5-year Cumulative Incidence Of Relapse 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.

Nilotinib with or without cytarabine for Philadelphia-positive acute lymphoblastic leukemia

AbstractWe previously demonstrated that a reduced-intensity chemotherapy schedule can safely replace hyper-CVAD (cyclophosphamide-vincristine-doxorubicin [Adriamycin]-dexamethasone) cycle 1 when combined with imatinib in adults with Philadelphia-positive acute lymphoblastic leukemia. In the present randomized GRAAPH-2014 trial, we used nilotinib and addressed the omission of cytarabine (Ara-C) in consolidation. The primary objective was the major molecular response (MMR) rate measured by BCR::ABL1 quantification after cycle 4 (end of consolidation). All patients were eligible for allogeneic stem cell transplant (SCT), whereas those in MMR could receive autologous SCT, followed by 2-year imatinib maintenance in both cases. After the enrollment of 156 of 265 planed patients, the data and safety monitoring board decided to hold the randomization because of an excess of relapse in the investigational arm. Among the 155 evaluable patients, 76 received Ara-C during consolidation (arm A) and 79 did not (arm B). Overall, 133 patients (85%) underwent SCT, 93 allogeneic and 40 autologous. The noninferiority end point regarding MMR was reached with 71.1% (arm A) and 77.2% (arm B) of patients reaching MMR. However, the 4-year cumulative incidence of relapse was higher in arm B compared with arm A (31.3% [95% confidence interval {CI}, 21.1%-41.9%] vs 13.2% [95% CI, 6.7%-21.9%]; P = .017), which translated to a lower relapse-free survival. With a median follow-up of 3.8 years, 4-year overall survival was 79.0% (95% CI, 70.6%-89.3%) in arm A vs 73.4% (95% CI, 63.9%-84.4%) in arm B (P = .35). Despite a noninferior rate of MMR, more relapses were observed when ARA-C was omitted without impact on survival. ClinicalTrials.gov ID, NCT02611492.

Open-Label Randomized Controlled Study of Ciprofloxacin vs Rifaximin as Neutropenia Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation

Loss of microbiota diversity has been clearly associated with poor outcomes in the allogeneic hematopoietic stem cell transplantation setting. However, the choice of the optimal antibiotic prophylaxis during the pre-engraftment phase remains unclear. We designed a prospective randomized study to compare our standard-of-care neutropenia prophylaxis (ciprofloxacin) with rifaximin. We enrolled 38 consecutive adult patients who underwent allogeneic hematopoietic stem cell transplantation setting and were randomly assigned to receive ciprofloxacin (20 patients) or rifaximin (18 patients) at day -1. Pretransplant and transplant characteristics did not differ between groups. Cumulative incidence (CI) of acute graft-vs-host disease grade II to IV and moderate/severe chronic graft-vs-host disease was similar in both groups. With a median follow-up of 13.2 months (range, 6.8-30.2) in surviving patients, the 1-year CI of relapse was 20.8% in ciprofloxacin vs 17.8% in rifaximin (P = .616). Importantly, the 1-year CI of treatment-related mortality was significantly reduced in the ciprofloxacin group (10.2% vs 27.8%, P = .032), leading to higher 1-year overall survival (88.9% vs 74.6%, P = .038). In Cox-regression multivariate analysis, antibiotic prophylaxis remained the only predictor of overall survival, independently of donor type, disease risk index, and moderate/severe chronic graft-vs-host disease. Further studies are needed to assess the effects on microbiota diversity and confirm these outcomes.

Comparison of long-term outcomes between imatinib and dasatinib prophylaxis after allogeneic stem cell transplantation in patients with Philadelphia-positive acute lymphoblastic leukemia: A multicenter retrospective study.

Although the prognosis of Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the introduction of tyrosine kinase inhibitors (TKIs) and stem cell transplantation, prevention of relapse after transplantation remains a concern. The aim of this study was to compare the impact of TKI prophylaxis with imatinib and dasatinib on long-term outcomes after transplantation. Patients with Ph+ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) and received TKI prophylaxis after allo-HSCT were included in this retrospective analysis. Two cohorts were established based on the choice of TKI prophylaxis: the imatinib (Ima) and dasatinib (Das) cohorts. The survival and safety outcomes of these cohorts were compared. Ninety-one patients in the Ima cohort and 50 in the Das cohort were included. After a median follow-up of 50.6months, the 5-year cumulative incidence of relapse, nonrelapse mortality rate, and overall survival in the Ima and Das cohorts were 16.1% and 12.5%, 5.2% and 9.8%, and 86.5% and 77.6%, respectively, with no statistical differences. The cumulative incidence of mild chronic graft-versus-host disease was higher in the Das cohort. The most common adverse event was neutropenia (64.7% vs. 69.5%). The Das cohort had a higher incidence of gastrointestinal bleeding (25.5% vs. 2.3%) and gastrointestinal reaction (48.9% vs. 31.4%) than the Ima cohort. The proportion of patients treated on schedule was significantly lower in the Das cohort than in the Ima cohort, and drug intolerance was the main reason for protocol violation. For patients with Ph+ALL undergoing allo-HSCT in CR1, imatinib prophylaxis achieved long-term outcomes similar to those of dasatinib.

Continuous PEGasparaginase Dosing Reduces Hypersensitivity Reactions in Pediatric ALL: A Dutch Childhood Oncology Group ALL11 Randomized Trial.

The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule. Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome. During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions (P < .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions (P < .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 [0.032-0.653]). In addition, antibody levels were significantly lower in the continuous arm (P < .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms. A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.

Clinical analysis of 14 patients aged ≤ 50 years with high-risk multiple myeloma treated with allogeneic hematopoietic stem cell transplantation

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in young patients with high-risk multiple myeloma (HRMM) and analyzed the factors affecting patient prognosis. Methods: In this retrospective study, we analyzed the clinical data of 14 patients with HRMM with cytogenetic abnormalities or high-risk biological factors who underwent allo-HSCT at the Hematopoietic Stem Cell Transplantation Center of the Institute of Hematology & Blood Diseases Hospital between November 2016 and November 2022. Results: There were seven males and seven females included in the study, with a median age of 39.5 (31-50) years at the time of allo-HSCT. The median number of treatment lines before transplantation was 2 (1-6) . Before allo-HSCT, 42.9% (6/14) of the patients did not achieve complete remission, while 35.7% (5/14) of the patients achieved measurable residual disease positivity. After transplantation, all patients were evaluated for their treatment response, and the overall response rate was 100% (14/14) . All 14 patients successfully underwent allo-HSCT, with median engraftment times for neutrophils and platelets of 11 (10-14) days and 13 (9-103) days, respectively. Acute grade Ⅱ-Ⅳ graft-versus-host disease (GVHD) occurred in five patients (35.7%) , and two patients (14.3%) developed moderate-to-severe chronic GVHD. The median follow-up time after allo-HSCT was 18.93 (4.10-72.53) months, with an expected 2-year transplant-related mortality rate of 7.1% (95% CI 0%-21.1%) and an expected 2-year overall survival rate of 92.9% (95% CI 80.3%-100.0%) . Moreover, the expected 1-year and 2-year progression-free survival rates were 92.9% (95% CI 80.3%-100.0%) and 66.0% (95% CI 39.4%-100.0%) , respectively, and the 2-year cumulative incidence of relapse was 28.9% (95% CI 0%-56.7%) . Upfront allo-HSCT following complete remission after induced therapy and the presence of chronic GVHD might be favorable prognostic factors. Conclusion: allo-HSCT is an effective treatment for improving the prognosis of young patients with HRMM.

