Cumulative Incidence Of Relapse Rate Research Articles

The value of minimal residual disease and IKZF1 deletion for predicting prognosis in adult patients with B-cell acute lymphoblastic leukemia

Objective: To reassess the prognostic value of minimal residual disease (MRD) and IKZF1 gene deletions in adults with B-cell acute lymphoblastic leukemia (B-ALL) who received pediatric-specific chemotherapy regimens during the Nanfang Hospital PDT-ALL-2016 trial. Methods: We retrospectively analyzed the prognosis of 149 adult patients with B-ALL who were admitted to Nanfang Hospital from January 2016 to September 2020. Prognostic factors were identified using Cox regression models. Results: The complete remission rate was 93.2% in 149 patients, with a 5-year overall survival (OS) rate of (54.3±5.0) % and a cumulative incidence of relapse (CIR) of (47.5±5.2) %. The Cox regression analysis revealed that MRD positivity at day 45 (MRD(3)) after induction therapy was independently associated with relapse risk (HR=2.535, 95%CI 1.122-5.728, P=0.025). Deletion of IKZF1 gene was independently associated with mortality risk (HR=1.869, 95%CI 1.034-3.379, P=0.039). Based on MRD(3) and IKZF1 gene status, we categorized adult patients with B-ALL into the low-risk (MRD(3)-negative and IKZF1 gene deletion-negative) and high-risk (MRD(3)-positive and/or IKZF1 gene wild type) groups. The 5-year OS and CIR rates were (45.5±6.0) % vs (69.4±8.6) % (P<0.001) and (61.6±8.3) % vs (25.5±6.5) % (P<0.001), respectively, in the high-risk and low-risk groups, respectively. The multivariate analysis showed that the high-risk group was an independent risk factor for OS (HR=3.937, 95%CI 1.975-7.850, P<0.001) and CIR (HR=4.037, 95%CI 2.095-7.778, P<0.001) . Conclusion: The combined use of MRD and IKZF1 gene in prognostic stratification can improve clinical outcome prediction in adult patients with B-ALL, helping to guide their treatment.

Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML

AbstractWe conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) for patients with high-risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic stem cell transplantation (allo-SCT) after Ven and fludarabine/busulfan conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% with prior Ven exposure, and 96% with positive molecular measurable residual disease), 22 received maintenance therapy with Aza 36 mg/m2 intravenously on days 1 to 5, and Ven 400 mg by mouth on days 1 to 14 per assigned dose schedule/level (42-day cycles × 8, or 28-day cycles × 12). During maintenance, the most common grade 3-4 adverse events were leukopenia, neutropenia, and thrombocytopenia, which were transient and manageable. Infections were uncommon (n = 4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% confidence interval [CI], 0.3%-18%) and 22% (95% CI, 9%-40%), respectively. After a median follow-up of 25 months among survivors, the median overall survival (OS) was not reached. Among the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, nonrelapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43%-83%), 59% (95% CI, 36%-76%), 0%, and 41% (95% CI, 20%-61%), respectively. Immune monitoring demonstrated no significant impact on T-cell expansion but identified reduced B-cell expansion compared with controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered for patients with high-risk MDS/AML, but a randomized study is required to properly assess any potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT03613532.

Comparison of Therapeutic Effects between Young Haploidentical Donors and Elderly HLA-Matched Relative Donors for AML Patients Who Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Conditioning Regime Including ATG

Objective: Donor selection is one of the issues faced in allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aims to compare the impact of young haploidentical donors and elderly matched relative donors on the outcomes of AML patients undergoing allo-HSCT with conditioning regime including ATG, providing reference for donor selection. Methods: A retrospective analysis was conducted on 708 AML patients who underwent allo-HSCT at our hospital from 2014 to 2021. Among them, 354 patients were included in this study, with 289 patients receiving haploidentical transplantation from donors under the age of 50 (haplo group) and 65 patients receiving fully matched sibling transplantation from donors over the age of 50 (MSD group). Clinical characteristics and transplantation outcomes of both groups of patients and donors were compared. Results: Among the 354 AML-MRC patients, there were 178 males and 176 females, with a median age of 41 (18~56) years. The median follow-up time was 35 (95% CI 30~49) months, and the median overall survival (OS) was 78 (95% CI 23~) months. The 3-year OS rate was 63.1% (95% CI 45.6%~81.4%), the 3-year event-free survival (EFS) rate was 59.0% (95% CI 40.8%~66.1%), the cumulative incidence of relapse (CIR) was 26.8% (95% CI 16.6%~30.0%), and the transplantation-related mortality (TRM) was 22.7% (95% CI 13.2%~33.8%). There were no statistically significant baseline differences between the haplo group and MSD group. The 3-year OS rates for haplo group vs. MSD group were 0.660 (95% CI 0.597-0.731) vs. 0.670 (95% CI 0.558-0.806) (p=0.7), the 3-year EFS rates were 0.620 (95% CI 0.543-0.720) vs. 0.570 (95% CI 0.458-0.656) (p=0.6), and the TRM rates were 0.165 (95% CI 0.121-0.282) vs. 0.134 (95% CI 0.062-0.234) (p=0.6). The CIR rates were 0.199 (95% CI 0.147-0.250) vs. 0.275 (95% CI 0.165-0.397) (p=0.196), and the cumulative incidence of grade II-IV aGVHD was 0.288 (0.237-0.342) vs. 0.309 (95% 0.200-0.424) (P=0.891). The incidence of cGVHD was 0.140 (0.099-0.188) vs. 0.250 (95% 0.147-0.367) (p=0.032). Conclusion: For AML patients undergoing allo-HSCT with conditioning regime including ATG, compared to elderly fully matched donors, young haploidentical donors may reduce the occurrence of post-transplant cGHVD.

