Transplantation For Acute Myeloid Leukemia Research Articles

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 > 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<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<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 (>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<0.0001) and decreased survival (29% vs 77%, p<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<0.001), non-myeloablative conditioning (P<0.001), reduced intensity conditioning (P<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<0.001), more likely to be male (P<0.001), and have higher occupational status/ISEI (P<0.001) and TRM scores (P<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<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.

Measurable Residual IDH2 before Allogeneic Transplant for Acute Myeloid Leukemia

Introduction: Detection of measurable residual disease (MRD) in AML patients during remission is associated with adverse clinical outcomes after allogeneic hematopoietic cell transplant (alloHCT), including recent strong evidence from our group regarding residual NPM1 and/or FLT3-ITD variants (PMID: 36881031). Large studies examining the significance of other potential MRD targets, including isocitrate dehydrogenase isoform 2 ( IDH2), are needed. IDH2, which is mutated in approximately 12% of AML patients, is of particular interest due to the possibility of targeted clinical intervention. Methods: Patients over the age of 18 in first complete remission (CR1) with IDH2 mutated AML undergoing alloHCT transplant at a CIBMTR site between 2013-2019 with remission blood samples within 100 days of alloHCT and available clinical data were included in this study. Residual variants in IDH2, NPM1, and FLT3genes were detected by ultrasensitive error-corrected next-generation sequencing (NGS-MRD) on genomic DNA from pre-conditioning blood and validated by digital droplet PCR (ddPCR). The primary outcomes were overall survival (OS) and cumulative incidence of relapse with non-relapse mortality as a competing risk. The day of transplant was considered as time 0, and the median follow-up time was calculated for censored patients. Kaplan-Meier estimation (log-rank tests), Cox proportional hazards models, and Fine-Gray regression models were fitted to examine the clinical outcomes. Results: Among the 257 IDH2-mutated AML patients in this study, 57 (23%) experienced relapse, with 41 events occurring within 12 months after alloHCT. The median follow-up time was 25 months. Among 247 patients with pre-transplant remission flow cytometry results reported, 25% were positive, but no difference in rates of relapse or OS was observed between positive and negative patients. NGS MRD analysis detected residual IDH2 variants in remission samples of 130 patients (51%) with variant allele fraction (VAF) ranging from 0.05-56% (median: 3%), and 100% validation by ddPCR. NGS MRD IDH2 positive patients had increased rates of relapse (p = 0.03; 3yr: +11%, 95% CI: 0.2% to 22%) and decreased OS (p < 0.001; 3yr: -25%, 95% CI: -13% to -38%) compared to those who tested negative (Figure 1A). These OS differences were still observed between NGS MRD IDH2 positive and negative patients, regardless of age stratification (under 60yr p < 0.001, 3yr: -28%, 95% CI: -12% to -43%; over 60yr p = 0.04, 3yr: -19%, 95% CI: -1% to -40%); however, only patients over 60yrs had increased rates of relapse (p = 0.007; 3yr: +21, 95% CI: 6% to 36%). The impact of co-mutation status was examined by subdividing the cohort based on the presence of NPM1 or FLT3-ITD mutations at baseline. Residual IDH2 variants in patients without baseline NPM1 or FLT3-ITD co-mutations (n = 151) were associated with decreased OS and increased relapse ( IDH2+ vs IDH2-; OS p = 0.005, 3yr: -23%, 95% CI: -6% to -40%; Relapse p = 0.01, 3yr: +19, 95% CI: 6% to 32%; Figure 1B). In contrast, residual IDH2 variants were not predictive of relapse in co-mutated patients (n=106, p = 0.5). In these patients, the only prognostic marker for relapse was NPM1 and/or FLT3-ITD MRD, with similar relapse risk between IDH2 only positive and MRD negative groups (p < 0.001; 3yr: 83% vs. 11% vs. 15%; Figure 1B). In multivariable analysis, IDH2 MRD positivity was associated with decreased OS (HR 2.5, 95% CI: 1.5-4.2, p < 0.001) and increased rates of relapse (HR 2.1, 95% CI: 1.4-5.7, p = 0.003) after adjusting for other characteristics. Conclusion: In this study, we demonstrate that adult patients with IDH2-mutated AML who have IDH2 variants detected in CR1 prior to first alloHCT experienced increased relapse rates and decreased overall survival. However, this association is significant only in patients without baseline NPM1 and FLT3-ITD mutations. In co-mutated patients, NPM1 and/or FLT3-ITD MRD serve as superior prognostic markers. Subgroup analyses show the potential influence of factors such as conditioning intensity and age on clinical outcomes. Nevertheless, larger studies with balanced subgroups and more comprehensive baseline mutational information, including IDH2 mutation subtype, are needed to better define the clinical relevance of IDH2 MRD in this context.

