Case 99 – Summary

Thank you for your contribution in our #TeamHaem case this week.

This week we have been looking at Diamond Blackfan anaemia (DBA). This is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. It is one of the Inherited Bone Marrow Failure Syndromes (IBMFS), and probably the second most common IBMFS after Fanconi Anaemia. It has a prevalence of 5 to 7 cases per million live births.

  1. Most “Classical” cases present with anaemia in the neonatal period or in infancy, but not at birth, and hydrops fetalis has rarely been reported. 95% are diagnosed before the age of 2. Initial clinical features are an isolated anaemia, with symptoms such as pallor, shortness of breath while suckling, failure to thrive, systolic murmur. There is no organomegaly.
  2. However, non classical cases with less distinctive phenotypes can present in older children and adults. In fact more and more adults are being diagnosed with DBA.
  3. Cases are sporadic in 75% cases, with an equal sex ratio
  4. 10-25% have a positive family history
  1. It is a cancer pre-disposition syndrome – there is a moderately increased risk of developing MDS, AML, but also ALL, lymphomas and Hodgkin’s disease, as well as solid tumours such as osteosarcoma and other carcinomas. However the risk is not as high as that in FA.

Haematological features:

  1. Macrocytic anaemia
  2. Reticulocytopenia
  3. Variable platelet count, but often elevated
  4. Normal neutrophils, occasionally neutropenia
  5. Elevated HbF
  6. Elevated eADA (erythrocyte adenosine deaminase) activity is found in 90% of DBA patients [in non-transfused sample]. eADA is a key enzyme in purine metabolism but its relevance to DBA pathophysiology remains unexplained. eADA > 1.70 nmol/min/mg haemoglobin is strongly suggestive of DBA, even though eADA is non-specific.
  7. Bone marrow smears – absence or paucity of erythroid precursors which are morphologically normal in appearance (=< 5% of nucleated cells). Cellularity is normal and other haemopoietic lineages are normal.

Non-haematological features:

Congenital anomalies are associated with the anaemia in 10-40% of DBA-affected patients. Intrauterine growth retardation (a low birth rate is reported in 25% cases) and faltering growth are common. Many patients have a small stature, which can often be made worse by long term steroid therapy and iron overload. Height below 3rd centile is described in 30% children.

Congenital anomalies can include:

  • Craniofacial anomalies (most common) – representing 50% of congenital anomalies reported.
    • Hypertelorism
    • Broad flat nasal bridge
    • Microcephaly
    • Cleft palate
    • High arched palate
    • Pierre Robin syndrome
  • Those affecting the upper limbs
    • Triphalangeal thumb
    • Thumb duplication or hypoplasia
    • Radial hypoplasia
  • Structural defects of the heart e.g. VSD, ASD, coarctation of the aorta, patent foramen ovale, tetralogyof Fallot etc.
  • Abnormalities of the kidneys & genitourinary system e.g. absent, horseshoe kidney, duplicated collecting systems, hypospadias
  • Bones and teeth (e.g. defective enamel formation)
  • Congenital glaucoma, strabismus, congenital cataract

Differential diagnosis

  1. In children, transient erythroblastopenia of childhood (TEC) should be the major consideration. This is often related to viral illness and is self limiting with spontaneous resolution.

2. Other differentials include:

  • Pearson syndrome,
  • parvovirus B19
  • human immunodeficiency virus (HIV) and other infections,
  • drugs and toxins
  • immune-medicated disease should be ruled out before the diagnosis of DBA can be established.
  • Other inherited bone marrow failure syndromes e.g. FA, SDS & DKC must be ruled out

Important Investigations

1. Before first transfusion

  • FBC
  • Reticulocyte
  • HbF
  • E-ADA
  • Serology for parvovirus, hep B, C, HIV

2. To confirm diagnosis

  • Bone marrow aspirate & trephine
  • Cytogenetics & FISH (should be negative)
  • Parvovirus PCR on BMB – should be negative
  • Mutation analysis

3. Others

  • Examine for congenital anomalies
  • USS abdomen
  • ECHO
  • Hearing test
  • Ophthalmology review

4. Hepatitis B vaccination ideally prior to starting transfusion

5. Immunology investigations

6. Check vaccination response. MMR & Chickenpox vaccine prior to starting high dose steroid

7. Check vaccination response

8. HLA typing for index case and siblings

9. Extended red cell phenotyping

Genetics:

The understanding of DBA & DBA genetics is evolving.

DBA belongs to a group of disorders known as ribosomopathies. Inheritance are autosomal dominant, with heterozygous mutation in the ribosomal protein genes. The first identified DBA gene, also the most commonly mutated, is RPS19. It accounts for 25% DBA cases. RPS19 codes for a ribosomal protein located at chromosome 19q13.2. RPS19 protein haplo-insufficiency i.e. where the protein produced by a single copy of a normal gene is not sufficient to produce normal function. About 50% DBA patients have a single mutation in a gene encoding a ribosomal protein. More and more gene mutations as well as deletions are being identified. Recently mutations in GATA1, the first non-ribosomal protein gene, have been identified in some DBA families.

Ribosomal protein genes known to be affected include:

  • RPL5, RPL11, RPL35A
  • RPS7, RPS10, RPS17, RPS19, RPS24 and RPS26

These genes are responsible for the production of approximately 80 different ribosomal proteins, which are components for ribosomes.

Each ribosome is made up of two subunits – the large and small subunits.

RPL5, RPL11, RPL35A are found in the large subunits whereas RPS7, RPS10, RPS17, RPS19, RPS24 and RPS26 are found in the small subunits.

