Lymphoblastic Leukemia In First Remission Research Articles

How Much Have Post-Transplant Outcomes Improved Since 2000 for Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia in First Remission? a Study from the EBMT Acute Leukemia Working Party

Background Allogeneic hematopoietic cell transplantation (allo-HCT) remains an important curative modality for patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). Recent years have witnessed an improvement in transplant techniques and increased use of post-transplant pharmacological interventions aimed at reducing the risk of relapse. However, recent results using the combination of blinatumomab and second or third-generation tyrosine kinase inhibitors (TKI) have challenged the role of allo-HCT in CR1. To address these challenges, we assessed real-world changes over time in transplant characteristics and post-transplant outcomes in adult patients with Ph+ ALL in CR1, using a large dataset from the European Society for Blood and Marrow Transplantation (EBMT) registry. Methods We identified 3292 adult patients (45% female; median age 45 years, range 18-76) with Ph+ ALL allografted between 2001 and 2020 in CR1 from a matched sibling (38%), unrelated (54%) or haploidentical donor (8%).At transplant, 41% of patients were measurable disease (MRD) positive (pos). The comorbidity index (CI) was zero in 63% of patients with available data. Conditioning was myeloablative (MAC) in 77% of patients, and included total body irradiation (TBI) in 64% of patients. In vivo T cell depletion (TCD) and peripheral blood stem cells (PBSC) were given to 52% and 86% of patients, respectively. Most patients (66%) and donors (55%) were cytomegalovirus (CMV) positive. Median follow-up for live patients was 56 months (interquartile range [IQR] 28-32). Results We compared changes in patient and transplant characteristics over time in 245 patients transplanted in 2001-2005, 679 patients transplanted in 2006-2010, 1035 patients transplanted in 2011-2015, and 1333 patients transplanted in 2016-2020. Patients transplanted in recent years were older, were less likely to be MRDpos, and more likely to receive PBSC and TCD. The 3-year cumulative incidence of relapse (CIR) gradually and significantly decreased from 41% to 32%, 27%, and 19% over the 4 time periods (p=0.001), and non-relapse mortality (NRM) significantly decreased as well from 25% to 24%, 23% and 17% (p=0.001). The 3-year leukemia-free survival (LFS) and overall survival (OS) gradually and significantly improved over time from 34% to 44%, 50%, and 64% (p=0.001) and from 47% to 56%, 65%, and 75% (p=0.001), respectively. Finally, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) improved from 26% to 34%, 37%, and 49% (p=0.001). In a Cox regression multivariate analysis (MVA), a progressive and significant improvement in all transplant outcomes was noted including reduced acute and chronic GVHD, reduced CIR and NRM, and increased LFS, OS, and GRFS. LFS was also negatively affected by older age, male gender of both patients and donors, MRDpos pretransplant, and the use of reduced intensity conditioning while positively affected by the use of TBI. OS was also positively affected by younger age, female gender of patients, matched sibling donor, TBI, and TCD. This improvement in post-transplant outcomes over time was observed both in MRDpos but also in MRD negative (neg) patients. In MRDneg patients, 3-year CIR decreased from 34% to 30%, 24%, and 17% (p=0.001) over the 4 time periods whereas LFS improved from 41% to 46%, 52%, and 66% (p=0.001). Similarly, in MRD-positive patients, CIR decreased from 48% to 34%, 32%, and 23% (p=0.001) over the 4 time periods whereas LFS improved from 27% to 42%, 47% and 60% (p=0.001). Conclusion In patients with Ph+ ALL, we observed an impressive improvement over time in post-transplant outcomes with decreased CIR and NRM and improved LFS, OS, and GRFS, both in MRDpos and MRDneg patients. These large-scale, real-world data can serve as a benchmark for future studies in this setting, including those testing the combination of TKI and blinatumomab as an alternative to transplant.

Combination of Cytogenetic Classification and MRD Status Correlates with Outcomes of Autologous Versus Allogeneic Stem Cell Transplantation in Adults with B Cell-Acute Lymphoblastic Leukemia in First Remission

