Transplantation For Acute Myeloid Leukemia Research Articles

Multiple small-dose infusions of G-CSF-mobilized haploidentical lymphocytes after autologous haematopoietic stem cell transplantation for acute myeloid leukaemia.

This retrospective study analysed 106 acute myeloid leukaemia (AML) patients undergoing autologous haematopoietic stem cell transplantation (ASCT) to assess the impact of multiple small-dose infusions of granulocyte-colony-stimulating factor (G-CSF)-mobilized haploidentical lymphocytes as post-ASCT maintenance therapy. Among them, 50 patients received lymphocyte maintenance therapy, 21 received alternative maintenance therapy, and 35 received no maintenance therapy. Patients receiving lymphocyte maintenance therapy demonstrated significantly higher overall survival (OS) and disease-free survival (DFS) compared to those without maintenance therapy, with 4-year OS and DFS rates notably elevated. While there were no significant differences in recurrence rates among the three groups, lymphocyte maintenance therapy showcased particular benefits for intermediate-risk AML patients, yielding significantly higher OS and DFS rates and lower relapse rates compared to alternative maintenance therapy and no maintenance therapy. The study suggests that multiple small-dose infusions of G-CSF-mobilized haploidentical lymphocytes may offer promising outcomes for AML patients after ASCT, particularly for those classified as intermediate-risk. These findings underscore the potential efficacy of lymphocyte maintenance therapy in reducing disease relapse and improving long-term prognosis in this patient population.

Successful Treatment of Severe Steroid-Resistant Engraftment Syndrome Following Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia with Emapalumab: A Case Report

Successful Treatment of Severe Steroid-Resistant Engraftment Syndrome Following Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia with Emapalumab: A Case Report

Evaluation of European LeukemiaNet 2022 risk classification in patients undergoing allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: Identification of a very poor prognosis genetic group.

European LeukemiaNet refined their risk classification of acute myeloid leukaemia (AML) in 2022 (ELN 2022) according to the two new myeloid classifications published the same year. We have retrospectively assessed the prognostic value of the ELN 2022 in 120 AML patients undergoing allogeneic haematopoietic cell transplantation (allo-HCT), including 99 in first complete response (CR1) from 2011 to 2021 in our centre. Adverse risk patients (Adv) presented inferior outcome in terms of overall survival (OS) and leukaemia-free survival (LFS) (OS [p = 0.003], LFS [p = 0.02]), confirmed in multivariate analysis (hazard ratio [HR] for OS = 2.00, p = 0.037). These results were also seen in patients allografted in CR1. Further analysis identified a subgroup named adverse-plus (AdvP), including complex karyotype, MECOM(EVI1) rearrangements and TP53 mutations, with worse outcomes than the rest of groups of patients, including the Adv (HR for OS: 3.14, p < 0.001, HR for LFS: 3.36, p < 0.001), with higher 2-year cumulative incidence of relapse (p < 0.001). Notably, within this analysis, the outcome of Adv and intermediate patients were similar. These findings highlight the prognostic value of ELN 2022 in patients undergoing allo-HCT, which can be improved by the recognition of a poor genetic subset (AdvP) within the Adv risk group.

Peripheral blood stem cell versus bone marrow graft for patients ≥60 years undergoing reduced intensity conditioning haploidentical transplantation for acute myeloid leukemia in complete remission: An analysis of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether peripheral blood (PB) or bone marrow (BM) is the best graft source. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in acute myeloid leukemia (AML). From the EBMT registry database, we compared T-cell replete PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients over the age of 60 years who underwent Haplo-SCT with PT-Cy for an AML in first or second complete remission. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV: HR = 1.67, 95% CI [1.10-2.54], p = 0.01; Grade III-IV: HR = 2.29, 95% CI [1.16-4.54], p = 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower in the PB group (HR = 0.65, 95% CI [0.45-0.94], p = 0.02) and leukemia-free survival was significantly better (HR = 0.76, 95% CI [0.59-0.99], p = 0.04), with a trend toward better overall survival (HR = 0.78, 95% CI [0.60-1.01], p = 0.06). We conclude that in the specific context of Haplo-SCT with PT-Cy, PB grafts represent a valid option to decrease the risk of relapse and improve outcome of older AML patients who usually do not benefit from conditioning intensification.

Acute mixed-lineage leukemia treated with desensitization therapy prior to HLA-haploidentical transplantation with high donor-specific antibodies.

A 43-year-old woman was referred to our department for hematopoietic stem cell transplantation for acute myeloid leukemia, as she failed to achieve remission following induction therapy. Umbilical cord blood transplantation was initially planned; however, multiple anti-human leukocyte antigen (HLA) antibodies with a mean fluorescence intensity of over 10,000 were detected, and optimal umbilical cord blood could not be obtained. The plan was then switched to peripheral blood stem cell transplantation (PBSCT) from the patient's son, who had a 5/8 HLA haploidentical match. However, the patient had donor-specific antibodies against the donor's HLA-B 0702 and HLA-C 0702. To address this issue, after rituximab therapy, the patient was given platelet transfusions from B0702- and C0702-positive donors on day - 1 and day 0, and immunoglobulin on day 0, followed by PBSCT. Donor-specific antibodies decreased by over 90%, and engraftment was confirmed on day 13. Since then, the patient has remained relapse-free and healthy. This case suggests that appropriate management of donor-specific antibodies can enable safe transplantation, even in donors who test positive for these antibodies.

