Chronic Myeloid Leukemia: Reversing the Chronic Phase by Goldman

January 17, 2010

http://jco.ascopubs.org/cgi/content/full/28/3/363

An excellent overview of where we are today. Zavie

EDITORIALS

Chronic Myeloid Leukemia: Reversing the Chronic Phase M. Goldman

Imperial College London, London, United Kingdom

Despite considerable skepticism about any possible clinical value of

tyrosine kinase inhibitors (TKIs) in the early 1990s, Druker et al,1 in

conjunction with scientists at Ciba-Geigy in Basel, Switzerland (now

Novartis), developed a compound that seemed to inhibit the enzymatic

activity of the Abl protein and consequently also of the enhanced activity

of the Bcr-Abl oncoprotein that characterizes chronic myeloid leukemia

(CML). It was first used in the clinic under the name STI571 in 1998, and

promising results led rapidly to design and implementation in 2000 of the

well-known IRIS study, in which the agent, now renamed imatinib (Gleevec,

Novartis), was compared prospectively with the combination of

interferon-alfa and cytarabine in the management of newly diagnosed patients

with CML in chronic phase (CP). The results proved impressive.2–5 After 8

years of follow-up, the estimated survival for patients allocated to the

imatinib arm is 85%,6 which is substantially better than historical control

patients treated with interferon alone or interferon plus cytarabine. The

adverse effects of imatinib are definitely manageable in most instances.

Imatinib at an oral dose of 400 mg daily has now become standard initial

treatment for all CML patients who present in CP. It is highly effective,

too, in the short term for patients who present in advanced phases, but the

duration of response is usually much shorter and the probability of relapse

to blastic phase is high.

Even for CP, however, the drug is not perfect. Only approximately 60% of

patients are still taking imatinib at standard dosage after 6 years, which

means that approximately 40% have needed higher doses of imatinib or

alternative therapy.

4,6,7 There are now three newer TKIs, all of which are more active than

imatinib in in vitro assays. Dasatinib (Bristol-Myers Squibb, Princeton, NJ)

is a smaller molecule than imatinib, to which it bears little chemical

relationship; unlike imatinib, it inhibits the enzymatic activity of the

oncoprotein regardless of the position of the Bcr-Abl activation loop and it

targets a much wider range of tyrosine kinases. Nilotinib (Novartis) was

designed as a chemical modification of imatinib and like its precursor has a

relatively narrow spectrum of activity against kinases other than Abl. The

third and newest agent, bosutinib (Wyeth, Madison, NJ), is chemically

different from both dasatinib and nilotinib but is not yet licensed. There

are now well-defined criteria for imatinib failure8–10; patients still in CP

who are judged to have experienced treatment failure with imatinib, either

as a consequence of intolerance or of resistance, are routinely offered

treatment with either dasatinib or nilotinib. Clinical results are similar

with the two agents11,12; 40% to 50% of patients resistant to imatinib will

be in complete cytogenetic response 2 years after starting their

second-generation TKI. To a certain degree, the likelihood of such responses

can be predicted.13,14

The data summarized briefly above pose interesting clinical questions:

should one or other of the so-called second-generation TKIs now replace

imatinib as primary treatment for CML in CP, and if so, which of the two

agents should one choose? The two articles published in this issue of

Journal of Clinical Oncology, both from the M. D. Cancer Center

(Houston, TX), go some way to answering these questions, though final

conclusions must await careful analysis of the results of some of the

currently ongoing prospective clinical trials in which progression-free

survival or event-free survival is a primary end point. One of the Houston

articles15 reports the use of dasatinib at 100 mg once daily or 50 mg twice

daily as initial therapy for 50 patents with CML-CP. These results are

considerably better than comparable results of using imatinib 400 mg daily,

and also better than results of using imatinib at 800 mg daily at the same

institution. (It is worth noting that many patients cannot tolerate imatinib

at 800 mg daily.) Significant neutropenia occurred in 21% of patients and

thrombocytopenia in 10%. Nonhematologic toxicity, when present, was usually

only grade 1 to 2. The projected event-free survival at 2 years was 88%. The

second article16 reports the use of nilotinib 400 mg twice daily to treat 51

newly diagnosed CML-CP patients. At 1 and 2 years, the estimated incidence

of complete cytogenetic response (CCyR) was 97% and 93%, respectively. The

incidence of major molecular response (MMR) was 55% at 1 year and 53% at 2

years. Some complete molecular responses (meaning undetectable BCR-ABL

transcripts) were seen at 12 and 24 months. Again the results were much

better than those seen in comparable patients treated with imatinib 400 mg

daily and somewhat better than results in those who received imatinib at 800

mg. Neutropenia occurred in 12% of patients and thrombocytopenia in 11%. All

patients were alive at a median follow-up of 17 months.

