Cyclosporine/methotrexate versus tacrolimus/methotrexate with or without anti-thymocyte globulin as GVHD prophylaxis in adult patients with aplastic anemia
Annals of hematology. 2020
The impact of calcineurin inhibitor types and anti-thymocyte globulin (ATG) in conditioning on overall survival (OS) and GVHD-free, relapse-free survival (GRFS) has not yet been analyzed in detail for aplastic anemia. We herein examined 517 adult patients with aplastic anemia who underwent BMT from HLA-matched sibling donors (MSD, n?=?255) and unrelated donors (UD, n?=?262) and were treated with cyclosporine A (CSA) + methotrexate (MTX) (n?=?258) and tacrolimus (TAC) + MTX (n?=?259). In total, 330 patients received ATG in conditioning. CSA + MTX versus TAC + MTX did not have a significant impact on acute and chronic GVHD, OS, or GRFS in each donor type. The use of ATG in conditioning reduced the risk of grade II-IV acute GVHD in the MSD and UD cohorts (HR 0.42, P?=?0.014, and HR 0.3, P?0.001, respectively); however, a differential impact on GRFS was identified, namely, better GRFS in MSD recipients (HR 0.56, P?=?0.016), but not in UD recipients (HR 1.1, P?=?0.657). In conclusion, CSA + MTX and TAC + MTX were similar as GVHD prophylaxis regardless of the donor type, and ATG in conditioning increased GRFS in MSD transplants, but not in UD transplants.
Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia
Graft-versus-host disease (GVHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation (haplo-HCT) include post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing EBMT registry, we compared ATG versus PTCy based GVHD prophylaxis in adult acute lymphoblastic leukemia (ALL) patients undergoing haplo-HCT. Included were 434 patients; ATG (n=98) and PTCy (n=336). Median follow-up was ~2 years. Baseline characteristics were similar between the groups except that the ATG-group was more likely to have relapsed/refractory ALL (P=0.008), non-TBI conditioning (P<0.001), peripheral blood graft source (P=<0.001) and transplanted at an earlier time-period (median year of HCT 2011 vs. 2015). The 100-day grade II-IV and III-IV acute-GVHD was similar between ATG and PTCy, as was 2-year chronic-GVHD. On multivariate analysis (MVA), leukemia-free survival (LFS) and overall survival (OS) was better with PTCy compared to ATG prophylaxis. Relapse incidence (RI) was lower in the PTCy group (P=0.03), while non-relapse mortality (NRM) was not different. Advanced disease and lower performance score were associated with poorer LFS and OS and advanced disease with inferior GVHD-free/relapse-free survival (GRFS). Peripheral grafts were associated with higher GVHD compared to bone marrow grafts. In ALL patients undergoing unmanipulated haplo-HCT, PTCy for GVHD prevention resulted in lower RI and improved LFS and OS compared to ATG.
Graft-Versus-Host Disease in Multiple Myeloma Patients Treated With Daratumumab After Allogeneic Transplantation
Clinical lymphoma, myeloma & leukemia. 2020
INTRODUCTION Allogeneic hematopoietic cell transplantation (allo-HCT) represents an adoptive immunotherapy strategy for eliciting a graft-versus-myeloma, the effect for high-risk or relapsed multiple myeloma (MM). Allo-HCT recipients are at risk for graft-versus-host disease (GVHD) as well as associated increases in morbidity and mortality. Daratumumab, an anti-CD38 human immunoglobulin G1 kappa humanized monoclonal antibody, is used for treatment of MM. Daratumumab also affects CD38(+) nonmyeloma cells, including T cells, which mediate GVHD. The use of daratumumab after allo-HCT has not been well described, and its potential impact on GVHD is unknown. PATIENTS AND METHODS In a multicenter retrospective study, we evaluated incidence of GVHD in 34 patients with relapsed MM treated with daratumumab after allo-HCT. RESULTS Overall response to daratumumab (partial response or better) was 41% (95% confidence interval, 24-59). Five patients (15%) developed acute GVHD after daratumumab therapy; no chronic GVHD events were observed after daratumumab therapy. One of these 5 patients had a history of chronic GVHD and developed a flare of acute GVHD during daratumumab therapy. The remaining 4 patients did not have a history of GVHD before daratumumab. CONCLUSION The incidence of GVHD after daratumumab was low and did not result in increased exacerbation of GVHD in patients with a history of GVHD.
Effect of donor age and kinship on outcomes in haplo-identical stem cell transplantation may be modulated by GVHD prophylaxis strategies
Bone marrow transplantation. 2020
Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation
The Lancet. Haematology. 2020;7(2):e157-e167
Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.
