Chronic Lymphocytic Leukemia: Pharmacologic Management

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia diagnosed in adults in the United States and Europe.¹ The American Cancer Society estimates that fewer than 19,000 patients will develop CLL and approximately 4500 patients will die from the hematologic malignancy in 2023.²

CLL occurs when the bone marrow produces too many lymphocytes, which are often abnormal and fail to properly protect individuals from infection. As CLL does not completely interfere with the growth of other types of blood cells, its effects are typically less severe and instead only appear over many years as the number of leukemia cells increases in the blood, bone marrow, and related tissues.¹

Although individuals with CLL may live a long time with the disease, it is almost impossible to cure. Instead, clinicians use minimal residual disease status — or CLL counts so low as to be undetected by normal clinical tests — as a sign of treatment success.³

This article discusses current pharmacologic recommendations based on CLL treatment guidelines published by the National Comprehensive Cancer Network (NCCN) and the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) and outlines the use and monitoring of pharmacotherapies currently approved by the US Food and Drug Administration (FDA) to treat CLL.

Treatment Indications

In many cases, CLL is slow-growing and patients will experience few, if any, symptoms for years.¹ According to the iwCLL treatment guidelines, studies have shown that receiving CLL treatment during asymptomatic or early-stage disease confers no benefit in survival or outcomes.⁴ Thus, no treatment is necessary for indolent CLL, and patients should instead  undergo regular evaluations.

However, some types of CLL are fast-growing, or the leukemia begins to outnumber healthy blood cells over time, resulting in such symptoms as anemia or thrombocytopenia.¹ When symptomatic or progressive disease begins, patients benefit from pharmacologic management. The iwCLL guidelines suggest that therapy should begin once 1 of the following criteria has been met⁴:

• Progressive bone marrow failure;
• Large or progressive splenomegaly;
• Large or progressive lymphadenopathy;
• Rapidly progressing lymphocytosis (ie, <6 months lymphocyte doubling time);
• Autoimmune issues (eg, anemia);
• Symptoms resulting from the involvement of other tissues (eg, skin, kidney, or lung); or
• Severe disease-related symptoms, such as significant weight loss, fatigue, fevers, or night sweats.

Genetic Testing

To determine overall prognosis and the appropriate treatment, patients with CLL should undergo genetic testing to determine the presence of genetic abnormalities in cancerous cells, including⁴:

• Deletion of the short arm of chromosome 17 (or del[17p]);
• Mutation in the TP53 gene; 
• Deletion of the long arm of chromosome 11 (or del[11q]); and
• Mutation in the immunoglobulin heavy variable (IGHV) gene.

Generally, patients with del(17p) and/or TP53 mutations have an inferior prognosis and respond better to nonchemotherapy treatment, such as small molecule inhibitors, compared with patients without these genetic aberrations. Meanwhile, patients with IGHV mutations often fare better and typically respond well to combination chemoimmunotherapy consisting of fludarabine, cyclophosphamide, and rituximab.⁴

As additional genetic mutations can occur as the disease progresses, genetic testing should be repeated to guide subsequent CLL treatments following relapse or progression.⁴

Pharmacologic Management of Chronic Lymphocytic Leukemia

Depending on the patient’s genetic markers and overall health and age, CLL may respond well to several FDA-approved small molecule inhibitors, monoclonal antibodies, and standard chemotherapy agents as first-line therapy.

In the case of relapsed or refractory CLL, additional FDA-approved, second-line treatments in the form of targeted therapy or standard chemotherapy are available. However, some patients will not respond well to typical second-line chemoimmunotherapy, assuming⁴:

• Resistance to first-line chemoimmunotherapy develops;
• Progression occurs only 2 to 3 years after receiving fludarabine-based therapy; or 
• The presence of del(17p)/TP53 mutation-positive leukemia cells.

