Many thanks for all your thoughts and suggestions this week.

The case this week was an 81 year old lady who presented with AIHA. She had an incidental finding of mild lymphocytosis, small Ig M Paraprotein and splenomegaly and was diagnosed with Splenic Marginal Zone lymphoma (SMZL). 

She was successfully managed for haemolysis with 60mg prednisolone for 3 weeks and slow steroid weaning. She subsequently developed thrombocytopenia, anaemia and enlarging splenomegaly needing therapy. She received weekly Rituximab for 4 weeks and Rituximab maintenance to good effect and remains in remission.

The case this week was designed to consider the practical issues in managing AIHA in an older patient and to consider the challenges faced in diagnosis and management of SMZL.

Autoimmune Haemolytic Anaemia:

BSH guidelines are helpful in assisting with an approach to diagnosis of this condition

1. Is there Haemolysis?

Raised Reticulocytes, Unconjugated bilirubin and LDH

Low Haptoglobins (Consumed as binding free Hb)

Spherocytes or Polychromasia on blood film. It should be remembered that this pattern is not always seen for example in our case the patient had normal reticulocytes due to marrow infiltration.

2. Is it immune? 

DAT Ig G and C3d – can be non specifically positive in autoimmune conditions so needs careful interpretation. It can be positive in 7-8% of hospital inpatients.

3. Special situations?

Tx within three months?

 HSCT patient?

?HDN in newborns

?Drug induced?

Initial management of AIHA:

General measures:

Folic acid 5mg daily

Oral calcium and vitamin D for all patients

If >50years treat with Bisphosphonate if steroid dose >7.5mg for more than 3 months.

VTE Prophylaxis:

Should be given for all inpatients with haemolysis. If ambulatory it is reasonable to consider thromboprophylaxis if Hb <85g/l. BSH guidelines state rate of thrombosis for these patients is 20% without prophylaxis.

Transfusion:

ABO, Rh and Kell matched blood if problems with serological cross match (30% patients with AIHA will have allo Ab usually to Rh or Kell Ag)

Steroids:

80% patients respond to Prednisolone doses of 60-100mg/day and two thirds of patients will achieve a complete remission. It is important to remember that response can take several weeks. Steroid refractory disease can only be declared after 21 days. 

BSH guidelines suggest high dose therapy for 3 weeks then reduce to 20-30mg over 4-6 weeks then 5mg monthly after this. Important to remember the gastric side effects of steroids and consider PPI. 

IVIG :

Consider if life threatening anaemia 40% respond to 0.5mg/kg/day for 5 days.

Plasma Exchange: 

Reserved for life threatening anaemia.

For older patients 1mg/kg may lead to toxicity, this was the concern for our patient and hence steroid dose was capped at 60mg. Dose adjustment for elderly patients needs to be made on individual basis.

Marginal Zone lymphomas:

The Marginal Zone B cell lymphomas represent 5-15% of all non-Hodgkin lymphomas. 

They comprise of three very different subgroups:

Extranodal MZL of mucosal associated lymphoid tissue (previously described as MALT lymphomas) (66% of MZL) .

Splenic MZL with or without villous lymphocytes (20% of MZL).

Nodal Marginal Zone lymphoma with or without monocytes B cells (10% of MZL)

Splenic Marginal Zone lymphomas:

This is characterised by splenic involvement and usually the diagnosis can be obtained on peripheral blood/bone marrow morphology and flow cytometry without a splenectomy. 

Initial work up for suspected SMZL:

FBC, Blood film, Retics, U&E, LFTs, LDH, Ig screen, HIV and Hepatitis screen and DAT indicated (20% of SMZL will have an associated immune problem related to it as in our case).

Staging CT scan 

A bone marrow biopsy is indicated for a suspected case of SMZL.

