Chronic Lymphocytic Leukemia

Etiology

The exact etiology of CLL is unknown. Genetic factors, rather than environmental factors, are the most likely cause of CLL. However, a few known risk factors for CLL include occupational causes by exposure to certain chemicals, radiation exposure, and tobacco use. Reports of farmers working around rubber manufacturing facilities and of workers exposed to benzene and other heavy solvents have shown an increased risk of CLL/SLL. However, these associations have not yet been proven. In atomic bomb survivors, no known increase in the incidence of CLL/SLL has been noted. However, there has been an increased risk of other types of leukemia. The uranium mining population, which is exposed to ionizing and non-ionizing radiation, has shown increased CLL incidence. Tobacco users and cigarette smokers show a significantly elevated risk of CLL compared to non-tobacco users. The Veterans Affairs recognizes CLL as having a relationship to exposure to Agent Orange or other herbicides during military service.[1][2][3][4][5][6][7][8][9][10]

Epidemiology

CLL comprises 25 to 30% of total leukemias in the United States. According to the American Cancer Society, there were approximately 21,040 new cases of CLL and about 4,060 deaths in 2020. Worldwide, 191,000 cases and 61,000 deaths are attributed to CLL/SLL every year. CLL can affect adults as young as 30. However, it is most commonly seen in adults, with an average age of 70 years. CLL is extremely rare in children. The incidence is known to increase rapidly with age. CLL has a slightly higher incidence in male populations than female populations (1.3 to 1 to 1.7 to 1). However, studies have shown that women can have a more aggressive form of the disease than men.[11][12][13]

The incidence of CLL varies by geographic location and race. CLL is most commonly seen in adults in Western populations. It is high amongst the Caucasian population compared to the Asian Pacific Islanders or the African-American population. The incidence of CLL in Western countries is similar to that in the United States, but it is rare in Asian countries (China and Japan). CLL is common amongst the Jews of Eastern European descent. It is most commonly seen in Non-Hispanic Whites and least common in Asians. The incidence in African Americans is between those of the Caucasian and the Asian ethnic groups.[12][14][15][16][17][18][19]

CLL is reported to have a genetic basis and is known to run in families (familial CLL). The age at diagnosis of the second-generation offspring is nearly 20 years younger as compared to the parent. First-degree relatives (siblings, children, or parents) of CLL patients have double the risk for CLL. Moreover, 17% of first-degree family members of CLL patients had monoclonal B cell lymphocytosis, which is a precursor of CLL. Ultimately, only a small percentage of patients with monoclonal B-cell lymphocytosis (MBL) develop into CLL.[20][21][22]

Pathophysiology

The pathogenesis of CLL/SLL is a 2-step process that leads to the clonal replication of malignant B lymphocytes. The first step is the development of MBL cells secondary to multiple factors such as antigenic stimulation, genetic mutations, and cytogenetic abnormalities. The second step is the progression of MBL to CLL/SLL due to a further insult to the B-cell clone, either from additional genetic abnormalities or changes in the bone marrow microenvironment. B-cell antigen receptor (BCR) expression induces antigen-independent, cell-autonomous signaling, an important step in the pathogenesis of CLL.[23][24]

In CLL, CD5+ B cells are continuously activated by mutations leading to MBL. The accumulation of genetic abnormalities in more mature B cells leads to clonal expansion of neoplastic B cells within the lymph nodes. In CLL/SLL, the most common abnormal physical examination finding is lymphadenopathy, which is seen in 50% to 90% of patients. Cervical, supraclavicular, and axillary lymph nodes are the most commonly affected sites. These increased B cells eventually spill into the peripheral blood, leading to lymphocytosis on a CBC.[25][26][27]

