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Acute promyelocytic leukemia and chronic lymphocytic leukemia: concomitant presentation of two molecularly distinct entities.

INTRODUCTION

Secondary malignancies following treatment of chronic lymphocytic leukemia (CLL) and other malignancies are common. These include solid tumors as well as hematologic malignancies. (1,2) Acute myeloid leukemia (AML) occurring after treatment for other malignancies is frequently reported. However, AML following treatment of CLL patients is extremely rare. Although acute promyelocytic leukemia (APL) accounts for 12-15% of therapy-related AML (t-AML), these cases typically occur following chemotherapy with topoisomerase II inhibitor and only occasionally following radiation therapy. (3-6) To our knowledge, concomitant APL and CLL in untreated patient have not been found in literature, prompting this report.

CASE REPORT

A 52-year-old Caucasian male with a past medical history of hypertension, insulin-dependent diabetes mellitus, and coronary artery disease status post stent placement presented initially to an outside facility with substernal chest pain and dyspnea for two days. He did not report any fatigue, drenching night sweats or weight loss. On examination, there was no evidence of lymphadenopathy, splenomegaly or hepatomegaly. No petechiae or ecchymosis were evident. Complete blood count showed a white blood cell count (WBC) of 17,000 /[micro]L comprised of 97% lymphocytes and 2% blasts, hemoglobin of 6.0 g/dL, and a platelet count of 16,000 /[micro]L. He was found to have an elevated serum troponin 0.30 ng/mL (normal range 0--0.05 ng/mL). Other laboratory studies were unremarkable. Electrocardiogram (ECG) revealed ST-depression in lateral leads suspicious for a non-ST elevation myocardial infarction (NSTEMI). On admission, he received packed red blood cell and platelet transfusions with resolution of chest pain.

NSTEMI was conservatively managed due to thrombocytopenia. Work up for infection was negative. WBC count further increased to 69,000 /[micro]L and platelet count decreased to 9.000 /[micro]L. Coagulation studies revealed a slightly elevated prothrombin time (PT) of 16.7 seconds, normal activated partial thromboplastin time (aPTT), and normal fibrinogen.

Peripheral blood smear examination revealed conspicuous atypical lymphocytes and occasional promyelocytes (Figure 1A and 1B). Microscopic examination of the bone marrow aspirate (Figure 1C) and bone marrow clot sections (Figure 1E and 1F) revealed a hypercellular bone marrow with a marrow cellularity of 100%. 65% of the marrow cellularity was comprised of leukemic promyelocytes. On immunohistochemical staining (BenchMark ULTRA automated stainer, antibodies from Ventana Medical Systems, Inc., Tucson, AZ), these cells were positive for myeloperoxidase (Figure 1G) and CD117, but negative for CD34. The remaining 35% of the marrow cellularity was comprised of small atypical B lymphocytes. These cells expressed CD79a (Figure 1H) and BOB-1 on immunohistochemical staining, but did not express CD20. Other hematopoietic elements were virtually absent. Flow cytometric studies performed on the bone marrow aspirate revealed a prominent population of leukemic promyelocytes with expression of CD13, CD15, CD33, CD56, and CD117. CD45 expression was dim. CD34 and HLADR were negative. A population of clonal B cells was identified that expressed CD5, CD19, CD20 (dim), CD22, CD23, CD45, and HLA-DR, and were kappa light chain restricted. Molecular genetic studies by fluorescence in situ hybridization (FISH) were positive for PML/RARA with PML/RARA fusion signals identified in 122/200 cells (Figure 1D). Molecular genetic studies by FISH for CLL associated prognostic abnormalities detected a deletion in 13q. Morphologic features, flow cytometric findings, and molecular genetic studies were diagnostic of an acute promyelocytic leukemia (APL) with t(15; 17)(q22; q21); PML/RARA and concomitant B cell chronic lymphocytic leukemia (CLL).

Treatment for APL with All-trans retinoic acid (ATRA) and hydroxyurea was started immediately along with dexamethasone for prevention of differentiation syndrome. Anthracycline or arsenic trioxide-based therapy was not initiated concomitantly due to concern for cardiotoxicity in the context of recent NSTEMI. Twenty-four hours after his initial presentation and six hours after initiation of ATRA, he developed respiratory distress. X-Ray showed extensive patchy opacities in bilateral lung fields. WBC count further increased to 130,000 /[micro]L. Acute pulmonary edema due to recent NSTEMI, bilateral pneumonia (blood culture later reported as positive for Staphylococcus epidermidis), leukostasis, and differentiation syndrome were considered in the differential diagnoses. Broad spectrum antibiotics were continued and diuretics as well as non-invasive ventilation with bi-level positive airway pressure (BiPAP) were applied. Despite aggressive medical management, patient's condition deteriorated rapidly and he died from multi-organ failure within forty-eight hours of his presentation.

