Waldenstrom's macroglobulinemia: Drug options
By Steve Kirsch
Updated Sept 14, 2014
Newest drugs (just opening clinical trials right now):
Best new diagnostic
- Use PCR on detecting the MYD88 L256P mutation in the peripheral blood (Xu
Newest drugs (from ASH 2013)
Top 5 drugs as of March 26, 2014
1- Ibrutinib aka
Imbruvica (this is the go to drug for most people
due to efficacy and low side effects; 3 capsules/day; FDA approved)
2- Oprozomib (although has side effects)
3- Cytoxan/velcade/rituxan combination for more
aggressive disease but velcade causes PN
4- Carfilzomib/rituxan if we can get carfizlomib
5- Bendamustine and/or rituxan
Here are the most important things you should know about drugs for WM (some
of which apply to all diseases):
- There are some drugs that can kill you if you over dose. So if you are
going to deviate from what they told you, you should always deviate
downwards unless you really know what you are doing and you've talked to
your doctor about it.
- The dosing regimens on virtually all WM drugs is not optimized for
killing the disease and/or side effect on you. So for example, a lower
Rituxan dose might work better and have fewer side effect. Similarly, we
don't know if a spikey dosing regimen is better than a constant dosing
regimen. Nor do we really know whether it is better to give Rituxan once a
week for 4 weeks or for 8 weeks. Nobody has tried it longer than 8 weeks. It
could work fantastically if they didn't stop early. But nobody knows. So it
might be true that giving only 100 mg of Rituxan once a week for 52
consecutive weeks kills all your disease with minimal side effects. Or maybe
it will backfire and kill your immune system. We just
don't know. For many drugs, it is typically dosed by giving you less than
the maximum tolerated dose with the thinking that more is better. That isn't
always true. And it may be smarter to deliver the drug in spikes rather than
continuously. And the dosing frequency can have a huge effect on side
effects. For example, if you give Velcade once every 2 weeks instead of
twice a week, the risk of PN is probably minimal. But nobody has tried this.
So there is a lot that is unknown.
- Listen to your body.... if you are taking a drug and it starts giving
you PN or you start losing your short term memory, in my opinion you should forget the
protocol and stop taking the drug. There are doctors who disagree and want
you to take the drug no matter what (unless you are in danger). I know people who suffered permanent or
long-lasting debilitating side effects because they kept to the protocol
instead if listening to how their body reacts. These protocols never cover
100% of the patient reactions. They are geared to be safe for most people,
not all people. My opinion is that it is better to be safe than sorry and
pay attention to the signals your body is sending you. For example, I
noticed a higher amount of blood in my nose while taking LBH-589. It turned
out, my platelets dropped under 20 and I got an emergency transfusion that
night. Had I just followed the protocol they gave me, I could have been
- Research the drug. A "good drug" is an oxymoron. For example, people
have had excellent results on Bendamustine. But I also talked to a patient
(a former nurse) who lost nearly all her short term memory after 4 cycles.
Her IgM is 400, but she may never recover her short term memory. She started
to lose it after taking the drug. Could the drug have caused it or was it
just a delayed result from her other treatments? The moral is talk to as
many people as you can who have taken the drug and ask about the side
effects. In other cases, drugs like Fludarabine can dramatically increase
the risk that your cancer mutates into a cancer that is much more deadly.
philosophy has always been to triage the drugs by safety and side
effects...try the safest drugs first, before you have to resort to the more
dangerous ones. So I avoid drugs like Velcade and Fludarabine, for example,
due to their potential side effects (PN and transformation, respectively).
That's why I started with mono therapy Rituxan, then enzastaurin, then
LBH-589, and if I fail that, I'll look at the RAD001 related drugs. No sense
in using the heavy duty stuff now if the easy stuff works.
- Subscribe to and read the WM talklist every day. The more you know as a patient, the
better off you are. See
- If you ask 3 experts in WM what treatment they would recommend for you
and your case, you'll often get 3 different answers. There is a lot of
subjectivity in this disease with no "right" answer. You have only options.