Efficacy and Safety of the Second CAR-T Therapy in Patients with Refractory/Relapsed Acute B-Cell Lymphoblastic Leukemia

Background: Chimeric antigen receptor T (CAR-T) cells therapy has shown significant efficacy in relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), but a substantial proportion of patients still relapse after a period of remission. The efficacy of a second CAR-T cell infusion is uncertain. The aim of this study was to explore the efficacy and safety of the second CAR-T therapy in R/R B-ALL patients. Methods: Between August 2018 and October 2022, 35 patients with R/R B-ALL successfully received the second CAR-T treatment. Among them, 18 patients received single CD19 or CD22 CAR-T therapy, 14 patients received tandem CD19/CD22 CAR-T therapy, and 3 patients received sequential CD19 and CD22 CAR-T therapy. Results: The complete remission (CR) rates were 55.6% (10/18) in patients who received CD19 or CD22 CAR-T therapy, 85.7% (12/14) in patients who received tandem CD19/CD22 CAR-T therapy, and 33.3% (1/3) in patients who received sequential CD19 and CD22 CAR-T therapy (tandem CD19/CD22 vs. others, P=0.045). Tandem CD19/CD22 CAR-T therapy remained one of the significant favorable factors in multivariate logistic regression analysis of CR rate in all patients (hazard ratio, 0.128; 95% CI, 0.017-0.974). A total of 5 patients with severe cytokine release syndrome (Grade ≥ 3) were observed, including 2 patients in the single CD19 CAR-T group, 2 patients in the tandem CD19/CD22 CAR-T group, and 1 patient in the sequential CD19 and CD22 CAR-T group. Of the 23 patients who achieved CR, 4 patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 3 patients received decitabine (DAC) consolidation.With the median follow-up of 25.5 months (range, 1.1 to 33.5), the 2-year overall survival, leukemia-free survival (LFS) and cumulative incidence of relapse rates were 23.7%, 30.5% and 69.5%, respectively. Multivariate Cox regression analyses showed that a better LFS related to the absence of high-risk cytogenetics and genetic characteristics, DAC combination with fludarabine and cyclophosphamide lymphodepletion regimen, and bridging allo-HSCT or DAC consolidation. Conclusions: Our study showed that the second infusion of tandem CD19/CD22 CAR-T therapy obtains a better response than other infusion strategies. Bridging allo-HSCT or DAC consolidation had a significant survival benefit in patients with CR after the second CAR-T therapy.

Prognostic Features of CD9 in Childhood Acute Lymphoblastic Leukemia - a Retrospective Analysis of a Nation-Wide Multicenter Study in China

Background and objectives: The outcomes of children with acute lymphoblastic leukemia (ALL) have been incrementally improved with risk-directed chemotherapy but therapy responses remain heterogeneous in clinically defined risk groups. Parameters with added prognostic values are therefore warranted to refine the current risk stratification system and inform appropriate management. CD9, a cell surface protein presented on malignant lymphoblasts, may have such predictive characteristics as shown by our previous single-center study conducted in Hong Kong (Leung et al, Leukemia, 2020). This study aims to determine the precise prognostic features of CD9 in a nation-wide, multicenter childhood ALL cohort in China, and deliver algorithms for identification of patients who may benefit from early interventions. Study design and outcome measures: This multicenter cohort study included childhood ALL patients (aged &amp;lt;18 years) enrolled into the Chinese Children Cancer Group (CCCG)-ALL-2015 study from January 2015 to December 2019, with 7,640 patients from 20 tertiary hospitals in China treated with a uniform protocol. A total of 3,781 subjects (49.5%) from 16 sites had flow cytometry data on lymphoblast CD9 at diagnosis. The final study cohort comprised 3,395 B-ALL and 386 T-ALL patients with a median follow-up of 53.9 months. The primary outcomes were 5-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) for patients with CD9 + or CD9 - phenotypes (positivity defined by the presence of ≥20% CD9 + blasts evaluated through a univariate analysis demonstrating the highest odds for adverse events or relapse at this cut-off). The secondary outcomes were 5-year OS, EFS, and CIR rates of CD9 + and CD9 - patients after inclusion of known prognostic factors, including risk assignment, cytogenetic anomalies, and minimal residual disease (MRD) status. Survival benefits of CD9 + subjects from treatment intensification or hematopoietic stem cell transplantation (HSCT) were analyzed. Results: CD9 was expressed in 88.5% of B-ALL and 27.9% of T-ALL cases. It conferred a dismal EFS (82.1% vs. 89.3%, P=0.001) and a higher CIR (15.5% vs. 7.8%, P&amp;lt;0.001) in B-ALL but not T-ALL patients. The prognostic impact of CD9 is much more prominent in subjects with adverse presenting features or poor early treatment responses, as best exemplified in those assigned to the intermediate/high-risk arms (EFS: 72.8% vs. 83.2%, P=0.028; CIR: 23.1% vs. 10.2%, P=0.003) or those with positive MRD at day 19 (EFS: 65.2% vs. 82.0%, P=0.053; CIR: 30.3% vs. 9.7%, P=0.007). The adverse impact of CD9 is confined to specific cytogenetics, including BCR-ABL1 (CIR: 39.5% vs. 0%, P=0.019) and normal karyotype (CIR: 15.0% vs. 6.8%, P=0.034). In multivariate analyses, CD9 remains an independent factor predicting event-free survival (HR=1.917, P=0.001) and relapse (HR=2.208, P&amp;lt;0.001). The time to and site of relapse did not differ between CD9 + and CD9 - patients. For CD9 + patients with MRD at the end of induction, treatment upstaging only benefited initial low-risk subjects. HSCT at first remission did not improve the outcomes of high-risk subjects with a CD9 + phenotype. Conclusions: This is the largest study to evaluate the significance of CD9 in childhood ALL. We confirmed the results of our previous single-center study with this multicenter national study. CD9 positivity is definitively associated with a higher relapse probability particularly for patients with intermediate/high risk diseases, MRD positivity or specific cytogenetic background. BCR-ABL1 + patients with a CD9 - phenotype had excellent outcomes and HSCT may not be required. Whereas MRD + patients who were CD9 + had poor outcomes, and therefore should have early interventions with innovative treatments to reduce the risk of relapse. With these, we propose to incorporate CD9 into the diagnostic immunophenotyping panel to inform risk stratification and management of childhood ALL.

