Case 98 – summary

Following several obinutuzumab reactions, which resulted in overnight hospital admissions, our patient decided he did not wish to continue with obinutuzumab. He continues on chlorambucil monotherapy and has tolerated it reasonably well and his disease appears to be responding.

Thankyou for your help with this week’s cases.

This week we looked at CLL in fitter patients with adverse features and CLL in the less fit patient.

CLL is a form of chronic leukaemia which can run a very variable relapsing/remitting course. For all patients it is important that they are given information and appropriate support from diagnosis onwards.

When assessing a patient for potential CLL a thorough history and examination is needed. It is important to ask about general health and enquire about any b symptoms. Patients may also have lymphadenopathy and/or organomegaly and it is especially important to ask if there have been any rapidly enlarging nodes or rapidly evolving symptoms – important to keep Richter’s transformation in mind when assessing patients.


Basic investigations would include an FBC with blood film assessment (important to look for any signs of haemolysis as CLL can be associated with auto immune phenomena) and Immunophenotyping of peripheral blood. Before starting treatment it is important to make an assessment of performance status, check renal/liver function, immunoglobulins and DAT, beta 2 microglobulin. Bone marrow should also be considered if there are cytopenias of uncertain cause. Screening for viral infections. Cxr should be performed and consideration of other imaging eg CT if there is concern about lymphadenopathy however this is not usually indicated.

Prior to starting treatment patients should also have assessment of molecular genetics for del(13q), del(11q), del(17p), add(12) IGHV mutation and TP 53 mutations as these may effect treatment choice and prognosis.

Diagnosis can be made from peripheral blood, bone marrow or tissue biopsy if there is associated lymphadenopathy, but is almost always done by flowcytometry unless the patient has perhaps presented via a surgical clinic with lymphadenopathy.

For a diagnosis of cll there needs to be a peripheral blood lymphocytosis of ≥5 × 109/L B lymphocytes for at least 3 months. These must then have demonstrable clonality on flow cytometry. In SLL the patient will have lymphadenopathy, however will have a peripheral blood B cell lymphocyte count of <5×109/L, cytopenias related to marrow infiltration will also be absent.

Indications for treatment should be clearly documented. The iwCLL guidelines have a clear list of indications for treatment. In both our patients cases they had progressive marrow failure and sweats.


CLL cell will typically express CD5 as well as B cell markers CD19,CD20, CD23. There should also be kappa or lambda restriction. Expression of ZAP-70 and CD 38 are usually associated with an unmutated IGHV inferring a poorer prognosis.

The Immunophenotypic CLL score is used to aid diagnosis

A score of 4 or more is indicative of CLL, a score of 3 or less should make you consider alternative diagnosis.

Marker Points
CD5+ 1
CD23+ 1
FMC7 negative 1
CD79b wk 1
sIg wk 1

Molecular genetics

FISH is widely used and can detect changes in >80% of patients with CLL. The most common deletion is del(13q). Other common finding are trisomy 12, del(11q), del (17p). Molecular genetics can also be helpful if there is diagnostic uncertainty and may be used to differentiate from other conditions such as MCL.


The Rai and Binet staging systems have been widely used to stage CLL. Other prognostic tools eg CLL-IPI have since been developed which include other factors which have since been found to effect prognosis including molecular genetics and beta 2 microglobulin.

Molecular genetics have become increasingly important in prognostication and treatment choices. Patients with mutated IGHV having most favourable disease and in some cases having very prolonged remissions following chemo immunotherapy regimes. Patients with unmutated IGHV, complex cytogenetic, del (11q), NOTCH1, SF3B1, BIRC3 are considered higher risk and patients with del (17p) or TP53 mutations tend to have the poorest prognosis. Patients who are chemoimmunotherapy refractive or who have relapsed within 2 years or chemoimmunotherapy treatment also have a poorer prognosis.


Treatment will be guided by patient choice, fitness, previous treatments and molecular genetics. Trials should be offered to all patients where possible.

Fit patients who do not have del (17p)/TP53 mutation Chemoimmunotherapy is first line treatment. FCR is recommended as 1st line, or bendamustine and rituximab can be considered if there are specific contraindications to FCR or other concerns such as older age.

Less fit patients without del(17p)/TP53 mutation

For 1st line treatment the CLL11 trial and complement1 trial have led to the approval of chlorambucil with obinutuzumab or ofatumumab. The CLL11 trial showed improved PFS and TTNT with chlorambucil+obinutuzimab over chlorambucil+rituximab and an OS benefit when compared to chlorambucil alone. It is important to note that infusion reactions (grade 3-4) were significantly higher with obinutuzumab compared to rituximab (20%vs4%).

The COMPLEMENT-1 study showed a significant improvement in PFS with chlorambucil+ofatumumab compared with chlorambucil. They also noted a 10% grade 3-4 infusion reaction rate with ofatumumab.

