FYI: Activity and Safety of Dasatinib in CML and Ph+ ALL

[Guest guest]

Hi all,

I'm posting below a discussion in the wake of the ASH meeting. This is

from a series about CML from ASH that I am privvy to. I'm not posting

them all because there are too many (62 pages in a pdf) but will post

some of them. I have also removed links and references for my

convenience.

Below is the fifth and last one I am posting.

~ G.

www.cmlsupport.com <http://www.cmlsupport.com/>

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Activity and Safety of Dasatinib in CML and Ph+ ALL

Yang, MD, PhD:

The next set of abstracts specifically deals with dasatinib therapy.

O'Brien, MD:

A total of 529 patients have been evaluated in the dasatinib phase I and

II studies. The results of the 84-patient phase I study, originally

launched in 2003 for patients with CML and Ph+ ALL, were updated. The

dasatinib phase II dasatinib studies initiated in February 2005 were

designed for CML patients by stage of disease, as well as for patients

with Ph+ ALL, and included more than 1000 patients. Results from the

first 445 phase II patients were presented.

Because follow-up is quite short at only 5 to 6 months, we have to be

cautious about interpreting these data. However, the rates of

cytogenetic response are fairly encouraging, especially considering that

these patients failed prior imatinib therapy.

Dr. Apperley, you helped lead the START-A study, a phase II

investigation of dasatinib in imatinib-resistant or intolerant patients

with CML in the accelerated phase (Capsule Summary).[31] The results, as

presented here at ASH by Dr. Guilhot, suggest that dasatinib has

significant efficacy in this population, and most patients with BCR-ABL

point mutations had a response. A total of 107 patients were reported;

complete hematologic response was seen in 35 patients (33%) and no

evidence of leukemia in 28 (26%), for a major hematologic response rate

of 59%. Major cytogenetic responses were seen in 31% of patients

including complete cytogenetic response in 21%. Again, hematologic

toxicity was substantial, but manageable; the most common grade 3/4

hematologic toxicity was thrombocytopenia, occurring in 85 patients

(79%), and nonhematologic toxicities were usually mild or moderate.

Dr. Talpaz and colleagues[33] reported on START-B, a phase II study of

dasatinib in imatinib-resistant/intolerant patients with CML in myeloid

blast crisis (Capsule Summary). In this report on the first 74 patients,

hematologic response was seen in 51% of patients, and complete

cytogenetic responses were seen in 27% of patients. Responses were seen

both in patients who had BCR-ABL domain mutations and in

imatinib-resistant patients without mutations. Treatment was associated

with grade 3/4 myelosuppression, which occurred in the majority of

patients but was manageable with treatment interruptions. Nonhematologic

toxicities were not common and were typically grade 1 or 2. Given the

short follow-up, these results are quite encouraging.

We also saw a presentation of the START-C phase II study of dasatinib in

patients with imatinib-resistant or intolerant chronic phase Ph+ CML

(Capsule Summary).[8] These patients seemed to respond extremely well.

In this analysis that included 186 patients, hematologic response was

seen in 90%, and there were high rates of major cytogenetic response:

45% overall and 73% among imatinib-intolerant patients. Responses were

durable, according to investigators, with 86% of patients remaining on

therapy at 6 months. There was no progression among patients who had

achieved major cytogenetic response.

Finally, Dr. Ottmann reported results of START-L, a phase II study of

dasatinib in patients resistant or intolerant to imatinib with CML in

lymphoid blast crisis or Ph+ ALL (Capsule Summary).[34] Major

hematologic response was reported in 13 (31%) of 42 patients in lymphoid

blast crisis and in 15 (42%) of 36 of the Ph+ ALL patients. Rates of

complete cytogenetic response were 43% and 58% in those groups,

respectively. Again, myelosuppression was common, and grade 3/4

nonhematologic toxicities were uncommon.

Yang, MD, PhD:

With regard to these data, when should community oncologists consider

referring imatinib-resistant patients to trials with these new tyrosine

kinase agents, and which trial should they consider first?

Jane Apperley, MD:

That is difficult to answer. I think these new agents are extremely

valuable additions to the armamentarium for patients with CML.

Determining the moment that a patient fails imatinib has been a

controversial issue for the last couple of years for hematologists

around the world. But there are some very clear indications as to when

failing patients should be referred to clinical trials, such as loss of

a previous hematologic, cytogenetic, or molecular response. The failure

to achieve a cytogenetic response by 6 months or 12 months may also

indicate a need for referral to clinical trial, because the IRIS study

has informed us that those patients are not going to do as well as

others.[1]

O'Brien, MB ChB:

It may be a while before either of these agents receives US Food and

Drug Administration (FDA) approval. So, there may need to be some sort

of early access or expanded access program that makes the drugs more

fully available. However, the nature of such programs has not been

clearly defined yet.

