Friday, 20 November 2015

ClinicSpeak: secondary cancers on cladribine and fludarabine

What are the risks of developing cancer if I am treated with cladribine? #ClinicSpeak #MSBlog #MSResearch

"In response to my post on off-label fludarabine there were a lot of questions about the risk of so called secondary malignancies on both fludarabine and cladribine. Unfortunately, we can't answer this question until a large number of MSers have been treated with these drugs and followed for 10 or more years. At the moment there is no signal of secondary malignancies (see DrK's previous post). This doesn't mean there are no cancers or tumours in MSers treated with these drugs, simply the incidence of cancers is not higher than what would be expected from that what occurs in the general population."

"What I tell my patients is that cladribine is an immunosuppressive drug and it causes a mild long-term lymphopaenia (total lymphocyte counts never return to pre-treatment levels), which in other settings is associated with a slightly higher long-term cancer risk. The reason for this is that the immune system is responsible for tumour surveillance and elimination of cancers; if you suppress the immune system you get secondary cancers. The most frequent type of cancers associated with immunosuppression are haematological cancers, for example lymphomas and other lymphoproliferative disorders, and skin cancers. To date we have not seen a signal of these cancers in MSers treated with cladribine. Please note this issue of secondary or delayed cancer risk is not unique to cladribine and is an issue with natalizumab, fingolimod, dimethyl fumarate, mitoxantrone, alemtuzumab and possibly teriflunomide. All of these drugs are associated with immunosuppression to a greater or lesser extent."

"The study below is the best we have regarding delayed of secondary cancers in patients treated with cladribine or fludarabine. The data is from patients treated with these drugs who had chronic lymphoid leukaemia. Overall these patients had an approximately 50% higher risk of developing a secondary cancer. This study is confounded by the fact that people with cancer, or leukaemia, are already at higher risk of secondary cancers as part of their disease. In addition, people with chronic lymphoid leukaemia tend to be older and as a result are at higher risk of developing cancers. The authors of this study, taking these factors into account, conclude 'Despite their immunosuppression, nucleoside analogs can be safely administered to patients with CLL or HCL without a significantly increased risk of secondary malignancies'. Based on this data I personally think the risk of secondary malignancies in MSers treated with cladribine or fludarabine will be relatively low and probably no higher than the risk associated with other immunosuppressive DMTs. The only way we will find out for sure is by following up MSers treated with cladribine as part of a large post-marketing surveillance study. For the latter to occur we would need the EMA, and other regulatory agencies, to license cladribine as a treatment for MS. Without treating MSers we will never find out. Do you agree?"

Cheson et al. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol. 1999 Aug;17(8):2454-60.

PURPOSE: The nucleoside analogs fludarabine, 2'-deoxycoformycin (DCF), and 2-chlorodeoxyadenosine (CdA), commonly used in the treatment of patients with indolent lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL), are associated with myelosuppression and profound and prolonged immunosuppression. These complications raise the possibility of an increase in secondary malignancies in patients whose disease already places them at greater risk. The purpose of the present study was to assess the frequency of second tumors in patients with CLL who are treated with fludarabine and in patients with HCL who are treated with DCF and CdA.

PATIENTS AND METHODS: We reviewed the long-term follow-up data for 2,014 patients treated on National Cancer Institute Group C protocols with fludarabine for relapsed and refractory CLL and with DCF and CdA for HCL using a Second Cancer Report. The numbers of observed and expected secondary tumors were compared.

RESULTS: Median follow-up periods for the DCF (n = 409), fludarabine (n = 724), and CdA (n = 979) studies were 6.9, 7.4, and 5.1 years, respectively. The 111 malignancies were most commonly lymphoma (25 patients), prostate (19), lung (15), colorectal (nine), bladder (six), and breast (six), but also CNS, stomach, ovary, head and neck, melanoma, sarcoma, testicular, and myeloid leukemias. Compared with age-adjusted 1994 Surveillance and Epidemiology End-Results rates for the general population, the observed/expected frequencies for DCF, fludarabine, and CdA were 1.43 (95% confidence interval [CI], 0.93 to 2.10), 1.65 (95% CI, 1.04 to 2.47), and 1.50 (95% CI, 1.14 to 1.93), respectively, indicating a significant (at P =.05) increase in risk for patients treated on the latter two protocols compared with a normal population. However, these values are consistent with the increase already associated with these diseases.

CONCLUSION: Despite their immunosuppression, nucleoside analogs can be safely administered to patients with CLL or HCL without a significantly increased risk of secondary malignancies.

CoI: multiple


  1. Further reassurance: Rosenberg JD, et al. Clinical characteristics and long-term outcome of young hairy cell leukemia patients treated with cladribine: a single institution series. Blood 2014;123:177-83.
    In this 20-year follow-up of 88 patients diagnosed with hairy cell leukemia before the age of 40, no increase in the incidence of secondary malignancies was detected.

    I would also make the point that whilst licensing is desirable, it is not an absolute necessity as long as patients on DMTs sign up to the MS Register, and malignancies are consistently reported by their physicians.

  2. Will an increased cancer risk be an issue with ocrelizumab too?
    Rituximab has been used for long enough - is there an increased cancer risk?

  3. I' m using the same wording as Gavin when it comes to immunosuppression and cancer risk. Nevertheless, data from the large British Society for Rheumatology Biologics Register suggest there is no significant increase with biologics (including Rituximab). The cancer data in ORATORIO (0 malignancies in the placebo arm vs 9 in the Ocrelizumab cohort, bearing in mind randomisation was 2:1) most likely illustrate the problems of small sample size and short follow-up rather than a truly increased risk. It's the same ol' story, need to look at long term data, true for all DMTs.

  4. In the CLARITY study it was 0 placebo compared to 3 real malignancies in movectro groups with a 2 to 1 recruitment of similar group sizes also and based on one trial also. If you are saying 0 to 9 then isn't that much worse? Do you think that the regulators wiĺl ask for more trials for ocrelizumab?
    What happned to the cancer risk in the OPERA 1 &2 as this sounds like bad news?

  5. I believe in the OPERA studies they were more balanced, but I didn't snap those slides at ECTRIMS... I'd predict the regulators will ask for long term follow-up, as they would anyway. Pooling the data across studies may well dilute this contrast.

  6. I had a look over the ECTRIMS presentation of the OPERA results and it says six malignancies - four with ocrelizumab and two with interferon (Rebif). I hope we'll have follow-up data next year.

    1. So the PPMS was probably a fluke like the CLARITY data but so lets hope the mud doesnt stick to ocrlizumab like it did to movectro,

  7. Sorry to talk more off-topic, I was just wondering about dosage in the OPERA trials. I saw there were a lot of infusion reactions with the first dose, which was 300 mg while (a second 300 mg dose was given after 14 days).

    Could they be lowering the first dose further? Maybe split the 600 mg in three doses so they get fewer IRRs and potentially fewer people stopping treatment because of reactions to that first dose?

    1. It depends on why there were infusions reactions, if it the contents of cells being released like alemtuzumab then it will mean that people will need steroids maybe profG and drK will have answers

