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Single Cord Blood Transplantation Versus HLA-Haploidentical Related Donor Transplantation Using Post-Transplant Cyclophosphamide in Patients with Hematological Malignancies
Abstract Introduction: Unrelated cord blood (UCB) and haploidentical related donor transplantation using post-transplant cyclophosphamide (PTCy-haplo) have become alternative options to treat patients with hematological malignancies without a human leukocyte antigen (HLA)-matched donor. Although a previous phase III study showed better outcomes after bone marrow transplantation (BMT) using PTCy-haplo than those after double unit UCB, a donor selection algorithm including peripheral blood stem cell transplant (PBSCT) using PTCy-haplo or high-risk patients remains to be clarified. With the aim to assess the relative efficacies of UCB and PTCy-haplo transplant, we performed a multi-center retrospective analysis to compare the clinical outcomes in patients with hematologic malignancies. Methods: We included 517 patients aged 16 years to 70 years with hematological malignancies who received a first stem cell transplantation using a single UCB unit or PTCy-haplo between 2013 and 2019 in Kyoto Stem Cell Transplantation Group (KSCTG), which is a multi-center group of 18 transplantation centers in Japan. The primary endpoint was to compare overall survival (OS) between the UCB and PTCy-haplo groups. Secondary endpoints were relapse-free survival (RFS), GVHD- and relapse-free survival (GRFS), relapse, non-relapse mortality (NRM), neutrophil engraftment, platelet engraftment, grade II-IV acute graft-versus-host disease (GVHD), grade III-IV acute GVHD, chronic GVHD, and extensive chronic GVHD. Results: Among 517 patients, 460 received single UCB transplant and 57 received PTCy-haplo related donor transplant (53 PBSCT and 4 BMT). The median age of the UCB and PTCy-haplo groups was 55 and 52 years, respectively (P= 0.770). Myeloablative conditioning (MAC) was used more often in the UCB group than in the PTCy-haplo group (P< 0.001). In the PTCy-haplo cohort, the total dose of Cy was 80mg/m 2 (43.9%) or 100mg/m 2 (56.1%), and the median duration of tacrolimus and mycophenolate mofetil use was 173 and 34 days, respectively. The median follow-up periods of survivors were 2.2 and 2.4 years, respectively. OS in the UCB group was comparable to that in the PTCy-haplo group (2-year OS; 53.7%, 53.6%, P= 0.71 and adjusted hazard ratio (aHR) 1.00, P= 0.99), with similar risks of relapse (aHR 0.91, P= 0.99) and NRM (aHR 0.93, P= 0.69). This result was consistent regardless of disease risk. Neutrophil and platelet engraftment were significantly lower (92.2% vs 94.7%, P= 0.042 and 79.8% vs 82.5%, P= 0.003) and the incidence of acute GVHD in the UCB group tended to be higher (gradeⅡ-Ⅳ; aHR 1.64, p= 0.055, grade III-IV; aHR 3.60, P= 0.073) in the UCB group than those in the PTCy-haplo group. However, the incidences of chronic or extensive chronic GVHD after UCB transplant were comparable (chronic; aHR 0.89, p=0.68, extensive chronic; aHR 0.69, P= 0.35) to those after PTCy-haplo transplant. In the subgroup analysis of disease-specific comparison, acute leukemia patients have a significantly lower risk of relapse with UCB transplant (UBC vs PTCy-haplo, HR 0.55, P= 0.030) and lymphoma patients tended to have good results after PTCy-haplo transplant in terms of higher OS (UCB vs PTCy-haplo, aHR 2.13, P= 0.162) and lower relapse (aHR 3.43, P= 0.100). In terms of Cy toxicity in the PTCy-haplo group, transplant with a reduced dose of Cy (80 mg/m 2) tended to show higher OS (2-year OS, 64.8% vs 45.0%) and significantly lower NRM (2-year NRM, 8.0% vs 31.2%) without an increase in gradeⅡ-IV acute GVHD compared to those after standard-dose Cy (100 mg/m 2). Conclusion: Our findings suggest that UCB transplant gives outcomes comparable to PTCy-haplo transplant for patients without an HLA-matched sibling or unrelated donor. Disclosures Kanda: Amgen Astellas BioPharma: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; NextGeM Inc: Patents & Royalties; Novartis Pharma K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMITED.: Honoraria. Imada: Celgene Co., Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co. Ltd.: Honoraria; Takeda Pharmaceutical Co. Ltd.: Honoraria; Novartis Pharma K.K.: Honoraria. Kondo: Asahi Kasei Pharmaceutical: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Chugai Pharma: Honoraria; MSD Pharmaceutical: Honoraria; Sumitomo Dainippon Pharma: Honoraria. Takaori-Kondo: Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding.
