Transplantation In First Complete Remission Research Articles

Measurable Residual Disease Monitoring in AML With FLT3-ITD Treated With Intensive Chemotherapy Plus Midostaurin

Measurable residual disease (MRD) monitoring in acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITDpos) was hampered by the broad heterogeneity of ITD mutations. Using our recently developed FLT3-ITD paired-end next-generation sequencing (NGS)-based MRD assay with a limit of detection of 10-4 to 10-5, we evaluated the prognostic impact of MRD at different time-points in 157 FLT3-ITDpos AML patients enrolled in the AMLSG16-10 trial (NCT01477606) combining intensive chemotherapy with midostaurin followed by midostaurin maintenance. Achievement of MRD negativity (MRDneg) after two cycles of chemotherapy (Cy2) observed in 111/142 (78%) patients predicted for superior 4-year rates of cumulative incidence of relapse (CIR) (4y-CIR, 26% vs 46%; P=.001) and overall survival (OS) (4y-OS, 70% vs 44%; P=.012). This survival advantage was also seen for patients undergoing allogeneic hematopoietic-cell transplantation in first complete remission (4y-CIR, 14% vs 39%; P=.001; 4y-OS, 71% vs 49%; P=.029). Multivariate models for CIR and OS after Cy2 revealed FLT3-ITD MRDneg as the only consistent favorable variable for CIR (HR, 0.29; P=.006) and OS (HR, 0.39; P=.018). NPM1 co-mutation correlated with deeper molecular response as reflected by stronger MRD reduction and higher rate of FLT3-ITD MRDneg after Cy2. During follow-up, conversion from MRDneg to MRDpos was a strong, independent factor for inferior CIR (HR, 16.64; P<.001) and OS (HR, 4.05; P<.001). NGS-based FLT3-ITD MRD monitoring allows for the identification of patients at high risk of relapse and death following intensive chemotherapy plus midostaurin. Using NGS-based technology, FLT3-ITD emerges as a novel, clinically highly relevant target for MRD monitoring.

Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study

Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients.

Postinduction molecular MRD identifies patients with NPM1 AML who benefit from allogeneic transplant in first remission

AbstractSelection of patients with NPM1-mutated acute myeloid leukemia (AML) for allogeneic transplant in first complete remission (CR1-allo) remains controversial because of a lack of robust data. Consequently, some centers consider baseline FLT3–internal tandem duplication (ITD) an indication for transplant, and others rely on measurable residual disease (MRD) status. Using prospective data from the United Kingdom National Cancer Research Institute AML17 and AML19 studies, we examined the impact of CR1-allo according to peripheral blood NPM1 MRD status measured by quantitative reverse transcription polymerase chain reaction after 2 courses of induction chemotherapy. Of 737 patients achieving remission, MRD was positive in 19%. CR1-allo was performed in 46% of MRD+ and 17% of MRD− patients. We observed significant heterogeneity of overall survival (OS) benefit from CR1-allo according to MRD status, with substantial OS advantage for MRD+ patients (3-year OS with CR1-allo vs without: 61% vs 24%; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.24-0.64; P < .001) but no benefit for MRD− patients (3-year OS with CR1-allo vs without: 79% vs 82%; HR, 0.82; 95% CI, 0.50-1.33; P = .4). Restricting analysis to patients with coexisting FLT3-ITD, again CR1-allo only improved OS for MRD+ patients (3-year OS, 45% vs 18%; compared with 83% vs 76% if MRD-); no interaction with FLT3 allelic ratio was observed. Postinduction molecular MRD reliably identifies those patients who benefit from allogeneic transplant in first remission. The AML17 and AML19 trials were registered at www.isrctn.com as #ISRCTN55675535 and #ISRCTN78449203, respectively.

Mixed Phenotypic Acute Leukemia -Clinical Presentation, Prognosis and Outcomes of Patients Treated with Acute Lymphoblastic Leukemia like Protocols a Multi-Institutional Study from India

Mixed phenotypic acute leukemia (MPAL) is a rare and difficult to treat type of acute leukemia. Broad consensus favour use of acute lymphoblastic leukemia (ALL) like treatment protocols in the management of MPAL. Data regarding this rare diagnosis is limited mainly to retrospective studies and limited data available from low middle income countries (LMIC). We report epidemiology and real-world outcome data of MPAL patients treated with ALL like protocols among the multi-institutional data base set up by hematology cancer consortium (HCC) in India. In this retrospective multicentric study of a prospectively maintained data set, we collected data from eleven member centers of HCC using an electronic database. Patients who fulfilled the WHO 2016 classification criteria for MPAL were included. Patients diagnosed between January 2018 and March 2022 were included in the study. The data included demographic details, performance status (ECOG), comorbidities, CNS involvement, testicular involvement, presence of mediastinal mass, phenotype of MPAL (B+M, T+M, T+B), karyotype, FISH, PCR and NGS abnormalities. If treatment was not received by patients the reasons were also captured. We also evaluated the treatment protocol used and use of tyrosine kinase inhibitors. The primary objective was to evaluate event-free survival (EFS) and overall survival (OS) at 1year. The impact of the treatment protocol used, age, baseline WBC count, LDH, performance status, CNS involvement on EFS and OS were studied. A total of 114 patients were diagnosed to have MPAL during the study period. The baseline epidemiological features are tabulated in table-1. Sixty-six (58%) patients were treated with ALL like treatment protocols and 48(42%) patients did not receive any treatment due to various reasons at HCC centers. 49(74%) patients received paediatric inspired protocols and 17(26%) patients received adult-type of protocols. Forty three (65%) patients achieved a complete remission after induction. Ten(15%) patients died during induction. Six(9%) patients died after achieving CR of which 3 died due to infection,3 died due to progressive disease and rest were lost to follow up. Minimal residual disease (MRD) done using either flowcytometry or PCR was available in 37 patients. MRD negative status was achieved in 17(46%) patients post phase II of induction. After a median follow up of 12 months, EFS was 61% and OS was 67%(figure1). Estimated EFS and OS at 24 months were 42% and 55% respectively. There were no significant differences in EFS and OS between different MPAL phenotypes. Allogeneic stem cell transplant (ASCT) was performed only in 3 patients. Negative MRD status at the end of second phase of induction was significantly associated with improved EFS with a Hazard ratio of 0.349(CI-0.117-1.036). Age, cytogenetic profile, LDH, baseline WBC count and CNS involvement were analyzed by univariate analysis for effect on treatment outcomes. There was no significant effect of these variables on both EFS and OS. Our study is one of the largest studies conducted on MPAL patients in a resource limited setting. If patients received treatment, the outcomes were encouraging despite poor access to allogeneic stem cell transplant in first complete remission, when compared with similar real world multi-institutional analysis. Induction mortality of 10% was comparable to other similar studies. However, the worse 2-year EFS and OS may be explained by poor rates of allogeneic stem cell transplant (Allo-HSCT). The abandonment of treatment and limited use of Allo-HSCT in first complete remission were major limitations in improving overall outcomes in our patients.

