Transplantation For Acute Lymphoblastic Leukemia Research Articles

Allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia with an accompanying hereditary hemorrhagic telangiectasia

Allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia with an accompanying hereditary hemorrhagic telangiectasia

Novel strategies to prevent and overcome relapse after allogeneic hematopoietic cell transplantation in acute lymphoblastic leukemia.

The outcome of B-cell acute lymphoblastic leukemia (B-ALL) has improved over time with the incorporation of multi-agent chemotherapy in the treatment landscape as well as the recent approval of immunotherapeutic agents allowing a larger proportion of patients to undergo allogeneic hematopoietic cell transplantation (allo-HCT) which is still considered a potential curative approach. However, relapse post-transplant is still occurring and constitutes a common cause of treatment failure in B-ALL. The present review aims to discuss the novel strategies and therapies used to prevent and overcome relapse post allo-HCT in patients with ALL, focusing on the role of tyrosine kinase inhibitors in Philadelphia chromosome positive B-ALL, the role of innovative agents such as blinatumomab and inotuzumab ozogamicin, and finally the role of cellular therapy.

Total Body Irradiation for Myeloablative Allogeneic Hematopoietic Transplantation in Acute Lymphoblastic Leukemia: How Important Is It Really?

Total Body Irradiation for Myeloablative Allogeneic Hematopoietic Transplantation in Acute Lymphoblastic Leukemia: How Important Is It Really?

Fludarabine or cyclophosphamide in combination with total body irradiation as myeloablative conditioning prior to allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT.

In this registry-based study we retrospectively compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with acute lymphoblastic leukemia (ALL) following conditioning with total body irradiation (TBI) combined with either cyclophosphamide (Cy) or fludarabine (Flu). TBI 12 Gy + Cy was used in 2105 cases while TBI 12 Gy + Flu was administered to 150 patients in first or second complete remission. In a multivariate model adjusted for other prognostic factors, TBI/Cy conditioning was associated with a reduced risk of relapse (HR = 0.69, p = 0.049) and increased risk of grade 2-4 acute graft-versus-host disease (GVHD, HR = 1.57, p = 0.03) without significant effect on other transplantation outcomes. In a matched-pair analysis the use of TBI/Cy as compared to TBI/Flu was associated with a significantly reduced rate of relapse (18% vs. 30% at 2 years, p = 0.015) without significant effect on non-relapse mortality, GVHD and survival. We conclude that the use of myeloablative TBI/Cy as conditioning prior to allo-HCT for adult patients with ALL in complete remission is associated with lower risk of relapse rate compared to TBI/Flu and therefore should probably be considered a preferable regimen.

474 - Post-Transplantation Cyclophosphamide for the Prevention of Graft-Versus-Host Disease Should Not Limit Transplantation for Acute Lymphoblastic Leukemia in People with Trisomy 21

474 - Post-Transplantation Cyclophosphamide for the Prevention of Graft-Versus-Host Disease Should Not Limit Transplantation for Acute Lymphoblastic Leukemia in People with Trisomy 21

Association of CDKN2A/2B deletion with relapse after hematopoietic stem cell transplantation for acute lymphoblastic leukemia.

The most important prognostic factor for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is minimal residual disease (MRD). Previous studies have reported copy number variants of genes such as IKZF1, CDKN2A/2B, and PAX5. These gene mutations can be analyzed using multiplex ligation-dependent probe amplification (MLPA), which is less costly and easier to perform than large-scale gene mutation analyses. In this study, we performed copy number variant analysis of leukemia cells at the first onset of Ph+ALL in a case series of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using the MLPA method. We analyzed how it influenced allo-HSCT prognosis together with MRD information. CDKN2A/2B copy number variations significantly increased the rate of post-transplant recurrence (P=0.025) and significantly reduced disease-free survival (P=0.015). Additionally, patients with IKZF1 deletions had a significantly higher post-transplant recurrence rate (P=0.042). Although they were positive for pre-transplant MRD, no relapse was observed in patients with wild-type copy number variations in IKZF1 or CDKN2A/2B. CDKN2A/2B copy number variation is a crucial factor that can be confirmed at initial onset as a post-transplant prognostic factor of Ph+ALL.