Strategies to reduce relapse risk in patients undergoing allogeneic stem cell transplantation for acute myeloid leukaemia.

Allogeneic stem cell transplantation is a centrally important curative strategy in adults with acute myeloid leukaemia; however, relapse occurs in a significant proportion of patients and remains the leading cause of treatment failure. The prognosis for patients who relapse post-transplant remains poor, and the development of new strategies with the ability to reduce disease recurrence without increasing transplant toxicity remains a priority. In this review, within the context of our understanding of disease biology and the graft-versus-leukaemia (GVL) effect, we will discuss established, evolving and novel approaches for increasing remission rates, decreasing measurable residual disease pretransplant, future methods to augment the GVL effect and the opportunities for post-transplant maintenance. Future progress depends upon the development of innovative trials and networks, which will ensure the rapid assessment of emerging therapies in prospective clinical trials.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with BCR::ABL1 fusion.

BCR::ABL1 fusion is found in<1% of de novo acute myeloid leukemia (AML) cases and confers a poor prognosis. This Japanese nationwide survey analyzed patients with AML (n=22) and mixed phenotype acute leukemia (MPAL) (n=10) with t(9;22) or BCR::ABL1 who underwent allogeneic hematopoietic cell transplantation (allo-HCT) between 2002 and 2018. The 3-year overall survival (OS) rates were 81.3% and 56.0%, respectively (p=0.15), and leukemia-free survival (LFS) rates were 76.2% and 42.0%, respectively (p=0.10) in patients with AML and MPAL. The relapse rates were 9.5% and 14.0% (p=0.93), and the non-relapse mortality (NRM) rates were 14.3% and 44.0%, respectively (p=0.10) in patients with AML and MPAL. One in 17 patients with AML, with pre-transplant tyrosine kinase inhibitors (TKI), and three in five patients with AML, without pre-transplant TKI, did not achieve complete remission (CR) before allo-HCT (p=0.024). Among the 20 patients with known disease status after allo-HCT, 95.0% were in hematological or molecular CR. None of the four patients who received post-transplant TKI for prophylaxis or measurable residual disease relapse experienced hematological relapse. In conclusion, our results suggest that pre-transplant TKI could improve disease status before allo-HCT. Moreover, allo-HCT resulted in high OS, high LFS, low relapse, and low NRM rates in patients with AML with BCR::ABL1.

Impact of socioeconomic disparities on outcomes in adults undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

Racial and socioeconomic disparities impact outcomes after chemotherapy and limit access to allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML), yet studies have yielded mixed results on the influence of disparities on post-HCT outcomes. Therefore, we studied 1024 adults with AML who underwent allogeneic HCT between 5/2006 and 10/2021 at a single large university-affiliated cancer center. Collected data included non-biologic and demographic characteristics (including race/ethnicity, marital status, distance traveled, and household size), transplant- and disease-related characteristics, and area-level and individual-level socioeconomic factors (i.e., area deprivation index and occupational status). After multivariable adjustment, no socioeconomic- or non-biologic factors were associated with non-relapse mortality (NRM), overall survival (OS), relapse-free survival (RFS), or relapse except being married (associated with improved NRM: hazard ratio [HR] = 0.7 [0.50-0.97]) and having no insurance (associated with worse OS: HR = 1.49 [1.05-2.12] and RFS: HR = 1.41 [1.00-1.98]). Despite a relatively racially homogenous cohort, Asian race was associated with improved NRM (HR = 0.47 [0.23-0.93]) and American Indian/Alaskan Native race was associated with higher relapse risk (HR = 2.45 [1.08-5.53]). In conclusion, in our retrospective analysis, socioeconomic-, demographic-, and non-biologic factors had limited impact on post-HCT outcomes in AML patients allografted in morphologic remission. Further research is needed to investigate disparities among HCT-eligible patients.

WT1 and TP53 as valuable diagnostic biomarkers for relapse after hematopoietic stem cell transplantation in acute myeloid leukemia.

Relapse following hematopoietic stem cell transplantation (HSCT) occurs relatively frequently and is a significant risk factor for mortality in patients with acute myeloid leukemia (AML). Early diagnosis is, therefore, of utmost importance and can provide valuable guidance for appropriate and timely intervention. Here, the diagnostic value of two molecular markers, Wilms tumor 1 (WT1) and tumor suppressor protein p53 (TP53), were studied. Twenty AML patients undergoing HSCT participated in this investigation. Some had relapsed following HSCT, while others were in remission. Peripheral blood (PB) and bone marrow (BM) samples were collected following relapse and remission. WT1 and TP53 messenger RNA (mRNA) expression was evaluated using reverse transcription-quantitative polymerase chain reaction (RT‒qPCR). The diagnostic value of genes was evaluated by utilizing receiver-operating characteristic (ROC) curve analysis. ROC analysis showed WT1 and TP53 as diagnostic markers for relapse after HSCT in AML patients. The mRNA expression level of WT1 was elevated in individuals who experienced relapse compared to those in a state of remission (p value < 0.01). Conversely, the expression level of TP53 mRNA was lower in individuals who had relapsed compared to those in remission (p value < 0.01). WT1 and TP53 possess the potential to serve as invaluable biomarkers in the identification of molecular relapse after HSCT in patients with AML. Further studies for a definitive conclusion are recommended.

