Date: February 14, 2006
by Chaya Venkat
It is time to update the status of our strictly hypothetical hero and Round-headed Kid, aka Harvey. As we have described in previous articles on this subject (The Difficult Case of the Round-headed Kid, The Continuing Saga of the Round-headed Kid, Harvey's Chocolates, Remission Management for the Round-headed Kid, “Harvey” was diagnosed with CLL in the summer of 2001, and discovered to his chagrin a year later that his CLL had undergone clonal evolution, gaining the dangerous 11q deletion in addition to the more benign 13q deletion he started out with. This kicked him into the high risk “Bucket C” (What Type of CLL Do You Have?). We have described the logic that led to his development of his own “RHK” protocol, consisting of Rituxan + G-CSF (Neupogen / Neulasta) and EGCG (green tea extract). Harvey has used this approach four times thus far, and each time the remission lasted 9 -12 months, depending on whether he had 4 weeks of Rituxan infusion or 8 weeks. Since his disease was more centered in the lymph nodes rather than in the peripheral blood (classic for folks with 11q deletion), the decision of when to start therapy again depended upon when the lymph nodes got to be too big, typically when they were about 2 inches in diameter. Each time, he tolerated the Rituxan very wel with, barely any infusion related hassles (barring the intense boredom of sitting still for the 4 hours it took for the infusions). He was just beginning to enjoy the sense of control. He saw no reason why he could not keep doing what he was doing until the cows came home.
It is never a dull day living with CLL and I am sorry to report fate has thrown a new monkey-wrench into the works. Since Harvey has developed a modest following of his own, I thought I had best report on the new development. Harvey’s experience coincides with recently published reports on the adverse effects of Rituxan. While the post-marketing surveillance of Rituxan has thus far identified only a small percent of patients as having this problem, the danger is high and very real for these patients, and therefore worth discussing.
Right from the start, there were warnings that a small percent of patients may experience serious infusion-related side effects. These ran the gamut of chills, rigors, fever, low blood pressure, etc. Most often, these symptoms (what patients affectionately refer to as the “shake and bake” syndrome) were controlled by appropriate pre-medications (Tylenol, Benadryl, Tagamet). For those patients that experienced serious infusion-related effects, it was considered important that the rate of infusion be slowed down or even halted entirely for a while until the patient recovered. On the whole it turned out to be not a big deal for most patients. Like Harvey, most patients tolerated the drug very well, especially after the first or second infusion.
Tumor Lysis Syndrome is another issue we have discussed before. It is particularly important in the case of patients with high tumor load, since the concern is that too many cancer cells killed too quickly would place too much of a burden on the liver and kidneys as they try to get rid of the debris from the murder and mayhem of cell kill. That is why it is important to stay very well hydrated by drinking plenty of water for a couple of weeks ahead of Rituxan therapy, getting your system well flushed and better able to handle the waste disposal task coming down the turnpike when therapy starts. It is also recommended that you start taking allopurinol a week or so ahead of start of therapy — this is thought to provide an additional measure of protection for your kidneys. Unfortunately, a few people are allergic to this drug and break out in an itchy rash from hell when they take it. If this happens to you, be sure to tell your doctor about it and quit taking the allopurinol right away.
We must also mention that in a small subset of patients there was a risk of delayed onset neutropenia, hepatitis and viral reactivation . We have discussed these points before (Rituxan in the News and Topics Alert #49: Rituxan Warning) but for your convenience I have listed below more recent abstracts dealing with delayed onset neutropenia. In these cases, patients saw a decline in their neutrophil counts below acceptable levels a few weeks to couple of months after the last infusion. If you are in this minority, it is important that you monitor your blood counts religiously after Rituxan therapy and bring to the attention of your doctor any decline in neutrophil counts below 1.0K, since that is the semi-official definition of neutropenia. It is also important to let your oncologist know if you have had prior exposure to hepatitis.
Pharmacotherapy. 2005 Aug;25(8):1151-5.
Delayed-onset grade 4 neutropenia associated with rituximab therapy in a patient with lymphoma: case report and literature review.
Motl SE, Baskin RC.
College of Pharmacy, University o f Tennessee, Memphis, TN.