Outcome of High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation in Relapsed/Refractory Hodgkin Lymphoma after Different Numbers of Salvage Regimens.

The introduction of novel drugs (PD-1 inhibitors and/or brentuximab vedotin) into salvage regimens has improved the response rate and the outcome of patients with relapsed/refractory Hodgkin lymphoma. However, the impact of new drugs on the outcome has not been adequately investigated so far. We retrospectively analyzed 42 consecutive patients treated at our institution with high-dose chemotherapy/autologous stem cell transplantation after either one standard chemotherapy represented by BEGEV (n = 28) or >1 salvage therapy (ST) comprising novel drugs (n = 14). With a median follow-up of 24 months, the 2-year cumulative incidence of relapse was similar between the two cohorts: 26% for 1 ST and 18% for >1 ST (p = 0.822). Consistently, overall survival and progression-free survival did not differ among the two groups: 3-year overall survival was 91% and 89% (p = 0.731), respectively, and 3-year progression-free survival was 74% and 83% (p = 0.822) for only one and more than one salvage regimens, respectively. Of note, the post-transplant side effects and engraftment rates were similar between the 1 ST and >1 ST cohorts. In conclusion, consolidation with high-dose chemotherapy/autologous stem cell transplantation is a safe and curative option, even for patients achieving disease response after more than one rescue line of therapy.

Prognostic risk signature in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax

AbstractHypomethylating agents (HMAs) and venetoclax (Ven) represent the standard of care for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, the European LeukemiaNet (ELN) risk classifications have been validated for patients treated with intensive therapy. In this study, we validate a recently proposed new molecular prognostic risk signature (mPRS) for patients with AML treated with HMAs and Ven. This classification allocated patients to favorable, intermediate (N/KRAS or FLT3–internal tandem duplication mutations), and lower (TP53 mutations) benefit groups. We retrospectively analyzed 159 patients treated with HMA and Ven. The mPRS classification allocated 74 (47%), 31 (19%), and 54 (34%) patients to the higher, intermediate, and lower-benefit groups, respectively. The overall response rate was 71% (86%, 54%, and 59% in the higher, intermediate, and lower-benefit groups, respectively). The median overall survival (OS) and event-free survival (EFS) times were 30 and 19 months, respectively, in the higher-benefit group; 12 and 8 months in the intermediate-benefit group; and 5 and 4 months in the lower-benefit group (P < .001). The C-index for OS and EFS was higher when stratifying patients according to mPRS classification than with the ELN 2022 classification. The 2-year cumulative incidence of relapse was 35%, 70%, and 60% in the higher, intermediate, and lower-benefit groups, respectively (P = .005). The mPRS classification accurately segregated groups of patients with AML treated with HMA plus Ven. In these patients, N/KRAS and TP53 mutations appear to negatively affect outcomes; therefore, new treatment approaches are warranted.

Comparison of Two Venetoclax-Based Regimens As Salvage Therapies Bridged to Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Introduction ： Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for relapsed or refractory acute myeloid leukemia (R/R-AML) patients. However, it is not clear about appropriate salvage therapy bridged to allo-HSCT for R/R-AML patients. In this study, we compared the outcomes of R/R-AML patients treated with venetoclax plus hypomethylating agents (VEN-HMA) regimen or venetoclax plus azacitidine and homoharringtonine (VAH) regimen as salvage therapies bridged to allo-HSCT. Methods ： A total of 105 R/R-AML patients treated with VEN-HMA regimen or VAH regimen bridged to allo-HSCT between September 2018 and February 2023 were enrolled. The outcomes including survival, relapse and NRM after allo-HSCT were analyzed in two groups. Results ： Forty-four patients were treated with VEN-HMA regimen, and 61 with VAH regimen. Seventy-four patients had primary refractory AML and 31 relapsed AML, including 19 relapsed after chemotherapy and 12 relapsed after allo-HSCT. Thirty-one (70.5%) patients achieved composite complete remission (CRc) in VEN-HMA group including 20 (45.5%) with minimal residual disease (MRD) negative, as well as 52 (85.2%) with CRc including 40 (65.6%) with MRD negative in VAH group (P=0.09). Twenty-five (56.8%) patients were stratified with adverse risk in VEN-HMA group and 45 (73.8%) in VAH group according to the 2022 European Leukemia Net (ELN) classification (P=0.07). The 2-year overall survival (OS) and event-free survival (EFS) in VAH group were higher (78.4% vs 58.7%, P=0.03; 68.3% vs 38.7%, P=0.003), as well as 2-year cumulative incidence of relapse (CIR) was lower than VEN-HMA group (23.2% vs 42.4%, P=0.04). Among patients with CRc, the 2-year OS, EFS and CIR was 67.5%, 48.9% and 37.0% in VEN-HMA group, as well as 82.5%, 72.5% and 23.6% in VAH group (P=0.15, 0.05 and 0.24). Among patients with MRD negative, the 2-year OS, EFS and CIR was 75.5%, 55.5% and 31.6% in VEN-HMA group, as well as 90.8%, 80.0% and 17.5% in VAH group (P=0.15, 0.10 and 0.28). Among patients with adverse risk, the 2-year OS and EFS in VAH group were higher (79.3% vs 47.7%, P=0.01; 70.9% vs 24.1%, P=0.0002), as well as 2-year CIR was lower than VEN-HMA group (17.4% vs 45.8%, P=0.01). Non-relapse mortality (NRM) was similar between VEN-HMA group and VAH group (18.9% vs 8.5%, P=0.12). Conclusion ： VAH regimen is an effective salvage therapy bridged to allo-HSCT for R/R-AML patients compared with VEN-HMA regimen. Keywords ： Venetoclax, Azacitidine, Homoharringtonine, Relapsed/Refractory AML, Allogeneic Hematopoietic Cell Transplantation.

