Case 109 – summary

Thanks for all your help this week. This week’s case focused on Thrombocytopenia pregnancy that ultimately was ITP responsive to steroid therapy.

Mild gestational thrombocytopenia (with platelet counts <150×10^9/L) is common affecting up 5-10% of pregnant women.

Pregnant women with mild thrombocytopenia of platelets 100-150×10^9/L and normal blood film/screening blood tests should stay in primary care with monthly FBC and advice to refer to secondary care if platelet counts fall below 100×10^9/L.

Only 1% of pregnant women will have a platelet count less than 100×10^9/L which is the international working groups definition of thrombocytopenia and this is the range where further specialist investigation and referral to secondary care is appropriate.

A suggested approach to thrombocytopenia in preganancy is outlined below:

History:

• Previous FBC results: Thrombocytopenia prior to pregnancy points to causes other than gestational thrombocytopenia.

• Family history: Type IIb VWD although rare can present as thrombocytopenia in pregnancy.

• Medication History: Any changes in medications. Many drugs in common use can cause isolated thrombocytopenia – worth checking a patients medications.

• Features of Connective tissue diseases (CTD): Fatigue, Rashes, Joint stiffness, sore eyes etc.

• Gestation at onset: Later in pregnancy more likely to be due to pregnancy specific causes like Pre-eclampsia, HELLP, Acute Fatty liver of pregnancy etc. Gestational thrombocytopenia is more common in second and third trimesters.

• Personal Bleeding history: BAT score may help indicate if underlying bleeding disorder, particularly useful if no previous blood tests available and family history of bleeding.

 

Initial investigations:

• FBC repeat plus CD61 platelet count or citrate count: Confirm genuine thrombocytopenia.

• Blood film: Film crucial to exclude underlying marrow disorder and to look for fragmentation, signs of haemolysis, hereditary thrombocytopenia with giant platelets or white cell inclusions or for signs of infection.

• U&E, LFT’s: May be abnormal if HELLP/Pre-eclampsia/HUS.

• Coagulation screen inc D-Diner: Abnormal if DIC/HELLP.

• VWD screen: Useful particularly if family history to exclude type IIb VWD.

• Antiphospholipid antibodies

• ANA

• HIV, Hep B, Hep C

• B12/Folate: Rarely a cause of isolated thrombocytopenia

• Physical examination: Look for mucosal bleeding petichiae and any signs of Connctive tissue diseases.

Optional testing depending on findings:

  • TFT’s: Thyroid problems may be associated with ITP in pregnancy as part of autoimmune spectrum.
  • Ig levels: If history of frequent infections.
  • Other viral serology: if indicated from history or film.
  • H.Pylori serology.
  • DAT, LDH and Retics: If concern Evans syndrome due to spherocytes on film.
  • ADAMTS 13 testing if fragmentation on film.
  • Bone Marrow: If suspicion of primary blood disorder from film.

 

Establishing the Diagnosis:

Broadly speaking thrombocytopenia in pregnancy is best thought of in five distinct categories depending on the investigations above.

 

1) Normal Blood film and other investigations (most likely scenario):

• Gestational thrombocytopenia (GT) – accounts for 75% total

• ITP – 5%

 

Useful features to distinguish the two diagnoses:

Rare for GT to cause platelet count <50×10^9/L.

GT usually occurs mid-late second trimester and during the third trimester where as ITP can occur earlier (as in this case).

There may also be a history of previous thrombocytopenia in pregnancy that fully resolves post-partum in GT. hence very important to monitor platelet counts post partum.

 

2) Atypical lymphocytes on film, raised inflammatory markers:

• Infection

 

3) Microspherocytes, agglutination or clumping on film and positive DAT:

• Evans syndrome

 

4) Blasts on film

• Pimary bone marrow disorder

 

5) Schistocytes on film – 15% of patients

• TTP

• HUS

• DIC

• Pre-eclapsia/HELLP/Acute fatty liver of pregnancy

 

The rest of this case focuses on our lady who had a normal blood film and isolated thrombocytopenia. It is important that the possible cause of thrombocytopenia is established before embarking upon management as the approaches for management of HELLP or TTP vary greatly to the management of ITP for example.

 

Monitoring patients with Isolated thrombocytopenia thought to be ITP:

All patients should be referred for secondary care review if platelets <100×10^9/L and have an antenatal anaesthetics review.

There is little evidence to suggest what appropriate monitoring should be and it should be tailored to platelet count and the rates of decline seen rather than a rigid time based check for example every 4 weeks. The consensus seems to be monitoring should be somewhere between 2-6 weekly Depending on the individual. In the third trimester particularly after 34 weeks weekly checks if plt <80×10^9/L are suggested especially if treatment is given.

Patients with thrombocytopenia in pregnancy should be advised of who to contact in case of bleeding or concerns. They should also be asked to avoid IM injections, though BCSH guideline makes it clear low dose aspirin prescribed for obstetric reasons should not be automatically withheld unless high bleeding risk.

