Acute Lymphoblastic Leukemia In First Complete Remission Research Articles

Phase 2 study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission

AbstractThe detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10−4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) were in CR1 and seven (27%) in CR2+; 16 (62%) had Philadelphia chromosome–positive ALL. Fifteen (58%) had baseline MRD ≥ 1 × 10−3. A median of 3 cycles (range, 1-6) were administered. Eighteen (69%) patients responded and achieved MRD negativity. After a median follow-up of 24 months (range, 9-43), the 2-year relapse-free survival rate was 54% and the 2-year overall survival rate was 60% in the entire cohort. Most adverse events were low grade; sinusoidal obstruction syndrome was noted in 2 patients (8%). In summary, inotuzumab ozogamicin resulted in favorable survival, MRD negativity rates, and safety profiles for patients with ALL and MRD-positive status. This study was registered at www.ClinicalTrials.gov as #NCT03441061.

Thiotepa-Based Regimens Are Valid Alternatives to Total Body Irradiation-Based Reduced-Intensity Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia: A Retrospective Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, in elderly and unfit patients, in whom reduced-intensity conditioning (RIC) regimens are preferred, whether a TBI-based or a chemotherapy-based approach is better is unexplored. Thiotepa can be used as part of ALL conditioning regimens. The current study aimed to compare transplantation outcomes after RIC with TBI-based or thiotepa-based regimens in patients with ALL. The study cohort comprised patients aged ≥40 years undergoing allo-HSCT for ALL in first complete remission between 2000 and 2020 who received an RIC regimen containing either TBI (4 to 6 Gy) or thiotepa. We identified a total of 265 patients, including 117 who received a TBI-based RIC regimen and 148 who received a thiotepa-based RIC regimen. Univariate analysis revealed no significant differences in the following transplantation outcomes for TBI versus thiotepa: relapse, 23% versus 28% (P=.24); nonrelapse mortality, 20% versus 26% (P=.61); leukemia-free survival, 57% versus 46% (P=.12); overall survival, 67% versus 56% (P=.18); graft-versus-host disease (GVHD]/relapse-free survival, 45% versus 38% (P=.21); grade II-IV acute GVHD, 30% in both groups (P=.84); grade III-IV acute GVHD, 9% versus 10% (P=.89). The sole exception was the incidence of chronic GVHD, which was higher in the recipients of TBI-based regimens (43% versus 29%; P=.03). However, multivariate analysis revealed no differences in transplantation outcomes between the 2 groups. In patients aged ≥40 years receiving RIC, use of a thiotepa-based regimen may represent a valid alternative to TBI-based regimens, as no differences were observed in the main transplantation outcomes.

Allogeneic Stem Cell Transplantation in Patients >40 Years of Age With Acute Lymphoblastic Leukemia: Reduced Intensity Versus Myeloablative Conditioning.

The outcome in older patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory due to high relapse and nonrelapse mortality (NRM) rates. Allogeneic stem cell transplantation (alloHSCT) as postremission therapy has an important role in reducing relapse rate, albeit its application is limited in older adult patients due to alloHSCT-related morbidity and mortality. Reduced-intensity conditioning (RIC) alloHSCT has been developed as a less toxic conditioning regimen, but comparative studies with myeloablative conditioning (MAC) are limited in patients with ALL. In this retrospective study, RIC-alloHSCT (n = 111) was compared with MAC-alloHSCT (n = 77) in patients aged 41 to 65 y with ALL in first complete remission. MAC was predominantly applied by combining high-dose total body irradiation and cyclophosphamide, whereas RIC mainly consisted of fludarabine and 2 Gy total body irradiation. Unadjusted overall survival was 54% (95% confidence interval [CI], 42%-65%) at 5 y in MAC recipients compared with 39% (95% CI, 29%-49%) in RIC recipients. Overall survival and relapse-free survival were not significantly associated with type of conditioning after adjusted for the covariates age, leukemia risk status at diagnosis, donor type, and donor and recipient gender combination. NRM was significantly lower after RIC (subdistribution hazard ratio: 0.41, 95% CI, 0.22-0.78; P = 0.006), whereas relapse was significantly higher (subdistribution hazard ratio: 3.04, 95% CI, 1.71-5.40; P < 0.001). Collectively, RIC-alloHSCT has resulted in less NRM, but it was also found to be associated with a significantly higher relapse rate. These results suggest that MAC-alloHSCT may provide a more effective type of consolidation therapy for the reduction of relapse and that RIC-alloHSCT may be restricted to patients at higher risk for NRM.

Pediatric chemotherapy versus allo-HSCT for adolescent and adult Philadelphia chromosome-negative ALL in first complete remission: a meta-analysis.