Phase II Study on Venetoclax (Ven) Plus Decitabine (Dec) (Ven-Dec) for Elderly (≥60 &amp;lt;75years) Patients with Newly Diagnosed High-Intermediate Risk Acute Myeloid Leukemia (AML) Elegible for Allogeneic Stem Cell Transplantation: Final Report of Ven DEC GITMO Study

Background Allogeneic stem cell transplantation (allo-SCT) is widely regarded as the most effective consolidation treatment for patients with intermediate to high-risk ELN AML. However, despite its potential curative benefits, many elderly patients (aged ≥60) are unable to undergo this procedure due to comorbidities and/or inability to tolerate intensive chemotherapy and achieve a complete remission (CR). As a result, only a small proportion of these patients are able to benefit from allo-SCT. Aims The VEN-DEC GITMO trial is a prospective, multicenter, single arm, phase II study designed to assess the safety and efficacy of a “chemo-free” combination of Venetoclax and Decitabine (VEN-DEC) as a bridge to allo-SCT in elderly patients (60-75y) with intermediate to high-risk ELN AML. The primary endpoint of the study was the percentage of patients who underwent transplant in first CR. The study aimed to enroll 100 patients, with a projected dropout rate of 12%. The study was considered successful if 14 or more patients underwent transplant in CR. Methods Venetoclax (up to 400mg oral daily) plus decitabine (20 mg/m2 for 5 days every 28 days) were administered for 2 cycles. Patients who achieved complete remission (CR), defined according to ELN criteria as CR/CRi/MLFS, were required to undergo allo-SCT within 2 months. Patients who did not respond (NR) or achieved partial remission (PR) after C2 could receive an additional 2 cycles of the therapy, in order to achieve a CR prior to transplant. Patients who did not respond or achieved only a PR were discontinued from the study and could be treated according to the policies of their respective Centers. Results Overall, 100 patients were enrolled by 25 Italian GITMO transplant Centers as of December 2022. The data cut-off was on July 17th, 2023. Table 1 provides details on the cohort's characteristics. Notably, more than 50% of patients presented with myelodysplasia-related changes and/or therapy-related AML, and 47% of cases had an abnormal karyotype. Seven patients (7%) were excluded due to screening failure. The remaining 93 patients started the 1 st cycle of treatment, and 78 patients completed the 2 nd cycle of VEN-DEC and were evaluable for treatment response. Overall, 58 patients achieved complete remission (CR/CRi/MLFS) after 2 cycles (74%), while partial or non-response occurred in 20 cases. Four out of 20 (20%) PR/NR patients at C2 achieved CR after two additional cycles of therapy for a total of 62/93 (67%). Overall 51 and 26 patients received a third and/or a fourth cycle of treatment after achieving CR after cycle 2 while waiting for transplant, due to logistical issues. According to the study protocol, the 1 st cycle should be administered inpatient in all patients. C2, C3, and C4 were given outpatient in 79%, 93%, and 85% of cases, respectively. The median time to response was 65 days (range, 49-175). Overall, 38 (41%) patients were discontinued before transplant (7 cases for complications while on CR). A total of 19/93 (20%) patients died before transplant. At the data cut-off, 51/93 (55%) treated patients and 51/62 CRs (82%) had successfully undergone allo-SCT. Figure 1 illustrates the course of study treatment. A total of 139 grade ≥2 adverse events were reported in 56 patients (60%). Seventy events out of 139 (50%) were considered at least possibly related to study intervention. The following hematological toxicities were observed: prolonged grade ≥2 neutropenia was recorded in 34 out of 139 cases (24%), while anemia and decreased platelet counts were recorded in 7 cases (5%) and 3 cases (2%), respectively. Febrile neutropenia and infections were observed in 22 (16%) and 31 (22%) cases, respectively. Conclusions The results of the VEN-DEC GITMO trial demonstrate that the chemo-free VEN-DEC induction/consolidation regimen was highly effective, achieving a high rate of complete remission (CR 67%). Additionally, the regimen improved the feasibility of allo-SCT, with 55% of treated patients and 82% of those who achieved CR undergoing allo-transplantation (primary endpoint). Starting from C2, the regimen was administered in an outpatient setting in 80-90% of cases, which allowed patients to maintain their fitness and bridge to transplant in CR. The regimen also had a low clinical toxicity profile, with only 7 patients achieving CR discontinuing therapy due to adverse events. Acknowledgement Monica Bonzi, Sr. Clinical Lead - IQVIA RDS, Italy.

Machine Learning Provides Individualized Prediction of Outcomes after First Complete Remission in Adult AML Patients - Results from the Harmony Platform

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with high disease-related mortality and allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for a large proportion of patients. However, allo-HSCT has a significant transplant-related mortality (TRM), so a careful evaluation between risk of disease relapse and TRM is needed for the challenging decision of whom to transplant in first complete remission (CR1). The European LeukemiaNet (ELN) provides a 3-tier static risk classification which is already a useful guidance, although dynamic risk assessment using measurable residual disease (MRD) information should also be taken into account. However, the intermediate-risk group is characterized by a wide heterogeneity and there are also some favorable-risk patients who require allo-HSCT because of early relapses after CR1. Therefore, more precise prediction tools are warranted to provide additional information valuable for clinical decision-making. Aims: To develop and validate a model that provides individualized outcome estimations in adult AML patients achieving CR1 with intensive treatment approaches. Methods: From the HARMONY Platform including 7467 AML patients at the time of the analysis, we selected patients aged 18-70 years old who received intensive treatment, achieved CR and were not consolidated with allo-HSCT in CR1. Patients who were refractory to first line chemotherapy or who had a relapse-free survival (RFS) of less than two months after achieving CR were excluded. A Bayesian Additive Regression Trees (BART) nonparametric machine learning model was used to predict the individualized likelihood of RFS, cumulative incidence of relapse (CIR) and overall survival (OS) in 1863 AML patients who were also selected based on the availability of comprehensive mutational information by next-generation sequencing analysis. Genomic aberrations that were present in at least 10 patients were included in the model. In order to test the accuracy of the model, a 10-fold cross-validation was applied using the area under receiver operating curve (AUC) at predefined time points (1, 2, 3, 4 and 5 years). Subsequently, the model was validated using an external publicly available database (Tazi et al, Nat. Commun. 2022) which included 722 patients based on identical inclusion criteria. Results: The study population of 1863 adult AML patients in CR1 included 51.2% of males and median age was 50 years. Regarding ELN2022 classification, 52% of patients were classified as favorable, 30% as intermediate and 18% as adverse risk. Most frequently mutated genes were NPM1 (35.9%), DNMT3A (25.6%) and NRAS (21.6%). The HARMONY model was able to estimate individualized likelihood of RFS, CIR and OS for all patients, providing confidence intervals for all estimations. Moreover, we could predict outcomes with increased accuracy over ELN2022 at all predefined time points. At 5 years, the AUC value was significantly better for the HARMONY model than ELN2022 in predicting RFS (0.729 vs 0.679, p=0.003), CIR (0.729 vs 0.680, p=0.002) and OS (0.733 vs 0.675, p&amp;lt;0.001) ( figure 1A). Validation in an external independent AML cohort confirmed superiority of the HARMONY model in predicting RFS (5-year AUC 0.714 vs 0.609, p &amp;lt;0.001), CIR (0.713 vs 0.610, p &amp;lt;0.001) and OS (0.737 vs 0.638, p &amp;lt;0.001) as compared to the ELN2022 risk stratification ( figure 1B), despite the fact that there was a different distribution of risk categories (28% favorable, 45% intermediate and 27% adverse risk). Conclusions: Analysis of large well-defined AML cohorts allows the development of increasingly precise predictive models for clinically relevant scenarios. The HARMONY machine learning model provides individualized outcome prediction for patients aged 18-70 years in CR1 consolidated without allo-HSCT and might be used in the future for clinical decision-making. The model can be accessed online via an interactive web calculator () and, while it has been validated using a large independent AML cohort, future studies are required focusing on prospective validation. Furthermore, the incorporation of additional variables such as MRD and the inclusion of patients treated with targeted therapies and non-intensive approaches will provide more accurate risk predictions.

