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Chronic lymphocytic leukemia (Cll)

Updated : May 31, 2024





Background

The chronic lymphocyte leukemia or CLL is a malignancy that affects blood and bone marrow. It is happening due to the over production of abnormal lymphocytes, that are the white blood cells, thus leading to the development of a malignant tumor. 

Particularly in cases of CLL the abnormal lymphocytes are accumulated in the blood, bone marrow, lymph nodes and other organs, disrupting normal blood cell generation and immunity operations. While CLL is widely classified as a chronic or steadily progressing cancer, it still can pose a serious medical concern that can result in health issues over time. 

Epidemiology

Age: CLL in most cases appears in the elderly individuals, with a median age of diagnosis reaching approximately 70.  

Among the leukemia cases in the US, the chronic lymphocytic leukemia (CLL) occur in 25-30 percent. In the same year, the National Cancer Institute projected, CLL, a type of blood cell malignancy, would have led to about 4,060 deaths and 21,040 new cases. 

Anatomy

Pathophysiology

Abnormal B-cell Development: Clinically, the CLL disease is characterized by an abnormal proliferation of B lymphocytes that have reached the final stage of maturation, which is represented by the appearance of CD5-positive B cells. These cells would down regulate and bypass their control checkpoints, so they multiply themselves rapidly. 

Genetic Mutations: CLL is accompanied by the specific mutations in genes that have the goal of disruption of the oscillating mechanisms between cell growth and cell death. The mostly encountered abnormal genetic changes in the CLL involve the genes like TP53, ATM, NOTCH1, SF3B1, and others. It is through these mutations that leukemia cells perpetually break through whatever barriers designed to keep them in check, and they overcome any obstacle in their reproduction. 

Microenvironment Interaction: The local micro-environment in the bone marrow and lymphoid tissues guarantees the proper functionality of chronic lymphocytic leukemia. Interactions of immunological cells with CLL cells and stromal cells, and some immune cells, are what bring about disease progression and response to treatment. The microenvironment secretes several small molecular signaling molecules, cytokines, and chemokines that can support CLL cell survival and growth. 

Impaired Immune Regulation: CLL cells frequently use immune defenses to evade the control mechanism from the immune system. thus, these leukemia cells tend to replicate uncontrollably. T-cell function maladjustment, cytokine imbalance, and altered antigen exposure, are cytokines of immune dysfunction in CLL. 

Dysregulated B-cell Receptor Signaling: CLL is characterized by B-cell receptor (BCR) signaling pathway abnormalities, the overexpression of anti-apoptotic proteins and the upregulation of cyclins, which leads to leukemic B cell hyperproliferation and survival. The CLL B cells react through BCR immunization and lead to them acquire more life prolonging activity. 

Etiology

Genetic Predisposition: Studies have supported the hypothesis that genetic inheritances could play a role in the emergence of CLL. Members of families that are known to have a history of CLL and other blood-related cancers, are at a higher chance of acquiring CLL. 

Environmental Factors: Toxic exposition to benzene, as well as some pesticides, has been considered contributing factors to the increased risk of contracting CLL.  

Immunological Factors: It will be the non-functioning of immune system that can interfere with the development of CLL. The abnormalities in the B lymphocyte function regulation, which lymphocytes become altered in the CLL, may explain the pathological nature of the condition. 

Genetics

Prognostic Factors

The prognosis of CLL is different from person to person and it depends on different aspects of the condition in each patient depending on the stage of the disease at diagnosis, the presence of certain genetic abnormalities, the health of the patient and their response to treatment. 

Clinical History

Age group: 

The CLL disease (CLL) is more prevalent among adults, because it affects people after the age of 50, more specifically. The average age is approximately 70 years old, when diagnosis is established.  

Physical Examination

Blood tests  

Imaging studies 

Bone marrow biopsy 

Age group

Associated comorbidity

Secondary Infections 

Autoimmune Disorders 

Bone Marrow Failure Syndromes 

Thrombosis 

Associated activity

Acuity of presentation

Enlarged lymph nodes: Painless lymph nodes painless, and they should be around the neck, armpits, or groin lymph nodes. 

Fatigue: Increased lethargy or low energy  

Frequent infections: CLL affects production of white blood cells in the body, thus disrupting the body’s immunity leading to more susceptibility to infections. 

Weight loss: As for unintentional weight loss. 

Easy bruising or bleeding: As a result of platelet disorder. 

