Waldenstrom's macroglobulinemia: Treatment option analysis

I am writing this page to document the thought process I am using to decide how I would like to be treated for WM. I hope it is useful to me, to the physicians advising me, as well as to anyone else in a similar boat.

These are my personal opinions. Your conclusions may differ from mine. The purpose of this page is just to explain my reasoning behind each therapy.

First, I'm extremely grateful to doctors Ranjana Advani (Stanford), and Irene Ghobrial and Steve Treon (DFCI) for putting up with my endless amount of questioning. Sadly, the information you need to make the best decision isn't readily available on the web, so I've used up a lot of their precious time to explain things to me and for that I am very grateful and I've tried my best to accurately summarize it here so others can benefit from what I've learned.

My present situation is I'm a 50 years old male with an hct of 32, hgb of 10.7, and IgM serum of 4010, and SV of 2.9. Latest BMB was 40 to 50% involved. The numbers for the hct and hgb are a bit "pumped up" from what they would be because I was given 5 rounds (1 week per round) of IV iron (Ferrlecit). I was asymptomatic (other than the anemia) until recently when I noticed blurry vision in my right eye that would come and go. Treon told me to see an ophthalmologist immediately. My pupils were dilated (note: Maureen who teaches ocular disease, recommends with an IGM of 4,0000 one should have a dilated eye examination at least twice a year) and two different docs looked into my eyes looking for sausaging and/or enlarged veins. They said everything was normal except for a small drop of blood in the periphery of my right retina which they said was recent. Both eye doctors said both the drop of blood (a peripheral retina hemorrhage) and the blurred vision was consistent with a high SV.

Upon hearing the news, Treon told me to drop out of the statin clinical trial, get 3 rounds of PP (1x every other day for 3 sessions total; about 90 minutes per session), then start CPR which would be 1x every 3 weeks for a minimum of 4 cycles and we'll go from there.

As I'm writing this on Saturday December 8, I just finished by first PP round. Treatment day for CPR is scheduled for Thursday. So if I'm going to make a different decision, I don't have a lot of time.

There is not enough known about WM to make a definitive treatment recommendation and there is a cost/benefit tradeoff that different people weigh differently. That is why 3 different docs gave me 3 different treatment recommendations on the same symptoms. Everyone reacts differently and there isn't a physician in the world who can accurately predict in advance what treatment(s) are going to work on what patients and to what extent and for how long. Nobody can predict CRs for any given in advance. However, there is lots of data on what treatments are effective against your symptoms, e.g., if you have swollen lymph nodes, some treatments are more effective than others in reaching that. And there is lots of data on what treatments, in aggregate, produce the best results.

There is also a difference in philosophy of whether to start by treating pretty aggressively when you have your best shot (e.g., CPR as a first treatment), or to treat starting with low side-effect drugs (e.g., Rituxan only) and then escalating to harder drugs (e.g., CPR) if you don't respond or stop responding.

I asked three different docs and got 3 different opinions for my case. Of course, there are many more options available, but these are the 3 most favored by my physicians. My 3 options being:

For option 3, there are two variants. I could go on the Velcade + Rituxan clinical trial that Irene is doing. Or, subject to the approval of my physician (a low-probability event!), I could design my own off-label therapy since Velcade is FDA approved.

The V+R clinical trial at DFCI run by Ghobiral is Velcade 1.6 mg/m2 once a week for 3 weeks on an one week off for a total of 6 cycles ( 6 months). Rituxan once a week for 4 weeks for cycle1 and cycle 4 (first and 4th month) based on the extended rituxan trial.

If I "designed my own", I'd do V+R once a week for 4 weeks, while simultaneously doing 20 mg oral simvastatin once a day. If my numbers started heading up, I'd do a 1x/week for 3 weeks of Velcade. So it's similar to the V+R clinical trial, but only repeats the Velcade only if required to keep the numbers heading in the right direction.