Phase 1 Trial of Dendritic Cell/AML Fusion Cell Vaccine after Allogeneic Stem Cell Transplant in Acute Myeloid Leukemia

Introduction We have developed a vaccine in which patient-derived AML cells are fused with donor-derived dendritic cells (DCs). Vaccination after initial remission and consolidation was shown to elicit leukemia-specific immune responses. We hypothesized that donor-derived DC/AML vaccination post-transplant would elicit the durable expansion of leukemia-specific T cells within the donor T cell repertoire to effectively protect against disease relapse. We report updated results of a phase 1 clinical trial (NCT03679650) evaluating the use of DC/AML fusion vaccine following allogeneic transplant. Methods DC/AML fusion vaccine was generated with patient leukemia blasts, cryopreserved at the time of diagnosis, and donor-derived DCs, from leukapheresis of patients who achieved hematopoietic recovery and remained in CR 25-90 days after an allogeneic transplant. DCs were differentiated via culture of adherent mononuclear cells in the presence of GM-CSF, IL-4 and TNFa. Vaccine was administered starting day 70-100 post-transplant as long as the patient did not have active GVHD requiring therapy. Two doses of the vaccine were given subcutaneously at 3 week intervals, in conjunction with 100 mcg GMCSF daily at the vaccine site for 4 days. A booster vaccine was given 30-60 days following the taper of immune suppression, in the absence of GVHD. Longitudinal profiling of the immune landscape by single cell RNA sequencing and CyTOF from peripheral blood samples obtained before and after vaccination is underway. Immunologic response of leukemia-specfic T cells is being evaluated via IFN-gamma expression following stimulation with autologous tumor lysate. OS was calculated using Kaplan Meier Curve. Results 27 participants have been enrolled with median age 59 years (range 23-74). 15 patients were transplanted with a matched unrelated donor, 10 with a matched sibling donor and two with a haplo-identical donor. One patient relapsed prior to leukapheresis and was ineligible. The median yield of leukemia cells was 218x10 6 (range 62-818x10 6)and mean viability was 97%. The median yield of DCs was 106x10 6 (range 19-182x10 6) and mean viability 81%. Fusion vaccine was successfully generated in 25 of 26 patients who underwent leukapheresis; one patient had insufficient DC. Mean fusion efficiency was 47% with viability of 79%. Mean fusion vaccine dose was 3.8 x10 6 cells. 6 patients from whom vaccine was generated did not meet eligibility to initiate vaccination due to GVHD or COVID19 infection. 19 participants initiated vaccine administration and are evaluable for toxicity and immunologic response. The most common side effects were vaccine site reactions (n=10 grade 1, n=2 grade 2). 5 patients developed GVHD that was attributed as possibly related to vaccination, at a median time of 17 days after vaccination (range 5-70 days). Acute GVHD included two events of skin grade 2, one GI grade 2, one liver and skin grade 3. Chronic GVHD included a moderate event affecting 3 organs and severe event affecting 4 organs. There were 10 additional GVHD events with a median time of 108 days post vaccination (range 7-126 days), assessed as unlikely related or unrelated to vaccine based on pre-existing GVHD and timing of onset. Median time of follow-up is 23 months post-transplant (range 11-59 months). Amongst 19 vaccinated patients, 14 remained in CR and median overall survival estimate is 49 months post transplant. 3 died of relapsed disease, 2 died of GVHD and/or infection, and 1 died of unknown cause. Preliminary results of PB CyTOF from 4 patients in remission and 1 patient that relapsed indicate higher proportions of T cells and DCs in patients in CR. Interferon expression was higher in a patient with durable remission while absent from a patient with early relapse. Conclusions Vaccination using host-derived leukemia cells and donor derived DC was safe and feasible. Adverse events post vaccination have included injection site reactions as well as acute and chronic graft versus host disease. Vaccination may be a promising strategy to reduce relapse as 14 of 19 vaccinated patients remain relapse free. Albeit this approach is limited to patients who have not had early relapse or early GVHD. Immunologic response by interferon release upon lysate stimulation, CyTOF and single cell RNA sequencing of the immune milieu will be reported.