Blastic plasmacytoid dendritic cell neoplasm: a comprehensive review in pediatrics, adolescents, and young adults (AYA) and an update of novel therapies.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that can involve the bone marrow, peripheral blood, skin, lymph nodes, and the central nervous system. Though more common in older adults, BPDCN has been reported across all age groups, including infants and children. The incidence of pediatric BPDCN is extremely low and little is known about the disease. Pediatric BPDCN is believed to be clinically less aggressive but often with more dissemination at presentation than adult cases. Unlike adults who almost always proceed to a hematopoietic stem cell transplantation in first complete remission if transplant-eligible, the majority of children can be cured with a high-risk acute lymphoblastic leukemia-like regimen. Hematopoietic stem cell transplantation is recommended for children with high-risk disease, the definition of which continues to evolve, or those in relapse and refractory settings where outcomes continue to be dismal. Novel agents used in other hematologic malignancies and CD123 targeted agents, including chimeric antigen receptor T-cells and monoclonal/bispecific antibodies, are being brought into research and practice. Our goal is to provide a comprehensive review of presentation, diagnosis, and treatment by review of pediatric cases reported for the last 20 years, and a review of novel targeted therapies and therapies under investigation for adult and pediatric patients.

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.

A Retrospective Analysis of Autologous Stem Cell Transplantation Outcomes in Adult Philadelphia Chromosome Positive-Acute Lymphoblastic Leukemia

Abstract Introduction Philadelphia chromosome positivity (Ph + ) is a poor prognostic feature in adult acute lymphoblastic leukemia (ALL). Allogenic hematopoietic stem cell transplantation in first complete remission (CR1) is recommended. There is limited literature on the role of consolidation autologous stem cell transplantation (ASCT). This study was undertaken to assess the potential of consolidation ASCT in CR1 in adults with Ph + ALL. Objectives The aim of this study was to analyze the safety and efficacy of ASCT in CR1 in adults with Ph + ALL. Materials and Methods Adult patients diagnosed with Ph + ALL who underwent ASCT in CR1 after modified ALL-BFM95 protocol from 2015 to 2017 were included. Patients who achieved major molecular response or better were considered for ASCT with cyclophosphamide-total body irradiation regimen and peripheral blood stem cells infused on day 0. Toxicities as per Common Terminology Criteria for Adverse Event v4.0, disease-free survival (DFS), and overall survival (OS) were assessed. Inclusion criteria: Following patients were included—patients aged 18 years and above diagnosed with Ph + ALL; patients receiving BFM-95 induction chemotherapy protocol; patients who achieved CR after induction therapy; nonavailability of human leukocyte antigen match from a matched sibling donor or matched unrelated donor. Exclusion criteria: Patients not willing or unfit for ASCT and patients planned for allogenic hematopoietic stem cell transplantation were excluded. Results Six adult patients with Ph + ALL underwent ASCT in CR1 (median age: 23 [range: 19–36] years, five patients were males [83%]). Imatinib was started at a median of 11 days from the start of induction IA (range: 10–21). Five patients achieved morphological CR after induction 1A and, one patient at the end of induction 1B. The median time to ASCT (from diagnosis) was 8 months (range: 6.4–13). All the six patients had disease relapse and died due to progressive ALL. The median DFS and OS were 19.2 months and 23.3 months, respectively. Conclusion Consolidation ASCT yielded poor outcomes in this study. There was a significant delay from diagnosis to ASCT, which might have impacted the results.

Incorporation of Nelarabine (NEL), Pegylated Asparaginase (PEG) and Venetoclax (VEN) in the Frontline Therapy of Adult Patients with T-Acute Lymphoblastic Leukemia/T-Lymphoblastic Lymphoma (T-ALL/LBL)

Background: NEL is effective for patients (pts) with relapsed T-ALL/LBL, but its incorporation into the front-line therapy has not been investigated extensively in the adult population. In children, the addition of NEL to the induction regimen has shown to improve disease-free survival (DFS) but not the overall survival (OS). VEN has shown preclinical and clinical activity in relapsed T-ALL/LBL. We investigated the addition of NEL and PEG to the hyper-CVAD (HCVAD) regimen in adult pts with T-ALL/LBL. Further on, we explored the safety and efficacy of adding VEN to this regimen. Methods: Pts with previously untreated or minimally pre-treated T-ALL/LBL were eligible if they had an ECOG PS ≤3, creatinine ≤ 2 mg/dL, total bilirubin ≤ 2 mg/dL and ALT/AST ≤ 4 x ULN. Pts received 8 cycles of HCVAD (cycles 1,3, 5, 7) alternating with high dose ara-C and methotrexate (MTX) (cycles 2, 4, 6, 8) at approximately 3-week intervals. Two cycles of NEL (650 mg/m2 daily x 5) were initially administered after cycle 8 (cohort 1). Later, after a protocol amendment, they were administered after cycle 4 and cycle 5 (cohort 2). Subsequently, the protocol was amended to add PEG (1500 IU/m2 capped at 3750 IU) on day 5 of the NEL cycles (cohort 3) and more recently, VEN 400 mg daily was added on the first 7 days of each of 8th cycle of therapy (cohort 4) and this was later modified to be given for 7 days during the induction cycle and reduced to 3 days per cycle post-induction only in pts with ETP-ALL or those with persistent MRD. All other pts did not receive VEN after cycle 1 (cohort 5). Pts with ETP-ALL were referred for allogeneic stem cell transplant in first complete remission (CR). After the completion of the intensive phase, pts in all cohorts received 30 cycles of maintenance therapy with monthly POMP and early intensification with NEL/PEG on cycles 6 and 7 and late intensification with MTX/PEG in cycle 18 and HCVAD on cycle 19. All pts received 8 intrathecal chemotherapy with MTX alternating with ara-C and mediastinal radiation was considered in pts with bulky mediastinal disease. Results: Between 8/2007 and 6/2022, 128 pts were enrolled in the 5 study cohorts sequentially (cohort 1= 30, 2= 49, 3=17, 4=16, 5=16) (Table). Seventy-seven pts had T-ALL, 50 T-LBL and 1 biphenotypic T/myeloid leukemia. Median age was 35 yrs. (range 18-78), 98 pts were male (77%) and 110 pts (86%) had PS 0-1. In pts with T-ALL, median bone marrow blast percentage was 83% (range, 20-97) Six pts (5%) had CNS disease at presentation. Cytogenetics were diploid in 82 pts (64%), abnormal in 36 (28%), and unavailable in 10 pts (8%). Pts were further characterized as early T-cell precursor (ETP; n=24), near ETP (ETP + CD5) (N=19), early-non-ETP (n=3), thymic (n=54), mature (n=12), not otherwise specified (NOS; n=16). Twenty-five pts had received 1-2 cycles of therapy prior to enrollment, with 18 having achieved CR. The 30-day mortality was 0%. One hundred and twelve pts (88%) had ≥ 1 grade 3/4 non-hematological treatment-emergent adverse events (TEAE) with the most frequent grade 3/4 TEAEs being neutropenic infections in 96 pts (75%) and elevated liver enzymes in 25 pts (20%). The overall response rate (CR/CRi/PR) was 98% with CR/CRp in 120/128 pts (94%), PR in 5 (4%), and no response in 3 (2%). The median number of cycles to response (including a negative PET scans) was 1 (range 1-10). CR/CRp rate in T-ALL was 91% and T-LBL was 98%. At a median follow-up of 50 months (1-174), 84 patients (66%) are alive with a 5-year PFS and OS of 60% and 61% (Figure 1) and 79 pts (62%) remain in CR. Conclusion: The addition of NEL/PEG cycles to the HCVAD regimen is feasible. The addition of VEN to each cycle is associated with significant myelosuppression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Regularized Mixture Cure Models Identify a Gene Signature That Improves Risk Stratification within the Favorable-Risk Group in 2017 European Leukemianet (ELN) Classification of Acute Myeloid Leukemia (Alliance 152010)