TBI-Based Myeloablative Conditioning Prior to Haploidentical Versus Matched Donor Transplantation for Acute Lymphoblastic Leukemia

Data from the CIMBTR has previously demonstrated the non-inferiority of transplantation from a haploidentical donor (HAPLO) using post-transplant cyclophosphamide (PTCy) vs. matched related (MRD) or unrelated donors (MUD) for acute lymphoblastic leukemia (ALL) (Wieduwilt et al. Blood Advances 2022). However, total body irradiation (TBI)-containing myeloablative conditioning (MAC) was used in less than 60% of MRD/MUD patients and in approximately 40% of HAPLO patients. We aimed to better define the role of donor type (HAPLO vs. MRD/MUD) following TBI-MAC-based allogenic transplant for ALL. To this end, we analyzed 105 consecutive ALL patients receiving a first allogeneic transplant at our institution following TBI-MAC from an MRD [30], MUD [24] or HAPLO [51] donor between Jan 2011 to Sept 2021. HAPLO patients received a preparative regimen of fludarabine (90mg/m2) and TBI 1200 cGy, followed by post-transplant cyclophosphamide (PTCy), tacrolimus and mycophenolate mofetil. MRD/MUD patients received TBI 1200 cGy with either Cy (120mg/kg, n= 33) or etoposide (60mg/kg, n=21), followed by tacrolimus and methotrexate for GVHD prophylaxis. Baseline characteristics include a median age of 40 (range, 29-51) years, HCT-CI ≥3 in 53%, poor risk cytogenetics in 60% (Ph+ [37%], Ph-like [11%], complex karyotype [7%] and 11q23 translocation [5%]). PBSC was the graft source in 94%. Pre-transplant status was CR1, CR2/3, or PIF/relapse in 75%, 12% and 13% respectively. Pre-transplant measurable residual disease (MRD) was seen in 28%). Baseline demographics of HAPLO and MRD/MUD recipients were similar with the exception of race/ethnicity, where HAPLO recipients (vs. MRD/MUD) were significantly less likely to be non-Hispanic White (29% vs. 67%). Comparison of baseline disease characteristics revealed more T-cell lineage disease (27% vs. 4%) and less poor risk cytogenetics (47% vs. 72%) in HAPLO vs. MRD/MUD recipients, respectively. After a median follow-up of 70 months (range, 8-134), 5-yr overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) for the whole cohort was 62%, 54%, 29% and 18% respectively, with no significant differences between HAPLO and MRD/MUD transplants (see figure). In multivariable analysis, controlling for other significant covariates (race, pre-transplant disease status and pre-transplant MRD), donor type (HAPLO vs. MRD/MUD) did not have a significant impact on OS (HR 1.04, p=0.91)) or DFS (HR 0.99, p=0.97)). TBI-MAC-based HAPLO represents a favorable alternative donor source with comparable long-term DFS and OS. This is of particular importance to patients of racial/ethnic minorities, whereby rapid and practically universal access to a HAPLO donor allows for curative-intent therapy in the vast majority of high-risk ALL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ALL-228 Unfavorable Influence of Minimal Residual Disease on the Outcome of Allogeneic Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia in the First Remission