Impact of TP53 Allelic State on Outcomes of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Neoplasm

Background : Tumor protein p53 ( TP53) mutations are associated with dismal outcomes in myelodysplastic neoplasms (MDS). However, the impact of TP53 allelic state in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for MDS has not been fully explored. Method: We conducted a multi-center study in 347 MDS patients undergoing allo-HSCT between January 2017 and October 2022, with the median follow-up time among survivors of 28.6 (range, 4.7 - 76.6) months, and 45 had TP53 mutations among them. Results: Twenty-one patients were detected with TP53 monoallelic mutations ( TP531mut), while 24 had multiple hits ( TP53multi). Complex karyotype was more common in patients with mutated TP53 (52.4% of patients with TP531mutand 75.0% of patients with TP53multi), whereas this proportion was only 10.6% in patients with wild-type TP53 ( TP53wt). The prognosis varied according to different TP53 state, showing the 2-year overall survival (OS) rates of 51.4% (95% confidence interval [CI]: 33.7% - 78.6%) for TP531mut group versus 15.8% (95% CI: 3.3% - 76.4%) for TP53multi group versus 73.5% (95% CI: 68.5% - 78.9%) for TP53wt group ( P&amp;lt;0.001), and the 2-year cumulative incidence of relapse (CIR) rates of 28.6% (95% CI: 11.2% - 48.8%) for TP531mut group versus 47.3% (95% CI: 18.3% - 71.9%) for TP53multi group versus 10.8% (95% CI: 7.5% - 14.9%) for TP53wt group ( P&amp;lt;0.001). Similarly, the leukemia-free survival (LFS) and graft-versus-host disease-free/relapse-free survival (GRFS) of patients with TP531mut or TP53multi were obviously lower than those with TP53wt (both P&amp;lt;0.001). However, there was no significant difference on non-relapse mortality among these three groups ( P=0.424). The adverse effects of TP53 mutationson OS, LFS, GRFS and CIR were also found in patients undergoing haploidentical HSCT or those with molecular International Prognostic Scoring System high- and very high-risk categories (all P&amp;lt;0.05). In the subgroup with complex karyotype ( n = 32 with non-mutated TP53 and n = 29 with mutated TP53), significantly inferior OS, LFS and GFRS and higher CIR were observed in patients with mutated TP53 while in the subgroup without complex karyotype ( n = 270 with non-mutated TP53 and n = 16 with mutated TP53), there were no differences in these prognostic indicators (all P&amp;gt;0.05). Notably, among patients who received conventional conditioning regime without hypomethylating agents (HMA) ( n = 264 with non-mutated TP53 and n = 38 with mutated TP53), the inferior 2-year OS, LFS and GRFS rates, and the higher 2-year CIR rate of patients still presented in TP53 mutant patients(all P&amp;lt;0.05), but among those receiving conditioning regime containing HMA, similar outcomes were found between mutated ( n = 7) and non-mutated ( n = 38) TP53 groups (all P&amp;gt;0.05). Multivariable cox proportional hazards models demonstrated that monoallelic TP53 state was an independent risk factor for survival and relapse (HR OS=2.859, 95% CI: 1.372 - 5.957, P=0.005; HR LFS=2.566, 95% CI: 1.342 - 4.905, P=0.004; HR GRFS=2.146, 95% CI: 1.106 - 4.163, P=0.024; HR CIR=2.507, 95% CI: 1.033 - 6.086, P=0.042), and multi-hit TP53 state also predicted worse outcomes (HR OS=3.038, 95% CI: 1.453 - 6.356, P=0.003; HR LFS=2.716, 95% CI: 1.383 - 5.336, P=0.004; HR GRFS=1.882, 95% CI: 1.002 - 3.535, P=0.049). C onclusions: Monoallelic and multi-hit TP53 state identify a high-risk group for poor outcomes in MDS patients undergoing allo-HSCT, complex karyotype could amplify the adverse prognostic effect of TP53, and these patients might benefit from receiving conditioning regime containing HMA.

Genetic alterations and MRD refine risk assessment for KMT2A-rearranged B-cell precursor ALL in adults: a GRAALL study

AbstractKMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is widely recognized as a high-risk leukemia in both children and adults. However, there is a paucity of data on adults treated in recent protocols, and the optimal treatment strategy for these patients is still a matter of debate. In this study, we set out to refine the prognosis of adult KMT2A-r BCP-ALL treated with modern chemotherapy regimen and investigate the prognostic impact of comutations and minimal residual disease (MRD). Of 1091 adult patients with Philadelphia-negative BCP-ALL enrolled in 3 consecutive trials from the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), 141 (12.9%) had KMT2A-r, with 5-year cumulative incidence of relapse (CIR) and overall survival (OS) rates of 40.7% and 53.3%, respectively. Molecular profiling highlighted a low mutational burden in this subtype, reminiscent of infant BCP-ALL. However, the presence of TP53 and/or IKZF1 alterations defined a subset of patients with significantly poorer CIR (69.3% vs 36.2%; P = .001) and OS (28.1% vs 60.7%; P = .006) rates. Next, we analyzed the prognostic implication of MRD measured after induction and first consolidation, using both immunoglobulin (IG) or T-cell receptor (TR) gene rearrangements and KMT2A genomic fusion as markers. In approximately one-third of patients, IG/TR rearrangements were absent or displayed clonal evolution during the disease course, compromising MRD monitoring. In contrast, KMT2A-based MRD was highly reliable and strongly associated with outcome, with early good responders having an excellent outcome (3-year CIR, 7.1%; OS, 92.9%). Altogether, our study reveals striking heterogeneity in outcomes within adults with KMT2A-r BCP-ALL and provides new biomarkers to guide risk-based therapeutic stratification.

Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09–09): a randomised, open-label, multicentre, phase 3 trial

Acute myeloid leukaemia with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics. The aim of this study was to evaluate intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in participants with newly diagnosed, NPM1-mutated acute myeloid leukaemia. This open-label, phase 3 trial was conducted at 56 hospitals in Germany and Austria. Eligible participants were 18 years or older and had newly diagnosed NPM1-mutated acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned, using age as a stratification factor (18-60 years vs >60 years), 1:1 to the two treatment groups using allocation concealment; there was no masking of participants and investigators to treatment groups. Participants received two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of high-dose cytarabine (or an intermediate dose for those older than 60 years) and ATRA, without or with gemtuzumab ozogamicin (3 mg/m2 administered intravenously on day 1 of induction cycles 1 and 2, and consolidation cycle 1). The primary endpoints were short-term event-free survival and overall survival in the intention-to-treat population (overall survival was added as a co-primary endpoint after amendment four of the protocol on Oct 13, 2013). The secondary endpoints were event-free survival with long-term follow-up, rates of complete remission, complete remission with partial haematological recovery (CRh), and complete remission with incomplete haematological recovery (CRi), cumulative incidences of relapse and death, and number of days in hospital. This trial is registered with ClinicalTrials.gov (NCT00893399) and has been completed. Between May 12, 2010, and Sept 1, 2017, 600 participants were enrolled, of which 588 (315 women and 273 men) were randomly assigned (296 to the standard group and 292 to the gemtuzumab ozogamicin group). No difference was found in short-term event-free survival (short-term event-free survival at 6-month follow-up, 53% [95% CI 47-59] in the standard group and 58% [53-64] in the gemtuzumab ozogamicin group; hazard ratio [HR] 0·83; 95% CI 0·65-1·04; p=0·10) and overall survival between treatment groups (2-year overall survival, 69% [63-74] in the standard group and 73% [68-78] in the gemtuzumab ozogamicin group; 0·90; 0·70-1·16; p=0·43). There was no difference in complete remission or CRi rates (n=267 [90%] in the standard group vs n=251 [86%] in the gemtuzumab ozogamicin group; odds ratio [OR] 0·67; 95% CI 0·40-1·11; p=0·15) and complete remission or CRh rates (n=214 [72%] vs n=195 [67%]; OR 0·77; 0·54-1·10; p=0·18), whereas the complete remission rate was lower with gemtuzumab ozogamicin (n=172 [58%] vs n=136 [47%]; OR 0·63; 0·45-0·80; p=0·0068). Cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin (2-year cumulative incidence of relapse, 37% [95% CI 31-43] in the standard group and 25% [20-30] in the gemtuzumab ozogamicin group; cause-specific HR 0·65; 0·49-0·86; p=0·0028), and there was no difference in the cumulative incidence of death (2-year cumulative incidence of death 6% [4-10] in the standard group and 7% [5-11] in the gemtuzumab ozogamicin group; HR 1·03; 0·59-1·81; p=0·91). There were no differences in the number of days in hospital across all cycles between treatment groups. The most common treatment-related grade 3-4 adverse events were febrile neutropenia (n=135 [47%] in the gemtuzumab ozogamicin group vs n=122 [41%] in the standard group), thrombocytopenia (n=261 [90%] vs n=265 [90%]), pneumonia (n=71 [25%] vs n=64 [22%]), sepsis (n=85 [29%] vs n=73 [25%]). Treatment-related deaths were documented in 25 participants (4%; n=8 [3%] in the standard group and n=17 [6%] in the gemtuzumab ozogamicin group), mostly due to sepsis and infections. The primary endpoints of the trial of event-free survival and overall survival were not met. However, an anti-leukaemic efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid leukaemia is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants. The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukaemia. Pfizer and Amgen.

Outcomes of allogeneic or autologous stem cell transplantation followed by maintenance chemotherapy in adult patient with B-ALL in CR1 with no detectable minimal residual disease.

Autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for B-cell acute lymphoblastic leukaemia (B-ALL) has been rigorously debated in recent years. We retrospectively analysed the outcomes of 355 adult patients with B-ALL in first complete remission who had received auto-HSCT or allogeneic HSCT (allo-HSCT) in our centre. The treatment efficacy was evaluated from a model stratified on the risk classification and minimal residue disease (MRD) status after three chemotherapy cycles. Auto-HSCT demonstrated comparable 3-year overall survival (OS) (72.7% vs. 68.5%, p = 0.441) and leukaemia-free survival rates (62.8% vs. 56.1%, p = 0.383) compared to allo-HSCT for patients with negative MRD, while the advantage of lower non-relapse mortality (1.5% vs. 25.1%, p < 0.001) was offset by a higher cumulative incidence of relapse (CIR) rates (35.7% vs. 18.9%, p = 0.018), especially in high-risk patients. For patients at high risk and with positive MRD, there was a lower trend of 3-year OS (50.0% vs. 66.0%, p = 0.078) and significantly higher CIR rates (71.4% vs. 39.1%, p = 0.018) in auto-HSCT. However, no significant interaction was observed in the tests. In conclusion, auto-HSCT appears to be an attractive treatment for patients with negative MRD after three chemotherapy cycles. For MRD-positive patients, allo-HSCT may be a more effective treatment.

