Tallman, Martin S.

Abstract Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase–activating mutation in >95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor–based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.

Abstract Introduction:A comprehensive integration of significantly mutated genes and pathways with molecular subgroups is lacking in adult B-ALL. Furthermore, the genomic drivers underlying each subgroup remain to be identified.We aimed to perform genomic analysis on a large cohort of patients with adult B-ALL, and to correlate genomic markers with achievement of MRD negativity enabling blinatumomab randomization, and with subsequent response to blinatumomab. Methods:For genomic analysis, we studied 569 adults with newly diagnosed B-ALL registered for initial screening on the ECOG-ACRIN-led E1910 trial (NCT02003222), which evaluated the addition of blinatumomab to standard consolidation chemotherapy. The median age was 52 yrs (range 30 to 71 yrs), with 52% males. Analysis was performed on tumor and matched-normal samples using whole transcriptome sequencing (RNA-seq; tumor only; n=569), whole exome sequencing (n=490), whole genome sequencing (n=131), and single nucleotide polymorphism array (n=445). B-ALL cases were classified into 22 molecular groups. Outcome analysis was limited to patients enrolled and treated on E1910 (n=319). Results: Driver genes (n=268) were identified by the mutation-significance detection tool dNdScv or by the presence of pathogenic variants in known cancer genes, with NUP188 identified as a novel driver gene. Recurrently mutated pathways included: B-cell development (46%), cell cycle (44%), epigenetic regulation (30%), other transcriptional regulation (27%), Ras signaling (25%), RNA machinery (17%) and JAK-STAT signaling (8%). A high frequency of high-risk subtypes was observed including BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A (12%). Using tSNE analysis, we identified a new cluster of cases (n=20, 3.5%) lacking a known subgroup driver, with overexpression of CEBPA (n=13) or CEBPB (n=7), distinct from CEBPE/ZEB2, termed “CEBP-altered” ALL (CEBPalt). Five of 13 cases with high CEBPA expression harbored an IGH::CEBPA rearrangement and one harbored a RXRA::CEBPA enhancer hijacking alteration. Of the 7 cases with high CEBPB expression, 5 harbored IGH::CEBPB, and two of these had concomitant clonal BCR::ABL1 fusions. To identify additional mechanisms of CEBP deregulation, in situ Hi-C coupled to H3K27 acetylation immunoprecipitation (HiChIP) was performed on 5 cases. Four cases showed evidence of de novo CEBPA enhancer activity. In two cases, we identified novel insertions (12 and 34nt) ~2kb downstream of CEBPA. A novel translocation and enhancer hijacking event between LINC00426 and the 5' UTR of CEBPB was identified in the remaining case. Overall, we confirmed genomic alterations of CEBPA or CEBPB in 16 of 20 cases with available material. Thus, we have identified a new molecular subgroup of adult B-ALL characterized by genomic alterations that drive enhancer hijacking and oncogenic deregulation of CEBPA/CEBPB. Several subgroups were enriched in patients that failed induction chemotherapy (n=62) or were MRD-positive (n=63) compared to those that achieved MRD-negative status (n=194): BCR::ABL1-like (30 vs 14%, p<0.001), KMT2A (18 vs 9%, p=0.03) and BCL2/MYC (5 vs 1%, p=0.06). Conversely, the following subgroups were enriched in patients that achieved MRD-negativity: PAX5alt (6 vs 18%, p=0.002), TCF3::PBX1 (0 vs 5%, p=0.01) and ZNF384 (2 vs 6%, p=0.08) Within each molecular subgroup we compared the survival of patients who achieved MRD-negative status after induction and were randomized to receive blinatumomab plus chemotherapy (n=93) or chemotherapy only (n=91). Although numbers were low, blinatumomab improved relapse-free survival for patients with hyperdiploid, PAX5alt, BCR::ABL1-like and KMT2A ALL compared to chemotherapy alone. Clonal hematopoiesis of indeterminate potential (CHIP)-related gene mutations were identified in 121 of 417 cases analyzed (29% total: somatic 74%, remission 31%, both 5%). TP53 mutations were most frequent (n=65 patients), with the majority identified in patients with low hypodiploid (n=52). Interestingly, patients with CRLF2 rearrangements collectively harbored the highest number of other CHIP gene mutations (n=13), including DNMT3A (n=4), TET2 (n=3) and ASXL1 (n=3). Conclusions:We provide a comprehensive landscape of genomic alterations in adult B-ALL and identify a new group characterized by deregulation of CEBPA/CEBPB (CEBPalt). We also provide insights into the efficacy of blinatumomab in different molecular subgroups of adult B-ALL.

