Waldenstrom's macroglobulinemia: Drug options

By Steve Kirsch
August 1, 2008

I get email all the time from people telling me to look at alternative therapies. None of these suggestions come with any studies showing consistent efficacy for WM. Nor have any of the more than 1,000 members of the IWMF talk list anecdotally confirmed efficacy of any alternative treatment. If there is an alternative treatment that produces a partial response (more than 50% drop in IgM) in at least 50% of patients, I'm interested. If there is no data, I'm not.

There are a small number of new drugs with relatively modest side effects that are being tested against WM with some success. My understanding is that the current thinking is to use a cocktail of these "low side effect" drugs in order to attack the disease simultaneously on multiple fronts. So it's basically the r-CHOP type of combination approach, but using drugs that individually have far less "collateral" damage than the normal chemo drugs. For instance, Perifosine alone has a very modest effect on your IgM (e.g., a 33% reduction). But when used in combination with other drugs, it's expected it will be surprisingly effective against WM. A major benefit of Perifosine is to chase the WM cells out from their hiding place in the bone marrow and bring them out into the open where they can be more easily killed. Perifosine on its own has some effect, but it may not be enough to be FDA approved on it's own. It's unfortunate that the FDA doesn't allow such two-drug combination clinical trials unless the other drug is already approved as the "standard of care" for that disease. So you cannot run a Velcade-Perifosine trial, but you can run a Rituxan-Perifosine trial. This is a chicken and egg problem resulting from old theories about cancer. The FDA has know about this problem for years, it was expressly pointed out again in Cliff Leaf's excellent Fortune cover story "The war on Cancer" (Fortune, March 22, 2004), but nothing has changed. It's also illegal for you to use a drug that is proven to be safe but that isn't yet proven effective unless you are in a clinical trial. So there are cancer drugs, such as Xcytrin that can extend your life for years, but since the FDA isn't satisfied on efficacy, your doctor has to leave you to die.

Old therapies can work well. One person went from 9240 to 251 in 6 months on Rituxan and CHP. Chlorambucil (in pill form) has worked well for many, for example, Jerry took 7mg/day (reduced from standard 8mg/day):

My Igm was over 6000 when I began chlorambucil treatment, in August 2005. When I completed treatment in January, 2007, my Igm was 2300. My last bloodtest in May 2008, showed an Igm of 1590. Since the termination of my treatment, my Igm has been consistantly been decreasing. During my previous remission, between 2003 to 2005, my Igm began to rise after 12 months, also following chlorambucil treatment.

My Igm did start dropping immediately, but slowly and in spurts. So I could lose several hundred points and then gain some back.Thus it took me about 12 weeks to drop my Igm from about 6350 to below 5000. Chlorabucil is continued.till the patient ceases to respond.

Thus when two to three consecutive bloodtests indicate no further progress, the treatment is discontinued. Based upon my readings of the talklist, It appears that many chlorambucil treatments are discontinued prematurly' due to the impatience, or lack of knowledge, of the doctor/ and or the patient., I'd like to add, that some patients respond to chlorambucil much faster than I did.

On the flip side, however, chlorambucil causes MDS and leukemia in the long run, so we avoid it in young people.. it is not that effective either.. Some studies show responses after a year of taking it.. Not he greatest drug to start with.

Solo Fludarabine works wonders for some people where Rituxan doesn't work and vice versa.

Daily cytoxan pills work, e.g.,

12/92 - dx: IgM a bit above 4700.
1/93 to 4/95 - tx #1: daily oral CYTOXAN, 150 mg; lowering IgM to 240.
 

Notes from Steve Treon talk (taken by Ron Draftz):

He didn't cover the gamut on treatments and that was both good and bad. Bad
only because there were a lot of members who are not familiar with the range
of treatments that are available. Good because he did spend a lot of time
talking Velcade which he clearly likes when given with Rituxan. He did
slightly promote a large trial (150 patients) of Velcade (B-Bortezomib),
Cytoxan, Dex and Rituxan (BCDR) that will be run against the same drugs
minus Velcade. It is his opinion that prolonged remissions come from
treatments that successively rid us of most of our tumor cells and he thinks
this BCDR is the better combo instead of CVP-R or CHOP-R which he states do
too much damage to our immune system and marrow. He also doesn't like
Fludara or Cladribine given with R because of the tendency for the
nucleosides to cause transformation to DLBCL in time. I had the impression
he was looking for some drug combo he could use over and over to produce
long intervals of remission until treatment again becomes necessary No
mention of Rituxan maintenance at all.

