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.
Post-transplantation cyclophosphamide GvHD prophylaxis after hematopoietic stem cell transplantation from 9/10 or 10/10 HLA-matched unrelated donors for acute leukemia
HLA-matching largely contributes to unrelated donor hematopoietic cell transplantation (UD-HCT) success but, due to the selective deletion of alloreactive T-cells, post-transplantation cyclophosphamide (PTCy) could modulate its negative impact on outcomes. We retrospectively compared acute leukemia patients receiving 10/10 or 9/10 HLA allele-matched UD-HCT with PTCy-GvHD prophylaxis between 2010 and 2017, reported to EBMT registry. The 100-day incidence of grade ≥2 and grade ≥3 aGvHD were comparable for 10/10 and 9/10 UD (28% versus 28%, p = 0.8 and 10% versus 8%, p = 0.5, respectively). The 2-year cGvHD and extensive cGvHD were similar between 10/10 and 9/10 UD (35% versus 44%, p = 0.2 and 21% versus 20%, p = 0.6, respectively). The 2-year nonrelapse mortality was 20% after 10/10 and 16% after 9/10 UD-HCT (p = 0.1). Relapse incidence at 2-year was 24% for 10/10 and 28% for 9/10 UD-HCT (p = 0.4). Leukemia-free survival at 2-year was the same for 10/10 and 9/10 UD (56 and 56%, p = 0.6, respectively), with comparable overall survival (62 and 59%, p = 0.9, respectively). Multivariate analysis showed no effect of HLA-matching on outcomes. An advanced disease status and patient disability remained the most important factors portending a worse survival. PTCy could alleviate the detrimental effect of HLA-allele mismatching in UD-HCT, potentially expanding the donor pool for acute leukemia patients.
Acute leukemia patients receiving unrelated donor HSCT with PTCy-GvHD prophylaxis between 2010 and 2017 reported to EBMT registry (n=464)
10/10 allele-matched unrelated donor (n=305)
9/10 allele-matched unrelated donor (n=159)
The 100-day incidence of grade >/=2 and grade >/=3 aGvHD were comparable for 10/10 and 9/10 UD (28% versus 28% and 10% versus 8%, respectively). The 2-year cGvHD and extensive cGvHD were similar between 10/10 and 9/10 UD (35% versus 44%, and 21% versus 20%, respectively). The 2-year nonrelapse mortality was 20% after 10/10 and 16% after 9/10 UD-HCT. Relapse incidence at 2-year was 24% for 10/10 and 28% for 9/10 UD-HCT. Leukemia-free survival at 2-year was the same for 10/10 and 9/10 UD (56 and 56%, respectively), with comparable overall survival (62 and 59%, respectively). Multivariate analysis showed no effect of HLA-matching on outcomes. An advanced disease status and patient disability remained the most important factors portending a worse survival.
Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT
Journal of hematology & oncology. 2020;13(1):46
BACKGROUND The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. There is no information on the impact of donor types using homogeneous prophylaxis with PTCy. METHODS We retrospectively compared outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n = 215), MUD (n = 235), and Haplo (n = 789) donors registered in the EBMT database between 2010 and 2017. RESULTS The median follow-up was 2 years. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) and NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no differences in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). Interestingly, the use of peripheral blood was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). CONCLUSIONS The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD, and Haplo is safe and effective. Haplo-SCT had increased risk of acute GVHD and NRM and lower relapse incidence but no significant difference in survival.
Comparison of Haploidentical Bone Marrow versus Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Post-transplant Cyclophosphamide in Patients with Acute Leukemia
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020
BACKGROUND Post-transplant cyclophosphamide (PTCy) is increasingly being utilized as a principle graft-versus-host disease (GvHD) prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) are valid options in the absence of a matched related donor. EXPERIMENTAL DESIGN We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N=401) versus UD mobilized peripheral blood stem cells (UD-PB, N=192) transplantation in the setting of PTCy. RESULTS The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (p<0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (p<0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (p =0.21). In the multivariate analysis, the risk of grade II-IV acute GvHD (HR=0.53, p=0.01) and chronic GvHD (HR=0.50, p=0.02) was significantly lower in the haplo-BM group compared to the UD-PB group. There was no significant difference between the study groups, with respect to relapse incidence, non-relapse mortality, leukemia-fee survival, overall survival or, GvHD-free, relapse-free survival. CONCLUSION The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared to a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into the difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.
