Ketotifen Self-Determined Treatment of NF1 Neurofibromas

KSDT Compelling Anecdotes
by Vincent M. Riccardi MD, The Neurofibromatosis Institute

 

ABSTRACT
In this article, portions of the lives of nine persons with NF1 are shared so as to illustrate the experiences and consequences that characterize them as candidates for, or participants in, self-determined treatment with ketotifen, a mast cell stabilizer. First, amelioration of neurofibroma-associated itching, pain and tenderness was the most consistent finding. Second, there was a consistent reporting of an overall improvement in a general sense of well-being. And third, the rates of appearance and growth of cutaneous neurofibromas slowed considerably during ketotifen treatment. These unsolicited testimonies provide compelling evidence for the rationale of blocking mast cell degranulation as a safe, inexpensive and effective treatment modality for NF1.


INTRODUCTION

It has been more than 30 years since the initiation of several formal protocols – open-label and double-blind – to investigate the effectiveness of oral treatment with the mast cell stabilizer, ketotifen (Zaditen®, Sandoz), to minimize the impact of neurofibromas in the disorder, NF1. The results were published over 20 years ago in a peer-review journal(1, 2) and a book chapter,(3) analyzed in the book, Neurofibromatosis: Phenotype, Natural History and Pathogenesis (2nd edition)(4) and vetting in oral and poster presentations at various clinical and scientific meetings, including the annual gatherings of the American Society of Human Genetics, the American College of Medical Genetics and the European NF Association.

 

In the meantime, the aforementioned book and research in multiple scientific disciplines established the critical role of mast cells in the origin and progression of NF1 neurofibromas(5-7) and documented overlap of NF1 neurofibroma pathogenesis with other processes or disorders, such as wound healing,(8-10) fibrosis,(11, 12) mastocytosis(13, 14) and a variety of other benign and malignant tumors.(15-19) Moreover, one group documented that mast cells without NF1 gene compromise (mutation or deletion) contribute to NF1 neurofibroma initiation and progression.(20)

 

Thus, it is essentially ordinary mast cell functions that underlie these cells’ contributions to NF1 neurofibroma development and maturation. More precisely, it is not merely mast cell deficiency of the NF1 gene product, neurofibromin (Nfn), or its GTPase-activating-protein-related domain (GRD) that accounts for promoting the neurofibromas. This means that interrupting ordinary mast cell functions might be sufficient to preempt NF1 neurofibroma initiation and progression.

 

Interruption of ordinary mast cell functions to preempt NF1 neurofibroma initiation and progression likely involves two elements that overlap, but are mechanistically distinct. These two mechanisms of preemption take into account 1) the neurofibroma-specific maturation of the mast cell itself, and, subsequently, 2) the stepwise influences of the neurofibroma-specific functions of these distinctive mast cells. Through the present, we have presumed mast cell degranulation inhibitors (e.g., ketotifen) have their effects only in the second phase, simply blocking the functions of neurofibroma-mature mast cells. The 2015 report documenting the ability of ketotifen to be preemptive even before a cutaneous neurofibroma is apparent(21) requires consideration that ketotifen may also block the evolution of the mast cell from its bone marrow(22, 23) or lymph node(24, 25) initial immature state to its ultimate neurofibroma-mature state. Tissue-specific mast cell maturation is already well known, at least for the brain(26, 27) and the gastrointestinal tract (e.g., for helminth infections).(24, 28, 29) As suggested,(21) this reasoning suggests that initiation of ketotifen treatment to preempt NF1 neurofibroma origin/progression in young children is cogent, if not imperative. If the mast cell newly recruited to the nascent neurofibroma can be kept from maturing therein, the expectations go beyond the already established ability of ketotifen to reverse or abrogate post hoc a mature neurofibroma.(1-3)

 

And, finally, it is certainly possible that ketotifen has salutary effects on NF1 neurofibromas beyond its mast cell degranulation effects. For example, the ability of ketotifen to reverse the tachyphylaxis of the β2-adrenoagonists, isoprenaline and terbutaline may be important in its anti-neurofibroma effects.(30-32) It is also possible that ketotifen’s effects on adrenomedullin and the latter’s association with the NF1 neurofibroma burden(33) may contribute to the drug’s diminution of that burden.(34)

 

In this context, and respecting the lack of any data contradicting the earlier demonstration of oral ketotifen efficacy in treating NF1 neurofibromas,(1-3) my recent report of the drug’s salutary effects in two NF1 patients treated from childhood for 25 or 30 years21 is very encouraging. In the meantime, first, in 1989, a German-language article(35) found similar encouraging clinical results in three adult NF1 patients. And, second, in 2009, Yamamoto et al.36 reported that a ketotifen-comparable mast cell stabilizer, tranilast, disrupted the growth of human neurofibroma-derived Schwann cells and fibroblasts in cell culture. Their in vitro mast cell stabilization data fit with our clinical findings: “Tranilast significantly suppressed proliferation of the NF1 cells … These results suggest that tranilast retards tumor [neurofibroma] proliferation …”

 

Although oral ketotifen has never been approved by the USA Food and Drug Administration for routine clinical use, the lack of approval was based on concerns about efficacy for treating asthma, not on the basis of toxicity or adverse side effects. Ketotifen is routinely used throughout the rest of the world for multiple indications, including NF1. For example, there is the internet link deriving from one of Mexico’s most prestigious medical schools:http://www.facmed.unam.mx/bmnd/gi_2k8/prods/PRODS/Ketotifeno.htm.. At this site, under the heading “Esquemas de dosificación que han sido reportados,” the following indication and dosage schedule is noted: neurofibroma (2 to 4 mg/day for 30 to 43 months). My second reason presuming a more widespread treatment of NF1 with ketotifen is the unsolicited email I received on 24 March 2015. “Dear Prof. Riccardi, as a dermatologist I have been involved in NF patients’ follow-up in Moscow, Russia, for the past 20 years. This year I have come across a very unusual case, the first in my practice. [The patient] developed cutaneous neurofibromas on both upper extremities at the age of 47… neurofibromas from two sites were histologically confirmed with positive S100 staining.” In my same-day email response, I suggested treatment with ketotifen, 2 mg twice a day. Moments later, I received a follow-up email: “Thank you very much for your reply and the article.(21) We have prescribed ketotifen to all our patients with NF (based on the results of your valuable research) for many years, with good results, especially when started in childhood… Sincerely, Veronica Mordovtseva, MD, PhD, Prof. of Dermatology.”