Patients with any of these factors should instead seek alternative regimens, clinical trials, or potentially allogeneic hematopoietic stem cell transplantation.⁴

In addition to genetic characterization, the selection of therapy may also depend on whether a patient prefers or requires continuous or fixed-duration treatment.⁵

Targeted Therapy

Small Molecule Inhibitor Therapy

Small molecule inhibitors currently approved for the treatment of CLL include Bruton tyrosine kinase (BTK) inhibitors, phosphoinositide 3 (PI3)-kinase inhibitors, and a B-cell lymphoma 2 (BCL2) inhibitor.⁶ Although many of the BTK and BCL2 inhibitors are common first-line CLL treatments, PI3-kinase inhibitors are instead used in the case of CLL relapse.⁵

First-Line Therapies

Common BTK inhibitors used for first-line treatment of CLL include acalabrutinib (in combination with the monoclonal antibody obinutuzumab), ibrutinib, and zanubrutinib. Alternatively, the BCL2 inhibitor venetoclax is commonly used in combination with obinutuzumab as a first-line therapy.⁵ Table 1 highlights the use, dosage, and administration of these preferred first-line small molecule inhibitor regimens.

Table 1. First-Line Small Molecule Inhibitor Therapy Regimens for Chronic Lymphocytic Leukemia

Regimen	Dosing	Treatment Duration	Indication
Acalabrutinib + obinutuzumab	Acalabrutinib 100 mg orally every 12 hours with water Obinutuzumab 1000 mg IV following cycle 1 ramp-up	28-day cycle until disease progression or unacceptable toxicity: Cycle 1 onward: Acalabrutinib Cycle 2: Obinutuzumab on day 1 (100 mg), day 2 (900 mg), day 8 (1000 mg), and day 15 (1000 mg) Cycles 3-7: Obinutuzumab on day 1	NCCN-preferred first- and second-line therapy for patients regardless of del(17p)/TP53 status
Ibrutinib	Ibrutinib 420 mg orally once daily with water Note: May be coadministered with rituximab, obinutuzumab, or bendamustine + rituximab	Until disease progression or unacceptable toxicity	NCCN-preferred first- and second-line therapy for patients regardless of del(17p)/TP53 status
Venetoclax + obinutuzumab	Venetoclax 400 mg orally once daily with food and water following 5-week ramp-up Obinutuzumab 1000 mg IV following cycle 1 ramp-up Note: Venetoclax includes a 5-week ramp-up dosing schedule to reduce risk of tumor lysis syndrome by administering 20 mg daily on week 1, 50 mg daily  on week 2, 100 mg daily on week 3, 200 mg daily on week 4, and a normal dose daily on week 5	28-day cycle for 12 cycles or until disease progression or unacceptable toxicity: Cycle 1: Ramp-up venetoclax, obinutuzumab on day 1 (100 mg), day 2 (900 mg), day 8 (1000 mg), day 15 (1000 mg) Cycle 2: Ramp-up venetoclax, obinutuzumab on day 1 Cycles 3-6: Venetoclax, obinutuzumab on day 1 Cycles 7-12: Venetoclax	NCCN-preferred first-line therapy for patients regardless of del(17p)/TP53 status
Zanubrutinib	Zanubrutinib 160 mg orally twice daily or 320 orally mg once daily with or without food	Until disease progression or unacceptable toxicity	NCCN-preferred first- and second-line therapy for patients regardless of del(17p)/TP53 status

IV = intravenous.

From NCCN treatment guidelines and FDA-approved prescribing information.^5,7-11

One important distinction between choosing a BTK inhibitor or venetoclax is the duration of treatment. While BTK inhibitors are given continuously, the combination of venetoclax and obinutuzumab has a fixed treatment duration.⁵

Ibrutinib is typically recommended for patients with severe comorbidities or who are older than 65 years.⁵

Second-Line Therapies

Although NCCN considers the regimens described above as the preferred or 2A category-recommended treatment in case of subsequent treatment, 2 PI3-kinase inhibitors and venetoclax as a single agent or in combination with rituximab are other regimens recommended by NCCN for patients with del(17p)/TP53 mutation-positive cancer and approved by the FDA in the case of relapse when other treatments cannot be used or have not previously worked.^5,12,13

Table 2. Second-Line Small Molecule Inhibitor Therapy Regimens for Chronic Lymphocytic Leukemia