All patients should have repeat FBC 1-3 months post-delivery to check for spontaneous resolution of thrombocytopenia. This is important particularly if GT was thought to be the cause of thrombocytopenia as by this timepoint the thrombocytopenia should have resolved.

Treating patients with Isolated thrombocytopenia thought to be ITP:

BCSH guidelines suggest treatment for ITP should be in order to achieve “safe” platelet counts and not necessarily normalise platelet counts.  BCSH guidelines state that although no robust trials it is reasonable to leave asymptomatic pregnant women with platelet counts of 20-30×10^9/L without treatment until the third trimester.

Treatment approaches for ITP during pregnancy vary slightly but generally treatment is with prednisolone first line starting at 10-20mg dose of prednisolone with IVIG reserved in case of bleeding or as second line therapy.

Treatment is usually prednisolone for a week, adjusting to minimum dose of prednisolone that maintains a response. Response time is usually around 3-7 days. It is recommended that tapering of doses is suspended near term as often platelet count falls at term. Slow taper also recommended post-partum as quick tapering can affect the mother’s psychological state.

The treatment aims to achieve  a minimum platelet count of 50×10^9/L for vaginal delivery. Platelet counts of >80×10^9/L will usually be needed for neuroaxial anaesthesia.

Although steroids are relatively safe in pregnancy common side effects are impaired glucose tolerance, hypertension, mood change and weight gain.

Second line therapies and agents for ITP are less clear and would require discussion in an MDT setting depending on the individual patient.

Delivery planning for patients with ITP:

Mode of delivery should be based on obstetric indications there is no need for Cesarean section in ITP patients as no evidence to show this reduced ICH rates in thrombocytopenic neonates.

Ideally delivery should be in a hospital with Haematology and obstetric care.

General consensus both in How I treat and RCOG review of thrombocytopenia in pregnancy is that a platelet count >50×10^9/L is required for vaginal and operative delivery. For epidural anaesthesia platelet count needs to be >80×10^9/Land an anaesthetic review before delivery is recommended to discuss alternative analgesia if thrombocytopenia at delivery.

Platelet transfusions should be available in case of complications but should not be routinely administered.

Neonates born to mothers who have ITP do have a risk of thrombocytopenia due to passage of Ig G Ab across the placenta. 15-30% of babies born to mothers with ITP are thrombocytopenic though only 5% have counts <20×10^9/L. It is worth stating that antenatal steroids and IVIG have no effect on the fetal platelet counts. The passage of antibodies is unpredictable therefore mothers platelet counts won’t always indicate the likelihood of associated thrombocytopenia in the baby. A history of sibling with thrombocytopenia at birth, mother with previous splenectomy or platelet count <50×10^9/L at delivery are predictors of an increased risk of neonatal thrombocytopenia. This means all babies born to mothers with presumed ITP should be treated as possibly being thrombocytopenic. Fetal scalp electrodes and instrumental deliveries are ideally avoided and cord blood should be taken at delivery to confirm the platelet count. IM vitamin K should also be avoided. Platelet counts should also be checked at day 1 and 4 post delivery, as platelet nadir around this time. If platelets less than 50×10^9/L or symptomatic transcranial USS should be performed.

Postnatal care should include daily FBC of mother until day 5 post partum.

Prenatal counselling of mothers with ITP:

Pre-pregnancy counselling for a lady with ITP as recommended by RCOG should include:

• Discussion that ITP relapses may occur during pregnancy.

• Around a third of women will need treatment in pregnancy usually in third trimester.

• An epidural may not be possible if thrombocytopenic.

• There is an increased chance of a sibling being affected with thrombocytopenia if a mother has had splenectomy or previous baby with neonatal thrombocytopenia.

• Risk of adverse delivery outcomes for mother or major bleeding in neonates is thankfully low with correct planning and monitoring.

 

References:

Provan et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010 115:168-186.

B Myers. Diagnosis and management of maternal thrombocytopenia in preganancy. BJHaem, 2012, 158, 3-15.

B.Myers. Review Thrombocytopneia in pregnancy. RCOG 2009.

T Gernsheimer et al. How I treat thrombocytopenia in pregnancy. Blood 2013. 121.

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Case 109 – update 4

Thanks for your help so far. The lady thankfully had an uneventful normal vaginal delivery. She had chance to have an anaesthetics review prior to labour and had been attending joint obstetric and haematology clinic. Her pre prepared birth plan included the following points:

Mode of delivery based solely on obstetric indications.

Delivery should ideally be in a hospital with Haematology and obstetric care.

Target platelet count >50×10^9/L for vaginal and operative delivery.

For epidural anaesthesia platelet count needs to be >80×10^9/L.

Platelet transfusions should be available in case of complications.

Haematology team to be contacted if any concerns regarding platelet count or bleeding.

