Haematology

Question 1

What percentage of cases of neutropenia are suspected to be drug induced?

Answer 1

70%

Question 2

What are some of the main culprit drugs responsible for drug-induced neutropenia?

Answer 2

Antibiotics - Chloramphenicol, Dapsone, Isoniazid, Meropenem, Streptomycin, Sulfamethoxazole-trimethoprim

Antifungals - Terbinafine

Antimalarials - chloroquine, primiquine, quinine

Anti-inflammatories - diclofenac, ibuprofen, sulfasalazine

Anti-thyroid drugs - carbimazole, PTU

Antipsychotic drugs - chlorpromazine, clozapine

Antidepressants - mirtazapine, mianserin, tricyclics

Anti-epileptics - Carbamazepine, Ethosuximide, Phenytoin, Valproate, Zonisamide

Cardiovascular drugs - ACEIs, Acetazolamide, Digoxin, Flecainide, Procainamide, Propranolol, Spironolactone, Ticlopidine

Immunomodulators - hydroxychloroquine, leflunomide, rituximab

Others:
Colchicine
Deferiprone
Metoclopramide
Nitrous oxide
Pirfenidone

Question 3

Patients with chemotherapy-induced neutropenia is often dose-dependent, associated with other cell lines (due to bone marrow toxicity) with the nadir occurring at 7-14 days and recovery over 3-4 weeks - what is unusual of about the neutropenia that can occur in patients treated with chemotherapy + Rituximab therapy?

Answer 3

Patients who receive the anti-CD20 monoclonal antibody rituximab in addition to chemotherapy may, rarely, experience a delayed neutropenia beyond this 3-4-week period with unpredictable onset and recovery time

Question 4

Why is it important to differentiate between idiosyncratic drug-induced neutropenia and dose-dependent drug-induced neutropenia?

Answer 4

Because idiosyncratic drug-induced neutropenia is associated with increased rates of infection and mortality rates ranging from 2.5-25%

Question 5

How do you treat drug-induced neutropenia?

Answer 5

Cease the culprit medication immediately in patients with evolving neutropenia or agranulocytosis. However, if the effect is dose-dependent and mild, drugs can sometimes be continued with close monitoring, although making this distinction can be difficult

Question 6

What are the most common infectious-causes of neutropenia?

Answer 6

Viral infections

Short and self-limited:
Viral hepatitis
Viral exanthems (measles, rubella, varicella)
Influenza
Cytomegalovirus
Parvovirus

Prolonged:
HIV
EBV

Question 7

Can neutropenia be secondary to bacterial infection and if so, which ones in particular?

Answer 7

Brucellosis
Mycobacterial infections incl TB
Rickettsial infections
Malaria
Severe overwhelming sepsis - poor prognostic indicator

Question 8

How do you make the diagnosis of autoimmune neutropenia (ie related to autoimmune disease such as RA/SLE)

Answer 8

Largely clinical - as assays for antineutrophil autoantibodies are difficult to perform and generally considered to be unreliable or non-diagnostic

Question 9

What is the significance of autoimmune neutropenia?

Answer 9

Neutropenia can be triggered by a flare in the underlying disease and tends to track disease activity.

Question 10

How do you treat autoimmune neutropenia?

Answer 10

Most cases improve on management of the underlying condition and rarely require specific treatment

Question 11

What is the classic triad of Felty’s syndrome?

Answer 11

RA + neutropenia + splenomegaly

Question 12

What is the significance of recognising Felty’s syndrome?

Answer 12

Neutropenia tends to be severe and is associated with significant morbidity from infective complications and the RA is severe and deforming.

Question 13

How do you treat Felty’s syndrome?

Answer 13

Felty’s syndrome is currently rarely seen because of early and aggressive management as well as substantial advancements in the efficacy of available therapies

Controlling the RA tends to resolve the neutropenia, but G-CSF (filgrastim or pegylated filgrastim) may be necessary in refractory cases

Question 14

What nutritional deficiencies can cause neutropenia?