 

This transcontinental email exchange was consistent with my expectation that numerous persons with NF1 worldwide have been treated with ketotifen or other mast cell degranulation inhibitors such as disodium cromoglycate (DCG). More specifically, for many years I personally have been aware of multiple NF1 persons, American and otherwise, who obtained ketotifen from non-American sources to treat their disorder. What follows here chronicles several such persons, itemizing the benefits derived from that treatment.

 

CLINICAL DATA
The following sections describe specific interactions with nine Ketotifen Self-Determined Treatment (KSDT) persons known to me since the late 1980s through to the present. They have been selected based on the accuracy and consistency of the proffered details. The comments of the inquiring person are printed italicized, while my comments are in Times New Roman font and are enclosed in lines. The text has been edited to assure anonymity and, as well, to facilitate readability. (For interested readers, the original text is available under appropriate circumstances.) To save space, for a given date, paragraph breaks are denoted by the ¶ symbol. The gender and race of the person is specified (when known), respecting increasing evidence that at least some features (sensu strictu)(37) of NF1 reflect gender bias(38) and/or racial bias (e.g., optic pathway glioma; unpublished observations). In addition to the “medical” or “clinical” details,” the general and specific understanding of NF1 details and the overall civility and alacrity of the correspondents is striking, sometimes even astounding. One patient and his physicians provided NF1 neurofibroma mast cell density data at various time points during the ketotifen treatment,(39, 40) documenting a benefit by this criterion. The teamwork between the patients and physicians is striking at times.

 

KSDT-1 is a gentleman whose NF1 had been symptomatic in terms of renovascular dysplasia, at least one diffuse plexiform neurofibroma (DPN; epineurial neurofibroma) and multiple cutaneous (endoneurial) neurofibromas and subcutaneous (perineurial) neurofibromas.(41) He contacted me in July of 2010 to advise me of his prior treatments and his close-working relationship physicians in these regards. He expressed a keen and prescient concern that there was a realistic alternative treatment option. I suggested ketotifen. On the basis of my email-transmitted advice, he began taking ketotifen in September 2010.

27 July 2010. Dr. Riccardi, I am active in my country’s NF self-help group. I am a 45-year-old man with NF1. Over time, I have had a lot of problems with many cutaneous and subcutaneous neurofibromas. There have been many occasions when CO2-Laser and ordinary scalpel surgery were needed. My doctor also used Gleevec®, 200 mg a day, from 20 November 2009 until 8 February 2010. The first eight weeks were “OK.” My neurofibromas showed a color change and itched more, and I felt tired. In weeks 9 and 10, I was very, very tired. A lot of new neurofibromas were visible and a few neurofibromas had enlarged. My plexiform neurofibroma was also growing. We stopped the Gleevec®. In the last few months, I had many neurofibromas surgically removed. For some of them there were mast cell counts to assess the treatment. The mast cell densities of the neurofibromas varied from 160 to 310 cells per mm2. I hope that you can tell me more. What is a normal level of mast cells? What is a normal level for NF1? Is it OK or wrong to have high levels of mast cells? What is the cause of a higher level of the mast cells? How can we the best stabilize the mast cells? Can the higher mast cell level make the NF worse (more neurofibromas)?


28 July 2010. Sir, Gleevec® is not yet considered to be reasonable treatment of neurofibromas that are not life-threatening. Have your doctors tried ketotifen (brand name Zaditen®)? I have published on the efficacy of this medication for your type of situation: I am sure your doctors could find the references promptly. A dose of 4 mg to 6 mg a day for an adult is usually well tolerated, and perhaps even 8 mg a day may be considered. Please advise me if this information helps. Best wishes, VMR


29 July 2010. Thank you for your email. I will give this information to my doctor. He talked about ketotifen, but he is not convinced that it works. I will ask for it, I will try it. I read the introduction (first 150 words) of your article, “Mast cell stabilization to decrease neurofibroma growth: Preliminary experience with ketotifen.” The rest is “hidden” for me. The mast cell densities in neurofibromas from my head, arms and body were 160-310 per mm2. I will later give you more information. Thank you.
24 September 2010. I was seen today by my dermatologist. The NF-team accepted a test with ketotifen (Zaditen®), 4 mg per day. Monday I will start. Three weeks later he will see me again for a check-up. On 22 October, I go to the hospital for an operation (neurofibroma).
13 October 2010. Yesterday I was in the hospital for a check-up. The doctor was very content. In his eyes I look better and my skin seems restful. We go on with Zaditen® at 4mg a day. At the end of the month I go for a small operation: we will count the mast cells in the neurofibromas. I ask you if we may publish (post) your article about ketotifen treatment of NF on our website? We hope that we can help more patients with this information.


Thank you for this very important feedback. I will obtain PDF files of the articles about ketotifen treatment of NF1 and make them available soon. Attached is an edited version of our email correspondence. Please let me know if my rendering matches your thoughts and concerns. Ultimately these exchanges should be published, preferably with [your dermatologist] as a co-author. [Regarding the] mast cell number data … do you have a copy of the laboratory report that I might review to understand the material better? VMR


Thank you for your [interim] email. I do not yet have a copy of the laboratory reports. I will send the dermatologist a copy of this email and ask him for more information. Perhaps he can send you a report of my operations and skin condition. For me that is no problem: I give my permission to him and you. I did read your version of our email correspondence: it is OK.
16 December 2010. Thank you for your support in 2010. Report: I’m feeling fine. It seems I have more energy. The Zaditen® (5mg per day) is going OK. I feel no side effects of the drug. In the last study, mast cell density was lower than the lowest ever before: the neurofibroma had only 100 mast cells per mm2. At the beginning of January, I see the dermatologist for a check-up. Thanks for helping me.
15 February 2011. As agreed, here is an update. Last Friday, I saw the dermatologist: he was very happy. I feel good … got more energy … my skin looks better. The coloring of the neurofibromas is better. I have less pain and itching. On 2 March we will remove three neurofibromas. The neurofibroma mast cells will again be counted. I still take 5mg Zaditen® per day – it seems that it works.