Neonates born to mothers who have ITP do have a risk of thrombocytopenia due to passage of Ig G Ab across the placenta. 

15-30% of babies born to mothers with ITP are thrombocytopenic. All babies born to mothers with presumed ITP should be treated as possibly being thrombocytopenic. When writing birth plans and the following points need to be communicated to obstetric and paediatric team as happened in this case.

Foetal scalp electrodes and instrumental deliveries are ideally avoided.

Cord blood should be taken at delivery to confirm the platelet count.

IM vitamin K should also be avoided.

If platelets less than 50×10^9/L on cord blood or symptomatic transcranial USS should be performed.

Our lady had a healthy baby boy with a normal platelet count of 370×10^9/l on cord blood sampling.

Does the baby require any further platelet count monitoring? If so when would you check platelet count again?

The lady is keen to know of the implications of her ITP on future pregnancies, how likely is she to need treatment for ITP in further pregnancies?

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Case109 – update 3

The lady’s platelet count responded to 20mg Prednisolone and is now at 65×10^9 at 38 weeks gestation. 

The obstetric team are keen for a plan for delivery what advice would you give the team? 

What advice would you give to the neonatal team?

How common is transient neonatal thrombocytopenia in mothers who have ITP?

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Case 109 – update 2

You suspected ITP or possibly gestational thrombocytopenia and embarked on monitoring her platelet counts every few weeks. The lady is now 34 weeks pregnant and is otherwise well. Her platelet count has started to fall over the past 6 weeks and is now 30×10^9/L. She is well with no bleeding.

What is the most likely diagnosis now?

How would you manage this patient at this stage?

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Case 109 – update 1

The lady had a repeat FBC that confirmed isolated thrombocytopenia with a platelet count of 80×10^9/l Her blood film is shown below you check carefully and there are no platelet clumps. Her CD61 platelet count is 75×10^9/l

You establish that she has had a previous normal FBC two years ago. She is usually fit and well and takes no medications. She has no family history of thrombocytopenia. This is her first pregnancy and he has been well so far with no problems. She has not had any recent heparin.

What does the blood film show?

What is the differential diagnosis?

How would you monitor the patient  and who should do the monitoring?

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Case 109 – the beginning

A 32 year lady is 11 weeks pregnant. She has had her booking blood tests performed by her midwife and her FBC has shown an isolated thrombocytopenia of 90x10^9. 

What History would you like ask her?

What investigations would you like to perform?

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Case 108 – Summary!

Thank you for everybody’s contributions throughout the week!

We focused upon a 32 year old man who presented with asymptomatic unilateral cervical lymphadenopathy and was subsequently diagnosed with limited stage nodular lymphocyte predominant hodgkin lymphoma (NLPHL). He was treated with radiotherapy alone. As is classical of this disease he had a late relapse at 5 years with stage III disease involving splenomegaly and was treated with R-CHOP. 18 months after this he developed transformed T cell/histiocyte rich B cell lymphoma and was treated with salvage regime and ASCT with TLS prophylaxis and CNS prophylaxis due to the extent of disease. Below is a summary of NLPHL.

 Nodular Lymphocyte Predominant Hodgkin Lymphoma 

NLPHL is a rare subtype of Hodgkin Lymphoma (~5%) but is clinically and pathologically distinct from classical Hodgkin Lymphoma. Indeed it is often considered to have been misclassified originally due to the marked differences between the two diseases).

It is associated with an excellent OS (similar to normal-age matched controls) it is important to reduce long-term toxicity with therapies.

Clinical features

  • Bimodal age distribution – childhood (median age 13 years) and adults (median age 30-40 years)
  • Male preponderance
  • Typically present with early stage disease with peripheral lymphadenopathy (predominantly cervical lymph nodes)
  • Mediastinal disease, B symptoms and bulky disease is uncommon
  • Typically has an indolent clinical course with an overall favourable prognosis. However multiple, often late, relapses are characteristic and there is a risk of transformation to high-grade disease. Long-term follow-up is key.
  • PET avid and should be assessed by PETCT.

Morphology

  • Lymphocyte predominant cells (‘popcorn cell’ – multilobulated nucleoli) surrounded by rosette of small lymphocytes (follicular helper T cells). All within nodules of small B lymphocytes and histiocytes.
  • Plasma cells and eosinophlis are uncommon as opposed to classical Hodgkin lymphoma.
  • There are 6 histopathological variant patterns
    • Pattern A + B – LP cells embedded within B cell nodules
    • Pattern C-F – variation of location in relation to nodules, diffuse, pattern, T cell rich backgrounds.

Immunohistochemistry

Lymphocyte Predominant cells – CD20+, CD45+, CD79a, PAX5+, epithelial membrane antigen expressed. CD15-, EBV-, rarely express CD30.