Carefully weigh the pros and cons of each option based on your own tolerance
for risk. Your treatment should be your decision. Don't just pick a doctor
and do what they say. Find a doctor who is willing to allow you to choose
among acceptable alternatives.
- Find a doctor who is flexible. There are lots of doctors who insist on
treating you "by the book." But there are a lot of very smart doctors that
will take your history into account and also how you react to the drug,
e.g., give you less than the standard dose. My preference is to find those
doctors that are willing to deviate from "the book."
- If you are on a budget (e.g., Medicare, doughnut holes, etc.), then a
clinical trial might be less expensive than a more proven solution since you
get the drug for free. In general, other than a small handful of drugs (Rituxan,
chlorambucil, RAD001, Velcade, Cytoxan, Fludarabine, etc), there aren't very
many good FDA approved approved drugs for WM, so a clinical trial is often
your best bet.
- I tend to be of the school of get it under control now. I think waiting
too long can be dangerous because it may take a while to find a drug that
works for you. Most WM doctors however think you should only treat if there
are symptoms that are causing problems. But if your IgM is going up, it is
just a matter of time until you have problems.
- There is now convincing evidence that Rituxan maintenance therapy leads
to increase overall survival. Whether you do a maintenance regimen of once a
week for 4 weeks every 6 months, or 1 infusion every 3 months seems to make
no difference in outcome (they are pretty similar). Personally, I'd rather do the once every 3 months
since that is a lot less drug.
I used 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
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
Solo Fludarabine works wonders for some people where Rituxan doesn't work and
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.
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,
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
Comments from Irene Ghobrial:
by next year we should have the following oral drugs tested and some
possibly very active in WM:
LBH589 (oral drug)
BEZ235 (oral drug)
Amd3100 and RItuxan
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:
- >4 viscosity
- any amount of PN
- misc other serious symptoms (such as cryoglobulinemia, etc.)
- Fludaribine and cladribine: Can cause your WM to transform to a more
deadly lymphoma. Seldom used today, and if used, seldom more than for 4
cycles. There are both short and long term risks to consider. Shingles is
one of them, which is why we strongly recommend prophylaxis with acyclovir
or valtrex. Depression of the neutrophil count for short as well as long
periods of time is another important toxicity. The long
> term side effects are also important to consider as well.
- 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.
- Rituxan: Maintenance strategies that work are 4 doses every 6 months.
Another is 1 dose every 3 months. One person wrote: "Rituxan is my treatment of choice. I have had nothing else for 8 years
and having been doing just fine. I get four standard 375mg/ M^2 every 6
months and have now completed 64 treatments.my HGB is 13.9 which is below
the normal mean but still in the normal range."
- green tea extract: reduced lymph nodes 50% in 11 out of 12 patients. See
WM Torch Oct 2009 issue, page 14
Will drugs that target overexpression of MyD88 be the silver bullet that
Perhaps. Perhaps not. The problem is if you knock it out, there may be too
much collateral damage. Colin Perrott writes:
Although aberrant hyperactivity of the IRAK-4 /
MyD88 pathway has been observed in several malignancies (now including
WM), deficiency of IRAK-4 / MyD88 presents several problems
through diminished protection at the central and peripheral checkpoints for
self-reactive B-cells as well as skewing of the antibody repertoire as a
whole. So it seems to me that Maxwells' Silver Hammer is still somewhat
beyond reach, that therapeutic methods developed from these observations
will need refinement according to the circumstances to achieve levels of
control more subtle and durable than following a simple knock-out
philosophy... Hence we should not yet divert our interest from established
There is a general review of the immune role of
IRAK-4 / MyD88 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807984/
Newer WM drugs include:
G'day Steve. I have posted a few reports to the IWMF but folks over there
haven't seemed too interested at the moment. Imbruvica seems to be the go in
I started on the trial in July of last year. Absolutely no side effects,
although I know others have reported some diarrhea, low Hgb and low
My initial response to the drug was quite rapid and my Igm feel from 5300
to around 1900. It hasn't changed much in the past three months but I have a
review and tests at the end of September which will confirm, or otherwise,
my status. Hgb was initially 98 and climbed to 125, but has fallen back to
113 at last blood tests. What I can say is that 15 months ago I was
struggling in many respects: stamina, tiredness, etc. At this port of call
I'm out cutting my lawn and chopping wood, as well as getting out and about
as any normal person would.
