State of the Art Oncology in EuropeFont: aaa

Chronic lymphocytic leukaemia – 2015

UPDATED JULY 2015

1. General information

1.1 What is the disease and how is it treated?

What is chronic lymphocytic leukaemia?
Chronic lymphocytic leukaemia (CLL) is a cancer of the blood involving an abnormal increase in the number of B lymphocytes, the white blood cells that produce antibodies.

What are the causes of this disease?
The exact causes of chronic lymphocytic leukaemia are not known. However, some lifestyle factors can increase or decrease the risk of developing the disease: people living or working on a farm are at higher risk, while sun exposure has a protective role. Hepatitis C infection is a factor that seems to increase the risk. Furthermore, some people have genes that increase their risk.

Is it a frequent disease?
Chronic lymphocytic leukaemia is the most common leukaemia among adults, but it is an uncommon disease overall, with 4-6 new cases per 100,000 persons per year. It mainly affects older adults.

How is it treated?
About 30% of patients never develop serious symptoms and never require treatment. Those who do need treatment may receive one or several cycles of one or more drugs and, in a few select cases, bone marrow transplantation.

2. What is it, how does it occur, how is it diagnosed?

2.1 What is chronic lymphocytic leukaemia?

CLL is a cancer of the blood involving an abnormal increase in the number of B lymphocytes in the peripheral blood, in bone marrow, and in lymphoid organs . B lymphocytes (also called B cells) are the subgroup of white blood cells that produce antibodies to fight infections (disorders in which an excessive number of lymphocytes are produced are called lymphoproliferative disorders).
A high number of lymphocytes can have several causes, including an ongoing infection, and does not necessarily mean that a person has leukaemia. To be diagnosed with leukaemia, a patient must have at least 5×109/L B lymphocytes (5 billion B lymphocytes per litre of blood), and this high lymphocyte count should persist for more than 3 months. Furthermore, in CLL the lymphocytes are monoclonal.
In less frequent cases, the excessive lymphocyte number involves mainly the lymph nodes, and not the peripheral blood nor the bone marrow, so that there is no decrease in the number of other blood cells, such as red blood cells or platelets (cytopoenia), caused by bone marrow damage. This condition takes a different name, small-lymphocytic lymphoma, but it represents a different clinical manifestation of the same disease and it is managed in the same way.
If lymphocytes proliferate excessively and show the typical anomalies of chronic lymphocytic leukaemia, but their number remains below 5 billion per litre (5×109/L), and there are no other signs or symptoms of lymphoproliferative disorders, the condition is called a CLL-like monoclonal B cell lymphocytosis, a recently defined entity (see 2.5 “Monoclonal B cell lymphocytosis”).

2.1.1 Disease stats

Chronic lymphocytic leukaemia is the most common leukaemia among adults in Western Countries. Its incidence is similar in Europe and the US and ranges between 4 and 6 cases per 100,000 persons per year. The disease becomes more frequent with age, with more than 70% of patients being older than 65 years at diagnosis, but in the last decades diagnosis in younger individuals has increased, with almost 15% of patients being 55 years old or younger. It is slightly more frequent in men, with around 1.5-2 affected men for each woman.

2.2 Risk factors

Despite several studies, no environmental risk factors leading to chronic lymphocytic leukaemia development have been identified so far. However, some occupational and lifestyle factors can increase or decrease the risk: people living or working on a farm are at higher risk of disease development, while sun exposure has a protective role. Also, hepatitis C infection seems to increase the risk of several lymphoproliferative disorders, including chronic lymphocytic leukaemia.
Several lines of evidence show that some people have genes that increase their risk of developing the disease:

  • the strongest and most consistent risk factor for the disease is a family history of blood cancer (chronic lymphocytic leukaemia or non Hodgkin lymphomas). Relatives of chronic lymphocytic leukaemia patients have a 2-to-8-fold increase in the risk of developing the same disease and a 2-fold increase in the risk of developing non Hodgkin lymphomas, compared to the general population. Up to 10% of chronic lymphocytic leukaemia patients reported having two or more relatives affected by the same disease; in this case the condition is called “familial”, but it shares the same features as sporadic, non-familial cases and is managed in the same way;
  • the disease is rarer in the Eastern world (China, Korea, and Japan) and this lower incidence is maintained in migrants and their progeny, so it seems to depend on genetic causes and not on environmental factors;
  • finally, genetic studies have identified several gene variants that seem to increase disease susceptibility.