CPR (cytoxan-prednisone-rituxan) is basically rCHOP but without the Vincristine/PN risk and without the doxorubicin (aka hydroxyldaunorubicin so it is the H in CHOP). There is a wonderful writeup of rCHOP in "Patient from Hell" (herein after referred to PFH), pp. 67-91 which I've used in the Pro/Con table below because Schneider's writeup talks about things that the doctors may not tell you about beforehand (they didn't tell him beforehand either). rCHOP has more drugs than CPR; CPR basically omits the Vincristine which didn't add much to the effectiveness, but caused lots of peripheral neuropathy (PN).

Here are the pro/con arguments for each of the options. ORR=overall response rate (>25% reduction), MRD=median response duration, Minor Response is >=25% reduction; Major Response aka Partial Response is >=50% reduction in IgM.

All three doctors are right. We don't know enough to predict in advance for a particular patient, which is the "best" course of treatment. They are all good choices and I respect their reasoning. Reading it over, it is indeed very hard to pick a winner as all three doctors make an excellent case. But I'm glad I have 4 great options to choose from!

Also, whatever I choose, I'm going to try to persuade my doctors that taking 20mg simvastatin a day cannot hurt and has the potential to slow or even reduce my disease. The reason for this is that in my opinion, it is much much better to keep the disease "in check" while it is relatively small, rather than allow it grow to be huge.

When IgMs get to be really huge, your options and time get limited very quickly. For example, Sharon, who is the same age I am, reports the following:

Brian: If I were at your position it would be my choice as well. I was very sick at diagnosis (age 42) and so opted for PP + 2Cda, Cytoxin and Rituxin which turned out to be a very good combination for me (it was experimental at the time and I had to sign multiple wavers). I got about 7 years off and then had to repeat. Being mentally ready is as, if not more, important than the physical aspect. You'll do great. Good luck. As a p.s. I am in the minority of people who found cytoxin actually stimulating (akin to very mild amphetamine). I confess to enjoying the effect although drinking large amounts of fluids while taking it was a drawback :)

Ron: Unless you have some rare first time allergy, you will love CPR. For me it has been a gift that keeps on giving. I slept through infusions 2 thru 6, once the diphenhydramine hit, and while my first two month drop was only 400 points to 1850, over the last ten months I've gone steadily down to 1350. I'm seriously looking at statin trial, expecting clearance from my hematologist when I get home from FL. It is my cholesterol that is high, and any IgM reduction would be a bonus CPR is cheap, too -- being on SSDI, I paid only $400 for "supplies." If you are self insured, I have no idea. Blessings. Be glad and confident now your decision is made!

Geta: I have just started the same treatment that Treon has recommended for you. I had plasmapheresis 2x on Wed. and Thurs. of last week and CPR on Friday. Pleased to say I had no side effects and am feeling fine. Treon is my consulting doctor while I am receiving treatment down in Florida for the winter. I am really a Michigander. Good luck. It sounds like a good protocol to me. If you have any questions about my stats or anything, please ask. I read all your comments with interest.

Dan: Cytoxan/Prednisone/Rituxan. this a well used treatment with an alkylater, a steroid and a monoclonal antibody. I think this is a good enough choice and you were right about the first treatment giving you the best and longest response. You may want to ask the onc for a prescription to Ativan to take at bedtime to counteract the Prednisone side effect of not letting you fall off to sleep.

Robyn: Good luck Steve. I think it is a great choice and one that I will choose the next time I need treatment. I kind of wish I did it when I first chose Rituxan alone..but I am responding to the Rituxan now. But next time, it is the big guns!

Rinat: I was diagnosed in August with IgM 9200 Hgb 8.1 and total protein 10.5. Symptoms: fatigue, dizziness, blurred vision and nose bleedings. The treatment choice was CVP-R. My doc decided not to give me the regular dose of the Cyclophospharmide (1000/m2) but a lower dosage of 750/m2 because of the chance of developing a different kind of cancer in the future (one of the side effects of C). After the 3rd treatment my IgM was down to 3900 and Hgb up to 10.0 she decided to reduced the Vincristine by 50%. After the 5th treatment IgM is down to 1900, Hgb up to 11.7. Now, after the 6th treatment she is considering to stop the chemo and continue only with the Rituximab. She is not sure and didn't give me a final answer yet. I know she will consult with Dr. Treon about my case. Here in Israel they don't have much experience with WM. As to side effects, the first two treatments are the worse: headaches, extreme weakness and light nausea for 2 days. After that it gets a bit better with every treatment. After the first 3 treatments I needed Neupogen but after that your bone marrow gets "clean" of the cancerous cells and able to recover by itself. As to hair loss, from the beginning my doc said there's only 30% chance for it. I didn't lose completely my hair although my hair thinned. As I see it, the main problem is the side effects of 100 mg of Prednisone: insomnia (sleeping pills help), weight gain, nervousness (my husband suffers this one...), and swelling of the stomach (never take Prednisone on an empty stomach!)

