Case 79 – summary

Thankyou for your help this week!

This week we had a look at HHT. Our patient was diagnosed with HHT aged 30 after a history of epistaxis was noted. On further questioning she was also found to have cutaneous telangectasia.

Her mother died aged 35 when our patient was old 1 from a ‘brain haemorrhage’, however she also had a history of significant epistaxis and telangectasia. Her grandfather also had recurrent epistaxis, telangectasia and suffered with recurrent GI bleeding.

HHT is a rare systemic disorder of fibrovascular tissue. It is thought to be autosomal dominant with 5 genetic variants, most of which affect the VEG-F beta receptors. The condition results in an overgrowth of blood vessels and abnormal vessel formation. >90% of patients who carry the mutation will have some bleeding, this tends to worsen with age.

It can affect many systems, and can cause problems with GI tract, nasal, lungs, brain, liver and skin. Some mutations have also been associated with juvenile polyposis and primary PAH.

Diagnostic criteria for HHT- curacao criteria.

3 or more criteria met indicate definite HHT

2 criteria met indicate possible HHT

Less than 2 criteria met indicates HHT unlikely

1. recurrent and spontaneous nosebleeds which may be mild to severe

2. Multiple telangectasia on the skin of the hands, lips, face or inside of the nose or mouth. Telangectasia are small blood vessels that appear as bed spots that disappear when push on.

3. AVM (arteriovenous malformations) or telangectasia that affect internal organs such as brain/liver/lungs/gi tract/spinal cord.

4. A family history of a first degree relative who meets the criteria for definite HHT or who has been genetically diagnosed.

Haematologist may often find that they are caring for patients, either by ensuring that they are getting regular iron or blood transfusion, or other treatments, or by coordinating care and ensuring that the patient is being seen by the appropriate specialties for management or screening for complications.

ENT are very often involved for management of epistaxis. This may involve topical treatments. Teaching the patient low pressure packing techniques, cauterisation, or other procedures such as septodermoplasty (skin graft in the nose) or Young’s procedure (surgical closure of the nostrils)

The respiratory team will also be involved. 1/3 of patients with have pulmonary AVMs. This causes a right to left shunt, although they rarely bleed they can an can require coiling. Paradoxical emboli can occur causing stroke or brain abscess. As a result if any patient with known AVM or any unscreened patient requires dental work they should have prophylactic antibiotics. Patients can also develop pulmonary arterial hypertension, this may be primary or can be secondary to liver AVMs causing high output heart failure or recurrent VTE. 

The liver team may also be involved. 80% of patients will have liver AVMs, although only 5% will be symptomatic. These can cause portal HTN, biliary disease or high output heart failure.

The gastroenterology team may also be involved. 80% of patients will have lesions on endoscopy, although only 1/3 will have bleeding. Repeated endoscopy with coagulation of these lesions is often necessary. In patients who have juvenile polyposis they will need regular screening endoscopy.

The brain can affected 25% of patients. These can be telangectasia, AVM or venous malformations. Symptoms can include headaches, seizure and ICH.

Patients will need to be closely monitored through any pregnancy, they may require transfusion and problems with bleeding pulmonary AVM can occur. There is a 1% maternal mortality associated with pregnancy in the context of HHT.

Patients with HHT and chronic iron deficiency also appear to be prothrombotic, presumably due to the increase in factor VIII associated with chronic blood loss. 

If the patient develops AF with an indication for anticoagulation, although anticoagulation should not be withheld definitive treatment e.g. Definitive treatment for AF +/- left atrial appendage if ongoing anticoagulation is indicated.

When screening a new patient genetic testing should be considered, with screening of first degree relatives if a mutation is found.

A bubble echo to look for pulmonary AVMs should be considered, with a repeat every 5 years if negative. If positive further imaging is required.

MRA brain to look for cerebrovascular defects

Consider liver U/S

General managment will include ensuring adequate b12/folate/iron replacement and if regular transfusion is needed, appropriate vaccination and blood provision.

Drugs that have been used in the treatment of HHT include tranexamic acid, hormone therapy, tamoxifen, raloxifene, thalidomide and bevacizumab(avastin). Bevacizumab is a VEG-F inhibitor which is usually used in malignancies, but small studies and case reports have shown there may be benefit in certain patients with HHT. (Dupuis-girod 2014, JAMA)

Further information can be found in international guidelines for the diagnosis and management of hereditary haemorrhaging telangectasia, journal of medical genetics 2011 faughnan ME, Palma VA, Garcia-Tsao G et al

http://www.cureHHT.org
VASCERN.org – vascular European research network
Geisthoff et al 2015 BJHaem review 
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 Inherited bleeding | Tagged , , , ,

Case 79 – update 2

We have found out our patient has HHT.

We know she has epistaxis, and cutaneous telangectasia. She has also required courses of iron for iron deficiency, and is currently anaemic.

Patients with HHT may develop AVM and some teamhaem follower have suggested that we screen our patient for cerebral AVM and pulmonary AVM.

Where else might you develop problems? What other conditions can be associated with HHT?

What screening should patients with HHT receive?