The specific functions of each ribosomal protein within these subunits are unclear. However, it is thought that the perturbed ribosomal biogenesis leads to an accumulation of p53 which has a role in initiating apoptosis in the DBA erythroid precursor.

Family screening

  • Inheritance is autosomal dominant with variable penetrance and expressivity
  • Parents and siblings should be screened to search for mild or asymptomatic carriers.
  • A complete family history including a history of congenital anomalies, any persistent or intermittent anaemia and history of macrocytosis or presumed pernicious anaemia.
  • Tests should include: FBC, reticulocyte count, HbF, eADA
  • If a genotype is identified in the index case, then genotyping is performed in the parents
  • Genotyping in the sibling and other family members if applicable
  • Other possibly affected family members should also be evaluated even if not currently anaemic, as anaemia may present in the future and advice should be given to seek help should symptoms develop
  • In vitro fertilisation with pre-implantation genetic diagnosis may be available for families with known genetic mutations allowing for the selection of unaffected embryos. This is often done simultaneously for the selection of an HLA-identical donor for the DBA patient.

Treatment options

Spontaneous remission is achieved in 20% of patients. However, the majority of patients require treatment. Some patients can also achieve remission after having a period of treatment.

1. Red cell transfusion

  • Transfusion should be used in those below 1 year of age
  • In those who are steroid non-responsive (about 20%)
  • Or those having growth difficulties with steroid
  • Transfusion is individualised, given usually every 3 to 4 weeks according to growth and exercise tolerance,
  • Extended red cell phenotyping should be carried out to minimise allo-immunisation

2. Corticosteroid therapy

  • Steroids have a profound effect on linear growth as well as neurocognitive development in infants, therefore it should be delayed until after 1 year of age
  • However, in areas where there is difficulty obtaining safe blood products or difficulty with venous access, sometimes steroids may be started earlier
  • Approximately 80% of patients will respond to steroid. Those who fail to respond to steroid initially may respond on re-challenge.
  • About 35%-40% of DBA patients on the international registry use steroids to maintain transfusion independence
  • Start a Trial of prednisolone 2mg/kg daily for maximum of 4 weeks, commencing 1-2 weeks after a transfusion when Hb is 90-100g/L
  • If steroid responsive (Hb maintained > 90g/L without the need for transfusion), then steroid should be tapered to a maintenance dose of <0.5mg/kg/day, ideally on an alternate day regime e.g. 1mg/kg alt days. Some treatment centres aim for <0.5mg/kg alt days if achievable as it is felt that the long term steroid toxicity and impact on growth is minimised at this dosing regime
  • Steroid taper should be over a couple of months initially to around 1mg/kg/day (some centres prefer weaning alternate days to achieve 2mg/kg alternate days over 8 weeks), then a much slower taper after that. This is so that a patient can come off the high dose regime relatively quickly to minimise side effects from high dose therapy, and the slow wean thereafter to prevent the lost of steroid response
  • Steroid response usually occurs in 10-15 days with a rise in reticulocyte count
  • If steroid unresponsive after 4 weeks, it should be quickly weaned off over 2 weeks and a transfusion programme should be commenced.
  • A steroid re-trial can be attempted after 12-18 months, as some children may become steroid responsive subsequently

3. HSCT

  • The only curative treatment for DBA
  • An HLA-identical sibling donor should be used for a patient who requires regular transfusion
  • HSCT can restore erythropoiesis in about 90% of cases
  • Familial cord blood can also be used
  • Matched unrelated donors are increasingly used where there is no Sibling donor, and outcome have greatly improved in recent years
  • Careful evaluation of a family donor must be carried out, especially in the absence of a genetic mutation, the sibling must have a full evaluation including eADA to ensure the donor does not have a phenotypically milder DBA
  • HSCT complications are reduced in those with the least co-morbidities e.g. iron overload. Hence iron loading needs to be evaluated and iron chelation optimised
  • MUD HSCT seems to have higher rates of lung GvHD and gut toxicity from case reports
  • In general conditioning should include serotherapy to reduce GvHD

Steroid toxicity, monitoring & management

  • DBA is one disease where a patient may be on life-long steroid.
  • Even at low doses, there may be significant side effects and toxicity
  • Live vaccines e.g. MMR & chickenpox vaccines given prior to starting high dose steroid (or VZV status determined)
  • Ensure all other vaccinations are completed
  • Pneumocystis jirovecii (PCP) prophylaxis should be started after the first month of high dose steroid, and continued until the patient is on low dose alternate day therapy
  • Gastric protection should be used until patient is on low dose therapy, using a PPI or H2 antagonist
  • Stress steroid dose may be required in acute illness or surgery
  • Side effects such as pathological fractures, cataracts, avascular necrosis have been noted in high rates in DBA patients
  • DEXA should be performed periodically e.g. every 5 years, with a baseline carried out usually at age 5
  • Ophthalmology and audiology review annually
  • An accurate growth chart must be maintained for each patient
  • Steroid therapy needs to be reviewed if there are growth concerns or other toxicity
  • Endocrine review from 10 years of age until end of pubertal development (or earlier if issues with growth)
  • Dental review
  • Vitamin D supplementation, screen for impaired glucose tolerance, monitoring of blood films and periodic bone marrow biopsy
  • Ferriscan/MRI T2*