Persistence of minimal residual disease (MRD) is the most important adverse prognostic factor for patients with acute lymphoblastic leukemia (ALL), irrespective of classical risk factors identified at onset. Detection of MRD in the post-induction phase of ALL treatment is the only generally accepted risk factor that is considered a direct indication for inclusion in the treatment of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studies in recent years have shown that MRD determined before transplantation may increase the risk of disease relapse in ALL patients. To assess the impact of pre-transplant MRD status determined by multiparameter flow cytometry (MFC) on the long-term results of allo-HSCT in ALL patients. The study involved 98 patients with ALL in the 1st CR (n=58) and 2nd or 3rd CR (n=40) who underwent allo-HSCT in our center from November 2015 to July 2021. The median follow-up was 11.7 (1-65.5) months. To determine MRD, 12-color MFC was performed on bone marrow samples obtained before allo-HSCT. The probabilities of OS and DFS and the probability of relapse (PR) were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to assess the influence of various independent factors (donor type, conditioning regimen, graft source, GVHD prophylaxis, pre-transplant MRD status, age) on PR. Ten patients in 1st CR and 14 patients in 2nd or 3rd CR were identified as MRD+ before allo-HSCT. OS of MRD+ patients in 1st CR did not significantly differ from MRD- patients, although it was worse (28% vs. 78%, P=0.09). Significant differences were found in the DFS of MRD+ and MRD- patients (20% vs. 56%, P=0.0317); PR was also significantly higher in MRD+ patients (73% vs. 22%, P=0.0079). OS, DFS, and PR in MRD+ and MRD-patients were comparable. In our study, the presence of MRD before allo-HSCT (HR=3.858) was an independent factor influencing the probability of relapse. MRD determined by MFC is an independent predictor of the risk of relapse after allo-HSCT in ALL patients. Detection of MRD in patients with ALL in 1st CR before allo-HSCT is necessary to stratify the risk and identify patients who need post-transplant therapy.

Hematopoietic stem cell transplantation for acute lymphoblastic leukemia: why do adolescents and young adults outcomes differ from those of children? A retrospective study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC).

In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences. 891 patients, from the SFGM-TC registry, aged between 1 and 25years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts. Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA. AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population.

310 - Total Marrow Lymphoid Irradiation [TMLI] in Combination with Cyclophosphamide Is Associated with Good Early Outcomes in Patients Undergoing Stem Cell Transplantation for Acute Lymphoblastic Leukemia and Lymphoid Blast Crises in CML

310 - Total Marrow Lymphoid Irradiation [TMLI] in Combination with Cyclophosphamide Is Associated with Good Early Outcomes in Patients Undergoing Stem Cell Transplantation for Acute Lymphoblastic Leukemia and Lymphoid Blast Crises in CML

Serotherapy as Graft-Versus-Host Disease Prophylaxis in Haematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia.

Serotherapy comprising agents such as anti-thymocyte globulin, anti-T-lymphocyte globulin, and the anti-CD52 monoclonal antibody alemtuzumab is used widely to reduce the incidence of graft-versus-host disease (GvHD) after paediatric haematopoietic stem cell transplantation (HSCT). The outcome of transplants using matched unrelated donors now approaches that of matched sibling donors. This is likely due to better disease control in recipients, the use of donors more closely human-leukocyte antigen (HLA)-matched to recipients, and more effective graft-versus-host disease (GvHD) prophylaxis. The price paid for reduced GvHD is slower immune reconstitution of T cells and thus more infections. This has led to studies looking to optimise the amount of serotherapy used. The balance between prevention of GvHD on one side and prevention of infections and relapse on the other side is quite delicate. Serotherapy is given with chemotherapy-/radiotherapy-based conditioning prior to HSCT. Due to their long half-lives, agents used for serotherapy may be detectable in patients well after graft infusion. This exposes the graft-infused T cells to a lympholytic effect, impacting T-cell recovery. As such, excessive serotherapy dosing may lead to no GvHD but a higher incidence of infections and relapse of leukaemia, while under-dosing may result in a higher chance of serious GvHD as immunity recovers more quickly. Individualised dosing is being developed through studies including retrospective analyses of serotherapy exposure, population pharmacokinetic modelling, therapeutic drug monitoring in certain centres, and the development of dosing models reliant on factors including the patient's peripheral blood lymphocyte count. Early results of “optimal” dosing strategies for serotherapy and conditioning chemotherapy show promise of improved overall survival.

Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia: Why Do Adolescents and Young Adults Outcomes Differ from Those of Children? a Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)

Introduction:Adolescents and Young Adults (AYA) represent a specific population in the Acute Lymphoblastic Leukemia (ALL) landscape, often presenting high-risk diseases and increased chemotherapy-related toxicities. Indications of Hematopoietic Stem Cell Transplantation for pediatric patients (HSCT) have been restricted to those with early poor response to chemotherapy. The same trend has led to a decrease of HSCT indications in AYAs, which are nevertheless still more frequent than in younger counterpart. Outcomes of AYAs after HSCT seemed to be worse than the ones of children in two previous studies published in 2013 and 2014. In Minneapolis, the decrease of overall survival in AYA was attributed to an excess of Treatment Related mortality (TRM) (28% versus 14%; p=0.04), but because of small numbers, factors influencing TRM were not identified. Our study aimed to compare, in a large cohort, the outcomes of children and AYA with ALL after HSCT and to determine factors influencing potential differences.Material and Methods:All patients aged between 1 and 25 years, reported in the SFGM-TC (Francophone Society of bone marrow transplantation and cellular therapy) registry, who received a first HSCT in treatment for ALL between 2005 and 2012 were included. The AYA group was defined by age range between 15 and 25 years old, according to European studies and the SFGM-TC. Data about diagnosis and transplantation procedure were prospectively collected in the registry. Before transplant procedure, patients or their parents/guardians provide a signed consent in order to be included in the registry.Results:891 patients were included, 494 children and 397 AYA. Median time of follow up was 45.6 months (0 to 114). HSCT was performed in first CR for 56.8% of the AYAs, whereas 57.5% of children received HSCT in second CR or more advanced phase (p<0.001). HSCT procedures mainly included a Myelo-Ablative Conditioning (MAC) regimen. TBI was used more frequently in AYAs than in children (90.1% versus 83.1%, p=0.003). Bone Marrow (BM) or Cord-Blood (CB) were often used in children 60.2% and 29.4% versus 55.6% and 16.4% in AYA group respectively (p < 0.0001) . Peripheral Blood Stem Cells (PBSC) were more frequently used for AYA (28%) than for children 10.3% (p < 0.0001). Moreover, when being transplanted in an adult center, PBSC were more commonly used for AYA (30% of AYA's HSCT in adult centers versus 21.2% of AYA's HSCT in pediatric centers, p=0.051). BM and PBSC cells were provided by a match sibling donor (MSD) in 40.2% of children and 43.4% of AYAs and from a MUD in 57.2% and 55.1% of cases respectively (p = 0.474). Anti-thymoglobulins (ATG) were used for 336 patients (48% of children and 26% of AYA patients, p<0.001). See patient's characteristics in Table.Five-year OS was lower in AYA 53.1% versus 64% (p = 0.0012) and we confirmed higher 5-years TRM in AYA 19% versus 13% (p=0.04). TRM incidence markedly rose after 10 years of age (from 9% before 10 years old to 20% between 10 and 15 years, and 17% after 15 years).Graft versus host disease and Relapse Free Survival probability (GRFS) was lower in AYA: 36% versus 47% (p=0.007), while Cumulative Incidence of Relapse (CIR) and acute Graft versus Host Disease (GvHD) incidence were both similar in our two groups: 32% and 61% in AYAs versus 27% and 59% in children, (p=0.19 and p=0.62), respectively. Thus, chronic GvHD, which occurred more frequently in AYA than in children (32% versus 19%, p<0.001), mainly impact post-HSCT morbi-mortality in AYA (Figure 1 and 2).In our multivariate analysis, two factors were associated with higher risk of cGvHD: use of PBSC as stem cell source (HR 1.41 [0.96-2.07], p=0.083), and absence of ATG use (HR associated with use of ATG: 0.62 [0.42-0.92], p=0.017) (Figure 3). Of note a subgroup analysis in patients who received a bone marrow transplant after a MAC, showed no TRM difference between AYA and children.Conclusion:AYA or patients aged more than 10 years, compared to ones aged less than 10 years have a worse outcome after HSCT for ALL. Excess of death in this specific population is mainly due cGvHD. Transplantation practices in those patients, particularly choice of stem cells source and GvHD prophylaxis, should be discussed. Their treatment adherence should also be questioned and reinforced by development of multidisciplinary teams. [Display omitted] DisclosuresPeffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Forcade: Novartis: Other: travel grant.