EXABS-181-AML Achieving Best Response Is Desirable Prior To Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

EXABS-181-AML Achieving Best Response Is Desirable Prior To Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Cardiac tamponade due to eosinophilia treated with intravenous corticosteroid: A case report.

Cardiac tamponade, a condition in which the heart is compressed by pericardial fluid retention, is easy to diagnose; however, identifying the cause may be challenging since it can be caused by a variety of conditions, including trauma and pericardial disease. A 22-year-old man was admitted to the intensive care unit with respiratory failure. He had previously received allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and developed chronic graft-versus-host disease (cGvHD) that was treated with a corticosteroid. At this time, he developed bilateral femur head necrosis and underwent surgery after discontinuation of the corticosteroid but developed respiratory failure postoperatively. The initial diagnosis was cardiac failure, which temporarily improved with treatment; however, eosinophilia and pericardial effusions became prominent. Pericardial effusion gradually progressed, resulting in cardiac tamponade. Pericardiocentesis was performed. Eosinophilia could be the cause of cardiac tamponade; thus, corticosteroid was administered. Pericardial effusion improved remarkably after corticosteroid administration. The corticosteroid dose was gradually tapered, and the patient was discharged. This case presented with cardiac tamponade associated with eosinophilia, probably owing to graft-versus-host disease. This is an unusual condition associated with a history of hematologic neoplasms; although evaluation is challenging, appropriate assessment could help save the patient's life.

Haploidentical transplant with posttransplant cyclophosphamide vs matched related and unrelated donor transplant in acute myeloid leukemia and myelodysplastic neoplasm

Hematopoietic cell transplantation from haploidentical donors (haploHCT) has facilitated treatment of AML and MDS by increasing donor availability and became more feasible since the introduction of post-transplant cyclophosphamide (ptCY). In our single-center retrospective analysis including 213 patients with AML or MDS, we compare the outcome of haploHCT (n = 40) with ptCY with HCT from HLA-identical MRD (n = 105) and MUD (n = 68). At 2 years after transplantation, overall survival (OS) after haploHCT was not significantly different (0.59; 95% confidence interval 0.44–0.79) compared to MRD (0.77; 0.67–0.88) and MUD transplantation (0.72; 0.64–0.82, p = 0.51). While progression-free survival (PFS) was also not significantly different (haploHCT: 0.60; 0.46–0.78, MRD: 0.55; 0.44–0.69, MUD: 0.64; 0.55–0.74, p = 0.64), non-relapse mortality (NRM) was significantly higher after haploHCT (0.18; 0.08–0.33) vs. MRD (0.029; 0.005–0.09) and MUD (0.06; 0.02–0.12, p < 0.05). Higher NRM was mainly caused by a higher rate of fatal infections, while deaths related to GvHD or other non-relapse reasons were rare in all groups. As most fatal infections occurred early and were bacterial related, one potential risk factor among many was identified in the significantly longer time to neutrophil engraftment after haploHCT with a median of 16 days (interquartile range; 14.8–20.0) vs. 12 days (10.0–13.0) for MRD and 11 days (10.0–13.0) for MUD (p = 0.01).

Influence of conditioning regimen intensity on outcomes post-allogeneic hematopoietic cell transplantation for acute myeloid leukemia in complete morphological remission.

The literature comparing outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) for acute myeloid leukemia (AML) is conflicting. We retrospectively analyzed 451 patients who underwent allogenic hematopoietic cell transplantation (alloHCT) for AML in complete remission (CR) with either RIC (n = 331) or MAC (n = 120) with the use of dual T-cell depletion as graft-versus-host disease (GVHD) prophylaxis. Univariate analysis demonstrated nonrelapse mortality (NRM) at 2 years was 19.1% for MAC and 22.5% for RIC (p = .44). Two-year cumulative incidence of relapse (CIR) was 19.8% for MAC and 24.5% for RIC (p = .15). Two-year overall survival (OS) was 61% and 53% for MAC and RIC, respectively (p = .02). Two-year graft-versus-host disease relapse-free survival (GRFS) was 40.8% for MAC and 33.7% for RIC (p = .30). A propensity score-matched analysis was done matching patients for age, HLA match, in vivo T-cell depletion, and Disease Risk Index (DRI). Two-year OS was 67% for MAC, 66% for RIC (p = .95). A subgroup analysis identified that matched related donor transplants benefit from MAC with OS at 2 years 82.6% versus 57.3% for RIC (p = .006). In the matched-related donor setting, MAC regimens may offer superior survival. Overall, for our cohort of predominantly in vivo T-cell depleted patients the outcomes of MAC and RIC were similar.