How would you manage our patient currently?

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 Inherited bleeding | Tagged , , , ,

Case 79 – update 1

So we have an update

Our patient has presented with a long history of epistaxis.

There is no history of easy bruising. 

No bleeding after tooth extraction

Her mother died of a brain haemorrhage and also had significant history of epistaxis. The patient also thinks her maternal grandfather had significant history of epistaxis and gi bleeds, and needed several blood transfusions.

On examination, no hepatosplenomegally, no visible oral telangegtasia although there do appear to be several cutaneous telangectasia on the hands.

Fbc shows a microcytic hypochromic anaemia. Ferritin 5.

Pt 13

Aptt 27

Claus fib 4.0

Vwd screen 

Factor VIII 160%

Vw antigen 130%

VW activity 120%

RICOF 130%

Platelet function test normal

What are the thoughts now?

Are there any other investigations you would like? 

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 Inherited bleeding | Tagged , ,

Case 79 – the beginning

Welcome to our new case!
This week we start with a 30 year old lady who has come to her GP for a routine discussion for the contraceptive pill. In her medical history you note that she has had significant epistaxis which she has needed to attend A&E 3 times in the last year for, and has needed cauterising.
What questions would you like to ask in her history?
Are there any investigations you would like to 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

Posted in Inherited bleeding | Tagged , ,

Case 78 – Summary

Thanks for your help this week. We had a case of T-LGL associated with rheumatoid arthritis. In our case her planned surgery was postponed. She was given GCSF and responded to this and this was used pre operatively for optimisation. She commenced MTX weekly and continues on this with a reasonable Blood count response: HB 95, plt 200, wcc 2.5, neu 1.7. She has not had any infective complications from her T- LGL

Background:

T cell Large granular lymphocyte leukaemia is a rare disorder accounting for around 2- 5% of cases of chronic lymphoproliferative disorders in the USA. It is usually diagnosed in older patients >60 years with an equal proportion of men and women affected.  85% of cases are of a more indolent T cell type but an agressive NK cell LGL is recognised particularly in the far east where it is linked to EBV infection and has a poor prognosis. In this summary we will discuss T LGL only.

Aetiology:

T-LGL provides an interesting insight into the working of T cell mediated immunity. The response of the disease to immune suppression has lead researchers to feel that this was a condition caused by dysregulation of the immune system. This is also supported by the proponderance of this disorder in patients with pre-existing immune conditions.

T-LGL is derived from  CD 8 positive cytotoxic T cells. In healthy patients these function as part of the immune system and are activated via the TCR interacting with peptides expressed on MHC. Activated cytotoxic T cells then proliferate and cause cell death through perforin and granzyme release killing virally infected cells.

In the case of T LGL it is postulated that chronic antigen expression causes initial oligoclonal cytotoxic T cell expansion. Then a subclone is selected for over time in cases where antigen is chronically expressed. This hypothesis is backed up by detailed PCR of T-LGL cells TCR (T cell receptor) that show limited diversity of the TCR LGL suggesting they are clonal.

A recent blood article by Lamy et al 2017 describes 28-75% of T-LGL patients have a STAT3 mutation. This finding is an important step in understanding the pathogenesis of T-LGL. This STAT 3 signalling may also predict the patients who will respond to MTX therapy though this is still under investigation.

Here the expansion of a sub-clone of cytotoxic T cells that has a STAT 3 signalling mutation leads to increased cytokine production and cytotoxic granule release causing anaemia, neutropenia and fatigue. The faulty STAT 3 signalling allows the clone to escape the normal apoptotic mechanism via a variety of mechanisms including increased production of platelet derived growth factor and IL15 and also the cells secrete excessive amounts of soluble FAS ligand to act as decoy allowing these cells to evade apoptosis.

Diagnosis of T LGL requires the following

Appropriate clinical context:

Splenomegaly (50% cases)

Cytopenias (85% Neutropenia, 50% Anaemia and  20% Thrombocytopenia)

Lymphocytosis (though often this is mild)

History of an autoimmune disease (up to 40% cases linked RA but also associations with Red cell aplasia, post BMT, Post solid organ transplant, CML, Cyclical Neutropenia, Pulmonary hypertension, HIV infection).

Blood film:

Large granular lymphocytes with prominent auzorophillic granules >0.5 x10^9. It should be stressed that on morphology alone these cant be distinuguished from usual LGL cells.

Flow:

An excess of Large granular lymphocytes that express CD 3 and CD8, CD 57 and or CD16

Clonality:

PCR of TCR gama gene.

Rarely there will not be a lymphocytosis and there is not a good clinical background, in these cases a bone marrow is recommended as trephines can highlight areas of infiltration of LGL. It may also help exclude MDS or Aplastic anaemia as a cause for cytopenias.

When to treat LGL?

Watch and wait is a valid option if cytopenias are asymptomatic. Prognosis is often good >70% at 10 years. Many patients may never require any treatment and lamy et al point out that mortality from infection in LGL is low.