Two-Year Landmark Survival Analysis after Allogeneic Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia: An Analysis from the ALWP of the EBMT

BackgroundLong-term survival and late mortality risk compared to general population for patients (pts) who underwent an allogeneic hematopoietic cell transplant (HCT) is unknown. We analyzed long-term outcomes of 2-year (yr) HCT survivors with acute lymphoblastic leukemia (ALL).MethodsAdult pts with ALL who were alive and relapse-free at 2 yrs after first HCT from 2005-2012 were included. We excluded patients who had a cord blood transplant and ex vivo T cell depletion (TCD). Relative survival analysis was used to estimate HCT-related crude mortality taking into account for background population mortality rates of the general population, matched for age, sex, and country in the year of HCT (www.mortality.org).ResultsA total of 2701 pts were included with a median follow up interval of 99 months and median age of 34 (range 18 - 73.5) yrs. The majority (78.6%) of pts were in 1 st complete remission (CR1) with undetectable MRD (68.3%). There were similar numbers of matched sibling donor (MSD) (43.7%) and unrelated donor transplants (MUD) (53.2%). Most pts received myeloablative conditioning (MAC) (86.5%) and peripheral blood (PB) grafts (75.7%) without in vivo TCD (55.7%).The 10-yr probability for overall survival (OS) and leukemia-free survival (LFS) was 81.3% and 78.2%, respectively. Cumulative incidence of disease relapse and non-relapse mortality (NRM) at 10 years was 9.9% and 11.9%, respectively. The probability of chronic GVHD-relapse-free survival (cGRFS) at 10-yrs was 73.3% (Figure 1). Relapsed ALL and chronic GVHD were common causes of late mortality accounting for 33.9% and 29% of reported deaths, respectively, followed by infection and secondary malignancy. For patients transplanted in countries with available mortality data (92% of patients in our cohort), the probability of dying from another cause is negligible at 1.5% compared to the probability of dying from HCT (16.8%) 10 years after HCT (Figure 1F).ConclusionsIn a large registry-based study, we showed excellent long-term survival of 81.3% at 10-yr among the 2-yr survivors of HCT for ALL. There was no difference in long term outcomes with respect to conditioning intensity, but utilization of BM graft and in vivo TCD resulted in lower NRM, and better OS. Long-term mortality risk among HCT survivors remains significantly higher than expected for the general age-matched population. [Display omitted] DisclosuresLabopin: Jazz Pharmaceuticals: Honoraria. Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Bethge: Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Nicholson: Pfizer: Consultancy; BMS/Celgene: Consultancy; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Peric: Therakos, Servier, MSD, Astellas, Novartis, Abbvie, Pfizer: Honoraria. Dholaria: Janssen: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Higher Efficacy of TBI + Cyclophosphamide Than TBI + Fludarabine As Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia: An Analysis By the Acute Leukemia Working Party of the EBMT