Flow cytometry and SMZL:

Classical SMZL : CD 19+ CD 5 Neg CD 10 Neg CD 103 neg CD79b + sIg ++

It is important to appreciate that aberrant expression on flow can be seen in both SMZL and other B cell lymphomas:

This table has been adapted from Huan-You et al (see references below):

Pattern of ImmunophenotypeLymphoma subtype% of cases with phenotype
CD 5+ CD 10 NegMCL93-95%
 CLL80-92%
 SMZL20%
 LPL9-43%
   
CD5 Neg CD10 NegSMZL80%
 LPL50-90%
 CLL8-20%

In our case we had weakly positive CD 5 expression. This can be seen in up to 20% of SMZL cases. It would be important to consider MCL and CLL and we did check CCND1 to exclude MCL in the patients case.

We were also left with the possibility the patient in our case had Lymphoplasmacytic lymphoma rather than SMZL. 

This again can be tricky to determine but there are a few helpful features that may assist in correct diagnosis:

LPL:

Higher Ig M PP levels more commonly >3g/l are seen. 

Trephine infiltration pattern is usually paratrabecular in pattern and there may also be increase in eosinophils. 

MYD88 mutation is positive in 80-90% of LPL patients but up to 20% of MZL patients can have MYD 88 positivity so it isn’t diagnostic alone. Our patient was MYD 88 negative.

SMZL:

Often expresses Ig D and this may be a helpful pointer to the diagnosis.

Trephine biopsy can show intrasinusoidal trephine infiltrate

Staging of SMZL:

ESMO guidance suggests the use of a prognostic score but stress this shouldn’t be used to influence decisions to treat.

There are two commonly used scores:

The ILL score based on 300 SMZL patients useful in clinical practice as simple to perform. Parameters are Hb <12g/l, albumen <35g/l and elevated LDH. 

The HPLL score this was developed by the SMZL study group and validated on 600 patients. It uses Hb concentration, Platelet count, LDH and extrahiliar lymphadenopathy to identify three discrete risk groups 

Five‐year survival for Groups A, B and C was 94%, 78% and 69%

SMZL treatment:

Asymptomatic patients should embark on 3-6 monthly watch and wait.

Indications for therapy as per ESMO guidance:

Hb <10g/l

Plt <80

Neu <1

AIHA or ITP with SMZL is not a reason for treatment of lymphoma if responsive to steroids.

Splenectomy:

Traditionally provided PFS 50-60% over 5 years and OS 70-80%. Morbidity and Mortality associated with this procedure.

Rituximab:

375mg/m2 weekly for 4-8 weeks can provide ORR >80% with CR >40%. Long lasting with 10 year PFS >60%. Likely Rituximab Maintenance 2 monthly for 2 years can improve PFS further although no evidence to show it improves OS.  It can be very useful for frailer patients and for those who have autoimmune complications associated with SMZL as may allow steroid independence.

Chemoimmunotherapy:

This can be considered but generally is held in reserve due to excellent results with Rituximab monotherapy. May be indicated if young and troublesome constitutional issues or if disseminated disease or concern of High grade transformation.

Our patient is elderly and also has been troubled by previous haemolysis and therefore Rituximab monotherapy was felt to be the most appropriate therapy after discussion at MDT.

Thank you for all your contributions and I hope this case has been interesting, feel free to add any comments

References:

Zantek et al. The direct antiglobulin test: A critical step in the evaluation of hemolysis.Am. J. Hematol. (2012) 87:707–709.

Hill et al. The diagnosis and management of primary autoimmune haemolytic anaemia. BJ Haem (2017);176:(3) 395–411.

Available at: https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.14478


Zucca E et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines. Ann Oncol (2020); 31(1): 17-29. 
Available at: https://www.annalsofoncology.org/article/S0923-7534(19)35465-1/pdf

Wang HY et al. Diagnostic algorithm of common mature B cell lymphomas by immunohistochemistry. Arch Pathology Lab Med. (2017) 207(141)1236-1246.

Montalban et al.Stratification Approach for Splenic Marginal Zone Lymphoma Based on Hemoglobin, Platelet Count,High LDH and Extrahilar Lymphadenopathy: The HPLL/ABC System. Blood (2011) 118 (21) 1583.

Montalban et al. Risk stratification for Splenic Marginal Zone Lymphoma based on Haemoglobin concentration, platelet count, high lactate dehydrogenase level and extrahilar lymphadenopathy development and validation on 593 cases. BJ Haem (2012) 159:(2): 164-171.

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