I should point out that I've had WM for around 20 years now and I suspect
that the illness is developing quite a bit of resistance to treatment
options. How long before that happens with ABT 199 remains to be seen
Oprozomib, which is oral velcade like proteasome
inhibitor. It has an amazing response in WM and no neuropathy. There is one
complete remission and others having amazing lymph nodes and bone marrow
A CXCR4 antibody that we are presenting in ASH and
it works in the patients who have the CXCR4 mutation in WM. I will send you
the paper but we showed that CXCR4 mutation causes more aggressive disease
in WM and we can target this in WM with a new antibody.
12/4/13: IMO-8400. Now
opening trials for WM. Targets MYD88 pathways.
10/24/13: Sandoz and Novartis (yes, drug makers),
published in the Journal BioDrugs, showing that they found GP2013 to be
similar to Rituximab. GP2013 has been used in several phase III clinical
10/23/13: Interesting study results pointing to the
possibility of using lenalidomide, dex, and rituxan together, whereby the
lenalidomide makes it possible for rituximab to work in patients who
previously were resistant to it... The study, however, didn't include WM or
LPL patients...still, something to consider...Combined Lenalidomide,
Low-Dose Dexamethasone, and Rituximab Achieves Durable Responses in
Rituximab-Resistant Indolent and Mantle Cell Lymphomas
(TGTX-1101): Ublituximab, a novel, third generation chimeric monoclonal
antibody targeting a unique epitope on the CD20 antigen, has been
bioengineered for enhanced biological activity with an increased ability to
trigger an immune response, delivering superior ADCC effects to aid in
B-cell depletion. Created by TG Therapeutics, Inc. (OTCBB:TGTX). "Anti-CD20
monoclonal antibody therapy is a critical treatment component in WM; however
patients continue to relapse. This data highlights the excitement for
ublituximab, a new optimized anti-CD20 monoclonal antibody in the treatment
of WM," stated Professor Veronique Leblond, MD, PhD, Head of Hematology,
Hospital Pitié-Salpêtrière, Paris, France.
CX-5461: Cylene Pharmaceuticals today announced that
research collaborators at the Peter MacCallum Cancer Centre (Peter Mac) in
Melbourne, Australia have established, for the first time, that RNA
Polymerase I (Pol I) activity is essential for cancer cell survival and that
its inhibition selectively activates p53 to kill tumors. Published today in
Cancer Cell, the findings show that Cylene's Pol I inhibitor, CX-5461,
selectively destroys cancer by activating p53 in malignant but not in normal
PR Newswire (http://s.tt/1hpwd). clinical
trials to be done later this year (2012) with lymphoma & leukaemia patients
The studies being performed with a HuCAL antibody
(fully human antibody - see:
targets GM-CSF (granulocyte macrophage-colony stimulating factor). THis
could be of benefit to WM patients, as it could block the proliferation of
WBC if the GM-CSF was modulated successfully. Particularly what will bear
watching is a sister product produced by this company called MOR108, which
targets CD19 (and is an Fc-enhanced human antibody)...
Ublituximab (3/2012) has reportedly been
bioengineered for enhanced biological activity with an increased ability to
trigger an immune response, delivering superior antibody-dependent
cell-mediated cytotoxicity (ADCC) effects to aid in B-cell depletion.
Ublituximab has displayed high single agent activity in a Phase I/II trial
in patients with relapsed chronic lymphocytic leukemia (CLL). It is being
developed in multiple oncology and autoimmune indications and was granted
orphan status in Europe and in the U.S. for B-cell CLL.
