Results of a Two-Arm Phase II Clinical Trial Using Post-Transplantation Cyclophosphamide for Prevention of Graft-Versus-Host Disease in Haploidentical and Mismatched Unrelated Donors Hematopoietic Stem-Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 152-152 ◽  
Author(s):  
Sameh Gaballa ◽  
Isabell Ge ◽  
Riad O. El Fakih ◽  
Jonathan E. Brammer ◽  
Sa A. Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Disease Risk ◽  
Risk Index ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Equity Ownership ◽  
Reduced Intensity

Abstract Allogeneic stem cell transplantation offers curative therapy for many patients (pts) with high-risk hematologic malignancies. Donor availability remains a major limitation for many pts. The introduction of high-dose post-transplant cyclophosphamide (PTCy) has significantly improved the outcomes of pts undergoing haploidentical (HAPLO) stem cell transplants. The choice between a HAPLO or a one-antigen HLA mismatched unrelated donor (9/10 MUD) for pts lacking an HLA-matched donor remains unclear. Methods: We conducted a prospective non-randomized phase 2 clinical trial with two parallel arms, HAPLO (n=60) and 9/10 MUD (n=46) transplants, for pts with advanced hematologic malignancies or aplastic anemia who lacked an HLA-matched unrelated donor type at 10 loci (HLA-A, -B, -C, -DRB1, and -DQB1) using a MEL-based reduced-intensity conditioning regimen. The regimen included a single intravenous dose of MEL 140 mg/m2 (day -7), thiotepa 5 mg/kg (day -6), and four daily IV doses of fludarabine 40 mg/m2 (day -5 to day -2) (FM140). Thiotepa was intermittently available and was replaced by total body irradiation at a dose of 2 Gy on day -1. Pts >55 years (yr) old or with significant comorbidities received a lower MEL dose (100 mg/m2) (FM100). All pts with CD20-positive lymphoma received rituximab (375 mg/m2) on days -13, -6, +1 and +8. GVHD prophylaxis consisted of PTCy 50 mg/kg on day +3 and +4, and tacrolimus and mycophenolate for 6 and 3 months (mo), respectively. The stem cell source was unmodified bone marrow for both arms. Results: Patient characteristics are shown in Table 1. The median follow-up duration was 24 mo in the HAPLO arm and 29 mo in the 9/10 MUD arm. The cumulative incidence (CI) of neutrophil (ANC) recovery at day 45 was 95% and 98% in the HAPLO and 9/10 MUD arm, respectively. The median time to ANC recovery was 18 days in both arms; the median time to platelet recovery was 25 days in the HAPLO arm and 28 days in the 9/10 MUD arm. Primary graft failure developed in two pts in the HAPLO arm (one due to anti-donor HLA antibodies) and one patient in the 9/10 MUD arm. One pt in both arms developed mixed donor chimerism at day 100; otherwise, all pts in both arms achieved full (>95%) donor chimerism. Bone marrow was the graft source in all pts except 2 in the HAPLO arm and 8 in the 9/10 MUD arm who received a peripheral blood graft. The 1-yr overall and progression free survival were 70% and 60%, respectively, in the HAPLO arm (Fig. 1A) and 60% and 47%, respectively, in the 9/10 MUD arm (Fig. 1B). Day 100 CI of grade II-IV aGVHD and III-IV aGVHD were 28% and 3%, respectively, in the HAPLO arm versus 33% and 13%, respectively, in the 9/10 MUD arm; the 2-yr CI of chronic extensive GVHD was 13% and 14% in the two groups, respectively. The 1-yr CI of non-relapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, while the 1-yr relapse rate was 19% and 25% in the two groups, respectively. Conclusions: This study establishes PTCy, tacrolimus, and mycophenolate as an effective regimen for GVHD prevention in mismatched transplantation using both haploidentical and mismatched unrelated donor sources. Melphalan-based reduced-intensity conditioning is an effective regimen for a broad range of hematologic malignancies. Prospective randomized studies comparing haploidentical and unrelated donor sources are needed. Table 1. HAPLO (n=60) 9/10 MUD (n=46) Median Age, years (Range) 45 (20-63) 51 (20-64) Sex (M/F) 29/31 23/23 KPS ³90 53 (88%) 40 (87%) <90 7 (12%) 6 (13%) HCT-CI 0-3 50 (83%) 38 (83%) >3 10 (17%) 8 (17%) Disease Risk Index* Very high 5 (8%) 3 (7%) High 18 (30%) 15 (33%) Intermediate 29 (48%) 12 (26%) Low 8 (13%) 12 (26%) NA 0 4 (9%)** Conditioning Regimen FM100 20 (33) 18 (39%) FM140 40 (67%) 28 (61%) Diagnosis AML/MDS 33 (55%) 18 (39%) ALL 7 (11%) 5 (11%) Lymphoma 10 (17%) 13 (28%) Others 10 (17%) 10 (22%) Disease Stage Acute Leukemia CR1/CR2 24 (66%) 9 (56%) CR3 or higher/ CRpx 6 (17%) 5 (31%) Active disease 6 (17%) 2 (13%) Lymphoma CR 3 (30%) 8 (62%) PR 5 (50%) 3 (23%) Chemoresistant 2 (20%) 2 (15%) *Disease Risk Index by Armand et al; xCRp: Complete Remission with incomplete count recovery; **Patients had aplastic anemia. Figure 1. Figure 1. Disclosures Brammer: Celgene: Research Funding. Lee:Ziopharm: Equity Ownership; Cyto-Sen: Equity Ownership; Intrexon: Equity Ownership. Rezvani:Pharmacyclics: Research Funding. Alousi:Therakos, Inc: Research Funding.

