​Kembara Xtra - Medicine - Chronic Lymphocytic Leukemia

​Kembara Xtra - Medicine - Chronic Lymphocytic Leukemia 
A monoclonal disease called chronic lymphocytic leukemia (CLL) is characterized by a steady buildup of mature but ineffective cells.
The disease may be classified as CLL (10% prolymphocytes), prolymphocytic leukemia (PLL; >55%), or CLL/PLL (>10% and 55%) depending on the prolymphocyte proportion.
A lymphoma subtype of CLL is small lymphocytic lymphoma.
 Hematologic, lymphatic, and immunologic system(s) impacted

 Incidence

CLL is the most prevalent kind of adult leukemia in the US, with 21,050 new cases anticipated to be identified in 2021.
With a median age of diagnosis of 70 years, CLL primarily affects elderly people. In 2021, an estimated 4,320 adults in the United States died from the disease, making it the second greatest cause of death among adults with leukemia in that country after acute myeloid leukemia. Ages >55 continue to see an increase in incidence.
Male is more prevalent than female (1.6:1)
Caucasians are more likely to experience it than African Americans.

Pathophysiology and Etiology 
Clonal B cells, which are intermediate between pre-B cells and mature B cells in the B cell differentiation pathway, are the cell of origin in CLL. These cells resemble mature lymphocytes in peripheral blood; genetic abnormalities that cause defective function and longer survival of afflicted lymphocytes are postulated but not fully understood. CLL has an overexpression of the BCL2 proto-oncogene, which inhibits programmed cell death or apoptosis.
Genetics
True familial cases are quite uncommon. However, it has been demonstrated that CLL is more common among first-degree relatives of those who have the condition, and various somatic gene alterations have been discovered in CLL patients at notably higher rates (1).
RISK ELEMENTS
It is unclear what causes CLL specifically. Though suspected, potential chronic immunological stimulation is currently being assessed.
Monoclonal B-cell lymphocytosis has a 1% chance of developing into CLL.


Accompanying Conditions 
Dysregulation of the immune system is widespread.
Pure red cell aplasia (PRCA), immune thrombocytopenia purpura (ITP), autoimmune hemolytic anemia (AIHA), and

Diagnosed as an onset that is subtle. When CLL is diagnosed, up to 40% of individuals are asymptomatic (accidental discovery).
Others might exhibit the following signs:
- Ailments of B: fever, sweats at night, and >10% weight loss
- Fatigue and/or other anemia-related symptoms
- Exaggerated lymph nodes (LAD = lymphadenopathy)
- Petechiae or mucocutaneous bleeding
- Early satiety and/or discomfort in the abdomen brought on by an enlarged spleen
- Recurrent illness(es)

clinical assessment 
Organomegaly (splenomegaly, hepatomegaly), mucocutaneous hemorrhage (thrombocytopenia), leukemia cutis rash, and lymphadenopathy (localized or widespread).

Various Diagnosis Infectious:
– Bacterial (pertussis, tuberculosis)
- Infectious (mononucleosis)
Nylon Plastic
- Non-Hodgkin lymphoma's leukemic phase
Leukemia with hairy cells
Large granular lymphocytic leukemia, abbreviated PLL
- Macroglobulinemia Waldenström

Initial test results from the laboratory and imaging
CBC with differential: B cell absolute lymphocytosis with >5,000 B lymphocytes/L; frequently also demonstrates severe stages of anemia and/or thrombocytopenia
Blood smear: burst lymphocytes (also known as "smudge" cells) and maturing lymphocytes that seem tiny on morphological examination confirm the diagnosis by doing lymph node biopsy or flow cytometry immunophenotyping on peripheral blood: Low levels of surface membrane immunoglobulin (Ig)—either IgM or IgM and IgD—as well as CD19, CD20 (dim), CD23, and CD5 positivity, as well as the expression of just one Ig light chain ( or ), which confirms monoclonality, are present in CLL cells.
Added laboratories:
- High LDH and indirect bilirubin, low haptoglobin, +/ increased reticulocyte count (bone marrow infiltration), and low haptoglobin are the hemolysis lab results (in cases linked with high disease activity or AIHA).
- Poor prognosis due to high plasma 2-microglobulin levels
- Hypergammaglobulinemia
CT scan of the chest, abdomen, and pelvis: not required for staging but may show compression of internal organs or structures from enlarged lymph nodes. Positron emission tomography (PET) scan: not advised unless Richter transformation (RT) is suspected. Liver/spleen ultrasound: may show organomegaly and enlarged abdominal lymph nodes.
Tests in the Future & Special Considerations
The frequency and kind of follow-up are influenced by the severity of the symptoms and risk factors.