Outcomes after Hematopoietic Cell Transplantation for T-Lineage Acute Lymphoblastic Leukemia and Lymphoma: A Cooperative Study from the Adult Acute Lymphoblastic Leukemia Working Group and the Adult Malignant Lymphoma Working Group of the Japanese Society for Transplantation and Cellular Therapy

Background: T-lineage acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL) arise from immature precursor T cells and are currently considered a single disease entity according to the World Health Organization Classification. Patients with T-ALL or T-LBL typically receive ALL-type intensive chemotherapy if applicable, and those with high-risk features or relapsed disease undergo hematopoietic cell transplantation (HCT). Although autologous HCT for T-ALL is uncommon, it remains a choice in the general practice of T-LBL, resulting in different donor selection strategies for these diseases. However, there is limited data on outcomes for these patients. Methods: We analyzed nationwide registry data (Transplant Registry of Unified Management Program Japan, TRUMP) from 2000 to 2017 to evaluate outcomes after the first HCT and identify prognostic factors among p with T-ALL/T-LBL. Five patients who underwent autologous HCT for T-ALL were excluded from the analysis. Overall and disease-free survival (OS and DFS) were assessed using the Kaplan-Meier method with the log-rank test. Univariate and multivariate analyses were performed to identify the potential prognostic factors. The Cox proportional hazards method was used for the multivariate analysis to assess OS, whereas Gray's test and the Fine-Gray model were used to determine the cumulative incidence of relapse (CIR) considering competing risks such as relapse and non-relapse mortality (NRM). Results: A total of 1345 patients (T-ALL, n=808; T-LBL, n=537) were included in the database. The median follow-up period of survivors was 4.5 (interquartile range, 2.0-7.7) years. The median age at HCT was 32 (range, 16-70) years. The OS and DFS at 4 years after HCT were comparable between T-ALL and T-LBL (OS 51.7% vs. 52.0%, p = 0.494; DFS 48.3% vs. 45.4%, p = 0.066). However, higher NRM and lower CIR were observed in T-ALL compared with T-LBL (4-year NRM 21.8% vs. 14.5%, p = 0.002; 4-year CIR 29.9% vs. 40.1%, p &amp;lt; 0.001). In T-LBL, patients who received allogeneic HCT (allogeneic LBL, n = 402) had significantly worse survival than those who received autologous HCT (autologous LBL, n = 135) (4-year OS 47.4% vs. 66.2%, p &amp;lt; 0.001; 4-year DFS 47.4% vs. 66.2%, p &amp;lt; 0.001), with significantly worse NRM and comparable CIR (4-year NRM 18.0 vs 3.8%, p &amp;lt; 0.001; 4-year CIR 39.6% vs. 41.6%, p = 0.875). Compared with the allogeneic ALL or allogeneic LBL groups, the autologous LBL group had a significantly older age at HCT (the respective median age was 31 years [range, 16-70], 33 [16-86], and 49 [16-76]; p &amp;lt; 0.001). The allogeneic LBL group had a lower rate of first complete remission (CR1) and a higher rate of non-CR at SCT (CR1/non-CR: allogeneic ALL, 57.1%/30.4%; allogeneic LBL, 37.6%/47.0%; autologous LBL, 57.8%/31.1%; p &amp;lt; 0.001). Among patients in CR1 at HCT, OS and DFS were comparable among the allogeneic ALL (n = 461), allogeneic LBL (n = 151), and autologous LBL (n = 78) groups (Fig. 1, 4-year OS 69.3% vs. 72.6% vs. 76.7%, respectively, p = 0.389; 4-year DFS 64.9% vs. 65.5% vs. 67.1%, respectively, p = 0.830). However, the NRM was lower in the autologous LBL group (4-year NRM 16.6% vs. 8.3% vs. 0.0%, respectively, p &amp;lt; 0.001), and the CIR was lower in the allogeneic ALL group (4-year CIR 18.9% vs. 26.3% vs. 32.9%, respectively, p = 0.004). Among patients without CR at SCT, outcomes were comparable between allogeneic ALL (n = 246), allogeneic LBL (n = 189), and autologous LBL groups (n = 42) (4-year OS 18.4%, 24.6%, vs 36.9%, respectively, p = 0.347; 4-year DFS 17.4%, 21.9%, vs 23.6%, respectively, p = 0.818; 4-year NRM 29.8%, 28.0%, vs 12.7%, respectively, p = 0.107; 4-year CIR 52.8%, 50.2%, vs 63.7%, respectively, p = 0.347). In T-ALL, multivariate analysis identified age ≥ 41 years, male sex, PS ≥ 2, disease status other than CR1, HLA disparity ≥ 2 loci, myeloablative conditioning (MAC) without total body irradiation (TBI), and HCT before 2010 as factors associated with poor OS (Table 1, Upper). In T-LBL, PS ≥ 2, non-CR at HCT, MAC without TBI, use of anti-thymocyte globulin, and multiple treatment regimens before HCT were significant factors for poor OS (Table 1, Lower). Donor type did not affect OS. Conclusion: This largest-ever retrospective study shows comparable OS after HCT for T-ALL or T-LBL. Active disease, PS ≥ 2, and non-TBI MAC were potent poor prognostic factors. In T-LBL, autologous HCT can be a suitable option, which should be confirmed in further prospective studies.

A Single Center Retrospective Study on the Efficacy of Haploidentical Hematopoietic Stem Cell Transplantation in Patients with Myeloid Neoplasms over 50 Years Old