Impacts of perioperative hyponatremia relevant to outcomes and prognosis of non-small cell lung cancer in octogenarians

BackgroundA recent study reported the effect of preoperative hyponatremia on postoperative outcomes of patients with non-small cell lung cancer. However, the influence of postoperative hyponatremia on postoperative outcomes has not been completely investigated. MethodsWe retrospectively studied 75 octogenarians who underwent pulmonary surgery for non-small cell lung cancer between 2009 and 2018. We divided them into hyponatremic and non-hyponatremic groups, depending on preoperative and immediate postoperative serum sodium levels, and investigated their clinicopathological characteristics and outcomes. Disease-specific survival and cumulative incidence of relapse rates between the two groups were calculated and compared using the stratified Kaplan-Meier method. Univariable and multivariable analyses were performed to identify prognostic factors. ResultsPreoperative hyponatremia was associated with 66.7% of postoperative respiratory and 88.9% of non-cardiovascular complications. The long-term prognosis of the postoperative hyponatremic group was significantly worse than that of their counterpart. The 3-year disease-specific survival and 3-year cumulative incidence of relapse rate were 55.9% and 46.2%, respectively, and the median observation period after surgery was 37.4 (interquartile range, 23.7–51.0) months for the entire cohort. Kaplan-Meier curves showed that hyponatremia was associated with worse disease-specific survival and cumulative incidence of relapse. Multivariable analysis identified hyponatremia as a factor that predicted unfavorable disease-specific survival and cumulative incidence of relapse. ConclusionsImmediate postoperative hyponatremia is an independent predictor of non-small cell lung cancer outcomes among octogenarians. Preoperative hyponatremia was associated with a high frequency of postoperative respiratory and non-cardiovascular complications. Surgical indications in older patients with hyponatremia should be carefully considered with follow-up.

Impact of T-cell Receptor Status on Mutational Landscape and Outcome in T-ALL.

Impact of T-cell Receptor Status on Mutational Landscape and Outcome in T-ALL.

Effects of post-transplant maintenance therapy with decitabine prophylaxis on the relapse for acute lymphoblastic leukemia.

In adults with acute lymphoblastic leukemia (ALL), post-transplant relapse is a major risk factor for mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our study investigated the efficacy and safety of decitabine (dec) with ALL patients post-transplantation. We performed a retrospective cohort study to assess the efficacy of decitabine (dec) with post-transplant ALL at the First Affiliated Hospital of Zhengzhou University from February 2016 to September 2021. A total of 141 consecutive ALL patients were analyzed and divided into decitabine (dec, n = 65) and control (ctrl, n = 76) groups based on whether they were treated with decitabine after allo-HSCT. The 3-year cumulative incidence of relapse (CIR) rate in the dec group was lower than that in the ctrl group (19.6 vs. 36.1%, p = 0.031), with a hazard ratio of 0.491 (95% confidence interval [CI], 0.257-0.936). Additionally, subgroup analyses revealed that the 3-year CIR rate of T-ALL and Ph-negative B-ALL patients in the dec and ctrl groups was 11.7 vs. 35.9% and 19.5 vs. 42.2% (p = 0.035, p = 0.068) respectively. In summary, ALL patients, especially those with T-ALL and Ph-negative B-ALL, may benefit from decitabine as maintenance therapy following allo-HSCT.

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

Acute Lymphoblastic Leukemia in Patients 60 Years and Older Treated with Pediatric-Inspired Protocols, 20 Years of Follow-up

Background Chemotherapy-based approaches remain an essential component of current adult acute lymphoblastic leukemia (ALL) treatment. Poor outcomes in older patients with ALL result from the disease's adverse biology and poor tolerance to chemotherapy. Pediatric-inspired protocols have been used over the past 20 years in our center for patients > 60-year-old, both Philadelphia negative (Ph-), and Philadelphia positive (Ph+). Historically, Ph+ patients have been believed to have inferior outcomes. Our goal was to estimate the outcomes of this subgroup of patients and to compare outcomes between Ph- and Ph+ patients. Methods All newly diagnosed patients with ALL aged > 60 years, and receiving induction chemotherapy with a modified pediatric-inspired regimen between January 2002 and January 2022 were included. The treatment regimen consisted of induction, central nervous system prophylaxis, seven 3-week cycles of intensification, and 24 3-week cycles of maintenance (PM DFCI-based protocols). Only Ph- patients received asparginase. All Ph+ patients received a Tyrosine Kinase Inhibitor (TKI) during all phases of treatment and continued indefinitely after maintenance. There were adjustments in the type of drugs and dosages over the years. Standard descriptive statistics were used. Ninety-five percent confidence intervals were provided for estimates of interest where possible. Fisher's exact test was used to assess the impact of categorical covariates. P < 0.05 were considered to indicate a significantly different result. Kaplan-Meier survival estimate was used to evaluate Leukemia free survival (LFS) and overall survival (OS). Results A total of 122 patients were included: Ph- B-ALL, 50% (N=61); Ph+ B-ALL, 38% (N=46); Mixed Phenotype Acute Leukemia (MPAL), 4% (N=5); and T-ALL, 8% (N=10). Out of the Ph+ patients, only one had an MPAL diagnosis, the rest of them had B-ALL diagnoses. Patient and disease characteristics by Ph status are presented in table 1. For the whole cohort, the complete remission rate after induction (CR) was 83% (N=101), and allogeneic stem cell transplantation (alloSCT) in CR1 was carried out for 10% (N=12). Ten patients (8.2%) died during induction and the cumulative incidence of relapse (CIR) at 1-year was 11.7 % (95% CI 6.7 - 18.2). CR, mortality at induction, alloSCT, and CIR rates were similar in the Ph- and Ph+ groups. With a median follow-up of 52 months (range 4-209 months) among survivors, the median OS was 54 months (95%CI: 28-82). The 1-year and 4-year OS rates were 76% (95%CI: 68-83%) and 51.2% (95%CI: 41.4-60.2%), respectively. Leukemia-free survival (LFS) at years 4 years was 41.9% (95%CI: 32.7-50.9). There were no statistical differences in median OS and LFS between Ph- and Ph+ patients. OS at 4 years for patients with Ph- ALL was 49.7% (95%CI: 37.1-61) vs 53.9% (95%CI:37.9-67.5) in Ph+ ALL patients (p=0.72) (Figure 1). At 4 years LFS was 40.8% (95%CI: 29 - 52) for Ph- patients and, 43.6% (95%CI: 28 - 57) for the Ph+ population (p=0.68). Conclusion Pediatric-inspired chemotherapy protocols with appropriate dose adjustments for age are associated with good outcomes in older ALL patients. Clinical and disease characteristics and outcomes were similar between Ph- and Ph+ ALL patients. We aim to further define the optimal therapy for this group of patients with this challenging disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chemotherapy or Hematopoietic Stem Cell Transplantation in B-Lineage Acute Lymphoblastic Leukemia Patients Based on IKZF1 and MRD Status