Transfusion, iron chelation and monitoring for iron overload

  • Long term transfusion necessitates iron chelation
  • Other than transplant related mortality, transfusion-associated iron overload is the leading cause of death in DBA patients
  • Chelation should be started after 10-20 transfusions at 10-15ml/kg per transfusion
  • Serum ferritin is used as a surrogate marker for total body iron burden, but is an unreliable measure, even though ferritin trend may be helpful over time
  • Multiple parameters are required to assess iron burden e.g. T2*MRI of liver and heart, ferriscan in some centres and liver biopsy
  • Liver iron concentration (LIC) of < 3mg/g dry weight is considered normal
  • LIC >15mg/g dry weight is associated with clinically significant cardiac iron overload and risk of cardiac death in Thalassaemia patients
  • However, hepatic iron appears to be a poor surrogate for cardiac iron burden in general and particularly in DBA patients
  • Cardiac MRI T2* < 20 ms associated with decreased ejection fraction
  • Cardiac MRI T2* < 10 ms is associated with heart failure, and is an indication of severe iron loading and requires urgent iron chelation. Cardiac siderosis can result in toxic cardiomyopathy or fatal arrhythmia and has been the cause of death in DBA patients in registries
  • Liver biopsy is invasive but has the advantage of identifying fibrosis and cirrhosis
  • Iron chelation:
    • Oral deferasirox – needs to monitor for GI bleeding and liver toxicity
    • Subcutaneous or IV desferrioxamine
    • Deferiprone – but associated with cytopenias and only reserved in extreme cases of cardiac iron overload and congestive cardiomyopathy
    • Oral deferasirox & desferrioxamine maybe used in combination
  • Patients require
    • Regular ophthalmology, audiology, endocrine review
    • Cardiology review annually with ECG & ECHO
    • Refer to endocrinologist by 5 years of age to monitor for growth and diabetes, as well as thyroid and parathyroid problems

Gene therapy

  • This is currently under development targeting RPS19 mutation

Reproductive choices

  • Pregnancies should be planned as far as possible
  • Intensification of iron chelation should be performed before conception
  • Genetic testing as discussed above, inheritance is autosomal dominant
  • Full evaluation should be carried out in terms of blood-borne infections, iron overload, diabetes mellitus, hypothyroidism, cardiomyopathy and any other DBA or treatment related comorbidities. Pregnancy should be managed as high risk
  • Complications of pregnancy include
    • Fetal loss
    • Pre-eclampsia
    • Preterm delivery
    • Intra-uterine death
    • Intra-uterine growth retardation
    • Congenital abnormalities
  • The cause of pregnancy complication is an area of debate but is likely to be multi-factorial, to do with DBA itself, anaemia and treatment complications/toxicities

The science and the understanding of DBA is rapidly evolving. Therefore DBA management is also likely to evolve with time.

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week.

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 99 – update 5

Genetic testing on both parents and her brother are carried out and are all negative. Hence this is a de novo mutation of RPL5 in our little girl.

You also carry out HLA typing on her and her brother, who turns out to be HLA identical.

She is now 16 months old and has recovered from her cleft palate repair. You decide to give her a steroid trial to see if she can become transfusion independent.

Questions:

1. How do you plan to start steroids?

2. What supportive measures are necessary to minimise steroid toxicity in the short and long term?

3. When do you expect to see a steroid response and how do you proceed if she is steroid responsive?

4. How do you proceed if steroid non-responsive? What other treatment options are available other than transfusion?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week.

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 99 – update 4

Based on a diagnosis of Diamond Blackfan anaemia, a decision is made to start a regular transfusion programme until she is over 1 year of age to minimise the impact of steroids on her growth. It will also allow her to have her cleft palate repair in the mean time, and to complete her immunisation.

USS abdomen and ECHO do not show any abnormalities.

Meanwhile, genetic studies have demonstrated a mutation in RPL5.

Questions:

1. What is the implication of the mutation? What inheritance pattern might you expect?

2. How do you manage the rest of the family?

3. What difference does it make if NO mutation has been identified? Would that change your diagnosis or management?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week.

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 99 – update 3

A bone marrow biopsy has been carried out: (see below)

Aspirate shows erythroid hypoplasia but no dysplastic features. Cellularity is normal and megakaryocyte & granulocyte lineages are normal.

For interest, also see Trephine IHC with Glycophorin-C staining – demonstrating reduced but organised erythropoiesis.

Parvovirus serology is negative, EMA is normal, but eADA is elevated.

HbF 14% (elevated).

Mutational analysis has been sent.

It is now 2 weeks since her first transfusion.

Questions:

1. What is your preferred diagnosis? What other differentials have you ruled out?

2. What treatment strategy would you employ at this point & why?

2. What can you do to minimise any problems from your treatment of choice?

3. What other investigations should be carried out in this patient based on your diagnosis?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week.

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 99 – update 2

A blood film has been looked at, no specific findings are noted except for anaemia and occasional spherocytes. There are no red cell fragments, no dysplastic features and no primitive cells.

EMA & G6PD are in progress.

Parvovirus B19 serology is sent off.

Other results are now available:

Reticulocyte 9 x 10^9 (50-150)

B12 913 pmol/L (145-569)

Folate > 20ug/L (3.9-26.8)

Haemoglobinopathy screen – no variant haemoglobin, HbF 14% (elevated)

You now have a bit more history. The baby was born at full term with a below average birth weight but has maintained her growth just above the 2nd centile. Other than a cleft palate, she is normally fit and well with no other health concerns. She is waiting for surgery for cleft palate repair, though that has been delayed because parents do not want any surgery until she is a little older. They do not feel that the cleft palate has had any significant impact on her so far and she never had issues with feeding.