A recent study from Italy17 reported the use of nilotinib, also at 400 mg

twice daily, to treat 73 patients with CML in early CP. At 1 year, the

incidence of CCyR was 96% and of MMR was 85%. The authors were impressed by

the rapidity of the responses and reported 78% of patients in CCyR and 52%

in MMR at 3 months. Myelosuppression was relatively minor; one patient

proceeded to blastic crisis and another stopped treatment as a consequence

of increased serum lipase levels. The 1-year MMR rate was higher in this

study than in the Houston report, but this could have been due to

differences in PCR technology, which are not yet widely standardized.18

Are we now ready to recommend use of one or other of these agents as primary

treatment for CML-CP? In favor is the observation that the cytogenetic and

molecular responses do seem to be much more rapid than those achievable with

standard dose imatinib; this could be beneficial if the risk of disease

progression is related to the quantity of residual disease in a patient's

body and the time during that quantity is above a still ill-defined

threshold. The adverse effects attributable to both agents seem to be

relatively minor or nonexistent in most instances. One could reasonably

speculate that the fraction of patients who currently start imatinib but

develop resistance while still in CP and then respond to dasatinib or

nilotinib would not have developed any TKI resistance if they had started

the second-generation TKI de novo, and indeed some of those with imatinib

resistance who do not respond to second-generation TKIs might never have

experienced treatment failure if they started other TKIs drugs as initial

treatment. These considerations might raise the overall success rate using a

second-generation TKI as up-front therapy to 80% or more. Conversely, it

could be argued that with 11 years experience of using imatinib, the safety

profile is well established and 60% of patients do not need any stronger

TKI. Do we really know that more rapid responses translate to superior

survival, which must be the ultimate arbiter of whether to start treatment

with imatinib or a second-generation TKI? Will use of a second-generation

TKI increase the proportion of patients in whom we could safely stop

therapy? Only time will tell. Finally, in some countries considerations of

cost also enter the equation.

If you do decide to use a second-generation TKI as primary therapy, which

one would you choose? There seems little difference in efficacy. The adverse

effect profiles are different; nilotinib is more likely to cause chemical

disturbance of liver function and dasatinib more likely to cause pleural or

pericardial effusions, but these problems all resolve if the relevant drug

dosage is reduced or stopped, in which case one could switch to the other

second-generation TKI. Kinase domain mutations may guide choice of therapy

in patients resistant to imatinib, but they are exceedingly rare in newly

diagnosed patients and thus contribute nothing to choice of initial therapy.

Thus there is no good reason for preferring one or other of the newer TKIs.

An interesting compromise strategy would be to use two or three TKIs in

sequence.19 One could, for example, start with imatinib, switch after 6

months to dasatinib (or nilotinib), and then switch again to nilotinib (or

dasatinib). At least one such trial is currently in progress. It could prove

superior to use of a single second-generation TKI, but this is far from

certain. The problem here would be to define realistic convincing end

points. Studies based on survival would be the gold standard but would also

take many years to complete. A more realistic end point might be the

incidence of complete molecular response at 1 or 2 years once the RQ-PCT

technology is fully standardized or indeed the use of a genomic PCR for the

BCR-ABL fusion gene, which may be more sensitive than an RQ-PCR for BCR-ABL

transcripts. The good news for today is the fact that survival for most

patients presenting in CP has improved dramatically compared with 15 or 20

years ago. The challenge is to decide how exactly that survival can be

improved further or—better still—how to ensure that therapy can safely be

discontinued, as seems to be the case now in a small percentage of

patients.20

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following

author(s) indicated a financial or other interest that is relevant to the

subject matter under consideration in this article. Certain relationships

marked with a " U " are those for which no compensation was received; those

relationships marked with a " C " were compensated. For a detailed description

of the disclosure categories, or for more information about ASCO's conflict

of interest policy, please refer to the Author Disclosure Declaration and

the Disclosures of Potential Conflicts of Interest section in Information

for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: M.

Goldman, Novartis ©, Bristol-Myers Squibb © Stock Ownership: None

Honoraria: M. Goldman, Novartis, Bristol-Myers Squibb Research Funding:

None Expert Testimony: None Other Remuneration: None

NOTES

See accompanying articles on pages 392 and 398

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