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  Table of Contents    
CASE REPORT  
Year : 2013  |  Volume : 56  |  Issue : 3  |  Page : 303-305
Chronic lymphocytic leukemia developing in a case of chronic myelogenous leukemia - accelerated phase: A rare case with review of the literature


1 Department of Hematology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
2 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India

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Date of Web Publication24-Oct-2013
 

   Abstract 

Chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) are two different and common hematological neoplasms. Their coexistence is rare, especially CLL developing in a patient of CML. Till date, only a few cases are reported and all had chronic myeloid leukemia - chronic phase earlier. We report the first case of CLL developing in a patient initially diagnosed in an accelerated phase of chronic myeloid leukemia. The clonality of both CML and CLL was proven by cytogenetic, molecular and flow cytometric studies.

Keywords: Bone marrow, chronic lymphocytic leukemia, chronic myelogenous leukemia, flow cytometry, imatinib

How to cite this article:
Kumar N, Ahluwalia J, Malhotra P, Sachdeva MS. Chronic lymphocytic leukemia developing in a case of chronic myelogenous leukemia - accelerated phase: A rare case with review of the literature . Indian J Pathol Microbiol 2013;56:303-5

How to cite this URL:
Kumar N, Ahluwalia J, Malhotra P, Sachdeva MS. Chronic lymphocytic leukemia developing in a case of chronic myelogenous leukemia - accelerated phase: A rare case with review of the literature . Indian J Pathol Microbiol [serial online] 2013 [cited 2020 May 25];56:303-5. Available from: http://www.ijpmonline.org/text.asp?2013/56/3/303/120406



   Introduction Top


Chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) are distinct hematological malignancies. CLL is the most common leukemia of adults in the western world, whereas CML is the most common myeloproliferative neoplasm characterized by the t (9; 22) (q34; 11) cytogenetic abnormality. The usual clinical course of CML progresses through a chronic phase, an accelerated phase and a blast crisis. The subsequent development of CLL in a patient of CML is an extremely rare event. Till now, only a few cases had been reported in the literature. [1],[2],[3],[4] All these cases initially had chronic phase CML and subsequently developed CLL. These cases raise the question of whether the two malignancies arose from the same clone or whether there is a hidden link that is still unexplored. We report a patient who developed a CLL 8 months after the diagnosis of a Ph-positive chronic myelogenous leukemia-accelerated phase (CML-AP). To the best of our knowledge, this is the first case in the literature in which CLL developed in a patient with CML-AP.


   Case Report Top


A 45-year-old female presented in April 2011 with generalized weakness, shortness of breath and loss of appetite and weight for the last 2 years. She also perceived heaviness on the left side of the hypochondrium. On palpation, she had massive splenomegaly (36 cm in the long axis). Hemogram showed hemoglobin (Hb) 9.4 g/dL, white blood cell (WBC) count 358.2 × 10 9 /L (49% neutrophils, 1% eosinophils, 1% basophils, 3% lymphocytes, 1% monocytes, 16% blasts, 5% promyelocytes, 16% myelocytes and 8% metamyelocytes) and platelet count 244 × 10 9 /L [Figure 1]a. Bone marrow (BM) aspirate was hypercellular with similar blast percentage (16%) [Figure 1]b and c. BM biopsy was hypercellular with an increase in immature myeloid cells [Figure 1]d. Cytogenetic analysis revealed a 46, XX, t (9; 22) (q34; q11) karyotype [Figure 2] in 16 of 20 metaphases examined. There was no evidence of any other cytogenetic abnormality related to CLL. Reverse-transcriptase polymerase chain reaction (RT-PCR) for BCR/ABL was positive. The diagnosis of CML-AP was made and the patient was started on Imatinib mesylate 600 mg OD. The patient achieved hematological remission in 4, 6 and 8 weeks. Splenomegaly regressed in 3 months time.
Figure 1: Morphology of peripheral blood, bone marrow aspirate and biopsy of accelerated phase of chronic myeloid leukemia. Peripheral blood smear showing leukocytosis with increased number of blasts (MGG-Giemsa stain, x400) (a). Bone marrow aspirate showing megakaryocyte and myeloid cells with excess of blasts (MGG-Giemsa stain, x200, x1000) (b and c). Bone marrow biopsy is hypercellular with myeloid and megakaryocytic hyperplasia (Hematoxylin and Eosin, x400) (d)