CLL symptomatic onset has a great variation among individuals. Some people may suffer from disease with aggressive progression which would present itself with the appearance of symptoms quickly, whereas others may experience disease where the patient may be asymptomatic for many years. 

Differential Diagnoses

Other leukemias 

Lymphomas 

Lymphoproliferative disorders 

Drug-induced lymphocytosis 

Secondary cancers 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Chemotherapy: Chemotherapy medications, including bendamustine, cyclophosphamide, and fludarabine, are frequently used to eradicate cancer cells. They can be used both on their own and in conjunction with other therapies. However, as more advanced targeted medicines are created, chemotherapy is becoming less popular. 

Targeted Therapy: A class of drugs which are directed at the molecules needed by the CLL cells to multlipy and survival are a result of the revolution of the treatment of CLL. Examples include: 

BTK Inhibitors:  Medication such as ibrutinib, acalabrutinib, and zanubrutinib inhibit the protein called bruton’s tyrosine kinase (BTK), which is essential for CLL cells to endure and proliferate. 

BCL2 Inhibitors: Venetoclax is a medicine that interferes with BCL2 function by blocking the process in which BCL2 helps cancer cells remain alive. It is normally combined with other medicaments. 

Anti-CD20 Antibodies: The monoclonal antibodies, such as rituximab, obinutuzumab, and ofatumumab, have as a target on CLL cells the CD20 protein which instructs immune system to draw it out. 

Immunotherapy: Immunotherapy turns off the immune system that boosts it to identify the cancer cells and attack them. These include 

Checkpoint Inhibitors: Drugs such as pembrolizumab and nivolumab that target the protecting proteins is by hampering the immune system’s attack against cancerous cells. 

CAR T-cell Therapy: This is a form of immunotherapy for which T cells are extracted from a patient and are prepared to serve the cancer cells better by recognizing and destroying them. CAR T-cell therapy, a treatment still in its initial stage for CLL and not yet widely accessible, is under evaluation. 

Stem Cell Transplantation: Younger individuals with CLL who are high-risk and not getting any benefits from other treatments may be an option for a stem cell transplant. With this, the donor marrow stem cells are transplanted in the body of the patient to replace the diseased cells. This is how the disease is cured. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Lifestyle modifications in treating CLL

Reducing Exposure to Infections: One of the most important issues for those who are dealing with CLL conditions is the fact that most of them have impaired immunity levels. This makes the prevention of infections a top priority. Such measures may include daily handwashing especially in flu seasons, and ensuring vaccinations is up to date which includes the flu shot and the appropriate vaccine. 

Avoiding Environmental Toxins: Use limiting conditions for environmental toxins for example cigarette smoke, pesticides, and other chemical groups that might compromising the health. 

Adequate Rest: Encourage the individual to meet the recommended amount of rest and sleep. Resting the right way is as vital to having a strong immune system and general health as other factors may appear. 

Emotional Support: Supporting the emotional well-being of the patient and fostering a positive atmosphere around the disease are way to significantly help with CLL. 

Use of antineoplastic agents in treating CLL

Pentostatin 

The mechanism of pentostatin is based on the blocking of ADA as the result of which DNA and RNA synthesis in lymphocytes is disrupted, leading to their death. The decrease of the number of cancerous lymphocytes in the body and will slow down, at least for a time, the disease progress. 

Chlorambucil 

Chlorambucil is a drug subcategory of the alkylating agents. By connecting an alkyl group with the DNA of cancer cells, the alkylating agents work with the consequence of the distraction of the DNA replication working correctly. Cancer cell continues to increase, feed on nutrients, and disrupt healthy tissue until it ultimately leads to cell death thereby reducing the number of cancerous cells in the body. 

Effectiveness of bruton tyrosine kinase inhibitors in treating CLL

Ibrutinib: Ibrutinib in CLL works by inhibiting the BTK. In this way, it disrupts the functioning of several signalling paths which are very significant to cancerous B cells for propagation and survival. Hence, it results in the death of the malignant B cell precursors that are responsible for the tumorigenesis of CLL and helps to slow down the growth of the disease. 

Pirtobrutinib: Pirtobrutinib represents a drug that acts by blocking BTK’s activities thus preventing the profusion and survival of CLL. Pirtobrutinib works by targeting the specific pathway, can be helpful in this disease to slow down its progress and thus reduce the symptoms. 