Bendamustine+rituximab can also be considered as an alternative.

Although ibrutinib is licenced for 1st line treatment in patients with none TP53 mutated/deleted disease, it is not NICE approved for this.

In very frail patients, or in patients who are intolerant of anti CD20 antibodies chlorambucil alone can be used. Corticosteroid monotherapy could also be considered.

Treatment of patients with TP53 disruption

Upto 10% of patients can have evidence of del(17p)/TP53 mutation at diagnosis. These patients have significantly worse response/duration of response/OS when treated with standard chemo immunotherapy.

Treatment with BCRi (ibrutinib monotherapy, or idelalisib with rituximab), or the BCL2 inhibitor venetoclax have been shown to improve PFS and OS in this group or patients. Ibrutinib is now NICE recommended as first line treatment for patients with TP53 disruption. There are concerns with idelalisib and increased risk of infection and deaths (including CMV and PCP), and it is only recommended 1st line in patients with del17p/TP53 mutation who can not have ibrutinib (eg patients with significant cardiac disease or patients on warfarin). Patients who do have idelalisib should have regular CMV monitoring and PCP prophylaxis. And concern regarding CMV disease eg CMV colitis should be investigated promptly.

Second line treatment

Relapsed, but asymptomatic patients can be monitored until such a time that they need treatment for symptomatic disease. And treatment criteria should be as per the iwCLL guidelines. At the point of retreatment all patients (regardless of previous status) should have TP53 status assessed.

Chemoimmunotherapy is not recommended for patients that have not responded to previous chemoimmunotherapy, relapsed within 24-36 months of FCR or BR, or who have TP53 disruption.

Ibrutinib monotherapy or idelalisib with rituximab can be used, however they need to meet specific criteria set out by NHS England.

In previously chemoimmunotherapy treated patients, if they have had a previous long remission and are still fit further chemoimmunotherapy can be considered.

If a patient has failed a BCRi then venetoclax can be used, however this is currently funded by the NHS cancer drugs fund. There is significant risk of TLS with venetoclax and there should be strict monitoring for TLS with dose increments over 5 weeks

Response to treatment

Criteria for response to treatment are clearly documented in the iwCLL guidelines. It should be noted the patients starting ibrutinib may get a rise in lymphocytes that persists for many months despite other indicators of disease response due to redistribution of lymphocytes.

Allogenic transplant

Allo SCT remains a treatment option for a select group of patients to offer durable remissions, although does not come without risk and is only used in selected patients following thorough assessment.

Patients who may benefit from ALLO if they are fit and have failed chemoimmunotherapy and BCRi irrespective of TP53 status, and patients with TP53 disruption who are relapsing/not responding to BCRi treatment. Patients with richters transformation should also be considered.

If the donor is a familial donor can screen for clonal lymphocytosis as there is an increased familial risk.

Infection prevention

Patients with CLL can develop reduced immunity, and can have reduced numbers of CD4 cells as a result of treatments leaving patients open to infections such as PCP. Most patients with relapsed CLL have secondary immunodeficiency and starting treatment can leave them open to opportunistic infections. All patients at relapse treatment should have PCP prophylaxis during, and for a minimum of 6 months after treatment.

Hepatitis B and C reactivation has been seen with various treatments and all patients should be screened prior to treatment. Any patient with previous hep B or C should be managed jointly with hepatology.

Patients with recurrent infections with an igG of <5g/L who have failed a 3 month trial of broad spectrum antibiotics should be offered immunoglobulin replacement.

Live vaccines are not recommended for patients with CLL.

Patients should be offered vaccination against pneumococcal and influenza. Patients with symptomatic secondary immunodeficiency should have assessment of response to pneumococcal vaccination and failure of response should give access to immunoglobulin replacement.

Autoimmune cytopenias

Upto 10% of patients with CLL can have autoimmune cytopenias. Without other indication for CLL treatment the auto immune phenomena should be treated as would an idiopathic autoimmune cytopenia.

It has been found that fludarabine and chlorambucil can exacerbate/trigger auto immune cytopenias and are advised to be avoided in the setting of autoimmune cytopenias. If CLL treatment triggers autoimmune cytopenias then treatment should be stopped and immunosuppressive treatment commenced. Other treatment options in the setting of autoimmune cytopenias are rituximab/cyclophosphamide/dexamethasone (RCD), campath, ibrutinib or idelalisib.

Thank you for all your input over the last week. There have been many new developments in CLL over the last few years and with CAR-T cells and other new therapies on the horizon hopefully we will be able to continue to improve the prognosis for some of these patients.

Is there anything you would like to ask/add?

For further reading we suggest

How and when I do allogenic transplant in CLL – John Gribbon

iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL – Hallek et al

Guideline for the treatment of chronic lymphocytic leukaemia – Schuh et al

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