How I treat authors describe four situations where they feel treatment is valid:

  1. Recurrent infections and neutrophils <1
  2. Systemic treatment needed for other autoimmune condition
  3. Transfusion dependent anaemia
  4. Severe neutropenia neu <0.5

 

Treatment options:

It should be noted that large scale trials are lacking in T LGL treatment and many of the treatment evidence bases are built on small case series. These recommendations are from the Blood How I treat paper 2011 and recent Lamy et al paper 2017.

Prednisolone:

  • Not a longterm option but may be useful as adjunct while other therapy taking time to have effect. How I treat authors advocate its use if neu <0.5 at initiation of therapy suggesting 1mg/k for a month and then tapering.

Methotrexate:

  • Proven treatment benefit as DMARD in RA hence useful treatment in this context.
  • Starting dose 10mg/m2 weekly
  • Around 50% ORR
  • 2-12 weeks for response
  • May not be durable beyond a few years?
  • lamy et al describe recent data that suggests STAT3 mutated patients respond better to MTX
  • Monitoring for Liver toxicity and pulmonary complications important

Cyclophosphamide:

  • 50-100mg daily
  • ORR 50-60%
  • Up to 4 months response
  • Adinistration beyond a six months to a year not recommended due to carcinogenesis and bladder toxicity. Need to re-start if progressing cytopenias after treatment break.

Ciclosporin:

  • Possibly useful if severe anaemia/ red cell aplasia or in context of a solid organ transplant where ciclosporin may already be required
  • Needs level monitoring
  • Problematic if Hypertension or pre-existing renal impairment

If above options fail:

  • Campath – Need to be fit and usually older demographic affected. Lower CD 52 expression on T LGL cells compared to usual cytotoxic T cells  hence only about 60% response rates seen.
  • Purine analogues – Need to be fit and usually older demographic affected. Up to 70% ORR and these can be durable lasting several years.
  • Splenectomy – very limited evidence for benefit.
  • ?JAK/Stat inhibitors – Lamy et al describe early data showing use of JAK 3 inhibitor Tofacitinib citrate used in 9 patients T LGL and 6 patients responded.

Assessment of Treatment response

  • Assess after 4 months
  • CR – Normalisation of FBC
  • PR – Improvent in FBC
  • PD – No response to cytopenias at 4 months

Many thanks for your help with the case this week. Please feel free to tweet any questions or comments. 

References:

Lamy et al. LGL Leukaemia:from pathogenesis to treatment. Blood 2017;129 (9) 1082-1094.

Lamy T, Loughran T. How I treat LGL leukaemia. Blood 2011;117 (10) 2764-2774.

Rose M, Berlinder N. T cell large granular lymphocyte leukaemia and related disorders. The Oncologist 2004;9:247-258

 

 

Posted in Chronic leukaemia | Tagged , , , , , , ,

Case 78 – update 2

Flow results are back:

CD 3 pos, CD 8 pos, CD 4 neg, CD 56 neg, CD 16 neg, CD 5 neg, CD7 wk/variable, TCR alpha/beta pos

PCR TCR studies confirm clonality

A Diagnosis of T Large Granular Lymphocytic leukameia is confirmed

What are the options for treatment?

What are the indications for treatment of T LGL?

If surgery is required what options are available to improve neutropenia?

Posted in Chronic leukaemia | Tagged , , , , , ,

Case 78 – Update 1

Thank for all the suggestions so far. We followed your advice and the lady has had her surgery postponed and we have established the following:

History:

  • Chronic anaemia since 2011 stable at around 90.
  • No history of bleeding/Malena
  • No weight loss
  • No night sweats
  • Neutropenia since Jan 2016, progressive but no history of infections.
  • RA diagnosed thirty years ago following birth of third child previously on Methotrexate, stopped at patient request as stable for several years.
  • PMHx: Hypertension, Previous gastric ulcer secondary to NSAIDs 20 years ago, Rheumatoid arthritis with previous knuckle replacements 20 years ago and a previous left hip replacement 10 years ago.
  • Medications: Amlodipine for hypertension and Co-codamol for hip.
  • No alcohol intake
  • Non-smoker

Examination:

  • No features of acute joint inflammation noted however she has rheumatoid nodules at elbows and deformity of hands due to previous failed knuckle replacements for rheumatoid arthritis of hands (see pictures).
  • Noted to have spleen tip palpable on examination
  • No lymphadenopathy

Investigations:

  • Normal B12/folate
  • Serum Ferritin 500
  • Imunoglobulin screen Normsl and Normal SFLC Ratio
  • HIV/Hepatiitis screen – negative
  • Rheumatoid factor positive and Anti CCP antibodies positive
  • CRP 30
  • ESR 50
  • Negative DAT, Normal LDH, Normal Haptoglobins and Retic count
  • Normal LFTs and Renal function
  • Film: Re-reviewed noted to have many large lymphocytes some with granulation – sample sent for flow cytometry.
  • USS confirms mild splenomegaly

 

What is the possible diagnosis in this case?

Is the history of Rheumatoid arthritis relevant to the case? – if so how?

What flow results may you expect given the possible diagnosis? 

