If you have come to this blog for the first time, I think starting at the following page first may be useful. . . .
Unless otherwise specifically noted, all the information I present on this page is in regards specifically for a BEAM fully myeloablative HSCT treatment protocol. So I think this particular blog posting page will have a lot of useful and important information for any MS patients that are seriously interested in actually having a stem cell transplantation procedure to cure their MS disease progression. For those that are not interested in the scientific & practical aspects and results of the treatment, you may find this posting rather verbose and boring. But I think there are likely some people that will find this information useful. And because I may forget a few items in my first-pass writing, I may come back and add or change a few items as time passes. And of course as I continue to track my MS (expected "cure") status over time, I will make future posts to update on that subject.
So today is day +58. Nearly two months since my transplant and closing rapidly on the 60 day mark (which some would argue is the most critical recovery period prone to infections). Total recovery of my immune system will stretch out to a year (I will explain further later in the posting), but it can be argued that the initial most critical time has just about passed. The next most important time to stay alert is until six months out. And then the last phase out to one year. After that (and some childhood immunizations) I should be home free in worrying about possible infections. As I had mentioned before, I'm glad to be back at home with my wife and son. Seven weeks away from Riki was a long time. In fact, of all the discomfort of the procedure that I had to endure, not seeing my son for seven weeks was the hardest.
A bit about my current (today, Feb 24, 2010 - two months following my transplant) health status. . . . . I feel very good but I'm still often quite tired. There are two reasons for this; first because I'm still somewhat anemic and the second is that it takes some time to completely recover from the chemo damage adverse effects.
When I left Germany my red blood cell (RBC) count was about 25% under minimum normal. That made me very winded and tired after even a modest amount of physical effort making it somewhat difficult to do even normal physical activity (I was tired just standing in the shower. . . . I should have purchased a plastic outdoor patio chair to sit in while in the shower similar to the shower bench available while in the hospital which I suggest anyone else to do for their own home shower following HSCT). Based on my blood test from about a week ago, my RBC count is improved now at only about 10% under minimum normal (range minimum normal is 4100 and mine is currently 3700), so I'm not out of breath quite as badly as I was earlier. I'm temporarily taking a multi-vitamin supplement containing 18mg daily Iron to help (men usually should not be taking any Iron supplentation because they don't loose blood like women due to menstration). There are two reasons for the low RBC counts; the first being that when my bone marrow was ablated my body's ability to create new RBC's stopped during the period of time when I had no functional bone marrow. And since RBC's have a limited lifetime (mean half life 50 days), the old ones were not being replaced during this ablation period. Additionally, the daily blood test draws during my hospital stay also contributed to the depletion of my RBC's. (There were a LOT of blood sample draws.) It takes time for the body to manufacture RBC's, so the recovery is slower as compared to the leukocytes and platelets.
Interesting that when I checked out of the hospital my weight was 61.5 kg (135 lbs). I have been trying my best to regain my weight back toward my normal of 68kg (150 lbs), but I have to tell you that it is turning out to be a much harder task than I imagined just to gain my weight back. I'm currently up to 62.5kg (138 lbs) And have decided to just not worry about it. I'm eating just fine (seems like nearly the same as before the transplant procedure, minus sushi), so I've decided to let my body find it's normal homeostatic weight level on it's own. I figure after several more months I will return to a normal weight where it will naturally settle. Probably right aroung a BMI of 21.5 where I have been my entire adult life. In the mean time I just have to cinch my belt a little tighter for now so my pants don't fall down because I'm definitely skinnier that normal. [Post transplant note: my weight recovered normally in another 6-8 weeks later, about four months post-transplant.]
Regarding my taste. . . . I am surprised that as of today my taste is now completely back to normal. Even before I checked out of the hospital my taste was shot from the chemo damage. I couldn't taste anything good. But in a matter of just three weeks following discharge (that's about four weeks since my taste went away), my taste has returned and this happened much more quickly than I expected. I can now pretty much taste everything again. I am so happy. It makes eating so much better, easier and enjoyable!
And then there's the issue of body hair. . . I was warned, and I expected, to loose all the hair on my body. But to my surprise it didn't happen. Not completely, anyway. I lost all the hair on the top of my head and facial area (which I wore as a "badge of honor" indicating the cure for my MS), but didn't lose the eyebrows and eyelashes. And I only experienced "partial" loss on other parts of my body. But I think what surprised me the most is that my tenacious leg hair refused to come out at all. It's all there still intact as it always has been. (Although not all the hair on my body fell out, all the hair on my body ceased growing for some time due to the chemo, including the leg hair. Interestingly, also my fingernails and toenails stopped growing during the same time of the chemo and after they started to grow again there was a "dent" (period of no nail growth) in the nail that occured the same time as the treatment. That marked the time I had the chemo, much the way rings of a tree trunk mark trauma or environmental changes in the history of the tree growth.) As for the hair on the top of my head and face, nascent pubescent baby hair has already started to grow back. On the top of my head it's starting to look a little like a thin layer of dryer lint. So although it doesn't look or feel like my normal hair, I suspect that it will return within a couple of months. Right now I have to shave the peach fuzz off my upper lip every few days. [At four months post-transplant all my hair was growing normally again.]
And here is my two-month post-transplant blood test result (click to enlarge). . .
