Case 151 – The final update

This child underwent an allogenic stem cell transplant. He had to be treated for his HLH initially. Part of it involved chemotherapy (FLA) as JMML was the underlying cause driving the HLH.

The choice between ‘watch and wait ‘ vs HSCT depends on the underlying genetic subgroup along with presence or absence of somatic and germline mutations.

Increasingly DNA methylation status is being used determine prognosis and probability of relapse.

The use of azacytidine prior to HSCT in one subgroup is also being explored. Other targeted therapy trials for relapsed refractory patients are in the pipeline.

Most patients as of now, eventually require allogenic HSCT for cure of their disease.

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Case 151 – Update 3

So , the diagnosis is JMML – Juvenile myelomonocytic leukemia.

We will have a summary later but just a few brief points to note :

  • JMML is unique aggressive myeloproliferative/myelodysplastic disorder of infancy and early childhood caused by proliferation of cells of monocytic and granulocytic lineage.
  • Median age of onset is 2 years of age. Children typically present with fever , splenomegaly thrombocytopenia , high WBC count and monocytosis.
  • Blood film often shows leuco-erythroblastic picture and elevated Hb F for age is found is around 50% of the patients. Monocytosis is quite characteristic.
  • Bone marrow is important to rule out AML and must have fewer than 20% blasts. Bone marrow are not solely diagnostic but findings are consistent with the diagnosis.
  • Flow cytometry is often helpful to rule out other leukemias but is not diagnostic unless we are worried about progression to AML.
  • We need to rule out BCR /ABL fusion gene at presentation
  • 90% of the patients carry either somatic or germline mutations of K-RAS , N-RAS , PTPN-11 , CBL or NF1 in their leukemic cells and this has treatment implications.
  • Mutations in the genes involved in the RAS signalling pathway play a crucial role in disease pathophysiology.
  • Diagnostic criteria is as per 2016 WHO classification.

Now that we know it is JMML , what are the treatment options for this child ? Does every child need allogenic HSCT?

Can JMML’s spontaneously regress ? What are the determining factors in each scenario ?

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Case 151 – Update 2

Going forward , we test and rule out other underlying problems :

  • Genetic mutation for primary HLH is negative
  • Workup for organic acidemias and inborn errors are negative
  • Extended viral panel and AFB does not help
  • There is no evidence of double negative T cells
  • Workup for immune deficiency is negative

Meanwhile Ferritin continues to rise and there is ongoing monocytosis with cytopenias.

So there is HLH which is driving the fever, but what is the primary problem ?

Out of the blue we receive a call from the molecular lab :

  • The bone marrow sample which was tested is positive for k-RAS !!

What do you think now ? Does it tie everything into a neat bow ?

Can we fit everything into one diagnosis?

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Case 151 – Update 1

Thanks a lot for your responses.

Fevers continue despite good antibiotic cover. All cultures are sterile. Lymphadenopathy persists and he has ongoing splenomegaly.

Peripheral blood is sent for flow cytometry. There is only 1% of CD 45 weak population positive for CD 34 , HLA-DR and CD 117. Other markers are negative. CD14 positive monocytes comprise 72% of the nucleated population.

Platelet count keeps dropping and he now requires daily platelet transfusions over the last 72 hours.

Viruses including EBV/CMV/Adenovirus and TORCH panel are all negative. HbF percentage is 8.2% which is normal for age. LDH is 892 and rising , Clauss Fibrinogen is 1.2 g/L and Ferritin is 9500 mcg/L.

Ultrasound of the abdomen shows enlarged liver with splenic parenchymal infiltrates. A CT TAP does not aid apart from confirming cervical lymphadenopathy and splenic infiltrates.

He is wheeled into theatres for a bone marrow under GA. Aspirate is aparticulate and there is left shifted granulopoiesis. There is dyserythropoiesis along with basophilia and prominent promonocytes and monocytes. Blast population is 2%. No morphological evidence of acute leukemia.

