Inhibition of Lymphocyte Trafficking Using a CCR5 Antagonist – Final Results of a Phase I/II Study

Abstract 1011

Inhibition of lymphocyte trafficking early after allogeneic stem cell transplantation (SCT) may prevent GvHD without interfering with GvL activity. Animal models and genomic data in humans indicate that the interaction between CCR5 and its ligands CCL3, CCL4 and RANTES is pivotal in the pathogenesis of GvHD. Maraviroc (MVC; Selzentry^®, Pfizer) is the first oral CCR5 antagonist in clinical use. The antiviral properties of MVC in HIV infection are known, but its effects on chemotaxis and immune function in patients without HIV infection have not been explored. We hypothesized that CCR5 inhibition early after allogeneic SCT would reduce lymphocyte chemotaxis and result in low rates of acute GvHD without impairing engraftment or antitumor activity.

In vitro, MVC effectively and specifically inhibited CCR5 internalization and reduced RANTES-induced chemotaxis in concentrations achievable in humans, recapitulating a defect observed in homozygotes for the del32-CCR5 polymorphism. MVC had no effect on hematopoietic colony formation, T-cell mediated cytotoxicity and T-cell proliferation.

Between May 2009 and March 2011, we enrolled 38 pts in a phase I/II study of reduced intensity conditioned (RIC) allogeneic SCT. Patients had high-risk features by age (median=62, range 21–74), donor source (matched related 34%, matched unrelated 50%, single-antigen mismatch 16%) and comorbidities (comorbidity index: low 55%, intermediate 34%, high 11%). Underlying diseases were AML (15), MDS (6), NHL (8), myelofibrosis (4), aplastic anemia, myeloma, CLL, Hodgkin, CML (1 each). Pts received fludarabine 120mg/m² and IV busulfan 6.4 mg/kg followed by peripheral blood stem cells. In addition to standard GvHD prophylaxis with tacrolimus and methotrexate, MVC was given from day −2 to +30. Pharmacokinetic analysis on the first 13 pts identified 300 mg bid as the appropriate dose (Reshef, ASH 2010). MVC was well tolerated, and adverse events were similar to the expected toxicity observed in patients undergoing RIC SCT. The median time to ANC>500/μL was 15 d (range 10–27) and to platelets>20k/μL was 19 d (range 9–84). The median whole blood and T-cell donor chimerism at day 100 was 96.5% (range 0–100%) and 85% (range 0–100%) respectively.

Median follow-up was 200 days (range 12–760). Among 35 evaluable patients, the cumulative incidences of any acute GvHD and grade III–IV acute GvHD at day 100 were 14.7 ± 6.2% and 2.9 ± 2.9%, respectively. Importantly, in the first 100 days, there were no cases of acute GvHD involving the liver or gut. At day 180, the rate of acute GvHD was 20.7 ± 7.1%, largely confined to the skin with low rates of GvHD in the liver (3 ± 3%) and gut (7.4 ± 5.3%). In evaluable pts who received a graft from their HLA-matched sibling (11), there was no GvHD before day 100 and only two cases of acute GvHD before day 180.

We compared these results to a cohort of 38 well-matched consecutive patients treated at our institution with RIC SCT using an identical regimen but without MVC between 2009 and 2011. We observed a similar incidence of acute GvHD (all grades) at day 100 (14.7 ± 6.2 vs. 16 ± 6.1%; P=0.88), but a 64% decrease in the MVC group at day 180 (20.7 ± 7.1 vs. 45.4 ± 9%; P=0.03). The incidence rates of severe GvHD (grade III–IV) were 2.9 ± 2.9% in the MVC group vs. 5.5 ± 3.8% in the comparator group at day 100 (P=0.59) and 6.5 ± 4.5% vs. 18.1 ± 6.8% at day 180 (P=0.15).

Treatment-related mortality in pts receiving MVC was low. At 1 year, non-relapse mortality rate was 7.6 ± 5.5% (control group: 15.7 ± 6.6%; P=0.35). Infectious complications were seen at a rate that is expected with RIC SCT. Recovery of lymphocyte counts and lymphocyte subsets was not impaired by MVC.

We evaluated whether a protective effect against GvHD was associated with an increase in relapse. In the MVC group, the incidence of relapse was 34.2 ± 8.8% at day 180; this was not significantly different from the comparator group (43.9 ± 8.8%, P=0.44), implying preservation of the graft-versus-tumor effect with MVC. Rates of overall survival and relapse-free survival were similar in both groups.

Pharmacodynamic testing revealed that sera from patients taking MVC prevented CCR5 internalization by RANTES and blocked T-cell chemotaxis in vitro, providing evidence for in vivo biological activity and supporting the hypothesized mechanism of action.

In summary, inhibition of lymphocyte trafficking is a novel, specific and potentially effective strategy to reduce the incidence of acute GvHD.