Low Dose Post-Transplant Cyclophosphamide in Combination with Alemtuzumab As Gvhd-Prophylaxis Is Associated with Improved Outcomes and Safe Side Effect Profile in HLA-Mismatched Unrelated Transplantation

Introduction

Over the last years, there has been increasing interest in the use of posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GvHD) prophylaxis, given its huge success in the haploidentical setting. PTCy has been increasingly used in patients with HLA-matched related and unrelated donors, with encouraging results in terms of improved TRM and GvHD-free relapse-free survival. However, this comes at the cost of higher risk of side effects (such as hemorrhagic cystitis and viral infections) and delayed hematopoietic reconstitution, along with a potential increased risk of relapse. In an effort to mitigate this risk, we aimed to evaluate whether a reduced dose of PTCy can improve clinical outcomes.

Materials and Methods

This is a single centre study, evaluating the ability of a low dose of PTCy to prevent GvHD, in patients with HLA-mismatched (9/10) unrelated donors. The GvHD prophylaxis regimen that was used was: Campath 5mg IV on days -2 and -1, PTCy on days +3 and +4 and cyclosporin (starting on day -1). The initial dose of PTCy that was trialled was 15mg/kg, which was then escalated to 25mg/kg, in an effort to improve efficacy. The % occurrence of acute (aGvHD) and chronic (cGvHD) GvHD was evaluated, along with the overall survival (OS), the GvHD-free relapse-free survival, the relapse rate, and the non-relapse mortality (NRM).

Results

62 patients with various haematological malignancies (mainly acute leukemias and MDS) were included in the study (40 males and 22 females), with a median age of 51 years (range, 20-69). The disease risk index (DRI) was low/intermediate in 25 patients and high/very high in 37 patients. 33 patients received PTCy at a dose of 15mg/kg and 29 patients at a dose of 25mg/kg on days +3 and +4 after transplantation. 30 patients had a donor of >30 years old and 32 patients <30 years old. In 17 cases, there was a female donor to male recipient. 12 patients had DRB1-mismatch and 25 patients had non-permissive DRB1-mismatch. B-leader mismatch was present in 2 patients.

Acute GvHD grade 2-4 was observed in 25.8% of patients, with grade 3-4 occurring in 7.1% of patients. Chronic GvHD (all grades) was noted in 14.6% of patients, with moderate/severe cGvHD occurring in 6.4% of patients. The cumulative incidence (CI) of NRM was 17.6%. In a multivariate analysis of NRM (HR 3.86, 95% CI: 1.11-13.44, p=0.033), the female donor to male patient was found to be a significant contributor to NRM, whereas the PTCy dose (15mg/kg vs 25mg/kg) was not found to have a significant impact (p=0.082). The cumulative incidence of relapse was 21.7%, with the low DRI being associated with significantly reduced relapse risk vs the high DRI (13.1% vs 27.9%, p=0.03). The OS was 70.9% and the GvHD-free relapse-free survival was 51.8%. Again, in a multivariate analysis the female donor to male recipient was found to have a significant impact on the GVHD and Relapse Free Survival (GRFS) (HR 2.31, 95% CI: 1.07-5.00, p=0.02). In terms of side effects, haemorrhagic cystitis was reported only in 1/62 patients (grade 2), which resolved with hydration, whereas the median neutrophil engraftment was 13 days (range 11-16). There was a trend for decreased relapse rate and improved NRM and OS in patients with non-permissive DPB1-mismatched and/or DRB1-mismatched donors, although this association did not reach statistical significance in multivariate analysis.

Conclusion

Our data suggest that low dose PTCy in combination with alemtuzumab is associated with low relapse rates and acute and chronic GvHD, with a safe side effect profile, translating into improved outcomes in patients with HLA-mismatched unrelated transplants. This is the first time to our knowledge that low dose PTCy in combination with alemtuzumab has been tested for GvHD prophylaxis with very encouraging results. Our study is ongoing, as the results above need to be validated in a larger cohort.