Low dose Rituximab (Rituxan) research

We have several threads where readers have shared their experiences with low dose Rituxan for treatment of ITP, but I am starting this thread to discuss actual research into that topic. I want to share the results of my online efforts, and ask if anyone has any thoughts regarding the research, or has anything to add that is evidence-based, as opposed to anecdotal.

Low dose Rituxan is typically 100 mg x 4 weeks, whereas standard dose Rituxan is 375mg/square meter, which is a function of weight and height averaging about 700 mg, also x 4 weeks.

I have found a total of four studies of low dose Rituxan for treating ITP, which I will list below. Two of the studies, totaling 52 treatment subjects, used low dose Rituxan along with high dose dexamethasone. The other two studies, totaling 55 treatment subjects, used low dose Rituxan alone. In all four studies, results were comparable to typical standard dose treatment. It appears that adding dexamethasone to the treatment increases the effectiveness, but I did not have access to the full text of all of the articles, so I cannot be sure of comparing apples to apples.

It is clear from the studies that better comparative research is warranted.

High response rate to low‐dose rituximab plus high‐dose dexamethasone as frontline therapy in adult patients with primary immune thrombocytopenia
David Gómez-Almaguer, et al First published: 2 April 2013
N=21 Complete sustained response at 6 month 76.2%
onlinelibrary.wiley.com/enhanced/doi/10.1111/ejh.12102/#author1
www5.medicine.wisc.edu/~williams/ld_ritux_dex_itp.pdf

Low-dose rituximab combined with short-term glucocorticoids up-regulates Treg cell levels in patients with immune thrombocytopenia.
Li Z, Mou W, Lu G, Cao J, He X, Pan X, Xu K
International journal of hematology 93:1 2011 Jan pg 91-8
N=31 plus controls. Sustained response 77.4%.
www.unboundmedicine.com/medline/citation/21188563/Low_dose_rituximab_combined_with_short_term_glucocorticoids_up_regulates_Treg_cell_levels_in_patients_with_immune_thrombocytopenia_

Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults.
Provan D1, Butler T, Evangelista ML, Amadori S, Newland AC, Stasi R.
Haematologica. 2007 Dec;92(12):1695-8.
N=7. Sustained complete responses 57.1% (no glucocorticoids)
www.haematologica.org/content/92/12/1695.full.pdf

Low-dose rituximab in adult patients with primary immune thrombocytopenia.
Eur J Haematol. 2010 Oct
Zaja F1, et al
N=48 Overall response Overall and complete responses (CR) (platelet level ≥ 50 and 100 × 10(9) /L) were 60.5% and 39.5%, respectively. (no glucocorticoids)
www.ncbi.nlm.nih.gov/pubmed/20546023

Rob:

All I can say is this. Having been so involved with ITP patients over the past 16 years, I now believe that less is better. Since this can be a chronic, long-term disorder and treatments can be an ongoing thing, the side effects and toxicities add up. If you can get away with a lesser amount and get the same result, why not try it?

The larger dose of Rituxan initially used for ITP patients is the same dose used for lymphoma. That's where that dose came from; it wasn't specifically tailored for ITP. If the studies show that the lower dose is causing good responses and you trust the data, I'd go for the lower dose.

When I was diagnosed in 1998, no one ever thought that counts below normal were acceptable. Everyone pushed for above normal counts and did what it took to get there and stay there. I was the same way, but thinking has changed. At this point, I wouldn't care what my counts were as long as they were above 30k - 50k (the count I should have in order to take aspirin). My Hemo had me on 60 mg's of Prednisone back then when my counts were 60k (no aspirin then either). No way would I do that now. The things you do when you don't know any better!

Anyway, you have a goal to reach and aspirin to juggle, so you have to do what it takes to get there, without overkill. You are a very cautious person and research well. Good luck with what you decide and I hope it works!

I had been looking for studies just this week, and found these two that aren't on your list.

