Early and risk adapted therapy with Fludarabine in high risk binet stage a chronic lymphocytic leukemia patients

Background Fludarabine, a nucleoside analogue, has established
itself as a very potent and effective substance for treating CLL.
It induces (as a mono therapy in comparison with other drugs used
also in a mono therapy strategy) superior response rates and
progression free survival. Particular information, however,
concerning the efficacy of Fludarabine in CLL stage Binet A
patients with high progression risk still unfortunately lacks. To
find out whether an early Fludarabine mono therapy would bring
clinical benefits, particularly regarding response rates and
survival rates for this group of CLL patients, the German CLL Study
Group (GCLLSG) conducted the CLL-1 study; a multicentre and
randomized trial with 877 patients with previously untreated Binet
stage A CLL. Methods The patients were assessed in terms of their
progression risk through bone marrow histology (infiltration type),
lymphocyte doubling time (LDT), serum thymidine kinase level and
the serum-ß2-microglobulin level. The combination of a non-nodular
bone marrow infiltration type or a LDT 7 U/l or a serum-ß2-microglobulin
>3.5 mg/l indicates a high progression risk. Patients with high
progression risk would be randomized into the treatment arm or the
“watch and wait” arm. Patients in the treatment arm (cohort I)
received Fludarabine i.v. (25 mg/m2/day 5 days long, cycle repeat
on day 28, maximum 6 cycles), whereas patients in the “watch and
wait” group (cohort II) were only being observed. The third group,
consisting of patients with low progression risk according to the
definition above (cohort III) was also only being observed. 98
patients were randomized into cohort I (also called HR-F) and 95
patients into cohort II (also called HR-WW). The median follow-up
time was for the treatment arm 44.6 months long and for the “watch
and wait” arm 40.0 months. Observation points were progression free
survival (PFS), overall survival (OS), response rates, adverse
events and severe adverse events (SAE). Results Patients treated
with Fludarabine gained an overall response rate of 85%, including
32% complete remission rate and 53% partial remission rate.
Infection rate was higher in the treatment arm (23.5% vs. 9.6% of
the patients) than in the “watch and wait” arm, none of the
infections reached the CTC0 4, while only 3 of them reached the
CTC0 3. Progression free survival after Fludarabine therapy was
significant prolonged (p-value = 0.002) as the patients who
received Fludarabine reached 27.9 months and those who did not
receive it reached 15.3 months. Looking at the comparison
concerning the overall survival between the two arms, no advantage
of prolongation for the treatment arm could be noticed though.
Conclusions Fludarabine prolongs progression free survival in CLL
Binet stage A patients with high progression risk but not the
overall survival. It cannot therefore replace the “watch and wait”
strategy, which remains as the standard option for CLL Binet stage
A patients with or without high progression risk.