Acute Lymphoblastic Leukemia In CR1 Research Articles

Haploidentical vs. HLA-matched donor hematopoietic stem-cell transplantation for pediatric patients with acute lymphoblastic leukemia in second remission: A collaborative retrospective study of the Spanish Group for Bone Marrow Transplantation in Children (GETMON/GETH) and the Spanish Childhood Relapsed ALL Board (ReALLNet).

Studies addressing the role of haploidentical as alternative to HLA-matched donors for stem cell transplantation (SCT) often include patients with diverse hematological malignancies in different remission statuses. We compared outcomes of children with acute lymphoblastic leukemia (ALL) undergoing SCT in second complete remission (CR2) from haploidentical (n = 25) versus HLA-matched donor (n = 51). Patients were equally distributed across both groups according to age, immunophenotype, time to and site of relapse, relapse risk-group allocation, and minimal residual disease (MRD) before SCT. Incidence of graft failure, acute graft versus host disease (GVHD), and other early complications did not differ between both groups. We found no differences in overall survival (58.7% versus 59.5%; p = .8), leukemia free survival (LFS) (48% versus 36.4%; p = .5), event free survival (40% versus 34.4%; p = .69), cumulative incidence (CI) of subsequent relapse (28% versus 40.9%; p = .69), treatment related mortality (24% versus 23.6%; p = .83), CI of cGVHD (4.5% versus 18.7%; p = .2), and chronic GVHD-free and leukemia-free survival (44% versus 26.3%; p = .3) after haploidentical donor SCT. Chronic GVHD (HR = 0.09; p=.02) had protective impact, and MRD ≥ 0.01% before SCT (HR = 2.59; p=.01) had unfavorable impact on LFS. These results support the role of haploidentical donor SCT in children with ALL in CR2.

Autologous versus allogeneic hematopoietic cell transplantation for older patients with acute lymphoblastic leukemia. An analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced intensity conditioning (RIC) is an option for elderly patients with acute lymphoblastic leukemia (ALL). We retrospectively compared results of RIC-allo-HCT from either a matched sibling donor (MSD, n = 209) or matched unrelated donor (MUD, n = 209) with autologous (auto, n = 142) HCT for patients aged 55 years or more treated in first complete remission (CR1) between 2000 and 2018. The probabilities of leukemia-free survival (LFS) at 5 years were 34% for RIC-allo-HCT versus 39% for auto-HCT (p = 0.11) while overall survival (OS) rates were 42% versus 45% (p = 0.23), respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) was 41% versus 51% (p = 0.22) and 25% versus 10% (p = 0.001), respectively. In a multivariate model, using auto-HCT as reference, the risk of NRM was increased for MSD-HCT (Hazard ratio [HR] = 2.1, p = 0.02) and MUD-HCT (HR = 3.08, p < 0.001), which for MUD-HCT translated into a decreased chance of LFS (HR = 1.55, p = 0.01) and OS (HR = 1.62, p = 0.008). No significant associations were found with respect to the risk of relapse. We conclude that for patients with ALL in CR1, aged above 55 years, auto-HCT may be considered a transplant option alternative to RIC-allo-HCT, although its value requires verification in prospective trials.

Risk Factors Influencing Transplant Outcomes of Adults with Acute Lymphoblastic Leukemia in First Complete Remission: A Retrospective Analysis from the ALWP of the EBMT

