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Chronic lymphocytic leukaemia

By Dr Moustafa Abdou, Consultant Haematologist, Lister Hospital, UK - 05th Apr 2022

Dr Moustafa Abdou – Consultant Haematologist, Lister Hospital, UK |

While still generally incurable, there are a range of treatment approaches for chronic lymphocytic leukaemia, with a number of newer agents providing good results

Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world. It is a low-grade lymphoproliferative malignancy in which there is a proliferation of small mature lymphocytes (almost always B cells) in the blood, bone marrow, spleen, and lymph nodes. 

CLL occurs mainly in the older population; 75 per cent of cases are diagnosed in patients >60 years. CLL is twice as common in men compared ot women. The disease is rare in Japan and China. 

Although the cause of CLL is unknown, some cases appear to have a hereditary component. 

Symptom-wise, there is usually a gradual onset of fatigue, malaise, and lymphadenopathy. 

The most common symptoms of CLL are: 

  • Aching bones and joints; 
  • Getting infections more frequently, and recovering more slowly from infections; 
  • Headaches; 
  • Night sweats and fever; 
  • Dyspnoea; 
  • Lymphadenopathy; 
  • Splenomegaly; 
  • Fatigue, malaise and looking pale; 
  • Unexplained bruising or bleeding; 
  • Weight loss/loss of appetite; 
  • Hepatomegaly is usually a late feature. 

CLL is confirmed by examining the peripheral smear and bone marrow; the hallmark is sustained, absolute peripheral lymphocytosis (>5000/μL) and increased lymphocytes (>30 per cent) in the bone marrow. 


In about 98 per cent of cases of CLL, CD5+ B cells undergo malignant transformation, with lymphocytes initially accumulating in the bone marrow and then spreading to lymph nodes and other lymphoid tissues, eventually inducing splenomegaly and hepatomegaly. 

Figure 1: Chronic lymphocytic leukaemia blood film 
Figure 2: Prolymphocytic leukaemia 

As CLL progresses, abnormal haematopoiesis results in anaemia, neutropaenia, thrombocytopaenia, and decreased immunoglobulin production. Many patients develop hypogammaglobulinaemia and impaired antibody response, perhaps related to increased T-suppressor cell activity. 

Patients with CLL have increased susceptibility to autoimmune disease, characterised by immune haemolytic anaemia (usually Coombs test positive) or immune thrombocytopaenia and a modest increase in the risk of developing other cancers. 

In 2-to-3 per cent of CLL cases, the clonal expansion is T-cell type, and even this group has a subtype (eg, large granular lymphocytes with cytopaenias). 

Figure 3: FCM scoring system for CCL 

In addition, other chronic leukaemic patterns have been categorised under CLL: 

  • Prolymphocytic leukaemia (PLL). 
  • Leukaemic phase of cutaneous T-cell lymphoma (Sézary syndrome). 
  • Hairy cell leukaemia. 
  • Lymphoma progressing to leukaemia (ie, leukaemic changes that occur in advanced stages of malignant lymphoma). 

Differentiation of these subtypes from typical CLL is usually made by using light microscopy and phenotyping. 

Figure 4: CLL BM biopsy 


There is usually a mild normocytic anaemia in CLL. This becomes more marked as the disease progresses or if there is associated autoimmune haemolytic anaemia (5- to-10 per cent). 

The granulocyte count and platelet count only fall late in the disease. 

Most cases of CLL are B-cell neoplasms, however, rare cases of CLL are T-cell neoplasms. 

In patients with CLL, the full blood count (FBC) with differential shows absolute lymphocytosis, with more than 5,000 B-lymphocytes/μL. Lymphocytosis must persist for longer than three months. Clonality must be confirmed by flow cytometry. The presence of a cytopaenia caused by clonal bone marrow involvement establishes the diagnosis of CLL regardless of the peripheral B-lymphocyte count. 

