Randomized phase II trial of extracorporeal phototherapy and steroids vs. steroids alone for newly diagnosed acute GVHD
Bone marrow transplantation. 2021
Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1?mg/kg at day 28 and <0.5?mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n?=?51) or steroids alone (n?=?30). Median age was 54 years (range: 17-75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.
Patients with newly-diagnosed acute graft-versus-host disease (AGVHD, n=81)
Prednisone with extracorporeal photopheresis (ECP, n=51)
Prednisone alone (n=30)
The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively).
Community health status and outcomes after allogeneic hematopoietic cell transplantation in the United States
BACKGROUND The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes. METHODS This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied. RESULTS The median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM. CONCLUSIONS Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.
Molecular disparity in human leukocyte antigens is associated with outcomes in haploidentical stem cell transplantation
Blood advances. 2020;4(15):3474-3485
Haploidentical donors are increasingly used for patients requiring hematopoietic stem cell transplantation (HSCT). Although several factors have been associated with transplant outcomes, the impact of HLA disparity in haploidentical HSCT (haplo-HSCT) remains unclear. We investigated the impact of HLA disparity quantified by mismatched eplets (ME) load of each HLA locus on the clinical outcome of 278 consecutive haploidentical transplants. Here, we demonstrated that the degree of HLA molecular mismatches, at individual HLA loci, may be relevant to clinical outcome in the haplo-HSCT. A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = .003) and class I loci (HR, 0.99; 95% CI, 0.97-0.99; P = .045) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95; 95% CI, 0.92-0.98; P = .004). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19; 95% CI, 0.06-0.59; P = .004) without a concurrent increase in GVHD. These findings indicate that alloreactivity generated by HLA disparity at certain HLA loci is associated with transplant outcomes, and ME analysis of individual HLA loci might assist donor selection and risk stratification in haplo-HSCT.
Patients receiving haploidentical transplantation (n=278)
HLA disparity quantified by mismatched eplets (ME)
A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97) and class I loci (HR, 0.99) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19) without a concurrent increase in GVHD.
Haploidentical Transplants for Patients with Graft Failure After the First Allograft
American journal of hematology. 2020
Cytogenetics and Blast Count Determine Transplant Outcomes in Patients with Active Acute Myeloid Leukemia
Acta haematologica. 2020;:1-8
Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.
Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consistent of both transplant and non-transplant experts was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.
Comparing transplant outcomes in ALL patients after haploidentical with PTCy or matched unrelated donor transplantation
Blood advances. 2020;4(9):2073-2083
We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.
What is known?
Allogeneic stem cell transplant is a potentially curative treatment option for adults with acute lymphoblastic leukaemia (ALL). Transplant outcomes are, amongst other factors, dependent on optimal donor selection; despite a plethora of recent advances, donor availability is an area of unmet need for many patients. A fully HLA matched sibling donor is the preferred donor choice but is available in <30% of patients. Several studies have shown that comparable results can be achieved with a fully matched unrelated donor (MUD), but availability can be as low as 20% in non-Caucasian individuals. Haploidentical donor options are available for the vast majority of patients but historically their utility was limited by high rates of GvHD, treatment related morbidity and mortality and graft rejection. The addition of post-transplant cyclophosphamide (PtCy), calcineurin inhibitors (CNI) and mycofenolate mofetil (MMF) as GvHD prophylaxis has reduced these risks and is now a frequently employed approach for haploidentical haematopoietic stem cell transplant (HaploSCT) making it an attractive alternative to conventional donor transplant.
Several recent studies have compared MUD alloSCT and HaploSCT approaches in ALL in recent years. Most notably this has included an analysis of the European Bone Marrow Transplant (EBMT) group registry which included 1234 patients with ALL and shows comparable outcomes between HaploSCT and MUD alloSCT.
What did this paper set out to examine?
This retrospective multicentre cohort study aims to compare outcomes of HaploSCT & PtCy with MUD alloSCT in ALL in terms of engraftment, acute and chronic graft versus host disease (GvHD) incidence and severity, relapse free survival (RFS), non-relapse mortality (NRM) and overall survival (OS).
It is the first study to explicitly compare haploidentical allogeneic stem cell transplant (HaploSCT) with matched unrelated donor allogeneic stem cell transplant (MUD alloSCT) in terms of conditioning intensity, Philadelphia chromosome status and graft source. It also provides additional extensive, multinational data with matched pair analysis on outcomes of patients in both groups.
What did they show?
The authors compared data from 1461 adult patients (HaploSCT = 487 vs MUD = 974). Data from two separate registries was used: the EBMT registry alone was used for MUD alloSCT while the Haploidentical Transplant and Cellular Therapy Research Consortium (TCT-RC) was used in combination with Acute Leukaemia Working Party subgroup of the EBMT registry data for assessment of HaploSCT. The reason for using two databases is not explicitly stated although it is believed that this was done to increase sample size in the HaploSCT cohort.
