Chronic B-Cell

Overview of Chronic/Mature B-Cell Leukemia/Lymphoma

Definition: A diverse group of lymphoid neoplasms arising from mature B lymphocytes. These are generally indolent (slow-growing) malignancies, though some can be more aggressive
Key Features:
- Clonal Proliferation: Proliferation of a single, abnormal clone of B cells
- Mature B-Cell Phenotype: Cells express markers of mature B cells (e.g., CD19, CD20)
- Variable Morphology: Cells may have variable size, shape, and nuclear features
- Lymph Node and Bone Marrow Involvement: Often involve lymph nodes, spleen, liver, and bone marrow
Classification: The World Health Organization (WHO) classification is used to categorize these disorders based on clinical, morphological, immunophenotypic, and genetic features
Common Disorders Included:
- Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
- Prolymphocytic Leukemia (PLL)
- Hairy Cell Leukemia (HCL)
- Burkitt Lymphoma
- Waldenström Macroglobulinemia (WM)

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Definition: CLL and SLL are considered the same disease, differing primarily in the site of involvement. CLL primarily involves the blood and bone marrow, while SLL primarily involves the lymph nodes
Diagnostic Criteria:
- Peripheral Blood:
  - Sustained absolute lymphocytosis (≥5.0 x 10^9/L) with a characteristic immunophenotype
  - Smudge cells are often present on the peripheral blood smear
- Bone Marrow (Usually Not Required for Diagnosis):
  - Lymphocytic infiltration
- Immunophenotype (by Flow Cytometry):
  - CD5+, CD19+, CD20 (dim), CD23+, sIg (weak), CD10-
Pathophysiology:
- Clonal proliferation of mature, usually naive B cells that express CD5 (a T-cell marker)
- Cells accumulate in the bone marrow, lymph nodes, spleen, and blood
- Abnormal B cells are relatively immunocompetent, leading to increased susceptibility to infections
Clinical Features:
- Often asymptomatic at diagnosis
- Lymphadenopathy (swollen lymph nodes)
- Splenomegaly (enlarged spleen)
- Fatigue
- Weight loss
- Night sweats
- Increased susceptibility to infections
Laboratory Findings:
- CBC:
  - Lymphocytosis (often marked, >20 x 10^9/L)
  - Anemia (in advanced stages)
  - Thrombocytopenia (in advanced stages)
- Peripheral Blood Smear:
  - Small, mature lymphocytes with condensed chromatin
  - Smudge cells: Fragile lymphocytes that rupture during smear preparation
- Flow Cytometry Immunophenotyping:
  - Confirms the diagnosis and differentiates CLL from other lymphoproliferative disorders
  - CD5+, CD19+, CD20 (dim), CD23+, sIg (weak), CD10-
- Cytogenetic Analysis:
  - Used to assess prognosis
  - Common abnormalities: del(13q14), trisomy 12, del(11q22.3), del(17p13.1)
Staging:
- Rai Staging System (for CLL): Based on the presence and extent of lymphadenopathy, splenomegaly, hepatomegaly, anemia, and thrombocytopenia
- Binet Staging System (for CLL): Similar to Rai staging, but based on the number of involved lymphoid areas
Prognosis:
- Variable; some patients have an indolent course, while others have a more aggressive disease
- Prognostic factors: Stage, cytogenetic abnormalities, immunoglobulin heavy chain variable region (IGHV) mutation status
Treatment:
- Watch and Wait: Many patients with early-stage CLL do not require immediate treatment
- Chemoimmunotherapy:
  - Combination of chemotherapy drugs (e.g., fludarabine, cyclophosphamide) and monoclonal antibodies (e.g., rituximab, obinutuzumab)
- Targeted Therapies:
  - BTK Inhibitors: Ibrutinib, acalabrutinib
    - Inhibit Bruton’s tyrosine kinase (BTK), a key signaling molecule in B-cell receptor pathway
  - BCL-2 Inhibitors: Venetoclax
    - Inhibits BCL-2, an anti-apoptotic protein
  - PI3K Inhibitors:
    - Copanlisib, duvelisib
- CAR T-Cell Therapy:
  - Chimeric antigen receptor (CAR) T-cell therapy: Genetically engineered T cells that target CD19 on B cells