Oct 2011: Biovest ... today announced that the FDA has granted Orphan Drug
Designation to BiovaxID® for the treatment of WM. This milestone advances
Biovest's plans to develop and commercialize BiovaxID as an autologous
active immunotherapy (personalized cancer vaccine) for the treatment of
multiple subtypes of B-cell non-Hodgkin's lymphomas. We believe WM is an
ideal indication for BiovaxID to potentially provide significant clinical
benefit for patients by extending remissions and potentially delaying and/or
avoiding alternative treatment options such as stem cell transplant or
removing the patient's spleen. Our study data to date suggests that BiovaxID-treated
patients who express a certain type of protein isotype called IgM on their
lymphoma cells are much more likely to remain cancer-free longer after
achieving a remission following induction therapy. Since most WM patients
express this IgM isotype, we look forward to conducting future clinical
trials to evaluate our vaccine's utility in treating this rare B-cell blood
- Azacitidine: see
describes using this drug with Rituxan and getting a complete remission of
WM. This is quite amazing. 60% infiltration and now the bone marrow is free
- AVL-292: (from Avila Therapeutics) A Btk inhibitor, co-funded by LLS,
should be in trials in late 2010. WM Patients have had good results on this
drug (holds IgM steady after several weeks of treatment).
After being put in the ineligible category for the PCI trial due to more
than 4 previous treatments, I am now on the waiting list for the newer Btk
inhibitor, AVL 292, at the Cleveland Clinic under Dr. Hill. AVL is in phase
1b with a fixed dose. The trial is available at many sites for B cell NHL,
CLL and Waldenstrom's - can be found at www.clinicaltrials.gov. There is no
limit on the number of previous treatments for this trial. It's too soon to
know if AVL will work as well as PCI. My wait for the trial is probably
about 2 months. I've heard that PCI will probably be approved for CLL within
Dr. Treon makes it clear that you need to have MYD88 in order for Ibrutinib
- PCI- 32765 aka Ibrutinib: David Sellers (who is in the trial in NY and started with Hgb of 10.5...which had been as low as 9 posted on the IWMF talklist on 4/27/10: I am
starting tomorrow on a trial of a new Btk inhibitor drug named PCI- 32765.
It is hoped that the drug will inhibit the growth of B-cell malignancies.
The drug is administered in the form of a daily pill. I will take the pill
daily four four weeks, have one week off and then take it again for another
four weeks. My doctor has several CLL patients on the trial who are having
positive responses. I will be his first (THE first??) Waldenstrom's patient
in the study.
I mentioned a few weeks ago that I was participating in a
phase 1 trial of the btk inhibitor drug PCI-32765. It is taken in pill form.
After 3 weeks on the drug, my hemoglobin has risen from 11.2 to 12.7, and my
IgM has dropped from 4820 to 2880. I feel better than I have in years. The
only downside so far is that my platelets have taken a hit (down to 64), but not so low
that I need to be infused with any. I have had no other side effects so far.
I'll keep the list informed as the trial continues. I should also mention,
that my lymphadenopathy and splenomegaly are both responding as well. My
spleen is greatly reduced in size, and my swollen nodes are shrinking. I am
fully aware that this is only a phase 1 trial, but I am hopeful.
I had a two week break while I was out of the country. Normally, this would
be a one week break according to the trial protocol, but I had a previously
planned vacation. Anyway, my hemoglobin fell back to 10.1 while I was away,
and my IgM went back up to 3910. Platelet count went back up to 198. I
started another 4 week cycle last Thursday. I will have my blood tested
tomorrow. Anecdotally, I can see that my nodes are shrinking again, and I
already feel more energetic.
Date: Sat, 25 Sep 2010 07:41:26 -0400
From: David Sellers
Subject: My Progress on PCI-32765 Trial
I have been on the trial drug PCI-32765 now for 5 months. Here are my
current numbers compared to those on the day I started the trial:
04/27/2010 IgA <6.67 09/
23/2010 IgA 7.0
04/27/2010 IgG 212
09/23/2010 IgG 306
As you can see, there has been marked improvement in my IgM and
hemoglobin levels. The only negative side effect has been a reduction in my
platelet level, but not so low that I have ever needed a transfusion. I have
not had a BMB since the one I had at the start of the trial, but I recently
had a CT which showed reduction in the size of my lymph nodes and spleen.