I am very pleased for you. Please keep me informed as time goes on. VMR


4 October 2011. It is now 1 year since I started Zaditen. I am very happy that I started it. My skin looks much better and there is less pain (pinpricks) and less itchiness. My neurofibromas look calmer than before. I have more energy and I feel contented. No surgery is needed at this moment. In August, I had my best holiday in three years: over 15 days, we walked more then 120 km (75 miles). The hot temperature (35°-40°C) was no problem for me and the NF. Last Friday the dermatologist was satisfied with our results. I keep going on with the Zaditen®, 5mg a day. By the way, do you have PDF files of the articles about ketotifen treatment of NF1? May I have copies of them? I will email feedback if there is news.


I am pleased that you have had this very positive response to the treatment. VMR


12 December 2011. The MRI scans look good: no neurofibromas found about the head and spinal cord. The PET scan shows something in the head of the pancreas. On 29 December, I will have a CT scan of the abdomen. Merry Christmas.
3 January 2012. I wish you a happy and good 2012. I hope you can help me with a problem. In the past two weeks, twice I was asked the same question. One child, 2 years old, has a glioma on both optic nerves. He has increased brain pressure. The child is known to the NF team at the academic hospital. We look forward to hearing your advice in this. We thank you very much for your answer.


I expect this child needs surgery – IMMEDIATELY. VMR


9 March 2012. Good news to report. The Zaditen® does its job. The number of neurofibroma mast cells has declined further. The highest number previously was 308 and the counter stops now at 74. More information will follow soon.


This is all very good news – both for you personally and for instigating me to follow-up and promote the more aggressive approach to using ketotifen. Thank you for keeping me informed of your progress. VMR


18 June 2012. Please note the following. At first, we thought I had a problem with my prostate, but my [PSA] blood level was good (0.4). A bladder infection was excluded. My primary care doctor inquired about the Zaditen®. I have taken this now for more than 1½ years. The drug-packaging leaflet states that cystitis can occur. What are your experiences with this? For me it is a rather annoying side effect that does not outweigh the decrease in mast cells. But, it does pose social constraints, as I go to the toilet very often. Do you have advice for me? Tomorrow I will discuss this problem with the dermatologist.


Based on my personal (patient-related) experience and a very recent search of the biomedical literature, I am reluctant to presume a causal relation between possible prostate pathology and ketotifen administration. VMR


19 June 2012. Today I saw the dermatologist in connection with the problems noted yesterday. He read your comment and a consultation with a urologist was requested. I also have some lab results for you, specifically, neurofibroma mast cell densities, expressed as the number of mast cell per 2 mm2 for each neurofibroma.

15 Jan 2010 200
11 Jun 2010 160
25 Jun 2010 216; 219; 326
16 Jul 2010 236; 218
22 Oct 2010 100
2 Mar 2011 103; 106; 91
24 Feb 2012 72


These numbers are very helpful. Thank you. VMR


20 June 2012. I started Zaditen® on 28 September 2010. In addition to the results provided yesterday, I also have less itching and pain. Another consideration is that I have much more energy than before. I use 5 mg per day of Zaditen®, 2 mg in the morning and 3 mg after dinner.


The data are better than I had hoped. We really must publish this. I will begin the writing and will be asking for your input on various details. Thank you for starting something that will help so many other people. VMR


Thank you for your [interim] response. I feel honored you are going to publish our work together … it looks promising. I am feeling OK. I am willing to provide as much information as possible in the interest of fellow sufferers.
26 September 2012. Here everything goes well. In 14 days we will remove some neurofibromas – wondering how the mast cells are behaving. I recently saw the urologist and he has not been able to find anomalies. Perhaps my bladder is just occasionally “stimulated.” ¶ I am still getting good help with the Zaditen®.


I am pleased you are doing so well. VMR


9 February 2013. Everything is going well with me. I continue using 5 mg Zaditen® per day and I feel like “a fish in water.” Twice a week I engage in sports for 1½ to 2 hours, focusing on “cardio fitness.”


10 February 2013. I am pleased you are doing so well on the Zaditen®. VMR


23 April 2013. I have the results of the mast cell counts for two neurofibromas removed at the end of 2012. Unfortunately, the results are disappointing. While the values ​​of 160-308 mast cells per mm2 had dropped to 74 per mm2, we now have a neurofibroma with 150 mast cells per mm2. Have you seen this development in your research? I also went camping recently with some problems. My plexiform neurofibroma has grown and it feels different (sometimes pain). I sweat less or not at all during exercise (cardio fitness). I have [edema] in my lower extremities. Could this be from long-term use of Zaditen®? I have used it for 31 months at 5 mg per day.


Remember that ketotifen is only part of the picture. Likewise, mast cells are only part of the picture. But, for the time being, the ketotifen is a reasonable approach to avoiding maximum neurofibroma growth. I encourage you to continue the Zaditen at the present dosage. VMR


24 April 2013. I will continue to use the Zaditen® at 5 mg per day. It is reassuring to hear from you that it is only one link in a great chain. I am so happy that I have much less pain and barely any itching. Thank you very much for your support.


12 November 2014. It has been a while since we last visited. In the meantime, I have become especially enthusiastic about using ketotifen for early treatment of NF1. If treatment is early enough, it seems to arrest the cutaneous neurofibromas at a very early stage. I would like to hear from you in terms of your ketotifen experience – whether or not it fits my expectations. As a start, please let me know how you are doing now and what is your ketotifen status? We will go from there. VMR


Thank you for your message. I had been anticipating the opportunity to send you an update. Things are actually very good with me. I have been using Zaditen® for over 4 years. I now experience much less itching and pain. There are no or barely any new neurofibromas; some have even become smaller or disappeared from the picture. I continue using 5 mg per day. I did not need surgery last year. My renal artery stenosis and aneurysm are stable and my blood pressure is well controlled [with antihypertesive medication]. I wonder whether there is new information about Zaditen® and NF.