Objective: This study aims to evaluate the efficacy and safety of haploidentical hematopoietic stem cell transplantation in patients with myeloid neoplasms over 50 years old, and to compare the differences in survival, recurrence, and adverse reactions between patients aged 50-55 and over 55 years old. Methods: The patients with myeloid neoplasms over 50 years old who received haploidentical hematopoietic stem cell transplantation from November 2016 to December 2021 in the Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University, School of Medicine were enrolled. According to the age at the time of transplantation, patients were divided into Group A (50-55 years old) and Group B (≥ 55 years old). The differences in Overall survival (OS), progression free survival (PFS), non-relapse mortality (NRM), cumulative incidence of relapse (CIR), incidence of graft versus host disease (GVHD), and infection rate between the two groups were analyzed. Results: A total of 163 patients (group A, n=77; group B, n=86) were enrolled, including 112 cases of acute myeloid leukemia (AML), 39 cases of myelodysplastic neoplasms (MDS), 4 cases of chronic myeloid monocyte leukemia (CMML), 3 cases of primary myelofibrosis (MF), and 5 cases of chronic myeloid leukemia (CML). There were no statistically significant differences in baseline data between the two groups, including follow-up time, disease categories, HCT-CI score, remission status of AML patients, minimal residual lesion (MRD) level of AML patients, and IPSS-R score of MDS patients. However, more patients in Group A received myeloablative (MAC) conditioning than patients in Group B (92.2% vs 50%, P=0.000). The median follow-up time was 741 (7-2377) days. The overall 2-year OS is 73.0% ± 3.5%, 2-year PFS is 71.3% ± 3.6%, 2-year NRM is12.23%（7.65%-17.93%）, and 2-year CIR is 17.20%（11.64%-23.69%）. All patients in group A achieved hematopoietic reconstitution except one patient died of graft failure, while 5 patients of group B died of graft failure(P=0.126). Neutrophils and platelet reconstruction in Group B was slightly longer than in Group A. The neutrophils reconstruction occurred at a median of 12 (8-20) day and 13 (9-25) day, respectively (P=0.007), and platelet reconstruction occurred at a median of 12 (9-28) day and 13 (8-37) day, respectively (P=0.055). The 2-year OS of Group A and Group B was 76.6% ± 4.8% and 69.0 ± 5.1%, respectively (P=0.199); The 2-year PFS was 76.2% ± 4.9% and 66.9 ± 5.1%, respectively (P=0.236); The 2-year NRM was 9.16% (4.00% -16.96%) and 18.61% (11.18% -27.51%), respectively (P=0.094); The 2-year CIR was similar, with 14.66% (7.74% -23.67%) and 19.16% (11.48% -28.33%), respectively (P=0.782). Interestingly, there was a difference in NRM between patients receiving reduced-intensity (RIC) and MAC conditioning in Group B, which was 10.2% (3.69% -20.61%) and 25.58% (13.64% -39.34%), respectively (P=0.043), while there was no difference in CIR, which was 17.31% (7.88% -29.80%) and 18.90% (8.71% -32.06%), respectively (P=0.933). It is suggested that in older patients, the strength of conditioning regimen has a greater impact on NMR. The incidence of grade 3-4 aGVHD within 100 days in all patients was 11.84% (7.31% -17.56%), and the incidence of 2-year intensive cGVHD was 8.19% (4.58% -13.14%). The incidence of grade 3-4 aGVHD within 100 days was similar between the two groups, with 9.46% (4.13% -17.46%) and 14.10% (7.46% -22.81%) (P=0.368), respectively. The 2-year intensive cGVHD was 8.07% (3.26% -15.72%) and 8.28% (3.62% -15.42%) (P=0.890), with similar incidence rates. The incidence of bacterial septicemia, pneumonia, invasive fungal infection, herpes virus and other infections were similar in both groups. Univariate and multivariate analysis both showed that 50-55 years old was an independent protective factor of OS (2.384 (1070-5.312), P=0.034) and GRFS (2.683 (1.181-6.094), P=0.018) in AML patients. Conclusion: Haploidentical hematopoietic stem cell transplantation is an effective and safe treatment for myeloid neoplasms over the age of 50. Compared with patients aged 50 to 55 years old, patients with myeloid neoplasms aged over 55 years old had similar efficacy and safety. The impact of MAC and RIC pretreatment on the prognosis of patients at different ages may be different. This retrospective study is limited in number and needs more cases and prospective cohort study to further verify.

Effect of Early Cytomegalovirus Reactivation on Relapse in Adult Patients with Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: A Registry Study from the Japan Society for Transplantation and Cellular Therapy (JSTCT)

Background Cytomegalovirus reactivation (CMVR) is a well-known complication contributing to morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Previous studies have demonstrated that CMVR is associated with poor clinical outcomes following HSCT. However, some studies have shown that CMVR following HSCT may have a recurrence-suppressing effect on hematological diseases, including acute myeloid leukemia and acute lymphoblastic leukemia. Conversely, data on the relevance between CMVR and relapse in patients with myelodysplastic syndromes (MDS) following HSCT remain limited and inconclusive. This nationwide retrospective study aimed to examine the association between CMVR and MDS relapse following HSCT. Methods This study was conducted by the Adult Myelodysplastic Syndromes Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT). Clinical data were collected by the JSTCT and the Japanese Data Center for Hematopoietic Cell Transplantation employing the Transplant Registry Unified Management Program (TRUMP). Overall, 1,082 patients aged ≥16 years who were diagnosed with de novo MDS, underwent initial allogeneic HSCT between 2010 and 2018, and survived until 100 days post-transplant without disease relapse were examined. Patients who received cord blood transplantation, in vivo T-cell depletion, and prophylactic anti-CMV treatment were excluded. CMVR was defined as the initiation of CMV preemptive or definitive therapy within 100 days post-transplant. Patients underwent pp65 antigenemia monitoring commencing at the time of neutrophil engraftment after HSCT. Preemptive therapy was typically instituted upon the detection of a minimum of 2 CMV pp65 antigen-positive cells per 50,000 white blood cells. In analysis, CMVR and acute/chronic graft-versus-host disease (GVHD) were evaluated as time dependent covariates. This retrospective study was approved by the Data Management Committee of the JSTCT and the ethics committee of the Ehime University School of Medicine. Results Of the 1,082 patients, 622 (57.5%) experienced CMVR. The median time from HSCT to the onset of CMVR was 46 (range, 4-97) days. In contrast, reactivation beyond 100 days after HSCT was observed in 20 patients (1.8%). End-organ disease due to CMV infection was detected in 79 (7.3%) patients with a median of 61 (range, 19-385) days. CMV infections included enteritis (n = 65), retinitis (n = 5), pneumonitis (n = 4), hepatitis (n = 3), and others (n = 3). Of the whole cohort, the 5-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), disease-free survival, and overall survival (OS) were 15.6%, 26.7%, 57.7%, and 60.5%, respectively. The OS of patients with CMVR was significantly lower than that of patients without CMVR (P = 0.047). A total of 423 patients died at the time of analysis, and no difference in the cause of death was found between patients with and without CMVR. Then, the effect of CMVR on relapse after HSCT was analyzed by patient, disease, and transplant characteristics. Interestingly, in patients with &amp;lt;5% bone marrow blast count at the time of HSCT, CMVR was significantly associated with a lower CIR (5-year CIR, 7.6% vs. 16.4%; P = 0.002). On the contrary, no difference in the CIR was found between patients with and without CMVR in the group with ≥5% bone marrow blast count (5-year CIR, 19.4% vs. 18.0%; P = 0.72). Moreover, the OS of patients with CMVR was significantly lower than that of patients without CMVR in the group with ≥5% bone marrow blast count (P = 0.009). However, the OS of patients with &amp;lt;5% bone marrow blast count was similar between with and without CMVR (P = 0.82). In the multivariate analysis, CMVR was significantly associated with a lower CIR in the group with &amp;lt;5% bone marrow blast count (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.23-0.70; P = 0.001). Furthermore, in the analysis excluding patients with grade II-IV acute GVHD, CMVR was similarly associated with a lower CIR in the group with &amp;lt;5% bone marrow blast count (HR, 0.38; 95% CI, 0.18-0.80; P = 0.011). Conclusion This study presents that CMVR may have different effects on MDS relapse depending on the bone marrow blast count at the time of HSCT. Although more studies are needed to understand the underlying mechanisms of this association, these findings may serve as a basis for devising effective CMV prophylaxis after HSCT.