2.3 What are the symptoms?

Most patients have no symptoms at diagnosis and the disease is detected through increased lymphocyte count at blood tests performed for unrelated reasons. In some cases the disease is detected because the doctor finds enlarged lymph nodes (lymphoadenopathy) or enlarged spleen (splenomegaly) and decides to perform further investigations.
A group of symptoms called “B symptoms” (fever of unknown origin higher than 100.5°F or 38.0°C for at least 2 weeks without infection; unintentional weight loss of 10% or more within the previous 6 months; night sweats for more than 1 month without evidence of infection), typical of advanced lymphomas, are rarely present in chronic lymphocytic leukaemia.
Patients with advanced disease can show fatigue and intolerance to physical exercise due to anaemia, due to damage caused by cancer cells to the bone marrow, while bleeding due to low platelet count is very rare.
CLL confers a higher vulnerability to infections, because it damages the immune system, impairing the response to germs. Even after an effective treatment the immune function does not improve and is actually worsened by the majority of available therapies, because most treatments target the diseased cells, but also damage healthy immune cells.
Bacterial infections involving the upper and lower respiratory tract and urinary tract are the most frequent infections, though reactivation of dormant viruses remaining in the body from previous infections (e.g., herpes zoster) has also been reported.
Advanced disease is frequently characterised by worsening infections – partly due to previous treatments – which are the main cause of death.
Some patients also suffer autoimmune disorders, in most cases directed against hematopoietic cells : this happens because leukaemia causes a profound immune system dysregulation, so your body produces antibodies against your own red blood cells or platelets. This causes disorders such as low red cell number (autoimmune haemolytic anaemia, in 10%-25% patients, or pure red cell aplasia, in less than 1%), reduced platelet number (immune thrombocytopoenia, 1%-5%), and other very rare manifestations (such as autoimmune neutropoenia – a reduced number of neutrophils – in 0.2% of cases). Other rare autoimmune complications involve tissues other than the blood (such as paraneoplastic pemphigus, acquired angioedema, and cold agglutinin disease).
Unlike other leukaemias, the high lymphocyte number does not cause leukostasis and does not require therapeutic intervention.

2.4 Diagnosis

The most up-to-date criteria to diagnose chronic lymphocytic leukaemia were defined in a workshop in 2008 (the International Workshop on Chronic Lymphocytic Leukaemia).
For chronic lymphocytic leukaemia to be diagnosed, the following two criteria need to be met:

  1. at least 5 billion B lymphocytes per litre (5×109/L) in the peripheral blood;
  2. specific biochemical features (a so-called peculiar immunophenotypic profile). An exam called flow cytometry shows a specific pattern of immune cell proteins in the blood: some proteins are present at high levels, some at low levels, and some show that the proliferating lymphocytes are monoclonal.

Small lymphocytic lymphoma (SLL) is diagnosed if there are less than 5 billion B lymphocytes per litre in the peripheral blood and enlarged lymph nodes (lymphoadenopathy) or enlarged spleen (splenomegaly); for diagnosis to be certain, it should be confirmed by examining the affected tissue whenever possible (histopathology evaluation).

If there are less than 5 billion B lymphocytes per litre in the peripheral blood, and no enlarged lymph nodes, spleen, or liver nor disease-related cytopoenia or B symptoms (see 2.3), the patient has a less serious condition known as monoclonal B-cell lymphocytosis (see 2.5).
A bone marrow biopsy is no longer required to diagnose CLL or SLL if there is no cytopoenia. However, bone marrow evaluation is still necessary to determine the disease’s stage and decide the treatment, and to confirm complete disease remission at the end of treatment.

