Case 132 – the summary!

Thank you for all the contributions throughout Case 132.

We discussed the case of a 66-year-old gentleman who was diagnosed with chronic lymphocytic leukaemia after he presented with cervical lymphadenopathy. He required treatment as he was symptomatic (B symptoms) and had cytopenias secondary to marrow infiltration of the CLL. He had no TP53 disruption but had poor prognostic markers (IGHV unmutated and 11q deletion). We commenced him on acalabrutinib (accessible as first line therapy for TP53 non-deleted CLL throughout the COVID-19 pandemic in UK).

After 20 months of treatment our patient developed acute onset of weight loss and night sweats. Imaging revealed a large retroperitoneal mass which was out of keeping with the degree of low volume lymphadenopathy elsewhere with a much more FDG avid on PET. It was confirmed to a Richter’s transformation as it was clonality related to his CLL as opposed to a de novo DLBCL. Therefore, he was commenced on R-CHOP with prophylaxis for tumour lysis with intention of completing #6 and consolidating with an allogenic HSCT.

Below is a summary of Chronic Lymphocytic Leukaemia:

CLL is a chronically relapsing and remitting B cell lymphoproliferative disorder.

Incidence of ~3700 people per year in the UK.

Incidence increases with age with a preponderance in males.

Presentation:

  • Commonly incidental finding of asymptomatic lymphocytosis on FBC performed for unrelated reasons
  • B symptoms
  • Cytopenias (anaemia, thrombocytopenia, leucopenia)
    • NB cytopenias can result due to direct marrow infiltration of the CLL or be related to autoimmune manifestations
  • Lymphadenopathy / hepatosplenomegaly
  • Recurrent infections secondary to hypogammaglobulinaemia

Diagnostic criteria:

  • Lymphocytosis with circulating clonal B cells accounting for >5×109 for at least 3 months
  • 92% of CLL cases have a typical immunophenotype (CLL score of ³ 4/5)
    • CD5+
    • CD23+
    • CD79-/weak
    • FMC7-
    • Weak surface membrane immunoglobulins

  • NB:
  • Monoclonal B cell lymphocytosis: <5×109circulating clonal lymphocytes with no lymphadenopathy
  • Small lymphocytic leukaemia: Presence of lymphadenopathy but <5×109circulating clonal lymphocytes

Staging Systems available:

  • Rai
  • Binet
  • CLL-IPI

Rai / Binet staging systems risk stratify based on presence cytopenias and lymphadenopathy / hepatosplenomegaly and number of lymphoid organs involved. However, CLL-IPI includes additional prognostic parameters including stage, age, several biomarkers (i.e B2 microglobulin, TP53 mutations).

Prognostic markers

Patient factorsDisease-related factors
Poor riskLower risk
Age Gender Co-morbiditiesB2 microglobulin >3.5 CD 38+ TP53 disruption IGHV UNmutated -11q ZAP-70Trisomy 12 -13q IGHV mutated

Management:

Supportive measures:

  • Vaccinations:
    • Seasonal influenza – annually
    • S. pneumoniae + H.influenza B
    • NB: Live vaccines are contraindicated
  • Intravenous immunoglobulin
    • Consider if recurrent bacterial infections and confirmed hypogammoglobulinaemia
  • Consider GCSF

Indications for initial treatment

Approximately 30% of patients will never require treatment due to the indolent nature of their disease.

  • Progressive marrow failure
    • Typically Hb <10g/l, Plts 100×109/l but if patient asymptomatic / cytopenias stable may not require treatment at this level.
  • Splenomegaly (>6cm, progressive or symptomatic)
  • Lymphadenopathy (>10cm, progressive or symptomatic)
  • Lymphocytosis
    • >50% increase over 2 months
    • Doubling time <6 months (providing initial lymphocytosis not <30×109)
  • Autoimmune complications i.e ITP, AIHA poorly responsive to steroids / standard treatment
  • Constitutional symptoms
    • Weight loss >10% in 6 months
    • Fevers >38oC for ³2 weeks with no infective component
    • Night sweats ³1 month with no infective component
    • Marked fatigue

Baseline investigations prior to treatment:

Blood testsImagingHistology
FBC Reticulocyte count DAT U+Es, LFTs Immunoglobulins HIV, hepatitis B/C, CMV Immunophentype Cytogenetics / molecular markersCXR   CT CAP (Consider to assess degree of lymphadenopathy and therefore response to treatment)   PET (Consider if concern re Richters transformation)Bone marrow (Consider if cause of cytopenias unclear ?infiltration vs autoimmune)   Lymph node biopsy (Consider if concern re Richter’s transformation)