Comparison of Myeloablative Conditioning with Cyclophosphamide and Total-Body Irradiation (Cy/TBI) Vs. Fludarabine, Melphalan, and Total-Body Irradiation (Flu/Mel/TBI) in Patients Undergoing Allogeneic Stem Cell Transplant for AML/ALL

Background: Cyclophosphamide combined with total-body irradiation (Cy/TBI) has been widely used worldwide as the standard myeloablative conditioning (MAC) for allogeneic stem cell transplantation (allo-HCT), but there are concerns about the antitumor effects of CY, as well as side effects, including cardiotoxicity and mucosal toxicity. A few studies suggest that the addition of an anticancer agent to a Cy/TBI regimen may reduce recurrence rates, but comparative studies of Cy/TBI regimens versus other TBI regimens are scarce. Furthermore, the recent expansion of post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis has increased its utility for cyclophosphamide-free conditioning regimens. Our institution has extensive experience with cord blood transplantation for relatively elderly patients with high-risk leukemia and has worked to develop safer and more effective MAC regimens other than Cy/TBI. The purpose of this study is to examine the safety and efficacy of fludarabine and melphalan combined with total-body irradiation (Flu/Mel/TBI) regimen, which is widely used at our institution, compared to Cy/TBI. Methods: We retrospectively analyzed adult acute leukemia patients who underwent allo-HCT between August 1994 to February 2023 at Toranomon Hospital. The inclusion criteria were as follows: a diagnosis of acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), the first allo-HCT, and Cy (120mg/kg) /TBI (8-12Gy) or Flu (180mg/m 2) /Mel (80-120mg/m 2) /TBI (8-12Gy) as MAC regimen. We excluded patients who underwent haploidentical transplantation with post-transplant cyclophosphamide. The primary endpoint was the 5-year cumulative incidence of relapse, and the secondary endpoints were the 5-year cumulative incidence of non-relapse mortality (NRM), 5-year overall survival (OS), and relapse-free survival (RFS). OS and RFS were estimated by the Kaplan-Meier method and multivariate Cox proportional hazard models. The cumulative incidence of relapse and NRM were investigated with a competing risk analysis using Gray's test and multivariable Fine and Gray competing risk regression. Results: A total of 198 patients were included in this study, comprising 101 patients treated with Cy/TBI and 97 treated with Flu/Mel/TBI. Patients who received Flu/Mel/TBI were of higher age (Median age: Cy/TBI 36 years vs. Flu/Mel/TBI 53 years, p&amp;lt;0.01), higher ECOG PS score (PS≥1: 51.5% vs. 66.0%, p=0.044), fewer AML (49.5% vs. 22.7%, p&amp;lt;0.01), and more frequent CBT (45.5% vs. 76.3%, p&amp;lt;0.01). Disease status at HCT (CR1: 53.5% vs. 43.3%, p=0.154) and HCT-CI scores (HCT-CI≥1: 35.6% vs. 44.3%, p=0.214) were not different between the two regimen groups. Regarding the primary endpoint, the 5-year cumulative incidence of relapse was significantly lower in Flu/Mel/TBI group (36.8% vs. 24.9%, p= 0.035). The cumulative incidence of NRM was not significantly different between the two groups (19.1% vs. 25.2%, p=0.345). In the multivariate analysis, conditioning with Flu/Mel/TBI was significantly associated only with a lower risk of relapse (HR: 2.817; 95%CI: 1.183-6.712; p=0.019). Regarding NRM, only disease status not in CR1 was associated with a higher risk (CR1 vs. non-CR1 HR: 2.21; 95%CI: 1.095-4.468; p=0.027). There was no significant difference in 5-year OS (Cy/TBI 48.1% vs. Flu/Mel/TBI 51.4%, p=0.604) and RFS (44.2% vs. 49.9%, p=0.24). Conclusion: Despite older age and worse PS in the Flu/Mel/TBI group, Flu/Mel/TBI had a significantly lower 5-year cumulative relapse rate than Cy/TBI, with no significant difference in NRM. Our results suggest that Flu/Mel/TBI is a reasonable alternative to CY/TBI and may be a superior TBI-containing MAC regimen.

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.

Outcomes of Allogeneic HSCT in Elderly Patients (70 years old and above) -a Canadian Experience

Introduction: Allogeneic hematopoietic cell transplant (alloHCT) in elderly patients is a challenge, as with increasing age, there is higher incidence of co-morbidities and pre-frail status. In our recent study on alloHCT in patients 60 years (y) or older, those who were 70y or more had worse outcome and high 2-y non-relapse mortality (NRM) of 53% (Al-Shaibani E et al. Ann Hematol, 2023, 102: 917-926). We therefore implemented a number of changes to improve outcomes in elderly patients undergoing alloHCT. In this study, we analyze transplant outcomes in patients ≥ 70 y, and compare the earlier cohort with the more recent cohort. Methods: This is a retrospective analysis of all consecutive patients 70y or older, who had an alloHCT from Jan 2015 to Dec 2022. We compared those who underwent an alloHCT from 2015-2019 (Cohort A, n=44) with those who had a transplant from 2020-2022 (Cohort B, n=40). The median age of the patients was 71y (range 70-76). The underlying diagnosis was mainly a myeloid malignancy (AML, MDS, MPN, CMML, n=82; lymphoid (ALL, TPLL, n=2). There were 54 males. Stages of disease at transplant were in CR1 (n=51), CR2 (n=4) or stable disease (n=15, MDS, MPN or CMML pts). All patients received RIC regimens for conditioning including Flu4/Bu2/TBI200 (n=73), Flu4/Treo30 (n=7) and Flu/Treo42 (n=3). The GVHD prophylaxis regimens used included ATG2/PTCy/CSA (n=32), ATG4.5/PTCy/CSA (n=35), ATG4.5/CSA/MTX (n=7), ATG2/CSA/MTX (n=3). The donors were either matched related (n=10), matched unrelated (including minor mismatch) (n=57) or haploidentical (n=16). Graft source was peripheral blood in all except one who received bone marrow. (Details in Table). The overall survival (OS), event free survival (EFS), NRM, cumulative incidence of relapse (CIR), incidence of acute and chronic GVHD, length of transplant hospitalization and the number of hospital re-admissions in first 6 months were assessed. The Kaplan Meier curves were plotted for OS and EFS for the overall sample, as well as stratified by the two eras (cohort A and B) and the differences assessed using log-rank tests. Cumulative incidence curves for NRM and CIR were generated, and differences assessed using Gray's K-sample. Results: For all patients transplanted in 2015-2022, the 1-year OS was 53%, the 1-year EFS was 45% and the 1-year NRM was 35%. The median number of days of transplant hospitalization for the whole population was 33.5 days (range 16 - 116). The incidence of grade I-II aGVHD was 32%, and grade III-IV aGVHD was 9.5%; mild to moderate cGVHD was 14% and severe cGVHD was 2%. The 1-year CIR was approximately 18%. Comparing the two cohorts A and B, the 1y OS was 45% vs 62% (p=0.10) respectively; the 1-year EFS was 37% vs 58% (p=0.07) respectively and the 1-year NRM was 45% vs 23% (p=0.04) respectively (Figures attached). The incidence of GVHD and CIR were similar in both cohorts, despite reducing the ATG dose in cohort B. Conclusions: Our study shows that there were statistically significant improvements in NRM and a trend towards improvement in the OS and EFS in the patients transplanted during 2020-2022 compared to patients undergoing alloHCT from 2015-2019. This improvement may be due to one or more changes implemented in recent years, although it is not possible to identify a single factor. These changes were (a) introduction of Frailty testing in all patients (Salas MQ et al. BMT. 2021; 56:60-69). (b) capping the CD34 cell dose in grafts (c) introduction of Treosulfan for selected indications (MDS/CMML) (Pasic I et al. Leuk Res 2023, 128: 107131). (d) Letermovir for CMV prophylaxis (e) reducing ATG dose for GVHD prophylaxis and (f) focus on diet, nutrition, exercise. While alloHCT should be offered to medically eligible elderly patients, there is a special need to minimize the risks that are part of age related vulnerabilities.