In the beginning my doc defined this treatment as "light chemo" and I think she is right. Although all of the above it's bearable and the positive blood test results give you strength to continue with the chemo.

Peter: Given your condition and the options available to you...I'd probably opt for the same thing. Just make sure they give you the appropriate "ancillary" meds to counter any problems with the treatment process (infections, rituxan reactions, etc.).

I was treated at age 43 first with 2CDA (no effect) then a few months later with FCR (at the time - in 2005 - it was still felt that FCR was a good approach to take).

Didn't have tremendous hair loss with FCR (had some but it was more a thinning that a loss)....and most days, I was able to drive the hour to the hospital and then drive home afterwards, although they counsel against doing that.

Will you have a port, or will your treatments be via IV/pill? If going for IV, always make sure that the nurse/phlebotomist knows what they're doing when they stick you - I've had some wonderful adventures with them. If you're not comfortable with the nurse doing it - ask for the IV team . You'll come to know right away from their behavior whether they know what they're doing.

And make sure they follow the rituxan flow process correctly. At the slightest hint of flushing of face/neck, etc get to the nurses and have them stop and start slowly again - even if it has to take many more hours....I didn't have a reaction during my first infusion, but did on my second, and did not on any other infusions - go figure! (again, we're all different in our tolerance of treatments).

Make sure to keep an eye out for any odd feelings you may have throughout the process...I also somehow came down with a urinary tract infection - I began to urinate fairly frequently, but thought nothing of it until the urge to urinate became trememdous during my hour drive to the hospital (made even worse by the fact that I noticed every drop of rain that was falling, every person drinking from water bottles on the sidewalks, every dog urinating on a fire hydrant....) - a quick dose of antibiotics took care of it in short order. Bottom line - don't hesitate to discuss all the odd aches and pains...

Also, even though you shouldn't see dramatic results immediately - make sure to ask the nurses for copies of the lab reports (at my hospital they generally don't give them to you unless you ask), so you can track your progress and be better prepared to ask the doctor some pointed questions as time goes on.

Dave: Steve, I don't know enough about your situation to "pick a drug", but chlorambucil's best use is for older patients with mild symptoms that do not need immediate attention. In younger WM, the risk is that some future date will show damage to the DNA as a result of the prior use- like me 20 years later. The CP-R or CHOP- R regimens give a high rate of remission with little major damage and gives a young person the later option of a stem cell transplant - freezing stem cells for later "reset" option.

Jerry's advice is fine for the typical older patient of 65+ years, the CPR better advice for a younger WM which I must have assumed that you were. Of course, I have assumed a lot here! Always bad! The Velcade option has been effective while in use, but there is not enough evidence to show that it can be successfully discontinued, and the effects can be brutal. I would save that option until it has been better refined in WM because of the fine options that have been shown to be successful in WM now in use.

We often try to jump to the newest and "hottest" new drugs prior to gaining the best use of existing drugs and treatments. Hope this helps! Just finished a rapid infusion Rituxan, and am seeing good results so far! Plain vanilla! Hope you are well!

Don: My first line treatment was PP (18 times in 4 months) with Rituxan/Fludara in April 2002 for 4 months (one Rituxan per month with 5 days of Fludara) and added Cytoxan later for months 5 and 6. At that time most popular first line treatment was deciding between Ritux/Flud or Rituxan and Cladribine. It wasn't until I added the Cytoxan that my hyperviscosity stopped with my viscosity staying under 4.0 - never had a PP since. I will never know for sure if Cytoxan/Ritux would have done the trick alone with a little Prednisone added. My numbers didn't start coming down dramatically until Christmas 2002 when the doctor and I decided to added Dexamethasone (strong steriod) to my low dose Thalidomide protocol. I felt that the residual Rituxan and Dex were key drugs for me or maybe it was just a Christmas blessing?? Be a patient patient! Sounds to me that you are making a wise decision with many unknowns after considering many options. I will add you to my prayer list.