First line treatment

  • Aim of treatment should be to achieve the deepest MRD response as possible. MRD negative remission is an independent marked for improved OS and PFS as resulted in CLL8 trial. Therefore, aim to use most effective available initial treatment providing the toxicity is acceptable.
  • Patient factors as well as TP53 disruption status should help guide treatment decisions. Chemoimmunotherapy is ineffective in TP53 disruption.
  • Consider trial options if available
NO TP53 Disruption
Chemoimmunotherapy options:Non-chemotherapy options:
Fit patientsFludarabine, cyclophosphamide, rituximab (CLL10 trial)Acalabrutinib Second generation BTK inhibitor (In UK current access for frontline therapy in >65yo due to COVID-19 pandemic)
Rituximab and bendamustine (less toxic than FCR)
Less fit patientsChlorambucil and Obinutuzumab (CLL 11 trial)
Frail patientsChlorambucil monotherapy Corticosteroid monotherapy 
TP53 Disruption
Ibrutinib (RESONATE / RESONATE 2 trials, illuminate trial) If ibrutinib cautioned / contraindicated: Idelalisib and Rituximab Venetoclax if either B-cell receptor pathway inhibitor above is unsuitable

Richters’ transformation:

  • 5-15% of patients with CLL
  • 80% transform to DLBCL, 20% Hodgkin lymphoma
  • Consider in individuals with:
    • Rapid nodal enlargement
    • Bulky lymphadenopathy (often degree of lymphadenopathy out of keeping of degree of widespread lymphadenopathy)
    • Extranodal disease
    • Rapid onset B symptoms
    • Markedly raised LDH
  • Aim to confirm with histology. PET imaging often helpful to identify biopsy site.
  • Essential to determine if high grade disease is clonally related to CLL.
    • If not treat as de novo DLBCL / HL
    • If clonally related: poor prognosis.
      • For DLBCL: Consider R-CHOP and consolidate with transplant

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.

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.

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Case 133: The beginning

Its your first day oncall as a new haematology ST3. You are called by the paediatric A&E nurse.

A 2 year old boy has been brought in by his Mum with a swollen right knee. 

His mum says he has a bleeding disorder but has never been seen in this hospital before.

What do you want to know?  What history do you need immediately?

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Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

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Case 132 – Update 6!

Thank you for your ongoing input.

Unfortunately the investigations performed to assess our patients new onset B symptoms and mild lymphocytosis whilst on acalabrutinib have revealed that he has diffuse large B cell lymphoma:

  1. LDH: 1200
  2. CT: widespread mild lymphadenopathy (predmoninantly <3cm) and a large 8cm mass in retroperitoneum
  3. PETCT: Retroperitoneal mass and intrabdominal nodes significantly more FDG avid than other other low volume lymphadenopathy (SUV max 15).
  4. Retroperitoneal mass histology: DLBCL

Questions:

  1. What further investigations/additional information would you want to acertain?
  2. How would you manage this patient?

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Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

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Case 132 – Update 5!

Thank you fo everyone’s ongoing input.

Our patient had been stable on acalabrutinib for 20 months following a complete remission (complete resolution of his lymphocytosis (after 13 months), resolution of his cervical lymphadenopathy and cytopenias).

However when he attends clinic he mentions that he has not been well. Over the past month he has become lethargic, lost weight and developed night sweats. He has no palpable lymphadenopathy.

FBC:

Hb 118, Plts 162, WCC 15, neuts 3.1, lymphocytosis 10.2.

Questions:

  1. What investigations would you want to perform?
  2. What is the possible differential diagnosis?

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Case 132 – Update 4!

The peripheral blood flow cytometry has demonstrated a CLL score of 5/5 confirming the suspected diagnosis of CLL.

Cytogenetics / biomarkers:

NO TP53 deletion/disruption, IGHV UNmutated, 11q deletion

His staging CT (neck, chest abdo pelvis) demonstrates widespread bilateral lymphadenopathy (stage III) with the largest measuring 4cm intra-abdominal nodes and moderate splenomegaly at 15cm.

You review him in a follow-up clinic to go through the above results and he informs you he has had a further 1/4 stone of weight loss in the past 6 weeks. No bleeding issues.

FBC: Hb 108, Plts 50, WCC 60, neuts 2.1, Lymph 54

B2 microglobulin 4. Renal / liver function normal. HIV / hep B/C negative.

Questions?

