My husband has TCell rich Large B Cell Lymphoma and received 7 cycles of RCHOP. He has been very ill, hospitalized after each cycle. He has 1 more cycle but does not want to finish his last one. Any research about prognosis and # of treatments?

loveofmylife:
TCRBCL is a very, very tricky diagnosis. However, on the plus side it's considered a variant of diffuse large b-cell lymphoma and despite the population of t-cells, it's not a t-cell lymphoma-- b-cell lymphomas have better prognoses in general, and DLBCL is sometimes curable.

the literature is a little thin on TCRBCL but R-CHOP is not surprisingly the chemo of choice. I read one case in which the patient received 6 cycles of R-CHOP for TCRBCL in the sinuses and 5 years after those 6 rounds (which were preceded by radiation), he was still cancer-free. Looking at the NCCN's treatment guidelines, they have 6-8 cycles. Seems as though your husband can no longer tolerate the chemo and that these cycles are threatening his life. Why can't they re-stage him now with PET/CT, allow him to opt out of the final chemo cycle? I would be surprised to find any specific studies on whether 6, 7 or 8 are better; you would think that it would be a brilliant research path - and in fact such a thing has been undertaken in Hodgkin's treatment - but in this case, I don't know of any. Either way, until your husband is restaged there's no telling whether the chemo's even working, and they would restage him anyway after 8, seems like those cycles are too much to endure even one more when it may not be necessary.

Ross

Hi,

As you know Chemo alone is toxic enough without the radiation and different patients will have different reactions.

I am a DLBC Lymphoma Stage IV survivor from 3 years ago. (Click my user name for more information).

I had 6 cycles of R-CHOP then. One Medical Oncologist I consulted for an opinon told me that he would have given me 8 cycles. Like my brother kept reminding me then "different generals have different battle plans".

I found drinking warm water cleared headaches and other reactions.
I would gulp 2 half pint mugs of water (about 500ml).
I would wait to urinate and then take 2 more mugs.
I continued this routine until I felt better.

Sometimes I would sit up at night drinking water in this manner and would fall asleep in the wee hours of the morning. Wake up around 9am and have breakfast.
I made it a point to drink up 20 mugs of water in 24hours.
By the last chemo I was up to 31 mugs as I found I had to increase the water.
I wrote everything down. It helped me track what helped and what didn't.

I was given Neupogen to boost my Neutrophil counts (important for fighting infection) whenever they went too low after Chemo.

Taking fluids in general (especially fresh fruit drinks like carrot, water melon, orange, banana, kiwi, soursop) will help boost his immune system that is so important for fighting infection.

Encourage your husband to eat raisins, dates, spinach to help get his haemoglobin levels up (important for carrying oxygen which helps fight cancer).

You may also want to contact Dr James Armitage of the University of Nebraska Medical Center for a second opinion.

He is a globally respected authority on Lymphoma treatment. (I did not know of him early enough but a doctor known to me contacted him on my behalf for an opinion about post-Chemo follow up treatment. I took his advice.)
http://app1.unmc.edu/intmed/onchem/index.cfm?conref=11

Above all ask your husband not to give up. Tell him that it is a message from a survivor named Felix.

God bless
Felix

Ross and Felix thank you. Felix that is wonderful. I was convinced this was a 100% death sentence within a short amount of time. Ross part of it was because I was under the impression that T-Cell rich meant it was a T Cell lymphoma which I have read is harder to treat (controversial).

I am sorry I forgot to mention in my original post that my husband was in remission per PET scan after his 4th cycle but in spite of this, his oncologist wants to go for 8 cycles.

I decided to call Genentech and did a little research on the FDA website. To my dismay, Genentech was recently issued a Warning Letter by the FDA for providing false or misleading information that makes unsubstantiated efficacy claims and that omits and minimizes important risk information for Rituxan. Here is the link to the letter.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati...