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains a standard of care for adult patients with acute lymphoblastic leukemia (ALL) at high risk of relapse, i.e. high-risk features at time of diagnosis (ex. Philadelphia (Ph) positive ALL), or detectable minimal residual disease (MRD+). The aim of our study was to identify risk factors influencing transplant outcomes in ALL patients transplanted between 2015 and 2021. Methods: We included adults undergoing allo-HSCT for ALL in CR1 with available data of ALL phenotype, Ph-status, and MRD pre-transplant. All donor types and stem cell sources were eligible, except cord blood. Ex-vivo T-cell depletion (TCD) represented an exclusion criterion. Results: We identified 2349 transplanted patients including 870 from HLA-matched sibling (MSD), 1150 from unrelated (79% 10/10 and 21% 9/10 UD), and 329 from haploidentical donors (Haplo). Median age was 42.6 (range 18-76.1) years. Median follow-up was 23.5 (95% CI 21.8-24.2) months. The entire cohort was composed of 667 patients (28.4%) with Ph-negative B-ALL, 1325 (56.4%) with Ph-positive B-ALL and 357 (15.2%) with T-ALL. Median time from diagnosis to allo-HSCT was 5.8 (range 1.3-18) months. Stem cell source was peripheral blood (PB) in 85.3% of cases. Conditioning regimen was reduced-intensity (RIC) in 21% and myeloablative (MAC) in 79% of cases. Total body irradiation (TBI) was used in 65.8% of patients, mostly as a MAC (93.9%). Pre-transplant MRD+ was reported in 35.4% while in-vivo TCD was used in 51.5% of cases. At 180 days, cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (aGVHD) were 29.2% (95% CI 27.3-31.1) and 10.1% (95% CI 8.9-11.4), respectively. Two-years overall and extensive chronic GVHD (cGVHD) were 34% (95% CI 31.7-36.3) and 15% (95% CI 13.2-16.8), respectively. At two years, relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS) were 22.2% (95% CI 20.3-24.2), 15.4% (95% CI 13.8-17.1), 62.3% (95% CI 60-64.6) 73.9% (95% CI 71.7-76) and 48% (95% CI 45.6-50.3), respectively. By multivariate analysis, MSD (reference group) was associated to higher RI compared to 9/10 UD (HR 1.47, 95% CI 1.01-2.12; p<0.05) and Haplo (HR 1.64, 95% CI 1.15-2.27; p<0.01) but lower NRM and grade II-IV aGVHD compared to both 9/10 and 10/10 UD (for NRM HR 0.54, 95% CI 0.36-0.81; p<0.01 and HR 0.65, 95% CI 0.48-0.88; p<0.01; for aGVHD: HR 0.58, 95% CI 0.44-0.78; p<0.01 and HR 0.70, 95% CI 0.56-0.87; p<0.01). Compared to Ph-negative ALL (reference group), Ph-positive ALL was associated with a lower RI (HR=0.61, 95% CI 0.49-0.77; p<0.01) and higher LFS (HR=0.71, 95% CI 0.60-0.85; p<0.01), OS (HR=0.59, 95% CI 0.48-0.72; p<0.01) and GRFS (HR=0.81, 95% CI 0.70-0.94; p<0.01), while T-ALL was associated to lower NRM (HR 0.58, 95% CI 0.37-0.91: p<0.02) and cGVHD (HR 0.73, 95% CI 0.54-0.98; p<0.04). MRD+ group faced higher RI (HR=1.74, 95% CI 1.42-2.12; p<0.01), lower LFS (HR=1.41, 95% CI 1.21-1.65; p<0.01), OS (HR=1.31, 95% CI 1.08-1.58; p<0.01) and GRFS (HR=1.31, 95% CI 1.14-1.49; p<0.01). Use of TBI enabled lower RI (HR 0.78, 95% CI 0.61-0.99; p=0.04), higher LFS (HR=0.80, 95% CI 0.67-0.96; p<0.02) but higher grade II-IV aGVHD (HR 1.54, 95% CI 1.23-1.92; p<0.01) and cGVHD (HR 1.47, 95% CI 1.16-1.87; p<0.01) compared to chemotherapy. Patients receiving a RIC had a higher RI (HR=1.52, 95% CI 1.17-1.98; p<0.01) and a lower NRM (HR=0.55, 95% CI 0.39-0.77; p<0.01). In vivo TCD allowed lower risk of cGVHD (HR=0.69, 95% CI 0.55-0.85; p<0.01) and higher GRFS (HR=0.78, 95% CI 0.66-0.91; p<0.01). PB stem cells and female-donor to male-recipient were independently associated to higher risk of cGVHD. Elderly patients faced lower LFS, OS and GRFS. Conclusions: Our study reported overall favorable outcomes in the population of recently allografted patients with ALL in CR1 (LFS> 60% et OS> 70% at 2 years). Prognostic role of pre-transplant MRD is confirmed. Results in Ph-positive ALL are not inferior compared to Ph-negative ALL, most probably due to the use of tyrosine kinase inhibitors. Whether incorporation of novel agents will change the role of allo-HSCT in Ph-positive ALL is under investigation. Use of TBI and HLA mismatches are both associated with lower RI despite a higher risk of GVHD, highlighting the importance of tailoring GVHD prophylaxis in these settings.

Prognostic Significance of Measurable Residual Disease for Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Stem Cell Transplant in Second Complete Remission and Beyond

Introduction: For patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HCT) in first complete remission (CR1), measurable residual disease (MRD) prior to HCT is strongly associated with post-HCT relapse rates and overall survival (OS). However, for a growing number of patients with ALL, HCT is deferred until the second remission (CR2) or beyond. It is unclear whether pre-transplant MRD assessment is also prognostic in the setting of HCT beyond CR1. Methods: We performed a single center retrospective study to test the hypothesis that pre-transplant MRD positivity is associated with outcomes in patients receiving HCT in CR2 or beyond for ALL. MRD was measured by 6-color flow cytometry with a sensitivity of 0.01%. Consecutive pediatric and adult patients who underwent first allogeneic HCT between the years 2004-2021 for ALL in CR2 or beyond were included. Results: We identified 162 patients (Table 1), 123 (76%) with B-ALL and the remainder with T-ALL. The majority (80%, n=129) of patients were in CR2 at the time of HCT, the remainder in third CR or beyond (CR3+). One hundred and five (65%) patients were male and median age at transplant was 31 (range 4-69) years. Graft source was either matched unrelated donor (MUD) (43%, n=69), matched sibling donor (MSD) (24%, n=39), haploidentical (18%, n=29) or cord blood transplantation (CBT) (15%, n=25). Pre-HCT MRD status was determined for 150 (93%) of patients and of those was positive in 43 (26%). Subsequent analyses were limited to the subset of patients with known MRD status. There was no statistical difference in characteristics according to MRD status except for higher proportion of CR3+ patients (33% vs. 16%, p=0.02) and comorbidity index >2 (70% vs. 40%, p=0.001) in MRD positive vs. negative patients. The median follow-up in surviving patients was 62 (range 20-104) and 47 (range: 2-171) months in MRD positive and negative patients, respectively. In multivariate analysis (MVA) evaluating transplantation outcomes at 3 years, pre-HCT MRD positivity was associated with a higher rate of disease relapse (HR 1.9, 95% CI 1.1-3.6; p=0.02); but it had no impact on non-relapse mortality (NRM) (HR 0.8, 95% CI 0.4-1.8; p=0.6). Subset analyses showed that these trends were consistent for patients receiving HCT in CR2 or CR3+; however the impact on disease relapse was more pronounced for patients in CR2 at HCT. MRD positivity was also associated with less favorable overall (HR 1.96, 95% CI 1.2-3.3; p=0.01) and progression-free survival (PFS) (HR 2.5, 95% CI 1.5-4.2; p<0.001) for patients receiving HCT in CR2. MRD was not associated with OS (HR 0.9, 95% CI 0.4-2, p=0.8) or PFS (HR 0.8, 95% CI 0.3-1.7, p=0.5) for patients receiving HCT in CR3+. As shown in Figure 1 A-B, OS and PFS were significantly superior for MRD negative patients receiving HCT in CR2. OS and PFS for MRD positive patients in CR2 were comparable to patients receiving HCT in CR3+. Conclusions: Pre-transplant MRD positivity is predictive of disease relapse in patients undergoing HCT for ALL in CR2 or beyond; however, the survival advantage associated with MRD negativity maybe limited to patients undergoing HCT in CR2. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The role of allogeneic transplant for adult Ph+ ALL in CR1 with complete molecular remission: a retrospective analysis