  1. How would you manage this man?
  2. If you plan to start treatment what option would you choose and why?

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Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

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Case 132 – Update 3!

Thank you for everyone’s input and you’ve all correctly noted the blood film findings of consistent of abnormal population of predominantly mature lymphocytes (prolymphocytes only 10%) inkeeping with a lymphoproliferative disorder and genuine thrombocytopenia.

The flow cytometry is as follows:

CD3-, CD5+, CD10+, CD19+, CD23+, CD79b weak, FMC7-, Igs+/-.

Questions:

  1. What is the diagnosis?
  2. What cytogenetic abnormalities would help you to prognosticate?
  3. What other baseline investigations would you request?

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Case 132 – Update 2!

Thank you for everyone’s contributions! Our list of differentials for this man with cervical lymphadenopathy, weight loss and recurrent respiratory tract infections is appropriately wide.

Luckily you’ve some of your requested investigations are back:

FBC: Hb 110 Plts 60 WCC 54 Neuts 2.0 Lymphs 51

Renal and liver function: Normal

Serum electrophoresis: No paraprotein

HIV / hep B / C normal.

Blood film:

Questions:

  1. What does the blood film show?
  2. What is the most likely diagnosis?
  3. What further investigations would you request?

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.

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Case 132 – Update 1!

Thank you for everyone’s contributions regarding our new referral of a 66 year old man with bilateral cervical lymphadenopathy. From your thorough clinical assessments we now the following information:

He first noticed his neck lumps whilst shaving approximately 2 months ago and feels they have gradually increased in size since then. They are not tender.

He has lost approximately half a stone in the last 4 months despite a good appetite. He has not had any night sweats.

He has recurrent respiratory tract infections but has not presented to medical services for these.

He frequently travels to Asia with work and has had the appropriate vaccinations for this.

PMH: type 2 diabetes mellitus (well controlled).

Drug history: Metformin. No recent changes. No over the counter meds.

Social history: Occasional alcohol. Never smoked. No illicit drugs.

Questions:

  1. What are the possible differentials?
  2. What investigations would you request?

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.

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Case 132 – The beginning

You are the haematology registrar and are just about to review a new haematology referral in an outpatient clinic. The brief referral letter states:

‘Please review this 66 year old gentleman who has a background of diabetes mellitus. He has bilateral neck lumps which he first noticed approximately 2 months ago. I’d be grateful for you review with regard to his presumed lymphadenopathy’

Questions:

  1. What further information would you specifically enquire about in your history?
  2. What would your examination focus upon?

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.

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Case 131 – Summary

This week, we followed a patient with HIV-associated Burkitt’s lymphoma. Burkitt’s lymphoma is one of a handful of true haematological emergencies and thankfully it’s very rare in the general population. However, in HIV-positive patients, it has a high incidence despite effective anti-retroviral therapy.

Epidemiology (in HIV-positive patients)

  • 25% of systemic NHLs
  • 10-20% lifetime risk
    • Incidence static despite effective ART
  • 25-40% EBV-positive


Pathogenesis

  • Not associated with low CD4 count
  • MYC re-arrangement – universal finding
    • t(8;14) > t(2;8) > t(8;22)
    • Leads to MYC overexpression
  • Other potential mutations
    • TP53, ID3, TCF3, CCND1
  • HIV lymphomagenesis
    • Burkitt’s associated with higher CD4 counts compared to other NHLs
    • Chronic B cell dysregulation
    • HIV protein Tat promotes MYC translocation
    • Role of EBV co-infection in proportion of cases


Clinical features

  • Higher rates of nodal disease compared to endemic and sporadic forms
  • Extra-nodal disease common at presentation
    • GI tract
    • Bone marrow (previously called ALL L3)
    • CNS (leptomeningeal disease)
  • Advanced stage disease
  • B symptoms
  • Symptoms of HIV/AIDS
  • Spontaneous tumour lysis syndrome


Pathology

  • Morphology
    • Medium-sized, monomorphic cells
    • Round nuclei, multiple nucleoli
    • Deeply basophilic cytoplasm
  • Histology
    • ‘Starry-sky’ appearance
      • Benign macrophages (stars) on background of sheets of basophilic Burkitt’s cells (sky)
    • Ki-67 index 100%
  • Immunophenotype
    • Positive: IgM, Bcl-6, CD19, CD20, CD22, CD10 and CD79a
    • Negative: CD5, CD23 and TdT
  • Cytogenetics
    • MYC re-arrangement (as above)