Pediatric-inspired chemotherapy significantly improves survival for adolescent and adult patients with acute lymphoblastic leukemia (ALL). However, the benefits over allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear. To compare clinical outcomes between pediatric-inspired chemotherapy and allo-HSCT in consolidation therapy of adolescent and adult Philadelphia chromosome-negative (Ph-neg) ALL in first complete remission (CR1), related studies from MEDLINE, Embase, and Cochrane Controlled Register of Trials updated to July 2022 were searched. A total of 13 relevant trials including 3161 patients were included in the meta-analysis. Compared with allo-HSCT, pediatric-inspired chemotherapy achieved better OS (hazard risk (HR), 0.53; 95% confidence interval (CI), 0.41 to 0.68) and DFS (HR, 0.64; 95% CI, 0.48 to 0.86), with a significant reduction in NRM (risk ratio (RR), 0.30; 95% CI, 0.18 to 0.51), but no difference in the relapse rate (RR, 1.13; 95% CI, 0.93 to 1.39). When only studies based on intention-to-treat analysis were included, pediatric-inspired chemotherapy consistently conferred a survival advantage. In subgroup analyses, patients with baseline high-risk features demonstrated similar OS and DFS between pediatric-style chemotherapy and allo-HSCT, while pediatric-style chemotherapy had an OS and DFS advantage in standard-risk subgroup. Particularly, patients with positive minimal residual disease (MRD) achieved better OS and DFS if proceeded to allo-HSCT.

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.

Comparison of reduced-intensity conditioning regimens in patients with acute lymphoblastic leukemia >45 years undergoing allogeneic stem cell transplantation-a retrospective study by the Acute Leukemia Working Party of EBMT.

The optimal reduced-intensity conditioning (RIC) for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively analyzed 417 patients > 45 years with ALL in first complete remission who underwent a matched sibling or unrelated allo-HSCT and compared outcomes between fludarabine/busulfan (FLUBU, n = 127), fludarabine/melphalan (FLUMEL, n = 190), and fludarabine-TBI (FLUTBI, n = 100) conditioning. At 2 years, there were no differences between the groups in terms of cumulative incidence (CI) of relapse (40% for FLUBU vs 36% for FLUMEL vs 41% for FLUTBI, p = 0.21); transplant-related mortality (TRM) (18% for FLUBU, 22% for FLUMEL, 14% for FLUTBI, p = 0.09); overall survival (55% for FLUBU, 50% for FLUMEL, 60% for FLUTBI, p = 0.62) or leukemia-free survival (43% for FLUBU, 42% for FLUMEL, 45% for FLUTBI, p = 0.99), but GVHD-relapse-free survival was significantly lower in the FLUTBI group than FLUBU and FLUMEL group (18% vs 35% vs 28%, p = 0.02). However, this difference was lost in the multivariate analysis when adjusted for the in vivo T-cell depletion. Finally, the FLUMEL regimen was shown to be an independent risk factor for a higher TRM (HR 1.97, 95% CI 1.05-3.72, p = 0.04). We conclude that the three most popular RIC regimens yield similar transplant outcomes.

Hematopoietic Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Updated 2019 Evidence-Based Review from the American Society for Transplantation and Cellular Therapy.

The role of hematopoietic cell transplantation (HCT) in adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based on the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL, and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.

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.

Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission

For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n = 257, 40%) or second complete remission (CR2; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated.

Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m2. The target daily area under the curve was 5500 µmol/min for patients aged <60 years and 4000 µmol/min for patients aged >59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n = 7) or CR2 (n = 4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens.

Patients over Age 40 with Ph-Negative Acute Lymphoblastic Leukemia Do Not Benefit from Allogeneic Transplant in First Remission. Retrospective Analysis from a Large Tertiary Center

