Treatment of acute and chronic graftversus- host disease after posttransplantation cyclophosphamide with calcineurin inhibitors monоtherapy

Summary

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for oncohematological and non-malignant diseases. However, the procedure is associated with a high risk for the patients in the posttransplant period, primaryly due to development of the graft versus host disease (GVHD). Since the late 1980’s, application of systemic glucocorticosteroids (GCS) has been the standard of GVHD treatment, when calcineurin inhibitors have been used as a prophylaxis for GVHD. However, prolonged use of systemic GCS can lead to secondary infections and other life-threatening complications. So far, there are no publications on the opportunity for usage of calcineurin inhibitors (CNI) for GVHD treatment as a first-line therapy after prophylaxis with cyclophosphamide as a single agent post-transplantation (saPTCy). Therefore, the aim of this study was to analyze the effectiveness of GVHD treatment without systemic GCS.

Patients and methods

A retrospective analysis was performed based on the case histories of 29 patients (11 cases with acute GVHD, and 21, with chronic GVHD). Median age was 34 years (19-58). Acute leukemia was the primary diagnosis in 13 patients; other patients received HSCT for chronic lymphocytic leukemia, Hodgkin’s lymphoma, etc. Twenty-one patients received matched related transplants, 8 patients had matched unrelated donors. The criteria for inclusion into the study were as follows: usage of single-agent PTCy GVHD prophylaxis without additional immunosuppression, and development of acute GVHD (2-4 degree), or chronic GVHD of moderate and severe grade requiring systemic treatment. Severity assessment of acute and chronic GVHD cases was done according to the criteria of Consensus Conference 1994 (Przepiorka D. et al.) and NIH 2005 (Lee S.J. et al.), accordingly. All the patients received CNI’s as the first-line therapy. 14% of the patients (N=4) exhibited acute GVHD grade 2; 24%, grade 3 (N=7). Multiple organ involvement in chronic GVHD patients was observed in 12 patients (41%). Median time to acute GVHD was 47 days (23-70), for chronic GVHD, 101 days (74-413).

Results

In the group with acute GVHD, a complete response was observed in 18% of cases (N=2), in chronic GVHD, the complete response rate was 50% (N=9). Partial response was observed in 9% patients with aGVHD (N=1), and in 28% patients with chronic GVHD (N=5). 73% of patients with acute GVHD (N=8) and 36% of patients with chronic GVHD (N=4) did not show any response. 21% (N=6) of all patients developed steroid-refractory GVHD. 9% (N=1) of patients had a chronic GVHD which followed treatment of acute condition. The second line of therapy (glucocorticoids, ruxolitinib, or extracorporeal photopheresis) was required in 35% of the cases (N=10). There were no predictors of a response to the calcineurin inhibitors with the present sample size (p>0.1). Secondary bacterial infections were observed in 96% of treated patients (N=28), viral infections, in 72% (N=21), fungal invasions, in 7% f the cases (N=2). Moreover, the rate of infections didn’t significantly affect the survival of patients (p=0.2). The one-year survival rates for patients, who responded to the calcineurin inhibitor therapy versus those who didn’t respond, did not differ significantly (90% vs 83%, p=0.81).

Conclusion

Our study has demonstrated that monotherapy of GVHD with CNI’s could be feasible after saPTCy prophylaxis. However, the response probability in acute GVHD seems less likely than in chronic GVHD cases. This assumption, as well as the predictors of CNI response, should be tested in large multicenter studies.

Keywords

Hematopoietic stem cell transplantation, acute and chronic GVHD, cyclophosphamide prophylaxis, calcineurin inhibitors, clinical effects.