Waldenstrom's macroglobulinemia: My treatment plan
By Steve Kirsch
I was diagnosed with Waldenstrom's macroglobulinemia six months ago (see Waldenstrom's macroglobulinemia: Steve Kirsch's story).
Note this page is superceded by Waldenstrom's macroglobulinemia: Low dose Rituxan which is my current plan.
The stuff on this page with AMD3100 is about 6 months away.
After 6 months of learning about this disease, I think there is an excellent chance that by modifying current treatment protocols and by using existing drugs in combination, that this disease can be cured or at a minimum, put into permanent remission.
In summary, here are the 3 bets I think could cure my disease.
I think all of these 3 will work on their own. But I could be wrong. But if just one of them works, I'm in good shape:
Smart Ritxuan dosing
I like Rituxan. It's very targeted and the cells responsible for WM express CD20 in their early stages. The drug itself is a potent killer of cells expressing CD20. For example, in just the first 30mg, 75% of circulating cd20 positive cells are killed. Rituxan is a great targeted drug with very little side effects.
The problem is nobody gets a complete remission from Rituxan alone. There are zero complete remissions from Rituxan monotherapy. But I think that might be the fault of the dosing regimen and not the drug itself. With a slight modification to the current dosing schedule, I think we can get more complete remissions than 0% we get today.
Currently, they give you a big bang dose at the start of treatment, and then do infrequent (once every 3 month) maintenance doses to attempt to maintain the gains you made with the big bang.
I think it MIGHT work better the other way around, i.e., the current maintenance phase should instead be used for reducing the disease burden so that you get a consistent and steady decrease in disease burden over several years.
In my proposal, you give a big dose up front to kill the low-hanging fruit which is the same as they do now, but then you immediately follow it up with a consistent dosing regimen with high enough concentration to keep beating down the disease over time.
So in my proposal, the bulk of the killing is done after the initial 4 doses. WM is therefore killed slowly, over time. We therefore take the view that fighting WM is a very long chess game, one that is not won with a few doses, but with a consistently lethal dose over a long period of time.
Unfortunately, the big problem with such a treatment regimen is that with constant Rituxan dosing, your IgG and, in general, immunity to any NEW diseases might be compromised. On the other hand, there have been patients on maintenance Rituxan for years without problems. So you might win the WM battle, only to die of something else! No free lunch. That's why the AMD3100 + Rituxan approach seems much more promising to me.
Once you completely stop Rituxan, it will take 6 months to 1 year to regain your normal immunity.
If we were to treat with monthly Rituxan dosing, what follows is how it might work.
The trick to Rituxan dosing is to have a high concentration at the start, then maintain a minimum killing concentration thereafter. For example, see Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody which is for Humax, but the same principles should apply to Rituxan. This paper points out the advantages to starting with a 100µg/mL concentration initially, and then maintaining at least a 10µg/mL concentration in order to continually make progress against the disease.
The current dosing regimen for Rituxan achieves the first objective, but fails on the second (see Figure 2C in the Pharmacokinetics article). Most people are given 4 or more rounds at the standard dose and then you are stopped, sometimes for years. Some people are put on maintenance immediately, but even the current maintenance protocols are inadequate for maintaining an adequate concentration which appears from human studies to be around 25µg/mL (but it could be less). The current maintenance dosing is adequate only to maintain your gain if you are lucky, or allow the disease to progress if you are not so lucky (your disease grows really faster or you clear Rituxan from your body faster than average).
We need good human studies for WM, similar to the mouse and monkey studies done in Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody. Drug companies are working on such smarter dosing for the next generation of CD20 monoclonal antibodies.
Another recent paper discusses the dosing as well: Pharmacokinetics of rituximab and its clinical use...[Crit Rev Oncol Hematol. 2007]. That paper points out 1) the measurement of Rituxan concentration in the blood is not standardized, 2) clinical response depends on Rituxan concentration (not dose) and 3) Rituxan concentrations are variable depending on the person (disease type and disease burden) and 4) responders generally were at a median serum concentration of 25µg/mL concentration.