Follicular helper T cells – CD4+CD57+PD1+

Differential diagnosis

  • Lymphocyte rich classical Hodgkin lymphoma
    • Reed-sternberg cells, CD30+, CD15+, CD20-
  • Progressive transformation of germinal centres
    • Don’t contain lymphocyte predominant cells, no T cell rosettes, BCL2+.
    • Rarely exist within the same lymph node as NLPHL
  • T cell/histiocyte rich B cell lymphoma
    • Difficult to distinguish but absence of follicular dendritic cell meshwork and loss of background of small B cells.

Prognostic factors

Inferior PFS / OS associated with:

  • Advanced stage
  • Albumin <40g/l
  • Anaemia (Hb <105g/l)
  • Histiopathological variant C-F
  • Lymphopenia (<8% of WCC)
  • Male sex

 

Management

Early Stage Disease Guidelines:

  • ESMO guidance
    • Stage IA and no clinical risk factors: Radiotherapy alone (IFRT 30Gy)
    • Stage IIA and no clinical risk factors: 2#R-ABVD + 20Gy RT
    • Early stage and unfavourable risk factors: 4-6# ABVD + 30Gy IFRT
  • NCCN guidance:
    • Stage I-IIA and no clinical risk factors: Radiotherapy alone (IFRT 30-36Gy)
    • Early stage and unfavourable risk factors: 4-6# ABVD + 30Gy IFRT

Early stage Disease Info:

  • Associated with overall survival >90%
  • Observation
    • Can be considered in selected patients – asymptomatic, fully resected stage IA without unfavourable features.
  • RT alone for stage IA associated with 10yr PFS/OS 89%/96% (Chen et al)
  • No prospective data comparing combined modality treatment versus radiotherapy and most regimens extrapolated from classical Hodgkin lymphoma.
  • Single agent rituximab not appropriate (responses are not durable)

 

Advanced Stage Disease

 ESMO / NCCN Guidance

  • Offer option of R-CHOP and R-chemo (treatment regimes identical to treatment for classical HL with addition of anti-CD20 antibody)

 Advanced Stage Disease Info:

  • ~20% present with advanced stage disease
  • Associated poorer prognosis
  • Ensure biopsy from appropriate site as advanced stage is significant risk factor for transformation
  • R-CHOP associated with better PFS vs R-ABVD

Relapsed Disease

  • Late relapses are characteristic of NLPHL
  • Re-biopsy essential to exclude transformation

Limited Stage Relapse

  • Single agent rituximab (greater benefit also if had long disease free interval)
  • Radiotherapy (ISRT)

Advanced Stage Relapse (or short disease free interval)

  • High dose chemotherapy and ASCT (e.g R-CHOP)

 

Transformed Disease

  • ~15% transformed to an aggressive large B cell NHL by 10 yrs
  • Typically transforms to T cell/histiocyte rich B cell lymphoma
  • Risk factors for transformed disease:
    • Advanced stage disease
    • Infradiaphramatic involvement
    • Splenic involvement
    • Histopathological variant patterns C-F
  • Always important to re-biopsy ‘relapsed’ disease to ensure no transformation
  • No standard treatment
  • NCCN / ESMO guidance: as per standard treatment regime for de novo DLBCL
  • Associated with prognosis similar to de novo DLBCL

 

References

  1. Spinner et al. Modern Principles in the management of NLPHL. British Journal of Haematology. 2019. 17-29.
  2. Eichenauer et al. Hodgkin Lymphoma: ESMO Clinical Practice Guidelines. 2018. https://oncologypro.esmo.org/Guidelines/Clinical-Practice-Guidelines/Haematological-Malignancies/Hodgkin-Lymphoma
  3. Advani et al. How I treat NLPHL. Blood. 2013. 122:4182-4188
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Case 108 – Update 4!

Our patient achieved complete metabolic remission following #6 R-CHOP chemotherapy for his relapsed advanced stage NLPHL.

Unfortunately 18 months after completing treatment he attended with drenching night sweats, intermittent fevers and marked malaise. His spleen was palpable just below the costal margin but examination was otherwise unremarkable. A biopsy is pending following his repeat PET scan (see image below):

PET

Questions:

  1. What is the most likely diagnosis? What risk factors were there for this?
  2. What further investigations would you want to perform?

 

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.

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Case 108 – Update 3!

Thank you for the ongoing contributions to our case!

Our patient achieved a complete response following radiotherapy treatment alone (30Gy) and remained under haematology follow-up.

Unfortunately 5 years later he attends the haematology clinic earlier than scheduled as he has unintentionally lost 2kg over the past 4 months and more recently has noted an inguinal mass.

A repeat PET scan which shows non-bulky, stage 3 disease including 5cm splenomegaly.

Questions:

  1. How would you manage our patient now? Any further investigations?

 

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.

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Case 108 – Update 2!

Thank you for everyone’s contributions in obtaining the diagnosis of Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)!

The lymph node morphology demonstrates large atypical cells with multiple nucleoli (lymphocyte-predominant cells) embedded within follicles.