Baseline investigations

  • Bloods
    • Routine (FBC, U/Es, LFTs, etc.)
    • LDH, urate
    • HIV serology (viral load and CD4 count if HIV-positive)
    • Hep B/C serology
  • Imaging
    • CT neck/chest/abdomen/pelvis
    • PET-CT
    • Echocardiogram
  • Other investigations
    • Tumour histology
    • Bone marrow biopsy if suspected marrow disease
    • CSF for cytospin and flow cytometry


Treatment

  • Continue antiretroviral therapy
    • Involve infectious diseases team throughout treatment
  • Chemotherapy regimens (for medically-fit patients)
    • R-CODOX-M/R-IVAC
    • R-Hyper-CVAD
    • DA-EPOCH-R
  • High risk for CNS relapse – most regimens have intrathecal chemotherapy and high dose methotrexate and/or cytarabine built in
  • Rituximab – avoid if CD4 count < 50 (rare in Burkitt’s)
  • Tumour lysis syndrome (can occur spontaneously)
    • Prophylaxis
      • IV hydration (at least 3 L per day) and prophylactic rasburicase
      • Frequent blood monitoring
    • Treatment of established TLS
      • Early recognition
      • Treatment dose rasburicase
      • IV fluid resuscitation
      • Treat hyperkalaemia
      • May require dialysis
    • Curable disease but outlook worse than non-HIV infected counterparts
    • Prognosis for relapsed or refractory disease is especially poor


References

Atallah-Yunes SA, Murphy DJ, Noy A. HIV-associated Burkitt lymphoma. Lancet Haematol. 2020;7(8):e594-e600. doi:10.1016/S2352-3026(20)30126-5

Blum KA, Lozanski G, Byrd JC. Adult Burkitt leukemia and lymphoma. Blood. 2004;104(10):3009-3020. doi:10.1182/blood-2004-02-0405

Freedman AS, Aster JC. Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma. UpToDate. Updated: 08/01/2020.

Kaplan LD, Ai W. HIV-related lymphomas: Epidemiology, risk factors, and pathobiology. UpToDate. Updated: 23/08/2019.

 

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Case 131 – update 4

The case is discussed in MDT with a decision to proceed with R-CODOX-M/R-IVAC. Infectious diseases advise to continue ART.

After 4 cycles, he has a complete response and enters a period of surveillance.

6 months later, he presents to A+E with intractable headaches and double vision – the examining doctor identifies a left abducens nerve palsy.


What are you worried about here?

What investigations would you perform?

 

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Case 131 – update 3

Bone marrow biopsy with IHC is in keeping with Burkitt’s lymphoma (EBV-negative).

The diagnosis is confirmed by interphase FISH studies:

FISH: IGH-MYC fusion POSITIVE t(8;14)(q24;q32) [35/100] / BCL6 NOT rearranged [100] /
BCL2 NOT rearranged [100] 

PET-CT shows markedly increased FDG uptake throughout the axial skeleton in keeping with diffuse marrow infiltration. No other areas of disease are identified.

LDH is markedly elevated at 7900. His ECOG is 1.
What treatment would you offer this patient (no right answer)?

Does the patient’s HIV status affect the treatment options and what would you do with the antiretroviral therapy?

What are the potential complications of treatment and how would you reduce the risk of these complications?

 

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.

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Case 131 – update 2

Peripheral blood flow cytometry identifies a population of cells (44% of total nucleated cells) with the following immunophenotype:

CD19+, CD5 negative, CD200 negative, CD10 weak, FMC7+, CD23 negative, CD38+, CD11c negative, CD103 negative, CD20+, sIg+ (lambda-restricted), CD34 negative, nTdT negative

 

What is the most likely diagnosis and how would you confirm it?

Given the most likely diagnosis, what further investigations are required prior to starting treatment?

 

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Case 131 – update 1

The patient reports a 2 week history of exertional dyspnoea, fevers and weight loss. Examination does not demonstrate any lymphadenopathy or hepatosplenomegaly. Other than a few bruises on his arms and pallor due to anaemia, there are no other remarkable findings. Observations are normal except for a low grade temperature of 37.7 – there are no focal signs of infection.

The patient is known to be HIV positive and has been on HAART for several years now – his last HIV viral load from a month ago was undetectable and his CD4 count was normal (510). He has no other significant past medical history and no transfusion history.

His U/Es, LFTs and coagulation are within the normal range, but his reticulocyte count is low. Haematinics, TFTs and LDH are pending. He does not drink alcohol. His only regular medications are his HAART (emtricitabine, tenofovir and efavirenz).