Early Infection by West-Nile Virus Causing Neuroinvasive Disease After Haploidentical Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Early Infection by West-Nile Virus Causing Neuroinvasive Disease After Haploidentical Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with hyperdiploid complex karyotype.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the best consolidation strategy for acute myeloid leukemia (AML) with complex karyotype (CK). However, CK is a heterogenous and highly diverse entity. Numerical abnormalities have been associated with a controversial prognosis and AML with only multiple numerical abnormalities known as pure hyperdiploid karyotype (HDK) may have a distinct prognosis after allo-HCT compared to non-pure HDK CK AML. A total of 236 patients were identified within the EBMT registry as having HDK comprising 95 pure (pHDK) and 141 with other cytogenetic abnormalities (HDK+). The 2-year probability of leukemia-free survival (LFS) was 50% for pHDK and 31% for HDK+ (p = 0.003). The 2-year probability of overall survival (OS) was 57% for pHDK and 36% for HDK+ (p = 0.007). The 2-year cumulative incidence of relapse (RI) was 22% for pHDK and 44% for HDK+ (p = 0.001). The 2-year probability of graft-versus-host disease (GvHD)-free and relapse-free survival (GRFS) was 36% for pHDK and 21% for HDK+ (p = 0.01). On multivariate analysis, pHDK remained associated with significantly better LFS, OS and GRFS and lower RI (all p-values <0.004). pHDK AML constitutes probably a distinct cytogenetic entity from HDK+ or other non-hyperdiploid CK AML with better outcomes after allo-HCT.

Haploidentical and Matched Sibling Transplantation for Acute Myeloid Leukemia: A Hospital-Based Study.

Allogeneic peripheral blood stem cell transplantation (PBSCT) has been increasing for the last years in Latin America. The objective of this study was to describe clinical outcomes in acute myeloid leukemia (AML) receiving allogeneic PBSCT between 2013 and 2019 in a single center of Cali, Colombia. A retrospective cohort study was conducted in Fundacion Valle del Lili. Patients diagnosed with AML who received an allogeneic PBSCT between 2013 and 2019 using human leukocyte antigen (HLA)-matched sibling donors (MSDs) or haploidentical related donors (HRDs) with myeloablative conditioning regimen were included. Cases with diagnosis of promyelocytic leukemia, myelodysplastic syndrome-related AML and therapy-related AML were excluded. Data were obtained directly from the hospital PBSCT database and clinical records. A total of 50 patients were included (HRD, n = 32; MSD, n = 18). Sixty-two percent was in the first complete remission (CR1) at the time of the transplant, of which 26% were MSD and 74% were HRD. The European Group for Blood and Marrow Transplantation (EBMT) risk score was: 44% vs. 50% low, 28% vs. 28% intermediate and 28% vs. 22% high for MSD vs. HRD, respectively. Overall survival at 5 years for MSD was 62% (95% confidence interval (CI): 31-83%) and 43% (95% CI: 25-60%) for HRD. Event-free survival was 56% (95% CI: 26-78%) and 35.6% (95% CI: 18-53%), respectively. Non-relapse mortality at day-100 was 6% (95% CI: 0.8-35%) and 20% (95% CI: 9-39%). Relapse at5 years was 18% (95% CI: 4-58%) and 25% (95% CI: 10-52%). Overall mortality rate was 46%. The grade II-IV, III-IV acute graft-versus-host disease and severe chronic graft-versus-host disease was 44%, 11% and 12% for MSD, and 43%, 9% and 0% for HRD. These results underline that MSD remains the first donor choice for AML patients in CR1 when available. HRDs are still our next option among alternative donors. It is necessary to find strategies that have a positive impact on those outcomes that markedly affect the quality of allogeneic PBSCT and the prognosis of patients. Comparative, randomized, prospective studies with longer follow-up of haploidentical allogeneic PBSCT with other donor types are required to definitely establish its role among alternative donors.

