Clinical Trials el pt

Mitoxantrone plus FCR — British Version

Date: August 18, 2024

by Chaya Venkat

A Comparison of the U. K. and M. D. Anderson Protocols

Related Articles:
Mitoxantrone plus FCR;
More on Mitoxantrone plus FCR.

Several readers have written to us in the last few days, requesting a comparison of the FCR+M clinical trial at M. D. Anderson (see our review of this trial at Mitoxantrone to Turbocharge FCR Combo? and More on Mitoxantrone plus FCR) with the trial announced earlier the U.K., using the same four drug combination. Don’t let the alphabet soup get to you, FCR+M is the same as FCM+R. To recap, the four drugs are fludarabine (F), cyclophosphamide (C), Rituxan (R) and mitoxantrone (M).

Since we have reviewed the rationale for this drug combination in our earlier articles, we will not cover that ground again. In this update we will describe the design of the U. K. trial, with a few comments on how it seems to differ from the M. D. Anderson approach. Drs. Peter Hillmen and Andy Rawstron are both involved in this U.K. trial. Our information is based on Patient Information Sheet dated October 2024. Please bring it to our attention if there are later versions of this information sheet, especially if the later versions differ substantially from the details below.

The U.K. Trial Design

• This phase – II clinical trial is offered at 10 – 20 hospitals in the U.K. The target recruitment is 56 patients. Half the patients will be randomly assigned to get FMC, the other half will have Rituxan added, in other words FCM+R. The randomization means that you have a 50:50 chance of being in either arm of the trial. The M. D. Anderson design is single arm, roughly half the size in terms of patients recruited (30), and all participants will get all four drugs.
• The U.K. trial limits participation to CLL patients who have relapsed after initial therapy, where as the M. D. Anderson version is recruiting chemo-naïve patients. This is a substantial difference in the philosophy of the two trials.
• The end points measured by both trials are the same: response statistics and the number of patients who get squeaky clean bone marrow. Too bad that there are no plans to monitor these patients long enough to arrive at overall survival statistics. I can understand this is difficult to do, and probably expensive. But from a patient’s perspective, the real endpoint that makes a difference is whether this drug combination allows us to live longer, with better quality of life.
  
  For example, in its heyday, fludarabine was hailed as the best thing since sliced bread, since it gave much higher response rates and higher percent of CRs, compared to chlorambucil. But to our disappointment, there has been no confirmation that the higher response rate obtained by fludarabine therapy translates into longer survival, or even better quality of life. Quite the contrary. There has been a steady drum beat of new articles identifying deep immune suppression (especially toxicity to T-cells) causing all sorts of problems (Fludarabine Monotherapy No Longer Gold Standard and Topics Alerts #6, #97, #108) We will have to wait and see if the higher response rates expected with combinations such as FRC or FRC+M translate into longer and healthier lives for our patients.
• If you have read our previous articles on the FRC+M trial at M. D. Anderson, you know that we have expressed concern on the lack of cardiac pre-screening for patients participating in this mitoxantrone-containing regimen. In fact, there is no mention of potential for cardiac toxicity in their description of the clinical trial, either the short form on their website or the more detailed protocol given to patients.
  
  We are happy to report this is not the case with the U. K. trial. Patients will be screened for cardiac function by means of ECG, chest X-ray, and even a CAT scan in some of the patients. Potential damage to heart muscle as a consequence of mitoxantrone therapy is listed as one of the possible adverse reactions. The U.K. clinical trial write-up suggests that cardiac toxicity is not a likely adverse effect at the dosages used in this study, and in any case the damage and changes in heart rhythm will be temporary. But nevertheless all patients will be screened for their cardiac status prior to start of therapy. Amen to that.
• On the first day of each cycle patients will get the drugs that are given intravenously (I expect this will be Rituxan and mitoxantrone), followed by four days of oral medications (cyclophosphamide and fludarabine) at home. Oral fludarabine is approved in Europe. Unfortunately that is not the case here in the U.S. There are a total of 6 cycles, repeated every four weeks. This is similar to the M. D. Anderson design. In other words, it will take about 6 months to get all 6 cycles.
• We are happy to note the U.K. trial plans to follow trial participants for 2 years. We wish it could be longer!
• A weakness shared by both the U.K. design as well as the M. D. Anderson design is that neither trial attempts to recruit on the basis of modern prognostic indicators. (I am under the impression this may be changed in the latest version of the U.K. design, but that point is yet to be confirmed. If you have information on this, please write and let us know.)
  
  Surely there is enough evidence now to suggest that IgVH gene mutation status should be one of the criteria used for risk stratification of patients? Inclusion in aggressive therapy combinations such as this should be limited to poor prognosis patients. People with unmutated IgVH genes and / or high risk chromosomal defects such as 17p deletion are the ones who have few good options. Getting high response statistics in such a tough crowd would be worth writing home about. I worry that in the absence of risk stratification, there may be too many patients with good prognostic indicators in these clinical trials. Recruitment bias is always an issue in trials conducted with small cohorts of patients, even when there is no conscious effort to “cherry pick” candidates likely to give stellar results. Out of the 30 patients to be recruited for the M. D. Anderson trial or the 28 patients in the U.K trial that will get all four drugs, how many are good prognosis “Bucket A” patients? These are patients that will respond to just about any therapy, and their participation in these trials will skew the results to look better than they would be otherwise.