Richter Transformation in CLL

Richter Transformation (RT)

• Defined as a histological transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma
• Commonly transforms to diffuse large B-cell lymphoma (DLBCL)
• Less often, it transforms to classical Hodgkin lymphoma
• Very rarely transforms to plasmablastic lymphoma or other lymphoma/leukemia types

Incidence

• RT occurs in 2-10% of CLL patients
• Usually during the disease course, not at presentation
• Most commonly presents as DLBCL-RT (~90%)
• Hodgkin lymphoma-RT (~10%)
• Other lymphoma/leukemia types are very rare (<1%)

Risk Factors at CLL Diagnosis

• Advanced Rai stage (III-IV)
• Lymph nodes >3 cm on physical examination

Biological Characteristics of CLL-B-cells

• CLL B-cells that lack IGHV somatic mutations are at a 4-fold increased risk of RT compared to those with IGHV mutated B-cells
• Shorter telomere length (marker of genetic instability) is associated with an increased risk of RT
• CD38 and CD49d status have been linked to the risk of future RT
• Cytogenic abnormalities (e.g., del(11q22.3), del(17p13), del(15q21.3), del(9p21)) may be associated with RT

Heritable Germline Polymorphisms

• Polymorphisms in BCL2 and CD38 have been reported to increase RT risk

Clinical Presentation

• RT onset is marked by an accelerated, pronounced increase in lymphadenopathy (often abdominal), splenomegaly, and B symptoms (fever, night sweats, weight loss)
• Extra-nodal involvement may be present, especially in the gastrointestinal tract, bone marrow, central nervous system (CNS), or skin
• In some cases, RT may only present as an extra-nodal mass

Clinical Signs and Symptoms

• Extranodal involvement may manifest as early satiety, gastrointestinal bleeding, rash, pathologic fractures, headache, blurred vision, or dyspnea
• Physical examination may reveal asymmetric and rapid growth of bulky lymph nodes (>3 cm), splenomegaly, and/or hepatomegaly

Lab Findings

• Complete Blood Count (CBC):
  • Anemia
  • Thrombocytopenia (<100 x 10⁹/L often present)
  • New onset of absolute lymphocytosis (≥5.0 x 10⁹/L)

Biochemical Investigations

• Elevated serum beta-2 microglobulin (B2M) level (>2 mg/L)
• Elevated lactate dehydrogenase (LDH) levels (>1.5 times upper limit of normal)
• Paraproteinemia
• Hypercalcemia

Tissue Biopsy

• The gold standard for RT diagnosis is a biopsy of an affected lymph node or extra-nodal site
• RT onset is usually not disseminated or simultaneous in all lymphatic regions
• Imaging studies like FDG-PET/CT aid in the decision to biopsy and optimal site selection
• SUV (standardized uptake value) >5.0 by PET/CT indicates a need for tissue evaluation
• Biopsy should target the index lesion (lesion with highest FDG uptake)
• Excisional biopsy is the gold standard, as fine-needle aspirations may not capture the entire pathological architecture of the tumor

Histologic Variants of Richter Transformation (RT): DLBCL

• DLBCL is the most common histologic variant in CLL patients
• DLBCL occurs 1.8-4.0 years after initial CLL diagnosis and can develop before or after CLL treatment
• Annual incidence rate of DLBCL in newly diagnosed CLL patients is 0.5%. It is ~1% in CLL patients with prior therapies

Pathologic Features of RS-DLBCL

• Most cases show diffuse effacement of lymph nodes or extra-nodal sites by large cells with centroblastic morphology
• A minority of cases may show immunoblastic features
• Mitotic figures, apoptotic bodies, a starry-sky pattern, and tumor necrosis are common
• WHO criteria dictate that B-lymphoid cells showing diffuse growth pattern and a nuclear size equal to or exceeding that of a normal macrophage nucleus should be considered.