2.4.1 Differential diagnosis

When a high lymphocyte number is found, it is necessary to distinguish if it is due to CLL or to other reasons. Two main alternative causes should be considered:

  • it can be a reaction to infections or
  • it can be due to other lymphoproliferative disorders, such as lymphomas (with names such as mantle cell lymphoma, splenic marginal zone lymphoma, or follicular lymphoma) or other leukaemias (such as hairy cell leukaemia, and B-cell prolymphocytic leukaemia).

To distinguish between these diagnoses, several laboratory evaluations are performed (see Table 2 in the Professional area).

2.5 Monoclonal B cell lymphocytosis

This condition has been recently defined. It is diagnosed when there is a population of B lymphocytes similar to those of CLL (monoclonal and with the same biochemical features), but less numerous than 5 billion cells per litre, and with no other signs or symptoms of disease such as lymphoadenopathy or hepatosplenomegaly .
If lymphocyte concentrations are not very high (less than 0.5 billion cells per litre), it could be just an anomalous laboratory value, which does not indicate an overt disease. On the contrary, patients with higher B lymphocyte count (higher than 0.5 billion cells per litre) carry a risk of progression into CLL requiring treatment of 1%-2% per year. For this reason, subjects with monoclonal B cell lymphocytosis should be followed-up lifelong with complete blood cell count and clinical evaluation every 6-12 months.

3 How is chronic lymphocytic leukaemia treated?

3.1 General information

It has been recently demonstrated that if chronic lymphocytic leukaemia patients are managed by haematologists who are well trained in this specific disease, they get several advantages: a longer time before they need to begin treatment, a significantly slower disease progression, and an important improvement in overall survival. In fact, patients referred to qualified haematology/oncology centres are more likely to perform prognostic testing, receive up-to-date treatment, and be enrolled in clinical trials. This is particularly relevant for high-risk patients (see 3.5c), whose adverse prognosis could be improved only through access to novel experimental drugs.

3.2 When to treat CLL

The management of patients poses two main issues: when to start treatment and which treatments to choose. International guidelines clearly specify that treatment should not necessarily start as soon as the disease is diagnosed, but only when it progresses or causes bothersome symptoms (this approach is called watchful waiting or wait-and-see). Signs of active disease deserving treatment include the following events (see also Table 6 in the Professional area):

  • the bone marrow is failing: the number of red blood cells or platelets becomes too low, or begins to drop faster (anaemia or thrombocytopoenia), because cancer cells are damaging the bone marrow;
  • the disease becomes bulky: there is a massive (more than 10 cm) or rapid progressive enlargement of lymph nodes (lymphoadenopathy), or a massive or rapid progressive enlargement of the spleen (splenomegaly);
  • the patient’s body uncontrollably attacks its own blood cells, causing a depletion of red blood cells or platelets (autoimmune anaemia or thrombocytopoenia) that does not improve with steroid treatment;
  • lymphocytes begin to proliferate very quickly (doubling their number in less than 6 months, or increasing their number by more than 50% in 2 months);
  • so-called B symptoms appear, a group of symptoms including: fever higher than 100.5°F or 38.0°C for at least 2 weeks without infection or other known causes; unintentional weight loss of 10% or more in the last 6 months; drenching night sweats for more than 1 month; extreme fatigue (a grade of 2 or more on a scale called ECOG performance status).

Other criteria have to be considered to correctly interpret these symptoms, so your doctor will evaluate when these events mean that you need to start treatment.

