Background

Richter’s syndrome is defined as the development of high-grade lymphoma in patients with chronic lymphocytic leukemia (CLL), previously diagnosed as small lymphocytic lymphoma [1, 2]. Occasionally, transformation to other types of hematological malignancies, including high-grade prolymphocytic leukemia or acute leukemia, can occur. This concept includes various possibilities for malignant transformation to more aggressive types of lymphoid malignancies. In some rare cases, the cell lineage could even be altered; for instance, from B-cell neoplasm to T-cell neoplasm. Although there have been numerous reports describing the transformation of B-CLL to diffuse large B-cell lymphoma (DLBCL), the transformation to T-CLL and T-prolymphocytic leukemia has been rarely reported [3, 4]. Thus, the various patterns of transformation are referred to as Richter’s syndrome in the literature. We encountered a case of transformation of B-CLL to DLBCL followed by peripheral T-cell lymphoma (PTCL).

Ofatumumab is an anti-CD20 antibody indicated for refractory/relapsed CLL that has been commercially available in Japan since April 2012. On October 27, 2009, the Food and Drug Administration (FDA) approved ofatumumab (Arzerra®, GlaxoSmithKline) for treatment of CLL. CLL is recognized as a slowly progressive hematological disease [5], with a number of mature lymphocytic tumor cells proliferating or circulating in the bone marrow or peripheral blood. On the other hand, Richter’s syndrome is described as an aggressive hematological malignancy that occurs during the histological transformation of CLL. Given that Richter’s syndrome exerts a progressive and aggressive clinical course within a couple of weeks, treatment should be initiated as soon as possible [1,2,3]. However, the efficacy of ofatumumab for treatment of Richter’s syndrome is still under investigation. The present case provides information on the biology of CLL, which has a tendency to transform from a low-grade chemosensitive status.

Case presentation

The patient was a 64-year-old male who was diagnosed with CLL 6 years and 5 months before presentation. The patient had no family history of cancer/lymphoma and was not considered to be at a higher risk of cancer due to smoking. His blood data on admission was as follows: white blood cell count of 11,070/μL, hemoglobin concentration of 15.0 g/dL, and platelet count of 15.8 × 104/μL. A physical examination showed systemic lymphadenopathy of the cervical, axillary, and inguinal regions. He sometimes received oral cyclophosphamide and prednisolone for better control of lymphocytosis (lymphocyte count > 10,000 cells/μL). His lymphadenopathy systemically progressed over the course of several years and mainly included bilateral cervical, intra-abdominal, paraaortic, and bilateral femoral lesions. Nevertheless, he remained treatment-free with a clinical status of Rai classification stage I and Binet classification B. He was treated with fludarabine-based chemotherapy for his febrile status, which was occasionally complicated. Upon reaching the age of 69 years, his CLL transformed into aggressive lymphoma, which was histologically diagnosed as DLBCL in his cervical lymph node. His clinical presentation during the transformation revealed leukocytosis, hepatosplenomegaly, and high fever with chills.

He underwent ofatumumab therapy, which relieved his febrile lymphadenopathy. He received a total of 11 courses of ofatumumab until disease progression. On the day of the twelfth course of ofatumumab, his body temperature was 38.6 °C and a computed tomography study revealed multiple low-density liver masses that appeared to be similar to multiple liver abscesses. Liver biopsy confirmed T-cell lymphoma of the liver. CD20-lacking CLL cells were confirmed in his peripheral blood and bone marrow by flow cytometry. Moreover, his left cervical pathological diagnosis remained as CD20-positive DLBCL. Thereafter, he was diagnosed with three different types of lymphoma pathologies:

  1. (1)

    CD20-positive DLBCL in the lymph nodes, which was pathologically confirmed in the cervical lymph nodes and transformed from Richter’s CLL (Fig. 1)

  2. (2)

    CD20-lacking CLL in the peripheral blood and bone marrow, which escaped from CD20-positive CLL (Fig. 2)

  3. (3)

    PTCL in the liver (Fig. 3)