Just today, I discussed with my doctor his recommendation that I start a course of Rituxan. I didn't want to take it at all but decided that if I were going to, it would have to be the lower dose regimen. Side effects were my biggest concern. He told me that side effects aren't dose-dependent, and the risk would be the same either way. Whether I believe that or not... Well, you know. It doesn't make sense.
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Lower dose rituximab is active in adults patients with idiopathic thrombocytopenic purpura.
Zaja F, Battista ML, Pirrotta MT, et. al.
Overall (platelet count > 50×109/L) and complete responses (platelet count > 100×109/L) were achieved in 21/28 (75%) and 12/28 (43%) patients respectively.
After a median follow-up of 11 months (range 3–18), 7/21 (33%) patients relapsed and 3 needed further treatments.
www.haematologica.org/content/93/6/930.full

Clinical efficacy of lower dose rituximab for chronic refractory immune thrombocytopenic purpura
Zhonghua Xue Ye Xue Za Zhi. 2012; 33(3):204-6 (ISSN: 0253-2727)
Li Y; Wang XM; Mao M; Zhang XY; Fu L; Ai HM; Zhang LX
Department of Hematologe, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
The responses were of 11(55%) CR, 4 (20%) R and 5 (25%) NR, respectively, with median response duration of 8 months (5 - 23 months).
reference.medscape.com/medline/abstract/22781608

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This PDSA newsletter archive page also contains some links:
www.pdsa.org/treatments/conventional/b-cell-depletion.html

Janet:

Thanks for adding to the list. I thought the two with "Li" as the lead author were duplicates, but they are two different Li's; the two Zaja papers turned out to be separate studies, so we are up to six studies, all totaling over 150 treatment subjects, and with the same conclusion, that low-dose Rituxan is effective.

With the two studies you have added I am even less sure whether adding steroids to the Rituxan treatment will increase long-term effectiveness.

I don't believe for a moment that the side effects are independent of dosage; I agree: it defies common sense. There are other studies on low-dose Rituxan for different conditions, but no one study is large enough to evaluate serious complications, as they are fairly rare. My impression, though, is that the "annoying" side effects are less. For example:
bloodjournal.hematologylibrary.org/content/119/16/3691.full.pdf
I hope someone will do a meta-study to examine safety and side effects.

More on the topic of safety and side effects, from the Gomez-Almaguer study cited earlier:

Overall, the combination therapy in our group was well tolerated. There was a lower incidence of infusion-related adverse effects in this trial in comparison with the data reported in previous studies (24) (9.5% vs. 17%). This difference can be explained by the use of a considerably lower dose of rituximab. Dexamethasone was well tolerated, considering that only a single course was used in the majority of patients.
www5.medicine.wisc.edu/~williams/ld_ritux_dex_itp.pdf

There ya go!

Here are some Rituxan safety data for treatment of rheumatoid arthritis, where there is much more data. The dosage for RA is usually 1,000 mg x 2; for most people this is higher than the "standard" dose, but taken 2x instead of 4x. This data is pooled from multiple studies.

I am still looking for data for low-dose Rituximab.

Safety of rituximab in rheumatoid arthritis patients ~ (pooled data from randomized controlled trials/registries)

Adverse event	Pooled incidence
Infusion reaction	25% during first infusion; usually mild to moderate in severity; reduced incidence on subsequent infusions
Immunogenicity	11%; no relationship with efficacy of B cell depletion, infusion reaction, initial or retreatment clinical efficacy
Hypogammaglobulinemia	Low serum IgM (22.4%), IgG (3.5%), or IgA (1.1%) levels for more than 4 months; serious infections more common in those with low IgG levels
Serious infection	3.94/100 patient-years; comparable to those treated with methotrexate or placebo in controlled trials; infection rate static over 5 years of treatment; serious opportunistic infection rare (0.06/100 patient-years)
Herpes zoster reactivation	9/1,000 patient-years, similar to those treated with MTX alone and the general population
Tuberculosis	2/3, 194 cases (0.06%)
Hepatitis B infection	1/3, 194 case (0.03%) of new hepatitis B infection; no cases of hepatitis B reactivation reported
Progressive multifocal leukoencephalopathy	Rare (2.3/100,000 patient-years)

www.ncbi.nlm.nih.gov/pmc/articles/PMC3883598/#!po=39.0625

Rob,

Forgive me if this is something you have already found but I came across this a couple of nights ago and it was on this subject so I thought I would throw it out there in case you hadn't already read it.

See "First Line Therapy for ITP" approximately 1/4 of the way down the article.

asheducationbook.hematologylibrary.org/content/2013/1/276.long

Just trying to help.
JM

Thanks, JM

At first this part sounded scary:

Side effects of rituximab include infusion-related reactions, infectious complications, and serum sickness. Pooled data from adult studies showed that ∼ 22% of patients experienced a mild or moderate adverse event, with the majority (83%) being related to the infusion.³³ There were an additional 10 patients (3.7%) who developed severe or life-threatening events and 9 (2.9%) patients died, 4 from fatal infections.³³

Then I read the cited meta-analysis study and learned that the serious adverse events were not necessarily related to Rituxan, and included unrelated events such as atrial fibrillation. For all we know, three percent mortality may be normal for this population even without taking Rituxan.

