Does Body Weight Matter with Gleevec Therapy?
Japanese doctors recently (2008) published a study correlating body weight of patients to Gleevec dose
and response. The article appeared in the American Journal of Hematology titled ‘Multicenter prospective
trial evaluating the tolerability of Imatinib for Japanese patients with CML in chronic phase: does body weight
matter?’ Doctors from the Tokyo STI study group did the study. I am paraphrasing the article.
The 6-year follow-up of the IRIS trial, which revealed 0% incidence of disease progression between years
5 and 6 used the standard dose of Gleevec (400mg a day) for the trial. However, for pediatric patients, the
dose of Gleevec is prescribed according to body surface area with the recommended dose of 260mg/m2/day.
The smaller size of Japanese adults compared to their Western counterparts and the consequent worry that
400mg would be too excessive for Japanese patients formed the motivation of this study. In addition, the fact
that side-effects could differ among different races formed a second motivation for the trial. Therefore, 89
patients were included in the study with a median age of 53 years and median body weight of 62.8 kg. There
were 65 men and 24 women and the follow-up time was median 31 months. 17 patients had received prior
treatment with Interferon.
The results showed that on the 400mg dose, 30 patients (34%) developed Grade 3 and Grade 4 toxicities
and discontinued therapy. 10 patients with Grade 2 toxicity also discontinued therapy. For most patients,
discontinuation occurred within 3 months of starting therapy. Common side-effects included low blood counts,
edema, myalgia and skin rash. In total, 18 patients discontinued due to low blood counts, 16 due to non-
hematologic side-effects and 6 due to both. Resumption of therapy occurred in 40 patients in small doses
with gradual dose increase over time. The final maintenance dose was 400mg in 13, 300mg in 16, 200mg in 5
and 100mg in 2 patients. 4 patients could not tolerate Gleevec at all.
49 patients took 400mg Gleevec continuously for 6 months. Therefore, in total, the dose was 400mg for
62/89 patients or 70%. However, the percentage of patients taking Gleevec at 300mg a day continued to
increase in the next 2 months.
Risk factors for discontinuation of 400mg Gleevec were older age and lower body weight. These factors
had an impact on maintenance dose. The mean final maintenance dose was 375mg in patients younger than
50 years and 329mg a day in patients at least 50 years of age. The mean maintenance dose was 394mg for
those weighing at least 60kg and 304mg for those weighing less than 60kg. All patients who weighed at least
60kg and were younger than 50 years tolerated the 400mg dose of Gleevec. Only 42% of patients who
weighed less than 60kg and were at least 50 years old tolerated the 400mg dose.
How did the patients in the study respond to Gleevec? 98% of patients achieved a complete hematologic
response in the first 6 months. The incidence of CCR was 60% at 6 months and 90% at 1 year. There was a
direct correlation between CCR and the maintenance dose of Gleevec. The mean final maintenance doses
were 379mg and 319mg a day for those who achieved CCR and those who did not. Older patients and those
with lower body weight were those who were less likely to achieve a CCR and again this correlates with the
lower dose of Gleevec the patients took. 81% of the patients who achieved CCR also achieved MMR and
29% of the CCR patients achieved PCRU.
Although the percentage of patients on lesser than 400mg a day was less in the IRIS study (30% vs 8%),
the incidence of CCR was higher in this study compared to the IRIS study. The median body weight of
patients in the Japanese study was 62.8kg compared to 83.6kg (men) in the IRIS trial. The good responses
correlating to lower body weight may be due to higher Gleevec blood levels but racial differences could also
be a contribution. One obvious flaw of this study is that the Gleevec PK levels, which would shed more light
on the weight of patient/response to Gleevec issue are not measured. However, such a study is now in
progress. Larson’s study has shown that patients who have severe side-effects of edema, rash, etc all have
higher Gleevec PK levels.
The fact that patients with lower body weight had to discontinue the 400mg Gleevec dose implies that
these patients may have had too much Gleevec in their blood giving rise to toxicities. Gleevec trials in the
West did look at correlation between body weight and incidence of side-effects and found no correlation. The
Japanese doctors postulate that the Gleevec blood levels of Western patients may increase with lower body
weight but continue remaining at safe levels without giving rise to toxicity. Whereas in Japanese patients, the
significantly lower body weight results in toxic levels of Gleevec in the blood.
However, if the Gleevec levels in the blood are high (we have to wait for the Gleevec PK data, this was
just hypotheses on the part of the doctors), why is CCR not achieved in the patients with low body weight?
The doctors answer this question by saying that although Gleevec levels are high in patients with low body
weight, reducing Gleevec dose in proportion to the weight can give rise to inadequate response. For
example, if 400mg dose is the dose for a man weighing 80kg, administration of 300mg Gleevec to a patient
weighing 60kg or 200mg to those weighing 40kg will give rise to inadequate Gleevec levels in the blood. This
suggests that for patients with low body weight who cannot tolerate 400mg a day, 300mg a day will not be the
answer but a dose somewhere in between may be the ticket.
The doctors conclude that the starting dose of Gleevec should be at least 400mg a day even for patients
who have a small body size. If patients have very severe side-effects, dose can be reduced but the doctors
recommend physicians to administer higher doses of Gleevec whenever possible otherwise the response is
not good. For patients with severe side-effects on 400mg dose, doctors can administer 300mg dose with
addition of 100mg of Gleevec every other day, in other words, 300mg one day, 400mg the next day.