Patients with acute leukaemia (n=593)
Haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PTCy) (haplo-BM, n=401)
Matched unrelated donor transplantation with mobilised peripheral blood stem cells (UD-PB, n=192)
The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively. Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively. Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively. In the multivariate analysis, the risk of grade II-IV acute GvHD and chronic GvHD was significantly lower in the haplo-BM group compared to the UD-PB group. There was no significant difference between the study groups, with respect to relapse incidence, non-relapse mortality, leukemia-fee survival, overall survival or, GvHD-free, relapse-free survival.
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%.
Post-transplantation cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation from HLA-identical sibling donors: A retrospective analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
BACKGROUND Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Addition of antithymocyte globulin (ATG) or post-transplantation cyclophosphamide (PTCY) to standard immunosuppressive agents reduces GVHD in different donor settings. METHODS We compared the outcomes of adults with acute myeloid leukemia undergoing allo-HSCT from HLA-identical sibling donors after the use of PTCY (n = 197) or ATG (n = 1913). RESULTS Patients in the PTCY group were younger than those in the ATG group (median age, 47 vs 54 years; P < .01). Peripheral blood was the most frequently used stem cell source, being significantly more frequent in the ATG group than in the PTCY group (95% vs 70% P < .01). The conditioning regimen was more frequently myeloablative in the PTCY group than in the ATG group (59% vs 48%; P < .01). Time to neutrophil engraftment was shorter in the ATG group than in the PTCY group (17 vs 20 days; P < .01). No differences were observed according to the other transplantation outcomes, except for chronic GVHD of all grades and extensive chronic GVHD at 2 years, which were significantly lower in the ATG group compared with the PTCY group (P < .02). CONCLUSION PTCY is feasible in an HLA-identical sibling setting, and despite similar outcomes, ATG may be associated with lower incidence of chronic GVHD.
Haploidentical transplant with post-transplant cyclophosphamide for T-cell acute lymphoblastic leukemia: a report from the EBMT acute leukemia working party
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients with no HLA identical donor, haploidentical transplantation (haplo-HCT) is becoming the leading source of stem cell donation. However, data is scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age 31 years; range 18-68) with T-ALL who received a haplo-HCT with post-transplant cyclophosphamide (ptCy) between 2010 and 2017. Median follow-up of living patients was 23 months. The 2-year relapse incidence and non-relapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 34%, 42% and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplant, being 49% and 55% respectively for first complete remission (CR1), 34% and 50% respectively for CR2, 8% and 12% respectively for patients with active disease. On multivariate analysis, only disease status affected LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in CR. Despite the limitation of the small sample size, results were not affected by the type of conditioning, questioning the need for total body irradiation based-myeloablative conditioning (TBI-MAC) in that setting.
Adults with T cell acute lymphoblastic leukaemia (n=122)
Haploidentical transplantation with post-transplant cyclophosphamide (ptCy)
The 2-year relapse incidence and non-relapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 34%, 42% and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplant, being 49% and 55% respectively for first complete remission (CR1), 34% and 50% respectively for CR2, 8% and 12% respectively for patients with active disease. On multivariate analysis, only disease status affected LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at haplo-HCT negatively affected LFS and OS.
Outcome of Patients with Fanconi Anemia developing myelodysplasia and acute leukemia who received Allogeneic Hematopoietic Stem Cell Transplantation: A retrospective analysis on Behalf of EBMT group
American journal of hematology. 2020
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured. This article is protected by copyright. All rights reserved.
Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT)
Bone marrow transplantation. 2020
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman-Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I-IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8-10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8-73.4) and 19.8% (95% CI 10.8-30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.
Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study
Bone marrow transplantation. 2020
Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.