Regimen	Dosing	Treatment Duration	Indication
Duvelisib	Duvelisib 25 mg orally twice daily	Until disease progression or unacceptable toxicity	NCCN-recommended second-line therapy for patients with del(17p)/TP53
Idelalisib + rituximab	Idelalisib 150 mg orally twice daily with or without food Rituximab 375 mg/m2 IV during cycle 1 and 500 mg/m2 IV afterward	28-day cycle until disease progression or unacceptable toxicity: Cycle 1: Ibrutinib, rituximab on day 1 Cycles 2-6: Ibrutinib, rituximab on day 1 Cycle 7 onward: Ibrutinib	NCCN-recommended second-line therapy for patients with del(17p)/TP53  Approved by the FDA for relapsed CLL in patients who cannot be treated with rituximab alone due to other health complications
Venetoclax	Venetoclax 400 mg orally once daily with food and water following 5-week ramp-up Note: Venetoclax includes a 5-week ramp-up dosing schedule to reduce risk of tumor lysis syndrome by administering 20 mg daily on week 1, 50 mg daily on week 2, 100 mg daily on week 3, 200 mg daily on week 4, and a normal dose daily on week 5	Until disease progression or unacceptable toxicity	NCCN-recommended second-line therapy for patients with del(17p)/TP53
Venetoclax + rituximab	Venetoclax 400 mg orally once daily with food and water following 5-week ramp-up Rituximab 375 mg/m2 IV during cycle 1 and 500 mg/m2 IV afterward	28-day cycle for 24 cycles until disease progression or unacceptable toxicity: Cycle 1:Venetoclax, rituximab on day 1 Cycles 2-6: Venetoclax, rituximab on day 1 Cycle 7 onward: Venetoclax	NCCN-preferred second-line therapy for patients regardless of del(17p)/TP53 status

CLL = chronic lymphocytic leukemia; FDA = United States Food & Drug Administration; IV = intravenously.

From NCCN treatment guidelines and FDA-approved prescribing information.^5,10,12-14

Monoclonal Antibody Therapy

Monoclonal anti-CD20 antibodies — such as obinutuzumab, ofatumumab, and rituximab — have all been approved alone or in combination with other monoclonal antibodies, small molecule inhibitors, or chemotherapy agents to treat CLL.^5,8,14,15 Alemtuzumab, an anti-CD52 monoclonal antibody, is also under investigation for the treatment of CLL and may potentially destroy remaining leukemia found in minimal residual disease, although researchers are unsure if doing so improves patient outcomes.^3,16 

Rituximab, when administered with other chemotherapy agents, is also approved by the FDA to be given in combination with hyaluronidase. Although hyaluronidase does not actively fight cancer, it can promote absorption of rituximab when administered subcutaneously.¹⁷

Although single-agent monoclonal antibody therapy has been less efficacious in clinical studies, NCCN still recommends single-agent monoclonal antibodies as an option for patients with significant comorbidities that prevent them from using other chemotherapy agents or small molecule inhibitors.⁵

Dosing and administration of common first- and second-line monoclonal antibody treatments are outlined in Table 3.

Table 3. First- and Second-Line Monoclonal Antibody Regimens for Chronic Lymphocytic Leukemia

Regimen	Dosing	Treatment Duration	Indication
Alemtuzumab + rituximab	Alemtuzumab 30 mg IV 3 times per week following 1-week ramp-up (3 mg, 10 mg, 30 mg) Rituximab 375 mg/m2 IV every other week	18 weeks: Alemtuzumab 3 times per week for 18 weeks total Rituximab every other week starting week 3, for total of 8 doses	NCCN-recommended first- and second-line therapy for patients with del(17p)/TP53 when BTK inhibitors and venetoclax are not appropriate
Obinutuzumab	Obinutuzumab 1000 mg IV following cycle 1 ramp-up	28-day cycle for 6 cycles or until disease progression or unacceptable toxicity: Cycle 1: Obinutuzumab on day 1 (100 mg), day 2 (900 mg), day 8 (1000 mg), day 15 (1000 mg) Cycles 2-6: Obinutuzumab on day 1	NCCN-recommended first- and second-line therapy for patients with del(17p)/TP53 when BTK inhibitors and venetoclax are not appropriate
Ofatumumab	Ofatumumab 2000 mg IV following ramp-up	12 doses: Dose 1: week 1 on day 1 (300 mg) Doses 2-8: every 1 week, starting 1 week after dose 1 Doses 9-12: every 4 weeks, starting 4 weeks after dose 8 Note: For refractory CLL	NCCN-recommended second-line therapy for patients with del(17p)/TP53 when BTK inhibitors and venetoclax are not appropriate
Rituximab (+ HDMP)	Rituximab 375 mg/m2 IV during cycle 1 and 500 mg/m2 IV afterward	28-day cycle for 6 cycles until disease progression or unacceptable toxicity: Cycles 1-6: Rituximab on day 1	NCCN-recommended first- and second-line therapy regardless of del(17p)/TP53 status when BTK inhibitors and venetoclax are not appropriate

