Overview of the complications of chronic lymphocytic leukemia

INTRODUCTION — Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder (lymphoid neoplasm) characterized by the progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin.

CLL is considered to be identical (ie, one disease with different manifestations) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), a clinically indolent non-Hodgkin lymphoma. The term CLL is used when the disease manifests primarily in the blood, whereas the term SLL is used when involvement is primarily nodal.

The major complications of CLL/SLL will be discussed here. The diagnosis of CLL/SLL and treatment of the underlying disorder are presented separately. The risk of infections and prevention of infections in patients with CLL are also discussed in detail separately.

●(See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

●(See "Overview of the treatment of chronic lymphocytic leukemia".)

●(See "Risk of infections in patients with chronic lymphocytic leukemia".)

●(See "Prevention of infections in patients with chronic lymphocytic leukemia".)

INFECTION

Immune defects and spectrum of infections — Patients with CLL/SLL have abnormal cellular and humoral-mediated immune responses due to quantitative and qualitative defects in immune effector cells. These defects can be due to the underlying disease process or to therapy used for treatment. This is described in more detail separately. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Immune defects'.)

The spectrum of infections in patients with CLL/SLL has changed over the past several decades with the introduction of CLL/SLL therapies that have specific effects on immune function, particularly on cell-mediated immunity. The infectious complications seen in these patients have evolved in relation to the specific agents used and is discussed separately in relation to the various classes of CLL/SLL therapy. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Spectrum of infections'.)

Prevention — Given the high rate of infection and associated morbidity and mortality among patients with CLL/SLL, attempts have been made to decrease the rate of infection by using vaccines, intravenous immunoglobulin, prophylactic antimicrobials, and myeloid growth factors. This is discussed in more detail separately. (See "Prevention of infections in patients with chronic lymphocytic leukemia".)

Evaluation of suspected infection — Patients with CLL/SLL who develop signs of symptoms concerning for infection should undergo an initial evaluation that includes:

●A thorough general medical history and physical examination

●A complete blood cell count with differential, transaminases, bilirubin, electrolytes, blood urea nitrogen (BUN) and creatinine, blood cultures, sputum Gram stain and culture, and urine Gram stain and culture

●A chest radiograph

If localizing signs or symptoms are present, other tests should be considered for further investigation. Lumbar puncture is not necessary routinely but should be performed in patients who have a change in mental status, headache, or other neurological symptoms. (See "Diagnostic approach to the adult cancer patient with neutropenic fever".)

Opportunistic infections should be considered in any patient who develops persistent fever or unexplained pulmonary infiltrates. For patients with unexplained or unresponsive pulmonary infiltrates, we advocate the use of bronchoscopy with bronchoalveolar lavage or transbronchial biopsy to identify opportunistic pathogens such as Aspergillus (or other fungi), cytomegalovirus, herpes simplex virus, Pneumocystis jirovecii, or mycobacterial infections. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

Treatment — The management of infections in patients with CLL/SLL depends on the patient's risk factors for life-threatening infections (eg, neutropenia, recent therapy) and whether the patient appears septic or toxic at presentation.

Patients who are septic and/or have an absolute neutrophil count (ANC) less than 500 to 1000 cells/microL should be treated on an emergency basis with empiric broad spectrum coverage with activity against Pseudomonas aeruginosa and other gram-negative and gram-positive pathogens. (See "Overview of neutropenic fever syndromes" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

Patients who are not septic and have an ANC above 1000 cells/microL can often be treated with antibiotics directed at the most likely pathogen given the presenting signs and symptoms.

As an example, patients with signs and/or symptoms of a sinobronchial infection can often be treated with conventional antibiotics used for the general population. Dose adjustment may be needed due to drug interactions with some medications (eg, azoles, macrolides). Most patients respond to such treatment, but some patients develop chronic sinusitis that may require referral to an ear, nose, and throat specialist. (See "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment".)

Herpes simplex and herpes zoster infection often complicate advanced stage disease. Treatment with antivirals should be instituted early. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster" and "Treatment of herpes zoster" and "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults", section on 'Treatment of HSV-1 infection'.)

COLITIS AND HEPATOTOXICITY — The phosphoinositide 3-kinase (PI3K) delta inhibitors idelalisib and duvelisib have been associated with serious, potentially fatal diarrhea and/or colitis in a minority of patients [1]. Diarrhea can occur at any time and the concurrent use of other drugs that cause diarrhea should be avoided. Idelalisib-associated diarrhea does not usually respond to antimotility agents. The package insert describes management by severity:

●Moderate diarrhea (increase of 4 to 6 stools/day over baseline) – Continue treatment and monitor the severity of diarrhea at least weekly, until resolved.