She is up to date with her immunisations and there has been no recent illness. She has an older brother aged 4 who is fit and healthy. Mum was told she had folate deficiency in her teens and required folic acid supplement for a time but otherwise no other history of anaemia in the family and no neonatal jaundice.

Our baby girl remains stable but her haemoglobin is now 52g/L and she is becoming more symptomatic. A blood transfusion is planned.

Questions:

1. What other tests are useful to do prior to starting transfusion?

2. How to you confirm the diagnosis?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week.

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 99 – update 1

You call Mum and repeat the baby’s blood count urgently.

Her repeat bloods show:

Hb 63g/L

Platelet 506 x 10^9

MCV 99.9fL,

WBC 9.36x 10^9

Neutrophil 3.46 x 10^9

You explain to Mum that her baby is anaemic and you would like to admit her to hospital for observation and for some further tests to get to the bottom of her anaemia.

Questions:

1. What other blood tests & investigations might be helpful at this stage?

2. Are any other clinical findings or history which might be useful?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week.

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 99 – the beginning

Welcome to our new #TeamHaem case.

You are working in General practice.

You see a 9 month old baby girl in the morning. Her mother tells you that in recent weeks she has needed more naps and has not been eating as much as usual. Mum has not noticed any significant weight loss, but she has always been very petite.

She seems bright and playful but is a little pale. So you do some blood tests just in case, and reassure Mum.

Later that day you receive a phone call from the lab informing you that the blood results show a haemoglobin of 65g/L, and ask for a repeat sample to confirm.

Questions:

1. What other information would you like to know at this point?

2. What would you do next?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week.

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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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.

Investigations

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.

Immunophenotyping

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.

Staging/Prognostication

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

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

http://www.bloodjournal.org/content/bloodjournal/early/2018/05/11/blood-2018-01-785998.full.pdf?sso-checked=true

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

http://www.bloodjournal.org/content/131/25/2745?sso-checked=true#T1

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

https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.15460

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

Posted in Chronic leukaemia | Tagged , , , , ,

Case 98 – part 2 – update 1

We have confirmed progression in our patient’s CLL.

There is no evidence of haemolysis.

He has a pmh of HTN, diabetes, mild copd and osteoarthritis which limits his mobility. He has an ecog of 2 (was 1 prior to the progression of his cll and resultant fatigue).

He has been started on chloramucil and obinituzumab however during the first obinutuzumab infusion he develops pyexia, and rigors.

  • What do you think is happening?
  • What would you do?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 98 – part 2 – the beginning

Thankyou for your help with part 1. Here is the second part of this weeks case.

You are in the haematology clinic and are seeing an 82 year old gentleman who was diagnosed with CLL 10 years ago. He has been on watchful waiting for the last 10 years however recently has been increasingly tired and his blood results show a rising lymphocytosis over the previous few months.

Fbc (previous clinic results from 2 months ago in brackets)

  • Hb 90 (110)
  • Plt 70 (130)
  • Wcc 120 (50)
  • Lymphocytes 110 (45)

Questions:

  • Would you like to know anything else?
  • What would you do next?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

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Case 98 – part 1 – update 3

Our patient has been started on venetoclax and has had an excellent response.

Following discussions with our patient and referral to the transplant team he has decided to go ahead with a sibling allo SCT.

  • What considerations are there for potential donors?
  • What are the indications for consideration for allo SCT in patients with CLL?
  • Does anyone have any questions currently?

We will start the second case later today, please join us for that.

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 98 – part 1 – update 2

Our patient has been diagnosed with CLL and has been found to have deletion 17p on cytogenetics.

He has now been on ibrutinib for 15 months. He has tolerated it very well and did get an improvement in his Hb with resolution of his fatigue and sweats. His lymphocyte count had reduced, although it has never gone below 6. He is beginning to feel tired again and is concerned that the CLL may be progressing.

Looking at his fbc (previous clinic fbc from 2/12 ago in brackets)

  • Hb 100 (115)
  • Plt 90 (130)
  • Wcc 40(20)
  • Lymphocytes 32 (10)

Questions:

  • What information do you what?
  • What would you do next?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 98 – part 1 – update 1

We have found our patient has a lymphocytosis with mild anaemia and mild thrombocytopenia.

Blood film show lymphocytosis with mature lymphocytes and smear cells.

We have some flow results.

  • What do these show?
  • What is our diagnosis?
  • Would you like any more information?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

Posted in Chronic leukaemia, Laboratory morphology | Tagged , ,

Case 98 – part 1 – the beginning

Welcome to our new case!

We will do 2 short cases this week.

In our first case we start in general practice.

A 42 year old patient has come to see you as he has been training for a marathon and he isn’t getting the times he expects to (although he can still do 26 miles in about 3.5 hours!). He is a regular marathon runner and normally does a lot better than this.

He had his appendix removed for acute appendicitis aged 21 but has no other PMH.

  • What would you like to know?
  • What would you do next?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

Posted in Chronic leukaemia

Case 97 – Summary

This week we looked at a neuropathy presenting via the neurology team associated with a plasma cell dyscrasia.

This area of haematology is often challenging! The diagnosis can be difficult and even after diagnosis there is a lack of evidence to formulate management plans. It is important to diagnose correctly as it is estimated that 10% of all idiopathic neuropathies are associated with an M protein (1).