AbstractHistorically, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with poor outcomes, and allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1). However, in the tyrosine kinase inhibitor (TKI) era, rapid attainment of a complete molecular remission (CMR) is associated with excellent outcomes without allo-HCT, suggesting transplant may not be required for these patients. To test this hypothesis, we retrospectively identified adult patients with Ph+ ALL treated with induction therapy, including TKIs, and attained CMR within 90 days of diagnosis at 5 transplant centers in the United States. We compared outcomes of those who did and did not receive allo-HCT in first remission. We identified 230 patients (allo-HCT: 98; non-HCT: 132). The allo-HCT cohort was younger with better performance status. On multivariable analysis (MVA), allo-HCT was not associated with improved overall survival (adjusted hazard ratio [aHR]: 1.05; 95% CI, 0.63-1.73) or relapse-free survival (aHR: 0.86; 95% CI, 0.54-1.37) compared with non-HCT treatment. Allo-HCT was associated with a lower cumulative incidence of relapse (aHR: 0.32; 95% CI, 0.17-0.62) but higher non-relapse mortality (aHR: 2.59; 95% CI, 1.37-4.89). Propensity score matching analysis confirmed results of MVA. Comparison of reduced-intensity HCT to non-HCT showed no statistically significant difference in any of the above endpoints. In conclusion, adult patients with Ph+ ALL who achieved CMR within 90 days of starting treatment did not derive a survival benefit from allo-HCT in CR1 in this retrospective study.

Durable outcomes of double cord blood transplantation in adults with acute lymphoblastic leukemia: high-risk features for early and long-term mortality.

Background:Cord blood transplantation (CBT) has been reported as an acceptable option with comparable outcomes to conventional donors in adults with acute lymphoblastic leukemia (ALL). We aimed to analyze the long-term CBT outcomes and risk factors for early and long-term mortalities.Methods:Between 2006 and 2020, 112 patients (median age: 35 years; 62 Ph-negative ALL and 50 Ph-positive ALL) were treated with double CBT. Conditioning regimen consisted of total body irradiation (12 Gy) plus cytarabine (9.0 g/m2) plus fludarabine (150 mg/ m2), and graft-versus-host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil.Results:The median time for neutrophil and platelet recovery was 25 days (range: 5–59 days) and 34 days (range: 7–185 days), respectively. The cumulative incidence of acute GVHD at 1 year was 43.8%, and the incidence of acute GVHD with grades III–IV was 8.9%. The overall cumulative incidence of chronic GVHD was 22.0%, and the incidence of moderate to severe chronic GVHD was 8.5%. After a median follow-up of 60.1 months (range: 5.7–181.3 months), the 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) were 15.9% and 28.5% (9.7% and 27.2% for CR1), respectively, and the 5-year overall survival (OS) was 57.9% (66.5% for CR1). In multivariate analysis of 88 patients receiving double CBT in CR1, delayed CR1 was related to high CIR, and age older than 40 years was associated with high NRM and early mortality. Unexpectedly, Ph-positive ALL with MRD had a higher NRM and early mortality than Ph-negative ALL and Ph-positive ALL without MRD subgroups, possibly due to delayed neutrophil and platelet recovery.Conclusion:Our data suggest that double CBT for adult ALL in CR1 has a greater benefit in younger patients and in patients with Ph-positive ALL without MRD or Ph-negative ALL.

Decision Analysis for Unrelated Bone Marrow Transplantation or Immediate Cord Blood Transplantation for Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission

An HLA-matched relative is the first-choice donor for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The most promising alternative donor is thought to be an HLA-matched unrelated donor (MUD) in patients who do not have an HLA-matched related donor. Cord blood transplantation (CBT) is an alternative option. Higher rates of engraftment failure and nonrelapse mortality (NRM) are significant problems, but the ready availability of cord blood can be an advantage, because patients can immediately undergo transplantation before progression. This study was conducted to identify an appropriate alternative donor in patients with Ph-negative ALL in CR1 who do not have an HLA-matched related donor (MRD). Decision analyses using a Markov model were performed to compare immediate CBT, in which CBT was performed at 1 month after the achievement of CR1, with elective unrelated bone marrow transplantation (uBMT) from an 8/8 MUD (8/8 uBMT) or uBMT from a 7/8 MUD (7/8 uBMT), in which uBMT was performed at 4 months, in patients age 16 to 55 years with Ph-negative ALL in CR1 who did not have an MRD. We constructed a decision tree. The cycle length was set at 3 months, and analyses were performed for 19 cycles for uBMT and 20 cycles for CBT, resulting in evaluation of the 5-year life expectancy after both decisions. Transition probabilities (TPs) and utilities were estimated from prospective and retrospective Japanese studies and the registry database of Japan. Subgroup analyses were performed according to risk stratification based on WBC count and cytogenetics at diagnosis and according to age stratification, with a cutoff of 25 years. One-way sensitivity analyses for TPs and utilities were performed as well. The baseline analyses showed that 8/8 uBMT or 7/8 uBMT had superior results to CBT, with quality-adjusted life years (QALYs) of 2.86 in 8/8 uBMT, 2.84 in 7/8 uBMT, and 2.75 in CBT. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probability of NRM in CBT improved. Subgroup analyses showed similar results in younger, older, and high-risk patients. However, QALY was worse in 8/8 uBMT compared with CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in younger and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the one-way sensitivity analyses. For patients with Ph-negative ALL in CR1 who decide to undergo transplantation from an alternative donor, elective uBMT from either an 8/8 MUD or a 7/8 MUD is expected to yield a better outcome than immediate CBT. Nonetheless, CBT is a viable option, and improvements to reduce the risk of NRM in CBT may change these results.

Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Positive Acute Lymphoblastic Leukemia in First Complete Remission: A Systematic Review and Meta-Analysis

IntroductionPhiladelphia positive (Ph+) acute lymphoblastic leukemia (ALL) presents with an aggressive clinical course and carries a high risk for relapse. The addition of tyrosine kinase inhibitors (TKI) has revolutionized the induction and maintenance treatment for this disease and has increased the patients achieving and maintaining complete remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care at this time for patients who achieve first complete remission (CR1); however, its impact on outcomes is debated. This systematic review and meta-analysis aimed to compare the outcomes of TKI maintenance therapy with or without HSCT in Ph+ ALL patients in CR1.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for “ Philadelphia chromosome ”, “hematopoietic stem cell transplantation” and “ protein kinase inhibitors ” from date of inception to May 01, 2021. A total of 1691 records were discovered using database searching. All search results were imported into the Endnote X9.0 reference manager, and duplicates were removed. The primary and secondary screening was performed, and after excluding irrelevant and review articles, a total of 6 (3 retrospectives, 3 phase II randomized controlled trials) original articles were included reporting separate outcomes of TKI maintenance therapy (TKI cohort) and HSCT followed by TKI maintenance therapy (HSCT-TKI cohort) for Ph+ ALL in CR1. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with a 95% Confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the RevMan (version 5.4-1). RESULTSA total of 413 patients from 6 studies were included for this systematic review and meta-analysis. Out of these, 222 (53.8%) had TKI maintenance after consolidation therapy and 191 (46.2%) patients had HSCT followed by TKI maintenance in CR1. The median age of the whole cohort was 49.3 (17-84) years, while the median age for HSCT-TKI patients was 47 (14-84) years. The proportion of males was 26.2% (n=90) in TKI group versus 37.5% (n=137) in the HSCT-TKI group, as reported by 5 studies. The median follow-up was 28 (0.6-149) months. Imatinib mesylate (first-generation TKI) was used in 55.6% (n=125) patients and Dasatinib (second-generation TKI) was given to 44.4% (n=100) patients. (Table 1) Overall survival (OS) was reported from 100% and 93.3% at 1 year to 49% and 33% at 5 years for TKI and HSCT-TKI cohorts, respectively. At median follow-up time of 4 (3-5) years, a trend towards poor OS was seen with TKI group as compared to HSCT-TKI group (OR 0.46, 95% CI 0.17-1.23, I 2=70%); however, the association was not statistically significant. Disease-free survival (DFS) was reported from 49.3% and 71.3% at 4 years to 38.1% and 50.5% at 5 years for TKI and HSCT-TKI cohorts, respectively. At a median follow-up time of 4 (3-5) years, the pooled analysis showed poor DFS for TKI as compared to HSCT-TKI cohort (OR 0.30, 95% CI 0.17-0.53, I 2=0%). Four studies (n=292) reported separate outcomes for relapse, it was 59.1% (87/147) for TKI versus 14.5% (n=21/145) for HSCT-TKI patients, and odds of developing relapse were higher among patients receiving TKI as compared to HSCT-TKI (OR=8.08, 95% CI=3.81-17.14, I 2=0%). ConclusionHematopoietic stem cell transplant in Philadelphia positive acute lymphoblastic leukemia in first complete remission followed by tyrosine kinase inhibitor maintenance therapy confers disease-free and overall survival benefit compared to tyrosine kinase inhibitors maintenance alone. Our findings confirm HSCT as a standard of care in Ph+ ALL in CR1 followed by TKI maintenance and the need for a prospective randomized clinical trial to validate these findings. [Display omitted] DisclosuresLin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding.

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.

Long-Term Outcomes of Total Body Irradiation Plus Cyclophosphamide Versus Busulfan Plus Cyclophosphamide As Conditioning Regimen for Acute Lymphoblastic Leukemia: A Comparative Study

