Coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma with antecedent chronic lymphocytic leukemia: a case report and review of the literature

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western world. It is characterized by progressive accumulation of mature B or T lymphocytes in the peripheral blood, bone marrow, liver, and lymphoid organs [1, 2].

CML is a chronic myeloproliferative neoplasm with an annual incidence of 1–2 cases per 100,000 people per year. It originates from abnormal hematopoietic stem cells induced by the BCR-ABL oncogene, resulting in the involvement of multiple hematopoietic lineages, but predominantly myeloid cells [3].

Despite the frequent occurrence of CLL and CML in adults, it is rare for the two to coexist [4‐9]. The association between lymphoproliferative disorders (LPD) and myeloid malignancies, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative disorders, is not well understood; however, it is possible that two malignant clones might arise from the same cancerous stem cell [10].

In CLL, Richter’s transformation (RT) to Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), is frequently observed and usually has a poor outcome [11, 12].

To the best of our knowledge, CLL, CML, and DLBCL have never been reported to coexist. Here we describe the first case of the coexistence of CML and DLBCL in a patient with antecedent CLL.

A 60-year-old Saudi man with a history of diabetes, hypertension, and chronic active hepatitis B, an entrepreneur, married with seven children, who denied tobacco smoking, alcohol consumption, and illicit drug use, was initially seen at our facility and was diagnosed as having Rai stage II CLL in December 2012. His physical examination at presentation revealed a moderately built man. His respiratory and cardiovascular examination was normal. His liver was normal in size but his spleen was palpable (8 cm below the costal margin). He had generalized lymphadenopathy involving his neck, axillae, and bilateral inguinal regions; however, the lymph nodes were 1–3 cm in size. A neurological examination revealed no focal neurological deficit. His serum creatinine at presentation was 72 umol/L, and his blood urea nitrogen (BUN) was 4.3 mmol/L. The results of his liver function test were: aspartate aminotransferase (AST) 22 unit/L, alanine transaminase (ALT) 27 unit/L, total bilirubin 12.1 umol/L, albumin 3.5 g/dL, and alkaline phosphatase of 68 unit/L. His blood count at presentation showed a white blood cell (WBC) count of 28.9 × 109/L, hemoglobin (Hb) level of 13.4 g/dl, a platelet count of 106 × 109/L, and an absolute lymphocyte count (ALC) of 25.1 × 109/L (Fig. 1). Peripheral blood flow cytometry revealed 43% of total acquired events co-expressing CD5, CD19, CD23, CD79b, and cytoplasmic CD79a, but lacking surface immunoglobulin light chains, CD10, and CD38. Bone marrow aspirate and biopsy (BMAB) showed hypercellular bone marrow with diffuse intestinal and focal paratrabecular lymphocytic infiltrate. The lymphocytes were mature, small, and positive for CD20, CD79a, PAX-5, CD5, CD23, and BCL2, but negative for cyclin D1 and CD10 (Fig. 2). Conventional cytogenetic tests and fluorescence in situ hybridization (FISH) revealed that 27% of analyzed cells displayed rearrangement of the CCND1 gene in chromosome 11 and 15% of cells had trisomy 12, but t(11;14) (q13;q32) was not detected (Fig. 3).

A computed tomography (CT) scan of his neck, chest, abdomen, and pelvis showed hepatomegaly with focal hypodense liver lesions and massive splenomegaly (20.9 × 7.3 cm) (Fig. 4a, b). A liver biopsy showed infiltration with small lymphocytic lymphoma (SLL; Fig. 5). He remained under surveillance until January 2016, when he developed anemia, thrombocytopenia, and significant constitutional symptoms. He was started on chemoimmunotherapy with fludarabine 25 mg/m² on days 1–3, cyclophosphamide 250 mg/m² on days 1–3, and rituximab 375 mg/m² on day 1 (FCR) for a total of six cycles, until 27 July 2016. His blood counts normalized (Fig. 1). And an end-of-therapy CT scan showed resolution of the liver lesions, and significantly reduced lymphadenopathy and splenomegaly.

One month after completing FCR therapy, his leukocytosis (mostly neutrophilia) returned, with myeloid left shift. His spleen was palpable 10 cm below the costal margin. His WBC count reached 93 × 109/L, Hb 10.9 g/dl, platelet count 61 × 109/l, absolute neutrophil count 42 × 109/L, and eosinophil count 3 × 109/L. Peripheral blood blasts and basophils were 1% each (Fig. 1). BMAB was suboptimal. Conventional cytogenetic analysis using bone marrow showed Philadelphia chromosomes in all examined cells with no other cytogenetic aberrations. FISH analysis revealed presence of the BCR-ABL fusion gene in 100% of cells examined, and quantitative reverse transcription polymerase chain reaction (RT-PCR) of peripheral blood showed a ratio of BCR-ABL/ABL of 21% (Fig. 3).