This is a travesty for lymphoma patients because I think everyone views this drug as the treatment of choice for Lymphoma. The FDA letter states among other things, "...The table top panels are misleading because they suggest that Rituxan is more effective than has been demonstrated by substantial evidence or substantial clinical experience..."

I think many have accepted this drug as the gold standard when in fact it may not be the case and in the meantime we could be researching other treatment options. My understanding is that Rituxin targets CD20 cells yet my husband only had 6% of CD20 cells so I don't understand how Rituxin was the best choice in his situation. Or was it that Rituxin (+CHOP)is the only available option at this point and was better than nothing but no one wants to say it?

The path report also indicates that he has 94% CD3 T Cells, 83% CD4 Helper T Cells. He only has 18% CD8 Suppressor Cytotoxic NK cells. Is this a good thing? I am guessing that it is?

As far as my conversation with Genentech. I thought if anyone would have done research or had info about the efficacy of 4 versus 8 treatments, Genentech would. After all they would stand to gain more if they could sell 8 cycles versus 4 cycles. They couldn't come up with anything and I agree with Ross, the literature is thin.

If research is lacking to justify 8 cycles, are oncologists picking an arbitrary number? I know one reason for STOPPING at 8 cycles is because the risk of developing heart failure increases rapidly with increasing total cumulative doses of doxorubicin(over 450 mg/m²).

Felix, did you need blood transfusions? My husband got neulasta injections the day after chemo and initially they seemed to work because his NADIR was short lived-only 3 days wheras with the last 3 cycles, his NADIR lasted more than 2 weeks.

Because the cardiac toxicity that can occur at lower cumulative doses in patients with prior mediastinal irradiation, my husband decided he is going to stop at 7 cycles and take his chances. At this point the risks outweigh the benefits. I am nervous either way. I told my husband I will support his decision either way but it has to be his decision because if he relapses I would never forgive myself. I did the research for him but want to make sure I am not missing anything. Wednesday we see his oncologist and this is when we will give him the news. If there is anything you can add that I might be missing I would appreciate your thoughts.

love-
True about T-cell lymphomas, they are VERY difficult to diagnose and, being more rare, they are indeed harder to treat. In general.

As for Rituxan, I can't access the FDA letter you linked but I'm A) surprised I haven't read about this before simply because I spend my days catching these kinds of things, and B) not surprised, because Rituxan is really green. It's no more than maybe a decade old? There was a Cochran Review some months ago that raved about the drug in maintenance situations; that was followed by a suspected link between rituxan and a fatal brain virus that people were mistaking for Alzheimer's or Dementia. Bottom line: We just don't know what kind of long-term issues the drug will create in some people.

As immunotherapy, rituxan is cutting edge stuff. And yes, it targets cells that express CD20. That your husband only has 6% ... to that I might say that rituxan, when added to a chemo regimen, becomes one 'weapon' in the chemo barrage. The drugs in R-CHOP all have their own methods of inducing cell death- one adds an agent to the process of mitosis, another blocks an agent, etc. So each has a role, and the hope is that the cancer cells are dividing at a clip sufficient for the multiple chemo agents to find their moment to work.

As for the number of cycles etc, the only thing I can offer you is a not terribly relevant bit of research from December at the American Society of Hematology meeting by the German Hodgkin's Study Group, it's HERE and what it says is that, in a very large study, they GHSG found that for many patients with Hodgkin's lymphoma, 2 chemo cycles was equally as effective as 4 chemo cycles, but plenty less toxic.

My feeling is that Hodgkin's lymphoma has reached a stage where medicine can say 'OK, we have an effective cure for this disease, but it's causing long-term problems, what can we do to maintain the curative effect today without selling out the patient's future?' This is a big step. A luxury, really. There's not much precedent for it, at least in lymphomas.