Introduction: Total body irradiation-Cyclophosphamide (TBI-Cy) and Busulfan-Cyclophosphamide (Bu-Cy) are the most commonly used conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HCT) for acute lymphoblastic leukemia (ALL). TBI-based conditioning regimens may have a better antitumor effect at sanctuary cites compared to chemotherapy regimens. However, some controversy still remains concerning the role of TBI in adult ALL. Therefore, we aimed to retrospectively investigate long-term treatment outcomes of ALL patients post allo-HCT and identify prognostic factors and the impact of the conditioning.Methods: We enrolled consecutive patients with ALL who underwent alloHCT from 1990 to 2016 in our center, following a TBI- or a Busulfan (Bu)-based conditioning regimen. TBI at 14.4Gy was divided at 6 fractions over 3 days and Bu (mainly oral) at 4mg/kg/day. Both regimens included 120mg/kg Cy. Graft source was mainly mobilized peripheral blood stem cells.Results: We studied 151 ALL (114 B-ALL, 35 T-ALL and 2 biphenotypic) patients aged 28±12 years, transplanted in CR1 (60), other CR (33) or relapsed/refractory disease (58) from sibling (87), HLA matched (42) or mis-matched (17) unrelated and alternative donors (5). TBI-based conditioning was administered in 84, whereas non-TBI in 67. No differences were observed in baseline characteristics, except for disease phase, disease risk index (DRI) and graft source. The majority of non-TBI patients had relapsed/refractory disease at transplant (50.7% versus 28.6% in TBI-conditioning, p=0.043) and subsequently significantly higher DRI (p=0.025). Furthermore, bone marrow was the graft source in significantly higher number of non-TBI patients (28.4% versus 8.3% in the TBI group, p=0.001).With a follow-up of 19.0 (0.5-170.5) in TBI and 14.5 (1.2-319.1) months in the non-TBI group, there was no difference in the incidence of acute (Grade 2-4) or chronic GVHD, thrombotic microangiopathy, bacterial or fungal infections. Only viral infections were significantly increased in the non-TBI group (59% versus 41% in the TBI group, p=0.03). Therefore, there was no significant difference in the cumulative incidence (CI) of treatment-related mortality (5-year CI of 24.1% in non-TBI versus 27.7% in the TBI group, p=0.678) or relapse mortality (5-year CI of 29.2% in non-TBI versus 37.1% in the TBI group, p=0.283).Overall survival (OS) was similar in the TBI and non-TBI group (5-year 46.7% compared to 35.8%, p=0.201). In the multivariate analysis, unfavorable pre-transplant predictors of OS were age (p=0.024), higher disease risk index (DRI) (p=0.007) and female to male donor (p=0.006). Disease-free survival (DFS) was similar in the TBI and non-TBI group (5-year 47.1% compared to 35.4%, p=0.134), with age, higher DRI and female to male donor being unfavorable predictors. When the analysis was limited to patients transplanted in CR1 (40 in the TBI versus 20 in the non-TBI group), there were also no significant differences.Interestingly, age predicted OS and DFS only in the TBI group. TBI patients younger than 40 years had significantly high OS (55.1%, p=0.023) and DFS (55.5%, p=0.02) versus the older ones. Older TBI patients had higher TRM (43.3% versus 20.1%, p=0.135) and relapse mortality (45.8 versus 24.7, p=0.238) that did not reach levels of statistical significance. However, the same was not true for the non-TBI group (p=0.233 for DFS, p=0.326 for OS).Conclusion: In our retrospective data of the last 3 decades, the type of conditioning regimen did not influence the outcome of transplantation. Based on our results, high dose TBI is a feasible conditioning in terms of a prolonged DFS and OS for younger patients and seems an efficient tool to cure high-risk ALL in CR1. It should be kept in mind that intravenous BU is also used with stable pharmacokinetics. Since our data were not powered to appraise superiority of one regimen in terms of efficacy and toxicity, the choice between TBI or Bu conditioning regimens is still under consideration. Treatment is complex for adult ALL patients and remains a field of debate and a challenge for prospective studies in the future. DisclosuresGavriilaki:European Hematology Association: Research Funding.

Indications for Allogeneic HCT in Adults with Acute Lymphoblastic Leukemia in First Complete Remission.

Acute lymphoblastic leukemia (ALL) in adults is associated with poor outcomes as compared to children when treated with chemotherapy, leading to a considerably inferior cure rate. Historically, consolidation with allogeneic hematopoietic cell transplant (alloHCT) was routinely recommended for eligible adults with ALL in first complete remission (CR1) if a donor was available, since randomized studies showed superiority over continuing chemotherapy. With the increasing use of pediatric-inspired frontline regimens in young adults with ALL and the availability of novel salvage agents for relapsed/refractory B-cell ALL that have high potential in inducing a second CR, the role of early alloHCT in the treatment paradigm for ALL needs to be reevaluated, and the decision should be individualized for each patient. Simultaneously, alloHCT has evolved considerably lately, and historical randomized studies that have proven the benefit of alloHCT in adults with ALL in CR1 did not included the increasing use of reduced intensity conditioning and haploidentical transplants, and therefore, data may not entirely apply. Nowadays, detectable minimal residual disease (MRD) is the most prognostic determinant of ALL outcome and should be a major consideration in the decision to perform alloHcT in CR1. Nonetheless, other biological and clinical factors remain relevant and can support the complex decision-making. Such factors include high-risk leukemia genetics, the type of administered chemotherapy regimen and the ability of the patient to tolerate all key components of the regimen, and the availability of effective salvage therapies that allow alloHCT to be performed in CR2 in case of relapse after chemotherapy.

Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT

BackgroundThere is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL).MethodsWe retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n = 78), matched unrelated (MUD) (n = 94) and haploidentical family (Haplo) (n = 297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years.ResultsMedian age of patients was 38 years (range 18–76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II–IV and III–IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p = 0.4); 13%, 15%, and 15% (p = 0.8); 35%, 50%, and 42% (p = 0.01); and 11%, 17%, and 21% (p = 0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p = 0.8); and 21%, 18%, and 21% (p = 0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p = 0.8); 66%, 69%, and 62% (p = 0.8); and 46%, 44%, and 35% (p = 0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS.ConclusionsDonor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Impact of donor type on long-term graft-versus-host disease-free/relapse-free survival for adult acute lymphoblastic leukemia in first remission.