Use of Pre-Transplant Minicog Cognitive Impairment Screening and Validation of Frailty and Functionality Assessment Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Background: We demonstrated that impaired functionality and frailty have a negative impact on survival after allogeneic hematopoietic cell transplantation (HCT) (Salas et al., 2019). This impact is independent of other predictive models including HCT comorbidity index (HCT-CI) and disease risk index (DRI). Cognitive changes are frequently reported among survivors of autologous and allogeneic HCT. However, impact of the presence of cognitive impairment prior to allogeneic HCT has not been studied. We hypothesized that the presence of cognitive impairment before transplantation could have a negative effect on the outcomes of allogeneic HCT. Patients and methods: We evaluated transplant outcomes of 277 patients who underwent our updated frailty assessment including the MiniCog scale, incorporated as standard of care in April 2020. The MiniCog assessment included recalling of three unrelated words, for a total of three points and drawing of a clock with the face, number and hands indicating a specific time, for a total of 2 points. We used the cutoff score of &amp;lt;3 as a marker of cognitive impairment and evaluated the effect of cognitive impairment on: overall survival (OS), relapse free survival (RFS), non-relapse mortality (NRM). We further sought to validate our previously described frailty scale in prediction of transplant outcomes, including OS, RFS, and NRM, in the new cohort and compare its performance in outcome prediction to the MiniCog scale. Our frailty evaluation included the following variables: Clinical Frailty Scale (CFS), Lawton's instrumental activities of daily living (IADL), timed to get up and go test (TUGT), grip strength (GS) using a hydraulic hand dynamometer, self-rated health questionnaire (SRH), a question on number of falls in the last year (F), C-reactive protein (CRP) and serum albumin (Alb) levels at the time of the consult. The frailty scale was calculated according to the following formula: 1.5×CFS + 1×IADL +1×GS + 1.5×TUGT +1×SRH+1×F+ 1.5×Alb+2×CRP. The frailty scale score ranged from 0-10.5. With these results we stablished 3 frailty cohorts for the patients being planned for alloHCT, fit (≤1), pre-frail (&amp;lt;1 to ≤5.5), and frail (&amp;gt;5.5), based on this risk model. Results: Median age at transplantation was 59 years and 85 (31%) patients were ≥ 65 years. Of all the patients, 36 (14%) had a Karnofsky Performance Scale Index (KPS) of &amp;lt;90%, 206 patients had a low-intermediate risk disease risk index (DRI). Median time of follow up was 9 months. Majority of the patients (46%) underwent transplantation for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Of all patients, 246 (88.8%) had a normal MiniCog score (&amp;gt;3). There was no difference in 2-y OS between patients with normal and low MiniCog score: 67% (95% confidence interval (CI): 59%-74%) vs 60% (95% CI: 36-78%), p=0.21. NRM at 24 months was 26% (95% CI 10-46%) for patients with an abnormal MiniCog vs 23% (95% CI 17-30%), p=0.80. There was no difference in 2-year RFS between patients with normal and low MiniCog score: 65% (95% CI 57-72%) vs 43.5% (95% CI 23-63%), p=0.09. Using the frailty scale, 144 (56%) patients were considered fit, 30 (12%) pre-frail and 81 (32%) frail. Using our original frailty scale, the 2-y OS among the fit, pre-frail and frail patients was: 78% (95% CI 65%-87%), 64% (95% CI 53%-74%) and 27% (95% CI 5.6%-55.6%) p=0.005. 2-year NRM was 19.2% (95% CI 9-31%), 23% (16-32%), and 41.6% (95% CI 11-70%) for the fit, pre-frail and frail patients respectively, p=0.12. Relapse free survival at 24 months was 72.5% (95% CI 58-83%), 60.5% (95% CI 50-70%), and 29% (95% CI 6-57%), p=0.003. Conclusions: In our cohort the sole presence of cognitive decline, based on the MiniCog assessment failed to be a predictor of outcomes after allogeneic HCT. However, ability of our preciously established frailty scale to predict transplant outcomes in this new cohort of patients further validates the results of our previous findings. The presence of frailty is an independent predictor of adverse outcomes after allogeneic HCT.

Antithymocyte Globulin in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia: Evaluating Outcomes According to Cytogenetic Risk

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an essential therapeutic approach for the management of acute myeloid leukemia (AML). Nevertheless, graft-versus-host disease (GVHD) remains a significant complication, significantly affecting the recipients' quality of life and overall survival. Antithymocyte globulin (ATG) has demonstrated promise in preventing GVHD during allo-HSCT. However, concerns persist regarding its potential impact on disease relapse. This retrospective single-center study aims to evaluate the prognostic implications of ATG based on cytogenetic risk stratification in AML patients undergoing transplantation from an HLA-matched sibling. A total of 124 AML patients who underwent allo-HSCT from an HLA-matched sibling in their first complete remission state between 2003 and 2022 were eligible for the study. Among them, fifty patients received rabbit ATG at a dose of 2.5mg/kg/day for days -2 to -1, while 74 patients did not receive ATG. All patients received cyclosporine and methotrexate in addition to their respective conditioning regimens (ATG or no ATG). The ATG group consisted of 38 patients classified as having a non-high cytogenetic risk, and 12 patients classified as having a high cytogenetic risk. Conversely, the non-ATG group included 68 patients with a non-high cytogenetic risk and 6 patients with a high cytogenetic risk. After a median follow-up of 48 months, there were no significant differences in median overall survival between the ATG and Non-ATG groups, regardless of cytogenetic risk status (non-high cytogenetic risk; 12.4 months vs. NA, p = 0.578; high cytogenetic risk; 13.2 months vs. 14.2 months, p = 0.729, Figure A-1,B-1). The ATG group in the non-high cytogenetic risk group demonstrated a significant decrease in the 1-year cumulative incidence (CI) of chronic GVHD compared to the non-ATG group (21.7% vs. 54.4%, p = 0.001, Figure A-2; and in those with moderate to severe cGVHD, it was 21.6% vs. 51.5%, p = 0.003, respectively). Additionally, the 1-year Chronic GVHD-free and relapse-free survival (cGRFS) was higher in the ATG group of the non-high cytogenetic risk group (45.8vs. 26.5%; p = 0.048, Figure A-3). Moreover, there were no significant differences in 1-year CI of relapse and 1-year non-relapse mortality (NRM) within the non-high cytogenetic risk group (ATG vs. non-ATG; 29.7% vs. 20.6%, p = 0.225; 8.4% vs. 4.4%, p = 0.635, Figure A-4,5). In the subgroup analysis of patients with high cytogenetic risk, although there was no statistical significance, the ATG group showed a trend towards decreased 1-year CI of chronic GVHD and higher cGRFS compared to the non-ATG group (10.4% vs. 40.0%, p = 0.342; 31.2% vs. 16.7%, p = 0.929, Figure B-2,3). However, the ATG group exhibited a significantly higher 1-year CI of relapse compared to the non-ATG group (60.0% vs. 16.7%, p = 0.019, Figure B-4). In conclusion, our study findings indicate that ATG was effective in preventing chronic GVHD and demonstrated higher cGRFS in AML patients undergoing matched sibling donor HSCT. However, AML patients with high cytogenetic risk should carefully consider the use of ATG due to the associated higher risk of relapse. Further investigations are warranted to validate these findings and determine the appropriate dosage of ATG for high cytogenetic risk AML patients.