Equivalent Survival Following Fludarabine/Melphalan Reduced Intensity Conditioning with or without Rabbit ATG As Part of GvHD Prophylaxis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1959-1959
Author(s):  
J. Mark Prichard ◽  
Samatha Muppidi ◽  
Christopher R Flowers ◽  
Jonathan L. Kaufman ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Donor Cell ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Abstract 1959 Introduction: Reduced intensity conditioning (RIC) prior to allogeneic transplantation allows donor cell engraftment with the maintenance of a graft versus malignancy effect. A recent CIBMTR registry study suggested worse outcomes for patients receiving anti-thymocyte globulin (ATG) as part of the conditioning regimen. To further study the role of ATG when added to a fludarabine and melphalan RIC regimen in the unrelated donor (URD) setting, we have retrospectively studied 76 consecutive patients with advanced hematologic malignancies who underwent URD transplantation. Comparisons were made between cohorts that did or did not receive ATG (given primarily for HLA disparity) for pretransplant graft vs. host disease (GvHD) prophylaxis. Pateints and Methods: Seventy six patients with advanced hematologic malignancies (43% CIBMTR high-risk) received fludarabine and melphalan (FluMel) conditioning with or without pre-transplant rabbit ATG 6 mg/kg as part of GvHD prophylaxis. Twenty five patients who received ATG (24 of whom received grafts from donors mismatched at 1 or 2 HLA loci) were compared with 51 patients who did not receive ATG (45 of whom received grafts from HLA matched donors with six donors mismatched at a single locus). The majority of patients received post-transplant tacrolimus with either methotrexate (MTX) or mycophenolate mofetil for GvHD prophylaxis. With the exception of HLA disparity, pre-transplant patient characteristics were similar between groups (Figure 1). Results: With median follow up of 481 days and 376 days for the ATG and no ATG cohorts, respectively, K-M overall survival estimates were similar, with 2 year OS of 62 vs. 47 percent, respectively, for the ATG vs no ATG groups (p=.34). On multivariate analysis, the inclusion of MTX in GvHD prophylaxis was favorably associated with overall survival (p=.004), and was associated with a significant reduction in the incidence of severe (gr 3–4) acute GvHD (p=.03). There were no significant differences in pre-transplant creatinine, age, or comorbidity index scores between patients who did or did not receive MTX. Conclusions: Fludarabine and melphalan RIC, with or without pre-transplant ATG, produced similar outcomes following URD transplantation, despite the fact that patients receiving ATG in this series were more likely to have received a HLA mismatched graft. The inclusion of MTX for GVHD prophylaxis resulted in less severe acute GVHD and better survival when compared with tacrolimus/MMF. Disclosures: Flowers: Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Kaufman:Merck: Research Funding; Keryx: Consultancy; Novartis: Consultancy; Onyx Pharmaceuticals: Consultancy; Millenium: Consultancy; Celgene: Research Funding. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Sinha:Celgene: Research Funding.