Abstract Introduction: High-dose post transplant cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplant (HSCT) and offer low rates of GVHD in the setting of HLA identical transplant. The objective of our study was to compare the outcomes of haplo vs HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. Patients and methods: We conducted a retrospective study of 229 patients undergoing a first HSCT for AML using PTCY, 130 from an haploidentical donor between 2013 and 2018 (median follow up 62.5 months) and 99 from a matched sibling (MSD) (n=38) or unrelated donor (MUD) (n=61) (median follow up 27 months) between 2013 and 2019, in 20 centers in Spain. Last update of the cohort was performed in March 2021. Results: Baseline characteristics are summarized in Table 1. There were more patients with active disease at transplant (5% MSD/MUD vs. 20% haplo, p=0.001), high/very high DRI (32% vs. 67%, p=0.000) and prior autologous HSCT (2% vs. 11%, p=0.010) in the haplo group. Mobilized peripheral blood stem cells was the most frequent stem cell source in both groups. Most patients received myeloablative conditioning (55% vs. 64%, p=0.170). All Patients in the haplo group received PTCY days +3+4 followed by a calcineurin inhibitor (CNI) and MMF from +5. In the MSD/MUD group, 37% received both CNI+MMF, 33% only CNI and 30% PTCY with sirolimus+MMF (this group included only MUD donors). None of the patients received ATG. Cumulative incidence of neutrophil recovery at day 28 was 97% in both groups, with a median of 16 and 17 days respectively (p=0.948). Both 2-year overall survival (OS) (72% vs. 62%, p=0.07) and event-free survival (EFS) (70% vs. 54%, p=0.055) were higher in the MSD/MUD group, but the difference was not statistically significant (Figure 1). Multivariate analysis only identified age and pre-transplant status as independent risk factors for OS, and pre-transplant status for EFS. No differences were found in the cumulative incidence of relapse at 2 years (19% vs. 25%, p=0.13) and non-relapse mortality (14% vs. 19%, p=0.145). Cumulative incidence of grade II-IV acute GVHD was lower in MSD/MUD (14% vs. 47%, p=0.000, Figure 2), while III-IV aGVHD was similar (4% vs. 9%, p=0.14). Cumulative incidence of chronic GVHD and moderate-severe cGVHD at 2 years was similar for both groups (42% vs. 33% (p=0.051); 22% vs. 19% (p=0.28)). No differences were found in GRFS (48% vs. 46% (p=0.506)). Most frequent cause of death in the early post-transplant period was non-GVHD related infection in both groups. Conclusions: in our experience, PTCY as GVHD prophylaxis in both MSD/MUD and Haplo transplant in AML using mostly PBSC effectively prevents GVHD and offers similar NRM, relapse and survival rates. Poor control of the disease before transplant was the only factor affecting OS and EFS in this setting. Prospective studies are needed to confirm our results. Figure 1 Figure 1. Disclosures Bailen: Pfizer, Kite-Gilead, Gilead: Honoraria. Guerreiro: Novartis, Gilead: Consultancy, Honoraria. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.