It should be noted that in an aging population having an M protein is common indeed MGUS is seen in 1% of the population over age 50 (1). However, it should also be noted that MGUS is ten times as common in patients with polyneuropathies as it is with controls (2). This means that not all patients with an M protein have a treatable autoimmune neuropathy. The challenge is therefore in trying to identify the patients where the M protein is significant. It is now known that patients with CIDP like polyneuropathy and an Ig A or Ig G MGUS most likely have a coincidental MGUS that isn’t the key to the neuropathy. In contrast an Ig M M protein patient with neuropathy does usually have a distinct phenotype and should always be treated as Ig M associated autoimmune neuropathy. (2)

The above points although interesting don’t really assist you in clinical practice in assessing a patient in clinic with an M protein and a neuropathy.

The differential diagnosis for neuropathies can be assisted by knowing the type of M protein and associated light chain, the pattern of neuropathy and predominant feature of the neuropathy (sensory/motor/sensorimotor or autonomic). The associated clinical features and Electromyograph may also help. It should be stressed there are no definites as in every branch of medicine and some patients may have both axonal and demyelinating features on their EMG so in some cases tests may not be as conclusive as you would hope! Therefore involvement of the neurology team is critical with these patients as neuropathy is compex!

Here is a useful table that has been adapted from two different useful journal articles (References 1 and 3) that may help you in determining the cause of an autoimmune neuropathy:

M Protein type Disorder Pattern of neuropathy Associated clinical features EMG pattern Demyelination (DM) or Axonal
IgM
Ig M kappa LPL Slowly progressive distal sensory/ sensorimotor. (Similar to CIDP) Anaemia

Weight loss

Headaches

Visual disturbances

DM
Ig M Kappa MM/ MGUS Usually mild symmetrical distal sensory/sensorimotor Bone pain

Renal failure

Hypercalcaemia

Anaemia

Axonal
Ig M Cryoglobulinemia Symmetrical distal or multifocal painful sensory or sensorimotor. Occasionally mononeuritis Raynauds phenomenon

Purpura

Arthralgia

Leg ulceration

Axonal
Ig G/A
Ig G Cryoglobulinemia Symmetrical distal or multifocal painful sensory or sensorimotor. Occasionally mononeuritis Raynauds phenomenon

Purpura

Arthralgia

Leg ulceration

Axonal
Ig G Lambda

 

Ig A Lambda

POEMS Symmetrical and Proximal and distal sensorimotor.

Motor often predominant

Organomegaly

Papilloedema

Hypothyroidism

Effusions

Thrombocytosis

Clubbing

Hyperpigmentation

DM
Ig G Lambda Ig A Lambda Amyloidosis Symmetrical, distal painful sensory and autonomic neuropathy CCF features

Organomegaly

Macroglossia

Axonal
Ig G or Ig A Kappa MM/MGUS Usually mild symmetrical distal sensory/sensorimotor Bone pain

Renal failure

Hypercalcaemia

Anaemia

Axonal

Red Italics: useful diagnostic features

Initial history and examination should focus on signs of the above disorders (see table for details). Consider establishing features of hyperviscosity Raynauds phenomenon/ purpura if an Ig M M protein. If considering amyloidosis, cryoglobulinemia or POEMS a good systemic inquiry is essential. It is  important not to neglect to consider other causes of neuropathy as after all not all Patients with an M protein will have neuropathy attributable to this.

Useful aide to memory for distal peripheral neuropathies:

A – Alcohol

B – B 12

C – Connective tissue disorders

D – Diabetes /Drugs

With regards to investigations these should again be focused depending on type of M protein but should include:

M protein characterisation: FBC, U&E, LFT, Bone profile, SFLC, serum protein electrophoresis.

Neuropathy investigation: B12 and folate, Glucose, Nerve conduction studies and Anti MAG Ab and anti-ganglisoide antibodies. These should involve a neurologist if possible.

Specific tests that may be needed depending on presentation:

Amyloid: 24 hour urine protein, Echo, ECG and possible fat pad biopsy.

POEMS: VEGF level, TFT’s, skeletal imaging

LPL: CT scan, Bone Marrow Biopsy with testing for MYD88.

Myeloma: Skeletal imaging, Bone marrow biopsy with cytogenetics.

Cryoglobulinemia: check for cryoglobulinemia, Bone Marrow biopsy, Hepatitis screen, Auto Antibodies.

Our patient had an Ig M M protein without signs of hyperviscosity. He had loss of proprioception, temperature and fine touch symmetrically to around ankle level. He also has got bilateral reduced ankle jerks with preserved knee reflexes. This pattern of sensory symmetrical distal peripheral neuropathy that slowly progresses to some motor involvement is typical of Ig M associated Anti MAG Ab secondary to LPL.

Ig M Anti MAG Ab associated with an LPL:

Before going further it is important to understand what an Anti MAG Antibody is. Myelin associated glycoprotein (MAG) is a glycoprotein which is part of the central and peripheral nerve myelin. It was found that around 50% of patients with neuropathy and Ig M M-Protein gave serum that will react with MAG (2). These patients will also  have serum that co reacts with a specific glycolipid on the nerve which was identified as sulfogluconyl glycosphingolipid (SGPG). SGPG is found only in peripheral nerves and is part of the large MAG molecule and other parts of the peripheral nerve structure. All patients with Anti-MAG antibodies will also react to SGPG.

The testing therefore is for Anti MAG Ab using an ELISA principle, occasionally labs do use SGPG as their antigen instead of MAG and this may cause low affinity MAG Ab to be missed as binding to MAG is 10-100x stronger than to SGPG and it is worth bearing this in mind (2).

It is now thought that Anti MAG Ab are related to the neuropathies seen clinically for a few reasons:

  1. Biopsies from these patients show IgM and compliment in nerve fibres suggesting Ab is able to activate the compliment system to cause the characteristic demyelination.
  2. Animal studies have also shown that injecting the purified anti MAG Ab does seem to induce neuropathy in other animals.