Abstract Copy Number Alterations (CNAs), including chromosomal gains and losses, shape the genetics and clinical management of acute myeloid leukemia (AML), particularly in complex karyotypes (e.g. CK-AML). Traditionally, AML associated CNAs have been studied using cytogenetic approaches, i.e., karyotyping, that are limited in resolution and sensitivity. Here, low-coverage, sparse whole genome sequencing followed by machine learning applied to over 600 AML patient samples (ECOG-ARCIN trials: E1900, E3999) reveals novel genetic, biologic, and clinical correlates in AML disease. We find that multi-variate Cox-regression analysis applied to the data identifies select patients exhibiting focal and cryptic hemizygous deletions at 17q, 21q, and 3p, in otherwise diploid genomes, associate with inferior survival compared to other patients (median overall survival; OS = 65.5 compared to 421 days, Chi-square test pval=6x10-11), independent of factors such as age, treatment, and karyotype complexity status. In addition, we confirm that amplifications at 11q23, encoding the KM2TA gene, are associated with inferior outcome, and further identify unique breakpoint event features as well as transcriptional signatures suggestive of distinctive KM2TA-translocation independent biology. Applying machine learning approaches to the data, more specifically Non-negative Matrix Factorization (NMF), we develop a prognostic model that captures clinically adverse, cryptic variation such as focal 5q deletions, missed by conventional chromosome analysis and thereby, adds novel, complementary information to traditional, cytogenetic based risk-stratification (e.g. ELN). The model also associates gain of chromosome 8 in Intermediate risk patients with worse outcome compared to other Intermediate risk patients (median OS = 186 compared to 446 days, Chi-square test pval=0.005) and identifies a subgroup of patients within the adverse risk category that lack deletions on chromosomes 5, 7, and 17, and that fare better than the rest of the adverse risk patients (median OS = 188 compared to 97.5 days, Chi-square test pval=0.02), likely reflecting previously identified “atypical” CK-AML patients. Last, we develop a prognostic classifier based on a combination of Neural-Network and Random-Forest based learning, that predicts disease outcome with high accuracy and is based on a three genomic feature list on chromosome bands 5q31.2, 7q31.33, and 8q24, suggesting potential for clinical implementation. Altogether, our results show that low coverage, sparse whole genome sequencing combined with advanced learning methods can be applied clinically to support the diagnosis and clinical management of AML disease as well as serve as a powerful tool to further a basic understanding of the genetics and biology of CNAs in myeloid neoplasms and other cancers.

Abstract Background: The addition of the CD19/CD3 bispecific T-cell engager, blinatumomab, to standard consolidation chemotherapy in adults with ALL who achieved a measurable residual disease negative (MRDneg) remission (CR), demonstrated an improvement in 3-year overall survival (OS, 85% vs 68%, HR 0.41, P=0.002) and 3-year relapse-free survival (RFS, 80% vs 64%, HR 0.53) compared to conventional chemotherapy in the ECOG-ACRIN E1910 study (Litzow et al, NEJM 2024). Given the complex therapy in this study, treatment delays and modifications are expected. We herein explored the impact of such delays on patient outcomes. Methods: In the phase 3 ECOG-ACRIN E1910 trial (NCT02003222), adults aged 30-70 years with newly diagnosedALL who had achieved MRDneg CR following induction and intensification were randomized to consolidation chemotherapy with blinatumomab (blina arm) or chemotherapy alone (chemo arm). We examined the association between the timing of the initiation of maintenance therapy and OS and RFS. The expected duration of consolidation was 252 days vs 126 days for patients on the blina and chemo arms, respectively. For this analysis, participants were classified into two groups (no/short delay or long delay) depending on whether they started on time/before or after the median time between the beginning of consolidation and start of maintenance therapy for their treatment group (medians: 335 days, range, 181-457 days vs 176 days, range, 139-265 days for blina and chemo arms, respectively). Multivariate analyses of OS and RFS were performed to examine the effect of no/short delay vs. long delay in starting maintenance. Patients were stratified according to their assigned consolidation treatment arm, and the models were further adjusted for age, sex, white blood cell