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 78 – the Beginning

A 72 year old lady has attended pre- assessment clinic for an elective hip replacement and had routine bloods taken.

Blood results:

Hb 93, MCV 97, Plt 220, Wcc 7.5,  Neu 0.9, lymph 6.0.

Normal Liver and Renal function 

Blood film report:

“Mild normocytic anaemia with normal red cell morphology. Mild neutropenia, neutrophils are normal in morphology with no dysplastic features. There are some Large atypical lymphocytes, some with prominent granulation. No previous full blood counts available on system. Given anaemia suggest check haematinics. Lymphocytosis may be reactive, particularly in combination with neutropenia please correlate with clinical details, consider repeat sample if results unexpected. Please discuss if persisting as I note this is a pre-op sample.”

You receive a call from the pre-assessment clinic, they tell you that they repeated her blood count and the results were similar. She has recently moved to the area but has had chronic anaemia, with a Hb of around 90 since 2011. She has been noted to have progressive neutropenia since Jan 2016, however the most recent results are the first result when her neutrophils have been less than one. She is not on any regular medications apart from Amlodipine and Co-codamol.

She is due an elective hip replacement as she has a history of Rheumatoid arthritis. Over the last few years she has not required any treatment for her arthritis but she was previously on methotrexate up to 2014.

What further history would you like from the patient?

What would you ask the team to examine for?

What further tests should be undertaken to investigate the chronic anaemia and neutropenia?

Should surgery be delayed while these investigations are performed?

 Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.
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 77 – summary

Case 77 Summary

 

Thanks to everyone who contributed to the case this week.

 

Our case started with a blood film to test our morphology skills.  We picked up that the blood film showed:

  • Dysplastic neutrophils
  • Blasts
  • NRBCs
  • Tear drop poikilocytes
  • Thrombocytopenia

IMG_2154

The FBC indices identified that the patient was anaemic, thrombocytopenic and neutropenic.  The initial response to these bloods should be to ensure the safety of the patient – i.e. evidence of bleeding/sepsis/ symptomatic anaemia.  As a haematologist reviewing the blood film I would also look for any previous results on the system for this patient or clinic letter i.e. was he known to haematology already.    Urgent discussion with GP is required if these are new findings to ensure they are aware of the results, and allow the GP to make a judgement on the clinical symptoms and whether urgent haematology review is required.  If the patient is symptomatic he should be admitted to hospital urgently.  However if he remains relatively stable, he could be assess as an outpatient on an urgent basis.

 

The next step was a bone marrow marrow biopsy.  In real life we would also suggest checking haematinics/medication history/review comorbidities.  We requested a coagulation screen also for this patient which I think is useful, specifically if he was bleeding, given the thrombocytopenia.  A clotting may also be useful if we felt this picture may have developed due to an underlying sepsis so ensure there was no evidence of DIC.

 

The bone marrow showed evidence of dysplasia and 13% blast count.  Previous diagnostic criteria would have classified this as RAEB-2, however WHO classification has recently been revised and the diagnosis would be MDS-EB-2

 

WHO classification for MDS 2016.

PB and BM findings and cytogenetics of MDS

Name Dysplastic lineages Cytopenias* Ring sideroblasts as % of marrow erythroid elements BM and PB blasts Cytogenetics by conventional karyotype analysis
MDS with single lineage dysplasia (MDS-SLD) 1 1 or 2 <15%/<5% BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with multilineage dysplasia (MDS-MLD) 2 or 3 1-3 <15%/<5% BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with ring sideroblasts (MDS-RS)
 MDS-RS with single lineage dysplasia (MDS-RS-SLD) 1 1 or 2 ≥15%/≥5% BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with isolated del(5q)
 MDS-RS with multilineage dysplasia (MDS-RS-MLD) 2 or 3 1-3 ≥15%/≥5% BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with isolated del(5q) 1-3 1-2 None or any BM <5%, PB <1%, no Auer rods del(5q) alone or with 1 additional abnormality except −7 or del(7q)
MDS with excess blasts (MDS-EB)
 MDS-EB-1 0-3 1-3 None or any BM 5%-9% or PB 2%-4%, no Auer rods Any
 MDS-EB-2 0-3 1-3 None or any BM 10%-19% or PB 5%-19% or Auer rods Any
MDS, unclassifiable (MDS-U)
 with 1% blood blasts 1-3 1-3 None or any BM <5%, PB = 1%,no Auer rods Any
 with single lineage dysplasia and pancytopenia 1 3 None or any BM <5%, PB <1%, no Auer rods Any
 based on defining cytogenetic abnormality 0 1-3 <15%§ BM <5%, PB <1%, no Auer rods MDS-defining abnormality
Refractory cytopenia of childhood 1-3 1-3 None BM <5%, PB <2% Any

 

 

Assessing risk

Once the patient has been diagnosed, we need to be able to assess the patients isk in order to develop an optimal management plan for that individual.  Important factors to take into account are the patients age, co-morbidities and ECOG status, as these will potential affect the type of treatment appropriate for each individual patient.

IPSS-R is a decision support tool designed to assess risk of disease and therefore prognosis based on blood indices, cytogenetics, and blast count.