Background: The use of post-transplant cyclophosphamide (PTCy)/tacrolimus/mycophenolate mofetil (MMF) for GVHD prophylaxis has improved outcomes in haploidentical hematopoietic cell transplantation (haplo-HCT). PTCy is now being evaluated in matched-related (MRD) and matched-unrelated (MUD) allo-HCT. Previous studies demonstrated improved GVHD-free/relapse-free survival (GRFS) when PTCy was combined with two immunosuppressive agents and PTCy has also been associated with better relapse-free survival (RFS) as demonstrated in De Jong et al 2019, though only one immunosuppressive agent was used. Currently, there is limited published data comparing outcomes using PTCy/tacrolimus/MMF to standard MRD/MUD GVHD prophylaxis of methotrexate (MTX)/tacrolimus. The importance of studying this comparison may help to improve GVHD outcomes in MRD and MUD allo-HCT. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 19) who received allo-HCT from 2018 to 2020. The primary end-points assessed were incidence and severity of 1-year aGVHD and cGVHD. Secondary end-points included day+100 mortality, 1-year overall survival (OS), 1-year RFS, 1-year transplant-related mortality (TRM), and 1-year GRFS, defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the 1-year post-HCT period. Results: A total of 65 adult MRD and MUD allo-HCT recipients and 53 haplo-HCT patients were reviewed. Of the MRD/MUD patients evaluated, approximately 51% (n = 33) were female and 49% (n = 32) were male. The age range was 20-69 years old (median = 46), and the most common diseases included ALL (46%), AML (31%), MDS (11%), and others (i.e. lymphoma, aplastic anemia (AA), myelofibrosis) (12%). 34% (n = 22) of patients received PTCy on D+3 and D+4 with tacrolimus/MMF/ on D+5 as GVHD prophylaxis and 66% (n = 43) of patients received MTX/tacrolimus on D+1, +3, +6, and +11 as GVHD prophylaxis. All haplo-HCT patients received standard PTCy/tacrolimus/MMF. Stem cell source was primarily PBSC except in HLH and AA patients. The PTCy group had more MUD allo-HCT (64%), degree of antigen mismatch (56%), and median age of 50.5 years compared with the MTX group at 44%, 47%, and 44 years respectively. 70% in the MTX group received MAC compared with 45% in the PTCy group. The haplo group had similar demographics to the MTX group. The mean CD34 cell doses in the PTCy, MTX, and haplo groups were 4.87, 5.36, and 7.24x106 cells/kg respectively. Incidences of total GVHD, aGVHD, and aGVHD grade 3 or 4 in the PTCy group were 55%, 50%, and 4.5% respectively compared with 65%, 35%, and 7% in the MTX group, though not significant. The haplo group had 68%, 55%, and 1.9% respectively. Incidence of total cGVHD and cGVHD requiring systemic therapy in the PTCy group was 4.5% and 0% respectively compared with 30% (p = .02) and 23% (p =.01). The haplo group had 13% and 1.9% respectively. Day+100 mortality, 1-year OS, 1-year RFS, 1-year TRM, and 1-year GRFS in the PTCy group were 0%, 80%, 60%, 0%, and 64% respectively compared with 7%, 88%, 90%, 7.3%, and 59%. The haplo group had 3.8%, 86%, 89%, 14%, and 66%. In a univariate analysis, factors significantly associated with GVHD were disease status (p = .0.12) and CD34 dose (p = 0.015) and antigen mismatch (p = 0.04) was associated with increased mortality. Discussion: Our results demonstrate improved overall and extensive cGVHD outcomes in the PTCy group and thus an improvement in 1-year GRFS. Furthermore, incidence and severity of 1-year cGVHD in this group are improved when compared with previously reported outcomes. 1-year GRFS reported in De Jong et al 2019 was 45% and 1-year GRFS reported for all groups in our study is higher at 66%, 64%, and 59% for the haplo, PTCy, and MTX groups respectively. Although this was not significant, it may be clinically meaningful given the significant improvement in extensive GVHD and improvement in all other secondary end-points except 1-year OS and RFS. Furthermore, the PTCy group had a higher percentage of mismatched antigens yet demonstrated superior outcomes. 