Chronic Lymphocytic Leukemia is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. It is the most common adult leukemia in Western populations. Chronic lymphocytic leukemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing neoplastic lymphocytes in the blood, marrow, and secondary lymphoid tissues, resulting in lymphocytosis, leukemia cell infiltration of the marrow, lymphadenopathy and splenomegaly. Genetic factors contribute to the development of CLL; although CLL is the most common adult leukemia in western countries, it is less common in Asia and relatively rare in Japan and Korea, even among Japanese people who immigrate to western countries.
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on there are typically no symptoms. Later non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur.[rx][rx] It typically worsens gradually over years.[rx]
Staging
Staging, determining the extent of the disease, is done with the Rai staging system or the Binet classification [rx] and is based primarily on the presence of a low platelet or red cell count. The early-stage disease does not need to be treated. CLL and SLL are considered the same underlying disease, just with different appearances.[rx]:1441
Rai staging system
Stage 0: characterized by absolute lymphocytosis (>15,000/mm3) without lymphadenopathy, hepatosplenomegaly, anemia, or thrombocytopenia
Stage I: characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia
Stage II: characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy
Stage III: characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly
Stage IV: characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia[rx][rx]
Binet classification
Clinical stage A: characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II)
Clinical stage B: characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II)
Clinical stage C: characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV)[rx]
Array-based karyotyping
Array-based karyotyping is a cost-effective alternative to FISH for detecting chromosomal abnormalities in CLL. Several clinical validation studies have shown >95% concordance with the standard CLL FISH panel.[rx][rx][rx][rx][rx]
Causes of Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (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. Moreover, 17% of first-degree family members of patients with CLL had monoclonal B cell lymphocytosis, which is a precursor of CLL.[rx][rx][rx]
CLL is caused by multiple genetic mutations and epigenetic changes. Men are about twice as likely to get CLL as women, and risk increases with age.[rx] It is relatively rare among Asians. Some relevant genetic mutations may be inherited; in around 9% of CLL cases a parent had CLL. Exposure to Agent Orange increases the risk of CLL, and exposure to hepatitis C virus may increase the risk.[rx] There is no clear association between ionizing radiation exposure and the risk of developing CLL.[rx] Blood transfusions have been ruled out as a risk factor.[rx]
Symptoms of Chronic Lymphocytic Leukemia
Many people with chronic lymphocytic leukemia have no early symptoms. Those who do develop signs and symptoms may experience:
Enlarged, but painless, lymph nodes
Swollen lymph nodes in your neck, armpits, stomach, or groin. Lymph nodes are pea-sized glands in these and other areas of your body.
Shortness of breath
Pain or fullness in your stomach, which may be because the disease has made your spleen bigger
Night sweats
Fever and infections
Loss of appetite and weight
Fatigue
Fever
Pain in the upper left portion of the abdomen, which may be caused by an enlarged spleen
Weight loss
Frequent infections
Diagnosis of Chronic Lymphocytic Leukemia
Histopathology
Classical smudge cells are seen on peripheral blood smear; these are pathognomic of CLL. On peripheral blood flow cytometry, immunophenotypic analysis of the peripheral circulating lymphocytes can be performed which can help to diagnose CLL. The presence of B-cell antigens such as CD19, weak CD20 and CD23, T-cell antigen CD5 and low levels of surface membrane immunoglobulins which is usually IgM or both IgM and IgD and only one type of light chain suggesting the monoclonality of the lymphocytes. However, in some cases, biclonal CLL, expressing both light chains or different levels of expression of other immunophenotypic antigens, is also seen.
History and Physical
The presentation of CLL can range from asymptomatic to more severe complications due to the disease. Patients may be diagnosed after they are found to have incidental lymphocytosis on a complete blood count (CBC) done for an unrelated condition. Some patients may notice non-tender swelling of lymph nodes, particularly in the cervical region. The swelling comes and goes. Only 5% to 10% of patients present with the B symptoms of fever, weight loss, night sweats, and fatigue.
Some other presenting symptoms include hypersensitivity to insect bites, autoimmune hemolytic anemias, and recurrent infections.
The most common physical examination finding is lymphadenopathy. It could be localized or generalized and is firm, non-tender, and mobile when palpated.
Splenomegaly and hepatomegaly are other signs for which to look.
Skin examination is an important part of physical examination because skin cancers are a relatively frequent complication of CLL. Sometimes CLL cells infiltrate the skin resulting in a condition called leukemia cutis which can manifest as plaques, papules, nodules, among others.