3.3 Response criteria

During treatment, a group of clinical criteria (enlargement of lymph nodes and spleen, lymphocyte number, abnormal cells and nodules in the bone marrow, number of platelets and neutrophils, haemoglobin levels) shows if the treatment is working or if a different strategy is needed. The response is classified according to the following categories (see Table 7 in the Professional Area):

  • complete response: complete disappearance of disease according to the clinical criteria listed above, including bone marrow evaluation; if all other clinical parameters are normal, but the bone marrow still shows some anomalies, it is called a complete response with incomplete bone marrow recovery;
  • partial response: the disease burden (the burden of signs and symptoms listed above) decreases by 50% or more, but does not disappear;
  • stable disease: the disease burden remains more or less the same, increasing or decreasing by less than 50%; in this case although the patient did not achieve a complete or partial response, there is no progressive disease;
  • progressive disease: the disease burden increases by 50% or more.

If the treatment achieves a complete or partial response, it is considered beneficial, while stable or progressive disease are considered treatment failures.

3.4 Treatment options

To choose the best treatment, doctors need to carefully evaluate different factors, including the following:

  1. patient fitness status: whether other illnesses are present, the patient’s general mental and physical status and performances, and whether the patient needs a caregiver;
  2. whether a gene called TP53 is altered;
  3. disease status: if it is a first-line or subsequent line of treatment; if the disease is relapsing or it became refractory to the last treatment.

3.5 First-line treatment

Fit or go-go patients: patients are defined as “fit” or “go-go” if they have normal renal function (creatinine clearance >70 ml/min) and no or few other disorders (which usually means getting a score of 6 or less on a scale called CIRS – comorbidity index of rating scale).
For these subjects, if they are experiencing progressive disease requiring treatment, the current standard of care is a therapy with three drugs, called FCR: fludarabine, cyclophosphamide, and rituximab. This combination is called immunochemotherapy (or chemoimmunotherapy) as it combines two treatments: immunotherapy and chemotherapy .
The former standard treatment used only two drugs (fludarabine and cyclophosphamide), but the new treatment has proved superior: it achieves a higher response rate, with 90% of patients experiencing an improvement and 40% achieving a complete response, and a better overall survival and survival without a progression of the disease; a relevant proportion of patients remains without detectable disease 10 years after the end of treatment.
This impressive result comes at a price, as the new treatment causes a higher frequency of some adverse effects, including severe neutropoenia (though apparently not more infections) during treatment, more bacterial and viral infections for 2 years after treatment, and possibly problems due to bone marrow damage, such as neutropoenia or other types of cytopoenia . In several patients, especially people older than 70 years, the adverse events require early treatment stop or dose reduction.
So it is now actively debated and studied whether the standard treatment scheme, which includes 6 courses, can be safely reduced to 3 or 4 cycles, reducing toxicity without compromising efficacy.
An alternative option for first-line treatment in fit patients is the use of two drugs, bendamustine + rituximab. In a recent trial, this combination proved less toxic in comparison to FCR, but also less effective (at least in individuals <65 years).

Unfit or slow go patients: if patients have a relevant burden of diseases in addition to leukaemia (CIRS score >6) or impaired renal function (creatinine clearance <70 ml/min) they are defined as “unfit” or “slow go”. Unfortunately, the vast majority of patients are included in this category, as the disease is usually diagnosed in advanced age, and treatment may begin many years after diagnosis.
In these patients, less toxic therapies are employed: chlorambucil can be used alone or in combination with other recently approved drugs (such as obinutuzumab or ofatumumab), which significantly improved response without adding too much toxicity.
Considering that the process of ageing is extremely heterogeneous and that nowadays many elderly patients maintain a very good performance status, more intensive treatment combinations have been tested in this population; among them, a light version of FCR immunochemotherapy with reduced doses. Though preliminary results are promising, these combinations still need further studies to confirm they are effective and safe for these patients.