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Approximately 8 months later (in December 2011), a routine hemogram revealed Hb 6.2 g/dL, WBC count 36 ×10 9 /L (16% neutrophils, 4% eosinophils, 1% monocytes and 79% lymphocytes) and platelet count 76 × 10 9 /L [Figure 3]a. The absolute lymphocyte count was 28.44 × 10 9 /L. There were no basophils or myeloid precursors in the peripheral blood. Physical examination did not reveal any lympadenoapthy or hepatomegaly. The splenomegaly had regressed completely. In view of the absolute lymphocytosis, a bone marrow examination was performed. It showed a hypercellular marrow with 89% mature-appearing lymphocytes [Figure 3]b-d. Cytogenetic analysis at this time and RT-PCR for BCR/ABL were negative (complete cytogenetic and molecular response of the CML). Immunophenotyping of the blood/bone marrow revealed lymphocytes expressing CD5, CD19 and CD23 with κ-light chain restriction (dim expression). There was no expression of CD10, CD20, CD79b, FMC7, CD33 or CD34 [Figure 4]. The findings were consistent with CLL, Rai stage C. Currently, she continues in hematologic, cytogenetic and molecular remission of CML. Because of financial constraints, she was considered for chlorambucil-based chemotherapy for CLL.
Figure 2: G-banded karyotype from the bone marrow cell showing (black arrows) the deleted part of the long arm of chromosome 22 translocated to the long arm of chromosome 9; t (9; 22) (q34; q11)

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Figure 3: Morphology of peripheral blood, bone marrow biopsy and aspirate at the time of developing chronic lymphocytic leukemia (CLL). Peripheral blood smear shows mature lymphocytes and smudge cells (MGG-Giemsa stain, x400) (a). Bone marrow aspirate shows predominantly mature lymphocytes, a few myeloid cells and occasional megakaryocytes (MGG-Giemsa stain x100, x400) (b and c). Bone marrow biopsy is hypercellular and shows involvement by CLL (Hematoxylin and eosin, x400) (d)

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Figure 4: Panel of scatter plots depicting the multicolor immunophenotyping of bone marrow aspirate sample by flow cytometry. The gati ng of cells in each tube has been done on side scatter versus CD19 plot, with the gated P2 population showing surface CD19 expression (a). The gated cells show dual CD5 and CD23 expression (b) along with dim expression of kappa light chain (c). The same cell populati on lacks expression of CD10, CD22, CD79b and FMC7 (d and e). The gated cell population shows expression of Human leukocyte antigen-DR (HLA-DR) but lacks CD34 expression (f)

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Table 1: Previous case reports of patients developing chronic lymphocytic leukemia (CLL) after the diagnosis of chronic myelogenous leukemia (CML)

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   Discussion and Review of the Literature Top


We describe a rare sequential occurrence of CLL in a patient of CML-AP. CLL is the most common leukemia of elderly patients. Its incidence is increasing in patients >60 years old, and occurs at a rate of 20/100,000 per year. [5] CML, on the other hand, is a chronic myeloproliferative neoplasm arising in abnormal pluripotent stem cells and resulting in involvement of multiple hematopoietic lineages with predominant involvement of myeloid series. Patients with CML have a natural history of evolution to blast crisis, and are only rarely associated with a second hematological malignancy. [5],[6]

The association between CLL and CML has been reported very rarely and a few studies described that CLL preceded the development of CML, or that there is simultaneous occurrence of both these disorders. [7],[8] There are only four case reports in which CLL develops later in the course after CML [Table 1]. [1],[2],[3],[4] In all these cases, the patients were in the chronic phase of CML and CLL developed after 6-74 months of the onset of CML. Our case was similar with respect to the time period between occurrences of CLL after CML, i.e. 8 months. All prior cases were of older age (range 54-88 years) without any gender preponderance (M:F; 2:2). Our patient is relatively younger (45 years) as compared with the earlier reports. All these reported cases previously had a chronic phase of chronic myeloid leukemia (CML-CP), and the index case is the first case report where CLL developed in the accelerated phase (CML-AP). Although-CP is known to be relatively stable, conversion to the accelerated phase is associated with genetic instability and acquisition of other cytogenetic abnormalities We were unable to document any other abnormalities in the index case, but do accept that a submicroscopic genetic alteration is not excluded. It is also not possible to comment on a small CLL clone being present at the time of the initial diagnosis, as our routine immunophenotyping panel does not include CD5 or CD23 at the time of CML-AP.