Patients >18 years old with ALL over a 13.5-year period from January 2005 to June 2018 receiving their first alloSCT were included in the analysis. Exclusion criteria were fairly selected. GvHD prophylaxis was with PtCy, CNI and MMF in the HaploSCT group and with CNI and methotrexate or MMF in the MUD group. 64% of MUD patients also received ATG. Cohorts were matched at 1:2 (HaploSCT : MUD) for sex, cytogenetic risk, Philadelphia chromosome status, disease stage and intensity of conditioning (reduced intensity vs myeloablative). Statistical analysis was appropriate for the question to be answered.
RESULTS: HaploSCT and MUD alloSCT were comparable in terms of neutrophil engraftment, RFS and OS regardless of conditioning intensity, Philadelphia chromosome status and graft source. 3-year OS was 44% in the HaploSCT group vs 51% in the MUD group using myeloablative conditioning (p=5.56) with rates of 43% (HaploSCT) and 42% (MUD) for reduced intensity conditioning (p=5.6).
The overall incidence of acute and chronic GvHD was similar between the groups but there was an increased incidence in grade III-IV GvHD in HaploSCT when peripheral blood stem cells were used. Additionally, mortality form GvHD was higher in the MUD group. This is in keeping with results reported in the literature.
What are the implications for practice and for future work?
HaploSCT is becoming an increasingly attractive option for patients without matched sibling transplant. The comparable overall survival and now much more manageable GvHD risk will afford a previously difficult to manage cohort of patients a further option of curative treatment.
This study adds to the growing evidence base but did have some limitations. Firstly, the study is retrospective and uses registry-based data. While the registries used are of high quality, there are inherent concerns about missing data points and differences between the two databases used. The authors agreed that the variability of the condition regimes used added a further layer of complexity.
Prospective data with intention to treat analysis is required to further assess the comparability of HaploSCT and MUD for ALL patients.
Adult patients with acute lymphoblastic leukaemia (n=1461)
HSCT from a haploidentical donor (n = 487)
HSCT from a matched unrelated donor (n = 974)
In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88%. The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% for aGVHD and 29% vs 31% for cGVHD; RIC, 31% vs 30% for aGVHD and 24% vs 29% for cGVHD. Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD. Corresponding rates after RIC were 43% and 42%.
Validation of a Hematopoietic Cell Transplant - Composite Risk (HCT-CR) Model for Post Transplant Survival Prediction in Patients with Hematologic Malignancies
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020
PURPOSE Allogeneic hematopoietic stem cell transplantation (AHCT) outcomes depend on disease and patient characteristics. We previously developed a novel prognostic model, hematopoietic cell transplant composite-risk (HCT-CR) by incorporating the refined disease risk index (DRI-R) and hematopoietic cell transplant - comorbidity/age index (HCT-CI/Age) to predict post-transplant survival in patients with AML and MDS. Here we aimed to validate and prove the generalizability of the HCT-CR model in an independent cohort of patients with hematologic malignancies receiving AHCT. MATERIALS AND METHODS Data of consecutive adult patients receiving AHCT for various hematologic maliganacies were analyzed. Patients were stratified into 4 HCT-CR risk groups. The discrimination, calibration performance and clinical net benefit of the HCT-CR model were tested. RESULTS The HCT-CR model stratified patient into 4 risk groups with significantly different OS. Three-year OS was 67.4%, 50%, 37.5% and 29.9% for low, intermediate, high and very high-risk group, respectively (P<0.001). The HCT-CR model had better discrimination on OS prediction when compared with the DRI-R and HCT-CI/Age (C-idindex was 0.69 vs. 0.59 and 0.56, respectively, P<0.001). The decision curve analysis showed that HCT-CR model provided better clinical utility for patient selection for post-transplant clinical trial than the "treat all" or "treat none" strategy and the use of the DRI-R and HCT-CI/Age model separately. CONCLUSIONS The HCT-CR can be effectively used to predict post-transplant survival in patients with various hematologic malignancies. This composite model can identify patients who will benefit the most from transplantation and helps physicians in making decisions regarding post-transplant therapy to improve outcomes.
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.
Idiopathic refractory ascites after allogeneic stem cell transplantation: a previously unrecognized entity
Blood advances. 2020;4(7):1296-1306
At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)-related portal hypertension after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient [HVPG] >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension. From our institutional database, we identified 40 patients who developed IRA after allo-HSCT between 2004 and 2018. The patients' median age at the time of allo-HSCT was 54 years (range, 21-73 years). The median time to development of IRA after allo-HSCT was 80 days (range, 16-576 days). The median number of paracentesis was 3 (range, 1-11), and 15 (38%) patients had an intraperitoneal catheter placed for continued drainage of the rapidly accumulating ascites. Portal pressures were measured in 19 patients; 6 (15%) had moderate portal hypertension (HVPG 6-9 mm Hg), and 13 (33%) had severe portal hypertension (HVPG ≥ 10 mm Hg). Liver biopsy was performed in 24 patients. None of the patients met the criteria for classical VOD/SOS (clinical/histological) or cirrhosis (histological). The cumulative incidence of nonrelapse mortality was 63%, and the median survival duration after the development of the IRA was 7 months (range, 0.8-125.6 months). IRA is a poorly understood and often fatal complication of allo-HSCT.