14 November 2014. Thank you for your prompt reply. I have recently come to realize there is a fairly large number of persons with NF1 who have been treat treated (or treated themselves) with ketotifen/Zaditen®. The results seem to be uniformly positive, with a definite decrease in the symptoms and growth rate of the neurofibromas. However, many in the NF1 field are skeptical. Why? I do not know. In any event, we need stories such as yours to clarify that ketotifen works in NF1. For the time being, what you have provided is enough. And I will keep you informed of progress. Believe me – I am pressing this matter so as to improve the situation for many persons with NF1. Remember, one of the problems is that the USA FDA has not approved the drug for routine clinical use, which means that most American physicians just ignore this as a treatment approach. I will not ignore this matter. With your help – outside the jurisdiction of the FDA – we will make progress here. VMR
14 January 2015. I have spent most of today and much of the previous week going over material that substantiates the utility of ketotifen in treating NF1. In particular, I have been reviewing our correspondence since 27 July 2010. I think that together you and I have been a great team: we will use your information in the context of my additional experiences so that – once and for all – we shall MAKE CLEAR THAT KETOTIFEN IS EFFECTIVE TREATMENT FOR NF1 NEUROFIBROMAS. It is not “perfect,” but we have made very substantial progress. As I proceed with the manuscript, I will keep you posted and seek your feedback at certain points. In the meantime, I hope that your New Year is off to a good and that 2015 will be good for you. VMR


18 February 2015. Dear doctor Riccardi, today I received the following message from a fellow sufferer. He has also recently started Zaditen. Slowly doctors dare to give Zaditen. [He] wrote: “We started with a dose of 2×2, but today it is [increased] to 3 & 2. Crazy … I feel much fitter and [have] less itching … my doctor told me this morning that it could take 6-9 months before the body has adapted all [the way]. To date, no side effects or anything, but if I feel better (maybe it’s mentally) then that’s fine. I’ll keep you informed of developments …” I hope to have informed you sufficiently.


KSDT-2
is a man who began our engagement when he was 68 years old.

26 January 2001. Dr. Riccardi: I was fortunate to get from a friend, who brought them from Thailand, several hundred ketotifen tablets. However, I have run out. He said that they cost $20.00 per hundred in that country. I first came upon this wonder drug from your posting on the internet several years ago. ¶ I’ll tell you this … if nothing else I have been free from the itch for the first time in memory. Also there is a feeling of overall well being that seems to accompany the loss of serious itch sensations. I am 68 years old and full of lumps on my arms, legs and groin areas. A couple of those nodules and the dark spot on my right leg that was 15 inches long and shaped like California has lightened up and is hardly discernable. I met a cab driver recently that had the worst case [of NF1] I’ve seen and I [thereby] know how lucky I am having no facial conditions at all. ¶ My wife and I have no children because that is the civilized thing to do. I only wish more people would have that [same] responsible position. People should forget their egos and not have children until this dreadful disease is dealt with. ¶ I hope you can help me. First, what I need to know is what do they call ketotifen in Mexico? Recently a young man I am acquainted with now lives in Mexico. He said that he would gladly send me a supply and I am hoping that he can do that. If there is another way that you know of to obtain the pills please let me know. My Doc has given me a prescription. ¶ Thank you for ketotifen. I‘d appreciate your timely reply.


Sir, more later, but, now simply a note to acknowledge your very important (unsolicited) testament. You’re right on the money and reflect the sentiments of many others who’ve used ketotifen in the midst of their NF1. The brand name is Zaditen®, anywhere, including Mexico. Best wishes. I’ll be in further contact soon. VMR


5 February 2001. Since I wrote to you recently, I have exhausted my supply of Zaditen®. I did a long search on yahoo for a source in Mexico with no success. The liquid form for eye itching is all I found listed. Could you possibly recommend a source? ¶ When I stopped taking the pill, my itching and general well being was almost immediately affected. In fact, at first it seemed to be more severe but has eased up some today. Three small [neurofibromas] in the palm of my right hand definitely appeared to swell up and I could see a redness that had appeared in the area. ¶ Mostly what I found in my search were sites wanting to sell lists of pharmacies. I also thought that maybe since it was not a prescription drug in Mexico that could be the reason I could not find it on the few sites offering drug lists to search. I appreciate any help you might provide.
12 August 2007. Dr. Riccardi …. back in 2001 you sent me a reply to my email to you. You stated in your email to me “more later”, however, I did not hear from you again. That’s ok! ¶ I want you to know that since 2000 I have been taking ketotifen. 2 pills a day in the morning. That’s about 7+ years of use of ketotifen. I [previously] got it at a very reasonable price from a reliable pharmacy in Thailand: $28 per hundred. I order 300 at a time. ¶ I definitely can state that using ketotifen has controlled itching. Also it appears to me that I have not had additional growths although some seem to be somewhat larger. I think that may be due to loss of body [tissue] due to aging. ¶ I am writing to you regarding is there any new advanced knowledge regarding ketotifen. My personal Doc knows I take ketotifen but never has even commented on that fact. Believe me, when you mention NF in medical circles it comes up empty. ¶ Most of my growths are on my arms and legs with an additional number scattered about my body. My one very large brown spot which was on my upper left thigh, running from above my knee to my torso, has completely disappeared. ¶ What I was interested in knowing is … has any updated info regarding ketotifen come on line since I last emailed you? Plus I put myself available if my time using ketotifen may be of any importance. ¶ I must add that my wife, many years a nurse, has provided me with strong support. ¶ Oh! I almost forgot to mention that “Zaditor®” eye drops, the active ingredient of which is ketotifen, is now available over-the-counter in the US. I have always had dry eye, out of focus at times, eye problems, and this one drop a day regimen has stopped this problem 90%. So one can’t purchase ketotifen tablets in the US but one can in eye drops and without a prescription. How about that. I’d appreciate your reply.