A 53-year-old man developed delayed-onset neutropenia 6 weeks after completing first-line therapy with rituximab, cyclophosphamide, mitoxantrone, vincristine, and prednisone for high-grade B-cell lymphoma. Bone marrow biopsy demonstrated hypercellular marrow with normal maturation. He also developed interstitial pneumonitis, an adverse event associated with rituximab use. Infiltrates of T cells were found in the patient's lungs. For the next 6 months, the patient required subcutaneous granulocyte colony-stimulating factor 300 mug twice/week to maintain a granulocyte count above 1000 cells/mm3. He also received oral antibiotics for mouth sores and thrush. Based on the existing evidence, monitoring blood counts for as long as 8 weeks after rituximab therapy may be advisable, although the literature reports that neutropenia can develop up to 1 year after treatment. The development of a registry and uniform testing may help uncover the cause of this delayed-onset neutropenia.
[PubMed - indexed for MEDLINE]
Blood. 2005 Aug 1;106(3):795-802. Epub 2005 Feb 17.
B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis.
Dunleavy K, Hakim F, Kim HK, Janik JE, Grant N, Nakayama T, White T, Wright G, Kwak L, Gress R, Tosato G, Wilson WH.
Experimental Transplantation and Immunology Branch, CCR, NCI, Bldg 10, Rm 12-N-226, Bethesda, MD.
The occurrence of delayed neutropenia following rituximab is poorly defined and of unknown cause. We hypothesized it may be related to perturbations of stromal derived factor-1 (SDF-1) and granulocyte homeostasis. Late-onset neutropenia (LON) was investigated in 130 patients with untreated aggressive B-cell lymphoma receiving DA-EPOCH (dose-adjusted etoposide, prednisone, Oncovin [vincristine], cyclophosphamide, and hydroxydaunorubicin) chemotherapy with or without rituximab. All patients were in remission and had no known causes for neutropenia. LON occurred in 6 (8%) of 76 patients receiving rituximab and 0 of 54 patients not receiving rituximab (P = .04). The median onset was 175 days (range, 77-204 days) after treatment with a median duration of 14 days (range, 11-16 days). In a subset of 24 patients, a significant correlation was found between rapid B-cell recovery and granulocyte decline over the 6-month recovery period (R = -0.53; P = .04). Rapid B-cell recovery directly correlated with prerecovery SDF-1 levels (R = 0.65; P = .015) and SDF-1 decline (R = -0.67; P = .013) after recovery. Our results suggest that early B-cell lymphopoiesis is important for B-cell recovery following rituximab, and that perturbation of SDF-1 during B-cell recovery retards neutrophil egress from the bone marrow. These findings illustrate the dual role of SDF-1 in human B-cell and granulocyte homeostasis.
Swiss Med Wkly. 2004 Feb 7;134(5-6):79-80.
Delayed-onset and long-lasting severe neutropenia due to rituximab.
Hofer S, Viollier R, Ludwig C.
Department of Medical Oncology, St. Claraspital, Basel, Switzerland.
BACKGROUND: Rituximab, a monoclonal antibody, is effective in CD20-positive B-cell lymphoma and is now widely used either as a single agent or in combination with chemotherapy. The antibody's toxicity is generally mild and transient. There are reports of protracted neutropenia in patients treated with rituximab.
CASE REPORT: We report on a patient with Burkitt's lymphoma treated with the hyper-CVAD chemotherapy regimen combined with rituximab. Four weeks after the five months' treatment marked neutropenia and hypogammaglobulinaemia occurred and persisted for one year. Both laboratory findings were not associated with severe infections in our patient.
CONCLUSIONS: Delayed-onset neutropenia is a newly recognised toxicity of rituximab treatment which may last up to one year and be complicated by serious infections.
Our hypothetical patient “Harvey” got his usual vigorous response to his “RHK” protocol. His absolute lymphocyte count after the last infusion in the first week of November 2005 was a puny 1.2K. All other counts looked good as well, and he was a happy camper. That is, until he started noticing some skin and mouth problems a couple of months later. First to go was the inside of his mouth. The mucositis was pretty heavy duty, and he particularly minded it since it meant he could no longer eat the spicy Asian food he liked. A couple of days later he noticed small red patches on his legs, arms and torso. He had seen these patches on his skin in prior years and since they did little more than itch a bit and gradually fade away, he took little notice of them this time either. Then, almost over a couple of days, the problems got a lot bigger. The red skin patches grew bigger, there were many more of them, they itched like crazy and hurt too. Pretty soon he looked like some one who had tangled with a whole yard of poison ivy, and lost. The sores on the inside of his mouth made it hard to eat, and the heavily chapped lips made it hard to smile even. Last but not least, he also developed diarrhea.