Purpose： We aimed to investigate the outcomes of different post-remission treatment choices based on IKZF1 detection by RT-PCR and dynamic measurable residual disease (MRD) by multiparameter flow cytometry in B-ALL. Prospectively confirm the role of MRD and IKZF1 deletion as a significant predictor of post-remission treatment, replacing the definition of clinical risk categories for patients after complete remission (CR). Patients and Methods： There were 202 patients with B-ALL enrolled in this registry-based cohort study including 99 who received chemotherapy (CMT), and 103 allogeneic stem cell transplantation (allo-SCT). The primary endpoint was the 5-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR). Subgroup analyses were performed based on IKZF1deletion and dynamic MRD 14,24,45 days after induction therapy. Results： In subgroups of patients with IKZF1wt and MRD negative patients， the 5-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse(CIR) probabilities for patients assigned to chemotherapy were 67.6%, 55.2%,36.5% and 71.4%,60.7%,28.6%, for those assigned to HSCT respectively. In subgroups of patients with IZKF1 del or MRD positive patients after CR, with OS, EFS, and CIR rates for patients assigned to chemotherapy were 30.1%, 10.3% and76.2%, and 71.8%, 39.8%, and 43.7%for those assigned to HSCT, respectively. Conclusion： The results thus suggest a clear distinction between HSCT and CMT inIKZF1del or MRD positive Patients. While IKZF1wt patients and MRD negative had significant differences. Affected patients should thus be carefully monitored for IKZF1 and minimal residual disease to decide on the post-remission treatment after CR.

Mutations of TP53 Gene in Acute Lymphoblastic Leukemia Do Not Affect the Survival Outcomes after Haploidentical Stem Cell Transplantation

Introduction: Mutations and deletions in TP53 are found in all hematological malignancies, Whereas TP53 mutations (TP53mut) were described to occur quite frequently in acute lymphocytic leukemia (ALL). Previous studies have demonstrated that TP53 mutation was associated with poor prognosis in ALL. Allogeneic hematopoietic stem cell transplantation (HSCT) represents an effective therapy for reducing the chances of relapse of ALL. Recent medical progress has led to haploidentical-SCT (haplo-SCT) achieving transplant outcomes similar to those with matched-sibling donor SCT and matched-unrelated donor SCT in patients with hematological malignancies, haplo-SCT provided an alternative treatment for ALL patients for whom identical donors are unavailable. However, the impact of TP53mut in ALL on survival outcomes in haplo-HSCT setting remains unknown. This study aims to investigate the effect of TP53 mutations on survival outcomes of ALL treated with haplo-SCT at a single institution. Methods: 78 subjects with available TP53 status at diagnosis were retrospectively considered. We excluded 11 subjects who received HLA-matched related transplantation and 2 subjects with HLA-matched unrelated donor transplantation. The remaining 65 subjects with haplo-HSCT were enrolled. TP53 mutation analysis was assessed on bone marrow (BM) samples. LFS and OS were estimated using Kaplan and Meier method and tested between groups using a log-rank test. Cumulative incidence of relapse (CIR) was treated as a competing risk for non-relapse mortality (NRM). Results: A cohort of 65 patients was included with a median(range) age of 30 years (14-51) and was followed up for a median duration of 602 days (range;42-2017 days). 60% of patients were male. 24 of 65 patients showed TP53 mutations. The baseline characteristics including sex, age, white blood cell, diagnosis, Ph/Ph-like chromosomes, IKZF1 mutation, donor-recipient gender, donor-recipient relation, ABO mismatched, CR status before SCT, pre-MRD status were similar between the two groups. 7 (10.8%) patients suffered platelet engraftment failure, the cumulative incidence of grade II-IV aGVHD or cGVHD was comparable between the two groups (TP53mutvs TP53wt:38.8% vs 30.2%, P=0.80; 69.0% vs 63.4%, P=0.98). The 2-year cumulative of CIR rates were 13.1% and 12.5% (P=0.96) among TP53mut and TP53wt patients. The 2-year LFS rates of TP53mut patients were similar to patients with TP53wt (74.2% vs 77.4%, P=0.80). No significant differences in 2-year OS rates (82.9% vs 87.3%, P=0.61) or 2-year NRM rates (12.7% VS 10.2%, P=0.69) were observed in TP53mut and TP53wt patients. TP53 played no prognostic role in multivariate analysis. WBC count at diagnosis (>50x109/L: HR=3.860, P=0.016) and age (>40 years old: HR=4.120, P=0.012) were independent risk factors associated with 2-year LFS, additionally, cGVHD showed protective effect for 2-year LFS in univariate analysis (P= 0.06), but significant was not confirmed in a multivariate analysis. WBC count at diagnosis (>50 x109/L: HR=5.483, P=0.042) was the only independent risk factor of 2-year CIR. To assess the prognostic impact of TP53mut in a homogeneous population, we reanalyzed patients with B-cell immunophenotype. There was no significant difference in survival outcomes between TP53mut and TP53wt groups when only B-ALL were assessed (TP53mutvs TP53wt: 2-year OS: 82.2% vs 93.0%, P=0.23; 2-year LFS: 73.0% VS 82.7%, P=0.44; 2-year NRM:13.3% vs 7.1%, P=0.40; 2-year CIR:13.7% vs 10.2%, P=0.81). Conclusion: Our study showed that TP53 mutations may not be related to the unfavorable impact on survival in ALL patients after treatment with haplo-HSCT. The results imply that haplo-HSCT may be a viable treatment for this subgroup of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact on Outcome of Minimal Residual Disease after Hematopoietic Stem Cell Transplantation with Fludarabine, Amsacrine, and Cytosine Arabinoside-Busulfan Conditioning: A Retrospective Monocentric Study

