Mature B, T and NK Cell Neoplasms - Chronic Lymphocytic Leukemia (CLL)
They are a diverse group of mature B, T, and NK-cell neoplasms that have prominent involvement of the peripheral blood (PB) and bone marrow (BM).
Lymphomas predominantly arise in the lymph nodes (LNs) but can arise in other organs (extranodal lymphomas). Almost all lymphomas may involve the PB and/or BM, especially when they are advanced.
Classification of the chronic lymphoid leukemias and leukemia/lymphoma syndromes.
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B-Cell
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T-Cell
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Chronic
Lymphoid Leukemias
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Chronic lymphocytic
leukemia
(CLL).
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Prolymphocytic leukemia (PLL)
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Hairy cell leukemia (HCL)
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Plasma cell leukemia
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Large granular
lymphocytic
leukemia
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T-cell prolymphocytic
leukemia
(T-PLL)
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Leukemia/Lymphoma
Syndromes
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Splenic lymphoma with
villous
lymphocytes
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Follicular lymphoma
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Mantle cell lymphoma
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Lymphoplasmacytic lymphoma
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Large cell lymphoma
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Sezary syndrome
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Adult T-cell leukemia/
lymphoma
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Large cell lymphoma
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Diagnosis
This group is characterized by chronic persistent lymphocytosis. Subtypes are distinguished by:
1. Morphology.
2. Immunophenotype.
3. Cytogenetics
4. DNA analysis may be useful in showing a monoclonal rearrangement of either Ig (for B-cells) or TCR genes (for T-cells).
Chronic Lymphocytic Leukemia (CLL)
CLL is a low-grade clonal LPD characterized by progressive accumulation of usually well-differentiated CD5+ lymphocytes in the marrow with an accompanying peripheral lymphocytosis.
Involvement of LN, spleen, and liver invariably occurs sometimes during the disease course.
The etiology is unknown. There is a seven-fold increased risk of CLL in the close relatives of the patient. CLL is the most common of chronic lymphoid leukemia, accounting for 60% of cases, and it is the most common in the West representing about 25% of all leukemias in adults > 50 years.
Clinical features of CLL
1. Asymptomatic; most cases are diagnosed when a routine blood test is performed.
2. Lymphadenopathy: Symmetrical enlargement of cervical, axillary, or inguinal LNs is usually discrete and non-tender.
3. Features of anemia & thrombocytopenia may be present.
4. Splenomegaly and less commonly hepatomegaly are common in intermediate & later stages.
5. Early bacterial infections predominate but with advanced disease, viral and fungal infections such as candidiasis and herpes zoster are also seen.
Laboratory findings
• Lymphocytosis; the absolute lymphocyte count is > 5 × 109/L. The predominant cells are small lymphocytes with compact dark-staining round nuclei, scanty cytoplasm, and little variation in size.
The CLL lymphocytes are fragile and are frequently disrupted during the preparation of smears, which produces characteristic smudge cells.
• Anemia and Thrombocytopenia are seen in later stages due to BM failure, or hypersplenism, or autoimmune process.
• BM examination: BMA shows lymphocyte infiltration >30 % of all nucleated BM cells. BM biopsy reveals an early interstitial and late diffuse pattern of involvement.
• Immunophenotype shows pan-B-cell markers (CD19+ & CD22+) with CD5+ & CD23+, weak expression of surface membrane immunoglobulin with weak or negative FMC7 and CD79b.
•Karyotype. The most common cytogenetic abnormalities are deletion of 13q14 which is associated with a good prognosis.
Trisomy 12, deletion at 11q23, and structural abnormalities of 17p involving the p53 gene have a bad prognosis.
Staging of CLL
It is useful to stage patients at presentation both for prognosis and for deciding on therapy.
The stage is determined by several variables such as peripheral lymphocyte count, BM lymphocyte percentage, presence, or absence of lymphadenopathy, hepatosplenomegaly.
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Rai Classification for CLL
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Stage
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Risk and Median Survival
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Stage 0: lymphocytosis in PB and
BM only.
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Low; 10 years
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Stage I: lymphocytosis plus
enlarged lymph nodes.
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Intermediate; 6 years
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Stage II: lymphocytosis plus
enlarged liver and/or spleen
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Intermediate; 6 years
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Stage III: lymphocytosis plus
anemia (Hgb<11g/dL).
lymph nodes, spleen, or liver may
be enlarged
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High; 2 years
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Stage IV: lymphocytosis and
thrombocytopenia; anemia and organomegaly may be present
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High; 2 years
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Binet staging system for CLL
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Stage
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Risk and Median Survival
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A: Hgb ≥10 g/dL; plt ≥100 x 109/L;
<3 anatomic
sites* involved
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>120 months
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B: Hgb ≥10 g/dL; plt ≥100 x 109/L;
≥3 anatomic
sites involved
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61 months
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C: Hgb <10 g/dL; plt <100 x
109/L
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32 months
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*Anatomic sites: inguinal lymph
nodes, axillary lymph nodes, cervical lymph nodes,
liver or spleen.
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Markers of poor prognosis in CLL
• Advanced Rai or Binet stage
• Peripheral lymphocyte doubling time <12 months
• Diffuse marrow histology
• Increased number of prolymphocytes or cleaved cells
• Poor response to chemotherapy
• High b2- microglobulin level
• Abnormal karyotyping
Treatment
– B-CLL – indolent lymphoma, but incurable
– Elderly patients – the risk of additional diseases
– Course of the disease can be very long, indolent for many years, the patient can die because of another reason which is not connected to B-CLL.
• Decision about treatment depends on clinical stage, prognostic factors, and patient’s condition.
Indications of treatment
• Leukemia cell doubling time <6 months
• Grade 2 or greater fatigue
• Night Sweats
• B symptoms for >2weeks
• Lymph nodes of >10 cm
• Symptomatic liver or splenic enlargement (> 10 cm)
• Anemia Hb <10 gm/dl
• Thrombocytopenia <100 x 109/L) platelets
• Severe paraneoplastic process related to CLL
- Alkylating agents (chlorambucil, cyclophosphamide)
- Nucleoside analogs (cladribine, fludarabine)
- Biological response modifiers
- Monoclonal antibodies
- Bone marrow transplantation
- And systemic complications requiring therapy
- antibiotics
- immunoglobulin
- steroids
- blood products
Prognosis:
For practical purposes, CLL is an incurable disease that is usually indolent with prolonged survival.
In general, patients diagnosed when more than
60 years of age will die from unrelated causes and younger patients from the CLL, usually due to infection.
The overall median survival is seven years. Several factors have an adverse influence on survival, including the following:
• CLL/PL variant
• Diffuse involvement of the BM
• Richter or prolymphocytic transformation
• CD38 positivity
• ZAP‑70 positivity
• Chromosomal abnormalities (trisomy 12, deletions at 11q22‑23, TP53 abnormalities)
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