count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status and genetic-genomic risk at diagnosis. Results: Of the 488 patients enrolled, 224 MRDneg patients were randomized to consolidation chemotherapy with or without blinatumomab and 135 of the 224 went on to maintenance therapy on study (N= 66 on blina arm and 69 on chemo arm, respectively). The median follow-up from the time of maintenance registration was 43.4 months. There were no significant differences in baseline characteristics between patients in either arm who experienced no/short delay or long delay. In the blina group, 60 of 66 patients (90.9%) received all 8 cycles of consolidation therapy of which 31 (45.6%) had long delays. Sixty-eight of 69 patients on the chemo arm (98.5%) received all cycles of consolidation therapy, of which 34 (50%) had a long delay. Strikingly, patients who had a long delay before initiation of maintenance had a significant improvement in OS in multivariate analysis compared to patients who had no/short delay (HR 0.31, 95% CI: 0.11-0.91; P =0.03). However, within each treatment group, OS benefit did not reach statistical significance (blina arm: HR 0.04, 95% CI: 0.001-1.64; P =0.09; chemo arm: HR 0.32, 95% CI: 0.08-1.38; P =0.13). Similar results were observed for RFS in multivariate analysis (HR 0.40, 95% CI: 0.16-1.01; P =0.05), though this impact on improved RFS was noted in the chemo arm but not in blinatumomab treated patients (blina arm: HR 0.56, 95% CI: 0.10-3.24; P =0.52; chemo arm: HR 0.19, 95% CI: 0.04-0.83; P=0.03). Additionally, patients who had no/short delay before starting maintenance experienced a longer median duration of maintenance treatment (blina arm, 548 days; chemo arm, 708 days) compared to patients who had a long delay (blina arm 488 days; chemo arm 598 days) before initiation of maintenance (P=0.0008). Conclusion: In the phase 3 randomized ECOG-ACRIN E1910 clinical trial, long delays between initiation of consolidation therapy and start of maintenance therapy were associated with improved OS compared to no/short delays. However, within each treatment group (blina or chemo), no significant difference of OS was observed. We postulate that these longer delays allowed more patients to receive all of the recommended protocol-assigned therapy thereby resulting in improved survival. Furthermore, patients who had no/short delays had a significantly longer duration of maintenance therapy. These data indicate that treatment delays during consolidation do not worsen survival. Further studies are being done to better understand why patients with long delays had better overall survival.

Abstract Background We performed a prospective study evaluating a baseline GA battery and clinical outcomes in fit older adults (age ≥60 years) with AML and normal cardiac and renal function in the recent E-A NCTN E2906 phase 3 study. A patient-reported outcomes (PRO) assessment of Depression, Activities of Daily Living (ADL), Cognitive Function, Social Support (SS) domains, and comorbidity was performed at study registration to evaluate the prevalence of vulnerabilities and their impact on overall survival (OS) and 30-day induction mortality rates (IM) in this cohort selected for fitness to receive IC. Methods E2906 study design and results have been presented previously [n=727, age ≥60 years, randomized 1:1 to ‘standard 7&3‘ & high dose cytarabine (Arm A) vs. single agent clofarabine (CLO, Arm B), as remission induction (Step 1) and consolidation (Step 2)]. There was no difference in composite complete remission (CCR, 50%) or IM (8.5%), and CLO was inferior for OS. A baseline GA was a key secondary protocol objective, offered to all patients, and n=532 (73%) participated. We assessed Geriatric Depression Scale (GDS, none vs. any depressive symptoms, n=524); cognitive screen using Mini-Mental Exam Section (MMES, score 8/8 vs. <8, n=516); ADL & Instrumental ADL (iADL), (need for assistances vs. not n=526); a Medical Outcomes Study SS Survey (MOS-SS, measured as per unit increase, n=527); a Comorbidity survey ( ≤4 vs. ≥5 patient-reported comorbidities, n=530), patient-reported prescription medications use (PM, 0-3 vs. ≥4, n=519); and a survey of Sexual Desire (n=491) and Sexual Activity (n=477) within 4 weeks of AML diagnosis. Association of GA domains with OS, IM, and achievement of CCR was evaluated using the Chi-squared, Fisher's exact, and Wilcoxon rank sum test. Survival analysis was performed using the Cox proportional hazards models, adjusted for treatment arm. All p-values are 2-sided. Results The median age among those participating in GA battery was 67 yrs (range 60-85), including 38% age ≥70. There were 42% females, and ECOG performance status was 0 (28%), 1 (54%), 2 (16%), or 3 (2%). Central Cytogenetic review was classified (ELN2017) as Favorable (3%), Intermediate (66%), and Adverse (31%) risk. There was a notable rate of GA scores outside ‘normal’ clinical cutoff, including Depression (GDS 31%), cognitive and functional impairment [MMSE (37%), ADL (25%) and iADL (32%)], ≥5 Comorbidities (23%), and ≥4 PM's (44%). 