Patients with fewer than 5,000 B-lymphocytes/μL with lymphadenopathy and without cytopaenias more likely have small lymphocytic lymphoma (SLL), although this diagnosis should be confirmed by lymph node biopsy. 

Patients with a clonal B-cell population less than 5000/ μL without lymphadenopathy or organomegaly, cytopaenia, or other disease-related symptoms have monoclonal B-lymphocytosis (MBL). MBL will progress to CLL at a rate of 1-to-2 per cent per year. 

Microscopic examination of the peripheral blood smear is indicated to confirm lymphocytosis. It usually shows small lymphocytes predominating and the presence of smudge (smear) cells, which are artefacts from lymphocytes damaged during the slide preparation. 

Large atypical cells, cleaved cells, and prolymphocytes are also often seen on the peripheral smear and may account for up to 55 per cent of peripheral lymphocytes. If this percentage is exceeded, B-cell PLL is a more likely diagnosis. 

Peripheral blood flow cytometry is the most valuable test to confirm a diagnosis of CLL. It confirms the presence of circulating clonal B-lymphocytes expressing CD5 (normally expressed on T-cells), CD19, CD20, CD23, and an absence of CD10 and FMC-7 staining. The cells express light-chain restricted monoclonal Ig, usually IgM ± IgD. 

Immunophenotyping is essential for the diagnosis of CLL. The scoring proposed in the modified Matutes score has been the basis of diagnosis for the past 15 years and is defined by strong expression of CD5 and CD23, low or absent expression of CD79b, sIgM, and FMC7 (Figure 3). 

Bone marrow aspiration and biopsy with flow cytometry are not required in all cases of CLL, but may be necessary in selected cases to establish the diagnosis and to assess other complicating features such as anaemia and thrombocytopaenia. For example, bone marrow examination may be necessary to distinguish between thrombocytopaenia of peripheral destruction (in the spleen) and that due to marrow infiltration. 

Consider a lymph node biopsy if lymph nodes begin to enlarge rapidly in a patient with known CLL, to assess the possibility of transformation to a high-grade lymphoma. When such transformation is accompanied by fever, weight loss, and pain, it is termed Richter syndrome. 

The bone marrow is infiltrated by small lymphocytes (see Figure 4). Biopsy of affected lymph nodes shows a diffuse infiltration with small lymphocytes. 

Hypogammaglobulinaemia occurs in approximately one-third of CLL cases; ‘M’ bands (usually IgM) are found in approximately 5 per cent. 

Consider obtaining serum quantitative immunoglobulin levels in patients developing repeated infections, because monthly intravenous immunoglobulin administration in patients with low levels of immunoglobulin G (IgG) (<0.5gm) may be beneficial in reducing the frequency of infectious episodes. 

A positive direct Coombs test (DCT) occurs in 25 per cent of cases (usually without haemolysis) at some stage during the disease. 

CLL cytogenetics 

Chromosomal evaluation using FISH testing can identify certain chromosomal abnormalities of CLL with prognostic significance. 

Patients with a deletion in the short arm of chromosome 17 [del(17p)/p53 gene] tend to have a worse prognosis, as well as resistance to therapy with alkylating agents and purine analogues. 

Patients with deletions in the long arm of chromosome 11 [del(11q)/ATM gene] also have a worse prognosis and bulky lymphadenopathy at presentation. 

The poor prognos is seen with del(17p) and del (11q) are independent of the patient’s stage at presentation. Patients with these abnormalities may benefit from treatment with the monoclonal antibody alemtuzumab. 

IgVH status has shown potential as a prognostic marker for CLL as well. ZAP-70 and CD38 expression tend to correlate with unmutated IgVH and a poorer prognosis; however, these associations are not absolute. 

None of the poor prognostic markers have been validated as an indication to initiate treatment in asymptomatic patients. 