Answer 14

Vitamin B12 (assoc macrocytic anaemia)
Folate (assoc macrocytic anaemia)
Copper
Global - anorexia nervosa

Question 15

What features may suggest a bone marrow failure/infiltration/dysplasia as cause of neutropenia?

Answer 15

• Other cell lines affected (eg anaemia)
• B symptoms incl fevers, weight loss, night sweats
• lymphadenopathy or bone pain
• blood film abnormalities incl blasts or in solid organ malignancies assoc with marrow involvement -> leukoerythroblastic anaemia (that is, nucleated red cells and neutrophil precursors)

Question 16

What features does T-cell large granular lymphocytic leukaemia (T-LGLL)-associated neutropenia share with Felty’s syndrome?

Answer 16

An association with RA
Splenomegaly
Severe neutropenia
An association with HLA-DR4.

Question 17

How do you differentiate T-cell large granular lymphocytic leukaemia (T-LGLL)-associated neutropenia from Felty’s syndrome?

Answer 17

Monoclonal lymphocytes in T-LGLL
vs
Oligoclonal or polyclonal lymphocytes in Felty’s syndrome

Question 18

How do you diagnose Chronic Idiopathic Neutropenia?

Answer 18

Once you have excluded other causes eg with history and exam + bone marrow biopsy

More common in px with mediterranean ancestry + mild-to-mod neutropenia (rarely dips <0.8 or requires treatment)

Question 19

What is constitutional neutropenia (previously called benign ethnic neutropenia)?

Answer 19

A form of chronic, mild neutropenia in patients of the relevant ethnicity, with no other evident causes

Ethnicities - some Mediterranean, African, Yemenite Jewish, Ethiopian, Middle Eastern, Caribbean and West Indian populations

The diagnosis requires at least three blood tests showing neutropenia at least two weeks apart + exclusion of other causes

Note no associated increased rates of infection

Question 20

What are the core features of cyclic neutropenia (CN)?

Answer 20

Cyclic neutropenia (CN) is a rare condition characterised by self-limiting neutropenia associated with fever, skin or oral ulcers, and/or cervical lymphadenopathy during a neutrophil nadir that occurs every 2-5 weeks

Patients are generally well between episodes

The absolute neutrophil count oscillates and severe neutropenia typically lasts 4-5 days each cycle, during which patients are also prone to infections

Cycle lengths vary between patients but are consistent in an individual.12

To diagnose CN, serial FBCs are required 2-3 times a week for at least six weeks to establish the pattern of neutropenia

The diagnosis can be confirmed with genetic testing for ELANE gene mutations and does not routinely require a bone marrow biopsy.

CN is an autosomal dominant condition resulting from mutations in the ELANE gene, the same gene implicated in many cases of SCN

Question 21

What initial investigations should be ordered for a patient with neutropenia?

Answer 21

Recommended for all patients:
- FBC with differential.
- Blood film.
- EUC.
- LFTs.

Focused investigations based on clinical assessment:
- Septic screen (including blood culture).
- ANA, dsDNA, RF, anti-CCP, ESR/CRP.
- Flow cytometry
- B12/folate/copper
- HIV, HCV, HBsAg, HBsAb, HBcAb and other viral serology as appropriate.

Specialised investigations considered by a haematologist:
- Bone marrow biopsy.
- Genetic studies.

Question 22

What are the main risks with G-CSF (Filgrastim) therapy

Answer 22

bone pain, myalgias, splenomegaly and osteoporosis

There is also a theoretical increased risk for AML in Severe Congenital Neutropenia

G-CSF is safe in acquired causes of neutropenia with no identified increased risk for AML

Question 23

What are the indications for considering bone marrow transplant in a patient with Cyclic Neutropenia?

Answer 23

Disease refractory to G-CSF, recurrent severe infections, bone marrow failure and malignant transformation