Weisdorf, Daniel J.

Abstract Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

Importance Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized. Objective To determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants. Design, Setting, and Participants In this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research. Exposure Centralized DNA sequencing of banked pretransplant remission blood samples. Main Outcomes and Measures The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models. Results Of 1075 patients tested, 822 had FLT3 internal tandem duplication ( FLT3- ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3 -ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3 -ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P < .001) and decreased survival at 3 years (39% vs 63%; difference, −24% [2-sided 95% CI, −39% to −9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P < .001). Conclusions and Relevance Among patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.

7006 Background: Measurable residual disease (MRD) prior to allogeneic hematopoietic cell transplantation (alloHCT) is associated with increased relapse and death in patients with acute myeloid leukemia (AML) in cytomorphological complete remission (CR). We recently demonstrated AML MRD detected in pre-alloHCT blood by DNA-sequencing was associated with increased relapse and decreased overall survival in patients randomized to reduced intensity conditioning (RIC) versus myeloablative conditioning (MAC). The clinical utility of such ultra-deep next-generation sequencing (NGS-MRD) had not yet been reported in a large multi-center cohort. Methods: Patients aged 18 or older who underwent first alloHCT between 2013-2017 for AML in first CR (CR1), reported to be FLT3, NPM1, IDH1, IDH2 and/or Kit mutated at diagnosis, with a pre-conditioning remission blood sample available in the CIBMTR biobank were eligible for this study. Ultra-deep anchored multiplex PCR-based NGS-MRD for the above mutations was performed on 500ng gDNA with error-corrected variant calling as previously described. The pre-specified statistical analysis plan was registered on OSF. Results: Of 457 patients with a sample available, 448 had sufficient clinical annotation and DNA for analysis. 147 of these 448 patients (33%) experienced relapse at a median of 5.6 months post-alloHCT. NGS-MRD was positive in 129 pre-alloHCT patient samples (29%), averaging 1.35 mutation(s)/patient (range: 1-4). 173 mutations were detected with a median VAF of 0.18% (range: 0.0054-62%), most frequently FLT3-ITD (n = 43 patients), NPM1 (n = 48), and IDH2 (n = 46). Testing positive by NGS-MRD prior to alloHCT was associated with a 3yr RFS of 36% (95% CI: 28-45%) compared with 56% (51-62%) in those testing negative (p < 0.001). Detection of NPM1 and/or FLT3-ITD mutations prior to alloHCT was associated with a 3yr relapse probability of 55% (43-67%) and RFS of 26% (16-37%). NGS-MRD impact was modified by conditioning intensity: positive patients receiving RIC/NMA had the highest relapse of 57% at 3yr, testing negative followed by RIC/NMA had the same relapse rate at 3yr (35%) as those who tested positive but received MAC (p < 0.001). At three years, those positive for FLT3-ITD and/or NPM1 mutations prior to RIC/NMA alloHCT had a relapse probability of 67% (50-83%) with a RFS of 19% (8-33%). HR for relapse if NGS-MRD positive pre-alloHCT in CR1 was 2.3 (p < 0.001, 95% CI 1.6-3.1) when adjusting for conditioning intensity and age group. Conclusions: In this largest cohort of NGS-MRD testing prior to alloHCT for AML reported to date, we confirm the ability to identify patients in CR1 but at high-risk of subsequent relapse. This evidence provides the foundation for future precision medicine approaches to reduce post-transplant AML relapse.

Abstract Leukemia relapse and treatment related mortality (TRM) remain major obstacles for successful allogeneic hematopoietic cell transplantation (allo-HCT). The number of induction cycles using intensive chemotherapy at AML diagnosis to achieve complete remission (CR) and the number of consolidation cycles and disease status at the time of allo-HCT for patients with acute myeloid leukemia (AML) may each affect TRM and relapse rates. We investigated the impact of the number of induction/consolidation cycles and disease status on the success of allo-HCT in 3113 AML patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2019). They received allo-HCT in first CR or with persistent leukemia (primary induction failure-PIF) receiving myeloablative (MA) or reduced-intensity (RIC) conditioning. 1473 AML patients (median age, 47 years) in CR received MAC; 862 (58%) achieved CR after 1 cycle of intensive induction chemotherapy and 74% of these had no evidence of measurable residual disease (MRD). 454 (31%) patients required 2 cycles to CR (72 % MRD negative) and 157 (11%) patients (69% MRD negative) after ≥ 3 cycles. The overall survival (OS), relapse and TRM by induction cycle number is shown in Table 1. Multivariate analysis demonstrated that CR after 1 cycle led to higher OS vs. 2 cycles (HR 1.32 95%CI 1.11-1.56, p&lt; 0.01) or ≥ 3 cycles (HR 1.47 95%CI 1.16-1.87, p&lt; 0.01), while OS after 2 cycles or ≥ 3 cycles were similar (HR 1.2 95%CI 0.87-1.4, p=0.38). Higher TRM was observed in patients receiving 2 or ≥ 3 cycles vs. only 1 induction cycles (HR 1.34 95%CI 1.05-1.72, p&lt; 0.02). Relapse risk was greater in those needing ≥ 3 cycles to achieve CR. Consolidation therapy after CR was associated with improved OS vs. no consolidation therapy (HR 1.57 95%CI 1.24-1.99, p&lt; 0.01). The need for ≥2 induction cycles plus consolidation therapy was associated with higher TRM (HR 1.34 95%CI 1.05-1.72, p&lt; 0.02). 1162 AML patients (median age, 63 years) in CR received allo-HCT after RIC; 714 (61%) achieved CR after 1 cycle of induction chemotherapy (72% MRD negative); 310 (27%) patients after 2 cycles (67% MRD negative) and 138 (12%) patients (58% MRD negative) after ≥ 3 cycles (Table 1). Multivariate analysis demonstrated that the number of induction cycles did not affect the OS or TRM. Relapse risk was greater in patients requiring ≥2 cycles to achieve CR. The use of consolidation therapy did not affect OS or TRM. MRD status at the time of allo-HCT did not have a significant impact on OS, TRM and relapse rates after either MA or RIC conditioning. 478 AML patients received allo-HCT after PIF (328 patients with MAC [median age, 51 years], 150 patients RIC [median age, 61 years], Table 1). After MAC, OS and relapse were significantly worse in PIF patients compared to any CR patients (p&lt;0.01). After RIC, relapse was significantly more frequent in PIF patients vs. CR patients after 1 or more induction cycles (p&lt;0.01). TRM was similar for PIF vs CR patients after MAC or RIC allo-HCT. These data demonstrate that among patients eligible for allo-HCT, the need for only one induction cycle to achieve CR, particularly when combined with consolidation therapy is associated with better outcomes after MA conditioning. Achieving CR prior to allo-HCT needing one or more induction cycles is associated with lower relapse rates and improved OS compared to patients with PIF that receive allo-HCT. Figure 1 Figure 1. Disclosures de Lima: BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hourigan: Govt. COI: Other. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Saber: Govt. COI: Other. Weisdorf: Incyte: Research Funding; Fate Therapeutics: Research Funding.

Abstract Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P &lt; .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P &lt; .001), as was overall survival (HR, 1.32; P &lt; .001, and HR, 1.45; P &lt; .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Abstract The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P &lt; .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P &lt; .001) and grade 3 to 4 aGVHD (HR, 1.97; P &lt; .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.

Abstract There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P &lt; .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P &lt; .001). Long-term relapse was lower with FM (HR = 0.65, P &lt; .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Abstract Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).