The first step in evaluation is to perform a CBC which demonstrates lymphocytosis. There could be some degree of anemia and thrombocytopenia depending on the stage of the disease.[rx][rx][rx][rx]
Complete blood count and differential white blood cell count;
Count the number of cells in a blood sample – A complete blood count may be used to count the number of lymphocytes in a blood sample. A high number of B cells, one type of lymphocyte, may indicate chronic lymphocytic leukemia.
Determine the type of lymphocytes involved – A test called flow cytometry or immunophenotyping helps determine whether an increased number of lymphocytes is due to chronic lymphocytic leukemia, a different blood disorder or your body’s reaction to another process, such as infection. If chronic lymphocytic leukemia is present, flow cytometry may also help analyze the leukemia cells for characteristics that help predict how aggressive the cells are.
Analyze lymphocytes for genetic abnormalities – A test called fluorescence in situ hybridization (FISH) examines the chromosomes inside the abnormal lymphocytes to look for abnormalities. Doctors sometimes use this information to determine your prognosis and help choose a treatment.
PB immunophenotyping – at least a 4-color panel of the fluorochromes FITC, PE, PerCP or PerCPCy5.5, and APC performed according to the consensus of the Brazilian Group of Flow Cytometry (GBCFLUX) for Chronic Lymphoproliferative Disorders (in press). This panel should include one screening tube (CD8/Lambda, CD56/Kappa, CD19/CD4, CD3) and two diagnostic tubes, including CD45, CD20, CD19, CD5, CD79b, CD23, CD19, and CD200. The Brazilian Group of CLL also recommends two additional tubes for prognostic and minimal residual disease (MRD) purposes, including CD38, CD305, CD19, CD49d, CD81, CD43, CD19, and sIgM. ZAP-70 is considered an optional prognostic marker. Panels using six, eight, or more colors should use the same markers inappropriate combinations. The Euroflow group[rx] designed an 8-color panel of monoclonal antibodies (MoAbs) to improve diagnosis and to differentiate CLL from other B cell lymphoproliferative disorders. They included all MoAbs proposed by Matutes with the exception of FMC7 and CD22, and they incorporated other markers such as CD43, CD81, CD38, CD20, and CD200. CD200 is particularly useful for differentiating CLL from mantle cell lymphoma.
Bone marrow aspiration – though not needed for diagnosis often are done as a part of a diagnostic workup or before treatment. These show more than 30% involvement by CLL cells for diagnosis of the disease. Reduction of lymphocytic infiltration to less than 30% on treatment indicates a complete response.
Flow cytometry – can be performed on both peripheral blood and bone marrow aspirate to look for the classical immunophenotypic markers of CLL. Lab studies which are of importance include serum lactate dehydrogenase (LDH) and beta-2 microglobulin (read with creatinine because it can normally be elevated in patients with elevated creatinine) which correlate with disease activity. Serum immunoglobulins and free-light chains are also measured at baseline to look at immune deficiency and on treatment to look at immune reconstitution especially with the newer generation B-cell receptor signaling drugs.
Bone marrow biopsy and aspiration – are NOT recommended for routine CLL diagnosis. This procedure may be performed in patients who will participate in clinical trials and/or patients with persistent cytopenias after treatment to differentiate leukemic infiltration from therapy-related toxicity. The bone marrow smear should be characterized by the presence of CLL cells, the percentage of which is typically above 30%. Infiltration in a bone marrow biopsy may have a nodular, interstitial, or diffuse growth pattern.
Imaging techniques – such as ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography-CT (PET-CT) scanning, are NOT recommended for routine CLL diagnosis or staging.
Lymph node biopsy – In some cases, removing and examining a swollen lymph gland can help confirm a diagnosis of CLL. This is known as a lymph node biopsy. The gland is removed during a minor operation carried out under either local or general anesthetic, where you’re asleep. You will not usually need to stay in the hospital overnight. After the operation, you’ll be left with a small wound that will be closed with stitches.
Genetic tests – Tests may also be carried out on your blood and bone marrow samples to check for any unusual genes in the cancerous cells. Identifying unusual genes in these cells can help your doctors decide how soon you should start treatment and which treatment is best for you.