Prolymphocytic Leukemia (PLL)

Definition: A rare, aggressive B-cell or T-cell neoplasm characterized by a high white blood cell count and a predominance of prolymphocytes in the peripheral blood
Types:
- B-PLL: More common; derived from mature B cells
- T-PLL: Less common; derived from mature T cells
Pathophysiology:
- Clonal proliferation of prolymphocytes in the bone marrow, spleen, and peripheral blood
Clinical Features:
- Marked splenomegaly
- Lymphadenopathy (less common than in CLL)
- High WBC count
- Fatigue
- B symptoms (fever, weight loss, night sweats)
Laboratory Findings:
- CBC:
  - Elevated WBC count (often > 100 x 10^9/L)
  - Anemia
  - Thrombocytopenia
- Peripheral Blood Smear:
  - Predominance of prolymphocytes (typically >55% of WBCs)
    - Prolymphocytes: Medium to large lymphocytes with a prominent nucleolus and moderately condensed chromatin
  - Smudge cells are uncommon
- Immunophenotyping:
  - B-PLL: CD5-, CD19+, CD20+, CD22+, CD23 (variable), FMC7+, sIg (bright)
  - T-PLL: CD3+, CD4+ or CD8+, CD7+, CD5 (variable), CD26-
- Cytogenetic Analysis:
  - Common abnormalities: t(11;14)(q13;q32) in B-PLL; inv(14)(q11q32) or t(14;14)(q11;q32) in T-PLL
Treatment:
- Chemoimmunotherapy:
  - Alemtuzumab (anti-CD52 monoclonal antibody) in combination with chemotherapy
- Targeted Therapies:
  - BTK inhibitors (e.g., ibrutinib)
- Hematopoietic Stem Cell Transplantation (HSCT):
  - Potentially curative option

Hairy Cell Leukemia (HCL)

Definition: A rare, indolent B-cell neoplasm characterized by infiltration of the bone marrow, spleen, and liver by small lymphocytes with “hairy” cytoplasmic projections
Pathophysiology:
- Clonal proliferation of mature B cells with distinct immunophenotype
- Almost all cases have a BRAF V600E mutation
- Cells infiltrate the bone marrow and spleen, leading to cytopenias and splenomegaly
Clinical Features:
- Splenomegaly (often massive)
- Pancytopenia (anemia, thrombocytopenia, neutropenia)
- Fatigue
- Infections
Laboratory Findings:
- CBC:
  - Pancytopenia (variable severity)
  - Monocytopenia (almost always present)
- Peripheral Blood Smear:
  - Hairy cells: Small lymphocytes with irregular cytoplasmic projections (“hairy” appearance)
- Bone Marrow Aspiration and Biopsy:
  - Infiltration of the bone marrow by hairy cells
  - “Fried egg” appearance of hairy cells on biopsy
- Immunophenotyping:
  - CD19+, CD20+, CD22+, CD11c+, CD25+, CD103+
  - Annexin A1+
- Molecular Testing:
  - BRAF V600E mutation
Treatment:
- Purine Analogs:
  - Cladribine (2-CdA) or pentostatin
  - Highly effective in inducing durable remissions
- Rituximab (anti-CD20 monoclonal antibody):
  - May be used as a single agent or in combination with purine analogs
- Splenectomy:
  - May be considered in patients with symptomatic splenomegaly or cytopenias that do not respond to other treatments