The good news is that all the "measured" numbers are back into the normal range (including the "innate" immune system, although the "adaptive" immune system has a ways to go before complete recoverey). So the most critical parameters are are doing well, and even my RBC count will be back to normal soon (probably sometime next month). You might notice that after rising, my platelets have dropped back down (although still in the normal range). I think this is an anomoly of the blood test and it doesn't concern me at all. I think the next blood test will show a rise in value that is normal. But it is important to note that this is not the whole story of my blood & immune system. . . . . I borrowed the following graph from the Journal of Biology for Blood and Marrow transplantation (BBMT) of the American Society for Blood and Marrow Transplantation (ASBMT). It shows the relative blood constituent recovery time dependency for various immune cell types following myeloablative stem cell transplantation. You can see that the bacterial- and fungi-fighting Neutrofils, part of the "innate" immune system, come back almost immediately (a good thing). The B-cells, part of the "adaptive" immune system which make antibodies against foreign antigens take a little longer to come back at about six-to-twelve months (and also have a changed epitope and are now "unprogrammed," which is an explanation for why this is a cure for MS). Also, recovery of the CD 3+/4+ cells, T-cells (also with a changed epitope) that directly fight viral infections take nearly a full year to substantively recover, at the minimum. And even following this, stretching out several more years the CD4+ / CD8+ cellular population ratio remains inverted compared to normal. (I find it quite fascinating that this innocuous immune cellular repertoire imbalance persists for such a long time following stem cell transplantation.) So it is logical to understand that right now (at two months post-transplant) my body's full & complete ability to combat viral infections is not yet recovered. So I need to be extra careful not to get sick from a viral infection (although a common cold would probably not be considered a life-threatening condition and my body would probably handle it). My oncologist overseeing my recovery made it clear that if I get a fever of 101.5F (38.6C), or greater, that I should immediately go to hospital emergency and let them know that I am immuno-compromised so that I can be treated immediately. The low CD 3+/4+ T-cells along with the "Natural Killer" NK cells & dendritic cells are also the reason that I have to wait until one year following my transplant to be re-immunized against the childhood diseases that my immune system has "forgotten" how to fight, such as polio, tetanus, measles, etc. HSCT also restores normal immune "self-tolerance" effectively ending the underlying activity & progression of my MS (click to enlarge).
Some detail if you're interested. . .
Immune Reconstitution and Immunotherapy After Autologous Hematopoietic Stem Cell Transplantation
And this last image I also borrowed from the BBMT shows the basic forms of common pathogens (bacterial, viral and fungal) that I need to be vigilant against for the one year immune recovery time (click to enlarge).
The ASBMT reccommends a prophylaxis regimen of Trimethoprim (Bactrim) antibiotic for six months (twice-per-day, three days per week M-W-F) to reduce the risk of pneumocystis, as well as Acyclovir (twice per day, every day) also for six months for prevention of an outbreak of VZV (Varicella Zoster Virus), EBV (Epstein Barr Virus) or CMV (CytoMegalo Virus). I am currently taking both for six months. The Acyclovir is especially important because the only deaths to occur during the early (phase I) stem cell transplants (that also used TBI) for MS clinical trials was due to re-activation of dormant EBV and CMV, both of which are of the herpes virus family just as is chickenpox and shingles (VZV). (There have been no deaths with the updated & "safer" phase II clinical trial protocols that have omitted the (now understood) unecessary total body irradiation (TBI).) So because my body has limited viral-fighting capability at the moment, the Acyclovir should help in case I have any dangerous reactivation of a dormant herpes-like virus (CMV, EPV, VZV). I hear that shingles is especially painful. Luckily, the clinical trial data indicates the majority of these (few-in-number) complications arise within the first six months following the transplant (although there were a few uncommon occurences later than this). Just an interesting note regarding my leukocyte numbers. . . . I still think back that my measured leukocyte number while I was still on Avonex was 2600 (doing it's job to supress T-cell production). And now the total number is around 5800. But compared with before, the good thing now is that the current leukocytes/lymphocytes have a changed epitope which means that they now lack the "programming" to attack my body. This restoration of immune self-tolerance is the reason that I am now cured of MS. So I'm still extremely careful in my attempt to to avoid any viral contact. No hand-shaking and no personal contact with other people (except my wife) and avoiding skin contact of public surfaces (door knobs & hand rails) wherever I can be vigilant in doing so. I always have to apologize to people in advance for not shaking thier hands (just for the next few months). The one big danger spot that is extremely difficult for me to control is contact with my son, Riki. He's two and a half years old and in day care. A breeding ground for the most virulent of childhood germs. This is the weak link in the chain of avoiding viral agents. All I can do is always use alcohol-based hand sanitizer gel (I keep a bottle in every room of my home and also always have a small bottle in my pocket when going outside which I use constantly), along with some serious prayer that nothing bad will happen. I think it would be one thing to become exposed to a cold or flu, and probably not a huge deal at this point. But what is kind of scary is the unlikely exposure of a real disease such as chikenpox, measles or polio. Children often come through such infections with little, or no long term effect. Unfortunately these diseases contracted as an adult are usually not so mild. For example, adults that get an active form of chickenpox have a 4% death rate (and an even greater risk for measles). And getting polio as an adult often results in some form of lifetime paralysis. And there are so many CRAZY parents out there that have the (mental sickness) idea that vaccinations cause autism, which they DO NOT.
No Scientific Link Between Childhood Vaccines And Autism
Autism, Measles Vaccine: No Link
Lancet retracts 'utterly false' MMR paper
Autism and Vaccines
Right now (at two months post-transplant) herd immunity is all I have to protect me (and other immuno-compromised people) from infection of a serious communicable disease. And there are a lot of un-immunized children running around out there that creates this danger. Such a condition not only endangers the child, but also puts immuno-compromised people like me (and others) at terrible risk of death if I am exposed. Other than locking myself in a room by myself for a year, I'm not sure what else I can do to reduce my risk of contracting such dangerous diseases. Just gotta keep continuously washing my hands! Virtually all myeloablative HSCT recipients rapidly lose all T- and B-lymphocytes after chemotherapy conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens and vaccines; forming a new antigen-naive immune system and re-establishing immune self-tolerance. So because my immune system is now reset (and does not recognize these childhood diseases), beginning at one year through two years, I will work with my general practitioner to be re-immunized against all these diseases (same as if I were an un-immunized child). Funny to think that right now my son Riki, at 2.5 years old has a more complete immune system than I do (Yuko and I made sure he has received all his recommended inoculations to date). I'm going to have to catch up!