Posttransplantation cyclophosphamide improves transplantation outcomes in patients with AML/MDS who are treated with checkpoint inhibitors
BACKGROUND There have been concerns regarding increased peritransplantation complications, especially severe acute graft-versus-host disease (aGVHD), in patients with prior use of checkpoint inhibitors (CPI) before hematopoietic stem cell transplantation (HSCT). METHODS The authors performed a retrospective study of 43 patients with acute myeloid leukemia and/or myelodysplastic syndromes who were treated with an antiprogrammed cell death protein 1 (PD-1) (32 patients) or anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (9 patients) blockade or both (2 patients) prior to HSCT with the primary outcome of aGVHD by day 100 after HSCT. Outcome analyses were stratified by GVHD prophylaxis as use of post-HSCT cyclophosphamide (PTCy) (22 patients) or not (non-PTCy) (21 patients). RESULTS The PTCy group demonstrated a trend toward lower grade 3 to 4 aGVHD when compared with the non-PTCy group (5% vs 22%), although the rates of grade 2 to 4 aGVHD were comparable (49% vs 56%). The interval between CPI and HSCT did not appear to impact the incidence of aGVHD. However, a higher incidence of grade 3 to 4 aGVHD was observed in patients who received >4 treatments of CPI prior to HSCT if they were not given PTCy as GVHD prophylaxis (43% vs 12%). Matched control analyses using patients with no prior use of CPI confirmed the increase in grade 3 to 4 aGVHD with those agents. However, that increased risk was limited to patients who did not receive PTCy and was not observed in patients who received PTCy as GVHD prophylaxis. Despite persistent improvement in GVHD with the use of PTCy, disease control was not compromised and progression-free survival at 1 year was found to be superior for patients treated with PTCy compared with those not receiving PTCy among patients with prior use of CPI (55% vs 22%). CONCLUSIONS The results of the current study indicated that HSCT with prior use of CPI appears feasible in patients with acute myeloid leukemia and/or myelodysplastic syndromes and the use of PTCy as GVHD prophylaxis improves outcomes.
Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation
Leukemia & lymphoma. 2020;:1-7
Anti-thymocyte globulin (ATG) has been associated with decreased rates graft versus host disease (GVHD) but with a potential risk of increasing risk of infection and relapse. We retrospectively studied the impact of single dose low dose (2.5 mg/kg) ATG in patients undergoing allogenic hematopoietic cell transplantation (HCT) from 8/8 matched unrelated donors (MUD). Of the total 209 patients identified, 129 received ATG. At baseline, the ATG group had more intermediate and high disease risk index (DRI) (64.6% vs. 54.3%) (28.3% vs. 23.7%) p < .001, respectively, and who received reduced intensity or non-myeloablative conditioning (RIC) (69.0% vs. 47.5%, p .003). There was no significant difference in the overall survival (OS) HR = 1.3, 95% CI [0.99, 1.0], p = .350 or relapse-free survival (RFS) HR = 1.2, 95% CI [0.74, 1.8], p = .526 between the two groups. Patients receiving ATG had a lower incidence of chronic GVHD (cGVHD) (10.1% vs. 25%, p = .007) and less moderate to severe cGVHD (8.5% vs. 25%, p = .002). ATG was associated with a reduced incidence of moderate to severe cGVHD OR = 0.28, 95% CI [0.12, 0.61], p < .01. There was no difference in the incidence of Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) reactivation, CMV disease, invasive fungal infection, or grade III-IV acute GVHD (aGVHD). Our study shows that low dose ATG results in similar OS and RFS with lower rates of cGVHD. Additional prospective studies are needed to confirm these findings.
Post-transplant cyclophosphamide combined with anti-thymocyte globulin for graft-vs-host disease prophylaxis improves survival and lowers non-relapse mortality in older patients undergoing allogeneic hematopoietic cell transplantation
Annals of hematology. 2020
Graft-versus-host disease (GVHD) represents a major contributor to morbidity and mortality in recipients of allogeneic hematopoietic cell transplants (HCT). Several strategies exist for GVHD prophylaxis and include post-transplant cyclophosphamide (PTCY) and anti-thymocyte globulin (ATG). While several groups have described the use of PTCY in younger patients, there is a paucity of data about the efficacy of PTCY in older individuals, particularly when combined with ATG. We investigated the effect of PTCY and ATG combination on transplant outcomes in older patients at Princess Margaret Cancer Centre, Toronto, Canada. Compared to those patients who received other forms of GVHD prophylaxis, individuals who received ATG-PTCY combination had higher 2-year overall survival (OS), 57% (95% confidence interval, 44-69) vs 37% (26-49), P = 0.02; higher 2-year graft-vs-host- and relapse-free survival (GRFS), 27% (17-39) vs 12% (6-21), P = 0.01; lower 2-year non-relapse mortality (NRM), 21% (12-32) vs 45% (33-56), P = 1.00 x 10(-3); lower 100-day incidence of grade 2-4 acute GVHD (aGVHD), 11% (5-21) vs 28% (18-39), P = 0.02; and lower 100-day incidence of grade 3-4 aGVHD, 0% vs 7% (3-15), P = 0.02 without an increase in the 2-year cumulative incidence of relapse (CIR), 31% (20-43) vs 21% (12-32), P = 0.14. Therefore, in older HCT recipients, use of PTCY combined with ATG is associated with improved OS, lower NRM, decreased risk of aGVHD, and improved GRFS without a significant increase in relapse risk. Therefore, the PTCY with ATG combination represents an effective strategy for GVHD prophylaxis in older allogeneic HCT recipients.