Other/Diagnostic Procedures
Although not frequently done, a bone marrow biopsy can be useful for determining the cause of cytopenia that was discovered along with a CLL diagnosis.
 Lymph node biopsy: Take into account if lymph node(s) in a patient with established CLL begin to rapidly enlarge in order to estimate the likelihood of transformation to a high-grade lymphoma (RT), particularly when accompanied by fever, weight loss, and painful lymphadenopathy.
Interpretation of Tests
Bone marrow biopsy aspirate typically contains greater than 30% lymphocytes.
Cytogenetics (fluorescence in situ hybridization) may reveal prognostic chromosomal changes:
- Unfavorable: immunoglobulin heavy-chain variable (IGHV) without mutation, del(11q), or TP53 mutation
- Neutral: trisomy 12, normal
- Favorable: IGHV with a del(13q) mutation

Management 

Intravenous immunoglobulin (IVIG) infusions are probably beneficial for patients who experience repeated infections as a result of hypogammaglobulinemia.
 Genetic risk assessment in treatment choice for symptomatic or advanced CLL
- TP53 and/or del (17p) mutations are indicative of very high-risk diseases.
IGHV unmutated (without 17p del or TP53 mutation) is a high-risk illness.
IGHV mutation (without a 17p del or TP53 mutation): Standard risk disease

First Line of Medicine
Standard of care for newly discovered diseases that have no symptoms or are in an early stage is observation.
The recommended course of treatment for new diagnoses with symptoms (B symptoms, symptomatic anemia and/or thrombocytopenia due to progressive marrow failure, AIHA and/or thrombocytopenia poorly responsive to corticosteroids, progressive organomegaly), steroid-refractory autoimmune cytopenias, or progressive lymphocytosis (increase >50% in 2 months or a doubling time of 6 months) is as follows: Start a treatment.
 Rai stage 0 low-risk disease: observation with recurrent follow-up
Group at intermediate risk, Rai stages I and II: Monitor for signs of illness progression or the emergence of symptoms.
Patients at high risk in Rai stages III and IV should start treatment.
Based on the patient's functional status (age, performance status, and medical comorbidities), as well as their genetic risk stratification for CLL (above), the first-line therapy is chosen.
Principal categories of therapeutic agents:
- Targeted therapy are favored, particularly for patients at extremely high and high risk.
Ibrutinib, acalabrutinib, and zanubrutinib are Bruton tyrosine kinase (BTK) inhibitors.
Venetoclax, an inhibitor of BCL2.
A. Immunotherapy
- Chemotherapy: rituximab (R), obinutuzumab, and ofatumumab, monoclonal anti-CD20 antibodies.
cyclophosphamide (C), chlorambucil (C), and bendamustine (B) are alkylators.
Fludarabine (F), cladribine (C), and pentostatin (P) are examples of purine analogs. Rituximab or obinituzumab can also be used with ibrutinib or acalabrutinib (newer medicines with less adverse effects).
Venetoclax, obinituzumab, and BTK inhibitors provide very efficient regimens with a defined duration.
Venetoclax-containing combinations are being looked at for the potential of time-limited therapy for CLL patients who have a complete molecular response.
Combination regimens are less frequently utilized, although FCR with a BTK inhibitor can provide time-limited and very successful treatment for IGHV-mutated CLL. FC, FR (reduced toxicity), BR, PCR, and FCR.
High dosage steroids are helpful for CLL autoimmune symptoms (AIHA, ITP).