The IHC is as follows:

  • Lymphocyte-predominant cells:CD20+, CD45+, CD75+, PAX5+, CD5-, CD15-, CD30-, EBV-
  • Follicles (T cell rosettes around the LP cells): CD4+, CD57+, PD1+

This histopathological form is consistent with the typical pattern of NLPHL (pattern A or B).

A PETCT has revealed stage 1A disease with several non-bulky unilateral cervical lymph nodes.

Questions:

  1. How would you treat our patient?
  2. Any additional information you’d like to help aid your decision?

 

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.

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Case 108 – Update 1!

Thank you to all the contributions so far!

We have now established that our 32 year old mans neck mass has been gradually increasing in size since he noted it 6 months ago. He has otherwise been well in himself except for feeling more tired. He has no other associated symptoms, no travel history, other medical conditions. he is not on any medications.

His examination reveals unilateral cervical lymphadenopathy (approx 3cm).

An ultrasound demonstrated the mass was indeed a lymph node with disrupted architecture with an uniformly hypo‐echoic enlarged node with the loss of the fatty hilum.

Subsequently histology was obtained by an excision biopsy:

Questions:

  1. Any suggestions on the diagnosis? What immunohistochemistry would you request to help?
  2. What further investigations would you perform?

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.

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Case 108 – Update 1

Thank you to all the contributions so far!

We have now established that our 32 year old mans neck mass has been gradually increasing in size since he noted it 6 months ago. He has otherwise been well in himself except for feeling more tired. He has no other associated symptoms, no other medical conditions and no significant travel history. He is not on any medications.

His examination reveals unilateral cervical lymphadenopathy (approx 3cm).

An ultrasound demonstrated the mass was indeed a lymph node with disrupted architecture with an uniformly hypo‐echoic enlarged node with the loss of the fatty hilum.

Subsequently histology was obtained by an excision biopsy:

 

Questions:

  1. Any suggestions on the diagnosis? What immunohistochemistry would you request to help?
  2. What further investigations would you perform?

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.

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Case 108 – The Beginning

You review a 32 year old man in outpatients who has been referred for a neck lump. On examination he has a 2cm cervical lymph node which he originally noticed approximately 6 months ago. He has had no night sweats but feels tired although states he has been working nights.

Questions:

  1. What is your differential diagnosis for a neck lump?
  2. What investigations would you perform?

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.

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Case 107 – summary

Thank you for your contribution in this week’s #teamhaem case.

This week we have been looking at Transient Leukaemia of Down Syndrome (TL-DS).

Background

Between 5%- 30% children with Down syndrome (DS) are born with Transient Leukaemia of Down syndrome (TL-DS), aka transient abnormal myelopoiesis (TAM) or transient myeloproliferative disorder (TMD).

  • A clonal disorder, with circulating megakaryoblasts and dysplastic changes in peripheral blood

  • TL-DS is driven by mutations in the haematopoiesis transcription factor gene GATA1, and is only seen in conjunction with trisomy 21, either constitutional or acquired

  • May present with overt clinical features but some are only identified through blood film and/or by GATA1 mutation analysis

  • Many cases resolve without treatment

  • 15-23% cases result in early death

  • 20-23% survivors will develop acute myeloid leukaemia of Down syndrome (ML-DS) in the first 4 years of life

  • Overall event-free survival 63-68%

  • Those with previous TL-DS has a Risk of ML-DS 150 times greater than non-DS children (AML risk in all DS is about 1-2%)
  • Risk of ALL in previous TL-DS 30 times greater than those without DS (and with poorer outcome)

Definitions, clinical features and diagnosis:

  • A congenital leukaemia unique to neonates with DS or mosaic trisomy 21

  • Clonal disorder

  • TL-DS cells spread throughout the body, infiltrating the liver, pleural and pericardial spaces, skin and to a LESSER extent, the bone marrow

  • Presence of an acquired N-terminal mutation in exon 2 or exon 3 of the key haematopoietic transcription factor gene GATA1, resulting in a truncated GATA1 protein

  • Paired TL-DS and ML-DS samples show the same GATA1 mutations, indicating that they are clonally linked conditions

  • GATA1 mutations are not detected in remission samples after treatment of ML-DS nor are they present in other DS and non DS leukaemias

  • GATA1 mutation(s) are not leukaemogenic in cells that are not trisomic for chromosome 21

  • Studies using next generation sequencing (NGS) indicate that cases classified clinically as TL-DS or by blast >10%, all have detectable GATA1 mutations

  • Of note, in studies, 98% of neonates with DS had circulating blasts, the great majority had no clinical features of TL-DS and no detectable GATA1 mutation

  • Hence TL-DS = the presence of a GATA1 mutation in a neonate with DS or mosaic DS, combined with an increased blast count, or features suggestive of TL-DS

Blast count threshold

  • > 10% peripheral blasts in the first week of life identifies all neonates with clinical features of TL-DS