23 August 2007. Thanks for your note. I am pleased that you are able to achieve the relief you have documented so well. Mast cells – the target of ketotifen – are now very important in NF1 research. The dilemma of Zaditor® versus Zaditen® is interesting and reflects decisions made both by the FDA and the manufacturer, Sandoz. I look forward to hearing from you periodically. VMR


3 March 2009. I have NF-1 and have been taking 2-mg of ketotifen twice per day regularly for approximately 12 years. I started taking ketotifen after reading your article and after securing a source for the drug. Have you continued to follow any patients who have also taken the drug for an extended period? It seems that more attention is being paid to the role of mast cells since your publication. Do you have any new thoughts about whether ketotifen is useful to NF patients?


4 March 2009. I am gratified to hear that you have maintained the 4 mg per day of ketotifen as treatment for your NF1. There is no question in my mind about whether this medication decreases the number and rate of growth of neurofibromas. The only question has been whether there is a better medication than ketotifen. There probably is. However, due to institutional politics, the early work was treated with disfavor by [one organization], the net effect of which [has been] delay in finding a better medication (see Appendix 1). However, now that institutional politics has been trumped by documentation of the key role of mast cells in mice neurofibromas,7, 42, 43 we will be advancing towards improvement on the ketotifen. In the meantime, you have done yourself well and I expect that others such as yourself will come forth and provide another type of documentation that mast cell blockers are important in treating NF1. In short, until a more efficient, more effective drug is available, I continue to encourage the use of ketotifen as a means of decreasing the number and growth of cutaneous neurofibromas and decreasing the rate of growth of subcutaneous, nodular plexiform and diffuse plexiform neurofibromas. I look forward to learning more about the course of your NF1 over these 12 years that you have been treated with ketotifen. Best wishes, VMR


 

KSDT-3 is a 40-year-old woman who originally contacted me in early 2009.

10 March 2009. Dr. Riccardi, thank you for your e-mail and I apologize for my delayed reply. I definitely believe that ketotifen has reduced the rate of formation of new [lesions], especially the subcutaneous ones. These are the ones that I would describe as hard, under the skin and painful when hit. I think most or all of the subcutaneous ones that I developed over the years were a result of trauma. I remember your commenting on the role trauma may play in the formation of neurofibromas at a lecture [I attended]. You spoke of a patient who was bitten by a horse and subsequently developed a neurofibroma. The only time when I deviate from my dose of 2 mg of ketotifen in the morning and evening is if I have some sort of physical trauma occur. In that case, I immediately take 1 mg. It may have more of a placebo effect, but over the last 12 years, I have had [only a] few new subcutaneous neurofibromas form of which I am aware and the size of existing ones has remained stable. I have met other NF patients who can associate particular neurofibromas with physical trauma. One in particular developed a neurofibroma after being bitten by her dog as a child. ¶ I am 40 years old and have had many issues with NF1: scoliosis (rod-fixation and fusion), hydrocephalus (ventriculo-atrial shunt with several revisions), glomus tumor (removed from left middle finger), optic glioma (my corrected vision is 20:20 but have a small defect in my left visual field), and an odontoma (removed at age 15). Even though my hydrocephalus and shunt have the potential to be most catastrophic to my health, the cutaneous problems associated with NF-1 have always been the most difficult with which to cope. To my knowledge, I have no learning disabilities. I earned a Masters in Computer Science and a Masters in Math for Teaching. ¶ In 2008, I had three electro-desiccation surgeries. The first focused on removing several hundred cutaneous lesions from my anterior surface, especially the face. The second surgery focused on cutaneous lesions on the posterior surface and the third focused on removing about 30 painful subcutaneous lesions from all over my body, as well as any lesions that were missed during the previous surgeries (see Appendix 1). I have not felt this comfortable in my body in many years. Insurance has always paid for the removal of my neurofibromas, whether by traditional excision method or electro-desiccation. The cost difference is remarkable. Even taking the hospital, anesthesia, pathology and surgeon’s bills into consideration, the cost per lesion is $30 using [electro-desiccation] and $300 using excision. ¶ I will continue taking the ketotifen as long as I have access to it. It is disappointing to me that ketotifen has never become available in the US in tablet form. If you want additional information from me I would be happy to provide it.


11 March 2009. Attached is an MS Word file that is simply a copy of our email exchanges on the first two pages and an “anonymous” version on pages 3 and 4. I would like to have your permission to show the material of pages 3 & 4 to colleagues and other interested parties to promote the potential benefits of ketotifen. Please specifically give me your permission to do so in a follow-up email. I also find it very important that you have the Masters Degree in the fields you do. I would like to discuss some of the reasons why and also to ask you other questions having to do with spatial-based cognitive talents, as well as questions about your sleep patterns. Perhaps we can speak by telephone sometime soon at your convenience. Best wishes, VMR


13 March 2009. Here is my statement giving you permission to use my feedback. ¶ I give Dr. Vincent Riccardi permission to use any of the information from our email exchanges in whole or part. [signed] ¶ I would be happy to speak with you. After 4:00 PM would work best for me… it would allow me to leave work and speak with you more openly from my home. I look forward to hearing from you.

 

KSDT-4 is an intensely motivated woman.

16 October 2007. Dr. Riccardi, it has been a long time since I have sent anything to regarding your awesome past research on ketotifen. You may recall I have taken ketotifen since 1991 – and with great success. We spoke several years ago, when you sent out letters to many of those you were following who used/use ketotifen, myself included. I have decided again to go off it for a while and I am searching for another mast cell blocker available here in the USA that may be somewhat comparable. I know there is nothing [exactly] comparable, but a close match would be nice. I have taken Cell Forte® in the past and have started again. There has been some research into its ability to shrink cancer tumors and at one point a woman felt it might being doing same for her son’s plexiform neurofibroma. I have a plexiform neurofibroma on which there have been several surgeries, including a reconstruction of the lower orbital area. As you know, it grows at will. There are new accomplishments being made with NF, but you have always been the one I felt did most and was the least acknowledged. If you have any suggestions on the mast cell products available here, I would greatly appreciate it. Singulair® did not work for me on the allergy or itching areas. If [you have no suggestions] I guess I will do my own hit-or-miss experiment. I thank you for your time and all your research in NF. God bless you.
20 January 2015. [Respecting our telephone conversation yesterday, please consider the following.] Ketotifen was a remarkable treatment for my NF 1. I took ketotifen for eleven years to treat a large plexiform [neurofibroma] that encircled my left eye and cheek. The time [interval] between surgeries while on ketotifen for this neurofibroma went from two years to seven. The ketotifen remarkably slowed the re-growth down. At one point, the extensive bleeding issues I had experienced during surgery before ketotifen required an over night hospital stay. The ketotifen greatly reduced the [surgery-associated] bleeding. I also had experienced extreme itching (common to NF1) that ceased after starting ketotifen. Ketotifen was a life saver for me. My regret is the unavailability – [it is very difficult] for me to get it now. For those who have NF1 and have access to ketotifen, I would recommend obtaining it.