Because the patient was on Imatinib mesylate for CML-AP treatment, a detailed search in the literature was performed to determine whether this could be a drug-related side-effect. Imatinib is generally a well-tolerated drug. The most commonly reported adverse event is edema, and events include periorbital edema, pleural or pericardial effusion, ascites and anasarca edema The literature showed that predominantly carcinomas (skin cancers, prostate, GIT, renal, etc) and a few lymphoma (large B cell lymphoma) arise after tyrosine kinase inhibitor (TKI) intake. The interval between TKI treatment and the development of secondary cancer in these cases was 6-36 months (mean 30 months). [9],[10] Verma et al. had concluded that patients who develop secondary malignancy after TKI therapy were analyzed in the context of the underlying lifetime risk of developing cancer by the general population and, in cancer survivors, there is no evidence at the moment to suggest that exposure to TKI is carcinogenic. [10]

Cases of CML developing a second malignancy are challenging to treat. No specific therapy was given for CLL to any of the cases reported in the literature. [1],[2],[3],[4],[10] Our patient received chlorambucil-based chemotherapy. We do expect to remain vigilant as the very high lymphocyte counts in this patient may indicate a relatively more aggressive disease.

We present a patient who developed CLL 8 months after the diagnosis of CML-AP. To delineate the clonal involvement in each disorder, we demonstrate the BCR/ABL fusion gene and Ph chromosome at the time of diagnosis of CML-AP and flow cytometry (CD 19, CD 5 and CD 23 positive cell population) for CLL. At this time, we are unable to detect Ph chromosome or BCR-ABL fusion gene. In conclusion, we report a patient who developed CLL 8 months after the diagnosis of CML-AP. To the best of our knowledge, this is the first case in the literature where CLL develops after CML-AP.

 
   References Top

1.Salim R, Wang L, Lin K, Clark RE. Chronic lymphocytic leukemia developing in the course of chronic myeloid leukemia. Leuk Lymphoma 2002;43:2225-7.   Back to cited text no. 1
    
2.Chang H, Sutherland R, Nayar R, Li D, Kamel-Reid S, Mile MA, et al. Chronic lymphocytic leukemia in the course of chronic myelocytic leukemia: Evidence of independent clonal origin as shown by interphase fluorescence in situ hybridization and fluorescence-activated cell sorting. Cancer Genet Cytogenet 2004;152:146-8.  Back to cited text no. 2
    
3.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 Genet Cytogenet 2005;161:74-7.   Back to cited text no. 3
    
4.Bhagavathi S, Borromeo V, Desai H, Crisan D. A Rare Patient with Chronic Myeloid Leukemia and Chronic Lymphocytic Leukemia. Ann Clin Lab Sci 2008;38:405-9.   Back to cited text no. 4
    
5.Rai KR. Chronic lymphocytic leukemia. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, editors. Hematology Basic Principles and Practice. London: Churchill Livingstone; 1991. p. 990-1001.   Back to cited text no. 5
    
6.Jin HH, Won HJ, Seong CM, Lee M, Soon Chung W. Acute lymphoblastic leukemia without Philadelphia chromosome occurring in chronic myelogenous leukemia with the Philadelphia chromosome. Am J Hematol 2003;74:218-20.  Back to cited text no. 6
    
7.Nanjangud GJ, 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;22:355-9.  Back to cited text no. 7
    
8.Crescenzi 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;16:955-6.  Back to cited text no. 8
    
9.Duman BB, Paydas S, Disel U, Besen A, Gurkan E. Secondary malignancy after imatinib therapy: Eight cases and review of the literature. Leuk Lymphoma 2012:53;1706-8.  Back to cited text no. 9
    
10.Verma D, Kantarjian H, Strom SS, Rios MB, Jabbour E, Quintas-Cardama A, et al. Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood 2011;118:4353-8.  Back to cited text no. 10
    

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Correspondence Address:
Narender Kumar
Department of Hematology, Level 5, Research Block A, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.120406

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