These neoplastic B cells escape apoptosis and continue to divide over time within the lymph nodes. They then infiltrate the spleen and bone marrow, causing splenomegaly and hypercellular bone marrow (on bone marrow biopsy). Splenomegaly increases sequestration of RBCs and platelets, leading to anemia and thrombocytopenia by decreasing the number of RBCs and platelets. Patients are more susceptible to autoimmune hemolytic anemia (positive Coombs test) and autoimmune thrombocytopenia. These B cells eventually spread throughout the body, causing systemic symptoms such as fever, night sweats, unintentional weight loss, fatigue, and early satiety. A lack of functional B cells reduces the body's ability to mount immune responses, leading to hypogammaglobulinemia and an increased risk of infection.[28][29][30][31][32]

Skin is the most commonly affected nonlymphoid tissue in patients with CLL. Leukemia cutis (skin lesions) mainly involves the face and manifests as papules, macules, plaques, ulcers, blisters, or nodules. A skin biopsy can help confirm the diagnosis of CLL. Nonspecific secondary cutaneous lesions may occur due to bleeding, vasculitis, and infection. Exaggerated reactions to insect bites have also been reported in patients.[33][34][35][36]

Histopathology

The first and foremost laboratory abnormality in CLL is peripheral blood and bone marrow lymphocytosis. The peripheral blood smear shows leukemic cells, which are small, mature lymphocytes with darkly stained nuclei, condensed chromatin, and indistinguishable nucleoli, with a narrow rim of basophilic cytoplasm. Classical "smudge" cells ("basket" cells) are also seen on peripheral blood smear; these are pathognomic of CLL. Smudge cells are more fragile than normal lymphocytes and are disrupted during the process of being spread on a glass slide.[25][37]

Immunophenotypic analysis of peripheral circulating lymphocytes by flow cytometry can be performed to help diagnose CLL. Most cases of CLL can be identified using antibody specific panel for CD5, CD19, CD20, CD23, and immunoglobulin light chains. Characteristic CLL/SLL lymphocyte phenotype features include the following: low levels of immunoglobulins (most often IgM immunoglobulin and sometimes both IgM and IgD); expression of B-cell-associated antigens (CD19, CD20, CD21, CD23, and/or CD24); and expression of CD5, which is a T-cell-associated antigen. The most common immunophenotype expression of CLL/SLL is the coexpression of CD5, CD19, and CD23. As for light-chain immunoglobulins, only 1 type is present, suggesting monoclonality of the lymphocytes. However, in some cases, biclonal CLL expressing both light chains or exhibiting different levels of expression of other immunophenotypic antigens is also seen.[38][39][25][40][41][42][43]

Fluorescence in situ hybridization (FISH) is a highly sensitive test used to detect chromosomal abnormalities in patients with CLL/SLL. Cytogenetic evaluation of the peripheral blood smear with FISH for 17p. deletion, 11q. deletion, 13q. Deletion and trisomy 12 are routinely evaluated in patients with CLL. Though all patients with symptomatic and advanced-stage CLL/SLL are treated similarly, patients with 17p. deletion or 11q. Deletion requires special consideration.[44][45][46]17p deletion causes CLL by TP53 mutation. TP53 is a tumor suppressor gene that is located on the short arm of chromosome 17. The normal "wild–type" TP53 gene is activated in response to damaged DNA and/or other stressors, such as hypoxia, leading to cellular apoptosis. Deletion or point mutation of TP53 leads to CLL. The 11q chromosome contains the ataxia-telangiectasia mutated (ATM) gene. ATM kinase is responsible for delaying cell cycle progression in response to DNA damage, allowing the cell to repair the damage. ATM kinase phosphorylates the tumor suppressor p53 protein in the presence of DNA damage. The phosphorylation of the p53 protein ultimately leads to cell cycle arrest/apoptosis of cells with DNA damage. In the absence of ATM kinase in 11q. In deletion, phosphorylation of p53 does not occur, which prevents cell cycle arrest in DNA-damaged cells.[44][47][48][49][50]