Immunophenotypic Characteristics of RS-DLBCL

• Neoplastic cells typically express B-cell markers (CD19, CD20, CD22, PAX5) and monotypic immunoglobulin light chain
• CD38, ZAP70, and CD49d are often positive
• CD5 and CD23 expression is retained to a varying extent

Non-GCB and GCB Immunophenotypes

• 80% of RS-DLBCL have a non-germinal center B-cell-like (non-GCB) immunophenotype (negative for CD10 and positive for MUM1)
• 20% have a GCB immunophenotype (positive for CD10 and/or BCL6+, MUM1-)
• TP53 overexpression and a high Ki-67 proliferation index (>70%) are also common in RS-DLBCL

Clonal Relationship to Underlying CLL

• About 70-80% of RS-DLBCL cases are clonally related to the underlying CLL (sharing similar IGVH sequences)
• RS-DLBCL often arises from a dominant CLL clone after acquiring additional somatic mutations
• Differences are present in both clinical outcome and genetics which affect treatment.

Hodgkin Lymphoma

• Less than 1% of CLL patients develop Hodgkin lymphoma (RS-HL)
• Typically occurs in the seventh decade of life (range 30-88 years)
• Characterized by Hodgkin and Reed-Sternberg (HRS) cells in a polymorphous inflammatory background distinct from CLL
• This background contains T-cells and histiocytes and may include abundant eosinophils
• HRS cells commonly express CD30, CD15, and PAX5 (dimmish) and are frequently positive for EBV by immunohistochemistry
• HRS cells may also express CD20, but intensity is usually variable
• Clonal relationship to underlying CLL has been shown with similar immunoglobulin gene rearrangements in about 80% of cases.

Plasmablastic Lymphoma (PBL)

• Aggressive B-cell malignancy, thought to be related to DLBCL, characterized by morphologic and immunophenotypic plasma cell features
• Commonly arises de novo in an immunocompromised state, however, a minority of RS-PBL cases are reported in CLL.
• Most patients are men (~52–77 years of age)
• Serum or urine paraprotein may be detectable
• Residual CLL cells might be present in certain areas
• Neoplastic cells usually express CD38, ZAP70, CD138, BLIMP1, IRF4/MUM1, and XBP1
• CD5, CD20, PAX5, and IRF8 are usually negative
• Molecular studies show monoclonal IGH and MYC rearrangements
• Prognosis for RS-PBL is poor

B-lymphoblastic Leukemia/Lymphoma (B-LBL)

• Neoplasm derived from progenitor B-lymphoid cells, affecting bone marrow, peripheral blood, and less commonly lymph nodes
• Acute lymphoblastic transformation of CLL (RS-LBL) is a rare presentation
• Predominantly affects men (42–76 years of age)
• Presentation interval between CLL diagnosis and RS-LBL is widely diverse (2 months to 7 years)
• Characterized by numerous lymphoblasts with intermediate size, indented nuclei, fine chromatin, and scant cytoplasm
• Neoplastic cells express HLA-DR, surface Ig, pan-B cell markers, and TdT, although TdT-negative cases are also documented
• CD5, CD10, CD22, and CD23 expression is variable

T-cell Lymphomas

• Rare in patients with CLL
• Relationship between CLL and these neoplasms is not fully understood

Differential Diagnoses

• Accelerated/progressed CLL (A/P CLL): Expanded proliferation centers but lacks diffuse large cell features
• Pseudo-Richter: Seen after ibrutinib discontinuation; responds well to therapy resumption. Characterized by high Ki-67 index and preserved CD5/LEF-1 expression
• HSV Lymphadenitis: Mimics RT with necrosis and high proliferation rates; features viral inclusions, often diagnosed with immunohistochemistry and treated with antivirals
• Other Lymphomas: Mantle cell and marginal zone lymphomas may coexist with CLL; less common T and B subtypes exist

Prognosis

• Prognosis varies depending on the histological subtype of RT
• In DLBCL-RT, clonal relationship between CLL and DLBCL is important in prognostication
• Clonally unrelated DLBCL cases have a significantly longer survival (~5 years) compared to clonally related cases (8–16 months)

Management of DLBCL-type Richter Syndrome

• Clonally unrelated CLL and DLBCL: Treated as de novo DLBCL

• First Line: R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)

• Second Line (if needed): Stem cell transplant (SCT) reserved for lack of response or relapse post-R-CHOP

• Clonally related CLL and DLBCL: treated with chemoimmunotherapy (R-CHOP) followed by consolidation with reduced-intensity conditioned allogeneic/autologous SCT based on fit and donor availability.