Waldenstrom's macroglobulinemia: My treatment plan

By Steve Kirsch
January 2, 2008

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Note this page is superceded by Waldenstrom's macroglobulinemia: Low dose Rituxan which is my current plan.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.

• Smarter dosing of Rituxan to avoid resistance and maximize impact
• Using AMD3100 in combination with either smart dosing of Rituxan or Humax
• Smart dosing of Humax

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

• it wasn't shown to make a significant difference when Treon tested it in Extended rituximab therapy in Waldenström's macroglobulinemia

• intuitively, lower drug concentrations reduce the chance of serious side effects (see below). However, it's generally agreed among all physicians I talked to that the dosing levels are safe and that Rituxan side effects are independent of dose, so this is just an irrational fear on my part

• people achieve a CR using CPR (cytoxan-Prednisone-Rituxan), but there the Rituxan dosing is once every 3 weeks so it must work. Chemo and Rituxan are not synergistic according to one study, but other studies show incredible synergism. Depends on the chemo treatment and the disease!

• intuitively, lower dosing of Rituxan (once every 4 weeks) might cause less IgM flare possibility (at least it shouldn't increase it)

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

doi:10.1016/j.critrevonc.2006.09.004
Copyright © 2007 Published by Elsevier Ireland Ltd.
Pharmacokineticsof rituximab and its clinical use: Thought for the best use?

A later study has compared concurrent and sequential combinations of chemotherapy and rituximab [26]. In this randomised trial, concurrent arm patients received six cycles of CHOP together with rituximab (375 mg/m2) and those of sequential arm received six cycles of CHOP followed by six courses of weekly rituximab (375 mg/m2). No difference was found in terms of response rate or survival between the two arms.

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):

Cancer. 2008 Jan 1;112(1):119-28.

Consolidation and maintenance immunotherapy with rituximab improve clinical
outcome in patients with B-cell chronic lymphocytic leukemia.

Del Poeta G, Del Principe MI, Buccisano F, Maurillo L, Capelli G, Luciano F,
Perrotti AP, Degan M, Venditti A, de Fabritiis P, Gattei V, Amadori S.

Department of Hematology, University "Tor Vergata," S. Eugenio Hospital, Rome,
Italy.

BACKGROUND.: Rituximab in sequential combination with fludarabine (Flu) allowed
patients with B-cell chronic lymphocytic leukemia (B-CLL) to achieve higher
remission rates and longer response duration. Based on their recent experience in
indolent non-Hodgkin lymphomas, in this study, the authors attempted to
demonstrate whether consolidation/maintenance therapy with rituximab could
prolong the response duration in this patient population. METHODS.: This Phase II
study was based on a consolidation/maintenance therapy with rituximab for
patients in complete remission (CR) or partial remission (PR) who were positive
for minimal residual disease (MRD), as determined by flow cytometry. Seventy-five
symptomatic, untreated patients with B-CLL received 6 monthly cycles of Flu (25
mg/m(2) for 5 days) followed by 4 weekly doses of rituximab (375 mg/m(2)). Then,
28 patients who were positive for MRD were consolidated with 4 monthly cycles of
rituximab (375 mg/m(2)) followed by 12 monthly low doses of rituximab (150
mg/m(2)). RESULTS.: Based on National Cancer Institute criteria, 61 of 75
patients (81%) achieved a CR, 10 of 75 patients (13%) had a PR, and 4 of 75
patients (5%) had either no response or disease progression. MRD-positive
patients in CR or PR who received consolidation therapy (n = 28 patients) had a
significantly longer response duration (87% vs 32% at 5 years; P = .001) compared
with a subset of patients who did not receive consolidation therapy (n = 18
patients). All patients experienced a long progression-free survival from the end
of induction treatment (73% at 5 years). It was noteworthy that, within the
subset of ZAP-70-positive patients, MRD-positive, consolidated patients (n = 12
patients) had a significantly longer response duration (69% vs 0% at 2.6 years; P
= .007) compared with MRD-positive, unconsolidated patients (n = 11 patients).
CONCLUSIONS.: The addition of a consolidation and maintenance therapy
withrituximab prolonged response duration significantly in patients with
MRD-positive B-CLL. Cancer 2008. (c) 2007 American Cancer Society.

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:

I was diagnosed with WM on February 27, 2004 at 47 years of age.  At time of diagnosis: IgM = ~6,600; serum viscosity data lost (or not tested?); bone marrow "packed", est. 90+% involvement; lymph node involvement in chest and abdomen; spleen was not involved.  I immediately had three rounds of plasma pheresis --> IgM down to ~1,000.  My oncologist Dr. Robert Dichmann (Central Coast Medical Oncology, Santa Maria) consulted with Dr. Stephen Treon on treatment.  The plan was six cycles of R-CHOP to be followed with Rituxan maintenance for two years.  Below is my Rituxan experience.  My dosing is not an exact fit to your request and I have no concentration data, but maybe the information will be of use in your analysis.