Objectives: To analyze overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) of patients with B cell-acute lymphoblastic leukemia (B-ALL) who received autologous or allogeneic stem cell transplantation and to provide the basis for the choice of transplantation method. Methods: We retrospectively investigated the outcomes of 388 adult patients with B-ALL in our center. The OS, LFS, CIR and NRM rate and the impact of minimal residual disease (MRD) within 3 chemotherapy cycles along with risk classification were explored. Results: Both univariate and multivariate analysis found that negative MRD within 3 chemotherapy cycles was the important factor associated with the prognosis. As to 355 patients who obtained first complete remission (CR1), we divided patients into 3 groups according to the risk stratification and MRD status within 3 chemotherapy cycles. For patients with negative MRD within 3 chemotherapy cycles and standard-risk group, the 3-year OS (82.5% vs 74.1%, P=0.364), LFS (74.5% vs 74.1%, P=0.904), CIR (25.5% vs 17.6%, P=0.648) and NRM rates(0% vs 8.3%, P=0.234) were not significantly different between autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) group（Figure 1）. In patients with negative MRD and high-risk factors, although auto-HSCT group and allo-HSCT group had similar 3-year OS(72.7% vs 68.5%, P=0.436) and LFS rate (62.8% vs 56.0%, P=0.375) , the lower NRM (1.5% vs 25.1%, P=0.000) was offset by higher CIR(35.7% vs 18.9%, P=0.018) in auto-HSCT group compared with allo-HSCT group（Figure 2）. As for other patients with high-risk factors and positive MRD after 3 chemotherapy cycles, the prognosis of auto-HSCT group was evidently worse than those of allo-HSCT group as there was a lower trend of 3-year OS (50.0% vs 66.0%, P=0.077), LFS rate (30.8% vs 47.1%, P=0.398) and significantly higher CIR rate(71.4% vs 39.1%, P=0.018) in auto-HSCT group compared to allo-HSCT group（Figure 3）. MRD within 3 chemotherapy cycles was also related to the selection of allogeneic transplantation methods and pretreatment schemes. The 3-year OS (67.4% vs 60.8% vs 65.2%, p=0.735), LFS (56.3% vs 48.3% vs 58.3%, P=0.538), CIR (21.7% vs 23.3% vs 13.3%, P=0.784) and NRM rate (22.1% vs 28.4% vs 28.3%, P=0.672) were similar in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT), haploid hematopoietic stem cell transplantation (haplo-HSCT) and unrelated donor hematopoietic stem cell transplantation (URD-HSCT) group patients who achieved negative MRD within 3 chemotherapy cycles. While MSD-HSCT group tended to have lower 3-year LFS (33.0% vs 54.1% vs 41.7%, P=0.198) and higher CIR rate (53.2% vs 33.7% vs 46.2%, P=0.233) when comparing with haplo-HSCT and URD-HSCT group patients whose MRD were still positive within 3 chemotherapy cycles. Moreover, in patients who achieved negative MRD within 3 chemotherapy cycles, there was no significant difference in 3-year CIR rate (24.5% vs 23.1%, P=0.784) between TBI group and non-TBI group, but the lower OS (64.2% vs 76.3%, P=0.027) and LFS (54.4% vs 71.3%, P=0.091) was mainly due to the higher NRM rate (17.8% vs 5.6%, P=0.062) in TBI group. For MRD positive patients, TBI group had advantages over non-TBI group, demonstrating a trend of higher 3-year OS (65.0% vs 42.9%, P=0.105), LFS (44.8% vs 27.1%, P=0.138), lower CIR (43.6% vs 63.8%, P=0.106) and similar NRM rate (11.7% vs 9.1%, P=0.671). In addition, we found that 8 most frequently mutated genes were KMT2D、FAT1、NRAS、PAX5、KRAS、SETD2、ASXL1、PTPN11 in 175 patients with preliminary second generation sequencing results（Figure 4）. Mutations in CARD11 and NOTCH signaling pathway were correlated with lower LFS (CARD11: 56.3% vs 16.7%, P=0.002; NOTCH signaling pathway: 59.2% vs 38.8%, P=0.049)（Figure 5）. Conclusions: Auto-HSCT with maintenance therapy after HSCT and non-TBI pretreatment schemes appears to be an attractive treatment option for patients with B-ALL especially for those who achieved negative MRD within 3 chemotherapy cycles. For MRD positive patients, allogeneic transplantation and TBI pretreatment schemes may be more effective. Key words: auto-HSCT, allo-HSCT, acute lymphoblastic leukemia, minimal residual disease Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Novel strategies in the treatment of acute lymphoblastic leukaemia

The outcome of paediatric acute lymphoblastic leukaemia is excellent, with a 90% overall survival rate. However, the overall survival of adults with acute lymphoblastic leukaemia with standard chemotherapy is only 40–50%. This outcome is typically worse with increasing age. Given this prognosis, novel therapies and strategies are needed to improve outcomes. In The Lancet Haematology, two different strategies are employed by the UKALL group: (1) the addition of the monoclonal anti-CD20 antibody, rituximab, to standard induction therapy in adults aged 25–65 years with precursor B-cell acute lymphoblastic leukaemia; 1 Marks DI Kirkwood AA Rowntree CJ et al. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022; 9: e262-e275 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar and (2) the use of in-vivo T-cell depleted reduced intensity allogeneic haematopoietic stem-cell transplantation (HSCT) in first remission for patients aged 41 years and older or for patients younger than 41 years considered unfit for a myeloablative allograft. 2 Marks DI Clifton-Hadley L Copland M et al. In-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission: results from the prospective, single-arm evaluation of the UKALL14 trial. Lancet Haematol. 2022; 9: e276-e288 Summary Full Text Full Text PDF PubMed Google Scholar Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trialStandard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient. Full-Text PDF Open AccessIn-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission: results from the prospective, single-arm evaluation of the UKALL14 trialFMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes. Full-Text PDF Open Access