Yang, MD, PhD:

What about these agents in the context of transplants? Traditionally,

after imatinib failure, patients would opt for transplant if a donor was

available. Now, with these drugs on the horizon, has your thinking about

transplantation changed?

O'Brien, MD:

It depends. For a young patient who is failing imatinib and has a good

donor, I would be very hesitant to recommend one of these new and as yet

unproven drugs when there is a potentially curative therapy available.

There would have to be very good reasons not to transplant that patient.

But as we discussed earlier, it is completely different for the

68-year-old who does not have a viable transplant option. In that case,

I would consider using one of these new agents.

Jane Apperley, MD:

In my opinion, it depends on why the patient has failed imatinib. A

patient who has progressed to an advanced phase of disease may derive

some temporary benefit from one of the new agents but is unlikely to be

cured or to have long-term survival. For these individuals, transplant

should be considered much earlier. For the individual in chronic-phase

CML without a 3 log10 reduction in molecular expression, it is an

entirely different matter.

Hagop Kantarjian, MD:

In that context, mutational analysis would be important, particularly if

specific mutations are detected that we know do not respond to the new

kinase inhibitors. In this circumstance, there is no point in enrolling

patients with those types of mutations in studies with these new agents.

Transplantation or alternative strategies that do not depend on mutation

status may make more sense.

O'Brien, MB ChB:

To summarize, the efficacy data for both these agents are exciting and

promising. We are awaiting further follow-up with great interest.

Hematological toxicity seems to be common with both agents and requires

frequent dose reductions.

Yang, MD, PhD:

One of the differences between the new agents and imatinib is that,

although they all cause edema, there appears to be a higher incidence of

grade 1 and 2 pleural and pericardial effusions with the new tyrosine

kinase inhibitors. Most of this occurs in patients with advanced-phase

disease. Although few patients have discontinued treatment because of

these problems, they are new problems to be aware of.

Hagop Kantarjian, MD:

The incidence of peripheral edema and severe peripheral edema appears to

be less common with the new kinase inhibitors than with imatinib. The

pleural effusions with imatinib are severe in about 1%-2% of patients,

and there are anecdotal reports of pleural-pericardial events. Severe

effusions did occur in the phase I and in the phase II dasatinib

studies, with more events observed in blast crisis than in the chronic

phase, and in the twice-daily higher-dose schedules than with the

once-daily lower-dose schedules. But if identified early, treatment can

be interrupted, or doses can be adjusted. Additionally, with the use of

diuretics like furosemide or steroid therapy, these effusions may not

become clinically significant.

Jane Apperley, MD:

Many patients were enrolled in these trials because they were intolerant

to imatinib because of skin rashes or abnormal liver function studies.

There does not seem to be cross-toxicity; people who develop abnormal

liver function studies on imatinib do not seem to have abnormal liver

function results with the new agents. I find that fascinating, because

the incidence of grade 1/2 liver abnormalities is common with both

agents.

O'Brien, MB ChB:

On the other hand, we found patients who had skin rashes on imatinib who

also got skin rashes on AMN107.

Jane Apperley, MD:

Our phase II dasatinib trial had only 22 patients who enrolled because

of abnormal liver function studies, and none of them developed serious

abnormal liver function test results (Capsule Summary).[31]

Hagop Kantarjian, MD:

Some of the patients in our phase II dasatinib study enrolled because of

severe intolerance to imatinib-mostly extramedullary toxicity, such as

liver dysfunction, rashes, severe muscle aches, bone aches, and cramps

(Capsule Summary).[33] As 40t does not appear that there is

cross-toxicity across these 2 agents.

Yang, MD, PhD:

What do you predict for the future with these agents? Should they be

used in combination? Are they to be used for imatinib-resistant patients

only? Are they ever going to be used as upfront treatment?

O'Brien, MD:

For the time being, I think the most obvious role is going to be in the

context of imatinib failure. I anticipate that studies will explore

their use in first-line therapy. We have very few, if any clinical data

to suggest that combination treatment is safe, viable, or desirable.

However, I think that is inevitably going to be explored over the next

year or so.

Jane Apperley, MD:

I think there will undoubtedly be studies exploring combination

therapies. Whether the toxicity of combining 2 or more agents will be

acceptable is another matter, in view of the extent of hematologic

toxicity observed with single-agent dasatinib and AMN107.