in situ hybridization. Leuk Lymphoma 2003;44:867-869. 7. Khojasteh A, Perri MC, Taylor HM. Chronic myelocytic leukemia developing as a second cancer in a patient with chronic lymphocytic leukemia. CA Cancer J Clin 1981;31:172-176. 8. Faguet GB, Little T, Agee JF, Garver FA. Chronic lymphocytic leukemia evolving into chronic myelocytic leukemia. Cancer 1983;52:1647-1652. 9. Teichmann JV, Sieber G, Ludwing WD, Karow J, Ruehl H. Chronic myelocytic leukemia as a second neoplasia in the course of chronic lymphocytic leukemia. Leuk Res 1986;10:361-368. 10. Whang-Peng J, Gralnick HR, Johnson RE, Lee EC, Lear A. Chronic granulocytic leukemia (CGL) during the course of chronic lymphocytic leukemia (CLL): correlation of blood, marrow, and spleen morphology and cytogenetics. Blood 1974;43:333-339. 11. Schreiber ZA, Axelrod MR, Abebe LS. Coexistence of chronic myelogenous leukemia and chronic lymphocytic leukemia. Cancer 1984;54:697-701. 12. Hashimi L, Al-Katib A, Mertelsmann R, Mohamed AN, Koziner B. Cytofluorometric detection of chronic myelocytic leukemia supervening in a patient with chronic lymphocytic leukemia. Am J Med 1986;80:269275. 13. Nanjangud DJ, Saikia TK, Chopra H, Kadam PR, Advani SH. Development of Ph positive chronic myeloid leukemia in a patient with chronic lymphocytic leukemia treated with total body irradiation: a rare association. Leuk Lymphoma 1996;22:355-359. 14. Mossafa H, Fourcade C, Pulic M, Jary L, Cheze S, Szpiro-Tapia S, et al. Chronic lymphocytic leukemia associated with myelodysplastic syndrome and/or chronic myeloid leukemia: evidence of independent clonal chromosomal evolution. Leuk Lymphoma 2001; 41:337-341. 15. Ramanarayanan J, Dunford LM, Baer LM, Sait SN, Lawrence W, McCarthy PL. Chronic myeloid leukemia after treatment of lymphoid malignancies: response to imatinib mesylate and favorable outcomes in three patients. Leuk Res 2006;30:701-705.
A patient with chronic myelogenous and chronic lymphocytic leukemias 409 16. Salim R, Wang L, Lin K, Clark RE. Chronic lymphocytic leukemia developing in the course of chronic myeloid leukemia. Leuk Lymphoma 2002;43:2225-2227. 17. Gargallo P, Cacchione R, Chena C, Dupont J, Garay G, Riveros D, et al. Chronic lymphocytic leukemia developing in a patient with chronic myeloid leukemia: evidence of distinct lineage-associated genomic events: Cancer Genetics Cytogenetics 2005;161:74-77. 18. Rai KR. Chronic lymphocytic leukemia. In: Hematology Basic Principles and Practice (Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Eds), Churchill Livingstone, London, 1991; pp 990-1001. 19. Bartik MM, Welker D, Kay NE. Impairments in immune function in B cell chronic lymphocytic leukemia. Semin Oncol 1998;25:27-33. 20. Hisada M, Biggar RJ, Greene MH, Fraumeni JF, Travis LB. Solid tumors after chronic lymphocytic leukemia. Blood 2001;98:1979-1981.
21. Jin HH, Won HJ, Myong SC, Lee M, Soon CW. Acute lymphoblastic leukemia without Philadelphia chromosome occurring in chronic myelogenous leukemia with the Philadelphia chromosome. Am J Hematol 2003;74: 218-220. 22. Zhang X, Ji L, Liu S, Wang J. Ph-negative acute lymphocytic leukemia occurring after interferon therapy for Phpositive chronic myelocytic leukemia. Leuk Res 2003;27: 367-369. 23. Peters DG, Klucher KM, Perlingeiro RC, Dessain SK, Koh EY, Daley GQ. Autocrine and paracrine effects of an ES-derived, BCR/ABL transformed hematopoietic cell line that induces leukemia in mice. Oncogene 2001; 20:2636-2646. 24. Crooks GM, Hao QL, Peterson D, Barsky LW, Bockstoce D. IL-3 increases production of B lymphoid progenitors from human CD34(+) CD38(-) cells. J Immunol 2000; 165:2382-2389.