HDMP = high-dose methylprednisolone; IV = intravenously.

From NCCN treatment guidelines, FDA-approved prescribing information, and primary literature.^5,8,14,16,18

Rituximab is often administered with high-dose methylprednisolone, a corticosteroid administered to help alleviate some of the common adverse reactions that occur with immunotherapies.⁵

In addition, rituximab and obinutuzumab are commonly used alongside different first-line treatment regimens, including acalabrutinib, venetoclax, bendamustine, chlorambucil, fludarabine, and others. Administration and dosing of such regimens are described in tables in the “Small Molecule Inhibitor Therapy” or “Chemotherapy” sections, as appropriate.

Chemotherapy

CLL is often treated using standard chemotherapy, which can consist of alkylating agents — including bendamustine hydrochloride, cyclophosphamide, and chlorambucil — and purine analogs, such as fludarabine phosphate. When treating CLL, these drugs are typically administered concurrently with an immunotherapy, such as rituximab or obinutuzumab, because chemoimmunotherapy often results in better outcomes than chemotherapy alone.

Genetic testing can help guide which first-line or subsequent chemoimmunotherapy regimen should be chosen. For example, patients with the IGHV gene mutation often perform well on combination fludarabine, cyclophosphamide, and rituximab, while patients who are del(11q)-positive should avoid using fludarabine alone, as they often respond better to chemotherapy regimens that include alkylating agents.⁵

Dosing and administration of common chemotherapy and chemoimmunotherapy regimens are described in Table 4.

Table 4. First- and Second-Line Chemoimmunotherapy Regimens for Chronic Lymphocytic Leukemia

Regimen	Dosing	Treatment Duration	Indication
Bendamustine + anti-CD20 antibody (obinutuzumab or rituximab)	Bendamustine 90 mg/m2 IV Obinutuzumab 1000 mg IV following ramp-up Rituximab 500 mg/m2 IV following ramp-up	28-day cycle for 6 cycles: Cycle 1: Bendamustine on days 2 and 3; obinutuzumab on day 1 (100 mg), day 2 (900 mg), day 8 (1000 mg), and day 15 (1000 mg); OR rituximab on day 1 (375 mg/m2) Cycles 2-6: Bendamustine on days 1 and 2, obinutuzumab on day 1 OR rituximab on day 1	NCCN-recommended first-line therapy for patients without del(17p)/TP53
Chlorambucil + obinutuzumab	Chlorambucil 0.5 mg/kg body weight orally Obinutuzumab 1000 mg IV	28-day cycle for 6 cycles: Cycle 1: Chlorambucil on day 1 and 15, obinutuzumab on day 1, day 8, and day 15 Cycles 2-6: Chlorambucil on days 1 and 15, obinutuzumab on day 1	NCCN-recommended first-line therapy for patients without del(17p)/TP53
Fludarabine + cyclophosphamide + rituximab	Fludarabine 25 mg/m2 IV Cyclophosphamide 250 mg/m2 IV Rituximab 375 mg/m2 IV during cycle 1 and 500 mg/m2 IV afterward	28-day cycle for 6 cycles: Cycle 1: Fludarabine on days 2 and 4, cyclophosphamide on days 2 and 4, rituximab on day 1 Cycles 2-6: Fludarabine on days 1 and 2, cyclophosphamide on days 1 and 3, rituximab on day 1	NCCN-recommended first- and second-line therapy for patients with IGHV gene mutations
Fludarabine + rituximab	Fludarabine 25 mg/m2 IV Rituximab 375 mg/m2 IV during cycle 1 and 500 mg/m2 IV afterward	28-day cycle for 6 cycles: Cycle 1: Fludarabine on days 2 and 4, rituximab on day 1 Cycles 2-6: Fludarabine on days 1 and 2, rituximab on day 1	NCCN-recommended first-line therapy for patients without del(17p)/TP53