Background: Survival of adult patients with Ph-negative acute lymphoblastic leukemia (ALL) with conventional therapeutic approaches remains poor. Given the ability to safely perform allogeneic stem-cell transplant (alloSCT) in this age cohort, older patients with ALL in first complete remission (CR1) are increasingly offered consolidation with this modality. We asked whether alloSCT in CR1 offers a survival advantage in older patients with ALL as compared to post remission chemotherapy.Methods: One hundred and seven patients ≥40 years were treated at the Dana Farber Cancer Institute for Ph-negative ALL from 1/1/2006 to 12/31/2013; of the 99 patients treated with curative intent, 80 patients (age 54.5 years; range 41-83) achieved first remission (81%; CR and CRi). Baseline characteristics of the chemotherapy and alloSCT post remission groups were compared using the Fisher exact and Wilcoxon rank-sum tests for categorical and continuous variables, respectively. The comparison of outcomes between the alloSCT and chemotherapy cohorts was made using a modified Mantel-Byar test to account for the waiting time to transplant. For graphical comparisons, the method of left-truncation was used to adjust for the time of wait from first CR/CRi to transplant. In Cox modeling of overall survival (OS) and disease free survival (DFS), treatment was included as a time-dependent variable. The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated and compared between groups from the time of CR/CRi to the time of the event with each considered as competing events. Retrospectively determining the reason for choosing one post remission approach over the other was not always possible. Furthermore, MRD status was available in a minority of patients. The effect and relation of these factors to patient selection and outcome therefore could not be assessed.Results: Eighty patients in first CR/CRi were analyzed. B-cell ALL was diagnosed in 86% of patients and T-cell origin was identified in 14% of patients; 6% of patients had therapy-related ALL. Median WBC, platelet and Hb levels at diagnosis were 5.3X109/L, 61X109/L and 9.6mg/dL, respectively. Cytogenetics were available for 63 patients (cytogenetics were not reported for referred patients (n=11) or were unsuccessful (n=6)) and were diploid (52%), near hyperploid (25%), hyperploid (11%), near hypoploid (5%) and hypoploid (2%). MLL rearrangement was identified in 12.5% of patients. Most patients had an ECOG performance status of 0-1; the median modified Charlson co-morbidity index score was 2 (range 0-10) and 56% of patients had ≥1 co-morbidities.In the alloSCT group, myeloablative and reduced-intensity conditioning were used in 55% and 45% of patients, respectively. Matched related and matched unrelated donors were used in 40% and 48% of patients, respectively, with the remainder receiving alternative donor sources.Forty patients received alloSCT in first remission and 40 patients were treated with chemotherapy only. Baseline characteristics did not significantly differ between the 2 groups except for lower Hb in the alloSCT group (p=0.028). Nine of 10 patients with MLL rearrangement were allocated to the alloSCT group.The median follow-up in the alloSCT and chemotherapy groups was 3.7 and 2.6 years, respectively. OS (Figure 1) and DFS did not differ between the groups at 3 years; the significantly higher CIR rate in the chemotherapy group was offset by the higher NRM in the alloSCT group (Table 1).Univariate Cox Modeling of 13 patient, disease and treatment-related factors including post remission modality were analyzed, none of which were shown to affect OS or DFS. WBC at diagnosis (≥20K vs. <20K) achieved borderline significance for DFS (p=0.053). The type of conditioning and donor source did not affect survival within the alloSCT group.Conclusion: AlloSCT in first CR is associated with a lower CIR but this benefit is offset by higher NRM as compared to chemotherapy. Although this should be confirmed in larger cohorts, these data suggest that alloSCT does not confer a survival benefit in patients ≥40 years with Ph-negative ALL.Table 1Outcome by CohortsOutcomeChemotherapy in CR1 (n=40)AlloSCT in CR1 (n=40)P-valueMedian Follow-up (years)2.6 (0.2, 8.2)3.7 (1.2, 7.0)0.223-yr % OS [95% CI]46 [31-68]39 [26-59]0.353-yr % DFS [95% CI]31 [18-52]40 [27-59]0.983-yr CIR %61 [41-76]28 [15-43]0.0113-yr NRM %9 [2-21]32 [17-47]0.014 [Display omitted] DisclosuresSteensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Stone:Agios: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; AROG: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Celator: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Merck: Consultancy.

Outcome of Younger Adults with Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse: A Graall Study

