Chronic Lymphocytic Leukaemia Flashcards
Chronic Lymphocytic Leukaemia - Indications for treatment
Indications for treatment
progressive marrow failure: the development or worsening of anaemia and/or thrombocytopenia
massive (>10 cm) or progressive lymphadenopathy
massive (>6 cm) or progressive splenomegaly
progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months
systemic symptoms: weight loss > 10% in previous 6 months, fever >38ºC for > 2 weeks, extreme fatigue, night sweats
autoimmune cytopaenias e.g. ITP
CLL - Mx
Management
patients who have no indications for treatment are monitored with regular blood counts
fludarabine, cyclophosphamide and rituximab (FCR) has now emerged as the initial treatment of choice for the majority of patients
CLL - Example Question
An 85 year old male is referred by the anaesthetic registrar after abnormal blood test results were noted during pre-assessment for an elective hip replacement. He is other wise fit and well, independent with all activities of daily living and continues to drive. His past medical history includes diet controlled type 2 diabetes mellitus and hypertension. On examination, he is alert and well, reports no discomfort, pain, or non-specific malaise. No skin bruises or conjunctival pallor are noted. You note a rubbery, non-tender and firm 3cm lymph node in the left cervical chain and non-tender splenomegaly at 8cm below the costal margin. His chest is clear and normal heart sounds are noted. His blood tests are as follows, with blood tests from his GP 6 months ago in brackets:
Hb 8.9 (9.5) g/dl
Platelets 78 (76) * 109/l
WBC 67 (32) * 109/l
Blood film mature lymphocytes and smudge cells
What is the appropriate treatment?
Monitor and repeat blood count in 6 months > Fludarabine, cyclophosphamide and rituximab treatment immediately Delayed chlorambucil treatment in 6 months Platelet transfusion Intravenous immunoglobulin
This patient is on the cusp of requiring immediate treatment for chronic lymphocytic leukemia. The latest guidelines are provided by the British Committee for Standards in Haematology (BCSH) 20121, recommending immediate treatment to commence if the patient demonstrates signs of: progressive marrow failure, massive or symptomatic splenomegaly greater than 6cm below the costal margin, massive or symptomatic nodes greater than 10cm in longest diameter, progressive lymphocytosis with doubling in 6 months, autoimmune thrombocytopaenia or anaemia, or significant constitutional symptoms within the previous 6 months. It is important to note that doubling of lymphocytosis is calculated only if the initial count is greater than 30 x 109/l.
Asymptomatic patients not meeting these criteria do not benefit in long term survival when receiving immediate chlorambucil therapy versus delayed treatment2. Regular blood test monitoring is more appropriate for this group of patients. Be aware that despite increased white cell counts, the mature lymphocytes are non-functional and patients are hence at increased risk of infections. Intravenous immunoglobulin may be appropriate if the patient shows features of a significant infection. Similarly, significant progressive marrow failure, demonstrated by symptomatic anaemia or thrombocytopaenia may require replacement. In this case, the patient fits criteria for immediate treatment based on his lymphocytosis doubling time and splenomegaly.
CLL and Fludarabine
Fludarabine is a purine analogue that prevents DNA synthesis through the inhibition of ribonucleotide reductase and DNA polymerase. It is associated with profound lymphopenia, and significantly increases the risk of opportunistic infections. Patients treated with fludarabine are at particular risk of morbidity and mortality secondary to pneumocystis pneumonia. It is essential that these patients receive regular prophylactic co-trimoxazole.
Purine analogues can lead to herpes simplex, herpes zoster, and cytomegalovirus reactivation and aciclovir is often given as prophylaxis against this. Fluconazole is also frequently given as fungal prophylaxis.
Example Question:
A 68-year-old gentleman with known chronic lymphocytic leukaemia (CLL) is reviewed in the Haematology Clinic.
He is normally an active gentleman who enjoys playing golf 3 times per week, but he complains that he has been feeling increasingly fatigued since his last appointment 6 months previously. He states that he has not been able to play golf for several weeks and his wife tells you that he has started napping during the afternoons. His past medical history is otherwise unremarkable and he takes no regular medications.
Examination reveals a tired gentleman with marked axillary and inguinal lymphadenopathy. His abdomen is soft with mild upper abdominal tenderness. A liver edge is palpable 3cm below the costal margin and his spleen is markedly enlarged.