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).

Full CD34 Donor Chimerism Following CD34 Chimerism Directed Donor Lymphocyte Infusion Results in Reduced Relapse and Superior Overall Survival Compared with Mixed Chimerism Status in Allogeneic Haemopoietic Stem Cell Transplant Recipients

Introduction Peripheral blood CD34 donor chimerism (DC) is a clinically valuable method for detecting relapse of myeloid malignancies following allogeneic hematopoietic stem cell transplantation (alloHSCT). Our institution has recently shown that CD34 DC ≤80% was superior to CD3 DC for predicting relapse (1). While pre-emptive DLI has demonstrated efficacy in preventing relapse in the setting of falling whole unfractionated and CD3 DC, little has been reported about its utility in falling CD34 DC. Methods We conducted a retrospective analysis of consecutive patients who received DLI at the Alfred Hospital in Melbourne, Australia between January 2012 and January 2023. Peripheral blood CD34 DC was monitored in alloHSCT patients transplanted for myeloid malignancies or acute lymphoblastic leukaemia (ALL). CD34+ cells were enriched using magnetic beads and DC measured using an STR-PCR method, which had a sensitivity of 1%. DLI was administered to patients with CD34 ≤80% that did not respond to immunosuppression taper. DLI doses were based on donor type and recipient weight, with subsequent doses administered incrementally according to a predefined protocol. Starting doses were 3x10 6/kg for sibling donors, 1x10 6/kg for unrelated donors and 0.5x10 6/kg for haploidentical donors. DLI was discontinued upon achieving full DC (FDC) defined as CD34 DC &amp;gt; 95%, clinically significant graft-versus-host disease (GVHD), disease progression, or lack of available donor cells. Results One hundred and six patients received DLI between 2012 and 2023. Twenty-five of these patients received DLI for CD34 DC ≤80% without morphologic relapse. Eleven of 25 (44%) patients received DLI alone, while 14 (56%) patients received it in combination with other therapies, primarily a hypomethylating agent. At the time of DLI, 5 (20%) of the 25 patients had concurrent decreased CD3 DC ≤ 80%. The median follow-up period was 1.84 years (range 0.58 to 8.43 years). Sixteen of 25 (66.7%) patients achieved CD34 FDC while 8 (33.3%) had persistent CD34 mixed DC (CD34 MDC). One patient could not be assessed due to death from infection. Patient characteristics and outcomes according to response to DLI are presented in Table 1. The cumulative incidence of relapse was significantly lower in the CD34 FDC group (12.5% vs 75% at 2 years, p&amp;lt;0.001). Patients achieving CD34 FDC had improved progression-free survival (PFS) and overall survival (OS) compared to the CD34 MDC group (PFS median years not reached [95% CI 1.94-ND] vs 0.29 years [95% CI 0.09-ND], p&amp;lt;0.001; OS median years not reached vs 0.68 years [95% CI 0.58-ND], p=0.003; Figure 1). Rates of grade II-IV acute graft-versus-host-disease (aGVHD) post-DLI were 12.5% in those achieving FDC and MDC (Table 1). A significant proportion of patients (37.5%) achieving FDC developed moderate-severe cGVHD while the MDC group did not survive long enough to develop cGVHD (Table 1). The non-relapse mortality observed in the CD34 FDC group was 12.5% at 3 years post-DLI. Conclusion Our centre experience demonstrated that CD34-directed DLI reduced relapse risk and improved overall survival when FDC is restored in alloHSCT patients, with an acceptable toxicity profile. Only 20% of patients with CD34 MDC had concurrent CD3 MDC, highlighting the additional value of CD34 monitoring in guiding salvage DLI administration. In patients with CD34 MDC ≤80%, the target of DLI should be to achieve FDC (&amp;gt;95%) given the clear association with improved outcomes in this group. References 1/ Das TP, North D, Fleming SA, Tan JLC, Ivey A, Cummings NJ, Spencer A, Patil SS, Widjaja JML, Swain MI, Bourke C, O'Brien ME, Kliman DS, Curtis DJ. Peripheral Blood CD34 Donor Chimerism has Greater Clinical Utility Than CD3 for Detecting Relapse after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia or Myelodysplastic Syndrome. Transplant Cell Ther. 2023 Jul;29(7):454.e1-454.e8. doi: 10.1016/j.jtct.2023.03.025.