In spite of his desire to still hit the tumor cells hard he has continued
his willingness to use lower dose treatments for Thalidomide and Velcade to
overcome the PN problem. But he also said that WM patients don't really
need the aggressive treatments that are used for myeloma or other lymphomas.
He would hate my comparing his having finally using the approach that Mayo
has quietly pursued for a long time when it comes to moderate treatment
protocols. It will be quite interesting to see what happens in Stockholm
and whether the consensus panels finally begin to align when it comes to
using less aggressive treatments for first timers.

He made a very brief statement that RADOO1 looks like a drug that is producing extremely good results for WM. Perhaps we will see RAD001 (which I like to call RAD-ONE) used in combination once they better understand the outcomes of this drug. Those yet to be developed combo's may be what keeps all us going for a long, long time. Dr. Treon has only included WM patients in his RAD001 trial and accounts for 13 of the total of 19 WM patients at all trial sites. BTW, he is touting an unofficial disease-specific median survival of 16 to 19 years based on some recent, though yet unpublished, studies.

It's too bad he only could stay for 40 minutes of questions. We would have
enjoyed twice that. This was Steve at his best, almost as though all 56 of
us were seated and sipping coffee around a table as we discussed the outlook
for WM.

Comments from Irene Ghobrial:

by next year we should have the following oral drugs tested and some possibly very active in WM:
Perifosine
RAD001
Enzastaurin
LBH589 (oral drug)
BEZ235 (oral drug)
Amd3100 and RItuxan
Humax

We will also have the following combination trials:
RAD001 and rituxan
Rad001, velcade and rituxan
 

WM patients normally have:

• monoclonal IgM spike
• low Hct
• low PLT
• low WBC

Criteria for treatment is typically:

• Hgb<10
• PLT<100,000
• >4 viscosity
• any amount of PN
• misc other serious symptoms (such as cryoglobulinemia, etc.)

Older drugs:

• Fludaribine and cladribine: Can cause your WM to transform to a more deadly lymphoma
• Cytoxan: One person wrote: Cytoxan caused my bladder to bleed after 5.5 years (with prednisone).
  I'd been warned. It was effective, but not benign.

Newer drugs include:

• GA101 is a new generation "humanized " anti-CD20 monoclonal antibody in phase I/II clinical trials
• Blinatumomab: BiTE antibody causes T-cells to attack CD19+ cells. Has been used in WM successfully. This is interesting because the side effects are minimal and reversible, the treatment is for 2 months, and because it attacks the cells at an earlier stage of development, it has the potential to permanently cure WM. There is a clinical trial in Germany now and they are looking for WM patients. See http://www.micromet.de/index.php?id=64 and Clinical Data Published in 'Science' Show Tumor Regressions in Relapsed Lymphoma Patients Treated with T Cell Engaging BiTE Antibody Blinatumomab First T cell engaging antibody (BiTE) showing clinical benefit in cancer patients; Blinatumomab enables patients own T cells to recognize and attack cancer cells
• Bortezomib (Velcade PS-341): a Proteasome inhibitor that causes WM cells to die because nobody comes to pick up the waste products from the cell. In high dosages, causes neuropathy, mostly reversible. If you get it once a week, a lot of people go 6 months without problems. 72 hour efficacy time. Combining with Rituxan, you get practically no flare. The problem is that the PN (which has a much higher incidence for WM patients than other diseases) is not always reversible!
• Perifosine: an oral bioactive novel AKT inhibitor which prevents homing of the WM cells back into the bone marrow. It also has some killing effect on its own. It does not affect the white cell count, does not cause anemia, or neuropathy. The possible side effect is some nausea, vomiting. It does not suppress the immune system. It works slowly so it takes about 3 months to start seeing a response, although one patient had a 78% decrease in IgM the first month. Another had a 50% decrease, and two have 20% and 22% decreases and this is just in the early months. Early findings indicate the drug is safe and well-tolerated, with many having decreases in tumor burden of 50% or greater, but it varies by patient of course. The reason this drug is getting very interesting is because: 1) it attacks the signaling pathway in the development of most cancers; 2) it is often effective in cancers that are resistant to other forms of cancer therapy; and 3) it doesn't cause a toxicity response and is, in fact, well-tolerated. Not since Rituxan have we seen a drug that is this well-tolerated, and seemingly effective.  We do not have a single "approved" drug for Waldenstroms yet, so this trial is very important to us all. Trial started in March 2007 in WM patients. Seems to reduce Hgb in several people and when you stop it, the anemia gets better. It causes bone or joint pain in some. One person reported thinning hair. One person's numbers get worse, but most are stable or get better. One patient wrote: "I tried the perifosine due to falling counts, but found the side effects to be unmanageable and the benefits to be little. Daily vomiting and diarrhea with weight loss and fatigue continued through my use of it. The psychological impact and the 50 lb. weight loss left me flat on my back! I did have a slight reduction in igm, but had to pull out of the trial as my total other blood counts pushed me into a critical state."
• AMD3100: is a failed anti-HIV treatment. It is a stem cell mobilizer and CXCR4 inhibitor. It produces mobilization effects of WM cells out of the bone marrow and prevents homing. So like Perifosine, but the effect is more pronounced. 2 hours after injection, the cells are out of the bone marrow. Within 24 hours, they are all back in hiding. This looks very powerful in combination with Rituxan. Irene Ghobrial is doing experiments in mice with this combination.
• Lenalidomide (Revlimid): A nicer version of thalidomide. This is a pill that you take and people with WM have had great results with it. This looked very promising. Unfortunately, Lenalidamide (Revlimid) not recommended for WM because of its role in precipitating acute anemia in WM patients (just ask Dr. Treon about his "nightmare" phase II trial with Revlimid in WM). Out of 12 patients evaluated, 4 had to quit to be hospitalized for anemia. 10/12 experienced unexpected acute drops in hematocrit within 2 weeks and 6/8 dropped out before 28 days. Also 4 cases of grade 3/4 neutropenia (which is as bad as it gets). Thalidomide/Rituxan is probably a better choice. However, instead of giving out 25mg/day, it would be far smarter to start at a lower dose and ramp up. If you do that, you can get excellent response without ongoing side effects.
• Thalidomide: Use with Rituxan to enhance response. Unfortunately, it causes PN.
• RAD001 (Everolimus): This is what I'll try if solo Rituxan stops working for me. Great response rate (about 70% of the patients respond), low side effects. It's a pill you take once a day. At 2 5mg pills per day, it can cause myelosuppression, e.g., red cell production, platelet counts and WBC can plummet and people have had to be hospitalized so watch out for this. Reducing dose to 5mg/day results in higher IgM levels, but more normal blood counts (except maybe Hgb).
• Enzastaurin: An oral protein kinase inhibitor from Eli Lilly. Irene Ghobrial is running a clinical trial in WM with this now. It seems to be working very well. The first 2 pts, one had a drop of 1000 points within one month and the other already has a 50% reduction ( from 4000 to 2000) in 2 months. About half the patients respond to this drug. Side effects are milder than RAD001 (which also has low side effects).
• NPI-52: 72 hour efficacy time
• AZD0350
• HuMax-CD20 (Ofatumumab):  from Danish drug company Genmab which reportedly works better than Rituxan and less allergic effects since it is a fully human antibody (instead of an antibody from a mouse like Rituxan). This article, Monoclonal Antibodies, explains why Rituxan is from a mouse instead of a human, and the problem with HAMA. HuMax might be a lot better than Rituxan or could be about the same effect as Rituxan.
• Epratuzumab
• SGN-70 (an antibody that interferes with mast cell signaling): Looks very promising): the problem is that the company that makes this is not good at getting drugs to market.
• Campath (alemtuzumab): a mAb that targets CD52 found on WM and mast cells. Notorious for T-cell depletion. But it is effective in WM.
• Gleevec (Imatinib): targets CD117 which is expressed in WM cells. This can work for some people.
• HB22.7: kills cancerous B-cells while leaving healthy cells untouched.
• KX2-391 (KX01): now in phase I trial at MD Anderson, is an Src kinase inhibitor. Said to be effective against all cancer types.
• Zevalin or Bexxar: one shot of zevalin brings complete remission in 76% of NHL cases (36 month effectiveness). Can't use it if you have high bone marrow involvement (>25%) since it will kill too many good cells.
• PS-341: a reversible proteasome inhibitor that has shown remarkable efficacy in myeloma and appears to have activity in other hematological malignancies including lymphoma and WM. PS-341 is administered i.v. twice weekly for a varying number of weeks followed by 1 week of rest. With this scheduling, it is generally well tolerated and appears to have minimal myelosuppression. A Canadian NCIC study using this agent in a phase II study for symptomatic WM is in progress.
• UCN-01 (a protein kinase C inhibitor)
• Treanda (bendamustine): ORR 75%, MRD: >9.2 months, with 20% CR. This trial for indolent NHL was in people refractory to Rituxan. Side effects are was low white blood cell count with fever and pneumonia.
• AVN-944: IMPDH inhibitor. They would love WM patients for a phase I clinical trial they are doing. Contact J. Michael Hamilton, M.D.,
  Avalon Pharmaceuticals, 301-556-9894
• Veltuzumab: humanised anti-CD20 antibody now in phase I/II trials
• PR-171 (Carfilzomib)- a proteasome inhibitor made by Proteolix has had good results in WM patients. It's like Velcade without the PN. Currently in clinicial trials for WM in two places. See Proteolix clinical trials for more info.
• CNTO-328: Monoclonal antibody to IL-6 made by Centocor. 4 WM patients were in a trial at NY Hospital and did well. Side effects are supposed to be quite minimal. Robin was the first patient in the trial and wrote:
  • I have had great success! I had tried Rituxin and 2Cda (with no success) and finally was getting plasmapherised twice a week or as needed just to keep my IgM down and to feel okay. When the CNTO Trial opened up I was in the right place at the right time. I was on it for almost two years and have been stable for almost a year in Sept!
• BDR: this is velcade, Dexamethasone, rituxan: Very fast response and 22% get complete remission. But a lot get PN and it wasn't all reversible. Also, they should give you Valtrex during treatment because the Velcade puts you at risk for shingles
• Note: one of these treatments puts you at risk for shingles and taking valtrex during treatment can prevent that
• Rituxan maintenance: doing 1 full dose once every 3 months can keep things in check. The 2 years was an arbitrary cutoff. People have been using this for longer and it seems to work well.