  • Blast count requires careful examination of a peripheral blood film in the first week of life, ideally in the first 3 days of life, by a haematologist experienced in reviewing neonatal blood films
  • automated blast counts are not accurate
  • Blast count assessment after the first week of life may underestimate the prevalence of disease, as blast% falls rapidly after birth
  • Neonates with intra-uterine growth restriction (IUGR) or other history of placental insufficiency (e.g. maternal hypertension, pre-eclampsia or diabetes mellitus) may have lower blast counts despite large GATA1 clones

Clinical features

  • Clinical features can be variable and may be absent (or present in the absence of TL-DS)
  • they can spread locally, spill into the peripheral blood and infiltrate through the liver as well as distant tissues
  • Hepatomegaly, hepatic fibrosis
  • splenomegaly (30% cases, often due to portal vein obstruction, splenic infiltration is rare)
  • Malignant effusions in pleural and pericardial spaces
  • And/or as papular or vesicopustular rash due to skin deposits of blast cells (skin nodules are rare)
  • Hepatopathy – Jaundice, Abnormal LFTs (raised transaminases with conjugated hyperbilirubinaemia)
  • Hyperleucocytosis
  • Coagulopathy
  • Multi-organ failure
  • Thrombocytopenia (which is common in DS even without TL-DS)
  • Neutrophilia
  • Anaemia

Morphology

  • Leukaemic cells are megakaryoblastic, originate from abnormal megakaryocyte-erythroid precursors in the fetal liver
  • Blasts are pleomorphic, with prominent nucleoli and basophilic, blebbed cytoplasm, in keeping with erythroid-megakaryocytic origin
  • Megakarycotye fragments often a prominent feature

Immunophenotying

  • Distinct from other leukaemias
  • Variable co-expression of:
  • stem cell markers CD34 & CD117
  • Myeloid markers CD33/CD13
  • Platelet glycoproteins CD36, CD41, CD42, CD61
  • Aberrant expression of CD56, CD7, low expression of CD11a
  • HLA-DR in 30%
  • Negative for MPO, CD15, CD14, glycophorin A
  • Bone marrow examination is NOT useful, since blasts originate in the liver and marrow blasts are variable and lower than in peripheral blood. Bone marrow involvement does NOT correlate with disease severity

Investigations:

  • All neonates with known or a high suspicion of DS should be examined for features suggestive of TL-DS
  • FBC & blood film within first 3 days of life with formal assessment of blast %
  • Those with features of TL-DS should have additional tests:
    • LFTs including conjugated bilirubin
    • CXR
    • ECHO
    • AUSS
  • Those with features of TL-DS and blasts>10% should have peripheral blood tested for GATA1 mutation
  • Those who did not have a peripheral blasts performed in the first 3 days of life or where there was significant IUGR (where blast count may be suppressed) should be considered at risk in first 4-8 weeks of life and be monitored accordingly. Consider GATA1 mutation analysis

Silent TL-DS

  • Recent studies found that at least half of DS neonates with GATA1 mutations have blasts < 10% and have no clinical features of TL-DS.
  • The prevalence of GATA1 mutation in DS neonates with blast % 1-10% is around 20%
  • Where this is a GATA1 mutation and a peripheral blast =< 10% in the first week of life in a neonate with DS or mosaic trisomy 21 is termed Silent TL-DS or Silent TAM
  • These children have a much lower rate of transformation to ML-DS (<3%) compared to those with clinical TL-DS which has a transformation rate of 10-30%
  • Therefore routine screening for GATA1 is not recommended when blast % =<10%, unless blast % was not assessed or unreliable

Risk factors for poor outcome & life threatening symptoms

  • Most TL-DS resolve spontaneously without sequelae
  • Clinical TL-DS has an early mortality of 15-23%. This is in excess of any other childhood cancers in the UK
  • Risk factors/life threatening symptoms leading to early death:
    • Progressive hepatopathy with cholestasis (conjugated bilirubin > 83umol/L, ascites or massive hepatomegaly
    • Hepatosplenomegaly (beyond umbilicus or causing respiratory or feeding compromise)
    • WBC > 100 x 10^9/L or leucostasis
    • Multi-organ failure
    • Hydrops fetalis
    • Pleural or pericardial effusions
    • Renal failure
    • Disseminated intravascular coagulation/coagulopathy with bleeding

Treatment

  • Those with life threatening symptoms should be considered for treatment with cytarabine
  • TL-DS and ML-DS blasts are extremely sensitive to cytarabine
  • Very low doses of cytarabine can be successfully used
  • Cytarabine should be given urgently at a dose of 1-1.5mg/kg/day for 5-7 days either intravenously or subcutaneously
  • Monitor closely due to risk of neutropenia and sepsis
  • Repeated courses of cytarabine can be considered to achieve control if severe liver dysfunction persists
  • Exchange transfusion and leukapheresis may be used in acute count reduction but is not definitive treatment
  • Cytarabine should NOT be used to prevent later development of ML-DS

