Is fludarabine the next hope to knock cladribine off its perch

Greenberg SJ et al.Fludarabine add-on therapy in interferon-beta-treated patients with multiple sclerosis experiencing breakthrough disease. Therapeutic Advances in Neurological Disorders January 21, 20161756285615626049

Background: Patients with relapsing–remitting multiple sclerosis (RRMS) may experience breakthrough disease despite effective interferon beta (IFNβ) therapy. Fludarabine (FLU) is a chemotherapeutic agent used in lymphoproliferative disorders that may be synergistic when combined with immunomodulatory therapy to control active multiple sclerosis (MS).

Objective: The objective of this study was to explore the safety and tolerability of FLUversus monthly methylprednisolone (MP) in IFNβ-treated RRMS patients with breakthrough disease. Clinical and MRI effects of IFNβ-1a plus FLU were evaluated.
Methods: Eighteen patients with breakthrough disease [⩾2 relapses over the prior year and ⩾1.0-point increase in Expanded Disability Status Scale (EDSS) score sustained for ⩾3 months] after >1 year of IFNβ therapy were enrolled in this prospective, open-label, randomized, proof-of-concept, pilot study. Patients received intravenous (IV) MP 1 g daily for 3 days and then were randomized to receive 3 monthly IV infusions of FLU 25 mg/m2 daily for 5 consecutive days (n = 10) or MP 1 g (n = 8). All patients maintained their intramuscular IFNβ-1a treatment throughout the study. Analyses explored safety signals and directional trends; this preliminary study was not powered to detect clinically meaningful differences.

Results: Both combination treatments were safe and well tolerated, with all adverse events mild. Patients treated with IFNβ-1a plus FLU had similar relapse rates, EDSS scores, and MS Functional Composite scores, but significantly less acute corticosteroid use for on-study relapses and better responses on some MRI outcomes, versus patients treated with IFNβ-1a plus MP.

Conclusions: Further study of FLU for breakthrough disease in patients with RRMS is warranted.

Fludarabine is a chemotherapy drug used in the treatment of cancers of blood cells such as leukemias and lymphomas). 

Fludarabine is a purine analog, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy.
Fludarabine causes anemia, thrombocytopenia and neutropaenia, requiring regular blood count monitoring.

Fludarabine is like Cladribine is also a purine analog, Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell’s ability to process DNA. It is easily destroyed by normal cells except for blood cells, with the result that it produces relatively few side effects and results in very little non-target cell loss.

In this study they look at the effect of combining fludarabine with beta interferon and compare this with a combination of interferon beta and steroids (methylprednisolone) in people with breakthrough disease.

In the study they suggest that the action of fludarabine may be synergistic when used with beta interferon. Synergistic is a word used by many but seldom really show. Synergism occurs when the the action of two drugs is better than their additive effect alone. However when you use a non linear scale to assess efficacy it is very difficult to  to show true synergy over a simple additive effect so addition is 2 + 2 = 4 where as synergy is 2 + 2 = 5.

People were first given steroids for a week then went on to fludarabine 5 times in a month for 3 months of steroids once a month for 3 months whilst taking interferon once a week and assessors were not blinded and if neutrophil numbers became low you could have cytokine therapy to increase this and people on steroids could have more steroids if they relapsed. 

The study however only involved only 18 people and it is impossible to draw any real conclusions about efficacy or safety for that matter. There appeared to less However, the study was not based on any real sample size studies  and not surprisingly in the end because the trial was so small them there was no differences to be seen, so more trials need to be done. A few people continued to relapse

If fludarabine was as good cladribine, one may expect that it could be better than beta interferon and you could simply do fludarabine by itself. In the cladribine verses beta interferon trial presented at the AAN 2013, I believe Cladribine was better than interferon beta.

However in this study they use a trickle dose of repeated injections and I wonder if this is the way to take these types of drugs, as it may drip feed side effects/infection risk and maybe best to get larger dose for the drug to do its stuff.

Prof G has questioned about whether people and neurologists are risk adverse and will “wait and see”. This clearly shows there is some truth to be had and people are relapsing on treatment.

So the question one can have if people are failing beta interferon is, is it a good idea to carry on trying to treat people with interferons when they are relapsing or should they be switched onto a more effective treatments. 

 Maybe it time to read

This study was funded by Biogen in support of the lead author who is an employee of Abbvie, which makes daclizumab HYP. So is pharma now supporting off label:-)?…I’m only joking, but if you are having relapses time to escalate

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  • How much does fludarabine cost? Is it cheaper than cladribine? Being a tablet must make it more appealing as a treatment.

    • If you need 3-5 injections a year verses treatment every 5 days for so many months.

      I got this off Scotland data sheet

      Fludarabine 50mg injection for 5 days each 28 days. 3 courses £2340
      Fludarabine tablets 10mg for 5 days each 28 days 3 couse £1953.

      So twice the cost cladribine. May less efficacy and more side-effect when done as a drip-feed treatment. Offset by the cost of 5 syringes for claribine and cost of injection.

      However by coming in for your injection we can ensure that people do not take two pills and overdose and DrK has been very ingenious about this to ensure that treating people is cost-effecive for the hosptial.

  • Speaking of synergy. Would you think that HIV+HAART are synergistic against MS? To falsify that you would need to show that HAART alone suffice to treat MS.

    It would make sense that a DMT destroying misbehaved lymphocytes and an anti-viral drug would be synergistic as their action is independent from each other. (sorry I am kind of stubborn as I posted this hypothesis many times now).

    • HIV + HAART verses HAART is a none starter, but I believe ProfG down-under is aiming to try HAART

      Anti-viral plus DMT yes I can the logic butis it easy to work out if the anti-viral has additional effect over the DMT

    • The side effect profile of HAART does warrant consideration – when you have a moment look though these.

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