IGHV = immunoglobulin heavy variable; IV = intravenously.

From NCCN treatment guidelines, FDA-approved prescribing information, and clinical trial literature.^5,8,14,19-25

Historically, NCCN recommended coadministration of chlorambucil with obinutuzumab, ofatumumab, or rituximab; however, but NCCN has now determined that obinutuzumab outperforms rituximab, based on outcomes from clinical studies.⁵

Corticosteroids

Corticosteroids are often given alongside chemotherapy as palliative therapy. Specifically, dexamethasone and prednisone are approved by the FDA for administration during CLL treatment to reduce inflammation.⁶ These agents are often given concurrently with numerous chemoimmunotherapy medications, including rituximab or cyclophosphamide.⁵

Monitoring Side Effects, Adverse Events, and Drug-Drug Interactions

Treatments for CLL are associated with a variety of side effects, drug-drug interactions, and considerations for special populations, as described in Tables 5-8.

Table 5. Side Effect Profile for Small Molecule Inhibitor Therapy

Drug	Adverse Events	Drug-Drug Interactions	Special Population Considerations
Acalabrutinib	Common reactions: Anemia, neutropenia, upper respiratory infection, thrombocytopenia, headache, diarrhea, musculoskeletal pain Warnings: Serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies (eg. skin cancers), atrial fibrillation and flutter	Avoid use of CYP3A inhibitors or inducers with acalabrutinib; if this is not possible, acalabrutinib dosage should be reduced with inhibitors or increased with inducers	Acalabrutinib should not be used in pregnant or breastfeeding patients; avoid in patients with hepatic impairment
Duvelisib	Common reactions: Diarrhea, colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, anemia Warnings: Serious infections, serious diarrhea or colitis, serious cutaneous reactions, serious pneumonitis, hepatotoxicity, neutropenia, embryo-fetal toxicity	Avoid use of CYP3A inducers with duvelisib; if using CYP3A inhibitors or substrates with duvelisib, monitor for signs of toxicities and consider reducing duvelisib dose when coadministered with inhibitors	Duvelisib should not be used in pregnant or breastfeeding patients
Ibrutinib	Common reactions: Thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising Warnings: Hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension, second primary malignancies (eg, skin cancers), TLS, embryo-fetal toxicity	Avoid use of CYP3A inhibitors or inducers with ibrutinib or modify ibrutinib dose	Ibrutinib should not be used in pregnant or breastfeeding patients; avoid or use lower dose in patients with hepatic impairment
Idelalisib	Common reactions: Diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, rash Warnings: Serious hepatotoxicity, serious diarrhea or colitis, serious pneumonitis, serious intestinal perforation, severe cutaneous reactions, anaphylaxis, neutropenia, embryo-fetal toxicity	Avoid use of CYP3A inducers or substrates with idelalisib	Idelalisib should not be used in pregnant or breastfeeding patients; monitor patients with hepatic impairment for complications
Venetoclax	Common reactions: Neutropenia, diarrhea, nausea, anemia, upper respiratory infection, thrombocytopenia, fatigue Warnings: TLS, neutropenia, immunizations, embryo-fetal toxicity	Avoid use of CYP3A inhibitors and inducers with venetoclax or adjust venetoclax dose; avoid use of P-gp inhibitors or substrates with venetoclax	Venetoclax should not be used in pregnant or breastfeeding patients
Zanubrutinib	Common reactions: Upper respiratory infection, hemorrhage, musculoskeletal pain Warnings: Hemorrhage, infections, cytopenia, second primary malignancies (eg, skin cancers), cardiac arrhythmias, embryo-fetal toxicity	Avoid use of CYP3A inhibitors or inducers with zanubrutinib or adjust dose of zanubrutinib	Zanubrutinib should not be used in pregnant or breastfeeding patients; use a lower dose in patients with severe hepatic impairment

P-gp = P-glycoprotein; TLS = tumor lysis syndrome.