Monitoring & Follow up

  • Those without life threatening symptoms can be monitored without treatment, and most will resolve spontaneously
  • Peripheral blasts will disappear in days to months (most by 2 months)
  • Progression to ML-DS 20-23% in those with clinical TL-DS (numbers vary slightly in different studies)
  • FBC & blood film usually return to normal in most
  • TL-DS cases should be monitored with FBC, LFTs until spontaneous resolution
  • If persistent abnormal FBC, GATA1 mutation analysis should be considered
  • All children with previous TL-DS or silent TL-DS should be monitored for progression to ML-DS every 3 months till 2 years of age.
  • If FBC & film are normal, then monitor 6 monthly till 4 years of age, as most ML-DS will develop by the age of 2
  • Any abnormal blood counts should promt early bone marrow aspirate and trephine (as aspirate is frequently difficult due to marrow fibrosis and trephine biopsy is essential in diagnosing ML-DS)

References:

1. WHO Classification of Tumours of Haematopoetic and Lymphoid Tissues

2. Guidelines for the investigation and management of Transient Leukaemia of Down Syndrome – BSH Guidelines. 2018. BJH.

3. GATA factor mutations in Hematologic Disease. Blood Journal 2017

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.

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Case 107 – update 3

CXR and ECHO show no significant abnormalities. Abdo USS confirms hepatosplenomegaly but no ascites. There are no skin rashes and his blood tests are stable.

Blood film report:

Polycythaemic film. Pleomorphic blasts with evidence of cytoplasmic blebbing. Manual blast count 15%. Megakaryocyte fragments seen.

Immunophenotyping:

CD45 weak population = 12% of total nucleated cells.
CD34 variable (+/neg), CD13 weak, CD33+, CD7+, CD117+,

CD41a+
HLA DR variable (+/neg).                                                                

Flow cytometry has demonstrated a population of myeloid precursor cells with aberrant CD7 expression. There is megakaryocyte marker expression consistent with a picture of Transient Leukaemia in the context of Down syndrome (TL-DS).
Trisomy 21 and GATA1 mutation have been confirmed. Coagulation was checked and there is no evidence of DIC.

Questions:

1. What factors would determine whether treatment is required?

2. If treatment is indicated, what would you do?

3. How do you plan to follow up this baby and 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.

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Case 107 – update 2

You think the baby has some dysmorphic features. You look at his blood film.

You also check his conjugated bilirubin and request CXR, abdominal USS and ECHO.

Questions:

1. What are the main features and why?

2. What factors might affect the % of certain cells seen on the film?

3. What immunophenotyping would you be expecting? Why do conjugated bilirubin?

4. What do we look for in CXR and ECHO?

5. Would you do any genetic/mutation studies?

6. What is the role for bone marrow biopsy?

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.

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Case 107 – update 1

You meet the baby with his mother. He was a little floppy at birth and not feeding well with a low grade fever. He is on 2L oxygen but with no respiratory distress. He is visibly jaundiced.

The mother is a 25 year old, this is her second child, delivered normally at 38 weeks. The baby weighed 2.8kg. She did not attend regular antenatal appointments and had no prenatal screening.

You examine the baby and he is indeed a bit floppy. The liver and spleen are palpable at 1 and 2cm below costal margins, respectively. His ears and mouth seem rather small and he has upward slanting eyes. You also notice a deep crease in both palms.

These are the initial blood results:

Hb 236g/l (130-180)

MCV 100fl (82-98)

WCC 25×109/l (4-11)

Neutrophils 11.45×109/l (1.7-7.5)

Lymphocytes 2.1×109/l  (1.5-4.5)

Platelets 65×109/l (150-450)

Retics 200×109 (50-150)

U&E – normal

LDH – normal

Bilirubin 289umol/l (5-21)

Total protein 49

Albumin 30

Alkaline phosphatase 286iu/l (83-248)

Alanine aminotransferase 15iu/l (0-35)

Questions:

1. What is your interpretation of these results?

2. Any other additional clinical examinations / features should you look for which might be significant?

3. Based on your physical examination of the baby, what other additional investigations would be useful and 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.

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Case 107 – the beginning

Welcome to our new #TeamHaem case.

You are the haematology registrar. You get a phone call from a junior doctor on the neonatal ward. They have a 2 day old baby boy with jaundice. The baby seems stable, though he is needing some oxygen and not feeding as well as expected. They plan to do some blood tests and start phototherapy. She has been asked by her senior to discuss with haematology whether there are specific blood tests they should perform.

You decide to go and see the baby for yourself to make an assessment of the situation.

Questions:

1. What would you like to know about the baby in terms of history?

2. What would you look for in clinical examination?

3. What Initial investigations would you like?

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.

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Case 106 – Summary

Thank you all for your contributions this week.

 

We focused on a patient with a new diagnosis of primary immune thrombocytopenia (ITP), please refer to TeamHaem case 11 for a full summary of this condition.