The flow again shows only 4% of CD 45 weak nucleated cell population. Similar markers as the peripheral blood. Trephine is reported as : Disorganised marrow with a preponderance to left shifted
granulopoiesis. Monocytes mildly increased. Megakaryocytes and erythroid cells
are significantly reduced.

Samples from bone marrow for infectious pathogens including AFB are negative.

Karyotype is 46 XY , FISH is negative for BCR ABL and molecular studies are awaited

  • Is there a component of HLH here ? Is it primary or secondary to an underlying problem ?
  • Given the background and age – what further tests does would help us narrow down our differentials?
  • What specific molecular tests from the bone marrow would be helpful?
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Case 151 – The Begining

It is a friday afternoon and as the haematology registrar who has had a busy on call, the weekend looks quite inviting. The phone rings and it is the Paediatric SHO.

There is a 7 month old boy who has presented to the A & E. He has been irritable for the past week and has not been feeding well. He also has been reviewed by the GP for fever. A 5 day course of amoxycillin has not helped. Mum feels he is becoming more lethargic and poorly.

He was born at term. Sailed through his neonatal period with no concerns. Has been immunised till date and has remained well till now. Growing well and all the developmental milestones are appropriate for his age. He has one elder sibling and she is well.

The Paediatric SHO examines him and finds that he has palpable cervical and inguinal lymph nodes and some rashes. There is a 6cm palpable spleen and a 4cm palpable liver. A few scattered crepts on auscultation of the chest. No bleeding manifestations or jaundice was reported.

Promptly a chest Xray has been performed and everything is fine. Bloods show:

Hb 69 g/L
Plt 28 x10^9/L
WCC 42.47 x10^9/L
Neutrophils 6.85 x10^9/L
Lymphocytes 25.06 x10^9/L
Monocytes 4.25 x10^9/L
Eosinophils 0.5 x10^9/L
Basophils 1.7 x10^9/L

CRP is 11 and biochemistry is normal.

Urine and blood cultures are awaited .

You request the lab to do a blood film on him and this shows leucoerythroblastic blood picture with lymphocytosis , monocytosis and 1-2% suspicious atypical cells – likely blasts. There is true thrombocytopenia.

But the SHO is worried about the blood results and wants to know what to do next? What are the possibilities at this point ? What other tests would you request? Would you do a bone marrow ?

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Case 150 – summary

This week we discussed the case of a young lady with eosinophilia. She had some vague symptoms to begin with, but after thorough investigation, she was found to have disseminated strongyloidiasis complicated by E. coli bacteraemia. She was immunosuppressed due to a new diagnosis of HIV infection.

Strongyloidiasis is a tropical parasitic disease usually caused by the nematode Strongyloides stercoralis. This can be found in South America, South/Southeast Asia and Africa. It is often asymptomatic, but can cause severe disease in immunosuppressed states. As it often affects the bowel, it can facilitate translocation of gut organisms, and because of this is often associated with E. coli septicaemia. Stool microscopic examination often yields the diagnosis. Treatment is generally with ivermectin and treating any underlying cause – like HIV in our patient’s case.

This case illustrates how – more often than not – referrals to haematology can often result in unexpected non-haematological diagnoses. This is especially the case with non-specific abnormalities e.g. abnormal blood counts. It is important to keep an open mind when approaching these cases to avoid bias and ensure appropriate patient care.

Please see below a summary on eosinophilia, taken from case 41!

Eosinophilia can occur in 1-1.5% of blood counts in the UK.  Eosinophils  develop in the bone marrow and IL-3, IL-5 and GM-CSF are essential for their differentiation. Sometimes solid tumours can secrete these cytokines causing eosinophilia.  Eosinophils are involved with host defence against parasites, as modulators of innate and adaptive immunity, inflammatory responses and tissue repair, and affect mast cell activation and T-cell function.