Use of monoclonal antibody in treating CLL

Ofatumumab 

By linking to CD20, ofatumumab can also interfere with signalling pathways in the tumor cells for the growth and survival of CLL, which will further stop the cell’s proliferation. 

Rituximab 

Rituximab acts on CD20-expressing B cells to eliminate them, which lowers the total number of B cells in CLL patients. Improvements in the symptoms and course of the disease may result from this decrease. 

Use of B-cell lymphoma inhibitors in treating CLL

Venetoclax 

Venetoclax acts in two ways by prohibiting BCL-2 (a protein that inhibits cell death) and allowing the entry of cytochrome C thus induce apoptosis (programmed cell death) and destrution of CLL cells. 

Its primary mechanism of action involves inhibiting the protein BCL-2, which is overexpressed in CLL cells and helps them survive longer than normal. By inhibiting BCL-2, venetoclax promotes apoptosis (programmed cell death) in CLL cells, leading to their destruction. 

Role of intervention with procedure in treating CLL

Stem Cell Transplantation: For younger healthy patients with advanced stage CLL at high risk and who have responded poorly to other treatments, a stem cell transplant may be the next option. The procedure entails the substitution of the diseased bone marrow with stem cells provided by an unrelated donor. 

Splenectomy: In certain situations, B-cell lymphoma can cause the (splenomegaly) to enlarge the spleen (splenomegaly), and thus the patient’s discomfort and complication are possible. In case, the enlarged spleen affects the body ability to function properly or causes severe symptoms, the only option would be the surgical removal (splenectomy). 

Role of management in treating CLL

Monitoring and Observation: In early stage CLL, especially for one who is already asymptomatic, the physician may still prescribe a watchful strategy without immediate treatment, however, there is still need for scrutiny on how the disease is progressing. 

Treatment Initiation: When all other remedies have been exhausted or they do not resolve the situation, treatment may be the only answer. The treatment plan mostly provides chemotherapy, targeted therapy, immunotherapy, or the mixture of the several options. 

Remission Induction: Inducing remission as the main objective of treatment of CLL is a complete absence of symptoms and counts of white blood cells as normal. 

Maintenance Therapy: Achieving the remission is but not the case for some patients who will need to continue maintaining therapy to prevent relapse. Such treatment can last longer with lower doses, or it can be a treatment of a lighter intensity level. 

Supportive Care: These include symptom management, guarding against infection and dealing with the possible side effects caused by the drug. 

Follow-up and Surveillance: Continuous attendance to medical appointments and proper observation is important. Adjustment of medication as required should be done. 

Medication

 

vinblastine

initial dose:

3.7

mg/m^2

Intravenous (IV)

usual dose: 5.5-7.4 mg per m2 IV once every 7 days
Max: 18.5 mg per m2 once every seven days
The patient should not take a high dose if the white cell count reduces to 3000 cells per mm3



ibrutinib

420

mg

Oral

once a day

in combination with Obinutuzumab or rituximab.



duvelisib

25

mg

Capsule

Oral

two times a day in 28-day cycles


Continue the therapy until unacceptable toxicity or progressive disease occurs



idelalisib

150

mg

Tablet

Orally 

twice a day

If severe symptomatic pneumonitis occurs, discontinue the usage of idelalisib



acalabrutinib 

Indicated for monotherapy:


100mg orally every 12 hours

In combination with Obinutuzumab
Cycle 1-Days 1-28: 100mg orally every 12 hours
Cycle 2-Days 1-28: Acalabrutnib-100mg orally every 12 hours

Day 1: Obinutuzumab-100mg intravenous infusion
Day 2: Obinutuzumab-900mg intravenous infusion
Days 8 and 15: Obinutuzumab-1000mg intravenous infusion

Cycle 3-7:
Day 1-28: Acalabrutnib-100mg orally every 12 hours
Day 1: Obinutuzumab-1000mg intravenous infusion