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after conditioning with a sequential association of fludarabine, amsacrine, and cytosine arabinoside (FLAMSA) followed by a reduced-intensity conditioning regimen has emerged for patients with high-risk acute myeloid leukemia (AML), especially in refractory or relapsing patients. Here we aimed to address retrospectively the impact of pretransplantation minimal residual disease (MRD) by flow cytometry on the outcomes of high-risk AML patients who underwent allo-HSCT after sequential FLAMSA-busulfan (FLAMSA-Bu)-based conditioning regimens. We included 165 high-risk AML patients who underwent transplantation after FLAMSA-BU in this retrospective single-center "real life" study. All patients received in vivo T cell depletion with antithymocyte globulin (5 mg/kg). MRD detection was based on a leukemia-associated immunophenotype using the European LeukemiaNet recommendations, with a threshold of .1%. Univariate and multivariate analyses were performed using R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). With a median follow-up of 4.0 years post-transplantation, the median overall survival (OS) was 54.9 months. Overall, 41 patients (24.8%) relapsed post-transplantation, with a resulting cumulative incidence of relapse (CIR) of 26.7% at 2 years and 34.0% at 5 years. Detectable MRD preceding allo-HSCT and refractory status were associated with worse median OS and CIR rates compared with patients without detectable MRD; however, OS was not significantly different between pre-HSCT MRD-positive and refractory patients (median, .7 year versus 2.0 years; P=.3). Conversely, pre-HSCT MRD negativity was associated with a reduced 2-year CIR. Neither European LeukemiaNet risk stratification nor age had a significant influence on OS. In the multivariate analysis, only pre-HSCT MRD positivity and lower conditioning regimen intensity were significantly associated with a poorer OS. The cumulative incidence of extensive chronic graft-versus-host disease at 2 years was 26.15%. The estimated nonrelapse mortality (NRM) of the entire cohort at 2 years was 23.1%, with age and unrelated donor identified as risk factors for higher NRM. Our data ahow that FLAMSA-Bu conditioning did not reverse the pejorative effect of detectable pre-HSCT MRD, suggesting that such patients should be offered alternative strategies before HSCT to reach deeper remission.

PTCY and Tacrolimus for GVHD Prevention for Older Adults Undergoing HLA-Matched Sibling and Unrelated Donor AlloHCT

The use of post-transplantation cyclophosphamide (PTCY) for graft-versus-host disease (GHVD) prevention is becoming prevalent in the transplantation community when HLA-identical sibling and 10/10 HLA-matched (MUD) and 9/10 mismatched unrelated donors are selected for alloHSCT. However, reported evidence on outcomes from elderly patients receiving PTCY-containing GVHD prophylaxis remains limited. This study aims to compare the outcomes of PTCY- tacrolimus (TK) prophylaxis and conventional GVHD prophylaxis in patients aged >50 years undergoing peripheral blood alloHSCT from a single institution. A total of 161 consecutive patients aged >50 years undergoing alloHSCT between January 2014 and February 2021 were included. Data were collected retrospectively and updated in December 2021. Patients received grafts from HLA-identical sibling, and from 10/10 and 9/10 HLA matched and mismatched unrelated donors. Overall, median age was 60 years, and 91 (54.8%) received PTCY-TK for GVHD prevention. Time to neutrophil and platelet engraftment was longer in the PTCY-TK group (20 versus 16 days and 19 versus 11 days, P < .001). The cumulative incidences of grade II-IV and III-IV acute GVHD (aGVHD) at day 100 and moderate/severe chronic GVHD (cGVHD) at 2 years were 18.2%, 5.7%, and 9.5% for patients receiving PTCY-TK, and 26.0%, 9.6% and 39.5% for those who did not. The multivariate analysis showed that PTCY-TK reduced the probability of grade II-IV aGVHD (hazard ratio [HR] 0.41, P=.035), of cGVHD (any grade: HR 0.43 [P=.014], and of moderate/severe cGVHD [HR 0.15 {P < .001}]). At 2 years, the overall survival (65.4% versus 65.6%, P=.472), non-relapse mortality (17.4% versus 13.7%, P=.967), and cumulative incidence of relapse rates (24.2% versus 27.5%, P=.712) were comparable between both cohorts; GVHD-free/relapse-free survival (GRFS) was higher in the PTCY-TK group (2 years: 50.2% versus 21.8%; HR 0.42, P=.001). In patients aged ≥50 years. PTCY-TK was safe and a more effective drug combination than non-PTCY containing GVHD prophylaxis, even with the use of matched and mismatched unrelated donors, and resulted in comparable relapse rates and better GRFS.