 

In the wake of a new BSH good practice guideline, our goal this week was to evaluate our patient’s risk of developing glucocorticoid-induced osteoporosis following initiation of first line ITP management with steroids. How many of us have started steroid therapy for a patient without considering the impact their treatment may have on their bone health?

 

Background

Fragility fractures occur in up to half of all patients receiving long-term steroids, vertebral fractures are the most common. This is a major source of preventable morbidity and disability.

Steroids directly inhibit bone formation by triggering osteoblast apoptosis and blocking normal osteoblast activity. Indirectly, steroids also reduce bone mineral density by inhibiting calcium absorption from the gut.

Changes in bone mineral density and the increased risk of fragility fractures occur quickly after the onset of steroid use (within first 3-6 months). Therefore, osteoporosis risk assessment must occur at the time of treatment initiation.

For all adult patients commencing glucocorticoids:

  • Give lifestyle advice to reduce risk factors associated with fragility fractures
    • Weight-bearing exercise, smoking cessation, decrease alcohol intake
  • Check serum calcium and vitamin D levels
  • Adequate daily vitamin D (800 iu) and calcium (7001200 mg) intake in adults is recommended, consider oral supplementation 

Initial fracture risk assessment

  • Patients at high risk of fracture should be considered for oral alendronate or risedronate
  • Everyone aged ≥70 years, can be considered high risk and treatment should be considered without the requirement for further assessment 
  • Men aged ≥50 years and post‐menopausal women with a previous fragility fracture can also be considered high risk and treatment should be considered without the requirement for further assessment
  • Everyone else >40 years old should be assessed by FRAX score without bone mineral density (BMD) assessment at treatment onset ( www.sheffield.ac.uk/FRAX/tool.jsp) to define risk 
  • Intermediate risk should have a dual energy x‐ray absorptiometry (DXA) scan and femoral neck BMD entered into FRAX® to define high and low risk. However, a decision can be made clinically in patients where a DXA results is unlikely to be available in a timely manner).
  • Adults aged <40 years and children do not routinely require assessment.

Patients receiving similar glucocorticoid regimens for relapse 

  • Is there a steroid sparing alternative?
  • If the patient has previously had bone protection, restart it
  • If re-treated within a year consider men aged ≥50 years and post‐menopausal women high risk and treat with bone protection
  • Other adults aged ≥40 years should undergo fracture risk assessment 

Bisphosphonates

Contraindicated

·        Hypocalcaemia

·        Hypersensitivity

·        Severe renal impairment

·        Pregnancy

·        Lactation

Avoid

·        In patients who are unable to sit/stand for 30 – 60 minutes

·        Oesophageal stricture

·        Achalasia

Considerations

·        Risk of osteonecrosis

·        Dental health

Main learning points when commencing steroids for in a patient with new ITP:

  1. Adults should receive lifestyle advice (regular weight‐bearing exercise, stop smoking, reduce alcohol intake to ≤2 units/day).
  1. Adults should receive adequate daily intake of calcium (700–1200 mg) and vitamin D (800 IU) through diet if possible or supplements if needed
  1. Bone loss and increased fracture risk occur early after initiation of glucocorticoids, bone‐protective treatment should therefore be started at the onset of therapy in patients at increased risk of fracture.

References:

Hill, Q. A., Grainger, J. D., Thachil, J. , Provan, D. , Evans, G. , Garg, M. , Bradbury, C. , Bagot, C. , Kanis, J. A., Compston, J. E. and , (2019), The prevention of glucocorticoid‐induced osteoporosis in patients with immune thrombocytopenia receiving steroids: a British Society for Haematology Good Practice Paper. Br J Haematol. doi:10.1111/bjh.15735

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Case 106 – update 2

Our patient is in haematology outpatient clinic.

We have excluded any secondary causes for an isolated thrombocytopenia and are considering first line therapy with prednisolone 1mg/kg/day with gastric protection (our local #TeamHaem preference).

We have considered the potential risks of starting glucocorticoid therapy in our patient. We have recognised that osteoporosis needs to be assessed and have found a new good practice guideline from BSH to help!

 

So #TeamHaem… using the flowchart below, what should we do?

Questions:

  1. What general advice would you give to any patient commencing steroid therapy?
  1. If indicated, please calculate the FRAX score (https://www.sheffield.ac.uk/FRAX/tool.aspx) for our patient and make recommendations about her risk of glucocorticoid-induced osteoporosis
  1. What action would you take given our patient’s calculated risk?

References:

Hill, Q. A., Grainger, J. D., Thachil, J. , Provan, D. , Evans, G. , Garg, M. , Bradbury, C. , Bagot, C. , Kanis, J. A., Compston, J. E. and , (2019), The prevention of glucocorticoid‐induced osteoporosis in patients with immune thrombocytopenia receiving steroids: a British Society for Haematology Good Practice Paper. Br J Haematol. doi:10.1111/bjh.15735

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