Fig. 1
figure 1

Pathology of CD20-positive diffuse large B-cell lymphoma from the lymph nodes biopsy. EBV was negative. Cervical lymph node biopsy showed diffuse growth of mid-sized lymphocytes. Immunohistochemical analysis revealed proliferating lymphoma cells that were positive for CD20, CD79α, and CD5, but negative for CD3

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Fig. 2
figure 2

Pathology of CD20-lacking chronic lymphocytic leukemia in the bone marrow biopsy. Bone marrow biopsy revealed hypercellular marrow with diffuse proliferation of small-sized lymphocytes. Immunohistochemical analysis revealed that the proliferating lymphoma cells were positive for CD79α and CD5, but negative for CD20

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Fig. 3
figure 3

Pathology of peripheral T-cell lymphoma from the liver biopsy. Liver biopsy revealed mid- to large-sized atypical lymphocytes that were phenotypically T cells, positive for CD3, CD5, CD8, and CD45RO with diffuse growth. Lymphoma cells infiltrated the Glisson’s sheath. (CLL; chronic lymphocytic leukemia, DLBCL; diffuse large B-cell lymphoma, PTCL; peripheral T-cell lymphoma)

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He received intravenous and oral dexamethasone therapy as palliative care. He died because of an abdominal emergency due to the rapid progression of multiple liver masses 2 months after the diagnosis of double transformation CLL. Permission was given to perform an autopsy, which confirmed aggressive PTCL systemically involving the liver, spleen, gall bladder, pericardium, bone marrow, and mediastinal–paraaortic–intraceliac lymph nodes. Bone marrow involvement of PTCL was pathologically diffuse and intensive. There was no component of DLBCL in the bone marrow. A T-cell receptor rearrangement study of an autopsy specimen was supportive of a diagnosis of T-cell lymphoma as a synchronous lymphoma (Table 1). A chromosomal study could not obtain active cell division for detecting karyotype in the three types of transformed lymphoma. A cytogenetic study showed that the patient’s original CLL cells harbored del(11)(q?) or its idem, add(15)(q24) clones in all 14 analyzed cells. However, no clonal cytogenetic abnormalities were found in the three types of transformed clones described above (i.e., CD20-positive DLBCL, CD20-lacking CLL, and PTCL cells).

Table 1 T-cell rearrangements were identified in the patient’s autopsy specimens by TCR PCR (a) and TCR Southern blotting assay (b)
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Discussion

Ofatumumab is a humanized monoclonal antibody against CD20 that was designed to bind the CD20 peptide and was initially used for treatment of DLBCL. However, clinical data demonstrated that ofatumumab was active against rituximab-refractory indolent lymphomas [6]. The FDA approved the use of ofatumumab for treatment of CLL refractory to fludarabine and alemtuzumab [5]. Our case was refractory to fludarabine treatment and responded well to salvage treatment with ofatumumab alone. Although evidence for the efficacy of ofatumumab monotherapy against Richter’s syndrome is lacking, some combination regimens of cytotoxic drugs have produced promising outcomes [6, 7]. Although the mechanism of ofatumumab resistance by CLL has not been well characterized [8], in our case, the surfaces of B-CLL cells had no CD20 molecules, suggesting that B-CLL tumor cells lack the CD20 antigen because of transformation during ofatumumab therapy. Some past reports showed the possibility of transformation of CLL to more aggressive lymphoma including T cell lymphoma in concurrently [9] or consequently [10]. In our case, the transformation was followed by ofatumumab therapy and looked being promoted by resistant mechanism.

We observed a surprising replacement of B-CLL by PTCL in our case during autopsy. The clinical course of the PTCL lesion was clearly different from that of CLL/DLBCL. PTCL involved multiple organs and tissues in a highly invasive manner. A past case series reported seven cases of T-cell neoplasm associated with B-CLL [4] with clonal T-cell populations detected in eight of 100 unselected CLL patients and identical clonality of PTCL derived from B-CLL. Through these cases, we speculated that substantial T-cell clonality is present in B-CLL as a result of “clonal drift” beyond B- and T-cell lineages in CLL.

Conclusion

Richter’s syndrome includes not only transformation to DLBCL but also other types of malignant lymphoid neoplasms, including T-cell lineage neoplasm. This transformation could represent a general potent mechanism in CLL as low-grade B-cell lymphoma.