Rob, to supplement your Internet search, you might also try to contact the researchers you've already found. Back when I was considering low dose rituximab I exchanged several emails with Drew Provan, the author of one of the studies.

By the way, you might want to expand your search to include rituximab for multiple sclerosis, which was also researched at the same dose as RA.

I have a great hematologist at a teaching hospital, and when I discussed the idea of low dose rituximab, but wanted 2 doses @ 200 mg, she agreed that would likely attain the same results as 4 x 100. We did one 200 mg dose and a second one 3 weeks later, after making sure I wasn't a "quick responder".

In addition to putting less toxic stuff in your body unnecessarily, the cost of Rituximab should have patients and doctors making sure it isn't overused. And I say that as a patient who had a $20 copay for the rituximab that I did get in 2008.

Tamar

Tamar, you are right, it is informative to look at different treatment protocols for different conditions. I found, for example, that rheumatoid arthritis can be effectively treated with two 1000 mg doses two weeks apart. I found a study that shows that for ITP this protocol is comparably effective as the standard dose.

2013 Oct;88(10):858-61. doi: 10.1002/ajh.23518. Epub 2013 Sep 3.
Efficacy and safety of rituximab given at 1,000 mg on days 1 and 15 compared to the standard regimen to treat adult immune thrombocytopenia.
Mahévas MAm J Hematol.1, Ebbo M, Audia S, Bonnotte B, Schleinitz N, Durand JM, Chiche L, Khellaf M, Bierling P, Roudot-Thoraval F, Godeau B, Michel M.
www.ncbi.nlm.nih.gov/pubmed/23798363

Did you get good results with your 200 mg x 2?
It doesn't appear that anyone has studied just how low you can go without losing effectiveness. Somehow I doubt that Idec Genentec will be underwriting such a study.
Btw, the patent runs out in 2015!

One more low dose Rituxan study:

[Effect of different therapeutic regimens on regulatory T cells in patients of primary immune thrombocytopenia].
Zhonghua Xue Ye Xue Za Zhi. 2013 Jun;34(6):478-81.
Li ZY1, Li DP, Yan ZL, Xing WW, Liu KG, Cao J, He XP, Pan XY, Xu KL.
N=44 plus other treatment groups. Overall response (OR) rates of low dose Rituximab + HDD at day 28: 79.5%. 12 months sustained response (SR) : 66.7%.
www.ncbi.nlm.nih.gov/pubmed/23827100

Now we have seven studies with a total of 199 subjects in the treatment groups, all saying low dose Rituxan is comparably effective. Adding the high dose dexamthasone pulse does seem to help.

Rob16 wrote: Tamar, you are right, it is informative to look at different treatment protocols for different conditions. I found, for example, that rheumatoid arthritis can be effectively treated with two 1000 mg doses two weeks apart. I found a study that shows that for ITP this protocol is comparably effective as the standard dose.

1000mg is a very high dose compared with the 100mg low dose regime for ITP so it ought to be effective really.

[/quote]
Did you get good results with your 200 mg x 2?
It doesn't appear that anyone has studied just how low you can go without losing effectiveness. Somehow I doubt that Idec Genentec will be underwriting such a study.
Btw, the patent runs out in 2015![/quote]

Rob, I don't know if the low dose rituximab was effective. My platelets were ~40K at the start of treatment...they bounced around for 6 months, and then I topped 100K for the first time 6 months after the tx. Stayed between 90-130K for probably 3 years. I don't know whether the rituxan had anything to do with that. Now I'm back in the 40s. If I believed a low dose of rituxan did give or would give me several years around 100K I might do it again. It was just such a long time after the tx that my count rose that high that I don't know if rituxan had anything to do with it. Maybe when it goes off patent I'll give it another try.

If I do try it again, I would do a single 350-400 mg dose....why give up 2 afternoons?

You may as well do 400 mg since it comes in 100 mg units.

I have only found one study - in children - where a single dose was given. " A single dose of rituximab resulted in a response rate similar to that reported for cases in which 4 doses of rituximab were used." The dose was 375 mg per sq meter.
www.haematologica.org/content/90/2/281.abstract?ijkey=78873704fe05255bc16d48afd15c9d680f85e6e1&keytype2=tf_ipsecsha

Rob16 wrote: You may as well do 400 mg since it comes in 100 mg units.

