Waldenstrom's macroglobulinemia: Q&A on treatment

Inspired by reading the Patient From Hell, here are some questions that might be helpful to understand the treatment I'd require

It seems reasonable to assume that since WM is a slow moving cancer that the rate of cell division is slow. This is confirmed in cell lines which multiply slowly. Therefore, there is an exponential aspect to the disease: the more you have, the faster you progress. For example, suppose the doubling rate of WM is 1 year. Suppose you are 50% infiltrated. Then in just 1 year, you can go from a 50% infiltration to 100%!!! The bottom line is that you want to keep the counts low.

How fast do the precursor cells (cells which mature into bad WM cells) multiply? How long do they live? Does anything affect the rate of growth (days to to double), e.g., the IgM level or something else, or is it constant? NOTHIGN

two theories: might be a wm stem cell. maybe 80% of wm cells can divide. don't know even if MM. could be one or the other or both....

How fast do WM cells multiply (i.e., how many days to double)? How long do they live? Does anything affect the rate of growth (days to to double), e.g., the IgM level or something else, or is it constant? grow slowly. in vitro, doubles 2 to 3 days.  in vivo don't know since IGm stays stable. Hard to say. igm comes back from bone marrow since only. could be done in mice to see what would happen. look at mice flouresce. flourescent wm cell line. so can see. zevalin. could do in humans!!! 

could do constant phersis to see what would happen. but would be hard.

At what rate do WM cells produce IgM? NO. Person dependent. Is that production constant over their life? they can change over time, but usually rate is contstant. could be same # of cells. don't Does the rate of production depend on the amount of monoclonal IgM in your blood or is it independent of everything? BEAUTIFUL Q!!!!  They can test that!!!!!!!!!!!!!!!! How long do WM cells live? dunno.usually cells die for days. most won't live for week. cancer cells usually don't live for 10 dyas. CAN TEST THIS.

What is regulating IgM and keeping it within bounds? CAN TEST THIS. For example, if you have a plasma pheresis, your IgM's will go back to "normal" within a week to a month and then stay at that level. Is that because the WM cells stop producing IgM when the IgM level reaches a certain value? Or is it because there is another mechanism that kills IgM that causes the value to be steady state? How do we know which it is? Velcade kills machinery of making protein.

Why does IgM flare happen on Rituxan? Is it because the Rituxan kills cells that regulate the IgM production? Or because when WM cells are surrounded by the Rituxan, they produce more IgM? 50% do it. must test in vivo. test inside mice. is it cell death. can design an experiment. then you know what causes it. you can answer any q. people. How do you know which it is? And why does it happen in some patients and not others?

What is the relative number of precursor cells to WM cells? Is there any way to know this value?

Suppose we could magically filter out or kill every single B-cell from my blood and marrow. How long would it take for the WM to reoccur? This presumably would depend on how many precursor cells I have and how often they double in size.

How much Rituxan per kg of body weight does it take to "coat" all my cells? How many CD-20 cells get killed by Rituxan? All of them? or does Rituxan have a 50% chance of killing any given B-cell? And over what time? Does it take as much as a year to kill some B-cells? So what does the kill profile over time look like for the "standard" dosage of rituxan? do some b cells get killed immediately? or does it take 6 months to kill one B cell? what is the mean and std deviation of the kill profile? is it symmetric? 1month. sometimes 3 months. peak is 6 to 9 months.

Same question for cytoxan as for Rituxan. fast kill and gone.

why are people refractory to rituxan? does the body attack the rituxan? or is it because WM cells that are not cd20 survive? or some other reason. cells get smart or stay alive.

same question for cytoxan. yes you can be be. something is protection. less common.

is the rate and final IgM level after PP a good proxy for the state of the infection? rate could be predictive, but nobody's studies.

can you use PCR to look for WM cells? if we have your sequence, yes. don't have enough patients' in CR to do this yet. do it in CML now. Don't know what to look for. Design a PCR for the patient.

can you do PP on B cells instead of IgM? what would happen if you removed all B-cells? wouldn't it return based on % of WM cells in the marrow? Few of your WM cells are circulating. AMD3100 gets them out of the marrow. then do velcade and rituxan.  got approval. then do clinical trial. Yes, you can pherese out B cells. velcade 1x/wk.

Hard to believe that the the rate of production of the IgM is EXACTLY equal to the rate of natural death of the IgM so that IgM is stable. Without feedback, this is an unstable equilibrium. It is almost certain that either something is slowing the rate of production when the IgM concentration gets large, or there is something "kicking in" to kill the IgM when the IgM gets large (or possibly both). We should test this.

$200K, can answer all these questions.