Since it is necessary to be re-vaccinated following myeloablative stem cell transplantation, here is the recommended guidline from the US CDC that I am following:
Centers for Disease Control and Prevention recommendations for immunization in hematopoietic stem cell transplant recipients (click to enlarge):
Vaccination of Hematopoietic Stem Cell Transplant (HSCT) Recipients
So here I'll start making a list of things as I recall them and continue to update. . . . . .The big question - that everyone both in the US and in Germany ask me. . . . "why do you come to Germany to get this treatment?" The answer can be summed up in two words. . . tort limits. The US commonly performs autologous transplantation procedures all the time. But only for cancer. With the exception of Dr. Richard Burt in Chicago, no US medical facility will yet perform this procedure outside of a clinical trial for treatment of an autoimmune disorder such as MS because they are scared to death of getting sued and losing a ton of money in an out-of-control court judgement. However, Germany got it right and has enacted tort reform. There are strict limits on damage & malpractice payouts in Germany so the facilities are not so scared of doing things that are a little non-mainstream (but still scientifically rational), such as stem cell transplantation for a hematologically-rooted autoimmune disease.
On top of this, Germany "treats to outcome," as opposed to the US model where patients are "treated by procedure." The US model encourages costs to spiral out of control, as outlined in this article & link:
Study: Doctors [in the US] order tests out of fear of lawsuits
"Roughly one-fifth of tests that bone and joint specialists order are because a doctor fears being sued, not because the patient needs them, a first-of-its-kind study in Pennsylvania suggests."
Germany has better cost control combined with better patient outcomes because they focus on the health of the patient as opposed to ordering up unecessary and defensive treatments. This is why I found the 50,000 Euro price tag in Heidelberg quite reasonable compared to the more than >$200,000 for the same procedure performed in the United States. The US could learn a lot from Germany in the reform of our (broken) healthcare system. Here is a short video clip from PBS Frontline regarding the Germany healthcare system. If you have an opportunity, I suggest you watch the entire one hour show that you can access on the PBS Frontline website. It is very interesting and informative. . .
Mucositis - I am soooooo grateful that I didn't get it excessively bad. I did have the one mucositis lesion in my esophogial passegeway, and it did prevent me from eating for a week due to any food or drink going down causing strong transient pain and sometimes nausea. However, after a few days of not eating it usually wasn't painful sitting there by itself. Every other patient in the Ackermann ward had terribly painful mucositis at multiple locations in thier mouth, and elsewhere (but most of the people also did not receive Palifermin). I felt so bad for them. However, I did two things that I completely credit with saving me from this awful fate. . . . 1) I did receive the Palifermin IV drug for three consecutive days prior to hospital admission. Yes, it's expensive. Just get it. Cost should not be of any concern in this particular situation. And 2) working with my dentist to do the root planing/scaling and use of the chlorihexidine gluconte mouthwash was also extremely helpful. The mouthwash didn't taste great, but it never burned my mouth and I never got any mucositis in my mouth. I used it religously twice every day (morning and evening).
A side note about mouth cleaning during the hospital stay. . . near the end of my treatment (but while I was still cytopenic with low platelet levels) I tried to use my extra soft toothbrush and clean my teeth & gumline with a very gentle touch. Bad idea. As soon as I rinsed my mouth out with water, blood also came out as well. It's amazing how easily one bleeds when the platelets are near zero (especially from the gums). For anyone else considering this procedure, forget about the toothbrush for the duration and just rely on the mouthwash. Don't risk the likely occurrence of bleeding gums and the associated possibility of infection.
And I Should mention one small, but significant difference between the protocol utilized in the HALT-MS program, and the protocol I went through in Heidelberg. . . . . So this difference is rooted in the history of the phase I clinical trial experience. During the early part of the conditioning regimen (chemo administration) the body's leukocyte & lymphocyte levels (more specifically, the T-cells) temporarily rise, sometimes dramatically. And in the early clinical trial runs it was observed that this increased T-cell load sometimes (less than 10% of the time) caused an MS exacerbation flare-up. And a few of these flare ups had become so serious that they were considered life-threatening. Hence, for the phase II clinical trials the researchers decided to introduce the use of Anti Thymocyte Globulin (ATG, also often referred to as "Thymoglobulin," for short).
ATG is a substance derived from either horses or rabbits (and denoted as either h-ATG or r-ATG). It was originally developed as an anti-rejection drug for organ transplant patients (and is commonly and often used on organ transplant patients). Once administered (by IV infusion), ATG very rapidly kills off circulating plasma T-cells in the bloodstream. The chemo drugs (primarily Carmustine and Melphalan) also kill off the the circulating T-cells, but it occurs more slowly until cytopenia is acheived. So in an attempt to reduce the risk of T-cell induced MS exacerbations, the HALT-MS program includes r-ATG as part of the chemotherapy regimen with plasma T-cells dropping to zero in approximately two days following administration (click to enlarge):
Additionally, the collected stem cell solution (from apheresis) also has an abundance of T-cells present. The HALT-MS (but not the MIST protocol) also specially process' the collected autograft plasma solution to deplete the T-cells so that they are not present when re-introduced to the body.
I did not receive ATG as part of my protocol (although I did take immune-supressing prednisone during my G-CSF mobilization phase), nor was my collected stem cell solution manipulated to filter out T-cells. Instead I followed standard BEAM HSCT protocol that is administered as standard for an autologous transplant normally used for cancer patients. I did not suffer any MS-related attacks during this time, nor at any time following the treatment. So bottom line. . . ATG use quickly diminishes circulating T-cells, but eventually (a few days more) the BEAM drugs will accomplish the same thing (two of the BEAM drugs, carmustine & melphalan are strong alkylating agents that are also lymphoablative in addition to myeloablative.) Since many of the circulating leukocytes in the blood have a mean lifetime of only 5 days, once the bone marrow stops producing leukocytes during cytopenia, the leukocytes die off rather quickly. So long as there are no acute exacerbation effects the long-term outcome should not be any different wether or not r-ATG is used and the stem cell plasma autograft solution manipulated during treatment. So my MS is cured, even without the use of r-ATG.