BACKGROUNDAllogeneic hematopoietic cell transplantation (allo-HCT) is a standard of care for adults with high-risk acute lymphoblastic leukemia (ALL) in first or subsequent complete remission (CR). Myeloablative total body irradiation (TBI) combined with cyclophosphamide (Cy) is the most frequently used conditioning regimen. In order to reduce toxicity Cy may be replaced by fludarabine (Flu). The goal of this registry-based, retrospective study was to compare outcomes of allo-HCT following TBI/Cy vs. TBI/Flu conditioning. PATIENTS AND METHODSIncluded in the analysis were 2255 patients aged 18-65 years, treated with allo-HCT from either a matched sibling (43%) or unrelated (57%) donor in CR1 (83%) or CR2 (17%), between the years 2010-2020. Patients with Ph(-) B-ALL, Ph(+) B-ALL, and T-ALL were represented in equal proportions. TBI 12Gy + Cy was used in 2105 cases while TBI 12Gy + Flu was administered to 150 patients. Patients treated with TBI/Flu were significantly older (median 35 years vs. 33 years, p=0.006), with poorer Karnofsky performance score (<90, 27% vs. 20%, p=0.03), more frequently transplanted from unrelated donors (71% vs. 57%, p=0.0007) with less frequently use of bone marrow as a source of stem cells (5% vs. 21%, p<0.0001), and in more recent year (median 2018 vs. 2015, p<0.0001). RESULTSEngraftment rate was 99% for both TBI/Cy and TBI/Flu patients. In a univariate analysis the use of TBI/Cy as compared to TBI/Flu was associated with a tendency to reduced incidence of relapse (24% vs. 29% at 2 years, p=0.1), increased incidence of grade 2-4 acute graft versus host disease (GVHD, 35.5% vs. 28%, p=0.08) and improved leukemia-free survival (LFS, 62% vs. 57%, p=0.18). The rates and causes of non-relapse mortality (NRM) did not differ significantly between the two conditioning groups. In a multivariate model adjusted for other prognostic factors, TBI/Cy conditioning was associated with reduced risk of relapse (HR=0.69, p=0.049) and increased risk of grade 2-4 acute GVHD (HR=1.57, p=0.03) without significant effect on other transplantation outcomes.An additional analysis was performed with TBI/Cy treated patients (n=132) matched strictly to those treated with TBI/Flu (n=132) in terms of disease subtype, disease status and donor type with the nearest neighbor for patient age, patient and donor sex, in vivo T-cell depletion, Karnofsky score and source of stem cells; the use of TBI/Cy as compared to TBI/Flu was associated with significantly reduced rate of relapse (18% vs. 30% at 2 years, p=0.015) and a tendency to an improved LFS (65% vs. 59%, p=0.07) and overall survival (OS, 73% vs. 68%, p=0.16) without effect on NRM and GVHD. CONCLUSIONSThe use of myeloablative TBI/CY as conditioning prior to allo-HCT for adult patients with ALL in CR1 or CR2 is associated with stronger anti-leukemic effect leading to significantly lower relapse rate compared to TBI/Flu and therefore should be likely considered a preferable regimen. DisclosuresGiebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Labopin: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Forcade: Novartis: Consultancy, Other: Travel Support, Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support. Huynh: Jazz Pharmaceuticals: Honoraria. Spyridonidis: Menarini: Current Employment. Perić: therakos: Honoraria; servier: Honoraria; MSD: Honoraria; Astellas: Honoraria; NOVARTIS: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria. Mohty: Pfizer: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria.

Improved survival after allogeneic transplantation for acute lymphoblastic leukemia in adults: a Danish population-based study

We investigated trends of survival in a population-based cohort study of all 181 adults who received HCT for ALL in Denmark between 2000–2019. Patients had a median (min–max) age of 36 (18–74) years at HCT and were followed for a median of eight years. Overall survival (OS) improved over time with an estimated 2-year OS of 49% (CI 27–66%) in year 2000 versus 77% (CI 59–88%) in year 2019. More patients achieved cure over time (OR for cure per year 1.07, CI 1.00–1.15), while the rate of death in non-cured patients remained stable (HR of excess mortality per year 0.99, CI 0.93–1.06). Relapse decreased over time (HR 0.92 per year, CI 0.87–0.98), whereas non-relapse mortality did not change notably (HR 0.98 per year, CI 0.93–1.04). In conclusion, survival after HCT in adults with ALL has improved over the past two decades, primarily due to more patients achieving cure.