History and Physical

Patients with CLL are often asymptomatic at the initial presentation, when a routine CBC reveals abnormal lymphocytosis, leading to a CLL diagnosis. Approximately 5 to 10% of patients with CLL are symptomatic with B symptoms such as Fever of > 100.5° F for > 2 weeks with no evidence of infection; unintentional weight loss of >/= 10% of body weight over the last 6 months; drenching night sweats with no evidence of infection; extreme fatigue; and early satiety.[25]

Upon physical examination, 50 to 90% of patients with CLL present with localized/generalized lymphadenopathy. The most common sites include cervical, supraclavicular, and axillary lymph nodes. On palpation, the nodes are firm, non-tender, round, and freely mobile. Splenomegaly is the second most commonly enlarged lymphoid organ, seen in 25 to 55% of cases. On palpation, it is painless and non-tender with a smooth, firm surface. Hepatomegaly is seen in 15% to 25% cases. The liver is mildly enlarged and palpated 2-6 cm below the right costal margin. On palpation, the liver is firm and non-tender with a smooth surface.[26][27]

Skin examination is an important part of physical examination because skin cancers are a relatively frequent CLL complication. Skin is the most common non-lymphoid tissue involved in patients with CLL. Leukemia cutis (skin lesions) mainly involve the face and manifest as papules, macules, plaques, ulcers, blisters, or nodules. A skin biopsy can help confirm the diagnosis of CLL. Nonspecific secondary cutaneous lesions may occur due to bleeding, vasculitis, and infection. Exaggerated reactions to insect bites have also been reported in patients.[33][34][35][36]

Infiltration of the spleen and bone marrow with neoplastic B cells causes splenomegaly and hypercellular bone marrow. Splenomegaly increases sequestration of RBCs and platelets, leading to anemia and thrombocytopenia by decreasing the number of RBCs and platelets. Patients with anemia are symptomatic with fatigue and shortness of breath; patients with thrombocytopenia easily bleed/bruises, and petechiae can be seen on physical examination. A lack of functional B cells reduces the body's ability to mount immune responses, leading to hypogammaglobulinemia and an increased risk of infection.[28][29][30][31][32]

Evaluation

The first step in diagnosing CLL is a peripheral blood smear. The peripheral blood smear shows an absolute lymphocyte count greater than 5000/mcL and smudge cells, confirming CLL. Although the diagnostic criteria for CLL are >=5000/mcL B lymphocytes on peripheral smear, a large proportion of patients present with an absolute lymphocyte count > 100,000/mcL. In patients with SLL, peripheral blood smear shows an absolute lymphocyte count of less than 5000/mcL along with lymphadenopathy but without cytopenias. However, a lymph node biopsy is required to confirm the diagnosis of SLL.[25][51]

Immunophenotypic analysis of peripheral circulating lymphocytes by flow cytometry can be performed to help confirm the clonality of circulating B cells in CLL patients. Flow cytometry can be performed on both peripheral blood and bone marrow aspirate to look for the classical immunophenotypic markers of CLL. To reiterate, characteristic CLL/SLL lymphocyte phenotype features include low levels of immunoglobulins (most often IgM immunoglobulin and sometimes both IgM and IgD); expression of B-cell-associated antigens (CD19, CD20, CD21, CD23, and/or CD24); and expression of CD5, which is a T-cell-associated antigen. The most common immunophenotype expression of CLL/SLL is the coexpression of CD5, CD19, and CD23. However, different levels of expression of other immunophenotypic antigens are also seen. Serum immunoglobulins and free light chains are measured at baseline to assess immunodeficiency and during treatment to assess immune reconstitution, especially with newer-generation B-cell receptor signaling drugs. As for light chain immunoglobulins, only 1 type indicates monoclonality of the lymphocytes. Rarely, some patients express both kappa and lambda light chains, known as "biclonal CLL."[25][38][39][40][41][42][43]