We assessed the impact of donor type on long-term outcomes of allogeneic hematopoietic cell transplantation (HCT) in 440 consecutive adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1), particularly focusing on the donor type-specific difference in graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS). Donor sources were matched sibling donor (MSD; n = 199), matched unrelated donor (MUD; n = 110), 1-allele-mismatched unrelated donor (1-MMUD; n = 83), and cord blood (CB; n = 48). Cumulative incidence of severe chronic GVHD was 14.8% for MSD-HCT, 30.1% for MUD-HCT, 9.6% for 1-MMUD-HCT, and 4.2% for CBT, respectively (P < 0.001), while no difference was observed in grade III-IV acute GVHD. After a median follow-up of 58.1 months, cumulative incidence of relapse was 26.1% for MSD-HCT, 27.2% for MUD-HCT, 31.2% for 1-MMUD-HCT, and 7.2% for CBT, respectively (P = 0.042). Disease-free survival and overall survival were comparable among all donor sources. However, GRFS for MSD-HCT, MUD-HCT, 1-MMUD-HCT, and CBT was 33.1%, 14.5%, 42.1%, and 50.3%, respectively (P = 0.001). In multivariate analysis, CBT showed a comparable GRFS to MSD-HCT (HR, 0.78; P = 0.290), while MUD-HCT was associated with a poorer GRFS (HR, 1.53; P = 0.002). Given the encouraging GRFS of CBT, our data suggest that CBT remains a valid option for adult ALL in CR1.

Superior Survival with Post-Remission Pediatric-Inspired Chemotherapy Compared to Myeloablative Allogeneic Hematopoietic Cell Transplantation in Adolescents and Young Adults with Ph-Negative Acute Lymphoblastic Leukemia in First Complete Remission: Comparison of CALGB 10403 to Patients Reported to the CIBMTR

Optimal post-remission therapy for adolescents and young adults (AYAs, 16-39 years) with Ph-negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not well established. We hypothesized that post-remission therapy with a pediatric-inspired regimen would yield superior outcomes to myeloablative allogeneic HCT for AYA patients with Ph- ALL in CR1. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a contemporary matched AYA cohort undergoing myeloablative allogeneic HCT in CR1 reported to the CIBMTR (Table). The allogeneic HCT cohort consisted of patients 16-39 years of age with Ph- ALL in CR1 undergoing myeloablative transplant from a matched sibling/relative or unrelated donor using peripheral blood or bone marrow stem cells between 11/2002 and 8/2012 in the United States. Patients receiving post-remission therapy with pediatric-inspired chemotherapy had superior OS (P&amp;lt;0.0001), DFS (P=0.0011), and NRM (P&amp;lt;0.001) compared to allogeneic HCT. Patterns of relapse were time-dependent and examined in the Cox model. In multivariate analysis of Cox model, receiving allogeneic HCT was associated with inferior OS (HR 1.99, 95% CI 1.5-2.65, P &amp;lt;0.001), inferior DFS (HR 1.51, 95% CI 1.17-1.94, P 0.002), and increased NRM (HR 3.93, 95% CI 2.53-6.10, P &amp;lt;0.001; Figure). In the early post-remission period (≤15 months after CR1), relapse was more likely with allogeneic HCT (HR 1.63, 95% CI 1.03-2.59, p=0.04) whereas beyond 15 months after CR1 relapse was more likely in the chemotherapy arm (HR 0.35, 95% CI 0.19-0.62, P &amp;lt;0.001; Figure). Obesity (BMI ≥30) was independently associated with inferior OS (HR 2.22, 95% CI 1.69-2.91, P&amp;lt;0.001), inferior DFS (HR 1.96, 95% CI 1.52-2.53, P &amp;lt;0.001), increased relapse (1.90, 95% CI 1.37-2.64, P &amp;lt;0.001), and increased NRM (HR 1.99, 95% CI 1.33-2.97, P &amp;lt;0.001). Extramedullary disease at diagnosis was independently associated with inferior OS (HR 1.34, 95% CI 1.00-1.79, P=0.05). We conclude from this large retrospective study that post-remission therapy with pediatric-inspired chemotherapy as given on CALGB 10403 was superior to allogeneic HCT in CR1 for OS, DFS, and NRM in AYAs with newly-diagnosed Ph-negative B- and T-cell ALL. Late relapse was more likely with chemotherapy whereas early relapse was more likely with allogeneic HCT. Future study should aim to elucidate the impact of measurable residual disease at CR1 and high-risk genetics, including Ph-like ALL, on the superiority of post-remission pediatric-inspired chemotherapy over allogeneic HCT. Figure. Allogeneic HCT (HCT) vs. CALGB 10403 pediatric-inspired chemotherapy (chemo) after CR1: Adjusted (left-truncated) overall survival, disease-free survival, cumulative incidence of relapse, and cumulative incidence of non-relapse mortality. Disclosures Wieduwilt: Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership. Stock:Astellas: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Luger:Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Agios: Honoraria. Larson:Novartis: Honoraria, Other: Contracts for clinical trials; Agios: Consultancy; Celgene: Consultancy. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, 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; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents &amp; Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kebriaei:Kite: Honoraria; Jazz: Consultancy; Amgen: Research Funding; Pfizer: Honoraria. Weisdorf:Pharmacyclics: Consultancy; Incyte: Research Funding; Fate Therapeutics: Consultancy.