His full blood count today is as follows:
Hb 114 g/l Platelets 173 * 109/l WBC 30.4 * 109/l Neutrophils 5.8 * 109/l Lymphcytes 23.1 * 109/l
His lymphocyte count 2 months ago was 15.3 * 109/l and a decision to start the patient on fludarabine, cyclophosphamide, and rituximab (FCR) chemotherapy is taken.
Given the proposed treatment strategy, which of the following prophylactic medications is it most important to start?
> Co-trimoxazole Aciclovir Entecavir Fluconazole Penicillin V
Fludarabine is a purine analogue that prevents DNA synthesis through the inhibition of ribonucleotide reductase and DNA polymerase. It is associated with profound lymphopenia, and significantly increases the risk of opportunistic infections. Patients treated with fludarabine are at particular risk of morbidity and mortality secondary to pneumocystis pneumonia. It is essential that these patients receive regular prophylactic co-trimoxazole.
Purine analogues can lead to herpes simplex, herpes zoster, and cytomegalovirus reactivation and aciclovir is often given as prophylaxis against this. Fluconazole is also frequently given as fungal prophylaxis.
Entecavir is given to patients who are hepatitis B surface antigen (HBsAg) positive.
Penicillin V is given to patients with asplenia and is not routinely used in this setting.
Pneumocystis pneumonia is the most severe complication described. Co-trimoxazole is, therefore, the most essential of the medications listed above.
CLL - Accepted Indications for treatment:
Accepted indications for treatment include:
The development of anaemia +/ thrombocytopaenia
Progressive or massive splenomegaly (6cm) +/ lymphadenopathy (10cm)
Progressive lymphocytosis [50% increase in 2 months or doubling time of less than 6 months]
Systemic symptoms [fever, night sweats, weight loss >10% in 6 months, extreme fatigue]
CLL - Indications for treatment: Example Question
A 77-year-old lady was seen in the haematology outpatient clinic for her monthly follow-up. She has been seen in the haematology clinic for the last six months having been referred by her GP following an anomaly on her blood investigations. Overall she has been feeling well though for the last three weeks she has been feeling increasingly tired. She has noted that her appetite has been reduced for the last three months though she has not lost any weight during this time. In spite of the tiredness she is still able to lead an active life, regularly enjoying long distance rambling and gardening. She denied the presence of other symptoms, including the absence of fever or night sweats. She has a past medical history comprising asthma, hypertension, type 2 diabetes mellitus and hypercholesterolaemia for which she has been prescribed felodipine 5mg M/R OD, atorvastatin 20mg ON, Clenil modulite 2 puffs BD and metformin 500mg TDS.
Examination revealed the presence of a well elderly lady who was independently mobile. Her blood pressure was 122/82 mmHg, heart rate 82bpm and temperature 36.9 Celsius. Examination of her cardiovascular and respiratory systems revealed the presence of normal heart and breath sounds and a JVP of 3cm. Examination of her gastrointestinal and lymphatic systems revealed the presence of a smooth edge 2 fingerbreadth below the left subcostal margin and bilateral small cervical lymphadenopathy, with the maximum node size less than 1cm.
Investigations reveal the following:
Results from clinic three months ago:
Hb 112 g/l Platelets 242 * 109/l WBC 22.6 * 109/l Neutrophils 2.1 * 109/l Lymphocytes 19.9 * 109/l Eosinophils 0.4 * 109/l Monocytes 0.2 * 109/l
Renal and liver function tests were normal.
Blood film: lymphocytosis with atypical lymphocytes
Bone marrow aspirate: infiltration with 25% lymphocytes
Peripheral blood flow cytometry: presence of circulating clonal B-lymphocytes expressing CD5, CD19, CD20, CD 23, and an absence of FMC-7 staining
Results from clinic on this occasion:
Hb 106 g/l Platelets 162 * 109/l WBC 34.2 * 109/l Neutrophils 2.3 * 109/l Lymphocytes 31.5 * 109/l Eosinophils 0.3 * 109/l Monocytes 0.1 * 109/l
What is the single next best step management step?
Commence prednisolone therapy Commence chlorambucil therapy Commence fludarabine therapy Commence rituximab therapy > Observe in clinic and repeat tests in one month
This lady has chronic lymphocytic leukaemia (CLL) as manifested by the high lymphocyte count, lymphocyte marrow infiltration and evidence clinically of splenomegaly and lymphadenopathy. 70% of patients are asymptomatic and patients with stage A leukaemia as with this lady [no anaemia or thrombocytopaenia and less than 3 areas of lymphoid enlargement] have a median survival of 8 years. Treatment is therefore not indicated.