The causes of eosinophilia are extensive and are highlighted below:

Causes of eosinophilia

Common infectious/tropical causes include:

  • Strongyloidiasis – South/Central America, SE Asia, Africa, India
  • Hookworm – South/Central America, SE Asia, Africa, India
  • Filariasis – Tropical areas
  • Ascariasis – Tropical areas
  • Toxocariasis – dogs/cats
  • Trichinellosis – under cooked pork
  • Schistosomiasis – sub-Saharan Africa, South America, East Asia
  • Coccidiodomycosis – desert areas aspecially northern and central America
  • Fascioliasis – Somalia
  • Scabies
  • Aspergillosis/ABPA – history of asthma, cystic fibrosis

It must be remembered that the vast majority of cases of eosinophilia are transient and benign. In one case series these were the most common causes:

  • atopy including asthma 79.7%
  • parasites 8.2%
  • haematological neoplasm 2.4%
  • allergic / atopic skin disease 2.1%

There is no concrete evidence base to guide the best way to monitor or investigate patients with eosinophilia. Most bodies make decisions based on opinion. The British Committee for standards in haematology is writing a guideline currently on this topic.   However if a patient is found to have eosinophilia it is important to undertake a history and examination. The history should be focused on identifying a cause based on the list above. It is important to ask about any new medications, travel and allergic symptoms. This will reveal most causes. If no symptoms are obvious then a systemic enquiry asking about ‘red flag’ symptoms (weight loss, sweats, blood loss, anorexia etc.) is required.  An examination is useful to clarify points from the history and also document any enlargement of spleen and liver which may be asymptommatic. It is also useful to document examination findings to allow for assessment of changes. If the eosinophilia is mild (generally <1.5×109/L) and there is an obvious cause many may not feel the need to repeat, but appropriate safety netting is required. If there is no obvious cause on initial evaluation, or the patient has evidence of end organ damage (heart failure, respiratory symptoms, diarrhoea, rash) or the eosinophil count is >1.5×109/L then further evaluation and repeating is generally required. Generally it would be unusual for an allergic cause for the eosinophil count to be >2×109/L.

References:

  1. Lombardi C, Giovanni P. Eosinophilia and disease: a clinical revision of 1862 cases. Arch Intern Med 2003 163: 1670-3
  2. http://www.icid.salisbury.nhs.uk/ClinicalManagement/Haematology/Pages/Eosinophilia-CausesandInvestigations.aspx
  3. Investigation of an incidental finding of eosinophilia: http://www.bmj.com/content/bmj/342/bmj.d2670.full.pdf
  4. http://patient.info/doctor/eosinophilia
  5. Drug-induced eosinophilia: http://www.pharmaceutical-journal.com/learning/learning-article/drug-induced-eosinophilia/20000049.article
  6. Eosinophilic Myeloproliferative Disorders. http://asheducationbook.hematologylibrary.org/content/2011/1/257.full.pdf
  7. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864371/pdf/0950696.pdf
  8. Nordic guidelines: http://www.hematology.dk/index.php/vejledninger/kliniske/diverse-vejledninger/66-nordic-eos-guideline-revised-sept-2012/file
  9. https://www.cdc.gov/dpdx/strongyloidiasis/index.html

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Case 150 – update 5

Stool examination (wet mount) reveals a filariform larva of Strongyloides stercoralis – thus making the diagnosis disseminated strongyloidiasis secondary to HIV infection.

She is commenced on ivermectin and starts to improve. She has also been referred to the infectious diseases team to commence antiretroviral therapy.

Well done team!

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Case 150 – update 4

You receive a phone call from a very excited microbiologist, saying they’ve found something in this lady’s stools! See image below

What is this and how would you treat it?

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Case 150 – update 3

Our patient’s seizure was short lived and self-terminated. Her blood cultures grow E. coli. CT head is clear. She undergoes a lumbar puncture and the microbiology lab are able to see Gram negative bacilli in her CSF. She is commenced on appropriate antibiotics.

After 48h she has not had any further seizures but remains pyrexial, now with profuse diarrhoea and an eosinophil count of 19 x10^9/L.

