CLL (BSH 2018)

CD5+, CD23+, Surface Ig weak+, Strong CD43+, CD200+

CD79b -, FMC7-




Incidence 4.2 per 100,000 per year in UK

Median age of presentation 72

Men > Women

Caucasian > other ethnic groups

>80% incidental diagnosis




>5 x109/l circulating clonal B cells persisting for >3 months and of characteristic immunophenotype.


CLL Score (now outdated for many centres, as different CD proteins often used)

  • Surface Ig weak, CD5+, CD23+, CD79b-, FMC7-

  • One point for each

  • 92% of CLL scores 4 or 5



  • <15% (CLL), 15-55% (CLL/PL), >55% (B-PLL)


DDx for CD5+ LPD with a low score = atypical CLL, mantle cell, marginal zone


cMBL = clinical CD5+ monoclonal B cell lymphocytosis

  • MBL detectable on a routine FBC but <5 x109/l monoclonal cells

  • WHO 2016 splits <0.5x109/l (no concern) from 0.5-5 x109/l (annual FBC monitoring)





  • A: <3 lymphoid areas

  • B: 3 or more lymphoid areas

  • C: Hb <100 or Plt <100

  • (Five lymphoid areas are: uni or bilat. cervical, axillary, inguinal, hepatomeg, splenomeg)



  • 0: Low risk: Lymphocytosis only

  • I: Intermediate: Lymphadenopathy

  • II: Intermediate: Hepatomeg or splenomeg + lymphocytosis

  • III/IV: High risk: Hb <110 or Plt <100




Asymptomatic Stage A patients

  • FBC, reticulocyte, DAT, biochemistry, immunoglobulins, Hep B/C, HIV

  • Flow cytometry

  • TP53 deletion (FISH)

  • Lymph node biopsy only if diagnostic uncertainty

  • CT not required at diagnosis (perform later pre-treatment)


Diagnosing transformation

  • 5-15% of CLL transforms to DLBCL-like or HL-like

  • May be localized, biopsy the suspicious site

  • PET-CT may help identify best biopsy site.


Assessing prognosis

  • Binet / Rai systems predict outcome in advanced stage patients, but poor for early stage

  • Other factors:

    • Age, Gender, PS, co-morbidities

    • Marrow failure, immunodeficiency, autoimmunity, biomarkers

    • Type of treatment, Response, Toxicity, MRD status

  • Prognostic data should not influence timing of first treatment

  • Biomarkers include IGHV gene analysis, B2M, CD38 positivity



TP53 loss (17p del) occurs in 5-10% of patients at diagnosis, 30% in fludarabine refractory patients

TP53 mutation occurs in an additional 5% at diagnosis, 12% of refractory patients

Both TP53 loss and mutation are associated with lower response rates and short PFS when treated with chemoimmunotherapy (e.g. FCR or R-Benda).

—> Test TP53 status prior to each line of therapy and consider alternative treatments if detected, e.g. alemtuzumab or ibrutinib, which have TP53-independent mechanism of action.


IGHV gene mutations confer a better prognosis, with prolonged remissions in response to chemoimmunotherapy.

‘IGHV unmutated’ is associated with a poorer prognosis.

Current guidelines recommend considering analysis of IGHV mutation status



Indications to treat:

  • Lymphocyte doubling time <6 months (provided starting Lymph count >30)

  • Lymphocyte count increased >50% in 2 months

  • Progressive marrow failure

  • Massive (>6cm below costal margin) splenomegaly

  • Massive (>10cm) lymph nodes

  • Autoimmune anaemia / thrombocytopenia not controlled by standard therapy

  • Constitutional symptoms

    • Wt loss >10% in 6 months, fatigue (PS 2 or worse), Fever >38 for 2 wks, night sweats for >1 month.