1-year OS and RFS were superior in the MTX group however this is likely due to sample size differences. The improved extensive cGVHD and GRFS outcomes observed using PTCy/tacrolimus/MMF in the MRD/MUD setting should continue to be evaluated and currently there is an ongoing prospective, randomized study to further investigate. Disclosures Yaghmour: Jazz: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Background Allogeneic stem cell transplantation (Allo-SCT) from a matched related donor (MRD) is rarely performed for older patients because of lack of such a donor. Matched unrelated donor (MUD) is considered as an alternative for this population with limited access due to excessive expected toxicity. Recently, the development of allo-SCT from haploidentical donors (Haplo) with the use of high dose post-transplant cyclophosphamide showed promising results with outspreading diffusion despite HLA disparity. Donor search is early implemented when patients are referred to transplant team. The impact of this strategy on patients with high risk malignancies outcomes is not well known. We propose to address this question through an intention-to-treat trial. We also hypothesized that Haplo-SCT could be a valid alternative to MUD-SCT for older patients with hematological disease whenever allo-SCT is recommended. Study design and methods We performed a prospective, multicenter, open-label, randomized controlled trial (NCT02623309) comparing two strategies of allo-HSCT from UD or Haplo. Patients older than 55 years with hematological malignancies were randomly assigned to a Haplo and a MUD search soon after the absence of MRD was established. The goals of the study were to prospectively evaluate feasibility, safety and efficacy of these approaches in an intent-to-treat analysis and a HSCT-performed analysis. Results From February 2016 to June 2018, 108 patients were enrolled. One hundred and six patients were analyzed. Median age was 65 years (range 55-70). Diseases were myeloid malignancies in 84 patients (79%).DRI was low, intermediate and high in 5(5%), 59(55%) and 42(40%),respectively. Fifty-five patients were assigned to Haplo group and 51 patients to MUD group. Fifteen patients in Haplo group could not proceed to allo-SCT because of progression (n=9), contraindication (n=5), no donor (n=1) and 14 patients in MUD group because of progression (n=8), contraindication (n=4) and loss of indication (n=2). Among 40 patients in Haplo group, 9 patients (22%) actually received allo-SCT from MUD because of donor contraindication (n=6), donor specific antibodies (n=1), no Haplo identified (n=2). Eleven patients out of 37 patients (30%) in MUD group received allo-SCT from Haplo because of no MUD identified (n=7), donor refusal (n=2), donor contraindication (n=1), excessive search delay to identify a MUD (n=1). After cross over, 42 and 35 patients actually underwent per protocol allo-HSCT from a Haplo and a MUD, respectively. Median time from randomization to allo-SCT was 3 months (range 0.7-10). In intention-to-treat analysis from date of randomization, 2-year PFS and OS did not differ between the two groups (Haplo vs MUD arm: PFS: 42 vs 48 %, p=0.463; OS: 44 vs 61%, p=0.126). Non-relapse mortality (NRM) at 2 years was 31% for both groups while the 2-year cumulative incidence of relapse (CIR) was 14% and 18 % (p=0.99) after Haplo and MUD arm, respectively. In per-protocol analysis, with a median follow up of 26 months (range 3-34) after transplant 2-year NRM was 37% and 35% (p=0.893) after Haplo and MUD SCT, respectively. The cumulative incidence of grades 3-4 acute GVHD at 100 days was 21% and 17% (p = 0.402) in the Haplo and MUD SCT, respectively. No difference was observed in 2-year extensive chronic GVHD (Haplo vs MUD: 10% vs 15%, p = 0.534). 2-year CIR was 17% and 18% (p=0. 952) after Haplo and MUD SCT, respectively. No significant difference in 2-year PFS (Haplo vs MUD: 46% vs. 47%, p = 0.948) and OS (Haplo vs MUD: 55% vs. 52%, p = 0.944) was observed. Conclusion In an intent-to-treat analysis from the time of randomization, outcomes do not differ between the 2 groups. However, we observed that almost half of the patients did not receive the randomly attributed treatment 1/ Twenty-nine (27%) patients did not succeed to go to transplant 2/ Twenty (19%) patients were transplanted from another donor source that the one initially randomized to. It notably indicates that defining an early donor choice may be somehow dogmatic and should invite to more flexibility. We were able to demonstrate for older patients with high risk malignancies (IR: 17% Haplo; 18% MUD) a good disease control. Our per protocol analysis prospectively confirm in randomized study that Haplo-HSCT is a valid alternative in older patients. This suggests that HLA matching should not be necessarily considered as the most important factor for donor choice Disclosures Harbi: Sanofi: Honoraria. Chevallier:Incyte Corporation: Honoraria. Malard:JAZZ pharmaceutical: Honoraria; Astellas: Honoraria; Theralos/Mallinckrodt: Honoraria; Keocyt: Honoraria; Sanofi: Honoraria; Biocodex: Honoraria; Janssen: Honoraria. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Rubio:Neovii: Research Funding; Novartis: Honoraria; MSD: Honoraria; Gilead: Honoraria; Medac: Consultancy. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Blaise:Jazz Pharmaceuticals: Honoraria.
Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) has evolved as a curative therapy for various hematological malignancies. Regimen-related toxicity and transplant-related mortality (TRM) preclude the use of myeloablative conditioning (MAC) regimens in older and unfit patients. Reduced intensity conditioning (RIC) regimens have enabled AHSCT in such patients. There is a recent rise in use of RIC regimens even in younger patients in view of decreased toxicity and equal efficacy as reported in some studies. Fludarabine + Melphalan (FM) and Fludarabine + Treosulfan (FT) are 2 such regimens. There are no prospective randomised comparisons between these regimens. We retrospectively analysed these 2 regimens for toxicities and outcomes. Methods This is a retrospective single centre analysis of all consecutive patients with haematological cancers who received either FM or FT from April 2008 to December 2018. The entire cohort was divided into two groups - Matched Sibling Donor (MSD)/Matched Unrelated Donor (MUD) and Haploidentical (Haplo) transplants for analysis. We compared patient characteristics, toxicities and outcomes in both the groups based on conditioning regimen. The FT regimen consisted of fludarabine (30 mg/m2 on days − 6 to − 2) combined with treosulfan (12-14 gm/m2 on days − 6 to − 4) with or without 2 Gy TBI on day-1. The FM regimen consisted of fludarabine (30 mg/m2 on days − 7 to − 3) combined with melphalan (140 mg/m2 on day -1).Prophylaxis for GVHD consisted of calcineurin inhibitor (CNI) plus methotrexate (MTX)or mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide with CNI and MMF. Comorbidities were scored according to the HCT-CI. Disease Risk Index(DRI) and EBMT score were recorded for all patients. Neutrophil (NE) and platelet engraftment (PE) were defined as per standard criteria. Early toxicity after AHCT was graded according to CTCAE version 4. Total parenteral nutrition (TPN) was used in patients as per the physician's discretion. Acute GVHD and chronic GVHD were recorded according to standard criteria. All patients underwent chimerism studies at day 15, 30 and then monthly for 1 year. Mixed chimerism was defined as > 5% to < 95% donor chimerism. The toxicities in various arms were compared by Chi-square test or Fisher exact test, while OS was calculated by Kaplan Meier method and the survival probabilities were compared using log-rank test. Competing risk analysis was used to calculate cumulative incidence of relapse and TRM. Results The study included 138 patients, 98 males and 40 females. The diagnoses were AML- 53, ALL- 30, MDS/MPN- 49 and lymphoma -6. Patient characteristics are outlined in Table 1. MSD/MUD transplants were 105 (FM- 94; FT-11); 33 were Haplo (FM-17; FT-16) transplants. PBSC was the stem cell graft in 136 (99%) patients. In both MSD/MUD and Haplo groups, there were no significant differences in median age, gender, pre transplant CMV status, HCT-CI and EBMT score between the two conditioning regimens. In MSD/MUD group, significantly more patients had high/very high DRI in FT arm (45% vs 17%; P=0.056) Comparison of engraftment and toxicity variables of both FM and FT arms are outlined in Table 2. In MSD/MUD group, 44 (47%) patients in FM arm had grade 3/4 oral mucositis compared to 1 (9%) in FT arm (P=0.02). Corresponding numbers were 7 (41%) and 1 (6%) in Haplo group (P=0.039). Grade 3/4 diarrhoea was higher in the FM vs FT arm of Haplo group (41% vs 6%; P=0.039) but not in the MSD/MUD cohort. More patients received TPN in the FM arms of both MSD/MUD and Haplo groups (Table 2). Incidence of grade III-IV acute GVHD was higher in FT vs FM in MSD/MUD group (27% vs 17%; P=0.04). The median follow up of entire cohort was 4.8 years. The OS (figure 1) at 5 years was 62% in FM arm of MSD/MUD group vs 53% in FT arm (P=NS). Similarly OS (figure 2) at 5 years was 41% and 28 %( P=NS) in FM and FT arms respectively of Haplo group. The cumulative incidence of TRM and relapse at 2 years were not different in FM and FT arms of both MSD/MUD and Haplo groups (Table 2). Conclusion Grade 3 and 4 oral mucositis and diarrhoea were significantly less with FT than FM in both MSD/MUD and Haplo groups. FT provided comparable outcomes to FM in the MSD / MUD group in spite of having higher proportions of patients with high / very high DRI. Prospective randomised studies are required to compare various RIC regimens. Disclosures No relevant conflicts of interest to declare.