Bottom line for me is that I feel better than I have in years. My hgb is
in the normal range for the first time since I was diagnosed in 2001. The
drug is easy--it's in pill form which I take at home once daily. No
reactions, no chills, no hives, no pre-meds, no sitting in the hospital for
I am very happy, and I think that since I am the first WM patient in the
world to receive this drug, it should be named after me.
Joyfully yours, David Sellers 55 yo dx 10/2001
Mitch Orfuss wrote:
Since starting Ibrutinib, my IgM decreased in steps from 1800 (baseline prior to starting), to 770, and to 574 -- then to 420 yesterday. So it's flattening toward normal range in a series of smaller and smaller improvements.
My IgG has stayed fairly steady, within 20 points of 174. IgA has gone from 11 to "<26" -- maybe the lab now lumps everything below 26 that way now.
More info: http://clinicaltrials.gov/ct2/show/NCT01109069
- CAL-101: a P13K delta inhibitor Study to Investigate CAL-101 in
Combination With Bendamustine and Rituximab in Patients With Relapsed or
Refractory Indolent B-cell Non-Hodgkin's Lymphoma or Chronic Lymphocytic
Leukemia. Paul Listen wrote: Aug 3 I begin a phase 2 clinical trial for
an phosphatidylinositol 3 kinase (PI3K) delta inhibitor. As I understand it,
PI3K-delta is especially important in the proliferation of B cells. While
this drug affects all B cells, theoretically it affects malignant B cells
moreso because they rely on PI3K-delta much more than normal B cells.
one thing in particular they watch carefully on folks taking this drug is
liver function. In phase 1 studies, a good number of folks had their liver
enzymes go up, but most of them came back to baseline after stopping the
drug and most resumed the drug at a lower dosage.
Dr. Maloney in Seattle is who I'll be seeing once a month during the
He said there have been few WM/LPL patients take it thus far, but quite a
few CLL folks. With CLL they've been amazed at how readily CAL-101 pushes
the bad B-cells out of lymph nodes and into circulation. For folks like me
with bulky disease, that would be a useful thing.
They have just opened this trial in Seattle, and I am one of the first to
enroll. Paul reports lot of side effects: anemia, low platelets, low white
counts, low liver enzymes. Hgb low (two transfusions in a month!).
CAL-101 Summary: For eight weeks, August and September, we saw
improvements: I went from being transfusion dependent to hemoglobin level of
14.2 g/dL and lymphadenopathy reduced 50% in only 8 weeks. But then it
My main observation: compared to other treatments, the CAL-101 was
remarkable in how quickly benefit was seen, especially with regard to
lymphadenopathy. For me personally, neither R-CHOP nor Fludarabine was as
effective as CAL-101 in reducing lymph nodes.
paul had fanatstic results after 8 weeks, after 16 weeks was back to needing
transfusions and BMB was worse than before he started. the swollen lymph
nodes remained shrunken
BEZ235 should be better than CAL-101. CAL101 is a
PI3K delta inhibitor- BEZ235 is a pan-PI3K and mTOR inhibitor- so it will be
even more phenomenal- clinical trial to open soon.
- LBH-589 (aka Panobinostat) is a HDAC inhibitor. Fairly low side effects and can drop your
IgM by 50% in a month. This drug is hard to beat. I'm on it. the 30mg dose
is too much for most people; it will drop your platelets dangerously low (so
low for me that I needed a transfusion). The 20mg
dose is a nice level: minimal side effects for me while still being effective
(although not as effective as 30mg).
If you feel too nauseated or have a terrible headache, I suggest you skip a dose.
I've been using this drug for almost 2 years and my numbers are stable.