(NOT indications to treat - High lymphocyte count (in absence of rapid doubling time), hyperviscosity and hypogammaglobulinaemia (in absence of recurrent infection))

Choosing therapy

  • No single choice, patient-by-patient

  • Age, co-morbidities, creatinine clearance, PS, susceptibility to infection

  • Important to achieve maximal response

    • Achieving MRD negative remission is an independent marker for OS and PFS


Defining response

  • IWCLL criteria for CR, PR and progressive disease

  • Relapse = disease progression at least 6 months after achieving CR / PR

  • Refractory = treatment failure or disease progression less than 6 months after CR/PR


CLL response.jpeg


Treatment not required for Early / Stage A Disease

  • 6 monthly review in first year to assess rate of progress

  • Then annually if no concern, GP or hospital

  • Address patient and family concerns around leukaemia diagnosis and implications


Treatment Principles

  • Irradiated blood products

    • For life: purine analogies, bendamustine, campath

    • 3 months post-conditioning for autograft

  • MDT approach

  • Offer clinical trial

  • (The UK CLL Forum has up to date NICE licensing information)


Front-line: Current Guidelines

Fit patients without TP53 abnormality

  • FCR first choice (CLL8, CLL10)

  • R-Benda an alternative if specific co-morbidities prevent FCR use

  • (Watch this space - ASH 2018 reported ibrutinib better than FCR first line for all-comers…)

Not fit patients without TP53 abnormality

  • Chlorambucil-Obinotuzumab (CLL11 - PFS and TTNT benefit vs R-Chlormabucil)

  • Chlorambucil-Ofatunumab (COMPLEMENT-1)

  • R-Bendamustine an acceptable alternative

  • Ibrutinib an acceptable alternative (but not NICE approved)

  • (R-Chlorambucil is not recommended as shown to be inferior to the above)

Patients with TP53 disruption (deletions and/or mutations)

  • Ibrutinib - NICE approved

  • R-Idelalisib - acceptable alternative if specific issues prevent ibrutinib (e.g. cardiac disease, warfarin use)


  • No

  • Anti-CD2- antibodies and lenalidomide have been trialed - increase PFS but no effect on OS seen, and need to weigh the long-term toxicity

Relapse/Refractory: Current Guidelines

Relapse after a prolonged remission in fit patients without TP53 abnormality

  • Consider re-treating with chemoimmunotherapy (FCR or R-Benda)

When to avoid further chemoimmunotherapy?

  • Refractory to prior chemoimmunotherapy

  • Relapse within 2-3 years of FCR or R-Benda

  • Acquired TP53 disruption

  • Co-morbidities preventing delivery of chemoimmunotherapy

—> And so, in this setting:

  • Ibrutinib or R-Idelalisib are treatments of choice

Failed or unsuitable for BCRi therapy

  • Venetoclax (via Cancer Drugs Fund)

When to consider allogeneic stem cell transplant?

  • Fit patients who have failed chemoimmunotherapy and BCRi

  • Fit patients with Richter transformation


Supportive Care

  • Prophylactic antibiotics for hypogammaglobulinaemia with recurrent infections

  • PCP prophylaxis with intensive treatments or on treatment for relapsed disease

  • Aciclovir prophylaxis with intensive treatment or low CD4 counts

  • CMV monitoring post-alemtuzumab

  • Consider immunoglobulin replacement 3-4 weekly if low IgG and recurrent infection. Discontinue after 1 year if not reduction in rates of infection.

  • Annual flu vaccination

  • Pneumococcal vaccination - Prevnar followed by Pneumovax 2 months later

Drugs: A few notes

B-Cell Signalling Pathway Receptor Inhibitors (BCRi)

  • Bruton Tyrosine Kinase inhibitors (BTKi) - Ibrutinib

    • Causes acquired platelet function defect, beware of bleeding with interventional procedures / surgery

    • May trigger AF, VT and hypertension

    • Avoid CYP3A4 inhibitors - warfarin, fish oils, Vitamin E, St Johns Wort

    • Grapefruit and Seville oranges must be avoided

  • PI3 Kinase Inhibitors (PI3Ki) - Idelalisib

    • May trigger life-threatening pneumonitis or colitis

    • Monitor liver function

    • Monitor CMV PCR’s

    • Use PCP prophylaxis

BCL2 inhibtior - Venetoclax

  • Significant risk of tumour lysis

An increase in total lymphocyte count is commonly seen with use of new agents and reflects responding disease not progression.