Abstract Objectives Both haplo-identical transplant (haplo) and umbilical cord transplant (UC) are valuable graft options for patients without available matched relative. Previous studies showed inconsistent outcomes comparing Post transplant Cyclophosphamide based haplo (PTCy-haplo) and UC; therefore, we attempt to compare the studies by mean of meta-analysis. Methods We searched for titles of articles in MEDLINE (PubMed), Cochrane library, EMBASE database and Google scholar that compared transplantation with PTCy-haplo versus UC. We conducted a random-effect meta-analysis of seven studies involving a total of 3434 participants and reported the pooled odd ratios (OR) of acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), relapse and overall survival (OS) between PTCy-haplo and UC groups. Results We found a significantly decreased risk of aGVHD and relapse in the PTCy-haplo group compared to the UC group with a pooled OR of 0.78, 95% Confidence Interval (CI) 0.67-0.92, I2=0%, and 0.74, 95% CI 0.57–0.97, I2=23.9% respectively. We also found a significantly increased rate of cGVHD and OS with a pooled OR of 1.41, 95% CI 1.02–1.95, I2=56.8%, and 1.77, 95% CI 1.1–2.87, I2=82.5%, respectively. Conclusion Our meta-analysis of clinical trials demonstrated superior outcome from PTCy-haplo group compared to the UC group in terms of decreased rate of aGVHD and relapse as well as the increased rate of OS but inferior in terms of increased cGVHD risk compared to UC transplant.
Abstract Introduction: Haploidentical related donor (Haplo) and umbilical cord blood (UCB) stem cell sources represent common alternative donor strategies used when a matched sibling donor or matched unrelated donor is not available for hematopoietic stem cell transplantation (HSCT). The aim of this study was to compare the results of graft source on outcome of children and adolescents with hematologic malignancies after Haplo and UCB transplantation in the setting of targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic (PK) monitoring. Patients and methods: We retrospectively analyzed outcomes in 140 pediatric patients with hematologic malignancies who received allogeneic HSCT from Haplo donors (n=36), UCB (n=24), and unrelated donors (n=80) in Seoul National University Children's Hospital from January 2009 to February 2018. Because UCB transplantation had been conducted until 2016 while Haplo transplantation using posttransplantation cyclophosphamide (PTCy) was started from 2014 in our institution, differences over time of HSCT must be considered to compare them. Therefore, unrelated HSCT group was divided into Unrelated A group (n=51) who received HSCT from 2009 to 2013 and Unrelated B group (n=29) from 2014, which were compared first with the purpose of using them as a control to compare Haplo and UCB groups. Patients who received the first allogenic HSCT using an intensive PK monitoring, targeted busulfan-based myeloablative conditioning were included. The majority of UCB and unrelated groups received busulfan, fludarabine ± etoposide regimen with antithymocyte globulin. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine and mycophenolate mofetil were used in UCB group while tacrolimus and methotrexate in unrelated groups. Busulfan, fludarabine and cyclophosphamide with PTCy, tacrolimus and methotrexate for GVHD prophylaxis were used in Haplo group. Results: First of all, Unrelated A group was compared to Unrelated B group. The median follow-up time were 5.7 years (0.2-9.5) and 1.8 years (0.3-4.5) in the Unrelated A and Unrelated B groups, respectively. The event-free survival (EFS) rates at 2 years (78.1±5.8% versus 72.3±9.1%, P=0.917) and overall survival (OS) rates at 2 years (83.7±5.3% versus 77.8±9.1%, P=0.874) in Unrelated A and B groups were similar. Under the assumption that there was no significant survival difference over time of HSCT from 2009 to 2013 and that from 2014 in our institution, the outcomes of Haplo and UCB groups were compared subsequently. The median follow-up time were 4.8 years (0.1-9.3) and 1.8 years (0.3-4.5), respectively. The median time to neutrophil and platelet recovery were 15 days (13-21) versus 14 days (12-40) (P=0.059), and 27 days (13-71) versus 46 days (21-77) (P<0.001) in Haplo and UCB groups, respectively. Engraftment failure occurred in 1 patient of UCB group. The cumulative incidence (CI) rates of acute GVHD grade II-IV, grade III-IV, and extensive chronic GVHD in Haplo and UCB groups were 38.9% versus 54.2% (P=0.479), 2.8% versus 29.2% (P=0.004), and 11.7% versus 12.5% (P=0.906), respectively. The CI rates of nonrelapse mortality were significantly lower in Haplo group (0% versus 33.6%, P<0.001), while the relapse incidences were not different (18.3% versus 8.6%, P=0.272). The event-free survival (EFS) rates at 2 years (79.3±7.0% versus 54.2±10.2% %, P=0.034) and overall survival (OS) rates at 2 years (85.8±6.7% versus 65.7±9.9%, P=0.029) in Haplo and UCB groups were significantly different. Conclusion: In this study, the CI rates of nonrelapse mortality and acute GVHD III-IV was lower in Haplo group than in UCB transplants, which translates into a better EFS and OS rate in Haplo group. Our results suggest that haploidentical HSCT with PTCy using intensive PK monitoring, targeted busulfan-based myeloablative conditioning regimen is a safe and promising alternative option for patients with hematological malignancies who lack an HLA-matched donor. Disclosures No relevant conflicts of interest to declare.