Of the remaining 50% who don’t have a Anti MAG Ab about half of them will instead have another ganglioside Ab detected such as Anti GM 1 and Anti GM2 etc and these can be tested for by the neurology team and usually cause axonal neuropathies (2).

Given the above information it should make sense that in suppressing antibody production the patient would improve, however there is not great evidence to show large benefits when these patients  are treated as we will go on to discuss.

Returning to our patient he had Anti MAG Ab and LPL. With regards to his LPL he had no other indications for treatment apart from his neuropathy.  He didn’t have a lumbar puncture (LP) as he declined it. The clinical team felt as his symptoms were slowly progressive over more than 6 months and were consistent with a symmetrical distal neuropathy rather than Bing Neel syndrome and didn’t press the issue (4). If the patient had rapidly progressive symptoms or other odd neurology an MRI Brain and spine and LP should be performed with CSF examination. The CSF sent for cytology, flow and molecular studies for MYD 88. An MRI should be performed prior to LP to avoid false positive meningeal enhancement from the LP (4).

In making decisions regarding treatment of a patient with neuropathy secondary to Anti MAG Ab in context of otherwise asymptomatic LPL it is important to recall that cure is not possible and hence any treatment is only about improving quality of life. An MDT discussion is warranted as it is not always necessary or in the patients best interests to treat Anti MAG Ab neuropathy initially. Watch and wait is valid and this needs discussion with the MDT and the patient.

If treatment is being considered then generally Rituximab monotherapy is used without other chemotheraputic agents if neuropathy is the only problem related to LPL. Initially weekly rituximab for 4 weeks when neuropathy disabling.  The response to treatment in small case series of 13 patients has been reported at 60% with Rituximab monotherapy (4). Response times are slow as myelin regeneration is slow and typically 9 months is needed to perceive an improvement (4). Predictors of response include a lower pre treatment Anti MAG Ab titre, the authors postulate this may be because a particular threshold of Ab needs to be reached before improvements are seen (5).

There was a Cochraine meta-anaylsis (6) in 2016 looking at benefits and harms of immune therapies in patients with Ig M antibody that may bind to MAG it concluded that there was inadequate reliable evidence to support any particular treatment. There is it stated low quality evidence to show benefit from Rituximab in two small trials but again stressed larger well designed RCT’s are needed to assess the effectiveness.

In the case of our patient he felt he could not continue to function in his work without some treatment and he received Rituximab weekly and did derive some improvement after 6 months. He continues on a watch an wait follow up.

Thanks for your help with the case Please feel free to post any comments or questions.

References:

1) Rosenbaum E eat al. Diagnosis and management of neuropathies associated with plasma cell dyscrasias. Haematological oncology 2017. vol 36, Issue 1.

2) Dalakas, M. Advances in the diagnosis, immunogenesis and therapies if Ig M anti MAG antibody-mediated neuropathies. Theraputic advances neurological disorders. 2018; Vol 11.

3) Ropper, A et al. Neuropathies associated with paraproteinemia. NEJM 1998.Vol 38;22; 1601-1607.

4) Simon, L et al. How we manage patients with Waldenstrom Macroglobulinemia. British Journal of Haematology. 2018. Vol 181;737-751.

5) Benedetti et al. Predictors of response to rituximab in patients with neuropathy and anti-myelin associated glycoprotein immunoglobulin . Journal of the peripheral nervous system 2007. 12:102-107.

6) Cochraine Review Feb 2016 What are the benefits and harms of immune treatments for peripheral neuropathy caused by an Ig M paraprotein antibody that may bind to Myelin-associated glycoprotein (MAG)?

 

Posted in Lymphoma, Myeloma/paraproteins, Related to other specialities | Tagged , , , , , , , , , ,

Case 97 – update 3

Thanks for your help so far with this case.

so far we know our patient is a 54 year old male who presented to clinic with distal sensory loss and a broad based gait which has been slowly progressing over the past 9 months.

He has loss of proprioception, temperature and fine touch symmetrically to around ankle level. He also has got bilateral reduced ankle jerks with preserved knee reflexes.

All the test results are back for our patient and are summarised below:

FBC: Hb 14g/dl others all within normal range

U&E and LFT: Normal

Albumen : 42g/l (normal)

B12 and folate: Normal

Serum electrophoresis: Ig M Kappa paraprotein of 6g/dl.

Serum B2 Microglobulin: 3.2mg/l (Normal <2mg/l).

LDH: 540u/l (reference range 240-450u/l)

24 hour urine protein with electrophoresis : negative.

CT CAP: Nolymphadenopathy or organomegaly.

Bone marrow aspirate report: Plasmacytoid and lymphoplasmacytoid cells are relatively prominent.

Abnormal population: Kappa restricted B cell population = 18% of total nucleated cells.

Immunophenotype: CD19+, CD5 negative, CD23 negative/wk, CD10 negative, CD103 negative, CD11c+/-, CD38+/-, FMC7+, CD79b+, sIg++ (CLL score 0/5)

Molecular studies: The c.794T>C p.(Leu265Pro) mutation in exon 5 of the MYD88 gene is present at low levels.

Bone Marrow trephine: Diffuse infiltrate of small lymphoid cells with reactive mast cell infiltrate noted at peripheries.

(The immunophenotype confirms it is a B cell NHL, however no other markers to assist in identification – No CD 5 for CLL or MCL, no CD10 for FL and no CD103 for HCL despite the occasional lymphocyte with some projections on aspirate. Molecular testing has confirmed the presence of MYD88 mutation seen in up to 90% of LPL cases.)