 

KSDT-5 is a male physician.

11 May 2009. Hello. I am a pediatric hospitalist [in the Southern United States]. I’m writing to ask about your experience with antihistamines and plexiform neurofibromas. I have a special, personal, interest in this because my daughter, now 18 months, has a plexiform neurofibroma involving her right orbit and cavernous sinus. She has had this since birth and it had grown steadily during her first 12 months. About 3 months ago, one of her physicians prescribed Periactin® for her because of eating/appetite issues. It seemed to help a bit on that front. She had a follow-up MRI last week, and the cavernous sinus portion of her tumor had shrunk by about 15%. This led me on a search of the literature, which led me to your article “Mast-cell stabilization to decrease neurofibroma growth. Preliminary experience with ketotifen” from 1987. Though the data were early, I found it fascinating. It is quite possible that my daughter’s improvement is coincidental (I understand that plexiform neurofibromas grow in fits and starts) or that it is a measurement error on the MRI. It does seem biologically plausible, however, given the role of mast cells in NF1 pathology, that Periactin® could have played a role. My question to you is whether you know of any research done since your original study in this line of inquiry. If it hasn’t been done, it seems like a randomized control trial would be helpful (and I know several folks around here whom I could cajole into participating). Several medications like ketotifen or Periactin® or cromolyn might be promising, especially given the known safety and minimal side effects of these drugs. I appreciate your time and look forward to hearing from you – and thanks for all your work in NF1 research so far!


11 May 2009. Sir, thank you for your thoughtful email. Unfortunately, the original work I did with ketotifen was subjected to the oft-present tyranny of institutional politics. In short, [there were some who were] unscientifically averse to both the line of reasoning that led to the trials and to the results of the trials. So for some time it became a “back burner” issue, dormant, as it were. However, as the NF1 mouse models have made unequivocally clear, the mast cell is critical – as I proposed in the mid-1980s – to NF1 neurofibroma formation and progression. Thus, since the end of last year, more data dealing with patients have appeared, though nothing resembling a “trial.” I never considered ketotifen to be “the answer” to the optimal control of NF1 neurofibroma growth and progression. I rather thought the ketotifen work had established a “proof of principle” at the clinical level. The second study was a randomized double-blind protocol and was very convincing, with especial regard to ameliorating excessive pruritus and minimizing small vessel bleeding at surgery. Of course, corroboration from other centers is warranted, preferably with a medication even more potent than ketotifen. An adult has no problem tolerating 4-8 mg of ketotifen a day, especially if a portion is taken at bedtime. Other than minor drowsiness and unexpected [minor] weight gain, there are no significant side effects. For a child, especially a toddler, I insist that the child’s pediatrician prescribe and monitor the treatment. A syrup preparation is available. I have continued to monitor a number of patients who have continued ketotifen treatment of the NF1 for many years and there is every reason to be enthusiastic, nonetheless acknowledging the shortcomings of open-label adventures of that type. I am most impressed, however, with the number of people, who have drawn the conclusions you have. As you might imagine, a number of other such parents/patients have contacted me by telephone, post and email. If there is anything I can do to facilitate the lighting of some key intellectual “fires” to pursue anti-mast-cell treatment protocols, please let me know. Cromolyn is very poorly absorbed through the GI tract, but its direct application to mouse neurofibromas has the anticipated salutary effects. Its topical application may be an important consideration for treatment of neurofibromas of the cutaneous and diffuse plexiform types (sensu strictu). I look forward to visiting with you further in these matters as you see fit. VMR


1 June 2009. Thanks so much for your response. While not a cure-all, I do think there is promise in mast cell therapy for NF1. I have gotten one of our geneticists interested in the possibility of a study and need to assemble a few more folks to see if we can make this happen. If it’s OK with you, I may contact you again once we have thought through possible protocols in depth to get your thoughts. Again, thanks for your input.


Sir, please feel free to contact me, engage me, as often as you would like for the purposes of advancing our understanding and therapeutics of NF1. Best wishes, VMR


 

KSDT-6 is an 11-month-old American white male infant whose parents consulted me in November 2014 to consider possible strategies for minimizing the impact of his disorder over time. His NF1 diagnosis is based on more than six CLS and multiple early cutaneous neurofibromas, the latter having been identified early on by his mother and documented by histopathological means. At the present time, these appear to be his only NF1-related problems, although additional studies, such as cranial and whole-body MRI scanning and ophthalmologic examination have yet to be performed. I shared with the parents my sense of moral and ethical obligation to discuss with them the possibility of preemptive treatment with ketotifen to minimize the likelihood that such early-onset cutaneous neurofibromas were a harbinger of a substantial life-long cutaneous neurofibroma burden. To that end, we discussed the lack of American FDA approval of oral ketotifen (except for several research projects related to fibrosis and wound-healing) and that, therefore, obtaining the medication would require a source outside of the USA. The parents and I have carefully addressed the strategic and logistical issues, including proper close follow-up by both a general pediatrician and a Recklinologist and the actual procurement of the ketotifen. Obviously, this case is not presented to expound the success of ketotifen treatment. Rather, I include it to share the dilemma of having a potentially beneficial outcome compromised by living in the rare – if not the only – country in the world where its citizens have no ordinary access to ketotifen. At the least, this situation declares the need for both additional financial and manpower investment in documenting the benefits of NF1 ketotifen treatment and interim flexibility when so much is at stake.