FISH is a highly sensitive test used to detect chromosomal abnormalities in patients with CLL/SLL. Although not needed for diagnosis, bone marrow aspiration and biopsy are often done as part of a diagnostic workup or before treatment. If the biopsy specimen demonstrates greater than 30% lymphocytes of all nucleated cells in a normocellular/hypercellular bone marrow aspirate, this confirms the diagnosis of CLL. The reduction of lymphocytic infiltration to less than 30% on treatment indicates a complete response. Furthermore, 3 infiltrative patterns of lymphocytes have been recognized in the bone marrow biopsy specimens: nodular, interstitial, and diffuse. A biopsy sample can demonstrate a mixture of nodular and interstitial, or nodular and diffuse patterns. Studies have shown that patients with a diffuse biopsy pattern tend to have advanced disease and a poor prognosis, whereas patients with nodular or interstitial patterns ("non-diffuse" category) have a better prognosis.[52][53][54]

Excisional lymph node histology demonstrates diffuse effacement of the nodal architecture, with scattered residual structures likely representing germinal centers. These lymph node infiltrates are predominantly composed of small lymphocytes. However, large lymphoid cells, such as pro-lymphocytes, are always present in clusters and form "pseudo-follicles" (proliferation centers), a pathognomic finding, and are found in CLL/SLL patients. Spleen histology demonstrates infiltration of red and white pulp, with a more prominent white pulp involvement than red pulp. From an imaging standpoint, a CT scan helps evaluate the degree of lymphadenopathy and organ infiltration, as reflected in spleen and liver size.[25]

Diagnoses of CLL complications, such as autoimmune hemolytic anemia, include a positive direct antiglobulin (Coombs) test, increased reticulocyte count, elevated serum LDH, reduced haptoglobin, and elevated serum indirect bilirubin. Diagnosis of further complications, such as pure red cell aplasia and thrombocytopenia, can be made by a peripheral blood smear and a bone marrow aspiration and biopsy. Hypogammaglobulinemia (in less than 15% of cases), elevated uric acid levels, and elevated hepatic enzymes are other findings seen in CLL. Important lab studies include serum lactate dehydrogenase (LDH) and beta-2 microglobulin (measured with creatinine, as it can be elevated in patients with elevated creatinine), which correlate with disease activity.[55]

Treatment / Management

Not all patients diagnosed with CLL require treatment, as CLL is a heterogeneous disease. Some patients receiving no treatment have survival rates similar to those of the general population; current treatment regimens cannot cure CLL, except for allogeneic hematopoietic stem cell transplantation (HCT). Randomized controlled trials comparing immediate versus delayed treatment found no significant improvement in long-term survival with early treatment initiation.[56][57](A1)

According to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for "active disease," indications for treatment include:

• Constitutional symptoms in patients include fevers >100.5° F (38.0° C) for ≥2 weeks without evidence of infection, night sweats for ≥1 month without evidence of infection, unintentional weight loss of ≥10% within the previous 6 months, extreme fatigue, and early satiety. 
• Progressive lymphocytosis with >50% increase in lymphocytes over a 2-month period or lymphocyte doubling time (LDT) of <6 months. LDT is obtained by linearly extrapolating absolute lymphocyte counts at every 2-week interval over a time span of 2 to 3 months. Patients with initial blood lymphocyte counts of <30,000/mcL may need to be observed for a longer time period to help determine the LDT. Also, other factors contributing to lymphocytosis/lymphadenopathy (e.g., infection) other than CLL should be excluded.
• Patients with rapid disease progression, such as massive (ie, ≥6 cm below the left costal margin)/progressive/symptomatic splenomegaly or massive nodes (ie, ≥10 cm in longest diameter)/progressive/symptomatic lymphadenopathy.
• Autoimmune hemolytic anemia and/or autoimmune thrombocytopenia that is poorly responsive or unresponsive to corticosteroids. 
• Evidence of progressive bone marrow failure by developing/worsening/symptomatic anemia and/or thrombocytopenia.
• Patients with recurrent infections.[25]

Treatment of CLL is further classified into; 