The biomedical scientists have already prepared an urgent blood film (see below) and the sample has been sent for flow cytometry with results expected later this evening.

IMG_1376

How would you report this blood film?

Given the clinical history and blood film findings, what is your differential diagnosis?

 

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Case 131 – the beginning

It is 9 am and you’re the liaison haematology registrar. Having just finished your coffee, the A+E registrar calls you for some advice about a 42-year-old male with an abnormal full blood count (see below) who presented with shortness of breath. He was also noted to have small bruises on his arms.

Full blood count
Hb 54               (130-180)
MCV 92            (80-100)
Platelets 12     (150-450)
WCC 3.2           (4.0-11.0)
Lymph 0.5      (0.5-3.5)
Neut 1.2          (2.0-8.0)
Eosin 0.0         (0.1-0.5)
Baso 0.0          (0.0-0.1)
Mono 0.1        (0.2-1.2)

What other information would be helpful?

What investigations would you recommend/request?

What immediate advice would you give the A+E registrar regarding the management of this patient?

 

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.

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Case 130 – the summary

In this week’s case we investigated someone with a panreactive antibody screen. In simple terms, this means that something in the patient’s plasma is reacting with all of the red cell reagents we use in our panel.

This situation causes concern in the transfusion lab because, whatever the cause, the patient could have an underlying alloantibody which we cannot see, which could then cause a transfusion reaction if we transfuse blood to the patient with the corresponding antigen.

However, as always, no patient should come to harm due to a lack of blood. Further laboratory tests will take time, and it is better to deal with a haemolytic transfusion reaction in a living patient rather than having the perfect blood for a corpse!! If you need blood – the lab will supply the ‘least incompatible’ blood they have with the available results.

In our case, there was not an emergency need for blood, and so we can investigate further. Below are some general points to consider.

  • Clinical context is hugely important (when is it not?!) – key things to cover are:
    • Is there clinical or laboratory evidence of haemolysis to support an autoimmune haemolytic anaemia (anaemia, high unconjugated bilirubin, reticulocytosis, low haptoglobins, blood film showing spherocytes, polychromasia)
    • Is the patient on any relevant drugs, or have they had some treatment recently (IVIg, monoclonal antibodies including daratumumab)
    • If the patient is female, what is their obstetric history?
    • Has the patient had a previous blood transfusion? How recently?

 

  • Tests the transfusion lab will consider:
  1. DAT (direct antiglobulin test)

This detects whether there are antibody or complement coated RBCs in vivo ie in the patient’s circulation. This could be an autoantibody, an alloantibody to previously transfused RBCs or a drug effect. Remember – in the context of a panreactive antibody screen, a positive DAT does not exclude a clinically important alloantibody, it suggests there is ‘something’ else there to get rid of before we can be confident in our alloantibody screen

  1. Autoabsorptions

Using a reagent (called ZZAP – dithiothreitol and papain), we can remove autoantibody from the patient’s own red blood cells. You can then perform the antibody screen on the ‘clean’ sample to seek underlying alloantibodies. Note – if the patient has been transfused in the past 3 months, alloabsorption techniques are required, using selected reagent RBCs to remove alloantibodies

  1. Red cell eluate

If there is a history of recent transfusion or absorption studies are inconclusive, elution can be performed. An acid is used to remove antibody which is coating the surface of the patient’s red cells. The eluate refers to the plasma which is left behind (and so will contain any antibody to then be tested against reagent red cells)

 

Daratumumab

Daratumumab is an anti-CD38 licensed for treatment in multiple myeloma.  Daratumumab causes significant issues in transfusion testing, because CD38 is expressed on red blood cells. This means that the patient plasma sample used for the indirect antiglobulin test (antibody screen) will contain daratumumab, and so will coat all of the reagent RBCs, causing a universal positive result ie. panreactive antibody screen (see image below). This can persist up to 6 months from completion of daratumumab therapy.

DaraIAT

To get around this problem, reagent RBCs can be treated with DTT (dithiothreitol) to remove the daratumumab and allow antibody screening to proceed. DTT also removes the K antigen (from the Kell system) from the RBCs, and so you cannot establish the patients K status (unless they have had a sample processed pre-daratumumab). Therefore, if their K status is not known, give K-ve blood.