 

IPSS-R Cytogenetic risk groups*,**

Cytogenetic prognostic subgroups Cytogenetic abnormalities
Very good -Y, del(11q)
Good Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate del(7q), +8, +19, i(17q), any other single or double independent clones
Poor -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 abnormalities
Very poor Complex: >3 abnormalities

IPSS-R Prognostic Score Values*

Prognostic variable 0 0.5 1 1.5 2 3 4
Cytogenetics Very Good Good Intermediate Poor Very Poor
BM Blast % <=2 >2-<5% 5-10% >10%
Hemoglobin =>10 8-<10 <8
Platelets =>100 50-<100 <50
ANC =>0.8 <0.8  

 

IPSS-R Prognostic Risk Categories/Scores*

RISK CATEGORY RISK SCORE
Very Low <=1.5
Low >1.5 – 3
Intermediate >3 – 4.5
High >4.5 – 6
Very High >6

IPSS-R: Prognostic Risk Category Clinical Outcomes*

No. pts Very Low Low Intermediate High Very High
Patients (%) 7012 19% 38% 20% 13% 10%
Survival*** 8.8 5.3 3.0 1.6 0.8
AML/25%***,^ NR 10.8 3.2 1.4 0.7

 

Somatic mutation profile was also suggested by one of our followers.  This can also help provide prognostic information and risk stratification, but has not been incorporated into the IPPS-R scoring system currently.  Somatic mutations in MDS driver genes especially TP53, ASXL1, DNMT3A, EZH2, and RUNX1, are associated with poorer outcomes and have been shown to add independent prognostic information.  The number and types of specific mutations are strongly associated with disease outcome in MDS, and the addition of mutation data improves the prognostic value of existing risk-stratification schemes in MDS.

 

Approach to treatment

The patient in this case would be classified as very high risk disease given his IPSS-R score.  Given his age and relative fitness, the approach of transplant should be considered.  Options pre-transplant which were suggested included azacitidine, and AML – type chemo (AML 18 and AML 19 are trials currently available in the UK and would be options for this patient).  Discussion with the transplant team is important early, as some patient may be consider for transplants upfront if donors were available.

 

 

References:

  1. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.  Arber, Attilio Orazi, Robert Hasserjian, Jürgen Thiele, Michael J. Borowitz, Michelle M. Le Beau, Clara D. Bloomfield, Mario Cazzola and James W. Vardiman

Blood 2016 127:2391-2405; doi: https://doi.org/10.1182/blood-2016-03-643544

  1. Recent developments in myelodysplastic syndromes

Rafael Bejar and David P. Steensma

Blood 2014 124:2793-2803; doi: https://doi.org/10.1182/blood-2014-04-522136

  1. Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes Risk Assessment Calculator. International working group for the prognosis of MDS.  http://ipss-r.com/
  2. How I treat patients with myelodysplastic syndromes

    Richard M. Stone

 

Posted in Acute leukaemia, Bone marrow failure | Tagged , , , , ,

Case 77 – update 2

Bone marrow results:

13% blasts

evidence of dysplasia in the erythroid and myeloid cell lines

Cytogenetics:trisomy 8

 

How would you classify this patient? What would be your approach to management?

Posted in Acute leukaemia, Bone marrow failure | Tagged , , , , ,

Case 77 – update 1

So far, we have a 54 year old male who is pancytopenic.  He demonstrates features of myelodysplasia on blood film.

we have not had any clinical details, but most have suggested admission which does not seem unreasonable given the patients age and need for investigation.  If the patient is completely asymptomatic urgent outpatient review could be a possibility.

 

what would be your next step?

Investigations?

Think about what information is essentially in development management plan and prognosis.

Posted in Acute leukaemia, Bone marrow failure | Tagged , , , ,

Case 77 – the beginning

 

Let’s start this case with a blood film.

IMG_2154

IMG_2156

Can you describe the findings on the film? What information would you like as the registrar reviewing the film?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 Acute leukaemia, Bone marrow failure, Laboratory morphology | Tagged ,

Case 76 – summary

This case focussed on a newly diagnosed patient with haemophilia A. The patient was three days old and presented non-specifically unwell and feeding poorly. The differential here is wide from sepsis to hypoglycaemia to congenital heart defects and metabolic disorders. The cause wasn’t obvious from initial clinical assessment but because there was bleeding around the umbilical stump a clotting screen was performed which revealed a prolonged APTT. References ranges are difficult to establish in neonates and vitamin K-dependant factors (II, VII, IX, X) along with XI are frequently low at birth. However the APTT is longer than one may expect. The full blood count was normal.

A 50:50 mix is where normal plasma is added to the patient’s and the APTT is repeated. If the APTT corrects then it is more likely to be a factor deficiency and if it doesn’t correct it is more likely to be an inhibitor e.g. lupus anticoagulant. For investigation into a prolonged APTT see here.

Further investigations revealed a VIII <1%. This is in keeping with severe haemophilia A. You may also wish to document a von Willebrand screen and a 2 stage VIII result.