For best impact, the dose amount and scheduling should be adjusted to achieve the target concentration in me. Too low a concentration can cause the drug to be ineffective and it also can create drug resistance.
The hardest part of doing this is finding a doctor who will agree to modify the Rituxan maintenance dosing to be different from what is being done today. Most doctors go "by the book" and will only allow you to take a treatment protocol that has been proven in a clinical trial. They will not let you be a clinical trial of one. But 10% of doctors are more open minded, including some of the most celebrated cancer scientists in the world. There are excellent physicians who will allow you to take the dosing schedule below. But there is a risk. This can be worse than what we know now works OK. Or it could be better. Are you willing to take the risk?
Based on the data in the Pharmacokinetics of rituximab and Pharmacokinetic Behavior of Rituximab A Study of Different Schedules of Administration for Heterogeneous Clinical Settings papers, here's my rough calculation for dosing:
To measure your response, look primarly at Hgb and your IgM levels, not your Hct or RBC. If your physician can explain why, you've got a great physician (it has to do with how hyperviscosity thins the blood and causes it to be more diluted so we have more blood; if your viscosity goes up, your Hct goes down). See for example, Overestimation of Hemoglobin in a Patient With an IgA-κ Monoclonal Gammopathy.
David Maloney (fhcrc.org) strongly suggested using a second round of "once a week for 4 weeks" that is 1 month after the first round (rather than 2 months that is used in WM). Therefore, you have almost 4 months of over-saturation. However, see Extended rituximab therapy in Waldenström's macroglobulinemia which compared 2 rounds (2 months apart) vs. 1 round and found no significant difference in overall response rate (there were some single round studies that did better and others that did worse; see Table 2). However, the duration of the response appears to be consistently longer than those with only 4 rounds, but that's not surprising since the total amount of drug that was given was more and the treatment took longer, and the time is measured since the start of the treatment. So that's totally expected.
Here's the justification for not going with a second round of 4X doses
Therefore, it might be the giving of the Rituxan every 3 weeks (with no 4 doses that are normally done) that is instrumental in the CR's in CPR! Don't ask me why. But it seems possible that once every 3 weeks dosing is highly effective based on the above facts and that the 4 weekly doses are unnecessary to get substantial response. But again, it could be synergy with the chemo.
Here is the reference showing no synergy between chemo and Rituxan
However, they did not change the order in which the drugs were given! And in other diseases (other than the one from this study), there clearly IS synergy!
Some believe that given
Rituxan a few days before the chemo would yield superior results. This has never
been tested. Similarly, the order of giving Rituxan vs. chemo is random based on
the physician or hospital you get.
NOTE: in addition to measuring Rituxan levels, pre-infusion, we should also monitor HAMA and HACA levels (see patient story below), although if we just measure Rituxan levels, it should be an excellent indicator since if HAMA or HACA are present, Rituxan levels will be hard to detect. So just monitoring Rituxan levels should be sufficient to monitor progress and determine anti-body resistance.
If you go 4 weeks between infusions, that drops you down to about 25µg/mL at the start of the next infusion which means you are getting a good kill concentration for the entire 4 week period. So there is no value to going much beyond this. If you go 8 weeks between infusions, you drop down to about 10µg/m at the start of each infusion which is sufficient to prevent resistance but you probably reduce the kill rate (it would be interesting to measure this). See Fig. 2b in Pharmacokinetics of rituximab that shows this.
If you go 12 weeks between infusions, you definitely reduce the kill rate to something pretty close to the growth rate of the disease which is why the 3 month between doses is termed "maintenance" rather than "treatment." There are lots of reports where people take 1 standard dose every 3 months and it keeps their IgMs stable. That is further evidence that once every 3 months is insufficient if you want to rid yourself of the disease. Once every 3 months will just maintain the status quo at best. If you want to make progress towards reducing your disease burden, the "maintenance" dosing must be more frequent.
You could also do maintenance doses of lower amounts more frequently, e.g., 250mg/m2 every 3 weeks with an objective of achieving at least 25µg/mL at the start of each maintenance dose. This evens it out more (i.e., smaller difference between peaks and valleys), but increases your infusion costs and is less convenient.
