Triple Therapy: New Standard for CLL?

[Guest guest]

Triple Therapy: New Standard for CLL?

n = 817 adults seen at more than 100 centers in 11 countries who were followed

for a median of 26 months. Their mean age was 61 years, with a range of 36 to 81

years.

http://www.oncologystat.com/news-and-viewpoints/news/Triple_Therapy__New_Standar\

d_for_CLL__US.html

SAN FRANCISCO (EGMN) - The addition of rituximab to the standard chemotherapy

regimen of fludarabine and cyclophosphamide significantly improves

progression-free survival in patients with advanced chronic lymphocytic

leukemia, according to two large randomized phase III trials.

The triple therapy, called FCR, proved superior both in previously untreated

patients and in those with relapsed or refractory chronic lymphocytic leukemia

(CLL), the most common form of adult leukemia in the United States.

Progression-free survival increased from 32 to 43 months in treatment-naive

patients (P = .000007) and from 21 to 31 months in relapsed or refractory

patients (P = .0002). Investigators presented the results of the trials on Dec.

6 at a press conference during the annual meeting of the American Society of

Hematology.

" I will clearly say that when these data become public ... they will change

medical practice, " Dr. Hallek of the University of Cologne (Germany)

said in an interview. Dr. Hallek was the senior investigator in the phase III

trial involving treatment-naive patients. " FCR is very likely becoming the new

first-line treatment for CLL patients. "

At the briefing, Dr. Hallek added, " Of almost equal importance is the safety of

this combination. CLL is a disease of elderly patients. So we were relatively

surprised and actually very pleased to see that the FCR, while causing a little

bit more neutropenia, did not cause [additional serious] infections. "

The designs of the two trials were similar. Patients were randomized to receive

either fludarabine and cyclophosphamide (FC) or FC with the addition of

rituximab (FCR). All patients received six 28-day cycles of the treatment, which

included 25 mg/m² of fludarabine and 250 mg/m² of cyclophosphamide on days 1-3

of each cycle. Patients in the FCR groups additionally received 375 mg/m² of

rituximab at the start of the first cycle and 500 mg/m² on day 1 for all

subsequent cycles.

The study in treatment-naive patients involved 817 adults seen at more than 100

centers in 11 countries who were followed for a median of 26 months. Their mean

age was 61 years, with a range of 36 to 81 years.

Of the patients in the FC group, 23% achieved complete remission, compared with

45% of those in the FCR group (P less than .01). As a consequence of the

increase in the complete remissions, patients in the FCR group showed a

significant decrease in partial remissions, from 50% to 40% (P less than .01).

The incidences of neutropenia (34% vs. 21%) and leukopenia (24% vs. 12%) were

significantly greater in the FCR group. The higher incidence of severe

infections in the FCR group (19% vs. 15%) was not statistically significant,

however.

The trial of FC or FCR for second-line therapy - the REACH trial - involved 552

patients from 17 countries who were followed for a median of 25 months, said Dr.

Tadeusz Robak of the Medical University, Lodz (Poland). The patients' median age

was 63 years.

Of the patients in the FC group, 13% achieved complete remission, compared with

24% of those in the FCR group (P = .0007). There was no significant difference

in the partial response rate (45% for FC and 46% for FCR), but there was a

significant increase in the overall response rate (58% for FC and 70% for FCR, P

= .0034).

In this trial, adverse events were higher in the FCR group (80% vs. 74%) but

serious adverse events were similar (50% vs. 48%). There were marginal increases

in neutropenia (42% vs. 40%) and febrile neutropenia (15% vs. 12%) and for

thrombocytopenia (11% vs. 9%). But rates of grade 3/4 infections were similar

(18% vs. 19%), and there were no differences in bacterial, viral, or fungal

infections.

Both investigators acknowledged receiving funding from Hoffman-La Roche Inc.,

but the trial on treatment-naive patients was investigator initiated while the

other was initiated by the pharmaceutical company.

[Guest guest]

Is there somewhere this whole study is reported, rather than just the

summary? I would like to know how many unmutated persons responded and

for how long, for example? And other features as well.

Also, is this ongoing to look for survival differences?

And is there another study out there comparting FR to FCR? which seems

a more commmon head-to-head comparison.

Also, why the study results are certainly news from a large randomized

trial, I don't understand the comments about this study changing

practice. Almost everyone gets FCR now and has been for years.

What I am missing?

Helene

[Guest guest]

Memorial Sloan-Kettering has been using FCR as a first-line treatment

for years; 8 yrs ago when I first needed tx it was the only treatment

MSK offered me in 2000. I switched hospitals and did a different

therapy. Just observation over the past 10 yrs as a member of a CLL

chatlist—many of whose members chose FCR as their first tx—led me to

believe that a) FCR had the best and longest CR rate of any other known

tx for CLL and a sizeable # of people treated with FCR had trouble

finding effective treatments when out of remission and often appeared

to develop serious treatment-related complications over the next couple

of years that often led to death. I wasn't particularly surprised to

find that FCR hadn't been shown to lengthen our life expectancy.