●Severe diarrhea (increase of >6 stools/day over baseline) or hospitalization – Hold treatment and monitor the severity of diarrhea, until resolved. Once resolved, idelalisib may be resumed at a lower dose (100 mg twice daily).

●Life-threatening diarrhea – Discontinue treatment permanently.

More detailed recommendations for the evaluation and management of PI3K inhibitor-related diarrhea have been proposed by an expert panel [2]. These include the use of topical or systemic corticosteroids for severe diarrhea after the exclusion of infectious causes. Management of acute chemotherapy-related diarrhea is discussed separately. (See "Management of acute chemotherapy-related diarrhea".)

Idelalisib has also been associated with fatal and/or serious hepatotoxicity. Close monitoring of liver function tests especially during the first three months of treatment is recommended. This is discussed separately. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'PI3K inhibitors'.)

PNEUMONITIS — Fatal and serious pneumonitis can occur in patients treated with PI3K inhibitors and, less commonly, with ibrutinib [1,3]. Pneumonitis should be suspected in patients taking one of these agents who develop pulmonary symptoms (cough, dyspnea, hypoxia), interstitial infiltrates on radiologic examination, and/or a decline in oxygen saturation by more than 5 percent. These agents should be withheld during the investigation of suspected pneumonitis. Pneumonitis thought to be due to these agents has been managed with glucocorticoids. These agents should be discontinued permanently in patients with any severity of symptomatic pneumonitis. Rituximab has also been reported to cause pneumonitis, cough, dyspnea, and pulmonary infiltrates. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Idelalisib, duvelisib, and alpelisib'.)

ANEMIA — Anemia is a common complication of advanced CLL/SLL and it is often multifactorial. Causes of anemia in patients with CLL/SLL include:

●Gastrointestinal blood loss secondary to the use of corticosteroids, thrombocytopenia, mucositis or coagulopathy

●Hypersplenism

●Marrow suppression secondary to the use of chemotherapy

●Marrow infiltration by advanced disease

●Hemolytic anemia (see 'Autoimmune hemolytic anemia' below)

●Red blood cell aplasia (see 'Red cell aplasia' below)

The initial evaluation of a patient with CLL/SLL who develops anemia should include a complete blood count (CBC) with red cell indices, white blood cell count with differential, platelet count, reticulocyte count, direct antiglobulin test (DAT), serum bilirubin, lactate dehydrogenase (LDH), haptoglobin, and a review of the peripheral blood smear. Further studies, including iron studies, a urine hemosiderin or bone marrow aspiration and biopsy may be required for further evaluation. (See "Diagnostic approach to anemia in adults" and "Causes of anemia in patients with cancer".)

Autoimmune hemolytic anemia — The incidence of autoimmune hemolytic anemia (AIHA) in patients with CLL/SLL is difficult to determine with certainty. As many as one-third of patients with CLL/SLL may develop AIHA over the course of their illness unrelated to treatment modality [4], although most series suggest a rate in the range of 4 to 10 percent [5,6].

Risk factors include increasing disease stage and unfavorable biologic features (eg, unmutated IGHV, 17p deletion, TP53 mutation). The prevalence increases from a rate of approximately 4 percent in Binet stage A to 10 percent in stages B and C (table 1A-B). The incidence does not appear to increase following CLL/SLL treatment with targeted therapies (eg, ibrutinib, idelalisib, venetoclax) [7]. While initial studies suggested that the incidence of AIHA may be higher following purine analog treatment, it does not appear to be increased when fludarabine is used in combination with cyclophosphamide and/or rituximab.

The autoantibodies that cause AIHA can be produced by nonmalignant B cells or, less commonly, by the malignant CLL/SLL clone itself [8,9]. The mechanism is unknown and may be the result of interactions between the malignant CLL/SLL clone, abnormally functioning T cells, the microenvironment, and the larger immune system.

Diagnosis — The diagnosis of AIHA is typically made in a patient with an isolated fall in hemoglobin and a positive direct antiglobulin (Coombs) test, indirect hyperbilirubinemia, reticulocytosis, reduced haptoglobin, and elevation of serum LDH. However, not all patients with AIHA will demonstrate these laboratory findings. In one study, only 18 percent of those patients with CLL/SLL and hemolytic anemia had a positive Coombs test [10]. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Direct antiglobulin (Coombs) testing'.)

Management — Patients with CLL/SLL who develop AIHA are treated with medical therapies similar to those used for other patients with AIHA [11,12]. This subject is discussed in detail separately. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial management'.)