And regarding infused stem cell solution manipulation (of which my solution was not manipulated). . . . . Here is a passage from a 2005 technical paper authored by Dr. Richard Burt at NWU Feinberg school of medicine regarding stem cell engraftment solution T-cell depletion specifically for treatment of MS. . . . . .
Most mononuclear cells collected by peripheral blood apheresis are immune cells such as lymphocytes and monocytes not HSCs. While the true identity of human HSCs remains elusive, either purified CD34+ or AC133+ hematolymphopoietic progenitor cells are sufficient for hematopoietic and immune reconstitution. In general, a minimum number of 2 x 10E6 CD34+ cells per kilogram of recipient weight will ensure engraftment. Hematopoietic stem cells may be positively selected or enriched ex vivo using antibodies to CD34+ or AC133 or purified by negative selection by using antibodies to remove lymphocytes. In practice, the most common method of purging lymphocytes is via CD34-positive selection using either the Miltenyi CliniMACS (Bergish Gladbach, Germany) or the Baxter Isolex (Deerfield, Ill) cell separator device. Whether enriching the graft for CD34+ HSC is necessary or even superior to infusion of an unmanipulated graft remains unclear. CD34+ selection by removing lymphocytes is perhaps best viewed as another method of immune suppression. For an intense conditioning regimen, CD34+ selection may be unnecessary or even detrimental by increasing the risk of treatment-related infection.
Dr. Burt further authored a paper in 2008 titled "Hematopoietic stem cell transplantation for autoimmune diseases: What have we learned?" that goes on to make the following clear statements: "Manipulation or CD34 selection of the graft will increase infections and to date has not been demonstrated to improve efficacy. . . . There currently exists virtually no firm data on the benefit of CD34 selection, that is lymphocyte depletion, of the autograft."
So based upon the currently-understood clinical science, there is no evidence to suggest that T-cell depletion of the stem cell solution is beneficial. If anything, I think it is possible I was able to experience a more prompt post-transplant recovery because my stem cell solution was not depleted of non-hematopoietic stem cells. [Note added October 25, 2010: I spoke with a MS patient that just completed HSCT at Northwestern University under Dr. Burt's department care with a cyclophoshamide + rATG protocol. On my behalf he was kind enough to discuss the aforementioned issue regarding stem cell autograft solution manipulation with the staff there. He was told by the physcians/researchers that they no longer manipulate the collected stem cell solution to remove T-cells or isolate stem cells because they have found no difference in end-result curative efficacy for multiple sclerosis patients undergoing HSCT.]
So in the end, my neither having received rATG or a stem-cell isolated autograft does not concern me as to the efficacy of my MS curative results. Overall I think I received the best combination of immuno-ablation (BEAM protocol) to effectively & lastingly reset my body's defective autoreactivity, together with the most rapidly possible immune recovery following conditioning & engraftment.
[Sept, 2012 update: Heidelberg University hospital has made two important updates to their protocol since I was treated that I am very happy to see for all future MS patients. . . . they have added the lymphotoxic depleting drug Cyclophosphamide as part of the mobilization phase (to reduce the possibility of having an MS related flare from excess t-cells, as well as the drug ATG as part of the conditioning phase to ensure the most complete ablation of in-vivo (autoreactive) lymphocytes.]
BEAM treatment related mortality - It's hard to get most treatment facilities to quote a specific number for their own facility death rate directly related to an autologous transplant procedure. However, worldwide most facilities usually fall into the average norm of between 3% and 5% (including here in the US). However, some places are actually better than others. This includes Heidelberg University Hospital. This is mainly because they have been doing this a long time and they do so many of these procedures they have the treatment procedures down so well that they know exactly what to do even if something happens "outside the norm." There seemed to be no surprises in the Ackermann treatment ward (exactly what one would wish). Because of this I consistently heard from the doctors (and Professor Ho) that they have driven down the treatment mortality rate toward 1%. And that includes the entire population of people, including the elderly and very ill. So I figure that probably put my mortality risk at around 1%. Actually not bad at all. And while I was in the Ackermann ward (that houses 20 patients at one time with patients continuously rotating in, and out), there were no deaths.
Latent chemotherapy-induced cancer mortality from an autologous transplant - So here's some irony in this whole treatment regimen. . . . from the data collected from the many thousands of recipients of autologous hematopoietic stem cell transplant procedures to treat cancer, there is a well understood causal relationship of treatment and later deaths due to a secondary cancer caused from the conditioning regimen itself. Alkylating agents such as Carmustine and Melphalan (two of the BEAM drugs) are known to be carcinogenic, although not nearly as cancer-causing as total body irradiation (TBI) that is sometimes performed on some people for BMT. I did NOT receive TBI, nor was it necessary for me to have received it. And actually I have to give credit to my wife (a biomedical scientist) for bringing this to my attention. It turns out that the chemotherapy drugs themselves sometime cause cancer that may occur years after administration. The cancer is usually not at all related to the original cancer being treated in BMT procedures, but in a fraction of people will cause an unrelated cancerous fatality. This is just the nasty nature of the very powerful drugs used for killing cells in the human body.
The various studies to date do not indicate consistent results. Some people will get a form of fatal cancer later (sometimes a lot later) from the prior exposure to the BEAM drugs themselves. The malignancies are usually either myelodysplastic syndrom (MDS) or acute myelogenous leukemia (AML) (both types associated with bone marrow). Another irony is that the treatment for both of these conditions is "another" stem cell transplant, although it would probably require a far more challenging allogeneic procedure with a substantially greater risk of treatment-related mortality. So I just take this in as one more risk of being alive. Maybe it's being hit by a bus while crossing the street. Maybe it's a chance of cancer later in life. At least I won't have MS dragging the quality of my life down anymore!