Imaging revealed a small intracranial bleed. USS imaging is first line in suspected bleeding in a neonate if available. In larger hospitals; especially those with a haemophilia centre, it may be easy to get factor levels quickly but here we were in a district general hospital where it was going to be difficult to get further investigations in a timely manner. In this it would be appropriate to infuse fresh frozen plasma (virally inactivated) pending definitive investigation. It would be important to have enough sample to perform extended clotting factors prior to plasma infusion.

 

Haemophilia A

This is an X-linked genetic condition occurring in 1 in 5000 male births. 40% in neonatal period with bleeding. Common presentations include:

  • Stump bleed
  • Dental work/bleeding when teething
  • Easy bruising
  • Early surgery e.g. circumcision
  • Neonatal e.g. bleed, cephalomalacia
  • Epistaxis rare under two years old unless NAI or local cause
  • Adulthood if mild

 

30% have no family history but possibility of mother being carrier in a spontaneous case is 85%:

  • There is gonadal mosaicism in 13% (i.e. where mutation is in mother’s gonads but not in somatic cells and therefore her genotype is normal).
  • If no family history consider type 2N vWD as this is recessive (not in our case as the VIII is too low)
  • Most mutations occur in spermatogenesis therefore mutation occurs in maternal grandfather’s sperm leading to maternal carrier who passes onto son

Classification:

  • ≤1 – severe = 50%
  • 2-5 – moderate = 30%
  • >5 – mild = 20%

Genetic testing

Genetic testing is important:

  • Confirms diagnosis
  • Predicts inhibitor formation
  • Allows testing of other family members for same mutation (e.g. carriers)

Our patient’s family tree is shownHaemophilia family tree

We know haemophilia A is X linked and therefore passed on from mother to son:

  • Carrier females have a 50:50 chance of passing the mutation onto their son or daughter; therefore there is a 50:50 chance of a son being affected and a daughter being a carrier
  • Men with haemophilia will pass on their abnormal X chomosome to their daughters therefore all of their daughters will be carriers but sons will not be affected.

In the family tree above the mother (3) was a carrier as was her sister (4). It was presumed her mother was also a carrier and therefore the mutation was likely in spermatogenesis from her grandfather (the patient’s great-grandfather). The mother’s sister is currently pregnant and therefore it would be important to find out what sex the baby was as if male could be affected by severe haemophilia A. This would influence management of the woman in labour.

Haemophilia family tree 2

General management of patients with haemophilia

  • Enroll in haemophilia comprehensive care centres
  • MDT should include haematologist, nurses, physiotherapist, occupational therapist, social worker, health psychologist, biomedical scientists, orthopaedics, denists
    • Every 3-4 month if <5
    • Every 6 month if >5
  • 24 hour emergency treatment
  • Full records
  • Genetic counselling, family planning and carrier detection
  • Antenatal management and diagnosis
  • Link with infectious diseases
  • Medical card
  • School visits
  • Hepatitis vaccinations – if not using recombinant products
  • National database
  • Self-care e.g. tranexamic acid at home, education etc.
  • Co-ordinated surgery/pregnancy
  • Monitoring of treatment given
  • Avoiding NSAID/aspirin etc.

Treatment of severe haemophilia

Milder haemophilia may be treated with tranexamic acid and DDAVP but severe haemophilia must be treated with intravenous recombinant VIII replacement. The average half life is 12-14 hours and this may be less in children. For bleeding episodes treatment may be needed twice a day. In our case the patient had a intracerebal bleed and therefore VIII levels of at least 100% are needed. There needs to be regular monitoring of VIII levels to ensure adequate VIII replacement is given. Serial imaging can also guide treatment length.

 

Inhibitors

IgG4 alloantibody to foreign factor (not self, although may cross-react). 30% of patients with severe haemophilia A acquire inhibitors (25% if intron 22 mutation). Inhibitors make treatment of haemophilia difficult due to increased risk of bleeding. Risk factors include:

  • Higher risk if null mutation/large deletion/mutation inducing a stop codon (lower risk if small deletion or missense)
  • Ethnicity – increased risk if Hispanic/African
  • Family history of inhibitor – increased risk
  • Age
    • Increased risk if <5 and >60
    • Mild haemophilia A – risk increases with age
  • Age at first exposure – no effect
  • Reduced risk if HIV positive
  • Highest during early exposure days (10-15); up to 150 exposure days (especially first 50)
  • Intensity
    • Increased risk with ≥5 exposure days as first treatment especially if co-inflammatory stimulus e.g. surgery; therefore monitor closely
    • Prophylaxis – early may reduce risk

Monitoring for inhibitor formation is important to find them early as this makes eradication more straightforward. There is guidance on diagnosis, monitoring and management of inhibitors in haemophilia.