From FDA-approved prescribing information.^7,9-13

Table 6. Side Effect Profile for Monoclonal Antibody Therapy

Drug	Adverse Events	Drug-Drug Interactions	Special Population Considerations
Alemtuzumab	Common reactions: Cytopenias, infusion reactions, cytomegalovirus and other infections, nausea, emesis, diarrhea, insomnia Warnings: Serious cytopenias, serious infusion reactions, serious infections	None indicated	The effects of alemtuzumab have not been investigated in patients who are pregnant or breastfeeding
Obinutuzumab	Common reactions: Infusion-related reactions, neutropenia Warnings: Hepatitis B virus reactivation, PML, infusion-related reactions, hypersensitivity reactions (eg, serum sickness), TLS, infections, neutropenia, thrombocytopenia, immunization, embryo-fetal toxicity	None indicated	Obinutuzumab should not be used in pregnant or breastfeeding patients Patients positive for hepatitis B virus should be monitored for reactivation
Ofatumumab	Common reactions: Infusion reactions, neutropenia Warnings: Hepatitis B virus reactivation, PML, infusion reactions, TLS, cytopenias	None indicated	Ofatumumab should not be used in pregnant patients
Rituximab	Common reactions: Infusion-related reactions, neutropenia Warnings: Fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, PML, TLS, infections, cardiac adverse reactions, renal toxicity, bowel obstruction, immunizations, embryo-fetal toxicity	Avoid use of cisplatin with rituximab because of resulting toxicity	Rituximab should not be used in pregnant or breastfeeding patients; no benefit has been observed when using rituximab with fludarabine and cyclophosphamide in geriatric populations

PML = progressive multifocal leukoencephalopathy; TLS = tumor lysis syndrome.

From FDA-approved prescribing information.^8,14-16

Table 7. Side Effect Profile for Chemotherapy

Drug	Adverse Events	Drug-Drug Interactions	Special Population Considerations
Bendamustine hydrochloride	Common reactions: Pyrexia, nausea, vomiting, lymphopenia, anemia, leukopenia, thrombocytopenia, neutropenia Warnings: Myelosuppression, infections, infusion reactions, TLS, skin reactions, other malignancies, embryo-fetal toxicity	Avoid use of CYP1A2 inducers and inhibitors with bendamustine	Bendamustine should not be used in pregnant or breastfeeding patients; avoid  using or lower dose in patients with hepatic or renal impairment
Chlorambucil	Common reactions: Bone marrow suppression, anemia, leukopenia, neutropenia, thrombocytopenia, pancytopenia Warnings: Bone marrow suppression, secondary malignancies, embryo-fetal toxicity	None indicated	Chlorambucil should not be used in pregnant or breastfeeding patients
Cyclophosphamide	Common reactions: Neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, diarrhea Warnings: Myelosuppression, urinary tract and renal toxicity, cardiotoxicity, pulmonary toxicity, secondary malignancies, veno-occlusive liver disease, embryo-fetal toxicity	Use of protease inhibitors with cyclophosphamide may require dosage adjustments Use of ACE inhibitors, natalizumab, paclitaxel, thiazide diuretics, or zidovudine with cyclophosphamide may result in an increased risk of hematotoxicity or immunosuppression Use of anthracyclines, cytarabine, pentostatin, or trastuzumab with cyclophosphamide may result in an increased risk of cardiotoxicity Use of amiodarone or GM-CSF with cyclophosphamide may result in an increased risk of pulmonary toxicity Use of amphotericin B or indomethacin with cyclophosphamide may result in an increased risk of nephrotoxicity Use of azathioprine, busulfan, or protease inhibitors with cyclophosphamide may result in an increased risk of other toxicities	Cyclophosphamide should not be used in pregnant or breastfeeding patients; patients with renal impairment should be monitored for complications
Fludarabine phosphate	Common reactions: Myelosuppression, fever, infection, nausea, vomiting, fatigue, anorexia, cough, weakness Warnings: CNS toxicity, hemolytic anemia, pulmonary toxicity, bone marrow suppression, transfusion-associated graft-vs-host disease, infections, TLS, embryo-fetal toxicity	Avoid use of pentostatin with fludarabine phosphate because of risk of pulmonary toxicities	Fludarabine phosphate should not be used in pregnant patients; avoid using or lower dose in patients with renal impairment