Maintenance Treatment With Low-Dose Decitabine After Allogeneic Hematopoietic Cell Transplantation in Patients With Adult Acute Lymphoblastic Leukemia.

BackgroundPost-transplant relapse remains a principal leading cause of failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with adult acute lymphoblastic leukemia (ALL). The aim of this study was to investigate the efficacy and safety of low-dose decitabine on the prevention of adult ALL relapse after allo-HSCT.MethodsIn this prospective study, we enrolled 34 patients with ALL who underwent allo-HSCT from August 2016 to April 2020 and received low-dose decitabine maintenance treatment after transplantation. The primary objectives were cumulative incidence of relapse rate (CIR), overall survival (OS), and disease-free survival (DFS). The secondary objectives were graft-versus-host disease (GVHD) and safety.ResultsAmong the enrolled 34 patients, 6 patients relapsed and 6 patients died. The 2-year CIR, OS, and DFS were 20.2, 77.5, and 73.6%, respectively. Subgroup analysis revealed the 2-year CIR, OS, and DFS rates of 12 patients with T-ALL/lymphoblastic lymphoma (LBL) were 8.3, 90, and 81.5%, respectively. None of the seven patients with T-ALL relapsed. During maintenance treatment, only one patient (2.9%) developed grade IV acute GVHD and four (11.8%) patients had severe chronic GVHD. Thirty-two patients (94.1%) developed only grade I to II myelosuppression, and two patients (5.8%) developed grade III to IV granulocytopenia.ConclusionsMaintenance treatment with low-dose decitabine after allo-HSCT may be used as a therapeutic option to reduce relapse in patients with adult ALL, especially in patients with T-ALL. Our findings require confirmation in larger-scale controlled trials.Clinical Trial RegistrationChinese Clinical Trials Registry, identifier ChiCTR1800014888.

Personalized Circulating Tumor DNA Predicts Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Relapse is a main event of therapy failure for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (alloSCT). Hence, a novel strategy to detect minimal residual disease (MRD) is required for earlier therapeutic intervention in impending post alloSCT relapse. Recent evidence indicated that screening of driver mutations by next generation sequencing (NGS) followed by detection of circulating tumor DNA (ctDNA) via droplet digital PCR (ddPCR) is a promising approach for MRD monitoring in patients with MDS (Paul Y, et al. Blood. 2017). Here, in this study, we investigated whether serial ctDNA monitoring could identify patients who are most likely to relapse after alloSCT.Methods: We performed a retrospective study in 31 patients with AML and MDS undergoing alloSCT. Cell-free DNA (cfDNA) was extracted from serum samples. We subjected primary tumor DNA, extracted from a diagnostic peripheral blood or bone marrow (BM), and buccal swab DNA, to NGS, identifying one or two somatic driver mutations. We designed unique ddPCR assays for each somatic mutation identified (n=25). The primary endpoint was cumulative incidence of relapse rate (CIR) and the secondary endpoint was overall survival (OS). CIR and OS were calculated by the Kaplan-Meier method. The log-rank test was used for group comparison.Results: 31 patients were enrolled in our study: our cohort consisted of 10 patients with de novo AML, 15 with AML with myelodysplasia related changes, and 6 with MDS. The median age was 52 years (17-68 years) and 5 patients (16%) are in complete remission at alloSCT. Stem cell source included related bone marrow (n=2) and cord blood (n=29). The preparative regimen included myeloablative conditioning (n=17) and reduced intensity conditioning (n=14). NGS screening identified 26 somatic driver mutations in 30 of 31 (97%) cases, with 2 mutations found in 5 individuals. Overall, we could construct ddPCR assays for 29 of 31 (94%) patients: these mutations included NRAS, TP53, NPM1, DNMT3A, GATA2, etc. NGS and ddPCR assays had a good concordance in assessing the same tumor rich samples with regard to the variant allele frequency (VAF).The amount of cfDNA at diagnosis was significantly higher compared with paired cfDNA at remission (n=23; p=0.0133, paired t-test). Of 37 matched serial time points, VAF between BM and serum ctDNA indicates apparent correlation (r2=0.92, p<0.0001). CtDNA was detected in 10 of 25 (40%) samples at 1 month after alloSCT and 7 of 21 (33%) samples at 3 months (termed “ctDNA1-positive” and “ctDNA3-positive”, respectively).We next evaluated whether the positivity of ctDNA at 1 month and 3 months after alloSCT was associated with higher CIR and lower OS. As expected, patients with ctDNA1-positive and ctDNA3-positive had significantly superior CIR and inferior OS: 2-year CIR 51% in ctDNA1-positive patients vs. 9% in negative patients, p=0.0005 (Figure 1A); 2-year OS 48% in ctDNA1-positive patients vs. 83% in negative patients, p=0.0152 (Figure 1B); 2-year CIR 57% in ctDNA3-positive patients vs. 23% in negative patients, p=0.0055 (Figure 1C); 2-year OS 50% in ctDNA3-positive patients vs. 88% in negative patients, p=0.0344 (Figure 1D), respectively.Conclusions: In summary, personalized ctDNA monitoring could detect MRD, which alloSCT has failed to eradicate, and thus identify patients with high-risk of relapse. This might allow for clinicians to initiating earlier therapeutic interventions for impending relapse. Further prospective studies in a much larger cohort of AML and MDS undergoing alloSCT are required to confirm these findings.Figure 1. CIR and OS based on ctDNA status at 1 month and 3 months after alloSCT [Display omitted] DisclosuresNagamura-Inoue:Tsubakimoto Chain CO.: Research Funding; AMED grant: Research Funding; Rohto Pharmaceutical Co., Ltd.: Research Funding. Tojo:AMED grant: Research Funding.