But I also observed that often (though not always) the people who opted

for FCR rather than milder treatments were those whose disease symptoms

were worrisome enough to require the solid, fast punch of two strong

chemo agents (FC) and a biological agent ® that boostd the efficacy

of that combination of chemos. For that reason, stats regarding the

prognostic indicators Dan mentions in his intro, as they relate to the

2-yr follow up results (though I think the mean # yrs for duration of

CR for FCR may be 3) would be important—for showing if there's any

relationship between the predicted course of the disease before FCR

therapy and duration of CR and subsequent response to future tx after

FCR.

-ellen d.

> Thanks Karl,

>

> I'd be happy with easier access to full studies, patient

> characteristics, years followed, full methods, etc...even if they

> aren't good enough for FDA. If I can read all the facts, I can make up

> my own mind on how convincing/hopeful/or just hype it is.

>

> Helene

>

>

>

[Guest guest]

Ellen,

I found your post so helpful. I am also looking for how to connect

prognostic or cytogenic features to what can be expected duration of

response to FCR.

At the recent Lymphoma conference (I remember you there), both Drs.

Furman and Rai expressed preference for FR over FCR except in some

instances.

If you don't mind saying, what did you choose instead of FCR?

I also learned that Sloan is (or was) pushing FCR. I had thought

they were PCR folks.

In reference to what Karl mentioned, I think it is fine for ASH to

have less rigorous standards. I think hearing things that are early,

or not fully tested, can be tremendously interesting. As long as we

know what methods were used, we don't need every study to be

randomized prospective controls. There is much to be learned from

things not rigorous enough approvals, but " heuristics " that show us

where things could go.

Now, I understand some centers of Bendamustine & R as firstline. So,

when would one choose which? Studies to date don't make these kinds

of comparisons. They will get there, but I'd like more now!

Sorry to go on....the research is my main focus.

Helene

[Guest guest]

Dear Karl,

When the oncologist who first dx'd my CLL said to me: a positive

attitude is very important, I replied immediately, " then I'm sunk! "

As it turned out, I'm not as negative or unhappy as I thought I was and

more importantly, I didn't add stress to my body by keeping feelings

locked inside. I screamed my fear out when it arose and cried deep, sad

sobbing tears when I needed to. Each time, I felt 100% better after

and ready to face the beast again.

You're so right that when we're feeling lousy physically it's hardest

to keep happy feelings coursing through our body! It's when I most

envy people who deeply believe in the power of prayer; it's when you

need to laugh and need to have friends who love you reach out. While

many of us may feel a bit burdened by that particular shibboleth about

a positive attitude, I bet most of us are properly convinced by the

evidence that feeling happy in your body rather than stressed or full

of repressed emotions is much easier on our immune systems.

-ellen

Dec 12, 2008, at 8:55 PM, karlamonyc wrote:

> Appreciate your comments, Ellen. Similarly, I think, it's been

> observed that people who are less optimistic do poorly when fighting

> disease. So some will conclude that being pessimistic causes poor

> outcomes. It might contribute, but this observation doesn't prove

> that because people who are not feeling well may be more seriously

> ill, and will be less inclinded to optimism. That is, pessimism

> could be a marker for having more advanced disease ... as could

> initial use of FCR .. as you point out.

>

> Karl

>

>

> >

> > Memorial Sloan-Kettering has been using FCR as a first-line

> treatment

> > for years; 8 yrs ago when I first needed tx it was the only

> treatment

> > MSK offered me in 2000. I switched hospitals and did a different

> > therapy. Just observation over the past 10 yrs as a member of a

> CLL

> > chatlist—many of whose members chose FCR as their first tx—led me

> to

> > believe that a) FCR had the best and longest CR rate of any other

> known

> > tx for CLL and a sizeable # of people treated with FCR had

> trouble

> > finding effective treatments when out of remission and often

> appeared

> > to develop serious treatment-related complications over the next

> couple

> > of years that often led to death. I wasn't particularly surprised

> to

> > find that FCR hadn't been shown to lengthen our life expectancy.

> >

> > But I also observed that often (though not always) the people who

> opted

> > for FCR rather than milder treatments were those whose disease

> symptoms

> > were worrisome enough to require the solid, fast punch of two

> strong

> > chemo agents (FC) and a biological agent ® that boostd the

> efficacy

> > of that combination of chemos. For that reason, stats regarding

> the

> > prognostic indicators Dan mentions in his intro, as they relate to

> the

> > 2-yr follow up results (though I think the mean # yrs for duration

> of

> > CR for FCR may be 3) would be important—for showing if there's any

> > relationship between the predicted course of the disease before FCR

> > therapy and duration of CR and subsequent response to future tx

> after

> > FCR.