Introduction: The 2017 ELN Favorable-risk group comprises specific recurrent cytogenetic and molecular alterations. Assignment to this group has important clinical implications, as allogeneic stem cell transplantation in first complete remission (CR) is not advised due to a relatively good outcome of patients (pts) receiving chemotherapy and transplant-associated mortality. However, not all Favorable-risk pts experience long-term survival and their outcomes are affected by co-occurring genetic features making recognition of pts who would most likely be cured of high importance. Thus, we used our regularized mixture cure model (MCM) that embeds false discovery rate control to identify prognostically relevant transcripts that can distinguish pts cured from pts susceptible to lower- or higher-risk of relapse. Methods: We analyzed 312 pts <60 years with de novo AML classified in the 2017 ELN Favorable-risk group excluding APL who achieved a CR, had RNA-seq data available, and treated on one of 8 CALGB/Alliance frontline protocols with intensive 7+3-based induction chemotherapy. No pt received an allogeneic stem cell transplant in first CR. MCMs assume the population consists of 2 subgroups, cured and susceptible, thus there are 2 regression components, which permit identification of features associated with cure and/or latency of susceptible pts. 'Cured' is synonymous with attaining long-term relapse-free survival and thus pts have a survival probability of 1. We fit univariable MCMs to identify baseline demographic, clinical features, or selected gene mutations related to the probability of being cured and/or to the latency distribution (time to relapse). RNA-seq expression values were candidate covariates in a regularized MCM to identify a parsimonious list of transcripts associated with cure or latency. We then used 2017 ELN Favorable pts in an independent dataset (GSE37642) for validation. Results: The estimated proportion cured (39.5%) was significant (P < 0.001) indicating that a MCM should be fit. Other than % of bone marrow blasts (P = 0.009) and % of blood blasts (P = 0.048), no other pretreatment features were significant in univariable MCMs. CEBPAdouble and TET2 mutations were the only ones significantly associated with latency (P = 0.008 and P = 0.013, respectively), but neither was associated with cure (P = 0.881 and P = 0.507, respectively). Our regularized MCM identified 101 transcripts associated with cure and 71 transcripts associated with latency. Kaplan-Meier curves of cured vs susceptible pts as well as of those susceptible with lower vs higher risk of relapse or death were well separated. We mapped the 168 unique transcripts to GSE37642 Affymetrix HG-U133Plus2 GeneChip for validation and found that 65 cure-related probe sets and 57 latency probe sets mapped to 34 and 32 unique genes, respectively. The validation data yielded AUC=0.788 and C-statistic=0.887, indicating good predictive ability of the selected genes. As desired, the predicted cured group had a survival probability of 1 throughout the observation period (Fig 1), with good separation between predicted susceptibles in the lower- versus higher-risk groups (Fig 2). Cell death and survival was the top molecular/cellular function for both the cure and latency portions of the model with 22 and 20 transcripts involved, respectively, with only BRD2, HLA-A, HLA-B, NAIP, and TXNIP in common. Cell death and survival molecules unique to the latency portion of the model included CD300A, CRNDE, DDX39B, FAS, GPI, HLA-DRA, KLF13, LAT, let-7, LMO2, LSP1, NOTCH1, PLCG2, PSMB8, and U2AF1; those unique to the cure portion included ARID5B, BAG6, BMI1, CCL5, CDK7, DPPA4, ELOVL5, HLA-DRB1, IL18, INTS6, MAP4K4, mir-25, mir-491, NOMO1, NR1H3, RPS16, and TUBB. Conclusion: Our regularized MCM identified important subsets of genes associated with cure and latency in the 2017 ELN Favorable-risk pts. Our results suggest that the Favorable-risk group includes distinct transcriptionally defined subgroups with different biological properties, which may be useful for refining this risk category by identification of pts who might be cured with chemotherapy alone. Given similar treatment with 7+3-based cytotoxic chemotherapy, the identified subgroups (cured, susceptible lower risk, susceptible higher risk) seem to have different sensitivities to 7+3-based therapy. Support: R01LM013879, U10CA180821, U10CA180882, U24CA196171 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of High-Dose Cytarabine Induction Therapy and Flow Cytometric Measurable Residual Disease Monitoring for Children with De Novo Acute Myeloid Leukemia: A Report from the JPLSG-AML-12 Trial

