Complications
Patients receiving fludarabine-based chemotherapy, phosphoinositide 3-kinase (PI3K) inhibitors (e.g., duvelisib, idelalisib), or alemtuzumab are at high risk of CMV reactivation.[79][80][81][82]
Guidelines recommend that CMV viremia should be measured at least every 4 weeks in patients receiving fludarabine-based chemotherapy, PI3K inhibitors, or alemtuzumab.[33]
Antiviral therapy can be used prophylactically if CMV viremia is present or if the viral load is found to be rising during therapy. Consultation with an infectious disease expert may be required.
An oncologic emergency requiring immediate management.
TLS has been reported in CLL patients treated with targeted therapies and immunotherapies, particularly venetoclax, obinutuzumab, rituximab, lenalidomide, and chemoimmunotherapy regimens.[58][59][60][61]
Fatal cases have been reported, some in patients receiving venetoclax at its lowest dose and in those with low-to-medium TLS risk.[58][59][60]
Risk assessment for TLS should be carried out in all patients before administering venetoclax, taking into consideration comorbidities (particularly renal dysfunction) and other risk factors (e.g., tumor burden, splenomegaly).[58][59][60] Abnormalities in blood chemistry following treatment with venetoclax, which may occur as early as 6-8 hours following the first dose and at each dose increase during dose titration, should be managed promptly.[60]
Guidance on TLS prophylaxis (e.g., hydration and use of antihyperuricemics), laboratory monitoring (including blood chemistries), dose titration, and drug interactions should be strictly adhered to in all patients at risk for TLS (i.e., those receiving venetoclax, obinutuzumab, rituximab, lenalidomide, or chemoimmunotherapy regimens).[33][58][59][60][83]
CLL lymphocytes are dysfunctional and cannot produce the antibody needed to fight off microbial agents. Patients are often deficient in IgG, IgA, or IgM. These immunoglobulins are important for the host defense against microbial organisms, and deficiency leads to increased risk for infection.
Intravenous immune globulin (IVIG) given on a monthly basis is recommended for patients with serum IgG <500 mg/dL who have recurrent sinopulmonary infection requiring intravenous antibiotics or hospitalization.[33]
Occurs in 5% to 10% of patients with CLL.[34][35]
The pathogenesis of autoimmune cytopenias in CLL is unclear, but may involve antigen presentation by CLL cells leading to autoantibody production by normal B cells.[21]
Treatment of autoimmune cytopenias includes corticosteroids and immunosuppressants.
Most chemotherapy agents are cytotoxic to bone marrow progenitor cells. Leukocytes are destroyed and unable to help the host fight off infection.
The microbial source should be identified and the appropriate antibiotics administered.
Granulocyte colony-stimulating factor may be given to patients receiving myelosuppressive chemoimmunotherapy according to American Society of Clinical Oncology guidelines.[2][91]
Patients with CLL have a higher incidence of secondary malignancies (e.g., skin, prostate, breast, lung colorectal, and hematologic cancers), which may be related to the disease or to its treatment.[86]
Chemoimmunotherapy regimens (e.g., fludarabine plus cyclophosphamide plus rituximab [FCR]) are associated with secondary acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).[87]
T-cell malignancies have occured with CD19-directed chimeric antigen receptor (CAR) T-cell therapy (e.g., lisocabtagene maraleucel).[88]
Ibrutinib is associated with an increased risk for fatal and serious cardiac arrhythmias, and cardiac failure.[62][63][64][65]
These events have occurred particularly in patients with cardiac risk factors (e.g., hypertension and diabetes mellitus), in those with a previous history of cardiac arrhythmias, and in patients with acute infections. In light of these risks, clinical evaluation of cardiac history and function should be performed prior to initiating ibrutinib.
Patients should be carefully monitored during treatment for cardiac arrhythmias and signs of deterioration of cardiac function and clinically managed as appropriate. Blood pressure should be monitored and antihypertensive medication should be started or adjusted as needed. The risks and benefits of initiating or continued treatment with ibrutinib should be carefully assessed; alternative treatment may need to be considered.
Cardiac arrhythmias may occur with other BTK inhibitors (e.g., acalabrutinib, zanubrutinib), particularly in patients with cardiac risk factors. The same precautions for ibrutinib should be considered for patients on any BTK inhibitor.
In up to 15% of cases, CLL can undergo histologic (Richter) transformation to a high-grade non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma).[89] Typically presents with a sudden onset of B symptoms, rapidly progressive lymphadenopathy, and high serum levels of lactate dehydrogenase.
Whole body fluorodeoxyglucose (FDG)-PET/CT scan or chest/abdominal/pelvic CT with contrast are used to identify evidence of Richter transformation.[33] FDG-PET/CT can also aid in determining the optimal site for nodal biopsy (lesion with highest standardized uptake value).[2][33][36]
Lymph node biopsy (excisional), hematopathology review, and molecular analysis are required to confirm Richter transformation.[33]
The prognosis is poor.[90]
Fludarabine has been reported to cause pulmonary toxicities such as interstitial lung disease.[92] This can be treated with withdrawal of the drug and corticosteroids.
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic cell transplant. Clinical manifestations guide whether the signs and symptoms of GVHD are acute, chronic, or an overlap syndrome. Treatment usually involves the use of systemic corticosteroids with additional immunosuppressants as required, often as part of a clinical trial.[74]
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