81% & 76%, respectively, reported no sexual activity and low/none sexual desire. MOS-SS tended to be high in this cohort [mean (SD) score 87 (17)]. We observed a significant association of GA domains with OS & IM. For OS, absence of depressive symptoms [GDS, Hazard Ratio (HR) 0.79, 95% confidence Intervals (CI) 0.64-0.97, p=0.025)], MMES 8/8 (HR 0.78, 95%CI 0.64-0.96, p=0.016), requiring no assistance with ADLs (HR 0.65, 95%CI 0.52-0.82, p<0.001) and iADLs (HR 0.69, 95%CI 0.57-0.85, p<0.001), and ≤4 Comorbidities (HR 0.68, 95%CI 0.54-0.84, p=0.001) were significant for superior OS; use of ≥4 PM's was associated with inferior OS (HR 1.32, 95%CI 1.09-1.61, p=0.005). There was no association of sexual activity/desire, BMI ≥30 kg/m2, or MOS-SS with OS. IM was significantly higher among those with any depression symptoms (GDS, p=0.005), any ADL (p=0.010) or iADL (p=0.013) impairment, ≥5 comorbidities (p=0.037) and ≥4 PM's (p=0.001); there was no association with MOS-SS or MMES. There was no significant association of GA scores with cytogenetic risk group or with CCR rates. Only ADL independence (p=0.048), and possibly Comorbidity ≤4 (p=0.071), were associated with proceeding to Step 2. Conclusions In this large prospective cohort of fit older adults with AML selected to receive IC, we observed high rates of PRO-assessed GA vulnerability, which was significantly associated with inferior OS and higher IM rates, and (for ADL impairment) lower rates of proceeding to consolidation therapy. This suggests that functional and cognitive impairments are prevalent and can significantly impact outcome even in fit older adults. Despite potential long-term OS advantages of IC previously observed in E2906, efforts to systematically recognize those at higher risk based on GA PROs are needed to help identify patients who may be more appropriate for study of lower intensity treatment options to mitigate impact on IM and OS. SImilarly we plan to evaluate the potential benefit of GA-driven supportive care to improve patients' outcomes.

Abstract Background: Population registries and the Alliance co-operative group database have highlighted racial disparities in AML survival attributed to differential prevalence and impact of oncogenic drivers on disease biology. However, the small number of Black patients with well-annotated genomic profiles limits the validity of these findings. The current study leverages ECOG-ACRIN cytogenetic and outcomes data from newly diagnosed adult AML patients treated on intensive chemotherapy-based clinical trials over three decades. Methods: Self-reported race was categorized as White, Black or Other. Descriptive statistics were used to summarize baseline characteristics using the Wilcoxon rank-sum and Fisher's exact tests. Multivariable Cox proportional hazards regression models evaluated the association between race and survival outcomes adjusting for age, hemoglobin, platelet count, white blood cell count, blast percentage, performance status and ELN cytogenetic risk score (RS). All Cox models were stratified by protocol. Subgroup analyses of overall survival (OS) and disease-free survival (DFS) were performed using Kaplan-Meier curves stratified by race using log-rank tests. All statistical tests were two-sided. Analyses included only patients with complete data for the variables of interest. Results: Data was collected across 10 phase II and III interventional trials for newly diagnosed adult AML that accrued patients between 1984 and 2019. The study population included 3469 White, 184 Black, and 156 Other patients with a Black representation of 1.1-11% across trials. Blacks were significantly younger at diagnosis with a median age of 47.9 years compared to 53.5 years in Whites (p<0.001). Racial groups were well matched for gender and performance status. Black race was an independent prognostic factor for inferior OS (HR 1.212, CI 1.01 – 1.453; p = 0.0383) and DFS (HR 1.313, CI 1.05-1.641; p = 0.017). Complete cytogenetic results were available for 117 Black and 2162 White patients and revealed no significant racial differences in the distribution of ELN 2017 cytogenetic RS, although core binding factor AML was non-significantly enriched in Black patients (12.8% vs 8.3%). No