Background: High-dose cytarabine (HDAC) in initial induction therapy has been tested in several clinical trials both in children and adults with acute myeloid leukemia (AML), however, the trial results are conflicting. In addition, there is growing evidence on significance of measurable residual disease (MRD) monitoring to predict subsequent relapse, but MRD in AML is still challenging in terms of methodology and quality control. In the nationwide clinical trial AML-12 by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), the hematological malignancy subgroup of the Japan Children's Cancer Group (JCCG), a role of HDAC in initial induction and feasibility and efficacy of central reference laboratory-based flow cytometric MRD (FCM-MRD) monitoring were evaluated in children with AML. Patients & Methods: JPLSG-AML-12 trial (registered as jRCTs041180128) was designed as a seamless phase II/III trial; because of a safety concern in HDAC induction, children (0-18 years old) with newly diagnosed de novo AML (excluding acute promyelocytic leukemia and AML in Down syndrome patients) registered in selected institutions were randomized to receive either standard ECM (etoposide, standard-dose cytarabine, and mitoxantrone) or experimental HD-ECM (etoposide, HDAC, and mitoxantrone) induction, while patients registered in non-selected institutions were non-randomly allocated to receive standard ECM; in the following phase III part, all the patients were randomized. FCM-MRD were measured at two time points [end of Induction-1 (EOI-1) and end of Induction-2 (EOI-2)] at either of the two central reference laboratories (Mie University or Kyoto University) but was not used to guide subsequent therapies. Following complete remission (CR) evaluation at EOI-2, patients achieving CR were allocated to either of the 3 risk groups and received post-remission chemotherapies; core-binding-factor standard risk (CBF SR), non-CBF SR, or high risk (HR) group. Only HR patients were allocated to receive allogeneic hematopoietic stem cell transplantation in first CR. Primary endpoints of the trial were 3-year EFS and positive FCM-MRD (≥0.1%) rate at EOI-1. Results: Total 359 eligible patients were registered at 102 institutions between 2014-2018. CR, 3-year EFS, and 3-year OS rates of all patients were 94.0%, 63.1% (95%CI, 57.9-67.9%), and 80.3% (95%CI, 75.8-84.1%), respectively. Among all, 324 patients were randomized (ECM, n=168; HD-ECM, n=156). Median follow-up period of these patients was 50.9 months (range, 0.2 - 84.7 months). No significant difference in outcomes were observed between the 2 arms; CR rates were 94.2% vs. 93.8% (p=0.998), 3-year EFS rates were 64.3% (95%CI, 56.5-71.0%) vs. 61.2% (53.1-68.4%) (p=0.551), 3-year OS rates were 84.4% (95%CI, 78.0-89.1%) vs. 75.3% (95%CI, 67.7-81.4%) (p=0.053), 3-year cumulative incidence of relapse were 28.6% (95%CI, 21.5-36.0%) vs. 30.9% (95%CI, 23.3-38.8%) (p=0.585), and 3-year non-relapse mortality rates were 0.9% (95%CI, 0.1-6.4%) vs. 1.8% (95%CI, 0.4-7.1%) (p=0.832). These outcome parameters were not different within each risk groups as well. FCM-MRD at EOI-1 was evaluated in 135 patients (80.4%) in the ECM arm and 127 patients (81.4%) in the HD-ECM arm; the positive FCM-MRD rates were 21.5% vs. 25.2% (p=0.575). Regarding grade 3 or higher adverse events (AEs) evaluated by CTCAE version 4 during Induction-1, disseminated intravascular coagulation was more frequent in the HD-ECM arm (1.8% vs. 6.4%, p=0.046), but no significant difference was observed for other AEs. Univariable Cox regression analysis for baseline characteristics revealed that the intermediate-risk cytogenetics and positive FLT3-ITD were significantly associated with decreased EFS rate. However, in multivariable analyses for EFS after EOI-1 and EOI-2, FCM-MRD was the sole poor prognostic factor; hazard ratios were 5.24 (95%CI, 3.19-8.63) (p<0.001) at EOI-1 and 5.56 (95%CI, 2.93-10.54) (p<0.001) at EOI-2. Conclusions: Although HDAC in initial induction did not improve the outcome of children with AML, overall outcomes were comparable to the recently completed pediatric AML trials worldwide. Central reference laboratory-based FCM-MRD measurement was feasible and MRD at both EOI-1 and EOI-2 were the most powerful prognostic factors to predict outcome of children with AML. Therefore, FCM-MRD should be included in future risk stratification for children with AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Timing of Autologous Hematopoietic Cell Transplantation in Primary Central Nervous System Lymphoma: A University of California Hematologic Malignancies Consortium Retrospective Analysis

Background: Primary central nervous system lymphoma (PCNSL) is potentially curable when high-dose methotrexate-based induction is followed with intensive consolidation, which can consist of non-myeloablative chemotherapy (NMA-C) or myeloablative chemotherapy (MAC) followed by autologous hematopoietic cell transplantation (autoHCT). Although the efficacy of autoHCT has been demonstrated, very limited data is available regarding the optimal timing of autoHCT, i.e., to transplant in first complete remission (CR1) or second or later CR (CR2+). Moreover, the choice of consolidation differs between centers. Recently, the CALGB 51101 trial showed that MAC leads to improved progression-free survival (PFS) compared to NMA-C, but limiting this finding are that more patients who were randomized to receive NMA-C went off treatment prior to consolidation, either as a result of progression or death. To clarify the optimal timing of autoHCT in PCNSL and to support the findings of the CALGB 51101 trial, we conducted a multi-center retrospective analysis. Methods: We retrospectively analyzed patients ≥18 years treated at the University of California campuses in Davis, Fresno, Irvine, and Los Angeles who were diagnosed between January 2005-July 2021. Patients were divided into three cohorts: cohort A included those who underwent autoHCT in CR1, cohort B included those who underwent autoHCT in CR2+, and cohort C included those who underwent NMA-C in CR1 (irrespective of whether or not they underwent autoHCT in CR2+). In the first set of analyses, outcomes were compared between cohort A and B, and in the second set, outcomes were compared between cohort A and C. CR was defined by the lack of enhancement on magnetic resonance imaging. Patients in cohort A and B who were not in CR at the time of autoHCT, and those in cohort C not in CR at the time of NMA-C, were excluded. The primary endpoint was 2-year overall survival (OS), and secondary endpoints were 2-year progression-free survival (PFS), non-relapse mortality (NRM) and cumulative incidence of relapse (CIR). Time-to-event analyses were conducted using the Kaplan-Meier method and were compared by a log-rank test. NRM and CIR were calculated through a competing risk model, with NRM serving as a competing risk for CIR and vice versa. Univariate analyses were performed via Cox proportional hazards model. Patients alive at the end of the study were censored at their last follow-up date. Results: 69 unique patients were included, and their baseline characteristics are described in Table 1. 36 patients were included in cohort A, 10 in cohort B, and 28 in cohort C, 5 of whom underwent autoHCT in CR2+. The median follow-up times of cohorts A, B, and C were 67, 73, and 52 months, respectively. The 2-year OS from the time of diagnosis in cohort A was 94.3% (95% CI, 86.9-100) vs 90.0% (95% CI, 73.2-100) in cohort B (P=0.42), and 84.0% (95% CI, 70.7-99.8) in cohort C (P=0.072). The 2-year PFS from the time of transplant in cohorts A vs B were 91.2% (95% CI, 82.2-100) vs 67.5 (95% CI, 43-100) (P=0.008). The 2-year PFS from the time of diagnosis in cohorts A vs C were 91.4% (95% CI, 82.6-100) vs. 80.5% (95% CI, 66.4-97.6) (P=0.0016) (Figure 1). The 2-year NRM and CIR for cohorts A vs B were 5.8% vs 21.2% (P=0.179) and 2.9% vs 11.3% (P=0.037), respectively. The 2-year NRM and CIR for cohorts A vs C were 5.8% vs 3.6% (P=0.74) and 2.9% vs 16.0% (P<0.001) respectively. Univariate analyses including all 69 unique patients were performed for OS and PFS, and there were no significant associations based on age <60 vs ≥60 years, gender, ECOG performance status ≤1 vs ≥2, center of origin, and thiotepa/busulfan/cyclophosphamide (TBC) vs thiotepa/carmustine (TT-BCNU) conditioning. Conclusion: Although limited by the sample size and retrospective nature, whether autoHCT for PCNSL was performed in CR1 or CR2+ did not impact OS in our analysis, but CIR was higher and PFS was lower when autoHCT was performed in CR2+. Supporting the Alliance trial, autoHCT in CR1 produced longer PFS than NMA-C and patients deemed appropriate candidates for MAC consolidation in CR1 should be considered for autoHCT in this setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Allogeneic Hematopoietic Cell Transplantation in First Complete Remission in Addition to FLT3 Inhibition with Quizartinib in Acute Myeloid Leukemia with FLT3-Internal Tandem Duplication: Results from the Quantum-First Trial