In-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission: results from the prospective, single-arm evaluation of the UKALL14 trial

SummaryBackgroundThe outcome of chemotherapy in patients older than 40 years with acute lymphoblastic leukaemia is poor and myeloablative allogeneic haematopoietic stem-cell transplantation (HSCT) has a high transplant-related mortality (TRM) in this age cohort. The aim of this study was to assess the activity and safety of reduced-intensity conditioned allogeneic HSCT in this patient population.MethodsThis was a single-arm, prospective study within the UKALL14 trial done in 46 centres in the UK, which recruited patients to the transplantation substudy. Participants in UKALL14 had B-cell or T-cell acute lymphoblastic leukaemia, were aged 25–65 years (BCR-ABL1-negative) or 18–65 years (BCR-ABL1-positive), and for this subcohort had a fit, matched sibling donor or an 8 out of 8 allelic matched unrelated donor (HLA-A, HLA-B, HLA-C, and HLA-DR). On June 20, 2014, the protocol was amended to allow 7 out of 8 matched unrelated donors if the patient had high risk cytogenetics or was minimal residual disease (MRD)-positive after the second induction course. Patients were given fludarabine, melphalan, and alemtuzumab (FMA; intravenous fludarabine 30 mg/m2 on days –6 to –2, melphalan 140 mg/m2 on day –2, and alemtuzumab 30 mg on day –1 [sibling donor] and days –2 and –1 [unrelated donor]) before allogeneic HSCT (aged ≥41 years patient pathway). Donor lymphocyte infusions were given from 6 months for mixed chimerism or MRD. The primary endpoint was event-free survival and secondary and transplantation-specific endpoints included overall survival, relapse incidence, TRM, and acute and chronic graft-versus-host disease (GVHD). This study is registered with ClinicalTrials.gov, NCT01085617.FindingsFrom Feb 22, 2011, to July 26, 2018, 249 patients (236 aged ≥41 years and 13 younger than 41 years) considered unfit for a myeloablative allograft received an FMA reduced-intensity conditioned HSCT. 138 (55%) patients were male and 111 (45%) were female. 88 (35%) participants received transplantations from a sibling donor and 160 (64%) received transplantations from unrelated donors. 211 (85%) participants had B-precursor acute lymphoblastic leukaemia. High-risk cytogenetics were present in 43 (22%) and another 63 (25%) participants were BCR-ABL1-positive. At median follow-up of 49 months (IQR 36–70), 4-year event-free survival was 46·8% (95% CI 40·1–53·2) and 4-year overall survival was 54·8% (48·0–61·2). 4-year cumulative incidence of relapse was 33·6% (27·9–40·2) and 4-year TRM was 19·6% (15·1–25·3). 27 (56%) of 48 patients with TRM had infection as the named cause of death. Seven (15%) of 48 patients had fungal infections, 13 (27%) patients had bacterial infections (six gram-negative), and 11 (23%) had viral infections (three cytomegalovirus and two Epstein-Barr virus). Acute GVHD grade 2–4 occurred in 29 (12%) of 247 patients and grade 3–4 occurred in 12 (5%) patients. Chronic GVHD incidence was 84 (37%) of 228 patients (50 [22%] had extensive chronic GVHD). 49 (30%) of 162 patients had detectable end-of-induction MRD, which portended worse outcomes with event-free survival (HR 2·40 [95% CI 1·46–3·93]) and time-to-relapse (HR 2·41 [1·29–4·48]).InterpretationFMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes.FundingCancer Research UK.

Optimal treatment for Philadelphia-negative acute lymphoblastic leukemia in first remission in the era of high-intensity chemotherapy.