Rapid Immune Reconstitution after a Reduced-Intensity Conditioning Regimen and a CD3-Depleted Haploidentical Stem Cell Graft for Pediatric Refractory Hematologic Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5311-5311
Author(s):  
Xiaohua Chen ◽  
Gregory A. Hale ◽  
Raymond C. Barfield ◽  
Ely Benaim ◽  
Wing H. Leung ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

Abstract Haploidentical hematopoietic stem cell transplantation (HaploHSCT) from a mismatched family member (MMFM) donor offers an alternative option for patients who lack an HLA-matched donor. The main obstacles to successful haploidentical hematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections, and severe graft-versus-host disease (GvHD). Method: We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin. The graft was immunomagnetically depleted of CD3+ T-cells (CD3 negative selection) and contained a large number of both CD34+ and CD34− stem cells and most other immune cells especailly NK cells. This protocol was used to treat 22 pediatric patients with refractory hematologic malignancies. Results and Discussion: After transplantation, 91% of the patients achieved full donor chimerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor excision circle counts, TCRβ repertoire diversity and NK-cells during first four months post-transplantation. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft, and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

scholarly journals Comparable Survival Outcomes of Haploidentical Stem Cell Transplantation and Unrelated Bone Marrow Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4644-4644 ◽  
Author(s):  
Junichi Sugita ◽  
Yoshiko Atsuta ◽  
Mio Kurata ◽  
Hirohisa Nakamae ◽  
Naoki Kurita ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Research Funding ◽  
Proportional Hazards ◽  
Disease Risk ◽  
Risk Index ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Overall Mortality

Abstract Background: In the absence of an HLA matched related donor, unrelated donor hematopoietic cell transplantation (HCT) is an alternative. Recently, HLA-haploidentical HCT using posttransplant cyclophosphamide (PTCY-haplo) has been increasingly performed. Unrelated donor peripheral blood stem cell transplantation (PBSCT) program was initiated in 2011 in Japan with rather slow increase, therefore, bone marrow is the main stem cell source for HCT from unrelated donors, while PTCY-haplo is mainly PBSCT. We compared outcomes of unrelated donor bone marrow transplant (UBMT) and PTCY-haplo. Methods: This is a retrospective analysis of a registry data of the Japan Society for HCT and the Japanese Data Center for HCT using the Transplant Registry Unified Management Program (TRUMP). Patients with acute leukemia and myelodysplastic syndromes, aged between 16 and 69 years, who undergone their first HCT between 2012 and 2015 were included in the study. HLA-A, -B, -C, and -DRB1 allele-level 8/8 matched (n=1,470), 7/8 matched (n=859), and 6/8 matched (n=186) T-cell replete UBMT recipients, and 140 recipients of PTCY-haplo (PBSCT, n=133; BMT, n=6; PBSCT+BMT, n=1) were identified as subjects for analyses. Adjusted comparison of the groups on overall mortality was performed with the use of the Cox proportional-hazards regression model. For other outcomes with competing risks, Fine and Gray's proportional-hazards model for subdistribution of a competing risk was used. The models were used to estimate adjusted probabilities, with consideration of other significant clinical variables in the final multivariate models. Results: The median age for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT were 52(16-69), 46.5(17-68), 50(16-69), 50(16-68). According to refined disease risk index (rDRI), patients with high or very high rDRI were 32%, 54%, 34%, 34% for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT. Myeloablative conditioning was used in 74%, 51%, 73%, 68% of patients for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT. Median follow-up period of survivors for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT were 2.79 (0.03-5.603),1.82 (015-3.89), 3.00 (0.09-5.57), 3.17 (0.27-5.58). In adjusted comparison by multivariate analyses setting 8/8 matched UBMT as the reference, PTCY-haplo showed similar overall mortality (relative risk [RR]=0.97, 95% confidence interval [CI], 0.75-1.26, p=0.823), decreased risk of non-relapse mortality (RR=0.43, 95% CI, 0.25-0.74, p=0.003), increased risk of relapse (RR=1.57, 95% CI, 1.21-2.03, p=0.001), and decreased risk of grade II to IV acute GVHD (RR=0.68, 95% CI, 0.48-0.95, p=0.023). Relative risks for 7/8 matched and 6/8 matched UBMT were 1.08 (p=0.223) and 1.27 (p=0.032) for overall mortality, 1.29 (p=0.004) and 1.73 (p<0.001) for non-relapse mortality, 0.89 (p=0.201) and 0.81 (p=0.215) for relapse, and 1.30 (p<0.01) and 1.84 (p<0.001) for grade II to IV acute GVHD. Other predictive variables identified for overall mortality were patient age older than 50 years old compared to younger at transplant, male sex, refined disease risk index of Intermediate, High, or Very High compared to Low, and HCT-CI total points of 1 or 3 or greater compared to 0. Adjusted probabilities for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT at two years post-transplant were 61%, 58%, 52%, 60% for overall survival, 23%, 27%, 21%, 19% for relapse, and 20%, 6%, 24%, 33% for non-relapse mortality (Figure 1). Conclusions: PTCY-haplo showed notably low non-relapse mortality which contributed to comparable short-term survival outcomes with 8/8 matched UBMT. Disclosures Ishiyama: Alexion Pharmaceuticals, Inc.: Honoraria. Ichinohe:Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Mundipharma: Honoraria; Novartis.: Honoraria; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; MSD: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding.