Here is a summary of some studies regarding occurences of secondary cancer malignancies data that I was able to dig up. Keep in mind that this data is for the occurence of cancer, not actual deaths due to cancer. So the mortality rate must be substantially lower than the numbers shown here. (click to enlarge):
And this previous study data when combined with other data (shown below) for treatment-related mortality (that rises over time), it looks like deaths ultimately reach a maximum of approximately 40% of those later afflicted with a latent/secondary cancer. So with these two data sets if you combine cancer occurence (I use the reputable EBMT source data), then it would be worst case of 5% chance of getting cancer at 5 years and a 30% fatality rate. So that comes out to approximately a (30% x 5%) total of 1.5% chance of dying from the latent cancer occurence five years post-transplantation. Not huge. But also not insignificant. Similar mortality rate as the original BEAM procedure at Heidelberg. However, I believe that all of this data includes treatment utilizing total body irradiation (TBI) in addition to the chemo, of which TBI is far more cancer-causing, on balance, as compared to chemo drugs alone. So I don't know how a BEAM-only chemical protocol (my treatment) would separate out from this data. Certainly I would expect it to be less probability of cancer occurence & death, but don't know the actual number. If important to you then I would suggest further detailed research. I don't plan to look into this further. For me what's done is done. (click to enlarge):
Also a paper for general reference that also mentions malignancies:
Long-term care after stem-cell transplantation
- And excellent "must-read" documents for those preparing for HSCT that you can download to your computer and then print them out for you and the family to read:
Understanding Autologous Transplants: A guide for patients and families
Autologous Stem Cell/Bone Marrow Transplantation: A Medical & Educational Guide
- Also an important note regarding potential permanent side effects of this chemo conditioning regimen specific to my treatment which is a BEAM protocol which will not necessarily apply to all stem cell transplantation conditioning regimens, but likely does for myeloablative protocols. . . Other than being cured of MS, the likely permanent side effects from this myeloablative BEAM treatment is that sterility and hormonal dysfunction (gonadic failure) are likely to occur. This treatment is likely to cause irreversible sterility in most individuals (as it did in me), for both males and females. So if someone wants to have a child following the treatment then they will need to plan ahead. Expecting this I planned ahead and banked my sperm for the future possibility that my wife and I will have another child (which we did at two-years post-transplantation that you can read here: http://themscure.blogspot.com/2011/09/next-miracle.html ). This is obviously an easier problem for a man to overcome. For a woman wishing to become pregnant following BEAM HSCT would almost certainly require an IVF procedure using her own banked eggs, her own preserved embryos or a doner egg. The good news is that although becoming pregnant is more of a hurdle for a woman following HSCT, being pregnant is not. Following HSCT there shouldn't be any added difficulty with having a normal pregnancy and bring a normal healthy baby to term.
As for the hormonal dysfunction, this is something that should be expected from the BEAM chemo exposure that is likely to be permanent (as did for me) and is likely to occur in the majority of people undergoing myeloablative BEAM protocol HSCT. It appears that my leydig (testosterone-producing) gonadal cells were destroyed by the BEAM chemo regimen and my body eventually lost all of it's ability to produce testosterone and I have entered early andropause. However, this turned out to not be a big problem to overcome since I can easily use a transdermal testosterone skin gel to bring my body's testosterone levels back up into the normal range (>300 ng/dl plasma level). This treatment doesn't bother me at all and I still consider it a more-than-equitable trade off for curing my MS. I much prefer applying topical dermal testosterone compared to self injecting interferon MS medication that is no longer required since my MS is stopped. I'm satisfied & happy with this trade-off.
For females specifically it is likely that myeloablative BEAM HSCT-treated women will experience amenorrhea (which can be treated with HRT) which is most likely to be permanent. Early menopause is also likely to occur with the same myeloablative BEAM HSCT therapy.
I would like to add some additional info on the subject of sterility and hormonal failure as a write this paragraph +2 years post-transplantation now that I have had an opportunity to meet, discuss and have the feedback of many other transplantation recipients that have been through either the fully myeloablative HSCT protocol (there are many different fully myeloabltice chemotherapy protocols for cancer treatment, but I am specifically referring only the BEAM protocol which is used for the treatment of MS), and other MS patients that have received the non-myeloablative HSCT protocol. From my anecdotal perspective it is becoming pretty clear that an outcome trend is occurring where virtually everyone having received the myeloablative (BEAM) protocol is coming out both permanently infertile AND experiences permanent total gonadal failure that throws each individual into early and immediate andropause/menopause. Treating such a condition requires continuous chronic Hormone Replacement Therapy (HRT - testosterone for a man, estrogen/progesterone for a woman). So be prepared that this will occur if you receive the BEAM protocol; something your primary care physician can help you with. Planing ahead and being aware of this probability makes it very easy to treat; HRT being easy to administer/receive. Just be prepared to spend some money for it.
On the other hand, the non-myeloablative HSCT therapy (that I did not receive) is looking like it results in virtually no patients having permanently-impaired fertility or hypogonadism as a result of the treatment, although there is likely to be a temporary effect (both fertility and gonadal function) that is likely to resolve within the year post-transplantation.
There "may" be some exceptions to these conditions I have stated here regarding this specific fertility/hormone subject, but I have yet to see such exceptional conditions. Everyone I have met (so far) reports outcomes consistent with my statements.