Therefore, it's altogether possible that 8 R-CHOP cycles is, for some patients, forgive the term, overkill. The number isn't random; if you're to look anywhere, you could start with the studies that established CHOP and later R-CHOP. CHOP was established in 1976 [McKelvey EM et al, "Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma." Cancer, 1976] and R-CHOP in 2002 [Coiffier B. "Rituximab in combination with CHOP improves survival in elderly patients with aggressive non-Hodgkin's lymphoma."Semin Oncol 2002]. Both studies used 8 cycles- why they chose 8 to begin with, who knows (meaning I don't know how they come to it, probably some combination of chemistry, toxicity, cell biology etc) but once established, oncologists go with what they know to work.

But cancer's not that easy- meaning we can't apply cookie-cutter solutions to every patient. There probably isn't much in the way of a study determining the right number of cycles because it's going to be different for everyone- or at least each doctor should weigh the needs of each individual patient before administering treatment.

By the way, a very important conference is going to get underway soon, the American Society of Clinical Oncology's annual meeting. Abstracts of tons of new research studies have already started to hit the newswire, and this will go on into early June, but the public can search those abstracts now, and I bring this up because there may be something in there on your husband's subtype, or chemo regimen, or something. It's worth a basic search. You never know.

Let's see- yes, the makers of Rituxan would not be the ones to put 8 vs 4 cycles to the test. that wouldn't be in their best interests.

Oops, I overlooked the fact that they re-staged him at 4 cycles ... you say he was in remission, do you know what the report actually said? There are rather strict response criteria in place for lymphomas [Cheson BD, Horning SJ, Coiffier B et al: "Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphoma." J of Clin Oncol 17(4); 1999: 1244] that should be used to determine treatment and re-staging. If for instance he was showing a complete response, it wouldn't be surprising to do maybe 2 more cycles, or none, followed by a scan in 6 months' time or something. to do another 4 ... considering the shape he was in, and yes considering the cardiopulmonary toxicity potential of one of the drugs ... at any rate, keep in mind that he may relapse, but if he does you won't be able to directly point to 7 vs 8 and say that's the culprit. too many other factors at work.

ross

Hello again

No I was not given blood transfusions.
As I said, to get my Neutrophil count up, I was given Neupogen.
At one point I was given Neupogen injections (at the same time daily) for three consecutive days but normally received only one or none at all depending on the status a few days after Chemo.

My weakest point came ten days after Chemo. I took a lot of measures to try to reduce the toxicity within my body and recover to have the next Chemo infusion on schedule. Much to the astonishment of my treating oncologist I even refused to take medication for peripheral neuropathy that I had begun to develop because I did not want to add more toxins into my system.

I noticed during my ordeal that there was a lot of uncertainty on the part of the medical community with regard to treatment plans and expected outcomes. This has since been confirmed by members of the profession. See also an article at the following link under bullet point “Individualized Medicine”
http://www.mayoclinic.org/news2010/5604.html

My opinion is that you may indeed be missing something (unless you haven't told us about it). That is that you should have the benefit of a couple of more opinions when you see your husband’s oncologist.
I urge you to get an opinion from Dr James Armitage of Nebraska Medical Center whose advice benefited me.

http://app1.unmc.edu/intmed/onchem/index.cfm?conref=11

http://www.unmc.edu/ihs/secondopinion.htm

On this site JohnnyP on Wed, 09/30/2009 - 11:23 mentioned another doctor who had helped her fiancée.

Dr Jorge Castillo of the Miriam Hospital
Providence , RI 02906
phone: 401-793-2920
fax: 401-793-7132
Email: jcastillo@lifespan.org

Take care
Felix

Ross
Here is the letter

TRANSMITTED BY FACSIMILE
April 29, 2010
Michelle H. Rohrer, Ph.D.
Vice President, Regulatory Affairs
Genentech, Inc.
1 DNA Way, MS#241B
South San Francisco, CA 94080-4990
RE: BLA # 103705
Rituxan® (Rituximab) Injection for Intravenous Use
MACMIS # 18129

Dear Dr. Rohrer:
The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed professional table top panels (8271803) for Rituxan® (Rituximab) submitted by Genentech, Inc. (Genentech) under cover of Form FDA 2253. The table top panels are false or misleading because they make unsubstantiated efficacy claims for the drug and omit and minimize important risk information for Rituxan. Therefore, the table top panels misbrand Rituxan in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i) & (x); (e)(7)(viii).