Background Patients with acute myeloid leukemia (AML) exhibiting an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD+), face particularly poor outcomes, even after allogeneic hematopoietic cell transplantation (allo-HCT), which appears to only partially mitigate the poor prognosis associated with this mutation. (Döhner H et al., Blood 2017, Stone RM et al., NEJM 2017; Larson RA et al., Leukemia 2021). QuANTUM-First (NCT02668653) is a phase 3, global, randomized, double-blind, placebo-controlled trial evaluating the novel, highly potent, and selective type II FLT3 inhibitor quizartinib (Quiz) for patients with newly diagnosed FLT3-ITD+ AML who were treated with curative intent. This pivotal trial demonstrated that the addition of Quiz to intensive induction, consolidation including allo-HCT in CR1, followed by single-agent continuation therapy for up to 3 years resulted in a significant improvement in overall survival (OS) for this population. The objectives of our analyses were to evaluate the impact of allo-HCT in CR1 and the interrelationship with Quiz on clinical outcomes of QuANTUM-First and on the feasibility of continuation therapy with Quiz after allo-HCT. Methods Patients aged 18-75 years with newly diagnosed AML were centrally screened for FLT3-ITD before initiation of standard induction therapy. Patients were randomized to Quiz (40 mg/d, on days 8-21) or placebo (PBO) and stratified by region (North/South America, Europe, and Asia/other regions), age (<60 years, ≥60 years), and white blood cell count (WBC; <40 × 109/L, ≥40 × 109/L) at diagnosis. Patients who achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 years of continuation therapy with Quiz (30-60 mg/d) or PBO. Patients who underwent allo-HCT could start continuation therapy 30 to 180 days after allo-HCT. The primary endpoint was OS. The impact of allo-HCT in CR1 on OS was assessed as a time-dependent covariable in univariable and multivariable regression analyses. Results In QuANTUM-First, 539 patients with FLT3-ITD+ AML were randomized to Quiz (n=268) or PBO (n=271). There were 294 (54.5%) females and 245 (45.5%) males. Of the 539 randomized patients (median age, 56 years; range, 20-75 years), 297 (55.1% [297/539]; Quiz, 54.9% [147/268]; PBO, 55.4% [150/271]) achieved CR and 71 (13.2% [71/539]; Quiz, 16.8% [45/268]; PBO, 9.6% [26/271]) achieved CRi after 1 to 2 courses of induction. Allo-HCT was performed in CR1 in 157 patients (52.9% of CR patients [157/297]; Quiz, 57.1% [84/147]; PBO, 48.7% [73/150]) predominantly with grafts from unrelated donors (49.7%), followed by siblings (32.5%) and other related donors (17.8%). Patients proceeding toward allo-HCT in CR1 were younger (median age, 51 years) and had a slightly higher proportion of WBC ≥40 × 109/L at diagnosis compared with patients who did not undergo allo-HCT in CR1. After completion of allo-HCT, 61 patients in the Quiz arm (72.6%) and 36 patients in the PBO arm (49.3%) started 3 years of continuation therapy. An additional 115 allo-HCTs were performed within the trial outside CR1 (Quiz, n=60; PBO, n=55). Multivariable regression analysis was stratified by region, age, and WBC, including allo-HCT in CR1 as time dependent and adjusted for FLT3-ITD variant allelic frequency, as well for sex. The analysis revealed Quiz treatment (hazard ratio [HR], 0.770; 95% confidence interval (CI), 0.609-0.973; P = 0.0284) and allo-HCT in CR1 (HR, 0.424; 95% CI, 0.301-0.597; P < 0.0001) as favorable factors with respect to OS. Based on this model, at any given time, the HR was 0.326 (95% CI, 0.216-0.493) for the patients randomized to Quiz and proceeding to allo-HCT in CR1 compared with patients randomized to PBO who had not yet received allo-HCT in CR1 by that time. Conclusions In patients who underwent allo-HCT in CR1, longer survival was observed in those treated with quizartinib versus placebo. Furthermore, irrespective of allo-HCT performed in CR1, quizartinib when combined with standard induction and consolidation therapy and continued for up to 3 years as a single agent improves survival over placebo in patients with newly diagnosed FLT3-ITD+ AML.

Long-Term Follow-up of AML Patients Treated Intensively before the Era of Targeted Agents. a Big Data Analysis from the Harmony Collaboration

Background: Due to better understand of biology of acute myeloid leukemia (AML), in 2017 a new era of targeted therapy has began. Before that, since 1973 younger and fit patients were offered the 3+7 regimen (based on anthracyclines and cytarabine) followed by high-dose cytarabine and, generally allogeneic stem cell transplantation in first complete remission (alloHSCT). In 2008 azacytidine, a hypomethylating (HM) agent was approved in Europe for AML patients, who were not candidate for intensive therapy and alloHSCT. In 2010 the European LeukemiaNet (ELN), based on cytogenetic and molecular genetic characteristics, proposed a risk score classification to facilitate decisions, including indications for alloHSCT. In addition to these advances, improved supportive therapies over the last 25 years are thought to have lowered therapy associated mortality. Aims: We aimed to analyse changes in outcome of AML patients treated between 1997-2016 prior to the approval of novel drugs, in order to better understand important factors contributing to patient outcome that might also contribute to the efficacy novel treatment approaches. Methods: Quality controlled, Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) harmonized data of the HARMONY alliance database coming from 100 organisations in 18 European countries were used for this study. Out of all AML records, 5359 patients diagnosed and treated with intensive regimens between 1997-2016 were identified. Patients treated with intensive regimens were identified regardless from age by the type of chemotherapy (n=4287) or by the age ≤70 (n=1072) if there was no information concerning the therapy. Patients with acute promyelocytic leukemia and those treated with targeted therapy were excluded from the analysis. Patients were categorized into 4 calendar periods: 1997-2001 (gr1), 2002-2006 (gr2), 2007-2011 (gr3) and 2012-2016 (gr4). The main outcome parameters analyzed were patient characteristics, overall survival (OS) and relapse-free survival (RFS). OS and RFS were determined using Kaplan-Meier analysis. Results: 5359 AML patients were included into the analysis: 1127 in gr1, 1294 in gr2, 1821 in gr3 and 1117 in gr4. The median follow-up of all patients was of 1.9 [0-17.6] while of those who survived of 5.8 [0-17.6] years. 46.6% of patients were female. The median age of all patients was 53 years (18-85). There were 3745 patients <60, 1229 between 60-69 and 385 ≥70 years old. There were no differences in ELN risk between groups. Intensive regimens in ≥70 years AML, were less frequent through calendar period: 12% in gr1 vs 6% in gr2 vs 6% in gr3 vs 7% in gr4. AlloHSCT was performed in first remission in 1770 (33%) patients and according to calendar period: 24.1% in gr1, 37.5% in gr2, 39% in gr3, and 27% in gr4 (p<0.001). OS significantly improved over the time: 15.5 (95CI: 13.8-17.6) in gr1 vs 26.3 (23.7-31.6) in gr2 vs 39.3 (32.5-47.1) in gr3 vs 37.8 (31.6-49.2) months in gr4 (p<0.001). The OS improvement was observed for both sexes, across all 4 calendar periods, but mostly for women: 32.4 (28.8-37.8) vs 25.0 (22.5-27.7) months (p<0.001). A significant improvement in OS across the four groups was observed in AML with alloHSCT: 33 (26-56.8) vs 45.4 (34.1-65.6) vs 63 (46-not-reached) months, with group 4 not yet reaching median survival, Fig A. Interestingly, the median age to perform alloHSCT in group 1 was of 42.1 (18 - 71), while in group 2, 3 and 4 it was 46.9 (16 - 69) vs 49.9 (17 - 75) and 53 (18 - 77) years, respectively (p=0.028), Fig B. Conclusion: Here we report the results of a large cohort of AML patients intensively treated between 1997-2016. Improvement of survival was observed for patients treated between 2007-2016 vs 1997-2007 in parallel with performing alloHSCT at more advanced age, most likely due to better supportive care and a greater proportion of reduced-intensity conditioning alloHSCT. As the majority of AML patients are diagnosed at advanced age, alloHSCT should be considered a curative treatment option. Less frequency of intensive regimens in elder AML since 2002 could be related with introduction of HM agents. Less number of alloHSCT in gr4 most likely represents a bias of our data base or could be related to better patient's selection (ELN criteria) and need to be analysed in a further study. The better improvement in OS in women could be explained by the fact that globally, including AML, women live longer than men. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adolescent and Young Adults with ALL Who Complete Therapy on DFCI Consortium ALL Trials Have Excellent Long-Term Overall Survival