High-risk patients: this category includes mainly patients bearing certain genetic anomalies (del17p or TP53) that target the p53 protein, which controls cell replication. The presence of these mutations per se does not imply that the outcome will be poor or that treatment is necessary, because in some patients with these aberrations the disease progresses slowly. But if these alterations are detected in patients with progressive disease requiring treatment, their prognosis is dismal and unfortunately there is no standard treatment that can overcome this adverse clinical course. For this reason, it is strongly recommended for these patients to be enrolled in clinical trials with novel agents, in a qualified haematology/oncology centre.
For them, allogeneic stem cell transplantation (also called bone marrow transplantation, see 3.8) should be considered early during disease course, as most of the effective treatments applied to reduce disease burden (including FCR, or alemtuzumab in combination with other drugs such as high-dose steroids) obtain short-lasting responses at best, while stronger drug combinations are often too toxic.
More recently, both the US Food and Drug Administration and the European Medicines Agency approved novel drugs in first-line treatment for patients with some genetic aberrations (del17p) if chemotherapy is contraindicated. According to experts, these drugs should considerably change treatment in high-risk patients in the near future. Approved agents include ibrutinib and idelalisib.

3.6 Treatment for relapsed and refractory chronic lymphocytic leukaemia

When the disease responds to first-line therapy but relapses after several months or years, there is no standard choice for how to treat these patients. The regimen choice is mainly based on response duration to first-line treatment, patient fitness, and side effects experienced with previous therapy.
If patients still have stable or progressive disease after treatment, or they relapse within 6 months after completing a fludarabine-based combination, the disease is called refractory. Patients with refractory disease or unfavourable genetic abnormalities should always be considered for enrolment in clinical trials.
Patients treated with first-line immunochemotherapy combinations experiencing a response duration of more than 24-36 months after the end of treatment should receive the same combinations.
Patients relapsing within 24-36 months after the end of treatment, as well as refractory patients, represent a clinical challenge and should always be considered for enrolment in clinical trials, which may or may not include stem cell transplantation. Obviously, they should not be retreated with the same drugs used in the first-line regimen, and, to avoid unwarranted toxicities, the response to the new treatment should be carefully evaluated in order to interrupt treatment early if ineffective.
Till recently, the most frequently applied options included the following:

  • alemtuzumab-based combinations, such as fludarabine and alemtuzumab;
  • high-dose methylprednisolone with rituximab.

In addition, new drugs have recently been approved in the relapsed/refractory disease:

  • the novel kinase inhibitors idelalisib (plus rituximab) and ibrutinib;
  • ofatumumab, approved for patients refractory to both fludarabine and alemtuzumab (so-called double-refractory CLL).

3.7 Experimental agents

Beside the recently approved agents, other novel treatments are being tested for chronic lymphocytic leukaemia, raising hope that we are getting closer to a chemotherapy-free strategy with fewer side effects and the prospect of curing the disease. Some of these drugs are in advanced clinical development, but they are still under trial and can be used only for specific groups of patients, such as individuals with high-risk or refractory disease.

3.8 Allogeneic stem cell transplantation

A stem cell transplantation, also called a bone marrow transplantation, is the infusion into the body of healthy stem cells, gathered from the blood or bone marrow of a healthy donor, to replace the diseased bone marrow that produces leukaemic cells. As the cells come from another person, it is called an allogeneic transplantation (in some diseases, cells collected from the same person are transplanted. But this procedure, called autologous transplantation, is no longer performed in chronic lymphocytic leukaemia patients, as it does not give better results than drug therapy).
According to recently updated recommendations by the European Society for Blood and Marrow Transplantation, allogeneic stem cell transplantation should be strongly considered in fit patients showing refractory disease or bearing TP53 aberrations. These patients with high-risk disease should be offered the chance to receive novel drugs and, when the maximum response is reached, two main options should be considered:

  1. to consolidate the result by performing an allogeneic stem cell transplantation;
  2. to continue the treatment with novel agents until the disease progresses, and only then perform the transplantation, if advisable.

