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Alert Number 10

Is Rituxan More Dangerous Than Fludarabine?

Date: April 8, 2004

Just about every month I get a couple of emails from CLL patients facing their first therapy decision, whose local oncologists have stated categorically that Rituxan is "dangerous" and "unproven", while fludarabine is the proven "gold standard for" CLL. I thought I would put together this Topics Alert, so that I can cut, paste and send it out to all such emails in future.

I suppose it is human nature to prefer the old and familiar, and be some what suspicious of the new-fangled stuff. However, in the case of CLL where our understanding of the disease and the best way of controlling it are changing at break-neck speed, an oncologist that does not keep up with the latest literature, and hangs on for dear life to the conventional wisdom learned in medical school a decade or more ago, that can be downright dangerous. Like it or not, monoclonal antibodies like Rituxan and Campath are here to stay.

Don't get me wrong, purine analogs such as fludarabine (and its less well known siblings Pentostatin and Cladrabine) are very important drugs in our arsenal against CLL. However, just about every CLL patient becomes refractory to fludarabine after one or more uses. "Fludarabine refractory" is a phrase used to describe the hard-to-treat patients with poor prognosis. This is one bridge you do not want to cross, one bridge you do not want to burn ahead of time. Better to keep it as an option for the future, if and when it becomes necessary. May be we will come up with better options by that time and you never have to use it.

There is no contest between Rituxan and fludarabine on the subject of adverse reactions and toxicity. Fludarabine is a DNA damaging agent, mutagenic, and conventional chemotherapy drug. Below is a link to a reputable on-line drug information site, click on it to get detailed information on fludarabine. (Incidentally, you might want to add this link to your list of favorites, you can search for any other drug in future by entering the name in the search box). Here is a brief excerpt from the RxList on fludarabine: "Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with FLUDARA FOR INJECTION. During FLUDARA FOR INJECTION treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%. Myelosuppression may be severe, cumulative, and may affect multiple cell lines." (Fludarabine on

The first abstract below reflects the same concerns, in terms of immune suppression and hematological adverse events. The moral of the story - patients receiving fludarabine therapy either as a single agent on in combinations should make sure that they get pre-emptive medications ahead of time to protect them against bacterial and viral infections (Herpes, Shingles, pneumonia to name but a few), and that they get regular blood tests (CBC) done to monitor their neutrophil and red blood cell counts, as well as hemoglobin, platelets levels. If you get anemic or neutropenic, do discuss with your doctor the need for growth factors ("Procrit", "Neupogen" etc). You may be at increased risk of secondary cancers such as squamous cell carcinoma during the window of vulnerability when your t-cells are depleted as well as a result of fludarabine therapy. You can read about it in an article on this website titled Are You Dying to Get a Tan? Did you know that as a CLL patient you are 10 times more likely to get this form of skin cancer, and it is more likely to be of an aggressive variety? The odds go up even more if you have recently had immune suppressive chemotherapy.

Rituxan therapy is no perfect solution. It seems to work better in some patients than in others. It helps if you are chemo-naive, and it seems to help if you have a moderately high percentage of your CLL cells expressing CD20 marker that is the target of Rituxan (it does not seem to make a lot of difference even if the expression of CD20 is "dim"), and you do not have massive lymph nodes or "bulky" disease. The jury is still out on some of these criteria, all except the one about being chemo naive and not having bulky disease. Rituxan does not work as well in patients who have already been through standard chemotherapy.

Most patients have first-infusion-related chills and general flu-like symptoms with Rituxan. Some patients have a harder time than others, but a careful and very slow rate of administration of the drug the first time, along with pre-medications such as Tylenol, Benedryl and Tagamet seems to work very well for the great majority. It is particularly important to stay very well hydrated (drink lots and lots of water for a week ahead of time). Allopurinol is a drug that also helps to prevent possible kidney damage, but be aware that a small percent of people are allergic to Allopurinol. If you develop any kind of itch or rash while on the Allopurinol, make sure to contact your doctor right away. "Tumor Lysis syndrome" is something to be aware of if you have very high WBC in your blood. In simple terms, Rituxan does a quick job of killing the B-cells in your blood, and if there are too many of them to begin with, the cellular debris of the dead and dying cells can overwhelm the ability of the body to get rid of the waste products. Tumor Lysis syndorme can be dangerous if left untreated. Leukapheresis to bring down the WBC count ahead of Rituxan therapy is an option under such circumstances. Last but not least, Rituxan is a "chimeric" compound, part human and part mouse. A small percent of people may be allergic to Rituxan. This is why it is so important to go slow with the infusion on the first day, and have good nursing staff monitor you carefully. The vast majority of patients seem to have no further problems after the first infusion.