Dynamic Changes in Pre- and 3 Months Post-Transplant NGS MRD Status May Predict the Allogeneic Stem Cell Transplant Outcome of Patients with AML

Introduction: To deal with the high propensity for relapse and substantial genetic heterogeneity of AML, monitoring measurable residual disease (MRD) has become an effective approach to evaluate the response to chemotherapy and to predict relapse. However, the clinical implications of NGS MRD change after allogeneic hematopoietic cell transplantation (alloHCT) are still under investigation. The aims of this retrospective study are to verify whether alloHCT improved the outcome of AML patients with NGS MRD positive status in pre-transplant and to investigate how pre- and post-transplant NGS MRD status changes affect the outcome of patients with AML. Methods: This study analyzed patients of age more than 18 years who underwent alloHCT between 2018 and 2022 at single center. NGS mutation test was obtained at diagnosis, and every 3 months after stem cell transplant for 2 years with synchronized peripheral blood chimerism tests. Requirement for inclusion in this retrospective cohort study was availability of NGS mutation results at pre-transplant and at 3 months, as well as donor chimerism results after alloHCT. Patients with no mutations by NGS at diagnosis and at pre-transplant were excluded. Patients were classified by the NGS MRD status in pre-transplant and at 3 months post-transplant: Positive MRD to Positive MRD (Group A), Positive MRD to Negative MRD (Group B), Negative MRD to Positive MRD (Group C), and Negative MRD to Negative MRD (Group D). Patient characteristics are in Table 1. The Kaplan-Meier method and log-rank tests were used to estimate the survival and to compare the differences in survival. Statistical analyses were performed with GraphPad Prism version 9.1.0 (Prism Inc), Microsoft Excel (Microsoft Corporation). Results: Median follow-up was 21 months (range, 3-66). One hundred sixty-five patients met inclusion criteria. Among these, 104 (63.0%) were MRD positive, and 61 (37.0%) were MRD negative by NGS at pre-alloHCT. Fifty-one of the MRD positive patients (49%) became MRD negative by NGS at 3 months after alloHCT. The conversion rate to MRD negative from positive by NGS was not different by conditioning regimen (myeloablative (MA) 54.3% versus reduced intensity (RIC) 49.2%, p=0.67), or by AML risk group (intermediate 48.9% versus adverse 44.7%, p=0.84). Four years cumulative incidence of relapse (CIR) of each group was statistically different between Group A and the others (Group A 47.3%, Group B 17.7%, Group C 25.9%, and Group D 10.9%, p&amp;lt;0.001), but not different between Group B, C and D (p&amp;gt;0.5). Median OS was 17 months for Group A, 27 months for Group C, but the other groups did not reach. Four-year OS of each group was statistically different between Group A, Group B, and Group D (Group A 21.1% (95% CI: 2.0 - 53.8), Group B 55.2% (95% CI: 38.7 - 68.9), Group C 50.0% (95% CI: 20.8 - 73.6), and Group D 79.3% (95% CI: 63.7 - 94.9), respectively, p&amp;lt; 0.05). Among 12 patients who were MRD positive by NGS in post-alloHCT, but not in pre-alloHCT (Group C), 3 had clinical relapse, at 4 months, 6 months, and 26 months, respectively. Five patients had NGS mutations different from the initial diagnosis. They did not show clinical relapse and maintained 100% peripheral blood lymphoid (CD3) donor chimerism throughout the observation. Conclusion: This study showed alloHCT could convert 49% of pre-transplant MRD positive patients to MRD negative by NGS. However, there were no differences in conversion rate by intensity of conditioning regimen or by AML risk group. Combining pre- and 3 months post-transplant MRD status by NGS could discriminate prognostic subgroups in post-transplant MRD positive and negative group each and may be useful in designing post-alloHCT therapies.

Outcomes of Hematopoietic Cell Transplantation for Patients with Refractory Cytopenia with Multilineage Dysplasia: A Comparison Children with Adolescents and Young Adults

Background: The 2008 World Health Organization (WHO) classification proposed a new entity in childhood myelodysplastic syndrome (MDS), refractory cytopenia of childhood (RCC). The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia (hypocellular RCC) to those with normocellular BM and distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) defined for adults with MDS. The term of RCMD was revised to MDS with multilineage dysplasia in the 2017 WHO classification. In Japan, children who meet the criteria for RCMD have been diagnosed as RCMD distinguished from hypocellular RCC. Although hematopoietic cell transplantation (HCT) is a curative treatment for RCMD in children, there have been few reports of the outcomes of HCT for children with RCMD. Patients and Methods: To clarify the outcomes of HCT for children with RCMD, we retrospectively analyzed the clinical data in children (&amp;lt;16 years) with RCMD who underwent the first HCT from 2010 to 2021 and registered in the Japan Society for Hematopoietic Cell Transplantation Registry, and compared with those in adolescents and young adults (AYA; ≥16, &amp;lt;40 years) with RCMD who underwent the first HCT during the same study period. During the study period, 195 patients with RCMD (children, 69; AYA, 126) underwent HCT. The stem cell source was BM in 138 (children, 58; AYA, 80), peripheral blood (PB) in 27 (children, 2; AYA, 25), and cord blood (CB) in 30 patients (children, 9; AYA, 21). Myeloablative conditioning (MAC) regimen was defined as the use of total body irradiation (TBI) ≥8 Gy (MAC-TBI) and the administration of busulfan (BU) &amp;gt;8 mg/kg (MAC-BU). All other regimens were included in reduced intensity conditioning (RIC) regimen. Results: We retrospectively analyzed 195 patients with RCMD (male, 105; female, 90). The median age at HCT was 8 years (range, 0-15) in children and 29 years (range, 16-39) in AYA. Of the 195 patients, 20 (29%) and 52 (41%) had abnormal karyotypes in children and AYA, respectively. Of the patients who underwent HCT, 68 were from related (children, 22; AYA, 46), and 127 from unrelated (children, 47; AYA, 80) donors. MAC-BU was used for 46 (children, 9; AYA, 37), MAC-TBI for 51 (children, 1; AYA, 50), and RIC for 98 (children, 59; AYA, 39) patients. Of the 195 patients, 8 (children, 3; AYA, 5) developed primary graft failure, 16 (children, 5; AYA, 11) secondary graft failure, 10 (children, 3; AYA, 7) disease relapse, and 11 (children, 2; AYA, 9) secondary tumor. Twenty-four (children, 5; AYA, 19) patients died of HCT-related complications and four AYA of disease relapse. The 5-year overall survival (OS) rate was significantly higher in children (93%) than in AYA (82%) (p = 0.04). The 5-year event-free survival (EFS) rate was 76% in children and 64% in AYA. The 1-month cumulative incidence (CI) of neutrophil engraftment was 93% in children and 94% in AYA. The 5-year CI of relapse was 6% in AYA and 2% in children. The 5-year CI of treatment-related mortality (TRM) was 16% in AYA and 7% in children. The 5-year CI of graft failure was 12% in children and 12% in AYA. The 3-year CI of chronic graft-versus-host disease (GVHD) was significantly higher in AYA (37%) than in children (21%) (p = 0.04), while there was no difference in the 3-month CI of acute GVHD (gradeⅡ-Ⅳ) between children (35%) and AYA (39%). In children, the 5-year OS and EFS rates were significantly lower in CB (67% and 42%) than in BM/PB (97% and 81%) (p &amp;lt; 0.01 and p &amp;lt; 0.01), respectively, while the 5-year OS and EFS rates were not different between CB (91% and 76%) and BM/PB (80% and 62%) in AYA, respectively. Of the 59 children who underwent HCT using RIC, 43 without abnormal karyotypes showed 95% and 16 with abnormal karyotypes showed 88% in the 5-year OS rate. Even in AYA, there was no difference in the 5-year OS rate between RIC and MAC in both groups with (RIC, n = 14, 76%; MAC, n =38, 72%) and without (RIC, n = 25, 81%; MAC, n = 49, 90%) abnormal karyotypes. Conclusions: HCT for children with RCMD showed better OS rate than that for AYA with RCMD. HCT using RIC regimen provided good outcomes for RCMD in children with or without abnormal karyotypes. Even in AYA, HCT using RIC regimen showed OS rate comparable to MAC regimen in both groups with and without abnormal karyotypes.

