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Complications of CLL or CLL Treatment


CLL patients may be more susceptible to infections due to either the CLL itself and/or its treatment. A higher risk of infection is caused by 

  • The inability of the person’s CLL cells to make antibodies needed to fight infections 
  • The effect of treatment, which causes reduced blood cell counts for certain infection-fighting white blood cells in the blood, specifically neutrophils and monocytes.

Because of the increased risk for infection, vaccination for pneumococcal pneumonia (repeated every 5 years) and a yearly flu vaccine is recommended. CLL patients should never receive live vaccines (such as the Zostavax vaccine – live shingles vaccine) but can receive Shingrix® because it is an inactivated shingles vaccine.

Antibiotic therapy is usually required to treat bacterial or fungal infections during the course of the disease.

People who get recurrent infections may also receive injections of immunoglobulin (gamma globulin) on a regular basis to correct the immune deficiency. This treatment is expensive, but it does decrease the frequency of infections in CLL patients with low levels of immunoglobulin in their blood.

Cytomegalovirus (CMV) reactivation can occur in about 10 to 25 percent of patients with relapsed or refractory CLL treated with alemtuzumab. Rates of reactivation as high as 6 percent have also been reported in patients treated with idelalisib (Zydelig®). It is important to monitor for this potential problem during alemtuzumab or idelalisib therapy. Appropriate anti-infection prevention and routine monitoring for early signs of infection should be considered when patients receive therapy with alemtuzumab or idelalisib.

Hepatitis B virus (HBV) reactivation has been reported in patients treated with chemotherapy, with or without immunotherapy agents. It has also been reported in patients treated with alemtuzumab, ibrutinib and idelalisib. Prophylactic antiviral care and continuous monitoring for HBV are recommended for high-risk patients receiving therapy with CD20 monoclonal antibodies, alemtuzumab, ibrutinib and/or idelalisib.

Low Blood Cell Counts

Supportive care for CLL may include administering blood cell growth factors to improve low blood cell counts. The use of white blood cell growth factors may benefit patients who experience prolonged low white blood cell counts after treatment. Examples of white blood cell growth factors are

  • Granulocyte-colony stimulating factor (G-CSF) (filgrastim [Neupogen®] or pegfilgrastim [Neulasta®]) that can increase the number of neutrophils 
  • Granulocyte macrophage-colony stimulating growth factor (GM-CSF) (sargramostim [Leukine®]) that can increase the number of neutrophils and monocytes.

Richter Transformation

In about 2 to 10 percent of people with CLL, the disease transforms into something more complex. Of this small group, 95 percent may develop diffuse large-B cell lymphoma (DLBCL), and the other 5 percent may develop Hodgkin lymphoma. This is known as “Richter transformation” or “Richter’s syndrome.” This syndrome is much more common in patients with high-risk factors such as: advanced Rai stage; del(17p), trisomy 12, TP53 or NOTCH1 mutations; and IGHV-unmutated CLL.

Patients may have significantly enlarged lymph nodes, and may experience fevers and weight loss. Lymphocyte masses may also develop in parts of the body other than the lymph nodes.

Patients with Richter transformation whose CLL has transformed into DLBCL are treated with regimens designed for DLBCL. Allogeneic stem cell transplantation can also be considered following a response to initial therapy. 

Standard Hodgkin lymphoma therapy is used for patients with Richter transformation whose CLL has transformed to Hodgkin lymphoma. With aggressive therapy, these patients tend to do better and may be cured of this condition (although not the underlying CLL). 

These patients should also consider a clinical trial as a treatment option. Recently, some treatment responses have been reported with the use of checkpoint inhibitors and CAR T-cell therapy

Receive one-on-one navigation from an LLS Clinical Trial Specialist who will personally assist you throughout the entire clinical-trial process: Click Here

Autoimmune Cytopenias

The most frequent autoimmune cytopenias in CLL patients are as follows. Bone marrow tests are used to confirm the presence of these conditions. 

  • Autoimmune hemolytic anemia (AIHA)
  • Immune-mediated thrombocytopenia (also known as “immune thrombocytopenic purpura” [ITP])
  • Pure red blood cell aplasia (PRCA)

AIHA is the most common form of autoimmune cytopenia. Patients who have AIHA produce antibodies that work against their own cells. These “autoantibodies” are usually directed against the patient’s red blood cells and causes them to be removed rapidly from the blood. The loss of these red blood cells can worsen the effects of already low red blood cell counts. The direct antiglobulin test (DAT, also known as the “direct Coombs test”) is used to identify the autoantibodies; however, most patients with AIHA have a negative DAT test result. In these cases, additional serum markers, such as low haptoglobin (a blood protein) and elevated reticulocyte (immature red blood cell) levels are required to make the diagnosis. Patients with advanced disease; high-risk factors, such as unmutated IGHV gene status; increased serum beta-2 microglobulin levels; and high expression of ZAP-70 are also more likely to develop AIHA. Less often, the antibody works against the platelets. This condition, called “immune thrombocytopenic purpura” (ITP), results in significantly decreased platelet counts.

The drugs prednisone, rituximab (Rituxan®) and cyclosporine are sometimes used to treat AIHA and ITP. Splenectomy should be considered in cases where the patient does not respond to steroid therapy. The drugs romiplostim (Nplate®) and eltrombopag (Promacta®) are both FDA approved for the treatment of thrombocytopenia in patients with ITP that is resistant to other treatments.

Tumor Flare Reactions

Tumor flare is a painful enlargement of the lymph nodes that may be accompanied by elevated lymphocyte counts, enlarged spleen, low-grade fever, rash and bone pain. These reactions are commonly seen in CLL patients treated with lenalidomide (Revlimid®). Use of steroid medications to control the inflammation and antihistamines to manage the rash are recommended.

Tumor Lysis Syndrome 

Tumor lysis syndrome (TLS) is a potentially life-threatening condition that occurs when large amounts of tumor cells are killed at the same time by the cancer therapy, releasing their content into the bloodstream. Patients with bulky lymph nodes are considered at high risk for developing TLS, which is best managed if anticipated and treatment is started before chemotherapy. Treatment for TLS includes increased hydration, monitoring and treatment of electrolyte imbalances and abnormal uric acid levels, and therapy with the drug rasburicase (Elitek®), as needed.

Second Cancers

People with CLL have a higher risk than people in the general population of developing a second cancer. This may be due to abnormalities in immune function associated with the disease and to the use of chemotherapeutic agents, which can induce potentially long-lasting remissions but are also associated with prolonged immunosuppression.

The second cancers that are seen most frequently in CLL patients are acute myeloid leukemia, myelodysplastic syndromes, melanoma, gastrointestinal cancer, breast cancer, lung cancer, non-melanoma skin cancer, prostate cancer, kidney cancer, bladder cancer, and head and neck cancers.

Both treated and untreated people with CLL can develop acute myeloid leukemia or myelodysplastic syndromes. These complications are more common after treatment with fludarabine and cyclophosphamide (FC) or fludarabine, cyclophosphamide and rituximab (FCR).

Although all CLL patients should be counseled about their increased risk for developing a second cancer, studies indicate there are some factors that may help predict the development of other malignancies in CLL patients. These include 

  • Older age (older than 60 years)
  • Males
  • Elevated levels of certain blood markers, such as beta-2 microglobulin, lactate dehydrogenase and serum creatinine.

It is important to follow up with your oncologist on a regular basis because of the increased risk of second cancers associated with CLL.

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