Chronic Lymphocytic Leukemia (CLL)/ SLL

Background:

• 25% of all leukemias

• Morphologically mature but immunologically incompetent B lymphocytes

• Incidence increase with age

• Male/Female: 2

• Predominantly found in caucasians, less common in African-Americans, Hispanics and Asians

• Positive family history: 2-8 fold increased risk

Work-up:

• CBC:

  • Clonal B-lymphocytes >5000

  • Anemia and thrombocytopenia are common

• PBS: 

  • Small lymphocytes with round nuclei, clumped chromatin, scant cytoplasm

    • Medium/large sized cells: less than 10% of the lymphocytes

  • Smudge cells (bare nuclei that appear squashed)

• Flow Cytometry:

  • Positive CD19, CD5, CD23

  • Weak expression of CD20, CD22, surface Ig

  • Negative FMC7, CD10, CD103

• DAT:

  • Conversion of the DAT from negative to positive may herald the onset of AIHA

• LDH:

  • Typically normal in indolent CLL

  • High or rapidly rising LDH may be a sign of disease transformation

• Beta-2 microglobulin:

  • Associated with inferior treatment response and survival

• CT scan: 

  • Captures the extend of LN involvement

  • Preferred imaging to evaluate response to treatment

• LN biopsy:

  • Can distinguish between CLL and other lymphomas

  • Help to exclude transformation in patients with rapidly enlarging LNs

Differential diagnosis:

• Small Lymphocytic Lymphoma (SLL)

• Monoclonal B-cell lymphocytosis (MBL)

• Follicular lymphoma (FL)

• Mantle cell lymphoma (MCL)

• Marginal zone lymphoma (MZL)

	CLL	SLL	MBL
Monoclonal B-cell Count	≥ 5000	≤ 5000	< 5000
LAP, organomegaly	May be present	Required	None (all nodes <1.5 cm)
B symptoms, Cytopenias	May be present	May be present if due to tissue involvement	Absent
Diagnosis	Flow cytometry	LN or tissue biopsy	Flow cytometry + stable B cell count over 3 months
Immunophenotype	CD5+, CD19+, CD23+, weak CD20 and surface Ig, negative CD10 and cyclin D1	Same as CLL	Same as CLL
Distinguishing Feature	High B-cell count	Tissue-based disease, low B-cell count	No symptoms, low B-cell count, no tissue involvement

RAI staging system:

• Low risk:

  • 0: Lymphocytosis (>5000 clonal B cells in blood and/or >40% lymphocytes in BM)

• Intermediate risk:

  • I: Lymphocytosis + LAP

  • II: Lymphocytosis ± LAP + splenomegaly ± hepatomegaly

• High risk:

  • III: Lymphocytosis + anemia (Hb <11 or hematocrit <33%)

  • IV: Lymphocytosis + thrombocytopenia (plt <100,000)

Prognostic Factors:

• Ig variable region heavy chain gene mutation:

  • Unmutated IGHV genes (U-IGHV) causes a more rapid progression of disease than mutated genes (M-IGHV). 

• FISH: 11q, 13q, 17p, and 12 abnormalities are identified in approximately 80% of cases.

  • Inferior outcome with del 17p (p53 locus) or 11q (ATM locus).

• High B2 microglobulin

• ZAP-70:

  • Median OS is 9 years in ZAP-70 positive and 25 years in ZAP-70 negative patients.

• CD38

• CD49d:

  • Worst outcome: CD49d > ZAP-70 > CD38

• Lymphocyte doubling time (LDT):

  • LDT <12 months indicates progressive disease and is associated with decreased survival independent of stage.

Treatment:

Watchful waiting:

• Standard of care for patients with early stage

• Monitor labs q 3-6 months

Treatment indications:

• B symptoms

• Symptomatic/massive LAP (>10 cm) 

• Symptomatic/massive splenomegaly (>6 cm below costal margin)

• Worsening anemia and/or thrombocytopenia

• LDT <6 months

• Autoimmune cytopenias poorly responsive to corticosteroid (ITP, AIHA, pure red cell aplasia) 

Chemoimmunotherapy:

• 1st line for CLL without del 17p with good ECOG

• Needs prophylaxis for pneumocystis and herpes infections

• Regimens:

  • FRC: Fludarabine + Rituximab + Cyclophosphamide

    • FCR causes better PFS and ORR (CLL8 trial)

    • Causes grade 3-4 hematologic toxicities in 50% of patients

  • BR: Bendamustine + Rituximab

    • Preferred regimen for patients >65 years

  • Ofatumumab (anti-CD20 Ab) + Chlorambucil

  • Obinutuzumab (anti-CD20 Ab) + Chlorambucil

Targeted therapies: 

• BTK inhibitors:

  • Ibrutinib:

    • Dose: 420 mg PO once daily

    • Can cause a transient lymphocytosis 

    • Side effects: bruising, rash, diarrhea, arthralgia, myalgia, A-fib

  • Acalabrutinib

  • Zanubrutinib

  • Pirtobrutinib

    • Selective and noncovalent (reversible) BTK inhibitor

• BCL-2 inhibitor:

  • Venetoclax

    • Can cause serious TLS

• PI3Kα inhibitor:

  • Idelalisib

    • Mostly in combination with Rituximab for relapsed/refractory CLL

    • Can cause a transient lymphocytosis 

    • Black box warning for hepatotoxicity, severe diarrhea/colitis, pneumonitis, serious infections, intestinal perforation.

Cellular Therapies:

• Preferred option in double-refractory, high-risk CLL.

Treatment approaches:

• CLL ± del 17p :

  • Acalabrutinib ± Obinutuzumab

  • Zanubrutinib

  • Venetoclax + Obinutuzumab

• Relapsed/refractory CLL after both BTK and venetoclax-based regimens:

  • Relapsed/refractory CLL without del 17p:

    • Chemotherapy-based regimens such as BR, FCR or Obinutuzumab

  • Relapsed/refractory CLL with del 17p:

    • Chemotherapy-based regimens are not effective.

    • Preferred treatments:

      • Targeted agents (BTKi, BCL2i, PI3Ki), CAR-T cell therapy

        • CAR-T cell therapy and pirtobrutinib (BTKi) are the most promising options for double-refractory, high-risk CLL.

    • Summary of treatment approach:

      • First line → covalent BTK inhibitors or venetoclax-based regimen

      • If relapse with BTK inhibitors → BCL-2 inhibitor (Venetoclax) 

        • All BTK inhibitors share common resistance mechanism (do not switch to another BTK inhibitors in case of relapse)

      • If relapse with both covalent BTK inhibitors and Venetoclax-based regimen → noncovalent BTK inhibitor (Pirtobrutinib) is effective (BRUIN trial)

Complications:

• Autoimmune hematologic manifestations

  • Such as ITP and AIHA

    • pure red cell aplasia and autoimmune neutropenia are rare

  • Mostly in advanced diseases or during treatment with purine analogs (Fludarabine)

  • Often respond to prednisone or cyclosporine

• Infections

  • Hypogammaglobulinemia typically found in advanced disease.

    • If recurrent infections and IgG level <500 → IVIG 0.3-0.5 g/kg monthly to maintain IgG level >500

  • Rituximab increases risk of Hep B reactivation.

  • All CLL patients should be immunized and avoid live vaccines.

Richter’s Transformation:

• Transformation of CLL to large B-cell lymphoma or Hodgkin lymphoma

• Findings: B symptoms, rapid LN enlargement, LDH elevation, highly active nodal disease on PET