Females and low VIII

May get low VIII in females due to:

  • If develop haemophilia A mutation and have androgen insensitivity e. 46XY but insensitive to testosterone so phenotypically female
  • If develop haemophilia A mutation and have Turner’s syndrome 46XO
  • Mother being a carrier of haemophilia A and father being affected
  • vWD
  • Random process of X chromosome inactivation/Lyonisation
    • Occurs at 64-128 cell stage
    • Only one VIII gene functioning per cell
    • Carriers of haemophilia A have on average 50% of the mean normal factor VIII
    • As random may get more skewing towards inactivation of normal X – 7% have a 90:10% skew so can get significantly low VIII levels

Low VIII levels in a females with a family history of haemophilia implies carriership but a normal VIII does not exclude therefore need genetics on both.

Our patient’s mother had a low VIII and was found to carry the same mutation as her son. This may contribute to bleeding. VIII naturally rises in pregnancy and this may be why she has never suffered from bleeding during pregnancy.

According to our family tree patients 6 and 7 could be carriers. They should be offered/counselled for genetic testing when old enough (generally after 16 years of age and prior to pregnancy). However it is useful to do a VIII level prior to this as this may influence bleeding prior to procedures.

 

Our patient

He went on to have a full recovery. Serial monitoring for inhibitor was negative despite genetics showing a high risk mutation (intron 22). Given the lack of trauma associated with the bleed he was commenced on prophylaxis every 48 hours via a port. His mother was found to be a carrier. This case highlighted the importance of appropriate investigation when there is bleeding and vague symptoms/signs in unwell neonates and prompt treatment with factor replacement (FFP or recombinant VIII depending local availability prior to transfer to regional centre).

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 Inherited bleeding, Paediatric haematology | Tagged , , , , , , , , ,

Case 76 – update 4

Our patient is doing well with recombinant VIII replacement. Monitoring scans reveal shrinking of the haemorrhage. On further questioning his mother suffered bleeding post dental extraction requiring re-packing and menorrhagia along with easy bruising. Haemophilia A is an X linked condition meaning it usually only affects males.

 

Questions

  • Can females be affected by haemophilia A?
  • If so how?
  • She’s never had any bleeding during pregnancy/labour – why?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 Inherited bleeding, Paediatric haematology | Tagged , , , , , , , , ,

Case 76 – update 3

Our patient is started on recombinant factor VIII replacement and achieves a trough level of 100%. Neurosurgery is not required. Genetic samples are sent to examine the F8 gene to see where the mutation is as this can help investigate other family members and can also predict inhibitor formation.

 

‘Inhibitors’ are alloantibodies against the VIII replacement rendering them ineffective and therefore cause major interference with treatment of haemophilia when they occur.

 

Here is the family tree of our patient:

Haemophilia family tree

 

Questions

  • What increases the risk of inhibitor formation?
  • Which relatives would you be keen to counsel and test?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 Inherited bleeding, Paediatric haematology | Tagged , , , , , , , , ,

Case 76 – update 2

Factor assays are back. IX, XI and XII are within normal limits for neonates but VIII is <1%. This confirms the diagnosis of severe haemophilia A.

 

The child is transferred to the regional haemophilia centre for intensive VIII replacement and neurosurgical opinion.

 

Questions

  • How is haemophilia A inherited? What may you ask in the family history?
  • As well as a low VIII what other tests would you want to do?
  • How do you treat haemophilia A?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 Inherited bleeding, Paediatric haematology | Tagged , , , , , , , ,

Case 76 – update 1

Our three day old child is admitted unwell and has deranged clotting with a markedly prolonged APTT. The team wanted an ultrasound scan which confirms a small intraparenchymal bleed. Repeat coagulation testing shows:

  • PT 18s (12-14 adult)
  • APTT 92s (30-38 adult)
  • APTT 50:50 mix with normal plasma 38s
  • Clauss fibrinogen 2.6g/L (2-4)

Liver function tests are within normal limits. The parents are fit and well with no past medical history. The pregnancy was uneventful save for an element of iron deficiency which resolved with supplementation.

Questions

  • Given the clinical history and the coagulation results what are the differential diagnoses?
  • What does 50:50 mix mean?
  • You’re in a district general hospital – what would be your immediate management?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 Inherited bleeding, Paediatric haematology | Tagged , , , , , , ,

Case 76 – the beginning

You are working in the emergency department of a district general hospital. Parents bring a three day old child in for assessment as he has been non-specifically unwell, looking pale and feeding poorly. He was born at term by spontaneous vaginal delivery and was allowed home a day later. APGAR scores were 9 at one and five minutes. He has some bleeding around his umbilical stump so a FBC and coagulation screen were checked:

  • FBC – within reference range
  • PT 19s (12-14 adult)
  • APTT 89s (30-38 adult)
  • Clauss fibrinogen 2.5g/L (2-4)
  • Glucose – normal

 

Questions

  • What are your differential diagnosis of the coagulation results?
  • What are you concerned about with the baby?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 Inherited bleeding, Paediatric haematology | Tagged , ,

Case 75 – summary

Case 75 – Summary!

Thank you for all of the contributions with Case 75, where we encountered a 43 year old who presented with back pain and circulating plasma cells in his peripheral blood.

In summary we established that this young man had a mild leucocytosis (WCC 23) with marked anaemia and thrombocytopenia (Hb 73, Plts 45). He had associated acute kidney injury and hypercalcaemia. He had an IgA paraprotein (18g/l) with a discrepantly high serum free light chain ratio of 6543. B2 microglobulin 8.7 and hypoalbuminaemia 28.