Background
According to the Indications and Usage section of the FDA-approved product labeling (PI)1 for Rituxan (in pertinent part):
Rituxan® (rituximab) is indicated for the treatment of patients with . . . [p]reviously untreated follicular, CD20-positive, B-cell NHL [Non-Hodgkin’s Lymphoma] in combination with CVP chemotherapy . . . [and] [p]reviously untreated diffuse large B-cell, CD20-positive NHL [DLBCL] in combination with CHOP or other anthracycline-based chemotherapy regimens
The PI for Rituxan includes a Boxed Warning for fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML). Additionally, the PI for Rituxan includes several Warnings and Precautions, including Hepatitis B Virus (HBV) Reactivation, Infections, Cardiovascular events, Renal toxicity, and Bowel Obstruction and Perforation.
1 The PI submitted with the table top panels and referred to in this letter is dated September 2008. The most recent PI is dated February 2010. Although not relevant to the issues discussed in this letter, we note that the current PI contains major changes to the Indications and Usage – Limitations of Use section for Infections and the Warnings and Precautions sections for Infections, Renal, and Laboratory Monitoring.
Michelle H. Rohrer, Ph.D. Page 2
Genentech, Inc.
BLA# 103705/MACMIS# 18129

Unsubstantiated Efficacy Claims
The table top panels are misleading because they suggest that Rituxan is more effective than has been demonstrated by substantial evidence or substantial clinical experience. Specifically, the table top panels include the following claims and presentations for the follicular NHL indication:
•
“R-CVP more than doubled median PFS at 4.4 years of follow-up”2
•
“The R-CVP benefit was consistent across patient subgroups, including bulky disease and poor prognosis FLIPI score”3
•
Bar graph titled, “RITUXAN+CVP as first-line treatment improves median PFS”2 that includes claims “In first-line follicular NHL” – “2.83 years R-CVP vs 1.25 years CVP” – “At 4.4 year follow-up” – “127% improvement in median PFS” – “Marcus (M39021) trial”
•
Kaplan-Meier curve titled, “Marcus progression-free survival (N=322)”2,4 with cited p-value “p<0.0001”
These claims misleadingly overstate the efficacy of Rituxan in improving progression-free survival (PFS) and providing benefits across all patient subgroups for Rituxan for the follicular NHL indication. We note that the claims of improved results at 4.4 years of follow-up are based on results found within an abstract2 of a study by Marcus et al., that the table top panels cite the Marcus et al. article3 to support the subgroup analysis claim, “The R-CVP benefit was consistent across patient subgroups, including bulky disease and poor prognosis FLIPI score,” and that the table top panels cite the abstract and data on file4 to support the Kaplan-Meier progression-free survival curve. However, these references do not constitute substantial evidence or substantial clinical experience to support these claims and presentations. We note that the Marcus et al. study3 had a median follow-up of 30 months; the study’s original statistical analysis plan did not provide for statistically valid analyses at 4.4 years of follow-up. The reliability of these analyses cannot be substantiated; for example, FDA cannot confirm if there was differential follow-up for PFS following the analysis of the primary endpoint. Additionally, the abstract does not describe whether the PFS findings were based on an independent blinded review. As for the subgroup analyses claim, because the subgroup analyses are exploratory, the accuracy and consistency of PFS results in all subgroups described in the Marcus article cannot be confirmed. Furthermore, the updated p-value in the Kaplan-Meier curve cannot be interpreted based on the Marcus study’s original statistical analysis plan. If you have substantial evidence to support these claims, please submit them to FDA for review.
2 Marcus R, Imrie K, Catalano J, et al. Rituximab plus CVP improves survival in previously untreated patients with advanced follicular non-Hodgkin’s lymphoma. Paper presented at American Society of Hematology 48th Annual Meeting and Exposition; December 9-12, 2006; Orlando, FL. Abstract 481.
3 Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005; 105:1417-1423.
4 Data on File, Genentech, Inc.