Given that most patients with CLL are asymptomatic, treatment is not recommended for everyone. The recommendation for treatment depends on severe disease symptoms or rapidly progressing disease. Symptoms such as severe fatigue interfering with daily activities, B-symptoms, recurrent infections, or increased tumor burden are an indication for early treatment. Rapidly progressing disease such as an absolute lymphocyte count doubling time of fewer than 12 months is also an indication for early treatment.[rx][rx][rx]
For patients who are not considered for treatment, regular follow-up at 3-month intervals is recommended. At the 12-month mark, depending on the symptoms and pace of disease, a decision on whether treatment is needed can be made.
Symptomatic CLL is treated and despite many recent advances, remains to be an incurable disease.
The treatment indications are as follows:
Bone marrow failure manifested by the development of anemia and/or thrombocytopenia;
Massive splenomegaly (at least 6 cm below the left costal margin) that is progressive or symptomatic;
Massive lymph node (at least 10 cm in longest diameter) or a progressive or symptomatic lymph node;
Progressive lymphocytosis with an increase of more than 50% within two months or a LDT of less than six months. LDT can be determined by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of two weeks over an observation period of 2–3 months (this parameter should not be used if the initial lymphocyte count is less than 30 × 109/L). In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
Autoimmune disease (anemia and/or thrombocytopenia) with poor response to corticosteroids or other standard treatments.
Constitutional symptoms, which are defined as any of the following: unintentional weight loss of 10% or more in the past six months, significant fatigue [i.e., Eastern Cooperative Oncology Group (ECOG) of 2 or worse; inability to work or perform usual activities], fever higher than 38.0 °C for two or more weeks without evidence of infection, and night sweats for more than one month without evidence of infection.
Chemotherapy
Combination chemotherapy regimens are effective in both newly diagnosed and relapsed CLL. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:
FCR (fludarabine, cyclophosphamide, and rituximab)[rx]
CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)
Although the purine analogue fludarabine was shown to give superior response rates to chlorambucil as primary therapy,[rx][rx] no evidence shows early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.
Chemoimmunotherapy with FCR has shown to improve response rates, progression-free survival, and overall survival in a large randomized trial in CLL patients selected for good physical fitness.[rx] This has been the first clinical trial demonstrating that the choice of a first-line therapy can improve the overall survival of patients with CLL.
Alkylating agents approved for CLL include bendamustine and cyclophosphamide.
Targeted therapy
Targeted therapy attacks cancer cells at a specific target, with the aim of not harming normal cells. Targeted drugs used in CLL include venetoclax (a Bcl-2 inhibitor), ibrutinib (a Bruton’s tyrosine kinase inhibitor), idelalisib and duvelisib (inhibitors of some forms of the enzyme phosphoinositide 3-kinase), as well as monoclonal antibodies against CD20 (rituximab, ofatumumab and obinutuzumab) and CD52 (alemtuzumab).[rx][rx]
Stem cell transplantation
Autologous stem cell transplantation, using the recipient’s own cells, is not curative.[rx]:1458 Younger individuals, if at high risk for dying from CLL, may consider allogeneic hematopoietic stem cell transplantation (HSCT). Myeloablative (bone marrow killing) forms of allogeneic stem cell transplantation, a high-risk treatment using blood cells from a healthy donor, may be curative, but treatment-related toxicity is significant.[rx]:1458 An intermediate level, called reduced-intensity conditioning allogeneic stem cell transplantation, may be better tolerated by older or frail patients.[rx][rx]
Refractory CLL
“Refractory” CLL is a disease that no longer responds favorably to treatment. In this case, more aggressive therapies, including lenalidomide, flavopiridol, and bone marrow (stem cell) transplantation, are considered.[rx] The monoclonal antibody alemtuzumab (directed against CD52) may be used in patients with refractory, bone marrow-based disease.[rx]
Chlorambucil
Monotherapy with alkylating agents, including chlorambucil, has been the treatment of choice for many years[rx], and this therapy can still be an option, particularly for elderly and unfit patients for whom current standard treatments are not an option. The advantages of chlorambucil include its low cost, low toxicity, and convenience of being an oral treatment. The main disadvantage is very low, if any, rate of complete response and the risk of side effects with long-term use, such as myelodysplasia. Currently, the use of chlorambucil alone is avoided whenever a monoclonal antibody is available.[rx]
Purine analogs
Purine analogs are still one of the most important drugs in the treatment of fit patients, and fludarabine is the most studied drug. Response rates with fludarabine monotherapy range in different studies from 63 to 73% with approximately 7–40% of cases having a complete response, corresponding to a response that is superior to that achieved with chlorambucil.[rx] Long-term monitoring revealed a better OS for fludarabine,[rx] although a greater OS does not seem to be evident in older patients.[rx] Fludarabine monotherapy was also no less effective than more intensive regimens associated with alkylating agents.[rx], [rx]
Combinations of purine analogs and alkylating agents have synergistic cytotoxicity in CLL because both chemotherapies have different mechanisms of action and different toxicity profiles. The combination of fludarabine with cyclophosphamide (FC) is the most studied therapy and yields better overall response (74–94%) and complete remission rates (23–38%) than other regimens in the pre-rituximab era without increasing the risk of infection despite a higher incidence of neutropenia.[rx, rx, rx] Other purine analogs have also been studied, but there was no significant benefit over fludarabine.[rx]
Monoclonal antibodies: anti-CD20
In recent decades, the addition of monoclonal antibodies has changed the treatment of all lymphoproliferative disorders, including CLL, after the introduction of rituximab in treatment protocols.