The optimal treatment for Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) has not been established in the high-intensity chemotherapy era. The outcomes of patients with Ph-negative ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched related or unrelated donor in CR1 (HSCT-MRD group and HSCT-MUD group) were obtained from a Japanese registry database. Patients aged 16-24years and 25-65years were analyzed separately, and their outcomes were compared to those of patients who continued high-intensity chemotherapy in CR1 in studies (202U group and 202O group) by the Japan Adult Leukemia Study Group (JALSG). In the HSCT-MRD group, patients younger than 25years had lower overall survival (OS) than the 202U group, presumably due to the higher non-relapse mortality (NRM) in the HSCT-MRD group. Patients 25years and older had similar OS to the 202O group. The lower relapse rate was counterbalanced by higher NRM in the HSCT-MRD group. In the HSCT-MUD group, patients in both age groups had similar OS to their corresponding groups in the JALSG studies. In conclusion, high-intensity chemotherapy may change the role of HSCT for Ph-negative ALL.

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.

Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia and Poor Karnofsky Performance Status. a Study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Recently, an increasing number of patients with acute lymphoblastic leukemia with a poor Karnofsky Performance Status (KPS) score are considered for allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, there is paucity of available data about outcome of this fragile population. We report here the results of a retrospective study designed to evaluate outcome of ALL patients undergoing allo-HCT with KPS score ≤80%. The analysis included ALL patients aged ≥18 years, undergoing allo-HCT in first remission between 2000 and 2018, with a KPS score of 50% to 80% at the time of transplant. A total of 1,010 patients were identified. Median age at transplant was 43 years (18-76 years). Median year of transplant was 2011. The KPS score was =80% in 83% of the patients and On multivariate analysis, transplant from 10/10 UD was associated with higher incidence of aGVHD (HR 1.8, p In conclusion, allo-HCT is feasible in patients with acute lymphoblastic leukemia in first remission and KPS score ≤80%, with acceptable NRM and survival rates. Transplant from a MSD was associated with reduced risk of NRM and aGVHD as compared to 10/10 UD. Interestingly, despite the poor KPS score of the patients included in the analysis, a MAC protocol was associated with similar NRM, lower relapse and better LFS and GRFS as compared to RIC in the selected population. Finally, administration of ATG was associated with reduced acute and chronic GVHD rates.

Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia and Karnofsky Performance Status Score Equal or Lower Than 80%. a Study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Recently, an increasing number of patients with acute lymphoblastic leukemia with a poor Karnofsky Performance Status (KPS) score are considered for allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, there is paucity of available data about outcome of this fragile population. We report here the results of a retrospective study designed to evaluate outcome of ALL patients undergoing allo-HCT with KPS score ≤80%. The analysis included ALL patients aged ≥18 years, undergoing allo-HCT in first remission between 2000 and 2018, with a KPS score of 50% to 80% at the time of transplant. Patients who received manipulated grafts or had incomplete data about cytogenetics were excluded. Conditioning intensity was defined according to EBMT definitions (Aoudjhane M. et al, Leukemia 2005; 19: pp. 2304-2312). A total of 1,010 patients were identified. Median age at transplant was 43 years (18-76 years). Median year of transplant was 2011. The KPS score was =80% in 83% of the patients and &lt;80% in 17% of the patients. Diagnosis was Philadelphia chromosome (Ph) negative B-ALL, Ph positive B-ALL or T-ALL in 34%, 44% and 22% of the patients, respectively. Donor type was MSD or 10/10 UD in 60% and 40% of the patients, respectively. Conditioning was myeloablative (MAC) or reduced-intensity (RIC) in 78% and 22% of the patients, respectively, and it was TBI-based in 79% of the patients. Stem cell source was PBSC in 76% and BM in 24% of the patients, respectively. Anti-thymocyte globulin (ATG) was administered to 21% of the patients receiving MSD and 68% of the patients receiving 10/10 UD as donor type. Cumulative incidence of grade II-IV and III-IV aGVHD was 32% and 9%, respectively. The 2-year cumulative incidence of chronic GVHD (cGvHD) and severe cGVHD was 43% and 18%, respectively. Non relapse mortality (NRM) and relapse incidence (RI) at 2 years were 18% and 28%, respectively. At 2 years, leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) rates were 54%, 64% and 41%, respectively. On multivariate analysis, transplant from 10/10 UD was associated with higher incidence of aGVHD (HR 1.8, p&lt;0.0001) and higher risk of NRM (HR 1.7, p&lt;0.01) as compared to MSD. RIC conditioning was associated with higher risk of relapse (HR 1.2, p=0.02), lower LFS (HR 1.3, p=0.03) and lower GRFS (HR 1.3 p=0.02) as compared to MAC. NRM was not significantly different between MAC and RIC. Factors independently associated with improved OS were younger age at transplant, female sex, more recent year of transplant and Ph+ B ALL phenotype. Administration of ATG was associated with reduced risk of developing grade II-IV aGVHD (HR 0.6, p&lt;0.001), cGVHD (HR 0.5, p&lt;10-4) and severe cGVHD (HR 0.4, p&lt;10-4). In conclusion, allo-HCT is feasible in patients with acute lymphoblastic leukemia in first remission and KPS score ≤80%, with acceptable NRM and survival rates. Transplant from a sibling donor was associated with reduced risk of NRM and aGVHD as compared to matched unrelated donor. Interestingly, despite the poor KPS score of the patients included in the analysis, a MAC protocol was associated with similar NRM, lower relapse and better LFS and GRFS as compared to RIC in the selected population. Finally, administration of ATG was associated with reduced acute and chronic GVHD rates. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Socie:Alexion: Consultancy. Kröger:JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is a standard of care for adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) and high risk of relapse. However, the stratification systems vary among study groups. Inadequate response at the level of minimal residual disease is the most commonly accepted factor indicating the need for alloHSCT. In this consensus paper on behalf of the European Working Group for AdultAcute Lymphoblastic Leukemia and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize available evidence and reflect current clinical practice in major European study groups regarding both indications for HSCT and particular aspects of the procedure including the choice of donor, source of stem cells and conditioning. Finally, we propose recommendations for daily clinical practice as well as for planning of prospective trials.