Michelle H. Rohrer, Ph.D. Page 3
Genentech, Inc.
BLA# 103705/MACMIS# 18129

Additionally, the table top panels include the following claims and presentations for the DLBCL indication:
•
“R-CHOP improved 7-year OS by 47% vs CHOP alone (p=0.0004)”5
•
Bar graph titled, “RITUXAN+CHOP as first-line treatment increases OS in DLBCL”5– “In first-line DLBCL” – “53% R-CHOP vs 36% CHOP” – “At 7 years” – “47% increase in OS” – “GELA LNH 98-5 trial”
•
Kaplan-Meier curve titled, “GELA overall survival (N=399)”5,6 with cited p-value “p=0.0004” and an x-axis extending out to 8 years
These claims misleadingly overstate the efficacy of Rituxan for the DLBCL indication by suggesting that patients can expect an increase in overall survival beyond the 2-year and 5-year overall survival data presented in the PI. We note that the claims of improved overall survival at 7 years are based on results found within an abstract5 of a study by Coiffier et al, and that the table top panel cites the abstract and the Coiffier et al. article6 to support the “GELA overall survival” Kaplan-Meier curve. However, the abstract and the Coiffier article do not constitute substantial evidence or substantial clinical experience to support claims of improved overall survival at 7 years or the “GELA overall survival” Kaplan-Meier curve. The original statistical analysis plan for this study did not provide for statistically valid analyses at 7 years of follow-up. The reliability of these analyses cannot be substantiated. For example, the abstract does not describe whether the overall survival findings were based on an independent blinded review. Furthermore, the follow-up statistical analyses used in the Coiffier abstract and article do not support these overall survival results. Additionally, the abstract does not describe the p-value and the p-value cannot be interpreted based on the Coiffier study’s original statistical analysis plan. If you have substantial evidence to support these claims, please submit them to FDA for review.

Omission and Minimization of Risk Information
The table top panels are misleading because they omit or minimize important risk information, including information relating to fatalities associated with the use of Rituxan.
The table top panels state, “RITUXAN has also been associated with fatal hepatitis B reactivation with fulminant hepatitis, other serious viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation,” but the panels omit material facts regarding fatalities associated with the use of Rituxan related to some of these risks. For example, according to the Warnings and Precautions sections of the PI (in pertinent part, emphasis added):
Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies.
Abdominal pain, bowel obstruction and perforation, in some cases leading to death,
5 Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol; 2007; 25; suppl 18S. Abstract 8009 (June 20 Supplement).
6 Coiffier B, LePage E, Briere J, et al. CHOP chemotherapy plus Rituximab compared with CHOP alone in Elderly patients with diffuse large B-Cell lymphoma. N Engl J Med. 2002;346:235-42.

Michelle H. Rohrer, Ph.D. Page 4
Genentech, Inc.
BLA# 103705/MACMIS# 18129
can occur in patients receiving Rituxan in combination with chemotherapy.
Furthermore, the table top panels fail to present risk information with a prominence and readability reasonably comparable to the presentation of efficacy information, taking into account all implementing factors such as typography, layout, contrast, headlines, paragraphing, white space, and any other techniques apt to achieve emphasis. Specifically, the table top panels prominently present efficacy claims in bulleted format, with colorful, bolded words, colorful charts, plenty of white space, and large font. However, the risk information that is presented on the first two panels is relegated to the bottom of those panels and is presented in single-spaced block paragraph format in small, black font. Additionally, while these first two table top panels contain a disclosure of adverse reaction information, they fail to present the most significant risk information associated with Rituxan - the Boxed Warning. This is not presented until the third panel.
The overall effect of these misleading presentations undermines the communication of important risk information, thereby misleadingly suggesting that Rituxan is safer than has been demonstrated.
Conclusion and Requested Action
For the reasons discussed above, your professional table top panels misbrand Rituxan in violation of the Act, 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i) & (x); (e)(7)(viii).