401 - Impact of Two Different Types of Rabbit Anti-Thymocyte Globulin on Immune Reconstitution and Overall Results after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Children

401 - Impact of Two Different Types of Rabbit Anti-Thymocyte Globulin on Immune Reconstitution and Overall Results after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Children

259 - Comparison of Myeloablative and Reduced Intensity Conditioning Regimens in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia

259 - Comparison of Myeloablative and Reduced Intensity Conditioning Regimens in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia

Impact of Two Different Types of Rabbit ATG on Immune Reconstitution and Overall Results after Allogeneic Hematopoetic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Children

Introduction Thymoglobulin® and Grafalon® are 2 polyclonal rabbit anti-thymocyte globulin (ATG) used in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to prevent graft rejection and graft-versus-host disease (GvHD). Differences in manufacturing lead to different types and concentrations of antibodies in each product. Few studies compare their effects on post-transplant immune reconstitution: indeed, the latter is essential to prevent post-transplant infections as well as relapse (in case of hematological malignancies). Methods We conducted a retrospective study on children or adolescents who received a first unrelated allo-HSCT for an Acute Lymphoblastic Leukemia (ALL) between 2007 and 2018, in the department of pediatric hematology of the Robert Debré Hospital in Paris, France. During this time period, 2 types of ATG were used: Thymoglobulin® at 7.5mg/kg or Grafalon® at 60mg/kg. We included patients with a B or T phenotype ALL aged 2 to 18 years at the time of HSCT indication. Stem cell source could be from unrelated matched or mismatched bone marrow, peripheral blood or cord blood. All patients received a myeloablative conditioning regimen consisting of 12 grays total body irradiation and etoposide (60mg/kg). We compared patients for engraftment, counts of total lymphocytes, B and T lymphocytes, T CD4+ and CD8+ lymphocytes and their sub-types (naïve, effector memory, central memory and effector memory RA+), regulatory T cells, NK cells, and compared lymphocyte proliferation assays at 1, 3, 6 and 12 months after transplant. We used joint models of longitudinal and survival data to further analyze evolution of total lymphocytes, B and T cells, T CD4+ and T CD8+ cells, and NK cells. Finally, we compared clinical outcomes between the 2 groups. Statistical analyses were performed according to EBMT guidelines (Iacobelli, 2013). Results 76 children were included: 23 received Thymoglobulin® and 53 received Grafalon®. Stem cell source was peripheral blood or bone marrow for 61 patients and cord blood for 15 patients. Initial characteristics of patients, disease status and HSCT were similar between the two groups except for the median total nucleated cells and CD34+ progenitor cells of the graft, that were significantly higher in the Grafalon® group. We found a delayed cumulative incidence of engraftment in patients who received Grafalon® compared to those who received Thymoglobulin®: 29 days [interquartile range 22-36] versus 22 days [19.5-29.5], p=0.004. We observed significantly higher counts of total and T CD4+ lymphocytes 1 month after transplant in patients who received Thymoglobulin® as compared to those who received Grafalon®: 238/mm3 [172-466] versus 137/mm3 [51-306] respectively (p=0.005), and 40/mm3 [31.5-70.5] versus 16/mm3 [2.5-41.5], respectively (p=0.011). No differences in immune cell population counts were found 3, 6 and 12 months after transplant (figure 1). However, joint models found no difference in the evolution of lymphocyte subsets analyzed depending on the ATG used, except a non-significant difference in slopes over time for CD8+ cells (p=0.13). In patients given Thymoglobulin® compared to those given Grafalon®, we found a higher proliferation in response to stimulation by CD3 3 month after HSCT (CD3 index 20.4 [12.4;41] versus 5.9 [3.3;6.4] respectively, p=0.0039), and a higher proliferation in response to stimulation by adenovirus (ADV) antigen 1 year after HSCT (ADV index 78.6 [58.8;163.1] versus 15.7 [2.8;59.3] respectively, p=0.027). We found no effect of ATG type on overall survival (OS), disease-free survival (DFS), treatment-related mortality and chronic GvHD. In a multivariate analysis, we observed no effect of the type of ATG on OS and DFS. Conclusions We found a higher count of total and T CD4+ lymphocytes 1 month after unrelated allo-HSCT for ALL in children who received Thymoglobulin® at 7.5mg/kg compared to those who received Grafalon® at 60mg/kg. From 3 months after HSCT, we found no difference in immune reconstitution. Joint models for longitudinal data and survival found no significant difference in evolution of the lymphocyte subsets analyzed. Clinical outcomes were similar between the two groups. However, we compared an intermediate dose of Thymoglobulin® to a high dose of Grafalon® that is not still the standard in clinical practice. A prospective study comparing Thymoglobulin® to a lower dose of Grafalon® would be needed. Disclosures Baruchel: Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Bellicum: Consultancy. Dalle:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum: Consultancy, Honoraria; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