Cycle 8 and later cycles:
Day 1-28: Acalabrutnib-100mg orally every 12 hours

Management of grade adverse ≥3 reactions
• Grade ≥3 nonhematologic toxicities: The drug should be interrupted if the patient experiences grade≥3 nonhematologic toxicities. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• Grade 3 thrombocytopenia with bleeding: The drug should be interrupted if the patient experiences Grade 3 thrombocytopenia with bleeding. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• Grade 4 thrombocytopenia: The drug should be interrupted if the patient experiences Grade 4 thrombocytopenia. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• Grade 4 neutropenia lasting >7 days: If the patient experiences Grade 4 neutropenia lasting longer than seven days, the drug should be interrupted. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• First to the second occurrence: If the same toxicity occurs for a second time, the drug should be interrupted. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• Third occurrence: If the same toxicity occurs for a third time, the drug should be interrupted. Once the toxicity resolves to Grade ≤1, the dose should be reduced to 100 mg orally every day
• Fourth occurrence: If the same toxicity occurs for a fourth time, the drug should be discontinued



ofatumumab 

Previously untreated
Cycle 1: 300 mg intravenously on 1st day followed by 1000 mg 1 week later 8th day
Next 28-day cycles: 1,000 mg on 1st day for minimum 3-12 cycles until a best response is achieved

Relapsed CLL
ofatumumab is indicated in combination with cyclophosphamide and fludarabine for relapsed CLL
300 mg intravenously as 1st dose followed by 2nd dose a week later
2nd dose: 1000 mg intravenously, then
3rd dose: 1000 mg on 1st day of a subsequent 28-day cycle up to 6 cycles

Extended treatment
1st dose: 300 mg intravenously on 1st day, followed by a week later
2nd dose: 1000 mg for a week on 8th day, continued for 7 days and then
3rd dose: 1000 mg intravenously and then every 8th week for 2 years

Refractory CLL
1st dose: 300 mg intravenously, followed by the next dose a week later
2nd to 8th dose: 2000 mg intravenously every week for 7 doses
After 4 weeks: 9th to 12th dose: 4 doses of 2000 mg intravenously every 4 weeks
The total regimen contains 12 doses



bendamustine 

100 mg/m2 Intravenous infusion on days 1 and 2 of a 28-day cycle, to be repeated up to 6 times.
Dosage modifications
Nonhematologic toxicity
above Grade 3 clinical toxicity: On the first and second days of each cycle, reduce the dosage to 50 mg/m2.
Dose increase might be considered.
Hematologic toxicity
Above Grade 3: Decrease dosage to 50 mg/m2 on Days 1 and 2.
If grade 3 toxicity develops again, lower the dosage to 25 mg/m2 on Days 1 and 2.



obinutuzumab 

Give for 6 treatment cycles (each cycle of 28-day)
Cycle 1
100 mg Intravenous on day 1
900 mg Intravenous on day 2
1000 mg Intravenous on Days 8 and 15
Cycles 2 to 6
1000 mg Intravenous on day 1



 
 

Media Gallary

Chronic lymphocytic leukemia (Cll)

Updated : May 31, 2024




The chronic lymphocyte leukemia or CLL is a malignancy that affects blood and bone marrow. It is happening due to the over production of abnormal lymphocytes, that are the white blood cells, thus leading to the development of a malignant tumor. 

Particularly in cases of CLL the abnormal lymphocytes are accumulated in the blood, bone marrow, lymph nodes and other organs, disrupting normal blood cell generation and immunity operations. While CLL is widely classified as a chronic or steadily progressing cancer, it still can pose a serious medical concern that can result in health issues over time. 

Age: CLL in most cases appears in the elderly individuals, with a median age of diagnosis reaching approximately 70.  

Among the leukemia cases in the US, the chronic lymphocytic leukemia (CLL) occur in 25-30 percent. In the same year, the National Cancer Institute projected, CLL, a type of blood cell malignancy, would have led to about 4,060 deaths and 21,040 new cases. 

Abnormal B-cell Development: Clinically, the CLL disease is characterized by an abnormal proliferation of B lymphocytes that have reached the final stage of maturation, which is represented by the appearance of CD5-positive B cells. These cells would down regulate and bypass their control checkpoints, so they multiply themselves rapidly. 

Genetic Mutations: CLL is accompanied by the specific mutations in genes that have the goal of disruption of the oscillating mechanisms between cell growth and cell death. The mostly encountered abnormal genetic changes in the CLL involve the genes like TP53, ATM, NOTCH1, SF3B1, and others. It is through these mutations that leukemia cells perpetually break through whatever barriers designed to keep them in check, and they overcome any obstacle in their reproduction. 

Microenvironment Interaction: The local micro-environment in the bone marrow and lymphoid tissues guarantees the proper functionality of chronic lymphocytic leukemia. Interactions of immunological cells with CLL cells and stromal cells, and some immune cells, are what bring about disease progression and response to treatment. The microenvironment secretes several small molecular signaling molecules, cytokines, and chemokines that can support CLL cell survival and growth. 

