Low-dose anti-thymocyte globulin plus low-dose posttransplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood for patients with hematologic malignancies: a prospective, phase II study

Abstract

Nowadays, the most wildly used regimens for graft-versus-host disease (GvHD) prophylaxis in haplo-hematopoietic stem cell transplantation (Haplo-HSCT) are based on in vivo T-cell depletion (TCD) with anti-thymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy). To improve the efficiency of GvHD prophylaxis in haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood (Haplo-PBSCT-Cord), a novel regimen, which is composed of low dose of ATG (5 mg/kg) and low-dose PTCy (50 mg/kg) for GvHD prophylaxis, was evaluated in a prospective phase II clinical trial (Clinicaltrials.org NCT03395860). Thirty-two patients diagnosed with hematological malignancies were enrolled in this trial. All patients received myeloablative conditioning regimens except for three patients. The cumulative incidences (CIs) of grades II-IV and III-IV acute GvHD were 19.4% (95% CI, 5.5−33.3%) and 6.9% (95% CI, 0−16.3%) by day 100, respectively. The 1-year probability of relapse, disease free survival (DFS) and overall survival (OS) was 25.1% (95% CI, 7.3−42.9%), 59% (95% CI, 33.3−84.7%) and 78.4% (95% CI, 63−93.8%), respectively. The CIs of CMV and EBV reactivation by day 180 were 37.5% (95% CI, 19.8−55.2%) and 40.6% (95% CI, 22.6−58.6%), respectively. The results suggested that low-dose ATG with low-dose PTCy as GvHD prophylaxis in Haplo-PBSCT-Cord had promising activity.

Low-dose post-transplant cyclophosphamide and anti-thymocyte globulin as an effective strategy for GVHD prevention in haploidentical patients

“…It should be stated that despite the significantly decreased rate of grade III-IV aGvHD and total chronic GVHD in the ATG-PTCy cohort compared to control cohort, the incidence for moderate to severe chronic GVHD remains higher. And the rate of moderate to severe chronic GVHD was also higher or comparable than that in the high-dose PTCy plus ATG protocols reported to be 0-18.8% with smaller study population or shorter follow-up [12][13][14]17]. MAC and predominantly female donors especially female-tomale pairs [3] in the current study may be the attributable reasons as compared with previous reports on high-dose PTCy plus low-dose ATG regimens [12][13][14].…”

“…One of the characteristics of the PTCy studies has been a reduced incidence or even absence of PTLD [34]. Though we found EBV reactivation incidence was 21%, it was remarkably less in comparison with other studies using high-dose PTCy and ATG (32-64%) [11][12][13][14]17]. In order to reduce the infectious complications, the next step with testing ATG/PTCy (low-dose) strategy may be decreasing the ATG dose also.…”

“…Nonetheless, centers using PBSC in haploidentical transplants with PTCy have shown rates of extensive chronic GVHD as high as 38% [30]. Even with the addition of 4.5-5 mg/ kg ATG to a backbone of high-dose PTCy, the rate of moderate to severe chronic GVHD was reported to be 10-13% with 2-day PTCy [13,14] or 18.8% with 1-day PTCy [17]. This may partly explain why only total cGVHD was reduced with the current combined treatment while moderate to severe cGVHD was not.…”

“…As for disease control, it is speculated that low-dose PTCy had little impact on relapse, which is evidenced by our current data. Previous studies also demonstrated that high-dose PTCy with ATG is effective in alleviating GVHD without increasing relapse [13,14] with the relapse incidences reported to be 16-37% [11][12][13][14]17]. It was taken in the context of the fact that the combination of ATG and PTCy appears to increase infectious complications particularly regarding herpes virus control and may lose some of the protective effects of PTCy alone.…”

“…To date, the combination of conditioning regimens with lowdose ATG and high-dose PTCy after haplo-HCT [11][12][13][14] or unrelated donor (URD) HCT [15,16] for hematological malignancies has been documented in several reports with reduced rates of GVHD and acceptable relapse rate albeit with somewhat high rates of graft failure (8%) [11] or delayed engraftment [12]. Recently, results of a prospective trial have been available which analyze the efficacy of combined use of low-dose ATG and 1-day high-dose PTCy (50 mg/kg at + 3 days) in preventing GVHD among haplo patients [17].…”