Purpose: Pediatric-like protocols have yielded significant advances in younger adults with Ph-negative ALL. Nonetheless, the 5-year cumulative incidence of relapse was still estimated at 32% in the GRAALL-2003/2005 trials, approximately 25% of the relapses occurring after allogeneic stem cell transplantation (SCT). We report here on the outcome of these relapsing patients.Patients and Methods: Among 880 GRAALL-2003/2005 patients(18-60 years) with Ph-negative ALL in first complete remission (CR1), 264 relapsed. Data were available for 229 of them (151 B-cell precursor [BCP] ALL, 78 T-ALL; 45 standard-risk, 165 high-risk, and 19 unclassified ALL according to the risk classification used in these trials). Relapse site was bone marrow (BM), isolated CNS, combined BM/CNS and other in 181, 20, 17 and 11 patients, respectively. At relapse, median age was 35.7 years (range, 17-63). Median CR1 duration was 10 months (range, 0.5-74), 50 patients (22%) having CR1 > 18 months. Fifty-four patients (24%) had received allogeneic SCT during CR1. First salvage treatments were classified as follows: standard curative therapy, 194 (85%); low-intensity therapy, 21 (9%); allogeneic SCT, 6 (2.5%); and best supportive care (BSC), 8 (3.5%). Post-relapse allogeneic SCT was analyzed as a time-dependent event using Mantel-Byar estimations.Results: A total of 121 patients (53%) achieved CR2, including 100/194 patients after standard salvage, 7/21 patients after low-intensity salvage, and 14 patients after SCT (6 as first salvage, 8 as subsequent salvage after standard salvage failure). Thus, 107/215 patients (50%) treated with standard or low-intensity first salvage achieved CR2 and in multivariable analysis (including age, ALL lineage, ALL risk classification, CR1 duration, prior SCT, relapse site and salvage type), a younger age and a longer CR1 duration were associated with CR2 achievement in these patients. Of note, few patients with t(4;11) BCP-ALL reached CR2 (19%). A total of 77 patients received allogeneic SCT after relapse, including 55 patients in CR2 after standard salvage (52 in CR2 at SCT time), 4 patients in CR2 after low-intensity salvage (all in CR2 at SCT time), the 6 patients transplanted as first salvage (all reaching CR2), and 12 patients transplanted as subsequent salvage (8 reaching CR2). The median time between relapse and SCT was 111 days (range, 5-311). With a median post-relapse follow-up of 3.1 years, post-relapse overall survival (OS) was 19.3% (14-25%) at 2 years and 13.3% (9-19%) at 5 years (median OS, 6.7 months). In landmark analysis, OS was significantly longer in patients who achieved CR2 (HR, 0.19; p<0.001). Post-relapse OS was also longer in patients aged < 45 years old (HR, 0.68; p=0.016), in those with CR1 > 18 months (HR, 0.43; p<0.001), as in those who received SCT after relapse (HR, 0.37; p<0.001). Neither ALL lineage, ALL risk classification, prior SCT, relapse site nor the type of salvage (if excluding the 8 BSC patients) significantly influenced post-relapse OS. A worse OS was nonetheless observed in BCP-ALL patients with t(4;11) (HR, 2.13; p=0.002) or low hypodiploidy / near triploidy (HR, 2.96; p=0.001), as in T-ALL patients with a complex karyotype (HR, 5.55; p<0.001). Neither focal IKZF1 gene deletion nor NOTCH1/FBXW7/RAS/PTENstatus at diagnosis influenced post-relapse outcome, in BCP- and T-ALL patients respectively. In multivariable analysis (including the covariates listed above and not considering the 8 BSC patients), CR1 > 18 months and SCT after relapse were associated with longer OS (HR, 0.49 and 0.39; p=0.001 and <0.001, respectively). Among the 107 patients who reached CR2 after standard or low-intensity salvage, 62 experienced a second relapse and 73 died, including 15 deaths in CR2. In these patients, disease-free survival (DFS) was 29.0% (21-38%) at 2 years and 26.3% (18-35%) at 5 years (median DFS, 10.2 months). Again, CR1 > 18 months and SCT after relapse were the two factors that independently predicted longer DFS (HR, 0.36 and 0.44; p=0.001 and 0.003) and OS (HR, 0.39 and 0.57; p=0.004 and 0.043, respectively) in these patients.Conclusion: Adult patients relapsing after current ALL therapies still retain apoor outcome. Although a minority of them may be cured, especially if CR1 duration exceeds 18 months and if they may receive allogeneic SCT in CR2, new therapies are definitely needed for these patients. DisclosuresNo relevant conflicts of interest to declare.

Superiority of Pediatric Chemotherapy over Allogeneic Hematopoietic Cell Transplantation for Philadelphia Chromosome Negative Adult ALL in First Complete Remission: A Combined Analysis of Dana-Farber ALL Consortium and CIBMTR Cohorts

▪Introduction: In adults with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL), the optimal post-remission therapy remains uncertain. Although allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) has become a widely adopted curative strategy, the need for HCT may be supplanted by intensive, pediatric-style chemotherapy regimens. These two approaches have not previously been compared.Methods: We evaluated the outcomes of 422 related or unrelated donor HCT recipients aged 18-50 years with Ph-ALL in CR1 between 06/2002 and 12/2011 as reported to the CIBMTR. This was compared to a concurrent cohort of 108 Ph- ALL CR1 pts (18-50 years) who received a Dana Farber Cancer Institute (DFCI) ALL Consortium pediatric regimen consisting of intensive, non-HCT therapy. Primary outcome was disease-free survival (DFS). Patients in the DFCI chemotherapy cohort who received HCT in CR1 were censored at the day of HCT. Left-truncated analysis methods were used to adjust time from CR1 to transplant.Results: The HCT cohort was older (median age 34 vs. 30 years, p=0.001) and had higher diagnostic WBC counts (median 12x109/L [range <1-515) vs. 8x109/L [1-1424], p=0.001, respectively). The proportion of patients with T –ALL was lower in the HCT cohort (14% vs. 22%, p=0.03), while the incidence of t(4;11)/MLL was similar in both groups (8% vs. 10%, respectively). Of the HCT cohort 396 (94%) underwent myeloablative (MA) conditioning. Donor source was matched related donor in 176 (42%), 8/8 unrelated donors in 168 (40%), and 7/8 (18%) from 7/8 unrelated donors. In univariate analyses (Figure 1) cumulative incidence of relapse at 4 years was similar in both groups (HCT 25% [19-28] vs. chemo 23% [15-32] p=0.97). Two-year treatment-related mortality (TRM) was higher in the HCT cohort (HCT 33% [28-39] vs. chemo 4% [1-8], p<0.0001). At 4 years, DFS was superior in the chemo cohort (HCT 40% [35-45] vs. chemo 71% [60-79], p<0.0001). Four year OS also favored chemo (HCT 45% [40-50] vs. chemo 73% [63-81], p<0.0001). In multivariable analysis, independent factors predictive of treatment failure (relapse or death) were HCT (HR 3.11 [2.08 – 4.66], p<0.001) and the presence of CNS disease at diagnosis (HR 1.56 [1.03 – 2.38], p=0.04). The sole factor associated with poorer OS was the administration of HCT (HR 2.86 [1.88 – 4.34], p<0.0001). The favorable OS with chemo was maintained when restricting the HCT cohort to those recipients with related donors or fully matched (8/8) unrelated donors and those whose time from diagnosis to CR1 was <8 weeks (HR 2.14 [1.36-3.35], p=0.001). Similar outcomes were seen when restricting the HCT cohort to those who achieved CR1 < 8 weeks from diagnosis and received myeloablative conditioning.Conclusion: In this comparison of two cohorts of younger Ph- negative adults in CR1, post-remission therapy with an intensive, pediatric-inspired, chemotherapy-based regimen conferred a survival advantage when compared to allogeneic HCT. The high TRM associated with HCT is a major factor in determining outcomes after HCT. In an era of increasing adoption of pediatric regimens for adults with Ph- ALL, allogeneic HCT may no longer be required for the majority of patients who achieve CR1. These data support the need for randomized controlled studies in Ph- ALL comparing pediatric-inspired non-HCT regimens to allogeneic HCT-based therapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) In Adults With Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL): Results From The Group For Research On Adult ALL (GRAALL)