Impaired Immune Regulation: CLL cells frequently use immune defenses to evade the control mechanism from the immune system. thus, these leukemia cells tend to replicate uncontrollably. T-cell function maladjustment, cytokine imbalance, and altered antigen exposure, are cytokines of immune dysfunction in CLL. 

Dysregulated B-cell Receptor Signaling: CLL is characterized by B-cell receptor (BCR) signaling pathway abnormalities, the overexpression of anti-apoptotic proteins and the upregulation of cyclins, which leads to leukemic B cell hyperproliferation and survival. The CLL B cells react through BCR immunization and lead to them acquire more life prolonging activity. 

Genetic Predisposition: Studies have supported the hypothesis that genetic inheritances could play a role in the emergence of CLL. Members of families that are known to have a history of CLL and other blood-related cancers, are at a higher chance of acquiring CLL. 

Environmental Factors: Toxic exposition to benzene, as well as some pesticides, has been considered contributing factors to the increased risk of contracting CLL.  

Immunological Factors: It will be the non-functioning of immune system that can interfere with the development of CLL. The abnormalities in the B lymphocyte function regulation, which lymphocytes become altered in the CLL, may explain the pathological nature of the condition. 

The prognosis of CLL is different from person to person and it depends on different aspects of the condition in each patient depending on the stage of the disease at diagnosis, the presence of certain genetic abnormalities, the health of the patient and their response to treatment. 

Age group: 

The CLL disease (CLL) is more prevalent among adults, because it affects people after the age of 50, more specifically. The average age is approximately 70 years old, when diagnosis is established.  

Blood tests  

Imaging studies 

Bone marrow biopsy 

Secondary Infections 

Autoimmune Disorders 

Bone Marrow Failure Syndromes 

Thrombosis 

Enlarged lymph nodes: Painless lymph nodes painless, and they should be around the neck, armpits, or groin lymph nodes. 

Fatigue: Increased lethargy or low energy  

Frequent infections: CLL affects production of white blood cells in the body, thus disrupting the body’s immunity leading to more susceptibility to infections. 

Weight loss: As for unintentional weight loss. 

Easy bruising or bleeding: As a result of platelet disorder. 

CLL symptomatic onset has a great variation among individuals. Some people may suffer from disease with aggressive progression which would present itself with the appearance of symptoms quickly, whereas others may experience disease where the patient may be asymptomatic for many years. 

Other leukemias 

Lymphomas 

Lymphoproliferative disorders 

Drug-induced lymphocytosis 

Secondary cancers 

Chemotherapy: Chemotherapy medications, including bendamustine, cyclophosphamide, and fludarabine, are frequently used to eradicate cancer cells. They can be used both on their own and in conjunction with other therapies. However, as more advanced targeted medicines are created, chemotherapy is becoming less popular. 

Targeted Therapy: A class of drugs which are directed at the molecules needed by the CLL cells to multlipy and survival are a result of the revolution of the treatment of CLL. Examples include: 

BTK Inhibitors:  Medication such as ibrutinib, acalabrutinib, and zanubrutinib inhibit the protein called bruton’s tyrosine kinase (BTK), which is essential for CLL cells to endure and proliferate. 

BCL2 Inhibitors: Venetoclax is a medicine that interferes with BCL2 function by blocking the process in which BCL2 helps cancer cells remain alive. It is normally combined with other medicaments. 

Anti-CD20 Antibodies: The monoclonal antibodies, such as rituximab, obinutuzumab, and ofatumumab, have as a target on CLL cells the CD20 protein which instructs immune system to draw it out. 

Immunotherapy: Immunotherapy turns off the immune system that boosts it to identify the cancer cells and attack them. These include 

Checkpoint Inhibitors: Drugs such as pembrolizumab and nivolumab that target the protecting proteins is by hampering the immune system’s attack against cancerous cells. 

CAR T-cell Therapy: This is a form of immunotherapy for which T cells are extracted from a patient and are prepared to serve the cancer cells better by recognizing and destroying them. CAR T-cell therapy, a treatment still in its initial stage for CLL and not yet widely accessible, is under evaluation. 

Stem Cell Transplantation: Younger individuals with CLL who are high-risk and not getting any benefits from other treatments may be an option for a stem cell transplant. With this, the donor marrow stem cells are transplanted in the body of the patient to replace the diseased cells. This is how the disease is cured. 