- R7159/GA101 is a third generation "humanized " anti-CD20 monoclonal antibody in
phase I/II clinical trials made by Roche. In the lab, this drug is way more
effective (in terms of overall killing power) than Rituxan and it should
work even on people who are refractory to Rituxan. I'm very excited about
- 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
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
BETHESDA, Md. , June 14 /PRNewswire-FirstCall/
-- Micromet, Inc. (Nasdaq: M=
ITI) today announced the presentation of updated
results from a Phase 1 trial of the Company's lead product candidate
blinatumomab (MT103) in patients with relapsed non-Hodgkin's
lymphoma (NHL). A high objective response rate was maintained among
patients treated with blinatumomab using an adapted schedule, comparable
to that previously reported in patients receiving constant dosing.
Blinatumomab is the first in a new class of agents called BiTE
antibodies, designed to harness the body's T cells to kill cancer cells.
Amgen is to acquire Micromet Inc., producers of
blinatumomab, a Bispecific T cell Engager (BiTE) antibody, with proposed
uses in ALL and non-Hodgkins lymphoma. I believe that Amgen will
accelerate the development of this promising Mab - they have much deeper
pockets than Micromet. The drug mobilizes T-cells to attack B-cells
which express CD19, and has shown good results so far. (Reported at the
December 11 2011 ASH conference.) Another 'bullet' in the pipeline! See
- 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."
- AMD-3100 (aka plerixafor): 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.AMD3100 released white blood cell
progenitors from the bone marrow into the bloodstream. Because of this
activity, last December the U.S. Food and Drug Administration approved
AMD3100 for stem cell mobilization prior to autologous stem cell transplant
in multiple myeloma and non-Hodgkin lymphoma. The drug enables more
efficient capture of stem cells from the blood.
- G-CSF and Plerixafor: These cause stem cells and presumably WM cells to
leave the bone marrow where they can be killed by Rituxan if you combine the
drugs. Guy Sherwood and Hank Stupi have done G-CSF and it seemed to work
well, but G-CSF isn't that good a mobilizer; AMD3100 is much better, but it
- MDX-1338: a human anti-CXCR4 antibody proposed for therapeutic
application in AML and ALL. Possibly better than AMD3100. Unlike AMD3100,
it's an antibody and stays around longer.
- 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.
- Belimumab (Lymphostat
B): prevents the creation of all B-cells. There is a trial of Belimumab just
beginning for Waldenstrom's patients at two hospital in Melbourne, Australia
- Thalidomide: Use with Rituxan to enhance response. Unfortunately, it
- Afinitor aka 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). David wrote on iwmf talklist on 5/18/10:
- I was on the RAD001 study at Rochester. The initial dose was too high
and though it did bring my igm down significantly, it also led to shingles
and pneumonia. When the dosage was reduced, the igm did not go down but my
hemoglobin did. In the end my igm jumped from 5000 to 10,000 in one month
(it eventually climbed to 13,000). I am not sure that was a result of the
RAD, but I suspect so.
- In the first 28 days RAD001 cut the IgM from 6000 to 3000. In the
second 28 days it cut it to1000. The drug has worked fantastically well
for me. To this day I remain in the RAD001 study and my IgM remains
around 1000. I have been on the RAD001 study at Mayo, MN for about 15
If you have had the opportunity to read the "Consent Form", I
experienced about one fourth of the side effects listed. The most severe
were; the mouth sores in the beginning, the fatigue (all the time), PN
somewhat controlled by medication and anemia (requires a blood
transfusion every 4 weeks or so). My last BMB showed about a 25%
involvement. it was my dentist dr. connie winters who applied debacterol to
some initial mouth sores that cure them instantly
- 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).
I've been using Enzastaurin for almost a year now (since 1/28/09). I had no
side effects whatsoever and it has kept my WM which had been growing
aggressively from getting any worse. A great drug. I highly recommend it.
