Barts-MS rose-tinted-odometer ★★★
Using fiction to teach and learn about MS is what I am turning to more and more. An old-fashion case scenario is a powerful tool for illustrating the difficulties we have in clinical neurology. We can create a clinical problem that is not necessarily answered by trial data or reading the summary of product characteristics. This is where clinical acumen and reasoning by analogy are required to help make a decision relevant to that individual patient. The following is an example of a case I recently used. It was quite interesting that in a room of about 10 neurologists there was no obvious consensus to the questions posed by the case scenario.
Medical fiction – case scenario malignancy
A 47-year woman with active relapsing-remitting MS has recently failed on pegylated interferon-beta with a disabling spinal cord relapse and an MRI showing numerous new brain and spinal cord lesions. She had breast cancer diagnosed and successfully treated 7 years ago and has been told by her oncologist that she has no evident detectable disease (NEDD).
After researching the literature she is worried about going onto an immunosuppressive therapy, but realises she needs to be on treatment for her MS.
What would be the most suitable DMT in this situation?
How are we going to counsel her about the malignancy risk associated with each specific MS DMT?
Do you have an answer to these questions? Is there other information you would like before making a decision? Would you like to know my personal recommendation? Would you like more medical fiction on this blog?
CoI: multiple
re. ‘ with a disabling spinal cord relapse and an MRI showing numerous new brain and spinal cord lesions.’
Was the pwMS walking pre- relapse, then not walking during the relapse? or was it the arms? so we know the severity of the relapse. Thanks.
I am not sure the severity of the relapse is necessarily relevant. The relapse and MRI activity indicates that she has active MS.
Correction. From a UK perspective, the severity of the relapse or relapses may be relevant, i.e. you need to have two disabling relapses in a 12 month period to have rapidly evolving severe MS, which then allows you to become eligible for natalizumab.
So in a group setting the severity of the relapses will become a discussion point and we can then explore how this would affect decision making. For example, if it was relatively mild or non-disabling attack would that point to DMT A or DMT B. On the other hand if it was a disabling attack would you bypass DMT A and B and go straight for DMT X or Y?
Thanks, I ask this from a patient perspective, as if I had lost total leg/s or arm/s function, I would probably seek a more risky DMT. I would have to weigh up the risks, with my leg and arm function.
Tysabri as a holding DMT with further clinical review
What about brain secondaries? Surely natalizumab will prevent the immune system from preventing brain metastases?
Yes, you are correct, but not all breast cancers metastasise and not all metastasise to the brain. The unanswered question is how common in the latter? It may be very common and the immune system cleans up and prevents metastases from manifesting. I think most oncologists think this may be the norm. However, in this patient, the gap between the cancer treatment of her primary tumour and the need to treat her MS is 7 years, which makes the chances of her having subclinical CNS breast cancer metastases very low. Based on this I think natalizumab is one potential treatment option?
Wouldn’t you want to know her JCV status before recommending natalizumab?
Yes and no! As part of our #AttackMS paradigm, we can start natalizumab to get on top of MS disease activity and then make a decision what to do later. Even if you are JCV positive personalised or extended interval dosing may reduce the risk of PML to such low levels that it becomes just another factor in the decision-making process.
Yes, bypass some DMT’s, if it was a disabling attack.
Is there any one ideal DMT for this woman?
Surely she needs to be started on a non-immunosuppressive DMT? This will allow her immune system to functional normally and fight her cancer.
This is the obvious and most logical approach. But the only non-immunosuppressive DMTs are IFNbeta, GA and teriflunomide. IFN-beta is a non-starter. As I would really want her to be on a highly effective it makes GA and teriflunomide difficult choices. Of these, I would favour teriflunomide as it is more effective when used 2nd or 3rd line than as a 1st-line therapy.
Another option are the IRTs; although they cause transient immunosuppression they are generally highly effective. Therefore alemtuzumab and cladribine would both be options in this patient. Do you agree?
Thank you for the case. Generally because of malignancy GA and IFN would be safest, but no suitable here.