▪ PurposeThe pediatric-inspired intensified GRAALL protocol yielded a marked improvement in the outcome of adults with Ph-negative acute lymphoblastic leukemia (ALL) (Huguet et al,JCO 2009), raising the issue of the place of allogeneic HSCT in this new context. We report here the results associated with HSCT in first complete remission (CR) in younger adults treated in the GRAALL-2003/2005 trials. Patients and methodsIn these trials, HSCT was offered in first CR to patients aged 15-55 years with ALL at higher risk of relapse. High-risk factors included white blood count >30 x 109/L for B-lineage ALL, central nervous system (CNS) involvement, t(4;11)/MLL anomalies, t(1;19), low hypodiploidy/near triploidy, complex karyotype, early resistance to the steroid prephase (CsR), early resistance to chemotherapy (ChR) as assessed by poor bone marrow blast clearance at day 8, and late CR. Per protocol, HSC donor should be a matched sibling or an unrelated donor (10/10 or eventually 9/10 HLA matched) and conditioning regimen should include single fraction 10-Gy or fractionated 12-Gy total body irradiation (TBI) and high-dose cyclophosphamide. The role of HSCT was evaluated by HSCT versus no-HSCT cohort comparison (Mantel-Byar time-dependent analysis). ResultsAmong the 522 high-risk patients eligible, 283 (54%) actually received HSCT in first CR (185 B-lineage and 98 T-lineage ALL; median age, 31 years). There were no significant differences in baseline characteristics and early response between HSCT and no-HSCT cohorts, except more HSCT patients with t(4;11)/MLL anomalies. Among the 283 HSCT patients, 46 had t(4;11)/MLL anomalies, 13 had CNS disease, 116 had CsR and 176 had ChR ALL. Origin of HSC was 140 sibling and 143 unrelated donors, including 47 unrelated donors with 1 HLA mismatch. The following HSCT protocol violations were observed: a) conditioning did not include TBI in 17 patients; b) 10 patients received reduced-intensity conditioning (RIC); and c) 13 patients received cord blood HSCT. These patients remained in the HSCT cohort for the analysis. With a median post-transplant follow-up of 3.5 years, post-HSCT cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and relapse-free survival (RFS) were estimated respectively at 19% (95% CI, 15-25), 16% (95% CI, 12-21) and 64% (95% CI, 58-70) at 3 years, without any RFS difference between sibling and unrelated donors. A marked trend for a higher NRM was observed in patients aged 45 years or more (26% versus 13% at 3 years; HR, 1.6; p=0.059), while post-transplant CIR was similar in older and younger patients. Mantel-Byar RFS estimations showed no significant difference between both HSCT and no-HSCT cohorts (HR, 0.80; p=0.13), meaning that the risk factors used in these protocols failed to identify patients who could significantly benefit from HSCT in first CR. As minimal residual disease (MRD) had a major prognostic impact, we retrospectively analyzed the effect of HSCT in the 278/522 patients evaluated for 6-week Ig/TCR MRD level (154 HSCT and 124 no-HSCT patients, including 92 and 62 patients with MRD >=10-4, respectively). Mantel-Byar RFS estimations showed that HSCT did not benefit to patients with MRD <10-4 (HR, 1.2; p=0.67) as opposed to those with MRD >=10-4 (HR, 0.6; p=0.02), with a positive HSCT-by-MRD interaction (p=0.04) (Figure 1). [Display omitted] ConclusionIn adult patients with high-risk ALL in first CR treated in the GRAALL-2003/2005 trials, myeloablative allogeneic HSCT from sibling and unrelated donors was associated with a 64% RFS at 3 years. The 26% NRM observed at 3 years in patients aged 45 years or more suggests considering RIC-HSCT in these patients. MRD response appears to be a powerful tool to select patients who might benefit from HSCT. This selection tool will be prospectively evaluated in the next GRAALL-2013 trial.ND and AH contributed equally to the work. Disclosures:No relevant conflicts of interest to declare.

