Canterbury DHB

Relapsed or Refractory Patients

No precise guidelines can be given here. The decision for or against further treatment and its intensity will depend on several factors including:

• age
• performance status
• previous treatment given
• the duration of response to such treatment, and
• the time from the last therapy.

The patient's wishes must be taken into consideration. The choice of treatment will depend upon the aims of any therapy being considered, whether palliative or intensive.

For an individual perspective on this topic, see:

• Montserrat, E. et al. (2006). "How I treat refractory CLL." Blood 107(4): 1276-1283.
• Tsimberidou, A. M. and M. J. Keating (2009). "Treatment of fludarabine-refractory chronic lymphocytic leukemia." Cancer 115(13): 2824-36.
• Andritsos, L. A. and M. R. Grever (2011). "Salvage therapy for relapsed chronic lymphocytic leukemia." Expert Rev Hematol 4(2): 199-212.

Venetoclax

Venetoclax is designed to block the function of the Bcl-2 protein. In phase I/II trials, the response rate in heavily pre-treated patients was around 80%, even in patients with del(17p).

Determine tumour lysis risk before starting treatment and before each dose increase.

Due to the high rate of tumour lysis, it is essential to have a dose ramp-up period with strict measures to detect and treat tumour lysis syndrome.

Blood tests are required before each dose increase, and at 6 to 8 hours and 24 hours after each dose increase with results turned around and checked within 1 hour.

In NZ, it has been funded by special authority since 2020 for relapsed/refractory CLL.

References

• Gribben, J.G. (2020). "Practical management of tumour lysis syndrome in venetoclax-treated patients with chronic lymphocytic leukaemia." British Journal of Haematology 188(6): 844-851.
• Stilgenbauer, S. et al. (2018). "Venetoclax for Patients with Chronic Lymphocytic Leukemia With 17p Deletion: Results from the Full Population of a Phase II Pivotal Trial." Journal of Clinical Oncology (36)19: 1973-1980.

High dose methylprednisolone

Methylprednisolone (1 g/m²/day IV for 5 days), either alone or in combination with rituximab is an effective salvage regimen in patients who are refractory to fludarabine, have p53 abnormalities and/or have adverse cytogenetics. Infectious complications have been reported frequently including pneumonia, gram-negative septicaemia, pneumocystis and herpes viruses.

For further information on regimen and outcomes see:

• Thornton, P., E. Matutes, et al. (2003). "High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities." Annals of Hematology 82(12): 759-765.
• Dungarwalla, M., S. O. Evans, et al. (2008). "High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy." Haematologica 93(3): 475-6.

Ibrutinib

• Although chemo-immunotherapy (CI) is effective for 95% of newly diagnosed patients, the outlook is dismal for patients with refractory disease or those who relapse within 2 years of CI. These patients will often harbour the 17p deletion.
• Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase, which causes irreversible inhibition of B-cell receptor signalling which normally promotes cell survival and proliferation. The first randomised trial of ibrutinib compared it with ofatumumab, an anti-CD20 monoclonal antibody in relapsed/refractory patients.
• Common side effects were diarrhoea (48%), fatigue (28%), and nausea (26%) and were mostly mild. Petechiae and ecchymoses were more common with ibrutinib (44% v 12%) but major haemorrhage was rare. The overall response rate is around 60%. Progression-free survival at 6 months was 88% v 65%. The overall survival after 12 months was 90% v 81%, a difference likely to be underestimated due to the large numbers of patients who crossed over treatment arms.
• The incidence of atrial fibrillation is increased in patient on ibrutinib. The rate of atrial fibrillation in patients treated with ibrutinib was around 10% in clinical trials, compared to a base rate of 1-2% in the age-matched population and 3-4% in CLL patients. New-onset atrial fibrillation should be discussed with a cardiologist. If anticoagulation is required, ibrutinib should be discontinued due to the increased risk of bleeding. See Stephens, D. M. and J. C. Byrd (2019). "How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia." Blood 133(12): 1298-1307.

Topic Code: 5515