The Optimal Treatment Strategy for Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission in the Era of High-Intensity Chemotherapy

The Optimal Treatment Strategy for Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission in the Era of High-Intensity Chemotherapy

Unmanipulated haploidentical peripheral blood stem cell transplantation for patients with Philadelphia-negative acute lymphoblastic leukaemia in first complete remission

Haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) is a promising treatment option for patients with Ph-negative acute lymphoblastic leukemia (ALL). In this study, we retrospectively analyzed data from Ph-negative ALL patients who underwent haplo-PBSCT during their first complete remission (CR1), and compared the long-term outcomes between the standard-risk and high-risk patients. The 3-year probability of relapse was 7.6% and 16.7% for the standard- and high-risk group (p = .274). The 3-year probability of disease-free survival (DFS) and overall survival (OS) for the standard-risk versus high-risk groups were 84.6% versus 50% (p = .0063) and 92.3% versus 61.1% (p = .046), respectively. Univariate analysis showed that a diagnosis of high risk with fusion/mutation genes were associated with worse outcomes, which was confirmed by multivariate analysis (p = .016). In summary, haplo-PBSCT may be a promising alternative for patients with Ph-negative ALL in CR1, although the fusion/mutation genes in high-risk patients may relatively impair the long-term efficacy compared with standard-risk patients.

Haplo-HSCT Is Superior to Chemotherapy for Standard Risk ALL in CR1—Results of Prospective Multicenter Trial (NCT02042690)

Background In the present prospective multicenter trial (NCT02042690), we investigated whether haplo-HSCT has a favorable impact on survival as post remission treatment for standard risk acute lymphoblastic leukemia (ALL) patients in the first complete remission (CR1) by comparing with chemotherapy alone. Methods £°Inclusion criteria of ALL:(1) age 18 to 39 years; (2) without high-risk features, which consisted of elevated WBC count(>30 *109/L for B cell lineage or >100 *109/L for T cell lineage), or high-risk cytogenetic abnormalities, determined according to the National Comprehensive Cancer Network 2013 guidelines; and (3) achieving CR after 1 to 2 cycles of induction. Subjects without a suitable HLA matched sibling (MSD) or HLA-matched unrelated donor (iÝ8/10 URD) after 2 cycles of consolidation (Hyper-CVAD B/A*1) were eligible for haplo-HSCT or further chemotherapy (Hyper-CVAD B/A*3). Landmark analysis (4 months after CR1) was used when comparing the outcomes of patients receiving haplo-HSCT vs. chemotherapy. A propensity score (PS) was calculated using multivariable logistic regression for each individual. The hazard ratios (HRs) for Leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse(CIR), and nonrelapse mortality(NRM) were adjusted with PS. Results Newly diagnosed standard risk ALL patients meeting inclusion criteria (n=112) were consecutively enrolled at 5 centers including Peking University Peoplei¯s Hospital, Peking Union Hospital, Wuhan Union Hospital, First Hospital of Soochow University and General Hospital of PLA and between July 2014 and June 2017, with median follow-up 24.6 months. Patients were excluded in final analysis: 1) early relapse (n=6) within 4 months after CR1; 2) MSD-HSCT (n=16) or URD-HSCT (n=1). The remaining patients (n=89) either received haplo-HSCT (n=49) or chemotherapy (n=40). The 2-year LFS (70.5 [54.2-81.9]% vs 41.4[25.9-56.2]%, p=0.0073) and 2-year OS (81.3 [65.5-91.4]% vs 51.2[33.8-66.1]%, p=0.0073) of the Haplo-HSCT group was significantly higher than the chemotherapy group. In the multivariate analysis with propensity score adjustment, postremission treatment (haplo-HSCT vs chemotherapy) was an independent risk factor affecting the LFS (HR 0.388, 95% CI 0.172-0.873, P=0.022), OS (HR 0.346, 95% CI 0.156-0.140-0.853, P=0.003) and CIR(HR 0.247, 95% CI 0.098-0.624, P=0.003); Positive minimal residual disease after the first consolidation was an independent risk factor for LFS (HR 2.162, 95% CI 0.973-4.803, P=0.027) and CIR (HR 3.667, 95% CI 1.445-9.302, P=0.006). Diagnosis (T vs B) was an independent risk factor for OS(HR2.267, 95% CI 1.493-3.442, P=0.021). Conclusions Our results suggest that Haplo-HSCT is superior to chemotherapy alone as post-remission treatment for in adult patients (age 18-39) with standard risk ALL in CR1.

Allogeneic Stem Cell Transplantation from Unmanipulated Haploidentical Donors Versus Matched or Mismatched 9/10 Unrelated Donors in Acute Lymphoblastic Leukemia in First Complete Remission: On Behalf of the ALWP of the EBMT