difference was observed between Blacks and Whites in the prevalence of complex karyotype (CK), CK with -5/del(5q), -7/del(7q), or -17/del(17p), and AML-MRC including +8 and del(20q). Notably, the ELN 2017 cytogenetic RS effectively predicted OS in Black (57.8 vs 14.2 vs 5.8 months in favorable, intermediate and adverse RS, p = 0.018), and White patients (60.1 vs 15.2 vs 7.1 months, p < 0.0004 for Whites) but only predicted DFS for White AML patients (p < 0.0001 for Whites, p=0.48 for Blacks). In patients with molecular data for FLT3-ITD (n=1218), CEBPA (n=576), TP53 (n=572), or NPM1(n=683), no racial difference in the prevalence of these mutations was observed. However, NPM1 mutations were associated with inferior OS in Blacks compared to Whites (19.1 vs 8.9 months; p = 0.0095). Black and White AML patients had similar responses with complete remission rates of 58.2% vs 57.5%, p=0.55, and treatment tolerability with 30-day mortality of 7.1% vs 8.9%, p=0.50. However, consolidation approaches differed significantly. Among patients that underwent stem cell transplant (SCT), a significantly higher percentage of White patients received allogenic SCT compared to Blacks (48.5% versus 37.1%, p <0.01). Conclusions: This study represents one of the largest race-based comparisons of cytogenetic abnormalities and clinical outcomes in prospective trials of intensive chemotherapy in AML . Our data confirms the independent prognostic relevance of race in AML survival and validates the predictive ability of the ELN 2017 cytogenetic RS for OS across racial groups. There is ancestry-based attenuation of the survival benefit of NPM1 mutations as previously reported, underscoring the need to tailor the current treatment approach to NPM1 mutated AML based on race. The availability of NGS data limited the genomic analysis to a subset of patients. Future studies should examine the depth of treatment response incorporating MRD biomarkers and explore the effect of race on co-occurring mutations and the leukemic stem cell transcriptome to better explain the observed disparities. Finally, persistent disparities in access to allo-SCT even within the context of clinical trials reinforces the need to address diversity in the stem cell donor pool and social barriers to transplant.

Abstract Introduction Nadir bone marrow biopsies (BM Bx) are routinely performed around day 14 to assess early response to AML intensive induction therapy. The presence of residual disease prompts initiation of reinduction therapy, often with another cycle of intensive chemotherapy. Whether there are characteristics of nadir BM Bx that predict for response to intensive reinduction is unknown. To evaluate this, we analyzed data from ECOG-ACRIN clinical trials in AML of intensive induction chemotherapy with nadir biopsy information available to determine predictors of outcomes after reinduction. Methods We included patients from ECOG-ACRIN E1900 (Fernandez NEJM 2009) and arm A of E2906 (Foran ASH 2015) who received induction therapy with daunorubicin and cytarabine (7+3), had residual disease (blasts ≥5% or cellularity ≥20%) at nadir BM Bx and received reinduction chemotherapy. Nadir BM Bx characteristics that were evaluated included blast percentage and cellularity as well as both absolute and relative (percentage change, e.g. 20% to 10% = -50%) differences calculated between diagnosis and nadir for each parameter. Complete remission (CR) after reinduction therapy, disease free survival (DFS) and overall survival (OS) were outcomes for all analyses. Logistic regression models were used to evaluate associations with CR, and Cox proportional hazards models were used for DFS and OS. For models evaluating changes in blast percentage or cellularity as predictors, baseline blast percentage or cellularity was included as a covariate, respectively. Results Of 1013 patients identified, 750 (74%) had a nadir biopsy, 233 (23%) had evidence of residual disease, received reinduction therapy, and were included in the primary analysis. The median age was 58 and 42% were female. Cytogenetic risk category (by ELN2017) was adverse in 31%, intermediate in 66% and favorable in 3%. The median nadir BM Bx blast was 30% (range 0 to +97%) and cellularity was 20% (0 to +100%). The median absolute difference in blast percentage between baseline and nadir BM Bx was -15% (-95% to +66%) with a median relative difference of -36% (-100% to +400%). After reinduction, 118 patients (52%) achieved a CR. Neither absolute difference in blast percentage (OR 0.99, 95%CI 0.98-1.00, p=0.20) nor relative difference (OR 1.00, 95%CI 0.99-1.00, p=0.33) predicted CR. There was similarly