The neurology team have found the patient is positive for anti MAG Ab

Nerve conduction testing: prolonged conduction velocities consistent with demyelination in an axonal loss pattern.

You plan to present the patient at MDT this week as an LPL with disabling neuropathy secondary to anti MAG Ab

Would you treat this patient?

What are the management options?

The patient wants to know how likely any treatment is to work?

He also asks how fast any treatment will work what would you say?

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Case 97 – update 2

The bone marrow aspirate did appear to show an excess of Plasmacytoid and lymphoplasmacytoid cells.

Immunophenotype results:

Abnormal population: Kappa restricted B cell population = 18% of total nucleated cells.

Immunophenotype: CD19+, CD5 negative, CD23 negative/wk, CD10 negative, CD103 negative, CD11c+/-, CD38+/-, FMC7+, CD79b+, sIg++ (CLL score 0/5)

What are your thoughts regarding the possible diagnosis?

What other molecular test could be performed on the bone marrow that could assist in diagnosis?

Posted in Laboratory morphology, Lymphoma, Myeloma/paraproteins, Related to other specialities | Tagged , , , , , ,

Case 97 – update 1

Thanks for your help so far

The neurology team contact you as they have the results of the Nerve conduction studies they performed a few weeks ago these show “prolonged conduction velocities consistent with demyelination in an axonal loss pattern”

The neurology team have also sent away for some further bloods looking at cause of demyelination

The results from your clinic are available. He had unremarkable FBC (Hb 14g/dl), U&E and LFT unremarkable. Albumen was within normal range at 42g/l. His B12 and folate are normal.

His serum electrophoresis confirmed an Ig M Kappa paraprotein of 6g/dl. Serum B2 Microglobulin 3.2mg/l (Normal <2mg/l). LDH 540u/l (reference range 240-450u/l)

24 hour urine protein with electrophoresis negative.

A CT CAP showed no lymphadenopathy or organomegaly. You have booked him in for a bone marrow this week.

What other blood tests have the neurology team sent for given the nerve conduction findings and Ig M PP?

What is the likely mechanism for the neuropathy in this case?

Would you be happy to leave the lumbar puncture at the moment as the patient is not keen?

Posted in Lymphoma, Myeloma/paraproteins, Related to other specialities | Tagged , , ,

Case 97 – the beginning

Welcome to another #TeamHaem case

You are in the Haematology new patient clinic and receive a letter from the local Neurology team asking you to assess a 54 year old male who has an Ig M kappa paraprotein of 6g/dl and presented to their clinic with distal sensory loss and a broad based gait which has been slowly progressing over the past 9 months. The neurologist feels he may have a neuropathy secondary to a plasma cell dyscrasia and asks for your review.

On arrival in the clinic you note he has indeed got a broad based gait. His systemic enquiry apart from the neurological findings outlined above is unremarkable. He denies any weight loss or other B symptoms. He has no bone pains and hasn’t noted any lumps or bumps. His only past medical history is an underactive thyroid for which he takes levothyroxine. He is an accountant by profession and is a lifelong non-smoker and drinks around 10 units of alcohol a week.

Examination is unremarkable apart from you note he has loss of proprioception, temperature and fine touch symmetrically to around ankle level. He also has got bilateral reduced ankle jerks with preserved knee reflexes (However eliciting ankle jerks was never your strong point so you are not sure if this is a genuine finding! )There is no sign of muscle wasting and he appears to have power MRC grade 5/5 in all lower limb groups. His upper limb neurological exam and cranial nerves are all intact. You specifically also check for lymphadenopathy, organomegaly, retinal haemorrhages and papiloedema these are not present.

What are the possible haematological causes of a peripheral sensory neuropathy?

Considering the differential diagnosis what investigations may help you elicit the cause of his sensory neuropathy?

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not in a position of authority.It is an educational platform to provide discussion and learning.

Please use #TeamHaem in all your posts to allow others to see all the replies!

Posted in Lymphoma, Myeloma/paraproteins, Related to other specialities | Tagged , , ,

Case 96 – summary

Thank you for participating in our case this week.

This week we have been looking at a case of JMML (Juvenile myelomonocytic leukaemia), which is a rare clonal haematopoietic disorder of childhood, characterised by the proliferation of granulocytic and monocytic lineages. Blasts and promonocytes account for < 20% of the WBC in the peripheral blood and bone marrow. Erythroid and megakaryocytic abnormalities are often present. BCL-ABL fusion is absent. Mutations involving genes of the RAS pathway are characteristic.

Incidence is estimated as 1 in 1 million children. But with increased frequency in children with Noonan syndrome and neurofibromatosis (NF1). It accounts for < 2 – 3 % of all leukaemia in children, but for 20- 30 % of all cases of MDS/MPNs in those aged < 14 years. Age of diagnosis ranges from 1 month to early adolescence. 75% of cases are in children aged < 3 years. Boys are affected twice as frequently as girls.

