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Therapy Choices

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Rituxan plus Fludarabine Therapy

Date:April 3, 2003

by Chaya Venkat

Results of Phase II Clinical Trial at Ohio State University

Related Articles:
RF Risks and Benefits

Fludarabine Monotherapy Is No Longer Gold Standard

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Plenary Paper

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

The Clinical Trial

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.

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SEQUENTIAL REGIMEN

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

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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.

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CONCURRENT REGIMEN

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

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TOXICITY

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.

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RESULTS

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.

RF Clinical Trial Results
From Byrd, et al., Blood.
Response Concurrent % Sequential %
Induction Phase
CR 33 15
CR+PR 90 77
Overall After Consolidation Phase
CR 47 28
CR+PR 90 77

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.....

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DISCUSSION

  1. For CLL, this trial establishes that the concurrent administration of Rituxan and Fludarabine is quite effective and superior to both Fludarabine alone and sequential Fludarabine followed by Rituxan.
  2. The authors point out, the long-term benefit of this Concurrent combination therapy as regards duration of remission and overall survival is not yet known.
  3. Previous single-agent and combo studies of Rituxan in lymphoma have not suggested myelosuppression is much of an issue with regard to this monoclonal. It is therefore surprising that in this study, during the induction phase, patients in the Concurrent arm (receiving Rituxan and Fludarabine) had higher incidence of grade 3-4 neutropenia than in the Sequential arm, where patients received only Fludarabine. Possible explanations for this may be that the two drugs act synergistically not only in killing CLL cells, something to be desired, but perhaps the same synergism also means other cell lines such as neutrophils are also destroyed with the same increased efficiency. There is reason to believe a more complicated mechanism may exist that is currently not understood.
  4. Intelligent therapy choices based on prognostic indicators is much sought after goal. Recent studies have shown that chromosomal aberrations, including p53 mutations, CD38 expression, and IgVH gene mutational status are also important determinants for treatment outcome in CLL. Several of the older standard prognostic factors, including age, Rai stage, and B2M level, were not shown to be important in predicting treatment outcome in this trial. This makes it all the more important to continue to look for a better handle on patient prognosis. Right now, we are not that far from shooting in the dark, the prognostic indicators routinely used today do not give a clear enough picture on which to base therapy decisions. If I were going to take the pretty high risk of getting a grade 3-4 neutropenia as a result of this concurrent Rituxan plus Fludarabine therapy, at the very least I would like to know what my chances were of getting a good response. Right now, it is still a lot like buying a pig in the poke.
  5. Finally, the authors point out that while the "RFC" protocol at the MD Anderson have reported CR rate of 66% in previously untreated CLL patients, and this is higher than the 47% CR rate observed in this study using "RF" and no "C", the difference between the two results could be statistically not meaningful, it could vanish with results based on larger groups of patients. More importantly, the point is made that Fludarabine and Cyclophosphamide in combination have been shown to be more immunosuppressive than with Fludarabine alone. "It will be important to carefully define the importance of Cyclophosphamide to improving overall response and remission duration. The ultimate goal in treating CLL should be the achievement of a high CR rate that translates into prolonged remissions and possibly cure. Addition of less effective components to up-front treatment regimens not only has the potential to increase toxicity, but may also diminish the ability to add other active agents to the regimen".

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.

Abstract:

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.

PMID: 12393429
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