In CLL, rituximab – is less active as a single agent than in other lymphoproliferative disorders, which is probably because of the low density of CD20 in the cell membrane. Therefore, higher doses of this monoclonal antibody are recommended for CLL.[rx, rx] The combination of rituximab with fludarabine and cyclophosphamide (FCR) has a synergistic effect and efficacy that has been confirmed in several phase II studies and retrospective analyses. In the largest phase II study, FCR resulted in an overall response rate of 95%, a complete remission rate of 72%, OS at six years of 77%, and medium PFS of 80 months.[rx] These results led the German group to conduct the CLL8 study that demonstrated the superiority of FCR compared with FC, with better response rates and better PFS rates as well as no increase in toxicity or infection risk. Subgroup analysis showed benefits for all cytogenetic risk factors, except for individuals with del17p.[rx] The same beneficial results associated with FC were also obtained with second-line treatment.[rx] These results made the FCR combination the treatment of choice for fit patients with CLL. Because CLL occurs at a high frequency in older patients, an FCR-Lite scheme has been designed in an attempt to reduce toxicity while maintaining efficacy. In this combination, fludarabine dosages are reduced to 20 mg/m2, cyclophosphamide dosages are reduced to 150 mg/m2 on Days 2–4 in cycle 1 and on Days 1–3 in cycles 2–5, and the dosages are increased for rituximab (375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 14 of the first cycle and on Days 1 and 14 in all subsequent cycles). After the six cycles were completed, rituximab was given as a maintenance therapy at 500 mg/m2 once every three months until relapse.[rx]
Ofatumumab – is another monoclonal antibody that targets a specific epitope with increased affinity to CD20 and also with stronger complement-dependent cytotoxicity (CDC), as well as antibody-dependent cellular cytotoxicity (ADCC).[rx] This drug was approved in Europe and in the United States as a monotherapy for relapsed or refractory patients. It also has reasonable response rates in high-risk individuals, including those who are refractory to fludarabine and alemtuzumab or refractory to fludarabine and have bulky disease, with overall response rates of 58% and 47%, respectively.[rx] In the first-line treatment, the combination with chlorambucil in treatment-naïve unfit elderly patients yielded an excellent response rate of 82% with a 12% complete response rate.[rx]
Obinutuzumab – (GA101) is a humanized monoclonal antibody that showed impressive results in animal and pre-clinical studies, and it has been designed to have greater affinity for the type II CD20 epitope, greater ADCC, and lower CDC with higher direct cell death induction.[rx] The CLL11 study showed that the combination of obinutuzumab with chlorambucil yielded a response rate of 78.4% and a 20.7% complete response rate, with 19.5% MRD negativity in CLL patients not eligible for fludarabine-based treatment. It was far superior to chlorambucil alone and yielded better response rates than the combination of rituximab and chlorambucil.[rx] Obinutuzumab-related infusion reactions occur in nearly 65% of cases in the first cycle (21% grade 3 or 4), which leads to discontinuation in 7% of patients. The rate of infusion reactions drops to 3% in the second cycle and to less than 1% in subsequent cycles.
