The Big-C

T

Barts-MS rose-tinted-odometer: ★★★★★ (seeing grey – it’s a very grey Saturday)

Whenever you bring up the topic of using more effective DMTs or flipping the pyramid you get pushed back because of the potential risks associated with these treatments. One risk is the big-C or secondary cancers. It is therefore very reassuring that an analysis of the FDA adverse event reporting system database revealed no safety signal for increased cancer risk among the approved MS DMTs. 

The only potential safety signal that was detected in a so-called sensitivity analysis concerned interferon-beta-1a (Rebif/Avonex/Plegridy) and alemtuzumab. 

The message is that the cancer risk associated with MS DMTs is probably quite low and not nearly as high as the risk associated with more potent immunosuppressive therapies and the so-called mutagenic therapies. Please note none of our licensed DMTs is mutagenic. Please note this analysis does not include AHSCT, which typically uses cyclophosphamide to mobilise stem cells and to ablate the immune system. There is clear evidence that people who have had AHSCT are at increased risk of developing a secondary malignancy, which is almost certainly a consequence of exposure to cyclophosphamide and other chemotherapy agents given as part of the procedure.

This analysis also puts the FDA cladribine black box warning into perspective, i.e. the real-life data suggests there is no increased cancer risk with cladribine and supports my interpretation of the data that cladribine is not associated with secondary cancer risk. The apparent cladribine cancer risk in the phase 3 or CLARITY trial was driven by the fact that there were zero cases in the placebo arm, which was the outlier. Let’s hope this data will allow pwMS to put the ‘potential cancer risk’ of DMTs into perspective and give them the confidence to access more effective therapies earlier on in the course of their MS.

It has now become abundantly clear that the earlier the average person with MS is treated with a high efficacy DMT the better their outcome. The message is treat-early and treat-effectively. 

Stamatellos et al. Disease-modifying agents for multiple sclerosis and the risk for reporting cancer: a disproportionality analysis using US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Br J Clin Pharmacol. 2021 May 16.

Aim: While the efficacy of Disease-Modifying Therapies (DMTs) for patients with Multiple Sclerosis (MS) is established, little is known about their long-term safety. Cancer-risk after DMTs use remains unclear. This study aims to investigate whether the prescription of DMTs for patients with MS increases the risk of reporting cancer.

Methods: Data from the FDA adverse-event reporting system were extracted from 2004 until 2020. After data cleaning, the crude and adjusted Reported Odds Ratios (cROR, aROR) for cancer were calculated for DMTs with Interferon-beta1a as the reference drug. Sensitivity analyses investigated the group of reports with multiple registered DMTs, the effect of indication restriction, and the results when using the rest of the DMTs as reference.

Results: For malignant tumors, aROR (CI 95%) were: Cladribine 0.46 (0.18-0.95) Dimethyl fumarate 0.30(0.27-0.34), Fingolimod 0.61(0.53-0.70), Glatiramer 0.50(0.43-0.58), Alemtuzumab 0.84(0.64-1.08), Interferonbeta-1b 0.49(0.42-0.56), Natalizumab 0.36(0.34-0.39), Ocrelizumab 0.48(0.29-0.74), pegInterferonbeta-1a 0.35(0.26-0.48), Siponimod 0.89(0.47-1.54), Teriflunomide 0.25(0.21-0.30) adjusted to age, gender and concomitant medications. In the sensitivity analysis, when the rest of the drugs were used as a reference, Interferon-beta1a and pegInterferon-beta1a had aROR (CI 95%): 2.60 (2.47-2.74, p<0.001), and Alemtuzumab 1.47 (1.13-1.88, p=0.003).

Conclusions: No safety signal for increased cancer-risk was detected among the approved DMTs, although more robust evidence is needed. A potential safety signal detected in the sensitivity analysis concerning Interferon-beta1a, Alemtuzumab, requires further evaluation with more robust evidence.

Conflicts of Interest

Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

12 comments

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  • That is good news.