Intrabone Transplantation of a Single Unwashed Umbilical Cord Blood Unit with Antithymocyte Globulin-Free and Sirolimus-Based Graft-versus-Host Disease Prophylaxis: Fast Immune Reconstitution and Long-Term Disease Control in Patients with High-Risk Diseases

Several strategies have been explored with the attempt of improving the safety and feasibility of umbilical cord blood transplantation (UCBT) in adults. The aim of this retrospective analysis was to examine the safety and efficacy of intrabone transplantation of a single unwashed cord blood unit in an antithymocyte globulin-free, sirolimus-based graft-versus-host disease prophylaxis platform. We collected data for all consecutive UCBTs infused intrabone (IB) and unwashed at San Raffaele Hospital in Milan between 2012 and 2021. Thirty-one consecutive UCBTs were identified. All but 3 UCB units had a high-resolution HLA typing on 8 loci at the time of selection. At the time of cryopreservation, the median CD34+ cell count was 1 × 105/kg (range, .6 to 12.0 × 105/kg) and the median total nucleated cell (TNC) count was 2.8 × 107/kg (range, 1.48 to 5.6 × 107/kg). Eighty-seven percent of patients received myeloablative conditioning, and 77% underwent transplantation for acute myeloid leukemia. The median duration of follow-up among survivors was 38.2 months (range, 10.4 to 123.6 months). No adverse events were related to the IB infusion at bedside under short-conscious periprocedural sedation or to the no wash technique. After thawing, median CD34+ cell and TNC counts were .8 × 105/kg (range, .1 to 2.3 × 105/kg) and 1.42 × 107/kg (range, .69 to 3.2 × 107/kg). The median time to engraftment was 27 days for neutrophils and 53 days for platelets. One patient experienced graft rejection and was subsequently rescued with a salvage transplantation. The median time to a CD3+ cell count >100/μL was 30 days. The 100-day cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was 12.9% (95% confidence interval [CI], 4% to 27.3%), and the 2-year cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was 11.8% (95% CI, 2.7% to 28.3%). At 2 years, overall survival (OS) was 52.7% (95% CI, 33% to 69%), relapse incidence was 30.7% (95% CI, 13.7% to 49.6%), and transplantation-related mortality was 29% (95% CI, 14.3% to 45.6%). In univariate analysis, infused CD34+ cell count did not impact transplantation outcomes. In patients who underwent transplantation in first complete remission, relapse rate was 13%, with a 2-year OS >90%. In our cohort, IB infusion of a single cord blood unit was feasible, with no adverse reactions related to the no wash/IB infusion, low rates of cGVHD and disease relapse, and rapid immune reconstitution.

Hereditary angioedema with an acute attack resolved after bone marrow transplantation for acute myeloid leukemia: a case report

BackgroundHereditary angioedema (HAE), which is caused by C1-inhibitor (C1-INH) deficiency or dysfunction, is a rare and potentially life-threatening disease. In patients with HAE, excess production of bradykinin causes acute unpredictable recurrent attacks of angioedema in localized regions, including the larynx and intestines. Given the fact that HAE is an autosomal dominant disease, C1-INH produced in patients with HAE is 50% of that produced in healthy individuals. However, most patients with HAE present plasma C1-INH function of < 25% owing to the chronic consumption of C1-INH by kallikrein–kinin, contact, complement, coagulation, and fibrinolysis cascades. Recently, several therapeutic options have been developed for acute attacks and prophylaxis in the treatment of HAE; however, currently, there is no curative therapy for HAE.Case presentationHere we report the case of a 48-year-old male patient who presented with a long-standing history of HAE and underwent bone marrow transplantation (BMT) for acute myeloid leukemia (AML) at the age of 39 years and has been in complete remission of AML and HAE thereafter. Notably, after BMT, his C1-INH function gradually increased as follows: < 25%, 29%, 37%, and 45.6%. Since his 20 s, he intermittently presented with an acute attack of HAE once every 3 months from the initial attack. Further, after undergoing BMT, the number of acute attacks decreased to twice within 4 years until the age of 45 years, and subsequently, the patient has been free of acute attacks. C1-INH is mainly synthesized by hepatocytes, but it is known to be partially produced and secreted from peripheral blood monocytes, macrophages, endothelial cells, and fibroblasts. We speculate that the C1-INH function may be increased by extrahepatic production of C1-INH, possibly synthesized by differentiated cells derived from hematopoietic and mesenchymal stem cells after BMT.ConclusionsThis case report supports efforts to focus on extrahepatic production of C1-INH in the next strategy of new treatment development for HAE.