WHO diagnostic criteria for JMML (revised 4th edition, 2017):

1. Clinical and haematological criteria (all 4 criteria are required)

  • Peripheral blood monocytes > 1 x 10^9/L
  • Blast in peripheral blood and bone marrow < 20%
  • Splenomegaly
  • No Philadelphia chromosome or BCR-ABL fusion

2. Genetic criteria (any 1 is sufficient)

  • Somatic mutation in PTPN11, KRAS or NRAS (if a mutation is found, must consider whether it might be a germ line mutation and the diagnosis of TAM of Noonan syndrome considered)
  • Clinical diagnosis of neurofibromatosis type 1 or NF1 mutation
  • Germline CBL mutation and loss of heterozygosity of CBL

3. Other criteria

Cases that do not meet any of the genetic criteria above must meet the following criteria in addition to the clinical and haematological criteria above:

  • > 2 of the following :
    • Increased HbF for age
    • Myeloid or erythroid precursors on peripheral blood smear
    • Granulocyte-macrophage colony-stimulating factor (CSF2) hypersensitivity in colony assay
    • Hyperphosphorylation of STAT5

Clinical Features:

  • Most present with constitutional symptoms or infection
  • Generally marked hepato-splenomegaly
  • Spleen size may occasionally be normal at diagnosis but rapidly increases thereafter
  • 50% may have lymphadenopathy
  • Leukaemic infiltrations
    • Enlarged tonsils
    • Dry cough, tachypnoea, interstitial infiltrates on CXR (pulmonary infiltration)
    • Diarrhoea, GI infections (gut infiltration)
  • 25% may have rashes, cafe-au-lait spots may indicate NF1 or Noonan syndrome
  • Raised HbF
  • Polyclonal hypergammaglobulinaemia and presence of autoantibodies
  • In vitro hypersensitivity of JMML myeloid progenitors to granulocyte-macrophage colony-stimulating factor (CSF2) – though this is infrequently performed nowadays
  • Peripheral blood typically shows leukocytosis, thrombocytopenia and often anaemia.
    • Leukocytosis consists mainly of neutrophils, monocytes and some immature cells e.g. promyelocytes and myelocytes.
    • Blasts usually <5% and always < 20%
    • Eosinophilia and basophils can sometimes be present
    • Normocytic red cell indices is the most common, but macrocytosis can be seen particularly in monosomy 7
    • Thrombocytopenia can be severe

Molecular abnormalities:

  • RAS pathway mutation now allow molecular diagnosis in approx 85-90% of all JMML (PTPN11, NRAS, KRAS, NF1 and CBL)
  • Most common gene is PTPN11 – found in 35% of JMML
    • PTPN11 encodes a protein tyrosine phosphatase, SH2.
    • Germ-line missense mutations in PTPN11 are found in about 50% of Noonan syndrome patients, this is a more indolent JMML that may resolve spontaneously
    • The acquired PTPN11 mutations in JMML are not the same, and are more aggressive
  • Mutations in NRAS or KRAS are seen in about 30% of JMML
  • About 10-15% have homozygous mutations in CBL. These are also thought to be heterozygous germ-line events and somatic loss of heterozygosity
  • Germ-line mutations of NF1 found in about 10% of JMML
    • Children with NF1 are at 200-350 times increased risk of developing JMML

Genetics:

Monosomy 7 is present in about 25% patients. Other abnormalities in 10% and normal karyotype in 65%.

Immunophenotype

There is no specific immunopheotypic abnormalities reported in JMML.

Differentials:

In RAS pathway mutation-negative cases, other clinical and haematological conditions must be excluded, for example:

  • Infection
  • Wiscott-Aldrich syndrome (eczema-thrombocytopenia-immunodeficiency syndrome)
  • Malignant infantile osteopetrosis
  • HLH

Prognosis:

JMML with somatic PTPN11 mutation or in those with NF1 are rapidly fatal if left untreated. Median survival without allogeneic haematopoietic stem cell transplantation is about 1 year.

Poor prognostic factors include low platelet count ( < 33 x 10^9/L), aged > 2years and high Haemoglobin F levels at diagnosis.

KRAS and NRAS mutation generally has an aggressive course. Most children with JMML and germ-line CBL mutations experience spontaneous regression of JMML.

Management of JMML

JMML has a diverse molecular etiology. Clinical genetics assessment should be considered. Some JMML can be indolent particularly in the context of Noonan syndrome. But these are the exceptions.

Patients with CBL mutation can be managed with a watch and wait approach initially, and to consider HSCT if there is disease progression.

However, most cases of JMML require HSCT for cure. Even so, the relapse rate post HSCT is reported to be 40 – 50%.

If a matched sibling donor is unavailable, then a matched unrelated donor should be sought, or to consider unrelated umbilical cord blood unit transplant.

HSCT from an HLA-haploidentical relative is still experimental in JMML, but can be considered if an urgent allograft is needed but lack any other suitable donors.

Conditioning is usually a myeloablative busulfan-based regime (e.g. busulfan, cyclophosphamide and melphalan) without total body irradiation (TBI), in order to minimise the late effects from TBI in very young children.

ATG is often used in the conditioning regime if a MUD or UCBT is used in children with JMML, as it reduces the complications from GvHD.

GvHD prophylaxis should also be tailored according to patients’ genetic lesions and other risk factors influencing the relapse rate. Those with high risk relapse rate should be given low-intensity GvHD prophylaxis in order to maximise GvL effect.

Indiscriminate splenectomy prior to HSCT in children with spleen enlargement is not recommended. However, in the presence of massive splenomegaly with hypersplenism and/or platelet refractoriness, it could be considered in selected cases.

The use of conventional chemotherapy is an area of controversy and there are no established recommendations. Some have used 6-mercaptopurine and/or low dose cytarabine to reduce leukocytosis and spleen size. In children with blastic transformation or life threatening pulmonary infiltration, fludarabine and high dose cytarabine may be temporary holding measures.

Clinical trials are ongoing looking at azacitidine and MEK inhibitors.

In relapse disease following allograft, DLI is not recommended. A second HSCT should be used as salvage therapy, either from the same or a different donor.

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