Accepted indications for treatment include:
The development of anaemia +/ thrombocytopaenia
Progressive or massive splenomegaly (6cm) +/ lymphadenopathy (10cm)
Progressive lymphocytosis [50% increase in 2 months or doubling time of less than 6 months]
Systemic symptoms [fever, night sweats, weight loss >10% in 6 months, extreme fatigue]
Although this lady has been complaining of tiredness, this does not in itself constitute a ‘systemic symptom’ given the absence of other symptoms and her strong performance status. Her lymphocyte count is rising but does not meet the criteria for treatment at present. Should treatment be indicated, this comprises chemotherapeutic agents such as chlorambucil and fludarabine, immunological agents such as rituximab and steroids in advanced disease.
CLL - Indications for treatment
A 60 year old female with known chronic lymphocytic leukaemia (CLL) presents with coryzal symptoms. Examination findings are unremarkable. Her blood tests are as follows:
8 months previously, 2 months previously and then Today:
Haemoglobin:
113 g/l, 108 g/l, 106 g/l
WCC:
32.0 *10^9/l, 50.0 *10^9/l, 58.0 *10^9/l
Neutrophils
7.0 *10^9/l, 4.8 *10^9/l, 4.0 *10^9/l
Lymphocytes
25.0 *10^9/l 45.0 *10^9/l 54.0 *10^9/l
Platelets
358 *10^9/l 280 *10^9/l 268 *10^9/l
What is the most appropriate treatment option?
Chlorambucil Fludarabine and chlorambucil > Observation Prednisolone Fludarabine
CLL is typically an indolent disease which is often managed conservatively in the first instance. Indications for treatment are multiple but include constitutional symptoms, bone marrow failure and massive lymphadenopathy. Additionally, a lymphocyte doubling time of less than 6 months is an indication for treatment, but this is not met here. Chlorambucil, fludarabine and high dose corticosteroids are all possible therapeutic options in CLL.
CLL
= monoclonal proliferation of well-differentiated lymphocytes which are almost always (99%) B cells
Features:
- often none!
- Constitutional: Anorexia, Weight loss
- Bleeding
- Infections
- Lymphadenopathy MORE marked than CML
CLL - Cx
Cx:
- Hypogammaglobulinaemia leading to recurrent infections
- Warm autoimmune haemolytic anaemia in 10-15%
- Transformation to HIGH-GRADED Lymphoma = RICHTER’S TRANSFORMATION
CLL - Ix and Mx
Ix:
- Blood film = Smudge cells (B-cells) (also known as smear cells)
- Immunophenotyping
Example Case
Elderly female with a marked lymphocytosis
NB Steroids tend to cause a neutrophilic rather than a lymphocytosis
Chronic Lymphocytic Leukaemia - Poor Prognostic Factors
- Male sex
- Age > 70
- Lymphocyte count > 50
- Prolymphocytes comprising more than 10% of blood lymphocytes
- Lymphocyte doubling time < 12m
- Raised LDH
- CD38 expression positive
Chromosomal Changes:
- deletion of long arm of chrom 13 (del13q) = most common abnormality seen in 50% patients - assoc w good prognosis
- deletion of part of short arm of chromosome 17 (del 17p) are seen in 5-10% of patients and are assoc with poor prognosis
CLL - Indications for treatment BSHC Guidelines
The latest guidelines are provided by the British Committee for Standards in Haematology (BCSH) 20121, recommending immediate treatment to commence if the patient demonstrates signs of:
- progressive marrow failure indicated by autoimmune thrombocytopaenia or anaemia
- massive or symptomatic splenomegaly greater than 6cm below the costal margin
- massive or symptomatic lymph nodes greater than 10cm in longest diameter
- progressive lymphocytosis with doubling in 6 months
- significant constitutional symptoms within the previous 6 months.
It is important to note that doubling of lymphocytosis is calculated only if the initial count is greater than 30 x 109/l.
Asymptomatic patients not meeting these criteria do not benefit in long term survival when receiving immediate chlorambucil therapy versus delayed treatment. Regular blood test monitoring is more appropriate for this group of patients. Be aware that despite increased white cell counts, the mature lymphocytes are non-functional and patients are hence at increased risk of infections.