NHSBT have guidance on testing required for patients before they start daratumumab therapy to get around this issue:

  • ABO and D group and antibody screen
  • Direct antiglobulin test (DAT)
  • Extended phenotype (Rh CcDEe, MNSs, Kk, Jka and Jkb, Fya and Fyb)
  • If transfusion is required, give ABO, extended Rh and K compatible units (to limit the risk of alloantibody formation which may subsequently be difficult to elicit)

As always, communication is key – between the clinical team, transfusion lab and patient (they should have a card stating they are on daratumumab)

 

References/further reading:

NHSBT clinical guidelines: Managing patients on monoclonal antibody therapies:

https://hospital.blood.co.uk/clinical-guidelines/nhsbt-clinical-guidelines/

NHSBT clinical guidelines: Investigation and clinical management of patients with a positive DAT with and without haemolysis:

https://hospital.blood.co.uk/clinical-guidelines/nhsbt-clinical-guidelines/

Blooducation podcast: Investigation of the patient with a panreactive antibody screen:

https://blooducation.co.uk/portfolio/panreactive-antibody-screen

Blood Bank Guy podcast: Daratumumab Effect:

https://www.bbguy.org/2016/05/31/010/

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Case 130 – update 2

We have delved deeper into our 54 year old patient’s history and, as many of you guessed, he takes daratumumab for multiple myeloma. We have discussed with his clinical team and agreed to hold off transfusion until we can perform more serological tests.

As you have suggested, we sent his sample to NHSBT and they have treated the reagent RBCs with dithiothreitol (DTT) and repeated an antibody screen:

B30114D5-8970-4577-A98D-4AA6E3659194

We have no previous G&S sample for this patient. From our forward/reverse group we known he is group AB Rh D-ve. He has a likely NSTEMI with an Hb of 78 and so the clinical team wish to transfuse.

What does the enzyme panel show? How does this work with daratumumab?

Are there any further tests required pre-transfusion?

What red blood specifications would you use to transfuse?

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Case 130 – Update 1

Thanks for all the input thus far. We are dealing with a panreactive antibody screen (see below) in a patient not previously known to our hospital trust. The sample has been sent to NHSBT red cell immunohaematology (RCI). We are confident in the patient’s ABO and Rh D group (AB D-ve)

Abpanel

We call the patient’s GP (who sent the G&S request) for more information:

  • Mr X is 54 years old
  • He has recently moved back to the UK after spending 10 years working in the USA, and registered at the practice this week
  • He has a PMH of hypertension, ischaemic heart disease (MI in 2010), type 2 diabetes and multiple myeloma. All of these conditions were managed in the USA and the GP doesn’t have further information at present
  • He attended due to SOB and some anginal chest pains. The GP noticed his anaemia (Hb 78) and has requested he attends the nearest A&E for urgent RBC transfusion in view of his angina
  • He is now at your hospital’s A&E and the team state he is slightly tachycardic (HR 119) but BP is OK (114/78). There is no active bleeding. His ECG demonstrates some T-wave inversion, troponins are awaited. The A&E consultant is treating as an acute coronary syndrome (ACS) and is keen to transfuse ASAP
  • The A&E team relay that the patient states he has had several transfusions over the last few years with no issues as far as he is aware
  • It is now 10pm on a Tuesday evening…..

What further information do you require from the patient?

What tests would the NHSBT RCI lab perform?

Are you willing to authorise RBC transfusion for this patient? If so what specifications would you request?

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 130 – the beginning

It is 5pm. You are the haematology SpR and you have just congratulated yourself on clearing the blood films and aspirates to report – good job! But just as you are taking off your lab coat, a transfusion BMS pops round to discuss an issue they have.

A sample has been sent for Group and Screen (G&S) on a patient not previously known to the trust. The clinical details state: ‘Patient recently moved to area. For 2 units RBC ASAP.’ The lab have performed ABO and D typing as well as an antibody screen and subsequent panel. The results of these are shown below:

ABO group:

ABO

Antibody screen:

Abscreen

Antibody panel:

Abpanel

The BMS has sent a sample to the Red Cell Immunohaematology (RCI) lab at NHSBT to investigate further, but wants your advice on how to proceed clinically….

A few things to think about:

  1. What ABO group is the patient?
  2. What does the antibody screen and panel demonstrate?
  3. What further clinical information do you require?
  4. Would you request any additional tests?

 

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 129 – Summary

This weeks case was based around Cerebral venous sinus thrombosis (CVST). Thanks for everyone’s help really lovely that so many of you contributed your thoughts.

Incidence:

This is a rare disorder affecting 2-4/million of the adult population a year but is becoming increasingly common with more widespread availability of MRI scanning.

It is more common in females (accounting for up to 75% of cases), particularly in pre-menopausal women.