That did the trick: he and his wife Serena got to work. Were the skin and mucosal problems just one more manifestation of CLL itself? Hard to believe, since his counts at that point were all so good, hardly any trace of tumor load. What else could have caused it? Harvey was pretty sure this was not a case of contact dermatitis, poison ivy or bug bites and the like. It was an aha! Moment when they found the references — Rituxan induced skin and mucosal adverse effects. That explained all of the symptoms, the oral sores, the red patches on his body, and the diarrhea too. (Gentle reader, when doctors talk about mucosal problems, they are not talking of just the insides of your mouth and nose, this refers as well to the lining of your GI tract and pulmonary system as well. You cannot see if the lining of your GI tract is equally inflamed, but you sure as heck can tell something is wrong when you have to make too many trips to the loo. Along the same lines, you cannot see damage to the mucosal linings of your lungs, but you will be the first one to know when it becomes hard to breathe and you are hospitalized after a trip to the emergency room with a bad case of respiratory distress.)
Harvey was surprised by the potential seriousness of this particular adverse effect. He had a “punch biopsy” done of one of the many patches on his legs, and the pathologist who looked at the sample said it looked almost like classic graft-versus-host-disease. GVHD is one of the major complications of patients undergoing transplants, where the new immune system starts attacking the body that seems foreign to it. Very often, the first location of the attack is skin and mucosal surfaces. Since Harvey had not had a transplant, not even blood transfusions, the remaining choice was drug induced toxicity. While the exact mechanism of this phenomenon will take time before it is deciphered, it seems to be a case where perfectly healthy cells of the body come under attack, by an immune system sensitized by prior exposure to Rituxan. It is proposed by some researchers that dosage and frequency of Rituxan administration can increase the risk of precipitating this type of allergy. It is also suggested that the "chimeric" (part mouse and part human protein) nature of Rituxan may be responsible for this effect, and fully human monoclonal antibodies such as GenMab's Humax anti-CD20 monoclonal (Sons of Rituxan and Campath, Results from GenMab's HuMax Clinical Trial) are less likely to trigger similar reactions.
Hematology (Am Soc Hematol Educ Program). 2005;:335-9.
Targeting CD20 in Follicular NHL: Novel Anti-CD20 Therapies, Antibody Engineering, and the Use of Radioimmunoconjugates.
Rituximab (chimeric anti-CD20 monoclonal antibody) is widely employed in the treatment of patients with B cell non-Hodgkin lymphoma (NHL). This agent has activity in both indolent and aggressive disease, alone and in combination with chemotherapy. Unfortunately, however, many patients develop resistant disease. Ongoing efforts to improve outcomes include changes in dose and schedule, as well as the use of other biologic agents or antibodies that may enhance activity when administered together with rituximab. A relatively new focus is the development of engineered anti-CD20 antibodies that are optimized for their capability to mediate antibody-mediated cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Human or humanized structures have also been employed to potentially improve these attributes, as well as to improve on pharmacokinetics and immunogenicity. Other studies in NHL have clearly demonstrated that radiolabeled anti-CD20 antibodies (such as I-131 tositumomab and Y-90 ibritumomab tiuxetan) may be useful in relapsed and refractory disease, and have potential utility as part of initial treatment as well. Further studies of these modified anti-CD20 antibodies are ongoing in order to optimize their use for maximal clinical benefit.
Here are the points to remember:
I have found two specific documents that formally describe the latest information on potential skin and mucosal adverse effects due to Rituxan. The first is a “Dear Doctor” letter that went out from Hoffmann-La Roche (the company that markets Rituxan in Canada) to Canadian doctors. The link below will take you to the website where the full text of this letter is available. There is also quotation from the letter, bear in mind the highlighting is mine.
Severe bullous skin reactions (including toxic epidermal necrolysis and pemphigus) were previously described in the ADVERSE EVENTS, Post Marketing Experience section of the Product Monograph. However, as a result of a review of these cases, the Warnings section of the Product Monograph will be revised to include information regarding severe mucocutaneous skin reactions.
There have been 20 post-marketing reports worldwide of severe mucocutaneous reactions associated with the use of ‘Rituxan’. Eight of these resulted in fatal outcomes. These reactions are variably described as Stevens-Johnson Syndrome, toxic epidermal necrolysis, paraneoplastic pemphigus, lichenoid dermatitis or vesiculobullous dermatitis. The onset of the reaction in the reported cases has varied from days to several months following ‘Rituxan’ exposure. No definitive predisposing factors have been identified. Patients experiencing a severe mucocutaneous reaction should interrupt treatment with ‘Rituxan’ and seek prompt medical evaluation. Skin biopsy of these reactions may help to establish a diagnosis and guide subsequent treatment. The safety of readministration of ‘Rituxan’ in these patients has not been determined.