New Treatments for Relapsed Hematologic Malignancies After alloHCT

New Treatments for Relapsed Hematologic Malignancies After alloHCT

Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD.Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043).Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. DisclosuresKim:ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Comparable Long-Term Outcomes of Reduced-Intensity and Myeloablative Conditioning Allogeneic Hematopoietic Cell Transplantation By Minimal Residual Disease Kinetics during the Tyrosine Kinase Inhibitor-Based Chemotherapy Courses in Adults with Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia in First Remission

Background: The use of tyrosine kinase inhibitor (TKI)-based chemotherapy has demonstrated improved complete remission (CR) rates and increased applicability to allogeneic hematopoietic cell transplantation (HCT), thus allowing better survival in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, the sensitivity of Ph-positive ALL to reduced-intensity conditioning (RIC) versus myeloablative conditioning (MAC) by minimal residual disease (MRD) kinetics is not well established. Previously, we have confirmed that monitoring MRD kinetics is very important to predict long-term outcomes. Here, we examined a cohort of patients with Ph-positive ALL in CR1 and tried to compare the long-term outcomes of RIC-HCT vs MAC-HCT according to pre-HCT MRD kinetics.Methods: During the period between 2000 and 2014, 173 adults (median age, 39 years [range, 16-65 years]) with Ph-positive ALL were included in this analysis. All patients received allogeneic HCT (68 RIC [fludarabine 150mg/m2 + melphalan 140mg/m2] and 105 MAC [total body irradiation 13.2Gy + cyclophosphamide 120mg/kg]) in CR1 following two courses of first-line TKI (138 imatinib and 35 dasatinib)-based chemotherapy and had data on prospectively determined quantitative MRD kinetics. A total of 52 patients were excluded because of >CR1 pre-HCT status (n=26), transplants receiving umbilical cord blood grafts (n=14), and no TKI use before HCT (n=12). All but one RIC transplants received peripheral blood stem cells as a graft source (40 matched sibling donor, 11 matched unrelated donor, 17 mismatched unrelated donor), while MAC transplants used either bone marrow (n=73; 57 matched sibling donor, 8 matched unrelated donor, 6 mismatched unrelated donor) or peripheral blood stem cells (n=32; 2 matched sibling donor, 20 matched unrelated donor, 10 mismatched unrelated donor). The median time to transplant was 154 days (range, 119-291 days) in RIC transplants and 141 days (range, 112-280 days) in MAC transplants, respectively. Calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) and methotrexate was used for graft-versus-host disease (GVHD) prophylaxis and antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity) through handling of bone marrow samples.Results: After a median follow-up of 70.4 months (range, 16.0-176.8 mo), RIC regimen showed comparable 5-year cumulative incidence of relapse (CIR; 30.2% vs 27.9%, P=0.750), non-relapse mortality (NRM; 20.3% vs 15.5%, P=0.318), disease-free survival (DFS; 49.7% vs 56.6%, P=0.296), and overall survival (OS; 59.3% vs 62.1%, P=0.540) compared to MAC regimen. We further analyzed the impact of conditioning intensity on CIR and DFS according to MRD kinetics. Based on the MRD kinetics during the pre-HCT TKI-based chemotherapy courses, we classified patients into 3 subgroups: early-stable molecular responders (EMR, n=59), late molecular responders (LMR, n=57), and poor molecular responders (PMR, n=53). In all MRD-based subgroups of patients, no significant difference in CIR (EMR: 16.3% vs 6.2%, P=0.280; LMR: 10.5% vs 21.4%, P=0.334; PMR: 63.6% vs 59.4%, P=0.372) or DFS (EMR: 68.1% vs 78.1%, P=0.381; LMR: 49.6% vs 59.5%, P=0.369; PMR: 27.3% vs 34.2%, P=0.250) was observed between RIC and MAC. In multivariate analysis, LMR (HR, 2.36; 95% CI, 0.81-6.86; P=0.114) or PMR (HR, 9.05; 95% CI, 3.40-24.1; P<0.001) had higher relapse risk than EMR. Consequently, compared with EMR, LMR (HR, 2.02; 95% CI, 1.01-4.02; P=0.046) or PMR (HR, 3.79; 95% CI, 1.92-7.50; P<0.001) had poorer DFS. The presence of chronic GVHD, especially mild to moderate grade, was also independently associated with better DFS (HR, 0.28; 95% CI, 0.14-0.53; P<0.001). In addition, patients older than 40 years had higher risk of treatment failure in terms of NRM (HR, 4.25; 95% CI, 1.69-10.6; P=0.002).Conclusion:RIC-HCT showed comparable long-term outcomes to MAC-HCT in all MRD-based subgroups of patients with Ph-positive ALL in CR1. Our data suggest that RIC-HCT is worthy of further investigation in prospective trials of adult Ph-positive ALL. DisclosuresKim:ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Allogeneic transplantation is not superior to chemotherapy in most patients over 40years of age with Philadelphia-negative acute lymphoblastic leukemia in first remission.

