A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation

Abstract

Purpose: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.

Experimental design: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy.

Results: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients.

Conclusions: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.

Conflict of interest statement

Conflict of interest disclosure: The authors declare that they have no relationships that they believe could be construed as resulting in an actual, potential, or perceived conflict of interest with regard to the manuscript submitted for review.

©2015 American Association for Cancer Research.

Figures

Figure 1

Disposition of trial participants.

Figure 2

Cumulative incidence of treatment failure defined as discontinuation of randomized treatment due to chronic GVHD progression or treatment intolerance within 6 months after initial randomization or less than a significant clinical response at the 6-month assessment according to treatment arm.

Figure 3. Proportion of CD27+ B-cells at enrollment across treatment groups

A Percentage of CD27+ cells of the CD19+ parent gate in patients who later had treatment sucess (responder) or did not (non-responder) to either imatinib or rituximab. B. Representative flow cytometry showing baseline CD27 expression of CD19+ (CD3-) B cells.