DISCUSSION

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western hemisphere. The treatment of CLL is associated with a high incidence of secondary malignancies including non-melanoma skin cancer, Kaposi sarcoma, melanoma, cancers of the lung, gastrointestinal tract, breast, prostate, kidney, bladder, head and neck, and transformation to an aggressive large B-cell lymphoma (Richter's syndrome). It is noteworthy that AML developing in a background of CLL is extremely rare. Among those with treatment-associated AML (t-AML), exposure to topoisomerase II inhibitors (mainly Etoposide), alkylating agents and ionizing radiation are among the main contributing factors. Cases of AML have also been reported in patients treated with other topoisomerase II inhibitors such as Mitoxantrone (7) and Bimolane. (8) AML after treatment with DNA-topoisomerase 2 inhibitors has a short latency period, presents without a prior myelodysplastic syndrome, and is associated with 11q23 translocation.

In 2006, there were two reports of concurrent AML with CLL in untreated patients. Gottardi et al (9) documented simultaneous CLL and AML (FAB-M2) based on morphological and immunologic features. The AML component was CD34+/ CD13+/HLA-DR+/CD7+, and the CLL expressed VH3-53/ D3-22/JH4 Ig with 3.9% IgVH mutations. Further evaluation with IgH gene rearrangement on CD34+/CD19- and CD34-/ CD19+ immunomagnetically sorted cell populations revealed a shared molecular signature suggesting that genomic DNA from the CD34-/CD19+ cell fraction demonstrated IgH gene rearrangement, resulting in expansion of two independent clones and concomitant presentation of CLL and AML. In the case reported by Lu et al, (10) cytogenetic analysis revealed inv(16) (p13.1q22) and trisomy 22 in a second clone. Fluorescence in situ hybridization confirmed the CBFp rearrangement associated with inv(16) in myeloblasts and myelomonocytic cells but not in CLL cells, confirming that the AML and CLL did not share clonality.

The association between APL and CLL is even rarer. Molero et al reported a case of APL that developed two years after radiotherapy for prostate cancer in a patient with chronic lymphocytic leukemia. (11) Although no treatment was given for the patient's CLL, radiotherapy for prostate cancer in this patient might have contributed to the development of APL and is considered therapy-related. It has been suggested that there is a 0.1-0.2% risk of developing AML within 10 years in patients receiving radiation therapy, and the incidence is higher in patients with a mean bone marrow dose of greater than 3.5 Gy. (12) To date, no report in the literature has been found on simultaneous occurrence of APL and CLL in patients without any previous treatment, either for CLL or for other co-existing conditions. In our patient, further evaluation of CLL by FISH studies detected a deletion of 13q14.3. Common cytogenetic abnormalities associated with CLL include trisomy 12, del(13) (q14.3), del(11)(q22.3), and del(17)(p13.1). Isolated deletion of 13q14.3 as seen in our patient is considered a favorable prognostic marker in the absence of other adverse genetic markers. Based on the morphology, immunohistochemistry, cytogenetic and molecular analysis, it is apparent that our patient had co-existence of two unrelated hematological malignancies.

APL is a hematological emergency that is managed the same whether the disease is de novo or therapy-related. Treatment with ATRA should be initiated immediately. Anthracycline-based treatment and arsenic trioxide (ATO) as part of induction chemotherapy is recommended in patients with adequate cardiac function. Since disseminated intravascular coagulation (DIC) occurs in up to 85% of patients, coagulation studies should be monitored frequently, and DIC should be corrected aggressively by transfusion with fresh frozen plasma (FFP) and cryoprecipitate.

CONCLUSION

We report herein an extremely rare case of concurrent APL and CLL. To the best of our knowledge, this is the first report of APL presenting simultaneously with CLL in a patient without prior treatment. In addition to the distinct morphology of the leukemic components, the diagnosis was confirmed by molecular genetic and flow cytometric studies. Aggressive treatment should be initiated as soon as APL is suspected to avoid serious complications.

REFERENCES

(1.) Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leuk Lymphoma. 2005; 46:49-54.

(2.) Tsimberidou A, Wen S, McLaughlin P, et al. Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2009; 27:904-910.