Risk factors for CVST :

  • Hormonal contraceptives/Pregnancy
  • Inherited Thrombophillias
  • Acquired Prothrombotic states: Malignancy, Nephrotic syndrome, Myeloproliferative disorders, TTP, PNH etc
  • Head Injury
  • ENT and CNS infections
  • PEG Aspariginase in ALL therapy

Presentation:

This case illustrates that not all cases of CVST will present in the same way. The majority of patients will have headaches, however they are not always localised and of gradual onset and there are case reports of CVST mimicking Subarachnoid haemorrhage as in our case. Other important presentations not to miss include encephalopathy, generalised seizures and even new cranial nerve palsies.  Therefore it is important that a clinician remains alert to this in a differential diagnosis particularly in pre-menopausal women who are the highest risk group.

Pathophysiology:

The pathophysiology of CVST helps explain the varied clinical presentations that are seen:

  1. The thrombosis can occur at any site within the dural vein network.
  2. Initially in CVST collateral venous pathways and capillary dilation mitigates the effects, however these systems can be rapidly overwhelmed.
  3. The thrombosis obstructs the blood drainage from brain parenchyma. This increase in pressure leads to high venous and capillary back pressure causing oedema as plasma leaks into the interstitial space. The extra pressure then causes capillaries to rupture leading to local haemorrhage formation.
  4. Increased pressure in the venous system results in increased intravascular pressure causing a reduction in cerebral profusion which can cause ischaemic infarction.
  5. There is also a loss of CSF reabsorption that leads to elevated intracranial pressure and the symptoms and signs associated with this such as vomiting, visual loss, papilloedema and cranial nerve palsies.

Understanding these mechanisms can help to understand why anticoagulation is recommended even in the presence of cerebral haemorrhage.

Initial Management:

Initial management is with either unfractionated or more commonly LMWH. Evidence for recommendations are weak and based on the findings of a 2011 Cochrane review that looked at 79 patients in two RCT and it concluded

Based upon the limited evidence available, anticoagulant treatment for cerebral venous sinus thrombosis appeared to be safe and was associated with a potentially important reduction in the risk of death or dependency which did not reach statistical significance”.

The European Stroke organisation guidelines recommend treatment with heparin in acute setting even with those who have intracerebral haemorrhage at baseline. BSH guidelines are in agreement with the european guidelines and also suggest duration of initial LMWH should be for at least 7 days

Thrombolysis is generally not recommended unless clinical deterioration despite anticoagulation and it is clear this is deterioration isn’t related to new intra-cranial bleed. Surgical decompression is also an option in raised ICP with risk of herniation.

Our patient had an elevated BMI and therefore it is important to follow local trust protocol or summary of product characteristics of the LMWH for safe prescribing. Generally the advice is use a weight based therapeutic dose but split dose (to reduce bleeding risk). Anti-Xa monitoring should occur to ensure therapeutic levels are reached. Initial monitoring should be 3-4 hours after third dose.  In renal impairment unfractionated heparin would be a suitable alternative.

Long term anticoagulation:

Oral anticoagulation is to be avoided until patient is stable. There is no recommendation to re-evaluate with imaging but if concerns this could be considered especially if ongoing symptoms. In some centres this is done routinely prior to moving to long term anticoagulation. As with all Haemostasis and thrombosis situations the plan needs to be based on the specifics of the case and there is a lack of trial data to support decision making.

Recommendations for duration of longer term anticoagulation are based on the individual precipitating features for the CVST.

If there was a clear transient provoking factor then European stroke guidelines suggest 3-12 months of anticoagulation is sufficient. BSH guidance also suggests at least 3 months anticoagulation should be used. This guidance is based on two important observations:

  1. Recurrence of CVST is generally low between 1.5% to 4.4% based on retrospective studies.
  2. There is also evidence to show the majority of patients even those without anticoagulation do recanalise following thrombosis by 4 months.

 

Practically speaking patients with clear provoking factors generally have 3-6 months anticoagulation and unprovoked events may be anticoagulated up to 12 months or even longer term depending on perceived risks and benefits. Patients with recurrent CVST should be considered for long term anticoagulation.

Thrombophillia screens are generally not recommended in the guidelines and are unlikely to alter management unless strong family history of thrombosis. A young female patient with unprovoked event who may be contemplating pregnancy should have anticardiolipin antibodies checked as a minimum in line with RCOG Green top 37a guidance. It should also be pointed out that thrombophillia screening should not occur during acute phase of thrombosis or be performed on anticoagulation. Patients who have been deemed appropriate for long term anticoagulation should not have thrombophillia screening as unlikely to alter management in these cases.