I have only found one study - in children - where a single dose was given. " A single dose of rituximab resulted in a response rate similar to that reported for cases in which 4 doses of rituximab were used." The dose was 375 mg per sq meter.
www.haematologica.org/content/90/2/281.abstract?ijkey=78873704fe05255bc16d48afd15c9d680f85e6e1&keytype2=tf_ipsecsha

I think there are some people here on the site who had to stop treatment after a single (or two) doses due to reactions, but they still responded. It isn't in published studies, though.

I thought I heard that there would not be any more studies of rituximab for ITP, either because of synthetic or human substitutes being developed, or because of the black box warning, I can't remember. It looks like you are still finding recently published studies, so maybe what I thought I heard was wrong.

I only had one full dose treatment when I was going to do my second round of Rituxan. I responded very well. Never had the other three because of serum sickness (again).

Ellen would be tempted to go the single dose route, but her hema is strictly evidence-based, and there is not enough evidence for the single dose approach. I emailed the hematologist a long summary of the seven studies on the 100 mg x 4 weeks regimen and she agreed to go that way when Ellen is ready. It pays to do your homework!

I do not expect to find any more studies at this point, so I will summarize the results below, for anyone to use, to educate themselves or their doctor. Thanks to all for your input!

There are now seven studies that have tested the lower dose of Rituximab with favorable results. These studies included a total of 199 patients treated for ITP with low dose Rituximab (100 mg X 4 days). In each of the seven studies responses were comparable to typical standard dose treatment. In at least one study, infusion-related side effects were significantly fewer, so some side effects seem to be dose-dependent, though that may not be the case for all side effects.

Three of the studies, totaling 96 treatment subjects, used low dose Rituximab along with high dose dexamethasone at the first treatment. The other four studies, totaling 103 treatment subjects, used low dose Rituximab alone. It appears on the surface that adding HDD to the treatment may increase the effectiveness, though the studies do not report their results consistently, making comparison difficult.

1. High response rate to low‐dose rituximab plus high‐dose dexamethasone as frontline therapy in adult patients with primary immune thrombocytopenia.
David Gómez-Almaguer, et al First published: 2 April 2013
N=21 Complete sustained response at 6 month 76.2%
onlinelibrary.wiley.com/doi/10.1111/ejh.12102/abstract
www5.medicine.wisc.edu/~williams/ld_ritux_dex_itp.pdf

2. Low-dose rituximab combined with short-term glucocorticoids up-regulates Treg cell levels in patients with immune thrombocytopenia.
Li Z, Mou W,Lu G, Cao J, He X, Pan X, Xu K
International journal of hematology 93:1 2011 Jan pg 91-8
N=31 plus controls. Sustained response 77.4%.
www.ncbi.nlm.nih.gov/pubmed/21188563

3. [Effect of different therapeutic regimens on regulatory T cells in patients of primary immune thrombocytopenia].
Zhonghua Xue Ye Xue Za Zhi. 2013 Jun;34(6):478-81.
Li ZY, Li DP, Yan ZL, Xing WW, Liu KG, Cao J, He XP, Pan XY, Xu KL.
N=44 plus other treatment groups. Overall response (OR) rates of low dose Rituximab + HDD at day 28: 79.5%. 12 months sustained response (SR) : 66.7%.  
www.ncbi.nlm.nih.gov/pubmed/23827100

4. Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults.
Provan D1, Butler T, Evangelista ML, Amadori S, Newland AC, Stasi R.
Haematologica. 2007 Dec;92(12):1695-8.
N=7. Sustained complete responses 57.1% (no glucocorticoids)
www.haematologica.org/content/92/12/1695.full.pdf

5.Low-dose rituximab in adult patients with primary immune thrombocytopenia.
Zaja F, et al
Eur J Haematol. 2010 Oct
N=48 Overall response Overall and complete responses (CR) (platelet level ≥ 50 and 100 × 10(9) /L) were 60.5% and 39.5%,  respectively. The 12- and 24-month cumulative relapse-free survival was 61% and 45%, respectively. (no glucocorticoids)
www.ncbi.nlm.nih.gov/pubmed/20546023

6. Lower dose rituximab is active in adults patients with idiopathic thrombocytopenic purpura.
Zaja F, Battista ML, Pirrotta MT, et. al.
haematol June 1, 2008 vol. 93 no. 6 930-933
N=28. Overall (platelet count > 50×109/L) and complete responses (platelet count > 100×109/L) were achieved in 21/28 (75%) and 12/28 (43%) patients respectively. After a median follow-up of 11 months (range 3–18), 7/21 (33%) patients relapsed and 3 needed further treatments. In patients with idiopathic thrombocytopenic purpura, lower dose rituximab seems to show similar activity to standard dose.
www.haematologica.org/content/93/6/930.full

7. Clinical efficacy of lower dose rituximab for chronic refractory immune thrombocytopenic purpura
Li Y; Wang XM; Mao M; Zhang XY; Fu L; Ai HM; Zhang LX
Zhonghua Xue Ye Xue Za Zhi. 2012 Mar;33(3):204-6.  Department of Hematologe, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
N=20. The responses were of 11(55%) CR, 4 (20%) R and 5 (25%) NR, respectively, with median response duration of 8 months (5 - 23 months).
www.ncbi.nlm.nih.gov/pubmed/22781608#

My single dose was not intended. I was surprised that it worked. I did have four full dose infusions the year before and for some reason, people seem to respond longer to subsequent doses if they responded the first time.