Abstract Posttransplant cyclophosphamide (PTCy) is an effective prophylaxis for both acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We recently studied the immune reconstitution dynamics of each lymphocyte subset after PTCy-based transplant using murine haploidentical BMT model and reported that PTCy strongly promoted Treg-dominant T-cell reconstitution and stem cell-derived mature B-cell generation with broad BCR-diversity. We also found that the early reconstitution of Treg could contribute to promote naïve B cell emergence from bone marrow, indicating the T and B cell recovery might be mutually coordinated after PTCy-based transplant (Iwamoto et al, ASH2017). However, the detailed process of immune reconstitution in patients after haploidentical HSCT with PTCy has not been well studied. To address this issue, we here investigated the early dynamics of donor-lymphocyte subset chimerisms in patient after clinical PTCy-based haploidentical HSCT with comparing those in patients after low-dose ATG-based haploidentical HSCT and patients after cord blood transplantation. Laboratory studies were undertaken in 13 adult patients who received HLA-mismatched allogeneic graft; unrelated cord blood (n=5), and haploidentical related peripheral blood after ATG-based conditioning (n=5) and haploidentical related peripheral blood after PTCy-based conditioning (n=5). Blood samples were obtained before and at 1, 2, 4, 6 and 8 weeks after HSCT. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples by density gradient centrifugation and cryopreserved before being analyzed. After thawing, to analyze the subset-specific chimerism, PBMCs were stained with anti-HLA monoclonal antibodies and other subset-specific antibodies as follows: Pacific Blue conjugated anti-CD4, eFluor450 conjugated anti-CD3, PE-Cy7 conjugated anti-CD25, anti-CD14, APC conjugated anti-CD127, anti-CD56, and APC-eFluor780 conjugated anti-CD8a, anti-CD19. Gated lymphotes (CD4+Tcons, CD4+Tregs, CD8+T cells, B cells, NK cells, Monocytes) were analyzed their chimerism by flowcytometry. To examine the detailed phenotype of B cells, the expression of CD27, CD24, CD38 and IgD were tested. Flowcytometry-based method enables us to analyze the lymphocyte subset chemerism in the very early phase after HSCT. At 2 weeks after HSCT, our analysis revealed that CD4+Tcons, CD4+Tregs and CD8+T cells had already achieved complete donor chimerisms (>95% in all subsets) in patients after ATG-based SCT and had been approaching complete donor chimerisms (85.8%, 75.4% and 87.2%, respectively) in patients after CBT. In contrast, percentage of donor chimerisms of CD4+Tcons, CD4+Tregs and CD8+T cells after PTCy-based haplo-SCT was 73.5%, 59.6% and 59.2%, respectively, and those remained to be in the lower levels than other 2 groups. However, at 4 weeks after HSCT, all examined patients achieved complete donor chimerism of T cells, NK cells and Monocytes (>90%). At 8 weeks after HSCT, the number of B cells in PTCy-based haplo-group was higher than in ATG-based haplo-group (3494 vs 1901/mm3). Of note, B cell population in PTCy-based haplo-group at 8 weeks contained the significantly higher percentage of CD24+CD27-IgD+CD38+ transitional/naïve subset and the significantly lower percentage of CD24+CD27+IgD-CD38neg/dim activated/switched-memory subset when compared to B cell population in ATG-based haplo-group (59.9% vs 10.2%, 2.6% vs 21.5%, P<0.02 respectively), suggesting PTCy treatment might be associated with the favorable B cell reconstitution with naïve-subset dominant composition. Moreover, in patients after PTCy-based haplo-group, the percentage of activated/switched-memory subsets in B cell population at 8 weeks was inversely correlated with percentage of Treg in CD4 T cells at 4 weeks (P<0.05, r2=0.77). Taken together, consistently with our murine study, the current data from clinical samples again suggest that PTCy-based immune-modulation lead to coordinated T and B cell recovery, especially promoting naïve-subset dominant B cell recovery with help of the early expansion of Treg, which might reduce the risk of subsequent chronic GVHD. These data provide the important information for understanding the immunological reconstitution after PTCy-based haploidentical HSCT. Disclosures No relevant conflicts of interest to declare.