Some of her tests have come back:

-Peripheral blood cytogenetics: negative for BCRABL, PDGFRAPDGFRB and FGFR1
-HBV serology: HBsAb positive, HBsAg negative, HBcAb negative
-HCV PCR: not detected
-HIV PCR: detected
-Vasculitis screen: negative
-Echocardiogram: normal
-ECG: normal
-Stool: C diff negative, but culture still in progress

What would you do at this point?

And why is her eosinophilia getting worse despite antibiotics?

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Case 150 – update 2

Our patient has been admitted for further investigations. You feel she does not require urgent steroid therapy at this point.

You have arranged for peripheral blood cytogenetics looking for common mutations associated with primary eosinophilia. You also organise a vasculitis screen, HBV/HCV/HIV testing, stool culture, and an echo – results in progress.

She undergoes a CT CAP which shows widespread low volume lymphadenopathy above and below the diaphragm. There is no organomegaly.

The following day her eosinophil count has risen to 15×10^9/L. Her temperature is now 38.6C. As you prepare to review her on your ward round, she has a generalised tonic clonic seizure.

What are your top differentials at this point and what would you do next?

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Case 150 – update 1

You advise the GP to refer to the haematology clinic in view of her eosinophilia and unexplained weight loss.

When you see her clinic after about 4 weeks, she looks unwell. She tells you she has lost about 3kg in weight since she saw her GP. She is now experiencing significant diarrhoea and has developed a red itchy rash on her chest and thighs. She feels short of breath on exertion and extremely fatigued.

Her FBC is now:

Hb 91 g/L
Plt 168 x10^9/L
WCC 12.3 x10^9/L
Neutrophils 1.2 x10^9/L
Lymphocytes 2.1 x10^9/L
Monocytes 0.4 x10^9/L
Eosinophils 8.6 x10^9/L
Basophils 0.01 x10^9/L

Her blood film shows marked eosinophilia but is otherwise unremarkable.

How would you proceed at this point?

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Case 150 – the beginning

A 29 year old lady sees her GP due to feeling generally unwell. She thinks she has lost some weight over the last few weeks, and has also had cold type symptoms during that time (sore throat, runny nose, fatigue).

She has asthma for which she takes inhalers, but otherwise is fit and well. She works as a shop assistant and smokes 10 cigarettes daily. She drinks alcohol socially.

On examination she has small but palpable bilateral tender cervical lymph nodes with not much else to comment on. She looks otherwise well.

Her full blood count is as follows:

Hb 135 g/L
Plt 268 x10^9/L
WCC 10.9 x10^9/L
Neutrophils 1.8 x10^9/L
Lymphocytes 4.6 x10^9/L
Monocytes 0.9 x10^9/L
Eosinophils 3.6 x10^9/L
Basophils 0.01 x10^9/L

Her GP is concerned by the eosinophil count and calls the haematology team for advice. What questions would you ask and what advice would you give at this point?

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Case 149- summary

This weeks case focussed on the importance frailty assessment in making treatment decisions for an elderly patient with Diffuse large B cell lymphoma. This is an important topic as DLBCL affects an older population with mean age at diagnosis of 67 years. Historically there have been poor outcomes in the older frailer cohort of lymphoma patients. There is significant under representation in clinical trials and difficulties in evaluating fitness have hindered progress in improving outcomes. The role of the multi-disciplinary team and careful assessment of fitness is key to ensure patients are treated in an appropriate patient centred manner.

There is increasingly a recognition of the importance of focussing on cancer in an elderly population. Cancer is a disease that predominantly affects the elderly with cancer incidence peaking at 80-85 years of age in the UK. In the UK older patients are less likely to be referred via 2WR pathways and yet are more likely to have cancer compared to other age groups. Patients over 75 years account for a third of diagnoses of cancer in UK but according to recent Macmillan data account for over half of the total deaths in the UK.

The guiding principles in an older population with cancer should be according to a recent BJGP article adding “quality to years and not always years to life”.

There are often limitations to intensity of therapy that can be delivered and open and honest shared decisions are needed here

Objective measures of frailty are essential to underpin and frame the conversations that help in shared decision making.