Practice Patterns of Transplant Centers Regarding Maintenance Treatment Post Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia: A Survey on Behalf of the EBMT Acute Leukemia Working Party

Introduction: Disease recurrence in acute myeloid leukemia (AML) remains the major reason of allogeneic hematopoietic cell transplantation (allo-HCT) failure. Strategies to reduce the risk of relapse such as prophylactic pharmacologic interventions post allo-HCT are more frequently applied by some transplant physicians, especially after the growing evidence of its efficacy and tolerability. Others are still being skeptical regarding its implementation due to difficulty proving efficacy by large randomized trials, or concerns of long-term toxicities. The aim of this study was to conduct a survey among the European Society for Blood and Marrow Transplantation (EBMT)-affiliated transplant centers to identify clinical practice patterns regarding maintenance treatment post-allo-HCT in AML. Methods: After the approval of the board of the Acute Leukemia Working Party (ALWP), EBMT-affiliated centers received by email a questionnaire-based survey between January and June 2023. The questionnaire consisted of 13 questions assessing clinical practices regarding maintenance treatment post allo-HCT in AML, specifically the indications of maintenance, the type, the drug used, and the duration of the treatment. Results: A total of 115 (out of 424) EBMT-affiliated centers from 31 countries responded to the survey with a response rate of 27.12%. Overall, 102 (88.8%) centers implement maintenance strategy whether pharmacological intervention or cellular therapy post allo-HCT in AML, most of the centers (N=67, 58.3%) use it based on a personalized decision, 17 (14.8%) use it routinely, and 18 (15.7%) use it exceptionally. Regarding the indication, the majority of the centers recommend maintenance treatment for AML patients in second remission or beyond (N=64, 62.7%) or in AML patients in first remission with high risk of relapse based on cytogenetic or molecular data (N=61, 59.8%), whereas 34 (33.3%) centers recommend it only for FLT3-mutant disease, and 11 (10.8%) centers in all patients regardless of the risk of disease. The majority of centers (N=77, 75.5%) use a combination of pharmacologic and cellular therapies, and 20 (19.6%) centers use only pharmacologic therapies. Among centers using pharmacologic therapies, 62 (63.9%) use hypomethylating agents (HMA) (azacitidine N=51 (82.3%), decitabine N=6 (9.6%), HMA with venetoclax N=23 (37%), HMA with donor lymphocyte infusion (DLI) N=38 (61%), or a combination of modalities in 42 (67.7%)). In general, most centers (N=35; 87.5%) do it pre-emptively either minimal residual disease (MRD) driven or chimerism driven, whereas 22 (55%) centers do it prophylactically. The majority of centers continue HMA for one-year duration (N=37, 59.7%), 15 (24.2%) for two years and only 10 (16.1%) continue until disease recurrence or toxicity. Out of 97 responding centers regarding the use of FLT3 inhibitors as maintenance, 93 (95.9%) are implementing this strategy. The most common choice was sorafenib in 82/93 (88.2%) centers, midostaurin in 28 (30%), and gilteritinib in 30 (32.2%). Among these, 56 (83.5%) centers use FLT3 inhibitors as prophylaxis whereas 28 (41.7%) use a pre-emptive approach. The preferred maintenance duration was for two years in 51 (54.8%) centers, followed by one-year duration in 30 (32.3%) centers, continuous until disease relapse or toxicity in 9 (9.7%) centers, and for five years in only 3 (3.2%) centers. Novel agents are used in 71 (70.2%) centers as maintenance either alone or in combination with HMA, of them 52 (73.2%) use venetoclax, and 13 (13.2%) use enasidenib. Finally, regarding practice patterns, 32 (29.6%) centers claim that maintenance treatment is part of their routine practice, 46 (42.6%) only for FLT3 mutant AML. Others are not routinely implementing maintenance because they are still skeptical and need more evidence by randomized clinical trials (N=8), whereas 5 centers are concerned regarding tolerability, and 16 (14.8%) cannot implement because of regulatory restrictions or lack of access. Conclusion: In this survey, the majority of responding EBMT-affiliated transplant centers is implementing post-transplant AML maintenance treatment, predominantly HMA and FLT3 inhibitors. Further studies are needed to clarify the appropriate strategy and duration of maintenance therapy. The study will help the EBMT to incorporate post-transplant strategies as a routine registry capture parameter.

Measurable Residual FLT3-ITD before Allogeneic Transplant for Acute Myeloid Leukemia