Red cell aplasia — Pure red cell aplasia (PRCA) is characterized by the disappearance of red cell precursors from the bone marrow and a profound reduction in the absolute reticulocyte count [13]. The exact incidence of PRCA among patients with CLL/SLL is incompletely understood. Most studies have suggested that it is a rare complication of CLL/SLL, occurring in approximately 0.5 percent of patients. However, if this disorder is specifically sought with a bone marrow aspiration and absolute reticulocyte count, PRCA may be found in up to 6 percent of patients with CLL/SLL [14].

Identification — The diagnosis of PRCA is made based on an evaluation of a peripheral blood smear and a bone marrow aspiration and biopsy. Before attributing the PRCA to an autoimmune phenomenon, the patient should be evaluated for viral infections which have been associated with PRCA and (pan)cytopenia in general. These include cytomegalovirus, Epstein-Barr virus, and parvovirus. (See "Acquired pure red cell aplasia in adults", section on 'Diagnosis'.)

Therapy — The management of patients with PRCA includes the judicious use of red cell transfusions and immunosuppressants, such as cyclosporine and glucocorticoids. The majority of patients with CLL/SLL and PRCA will have a complete response to treatment with oral cyclosporine [13,15]. The usual dose is 10 to 14 mg/kg per day in two divided doses, with adjustment according to trough serum levels, response, and tolerance. In particular, renal and hepatic function and serum magnesium levels need to be closely monitored. Patients with refractory acquired PRCA may respond to therapy with rituximab [16]. (See "Acquired pure red cell aplasia in adults", section on 'Management'.)

In a series of 31 patients with CLL/SLL and anemia or thrombocytopenia of presumed autoimmune etiology (19 of whom had prior therapy for this complication), oral cyclosporine (300 mg daily) resulted in responses in over 60 percent of patients [17]. The initial, maximal, and duration of response were three weeks, 10 weeks, and 10 months, respectively. Elevation of creatinine (≤grade II) was observed in six patients, requiring dose adjustment.

Transfusion of packed red cells is usually indicated in patients who are clinically symptomatic from severe anemia. The risks of transfusion in patients with CLL/SLL are similar to those in other patients. Transfusion reactions are not common in patients with CLL/SLL. Leukocyte-depleted and, in rare instances, washed red cell products should be considered for patients who have repeated episodes of transfusion reactions. Irradiated blood products have been used in severely immunosuppressed patients in an attempt to reduce the risk of transfusion-related graft-versus-host disease. We recommend the use of irradiated blood products in patients with CLL/SLL. (See "Immunologic transfusion reactions" and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Specialized modifications and products'.)

Chemotherapy-induced anemia — The incidence of chemotherapy-induced anemia in patients with CLL/SLL depends on the chemotherapy regimen used. Management of symptomatic anemia from chemotherapy-induced myelosuppression includes transfusion of packed red blood cells and/or the administration of recombinant erythropoietin or darbepoetin. Issues surrounding the use of erythropoiesis-stimulating agents (ESAs) versus transfusion are discussed in detail separately. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion" and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer".)

As mentioned above, the risks of transfusion in patients with CLL/SLL are similar to those in other patients. Leukocyte-depleted and irradiated red cell products should be considered for all CLL/SLL patients. (See "Immunologic transfusion reactions" and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Specialized modifications and products'.)

ESAs are rarely used in CLL/SLL. A decision to use them must take into account the degree of anemia, response to therapy, and risk of thromboembolism. While ESAs can increase hemoglobin levels and decrease transfusion requirements, they increase the risk for venous thromboembolism. In patients with "active disease," treatment is usually associated with a prompt improvement in hemoglobin levels, and it is better to avoid the use of ESAs. ESAs are reserved for patients with persistent anemia with a hemoglobin level of 10 g/dL or less [18]. The ESA should be discontinued if there is no improvement in the anemia and/or transfusion requirements within six to eight weeks. Furthermore, other causes of anemia (eg, MDS) should be excluded. Iron supplementation may improve responses in patients treated with an ESA with or without iron deficiency.

THROMBOCYTOPENIA — Thrombocytopenia can occur at any time in the disease course of CLL/SLL. If it is present at the time of diagnosis, it is typically mild. A platelet count below 50,000/microL usually occurs only late in the disease. The causes of thrombocytopenia in patients with CLL/SLL include:

●Suppression of platelet production in the presence of extensive tumor burden

●Autoimmune destruction

●Hypersplenism

●Infection (particularly sepsis and associated disseminated intravascular coagulation)

●Chemotherapy

The initial evaluation of thrombocytopenia in a patient with CLL/SLL should include a complete blood count (CBC) and examination of the peripheral smear. The peripheral smear should be analyzed for an estimation of platelet numbers, morphology, presence or absence of platelet clumping, as well as evaluation of associated white and red blood cell changes. In patients with infections or fever, coagulation parameters should be checked, including the PT, aPTT, and fibrinogen. A bone marrow aspiration and biopsy can help to determine the underlying cause in difficult cases. (See "Diagnostic approach to thrombocytopenia in adults".)