A. Patients without "active disease": This is further divided into early-stage asymptomatic CLL and localized SLL.

1. Early-stage asymptomatic CLL

• Initial observation as standard care: For CLL patients who are asymptomatic or have early-stage disease (e.g., Rai stage <3, Binet stage A or B), observation is the standard of care, as they do not require treatment. During this observation period, the patient's clinical examination and blood counts should be performed every 3 months. Based on these evaluations, at the end of 12 months, a decision is to be made on whether the patient requires aggressive treatment or should continue observation. Several randomized controlled trials support observation over aggressive treatment in patients with asymptomatic/early-stage CLL.[57][58]
• International Prognostic Score for Early-stage CLL (IPS-E): Some early-stage CLL patients may require treatment within the first few years of diagnosis, while others remain asymptomatic without treatment for many years. The International Prognostic Score for Early-stage CLL (IPS-E) uses 3 variables (unmutated IGHV, lymphocytes >15,000/mcL, palpable lymph nodes) to further divide patients with early-stage CLL into 3 groups based on the number of risk factors to evaluate treatment requirement at 1 and 5 years:
  • Low risk (no risk factors) – <1 percent treated at 1 year; 8 percent treated at 5 years
  • Intermediate risk (one risk factor) – 3 percent treated at 1 year; 28 percent treated at 5 years
  • High risk (2 or 3 risk factors) – 14 percent treated at 1 year; 61 percent treated at 5 years [59] 
(A1)

2. Localized SLL

• Some patients present with small lymphocytic lymphoma (SLL), which involves a single lymph node site. First-line management for localized SLL is similar to that of patients with early-stage asymptomatic CLL, which is observation unless there is clear evidence of "active disease" for which radiation therapy is used. In patients with stage I SLL contemplating radiation therapy, extensive pretreatment staging evaluation with imaging and bone marrow biopsy is required to rule out extensive disease involvement. Limited data are available from small retrospective studies on the use of radiation therapy in localized SLL.[60]

B. Patients with Active Disease

The main purpose of systemic therapy is to provide symptomatic relief, prolonged remission, and prolonged survival for patients. Symptomatic CLL is treated, and despite many recent advances, it remains an incurable disease. For patients for whom treatment is considered, a pre-treatment assessment should be performed, including information on age and general health, other features such as TP53 abnormalities or adverse cytogenetics, relapsed disease, and treatment-naive status. The selection of initial therapy in patients with symptomatic/advanced CLL is based on the patient, patient preference, tumor characteristics, and therapy goals. Various treatment approaches for CLL use different combinations of the following agents. These agents differ significantly in their rates of time to progression, measurable residual disease (MRD), complete remission, and drug toxicities. There have been studies comparing different treatment modalities, and an individualized approach is warranted. Hence, patient preference plays a vital role in the ultimate treatment decision. Various drugs utilized in the management of CLL include;

• Bruton tyrosine kinase inhibitors (ibrutinib, acalabrutinib)
• BCL-2 inhibitor (venetoclax)
• Purine analogs (fludarabine, pentostatin)
• Alkylating agents (cyclophosphamide, chlorambucil, bendamustine)
• Monoclonal antibodies (rituximab, ofatumumab, obinutuzumab)
• PI3K inhibitor (idelalisib)

Choice of Therapy: The preferred initial treatment is based on tumor genetic risk stratification and patient fitness assessment.

1. Genetic risk stratification is described as follows:

1. Very high-risk disease: 17p deletion and/or TP53 mutations
2. High-risk disease: IGHV unmutated (without 17p deletion and TP53 mutation)
3. Standard-risk disease: IGHV mutated (without 17p deletion and TP53 mutation)