- Filter face mask - Before leaving I also purchased several 3M HEPA filter disposable face masks that come with a P100 rated filter (99.97% particle removal efficiency for particles down to less than a micron). I'm sure the P100/N100 and P95/N95 versions will all work well. I just suggest that for improved comfort the filter mask should incorporate a breath exhaust port (like the one I used). I used these in the hospital general public areas when walking around and also on the airplane when flying back to California. (On the airplane I also brought some blue nitrile gloves that I periodically wore when needed (in the lavatory) to avoid infectious agent exposure.) This mask is well-made (by 3M, but I'm sure you can also use one from a different manufacturer) and is very comfortable to wear for long periods of time, has a long useable lifetime (approximately 200 hours useable-breathing-efficient lifetime per mask) and I like it:
- My only significant drug-related allergic reaction while hospitalized - Ceftazidime (one of the constituent components of Fortum) which is a class of drug known as a cephalosporin which are closely related to penicillin commonly used to treat febrile neutropenia (almost every BEAM patient gets a fever and is treated with this drug, but most people (except me) don't have a negative reaction to it). For me it caused a very strong skin reaction (urticaria).
- Temporary worsening of existing (RRMS) symptoms - The clinical trials have shown a high incidence of transitory worsening of some existing symptoms in MS-treated patients directly following the transplantation procedure (likely due to the chemo stress on the body). However, this effect seemed to resolve in a matter of a few months (at most) with no permanently added disability. As for me, for several months following the treatment (starting at about the end of my hospital stay) I had some leg spasticity. Spasticity is common in many people that have MS, but I previously never had a problem with spasticity. My neurologist prescribed some Baclofen for me (of which I'm not completely sure if it helped, or not). But anyway, the spasticity has resoved about four months following hospital discharge. Clearly a temporary condition. I stopped taking the Baclofen upon symptomatic resolution. I'm sure this effect of type and duration will differ for different people.
- Time to recognize MS symptomatic improvement - Most HSCT-treated MS patients claim that they "notice" (at least some) reversal-of-disability at six months (also when I first started to notice my own symptomatic improvement). And then most patients report the improvements become "obvious" at twelve months. And then most say that improvement is "substantial" or "meaningful" at eighteen months. (Mine has been substantial at 1 year post-transplant with an EDSS score reduction of 1.0 and an even better result acheived at 2 years post-transplantation with a 50% reduction of my EDSS from baseline [see two year report for details].) I am going to add a couple of additional comments on this topic. . . . for those that experience HSCT success in stopping the underlying MS disease process, it appears that inter-cranial-origin MS symptoms seem to reverse first, usually directly following the HSCT procedure, just as happened for my own case. Such immediate symptomatic resolution/improvement includes heat (in)tolerance / abnormal temperature sensitivity, ataxia, vertigo, visual disturbances and other related issues. So if someone notices that these personal symptomatic issues improve immediately or soon after HSCT, then I think it likely a very good sign that the HSCT procedure worked to stop the underlying MS disease activity & progression. On the flip side, if these symptoms do not immediately dissappear in a given individual following HSCT, I don't think it specifically indicates that the HSCT did not work. So don't panic if this describes your case.
All of my pre-existing MS symptoms have improved (reversed), and continued to improve over time to 2 years post-HSCT. However, the rate of improvement after 12-18 months appears to have substantially slowed following the "expected" asymptotic trend curve of diminishing returns over time. That basically means that I have experienced a tremendous amount of improvement in the first 12-24 months following my HSCT I 'may' see additional gradual improvement over time, albeit only slightly, at best beyone two years post-transplant.
The general shape of this symptomatic improvement curve shown here is fairly representative of what can often be expected for MS patients following HSCT (and is what I am experiencing). However I'm sure the precise shape & slope of this curve will somewhat differ for each individual based upon several factors that includes the phase of disease activity (RR, SP, PP) and relative total disabiliyy at time of treatment. (click to enlarge):
So to say it again. . . . symptomatic improvement/reversal in any given individual will likely be strongly influenced by the stage and severity of the disease at the time of the stem cell transplantation. A stem cell transplant performed earlier in the cycle of the disease while still in a relapsing (RR) phase portends a faster, more complete and better outcome with reversal of existing deficit. The reason for this is because a RR disease mechanism is a "demyelinating" nerve pathology that will allow the body to heal nerve pathways once the stem cell transplant stops the body's immune system from attacking the nerve tissue with immune "self-tolerance" re-established. A later progressive stage of the disease (like mine) is dominated by "axonal dystrophy" and subsequent nerve death. Once the nerve is dead you can't bring it back to life. All your brain can do is to re-wire around the damage (which occurs very slowly over a matter of years, similar to the way stroke patients can recover some function following brain injury).
- So although extremely likely that the progression of MS disease activity will be stopped in all forms & phases of MS (both relapsing and progressive), I have created a couple of slides to categorize the expected relative probability of symptomatic improvement (damage reversal as measured by EDSS) following stem cell transplantation vs. disease status at time of treatment (click to enlarge):
- Brain atrophy - I have not previously heard it discussed much, but there has been some data compilation on brain atophy (which manifests as brain volume "shrinkage") following HSCT in the treatment of MS. This original report is from the Scientific Institute and University of San Raffaele, Milan, Italy. It has been observed that the brain shows a volumetric reduction (i.e. atrophy) for a limited time following HSCT in those with MS. It is most pronounced the first year (1.92% ave) following HSCT and then to a significantly lesser extent the second year (1.35% ave) and minimally the third year (0.69% ave). No additional shrinkage is observed after this time period indicating that the brain enters a stable volumetric state two-to-three years following HSCT. This is an interesting phenomenon because the precise shrinkage etiology has not been elucidated and some people may attribute it to the HSCT chemotherapy conditioning regimen insult to the brain tissue. However, I personally think that it is just temporary (momentum) continuation of brain shrinkage that normally occurs as a result of active MS disease progression (which is a well documented effect associated with MS). Regardless, the most important thing is that brain shrinkage stabilizes (stops) by latest the third year following HSCT. Further evidence of the curative efficacy of HSCT to stop the progression of MS disease activity.