Survival of patients ≥40years of age with Philadelphia-negative acute lymphoblastic leukemia (ALL) remains poor with current therapeutic approaches. It is unknown whether allogeneic hematopoietic stem-cell transplantation (HSCT) in first remission confers a survival benefit compared to a chemotherapy-only approach. We retrospectively compared the outcome of patients >40years treated with HSCT or chemotherapy alone in first remission (n=40 in each cohort). Three-year overall survival (OS) and disease-free survival (DFS) were not significantly different between the chemotherapy-only and HSCT groups (OS, 46% [31-68] vs. 40% [27-59], P=0.35; DFS, 31% [18-52] vs. 40% [27-59], P=0.98). The 3-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 61% [41-76] and 9% [2-21] for the chemotherapy-only group and 28% [15-43] and 32% [17-47] for the transplant group (CIR, P=0.011; NRM, P=0.014). Allogeneic transplantation for patients ≥40years with Ph-negative ALL in first remission is associated with a lower CIR, but this benefit is offset by considerable NRM as compared with chemotherapy-only approach. HSCT may be beneficial in patients with high-risk disease features. Am. J. Hematol. 91:793-799, 2016. © 2016 Wiley Periodicals, Inc.

Using multiple timescale models for the evaluation of a time-dependent treatment.

In survival analysis, the absolute measure of cumulative risk provided by the Kaplan-Meier estimator is still the most used quantity for its easy calculation and direct interpretability. However, for describing the survival after an intervention that may occur at different times from baseline observation, the Kaplan-Meier estimator generally yields to biased results if intervention is considered as fixed at baseline. The main focus of the present paper is to extend the use of a multiple timescale model in the presence of a time dependent intervention. The aim is to obtain 1) an estimate of treatment effect in terms of hazard ratios by flexible modeling, 2) a valid prediction tool, i.e. estimate of prognosis for a patient who changes treatment later in time, and 3) an appropriate graphical representation of survival in the presence of a time dependent treatment change, accounting for different timescales. We will show the advantages of this approach on the comparison of chemotherapy versus transplant in children with high-risk acute lymphoblastic leukemia in first remission. We considered a model with two timescales that accounts for the change in treatment at different times in the disease course. An alternative approach to survival estimates is also proposed which has some advantages over the traditional landmark approach: it uses all the data available to plot survival from the date of remission, it avoids the arbitrary choice of a landmark time and explicitly models the change in hazard due to transplant.

Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study

AbstractThe outcome of high-risk (HR) acute lymphoblastic leukemia patients enrolled in the AIEOP-BFM ALL 2000 study in Italy is described. HR criteria were minimal residual disease (MRD) levels ≥10−3 at day 78 (MRD-HR), no complete remission (CR) at day 33, t(4;11) translocation, and prednisone poor response (PPR). Treatment (2 years) included protocol I, 3 polychemotherapy blocks, delayed intensification (protocol IIx2 or IIIx3), cranial radiotherapy, and maintenance. A total of 312 HR patients had a 5-year event-free survival (EFS) of 58.9% (standard error [SE] = 2.8) and an overall survival of 68.9% (SE = 2.6). In hierarchical order, EFS was 45.9% (4.4) in 132 MRD-HR patients, 41.2% (11.9) in 17 patients with no CR at day 33, 36.4% (14.5) in 11 patients with t(4;11), and 74.0% (3.6) in 152 HR patients only for PPR. No statistically significant difference was found for disease-free survival in patients with very HR features [MRD-HR, no CR at day 33, t(4;11) translocation], given hematopoietic stem cell transplantation (HSCT) (n = 66) or chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months). Patients at HR only for PPR have a favorable outcome. MRD-HR is associated with poor outcome despite intensive treatment and/or HSCT and may qualify for innovative therapies. The study was registered at www.clinicaltrials.gov as #NCT00613457.