 

KSDT-7 is a 38-year-old Hispanic woman with NF1 who lives in a country where ketotifen is regularly available (under a variety of brand names). Specifically for her NF1 neurofibromas, ketotifen has been prescribed for over 11 years, at 4 mg per day. Physicians familiar with her case have informed me that the ketotifen has been without adverse side-effects and has remarkably decreased neurofibroma-associated symptoms (itching, pain) and retarded both the appearance of new cutaneous neurofibromas and the progression of established ones. When I visited with her in a social, non-clinical setting, her bare arms, collar regions and face were distinctively different from what is typical for an NF1 person in her age range: the skin surface was smooth and free of obvious neurofibromas. While this type of encounter hardly substitutes for a more rigorous professional examination, it exemplifies why ketotifen treatment can be so important to persons with NF1 – their disorder does not then declare itself under ordinarily casual, social circumstances(44-48) I was impressed.

 

KSDT-8 is 21-year-old Hispanic man with NF1. He lives in a country where ketotifen is regularly available (under a variety of brand names). He is the son of a physician who has overseen the prescription of ketotifen, 4 mg per day, for over 10 years. The father reports no adverse effects and notes that the ketotifen has remarkably diminished the rate of appearance and progression of cutaneous neurofibromas. There has also been an improvement in the son’s overall sense of well-being, at least to the extent that this young man is now much more casual and relaxed in public. Again, this is hardly scientific, but, as noted above, it touches on the day-to-day considerations that contribute to an NF1 person’s ordinary activities.(44-48) At the least, such considerations must be taken into account in the immediate and long-term assessment of the ketotifen – even as we endeavor to be more rigorous in our investigations and attempt to identify more effective pharmaceuticals.

 

KSDT-9 was initially evaluated as a 7-year-old white boy with presumed NF1, respecting his accompanying multiple CLS and neurofibromas. Although originally a participant in the Baylor NF Program (BNFP) Zaditen protocol 3093,(2, 3) his long-term treatment with ketotifen was based the self-determined commitment of his family to the treatment regimen. His main problem was a distinctive pattern of cervical and lateral facial subcutaneous neurofibromas that were extremely painful, tender and deforming, eventually requiring a permanent tracheosotomy for respiratory embarrassment and hearing aids for blocked external auditory canals (Neurofibromatosis: Phenotype, Natural History and Pathogenesis, 2nd Edition (4), pages 359-364). He responded well to the ketotifen, 4 mg per day over 17 months: a marked decrease in the itching, pain and tenderness, as well as a slowing of the apparent rate of growth compared with the prior 18 months. However, shortly thereafter he died in his sleep associated with a respiratory viral infection. We can only speculate that he could have had a much more benign outcome if the focus had been on early treatment and preemption of neurofibroma growth rather than simply waiting until these mass lesions were treated post hoc as neoplasms amenable only to anti-neoplastic agents and surgery. It is he who, over the years, who has most motivated me to pursue an approach to neurofibroma preemption, starting with promises of mast cell stabilization, currently (and then) in the form of ketotifen. Representative photographs are available as Figures 22-1, 22-2 and 22-3 in Neurofibromatosis: Phenotype, Natural History and Pathogenesis, 2nd Edition.(4)

 

KDST-10 is a friend of on of the other KSDT persons.

I and my son have NF1. We both have prescriptions for Zatiden®. My son consumes five mg per day, two in the morning and three in the evening.  I take two in the morning and two at night. Both of us – as far as we can see – show no external growth of the neurofibromas. They “stay stable.” And, very good news: there is also less itching and pain.  They also feel less “intense.” “Outsiders” – other persons who pay attention – apparently can see the difference.  I think the NF1 investigators in America will be happy with this information.

Having begun the treatment more recently, I certainly feel “fitter” taking the medication. My son has been on treatment for so long that he is uncertain about the “before and after” difference.  But what strikes me is that, while he is well into his puberty, yet we see no growth of existing neurofibromas or increases in their numbers.

I hope you are happy with this information.

 

KDST-11 was made known to me on 25 June 2015.  She is a European woman born in 1987. For four (4) years she has been taking ketotifen (Zaditen®). Based on her having NF1, she began at 1 mg twice a day, but has been 2 mg twice a day for some time.  While on the medication she has experienced less neurofibroma-associated itching and has not developed “new” neurofibromas.  She considers that she has responded “well.” She has been treated under the aegis of her primary care physician (GP), who was “open to it when she asked for this pill and when she asked to increase the dosage.”

 

DISCUSSION
NF1 is a potentially more manageable disease than it has been, providing that appropriate treatment strategies are employed. Currently, the treatment approach to NF1 neurofibromas is compromised for at least two reasons. First, treatment of NF1 neurofibromas presently is considered only after they have substantially intruded into the patient’s life, in terms of size and/or associated symptoms (e.g., itching, pain, tenderness). Second, NF1 neurofibromas are presumed to be tumors under any and all circumstances. As regards the latter, I have proposed previously(3, 4, 49) that, at least in the initial stages, NF1 neurofibromas are actually aberrant wounds, that is, “wound-healing gone awry.” Support for this pathogenetic schema has been provided by A. Lloyd and her co-workers,(20) who demonstrated the consistent development of neurofibromas at the sites of surgical trauma in Nf1+/- mice. Moreover, an initial wound-healing phase also reflects on the first prejudice, with consideration of treatment before the neurofibromas are fully developed.(8, 9) That is, early-stage treatment affords the potential of preempting maturation of early neurofibromas, a cogent alternative to a post hoc strategy of merely reducing the size and/or function of these mass lesions.

 

The data from the cases presented here, combined with the consequences of early childhood intervention,(21) the initial formal protocols,(2, 3, 50) a 1989 German publication,(35) and documented in vitro mast cell stabilization compromise of neurofibroma-derived cells(36) provide compelling evidence that early treatment of NF1 neurofibromas is a realistic therapeutic strategy. In addition, the combined data specifically substantiate the efficacy of ketotifen, a mast cell stabilizer, as an agent for employing this strategy.

