Richter Transformation in CLL

Richter Transformation (RT)

• RT is a histological transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma.
• Common transformation is to diffuse large B-cell lymphoma (DLBCL).
• Classical Hodgkin lymphoma (HL) is a less common transformation.
• Other lymphoma and leukemia types are very rare transformations (less than 1%).
• RT typically develops during the disease course, not at presentation.
• Incidence of RT in patients with CLL is 2-10%.
• DLBCL-RT occurs in approximately 90% of cases.
• Hodgkin lymphoma-RT occurs in approximately 10% of cases.
• Other lymphoma and leukemia types make up less than 1% of transformations.

Risk Factors

• Advanced Rai stage (III-IV) at CLL diagnosis is associated with an increased risk of future RT.
• Lymph nodes greater than 3 cm in size on physical examination are associated with an increased risk of RT.

Biological Characteristics

• Patients with CLL and leukemic B cells that are IGHV-unmutated have a 4-fold increased risk of RT compared to patients with IGHV-mutated cells.
• Shorter telomere length, a marker of genetic instability, is associated with an increased risk of RT.
• Phenotypic characteristics such as CD38 and CD49d status can be associated with RT risk.
• Cytogenetic abnormalities, such as del(11q22.3), del(17p13), del(15q21.3), del(9p21), are also associated with RT risk.
• Heritable germline polymorphisms in BCL2 and CD38 have been associated with a higher risk of transformation.

Clinical Presentation

• RT onset is often heralded by an accelerated and significant increase in lymphadenopathy (usually abdominal), splenomegaly, and B symptoms (fever, night sweats, weight loss).
• Extra-nodal involvement is common, especially in the gastrointestinal tract, bone marrow, central nervous system, or skin.
• Sometimes RT presents as an extra-nodal mass only.
• Signs and symptoms of extranodal involvement may include early satiety, gastrointestinal bleeding, rash, pathologic fractures, headache, blurred vision, or dyspnea.
• Physical examination may reveal asymmetric and rapid growth of bulky lymph nodes (greater than 3 cm), splenomegaly, or hepatomegaly.

Laboratory Findings

• Complete blood count (CBC) may show anemia, thrombocytopenia (platelet count less than 100 x 10⁹/L), and new onset of absolute lymphocytosis (lymphocyte count greater than or equal to 5.0 x 10⁹/L).
• Biochemical investigations may show elevated serum beta-2 microglobulin (B2M) level (greater than 2 mg/L), elevated lactate dehydrogenase (LDH) (greater than 1.5 times the upper limit of normal), paraproteinemia, or hypercalcemia.

Diagnosis

• Tissue biopsy of an affected lymph node or extra-nodal site is the gold standard for diagnosing RT.
• Imaging studies such as 18FDG PET/CT can aid in the decision of where to biopsy. An SUV (standardized uptake value) greater than 5.0 on PET/CT suggests areas warranting tissue evaluation. A lack of detectable lesions on 18FDG-PET scan is highly sensitive in excluding RT.
• Biopsy should target the index lesion (most avid 18FDG uptake).
• Excision biopsy is preferred over fine-needle aspiration.

Histologic Variants

• Diffuse large B-cell lymphoma (DLBCL): This is the most frequent histologic variant of RT. The development occurs approximately 1.8-4.0 years after initial CLL diagnosis and may occur before or after CLL therapy. The annual incidence rate of DLBCL in newly diagnosed CLL patients is 0.5% and ~1% in patients previously treated for CLL. DLBCL is most common in men over 60 years of age.

• Pathologic features often include diffuse effacement of lymph nodes or extranodal sites by sheets of large cells with centroblastic morphology, although a minority of cases may show immunoblastic features. Mitotic figures, apoptotic bodies, a starry-sky pattern, and tumor necrosis are frequently seen.

• The lymphoma cells typically exhibit a non-germinal center B-cell-like (non-GCB) immunophenotype (negative for CD10 and positive for MUM1), but approximately 20% have a GCB immunophenotype (positive for CD10 and/or BCL6, MUM1-).

Other Associated Lymphomas

• Hodgkin lymphoma: Less than 1% of CLL patients develop Hodgkin lymphoma transformation.
• Plasmablastic lymphoma (PBL): This is an aggressive B-cell malignancy that exhibits features of plasma cells. Most PBLs arise de novo, although a few RS-PBL cases can arise in patients with CLL. Patients who develop RS-PBL are usually men between 52-77 years of age.
• B-lymphoblastic leukemia/lymphoma (B-LBL): This is a rare but aggressive neoplasm derived from progenitor B-lymphoid cells usually involving bone marrow, peripheral blood, and sometimes lymph nodes.
• T-cell lymphoma: CLL patients rarely develop T-cell lymphomas.

Differential Diagnoses

• Accelerated/progressed CLL (a/pCLL): This shows expanded proliferation centers but lacks the diffuse-sheets of large cells typical of RT.
• Pseudo-Richter: Occurs after discontinuation of certain medications and may respond well to restarting them. Characterized by high Ki-67 index and preserved CD5/LEF-1 expression.

Other Considerations

• HSV Lymphadenitis can mimic RT (with necrosis and high proliferation rates ) appearing with viral inclusions. Should be treated with antivirals.
• Other rare lymphomas, such as mantle cell and marginal zone lymphomas, may coexist with CLL.
• Misclassification can affect treatment recommendations. Expert hematopathology and advanced diagnostics (FISH, IHC) are essential.

Prognosis

• Prognosis varies for different histological variants.
• For DLBCL, the clonal relationship between CLL and DLBCL is the most important prognostic factor. Clonally unrelated DLBCL often have a longer survival (~5 years) compared to RT-associated DLBCL (8–16 months).
• For HL-type RT, overall survival (OS) tends to be higher than DLBCL-type RT but inferior to de novo HL patients, with median OS reported of 2.6-3.9 years.

Management

• Different approach for clonal related vs clonal unrelated DLBCL type RT.
• Clinally unrelated is treated as de novo DLBCL using R-CHOP as first line and possible subsequent stem cell transplant (SCT).
• Clinally related is treated with chemoimmunotherapy followed by possible autologous or allogenic SCT.