The superiority of allogeneic hematopoietic stem cell transplantation from unrelated donor over chemotherapy for adult patients with high-risk acute lymphoblastic leukemia in first remission

For adult patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation(allo-HSCT) from HLA-matched related donors(MSD) is recommended for standard and high-risk patients. The role of unrelated donor transplantation (URD) in first remission has not been fully determined. We sought to compare directly the outcome of URD allo-HSCT and chemotherapy in patients with high-risk ALL. In this single center retrospective analysis, we included 74 consecutive adult patients with high-risk ALL in first complete remission(CR) and without a sibling donor, in which 32 patients received URD allo-HSCT in CR1 with busulfan-cyclophosphamide preparation regimen and in vivo T-cell depletion with anti-T-lymphoglobulin (ATG). The remaining 42 patients received chemotherapy consolidation and maintenance only in first remission. With median follow-up of 18 months, in the URD allo-HSCT group, the relapse rate(RR) was 30.6 ± 11.4 % which was significantly lower than that of the chemotherapy group (80.5 ± 10.1 %,p < 0.001), while non-relapse mortality (NRM) was higher(16.4 ± 6.7 % vs. 0, p = 0.028). Overall, 3-year leukemia free survival (LFS) was superior in the URD allo-HSCT group compared to chemotherapy group (57.8 ± 10.6 vs.19.5 ± 10.5 %, p = 0.002), as was 3-year overall survival(OS, 63.5 ± 13.3 vs. 31.6 ± 10.6 %, p = 0.016). URDHSCT was the only factor associated with improved OS, LFS and reduced RR in multivariate analysis. Based on our data, URD allo-HSCT significantly reduced the relapse in high-risk ALL and the benefit translated into improvement in both LFS and OS. Prospective studies based on availability of HLA-matched URD are warranted to evaluate the precise role of URD transplantation in adult ALL.

Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease.

The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Ph+ acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type, and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKI), mostly imatinib; 39% (RIC) and 49% (MAC) were MRDneg pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%;p=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (p=0.058). Overall survival was similar (RIC 39% [95% CI:27–52] vs. 35% [95% CI:270–44];p=0.62). Patients MRDpos pre-HCT had higher risk of relapse with RIC versus MAC (HR 1.97;p=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared to a similar MRDneg population after MAC (33%; p=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; p=0.057), but absence of pre-HCT TKI (HR 1.88;p=0.018), RIC (HR 1.891;p=0.054) and pre-HCT MRDpos (HR 1.6; p=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRDneg status is preferred pre-HCT.

Long-Term Follow-up of Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Impact of Tyrosine Kinase Inhibitors on Treatment Outcomes

The introduction of tyrosine kinase inhibitors (TKI) has revolutionized therapy for patients with acute lymphoblastic leukemia (ALL) who have the Philadelphia (Ph) chromosome. A retrospective analysis was conducted on 102 adults and 11 children who received a first-matched related (n = 60), matched unrelated (n = 40), mismatched cord blood (n = 12), or haploidentical (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for Ph-positive (Ph+) ALL in first complete remission (n = 71), second complete remission (n = 11), or with active disease (n = 31) between 1990 and 2009. Sixty-seven patients received TKI with upfront ALL therapy, and 32 patients received TKI maintenance following HSCT. With median follow-up of 5 years among survivors (range: 1.1-20.4 years), overall survival (OS) was significantly better for patients transplanted in first remission compared with HSCT in advanced disease: 43% versus 16%, P = .002. Disease stage and age at time of HSCT, the development of acute graft-versus-host disease (aGVHD), and decade of HSCT were found to significantly impact OS, progression-free survival (PFS), and nonrelapse mortality (NRM) in multivariate analyses. Allogeneic HSCT provides durable remission for patients with Ph+ ALL in first remission. Neither TKI use pre- nor post-HSCT were found to significantly impact transplant outcomes in univariate and multivariate analyses.