A recent BJHaem article by cordoba et al on frailty assessment advocates frailty assessments roles in shared decision making. Goode et al in their review on frailty in the older patient point out that frailty and haematological malignancy are bi-directional in their relationship both having an impact on each other and this interplay influences overall outcomes. They give many examples in their excellent review such as cancer related anaemia leading to deterioration in cardiac function and renal function leading to worsened anaemia. Infection post chemotherapy and mild cognitive impairment leading to delirium then a fall and hip fracture with worsening of delirium and anaemia. These situations are all too commonly seen in everyday clinical practice and often these adverse outcomes could have been predicted if more time had been given upfront into careful assessment of the patient in front of the clinician. .

When shared decision making is needed when faced with an elderly patient with haematological malignancy we need to consider ways of evaluating frailty, co-morbidity functional status and ADLs.

FRAILTY:

Frailty is defined as an age-related state of increased vulnerability and poor resilience to acute stressors. This can be assessed using a variety of frailty assessments:

G8 Screen – short test to indicate when a more detailed assessment is indicated if score <15 points. There is some limited data that show correlation between low G8 score and mortality in DLBCL.

Vulnerable elders survey, Groningen frailty indicator and Flemish version of triage risk score – some limited data exploring their use in showing inferior outcomes in NHL.

These tools are not perfect but help as short screening tools and will help highlight issues that you may not have immediately picked out when you take the usual social history.

CO-MORBIDITY

Co-morbidity is also an important consideration when contemplating treating an older patient with a haematological malignancy.

Charlton Co-morbidity index – This is a helpful screening tool that can help evaluate a 1 year and 10 year mortality for the individual in clinic without their haematological malignancy and this can be helpful to add context to frame difficult decisions. This index is used alongside age, ADL, Instrumental ADL in myeloma patients to evaluate patients into fit, intermediate fit and frail groups for therapy by the International myeloma working group.

Cumulative illness rating scale – validated tool for contemplating co-morbidity based on 14 items. This has been used by the Italian Lymphoma foundation alongside Age >80 years, ADL, and Instrumental ADL to define “ fit, unfit and frail” elderly patients with DLBCL and has been shown to be effective in highlighting the frail patients who have same outcomes if treated for cure vs palliative approach. Outcomes for the three groups were 3 year OS of 87%, 69% and 42% and this was the first score system that has been shown to stratify patients outcomes by integrating clinical and geriatric assessment in lymphoma patients.

ACTIVITIES OF DAILY LIVING:

ADL – 6 item scale to assess function. Integral to INMWG and also Italian lymphoma foundation work on frailty.

Instrumental ADL – 8 item questions to assess functionality.this is also part of INMWG and Italian foundation work on frailty.

The outcomes of considering the above should be to prompt consideration of any methods that could help mitigate overall frailty. These steps are simple but may have tangible benefits for patients. Examples include:

Consider polypharmacy and interactions.

Dietician review for nutrition optimisation.

Considering bone protection if using steroids to prevent fractures.

Occupational therapy for ADL issues.

Physiotherapy to enhance fitness.

Social service referral to improve support or provide pendant alarm in case of falls etc

THERAPEUTIC TOXICITY:

CRASH chemotherapy risk assessment scale for high age patients – 15% validation cohort had lymphoma.

 

CARG cancer and ageing research group – help to evaluate toxicity of therapy not validated in lymphoma population.

OTHER DLBCL SPECIFIC CONSIDERATIONS

In our case a steroid pre-phase was used and this can be very helpful in evaluating fitness in a new lymphoma patient where frailty is felt to be mainly due to disease.

Gode et al highlight the importance of consideration of what is causing the frailty is it the haematological malignancy or general frailty and this can be a real barrier to effective decision making around treatment when a patient isn’t known before and a trial of steroids can be very helpful here

1mg/kg Prednisolone for 5-7 days has been shown indirectly to reduce treatment related mortality in high grade lymphoma. This data is from LYSA study where there were 12 deaths in RHOP and R mini CHOP arms and none in the O CHOP arm where steroid pre phase was used as standard.