Sensitive Molecular Detection of JAK2 V617F Is a Predictive Marker of Relapse in Patients with Myelofibrosis after Allogeneic Stem Cell Transplantation

Background: Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) associated with JAK2 V617F mutation in approximately 50% of patients. Allogeneic stem cell transplantation (alloSCT) is the only curative treatment option for MF but a significant proportion of patients undergoing alloSCT experience relapse. Although measurable residual disease (MRD) is an established predictor of relapse in other hematological malignancies, the dynamics of JAK2 V617F variant allele frequency (VAF) in MF post-alloSCT and its prognostic impact are yet to be clearly delineated. In this study, we assessed the utility of sensitive molecular detection of JAK2 V617F as a marker of post-alloSCT outcomes in MF particularly with respect to the optimal threshold and time points for predicting early relapse. Methods: A retrospective analysis was conducted of consecutive patients with JAK2 V617F-mutated MF receiving alloSCT at our institution between 2016 and 2022. Data on clinicopathological features, alloSCT characteristics, treatment response assessments, graft-versus-host disease (GVHD) and outcomes were collected. JAK2 V617F was enumerated by droplet digital polymerase chain reaction (ddPCR) using the Bio-Rad QX200 ddPCR platform on archived bone marrow or peripheral blood samples at defined time points pre- and post-alloSCT. JAK2 V617F VAF was defined as the percentage of JAK2 V617F mutant copies amongst total JAK2 (mutant plus wild-type) copies, with a routine assay sensitivity of 0.05%. Results: 31 patients with JAK2 V617F-mutated MF underwent alloSCT during the study period (Table 1). Five patients experienced relapse at a median of 14.2 (range: 3.2-22) months post-alloSCT. 13 patients died of infection (n = 5), overt relapse (n = 4) or GVHD (n = 4). After a median duration of follow-up of 17.5 (range: 0.9-77.9) months, the 5-year overall survival (OS) and relapse-free survival (RFS) were 52.8% and 49.6%, respectively. The 2-year cumulative incidences of relapse (CIR) and non-relapse mortality (NRM) were 26.6% and 35.5%, respectively. On univariate analysis, superior OS and RFS were only significantly associated with chronic GVHD ( P = 0.017 and 0.013, respectively). A total of 174 samples were obtained within 1 month of alloSCT (n = 31) and on days +30 (n = 31), +60 (n = 30), +100 (n = 29), +180 (n = 23) and +360 (n = 21) after alloSCT. All patients had detectable JAK2 at the time of alloSCT with a median VAF of 43.8% (range: 0.2-95%). The incidence of JAK2 V617F detection was 45.2% on day +30, 43.3% on day +60, 44.8% on day +100, 34.8% on day +180 and 23.8% on day +360 post-alloSCT. Of 6 patients who received ruxolitinib for GVHD treatment post-alloSCT, one eventually relapsed while the other 5 had undetectable JAK2 prior to ruxolitinib commencement. JAK2 VAF was higher in patients who eventually relapsed than in non-relapsed patients on days +60, +100, +180 and +360 ( P = 0.008, 0.016, 0.001 and &amp;lt;0.001, respectively) (Figure 1). However, JAK2 positivity at each of these time points was not significantly associated with survival outcomes (OS, RFS, NRM or GVHD-free relapse-free survival [GRFS]). Receiver operating characteristic (ROC) analysis indicated that JAK2 VAF on days +100, +180 and +360 post-alloSCT were significant predictors of eventual relapse ( P = 0.022, 0.019 and 0.01, respectively). The optimal JAK2 VAF thresholds at each of these time points were 0.2% (sensitivity 80%; specificity 83.3%; area under curve [AUC] 0.788) at day +100, 7.1% (sensitivity 75%; specificity 94.7%; AUC 0.842) at day +180, and 11.7% (sensitivity 75%; specificity 94.1%; AUC 0.86) at day +360. Comparisons of JAK2 VAF at each time point to the immediately preceding VAF showed that ≥2-fold increases at days +100 (from day +60) and +180 (from day +100) were significantly associated with relapse ( P = 0.002 and 0.001 respectively). Conclusion: Although persistence of JAK2 is common for more than a year post-alloSCT for JAK2 V617F-mutated MF, serial sensitive molecular monitoring of JAK2 at defined time points appears to be a predictive marker of relapse. In this study, doubling of JAK2 VAF at days +100 and +180 post-alloSCT were associated with relapse. These data support the notion that sensitive molecular detection of JAK2 may have a role akin to MRD in informing the pre-emptive use of immunotherapeutic intervention in this setting, including immunosuppression withdrawal and/or donor lymphocyte infusions.