Comorbidities in transplant recipients with acute myeloid leukemia receiving low-intensity conditioning regimens: an ALWP EBMT study.

Older age and a high burden of comorbidities often drive the selection of low-intensity conditioning regimens in allogeneic hematopoietic stem cell transplantation recipients. However, the impact of comorbidities in the low-intensity conditioning setting is unclear. We sought to determine the contribution of individual comorbidities and their cumulative burden on the risk of nonrelapse mortality (NRM) among patients receiving low-intensity regimens. In a retrospective analysis of adults (≥18 years) who underwent transplantation for acute myeloid leukemia in the first complete remission between 2008 and 2018, we studied recipients of low-intensity regimens as defined by the transplantation conditioning intensity (TCI) scale. Multivariable Cox models were constructed to study associations of comorbidities with NRM. Comorbidities identified as putative risk factors in the low-TCI setting were included in combined multivariable regression models assessed for overall survival, NRM, and relapse. A total of 1663 patients with a median age of 61 years received low-TCI regimens. Cardiac comorbidity (including arrhythmia/valvular disease) and psychiatric disease were associated with increased NRM risk (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.13-2.09 and HR, 1.69; 95%CI, 1.02-2.82, respectively). Moderate pulmonary dysfunction, though prevalent, was not associated with increased NRM. In a combined model, cardiac, psychiatric, renal, and inflammatory bowel diseases were independently associated with adverse transplantation outcomes. These findings may inform patient and regimen selection and reinforce the need for further investigation of cardioprotective transplantation approaches.

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

Monitoring of donor chimerism (DC) may detect early relapse following allogeneic hematopoietic stem cell transplantation (allo-SCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Most centers use unfractionated peripheral blood or T-cells to monitor DC, although CD34+ DC may be more predictive. The limited adoption of CD34+ DC may be due to the lack of detailed, comparative studies. To address this knowledge gap, we compared peripheral blood CD34+ and CD3+ DC in 134 patients who underwent allo-SCT for AML or MDS. In July 2011, the Alfred Hospital Bone Marrow Transplantation Service adopted routine monitoring of DC in the lineage-specific CD34+ and CD3+ cell subsets from peripheral blood at 1, 2, 3, 4, 6, 9, and 12 months post-transplantation for AML or MDS. Immunologic interventions, including rapid withdrawal of immunosuppression, azacitidine, and donor lymphocyte infusion, were prespecified for CD34+ DC ≤80%. Overall, CD34+ DC ≤80% detected 32 of 40 relapses (positive predictive value [PPV], 68%; negative predictive value [NPV], 91%), compared with 13 of 40 relapses for CD3+ DC ≤80% (PPV, 52%; NPV, 75%). Receiver operating characteristic analysis showed the superiority of CD34+ DC, with the greatest value at day 120 post-transplantation. CD3+ DC provided additional value in only 3 cases, preceding CD34+ DC ≤80% by 1 month. We further show that the CD34+ DC sample can be used to detect NPM1mut, with the combination of CD34+ DC ≤80% and NPM1mut identifying the highest risk of relapse. Among the 24 patients in morphologic remission at the time of CD34+ DC ≤80%, 15 (62.5%) responded to immunologic interventions (rapid withdrawal of immunosuppression, azacitidine, or donor lymphocyte infusion) with recovery of CD34+ DC >80%, and 11 of these patients remained in complete remission for a median of 34 months (range, 28 to 97 months). In contrast, the other 9 patients did not respond to the clinical intervention and relapsed within a median of 59 days after detecting CD34+ DC ≤80%. The CD34+ DC was significantly higher in responders than in nonresponders (median, 72% versus 56%; P=.015, Mann-Whitney U test). Overall, monitoring of CD34+ DC was considered clinically useful (early diagnosis of relapse enabling preemptive therapy or predicting low risk of relapse) in 107 of 125 evaluable patients (86%). Our findings show that peripheral blood CD34+ DC is feasible and superior to CD3+ DC for predicting relapse. It also provides a source of DNA for measurable residual disease testing, which may further stratify the risk of relapse. If validated by an independent cohort, our results suggest that CD34+ should be used in preference to CD3+ DC for detecting early relapse and guiding immunologic interventions following allo-SCT for AML or MDS.

Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

This summary is intended to update the Brazilian Society of Bone Marrow Transplantation and Cellular Therapy (SBTMO) 2020/1 consensus on HSCT for Acute Myeloid leukemia (AML).

Advantages of Higher Busulfan Dose Intensity in Fludarabine-Combined Conditioning for Patients with Acute Myeloid Leukemia Undergoing Cord Blood Transplantation

The alkylating agent busulfan is commonly used as conditioning in allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). However, a consensus has not yet been reached regarding the optimal busulfan dose in cord blood transplantation (CBT). Therefore, we conducted this large nationwide cohort study to retrospectively analyze the outcomes of CBT in patients with AML receiving busulfan at intermediate (6.4 mg/kg i.v.; BU2) or higher (12.8 mg/kg i.v.; BU4) doses within a fludarabine/i.v. busulfan (FLU/BU) regimen. Among 475 patients who underwent their first CBT following FLU/BU conditioning between 2007 and 2018, 162 received BU2 and 313 received BU4. Multivariate analysis identified BU4 as a significant factor for longer disease-free survival (hazard ratio [HR], .85; 95% confidence interval [CI], .75 to .97; P=.014) and a lower relapse rate (HR, .84; 95% CI, .72 to .98; P=.030). No significant differences were observed in non-relapse mortality between BU4 and BU2 (HR, 1.05; 95% CI, .88-1.26; P=.57). Subgroup analyses showed that BU4 provided significant benefits for patients who underwent transplantation while not in complete remission (CR) and those age <60 years. Our present results suggest that higher busulfan doses are preferable in patients undergoing CBT, particularly those not in CR and younger patients.

Safety and efficacy of a modified busulfan/cyclophosphamide conditioning regimen incorporating cladribine for autologous hematopoietic stem cell transplantation in acute myeloid leukemia.

This is a small phase I study examining the safety and efficacy of a cladribine (CLAD)-containing conditioning regimen prior to autologous hematopoietic stem cell transplantion (auto-HSCT) for patients with acute myeloid leukemia (AML). All patients, aged 15-54years (median 32years), had favorable/intermediate risk AML (n = 20) or acute promyelocytic leukemia (APL; n = 2) and no evidence of minimal residual disease (MRD) prior to transplantation. Fourteen of the 22 patients received the conditioning regimen as follows: busulfan (Bu) + cyclophosphamide (Cy) + CLAD + cytarabine (Ara-c) or idarubicin. The conditioning regimen of 8 patients was without Cy nor idarubicin to reducing adverse cardiac reaction: the regimen of Bu + CLAD+ Ara-c for 6 patients; and the regimen of Bu + melphalan + CLAD + Ara-c for the other 2 patients. All 22 AML patients received peripheral blood stem cell transplantation. The number of infused mononuclear cells and CD34+ cells was 10.00 (2.88-20.97) × 108/kg and 1.89 (1.52-10.44) × 106/kg, respectively. Hematopoietic reconstitution was achieved in all patients, with a median time of 13 (10-34) days for neutrophils and 28 (14-113) days for platelets. Two patients suffered from pulmonary infection, 4 patients suffered from septicemia during the neutropenic stage, and the others suffered from infection or gastrointestinal reaction without exceeding grade 3 after conditioning, which were all alleviated by anti-infection and other supportive treatment. None of the patients died of transplantation-related complications. At a median follow-up of 29.5 (ranging from 4.0 to 60.0) months, three patients relapsed after auto-HSCT at a median time of 6 (ranging from 0.5 to 10.0) months. One patient died due to relapse at 18months after auto-HSCT. The remaining 21 patients were all alive, including 19 patients with negative MRD. The other 2 patients achieved negative MRD after allogeneic HSCT or chemotherapy. The estimated 2-year survival, relapse, and Leukemia-free survival rates were 94.1 ± 5.7%, 14.7 ± 7.9% and 85.3 ± 7.9%, respectively. A CLAD-combination conditioning regimen is efficient and safe for auto-HSCT, indicating an effective approach for AML treatment.