 

An estimated 90,000 Americans and 2,000,000 persons world-wide have NF1. Current treatment protocols for NF1 neurofibromas include 1) surgery for removal or size reduction and 2) non-specific co-opted anti-cancer chemotherapy. Moreover, the latter approach has been disappointing, with only occasional effectiveness.(51-53) In addition, as presented in this paper, most physicians and NF1 patients are unaware of ketotifen and its success when administered as a long-term early treatment. The patients discussed in this paper discovered the potential utility of ketotifen through their own library and internet researches. Each NF1 patient or their parents were looking for a “cure” for their condition or, at the least, relief from their symptoms. Each person was searching for a better quality of life, relying on literature searches and discussions with their physicians. Although there is no “cure” for NF1, the nine patients considered here have documented that ketotifen might be what they were looking for and that self-determined ketotifen might be a potential answer to their personal needs.

 

Each story is different. The patients reflect the broad spectrum of symptoms that NF1 presents. In this context, there are three significant conclusions to be drawn from their experiences.

· First, the available information on the efficacy of ketotifen as a potential NF1 treatment is limited. This is demonstrated by the      communications with me serving as the sole source of education and mentoring about ketotifen, particularly its potential use in NF1 and then how to obtain it (see Appendix 1).
· Second, the medical community is also insufficiently knowledgeable about this potential NF1 treatment and its apparent successful results. I have occasionally been contacted by a physician of an NF1 patient (or parent) who had brought this matter to the attention of the doctor. Once this contact was made, a number of physicians prescribed ketotifen as treatment for NF1. It is especially noteworthy that self-determined ketotifen treatment is relatively more likely when a parent is a physician himself or herself. As indicated herein, follow-up communication with the patient and/or physician has provided another format in which the ketotifen has been shown to be effective. In most instances, the NF1 patients have shown less neurofibroma-associated itching, pain and tenderness, fewer new cutaneous neurofibromas, slower neurofibroma growth and an increased overall sense of well-being, either or all which have contributed to an improved quality of life.
 · Third, oral ketotifen is not routinely available in the United States, reflecting primarily the decades-old lack of FDA approval for the treatment of asthma. (Lack of approval was not on the basis of toxicity or adverse effects.) Thus, for Americans seeking self-determined ketotifen treatment for NF1, they had to obtain the drug outside of the US.

 

For 90,000 Americans living with NF1 not to have the option of treatment with ketotifen is disappointing. This is an issue that needs to be addressed. At the least, the medical community should be informed. If there is something that might effectively, safely and inexpensively improve an NF1 patient’s quality of life, it should be more readily known to both the patients (or their parents) and the involved physicians. It is the goal of these patient/parent testimonials to enlighten the NF1 community – patients, family members, support groups, physicians and other health care providers – to pursue further action. Making ketotifen available in the United States as a treatment option should not rely on the “self-determined” approach portrayed in this treatise.

 

 

APPENDIX 1
The human genetic disorder, Neurofibromatosis Type 1 (NF1), is very complex in that it has many elements and becomes progressively worse over time. Among the elements are neurofibromas, which account for 1) the disorder’s name, 2) many of the disorder’s clinical elements, whether as features, consequences or complications(37), and(3) the disorder’s primary cause of death, malignant transformation to sarcomas, most often neurofibrosarcomas (sometimes referred to as a “malignant peripheral nerve sheath tumor” (MPNST).

 

Most often, neurofibromas are approached in the singular, one neurofibroma at a time, e.g, a cutaneous neurofibroma(41) on the hand, a diffuse plexiform neurofibroma involving the entire left lower extremity,41 a paraspinal nodular plexiform neurofibroma(41, 54) involving the right first thoracic dorsal root ganglion. More recently, however, especially with the advent of “whole body MRI” technology, we can address an NF1 patient’s NF1 neurofibroma burden (NNB), which designates the total number of neurofibromas (of all types) and the sum of the mass, e.g., “total tumor volume” (TV)(55-58) or “total surface area” (TSA).(59-63) By focusing on the NNB, we consider the NF1 person as a whole, both in terms of four specific parameters and in terms of a strategy to minimize (preempt) the entire NNB, not just the presence or consequences of just one or several already symptomatic neurofibromas.

 

The four specific NNB parameters include 1) the number of neurofibromas, 2) the summed TV or TSA, 3) the strategic location(s) of specific large or critically symptomatic neurofibromas, e.g., “internal,” such as paraspinal, or “external,” with cosmetic and other functional problems, and 4) the propensity of 10-15% of plexiform neurofibromas (other than those involving the Trigeminal nerve) to undergo malignant transformation (neurofibrosarcoma, MPNST, etc.).

 

In the early- to mid-1980s, I proposed a treatment strategy to address the entire NNB and not simply a post hoc decrease in size and/or symptoms of individual NF1 neurofibromas. To this end, as explicated in this article’s main text, I published material from a series of prospective treatment protocols using the mast cell stabilizer, ketotifen (Zaditen®), with corroborating clinical data from Germany and in vitro data from Japan. Then in 2015, the ability of ketotifen (Zaditen®) to decrease the NNB preemptively in two men treated for 30 and 25 years was published.21 And, finally, I have assembled a series of nine persons considering or implementing a ketotifen self-determined treatment (KSDT) approach. The data from these nine individuals are presented in this document. Added to the publications from 1987 through 2009 cited above, there is little doubt, if any, that mast cell stabilization (e.g., with ketotifen) has the potential to decrease the NNB. Only a Type I Error can account for the delay of such a conclusion. (A “Type I Error” means that a legitimate hypothesis has been discarded or abandoned for the wrong reason. This means that the potential benefits of the hypothesis have also been prematurely abandoned.) In turn, major financial and organizational commitments to reconsidering the original hypothesis are in order. With so much at stake (minimizing the overall NNB and the potential to abrogate the malignant transformation, the number one cause of NF1 deaths) and so little risk (financial and personal), further pursuit and expansion of the NF1 neurofibroma mast cell stabilization hypothesis seems reasonable, even imperative. It can be done.

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