Management of adult patients with acute lymphoblastic leukemia in first complete remission

The optimal postremission therapy in adults with acute lymphoblastic leukemia (ALL) is still a matter of debate. The objective of this study was to compare the various potential therapeutic options for patients who achieved first complete remission. The authors conducted a systematic review and meta-analysis of randomized trials, including patients with standard-risk (SR) All and high-risk (HR) ALL who received first postremission therapy. Outcomes assessed were all-cause mortality (ACM), disease recurrence (relapse), and nonrelapse mortality (NRM). Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. Overall, there was a significant reduction in ACM in the allogenic stem cell transplantation (alloSCT) arm (RR, 0.88; 95% CI, 0.8-0.97) compared with autologous stem cell transplantation (ASCT) or chemotherapy. Subgroup analyses revealed a similar pattern among SR patients (RR, 0.8; 95% CI, 0.68-0.94) but a nonsignificant advantage for alloSCT among HR patients (RR, 0.88; 95% CI, 0.76-1.01). There was an increase in NRM (RR, 2.99; 95% CI, 1.37-6.53) and a decrease in the relapse rate in the alloSCT arm (RR, 0.52; 95% CI, 0.33-0.83). There was no difference in ACM or the relapse rate between the ASCT and chemotherapy arms. Overall, alloSCT was superior to ASCT or chemotherapy for patients with ALL in first complete remission. The survival advantage was of greater statistical significance for patients with SR ALL than for patients with HR ALL.

One Year Reinductions with Vincristine, Asparaginase and Prednisone as Post-Remission Therapy Improves Outcome in Children with Intermediate Risk (IR) Acute Lymphoblastic Leukemia (ALL).

Abstract 2026Poster Board II-3 BackgroundThe ALL89 PETHEMA trial proved that delayed consolidation had a favorable influence on the outcome of children with IR-ALL.The subsequent ALL96 trial incorporated reinductions with vincristine, asparaginase and prednisone during the first year of maintenance therapy to the early and late consolidations of the previous protocol. We performed a historical comparison of both cohorts of children to evaluate the benefit of such approach in children with newly diagnosed ALL of low and intermediate risk in first complete remission. MethodsChildren aged 1 to 18 years were classified as low-risk (LR) if they were 1 to9 years of age and the WBC at diagnosis was < 50×10 9/l and as intermediate-risk (IR) if their age was >9 to 18 years or the WBC was > 50×10 9/l. High-risk patients [i.e. children with ALL carrying the t(9;22) or t(4;11) translocations or with WBC > 200×10 9/l] were excluded from analysis. The ALL89 trial assigned 213 with low (N=111) or intermediate (N=102) risk ALL in first complete remission to receive early or early and late consolidation cycles followed by 2 years of maintenance treatment with oral mercaptopurine and weekly intramuscular methotrexate. Children (86 IR and 233 LR) achieving CR in the ALL96 trial received similar early and delayed consolidations and additional monthly vincristine (2 mg IV), asparaginase (20000 UI/sq meter IV) and prednisone (60 mg/sq meter PO x 7 days) reinductions (VAP) were incorporated during the first year of maintenance treatment. The primary end point of the historical comparison was disease-free survival. ResultsMedian follow-up of children in continuous first CR was 6 years (range 0.3 – 12). Patients in both trials were comparable in terms of gender, age, performance status and characteristics of ALL at diagnosis. 109 children (75 LR and 34 IR) in the ALL89 trial were assigned to receive early consolidation only (Cohort 1 – C1) and 104 (36 LR and 68 IR) to receive early and delayed consolidation treatment (Cohort 2 –C2). 281 children (79 LR and 202 IR) in the ALL96 trial received a median of 7 (range 3-7) reinductions with VAP after early and delayed consolidations (Cohort 3 - C3).46 LR patients relapsed (24 in C1, 9 in C2 and 13 in C3). The 5-year disease-free survival rates were 67% (95%CI 58-76), 74% (95%CI 62-86) and 84% (95%CI 77-93) for C1, C2 and C3 respetively. The hazard ratios for patients in the C2 and C3 groups were 0.77 (95%CI 0.36-1.65, p=NS) and 0.45 (95%CI 0.22-0.93, p=0.031).80 IR patients relapsed (18 in C1, 27 in C2 and 25 in C3). The 5-year disease-free survival rates were 46% (95%CI 31-61), 57% (95%CI 46-68) and 80% (95%CI 75-86) The hazard ratios for patients in the C2 and C3 groups were 0.77 (95%CI 0.42-1.39, p=NS) and 0.29 (95%CI 0.16-0.52, p<0.001) respectively.Two children (1 in the C2 and 1 in the C3 group) died in first CR due to consolidation or reinduction related toxicity. ConclusionsMonthly vincristine, asparaginase and prednisone (VAP) reinductions during the first year of maintenance treatment significantly reduced the relapse rate and improved the disease-free survival of children with LR and IR ALL in first CR. The major benefit was obtained in IR ALL.Supported in part by grants P-EF/08 from José Carreras Leukemia Foundation, from grant PI051490 and RD06/0020/1056 from RETICS. Disclosures:No relevant conflicts of interest to declare.