ACE = angiotensin-converting enzyme; CNS = central nervous system; GM-CSF = granulocyte-macrophage colony-stimulating factor; TLS = tumor lysis syndrome.

From FDA-approved prescribing information.^22-25

Table 8. Side Effect Profile for Palliative Corticosteroid Therapy

Drug	Adverse Events	Drug–Drug Interactions	Special Population Considerations
Dexamethasone	Common reactions: Cardiovascular, dermatologic, fluid and electrolyte disturbances, GI, metabolic, musculoskeletal, neurologic, ophthalmic, abnormal fat deposits, decreased resistance to infection, hiccups, infertility, malaise, moon face, weight gain Warnings: Alterations in endocrine function, immunosuppression, alteration in cardiovascular/renal function, venous and arterial thromboembolism, ophthalmic effects, GI perforation, osteoporosis, behavioral and mood disturbance, Kaposi sarcoma, embryo-fetal toxicity	Avoid use of CYP3A inhibitors or inducers with dexamethasone Use of estrogen-containing therapies with dexamethasone may increase risk of thromboembolism	Dexamethasone should not be used in pregnant or breastfeeding patients
Prednisone	Common reactions: Fluid retention, alteration in glucose tolerance, hypertension, behavioral changes, weight gain Warnings: HPA axis suppression, infection, hypertension, GI perforation, behavioral disturbances, decreased bone density, ophthalmic effects, embryo-fetal toxicity	The effects of anticoagulant and antidiabetic agents may change with concurrent use of prednisone Use of CYP3A4 inducers and inhibitors with prednisone may require dose adjustment Use of cyclosporine and NSAIDs with prednisone may increase risk of other side effects	Prednisone should not be used in pregnant or breastfeeding patients

GI = gastrointestinal; HPA = hypothalamic-pituitary-adrenal; NSAIDs = nonsteroidal anti-inflammatory drugs.

From FDA-approved prescribing information.^26,27

Considerations for Specific Populations

When determining the best treatment for CLL, patients are often separated into comorbidity categories based on genetic markers, age, and overall health⁵:

• High-risk patients who are 65 years of age and older or have significant comorbidities
• Lower-risk patients who are younger than 65 years or do not have significant comorbidities

High-risk patients are less likely to be given chemoimmunotherapy and instead are often treated using first-line targeted therapies. In contrast, lower-risk patients are better able to withstand the complications that occur with chemoimmunotherapy. The presence or absence of IGHV gene mutations can heavily influence whether a patient is likely to benefit from chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR).⁵

The presence of del(17p) or TP53 mutation also suggests that patients are high-risk and are not likely to respond to chemoimmunotherapy. Patients in this category are often given the following treatment options³:

• Ibrutinib
• Combination venetoclax and obinutuzumab

Chronic Lymphocytic Leukemia Guidelines

The following guidelines are available to assist clinicians in the management of their patients with CLL: 

• The 2023 NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma⁵;
• The 2020 Chronic Lymphocytic Leukaemia: ESMO Clinical Practice Guidelines for Diagnosis, Treatment, and Follow-Up²⁸; and
• The 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines for Diagnosis, Indications for Treatment, Response Assessment, and Supportive Management of CLL.⁴

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Author Bio

Sierra Lear, PhD earned a Bachelor of Science degree in chemical engineering and neuroscience from Tulane University and will graduate with a PhD in bioengineering from the University of California, Berkeley and the University of California, San Francisco in September 2023. She has spent a decade in the lab developing gene editing and other molecular tools to understand and treat different diseases.