Because of the disease activity with spinal cord lesions I would prefer highly active drugs – so Dimethylfumarate and Gilenya (the last one esp. because of the probably increased malignancy risk) would be out. Depending on JC- V Status (and on other factors like fatigue) I would tend towards either Tysabri or anti- CD20. Esp. if we take in considerations the recent paper about cancer risk (https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25701?af=R) I would councel that with Tysabri we have no current data which shows increased risk of malignancy. In regards of Ocrevus there was the abnormal data in the phase III study (increased breast cancer risk, but 0 cases (unexpected) in the placebo group) which was not confirmed in subsequent studies. If the patient would still be worried we could think about Rituximab, which has more long term data without any signs of cancer risk.
Mavenclad is only recently approved in our country and alemtuzumab currently a third line option so I would not opt for these drugs.
Hasn’t anti-CD20 therapy been linked to the development of breast cancers? I think this would be a no-no.
This paper highlights the potential problem of anti-CD20 therapy and breast cancer. It seems as if B-cells are important antigen-presenting cells for tumour surveillance. Based on this I would not recommend an anti-CD20 in this patient.
Degnim et al. Alterations in the Immune Cell Composition in Premalignant Breast Tissue That Precede Breast Cancer Development. Clin Cancer Res, 23 (14), 3945-3952 2017 Jul 15.
Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD).
Experimental Design: A breast tissue matched case-control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm2 for CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophages and quantification of positive pixel measure for CD11c (dendritic cells).
Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8+ T cells, CD11c+ dendritic cells, CD20+ B cells, and CD68+ macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20+ cell density (P = 0.04). Nearly 42% of BBD cases had no CD20+ B cells in evaluated lobules compared with 28% of BBD controls (P = 0.02). The absence of CD20+ cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4-23.1) for subsequent breast cancer risk.
Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk. Clin Cancer Res; 23(14); 3945-52. ©2017 AACR.
The truth is no one knows enough about the risks of MS or cancer. If a patient has no treatment for MS they can still see a return of cancer, and if they do, the cancer will be blamed on the DMT. Who knows whether the relapses will continue. This is not an isolated situation as some Chemotherapies trash the kidneys, but what is the alternative? No chemo? In the end it’s up to the patient with all the known risks.
Personally I would give the DMT a miss.
I would definitely like to see more medical fiction, please…As a non-medical person it makes it more “real” in a weird way.
Agree! Also I really like the writing style 🙂
As a pwMS I’m encouraged to read responses by healthcare professionals engaging and learning from this blog.
Would be great to see more of you posting with a name and even a Gravatar rather than Anon:
https://en.gravatar.com/
Thanks so much
At business school most of the teaching is done via case studies. It seems to work in that arena.
Prof, Please stop saying that patients fail a drug. Its the pther way around. The drug failed the patient!
At first, I thought: “who cares.”
But after a second thought, I believe that Louise makes an excellent point.
Not sure I agree.
What happens if her disease activity was due to her not being adherent to the interferon-beta treatment? Of if her own immune system rejected the interferon by forming neutralizing anti-interferon-beta antibodies?
Without becoming a pedant; I think most people would understand that either way her MS did not respond as we would like to her treatment.
Agree. Like the case study approach though 🙂
would either look at natluzamab or Teriflunomide
Surely its the way to go to educate HCP and get discussion going
Natalizumab is a great option in active MS patient and low risk of malignancy
Would being on anti-oestrogen, for example tamoxifen, affect the DMT treatment decision?
Possibly. Tamoxifen induces chemical menopause. As menopause is associated with a worse clinical disease course I would probably recommend a more effective DMT.
However, the decision will remain the patients.
Surely alemtuzumab would be too immunosuppressive, despite being an IRT, to use in this patient?
Yes and no. If she is cured of her breast cancer the period of immunosuppression from alemtuzumab should not be a problem. I think it is up to the patient to decide on the risks and benefits.
I would definitely offer this patient both cladribine and alemtuzumab and would let her make the decision.
Would you offer her any other DMTs?
Yes, based on the discussion above teriflunomide would also be on the cards.
I don’t necessarily think natalizumab would be wise because of the potential risk of CNS secondaries or metastases. The latter opinion is based on scientific rationale and not data.
What about HSCT?
This patient would not be eligible for HSCT in London, i.e she has not failed two DMTs, one of which has to be a high efficacy DMT.
In 🇨🇦 natalizumab is not considered safe for JCV-positives after 12 months. Unless and until JCV seronegativity is confirmed it doesn’t seem wise to recommend it. I’m told there have been also been cases of PML in PwMS on ocrelizumab.