Two staging systems are in common use for CLL – the modified Rai staging system in the US and the Binet staging system in Europe. Neither is completely satisfactory, and both have often been modified. 

Differential diagnosis 

The differential diagnosis of CLL includes several other entities, such as hairy cell leukaemia, which is moderately positive for surface membrane immunoglobulins of multiple heavy-chain classes and is typically negative for CD5 and CD21. 

PLL has a typical phenotype that is positive for CD19, CD20, and surface membrane immunoglobulin; one-half will be negative for CD5. 

Large granular lymphocytic leukaemia has a natural killer (NK) cell phenotype (CD2, CD16, and CD56) or a T-cell immunophenotype (CD2, CD3, and CD8). 

The pattern of positivity for CD19, CD20, and the T-cell antigen CD5 is shared only by mantle cell lymphoma; these cells generally do not express CD23. 

Splenic lymphoma with villous lymphocytes is strongly positive for surface immunoglobulin, and positive for FMC-7, CD22, CD79b, and DBA-44. 

Follicular lymphoma is also strongly positive for surface immunoglobulin, positive for FMC-7, CD22, CD10, CD79b, and weak CD23. 


Despite medical advances in the recent years, CLL primarily remains a chronic, generally incurable disease. Treatment for CLL largely depends how far developed it is when it is diagnosed. 

Treatment in CLL focuses on symptom amelioration, supportive care, and specific therapy. 

Table 1

Symptom amelioration 

Patients with CLL do not need to be treated with chemotherapy until they become symptomatic or display evidence of rapid progression of disease, as characterised by the following: 

  • Weight loss of more than 10 per cent over six months. 
  • Extreme fatigue. 
  • Fever related to leukaemia for longer than two weeks. 
  • Night sweats for longer than one month. 
  • Progressive marrow failure (anaemia or thrombocytopaenia). 
  • Autoimmune anaemia or thrombocytopaenia not responding to steroids. 
  • Progressive or symptomatic splenomegaly. 
  • Massive or symptomatic lymphadenopathy. 
  • Progressive lymphocytosis, as defined by an increase of >50 per cent in two months or a doubling time of less than six months. 

Supportive care includes 

  • Transfusion of packed RBCs or erythropoietin injections for anaemia. 
  • Platelet transfusions for bleeding associated with thrombocytopaenia. 
  • Antimicrobials for bacterial, fungal, or viral infections. 

Because neutropaenia and hypogammaglobulinaemia limit bacterial killing, antibiotic therapy should be bactericidal. Therapeutic infusions of γ-globulin should be considered in patients with hypogammaglobulinaemia and repeated or refractory infections or for prophylaxis when ≥ two severe infections occur within six months. 

Specific therapy includes 

  • Chemotherapy. 
  • Corticosteroids. 
  • Monoclonal antibody therapy. 
  • Bruton tyrosine kinase inhibitors. 
  • CAR T-cell therapy. 
  • Radiation therapy. 
  • Stem cell transplantation (most commonly allogeneic transplant for CLL). 

These modalities may alleviate symptoms and prolong survival. Over-treatment is more dangerous than undertreatment. 


Alkylating drugs, especially chlorambucil, alone or with corticosteroids, have long been the usual therapy for B-cell CLL. However, fludarabine is more effective. Combination chemotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) more often induces complete remission. It also lengthens remission duration and prolongs survival. 

A phase 3 trial comparing bendamustine to chlorambucil in treatment-naive patients who were not deemed candidates for more aggressive regimens like FCR, showed no improvement in overall survival, but did show a complete response (21 per cent vs 10 per cent) and progression-free survival (PFS) (21 months vs nine months) favouring bendamustine without compromising the quality-of-life. 

A bendamustine/rituximab combination has had some renewed interest. In a German phase 2 study of 72 pre-treated patients, the overall response rate was 59 per cent, and PFS was almost 15 months. 

Patients with PLL and lymphoma/leukaemia usually require multidrug chemotherapy, eg, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and often respond only partially. 