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.

High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.

Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis

AbstractHematopoietic cell transplantation (HCT) and prolonged chemotherapy are standard postremission strategies for adult acute lymphoblastic leukemia in first complete remission, but the optimal strategy remains controversial. There are no randomized trials of allogeneic HCT. In the present study, updated individual patient data were collected and analyzed from studies with information on availability of matched sibling donor (used to mimic randomization) and from randomized trials of autograft versus chemotherapy. Data from 13 studies including 2962 patients, excluding Philadelphia chromosome–positive patients, showed a survival benefit for having a matched sibling donor for patients < 35 years of age (OR = 0.79; 95% CI, 0.70-0.90, P = .0003) but not for those ≥ 35 years of age (OR = 1.01; 95% CI, 0.85-1.19, P = .9; heterogeneity P = .03) because of the higher absolute risk of nonrelapse mortality for older patients. No differences were seen by risk group. There was a trend toward inferior survival for autograft versus chemotherapy (OR = 1.18; 95% CI, 0.99-1.41; P = .06). No beneficial effect of autografting was seen compared with chemotherapy in this analysis. We conclude that matched sibling donor myeloablative HCT improves survival only for younger patients, with an absolute benefit of approximately 10% at 5 years. Improved chemotherapy outcomes and reduced nonrelapse mortality associated with allogeneic HCT may change the relative effects of these treatments in the future.

The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation From Unrelated Donor Over Chemotherapy As Post-Remission Treatment for Patients with High-Risk Acute Lymphoblastic Leukemia in First Remission

AbstractAbstract 1986For adult patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched related donor (MSD) is recommended for standard and high-risk patients. The role of unrelated donor transplantation (URD) is not fully determined. In this single-center retrospective analysis, we included all consecutive adult patients with high-risk ALL in 1st complete remission (CR) without sibling donor between Jan 2007 to June 2012. Overall, 74 patients were included in the analysis in which 32 patients received URD allo-HSCT during 1st CR with busulfan-cyclophophamide preparation regimen and in vivo T cell depletion with anti-T-lymphoglobulin (ATG). The median time from remission to transplantation was 4.5 months (3∼13). Forty-two patients in the chemotherapy group with 1st CR more than 6 months received consolidation chemotherapy alone either due to lack of suitable URD (n=21), refuse to URD search (n=14), unwillingness to undergo transplantation with available URD (n=5) and donor refuse to donate (n=2). Salvage allo-HSCT was allowed after relapse and actually 5 patients in the chemotherapy group received transplantation from URD donor (n=2) or haplo-identical donor (n=2) in the subsequent remission. The clinical characteristics such age, sex, initial WBC, and Philadelphia chromosome are all distributed equally in the two groups. With a median follow-up of 18 months for the whole group, 30 patients relapsed with estimated 3-year relapse rate (RR) at 58.1±8.5%. The 3-year event-free survival (LFS), non-relapse mortality (NRM) and overall survival (OS) were 38.0±7.9%, 11.1±4.4% and 46.0±9.0% respectively. In the URD allo-HSCT group, RR was 30.6±11.4% which was significantly lower than chemotherapy group (80.5±10.1%, p<0.001) while NRM was higher (16.4±6.7% vs. 0, p=0.028). Overall, 3-year LFS was superior in URD allo-HSCT group compared to chemotherapy (57.8±10.6% vs. 19.5±10.5%; median not reached vs. 13 months, p=0.002) and 3-year OS was also improved in URD allo-HSCT group (63.5±13.3%, median not reached versus 31.6±10.6%, median 24 months, p=0.016). Based on our data, URD allo-HSCT significantly reduced the relapse rate in high-risk ALL and the benefit translated into improvement in both LFS and OS. Prospective randomized study based on availability of HLA matched URD is warranted to confirm the exact role of URD transplantation in adult ALL.Table 1Patient's characteristicsChemotherapyURD-allo-HSCTP valueNo of patientsN=42N=32Median Follow-up (months)15 (7.7∼48)22 (8.2∼49)Sex (M/F)19/2321/110.08Age24.5 (16∼60)25 (16∼57)0.10>351490.61<=352823Initial WBC (×109/L)80.3 (15.3∼97.9)61.5 (3.2∼98.4)0.12CytogeneticsPh+8100.33Ph−3322Table 2Clinical outcome in different treatment strategiesChemotherapyURD-allo-HSCTP valueNo of patientsN=42N=32OS31.6 ± 10.6%63.5 ± 13.3%0.016median24.9 monthsnot reachedLFS19.5 ± 10.5%57.8 ± 10.6%0.002median13.2 monthsnot reachedRelapse rate80.5 ± 10.1%30.6 ± 11.4%<0.001NRM0%16.4 ± 6.7%0.028 Disclosures:No relevant conflicts of interest to declare.