The second document I found is an October 2005 “Dear Doctor” letter from Biogen Idec. This one deals with their drug Zevalin. Why is this relevant in this discussion? It is relevant because Zevalin is nothing more than Rituxan carrying a payload of radioactive material. In fact, the company makes it clear in their letter that the comments made with reference to Zevalin in this letter are equally applicable to Rituxan. You can read the full letter and the new, improved “Black-Box label warnings” by clicking on the links below. I have also included a quotation from their Dear Doctor letter.
“Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some with fatal outcome, have been reported in association with the ZEVALIN therapeutic regimen. Patients experiencing a severe cutaneous or mucocutaneous reaction should not receive any further component of the Zevalin therapeutic regimen and should seek prompt medical evaluation.
There have been postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis in patients who received the ZEVALIN therapeutic regimen. Some of these events were fatal. The onset of the reactions was variable; in some cases, acute, (days) and in others, delayed (3-4 months). Patients experiencing a severe cutaneous or mucocutaneous reaction should not receive any further components of the ZEVALIN therapeutic regimen and should seek prompt medical evaluation.”
What surprises me is that I have not found a similar “Dear Doctor” letter for the U. S., specifically addressing the case of Rituxan. It is all very well to include a comment in the Zevalin letter, saying that oh by the way this is also applicable to Rituxan. Rituxan is one of the most profitable and widely used drugs that Genetech sells. Surely this important and potentially life threatening adverse effect needs to be publicized? There is a chance that I just did not find the letter in my search thus far, and Genetech has actually issued such a letter. We will pursue this further. Research abstracts are just beginning to appear on this subject. I wonder if we will see many more of this type of report, as we get more track history of Rituxan use. Below is one of the abstracts I found.
Ann Oncol. 2002 Dec;13(12):1948-50.
Stevens-Johnson syndrome after treatment with rituximab.
Lowndes S, Darby A, Mead G, Lister A.
Cancer Research UK Department of Medical Oncology, Royal South Hants Hospital, Southampton, UK.
Rituximab is a chimeric mouse/human anti-CD20 antibody licensed for the treatment of low-grade non-Hodgkin's lymphoma and has recently also been shown to have a role in the treatment of diffuse large B-cell lymphoma. We report a case of Stevens-Johnson syndrome after treatment with rituximab, which occurred in a 36-year-old man with relapsed follicular lymphoma. The patient developed mucositis and fevers after the first two injections, followed by a florid maculopapular rash with severe orogenital ulceration after the third infusion. Over several weeks his symptoms progressed with severe cutaneous, orogenital and conjunctival ulceration, leading to visual problems and malnutrition. No improvement occurred with steroids and immunosuppressant therapy. A review of the literature reveals this to be the first reported case of Stevens-Johnson syndrome associated with rituximab therapy.
We have more pages and more articles dedicated to discussing Rituxan than just about any other drug on this website. Rightly so, Rituxan has changed the landscape of how CLL and other B-cell diseases are treated. Its ability to target CD20, the marker expressed only by mature B-cells, has made it possible for the first time to focus our fire-power. Many of our modern therapy regimens use Rituxan (the exceptions use Campath, the other monoclonal drug available to us) in various combinations with other chemotherapy or immune system modulating drugs. Some familiar (and not yet so familiar) examples are: R, RF, FCR, FCR Lite, PCR, R+ chlorambucil, R+HDMP, R+Genasense, R+fenretinide, R+17-AAG, R+Campath. Invariably, all the old (and new) drugs are seen to be more effective when used in combination with Rituxan, better bang for the buck.
Therapy choices become sparser if Rituxan is no longer available, either because of its cost or because the patient can no longer tolerate it with safety. Carefully constructed game plans with fall back options for when / if single agent Rituxan stops working go out the window, if those fall-back options all included Rituxan. How many of you were aware mucosal and skin problems that you may have encountered months after the last successful Rituxan containing therapy may have been due to the monoclonal drug? How many of you recognize now that if you are in this group of patients that develop drug sensitivity to Rituxan, the problems will get worse with each new infusion, and the adverse effects can be exacerbated to the point where they can become life threatening? Harvey is just coming to grips with this new reality, I strongly urge all of you to be aware of the risk as well. Majority of you may be able to continue using this drug with no problem. But for the minority who do develop drug sensitivity, it may well be that you can no longer use Rituxan, the risks may be too high.
For those of you who are interested, Harvey is doing fine now. The skin and oral damage is gradually fading away. As he comes to grip with this new situation, he may well have to decide Rituxan is no longer for him, not as a single agent, not in his favorite “RHK” mix, not as a part of any of the many combination regimens. When he decides his new game plan, I hope to be able to tell you all about it.
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Topic: Rituxan Therapy