Drug monitoring for mycophenolic acid in graft-versus-host disease prophylaxis in cord blood transplantation
British journal of clinical pharmacology. 2020
AIMS: We performed the retrospective analysis to clarify the significance of drug monitoring for mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF), in prophylaxis for graft-versus-host disease (GVHD) in cord blood transplantation (CBT). METHODS We retrospectively analyzed the data of 46 patients who underwent first CBT and received GVHD prophylaxis with tacrolimus plus MMF. MPA levels were measured on days 7 and 21, and 24-hour areas under the curve (AUC0-24 ) were estimated. RESULTS The engraftment and 3-year overall survival rates of all patients were 94% and 78%, respectively. The cumulative incidence of sepsis before engraftment was higher in patients with AUC0-24 on day 7 of > 60 mug h/mL than in other patients (33% vs. 6%, p = 0.02). The cumulative incidence of grade II-IV acute GVHD was higher in patients with AUC0-24 on day 21 of ≤ 30 mug h/mL than in other patients (80% vs. 50%, p = 0.04). The cumulative incidence of human herpesvirus 6 reactivation was higher in patients with AUC0-24 on day 21 of ≤ 48 mug h/mL (median) than in other patients (50% vs. 19%, p = 0.03). CONCLUSIONS Blood level of MPA was associated with the risks of acute GVHD and infection. A prospective trial evaluating the benefit of personalized MMF dosing using MPA levels is needed.
Unrelated donor transplant recipients given Thymoglobuline have superior GRFS when compared to matched related donor recipients transplanted without ATG
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated (URD) and mismatched related donors (MMRD) typically have a higher incidence of acute and chronic graft-versus-host disease (GVHD) compared to matched related donors (MRD). Anti-T-cell globulins (ATG) are often used to reduce GVHD in these recipients. We report the outcomes of 211 adult peripheral blood stem cell transplant recipients with myeloid malignancies who received a standardized transplant protocol, in which ATG (Thymoglobuline 4.5mg/kg) was administered to recipients of URD and MMRD (n=147) but not MRD (n=64) transplant. For all patients, incidence of acute GVHD grades 2-4 was 21.4%, and chronic GVHD was 35.0%. Two-year overall survival was 63.2% (95% CI 55.8%-71.5%), relapse-free survival 55.3% (47.4%-64.6%) and GVHD-free, relapse-free survival (GRFS) was 30.7% (23.2%-40.8%). There were no differences between recipients of MRD and other donors in relapse, non-relapse mortality, overall and relapse-free survival. However, compared to MRD, recipients from URD and MMRD had reduced moderate-severe chronic GVHD (10.4% vs. 30.1%, p=0.002), less chronic GVHD requiring systemic therapy (19.4% vs. 38.9%, p=0.006) and superior 2-year GRFS (35.5% vs. 20.0%, p=0.003). In this retrospective review of non-randomized transplant groups, outcomes of HSCT performed using an URD with ATG during conditioning were superior to transplant from a MRD without ATG. The addition of Thymoglobuline to conditioning in HSCT from MRD should be further examined in prospective trials.
Adult peripheral blood stem cell transplant recipients with myeloid malignancies (n=211)
Patients with a mismatched related donor (MMRD) or unrelated donor (URD), who received anti-T-cell globulins (ATG) (n=147)
Patients with matched related donor (MRD) who did not receive ATG (n=64)
For all patients, incidence of acute GVHD grades 2-4 was 21.4%, and chronic GVHD was 35.0%. Two-year overall survival was 63.2% , relapse-free survival 55.3% and GVHD-free, relapse-free survival (GRFS) was 30.7% (23.2%-40.8%). There were no differences between recipients of MRD and other donors in relapse, non-relapse mortality, overall and relapse-free survival. However, compared to MRD, recipients from URD and MMRD had reduced moderate-severe chronic GVHD (10.4% vs. 30.1%), less chronic GVHD requiring systemic therapy (19.4% vs. 38.9%) and superior 2-year GRFS (35.5% vs. 20.0%).