R mini CHOP has been shown to be effective in an older patient cohort and is the standard therapy used for >80 years old patients. It has a 2 year OS of 59% and the survival curves do plateau indicating a durable response. It is important to state that in patients over 80 years the intended dose intensity is likely more important than the overall dose of anthracyclines used and there is very limited data to show any improved outcomes when using R CHOP at full dose compared to reduced doses for patients >80 years.

R CEOP is a valid option for management of elderly patients with impaired ventricular function and outcomes were comparable to R CHOP 58% vs 67% disease specific survival at 10 years.

Bone protection is an important issue post therapy with DLBCL with 11.4% risk of fracture in the first 18 months post RCHOP. This is an issue that can cause considerable co-morbidity and can be prevented if considered at start of therapy.

Postural drop and poor tolerance to steroid withdrawal are also common issues and a careful steroid wean and review of hypertension medications can also help deal with these issues.

Hopefully this case has provided you something to contemplate in your own experience of managing older patients with malignancy and there is an excellent review I have highlighted in the references if you wish to read more on this topic.

 

References:

Excellent 4 part series of papers on haematological malignancy in older people available for free at :

https://www.thelancet.com/series/haematological-malignancies-in-older-people

(Includes Cordoba et al A comprehensive approach to therapy of haematological malignancies in older patients. Gode et al frailty assessment in the care of older patients with haematological malignancies)

Cordoba R, Luminaries S and Eyre T. The use of ffrailty assessments in treating older adults with aggressive lymphomas. BJHaem (2021) 194, 677-685.

Booth et al. Fractures are common within 18 months following first line RCHOP in older patients with diffuse large B cell lymphoma. Blood (2020). 4 (18): 4337-4346

Jones et al. Investigating cancer symptoms in older people. What are the issues and where is the evidence? BJGP (2020). 70(696):321-322.

Older people living with cancer Designing the future health care workforce;

https://www.macmillan.org.uk/assets/workforce-report.pd

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Case 149 – Update 1

 

Our patient is a retired cleaner who lives in a house next to her only daughter and her two grand-children. She is a non smoker and drinks no alcohol. She tells you that her daughter tended to do the shopping since the COVID pandemic but she does her own cooking and washing. She tells you recently she has been very fatigued and has spent most of the day in her chair. Three months ago she was able to do some gardening and could get up a flight of stairs at home without problems. She has lost around 4 kg in weight recently and has a fair appetite. Her BMI is 24.

She lives alone having been widowed some 15 years ago. She has a Cat who she is very fond of and she is anxious to be home as soon as possible. She says she does want to have treatment for her lymphoma as long as it won’t make her have to be in hospital.

She had rheumatic fever as a child and was told she had a leaky heart valve but hasn’t seen a cardiologist for this. She has hypertension and is on Amlodipine 10mg for this. She is also on a statin but denies any previous cardiac events or strokes. She had a cholecystectomy age 40. She is also on a PPI for previous gastric ulcer a few years ago.

She had an echo that shows her Ejection fraction is >55% and she has mild MR.

Her viral screen is negative and her blood tests are unremarkable – FBC: Hb 130, plt 290, neu 2.4, Wcc 4. EGFR 90, LFTs normal, LDH 398 (high).

CT shows likely stage I disease with bulk >7.5cm.

What treatment options does she have?

What would be your preferred treatment option here?

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Case 149 – The Beginning

You are the on call haematology registrar working at a District general hospital when you receive a call from the medical team at 4pm on a friday. They have an 87 year old lady with neck lymphadenopathy that has grown rapidly over 6 weeks and the biopsy has come back showing DLBCL. They would like your assessment on what to do next.

She was admitted to hospital following a core biopsy of the lymphadenopathy with a pneumonia and is currently receiving antibiotics for this.

What history would you take?

What would you examine for?