Advanced disease — Patients with thrombocytopenia due to advanced disease typically demonstrate extensive infiltration of the bone marrow on bone marrow aspiration and biopsy. Thrombocytopenia due to extensive tumor burden often improves with chemotherapy. However, if patients are refractory to the chemotherapy chosen, thrombocytopenia may be worsened by treatment. (See "Overview of the treatment of chronic lymphocytic leukemia" and "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

Immune thrombocytopenia — Clinically significant immune thrombocytopenia (ITP) develops in 2 to 5 percent of patients with CLL/SLL [19]. Up to one-third of cases will have concurrent autoimmune hemolytic anemia, the combination of which is referred to as Evan's syndrome. The diagnosis of ITP is suggested by a rapid, unexplained fall in platelets in the absence of bone marrow failure or hypersplenism. Bone marrow aspirate and biopsy demonstrates normal to increased bone marrow megakaryocytes. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)

The treatment of ITP in the context of CLL/SLL is similar to that of patients with ITP who do not have CLL/SLL. Approximately half of patients will respond to initial therapy and 20 percent will have refractory disease despite trials of several agents [17,20,21]. Treatment options are presented in more detail separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults".)

Hypersplenism — Hypersplenism refers to the sequestration of platelets in an enlarged spleen. (See "Splenomegaly and other splenic disorders in adults", section on 'Imaging and biopsy'.)

The majority of patients with hypersplenism will have an improvement in their platelet count and decrease in their platelet transfusion requirements following splenectomy, whether or not they have splenic enlargement clinically [22-24]. Ideally, two to three weeks prior to splenectomy, patients should be vaccinated against pneumococcus, Haemophilus influenzae B, and meningococcus. In addition, some clinicians advocate lifelong penicillin (or equivalent) prophylaxis for pneumococcus due to uncertainty of immune response to vaccination. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Palliation of symptoms'.)

PSYCHOLOGICAL DISTRESS — A diagnosis of leukemia is an emotional challenge to patients. A discussion of the natural history of the disorder and positive reinforcement of the rapidly increasing range of treatment options will be sufficient to allay the fears of most patients. However, formal psychological counseling is appropriate for some patients to enable them to cope with the stress of knowing that they have leukemia. (See "Patients with cancer: Overview of the clinical features and diagnosis of psychiatric disorders" and "Management of psychiatric disorders in patients with cancer".)

SECOND CANCERS — Several retrospective studies have suggested that patients with CLL/SLL have a higher risk of developing other hematologic and solid malignancies. The most common are the same as in the non-CLL/SLL population: lung, breast, colon, and prostate cancers. It is unknown how much of this increased risk is due to the underlying disease and accompanying chronic immunosuppression and how much is due to the treatments given. There have been no studies of cancer screening in patients with CLL/SLL. Patients with CLL/SLL should undergo age and sex appropriate screening measures for solid tumors. (See "Overview of preventive care in adults", section on 'Cancer screening'.)

In 1 to 10 percent of patients, CLL/SLL transforms into a clinically aggressive lymphoma (called Richter transformation or Richter syndrome) or prolymphocytic leukemia. In addition, patients treated for CLL/SLL can develop therapy-related myeloid neoplasms, presenting as a myelodysplastic syndrome or acute myeloid leukemia. In particular, fludarabine-containing regimens are associated with an increased risk of myelodysplastic syndrome [25]. These are discussed in more detail separately. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma" and "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

Patients with CLL/SLL may also have a higher risk of developing secondary solid tumors [25-35]. The tumor types that have demonstrated increased rates have varied among studies.

The largest retrospective study was an analysis of 16,367 patients with CLL/SLL enrolled in the Surveillance, Epidemiology, and End Results (SEER) program and followed for an average of 5.2 years [29]. Eleven percent developed a second solid tumor, a rate that was significantly higher than that for the general population (odds ratio of 1.20, 95% CI 1.15-1.26). The highest excess rates were noted for Kaposi sarcoma, malignant melanoma, cancers of the larynx, and cancers of the lung.

Patients with CLL/SLL who develop a solid tumor may have inferior survival when compared with patients with solid tumors who do not have a pre-existing diagnosis of CLL/SLL.