Abstract Introduction: Haploidentical hematopoietic stem cell transplantation (HSCT) is a potentially curative intervention for various malignant and non-malignant hematological conditions. Its use has led to the near universal availability of donors, but major challenges compared to HLA-matched related donor (MRD) and HLA-matched unrelated donor (MUD) transplants still exist. Although the most frequently discussed complication of haploidentical HSCT is graft rejection or severe/fatal graft-versus-host disease (GVHD), infection remains a significant cause of morbidity and mortality compared to other forms of transplant. Methods: This was a retrospective, single institution study that analyzed the outcomes of 187 patients with various hematological diseases who received allogeneic HSCT with haplo donor transplants, MRD transplants, or MUD transplants from 2011-2018. Conditioning regimens included combinations of fludarabine, busulfan, cyclophosphamide, melphalan, antithymocyte globulin, and total body irradiation. GVHD prophylaxis included either the combination of cyclosporine, tacrolimus, and mycophenolate mofetil (MMF) or tacrolimus and methotrexate (MTX). All patients received anti-viral prophylaxis with acyclovir, anti-fungal prophylaxis with either an azole or echinocandin, and anti-bacterial prophylaxis with trimethoprim-sulfamethoxazole or levofloxacin if the absolute neutrophil count (ANC) was <500 cell/mm3. Statistical analysis was performed using the Fisher Exact Probability Test with p-values <0.05 deemed significant. Results: Of the 187 patients who underwent allogeneic HSCT, 45 (24%) of the transplants were from haploidentical donors and 142 (76%) from non-haplo donors (MRD and MUD). Amongst all patients, median time to neutrophil engraftment (ANC >500 cells/mm3) was 16 days (range 13-25 days). Acute GVHD was present in 41% of haploidentical patients and 42% of non-haploidentical patients (p >0.05). Rates of chronic GVHD were also similar between the two groups at 45% in haplo patients and 48% in non-haplo patients (p >0.05). The 100-day infection-related mortality rate following transplant was significantly higher in the haploidentical group at 9% compared to 1% in the non-haploidentical group (p = 0.03, Figure 1). In addition, the 1-year rate of infection-related mortality after transplant was also significantly increased at 16% vs. 4% in the haplo vs. non-haplo groups, respectively (p = 0.01, Figure 2). The proportion of patients who experienced bacterial and fungal infections over this time period was comparable between the two groups (41% vs. 42% for bacterial infections and 18% vs. 12% for fungal infections in haploidentical patients vs. non-haploidentical patients, p >0.05 for both) while the incidence rate of viral infections was significantly higher in the haplo group at 72% vs. 38% in the non-haplo group (p < 0.001). However, all cases of infection-related mortality were due to bacterial and fungal infections rather than viral with 27% of bacterial or fungal infections leading to patient death in haploidentical patients compared to 7% in non-haploidentical patients (p = 0.02, Figure 3). Conclusion: The results of our study showed that compared to non-haplo transplant recipients, patients who underwent haplo transplants had significantly increased risks of 100-day and 1-year mortality secondary to infections. This finding is supported by prior data demonstrating that there is a longer time to immune reconstitution, specifically of the T-cell subset and dendritic cell subgroup, in the haploidentical population (Chang et. al. Journal of Clinical Immunology 2011). Furthermore, our results showed that the increased risk of infection-related mortality is not due to higher rates of acute or chronic GVHD, implying that the risk may be due to haploidentical transplantation itself as opposed to increased amounts of immunosuppressive therapy. While there was a greater incidence rate of viral infections amongst haploidentical patients, no viral infections led to mortality in either transplant group. In contrast, despite similar rates of bacterial and fungal infections between haploidentical and non-haploidentical patients, these infections led to death more often in the haplo population. These findings are important in considering future approaches to infection prophylaxis and treatment in haploidentical transplant recipients. Disclosures No relevant conflicts of interest to declare.