Haploidentical stem cell transplantation after a reduced-intensity conditioning regimen for the treatment of advanced hematologic malignancies: posttransplantation CD8-depleted donor lymphocyte infusions contribute to improve T-cell recovery

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4771-4779 ◽  
Author(s):  
Anna Dodero ◽  
Cristiana Carniti ◽  
Anna Raganato ◽  
Antonio Vendramin ◽  
Lucia Farina ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity ◽  
Donor Lymphocyte Infusions

Abstract Haploidentical hematopoietic stem cell transplantation provides an option for patients with advanced hematologic malignancies lacking a compatible donor. In this prospective phase 1/2 trial, we evaluated the role of reduced-intensity conditioning (RIC) followed by early add-backs of CD8-depleted donor lymphocyte infusions (DLIs). The RIC regimen consisted of thiotepa, fludarabine, cyclophosphamide, and 2 Gy total body irradiation. Twenty-eight patients with advanced lymphoproliferative diseases (n = 24) or acute myeloid leukemia (n = 4) were enrolled. Ex vivo and in vivo T-cell depletion was carried out by CD34+ cell selection and alemtuzumab treatment. The 2-year cumulative incidence of nonrelapse mortality was 26% and the 2-year overall survival (OS) was 44%, with a better outcome for patients with chemosensitive disease (OS, 75%). Overall, 54 CD8-depleted DLIs were administered to 23 patients (82%) at 3 different dose levels without loss of engraftment or acute toxicities. Overall, 6 of 23 patients (26%) developed grade II-IV graft-versus-host disease, mainly at dose level 2. In conclusion, our RIC regimen allowed a stable engraftment with a rather low nonrelapse mortality in poor-risk patients; OS is encouraging with some long-term remissions in lymphoid malignancies. CD8-depleted DLIs are feasible and promote the immune reconstitution.

Allogeneic Stem Cell Transplantation for MDS Patients More Than 70 Years of Age: a Retrospective Study of the MDS Subcommittee of the Chronic Malignancies Working Party (CMWP) of the EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4390-4390
Author(s):  
Silke Heidenreich ◽  
Dimitris Ziagkos ◽  
Anja van Biezen ◽  
Jürgen Finke ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Remission Status ◽  
Unrelated Donors ◽  
Karnofsky Index ◽  
Reduced Intensity

