PML warning on Cladribine by MHRA.

There has been a warning about the development of PML after the use of cladribine for the treatment of haematological problems issued by the MHRA. Therefore please be vigilant. 

So far this is associated with the use of the generic cladribine, probably in cancer, rather than oral variant in MS. It says there have been three cases.

Lipomed who make the generic version have issued this warning.

  • Dosing in hairy cell leukemia is 10mg for 5 days = 50mg
  • Dosing in Non-Hodgkins lymphoma and chronic lymphocytic leukemia = 35mg monthly to a maximum of 6 cycles = 210mg
  • Dosing in multiple sclerosis. Dose used at QMUL = 30mg and up to 30mg one month later depending on lymphopenia. The mavenclad equivalent dose is about (25mg + 25mg a month apart) 50mg 

We can see the cases reported a few years ago

A case of PML was reported in someone (81 years old) with HCL who got pentostatin (a chemotherapeutic drug) 2 years later and 3 years later developed PML. Their T cell counts were extremely low at 67 and 28 cells/mm*3. Therefore severe lymphopenia seems to be a problem.

In another case (67 years old) reported 6 months after the last dose of cladribine had 160 CD4+ cells/mm3 and 360 CD8+ cells/mm3 but had been down to 100 lymphocytes cells/mm3).

The dosing schedule in use for oral cladribine aims to reduce the chances of severe lymphopenia <500 cells/mms (<200 CD4 T cells) = grade 3 lymphopenia, <200 cells/mm3 (<50cells/mm3) = grade 4 lymphopenia

In the warning it says “If PML is suspected, stop cladribine treatment immediately and ensure the patient receives specialist investigation”

However, as cladribine give long term depletion, if PML occurs it may be problematical.

At the heart of the use at QMUL, is careful monitoring to ensure that persistent lymphopenia does not occur. 

If you are taking mavenclad monitoring occurs to ensure that lymphopenia is reduced.

However, persistent lymphopenia is going to be a problem for any treatment. But which cell type deals with PML the best…I guess CD8. 

Will PML occur in MS after Cladribine?

This is quite possible, it has occurred with most MS drugs

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  • Just wondering if there have been any reported cases of PML following the use of Alemtuzumab as a first-line therapy, so without prior use of Natalizumab? I chose not to take Natalizumab because of the risk of PML but now could do with some reassurance about taking Cladribine to try and control my worsening MS. I do feel anxious about taking any of these strong drugs with their potential side effects but anxious too about the consequences of not taking any of them. Am I correct in thinking that Cladribine appears to be the safest of the most efficacious DMTs? Best wishes to all at Barts.

    • To the best of my knowledge there are no PML cases post-alemtuzumab in naive treated pwMS. Ditto for cladribine. I suspect cladribine will be safer than alemtuzumab in MS as it does not cull the peripheral T-lymphocyte numbers to the same level as alemtuzumab; cladribine 40-60% and alemtuzumab >95%.

      Please remember that alemtuzumab looks to be the more effective of the two agents; this is based on brain atrophy data. But until we do a head-2-head study we won't know.

      Now if you run cladribine or alemtuzumab against natalizumab in a head-2-head study and used NEDA as an outcome I suspect natalizumab will win. This is based on it being a maintenance therapy rather than an IRT (immune reconstitution therapy).

      Please remember that untreated or under-treated MS (smoldering MS) has a poor outcome.

    • What about the fact that Cladribine is the only DMT to penetrate the CNS? If there is continuing disease activity despite treatment with Cladribine, what could be 'safely' taken afterwards?

  • "if you run cladribine or alemtuzumab against natalizumab in a head-2-head study and used NEDA as an outcome I suspect natalizumab will win."

    NEDA-4? BVL?

    • Not really, the data comes from Leukaemia patients not MS and as I've said above with careful dose-titration and monitoring (courtesy of Dr K) serious leucopaenia (which is at the root of these cases of PML) can be kept at bay.
      So, you might like to re-think your pseudonym Merry Christmas;-).

