Dose of Rituxan? 2 vs 4, what is the total amount of meds given?

[me2]

Several years ago I got my first Rituxan treatment at the University of Washington Medical Center. They wanted to give me two infusions but everything I read said that people were getting four. My doctor at the time said that 4 was the British protocol and 2 was the American.
Knowing the British did the original work on the the drug I said I wanted four. He said OK and thats what I got.
In later times I found that 2 infusions were being done all over the US and considered by our best doctors to be adequate.
So, in a few days I am getting my six month 'booster' shot of 2 infusions. I don't know what the dose is but I thought it was 1000mg. I will ask this week before I go in and let you know if it is different.

[drz]

Their drug insert says following:

2.6 Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener’s
Granulomatosis) and Microscopic Polyangiitis (MPA)
 Administer Rituxan as a 375 mg/m
2
intravenous infusion once weekly for 4 weeks.
 Glucocorticoids administered as methylprednisolone 1000 mg intravenously per day for 1 to 3
days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per
clinical need) are recommended to treat severe vasculitis symptoms. This regimen should
begin within 14 days prior to or with the initiation of Rituxan and may continue during and
after the 4 week course of Rituximab treatment.
 Safety and efficacy of treatment with subsequent courses of Rituxan have not been established

[drz]

Has anyone found ones for two dosage protocol? This sounds pretty much by the book approach my doctors used for me in 2010. I wonder if the protocol has changed some since?

Rituximab in Granulomatosis with Polyangiitis (Wegener's) and Microscopic Polyangiitis

MAY 6, 2011

On April 19, 2011 the FDA approved rituximab (Rituxan) combined with glucocorticoids for the treatment of adult patients with granulomatosis with polyangiitis (GPA; Wegener’s granulomatosis) or microscopic polyangiitis (MPA). This new indication for rituximab provided the first ever FDA-approved therapy for these two diseases and the first alternative to cyclophosphamide (CYC) for the treatment of severe disease in almost 40 years.
The combination of CYC and glucocorticoids was introduced for the treatment of GPA in 1973 and has been the foundation of therapy since that time. While it has been proven to prolong survival and induce disease remission, this regimen is associated with substantial toxicity and does not prevent relapse. Rituximab, a chimeric anti-CD20 monoclonal antibody previously approved in 1997 for non-Hodgkin's lymphoma and in 2006 for rheumatoid arthritis had shown promise as a remission-induction agent in GPA/MPA from uncontrolled studies. This evidence supported the conduct of a randomized controlled trial comparing rituximab to CYC (the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis trial, the RAVE trial). This trial was designed as a pivotal trial and the results formed the basis of the FDA approval of rituximab for the treatment of patients with GPA (Wegener’s granulomatosis) or MPA.
Clinical Trial Results:
197 patients with active severe GPA or MPA were treated in a randomized, double-blind, double-dummy, active controlled, non-inferiority study. Patients were randomized in a 1:1 ratio to receive either rituximab 375 mg/M2 once weekly for 4 weeks or oral CYC 2 mg/kg daily for 3 to 6 months. Patients in both arms received 1000 mg of intravenous (IV) methylprednisolone per day for 1 to 3 days followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the CYC group received azathioprine to maintain remission. The rituximab group did not receive additional therapy to maintain remission.
The primary endpoint was a Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0 and prednisone dose =0 at 6 months. 63 patients who received rituximab (64%) reached the primary endpoint as compared with 52 (53%) in the CYC group, which met the criterion for non-inferiority (P< 0.001). Of those who entered the trial with relapsing disease, rituximab was more efficacious than CYC with 34 of 51 (67%) in the rituximab group reaching the primary endpoint as compared to 21 of 50 in the CYC arm (42%)(p=0.01).
Limitations of these data include:

• The duration of follow-up has thus far been insufficient to determine relapse rate, although 16 severe relapses (6 in the rituximab group) had occurred by the time of publication.
• As patients with a serum creatinine of > 4.0 mg/dL or respiratory insufficiency requiring ventilator support were excluded, there are insufficient data to determine the comparative efficacy of CYC versus rituximab in the most fulminantly ill patients.
• This trial enrolled only patients with severe disease who were ANCA-positive and thus it is unclear whether these results are generalizable to those who are ANCA-negative or have mild disease.
• The primary endpoint focused on remission induction and did not address the question of retreatment with rituximab.

Safety:
There were no significant differences between the CYC and rituximab groups in the number of total adverse events, serious adverse events, or non-disease-related events. This may have been influenced by the inclusion of disease and treatment related complications, including those related to glucocorticoids, the short study duration of 6 months during which time CYC toxicity might not have emerged, the limited duration of CYC exposure consistent with past studies of changing from CYC to azathioprine within 3-6 months, and a rigorous schedule of blood count monitoring to prevent CYC-induced leucopenia.
Serious infections (> grade 3) occurred equally in each group. The most common infections in the rituximab-treated patients were upper respiratory tract and urinary tract infections, and herpes zoster. Among patients with exposure to rituximab during the trial, malignant conditions developed in 5% as compared to 1% of those without exposure (p=0.26). Three patients (2%) died during the trial (1 received rituximab).
Practical issues:
The approved rituximab dosage for GPA/MPA is 375mg/M2 by IV infusion once weekly for 4 weeks. Glucocorticoids given as methylprednisolone 1000mg IV per day for 1-3 days followed by prednisone 1 mg/kg/day with subsequent taper are recommended for severe vasculitis. Pneumocystis prophylaxis is recommended during treatment and for at least 6 months following the last rituximab infusion.
The Bottom Line:
Rituximab is the first ever FDA approved treatment for GPA/MPA and represents an alternative to CYC for remission induction of severe disease.