I am currently enrolled in clinical trial for statin treatment of WM. It's essentially Zocor; a pill you swallow once a day. The hope is that this might completely stop the disease from progressing. But I had to drop out since my IgM had started to affect my vision.

Unlike most cancers which you want to treat early and aggressively, for WM the recommended procedure is to only treat if there are symptoms. That makes sense since the treatment can kill you (or cause serious or permanent side effects) and has not been shown to substantially increase survival time. So treatment is normally started only when it is absolutely necessary to address the symptoms due to quality of life issues, i.e., when the disease clearly becomes worse than the treatment. Unfortunately, for some people, when the symptoms start to appear, the effects are permanent.

So I think that it's wrong. I think it is much smarter to treat the disease before it takes root. Once you allow it to grow, it is much harder to kill. And so what happens, you'll develop some serious symptom requiring you to treat the disease. Then you'll find you have no time. So you end up using really harsh treatments like chemo. That further weakens you and if it doesn't work, they use either stronger stuff. It is way smarter to do all of this while the disease is young. You can then find out what works, starting with the mildest treatments first. You have time.

In general, the treatments are also a huge guessing game, even among the top experts. Nobody knows which therapy is best for you or how you will respond because the response is quite variable from patient to patient, even if you have exactly the same numbers as another patient. It is "try this... ok, that didn't work...let's try this..." One top expert told a patient who wasn't getting any better with aggressive treatment "let's watch and wait" while another doctor told him to go on maintenance Rituxan. He did the latter and his health and his numbers both improved. Unfortunately, the cancer adapts to avoid being killed by the treatments so treatments that worked before can't be relied on to work later. Since there are only a handful of drugs that are effective, the number of times you get to experiment are limited.

To make a donation to cure the disease
You can make an online donation right now using
the button to the left or this link:
Kirsch Fund for Waldenstrom's Research

More on my WM
Steve Kirsch health update
Kirsch Waldenstrom's Macroglobulinemia Diary: tracks my blood counts over time
Q&A on treatment: Questions I had (many of which are still unknown)
Case histories: Case histories of people with WM
How to cure WM: My initial thinking on how you get to a cure
What the math tells us: Some preliminary thoughts I had on how the disease operates
My treatment option analysis: pros and cons of the treatment options that were available to me
CPR treatment details: misc advice I have on CPR therapy which I decided to discontinue
Project Ideas: a list of things to consider funding
My treatment plan for WM: Here's how I originally planed to treat my disease and why
Low dose Rituxan: This is my most recent thinking on how to best treat this disease today
 

Articles by others about my WM
Steve Kirsch’s Tough Battle: blog posting by Wall St. Journal reporter Kara Swisher
Entrepreneur's funds shift to rare cancer : Front page story in San Jose Mercury News on Oct 5, 2007

Medical research
How to cure a disease
Success models for curing a disease

Opinion pieces
The real enemy isn't the terrorists: my op-ed about government funding for cancer research

Waldenstrom's info
International Waldenstrom's Macroglobulenemia Foundation
Research Fund for Waldenstrom's -- Dedicated to a cure
Waldenstrom's Macroglobulinemia Program: at Dana Farber
WM Audio library: highly recommended!

Medical technical info
Waldenstrom's Macroglobulinemia basic information
Waldenstrom's Macroglobulinemia technical papers from DFCI
International WM Workshop papers
Diagnosis And Treatment Of Peripheral Neuropathies: one of the most common WM side effects
Treatment for Waldenstrom's macroglobulinemia -- Chen 15 (4) 550 -- Annals of Oncology

Other sites
Kirsch Foundation: the foundation I started
Steve Kirsch home page: my personal home page