    It is worth mentioning that secondary cancer rates in patients who were treated with cyclophosphamide is strongly dependant on the dosage and exposition time. The lower the dosage the lower the rate of secondary cancer, in the groups treated with the amount not exceeding 20g of CYC the rate was the lowest – which is the case in almost all of the aHSCT for MS regimens, as it is usually between 12-18g I believe.

    Cheers

    • “The lower the dosage the lower the rate of secondary cancer, in the groups treated with the amount not exceeding 20g of CYC the rate was the lowest – which is the case in almost all of the aHSCT for MS regimens, as it is usually between 12-18g I believe.”

      Yes..what is the difference in CYC between myelo and non-myeloablative hsct..?
      Does anybody know..?

      What was used in Canada full myelo trials caused 3% brain loss first year.
      So that is why Burt..Russia..and Mexico all used non-myeloablative now as it causes
      less brain atrophy and is equally effective, Sweden no longer performs myelo I’ve been told.

      Still there have been 2 leukemia deaths out of 2500 patients from Mexico/Russia…which is in line with normal age related rate or so I’ve been told. But the man who’s wife died..posted
      that doctors(oncology) told her it was directly caused by the CYC she got from hsct. Sadly
      from his words..she greatly suffered from the leukemia. “We went there with a dream to
      stop the progression…but were not told of any cancer risk”

  • This is excellent news and I hope more doctors will see this. What is most frustrating that even if the risk was there, neurologists seem to not realize many pwMS would gladly risk cancer to avoid the nearly 100% risk of losing brain cells, function and quality of life without highly effective treatment to prevent this.

  • There was a post on here earlier about a 34 yr old female relapsing 3 days post vaccine… has it been removed?

  • “There is clear evidence that people who have had AHSCT are at increased risk of developing a secondary malignancy, which is almost certainly a consequence of exposure to cyclophosphamide..”

    Probably true..but you don’t help your case by not presenting the “clear evidence”
    As many have been treated with CYC for cancer and BMT’s..there should be clear
    stats related to CYC dosages used.

  • Do you know anywhere I can get numbers about the cyclophosphamide secondary malignancies, please? When I was talking to my neuro about non-myelo AHSCT, his biggest concern was the CYC giving an extra two points risk of basal cell carcinoma over the rest of your life, which doesn’t sound all that scary (I don’t know where his number came from). Being able to put numbers on the actual risk would be really helpful.

    • this all I find..nothing compared to the risk of ms..

      “Conclusions: Cyclophosphamide-related bladder cancer is dose dependent. For patients given cumulative doses between 20 and 49 g, the absolute risk of bladder cancer is on the order of three excess cancers per 100 NHL patients after 15 years of follow-up. At cumulative doses of 50 g or more, the excess risk increases to approximately seven excess bladder cancers per 100 NHL patients.

      Implications: The strong dose-response relationship and high absolute risk of bladder cancer underscore the importance of limiting the cumulative dose of cyclophosphamide to what is required to achieve therapeutic end points.”

      https://pubmed.ncbi.nlm.nih.gov/7707439/

      • Hmm, okay. 50g is a seriously high dose; if I were doing Mexican-style HSCT, the dose would be 15g. So it’s not great, but, like you say, MS is worse.

    • eyeLOPHOSPHAMIDE (Group 1)
      A. Evidence for carcinogenicity to humans (sufficient)
      Many cases of cancer have been reported following therapy with cyclophosphamide1.
      Excess frequencies of bladder cancer following therapy with cyclophosphamide for
      nonmalignant diseases have been clearly demonstrated in two epidemiological studies1,2.
      Three recent studies confirmed that cyclophosphamide is also a leukaemogen. Among 602
      patients treated predominantly with cyclophosphamide for non-Hodgkin’s Iymphoma in
      Denmark, nine cases of acute nonlymphocytic leukaemia (ANLL) or preleukaemia were
      observed, compared to 0.12 expected on the basis of incidence rates in the general.
      population3. ln the USA, three cases of ANLL or preleukaemia were observed among 333
      women treated only with cyclophosphamide for ovarian cancer; 1.2 were expected4. ln the
      German Democratie Republic, a case-control study was carried out of leukaemia arising as
      a second primary malignancy following breast or ovarian cancer. Relative risks of 1.5,3.3
      and 7.3 were estimated in association with cumulative doses of”:l0 g, 10-29 g and ),30 g of
      cyc1ophosphamide, respectively5.
      Cyclophosphamide is a far less potent leukaemogen than 1,4-butanediol dimethanesulphonate
      (Myleran; see p. 137) when used following surgery for lung cancer6. Similarly,
      melphalan (see p. 239) produces a much higher incidence of leukaemia than cyc1ophosphamide
      when used in the therapy of multiple myeloma7 and of ovarian cancer4.