2. Fitness Assessment: includes an assessment of comorbidities and the impact of these comorbidities on general function, liver function, and kidney function. Tools used for this assessment include the Eastern Cooperative Oncology Group performance status (ECOG PS), Cumulative Illness Rating Scale (CIRS), geriatric assessment tools, and creatinine clearance to estimate renal function. Eligibility for targeted agents varies depending on the agent's toxicity and the predicted tolerability based on the patient's general fitness and comorbidities. Eligibility is more restrictive for chemoimmunotherapy. Patients are usually considered unfit for chemoimmunotherapy with intense regimens such as fludarabine, cyclophosphamide, and rituximab (FCR) if they have 1 or more of the following findings: ECOG PS of >/=2, CIRS >6, significant hepatic impairment (Child-Pugh class B or C), and creatinine clearance (CrCl) <70 mL/min.[61](A1)

a. Very high-risk disease: 17p deletion and/or TP53 mutations: These patients are at high risk of not responding to initial treatment with chemoimmunotherapy, or relapsing immediately after achieving remission. Initial treatment options include:

• Single-agent ibrutinib until progression (all ages)–is preferred based upon good tolerability of the drug, longer follow-up, and high response rates.
• Ibrutinib plus rituximab until progression (younger patients)– studies have shown that the addition of rituximab improved outcomes in younger adults compared to older adults.[62]
• Fixed duration venetoclax plus obinutuzumab for 1 year (all ages) [63][64]
• Single-agent venetoclax until progression (all ages)
• Single-agent acalabrutinib until progression (all ages)

b. High-risk disease: IGHV unmutated (without 17p deletion and TP53 mutation): These patients do respond to initial treatment with chemoimmunotherapy; however, targeted agents are preferred due to an improvement in progression-free survival (PFS) and overall survival (OS) benefit compared to other chemoimmunotherapy. The treatment of choice is strongly guided by patient preference and comorbidities. Initial treatment options include:

• Single-agent ibrutinib until progression (all ages)
• Ibrutinib plus rituximab until progression (younger patients)
• Fixed duration venetoclax plus obinutuzumab (all ages, use in younger patients extrapolated from trials in older adults)
• Acalabrutinib until progression (all ages)

c. Standard-risk disease: IGHV mutated (without 17p deletion and TP53 mutation): In these patients, PFS and overall survival appear to be similar regardless of targeted therapy or chemoimmunotherapy being used in the patient. These patients are further categorized as Fit or Unfit based on their Fitness assessment.

Fit Patients: Clinically fit patients with IGHV-mutated CLL without 17p deletion or TP53 mutation may choose targeted therapy or chemoimmunotherapy, depending on patient preference and Fitness assessment. Intensive Chemoimmunotherapy (FCR or BR) may be preferred by patients desiring a long treatment-free interval. Options include:

• Fludarabine, cyclophosphamide, and rituximab (FCR for 6 cycles (younger patients).
• Bendamustine plus rituximab (BR) for 6 cycles (older patients).
• Ibrutinib as a single agent (all ages) or in combination with rituximab or obinutuzumab (younger patients).
• Fixed duration venetoclax plus obinutuzumab (all ages).
• Acalabrutinib as a single agent (all ages).

Unfit Patients: The management of patients with limited functional status is guided by tumor genetic features (17p deletion, TP53 mutation, and IGHV mutation status). Many clinically unfit patients with comorbidities may benefit from treatment with single-agent ibrutinib, fixed-duration venetoclax plus obinutuzumab, single-agent acalabrutinib, and/or the combination of bendamustine plus rituximab. Chlorambucil plus obinutuzumab is a treatment option for IGHV-mutated CLL in older patients with comorbidities.

Initial Treatment Options

1. Targeted Agents

Bruton tyrosine kinase (BTK) inhibitors

• Single-agent ibrutinib is an effective treatment for older patients with CLL. It has demonstrated improvement in both overall survival and progression-free survival (PFS) compared with chlorambucil in older patients and compared with the combination of bendamustine plus rituximab. In younger patients, ibrutinib plus rituximab or obinutuzumab has demonstrated overall PFS and overall survival benefits compared with the combination of fludarabine plus cyclophosphamide and rituximab. Acalabrutinib is another BTK inhibitor that improves PFS when compared to chlorambucil plus obinutuzumab.[65][66][67]
• A combination of venetoclax plus obinutuzumab is particularly used in patients in whom ibrutinib is contraindicated, such as patients with multiple comorbidities (example, history of severe bleeding, hepatic impairment, or atrial fibrillation) or if on any anticoagulation medications. Studies have shown that the combination of venetoclax plus obinutuzumab achieves higher PFS and overall survival than chlorambucil plus obinutuzumab.[63][64]
(A1)