Background: In the past year, multiple studies have demonstrated the drastically increased risk of relapse and death in patients with Acute Myeloid Leukemia (AML) who have persistent FLT3 internal tandem duplication (ITD) mutations detectable in clinical remission by next generation sequencing (NGS). Translating this evidence into a change in clinical practice requires both widely available testing and a clear understanding of the clinical implications of FLT3-ITD detection at defined threshold levels. In the largest of the recent studies (Pre-MEASURE, PMID: 36881031), we performed FLT3-ITD MRD detection in blood DNA collected from 608 patients at the time of first remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT). To evaluate cross-assay comparability and the impact of residual disease burden levels, we performed analysis on this cohort using a commercially available FLT3-ITD MRD NGS assay. Methods: Of the 608 patients aged 18 or older from the Pre-MEASURE study who received an alloHCT for FLT3-ITD mutated AML during CR1 at a CIBMTR reporting site in the USA between the years of 2013-2019, patients not experiencing non-relapse mortality and with sufficient DNA from pretransplant blood available were included in this analysis. A commercially available testing kit (IVS, Invivoscribe, San Diego, CA), which can detect FLT3-ITD MRD by NGS for up to 21 patients on one Illumina MiSeq flow cell, was used to establish a workflow following clinical testing standards and validated to detect ITDs down to a variant allele fraction (VAF) of at least 0.005%. Results were compared to those previously reported using an anchored multiplex PCR-based (AMP) targeted NGS assay. Overall survival (OS) and cumulative incidence of relapse were estimated with the day of transplant as time 0 using Kaplan-Meier estimation (log-rank tests) and Cox proportional hazards models. Results: A total of 451 patients were included in this study, of which 173 (38%) experienced relapse (median: 5.2 months; range 0.7-52.1) and 133 (29%) died (median: 10.7 months; range 2-53.8) post-alloHCT. The IVS assay identified 232 FLT3-ITD variants with a median VAF of 0.005% (range 0.0002-44%) and length of 51bp (range 5-228). IVS positive patients had a median of 1 FLT3-ITD variant (range 1-15) and median maximum VAF of 0.01% (range 0.0003-44%). Utilizing the same VAF cutoff of 0.01% for MRD positivity for the IVS test as used in the Pre-MEASURE study, patients testing positive prior to alloHCT exhibited higher rates of relapse (79% vs 31%, p&amp;lt;0.0001) and decreased survival (29% vs 77%, p&amp;lt;0.0001) at 3 years compared to testing negative. These results closely align with those previously reported using the AMP assay (Figure A). The IVS test has a superior limit of detection compared with the AMP test, allowing investigation of alternative VAF thresholds. In total, 151 patients (33.5%) were FLT3-ITD MRD positive by IVS of which only 75 (17%) had VAF ≥0.01%. A threshold-free approach for the IVS test improved the ability to identify patients at risk of relapse, predicting 63% of relapses within 6 months of transplant compared to 43% with the 0.01% cutoff, but resulted in decreased specificity as 42% of all positive patients relapsed within 6 months vs. 57% with the 0.01% VAF cutoff. In multivariable analysis, IVS FLT3-ITD MRD status was associated with both relapse and overall survival (Figure B). Additionally, stratifying patients by their level of residual FLT3-ITD disease burden prior to alloHCT revealed a dose-dependent increase in risk for death (Figure B) and relapse. Any detectable level of residual FLT3-ITD over 0.001% VAF exhibited increased risk, with VAFs ≥0.01% being the highest. Conclusions: In this analysis of patients with AML from the Pre-MEASURE study, we show cross-assay evidence that the detection of residual FLT3-ITD variants in pre-transplant blood during CR1 is associated with significantly increased risk of relapse and death after alloHCT. The highly sensitive assay used in this study could identify ~2/3 of patients who relapsed within 6 months and demonstrated that a dose-dependent correlation between residual FLT3-ITD level and adverse clinical outcomes exists, with VAF ≥0.01% representing the highest risk. This evidence provides strong justification for NGS-based AML MRD clinical testing for persistent FLT3-ITD prior to alloHCT to identify patients at high risk of post-transplant relapse and death.

Toward a Measurable Residual Disease-Based Algorithm for Selection of Allogeneic Hematopoietic Stem Cell Transplant in Acute Myeloid Leukemia

Background: The diagnosis and management of acute myeloid leukemia (AML) have transformed in recent years with an improved understanding of leukemogenesis and improved methods of measurable residual disease (MRD) detection. Current treatment algorithms include consideration of allogeneic hematopoietic stem cell transplant (HCT) for intermediate and adverse-risk AML. MRD negativity is widely accepted as a predictive and prognostic marker for disease-free survival and overall survival. However, the clinical use of MRD status in consolidative HCT planning remains unclear. Methods: Two hundred thirty-three consecutive patients achieving complete remission (CR) as defined in ELN 2022 after receiving therapy at Massey Cancer Center were analyzed. MRD status was determined either by multiparameter flow cytometry, PCR-based sequencing, and/or next-generation sequencing. Patients were analyzed via retrospective chart review to obtain baseline characteristics, molecular and cytogenetic profiles, and survival data. Median overall survival (mOS) was calculated and compared using the Kaplan-Meier method. Continuous variables were compared using one-way ANOVA. Categorical variables were analyzed using Fisher's exact test. Results: In total,109 patients achieved MRD-negative CR and 124 patients achieved an MRD-positive CR. Of the MRD-negative patients, 42 went received HCT (39%). In the MRD-positive cohort, 44 underwent HCT (35%). Among the MRD negative group, those receiving HCT tended to be younger (52.1 y. [range: 24.8-71.7] vs 61. 8 y. (range: 27.1-82.9) p = 0.026) with fewer co-morbidities (Charlson comorbidity index [CCI] score: 3 [range: 2-9] vs 4 (range: 0-14), p = 0.322). We observed a similar trend in those who had MRD positivity at best response or at the time of transplant (age 55 y. [range: 24.5-72.2] vs 62 y. [range: 25.1-88], p = 0.142; CCI 4 [range: 2-7] vs 5 (range 2-11], p = 0.014). In the MRD-negative/no HCT group, 49.3% had ELN favorable-risk disease at initial AML diagnosis, 28.4% had intermediate risk, and 22.4% had adverse risk. In the MRD-negative/HCT group, 31% were favorable risk, 33.3% intermediate risk, and 35.7% were adverse risk. In the MRD-positive/HCT group, 46.3% favorable risk, 23.8% intermediate risk, and 29.5% were adverse risk. There were no significant differences in ELN risk between any group. MRD-positive patients who underwent HCT had a mOS of 25.7 m. vs 20.7 m. for no HCT (HR=0.68 [95% CI, 0.41-1.11], p = 0.125). The median OS was not reached for MRD-negative patients, regardless of receipt of HCT (HR=0.61 [95% CI, 0.30-1.23], p = 0.168). Patients undergoing HCT in MRD-negative CR had improved OS compared to those undergoing HCT with persistent MRD positivity (p = 0.006). Discussion: MRD positivity is a known predictor of relapse and decreased survival despite HCT. However, the use of MRD as a decision point predicting which patients will benefit from transplant a priori needs to be better understood. Our data suggest that MRD negativity has a more significant impact on overall prognosis than HCT status.Likewise, the negative impact of MRD positivity was not significantly abrogated by subsequent HCT. This highlights the need for refinement in HCT selection beyond ELN 2022 intermediate/adverse-risk patients, and new validated algorithms incorporating MRD status are warranted.