Reducing Exposure to Infections: One of the most important issues for those who are dealing with CLL conditions is the fact that most of them have impaired immunity levels. This makes the prevention of infections a top priority. Such measures may include daily handwashing especially in flu seasons, and ensuring vaccinations is up to date which includes the flu shot and the appropriate vaccine. 

Avoiding Environmental Toxins: Use limiting conditions for environmental toxins for example cigarette smoke, pesticides, and other chemical groups that might compromising the health. 

Adequate Rest: Encourage the individual to meet the recommended amount of rest and sleep. Resting the right way is as vital to having a strong immune system and general health as other factors may appear. 

Emotional Support: Supporting the emotional well-being of the patient and fostering a positive atmosphere around the disease are way to significantly help with CLL. 

Pentostatin 

The mechanism of pentostatin is based on the blocking of ADA as the result of which DNA and RNA synthesis in lymphocytes is disrupted, leading to their death. The decrease of the number of cancerous lymphocytes in the body and will slow down, at least for a time, the disease progress. 

Chlorambucil 

Chlorambucil is a drug subcategory of the alkylating agents. By connecting an alkyl group with the DNA of cancer cells, the alkylating agents work with the consequence of the distraction of the DNA replication working correctly. Cancer cell continues to increase, feed on nutrients, and disrupt healthy tissue until it ultimately leads to cell death thereby reducing the number of cancerous cells in the body. 

Ibrutinib: Ibrutinib in CLL works by inhibiting the BTK. In this way, it disrupts the functioning of several signalling paths which are very significant to cancerous B cells for propagation and survival. Hence, it results in the death of the malignant B cell precursors that are responsible for the tumorigenesis of CLL and helps to slow down the growth of the disease. 

Pirtobrutinib: Pirtobrutinib represents a drug that acts by blocking BTK’s activities thus preventing the profusion and survival of CLL. Pirtobrutinib works by targeting the specific pathway, can be helpful in this disease to slow down its progress and thus reduce the symptoms. 

Ofatumumab 

By linking to CD20, ofatumumab can also interfere with signalling pathways in the tumor cells for the growth and survival of CLL, which will further stop the cell’s proliferation. 

Rituximab 

Rituximab acts on CD20-expressing B cells to eliminate them, which lowers the total number of B cells in CLL patients. Improvements in the symptoms and course of the disease may result from this decrease. 

Venetoclax 

Venetoclax acts in two ways by prohibiting BCL-2 (a protein that inhibits cell death) and allowing the entry of cytochrome C thus induce apoptosis (programmed cell death) and destrution of CLL cells. 

Its primary mechanism of action involves inhibiting the protein BCL-2, which is overexpressed in CLL cells and helps them survive longer than normal. By inhibiting BCL-2, venetoclax promotes apoptosis (programmed cell death) in CLL cells, leading to their destruction. 

Stem Cell Transplantation: For younger healthy patients with advanced stage CLL at high risk and who have responded poorly to other treatments, a stem cell transplant may be the next option. The procedure entails the substitution of the diseased bone marrow with stem cells provided by an unrelated donor. 

Splenectomy: In certain situations, B-cell lymphoma can cause the (splenomegaly) to enlarge the spleen (splenomegaly), and thus the patient’s discomfort and complication are possible. In case, the enlarged spleen affects the body ability to function properly or causes severe symptoms, the only option would be the surgical removal (splenectomy). 

Monitoring and Observation: In early stage CLL, especially for one who is already asymptomatic, the physician may still prescribe a watchful strategy without immediate treatment, however, there is still need for scrutiny on how the disease is progressing. 

Treatment Initiation: When all other remedies have been exhausted or they do not resolve the situation, treatment may be the only answer. The treatment plan mostly provides chemotherapy, targeted therapy, immunotherapy, or the mixture of the several options. 

Remission Induction: Inducing remission as the main objective of treatment of CLL is a complete absence of symptoms and counts of white blood cells as normal. 

Maintenance Therapy: Achieving the remission is but not the case for some patients who will need to continue maintaining therapy to prevent relapse. Such treatment can last longer with lower doses, or it can be a treatment of a lighter intensity level. 

Supportive Care: These include symptom management, guarding against infection and dealing with the possible side effects caused by the drug. 

