Comparable Data from Spirit Trial/imatinib/peginterferon patients

[Guest guest]

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of

Medicine, Harvard Medical School, Boston &

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Imatinib plus peginterferon alfa-2a produced significantly more " superior

molecular responses " than standard-dose imatinib, high-dose imatinib, or

imatinib plus cytarabine in patients with chronic-phase chronic myeloid

leukemia.

Note: responses were best with at least 12 months of therapy and that

fewer than one-half of patients were able to tolerate peginterferon for that

long. Adding pegylated interferon alfa-2a to standard therapy for chronic

myeloid leukemia significantly improved responses, researchers said.

After a year of treatment, 57% of patients taking both peginterferon and

imatinib (Gleevec) had a major molecular response, compared with 38% of those

taking imatinib alone, according to François Guilhot, MD, of the Centre

Hospitalier Universitaire de Poitiers in Poitiers, France, and colleagues.

But adverse effects of the peginterferon were so severe that less than

half of patients were able to take both drugs for a year, Guilhot and colleagues

reported in the Dec. 23 issue of the New England Journal of Medicine.

The findings come from the four-arm, phase III SPIRIT trial, which aimed

to see if adding other drugs to or using a higher dose of imatinib would improve

molecular responses, which have been associated with prognosis.

In the study, a major molecular response was defined as a decline of at

least 3 log10 units of transcripts of the BCR-ABL gene, the so-called

Philadelphia chromosome. A superior response was a 4 log10 drop and was a

molecular endpoint at the end of the first year of the study, Guilhot and

colleagues reported.

The researchers enrolled 636 patients with untreated chronic myeloid

leukemia in the chronic phase to get standard therapy -- imatinib alone at 400

milligrams daily -- or imatinib alone at 600 milligrams daily, imatinib (400

milligrams a day) plus cytarabine (Cytosar-U, DepoCyt), or the same dose of

imatinib plus peginterferon at 90 micrograms a week.

Enrollment in the high-dose imatinib and the imatinib/cytarabine arms was

stopped early by the study's data safety monitoring committee because of

toxicity and inferior results.

Subsequently, the study protocol was amended to reduce the dose of

peginterferon to 45 micrograms weekly for new patients. That amended protocol

marked a second stage of the trial, the results of which were not included in

the NEJM paper from Guilhot and colleagues.

The researchers found:

a.. At three months, all four groups had similar rates of complete

hematologic response -- between 89% and 95%.

b.. At 12 months, rates of complete cytogenetic responses ranged from

58% to 70% and were not significantly different among the groups.

c.. Also at a year, major molecular response rates were higher for

imatinib/peginterferon compared with standard-dose imatinib alone -- 57% versus

38% -- which was significant at P=0.005.

d.. Superior molecular response rates were also higher for

imatinib/peginterferon compared with standard-dose imatinib alone -- 30% versus

14% -- which was significant at P=0.001.

e.. The pattern was sustained through 18 and 24 months.

f.. At two years, 16% of imatinib/peginterferon patients had

undetectable residual disease, compared with 9% of those getting standard-dose

imatinib alone, a difference that was significant at P=0.01.

While the imatinib/peginterferon combination had superior efficacy, the

researchers said, only 46% of patients were able to take the drugs for a year.

Adverse events of any grade occurred more frequently with high-dose

imatinib, imatinib/cytarabine, and imatinib/peginterferon than with the standard

dose of imatinib alone, they reported, and toxic events were the main reason

patients gave for stopping either cytarabine or peginterferon.

The lack of tolerability, they reported, appears to be important, because

results were markedly better when patients were able to take the drugs for a

year or more. For example, the rate of superior molecular response was 23% in

patients treated for less than four months, compared with 49% if they were

treated for a year or more. A lower dose of peginterferon, they concluded,

might allow the combination to be given for longer and preserve its increased

efficacy.

The investigators also noted that superior molecular response has not been

validated as an endpoint in other studies, and that the second phase of the

study will examine whether molecular responses lead to prolonged survival.

The study had support from the French Ministry of Health, Novartis, and

Roche Pharma. Guilhot reported financial links with Novartis, Roche, and

Bristol-Myers Squibb. The primary source is from New England Journal of

Medicine.

http://tinyurl.com/2ug38pj

FYI,

Lottie Duthu