Impact of Socioeconomic Disparities on Outcomes in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Introduction: It is increasingly recognized that racial and socioeconomic disparities play an important prognostic role and contribute to differences in outcomes in adults receiving chemotherapy for acute myeloid leukemia (AML). Structural racism has also been implicated in limiting access to allogeneic hematopoietic cell transplantation (HCT). However, it is unclear to what degree racial and socioeconomic disparities impact post-HCT outcomes of patients with AML in contemporary practice. To address this uncertainty, we investigated the impact of socioeconomic, racial, and non-biologic disparities on outcomes in a large cohort of adults with AML undergoing allogeneic HCT while in first or second morphologic remission. Methods: We identified 1,004 adults with AML (2022 ICC criteria) who underwent allogeneic HCT between 5/2006 and 10/2021 at a single large university-affiliated cancer center. Data was collected on each patient's individual socioeconomic status (SES), including occupation, insurance type, and education attainment. Distance traveled, marital status, household size, country of birth, and religious affiliation were also recorded. Each occupation was classified by the International Socio-Economic Index (ISEI), a standard index of occupational status. Area-level SES was analyzed through the Area Deprivation Index (ADI), a validated measure of socioeconomic disadvantage which corresponds to U.S. census tract measurements. Collected HCT variables include the AML treatment-related mortality score (TRM), pre-HCT flow cytometric MRD status, HLA donor status, cytogenetic risk, conditioning regimen intensity, and incidence of severe acute and chronic graft-vs-host disease. Measured outcomes include non-relapse mortality (NRM), overall survival (OS), relapse, and relapse free survival (RFS). Cause-specific hazard models were used for univariate and multivariable regression analysis and C-statistics were calculated to quantify each model's ability to predict outcomes. Results: In univariate analysis, none of the socioeconomic or non-biologic factors were significantly associated with NRM, and all had poor predictive performance, with C-statistics not exceeding 0.53 for: marital status, larger household size (i.e., patients with children), distance traveled, ISEI, ADI, insurance status, educational attainment, or country of birth. TRM score (P&amp;lt;0.001), non-myeloablative conditioning (P&amp;lt;0.001), reduced intensity conditioning (P&amp;lt;0.001), CR2 (P=0.017) and marital status (P=0.014) were significantly associated with NRM in a multivariable model, but predictive performance of this model was only fair (C=0.69; Table 1). Marital status was only associated with NRM after multivariable adjustment but not on univariate evaluation, possibly because married patients were, on average, older (P&amp;lt;0.001), more likely to be male (P&amp;lt;0.001), and have higher occupational status/ISEI (P&amp;lt;0.001) and TRM scores (P&amp;lt;0.001), with age and sex as likely confounders (Table 2). African American patients (n=14) were found to have worse NRM in both univariate (P=0.036) and multivariate (P=0.024) models, consistent with previously identified racial/ethnic disparities in AML cohorts. Similar results were found for SES and non-biologic variables in regards to OS, relapse, and RFS. Notable exceptions after multivariable adjustment include: ADI was significantly associated with OS (P=0.036) and RFS (P=0.044) and marital status was not significantly associated with OS or relapse. Additional analyses demonstrated that ISEI and ADI were not associated with increased TRM or HLA donor status. Finally, distance traveled decreased in HCT recipients post-2013 (P&amp;lt;0.003), though the number of AML-related transplants remained unchanged. Conclusion: In this retrospective, single center analysis, socioeconomic and non-biologic factors had very limited impact on outcomes following allografting for adults with AML. While reassuring, patients able to undergo allogeneic HCT are highly selected (e.g. need for caregiver, insurance, etc.) possibly accounting for this finding, as could integrated, multidisciplinary cancer care networks and longitudinal care coordination post-HCT. Further research is needed to investigate disparities among HCT-eligible patients and improve access to HCT with a focus on reducing racial/ethnic disparities.