Abstract Introduction Myelodysplastic syndromes (MDS) are diagnosed at median age of 70 years. Allogeneic stem cell transplantation (HSCT) is the only curative treatment option, but with an increasing age, morbidity escalates. Treatment guidelines suggest HSCT for intermediate-II and high risk constellations up to the age of 65, and reduced intensity conditioning (RIC) regimens are commonly used up to 70 years of age. However, increasing life expectancy, availability of RIC regimens and good Karnofsky performance status (KPS) of MDS patients more than 70 years of age, has led to an increased use of HSCT. We performed a retrospective analysis to investigate results after HSCT for those patients and influence of KPS on outcome. Patients and methods We analyzed data of 345 patients in the EMBT database older than 70 years with MDS/sAML. The disease status at transplantation was available in 233 patients and most of the them were in more advanced stage of the disease: RA/RARS,RCMD (n=25) , RAEB (n=68) and RAEB-T/secondary acute leukemia (sAL, n=140). Donor were: related (n=88) and unrelated (n=257). Cytogenetic data were available only in 73 patients and classified as good (58), intermediate (6), poor (5) and very poor (4). Median follow up was 29.7 months. Median age at transplantation was 72 years (70-79 years) with 249 male and 96 female patients. KPS was defined in 300 cases, being 90-100% in 61% and 80% or less in 39%. Stem cell source was peripheral blood (94%) or bone marrow (6%). The intensity of the conditioning regimen was mainly reduced intensity (78%) rather than myeloablative (22%). Negative or positive CMV sero-status of the patient were seen in 35% and 65%, respectively. Results The number of HSCT for MDS patients of 70 years or more has increased over time. While 2000-2004 only 19 patients received transplantation, the following 3-year periods included 28 (2005-2007), 97 (2008-2010) and 200 (2011-2013) patients, respectively. The estimated 3-year OS was 33% (27-39%). A significant better 3 year OS in the univariate analysis was seen for Karnofsky (90-100%) vs 80% or less (41 vs 23%, p=0.008) and for CMV negative sero-status (46% vs 27%, p> <0.001) while disease status, remission status, intensity of the conditioning regimen, and donor source did not influence OS significantly. The cumulative incidence of relapse at 3 years was 40% (95% CI: 32-48) and significantly lower with unrelated than related donors (24% vs 43%, p =0.004). There was only a trend for a lower incidence of relapse after myeloablative conditioning in comparison to RIC (22% vs 31%, p=0.09), while remission status, T-cell depletion or disease stage did not influence the risk of relapse. The cumulative incidence of non-relapse mortality at 1 year was 36% (95% CI: 30-42) and significantly influenced by CMV sero-negativity of the recipient (22% vs 38%, p=0.02) and by Karnofsky index 90-100% (29% vs 34% and at 2 years: 32% vs 46%, p=0.01). A trend for lower NRM was seen for related donors (24% vs 35%, p=0.07) and after reduced intensity conditioning (29% vs 41%, p=0.09). No impact on NRM was seen for disease and remission status. In a multivariate analysis (MVA) significant factor for improved OS was Karnofsky index of 90-100% (HR 0.65: 95% CI: 0.48-0.88, p=0.001) and for worse survival CMV sero-positivity (HR 1.61; 95% CI: 1.15-2.21, p<0.001). For relapse the only significant factor was the use of unrelated donors (HR 0.50; 95% CI: 0.32-0.80, p=0.004). Significant factors for NRM in the MVA were Karnofsky index 90-100% (HR 0.63; 95% CI: 0.42-0.96, p=0.03), CMV sero-positivity of the recipient (HR 1.76; 95% CI: 1.12-2.76, p=0.001) and unrelated donors (HR 1.67; 95% CI: 0.16-2.76, p=0.04). Conclusion HSCT from related or unrelated donor after myeloablative or dose reduced intensity conditioning for advanced MDS patients 70-years and more is a curative treatment option with a 3-year OS of 33%. Good performance, determined by KPS, and sero-negativity for CMV in the patient increase the 3 year estimated overall survival to 41 and 46%, respectively. Disclosures Platzbecker: Boehringer: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Einsele:Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tischer:Sanofi-Aventis: Other: advisory board. Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Sill:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. de Witte:Novartis: Research Funding.

scholarly journals Comparison of Outcomes between HSCT Donor Sources for Pediatric Patients with Hematologic Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4611-4611
Author(s):  
Lauren Longo ◽  
Filippo Milano ◽  
Colleen Delaney ◽  
Marie Bleakley ◽  
Lauri S Burroughs ◽  
...  
Keyword(s):  
Research Funding ◽  
Pediatric Patients ◽  
Acute Gvhd ◽  
Disease Risk ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade Iii ◽  
Donor Source