Since the morphologic findings of both the blood smear and the cytogenetics were compatible with chronic phase CML, he was started on first-generation tyrosine kinase inhibitor (TKI) imatinib at a dose of 400 mg daily. As a result, his complete blood count normalized and his spleen shrank. Although he achieved an appropriate hematologic response within 3 months of imatinib treatment, on 21 March 2017 he demonstrated a suboptimal molecular response with a BCR-ABL/ABL ratio of 17%. Subsequently, he was switched to 300 mg orally administered nilotinib (a second-generation TKI) twice daily. After 3 months of nilotinib treatment, the BCR-ABL/ABL ratio dropped to 0.093%.

To screen for hepatocellular carcinoma, an abdominal CT scan was done in March 2017 and it revealed multiple hypoechoic liver lesions (Fig. 4c). Magnetic resonance imaging of his liver confirmed the presence of at least nine hepatic lesions (Fig. 4d, e). Positron emission tomography (PET) showed multiple metabolically active liver lesions (Fig. 4f). A liver biopsy performed in May 2017 confirmed RT to high-grade B cell lymphoma. After negative tests for c-MYC, the final pathological diagnosis was confirmed as DLBCL (Fig. 6). Staging BMAB was morphologically negative for CLL, CML, and DLBCL. FISH analysis on BMAB was negative for CCND1 gene rearrangement, trisomy 12, and BCR-ABL oncogene.

While awaiting c-MYC in situ hybridization he received two cycles of chemoimmunotherapy by infusion consisting of rituximab 375 mg/m² on day 1, etoposide 50 mg/m² on days 1–4, prednisone 60 mg/m² on days 1–5, doxorubicin 10 mg/m² on days 1-4, Oncovin (vincristine) 0.5 mg/m² on days 1–4, and cyclophosphamide (R-EPOCH). He was then switched to rituximab 375 mg/m² on day 1, cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, oncovin (vincristine) 50 mg/m² on day 1, vincristine 1.4 mg/m² on day 1, and prednisone 100 mg days 1–5 (R-CHOP); he completed four cycles. Radiological assessment with PET/CT at the end of chemotherapy was consistent with complete metabolic response.

There have been only 32 reported cases of CLL coexisting with CML in the same patient. The most commonly occurring pattern is for long-standing CLL to precede CML [4‐9].

The patient in the present case report remained under careful observation for 3 years after being diagnosed as having CLL. Soon after completing fludarabine-based chemotherapy, he was diagnosed with CML. It is possible that this CML already existed before and was only detected after his CLL was brought under control. Alternatively, it is possible that CML arose as a result of clonal evolution secondary to fludarabine treatment. However, this theory is less likely given the very short interval between receiving purine analog (PNA) and CML emergence.

Despite increasing rates of complete remission in CLL associated with fludarabine-based regimens, RT still occurs, warranting continued surveillance regardless of disease status. RT to NHL, HL, and multiple myeloma develops in approximately 3%, 0.5%, and 0.1% of patients, respectively. Risk factors for RT include advanced Rai stage at diagnosis, TP53 disruption, c-MYC abnormalities, non-deletion 13q cytogenetics, CD38 gene polymorphism, and unmutated immunoglobulin heavy chain variable region gene status [10‐13].

Patients treated for CLL with PNA and alkylating agents tend to have an up to three-fold increased risk of RT compared to those who have not received PNA [14, 15]. The median time from first treatment of CLL to the development of second LPD is 2.4 years [16]. Although our patient was in complete remission from CLL/SLL when he was diagnosed as having DLBCL, we believe that RT was the cause rather than de novo DLBCL. This is based on biopsy evidence of CLL infiltration of his liver at the time of his initial diagnosis in 2012.

The immune-compromised state of CLL patients means that they have a frequency of secondary tumors. These are not limited to LPD, but also include solid tumors such as cancers of the lung, colorectal region, bladder, breast, central nervous system, stomach, ovaries, head, neck, and testicles, as well as melanoma, sarcoma, and myeloid leukemias [17].

Cytogenetic analysis of our patient revealed trisomy 12, which is a cytogenetic abnormality frequently seen in CLL and associated with a higher frequency of RT to DLBCL attributed to activation of the NOTCH1 pathway [18]. In our patient, rearrangement of the CCND1 gene was also observed, which might have increased his risk of RT [19].

The development of TKIs, a major breakthrough in the therapy of CML, has dramatically improved the survival of patients with CML. However, the use of TKIs may be associated with the development of secondary malignancies. Around 7% of patients with TKI-treated CML develop non-hematologic secondary malignancies. On the other hand, this increased risk may be linked to CML itself rather than to TKI treatment [20]. The coexistence of CML with DLBCL in the same patient is even rarer, with only nine cases reported to date [21‐25]. In the case reported here, it is unlikely that TKI therapy contributed to the development of DLBCL; rather, DLBCL arose as a result of RT of the antecedent CLL.

To the best of our knowledge, this is the first reported case of concurrent CML and DLBCL against a background of CLL. This case represents a tremendous medical challenge, especially with the failure of CML to respond to first-line TKI and in a background of chronic liver disease.