Bendamustine
More recently, bendamustine, an alkylating agent with purine analog properties, was compared with chlorambucil in a multicenter, randomized trial and yielded a better response rate of 68% with a 31% complete response rate and PFS of 21.6 months. There was no difference in OS.[rx]
Promising results were obtained from the combination of bendamustine with rituximab (BR) in relapsed CLL patients at a dose of 70 mg/m2 of bendamustine on Days 1 and 2 and 375 mg/m2 of rituximab on Day 1 of the first cycle and 500 mg/m2 in the subsequent cycles, for a total of six cycles every 28 days.[rx]When used as first-line treatment, the BR scheme with a higher dose of 90 mg/m2 of bendamustine yielded a 97% response rate and complete remission rate of 31%. A CLL10 study demonstrated comparable results to FCR in terms of response rates but with fewer complete remissions. This difference was not confirmed in the sub-analysis of patients older than 65 years or who had more comorbidities.[rx] Unfortunately, bendamustine is not available in Brazil yet and is not approved for use.
Alemtuzumab
Alemtuzumab is a humanized monoclonal antibody against the CD52 antigen with proven activity in CLL. In patients with advanced-stage disease, alemtuzumab monotherapy yielded response rates of 30–50%, with a median PFS of 9–15 months after second-line treatment with fludarabine.[rx, rx, rx] Alemtuzumab also has proven effectiveness for both del11q and del17p.[rx] In a randomized study, alemtuzumab showed a higher response rate and better PFS in treatment-naïve patients than chlorambucil.[rx] The synergistic activity of alemtuzumab with fludarabine was effective and safe in a phase II study, with a response rate of 83% and complete remission rate with a negative MRD of 53%.[rx] In a phase III study, alemtuzumab in combination with FC was more toxic than the FCR regimen.91 In a phase II study, a combination treatment of alemtuzumab with FCR demonstrated excellent response rates of 92%, with 70% of all individuals achieving complete remission and 57% of del17p individuals achieving complete remission. This scheme can be an alternative bridge therapy to achieve remission before transplantation in del17p patients.[rx] In a multicenter phase II study, the combination of 30 mg alemtuzumab three times a week with 1.0 g/m2 methylprednisolone (MP) for five consecutive days every 4 weeks in TP53-deleted CLL resulted in an overall response rate of 85% and a complete response rate of 36%. The risk of infection was age-related and seemed only marginally higher in younger patients than the infection risk associated with FCR.[rx]
Alemtuzumab is no longer approved for use in Brazil for CLL and is marketed only for its indication in multiple sclerosis. However, alemtuzumab is available for patients with CLL through a compassionate-use program.
Lenalidomide
Lenalidomide is a medication with immunomodulatory and antiangiogenic effects. It has reasonable response rates in relapsed patients[rx], [rx] and has some activity in del17p patients.[rx] Phase II trials demonstrated good synergism with rituximab.[rx] An association between rituximab and fludarabine is also feasible, although a phase I study yielded ominous results, with an excess of side effects, myelosuppression and tumor flares.[rx]
Agents targeting B-cell receptor signaling
Ibrutinib – A new therapeutic drug class has shown promising results when used in conjunction with targeted therapy in CLL. The most prominent agent in this class seems to be the Bruton’s tyrosine kinase inhibitor ibrutinib. Phase I and phase II studies have shown a surprising response in relapsed or refractory patients, including high-risk groups (e.g., del17p patients or patients who relapsed within 24 months of previous treatment). PFS and OS at 26 months were 71% and 83%, respectively, and 57% and 70% in patients with del17p, respectively.[rx] The phase III RESONATE study included 391 relapsed or refractory patients, including 33% with del17p. Ibrutinib showed better PFS and OS results than ofatumumab. The excellent response rates were maintained in high-risk patients with del17p as well as in patients refractory to purine analogs. This medication is considered the best choice for second-line treatment in elderly patients and patients with comorbidities.[rx] The presence of lymphocytosis is common in ibrutinib patients, with peak lymphocytosis usually occurring four weeks after the beginning of treatment, but 80% of patients have had resolution or at least a 50% decrease in their lymphocyte count. This decline was faster in patients with unmutated IgHV.[rx] Ibrutinib treatment used as first-line treatment was tested in the RESONATE-2 study in elderly patients and was compared with chlorambucil, yielding excellent results. There was a 86% overall response rate, and OS was estimated at 24 months to be 98%.[rx] Combination therapy with rituximab[rx] and ofatumumab[rx] has been performed in relapsed patients with promising results, even in high-risk groups. The best approach for using these novel modalities is still a matter of debate. Ibrutinibe was recently approved in Brazil, only for relapsed/refractory CLL patients.