The transplantation procedure should be carefully discussed between patient and doctor, considering that the choice of an early transplantation in high-risk disease is more advisable when patients have relapsed/refractory disease and unfavourable genetic abnormalities (such as del17p, TP53 mutation, del11q), are younger and without other relevant diseases, and a well-matched donor (with tissues similar to the recipient) is available.
Before the transplant, patients need to undergo chemotherapy to kill their diseased stem cells and prepare their bone marrow for the new stem cells. This process is called conditioning. A milder form of conditioning (reduced-intensity conditioning) with fewer side effects is often employed in aged patients or in those with other health problems. Several studies have demonstrated that reduced-intensity conditioning achieves good results, with a low early mortality (less than 5%) and survival rates of 50%-60% at 5 years (up to 54%-79% for patients in the more favourable conditions).
After the transplant, a serious risk, in addition to disease relapse, is graft versus host disease, a complication that happens when the new immune cells see the patient’s tissues as foreign and attack them. This not only increases post-transplant mortality, but also affects the quality of life in at least 25% of surviving patients.

3.9 Significance of minimal residual disease

As more effective treatment strategies become available, disease eradication and cure become an achievable goal for the future, though still unattained to date. If blood tests after treatment find less than 1 cancerous cell per 100,000 leukocytes, this state is called minimal residual disease (MRD) negativity. Nowadays, minimal residual disease evaluation is not used in routine clinical practice, but it is performed in most recent clinical trials to understand if it can be used to predict disease progression and survival, and to guide treatment decisions.

4. Stages

Staging of a disease is the determination of distinct phases in its course, to help decide what exams and treatment the patient should undergo.
Two staging systems are currently applied in chronic lymphocytic leukaemia patients: the Rai and the Binet staging system. These two systems are based only on complete blood cell count and physical examination, and they are powerful prognostic indicators (see “Prognosis”).

4.1 Rai staging system

This system is mainly used in the United States. The original classification, proposed in 1975, differentiates 5 groups based on progressively shorter overall survival (see Table 3 in the Professional Area).
The system was later revised and risk categories have been adapted (see Table 4 in the Professional Area).

4.2. Binet staging system

This system is mainly used in Europe. It defines 3 different risk categories based on the number of lymphoid sites involved, i.e., that are found enlarged at physical exam (cervical, axillary, and inguinal lymph nodes, liver, spleen) and the complete blood cell count values (see Table 5 in the Professional Area).

5. Prognosis

5.1 General information

Prognosis indicates the likelihood that treatment will be successful. It is a statistical measure obtained from different studies that observe the progress of the disease in a high number of patients. It is important to remember that these statistics merely provide an indication: no doctor is able to predict exactly what the outcome of treatment in an individual patient will be, nor how long the patient will live, as prognosis depends on several factors, in relation with the individual patient.

5.2 Natural history

The clinical course of CLL patients is extremely varied. Median overall survival is 10 years (i.e., half of the patients survive more than 10 years after diagnosis and half survive less), but this rough figure has little value in predicting what will happen to each patient, as survival ranges from a few months to decades.
On the one hand, about one third of patients never require treatment, are regularly followed up over time, and die “with” leukaemia rather than “because of” the disease. On the other hand, about the same proportion has to be treated at, or shortly after, diagnosis due to anaemia, thrombocytopoenia and/or bulky lymphoadenopathy, or splenomegaly, and has a reduced life expectancy (around 2-3 years). Finally, roughly one third of patients develop disease-related signs and symptoms and require treatment at variable intervals of time from diagnosis.
Available treatments can often induce disease remission, but they are not able to cure the disease. CLL still remains an incurable disease in virtually all cases. As far as it is known, there is no benefit from early treatment, and early chemotherapy might actually be detrimental in increasing the risk that the disease will be resistant to drugs when it relapses.
Nowadays, there are no prognostic factors able to discriminate from the beginning whether patients will eventually progress or not. For this reason, long-term follow-up is advised once chronic lymphocytic leukaemia is diagnosed. Prognostication is an active research field and many studies have tried to define not only prognostic markers that can predict at diagnosis whether and how the disease will progress, but also predictive markers able to predict response to treatment, thus potentially influencing treatment choices.