▪Background:Unmanipulated T-cell replete haploidentical allogeneic stem cell transplantation has become an attractive alternative choice for patients with no HLA matched sibling or unrelated donors. However data of outcome in patients with Acute Lymphoblastic Leukemia (ALL) is still scarce. The Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) conducted this study to compare the outcome of allogeneic transplantation (Allo-SCT) from haploidentical donor (Haplo) versus matched (MUD 10/10) or mismatched (MMUD 9/10) unrelated donor for patients with ALL in first Complete Remission (CR1).Methods:The outcomes of 1,234 adult patients with Philadelphia positive or negative (Ph+ / Ph-) B ALL or T ALL in CR1 who underwent Allo-SCT between 2007 and 2016 were analyzed. Comparison was made between Haplo (136 patients), MUD 10/10 (809 patients) and MMUD 9/10 (289 patients).Multivariate analyses were performed using the Cox proportional-hazard model. To control potential confounding factors between treatments that could influence outcome, propensity score matching was also performed between Haplo and the 2 other groups.Results:Main population characteristics are depicted in Table 1. Recipients of Haplo, MUD 10/10 and MMUD 9/10 were comparable concerning median age, time from diagnosis to Allo-SCT and myeloablative versus reduced intensity conditioning (MAC/RIC). However, Haplo transplants cohort differed in several characteristics from the MUD and MMUD patients groups. The percentage of female donors was higher in Haplo transplants and female to male mismatch was higher accordingly, CMV matched negative status was lower in Haplo. The source of stem cells was bone marrow (BM) versus peripheral blood (PB) stem cells in significantly higher percentage of Haplo transplants (53.7% vs 15.1% and 16.6% for MUD and MMUD respectively, p<0.0001). Most Haplo patients received post-transplant cyclophosphamide for graft versus host disease (GVHD) prophylaxis (77%) while this regimen was rarely used in the other groups (about 3%, p=0.0005).Univariate analysis showed similar results in Haplo, MUD and MMUD. Disease free survival (DFS) at 3 years was 49±11%, 53±4% and 55±7%, respectively (p=0.67) (Figure 1). Overall survival (OS) was 54±11%, 62±4% and 62±6%, respectively (p=0.11) (Figure 2). Relapse incidence (RI) and non-relapse mortality (NRM) at 3 years were not different either, RI was 28±9%, 28±4% and 25±6%, respectively (p=0.7) and NRM was 23±8%, 19±3% and 20±6%, respectively (p=0.6). Acute GVHD (AGVHD), either grade II-IV or grade III-IV and chronic GVHD (CGVHD) did not differ between the 3 groups (p=0.1, p=1.0 and p=0.6 respectively). The GVHD-relapse free survival (GRFS) was also not statistically different between the groups, 43±10%, 43±4% and 46±7%, respectively (p=0.7).After adjustment for center effect, patient age, donor/patient gender, donor and patient CMV serostatus, ALL type (B Ph- vs B Ph+ vs T), time from diagnosis to SCT, type of conditioning and cell source (PB vs BM), the multivariate Cox model showed that Haplo recipients did not experience worse outcomes compared to MUD 10/10 and MMUD 9/10. Indeed, compared to Haplo, the Hazard Ratio (HR) for DFS was 1.1 for MUD (p=0.7) and 1.1 for MMUD (p=0.8). The HR for OS in MUD and MMUD did not differ from Haplo either (HR=0.9, p=0.4 and HR=1.0, p=1.0 respectively). Moreover, compared to Haplo, SCT from MUD and MMUD were not associated with lower hazards for RI (HR=0.9, p=0.8 and HR=0.7, p=0.2 respectively), NRM (HR=0.7, p=0.2 and HR=0.8, p=0.4 respectively), AGVHD II-IV (HR=1.1, p=0.8 and HR=1.2, p=0.3 respectively) and CGVHD (HR=0.8, p=0.2 and HR=0.9, p=0.6 respectively).Propensity matching confirmed the results of the multivariate Cox analysis with no difference in outcome between Haplo, MUD and MMUD. Compared to Haplo the HR for DFS and OS were 1.04 (p=0.84) and 0.85 (p=0.50) for MUD and 0.9 (p=0.66) and 0.82 (p=0.48) for MMUD.Conclusions:Outcomes of adult patients with ALL in CR1 receiving Haplo Allo-SCT are comparable to MUD or MMUD transplants. Haplo should be considered as an additional option for patients lacking a matched sibling donor. [Display omitted] DisclosuresTischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mohty:MaaT Pharma: Consultancy, Honoraria.

Prevalence and Safety of Intravenous Immunoglobulin Administration During Maintenance Chemotherapy in Children with Acute Lymphoblastic Leukemia in First Complete Remission: A Health Maintenance Organization Perspective

Children with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) experience hypogammaglobulinemia and are at risk of sepsis during maintenance chemotherapy. Intravenous immunoglobulin (IVIG) has been used to try to circumvent this risk, but no data exist regarding its safety and prevalence in a health maintenance organization. To evaluate the prevalence and safety of IVIG in children with ALL in CR1 during maintenance chemotherapy. A multicenter, retrospective cohort study of consecutive children with ALL in CR1 during maintenance chemotherapy from 2008 to 2014. Groups treated with or without IVIG were compared using nonparametric statistics. Multivariate logistic regression involved all variables available before maintenance therapy began. One hundred eighteen patients were included (53% males), aged 9 months to 19 years. Thirty of 31 patients (97%) who had immunoglobulins analyzed before IVIG were hypogammaglobulinemic. Thirty-six patients (30%) received IVIG during maintenance chemotherapy. Patients received an average of 10.5 IVIG doses (range = 1-31). Ninety-seven percent of doses were administered without a transfusion reaction. Other factors associated with IVIG use were prior double-delayed intensification (odds ratio = 5.36, 95% confidence interval = 1.3-27.49, p = 0.026) and episodes of bacteremia or fungemia before maintenance chemotherapy (odds ratio = 3.04, 95% confidence interval = 1.25-7.51, p = 0.015). Use of IVIG in children with ALL in CR1 with hypogammaglobulinemia occurred in approximately 30% of patients and was well tolerated. Administration of IVIG significantly correlated with a history of double-delayed intensification and prior bacteremia or fungemia.