American Journal of Neuroradiology - A Three-Year Study of Brain Atrophy after Autologous Hematopoietic Stem Cell Transplantation in Rapidly Evolving Secondary Progressive Multiple Sclerosis
- Bleeding from bandaged areas during cytopenia/neutropenia (while in the hospital) - Just a note that it becomes obvious and such areas needed to be wrapped tightly with bandaging. The nurses know how to properly deal with it.
- Dry skin - Every BEAM patient gets it quite badly as a normal side effect of the chemo, almost like finely-grated parmesan cheese on your skin. Use lots of moisturizing skin lotion during and after the hospital stay. It helped me quite a bit for several months following the transplant. And for a few months try to stay out of extended exposure to direct sunlight since the skin is more sensitive to UV light radiation damage following chemo and will sunburn very easily.
- Steroid fluid weight gain - Just like everyone receiving this chemo treatment, I was started immediatey on three types of oral steroid anti-nausea therapy when begining chemo. Overall, it worked. (Except once I needed a little "extra" to keep the nausea at bay and was administered a powerful IV anti-emetic that worked perfectly.) The steroids cause the side effect of sudden and massive fluid retention that also drives up the blood pressure. I went from 65kg to 73 kg in two days. That's equivalent to absorbing eight liters of fluid!, which also drove my blood pressure up to 180/110. I was then given a diuretic to try to eliminate some of the fluid. It somewhat helped, but I didn't completely rid my body of the fluid retention until the end of chemo cooincident with the discontinuation of the steroid anti-emetics. Within two days my weight & blood pressure was back down. Overall I'm grateful for the anti-nausea medication, even though my stomach always felt "unsettled."
- Fever - nearly everyone (~90%) gets an idiopathic fever during neutropenia, goes on precautionary prophylaxis IV antibiotics and then the fever usually resoves by the time signs of engraftment manifest in the blood test results with rising leukocyte levels (exactly as I experienced). It's an uncomfortable part of feeling ill from the chemo but everyone makes it through it. I kept thinking about the Winston Churchill quote. . . "If you are going through hell, keep going." My fever resolved when my leukocytes started to rise at day +9.
Here is a list of all the IV drugs I received during my in-patient hospital stay:
Ceftazidime (German name Fortum) 3x 2g per day for 2 days
Zienam (German-specific multi-component drug containing imipenem and cilastatin) 4x 500mg per day for 5 days
Pantoprazole 1x 40mg per day for 6 days (and have also taken this orally as a tablet at the start of treatment)
Vancomycin 2x 1g per day for 2 days
Flucanazol (diflucan) 1x 400mg per day for 3 days
Metoclopramide 2x for 1 day (This is a wonderful anti-emetic drug that that worked well for me. I also understand this drug is sometimes used to treat migrain headaches. Interesting.)
- English language for treatment in Germany (No problem! But try to learn a few German words if you go there. A good way to show some respect to the locals.) While in the hospital I found the words Übelkeit and Schmerzen (nausea and pain) useful at times to mention to the nurses regarding my mucositis, to which they responded very quickly to make me feel more comfortable. Other than that, please learn how to say "thank you" in addition to a few basic greetings.
- Eating after hospital discharge - Immediately following discharge stay away from acidic foods for a couple weeks (like tomato soup) because the intestinal mucosa can't handle it because it is still trying to recover from the chemo. For a longer time (2-3 months more) it's important to stay away from "live" foods such as probiotic yogurt and miso. Definitely nothing un-pastureized. And it's also necessary for a time to stay away from high-risk foods that may carry pathogens, like unwashed / uncooked non-peelable fruits & vegetables, salad (including Ceasar salad) and sushi. This is because the epithelial tissue barrier layer of the intestine remains compromised for several weeks following hospital discharge. By the third month following treatment I was totally back to my normal diet that included everything that I like to eat. And my taste came back less than two months following hospital discharge. Much more quickly than I expected and definitely a welcome aspect of recovery.
- How to transfer money overseas for treatment - (Unless you want to get raped, don't use your bank, use Oanda FXTransfer. The best exchange rate & lowest fees. A very economical & reliable method of overseas money transfer + currency exchange compared to using a bank. I think in total we saved about $4,000. That went a long way for paying for our airline tickets for travel.)
- C-Reactive Protein (CRP) number (an interesting, but not well understood significance blood marker for inflamation) - A CRP level of less than 5.0 is normal and less than 2.5 is desireable. Shorty following the start of chemo administration my CRP level skyrocketed 100 times! to approximately 180. I think this is usual for people undergoing chemotherapy. Normally CRP levels are an indication of inflammation from an infectious agent in the body. But in this case, I think it is a response to the tissue damage from the chemo drugs. What is the real-world significance to this high CRP number? No one knows, or has yet to explain it. My CRP levels returned to normal several months following treatment. Regardless of the actual CRP number during chemo & the stem cell transplant procedure, the doctors take no action from it. I think the doctors expect the rise from the chemo but then want to be sure it falls back to a normal (low) level following the treatment, as mine did. I suppose that they would be concerned if it stayed elevated long after the chemo. But even then I'm not sure they would know how to respond to such a probably-rare condition.
- Hair – Everone receiving a stem cell transplant will end up losing the hair on their head from the chemotherapy drugs. It's only temporary and for me my hair returned to look completely normal (but short) about four months following treatment. I think it goes without saying. . . . this is no big deal for men. I didn't even give it a second thought. But for many women it's probably a significantly bigger deal. In the hospital they offer to have a professional stop by and create a hairpiece for anyone that would like one.
- I wish I could have done this stem cell transplant ten years ago when my disease status was not as advanced. But I'm still very happy I did it now with absolutely no regrets whatsoever!
