Date:April 3, 2003
by Chaya Venkat
RF Risks and Benefits
Fludarabine Monotherapy Is No Longer Gold Standard
Below is the link to the recent pivotal and very important paper published by Dr. John Byrd, et al., in Blood on the results of their Rituxan plus Fludarabine clinical trial. The link provides free access to the full text article. The abstract (PubMed citation) is attached at the end of this article.
Link: Blood Journal Article
A total of 104 previously untreated CLL patients participated in this study. They were divided randomly into two groups. First group, called the "Sequential group" got Fludarabine only as the first step ("Induction Phase") over 6 cycles, each cycle lasting 5 days, once cycle per month. After that they received 4 standard Rituxan doses, once a week for 4 weeks, in a "Consolidation Phase". Second group, called the "Concurrent Group", got everything that the Sequential Group got, in addition they also got 7 infusions of standard dose Rituxan during the Induction phase. Below are the details of the dosages in the two groups.
Patients received Fludarabine (25 mg/m2) intravenously daily on days 1 through 5, with the treatment repeated every 28 days for a total of 6 cycles. This was called the "Induction Phase". Then there was an observation period of 2 months. Patients with stable disease or better were then treated with 4 weekly doses of Rituxan (375 mg/m2), this was called the "Consolidation Phase".
Fludarabine: 25mg/m2, for five days each. Repeated each month for 6 months.
25mg/m2 X 5 days X 6 months = protocol total of 750 mg/m2.
Rituxan at 375 mg/m2 four weekly doses.
375mg/m2 X 4 weeks = protocol total of 1,500 mg/m2
Folks, please remember the devil is in the details: don't let your eyes glaze over when it comes to looking at these dosage data, especially if / when it is your body that is going to be on the receiving end of these drugs. As discussed in this article, toxicity is very much an issue in all of these protocols, and there is little doubt that more heavy duty dosages of chemotherapy drugs means more toxicity. By now, I hope all of you know what the units "milligram per meter square" (mg/m2) means. The dosage of most chemotherapy drugs is dependent upon your body size, bigger people will get more than smaller people. "meter square" refers to your body surface area, or BSA, which is calculated by using your height and weight. Please refer to the article BSA - Drug Dosage where this was discussed in detail, or refer to the URL: BCCA – BSA Drug Dosage.
So, if your BSA is 2.0, and the dosage calls for 375mg/m2, you should be getting 375 X 2.0 = 750mg, for your size body.
Patients received Fludarabine in a dose and schedule similar to those described with the sequential regimen but with the addition of Rituxan. Rituxan (375 mg/m2) was administered on days 1 and 4 of cycle 1 of Fludarabine therapy. Only a single dose of Rituxan was then administered on day 1 of cycles 2, 3, 4, 5, and 6. In other words, during this "Induction Phase", patients received a total of 7 Rituxan infusions. After a 2 month observation period, patients with stable disease or better were treated with 4 weekly doses of Rituxan (375 mg/m2 ) as "Consolidation Phase", just as in the Sequential regimen.
Fludarabine: 25mg/m2, for five days each. Repeated each month for 6 months.
25 mg/m2 X 5 days X 6 months = protocol total of 750 mg/m2.
Rituxan at 375 mg/m2 7 doses over 6 cycles (Induction Phase), plus four more doses weekly in the "Consolidation Phase", for a total of 11 Rituxan infusions.
375mg/m2 X 11 infusions = protocol total of 4,125 mg/m2
Hematological toxicity, particularly grades 3 and 4 neutropenia, happened more with the concurrent regimen and occurred throughout the Induction Period, 76% when patients received Rituxan and Fludarabine, and 39% with the use of Fludarabine alone. This was true also in the consolidation phase (19% versus 8%), even though both groups received the same dosage of Rituxan in both groups. Grade 3 or 4 thrombocytopenia was noted in 20% and 10% of the patients on the concurrent and sequential arms, respectively, and anemia in 4% and 0% of the patients, respectively. These are not easy numbers to swallow, especially the grade 3-4 neutropenia. As some of our members can attest from first hand experience, severe neutropenia is associated with all sorts of other problems, like infections, fever, shingles etc. Other less common toxicities encountered in this study included 3 cases of grade 3-4 pulmonary toxicity (pneumonia of various sorts) on the concurrent arm. This was successfully treated in all patients by stopping Fludarabine infusion and giving the patients a short course of corticosteroid treatment. Two cases of autoimmune hemolytic anemia were noted in the sequential regimen during Fludarabine therapy, and one case each of idiopathic thrombocytopenic purpura (ITP) and pure red cell aplasia were observed with the concurrent regimen. Three cases of neurotoxicity were noted that required cessation of Fludarabine therapy (1 patient on the concurrent regimen and 2 on the sequential regimen, consisting of transient confusion and headache). These toxicities were resolved when Fludarabine therapy was stopped. The full paper (not the abstract) gives a lot more details on the toxicity, sit down with a good glass of pinot noir before you start reading.
The table below summarizes the results obtained for both the Concurrent and Sequential arms of the trial, right after the initial Induction Phase as well as at the end of the protocol, after finishing the Consolidation phase as well. No question about it, there is a statistically significant difference between the two groups, 90% overall response rate (CR + PR) is quite impressive.
|Response||Concurrent %||Sequential %|
Overall After Consolidation Phase
Now here is a surprising nugget: during a median follow-up period of 23 months after the end of the protocols, 35% of the patients in the Concurrent Group had relapsed, while a smaller number, 28% had relapsed in the Sequential Group. Hmmm.....
A lot to digest at one sitting. I think most of us newly diagnosed patients, or those who are looking at making that crucial first therapy choice, will at some point have to think of "RF" versus "RFC" therapy. Here is a lot of much needed information on the RF part, I am waiting with bated breath to hear the full details of the RFC story. I will report on that as soon as it is published.
Blood 2003 Jan 1;101(1):6-14
Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712).
Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA.
Division of Hematology-Oncology, Department of Medicine, The Ohio State University, Columbus, OH
Recent studies have suggested that rituximab has clinical activity and modulates anti-apoptotic proteins associated with drug resistance in chronic lymphocytic leukemia (CLL). We performed a randomized phase 2 study to determine the efficacy, safety, and optimal administration schedule of rituximab with fludarabine in previously untreated CLL patients. Patients were randomized to receive either 6 monthly courses of fludarabine concurrently with rituximab followed 2 months later by 4 weekly doses of rituximab for consolidation therapy or sequential fludarabine alone followed 2 months later by rituximab consolidation therapy. A total of 104 patients were randomized to the concurrent (n = 51) and sequential (n = 53) regimens. During the induction portion of treatment, patients receiving the concurrent regimen experienced more grade 3 or 4 neutropenia (74% versus 41%) and grade 3 or 4 infusion-related toxicity (20% versus 0%) as compared with the sequential arm. The consolidation rituximab therapy was tolerated well in both arms. All other toxicities were similar in the 2 arms. The overall response rate with the concurrent regimen was 90% (47% complete response [CR], 43% partial response [PR]; 95% confidence interval [CI], 0.82-0.98) compared with 77% (28% CR, 49% PR; 95% CI, 0.66-0.99) with the sequential regimen. With a median follow-up time of 23 months, the median response duration and survival have not been reached for either regimen. Rituximab administered concurrently with fludarabine in previously untreated CLL patients demonstrates marked clinical efficacy and acceptable toxicity. Phase 3 studies using this combination approach for patients with CLL are warranted.
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Topic: Therapy Choices