Bendamustine (Levact): increased risk of non-melanoma skin cancer and progressive multifocal encephalopathy (PML)

Periodically perform skin examinations in patients on bendamustine-containing regimens and consider PML in the differential diagnosis for patients on bendamustine with new or worsening neurological, cognitive, or behavioural signs or symptoms.

From:
Medicines and Healthcare products Regulatory Agency
Published
24 March 2021
Therapeutic area:
Cancer

Advice for healthcare professionals:

  • in clinical studies, an increased risk from background for non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) has been observed in patients treated with bendamustine-containing therapies
  • periodically perform skin examinations in patients on bendamustine-containing regimens, particularly in patients with risk factors for skin cancer – these include people with lighter natural skin colour; skin that burns, freckles or reddens easily; a large number of moles; and a personal or family history of skin cancer
  • very rare cases of PML have also been reported in patients being treated with bendamustine usually in combination with rituximab or obinutuzumab
  • consider PML in the differential diagnosis for patients on bendamustine with new or worsening neurological, cognitive, or behavioural signs or symptoms
  • if PML is suspected, undertake appropriate diagnostic evaluations and suspend treatment until PML is excluded
  • report suspected adverse drug reactions associated with bendamustine on a Yellow Card

Review of non-melanoma skin cancer and PML

Bendamustine is an anti-cancer medicine authorised for certain patients with chronic lymphocytic leukaemia, non-Hodgkin’s lymphomas, or multiple myeloma (see full indication in Background).

Patients treated with bendamustine have an existing increased risk for non-melanoma skin cancer due to their underlying disease and age. However, two published trials (BRIGHT[footnote 1] and GALLIUM[footnote 2]) show a higher number of cases of non-melanoma skin cancer with bendamustine-containing regimens than with other treatments used for lymphoma.

A European review of safety data has recommended these risks be added to the Summary of Product Characteristics alongside advice to periodically monitor patients for skin changes. Advice will also be added to the Patient Information Leaflet to state that patients should contact their doctor if they notice worrying skin changes. Advice on the NHS website about changes to moles may be helpful for this discussion.

In addition, very rare cases of progressive multifocal encephalopathy (PML) have been reported in patients on bendamustine-containing regimens. Although concomitant treatment was present in all cases where information was provided, a temporal relationship with bendamustine was evident in most cases and an increased risk of PML is thought plausible. These risks have been added to the product information and patients should be directed to the patient information leaflet to be aware of signs and symptoms of PML.

If PML is suspected, treatment with bendamustine should be suspended until PML is ruled out. Evaluation of PML includes, but is not limited to, brain magnetic resonance imaging (MRI), and lumbar puncture (cerebrospinal fluid testing for John Cunningham viral DNA).

Non-melanoma skin cancer: evidence from clinical trials

The BRIGHT trial is a completed, phase 3, open-label, randomised, parallel-group study of first-line treatments for patients with advanced indolent non-Hodgkin’s lymphoma or mantle cell lymphoma[footnote 1]. The trial compared outcomes in patients assigned to bendamustine plus rituximab versus alternative chemotherapy regimens (R-CHOP/R-CVP[footnote 3]).

In this trial, 14 of 221 (6.3%) patients treated with bendamustine plus rituximab and 5 of 215 (2.3%) patients treated with R-CHOP/R-CVP were reported to develop squamous cell carcinoma or basal cell carcinoma.

The GALLIUM trial was an open-label, randomised parallel-group study of previously untreated follicular lymphoma (grade 1 to 3a; stage III or IV disease)[footnote 2]. The trial compared outcomes in patients randomised to receive either obinutuzumab or rituximab plus a chemotherapy backbone with bendamustine or alternative chemotherapy regimens (R-CHOP/R-CVP).

This study took into account all malignancies occurring more than 6 months after first study drug intake. Basal cell carcinoma was reported in 16 of 676 patients (2.4%) receiving bendamustine versus 1 of 513 patients receiving CHOP/CVP. There were also increases in the number of reports of squamous cell carcinoma in patients receiving bendamustine, while no cases were reported in patients receiving CHOP/CVP.

Cases of PML

The European review of safety data also identified an increase in reporting of cases of PML when bendamustine-containing therapy is used. During the period reviewed (7 January 2018 to 6 January 2020), 42 cases of PML worldwide were reported, 11 of which were fatal. This compared to 9 cases in the previous period (7 January 2017 to 6 January 2018).

Concomitant treatment was present in all cases, with most receiving rituximab or obinutuzumab alongside bendamustine. However, a temporal relationship with bendamustine was evident in most cases. In 31 of the cases, bendamustine-containing therapy was the latest treatment before onset.

A contributory role of bendamustine to the development of PML is thought possible. It is known that bendamustine can cause prolonged lymphopenia and CD4-positive T-cell depletion. This effect is more pronounced when bendamustine is combined with rituximab.

Background

Bendamustine is indicated for:

  • first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate
  • indolent non-Hodgkin’s lymphomas as monotherapy in patients who have progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen
  • first-line treatment of multiple myeloma (Durie-Salmon stage II with progress or stage III) in combination with prednisone for patients older than 65 years who are not eligible for autologous stem cell transplantation and who have clinical neuropathy at time of diagnosis precluding the use of thalidomide- or bortezomib-containing treatment

Report suspected reactions on a Yellow Card

Please continue to report suspected adverse drug reactions to the Yellow Card scheme.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 14, issue 8: March 2021: 1.

  1. Flinn IW and others. First-Line Treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. Journal of Clinical Oncology 2019; volume 37: pages 984–91. ↩ ↩2

  2. Hiddemann W and others. Immunochemotherapy With Obinutuzumab Or Rituximab For Previously Untreated Follicular Lymphoma In The GALLIUM Study: Influence Of Chemotherapy On Efficacy And Safety. Journal of Clinical Oncology 2018; volume 36: pages 2395–404. ↩ ↩2

  3. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). ↩

Published 24 March 2021
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