That is not based on any legitimate data, just my lonesome observation. Anyone else agree?

I had 4 full doses and a 9 month remission. My counts dropped then from normal to 40s, and I'm one who feels very sick with low counts so I treated again. My doctor wouldn't do low dose but he did agree to two infusions. I've had 5 years remission so far from that.

A few times my counts dipped down, always for a reason like an illness. But they went back up to over 200 each time.
Erica

I hadn't really thought about this before, but the only thing that makes sense (IMO) for why the research divided the low dose into 4 treatments is so that they were only changing one thing (the total amount of the drug, not the treatment regimen).

I get making "evidence-based" decisions, but insisting on administering the low dose rituximab in 4 treatments just because that's the way the research was conducted seems a bit inflexible. Does he/she insist that every treatment be on the same day of the week, too, or is it okay to go 6 days or 8 days between doses? Where's the line?

Side effects are less likely the lower the dose, so splitting it up is a good idea. Four, as you say, has been historical and there's no real reason for it. I'm sure that two at 200mg would do just as well.

How much is each "regular dose" tx for an 150 lb adult? 150lb = 68kg...

And why is lb the abbreviation for pound?

Edit: okay I see Rob says it's about 700mg. I'm just doing all this math for myself. I think if I tried low dose Rituxan again, I'd do the 400mg in one sitting....it's still close to half of a single standard dose, which should reduce side effects, plus added convenience, plus lower cost for all the infusion related items and labor.

And if for some reason my doctor would not agree to low dose, I'd very likely do the single dose and then "change my mind" about continuing. This is just me, I certainly wouldn't recommend anyone else subvert their doctor's wishes.

Normal high dose is 375 x body surface area which is dependent on height and weight and can be worked out here

www.patient.co.uk/doctor/body-surface-area-calculator-mosteller

Weird that the low dose is 100 mg for everyone.

lb for pound is from the Latin, libra pondo.. pound weight shortened to libra then lb.

Thanks Ann. That means a regular dose for me would be 670mg x 4. I don't know what rituxan packaging is like, and if they'd round up or down to the nearest package size.

What I recall from the first low dose study was that when the checked, the b cells were depleted with the 400mg dose. I think I recall there was some theorizing that the b cell load (is that the right term?) was lower in patients with cytopenias than those with NHL and other cancers where rituxan had been used (and probably a maximum safe dose was desired--just a guess).

The researchers really took a huge leap in going from the 2500mg-3000mg standard dose to 400mg. I have to applaud their boldness.

I should caution everyone that not all side effects are dose-dependent. I will be lazy and cite Wikipedia:

Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. [...]
Idiosyncratic drug reactions appear to not be concentration dependent.[...]
The proposed mechanism of most idiosyncratic drug reactions is immune-mediated toxicity.
en.wikipedia.org/wiki/Idiosyncratic_drug_reaction

It appears that infusion-related side effects of Rituxan are at least partly dose-dependent, but some of the more serious adverse responses might still be independent of dose.

In other words, bad things might still happen at the lower dose.

Yes, that's why there's the black box warning. Anything can happen.

I haven't done Internet searches of this kind of stuff for a couple of years, so it's kind of fun.

Here's a low dose rituximab for RA that's recently published. It's a meta-analysis. I personally think that studies for autoimmune conditions can be informative even if they're not cytopenias.

www.arthritisresearchuk.org/news/general-news/2014/february/new-study-shows-benefits-of-low-dose-rituximab-for-rheumatoid-arthritis.aspx

The thumbnail summary is they cut the dose by 50% over earlier studies, and found the same level of effectiveness and also the same incidence of side effects.

Okay, THIS ONE IS AMAZING. If ever needed, I think that I might consider going even lower than 400mg.

www.empireneuro.org/sitebuildercontent/sitebuilderfiles/rituximab2012.pdf

By the way, this author calls 375mg/msq the "maximally tolerated dose." (dose edited)