He had >2 x 109/L of circulating cells with the following immunophenotype (CD20+, CD38+, CD138+, CD56-) confirming the diagnosis of primary plasma cell leukaemia (he had no previous history of myeloma). He had a high tumour burden in his bone marrow with 66% plasma cells. He had a normal karyotype (even though he has normal cytogenetics he has high risk disease and this would not influence our future management). Within our case we did not focus upon bone imaging.

He received treated with a bortezomib-based regime (velcade, thalidomide and dexamethasone). We would aim to consolidate with a melphalan autologous stem cell transplant and discussed with transplant team regarding the role of an allogenic stem cell transplant.

Plasma cell leukaemia
Primary plasma cell leukaemia is a rare, aggressive plasma cell dyscrasia with a poor prognosis. It is defined by the presence of >2×109/L peripheral blood plasma cells or plasmacytosis accounting for >20% of the differential white cell count, and does not arise from pre-existing myeloma.

Primary plasma cell leukaemia has different clinical, laboratory and biological in comparison to myeloma as listed below:

Clinical features:
Younger age at presentation
More advanced disease at presentation (>80% with Stage III disease)
More extensive bone disease
Extramedullary involvement is more common e.g hepatosplenomegaly, lymphadenopathy, plasmacytomas, leptomeningeal disease

Laboratory features:
Leucocytosis and more marked cytopenias in comparison to multiple myeloma
Higher incidence and severity of renal impairment, hypercalcaemia and LDH/B2 microglobulin

Blood film: commonly leucoerythroblastic along with circulating plasma cells
Bone marrow biopsy: typically high tumour burden

Immunophenotype: CD38+, CD138+. In comparison to multiple myeloma more likely to be:
• CD56- (likely due to higher incidence t(11;14)
• CD117-, HLA-DR-
• CD20+, CD23+

Cytogenetics:
There are usually multiple genetic abnormalities (and often high risk abnormalities) present at diagnosis as opposed to the gradual acquisition of genetic events that occur in end stage myeloma / secondary plasma cell leukaemia. In primary plasma cell leukaemia the genetic aberrations present result in bone marrow microenvironment-independent tumour growth.

Common cytogenetic abnormalities:
• IgH translocations – most commonly t(11:14), t(14:14), t(14:16)
• Hypodiploidy
• Del(17p), del (13q), del(1p21), ampl(1q21)

Management:
Given the rarity of this condition there is a paucity of data on treatment regimens and participation in a clinical trial, if available, is recommended. However, bortezomib are known to be associated with better outcomes as it more rapidly reduces tumour load and has been found to overcome some adverse cytogenetics including del(17p) and t(4;14).

Bortezomib-based therapies:
There is no evidence to guide a particular bortezomib-based regimen and various regimens are used internationally reflecting different countries historic use and also access to first line immunomodulating or novel agents.

Regimens commonly in used for first line therapy include:
• VTD – bortezomib, thalidomide and dexamethasone
• RVD – lenalidomide, bortezomib and dexamethasone
• PAD – bortezomib, doxorubicin and dexamethasone
• VCD – cyclophosphamide, bortezomib, dexamethasone

Commonly in the UK VTD is used as first line therapy. Whereas thalidomide is often replaced by lenalidomide in this regime in Europe where Lenalidomide is available as first line. Lenalidomide has been shown to be more efficacious than Thalidomide in multiple myeloma.

Supportive therapies
• Blood transfusions
• Antimicrobial prophylaxis
• Prophylaxis against tumour lysis syndrome should be instituted
• Bisphosphonates
• Consideration for radiotherapy for problematic plasmacytomas

Autologous Haematopoietic Stem Cell Transplant:
Autologous stem cell transplant improves both progression-free survival and overall survival and should be encouraged if the patient is considered fit to undergo the procedure providing they have achieved at least a partial response. Conditioning regimens are melphalan-based. Trials have discussed the potential role for consolidative treatment (e.g further cycles of VTD but this is not available within the UK) or maintenance therapy (e.g lenalidomide)

Allogenic Haematopoietic Stem Cell Transplant
Unfortunately the prognosis following autologous stem cell transplant remains poor and allogenic stem cell transplants are associated with reduced risk of relapse in comparison (albeit with higher rates of TRM). This could therefore be considered in young, fit individuals following discussion within the MDT. However, there remains to be limited data in this area and ideally this should be performed as part of a clinical trial.

References:
Niels et al. How I treat plasma cell leukaemia. Blood. 120(12), 2376-2389. 2012.

Posted in Myeloma/paraproteins | Tagged , , , , , ,

Case 75 – update 3

Bortezomib-based regimes are associated with better outcomes as it more rapidly reduces tumour load and reverses complications.

What would you combine Bortezomib with in our patient?

How would you consolidate this treatment if response achieved?

Would the cytogenetics results influence your treatment options?

Please reply with #Teamhaem so everyone can be involved!

Posted in Myeloma/paraproteins | Tagged , ,