- NPI-52: 72 hour efficacy time
- Arzerra aka 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
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. It was approved Oct 26, 2009 by
the FDA for use in CLL, so it can be used off-label for treating WM. WM
patients who are allergic to Rituxan have been able to use Arzerra (with the
proper pre-meds) and it has been amazingly effective for some, more than
Rituxan. Mitch wrote:
was way more effective--for me. I did not respond to Rituxan when I
tried it a year earlier, though my doc would not come out and say
that it didn't work--maybe it kept me flat when my numbers may have
otherwise skyrocketed, but that's of course idle speculation. Rick
Furman, who practices across the hall from my doctor (John Leonard,
Cornell-Weill), said that Ofa invades CD-20 in a different way from
Rituxan and was designed (?) in part to work for patients for whom
Rituxan failed. I had pretty severe allergic reactions to the Ofa
during the first infusion (as I did to Rituxan, by the way) but
I wasn't concerned or unnerved aside from discomfort. (No pain,
just amazingly hellish itching, I wanted to tear my scalp off
with a dull knife!, but how bad is that? These pass quickly when
the nurses are on the case, as they were.
- For anyone interested: I've been on Dr. Richard Furman's
single-agent Ofatumumab trial at Cornell-Weill. 18 months after the only
4 infusions I had, my CBC continues to be pretty strong--all but a
couple of measures in the normal range. WBC is a fraction low, and
Platelets are 139. HgB is 14.6, and I'd thought this might be slowly
declining so was happy to see it this high. Before the trial, my HgB was
6.7 and I needed a transfusion. The Proteins report will deliver in a
couple of days; three months ago IgM was 800. I feel fine. Best wishes
- 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): Bendamustine hydrochloride is an alkylating
agent recently approved by the FDA for treatment of Chronic Lymphocytic
Leukemia (CLL). 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. This medication
differs from many other chemotherapy agents in that it can be given
infrequently. Indeed, a recent study suggested that once-every-three weeks
administration of bendamustine can be effective. One WM doctor said "it is
like fludarabine- effective, but most likely has long term side effects that
we don't know yet." Dr. Treon doesn't think it will be nearly as bad a
fludarabine. I've heard of several cases where this drug has been miraculous
for people. One person went into complete remission after 3 treatments of
Bendamustine + Rituxan (given once a month) . However, beware that one patient after 4 treatments, got a great IgM result, but now has almost completely lost her short term memory.
But that is very rare. So
there are significant risks. Hardening of veins is common after just two
For those of you
that plan to be treated with Bendamustine, I would suggest that you speak to
your doctor or nurse about infusing it concurrently with a saline drip at
least for the first infusion to avoid possible vein irritation. I am told
that the irritation of my vein may take as much as six months to heal
itself. Also, keep an eye on the vein area just above the needle puncture
to see if any progressive redness develops during the infusion.
One person wrote: "All
in all, with possible vein damage, collapsing immune system, need for a port
etc. bendimustine sounds less and less like a desirable treatment. Chemo
is scary enough with plenty of unexpected consequences, now I don't know
what to do. "
One person wrote me:
My experiences are not typical but they do represent the concept
that all patients are unique and that a drug that works for 78% of
the subjects or 95% or even just a mere 20% may not work for ME or
YOU... or it may, and that a drug that is not recommended may be an
absolute miracle drug for someone.
I was diagnosed in Jan 2009 and began treatment with Rituxan and
Thalidomide in March. I already had PN in my rt foot and it did not
exacerbate it. The real problem came when we increased to the
recommended dosage. I went into hypercalcemia within 3 days and
nearly died from it. My calcium levels were over 16. Dr River (my
onc) then proceeded to use Treanda with the Rituxan (which was his
preference in the first place). In just two doses spaced 3 weeks
apart my IgM went from over 6500 to 1250 in 3 weeks and to <400
after 6 weeks. My IgM is now in the normal range at 267. Side
effects were minimal with nausea and fatigue being the sum total of
them. I never had a fever nor pneumonia or anything else for that
Your articles are excellent. I am just very glad I had not read
them before I went for treatment because I probably would not have
agreed to the use of the drug that saved my life. Your work in this
area is fantastic and appreciated. It is very much aimed at the
masses. I am just the oddball in that crowd.