• Rituximab combined with glucocorticoids is as effective as CYC to induce remission of severe GPA/MPA.
• The rate of adverse events in patients with severe GPA/MPA who receive rituximab and glucocorticoids remains high.
• Use of concomitant or sequential immunosuppressives other than glucocorticoids given with rituximab has not been adequately studied to determine safety or efficacy.
• There are insufficient data to determine the comparative efficacy of CYC versus rituximab in fulminantly ill patients (creatinine > 4.0 mg/dL, requirement of mechanical ventilation).
• Further studies are needed to determine the rate of relapse, the long term side effect profile, and the safety and efficacy of subsequent courses of rituximab versus maintenance therapies with other conventional immunosuppressive agents (e.g., azathioprine or methotrexate) in GPA/MPA.

1. Fauci AS, Wolff SM. Wegener’s granulomatosis: studies in 18 patients and a review of the literature. Medicine (Baltimore) 1973, 52:535-561.
2. Hoffman GS, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992, 116:488-498.
3. Stone JH, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010, 363:221-232.

Hotline author: Carol A. Langford, MD MHS, Director Center for Vasculitis Care and Research, Cleveland Clinic
Hotline Editors: Arthur Kavanaugh, MD, and Eric Ruderman, MD
Disclosures: Dr. Langford is an investigator member of the Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network (RAVE-ITN) Research Group. Dr. Ruderman and Dr. Kavanaugh have nothing to disclose.

In addition to review by the editors, this Hotline has been reviewed by all members of the ACR Executive Committee, Communications and Marketing Committee and Drug Safety Committee.

The ACR Hotline is provided by the ACR Communications and Marketing Committee as a service to members. This Hotline reflects the views of the author(s) and does not represent a position statement of the American College of Rheumatology.

[Sangye]

Awhile ago I asked Dr Seo why he was giving me 4 infusions when others were getting 2 for what seemed similar symptoms. He said that in the US some centers started with 4 and some started with 2 and that they both had success so they kept doing it out of routine. JHU was a 4 center. It's all changed now, as they are all experimenting with the different dosing protocols.

[me2]

Very interesting. I have really been scratching my head trying to figure out what is going on with Rituxan after initial treatment. I recently saw my primary care guy who is a 'big giant head' researcher for something definitive on figuring out what my treatment should be at this point.
He was quite annoyed with me asking but tried to help me anyway. He does not treat people with Rituxan but he looked around online and printed me out a study.
Before he left I said "Well, it looks like there ARE no definative guidelines for figuring out treatment protocol after initial treatment. It looks like the reason I can't find guidelines is because they exist in each doctors head and are patient specific."
He said "Yes , thats the way it looks. Patient specific."
So, each of us is different (oh man, can we be different) and each doctor will have their own ideas about treatment. Very much of it not proven or figured out yet. Once I knew that, I actually felt a lot better about it. I trust my doc, or I wouldn't be going to him.
My most recent visit I no idea in my head how my treatment should proceed. This is unusual, as I usually have some idea to bounce off the doc. This time his reasoning was that since I had three episodes in the last few months of 'mini flares' where I upped my pred for a few days , that I wasn't quite 'there ' yet. Is this hard science- no. But I'm ok with going with his experience and my own sense of what might be the best route or what is not.
To my knowlege the 'experimenting' that you refer to Sangye has not been written up yet. I guess its too soon. I also am suspecting that the long term treatment may stay pretty much the way it is, that the doc and the patient together feel their way along step by step.
Sangye, you are doing something different too. Each time one of us does that it helps the others. I wish you the best.

[Sangye]

Thanks Kirk. It is very individual. Dr Seo has always been up front with me about how much the dosing is really just guesswork. It'd be great if there were some sort of genetic testing that could help determine the best treatment, as there is for some types of cancer. I think that's the future of medicine.

[aewaustin]

This thread has been quite helpful, thanks to everyone for sharing what they know. Now I also feel better knowing that this is all guesswork

[Palmyra]

aewaustin,

I think it is truly all guess work...and varied per individual and responses over time. The less medication they can give to retain remission the better is my guess. The trick is to retain that remission. I heard a John's Hopkins trained VF specialist use those very words on web stream at the last VF forum that was live cast. Less pred, less cytox, less RTX...what ever it takes induce that remission and then the least necessary medication to retain it. Inflammation is bad...do all you can to suppress it. That means avoid germs this flu/cold season weggies! Eat real food, handle stress and listen to fatigue. Exercise as you are able.

I know that Ali's local rheumy treats her joint/localized flairs with a big IV/oral push of pred and then very quickly backs off, with no lingering, no taper. Individually she has been on no other drugs than bactrim, but I think that has been only because she has been lucky. It has served her well, but goes against all that I was familiar with from years of previous treatment for Crohn's and early Weg.

Again, I feel one of the best sources we have is a forum like this one....where we can share what treatment works under specific conditions, per certain individuals. Let's keep the group forum updated and all informed.

Best regards,
`JTF


~Jane