DDMAC requests that Genentech immediately cease the dissemination of violative promotional materials for Rituxan such as those described above. Please submit a written response to this letter on or before May 13, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Rituxan that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS# 18129 in addition to the BLA number. We remind you that only written communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Rituxan comply with each applicable requirement of the Act and FDA’s implementing regulations.
Sincerely,
/S/
Carole C. Broadnax, R.Ph., Pharm.D.
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications

Felix
That's a great program. Did you do an in-person consult with Nebraska Medical Center? Was it expensive? Did they shed any new light or make recommendations for changes in your treatment plan? Thanks again

Ross
I believe there is a black box warning for progressive multifocal leukoencephalopathy (PML)

(No I did not know about the Nebraska Medical Center's second opinion service at the time and have not directly used it).
In my case, the doctor who administered my Chemotherapy (primarily a radiation oncologist) and three other radiation oncologists recommended that I go through IFRT (Involved Field Radiation Therapy).
The Professor of Radiation Oncology who studied my case to give me IFRT to the right parietal bone warned me that I would develop cataracts in two years and suffer a partial loss of memory. These were the main drawbacks other than the immediate after effects of radiation therapy, I was told.
Also (taken for granted) is that I would develop another cancer at the site of irradiation in fifteen to twenty years (if the world survives).
Then a prominent Hematologist (who I was referred to for an opinion) contacted Dr Armitage for his views on whether I would require post Chemo IFRT in the first place.
Three medical oncologists (including Dr Armitage) and this dear hematologist recommended I avoid IFRT and watch through regular blood work and PET-CT scans.
I have been on watch ever since.
It has not been easy amidst the pressures of normal life but over these last three years I have learnt a lot on what I should do to stay healthy. I keep at it.
The warning by the Radiation Oncologists was that without IFRT I could expect it to come back sooner. How much sooner? No one could tell me.
My thinking was that I should remain stronger to fight another day if I was ever required to and not be weakened by the effects of IFRT.

In the end, there were a total of twelve oncologists whose opinions I sought at different stages. I also gathered information from within and without the medical community which helped me in my decision making. Throughout my ordeal, this allowed me to exercise a strict control of what I would allow the doctors to do for me. Once I had sufficiently understood and decided what that was (allowing what was crucial to my survival) I did anything else possible (appropriate food/fluid/rest/exercise etc) to help their efforts to help me have a better chance.

Hope that helps.

Dear BRINGITON

As you know each individual is unique and reactions will differ.
You may want to read the post I made just before this.
Click my username “Felix” to get some background first.

Your questions are very valid and are to be expected. The first person you should ask is your treating oncologist. BUT that is not the last person you should ask. As you may have noted (if you read my previous post here) I am an advocate of extra opinions.

Accuracy of diagnosis is the first hurdle to clear closely followed by the recommended treatment plan and adjustments thereto (whenever warranted).
As mentioned many times on this site, getting the diagnosis wrong could be disastrous as the treatment plan would not match.
So get an independent opinion or two on the diagnosis and associated treatment plans and reassure yourself by getting to know as clearly as possible of what had gone wrong and how it may be put right or as near right as possible.

I can share with you what I went through and how I coped albeit mine was NHL.
I realized that I would have to make a series of important decisions that will affect the lives of primarily my teenage children and all other loved ones.

Since I believe and practice that decisions should be based on appropriate information, I got busy gathering relevant information, opinions, views, data and the like.
I did not feel sorry for myself but knew that I had to do what I could to clear this off my plate.

I believe that I have been successful so far because of the attitude I consistently adopt.
Get a balanced view of what can be done and get it done. Imagining things leads to worry and that weakens us.

So don’t imagine and don’t worry but find out and take action.

Take care
Felix