Favorable Outcomes of Autologous Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Remission: On Behalf of the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)

AbstractAbstract 2021 Background:Postremission treatment for adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-)ALL] in first remission remains elucidated and the role of autologous stem cell transplantation (auto-SCT) is still controversial in the application for Ph(-)ALL patients. We retrospectively analyzed the consolidative role of auto-SCT as a postremission therapy for adult Ph(-)ALL in first remission. Patients and Methods:Among 1962 adult Ph(-)ALL patients registered in the JSHCT database, we selected cases receiving auto-SCT with myeloablative preparative regimens in first complete remission from 1983 to 2009. Results:A total of 155 patients with 86 male patients were analyzed. The median age was 25 years (range: 16 to 74) and 79% of patients were less than 45 years of age at transplant. The number of patients having white blood cell (WBC) count <30000/ul and ≥30000/ul at diagnosis was 81 and 21, respectively. The number of patients showing B- and T-cell phenotypes was 80 and 21, respectively. Cytogenetic data were available in 96 patients, of which 69 patients had normal karyotypes. Most patients (84%) underwent auto-SCT before 2002, and 42 out of 155 patients received TBI combined conditioning regimens. With a median follow-up of 10 years, the 10-year overall survival rate of all 155 patients was 41% (95%CI: 33 to 49). Among patients younger than 45 years, the survival rate of adolescent and young adult (AYA) patients (aged 24 years or less) was comparable to that of patients aged 25 to 44 years (p= 0.110). Cumulative incidence of relapse and non-relapse mortality (NRM) at 10 year after auto-SCT was 47% (95%CI: 39 to 55) and 10% (95%CI: 6 to 16), respectively. In univariate analysis, factors associated with worse overall survival were age 45 years or more [Hazard ratio (HR): 1.67, p=0.038] and usage of conditioning regimens without total body irradiation (TBI) (HR: 1.51, p=0.110). Factors associated with decreasing relapse rates were usage of TBI conditioning regimens (HR: 0.35, p=0.069) and transplant year 2000 and later (HR: 0.35, p=0.141). In multivariate analysis, factors correlated with increasing the overall survival rate and decreasing the relapse rate were age less than 45 years [HR: 0.59 (95%CI: 0.36 to 0.96), p=0.034] and usage of TBI conditioning regimens [HR: 0.55 (95%CI: 0.31 to 0.99), p=0.048], respectively. There were no significant factors associated with NRM in univariate and multivariate analyses.We next performed comparison of auto-SCT with allogeneic stem cell transplantation (allo-SCT) in adult Ph(-)ALL patients. Patients undergoing allo-SCT were selected from the same JSHCT database. A total of 921 patients were identified as cases receiving allo-SCT with myeloablative preparative regimens in first complete remission. With a median follow-up of 4.95 years, the 4-year overall survival rate was 63% (95%CI: 51 to 59). Allo-SCT yielded better overall survival rate than that of auto-SCT (63% vs. 48% at 4 year, p=0.0004). In subset analyses, we limited analyses to the groups of patients younger than 45 years and receiving TBI regimens followed by auto-SCT (n=31) or allo-SCT (n=685). There were no differences in baseline patients’ characteristics between the two groups except age [auto-SCT: 20 years (range: 16 to 40) vs. allo-SCT: 28 years (range: 16 to 44), p<0.001]. The 4-year overall survival rates in patients undergoing auto-SCT and allo-SCT were 71% (95%CI: 52 to 84) and 66% (95% CI: 62 to 70), respectively (p=0.510, Figure. 1). No statistically significant factors were found in the analyses of relapse and NRM. Conclusions:Our analyses demonstrated that auto-SCT produced excellent results showing a plateau in long-term survival and that clinical outcome of auto-SCT was comparable to that of allo-SCT in some part of patients. Candidates who obtained most benefit from auto-SCT was those younger than 45 years and well tolerated with TBI combined myeloablative conditioning regimens. Since optimal timing of postremission therapy is critical for adult Ph(-)ALL patients, auto-SCT in first complete remission could be one of promising treatment strategies for the patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.