Monday, May 16, 2011

Bendamustine as second line. An Italian look-back

Most people are agreed that FCR is the best first line therapy if you are fit enough. CAL-101 and PCI32765 both look promising as disease modifying agents that act a bit like Gleevec for CLL, though the jury is still out on long-term effects. What about second-line in patients who have responded well to FCR?

It seems that repeating FCR in patients who have had a 2-year remission and not suffered major problems with it first time around is probably the right idea. However, few people will be able to get six course in a second time and the older patient and one with co-morbidities might be better advise not to try.

Is there a place for bedamustine plus rituximab as second line in patients declared unfit for a second FCR? An Italian atudy has addressed this issue. They evaluated bendamustine plus or minus rituximab in a group of heavily pretreated patients.

109 patients of median age 66 (39-85) were included. There were 80 males. 20 had B symptoms. Median prior therapies was 3 (1-8). 38% had received previous fludarabine and 39% had had previous rituximab. 62 were resistant to their last treatment. 22 received bendamustine alone and 87 the combination of bendamustine + rituximab. There was no attempt to randomize between them and I can't really see the point of lumping the together. This was the B J Haem. In Leukemia Research we would have been a bit more stringent about how the trial was reported. In fact it wasn't a trial at all, but a retropective look back at how bendamustine had been used in 24 Italian centers. I am afraid I would have rejected the paper for Leukemia Research.

105 patients were evaluable for response. 30 obtained CR, 43 a PR and 32 obtained no response. The CR rate for B+R was 32.5% and only 13.6% for B alone. Responsive patients had a better response (84.8%) than resistant patients (57.6%) (p=0.004). The median duration of response was 13 months.

Only 36% of patients received the intended 6 courses. 7% received 5 courses, 21% 4 courses and 34% 1-3 courses. Four patients were stopped early because of toxicity (1 herpetic encephalitis, 1 relapse of a melanoma, 1 myocardial infarction and 1 grade 4 neutropenia. 16.5% had grade 4 neutropenia and 17.5% thrombocytopenia, 15.5% anemia and 4.5% infection. Three of the 34 deaths were thought to be treatment-related.

What to make of this study? In view of my previous posting, not much. This was not a trial with an independent review panel. Responses were assessed by the patients' individual doctors and bias easily creeps in. The median duration of response was just over a year - not very long. All we can say is that Bendamustine is a drug that has some response in previously treated patients. A year later roughly a third of those treated were dead. I'm not sure what was gained by publishing this report. I am not impressed.


Burke said...

I'm just starting my 5th year of an MRD neg CR after completing 4 cycles of FCR with slightly reduced F which I tolerated well, according to my Doc. From what I can tell, my doc is planning on giving me B when I relapse, probably because of my age. (I turn 70 in Dec.)

I'm reasonably healthy, so I'm wondering just how old is too old for FCR.

Anonymous said...

Thank you for your comments. I read the abstract from the BJH and, considering the concluding sentence, once again we note that "beauty is in the eye of the beholder"

I am especially appreciative of your commentary on such a paper as I have noted on the various internet sites about CLL that some would come across and report on this paper (or simply the abstract, depending upon how they set up their searches)and offer glowing reports on the utility of B & R, when, perhaps, we should all be more circumspect!

These sites are certainly an important source of information for people, but they may also serve to disseminate "misinformation".

I also wonder (only read the abstract) whether the reported anemia included any significant proportion of cases of drug-exacerbated AIHA?

Thank you onceagain for all of your help,


Terry Hamblin said...

FCR is still an option.

Terry Hamblin said...


There was no mention of autoimmunity.

Anonymous said...

What would then be a better option for relapse after FCR?

I believe Chlorambucil + Rituximab would not be effective after FCR.

Treatment again with FCR for older patient is also risky.

Terry Hamblin said...

We are waiting for data. At the moment I would go for PCI32765 or CAL-101.

Anonymous said...

Thank you for your timely commentary!

This is a very provocative paper.
For me such high responce rates (esp. CR) look very suspicious considering results from DCLLSG and the fact that 20% received B alone.


Anonymous said...

Some doctors in the US are now recommending B + R as front line treatment, over FCR or F + R etc.

Not sure why as the question on how the two compare has not been answered yet (Ongoing German CLL study). Maybe they think it is less toxic but as effective in getting a remission?

Curious as to what your thoughts on using B + R on patients less than 65 as initial treatment?

Terry Hamblin said...

I have never been convinced by bendamustine. It is a sort of expensive chlorambucil given in a more toxic dose.

Anonymous said...

CAL-101 or PCI32765 are not available in all the countries. So in that case for a relapsed patient after FCR, what would be the best option for treatment?

This is for elderly patient above 70 years but with good health otherwise.

Terry Hamblin said...

B+R is an option but it has been over-hyped and it's value is without any evidence. FCR is still an option if the last remission was 2 years of more.