Rituximab (Rituxan) has significant activity in
low-grade non-Hodgkins lymphoma (NHL), but lower responses were
noted in small lymphocytic lymphoma (SLL), a nodal variant of chronic
lymphocytic leukemia (CLL). Pharmacokinetic data showed that higher
serum rituximab concentrations correlated with response to therapy
and that SLL patients had low trough levels. These findings suggested
that once-weekly dosing, as administered to NHL patients, was not an
ideal schedule for CLL/SLL patients. Therefore, we initiated a phase
I/II study of rituximab in CLL/SLL patients using a thrice-weekly schedule.
All CLL/SLL patients had CD20 expression (dim to bright, as
determined by semiquantitative flow cytometry) and met the modified
National Cancer Institute (NCI) CLL response criteria for treatment.
Rituximab was administered on day 1 at a 100-mg dose over 4 hours to
minimize infusion-related events (stepped-up dosing).
Patients then received 250 mg/m² (cohort 1; N = 3 patients) or
375 mg/m² (cohort 2; N = 6 patients) on day 3 with the standard
NHL administration schedule, and thrice-weekly thereafter at this
fixed dose for 4 weeks (12 total treatments). Patients in cohort 3 (N
= 18) were treated identically to those in cohort 2 except that
rituximab was administered over 1 hour on the third and subsequent doses.
Response was assessed using the modified NCI criteria for CLL, which
require maintenance of response for 2 months post-therapy. To date,
27 patients have been enrolled (21 CLL/6 SLL); median age of these
patients was 64 years (range, 51 to 80 years). The median number of
prior treatments was two (range, zero to six). Of the 27 patients, 22
had high modified-Rai risk and 5 had intermediate risk. All 27
patients were evaluable for toxicity and 18 were evaluable for response.
Serious adverse events occurred in two patients. The first patient
died of a pulmonary hemorrhage that occurred 48 hours after the first
dose of rituximab (possibly drug related), and the second patient
developed septic arthritis (unlikely drug related). All other
patients completed therapy, including 16 in cohort 3.
Infusion-related events occurred in 13 patients (8 grade 1 and 5
grade 2 events) during infusion 1, 7 patients during infusion 2 (4
grade 1 and 3 grade 2 events), and 2 patients during infusion 3 (both
grade 1 chills). Six patients had pretreatment platelet counts
between 20 and 50 ×109/L, three of whom developed
grade 4 thrombocytopenia.
Of the 18 patients evaluable for response, 9 (50%) responded to
therapy (8 partial responses [PRs], 1 complete response [CR]).
Semiquantified expression of CD20 on tumor cells correlated with
clinical response (for 16 analyzed patients) as follows:
Responses for CLL (6/13; 46%) and SLL (3/5; 60%) were similar and
were more marked in blood, nodal, and splenic sites, as compared with
bone marrow. Response has also been noted in 3/7 (43%)
CONCLUSION: Our data demonstrate that this schedule of rituximab is
feasible and has significant clinical activity that may correlate
with density of CD20 expression in patients with CLL/SLL.