Interferon alfa, deoxycoformycin, and 2-chlorodeoxyadenosine (cladribine) are highly effective for hairy cell leukaemia. 

Radiation therapy 

Local irradiation for palliation may be given to areas of lymphadenopathy or for liver and spleen involvement that does not respond to chemotherapy. Total body irradiation in small doses is occasionally successful in temporarily ameliorating symptoms. 


Autoimmune haemolytic anaemia and thrombocytopaenia are indications for corticosteroids. 

Prednisone 1mg/kg po once/day may occasionally result in striking, rapid improvement in patients with advanced CLL, although response is often brief. The metabolic complications and increasing rate and severity of infections warrant caution in its prolonged use. 

Prednisone used with fludarabine increases the risk of Pneumocystis jirovecii pneumonia, formerly known as Pneumocystis carinii pneumonia (PCP), and Listeria infections and requires PCP prophylaxis with oral cotrimoxazole or pentamidine inhalation. 

Monoclonal antibody therapy 

Rituximab was the first monoclonal antibody used in the successful treatment of lymphoid cancers. In previously-untreated patients, the response rate is 75 per cent, with 20 per cent of patients achieving complete remission. 

Alemtuzumab (MabCampath) has a 33 per cent response rate in previously-treated patients refractory to fludarabine, and a 75-to-80 per cent response rate in previously-untreated patients. More problems with immunosuppression occur with alemtuzumab than with rituximab. 

Rituximab has been combined with fludarabine and with fludarabine and cyclophosphamide; these combinations have markedly improved the complete remission rate in both previously treated and untreated patients. 

Alemtuzumab is now being combined with rituximab and with chemotherapy to treat minimal residual disease (MCR) and has effectively cleared bone marrow infiltration. Reactivation of cytomegalovirus and other opportunistic infections has occurred with alemtuzumab. Reactivation of hepatitis B infection may occur with rituximab. 

Obinutuzumab (Gazyva) is a newer CD20-directed cytolytic monoclonal antibody that targets the same CLL cell surface protein as rituximab. The combination of obinutuzumab and chlorambucil was recently found to be superior to rituximab in prolonging PFS and achieving a complete response to treatment. In combination with bendamustine, obinutuzumab can be used for the treatment of patients with follicular lymphoma (FL) who have had prior therapy with a rituximab-containing regimen. 

In 2015, the US Food and Drug Administration (FDA) granted breakthrough therapy designation to venetoclax (Venclexta) for subjects with CLL who have relapsed or have been refractory to previous treatment and have the 17p deletion genetic mutation. Venetoclax is a highly selective inhibitor of BCL2, which was shown to have substantial anti-tumour activity in patients with relapsed CLL, including those with poor prognostic features. Responses appeared to be more durable among those who had a complete response than among those with a partial response. Gradual dose escalation appeared to minimise the risk of tumour lysis syndrome, the major toxicity associated with venetoclax. Targeted treatment with venetoclax–obinutuzumab has been shown to be effective in previously untreated patients with CLL and coexisting conditions and resulted in a significantly higher percentage of patients with PFS than standard treatment with chlorambucil–obinutuzumab. 

In Ireland, since December 2018, venetoclax has been reimbursed for the treatment of CLL; in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor. Since 2020 it has been reimbursed in combination with rituximab for the treatment of adult patients with CLL who have received at least one prior therapy; and, as of March 2022, in combination with obinutuzumab for the treatment of adult patients with previously untreated CLL. 

In general, monoclonal antibodies are well tolerated, although they may cause allergic reactions and significant immunosuppression. This favourable toxicity profile allows these agents to be combined with conventional chemotherapy, often with excellent clinical efficacy. 