Mike: DX 1985 Chlorambucil (10 years), CHOP, COP plus Vinblastine, Phase 3 trialist Fludara and Rituxan combo (3.25 yrs remission), Rituxan x3 cycles 2 plus years remission each time Very fit and well play 3-5 sets competitive doubles twice or more per week You and your oncologists no doubt discounted Fludara/Rituxan combo--its still possible to do stem cell harvest after Fludara ,and this combo is not really first line treatment It would be the aim to get it right first shot ,and Steve Treon is the expert in this field and we seem to be different responders ,WM being a fairly unique orphan lymphoma 3xpp first --logical Best to go chemo route first probably and certainly from my personal "anecdotal "experience CPR--- good choice--- hopefully it will be successful and I wish you well and that you get a great response and a long /complete remission which is what we all deserve Stay positive

Option	Pro	Con	ORR	MRD
CPR	Treon strongly favors this. It's a time proven therapy with the most data behind it (because it's basically an abbreviated form of rCHOP). It gives me the best chance of a permanent CR which is important because the fewer drugs you have to use, the better. The side effects are pretty minimal (relatively benign compared to other chemo therapy). Most importantly, the long term side effects are thought to be insignificant. Plus, there is no risk of PN since there is no Velcade or Vincristine. If you want to minimize the total amount of drugs you have to take to get to stable disease or CR, this is your best shot because the three drugs enhance each other. CPR is also excellent at reaching WM in the lymph nodes (mine are somewhat enlarged). In general, second remissions are harder to achieve than firsts, so if you are going to take a shot, this is the best shot. You could be totally done with just 4 doses (if you are lucky). Rituxan flare is reduced (compared to Rituxan alone). That's quite important since you don't want to do PP after the treatment since it will get rid of the Rituxan. Also, you don't want to risk eye damage, etc. caused by IgM flare. You probably won't miss any work. The Prednisone will give you a 5 day "high", so you'll see an energy drop on day 10 to 14 of each cycle. Since their is no doxorubicin, it's unlikely you'll lose your hair. Most people don't lose their hair from the cytoxan. Note: Be sure not to wait too long between Compazine doses (PFH, p. 81) and drink plenty of water to help move out the chemo from your body and keep it from toxifying your liver. When Cytoxan is given via IV, there is minimal toxicity to cells (i.e., permanent cellular damage to stem cells) which is why cytoxan is often given before stem cell harvests. Note: Cytoxan is 1gm/m2, Prednisone is 100mg/day for 5 days, Rituxan is 375mg/m2. Cycle is 3 weeks. 2 weeks after the 3rd cycle, he wants 3 red tops overnighted to DFCI. Treon and others recommend that C is given before R, but others say it doesn't matter. P is given after the infusion.	There is a some collateral damage from the cytoxan. You have a small chance of losing your hair during treatment and it may not grow back the same way (could be curly or less thick). You will be given extra meds to control side effects (like nausea). Your white cell counts may drop requiring neulasta with the second cycle. According to PFH (pg. 11), 20% of patients end up needing Neupogen or neulasta due to low white cell counts (neutrophils) during chemo, but at my age, it's less than 20% and PFH was on CHOP, not CPR which is more mild. Worst case is you may have to stay at home for a week (PFH, p.11), but most don't lose any time at work. Food will taste pretty bad while you are on chemo (PFH, pg. 83), although one person said a few puffs of marijuana gets rid of the bad chemo feeling and restores your taste. You'll probably suffer from a bad temper when you do a cold-turkey stop on the prednisone in each cycle (PFH, p. 82-83 and the story on p. 87). Your white and red blood cells and platelets may temporarily decrease. This can put you at increased risk for infection, anemia and/or bleeding. Your ability to conceive or father a child may be affected by Cytoxan Prednisone will make you hungry and cause you to gain weight. It will also make it very hard to sleep. Of course, the above are relatively minor, short-lived consequences. However, some people have reported some loss of mental and physical vitality after lots chemo treatments (but not 4 doses of this one specifically). If you only took less than 8 cycles of CPR and have long term mental or physical vitality differences, please let me know! There is a slight risk of developing a blood cancer such as leukemia or myelodysplasia after taking Cytoxan. Chemo drugs may permanently affect brain function (e.g., chemo brain). CAUTIONS: See Cytoxan, Cyclophosphamide, Neosar - Chemotherapy and Side Effects	80% get at least a 50% IgM reduction after 6 to 8 cycles	10% to 20% are estimated to get CRs on CPR per Treon verbal