Prognostic factors for survival after allogeneic transplantation in acute lymphoblastic leukemia

Allogeneic stem cell transplantation (allo-SCT) offers a curative option in adult patients with acute lymphoblastic leukemia (ALL). Prognostic factors for survival after allo-SCT have not been sufficiently defined: pheno-/genotype, patients´ age, conditioning regimens and remission at allo-SCT are under discussion. We analyzed the outcome of 180 consecutive adult ALL-patients undergoing allo-SCT at our center between 1995 and 2018 to identify specific prognostic factors. In our cohort 19% were older than 55 years, 28% had Philadelphia-positive B-ALL, 24% T-ALL. 54% were transplanted in first complete remission (CR1), 13% in CR2 after salvage therapy, 31% reached no remission (8% within first-line, 23% within salvage therapy). In 66% conditioning contained total body irradiation (TBI). With a median follow-up of 10 years, we observed an overall survival of 33% at 10 years, and a progression free survival of 31%. The cumulative incidence of relapse was 41% at 10 years, the cumulative incidence of non-relapse mortality 28%. Acute graft-versus-host disease (GvHD) II°–IV° occurred in 31%, moderate/severe chronic GvHD in 27%. Survival was better in patients reaching CR before allo-SCT and in those receiving TBI. No difference between patients younger/older than 55 years and between different phenotypes was observed. Survival after allo-SCT improved considerably over the last decades.

Bone marrow versus mobilized peripheral blood stem cell graft in T-cell-replete haploidentical transplantation in acute lymphoblastic leukemia.

The ideal stem cell graft source remains unknown in haploidentical haematopietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide (PTCy). This study compared outcomes of bone marrow (BM) versus peripheral blood (PB) stem cell graft for haplo-HCT in acute lymphoblastic leukemia (ALL). A total of 314 patients with ALL (BM-157; PB-157) were included in this study. The cumulative incidence of engraftment at day 30 was higher in the PB group compared with BM (93% vs. 88%, p < 0.01). The incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were not significantly different between the study cohorts. In the multivariate analysis, there were tendencies toward a higher incidence of grade II-IV acute GVHD (hazard ratio (HR) = 1.52, p = 0.07), chronic GVHD (HR = 1.58, p = 0.05), and nonrelapse mortality (NRM) (HR = 1.66, p = 0.06) in patients receiving PB versus BM graft, respectively. The use of PB grafts was associated with lower leukemia-free survival (LFS) (HR = 1.43, p = 0.05), overall survival (OS) (HR = 1.59, p = 0.02), and GVHD-free, relapse-free survival (GRFS) (HR = 1.42, p = 0.03) compared with BM grafts. There was no difference in relapse incidence (HR = 1.23, p = 0.41) between the study groups. In conclusion, use of BM graft results in better survival after haplo-HCT with PTCy in patients with ALL, compared with PB stem cell graft.