- SNS-032: A Phase I clinical trial of SNS-032, one of the first in a new
class of drugs that inhibit cyclin-dependent kinases, demonstrated the
drug's safety and potential clinical action against advanced chronic
lymphocytic leukemia (CLL). Cyclin-dependent kinases are enzymatic proteins
that are integrally involved in cellular metabolism, renewal and signaling,
and are thought to play key roles in the growth of cancers. The drug did not
demonstrate any clinical effect against advanced multiple myeloma, although
researchers hope it might still prove to have some benefit against this
blood cancer as part of combination therapy. The paper is published online
in the Journal of Clinical Oncology.
"No drugs that target this cancer mechanism are on the market today,"
says study author David S. Siegel, M.D., Ph.D., Co-Chief, Multiple Myeloma,
John Theurer Cancer Center at Hackensack University Medical Center. "I am
hopeful that larger studies will show that this targeted therapy is useful
against a number of advanced B cell malignancies."
- AVN-944: IMPDH inhibitor. They would love WM patients for a phase I
clinical trial they are doing. Contact J. Michael Hamilton, M.D.,
- Veltuzumab: humanised anti-CD20 antibody now in phase I/II trials
- ONXO912 (a chymotrypsin-like (CT-L) actrivity inhibitor): Found two
articles today in a recent issue of the journal Blood about a relatively new
type of orally available drug that may be a better approach to treating
WM....it's a special class of oral proteosome inhibitor, that inhibits
chymotrypsin-like activity (CT-L). Paper from Kirsch Lab at DFCI on this.
This is a velcade-like drug, but it doesn't cause PN. There is an IV version
(carfilzomib) and this one is the pill form (PR047). The IV is not easy
since it is 4 days a week, but the oral is not available until next year.
- PR-171 (Carfilzomib)- a proteasome inhibitor made by
Proteolix has had good results in WM patients.
It's like Velcade, but without the PN. DFCI did pre-clinical work. It was in clinical trials for WM in
two places but the study was closed due to slow accrual of patients. DFCI is
looking at opening up a trial there using the next generation of this drug. See
trials for more info. David Sellers wrote:
- I'm on a trial for a targeted drug called carfilzomib. Works like
velcade but without the danger of neuropathy as a side effect. In six weeks
of treatment, my IgM has declined by about one third with no significant
side effects. Still, it's not perfect, I guess...my hemoglobin remains in
the 8's, and I therefore feel pretty crappy. I'm going to do at least one
more round of treatments over the next 3 weeks, and then will evaluate
whether to continue.
- 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.
- tunicamycin: pre-clinical studies against WM look good (done at DFCI).
But it is not a drug, just a lab compound to test if ER stress is important.
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.
Combinations that are lower dose than recommended can have low side effects
but still be effective.
From: Ken Warner
Subject: Re: Drug Quantities Used for Treon's BDR Trial
I would never submit myself to enduring that particular protocol.
It's another scorched earth attack.
I get 1.6mg V; 10mg Dex; 750mg R every two weeks. It's working SLOWLY and I
have none of the side effects listed in Treon's paper.
Shock and awe looks good only on TV -- don't devastate the body to cure it.
International Workshop on Waldenstrom's Macroglobulinemia (Venice, Italy)
Good news - The new Mab GA101 is very good - better than Rituxan.
RAD001 doing good things - new trial soon with Rituxan (what about GA101???).
Combos still the best. Very early work started on identifying the "target" of WM
IgM - surprisingly, different WM patients have quite similar IgMs (fluke
finding?). Rituxan + Bendamustine the new holy grail. T-cells becoming more and
more important. Lots of new young researchers from all over the planet.
Bad news - WM seems to "march" on, even if your counts "stable" or in
"remission" - indolent doesn't mean arrested. Watch and Wait may not as wise as
folks might think. If you get treated, go for the kill, don't be happy with a
"25-50% reduction" in IgM many now think. Harvest your stem cells. Newer
targeted therapies mean that bone marrow biopsies are more important than ever -
not doing a BMD when appropriate is dumb. $$ for research tight.
Steve Kirsch's Waldenstrom