What investigations would you arrange?

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.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning

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Case 148 conclusion and summary

The patient is treated for serum sickness. Given the severity of the symptoms, he is given another pulse of methylprednisolone and converted back to oral prednisolone. He is also treated supportively with analgesia and antipyretics, as well as platelet transfusions. He makes a gradual improvement over the next week and is discharged with a slower taper of his prednisolone. He continues on ciclosporin with trough level monitoring. Two months later, he shows early signs of treatment response with a slowly improving neutrophils count. By 6 months, he is transfusion independent and bone marrow biopsy shows improving trilineage haematopoiesis. A slow taper of his ciclosporin is commenced and he remains under close outpatient follow up.

Aplastic Anaemia

Definition: pancytopenia with bone marrow hypoplasia

Aetiology:
Constitutional syndromes
Fanconi anaemia
Dyskeratosis congenital
Shwachman-Diamond syndrome

Marrow toxicity
Myeloablative chemotherapy/radiotherapy
Industrial toxic exposures, e.g. benzene, radiation accidents

Immune-mediated
Idiopathic (most common)
Idiosyncratic drug reactions (e.g. chloramphenicol)
Viral, e.g. HIV, hepatitis viruses
Associated conditions: sero-negative hepatitis, thymoma, eosinophilic fasciitis

Clinical features:
Symptoms/signs related to pancytopenia
If constitutional, then may have congenital abnormalities associated with underlying syndrome (e.g. developmental delay, short stature, etc.)
If associated PNH, then may have features of haemolysis or thrombosis
Clonal evolution (MDS, AML) – although usually a late complication rather than presenting feature

Diagnostic work-up:
Detailed clinical history and examination, including family history, drug history, toxic exposures
FBC with reticulocyte count and blood film
Haemolysis screen
B12 and folate
Autoantibody screen
Viral serology – EBV, CMV, HIV, parvovirus, hepatitis A-E
CT scan if concerns re: underlying malignancy, especially lymphoid

Bone marrow aspirate and trephine biopsy
Cytogenetics on marrow aspirate
PNH screen (peripheral blood flow cytometry)
Chromosomal breakage analysis
Further investigations for constitutional syndromes depends on degree of suspicion

Diagnostic criteria:

  1. Pancytopenia
  2. Marrow hypocellularity (<25% cellularity)
  3. No marrow fibrosis or abnormal infiltrate

Severe AA: at least two of neutrophils <0.5, platelets <20, reticulocytes <20
Very severe AA: as for severe AA but neutrophils <0.2
Non-severe: cytopenias do not meet criteria for severe or very severe AA

Other differentials for pancytopenia with hypoplastic marrow:
Hypoplastic MDS/AML
PNH
Lymphoma
Mycobacterial infections
Primary myelofibrosis

Treatment of severe/very severe acquired aplastic anaemia

Supportive care

Red cell and platelet transfusions
Consider phenotype red cells to reduce risk of alloimmunisation
Consider prophylactic antimicrobials in severely neutropenic patients (follow local guidelines)
Antibiotics for neutropenic sepsis

Immunosuppressive therapy
Horse ATG and ciclosporin
Pros:
1. Avoids transplant-related morbidity/mortality
2. Option in patients without BM donor
Cons:
1. Delayed response (3-4 months)
2. Less effective than stem cell transplantation
3. Adverse effects, e.g. serum sickness with ATG
4. Risk of clonal evolution to MDS and AML in longterm

Allogeneic stem cell transplantation
Treatment of choice for younger, fit patients with matched sibling donor
Matched unrelated donor an option for patients who fail to respond to immunosuppressive therapy
Pros:
1. Higher response/cure rate
2. Reduced risk of clonal evolution
3. More rapid response
Cons:
1. Transplant-related morbidity/mortality, esp. infection and GvHD
2. Small risk of graft failure
3. Need a donor

Treatment of older patients
Depending on fitness, options include:
1. ATG and ciclosporin
2. Ciclosporin alone
3. Eltrombopag for refractory disease
4. Best supportive care only