5.3 Traditional prognostic factors

Prognostic factors include clinical parameters (such as enlarged lymph nodes), laboratory data (such as the number of lymphocytes in the blood), and biological factors (such as gene mutations), that have been demonstrated to distinguish patients with low- or high-risk disease.
Among traditional prognostic factors, the Rai and Binet staging systems (see “Staging”) and lymphocyte doubling time are the most widely applied and they are also used to decide when to start treatment. Early stages, according to the Rai or Binet classifications, have longer overall survival, while a fast increase in the number of lymphocytes is frequently a sign of progressive disease.

5.4 Novel prognostic factors

In the last 15 years, biological markers have been identified that make it possible to classify patients according to their risk at diagnosis. These markers are currently in widespread use.
Biological prognostic factors include:

  • chromosome aberration del17p and mutations in gene TP53: these mutations target the protein p53, which controls cell replication. The presence of these mutations per se does not imply that the outcome will be poor, because in some patients with these aberrations the disease progresses slowly. But if these alterations are detected in patients with progressive disease requiring treatment, their prognosis is very unfavourable. Though the 2 mutations frequently occur together, in some patients only the TP53 mutation is present, so recent guidelines strongly suggest to search for both before starting treatment.

Only the presence of these 2 genetic aberrations, assessed in case of disease progression, is useful even in guiding clinical choices. Several other factors help predict the likely course of the disease, but their presence or absence is not important in deciding treatment.
These factors include chromosome aberrations detected with FISH :

  • del13q14: patients bearing this abnormality show a better prognosis;
    trisomy 12: patients bearing this abnormality show a less favourable clinical course and a somewhat shorter survival;
    del11q22-23: patients carrying this abnormality often show bulky enlarged lymph nodes and aggressive disease, with reduced overall survival.

Another relevant prognostic factor is mutations in the immunoglobulin gene IGHV; patients with these mutations have a better prognosis.
High levels of CD38 and CD49d proteins have also been proposed as independent markers of a worse prognosis. Another protein, ZAP70, is no longer used because of technical reasons.
In the relapsed/refractory disease, newly discovered prognostic gene mutations are:

  • NOTCH1 and SF3B1: their mutations have shown a negative impact in overall survival;
  • BIRC3: its mutations are associated with a very unfavourable prognosis, similar to that of TP53 mutated patients.

5.5 Response to therapy

For patients requiring treatment, response to therapy is per se the most powerful prognostic indicator for survival. Patients obtaining a complete response to treatment usually fare better than those with a partial response (see 3.3 “Response criteria”). As more effective treatment options are now available, recent clinical trials have demonstrated that reaching what is called minimal residual disease negativity predicts longer progression-free and overall survival (see 3.9 “Significance of minimal residual disease”).

6. What to do after treatment

6.1 Late sequelae

6.1.1 Infection risk

Patients affected by CLL are at increased risk of developing infections, because the disease impairs their immune response.
The risk increases if patients receive treatment, because therapy against diseased immune cells damages healthy cells too, further suppressing the patient’s immune response. The spectrum of infections changes according to the chosen drugs. Bacterial infections are the most common, but fungal and herpesvirus infections are also frequent. An increased risk for bacterial infections and reactivation of herpesvirus (remaining in the body from previous infections) can last for up to 2 years after intensive treatments like FCR (fludarabine, cyclophosphamide, and rituximab). Patients with hypogammaglobulinaemia and frequent, important infections benefit from preventive intravenous immunoglobulin administration; however, this treatment does not seem to be cost-effective in patients without clinically relevant infections.
In vary rare cases, monoclonal antibody drugs (in particular rituximab and alemtuzumab) can lead to a neurologic syndrome called progressive multifocal leukoencefalopathy, which is usually fatal. This is a viral disease caused by the JC virus, a common virus that causes mild infections without any consequence in people with normal immune function, but can seriously damage the brain in people with immune impairment.
Immunization, including vaccines for pneumococcus, influenza, haemophilus, tetanus, typhoid, and diphtheria, has been evaluated in CLL patients to prevent infections. However, responses to vaccines may be less effective because of the immune defects, and doctors are still not sure if, when, and how these immunizations should be used.