Idelalisib – Another important medication is an inhibitor of the class I phosphatidylinositol 3-kinase (PI3K) p110 δ isoform called . A phase I study in relapsed or refractory patients showed promising results, and a percentage of patients showed a partial response with lymphocytosis.[rx] Its combination with Rituximab was tested in treatment-naïve patients[rx] and in a relapse context.[rx] In a phase II study with idelalisib as a first-line treatment in elderly patients, combination treatment showed excellent results, with an overall response rate of 96.0% and a complete response rate of 14.1%, as well as PFS and OS rates at 36 months of 92.9% and 90%, respectively. The response was maintained in patients with del17p. The presence of diarrhea or colitis grade 3 or 4 can limit the use of this medication, mainly because the incidence of side effects was more common after multiple months of treatment.[rx] Idelalisib is not available in Brazil yet and is not approved for use.
Bcl-2 inhibitors
Other new therapeutic classes include Bcl-2 inhibitors. A phase I study with Venetoclax (ABT-199) showed excellent results, with an overall response rate of 79% and a 20% complete response rate, including 5% negativity for MRD and a PFS rate at 15 months of 66%. High-risk del17p patients had similar results, but with less sustained PFS.[rx] Venetoclax is not available in Brazil yet and is not approved for use.
Allogeneic HSCT is effective in CLL as shown by the 10-year complete remission rate of 69% and OS of 55% in a cohort of 49 consecutive patients with 20 years of follow up.[rx] However, the non-relapse mortality is still in the range of 20% in most series.[rx] An important finding is that prognostic factors that negatively influence the outcome of CLL under chemoimmunotherapy, such as unmutated IGHV gene, unfavorable genetic abnormalities, and purine analog refractoriness, do not adversely affect PFS or OS after HSCT.[rx] Currently, HSCT is still the only curative option for appropriate candidates (young, fit patients with an adequate donor). As there is no direct comparison between transplant and the novel agents (ibrutinib, idelalisib, or venotoclax), more data is needed to determine which patients should still be considered for HSCT, and which should be considered for prolonged treatment with one of these novel agents.
Complications
Chronic lymphocytic leukaemia (CLL) can sometimes cause a number of further complications.Some of the main problems people with the condition may experience are outlined below.
Frequent infections. People with chronic lymphocytic leukemia may experience frequent infections. In most cases, these infections are common infections of the upper and lower respiratory tract. But sometimes more-serious infections can develop.
A switch to a more aggressive form of cancer. A small number of people with chronic lymphocytic leukemia may develop a more aggressive form of cancer called diffuse large B-cell lymphoma. Doctors sometimes refer to this as Richter’s syndrome.
Increased risk of other cancers. People with chronic lymphocytic leukemia have an increased risk of other types of cancer, including skin cancer, such as melanoma, and cancers of the lung and the digestive tract.
Immune system problems. A small number of people with chronic lymphocytic leukemia may develop an immune system problem that causes the disease-fighting cells of the immune system to mistakenly attack the red blood cells or the platelets.
Infections – People with CLL usually have a weakened immune system and are more vulnerable to infections because they have a lack of healthy infection-fighting white blood cells. Treatment with chemotherapy can also further weaken the immune system.
If you have CLL, it’s a good idea to:
report any possible symptoms of an infection to your GP or care team immediately – things to look out for include a high temperature, aching muscles, diarrhoea or headaches
ensure your vaccinations are up-to-date – speak to your GP or care team for advice about any additional vaccines you might need, as some are not safe if you have a weak immune system
avoid close contact with anyone who has an infection – even if it’s an infection to which you were previously immune, such as chickenpox
You may also be prescribed regular doses of medications like antibiotics to help reduce the risk of infection.
Richter’s syndrome
In rare cases, CLL can change to become very similar to an aggressive form of non-Hodgkin lymphoma. This is called Richter’s transformation or Richter’s syndrome.
Richter syndrome is usually treated with a combination of chemotherapy and other powerful medicines.
Autoimmune haemolytic anemia
Another rare complication, CLL can develop a condition called autoimmune hemolytic anemia. This is where the immune system starts to attack and destroy red blood cells. It can cause severe anemia, making you feel breathless and easily tired.
Psychological effects
Being diagnosed with CLL can be very distressing and difficult to take in at first, particularly as it cannot necessarily be cured and you may be advised to wait for it to get worse before starting treatment. Having to wait years to see how the condition develops can also be very stressful and make you feel anxious or depressed.
About the author