Where does CLL / SLL fall in the spectrum of lymphoid malignancies?

Classification based on prognosis, where does CLL fall?
  • Indolent
    • Incurable, but prolonged progression free survival (7-10 yrs)
    • Follicular, MALT, CLL, Hairy Cell
  • Aggressive
  • Highly aggressive
    • Later two are curable, but short progression free survival
    • Later two includes
      • Diffuse Large B Cell
      • Mantle 
      • HD
      • Cutaneous T Cell - NHL

    • Express CD 5 and CD 23
    • If PBS suggests CLL, PCP can order for flow cytometry of peripheral blood (especially if unexplained LYMPHOCYTOSIS persists for > 3 months)
      • Note: Flow is usually performed in blood collected in EDTA tube 
    • Additional tests in patient with CLL include
      • Direct Coombs test (auto-immune hemolytic anemia)
      • Serum Immunoglobulins
    • Prognosis based on 
      • Modified RAI ( Stage 1 - 5), Binet (Stage A, B and C), ECOG, and combination of genetic and molecular markers
      • Good Prognosis features
        • Low Modified RAI or Binet A
      • Bad Prognosis
        • Advanced stage 
        • TP 53 deletion
    • Treatement:
      • Stage A: Usually good prognosis for Stage A patient even without treatment 
      • Stage B and C: Needs treatment


What are the risk factors for Richter transformation?

How do you diagnose Richter transformation

How do we treat Richter Transformation:
Important to decide clonally related vs clonally unrelated

Case Discussion
71 yo M patient has been followed for 3 yrs for Lymphocytosis. Labs today include the following. Bi and LFT are normal. 

Diagnosis of CLL was made. How is the diagnosis of CLL made. 

What is the finding of flow cytometry?

What other tests can you order?
  • Immunoglobulins
  • Coombs test 
CT scan of chest is done and shows the following. 

What is the stage for this patient?
  • RAI: RAI III due to Anemia. Until last year, patient was RAI II due to lymphadenopathy
  • Binet: Binet C due to Hgb < 10; Until last year patient was Binet B due to lymphadenopathy

What is the prognosis. 
Given advanced stage, it is poor. 

Is patient symptomatic. No symptoms other than Chills, Night sweats, and 40 lb weight loss in 2 yr. 

What is the complication of CLL?
  • Autoimmune Hemolytic Anemia: Patient has negative Coombs test. Bilirubin was normal as well. 
  • Richter’s transformation: conversion into an aggressive lymphoma, typically diffuse large-B-cell lymphoma 

How should this patient be treated?

  • Until few years back: Wait and watch as he was asymptomatic. 

  • Now the treatment options have changed with newer studies published in 2015 and 2016. 
    • Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables 

Note: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is standard in younger patients with CLL, but because of treatment-related toxic effects, this regimen is not suitable for older patients or those with coexisting conditions. NEJM 2015 

 What is Ibrutinib?
  • Bruton’s tyrosine kinase (BTK)  
  • BTK is essential for signaling by means of the B-cell receptor and chemokine receptors, which CLL cells use for survival, proliferation, and tis- sue homing. 
  • Ibrutinib also irreversibly inhibits alternative kinase targets hence is not selective. More recently, newer 2nd generation BTK inhibitor has been introduced. 

What are the other newer treatments for CLL?
  • Constitutively elevated expression of the anti- apoptotic protein BCL2 renders CLL cells resis- tant to apoptosis, resulting in the accumulation of long-lived, clonal lymphocytes that characterize the disease. 
  • BH3-mimetic drugs are a new class of anticancer agents that mimic the activity of the physiologic antagonists of BCL2 and related proteins to trigger apoptosis. The first potent BH3-mimetic inhibitor of BCL2 that was evaluated in clinical trials, navitoclax proved to be active against relapsed CLL 
  • Venetoclax (ABT-199/GDC-0199) is a highly selective inhibitor of BCL2 that is more potent than navitoclax but is less active against BCL-xL by a factor of more than 200 has just published phase 1 report. 
  • Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia NEJM 2016

What other test could we order? 

  • Immunoglobulin level. 
What are the types of Igb defects in CLL?
  • Usually IgG3, and IgG4 are mostly deficient
  • Hypogammaglobulinemia is related to defective functioning of T cells and non-clonal CD5-negative B cells (Uptodate)
  • Most common site of infection is respiratory tract, likely related to IgA and IgG4 defects (Uptodate)

The labs values on our patient was 

In one study, results showed that among the 83 CLL patients, the IgG, IgA and IgM levels were reduced in 12 (14.5%), 26 (31.3%) and 34 cases (41.0%) respectively.