Rituxan is a lot more expensive than fludarabine. Insurance companies do not like to spend money when they can get by with a cheaper drug. Also, while many oncologists and CLL experts are now routinely using Rituxan as frontline and single agent therapy for CLL, it is officially accepted by the FDA only for CLL patients who have relapsed, or in combinations with other chemotherapy drugs. I for one would like to see that FDA ruling changed, it makes no kind of sense to me.

If your oncologist still needs convincing, write to me and I will help you locate a full text copy of the Hainsworth paper (second abstract below) and a couple more similar articles. Print out hard copies of the papers and take them to your oncologist. What the heck, ask your oncologist to write to Dr. Hainsworth, his email address is below. PC and I had the pleasure of meeting with Dr. Hainsworth a couple of years ago, we found him to be a thoughtful and helpful research oncologist.

We probably have more articles on our website on the subject of Rituxan than just about any other drug. If you are going to be using Rituxan in the near future, you really owe it to yourself to get a good look at what it can do for you, what is involved, what to expect. Do visit the sections on Rituxan Therapy to learn more about it.

Be well,



Leuk Lymphoma. 2003 Nov;44(11):1947-50.

Conventional dose fludarabine-based regimens are effective but have excessive toxicity in elderly patients with refractory chronic lymphocytic leukemia.

Shvidel L, Shtalrid M, Bairey O, Rahimi-Levene N, Lugassy G, Shpilberg O, Polliack A, Berrebi A; Israeli Study Group on CLL. Hematology Institute, Kaplan Medical Center, Rehovot 76100, Israel.

The best approach to elderly patients with relapsing chronic lymphocytic leukemia (CLL) or disease refractory to conventional therapy with alkylating agents has not yet been established. Fludarabine and its combination with mitoxantrone and/or cyclophosphamide, which is the most effective treatment in younger patients, has not been extensively utilized in the elderly CLL. Here we report our results with fludarabine-based chemotherapy in 32 previously treated patients over the age of 65 years. The overall response rate was 59% with no complete remission, 3 nodular partial remissions and 16 partial remissions. The median time to progression of disease was 7 months. Only 10 patients completed the entire treatment program, because of poor compliance due to toxicity. Eight patients developed neutropenic fever, 14 severe bacterial infections and 2 patients showed progressive encephalopathy. For comparison, in a younger group of patients with refractory CLL (< 65 years), 38 of 50 patients completed the treatment plan, and the ORR was 80% (10 CR, 11 PR-nodular, 19 PR) with a median response of 12 months. Neutropenic fever was diagnosed in 10 and severe bacterial infection in 4 patients. In conclusion, fludarabine-based chemotherapy is effective for refractory CLL, however, excessive toxicity such as severe infections and neurological complications, do not allow completion of treatment in the majority of the elderly patients. Because maintenance of a good quality of life should be the main goal in the elderly CLL population, dose reduction of fludarabine and the appropriate use of myeloid growth factors and prophylactic antibiotics appear mandatory in this group of patients.

PMID: 14738148

J Clin Oncol. 2003 May 1;21(9):1746-51.

Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network.

Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network.

Sarah Cannon Cancer Center and Tennessee Oncology, Professional Limited Liability Corporation, Nashville, TN

PURPOSE: To assess the efficacy and toxicity of first-line single-agent rituximab, followed by re-treatment with rituximab at 6-month intervals, in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
PATIENTS AND METHODS: Forty-four previously untreated patients with CLL/SLL received rituximab 375 mg/m2 weekly for 4 consecutive weeks. All patients were required to have one or more indications for treatment. Patients with objective response or stable disease continued to receive identical 4-week rituximab courses at 6-month intervals, for a total of four courses.
RESULTS: The objective response rate after the first course of rituximab was 51% (4% complete responses). Twenty-eight patients received one or more additional courses of rituximab. At present, the overall response rate is 58%, with 9% complete responses. After a median follow-up of 20 months, the median progression-free survival (PFS) time was 18.6 months, and the 1- and 2-year PFS rates were 62% and 49%, respectively. Treatment was well tolerated, with only two episodes of grade 3 to 4 infusion-related toxicity. No cumulative toxicity or opportunistic infections occurred.
CONCLUSION: Single-agent rituximab, used at a standard dose and schedule, is active in the first-line treatment of patients with CLL/SLL, producing substantially higher response rates than previously reported in relapsed or refractory patients (51% v 13%, respectively). Re-treatment with rituximab at 6-month intervals is well tolerated. The PFS time of 18.6 months in patients with CLL/SLL seems shorter than the 36- to 40-month median PFSs previously reported with first-line plus maintenance rituximab in patients with follicular lymphoma. Additional follow-up is required to fully assess the impact of this treatment strategy.

PMID: 12721250

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