An analysis of more than 2.3 million patients with cancers of the breast, colorectum, prostate, lung, kidney, pancreas, or ovary enrolled in the SEER program identified 4494 cases (0.19 percent) with a prior diagnosis of CLL/SLL [36]. After adjusting for age, sex, race, and disease stage, patients with pre-existing CLL/SLL had inferior overall survival when compared with those without CLL/SLL following a diagnosis of cancer of the breast (hazard ratio [HR] 1.70; 95% CI 1.51-1.91), colorectum (HR 1.65; 95% CI 1.53-1.79), or prostate (HR 1.92; 95% CI 1.73-2.13). This inferior survival remained when CLL/SLL-related deaths were excluded.

It is unknown why patients with CLL/SLL who have a solid tumor appear to have worse survival. Solid tumors that develop in patients with CLL/SLL may be biologically different from those that develop in the general population. This could be related to the patient's underlying genetics or the impact of prior therapy for CLL/SLL. Alternatively, patients with CLL/SLL may be less able to tolerate preferred treatment strategies due to underlying cytopenias or immunosuppression. Further study is needed to determine whether the approach to treatment should differ from the standard approach.

LEUKOSTASIS — Leukostasis is a medical emergency characterized by an extremely elevated white blood cell (WBC) count and symptoms of decreased tissue perfusion. While a significant proportion of patients with CLL/SLL present with a high WBC count, symptoms of leukostasis are rare unless the WBC count exceeds 400 x 10⁹/L (400,000/microL). (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

TUMOR LYSIS SYNDROME — Tumor lysis syndrome (TLS) is characterized by hyperphosphatemia, hypocalcemia, hyperkalemia, and renal insufficiency. The inciting cause seems to be release of large amounts of phosphate and other products of cell destruction from lysed cells, which coprecipitates with calcium in the kidneys, leading to hypocalcemia and sometimes to oliguric renal failure. Hyperuricemia further contributes to this problem. The incidence of TLS in CLL/SLL varies with the treatment given. Some regimens require prophylaxis for TLS while others do not. The diagnosis and treatment of TLS is presented in more detail separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic lymphocytic leukemia/small lymphocytic lymphoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Chronic lymphocytic leukemia (CLL) in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Immune defects – Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) commonly develop complications associated with their intrinsic immune dysfunction resulting in immunodeficiency and autoimmune disorders. The most common complications are infection, anemia, and thrombocytopenia.

Patients with CLL/SLL have abnormal cellular and humoral-mediated immune responses due to quantitative and qualitative defects in immune effector cells. These defects can be due to the underlying disease process or to therapy used for treatment. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Immune defects'.)

●Prevention and treatment of infection – Given the high rate of infection and associated morbidity and mortality, attempts have been made to decrease the rate of infection by using vaccines, intravenous immunoglobulin, prophylactic antimicrobials, and myeloid growth factors. The approach to prophylaxis depends upon the type of treatment planned and its associated immune dysfunction (table 2 and table 3). (See "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Antimicrobial prophylaxis'.)

The management of infections in patients with CLL/SLL depends on the patient's risk factors for life-threatening infections (eg, neutropenia, recent therapy) and whether they appear septic or toxic at presentation:

•Patients who are septic and/or have an absolute neutrophil count less than 500 to 1000 cells/microL should be treated emergently with empiric broad spectrum coverage. (See "Overview of neutropenic fever syndromes" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

•Patients who are not septic and have an absolute neutrophil count above 1000 cells/microL can often be treated with antibiotics directed at the most likely pathogen given the presenting signs and symptoms. (See 'Treatment' above.)

●Anemia – Anemia is a common complication of advanced CLL/SLL and may be due to hypersplenism, marrow infiltration, gastrointestinal blood loss, chemotherapy-induced bone marrow suppression, (autoimmune) hemolysis, or red blood cell aplasia. Treatment should be directed at the underlying cause. (See 'Anemia' above.)

●Thrombocytopenia – Causes of thrombocytopenia in patients with CLL/SLL include extensive tumor burden, autoimmune destruction, and hypersplenism. Treatment should be directed at the underlying cause. (See 'Thrombocytopenia' above.)

●Tumor lysis syndrome – Tumor lysis syndrome is a rare but potentially life-threatening complication characterized by hyperphosphatemia, hypocalcemia, hyperkalemia, and renal insufficiency. The incidence of tumor lysis syndrome varies with the treatment given and some regimens require prophylaxis for tumor lysis syndrome. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

●Second cancers – Patients with CLL/SLL may have a higher risk of developing other hematologic and solid malignancies. Patients with CLL/SLL should undergo age- and sex-appropriate screening. (See 'Second cancers' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael J Keating, MD, who contributed to earlier versions of this topic review.