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) have good outcomes when treated on pediatric regimens but still face worse survival compared to younger children (Siegel JAMA Onc 2018). Pediatric patients who do not complete ALL treatment, particularly planned asparaginase (ASP), have inferior oncologic outcomes (Silverman Blood 1997). In the CALBG 10403 trial of a pediatric-inspired regimen in AYAs 17-39 years (yrs), only 39% of pts completed planned treatment (Stock Blood 2019). We aimed to describe the prevalence of treatment failure, reasons for treatment non-completion, and their effect on survival among patients treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: We identified Philadelphia chromosome negative (Ph-) pts aged 1-49 yrs treated on 4 sequential multi-center DFCI Consortium protocols between 2000 and 2018 (00-001, 05-001, 01-175, 06-254). Additional consecutive Ph- pts treated as per these protocols were identified by chart review. All pts were intended to receive 30 continuous weeks (wks) of ASP during consolidation. Treatment failure was defined as induction failure, induction death, relapse/progression on therapy, and remission death on therapy. Treatment non-completion was defined as transplant in first complete remission (CR), withdrawal due to toxicity or other reasons, loss to follow up, and ineligible status. Treatment completion was defined as no exit from treatment protocol before its completion, approximately 2 yrs from complete remission (CR). Per protocol, no patients were recommended for allogeneic hematopoietic stem cell transplant (HSCT) in CR1. ASP completion was defined as receiving at least 26 wks of ASP during consolidation (Silverman, Blood 2001). The protocols allowed for truncation of ASP for toxicity without exit from protocol. Median follow-up time was calculated using the reverse Kaplan Meier indicator. The chi square test was used to compare proportions between groups. Overall survival (OS) among groups was compared using the log rank test. Results: A total of 1,480 pts were identified: 1,149 children (< 15 yrs, median age 4.5 yrs) and 331 AYAs (15-49 yrs, median age 24 yrs). Median follow-up was 7.9 yrs. Treatment completion rate was lower among AYAs than children (61.3% vs. 89.9%, p < 0.001) (Table 1). This was driven by higher treatment failure rates among AYAs than children (19.9% vs. 5.5%) as well as higher treatment non-completion rates (19.0% vs. 4.6%), primarily driven by transplants in CR1 among AYAs. Treatment completion rates were lower among older (30-49 yrs) AYAs compared to younger (15-29 yrs) AYAs (50.5% vs. 65.7%, p = 0.009). Among 1235 pts who completed treatment, 1086 (87.9%) received ³26 weeks of ASP. ASP completion rate was lower among AYAs vs. children (79.2% vs. 89.6%, p < 0.001). A higher percentage of AYAs discontinued ASP because of toxicity than children (11.9% vs. 5.5%, p = 0.01). In a landmark analysis of patients who survived and had follow-up for at least 2 years from diagnosis, AYAs who completed treatment (with or without ASP completion) had an estimated 5-year OS of 92.7% (95% Confidence Interval (CI): 87.5%, 95.8%), while children who completed treatment had a 5-year OS of 97.9% (95% CI: 96.7%, 98.6%) (Log-rank test p = 0.002) (Figure 1). Patients alive at 2 years who failed or did not complete treatment had worse survival outcomes with a 5-year OS of 70.5% (95% CI: 53.9%, 82.1%) among AYAs and 76.1% (95% CI: 62.2%, 85.5%) among children (Log-rank test p = 0.598) Conclusions: AYAs in our cohort completed protocol treatment at higher rates than previously reported trials. Among AYAs who completed treatment protocol, oncologic outcomes were excellent (5-year OS above 90%) and comparable to (although statistically lower than) those of children. AYAs had higher treatment failure rates, likely due to more aggressive disease biology. AYAs had lower ASP completion rates and higher ASP discontinuation rates due to toxicity compared to children; the etiology and impact of that on survival will need to be further investigated. Introduction of novel agents to improve remission induction rates and prevent early relapse in AYAs might help further improve oncologic outcomes for this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Allogeneic Hematopoietic Stem Cell Transplantation in First Complete Remission and Additional Cytogenetic Aberrations at Diagnosis on Prognosis in 1256 Pediatric Patients with KMT2A-Rearranged Acute Myeloid Leukemia: A Retrospective Study By the I-BFM-SG

IntroductionKMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is a heterogeneous genetic subgroup with a frequency of about 25% in children with AML. At the 62 nd ASH annual meeting last year, we reported on the differences in outcome of various KMT2A subgroups based on translocation partner and the significance of minimal residual disease (MRD) status during and after induction as a follow-up study of Balgobind et al., Blood 2009. The impact of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) and the presence of additional cytogenetic aberrations (ACAs) on prognosis have not yet been described for our cohort.MethodsData on allo-HSCT in CR1 and the presence of ACAs of 1256 KMT2A-r de novo pediatric AML patients from 15 AML study groups affiliated with the I-BFM Study Group, diagnosed between 2005 and 2016, were retrospectively collected and studied. Karyotypes were reviewed and classified by two of the authors (RW&CH). Based on translocation partners, patients were classified to the KMT2A high-risk subgroup (6q27, 10p11.2, 10p12, 4q21, and 19p13.3) or non-high-risk subgroup (9p22, 19p13, 19p13.1, 1q21, Xq24, 17q21, 1p32, and 17q12). These two categories have been used to estimate a Cox model. Patients with unknown translocation partners were excluded from these analyses (n=126). Flow cytometry MRD levels at the end of induction course 1 (EOI1) and 2 (EOI2) <0.1% were considered negative, and levels ≥0.1% positive. Kaplan-Meier's methodology was used to estimate disease-free survival (DFS) and overall survival (OS). DFS was calculated from EOI1 for patients in CR to date of relapse or death/last follow-up. OS was calculated from the time of diagnosis to date of death/last follow-up. Two-sided P-values of ≤ .01 were considered statistically significant. Covariates with P-values ≤ .05 in univariate analyses were included in multivariate analyses; allo-HSCT in CR1 was included as a time-dependent covariate in the Cox model. MRD status at EOI2 was excluded from multivariate analyses as therapy could have been adjusted to the MRD status and the number of MRD positive patients was small.ResultsOf 1256 pediatric patients with KMT2A-r AML, data on HSCT in CR1 and ACAs were available for 1186 (94.4%) and 1204 patients (95.9%), respectively; 211 (17.8%) patients received HSCT in CR1 and ACAs were present in 601 (49.9%) patients. Compared with the KMT2A non-high-risk subgroup, patients in the KMT2A high-risk subgroup underwent HSCT in CR1 more often (23.8% vs 15.0%; P < .001). ACAs were borderline significantly more common in the KMT2A high-risk subgroup (54.1% vs 46.4%; P = .015).Univariate analysis of the probability of DFS (Table 1) showed that the KMT2A high-risk subgroup (HR 2.1; 95% CI, 1.7-2.5), age ≥10 years (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 1.5; 95% CI, 1.1-1.9) were associated with DFS. HSCT in CR1 was a borderline significant prognostic factor (HR 0.7; 95% CI, 0.6-0.9).In a multivariate analysis for DFS (n=515) (Table 1), the KMT2A high-risk subgroup (HR 2.0; 95% CI, 1.6-2.6), MRD ≥0.1 at EOI1 (HR 1.7; 95% CI, 1.2-2.3), and HSCT in CR1 (HR 0.6; 95% CI, 0.4-0.9) were associated with DFS.Univariate analysis of the probability of OS (Table 1) showed that the KMT2A high-risk subgroup (HR 1.8; 95% CI, 1.5-2.2), age ≥10 years (HR 1.6; 95% CI 1.3-2.0), WBC ≥100 x10 9/L (HR 1.4; 95% CI, 1.1-1.7), the presence of ACAs (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 2.1; 95% CI, 1.6-2.7) were associated with OS. HSCT in CR1 was not associated with OS. The effect of HSCT in CR1 was not significantly different between the KMT2A high-risk and non-high-risk subgroups.In a multivariate analysis for OS (n=557) (Table 1), the KMT2A high-risk subgroup (HR 1.9; 95% CI, 1.4-2.5), age ≥10 years (HR 1.5; 95% CI, 1.1-1.9), the presence of ACAs (HR 1.6; 95% CI, 1.2-2.1), and MRD positivity at EOI1 (HR 1.9; 95% CI, 1.4-2.5) were associated with OS.ConclusionsIn this cohort of KMT2A-r pediatric AML patients, the presence of ACAs at diagnosis was independently associated with inferior OS, but not with DFS. This may be due to the exclusion of refractory patients in DFS analysis, who were significantly more common in the group of patients with ACAs. Analysis has yet to be performed to distinguish karyotype complexity. In addition, allo-HSCT in CR1 was an independent predictor of improved DFS, but was not a prognostic factor for OS. [Display omitted] DisclosuresAbrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau.

Social Deprivation Independently Predicts Survival in Younger Patients with Acute Myeloid Leukemia (Alliance)

Social Deprivation Independently Predicts Survival in Younger Patients with Acute Myeloid Leukemia (Alliance)

The differential effect of disease status at allogeneic hematopoietic cell transplantation on outcomes in acute myeloid and lymphoblastic leukemia

This study aimed to compare the effect of disease status at the time of allogeneic hematopoietic cell transplantation (HCT) on post-transplant outcomes between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Japanese nationwide registry data for 6901 patients with AML and 2469 patients with ALL were analyzed. In this study, 2850 (41%), 937 (14%), 62 (1%), and 3052 (44%) AML patients and 1751 (71%), 265 (11%), 23 (1%), and 430 (17%) ALL patients underwent transplantation in first complete remission (CR1), second CR (CR2), third or subsequent CR (CR3 +), and non-CR, respectively. The probabilities of overall survival at 5years for patients transplanted in CR1, CR2, CR3 + , and non-CR were 58%, 61%, 41%, and 26% for AML patients and 67%, 45%, 20%, and 21% for ALL patients, respectively. Multivariate analyses revealed that the risks of relapse and overall mortality were similar for AML patients transplanted in CR1 and CR2 (P = 0.672 and P = 0.703), whereas they were higher for ALL patients transplanted in CR2 than for those transplanted in CR1 (P < 0.001 for both). The risks of relapse and overall mortality for those transplanted in CR3 + and non-CR increased in a stepwise manner for both diseases, with the relevance being stronger for ALL than for AML patients. These results suggest a significant difference in the effect of disease status at HCT on post-transplant outcomes in AML and ALL. Further investigation to incorporate measurable residual disease data is warranted.

Impact of FLT3-ITD Mutations in Patients with Normal Karyotype Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Introduction : For patients affected by acute myelogenous leukemia (AML) with normal karyotype, the presence of a mutation in FLT3-ITD identifies a subgroup of individuals with poor prognosis for whom allogenic transplantation in first complete remission is indicated; such therapy is not required in patients with mutations in NPM1 or CEPBA. The present study evaluated the impact of mutations in FLT3 on post-allogenic transplantation outcomes in patients with cytogenetically normal AML.Methods : A total of 68 patients with normal karyotype AML underwent to allogenic stem cell transplantation at our Department from March 2006 to March 2017. Median age was 51 years (range 15-70); there were 45 males and 23 females. The conditioning regimen was TBI or BU based regimen for full-dose transplantations, while TT-FLU-MEL was used in patients undergoing reduced intensity conditioning. Cyclosporine and short-term methotrexate was used as prophylaxis for graft versus host disease (GVHD) for transplantation with an HLA identical family member or unrelated donors. For haploidentical transplants, a post-transplantation infusion of cyclophosphamide (50 mg/kg) was administered at days +3 and +4 followed by mycophenolate mofetil and cyclosporine. All patients were investigated for mutations in the FLT3, NPM1, and CBPA genes.Results : Conditioning was full-dose in 46 patients, and reduced intensity 17 cases. In 5 patients, a haploidentical transplant was used. 38 patients were transplanted in first complete remission and 20 in second complete remission, while 10 were transplanted with active disease. Overall survival (OS) of the entire cohort was 57% with an event-free survival (EFS) of 54%. The main cause of death was recurrence of disease (n=19); 10 patients died of non-relapse mortality. All patients who were transplanted with active disease died.Considering the results of molecular characterization, 20 patients had a mutation in FLT3-ITD (FLT3+), while 48 did not (FLT3-). The presence of a mutation in FLT3-ITD was not associated with age, conditioning regimen, or donor type; 80% of FLT3+ patients were in first complete remission compared to 45% of FLT3- patients. OS in the FLT3+ subgroup was 35%, with a relapse rate of 45% (9/20); OS in the FLT3- subgroup was 66%, with a relapse rate of 25% (12/48). There were no differences in OS or EFS in the FLT3- subgroup among those undergoing transplantation during first or second complete remission.Signs and symptoms of chronic GVDH (cGVHD) were observed in 25 of 55 evaluable patients (37%); of these, 20 patients were FLT3- and 5 were FLT3+. The presence of cGVHD was associated with better survival in FLT3- patients; in fact, 8/21 (38%) patients without signs of cGVHD had relapse compared to 4/20 (20%) with cGVHD (p=0.02). In FLT3+ patients, 4/9 (44%) without cGVHD had relapse vs. 3/5 (60%) of those with cGVHD (p=0.78).Conclusions : The present data suggest that patients with mutations in FLT3 have a greater risk of relapse than FLT3- patients, although additional studies in larger patient groups are needed. The different impact of cGVDH in OS in the two groups appears to suggest different post-transplant strategies, reserving the use of donor leukocyte infusion for FLT3- patients with relapse or at high risk of relapse, and using FLT3 inhibitors in the subset of FLT3+ patients as they are at high risk. DisclosuresNo relevant conflicts of interest to declare.