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 factors	Disease-related factors
Poor risk	Lower risk
Age Gender Co-morbidities	B2 microglobulin >3.5 CD 38+ TP53 disruption IGHV UNmutated -11q ZAP-70	Trisomy 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 >38^oC for ³2 weeks with no infective component
  • Night sweats ³1 month with no infective component
  • Marked fatigue

Baseline investigations prior to treatment:

Blood tests	Imaging	Histology
FBC Reticulocyte count DAT U+Es, LFTs Immunoglobulins HIV, hepatitis B/C, CMV Immunophentype Cytogenetics / molecular markers	CXR   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 patients	Fludarabine, 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 patients	Chlorambucil and Obinutuzumab (CLL 11 trial)
Frail patients	Chlorambucil 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.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning. alang10