Prognosis:
Significantly improved over the last few decades
Untreated – one year mortality as high as 70%
With current treatment (in younger, fit patients) – long-term survival can be as high as 80-90%

References
Guidelines for the diagnosis and management of adult aplastic anaemia, BSH. https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.13853

Aplastic anemia, NEJM. https://www.nejm.org/doi/full/10.1056/nejmra1413485

How I treat acquired aplastic anemia, Blood. https://ashpublications.org/blood/article/129/11/1428/35931/How-I-treat-acquired-aplastic-anemia

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 148: update 3

HLA typing of this patient’s two siblings has not identified a match. Unfortunately, unrelated donor search has not identified any suitable donors. The patient is consented to immunosuppressive therapy with horse ATG and ciclosporin.

The patient is admitted and receives prophylactic platelet transfusions, IV methylprednisolone and IV chlorphenamine before each dose of ATG. He develops an infusion reaction with the first dose (fever and rigors), which quickly settles with supportive treatment. He is discharged on day five after his four doses of ATG with a tapering course of prednisolone and a plan for early outpatient follow up. Ten days later, he presents to the haematology day unit very unwell. He has a widespread urticarial rash that initially started two days ago and has rapidly spread. He is pyrexial at 39 degree Celsius and has widespread joint pains, including the knuckles, wrists and ankles.

What is the diagnosis?
How do you treat this complication?

Does the patient have any special blood requirements?

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Case 148: update 2

The patient is admitted for broad spectrum antibiotics and red cell transfusion. A bone marrow biopsy is performed, which demonstrates 10% cellularity with no dysplastic features, no excess of blasts, no abnormal infiltrate and no fibrosis. Cytogenetics demonstrate a normal karyotype. CT chest, abdomen and pelvis is unremarkable.

The patient is diagnosed with aplastic anaemia. Flow cytometry on peripheral blood did not demonstrate a PNH clone, and chromosomal breakage analysis excluded Fanconi anaemia. The patient is monitored over the course of the next month and supported with transfusions as required. Unfortunately, his blood counts continue to plummet with undetectable neutrophil count and ongoing red cell and platelet transfusion dependence.

What treatment options are available to this patient?
What are the pros and cons of these treatment options?

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Case 148: update 1

The gastroenterology team have kindly organised further investigations. B12 and folate are normal, viral serology (including HIV, CMV, EBV and parvovirus) are all negative. Autoantibody screen was also negative. LDH is normal and there is no evidence of haemolysis. Peripheral blood smear confirmed pancytopenia but did not identify any dysplasia or primitive cells. Examination did not identify any lymphadenopathy or hepatosplenomegaly. He has no significant PMH or family history and is not taking any regular medications. He denies any recreational drug use. He is referred to the haematology clinic and is seen two weeks later. He now feels breathless and is pyrexial. Repeat FBC is as follows:

Hb                      69  (130-180)
Platelets             43  (150-450)
WCC                 1.0 (4-11)
Neut                   0.2 (2-7)
Lymphocytes     0.4 (1-4.5)
Monocytes         0.3 (0.2-0.8)

What would you do now?
What further investigations are required?

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Case 148: the beginning

You are the liaison haematology registrar and receive a call from the gastroenterology team for advice about a 24 year old male patient under their care. He is a previously fit and well university student who initially presented 3 months ago with jaundice due to an unexplained acute hepatitis, which is now resolving. Extensive investigations have excluded any viral, toxic, metabolic, structural or autoimmune aetiology. His LFTs are nearly back to normal now and he is well in himself, but they have noticed that his blood counts are dropping with each clinic appointment (previously normal).

His FBC from today is as follows:
Hb                      93  (130-180)
Platelets             83  (150-450)
WCC                 2.2 (4-11)
Neut                   0.9 (2-7)
Lymphocytes     0.8 (1-4.5)
Monocytes         0.3 (0.2-0.8)

What further investigations would you advise?
What is your differential diagnosis?

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