Follow-up and Surveillance: Continuous attendance to medical appointments and proper observation is important. Adjustment of medication as required should be done. 

vinblastine

initial dose:

3.7

mg/m^2

Intravenous (IV)

usual dose: 5.5-7.4 mg per m2 IV once every 7 days
Max: 18.5 mg per m2 once every seven days
The patient should not take a high dose if the white cell count reduces to 3000 cells per mm3



ibrutinib

420

mg

Oral

once a day

in combination with Obinutuzumab or rituximab.



duvelisib

25

mg

Capsule

Oral

two times a day in 28-day cycles


Continue the therapy until unacceptable toxicity or progressive disease occurs



idelalisib

150

mg

Tablet

Orally 

twice a day

If severe symptomatic pneumonitis occurs, discontinue the usage of idelalisib



acalabrutinib 

Indicated for monotherapy:


100mg orally every 12 hours

In combination with Obinutuzumab
Cycle 1-Days 1-28: 100mg orally every 12 hours
Cycle 2-Days 1-28: Acalabrutnib-100mg orally every 12 hours

Day 1: Obinutuzumab-100mg intravenous infusion
Day 2: Obinutuzumab-900mg intravenous infusion
Days 8 and 15: Obinutuzumab-1000mg intravenous infusion

Cycle 3-7:
Day 1-28: Acalabrutnib-100mg orally every 12 hours
Day 1: Obinutuzumab-1000mg intravenous infusion

Cycle 8 and later cycles:
Day 1-28: Acalabrutnib-100mg orally every 12 hours

Management of grade adverse ≥3 reactions
• Grade ≥3 nonhematologic toxicities: The drug should be interrupted if the patient experiences grade≥3 nonhematologic toxicities. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• Grade 3 thrombocytopenia with bleeding: The drug should be interrupted if the patient experiences Grade 3 thrombocytopenia with bleeding. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• Grade 4 thrombocytopenia: The drug should be interrupted if the patient experiences Grade 4 thrombocytopenia. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• Grade 4 neutropenia lasting >7 days: If the patient experiences Grade 4 neutropenia lasting longer than seven days, the drug should be interrupted. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• First to the second occurrence: If the same toxicity occurs for a second time, the drug should be interrupted. Once the toxicity resolves to Grade ≤1, the dose should be resumed at 100 mg orally twice a day
• Third occurrence: If the same toxicity occurs for a third time, the drug should be interrupted. Once the toxicity resolves to Grade ≤1, the dose should be reduced to 100 mg orally every day
• Fourth occurrence: If the same toxicity occurs for a fourth time, the drug should be discontinued



ofatumumab 

Previously untreated
Cycle 1: 300 mg intravenously on 1st day followed by 1000 mg 1 week later 8th day
Next 28-day cycles: 1,000 mg on 1st day for minimum 3-12 cycles until a best response is achieved

Relapsed CLL
ofatumumab is indicated in combination with cyclophosphamide and fludarabine for relapsed CLL
300 mg intravenously as 1st dose followed by 2nd dose a week later
2nd dose: 1000 mg intravenously, then
3rd dose: 1000 mg on 1st day of a subsequent 28-day cycle up to 6 cycles

Extended treatment
1st dose: 300 mg intravenously on 1st day, followed by a week later
2nd dose: 1000 mg for a week on 8th day, continued for 7 days and then
3rd dose: 1000 mg intravenously and then every 8th week for 2 years

Refractory CLL
1st dose: 300 mg intravenously, followed by the next dose a week later
2nd to 8th dose: 2000 mg intravenously every week for 7 doses
After 4 weeks: 9th to 12th dose: 4 doses of 2000 mg intravenously every 4 weeks
The total regimen contains 12 doses



bendamustine 

100 mg/m2 Intravenous infusion on days 1 and 2 of a 28-day cycle, to be repeated up to 6 times.
Dosage modifications
Nonhematologic toxicity
above Grade 3 clinical toxicity: On the first and second days of each cycle, reduce the dosage to 50 mg/m2.
Dose increase might be considered.
Hematologic toxicity
Above Grade 3: Decrease dosage to 50 mg/m2 on Days 1 and 2.
If grade 3 toxicity develops again, lower the dosage to 25 mg/m2 on Days 1 and 2.



obinutuzumab 

Give for 6 treatment cycles (each cycle of 28-day)
Cycle 1
100 mg Intravenous on day 1
900 mg Intravenous on day 2
1000 mg Intravenous on Days 8 and 15
Cycles 2 to 6
1000 mg Intravenous on day 1