Rituxan	Advani favors this as an initial therapy. Rituxan is a very targeted therapy very little "collateral damage" with good results. Your numbers can get better for years after your last treatment (because you are killing both the B lymphocyte and the lymphoplasmacytic cells, both of which express CD20). Her reasoning is to start with this, see how it goes, and escalate later to CPR, R + V, or something else if needed. You risk only having wasted a little time. R has very little side effects and mostly limited to the first hour of infusion. You likely aren't going to miss work or be incapacitated in any way. The fewer the drugs, the less the side effects. The good thing about R alone is you can chart your personal reaction to R so you can better plan the timing of future treatments and maintenance. In engineering, we'd call it plotting out the impulse response. A start with R alone seems intuitively more consistent with the disease. Before my vision problems, it was debatable as to whether I "needed" treatment. The vision symptom pushes me over that line. But CPR is like chemical warfare compared to R only which is like a surgical strike. Intuitively it feels a bit odd to go from "treatment optional" to chemical warfare. However, on the other hand, there is a good case to be made for CPR above since the weapons are synergistic with each other.	Nobody ever gets a CR from Rituxan alone, so you are going to have to do more treatments after this. If you want to go for a quick possibly permanent fix in just a few visits, this isn't it. It is unknown if starting with R only reduces your chances for best effect compared to CPR as an initial treatment, but Advani thinks probably not. However, if you want to be super safe, you should assume that your best shot is your first shot; for example, see the story of Sharon below where R-CVP worked for 18 months then everything stopped working. You risk the biggest R flare using R alone. CPR has less flare and V+R has even lower IgM flare risk (and lower flares if they do occur).	For 4 cycles, there is 27% partial response (>50% igm decrease). For 4+4, it is 40% to 45% PR. There are never any CRs.	longest mean was 16 months (Dimopoulos) per Table 7 in Merlini, Treon
R + V (clinical trial)	Ghobrial favors this approach. Her reasoning is that it has minimal side effects, but about the same success numbers as CPR. So the benefits are the same as CPR, but the strain on your body is minimal and confined pretty much to a low risk of PN that appears to be both temporary and reversible. On her clinical trial, the amount of PN was minimal and it was all reversible. Chance of R flare is minimal and if there is one, it's relatively small. You can join the clinical trial at DFCI and help add to the knowledge of this disease. People have reported great efficacy with Velcade alone and there is a synergistic effect with Rituxan.	Others claim that in test results in other lymphomas, Velcade even once a week can cause significant PN. Some people never experience PN with Velcade, even at 2X/week dosage over 4 years. If you start experiencing PN with Velcade, my opinion is you should stop immediately. Guy Sherwood tried to be a hero since he was getting great numbers with Velcade on Treon's trial, but later regretted his toughing out the PN during treatment; after treatment stopped, he suffered through 18 months of excruciatingly painful PN. There is less data on R + V than on CPR. Unlike with Rituxan, there are reports that the gains you make while on V disappear pretty rapidly after you stop taking it.
R + V (custom)	Should produce a better benefit than R alone, but since there are only 4 V doses, the PN should be minimal if at all. So this should be better than R alone, with no additional side effects.	Very hard to find a physician who will allow you to design your own treatment protocol, not matter how logical it is. Note: That is too bad in my opinion because each patient is different in their response and each of us have a different risk-reward metric. It would be nice if medicine can be tailored to our individual responses rather than applied cookie cutter style to all patients, but I can also understand why this isn't done (because docs shouldn't experiment on patients outside of clinical trials and stick to proven regimens).