2. Chemoimmunotherapy

• Fludarabine, cyclophosphamide, and rituximab (FCR) is an initial treatment option in younger patients who can tolerate chemotherapy without 17p deletion/TP53 mutation but with IGHV mutated CLL. In patients with IGHV unmutated CLL, targeted therapy with ibrutinib is preferred over FCR due to improved overall survival and PFS. FCR is contraindicated in older patients due to the high risk of infections, adverse events, and high risk of immunosuppression.[62][68]
• Bendamustine plus rituximab as a treatment of choice for older patients (>65 years of age) without 17p deletion/TP53 mutation, but with IGHV mutated CLL. In patients with IGHV unmutated CLL, targeted therapy with ibrutinib is preferred over bendamustine plus rituximab due to improved overall survival and PFS.[65]
• Chlorambucil-based therapy is usually not used as initial treatment for CLL, as other targeted therapies (e.g., ibrutinib, venetoclax plus obinutuzumab) have demonstrated higher efficacy in patients with 17p deletion, TP53 mutation, or IGHV-unmutated CLL. Chlorambucil plus obinutuzumab is a combination that could be used in elderly patients with IGHV-mutated CLL, and recently it was shown that chlorambucil plus obinutuzumab is superior to rituximab plus chlorambucil in achieving a complete response and prolonging progression-free survival. This combination has demonstrated similar efficacy to ibrutinib-based therapy and venetoclax plus obinutuzumab combination therapy in patients with IGHV-mutated CLL. Adverse effects of chlorambucil include significant anemia, neutropenia, and/or thrombocytopenia. Less common adverse effects include hepatotoxicity, drug hypersensitivity, seizures, interstitial pneumonia, pulmonary fibrosis, and infertility.[64][66]
(A1)

C. Management of complications of CLL and its therapy

CLL/SLL is characterized by hypo/agammaglobulinemia, which increases the risk of infections, especially Staphylococcus, H. influenzae, Pneumococcus, and herpes. These infections can be managed with antimicrobials for bacterial, fungal, or viral infections. For refractory infections in patients with hypogammaglobulinemia, or for 2 or more severe infections within a timeframe of 6 months, monthly IVIG infusions are considered. CLL/SLL also produces autoantibodies directed against RBCs and platelets, leading to immune-mediated hemolytic anemia and thrombocytopenia. These can be acutely managed with packed RBC transfusion for anemia and platelet transfusion for bleeding secondary to thrombocytopenia. The cytopenias can eventually be treated with prednisone.

D. Relapsed/Refractory CLL

It is important to confirm relapsed/refractory CLL histologically prior to restarting treatment. Recurrent CLL in asymptomatic patients should be monitored for symptoms requiring treatment. Richter transformation should specifically be excluded. The treatment of choice at relapse depends upon the initial treatment used and the initial duration of response to that treatment. Ibrutinib is the first-line therapy to improve progression-free survival and response to treatment in relapsed/refractory CLL. Other drugs of choice for relapsed CLL include idelalisib (a phosphoinositide 3'-kinase [PI3K] delta inhibitor), Alemtuzumab (a monoclonal antibody directed against CD52, a cellular marker found in CLL), and venetoclax (Bcl-2 inhibitor). Venetoclax is actively used in refractory CLL patients with 17p deletion. Venetoclax induces brisk apoptosis and, occasionally, tumor lysis syndrome. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has also been active in refractory cases. Anti-CD20 monoclonal antibodies (rituximab, ofatumumab, obinutuzumab) may briefly alleviate symptoms in patients with relapsed/refractory CLL. 