Post-Induction Minimal Residual Disease (MRD) Defines a Large Subset of Adults with Favorable Ph-Negative Acute Lymphoblastic Leukemia (ALL), Who Do Not Benefit From Allogeneic Stem Cell Transplantation (SCT) in First Complete Remission: A GRAALL Study.

Abstract 577▪▪This icon denotes an abstract that is clinically relevant. Introduction:Allogeneic SCT is currently the preferred therapeutic option for most younger adults with ALL in first complete remission (CR), as recently confirmed by the large ECOG-UKALL Intergroup study (Goldstone, Blood 2008). In this study, however, early response to therapy was not taken into account. As Ig/TCR MRD is one of the main determinants for outcome in childhood ALL, we analyzed its impact on outcome and SCT results in adults treated within pediatric-inspired GRAALL trials. For that purpose, we focused on early MRD evaluations (MRD1: at CR achievement; MDR2: after the first consolidation). Patients & Methods:Among 507 patients aged 15-60 years with Ph-negative ALL in first CR after induction included in the GRAALL-2003 (Huguet, JCO 2009) or in the ongoing GRAALL-2005 trial until the first planned interim analysis, 212 patients (B/T lineage, 137/75; median age, 31 years) had an Ig/TCR MDR1 evaluation (with MRD2 evaluation for 77% of them) by CDR3 RQ-PCR or fluorescent competitive Genescan associated with a sensitivity allowing the classification into the following levels: negative (0); positive <10-4 (1); positive 10-4 to 10-3 (2); positive 10-3 to 10-2 (3); positive ≥10-2 (4) (Table 1). Allogeneic SCT was indicated in patients aged 55y or less with a donor (sibling or 10/10 HLA-matched unrelated) and high-risk ALL, as defined on baseline (WBC in B-lineage ALL, CNS involvement, cytogenetics) and response-related risk criteria (steroid- and chemo-sensitivity). Patient characteristics and outcome were identical according to trial, as well as in MRD-tested and non-tested patients. [Display omitted] Results:Cumulative incidence of relapse (CIR) was strongly predicted by 5-level MRD1 (P<0.0001). As CIR were similar in both levels 0-1 and in both levels 3-4, patients were eventually classified as MRD1-fav (level 0-1, N = 124 (59%); 3y-CIR, 13%), MRD1-int (level 2, N = 32 (15%); 3y-CIR, 38%), and MRD1-unfav (level 3-4, N = 56 (26%); 3y-CIR, 56%). Thirty-four of 62 patients at risk reached level 0 or 1 at MRD2 only, 22 of them from the MRD1-int subgroup. However, CIR was not different in these ‘slow responders‘ than in MRD2-int/unfav patients (P=0.27), suggesting that MRD1 alone may be used to stratify further therapy. Median age and baseline characteristics did not differ between MRD1-fav and MRD1-int/unfav patients, while MRD1-fav was associated with higher rates of steroid- and chemo-sensitivity (P=0.05 and P<0.001, respectively). In MDR1-fav patients, 3y-DFS and 3y-OS were 80% (95% CI, 70-87) and 82% (95% CI, 71-90), respectively. After SCT censoring, their 3y-CIR, 3y-DFS, and 3y-OS were 12% (95% CI, 6-24), 84% (95% CI, 72-91), and 86% (95% CI, 72-93), respectively. In multivariate analysis adjusted on protocol, MRD1-fav was the best predictor of lower CIR (RR = 0.22; P<0.001), prolonged DFS (RR = 0.25; P<0.001), and longer OS (RR = 0.20; P<0.001). Low WBC (for CIR, DFS, and OS) and steroid-sensitivity (for CIR only) remained independent risk factors. Similar results were observed in patients with B-lineage ALL, while the number of T-ALL patients was too small to allow a separate analysis. In 127/132 evaluable patients with high-risk ALL eligible for SCT, 3y-CIR was 4% in MRD1-fav and no-donor (N=27), 14% in MRD1-fav and donor (N=33; 30 actually grafted in CR1), 42% in MRD1-int/unfav and donor (N=41; 38 actually grafted in CR1), and 66% in MRD1-int/unfav and no-donor patients (N=26). The difference between donor and no-donor groups tended to be significant in MRD1-int/unfav patients (P=0.14), while not in MRD1-fav patients (P=0.60). Conclusion:Younger adults with ALL may be classified in a favorable subset with a low relapse rate, only based on post-induction MRD level. At least when treated with a pediatric-inspired protocol, this subset represents more than half patients with Ph-negative ALL. In GRAALL studies, those favorable patients, even when presenting initial bad-risk factors, do not seem to draw any benefit from allogeneic SCT in first CR. Disclosures:No relevant conflicts of interest to declare.