Table 2

Bruton tyrosine kinase inhibitors 

Bruton tyrosine kinase (BTK) is a nonreceptor tyrosine kinase that plays a central role in the signal transduction of the B-cell antigen receptor and other cell surface receptors, both in normal and malignant B lymphocytes. B-cell antigen receptor signalling is activated in secondary lymphatic organs and drives the proliferation of malignant B-cells, including CLL cells. During the last 10 years, BTK inhibitors (BTKi) are increasingly replacing chemotherapy-based regimens, especially in patients with CLL and mantle cell lymphoma (MCL). BTKi are particularly active in patients with CLL and MCL, but also received approval for Waldenström macroglobulinaemia, small lymphocytic lymphoma, marginal zone lymphoma, and chronic graft-versus-host disease. Current clinical practice is continuous long-term administration of BTKi, which can be complicated by adverse effects or the development of drug resistance. Alternatives to long-term use of BTKi are being developed, such as combination therapies, permitting for limited duration therapy. Second-generation BTKi are under development, which differ from ibrutinib, the first-in-class BTKi, in their specificity for BTK, and therefore may differentiate themselves from ibrutinib in terms of adverse effects or efficacy. 

Ibrutinib is a novel, oral inhibitor of BTK. Ibrutinib appears to be highly active in CLL particularly in the presence of 17p deletion or TP53 mutations and has induced durable remissions in some patients with relapsed or refractory CLL. Its role as a single agent or as part of combination chemotherapy is evolving. Ibrutinib is also active in relapsed or refractory MCL and Waldenström’s macroglobulinaemia. Ibrutinib monotherapy and idelalisib in combination with rituximab induce responses in the majority of patients in whom chemoimmunotherapy has failed, and these patients have improved outcomes. 

Idelalisib (Zydelig 150mg tablets) is indicated in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab) for the treatment of adult patients with CLL who have received at least one prior therapy, or as first-line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies. 

CAR T-cell therapy 

In chimeric antigen receptor (CAR) T-cell therapy, a patient’s own genetically modified T-cells are engineered to express receptors that latch on to a specific cell surface protein, connecting them to cancer cells to be destroyed. 

CAR T-cell therapy has already achieved remarkable remissions in some difficult-to-treat patients with B-cell malignancies. Although the clinical experience in CLL patients is limited, the proportion of remissions reached in this disease is clearly the lowest from the spectrum of B-cell tumours. 

Currently, CAR T-cell therapy is US FDA approved as standard of care for: 

  • Some forms of aggressive, relapsed or refractory non-Hodgkin lymphoma including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, transformed follicular lymphoma, MCL: 
  • Relapsed or refractory follicular lymphoma; 
  • Relapsed or refractory multiple myeloma; 
  • Relapsed or refractory acute lymphoblastic leukaemia. 

There are also many clinical trials of CAR T-cell therapy for other types of blood cancer and solid tumours. 

CAR-T therapy is available in more than 15 EU countries, has been publicly available in England through the NHS since 2018, and has very recently made its way to Ireland. The National Cancer Control Programme (NCCP) has designated St James’s Hospital, Dublin, as the initial National Adult CAR-T centre in Ireland and Children’s Health Ireland (CHI) in Crumlin as the National Paediatric CAR-T centre. In December 2021 the first patient in Ireland was treated with CAR T-cell therapy for lymphoma at St James’s Hospital. The HSE spent €8.18 million on Irish patients receiving this therapy in the UK in 2019 and 2020, via the Treatment Abroad scheme. 


The median survival of patients with B-cell CLL or its complications is about seven-to-10 years. Patients in Rai stage 0-to-II at diagnosis may survive for between five-to-20 years without treatment. Patients in Rai stage III or IV are more likely to die within three-to-four years of diagnosis. Progression to bone marrow failure is usually associated with short survival. Patients with CLL are more likely to develop a secondary cancer, especially skin cancer. However, as outlined in this article, there have been a number of positive therapeutic developments in recent years, with improving length of survival, and hopefully further improvements to come.


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