    • In comparison to Alemtuzumab where the vast majority of people get grade 3/4 lymphopeania on first dose In the the clad group we have had a few people with grade 3 and as per protocol dosing stopped and lymphocyte numbers recovered in all cases so far.

      In terms of safety you have to put it in context of what you are comparing with vitamin D or highly active DMT

    • The data has been submitted so it will be there for all to see.

      The problem of lymphopeania with clad seen in trials was that second dose was given prior to monitoring lymphopeania. This does not happy with the new licence.

    • Second dose cycle after 12 months to be specific not the month two dose. At BartsMS we assess lymphopeania after every dose cycle at month 1 &. 2 and 12 & 13 and dose adjust accordingly.

    • If someone with MS is unfortunate enough to end up battling cancer following the use of one of the most potent immunosuppressant DMTs, how would that affect their treatment with chemotherapy for the cancer? Would the DMT have to be stopped completely?

    • Sorry but not sure what you're saying – that people with MS don't tend to get cancer later in life, maybe years after their MS diagnosis and whilst potentially still taking a DMT?

  • At least natalizumab is reversible so you can just come off if you're JC+…what about Cladribine? I'm guessing there's not even JC virus test?

    I know the PML is with cancer patients but could this also happen with MS patients considering it's only recently been licenced for MS so not as much patients have taken it?

    • Precisely why I am staying on maintenance vs PIRTs.

      The non-reversible crowd seems to me a story of arrested development. You are betting that medical progress will be slower than your disease progression.

      Maintenance buys you time on the other hand.

      Atrophy figures is a different story of course. But nothing conclusive there unfortunately.

      Tony F

  • PML after several years sounds really scary. What can one do to prevent it if it happens when you are not on the drug? That is a major difference to other MS drugs.

    • But in these cases reported (blood cancers) compared to cladribine used for MS, it's not apples and oranges, it's apples and turnips.

    • How are they sure PML happened due to Cladribine if it happened many years after therapy and even after chemo?

      PS This reminds me arguments about HSCT for cancer and HSCT for MS. Yet you would never be on the other side for HSCT 🙂

    • Yesterday when I looked Hairy PML in Hairy Cell Leukakemia is someone who did not recieved cladribine and in two cases the person had received pentastatin in addition to cladribine.

      I think persistent lymphopenia is the worry.

      I don't know how frequent this is after cladribine, I will have a look at the trial data, I know the figure after 9 weeks but can look harder at this. I suspect it is not commen

      I would like to know more about DMF as there are people with persistent lymphopenia. It must be hitting cells the bone marrow to cause this.

  • I do not look to this blog for much with regard to treatment advice any more. Too many sea changes, too much I have found highly questionable, too biased. Best quote of 2017, from MD2: Reading this blog is not compulsory. And one of the worst, from Prof G: If I had PPMS, I'd want to be on Ocrelizumab. So, 10 years into Ocrelizumab treatment, I may have less progression, but also a buggered immune system and possibly cancer? When cancer therapy is neurotoxic? I don't think so.

    • This blog is so incredibly useful and provides much needed information to everyone with MS. The NHS is really struggling and neurologists/MS nurses are totally overstretched; I have had to wait months for results of MRIs (including my original diagnosis); appointments seem so brief there is little time to ask important questions about drug comparisons etc. I have learnt so much from reading this blog and feel truly grateful to all involved who are desperately trying to help people with MS. I wish everyone at Barts a very peaceful Christmas and 2018.

  • I talked to some friends oncologists and they said that it isn't common PML in treatment with Cladribine.

    But if they told to monitor, better monitor, right?!

  • Hi I have been offered Cladribine after years on Rebif 44 I don't feel that I have had many relapses while on Rebif but over the last 2 years my disease has worsened significantly I feel due to recurring Uti's and their debilitating effect on me, I have recently had a MRI which shows a number of new lesions could they have been brought by these UTI's? I can't make my mind up whether to take a chance on Cladribine reading about the side effects!

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