High Level T Cell Suppression Following Purine Analog Therapy for Patients with CLL Correlates with Important Clinical Benefit.

Purine analogs are potently immunosuppressive and result in profound suppression of normal CD4 and CD8 T lymphocytes. Despite developing pronounced lymphopenia, patients with CLL treated with these agents do not necessarily develop opportunistic infections and it is thought that other factors including neutropenia and response to therapy play an important role in determining the risk of infection. We evaluated 48 patients with CLL treated with purine analogs on 2 different studies in order to determine the degree of T cell suppression and its correlation with clinically important outcomes. In the upfront setting we analyzed 27 patients while in the salvage setting another 21 patients were evaluated (some analyses had fewer patients). Initial treatment was fludarabine (F) 25 mg/m2/d x 5d x 6 cycles, followed by high-dose cyclophosphamide (C) 3000 mg/m2 x 3 doses, and then a second consolidation with rituximab (R) 375 mg/m2 x 4 doses (F→C→R). The salvage regimen was pentostatin 4 mg/m2 and cyclophosphamide 600 mg/m2 with or without rituximab 375 mg/m2 x 6 cycles (PC(R)). CD4, CD8, and total T cell numbers were correlated with response, time to treatment failure (TTF), number of days hospitalized for infection and overall survival (OS). All patients had a prompt reduction in T cells. In untreated patients, 6 cycles of single-agent F results in a median decrease of 93% in the total T cell count from baseline. Subsequent therapy with C and R did not further reduce the total T cell count. In the salvage setting, 6 cycles of PC(R) reduced the T cell count a median of 82% from baseline. The frequency of complete response (CR) in previously untreated CLL patients with a T cell count below the median (282/μl) was 100% vs 22% (p=0.002) in patients whose T cell count remained greater than the median. Among previously treated patients those with a T cell count below the median (368/μl) after PC(R) had a CR frequency of 57% compared to 25% (p=N.S.) of patients with a T cell count > 368/μl. Despite profound T cell suppression, patients with T cell counts below the median level required fewer hospital days for infection when compared with patients whose T cell counts were above the median (median 1 vs 10 days (p=0.09) after F→C→R as initial therapy and 21 vs 44 days (p=N.S.) after PC(R)). CLL patients treated with PC(R) who had T cell counts below the median following therapy had improved TTF and OS compared to patients with less pronounced T cell suppression (TTF: 14 mos vs > 30 mos and OS: 32 mos vs > 38 mos). As expected, CLL patients have profound lymphopenia when treated with purine analogs. Interestingly, F as a single agent in an untreated population results in a similar degree of T cell suppression when compared with the combination of PC(R) given to relapsed/refractory patients. Despite low T cell counts, infections are not more common in patients with the most severe T cell suppression; in fact the converse is true. Patients with the most profound T cell suppression appear to have the greatest clinical benefit. The mechanism behind this clinical benefit is uncertain but we believe that the degree of T cell suppression may represent a surrogate for efficacy of chemotherapy (combining both AUC and an individual’s innate sensitivity to chemotherapy) and that patients with high quality responses and return of normal hematopoiesis have fewer infections than patients with persistent leukemia. In order to confirm these findings we are currently prospectively studying T cell suppression in patients receiving PCR as initial therapy.