What are your top two differentials?
Chronic lymphocytic leukaemia / small lymphocytic lymphoma and mantle cell lymphoma, based on CD5+ / 10- / 23+.
Which stain would you request to differentiate between them?
Cyclin D1, which is usually positive in mantle cell lymphoma.
Note that SOX11 is useful in identifying mantle cell lymphomas which are negative for cyclin D1. LEF1 is both sensitive and specific for CLL/SLL.
What are the components of the Marsden score?
CD5 (positive = 1 point, negative = 0 points)
CD23 (positive =1 point, negative = 0 points)
CD22/CD79b (weak = 1 point, bright = 0 points)
FMC7 (negative =1 point, positive = 0 points)
SmIg (weak = 1 point, bright = 0 points)
A score of 4 or more is indicative of CLL.
Original reference: Moreau et al., 1997.
What is the diagnosis?
What are the indications for treatment of this condition?
- Bone marrow failure not due to immune phenomena
- Massive or symptomatic organomegaly / lymphadenopathy
- Refractory autoimmune complications
- Symptomatic extranodal involvment
- B or constitutional symptoms
- Consider if lymphocyte doubling time is less than 6 months, or increase by >50% over 2 months
Source: updated 2018 CLL Guideline
Before starting treatment, what is the most important investigation to perform?
FISH for 17p deletion.
17p deletion is a poor prognostic marker which predicts poor responsiveness to chemo-immunotherapy. In a randomised phase 3 trial of up-front fludarabine, cyclophosphamide and rituximab vs fludarabine and cyclophosphamide, the CR rate for 17p deleted patients with FCR was only 5%, with an overall response rate of 68%. Of the 17p deleted patients, the progression-free survival at 3 years was only 18% (Hallek et al., 2010).
Ibrutinib has been shown to have activity in patients with 17p deletion. The RESONATE trial compared ibrutinib to ofatumumab 391 patients with relapsed or refractory CLL/SLL, a third of whom had 17p deletions. In the 17p deleted group, the median duration of progression-free survival was not reached in the ibrutinib group, compared with 5.8 months in the ofatumumab group. Ibrutinib was also associated with a significant 57% reduction in the risk of death compared to ofatumumab (Byrd et al., 2014).
There are two ongoing phase 3 trials of ibrutinib + rituximab vs FCR in fit patients (the FLAIR and ECOG1912 trials). The results of these trials should shed more light on the role of ibrutinib in the up-front setting (the RESONATE-2 trial compared ibrutinib with chlorambucil, which is no longer than standard of care for fit patients).
Good to read: Optimizing Frontline Therapy of CLL (ASH Education Book, 2017)