At present warfarin is recommended as the anticoagulant of choice for longer term anticoagulation. However, in context of active malignancy LMWH may be a more appropriate choice at preventing recurrent VTE. In pregnancy again LMWH should be continued.

In our patients case Direct oral anticoagulants are not suitable given the patients elevated BMI. There are however new studies that have been preformed looking at the possible safety of Dabigatran and other DOACs in CVST. Most of the evidence prior to 2019 had been based on single centre observational studies with less than 20 patients which concluded that Rivaroxaban and Dabigatran appeared safe.

The RE-SPECT CVT study which was a prospective randomised open-label trial with a blinded end-point adjudication reported in JAMA neurology in 2019. It recruited 120 patients in 9 countries across 51 sites. It found that Dabigatran and Warfarin were associated with low risk of recurrent VTEs (No VTE in both arms over 6 months follow up)  and that risk of bleeding was similar (1 Intestinal bleed on Dabigatran and 2 ICH in warfarin group) . The authors therefore conclude that “Dabigatran may be safe and effective in preventing recurrent VTEs”.  This trial was published after the European stroke guidelines were released as yet in Europe this approach has yet to be adopted into practice. It should be highlighted that DOACs are not recommended if thrombosis in context of antiphospholipid syndrome.

In summary CVST is an interesting condition with varied presentation and clinical course. Generally it has low recurrence rates and can be managed with short term anticoagulation. The mainstay of therapy is anticoagulation and haemorrhage associated with CVST is not a contraindication to therapy. In the future there may be a role for use of DOACs in the management of CVST but this remains the subject of clinical trials and is yet to be adopted by the guidance in UK and Europe.

The end of our case 129….

With all this evidence in mind our patient was reviewed in clinic. Her history revealed she had several possible risk factors for the CVST she has an elevated BMI and was on the COCP at the time of the event. She also had a finding of an isolated lupus anticoagulant at presentation without anticardiolipin or beta 2 glycoprotein 1 antibodies. Her antibodies were repeated while on anticoagulation and were negative at 12 week time point. She had no family history of VTE or personal history of thrombosis. She reported no issues on warfarin therapy and had been established on therapy for 8 months. She reported no neurological sequale or headaches.

She was clear she wished to become pregnant and that she wanted to stop her warfarin therapy. She was now 8 months from initial diagnosis and not on COCP so this was agreed. After discontinuing warfarin therapy her APTT was normal and her DRVVT was within normal range. The positive DRVVT at diagnosis of CVST was transient and not present on repeat sampling therefore she did not fulfil the criteria for Antiphospholipid syndrome (which would require two or more positive lupus anticoagulant tests more than 12 weeks apart in presence of VTE).

She was counselled about dietary advice as it was explained that high BMI was a modifiable risk factor for VTE. She was informed of the need to avoid hormone based contraceptives in future given the CVST. She was encouraged to address her lifestyle first before trying to conceive as this would improve her chances of a successful pregnancy outcome. It was explained to her that given her history of VTE while on hormonal contraception and her elevated BMI she would require thromboprophylaxis throughout her pregnancy and 6 weeks postpartum in line with RCOG Green top guidelines 37a.

Thanks for your help with the case and please feel free to post any comments.

References:

UpToDate cerebral venous sinus thrombosis section.

Coutinho  J, de Bruijn  SFTM, deVeber  G, Stam  J. Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database of Systematic Reviews 2011, Issue 8. Art. No.: CD002005.

Ferro et al. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis – endorsed by the European Academy of Neurology. European Journal of neurology 2017; 24 (10) 1203-1213.

https://onlinelibrary.wiley.com/doi/full/10.1111/ene.13381

Miyakis S et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal of thrombosis and haemostasis.2006;4 (2) pp295-206.

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2006.01753.x

RCOG Green Top Guideline 37a. reducing the risk of VTE during pregnancy and puerperum. April 2015.

https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37a.pdf

Tait C et al. Guidelines on the investigation and management of venous thrombosis at unusual sites.BJHaem 2012;159 (1) 28-38.

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2012.09249.x

Ferro et al. Safety and Efficacy of Dabigatran Etexilate vs Dose-Adjusted Warfarin in Patients With Cerebral Venous Thrombosis A Randomized Clinical Trial. JAMA Neurol 2019;76(12) 1457-1465.

https://jamanetwork.com/journals/neur/articlepdf/2749167/jamaneurology_ferro_2019_oi_190070.pdf

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