> > -ellen d.

> >

> > > Thanks Karl,

> > >

> > > I'd be happy with easier access to full studies, patient

> > > characteristics, years followed, full methods, etc...even if they

> > > aren't good enough for FDA. If I can read all the facts, I can

> make up

> > > my own mind on how convincing/hopeful/or just hype it is.

> > >

> > > Helene

> > >

> > >

> > >

> >

>

>

>

[Guest guest]

Another question: How does age play into the equation? At 44, I'm

trying to weigh the pros and cons of FCR as an initial treatment, and

it's hard to figure out whether to go for the more durable remission

with FCR or to plug along with less toxic treatments and " save " FCR for

later. I'm on W & W right now (I was diagnosed in July) and feel pretty

normal, but my nodes are definitely growing, so I figure I'm going to

have to come up with an answer soon. My onc/hem has presented FCR as

the best choice. I'll be getting another opinion soon, but would

appreciate hearing perspectives from people who've " been there " .

[Guest guest]

Ellen,

Since you are going strong eight years later, you clearly made wise

choices. None of us know at the time if our judgements will turn out

well, but thankfully yours did.

I think details of how choices were made and what transpired from

treatment to treatment is extremely educational.

It also is hopeful, in that you can make choices that your body feels

is the right " level " , so it isn't just completely a shot in the dark.

By listening to how " sick " you were at the time, you chose avenues that

would be suitable for those levels, so it makes empirical, not just

intuitive sense.

Thanks for posting, Helene

[Guest guest]

" Where I feeling very sick, I'd go for FCR. For those of us who feel

good, but have numbers moving badly, it seems much more appealing to do

something milder.

I am very interested in people discussing their choices to do one of

the other. "

It was our hope, despite 's miserable prognostic markers, that his CLL

would advance at tolerable rate. If it had, we'd probably have opted for

chlorambucil & Rituxan and saved the big guns for later. But a " kinder and

gentler " advancement was not to be.

Now, once his platelets recover and 's able to take his last round of FCR,

we're looking at bendamustine & Rituxan when the time comes rather than

repeating FCR. Actually, by the time he exits remission, we may be able to use

bendamustine and Humax CD-20. Research seems to be running at a somewhat better

clip. There may be some pleasant surprises approved by the FDA. Who knows?

Warm wishes,

Jan

[Guest guest]

Helene,

I agree it's helpful when people volunteer how they reached their tx

decisions and post about their outcomes. So far I " ve been very lucky

and it's easier to feel one's made good decisions when the outcomes go

well! But someone else with CLL making exactly the same choices might

have fared differently. Hope for all of us lies in the continued

development of therapies that don't do too much damage and a better

understanding of how individual differences lead to the wide variance

in reactions to the same drugs.

-Ellen

On Dec 13, 2008, at 1:50 AM, elmerleb wrote:

> Ellen,

> Since you are going strong eight years later, you clearly made wise

> choices. None of us know at the time if our judgements will turn out

> well, but thankfully yours did.

>

> I think details of how choices were made and what transpired from

> treatment to treatment is extremely educational.

>

> It also is hopeful, in that you can make choices that your body feels

> is the right " level " , so it isn't just completely a shot in the dark.

> By listening to how " sick " you were at the time, you chose avenues

> that

> would be suitable for those levels, so it makes empirical, not just

> intuitive sense.

>

> Thanks for posting, Helene

>

>

>

[Guest guest]

Reading Jan's post, I remember how each time I made my tx decisions I

was scared to death they were the wrong ones and I will be the next

time too. If we have good doctors and make the best decisions we can

given what we know at the time, second-guessing is not a sport we want

to indulge in. FCR is a valid choice for thousands of CLLers. Dr.

Furman and so many others are committed to finding less and less toxic

combinations that will help all of us—before, during and after the

treatments and consequences of them we're living with. -- Ellen D.

> " Where I feeling very sick, I'd go for FCR. For those of us who feel

> good, but have numbers moving badly, it seems much more appealing to

> do

> something milder.

>

> I am very interested in people discussing their choices to do one of

> the other. "

>

> It was our hope, despite 's miserable prognostic markers, that

> his CLL would advance at tolerable rate. If it had, we'd probably have

> opted for chlorambucil & Rituxan and saved the big guns for later. But

> a " kinder and gentler " advancement was not to be.

>

> Now, once his platelets recover and 's able to take his last

> round of FCR, we're looking at bendamustine & Rituxan when the time

> comes rather than repeating FCR. Actually, by the time he exits

> remission, we may be able to use bendamustine and Humax CD-20.

> Research seems to be running at a somewhat better clip. There may be

> some pleasant surprises approved by the FDA. Who knows?

>

> Warm wishes,

>

> Jan

>

>

>