What is Richter's transformation?

Richter's Transformation

Richter's transformation is the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), occurring in 2-15% of CLL patients with a transformation rate of 0.5-1% per year. 1

Definition and Types

• Most common form (80%): Transformation to diffuse large B-cell lymphoma (DLBCL)
• Less common form (19%): Transformation to Hodgkin lymphoma (HL) 2
• Typically occurs after several lines of chemoimmunotherapy 1

Diagnostic Approach

• Gold standard: Excisional lymph node biopsy or core needle biopsy 1
• PET/CT scan should be used to guide biopsy site selection but is not sufficient alone for diagnosis 1
• Essential workup includes:
  • Complete blood count with differential
  • Comprehensive metabolic panel
  • LDH and uric acid levels
  • Epstein-Barr virus evaluation (EBV-LMP1 or EBER-ISH) 1
• Clonality testing is crucial to establish relationship between CLL and DLBCL by comparing IGHV sequences 1
  • Approximately 80% of DLBCL cases are clonally related to the underlying CLL
  • 20% are clonally unrelated 3

Risk Factors

• Unmutated IGHV status
• Stereotyped B-cell receptor subset 8 combined with VH4-39 use
• Cytogenetic abnormalities (del(17p), complex karyotype)
• Genetic abnormalities:
  • NOTCH1 mutation
  • C-MYC activation
  • TP53 inactivation (present in 50-60% of cases)
  • CDKN2A/B inactivation 1, 4
• Prior exposure to multiple lines of chemoimmunotherapy 1
• Advanced Rai stage
• Biologic markers: ζ-associated protein-70(+), CD38(+), CD49d(+) 3

Clinical Presentation

• Rapidly enlarging lymph nodes
• Hepatosplenomegaly
• Elevated serum lactate dehydrogenase (LDH) levels 5
• Systemic B symptoms (fever, night sweats, weight loss)

Prognosis

• Clonally related DLBCL: Median survival less than 1 year with conventional chemoimmunotherapy 1, 3
• Clonally unrelated DLBCL: Prognosis similar to de novo DLBCL 3
• Transformation to Hodgkin lymphoma variant has better prognosis 1

Molecular Pathogenesis

• Inactivation of TP53 tumor suppressor gene in 50-60% of cases
• Activation of NOTCH1 and MYC pathways in about 30% of cases 6
• CDKN2A loss plays a crucial role in transformation 3
• RT on ibrutinib is frequently associated with BTK and PLCG2 mutations 4

Important Clinical Considerations

• RT can develop in treatment-naïve patients but is more common following therapy 6
• RT incidence is lower in CLL patients treated with novel agents in the front line compared to relapsed/refractory cases 4
• Higher incidence in patients with TP53 disruption 4
• Do not miss EBV testing, as EBV infection has been reported in 16% of RT patients and is associated with poor outcomes 1

Pitfalls to Avoid

• Relying solely on PET scan for diagnosis without tissue biopsy
• Delaying transplant evaluation for eligible patients
• Using more intensive regimens like R-hyperCVAD or OFAR as first-line therapy, as they have not improved outcomes and cause significant toxicity 1