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for pediatric patients with hematologic malignancies. Historically, matched sibling donors (MSD) have been the preferred donor source given ease of availability and lower rates of graft-versus-host-disease (GVHD). However, only 30% of patients have a MSD and relapse rates are high after MSD HSCT, raising the question of best donor choice. As conditioning regimens evolve, GVHD management improves and supportive care advances, it is important to evaluate the role of donor source on short and long-term clinical outcomes to inform donor selection. We performed a single-center retrospective analysis comparing post-HSCT outcomes in a cohort of pediatric patients undergoing MSD, matched unrelated donor (MUD), and umbilical cord blood (CB) transplants from 2006 to 2018. Methods: A retrospective analysis was performed on an IRB-approved protocol through Fred Hutchinson Cancer Research Center. 232 patients were included who received MSD (n=56), MUD (n=89) or CB (n=87) transplants. Of note, 24 CB patients received expanded CB cells in addition to unmanipulated unit(s). GVHD prophylaxis in all patients consisted of a calcineurin inhibitor and MMF or methotrexate. The vast majority received a high-intensity conditioning regimen (86%, 96%, and 82% respectively for MSD, MUD and CB). Overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method. Probabilities of non-relapse mortality (NRM), relapse, and acute GVHD were evaluated using cumulative incidence (CI) estimates with appropriate competing risks. The Cox regression model was used for adjusted analysis for age, year of transplant, sex, CMV status, MRD status, disease risk, and conditioning regimen. Results: Patient/treatment/donor demographics are shown in Table 1. Median follow-up was 2.6, 3.7 and 3.1 years for MSD, MUD and CB respectively. Patient diagnosis, disease risk, gender, age, and CMV serology were balanced between groups. CI of engraftment was similar as well, with only one graft failure in the MUD group (Fig 1). Median time to platelet recovery was significantly faster in MUD and MSD groups as compared to the CB group (p<0.0001; p<0.0001). There was no difference in unadjusted 5 year OS (Fig 2) and NRM (Fig 3) between groups. Five-year DFS was significantly higher in CB v. MSD (71% v. 54%, p=0.03) but not between CB v. MUD (71% v. 61%, p=0.18) or between MSD and MUD (p=0.38) (Fig 4). The CI of relapse at 5 years was 20% for CB patients, significantly lower than that of MSD recipients (49%, p=0.003) and not different from MUD (32%, p=0.11) (Fig 5). After adjusted analysis, the risk of DFS failures was higher among recipients of MSD than CB [HR: 1.88 (CI 95%: 1.01-3.47), p=0.04]. When CB versus MUD groups were compared, there was a trend of higher risk of DFS failures in the MUD group [HR: 1.28 (CI 95%: 0.96-1.66), p=0.09]. No difference was observed in risk of DFS failures between MSD versus MUD groups [HR:0.77 (CI 95%: 0.44-1.4), p=0.43]. Incidence of grade II-IV acute GVHD was 90% (95%CI: 82-95%), 75% (95%CI: 61-84%) and 88% (95%CI: 80-94%), for CB, MSD and MUD, respectively (p=0.25). Incidence of grade III-IV acute GVHD was 33% (95%CI: 23-43%) for CB, 9% (95%CI: 3-18%) for MSD, and 11% (95%CI: 5-18%) for MUD. Incidence of grade III-IV was significantly higher for the CB group compared to the other groups (p=0.001); however, nearly 60% of CB recipients with grade III-IV acute GVHD were diagnosed before engraftment had occurred and in retrospect met criteria for pre-engraftment syndrome. Among surviving patients, 23 CB recipients developed chronic GVHD (26% - 15 mild, 4 moderate, 4 severe) as compared to 14 MSD patients (25% - 13 mild, 1 moderate) and 40 MUD patients (45% - 27 mild, 11 moderate, 2 severe). Conclusions: Our data demonstrate no difference in unadjusted OS between MSD, MUD and CB recipients. Importantly, despite this equivalence, 5-year DFS was significantly better in the CB v. MSD group, reflecting the lower relapse rate observed in CB patients and seen previously by us and others. CB continues to be viewed as an "alternative" donor for HSCT due to the low stem cell dose in a CB graft resulting in delayed neutrophil recovery, primary graft failure and increased NRM. However, this was not observed herein, supporting the use of CB for pediatric HSCT perhaps especially in patients at high risk of post-transplant relapse. Disclosures Milano: ExCellThera: Research Funding; Amgen: Research Funding. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Bleakley:HighPass Biotherapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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