Next Line

Second-line treatment is based on time to progression and prior treatment.
 Targeted therapy is preferred for treating early relapse (within 1 year of chemoimmunotherapy, 2 to 3 years after FCR).
Venetoclax, a different BTK inhibitor, is used as monotherapy, in combination with rituximab, and in patients with 17p deletion who have relapsed or refractory CLL. 
- PI3K kinase inhibitors: Rituximab and idelalisib in patients with co-morbid conditions. Duvelisib (PI3K and PI3K) is a single medication that is approved for use in patients, while PJP prophylaxis is advised.- Ofatumumab and obinutuzumab, either alone or in combination with chlorambucil, for individuals with concomitant conditions and untreated CLL.
- The thalidomide derivative lénalidomide has various applications.
In high-risk and younger patients, especially those with refractory or RT, hematopoietic stem cell transplantation (hSCT) with allogenic (nonmyeloablative conditioning) may be an option.
QUESTIONS FOR REFERENCE
 Splenectomy consultation for individuals with refractory cytopenias and increasing splenomegaly
 Consultation with a radiation oncologist for big or bulky lymphadenopathy, especially if it is producing compressive symptoms

Further Therapies 
Allopurinol should be administered to patients who need therapy and are at high risk for tumor lysis syndrome to stop uric acid nephropathy.
Avoid live vaccinations (vaccines):
- Annual influenza vaccination - Five-year Pneumococcal vaccine
- COVID-19 vaccination; recombinant Zoster vaccine; adjuvanted for treatment-nave patients or those receiving BTK inhibitor;


AIHA or treatment-related complications (febrile neutropenia, tumor lysis syndrome) are acceptable reasons for admission. Venetoclax has been linked to tumor lysis syndrome, thus inpatient monitoring may be required.

Patient Follow-Up Monitoring
Patients in remission or those with low-risk CLL:
Every three to six months, get a CBC with differential (lymphocytosis), LDH, and 2-microglobulin. Have a physical exam (lymphadenopathy, organomegaly).

Diet: Watch your calorie and vitamin consumption and maintain a healthy weight.


Prognosis: In the US, the Rai system is utilized, while the Binet system is used in Europe. For estimating the period until the start of treatment, there is also an International Prognostic Score for Early-Stage CLL (IPS-E).
A staging system for Rai:
Stage 0: Lymphocytosis only; low-risk status Stage 1: Lymphocytosis and adenopathy Stage 2: Lymphocytosis +/ adenopathy and splenomegaly and/or hepatomegaly Stage 3: Lymphocytosis and anemia (hemoglobin 11 g/dL); high-risk status Stage 4: Lymphocytosis and thrombocytopenia (platelets 
IPS-E is useful for spotting people who may require treatment sooner.
– Giving 1 point for each of the following determines the IPS-E
Lymphocytes >15 109/L, palpable lymph nodes, and unmutated IGHV
A score of 0 indicated little risk, a score of 1 intermediate risk, and a score of 2 to 3 high risk of developing into an illness that requires treatment.
Adverse risk factors include advanced stage, peripheral lymphocyte doubling time of less than 12 months, diffuse marrow infiltration, an increase in prolymphocytes or cleaved cells, a poor response to chemotherapy, high levels of 2-microglobulin and thymidine kinase, low levels of micro-RNAs (miRNAs), abnormal karyotyping with del(17p) and del(11q), IGHV genes (expression of ZAP

Complications 

Effects of chemotherapy and targeted therapy, including short- and long-term effects, RT, AIHA (some cases may be related to fludarabine use), a slight increase in the risk of solid tumors, particularly Kaposi sarcoma, malignant melanoma, laryngeal, lung, and colon cancer, infection, and membranoproliferative glomerulonephritis (MPGN), and a few other conditions.

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