no association with DFS (HR = 1.00, 95%CI: 0.99-1.01, p=0.65) or OS (HR = 1.00, 95%CI 0.99-1.01, p=0.76). Blast reduction ≥50% similarly did not predict these outcomes. We also evaluated the impact of any reduction in blast percentage (responders) from baseline to nadir and again found no association with CR (OR 1.65, 95%CI 0.90-3.03, p=0.11). Similarly, there was no association with DFS (HR 0.74, 95%CI 0.51-1.09, p=0.13) or OS (HR 0.81, 95%CI 0.58-1.13, p=0.21) in responders vs nonresponders. No association with CR, DFS or OS were identified when performing the same analysis in intermediate and adverse cytogenetic subgroups. We found no association with CR when nadir cellularity was assessed as a continuous variable (OR 0.99, 95%CI 0.98-1.00, p=0.10) or by relative difference (OR 0.99, 95%CI 0.99-1.00, p=0.10). There was a trend towards association with absolute reduction in cellularity from baseline to nadir and CR (OR 0.99, 95%CI 0.98-1.00, p=0.06). No association was identified between relative difference in cellularity and DFS and OS, nor was there an association among cytogenetic risk subgroups with any outcome. Discussion In intensively treated patients with residual disease at nadir BM Bx (i.e. day 14) who received intensive reinduction, the likelihood of achieving a CR was not influenced by the magnitude of disease reduction nor the extent of disease at the time of nadir biopsy. Similarly, there were no nadir biopsy features that predicted DFS or OS after intensive reinduction therapy. Given alternative reinduction therapies such as hypomethylating agents and venetoclax are available, these results suggest that the decision to attempt a second intensive induction cycle following the unequivocal presence of residual disease should not be influenced by characteristics of the nadir BM Bx. Although patient-specific factors such as patient fitness may favor a switch to less intensive options, these results support consideration of intensive reinduction therapy in patients with residual disease at nadir biopsy, even without changes in blasts or cellularity.

ImportanceAcute promyelocytic leukemia (APL) is an acute illness that presents with cytopenia, infections, and disseminated intravascular coagulation. Achieving remission has been shown to make a major difference in patient outcomes; however, early death rates in the first month have been as high as 30% due to acute presentation, comorbidities, the rarity of APL, and clinician inexperience.ObjectiveTo develop treatment strategies that would decrease estimated 1-month mortality from 30% to below 15%.Design, Setting, and ParticipantsIn this nonrandomized clinical trial, a treatment algorithm that focused on supportive care was used to prevent early death in patients with APL treated at academic and community health centers between August 2017 and July 2021. Because of the rarity of the disease, expert support was available 24/7 from 7 designated APL experts at 6 participating academic lead centers, and included an additional 293 community centers. When a patient presented with APL, an expert was contacted and a consensus treatment plan was developed using the algorithm and expert suggestions. There were no exclusion criteria and all patients with a confirmed diagnosis of APL regardless of age or comorbid conditions were enrolled. Expert support was provided throughout induction. Initial data analysis was conducted May 2023.Main Outcomes and MeasuresOne-month mortality; additional objectives were to compare outcomes in academic and community centers and assess 1-year and overall survival.ResultsA total of 201 patients were enrolled from 43 centers; 62 at lead centers and 139 from 37 community centers. The median age was 53 years (range, 18-91 years), with 72 patients (35.8%) who were aged 60 years or older; 105 patients (52.2%) were male. Fifty-two patients (26.4%) were diagnosed with high-risk APL. The 1-month mortality rate was 6 deaths of 201 patients (3.0%; 95% CI, 1.1%-6.4%) after adjusting for 1 interim analysis. In a secondary analysis using the Kaplan-Meier method, the 1-month overall survival (OS) rate was 97.0% (95% CI, 93.5%-98.6%) and the 1-year OS rate was 94.5% (95% CI, 90.3%-96.9%).Conclusions and RelevanceIn this nonrandomized clinical trial, use of an algorithm combined with expert support resulted in a dramatic decrease in early death in academic and community centers. Population-wide survival improved in this highly curable disease, which suggests that implementing an accessible support system with APL experts for comanagement is the most logical next step.Trial RegistrationClinicalTrials.gov Identifier: NCT03253848