Prognostic Value of MRD By Flow Cytometry in Adolescent and Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia Treated with Pediatric-Inspired Regimen: A Post-Hoc Analysis from a Prospective Study of China

Background Minimal residual disease (MRD) is currently considered as one of the most powerful predictors in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph - ALL).The time points and thresholds for MRD monitoring in pediatric Ph - ALL have been well established. However, surveillance strategy in adult ALL has not yet been standardized. In this study, we explored the prognostic value of MRD levels and monitoring time points by flow cytometry (FCM) in adolescent and adult patients with Ph - ALL treated with pediatric-inspired regimen. Methods This analysis includes adolescent and adult patients who were treated according to a pediatric-inspired regimen revised based on Children's Oncology Group protocol (CCG-1961). This prospective study was registered at Chinese Clinical Trial Registry Website with the registration number of ChiCTR-OOC-15006328. MRD was measured using bone marrow aspirates with eight-color multiparametric FCM on day 14 of induction, at end of induction (EOI, days 29-42) , post the first consolidation (post-C1), and throughout the treatment period. MRD was defined as the percentage of lymphoblasts present in the total nucleated cells counted. MRD levels of &amp;lt; 0.01% and ≥ 0.01% was considered as negative and positive, respectively.Patients who were MRD-positive were further stratified into three groups according to MRD level: MRD low positive (MRD-lp), ≥ 0.01% to &amp;lt; 0.1%; MRD high positive (MRD-hp), ≥ 0.1% to &amp;lt; 1%; and MRD very high positive (MRD-vhp), ≥ 1%. Results From 2014 to 2021, a total of 415 patients with a median age of 27 (range: 14-69) years were treated. Three hundred and twelve patients presented with B-precursor ALL and 103 with T-cell ALL. With a median follow-up time of 40.8 months, the median overall survival (OS) of the cohort has not yet been reached. There were 386, 389, and 346 BM samples available for MRD evaluation on day 14 of induction, at EOI, and post-C1, respectively. Figure 1A presents the distribution of MRD status over time. Figure 1B depicts the compositions of MRD levels at EOI stratified according to disease types. Notably, Ph-like ALL and early T-cell precursor (ETP) ALL were associated with extremely lower achievements of MRD negativity at EOI compared with other types. The 5-year OS rates of patients with MRD negativity, MRD-lp, MRD-hp, and MRD-vhp at EOI were 68.0% (95% CI: 60.2%-75.8%), 44.8% (95% CI: 28.9%-60.7%), 52.4% (95% CI: 34.2%-70.6%), and 36.7% (95% CI: 24.2%-49.2%), respectively ( P &amp;lt; 0.001) (Figure 2A). If patients were censored at the time of hematopoietic stem cell transplantation, the 5-year OS rates of these patients were 74.9% (95% CI: 65.1%-84.7%), 39.7% (95% CI: 18.7%-60.7%), 42.3% (95% CI: 11.7%-72.9%) and 0%, respectively ( P &amp;lt; 0.001) (Figure 2B). Patients with a negative MRD at EOI had a more favorable OS than those with a positive MRD at EOI. There was no statistically significant difference in terms of survival time between patients with MRD-lp and MRD-hp. Further, patients with MRD-vhp had the worst survival. The relapse probabilities had a similar pattern. Patients with MRD negativity at EOI had a lower 5-year CIR than those with MRD positivity at any levels. Compared to MRD-lp and MRD-hp patients, patients with MRD-vhp experienced a significantly higher rate of early relapse. However, with a longer follow-up, the 5-year cumulative incidence of relapse (CIR) did not differ significantly among patients with a positive MRD in any of the three groups, with a rate of 47.4%, 43.8%, and 49.1% in patients with MRD-lp, MRD-hp, and MRD-vhp, respectively (Figure 2C). Multivariate analysis showed that positive post-induction MRD was one of independent predictors of both OS and Disease-free survival. Conclusion Our study confirmed that MRD negativity at EOI is an independent prognostic factor of OS in adolescent and adult patients with Ph - ALL treated with pediatric-inspired regimen. Patients with MRD-lp and MRD-hp at EOI had a lower OS and a higher relapse incidence than those with MRD negativity. Therefore, an early and deep MRD clearance is important, and even extremely low MRD levels can predict poor prognosis.

Mismatched Unrelated Donor Transplantation with Ptcy-Based Gvhd Prophylaxis Is Associated with Better Survival Than Double Unit Umbilical Cord Blood Transplantation in Patients with AML in First CR: A Study from the ALWP of the EBMT

Background: The best donor option for acute myeloid leukemia (AML) patients lacking an HLA-matched donor has remained unknown. The recently reported BNT CTN 1101 trial observed higher non-relapse mortality (NRM) and lower overall survival (OS) in patients randomized to double-unit unrelated umbilical cord blood transplantation (dCBT) in comparison to those randomized to HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis 1. In addition, recent registry studies observed at least as good transplantation outcomes in AML patients given grafts from 9/10 HLA-matched unrelated donor (UD 9/10) with PTCy-based GVHD prophylaxis as those given grafts from HLA-haploidentical donors 2,3. These observations prompted us to perform a retrospective registry study comparing hematopoietic cell transplantation (HCT) outcomes between UD 9/10 and dCBT. Methods: Inclusion criteria consisted of adult patient, AML in CR1 at transplantation, either peripheral blood stem cells (PBSC) from UD 9/10 with PTCy as GVHD prophylaxis or dCBT, transplantation between 2013 and 2021, and no in vivo T-cell depletion. Results: A total of 208 dCBT patients and 270 UD 9/10 allo-HCT were included. The 180-day cumulative incidence of grade II-IV acute GVHD was 29% in UD 9/10 versus 44% in dCBT recipients (P=0.001). The 2-year cumulative incidences of relapse and of NRM were 23.5% and 12.5%, respectively, in UD 9/10 recipients versus 27% (P=0.39) and 18% (P=0.07), respectively in dCBT recipients. Two-year OS and LFS were 70% and 64%, respectively, in UD 9/10 recipients versus 60% (P=0.016) and 55% (P=0.028), respectively in dCBT recipients. In multivariate analyses, in comparison with UD 9/10 recipients, dCBT patients had a higher non-relapse mortality (HR=2.35, 95% CI: 1.23-4.48; P=0.01), comparable relapse incidence (HR=1.12, 95% CI: 0.67-1.86; P=0.66), lower leukemia-free survival (HR=1.5, 95% CI: 1.01-2.23; P=0.047), and lower overall survival (HR=1.66, 95% CI: 1.08-2.55; P=0.02). Conclusions: In summary, our results suggest that transplantation outcomes are better with UD 9/10 with PTCy-based GVHD prophylaxis than with dCBT for AML patients in CR1. These data might support the use of UD 9/10 with PTCy-based GVHD prophylaxis in AML patients lacking an HLA-matched donor. References Fuchs, E. J. et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood 137, 420-428 (2021).Baron, F. et al. Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia. Bone Marrow Transplant. 57, 1657-1663 (2022).Battipaglia, G. et al. Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 57, 562-571 (2022).