Burkitt Lymphoma

Definition: A highly aggressive B-cell lymphoma characterized by rapid proliferation and a high rate of cell turnover
Genetic Abnormality: Translocation involving the MYC gene on chromosome 8 (typically t(8;14)(q24;q32)), leading to overexpression of MYC, a transcription factor that promotes cell growth and proliferation
Types:
- Endemic Burkitt Lymphoma: Associated with Epstein-Barr virus (EBV) infection; common in Africa
- Sporadic Burkitt Lymphoma: Not associated with EBV; occurs worldwide
- Immunodeficiency-Associated Burkitt Lymphoma: Occurs in individuals with HIV/AIDS or other immunodeficiency states
Clinical Features:
- Rapidly growing tumor mass, often involving the jaw, abdomen, or other extranodal sites
- B symptoms (fever, weight loss, night sweats)
- May present with bowel obstruction, abdominal pain, or other symptoms depending on the location of the tumor
Laboratory Findings:
- CBC:
  - May show leukocytosis, anemia, or thrombocytopenia
- Peripheral Blood Smear:
  - May show “starry sky” pattern due to numerous macrophages engulfing apoptotic cells
- Bone Marrow Aspiration and Biopsy:
  - Infiltration of the bone marrow by Burkitt lymphoma cells
- Flow Cytometry Immunophenotyping:
  - CD19+, CD20+, CD10+, BCL6+, Ki-67 (proliferation marker) is very high (approaching 100%)
  - CD5-, CD23-
- Cytogenetic Analysis:
  - t(8;14)(q24;q32) or other MYC translocation
Treatment:
- Intensive Chemotherapy:
  - Short-duration, high-intensity chemotherapy regimens are used to rapidly eradicate the tumor cells
  - Examples: R-hyperCVAD, CODOX-M/IVAC
- CNS Prophylaxis:
  - Intrathecal chemotherapy to prevent CNS involvement
- Management of Tumor Lysis Syndrome (TLS):
  - Aggressive hydration, allopurinol, and rasburicase to prevent TLS

Waldenström Macroglobulinemia (WM)

Definition: A rare, indolent B-cell lymphoma characterized by the presence of IgM monoclonal gammopathy and infiltration of the bone marrow and other tissues by lymphoplasmacytic cells
Genetic Abnormality: Most cases have a mutation in MYD88 gene
Pathophysiology:
- Clonal proliferation of lymphoplasmacytic cells (a mixture of lymphocytes and plasma cells) that secrete IgM antibodies
- Accumulation of IgM in the serum can lead to hyperviscosity syndrome
Clinical Features:
- Often asymptomatic
- Fatigue
- Weakness
- Weight loss
- Night sweats
- Lymphadenopathy
- Splenomegaly
- Hyperviscosity Syndrome:
  - Blurred vision
  - Headache
  - Dizziness
  - Neuropathy
  - Bleeding
- Cryoglobulinemia:
  - Precipitation of IgM antibodies at low temperatures, leading to vascular symptoms (e.g., Raynaud phenomenon, purpura)
Laboratory Findings:
- CBC:
  - Anemia
  - Thrombocytopenia (in some cases)
  - Leukocytosis or lymphocytosis (variable)
- Peripheral Blood Smear:
  - May show lymphoplasmacytic cells
  - Rouleaux formation (stacking of RBCs) due to increased serum protein
- Serum Protein Electrophoresis (SPEP):
  - IgM monoclonal spike
- Serum Immunofixation Electrophoresis (IFE):
  - Confirms the presence of IgM monoclonal gammopathy
- Bone Marrow Aspiration and Biopsy:
  - Infiltration of the bone marrow by lymphoplasmacytic cells
- Molecular Testing:
  - MYD88 L265P mutation (most common)
  - CXCR4 mutations (in some cases)
Treatment:
- Asymptomatic Patients:
  - Watchful waiting
- Symptomatic Patients:
  - Rituximab: Anti-CD20 monoclonal antibody
  - Chemotherapy: Cyclophosphamide, bendamustine
  - BTK Inhibitors: Ibrutinib, zanubrutinib
  - Proteasome Inhibitors: Bortezomib
  - Plasmapheresis: To remove IgM from the serum in hyperviscosity syndrome

Key Terms

Lymphoid Neoplasm: Malignancy originating from lymphocytes
Chronic Lymphocytic Leukemia (CLL): Indolent leukemia of mature B cells
Small Lymphocytic Lymphoma (SLL): Lymphoma of mature B cells, similar to CLL
Prolymphocytic Leukemia (PLL): Aggressive leukemia of prolymphocytes
Hairy Cell Leukemia (HCL): Indolent leukemia of B cells with “hairy” cytoplasmic projections
Burkitt Lymphoma: Highly aggressive lymphoma with a MYC translocation
Waldenström Macroglobulinemia (WM): Lymphoma with IgM monoclonal gammopathy
Immunophenotyping: Identification of cell surface markers using flow cytometry
Cytogenetic Analysis: The study of chromosomes and their abnormalities
B Symptoms: Fever, weight loss, night sweats

Acute Lymphoid

Chronic T-Cell