6.1.2 Second cancers

Patients affected by CLL have a higher risk of developing other cancers in comparison to people of the same age and gender. It is still unclear how much the increased risk depends on the immunologic defects caused by the disease itself and how much on therapies.
The risk of second cancers is more than doubled in these patients, with skin, prostate, breast, melanoma, lymphoma, gastrointestinal, and lung cancer being the most frequent. Second cancers are more common in older patients and male patients.
In addition, these second cancers also have an unfavourable prognosis, with inferior survival demonstrated for breast, colorectal, kidney, prostate, or lung cancer.

6.2 Follow-up

After diagnosis, patients who are candidates to a wait-and-see approach should be followed up at regular intervals, that need to be shorter at the beginning, to exclude a rapid increase in the disease burden. However, there are no clear indications about the frequency and the evaluation required for the follow-up of patients without symptoms. Follow-up is based on clinical evaluation and lab tests (complete blood cell count, kidney and liver function), while annual abdominal ultrasound is optional. Based on recently updated international guidelines, neither bone marrow biopsies nor CT scans are recommended at diagnosis or during follow-up, unless the disease becomes symptomatic or progressive.
Additional tests (including bone marrow biopsies and CT scans) should be performed in case of disease progression.
CT (or PET) scans are not useful in defining the disease status, but may be performed if signs and symptoms (such as fever, enlarged lymph nodes, and certain blood test results) raise suspicion of a rare but serious complication called Richter’s transformation (or Richter’s Syndrome). In Richter’s transformation, CLL or SLL suddenly progress to aggressive lymphoma. A CT scan helps doctors choose the optimal lymph node site for biopsy to confirm or disprove Richter’s transformation.

7. What to ask doctors

Here is a list of questions that you might wish to ask your doctor or any specialists you may consult.

General questions

  • What should I do if the discomfort increases, or if new symptoms appear?
  • May I phone you? What is the best time? If you are not available, may I ask for other specialists? Whom specifically?
  • What leaflets, books, or websites could I read to learn more about chronic lymphocytic leukaemia?
  • Is there a patient association I could contact?
  • Should I pay special attention to activities such as sports?
  • Do you have special advice regarding nutrition?
  • Is there any contraindication regarding vaccinations?
  • Does chronic lymphocytic leukaemia run in families?
  • Are my children at risk of getting chronic lymphocytic leukaemia?
  • Where can I get help dealing with my feelings?
  • Can you refer me for counselling?

Diagnosis and exams

  • What tests are you going to do?
  • What are you looking for?
  • Is biopsy painful? Is it performed under general or local anaesthesia?
  • How long will the exam take?
  • Is it painful?
  • Will I be asleep?
  • Is CT dangerous because of radiation exposure?
  • How long will it take to confirm diagnosis?

Treatment

  • Do I need a highly specialized centre? Which is the centre with the highest expertise in treating this disease in my country?
  • If the doctor suggests a wait-and-see approach, could the disease get worse while waiting?
  • What type of treatment do I need?
  • Is there any choice of treatments?
  • What are the risks and benefits of the treatments?
  • How can I help to reduce the side effects?
  • What signs should I recognize so that I can tell the doctor and ask if the approach needs to be changed?
  • What are the possible side effects of therapy? Will I lose my hair? Will I have nausea and vomiting?
  • Will treatment reduce my symptoms and discomfort?
  • During treatment, should I take special precautions or change my habits?
  • Is there any behaviour I could adopt to improve my prognosis?
  • Which supportive therapy is suggested during treatment?
  • How will my treatment affect me?
  • Will my treatment affect my sex life?
  • Will I need a special diet?
  • Will I be able to go back to work?