So we'd measure my Rituxan levels by measuring the pre-infusion level of Rituxan while on maintenance. If it is below 10µg/mL, then we increase the maintenance dose; if it is above that, we can decrease the maintenance dose.
So the bottom line is that by giving the "maintenance" dose 3 times more often, we can actually kill the disease over time, rather than just maintain the minimal gains from the first 4 doses.
This dosing schedule should result in a superior response. In fact, with just this simple dosing frequency change, we may be able to literally cure WM.
I asked on the WM talklist: has anyone done Rituxan maintenance dosing more frequently than once every 3 months. There are over 1,000 WM patients on the list. Not one tried a more frequent dose than once every 3 months. We seem to be afraid that we might kill the disease if we did that!
Monthly maintenance dosing with Rituxan has been done for other diseases with good results (although at a slightly reduced dosage):
Finally, we should worry about resistance, e.g., if we measure very low concentrations of Rituxan, it could be due to HAMA or HACA. For example, see Extremely high titer of anti-human chimeric antibody following re-treatment with rituximab in a patient with active systemic lupus erythematosus. That paper points out that "repeated treatment with rituximab seems to induce persistent suppression of B-cell function and reduce the likelihood of development of HACA."
Presence of the complement resistance antigensCD46, CD55 and CD59, can also reduce the effect of Rituxan. See Extended rituximab therapy in Waldenström's macroglobulinemia which noted CD55 expression in bone marrow lymphoplasmacytic cells significantly increased in non-responding patients after 6 months of Rituxan (see Figure 3). It also notes that "One patient experienced a grade 3 monoarticular arthralgia after receiving four infusions of rituximab which resolved after a 2-week course of steroid therapy."
Rituxan is not without risk, whether you are on a maintenance protocol or on the 4 weekly doses schedule. Here are examples of pretty severe side effects that do not seem to go away over time as a result of Rituxan treatment.
I received one email from a patient who reported:
Here's another posting:
But supposedly, those are outliers.
Other options are chlorambucil (a pill you take for 5 days then take 3 weeks off) or cladrabine.
The newer drugs, RAD001, for example, are not targeted to WM specifically.
Secondly, I'm funding a clinical trial for Humax in WM. Humax appears that it could be a much more potent killer of WM cells in the marrow because Humax kills using ADCC and CDC whereas Rituxan is believed to operate primarily via ADCC, and secondarily through CDC and other methods. Just as with Rituxan above, the dosing schedule for Humax is the key to a successful outcome.
AMD3100 + Ritxuan/Humax
Thirdly, I'm funding research and a clinical trial in the use of AMD3100 in conjunction with Rituxan. I'd prefer it be done with Humax, but the FDA only allows you to test one "new" thing at a time (which is a shame since it results in progress being slowed by years). AMD3100 mobilizes WM cells out of the marrow and into the bloodstream where the cells are very easily and completely killed by Rituxan. So it's like gassing a house to drive the occupants out of the house, and then shooting them with bullets now that they are out in the open where they can easily be killed. Based on data I've seen from multiple myeloma experiments, I'd expect the efficacy of Rituxan for WM can be improved at least 5-fold by giving AMD3100 before the Rituxan infusion.
That's my plan. Hopefully, one or more of these approaches will be wildly successful and we'll have a way to cure or control WM with a very low risk of any permanent side effects and very little side effects during treatment (since the initial dose will be much lower, lower infusion rates can be used which will cause a lot fewer infusion related incidents).
My limited experience with chemotherapy
In December of 2007, I tried CPR. I did one round and decided it wasn't for me. Chemo drugs rob you of your youth, increase your risk of getting cancer in the future, can permanently alter your sense of taste, and have pretty bad side effects while you are taking them (low energy, sick, low red cell counts, low white cell counts, etc). They are untargeted so using chemo is like bombing an entire country in order to kill one guy. I am still suffering from a little heartburn 4 weeks from my first (and only chemo); never had heartburn before.
I read a story of a man who was very healthy before chemo and the chemo reduced his body to a shadow of it's former self before he died:
So you can understand why I don't like the chemo route, especially when there are better alternatives with with very low risk of permanent side effects and little to no temporary side effects.