      https://publications.iarc.fr/139

      RESULTS: A total of 168 patients were included. Cumulative
      CYC dose was 7.45 g (range 0.5–205 g). Gastro-intestinal
      side effects were seen in 68 events, hair loss occurred
      in 38 events. A total of 58 infections were diagnosed
      in 44/168 patients (26.2%) with 9/44 suffering multiple infections.
      Severity grading of infections was low in 37/58
      cases (63.8%). One CYC-related infection-induced death
      (0.6%) was registered. Amenorrhoea occurred in 7/92 females
      (7.6%) with 5/7 remaining irreversible. In females
      with reversible amenorrhoea, prophylaxis with nafarelin
      had been administered. Malignancy was registered in 19
      patients after 4.7 years (median, range 0.25–22.25) presenting
      as 4 premalignancies and 18 malignancies, 3 patients
      suffered 2 premalignancies/malignancies each. Patients
      with malignancies were older with a higher cumulative
      CYC dose. Death was registered in 28 patients (16.6%)
      with 2/28 probably related to CYC.
      CONCLUSIONS: Considering the organ or life-threatening
      conditions which indicate the use of CYC, severe druginduced
      health problems were rare. Our data confirm the
      necessity to follow-up patients long-term for timely diagnosis
      of malignancies. CYC side-effects do not per se justify
      prescription of newer drugs or biologic agents in the
      treatment of autoimmune diseases.

      Cyclophosphamide: As bad as its reputation?
      Long-term single centre experience of cyclophosphamide side effects in the
      treatment of systemic autoimmune diseases

      https://smw.ch/article/doi/smw.2014.14030

      Cyclophosphamide in Multiple Sclerosis: Scientific Rationale, History and Novel Treatment Paradigms

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002608/

      Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma

      https://pubmed.ncbi.nlm.nih.gov/7707439/

      Lights and Shadows of Cyclophosphamide in the Treatment of Multiple Sclerosis

      https://www.hindawi.com/journals/ad/2011/961702/

      https://www.hopkinsvasculitis.org/vasculitis-treatments/cyclophosphamide-cytoxan/~~

      https://en.wikipedia.org/wiki/Cyclophosphamide

      This risk may be dependent on dose and other factors, including the condition, other agents or treatment modalities (including radiotherapy), treatment length and intensity. For some regimens, it is rare. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) carries an AML risk of less than 1/2000, with some studies finding no increased risk compared to background. Other treatment regimens involving higher doses may carry risks of 1–2% or higher. Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After nine years, the risk falls to background. When AML occurs, it is often preceded by a myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML

      You may also have to see cardiotoxicity

      I have 3 echocardiogram during hsct

  • So compared to most of these other therapies, interferon-beta-1a has a higher risk of cancer. But there is a lower risk of cancer overall in multiple sclerosis.

    https://multiple-sclerosis-research.org/2014/01/lower-cancer-risk-in-ms/

    One way to interpret the data is interferon/alemtuzumab is a bit dangerous but the others are safe.

    A second way is that all M.S. drugs cause cancer but interferon-beta-1a and alemtuzumab are just the worse of a bad bunch.

    A third way to interpret the data is that interferon beta 1a does nothing with cancer compared to the general population and the other therapies are good a preventing cancer. There is work being done to evaluate the potential of DMF in leukemia/lymphoma, glioblastoma, and cutaneous T cell lymphoma for example.

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