- Heidelberg University Hospital website:
- On-premise housing apartmant (Guesthouse) website:
The Hospital Guesthouse is administered by Mrs. Karla Von Klot. She is a very nice & wonderful person. She is the person to coordinate with to arrange a Guesthouse apartment that is very close (10 min) walking distance to the hospital. It worked out great for us.
E-mail for frau Von Klot: Karla.vonKlot@med.uni-heidelberg.de
- Mild-to-moderate bone pain during G-CSF stem cell mobilization in preparation for apheresis, which is a normal documented side effect of the mobilizing drug (Neupogen) - Some people have more bone pain than others and is treated with standard OTC doses of analgesics such as acetiminophen (called paracetamol in Europe) or ibuprofen. I would also expect that Naproxen Sodium (Aleve) would work well. Interesting that for me I had very little bone pain (almost didn't notice it) during my mobilization phase. My own theory to explain this is that I used interferon (Avonex) for so many years, I think my bones were "used" to the inhibition process of T-cell mobilization (from the bone marrow) and I didn't feel much of anything when I took Neupogen. (In previous years I had some mild bone pain taking Avonex.) I bet people that take Rebif or Betaseron probably would also have low bone pain during mobilization. Just my own theory, of course. I could be wrong, but I have no other explanation that fits the facts.
- Prednisone use during mobilization. I think this is important (dosage = 1mg per kg body weight), especially for anyone that is still in the relapsing phase of the MS disease to try to reduce the chance of an MS-related exacerbation. I didn't notice much side effect from this short temporary course of high-dose prednisone, except that I was more "awake" than usual. But I could still get a good night's sleep so long as I took the prednisone first thing in the morning, which is required. Update: Heidelberg has updated the mobilization protocol for MS patients and now administers cyclophosphamide as part of the drugs used during mobilization. This is really a very good protocol update because the cyclophosphamide will substantially diminish the circulating plasma T-cell population in the body and significantly reduce the probability of an MS-related exacerbation. If you receive cyclophosphamide as part of mobilization then should be no need to take prednisone.
- CVC vs. Removable (PICC) catheter - In the HALT study everyone gets a Central Venous Catheter (CVC) surgically insterted into thier superior vena cava below the breast bone (this is commonly done for cancer patients undergoing extended chemotherapy). The MIST study uses a Peripherally Inserted Central Catheter (PICC) similar to the one I had inserted into my jugular vein in my neck. The advantage of a PICC is that it can be easily removed by a nurse following chemo & stem cell infusion (mine was removed on day +1 which was a total of 9 days "as-installed.") The doctors in Heidelberg want to remove it as soon as practical following chemo & stem cell infusion so that it can be eliminated as a souce of potential trouble because dermal flora can easily intrude the catheter entrance point and possibly cause an infection. Upside: reduced chance of infection and easier to take a shower without worrying about keeping the catheter bandaging dry. Downside: Had to get daily needle sticks in my arms for daily blood test draws and cannulas installed in my forearms for IV infusions which was sometimes a little painful (insertion, not the drips). In the end, everything worked out fine for me and I have already forgotten about the discomfort. I have little to complain about in going this route.
- It is critically important that you must have someone with you through this process while you are hospitalized! This is not only for needed for emotional support, but also for practical logistics. Someone needs to take your dirty clothes away and bring back clean washed clothing. My wife stayed in the hospital guesthouse apartment close by (has a clothes washer & dryer in the basement that takes 2 Euro coins to operate) and came by to visit me on a regular schedule twice a day (afternoon and evening). For clothing to bring to the hospital I suggest normal/usual daytime casual clothing for the daytime (I wore jeans, khakis and T-shirts a lot), and shorts or sweatpants for nightime and sleeping. Overall casual clothes are fine at anytime. But walking around in your underwear is not. You have to frequently exit your room for various reasons and you get doctors & nurses visiting in your room around the clock. You don't want to embarass yourself with funky & immodest outer garments. Dress in the daytime like you're casually going to a friend's house to watch movies. I would just suggest that you get some slip-on footwear as the exception. Shoes go on and off constantly as you enter & exit your room and you don't want to be hassling with shoelaces all the time.
I am happy to answer any questions to the best of my ability for anyone that would like to know more about this experience & treatment. Here's my e-mail address:
If Heidelberg University Hospital rejects a given patient for HSCT treatment of MS, there are alternatives. Please see the following page:
Although it works well for Multiple Sclerosis (and several other autoimmune disorders), an autologous hematopoietic stem cell transplant will not cure every disease. However, it has been shown to have similar (good-to-excellent) curative results for other hematologic-based autoimmune diseases. If I were otherwise afflicted with any of these other types of hematologic-based autoimune disorders (there are likely many more than I have listed here), I would consider seeking the same transplant procedure myself to cure it:
- Rheumatoid arthritis
- Scleroderma (Systemic Sclerosis)
- Inflammatory Bowel Disease (Chrohn's disease & ulcerative colitis)
- Systemic Lupus Erythematosus (SLE)
- Evans syndrome
- Hashimoto's thyroiditis (before the thyroid is completely dead)
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
- Graves' disease
- Autoimmune hemolytic anemia
- Autoimmune blistering diseases
- Autoimmune lymphoproliferative syndrome
- Myasthenia gravis
- Psoriatic arthritis
- Wegener's granulomatosis
- Sjögren's syndrome (Mikulicz disease, Sicca syndrome)
- Churg-Strauss syndrome
- Microscopic polyangiitis
- Relapsing polychondritis
- Pemphigus vulgaris
- Ankylosing spondylitis
- Diabetes mellitus type 1 (but only if HSCT is performed within several months following disease onset)
- Sickle Cell Disease can be cured with a similar HSCT procedure utilizing mixed chimerism with a partial-match HLA doner
These images are just placeholders. . . . .
Infant Chickenpox. . .
Gene Cernan, Commander, Apollo 17. . . .
The following graph for post-HSCT Crohn's diseasse. . . .