Allogeneic Hematopoietic Stem Cell Transplantation is rarely performed in CLL but has been used in refractory cases in appropriate patients. Those with a very aggressive form of the disease, such as patients with 17p deletion, especially in younger patients, should be recommended to get a bone marrow transplant. Those without a matched donor or who are older can be given a trial of ibrutinib. Palliative radiation therapy can be given to chemotherapy-resistant areas of lymphadenopathy, liver, and spleen. Total body irradiation occasionally temporarily relieves symptoms. 

Differential Diagnosis

Differential diagnosis for chronic lymphocytic leukemia includes the following:

• Acute Lymphoblastic Leukemia (ALL)
• Acute promyelocytic leukemia
• Diffuse large cell lymphoma
• Follicular lymphoma
• Hairy cell leukemia
• Lymphoblastic lymphoma
• Mantle cell lymphoma
• Non-Hodgkin lymphoma
• Monoclonal B-cell lymphocytosis (MBL)
• Prolymphocytic lymphoma (PLL)
• Lymphoplasmacytic lymphoma
• Histologic transformation: CLL/SLL can progress to a more aggressive histology (Richter transformation), including diffuse large B-cell lymphoma or Hodgkin lymphoma.

Staging

Two staging systems are used in CLL patients. The modified Rai-Sawitsky staging in the United States and the Binet staging in Europe.

1. RAI Classification

• Stage 0: Absolute lymphocytosis of > 10,000/mcL in peripheral blood and >/= 30% lymphocytes in bone marrow
• Stage I: Stage 0 plus lymphadenopathy (enlarged lymph nodes)
• Stage II: Stage 0 plus hepatomegaly or splenomegaly
• Stage III: Stage 0 plus anemia with hemoglobin < 11 g/dL (< 110 g/L) due to bone marrow infiltration of tumor cells.
• Stage IV: Stage 0 plus thrombocytopenia with platelet counts <100,000/mcL due to bone marrow infiltration of tumor cells.

2. Binet Classification 

• Stage A:
  • Absolute lymphocytosis of > 10,000/mcL in blood and ≥ 30% lymphocytes in bone marrow
  • Hemoglobin ≥ 10 g/dL ( ≥ 100 g/L)
  • Platelets ≥100,000/mcL
  • ≤ 2 involved sites*
• Stage B: As for stage A, but 3–5 involved sites
• Stage C: As for stage A or B, but hemoglobin < 10 g/dL (< 100 g/L) or platelets < 100,000/mcL.

* Sites considered: Cervical, axillary, and inguinal lymph nodes; liver; and spleen.

Prognosis

In patients with CLL, survival can range from 2 to >20 years, with a median of 10 years. Patients who present with Rai stage 0-II may survive 5 to 20 years without treatment. Lymphocyte doubling time is a prognostic factor in CLL, defined as the number of months required to double the absolute lymphocyte count. A more aggressive expression of CLL is seen in untreated patients with a lymphocyte doubling time of <12 months. Favorable prognostic factors include a mutated Ig heavy chain variable region, 13q deletion, low ZAP-70 expression, and low CD38 levels on flow cytometry. Unfavorable prognostic factors include specific high-risk cytogenetic abnormalities, such as 17p and 11q deletions. Patients with multiple chain lymphadenopathy, hepatosplenomegaly, anemia, and thrombocytopenia have a worse prognosis. One of the commonly used tools for predicting CLL-related outcomes is the CLL-IPI (International Prognostic Index for Chronic Lymphocytic Leukemia).[69]

Complications

Complications accompanying CLL may include increased susceptibility to infections, particularly of the respiratory tract, progression to diffuse large B-cell lymphoma (Richter syndrome), an elevated risk of other malignancies (e.g., cancers of the skin, lungs, and GI tract), and immune system issues, where the immune system attacks red blood cells or platelets, although this is rare.[70]