All Rituxan doses were 750mg.

R-Chop:  six cycles, one every three weeks begining March 2004 and ending June 30, 2004.  Response: Complete.

Rituxan maintenance.  At the time two protocols were in vogue.  The European protocol was one dose every two months.  The U.S. protocol was four weekly doses done every six months.  I opted for the European protocol of one dose every two months (my thinking was to maintain a more level or even concentration), and we proceeded.  I made it thorough seven maintenance treatments: Aug., Oct., Dec. '04; Feb., Apr., June, Aug. '05.  I had to discontinue due to a suspected HAMA/HACA immune response to the Rituxan June, Aug. '05 treatments.  This presented as severe poly-arthralgia in fingers, hands, wrists, elbows, toes, feet, ankles and/or knees.  This problem continues to today (it has become a long story, presently going to UCLA rhuematology).

I find your concentration numbers of great interest. I assume that there is some maximum level (from Genetech trials or Dr. Treon), some level of toxicity. Through my entire Rituxan experience, things like concentration level, B-cell count (have % lymphocytes - B & T cells), HAMA/HACA levels were never done. Hindsight being 20/20, I think these measurements should have been done; would have made for a better experiment. Don't misunderstand me, I have the deepest respect for my doctors and I believe they act with the best of intentions. Also, more is known and understood now than ~4 years ago. And one can't fault a complete response against that which matters.

Here's another posting:

This is my first time posting to IWMF - Talk, I have read posting time to time, and learned a lot. I am newly diagnosed, July 2007. At first I was told that I should WW, my IgM was 3,700. The Hematologist I was seeing rotated out, and I got a new Hematologist. I had sat down and listed symptoms that might be related to WM. After reviewing my latest labs,, and going over my list, my major symptoms were blurred vision, and fatigue. I was scheduled for Rituxan infusion, once a week for four weeks.

I had a reaction to to the Rituxan, chills, and riggers. It took an hour and a half to get things under control. I was able to complete the four infusions, they had to give it at a lower rate. It has been four months, my IgM is now 1,950. The first thing I notched was that my blurred vision had gotten better, but my fatigue is worse. I am now noticing that I am haveing days of blurred vision again. It is off and on.

I have not been satisfied with the Homology Department, I am looking for a recommendation. I live in San Francisco. My PCP has referred me to UCSF, but I have not heard anything, in two months.

I have some questions, and wondering if these symptoms are from the WM, or is something else going on. If I go out for a few hours, I am down for two days, and sometimes three. I am experiencing blurred vision, night sweats, hot flashes, off and on during the day, I get winded just going up one flight of stairs, I have a ringing in my ears, this started during the Rituxan infusion, and has not stopped since. My abdomen has been tender since Rituxan.

I am a 55 year old, Jewish Male. BMB 57% infiltration. I have noticed symptoms for at least five years, the closest I got to a diagnoses was border line anemic. My Doctors explained the symptoms as side-effects to the medication I was taking. I have had more stress in the last couple of weeks, I hope to get things ironed out soon.

And another:

I too wish doctors would listen and believe instead of that"I know it all" attitude. I, too, have shortness of breath where I cannot walk more than a few steps and also ringing in my ears after receiving Rituxan. I do not believe it can be coincidence. Sometimes, just maybe, a doctor can learn something from a patient.

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.

Humax trial

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:

My father recently died this past November 2nd, after having been diagnosed with Waldenstrom's macroglobulinemia. He died 3½ years after he was diagnosed. Steve Treon was one of his doctors. When my father was first diagnosed, he was extremely optimistic, as I'm sure you were, that modern medicine would provide an easy answer. He visited the best cancer treatment centers in the country, including the ones in Cleveland and Boston.

As time went on though, I think he became somewhat depressed. Before chemotherapy he was an intimidating 6'4", 230 lbs. man, with dark graying hair and a beard.  Although he kept his hair, chemo reduced him to 150 lbs.  I remember him telling me that the doctors didn't know shit.  Some of the drugs involved in his chemo treatments have been in use since the 60s. 

And I remember him showing me and telling me about some of the drugs he was taking.  One was a derivative of snake venom, another, an ingredient of mustard gas.  From what I read on your website, I know that you are not naïve about this.  The medications and the chemo they give you are not really targeted.  They kill everything and they may very well end up killing you.  The chemo also severely compromised his immune system.  I remember that everyone had to keep their hands washed and no one who was sick was allowed near my dad.  With my mom, me, and my 5 younger sisters all living with him, this was no easy task.

Shortly after my father's chemo, he developed breathing difficulties.  Although the doctors deny it, we believe that the chemo was responsible for destroying his lung function.  After this he could barely do anything, he would always tell me that he could either eat or breathe, but he couldn't do both.  He would get winded just walking up the stairs.  He started to just sleep in our family room on the couch every night.

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.

Links
Waldenstrom's macroglobulinemia: Steve Kirsch's story