(3.) Pallicardo N, O'Brien S, Estey EH, et al. Secondary acute promyelocytic leukemia. Characteristics and prognosis of 14 patients from a single institution. Leukemia. 1996; 10:27-31

(4.) Leone G, Mele L, Pulsoni A, Equitani L, and Pagano L. The incidence of secondary leukemias. Haematologica, 1999; 84:937-945.

(5.) Bhavnani M, Azzawi S, Liu J, et al. Therapy-related acute promyelocytic leukemia. Br J Haematol. 1994; 86:231-232.

(6.) Chen Z, Mostafavi HS, Shevrin DH, et al. A case of therapy-related extramedullary acute promyelocytic leukemia. Blood. 1999; 9:3015-3021.

(7.) Ramkumar B, Chadha MK, Barcos M, Sait SN, Heyman MR and Baer MR. Acute promyelocytic leukemia after mitoxantrone therapy for multiple sclerosis. Cancer Genetics and Cytogenetics 2008; 182:126-129.

(8.) Xue Y, Guo Y, and Xie X. Translocation t(7; 11)(P15; P15) in a patient with therapy-related acute myeloid leukemia following bimolane and ICRF-154 treatment for psoriasis. Leukemia Research. 1997; 21:107-109.

(9.) Gottardi M, Gatei V, Degan M, et al. Concomitant chronic lymphocytic leukemia and acute myeloid leukemia: evidence of simultaneous expansion of two independent clones. Leuk Lymphoma. 2006; 47:885-889.

(10.) Lu CM, Murata-Collins JL, Wang E, Siddiqi I and Lawrence H. Concurrent acute myeloid leukemia with inv(16)(p13.1q22) and chronic lymphocytic leukemia: molecular evidence of two separate disease. Am Hematol. 2006; 81:963-968.

(11.) Molero T, Lemes A, De La Iglesia S, Gomez Casares MT, del Mar Perera M and Jimenez S. Acute promyelocytic leukemia developing after radiotherapy for prostate cancer in a patient with chronic lymphocytic leukemia. Cancer Genetics and Cytogenetics 2001; 131:141-143.

(12.) Gershkevitsh E, Rosenberg I, Dearnaley DP and Trott KR. Bone marrow doses and leukemia risk in radiotherapy of prostate cancer. Radiother Oncol 1999; 53:189-197.

Jingdong Su, MD, is associated with the Department of Hematology/ Oncology, LSU Health Sciences Center-Shreveport; Diana Veillon, MD, is associated with the Department of Pathology, LSU Health Sciences Center-Shreveport; Rodney Shackelford, MD, is associated with the Department of Hematology/Oncology, LSU Health Sciences CenterShreveport; James Cotelingam, MD, is associated with the Department of Pathology, LSU Health Sciences Center-Shreveport; Hazem El-Osta, MD, is associated with the Department of Hematology/Oncology, LSU Health Sciences Center-Shreveport; Glenn Mills, MD, is associated with the Department of Hematology/Oncology, LSU Health Sciences CenterShreveport; Reinhold Munker, MD, is associated with the Department of Hematology/Oncology, LSU Health Sciences Center-Shreveport; Srinivas Devarakonda, MD, is associated with the Department of Hematology/Oncology, LSU Health Sciences Center-Shreveport.

Caption: Figure 1. Peripheral smears, bone marrow aspirate, H&E and IHC staining show two distinct populations of leukemic cells. 1A. Peripheral blood smear showing CLL lymphocytes (Wright-Giemsa X1000). 1B. Peripheral blood smearshowing a leukemic promyelocyte, CLL lymphocyte, and a smudge cell (Wright-Giemsa, X 1000). 1C. Bone marrow aspirate showing several leukemic promyelocytes and a single CLL cell (Wright-Giemsa stain, X1000). 1D. Bone marrow aspirate. Positive FISH result with PML/RARA fusion identified in leukemic promyelocytes (15q22-24 LSI PML Spectrum Orange/17q21 LSI RARA Spectrum Green, X1000). 1E. Bone marrow clot section with a central focus of CLL surrounded by leukemic promyelocytes (Hematoxylin & Eosin, X 100). 1F. Bone marrow clot section showing the interface between CLL and APL (Hematoxylin and Eosin, X 400). 1G-H. Bone marrow clot section showing the interface between APL cells stained positive for myeloperoxidase (G) and CLL cells stained positive for CD79a (H) (Immunohistochemical staining for Myeloperoxidase and CD79a, X 400).
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Author:Su, Jingdong; Veillon, Diana; Shackelford, Rodney; Cotelingam, James; Osta, Hazem El-; Mills, Glenn;
Publication:The Journal of the Louisiana State Medical Society
Article Type:Case study
Date:May 1, 2017
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