Patients In First Complete Remission Research Articles

Upfront allogeneic hematopoietic stem cell transplantation for adult T-cell acute lymphoblastic leukemia/lymphoma in first complete remission: a single-center study.

Real-world data on outcomes of upfront allogeneic hematopoietic stem cell transplantation (allo-HCT) for adult T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patients in first complete remission (CR1) is still lacking. A single center retrospective study was conducted from 94 consecutive patients received their first allo-HCT between 2010 and 2021, which include 76 patients received upfront allo-HCT and 18 patients received allo-HCT in non-upfront settings. There were no significant differences in most variables. In the upfront allo-HCT group, 52 (68%) patients achieved CR1 with one cycle of induction regimen. 24 (32%) patients achieved CR1 with more than one cycle. In the non-upfront group, there were 14 patients with active disease and 4 patients in second CR before transplant. The majority of patients received antithymocyte globulin-based graft-versus-host disease prophylaxis. Median follow-up time was 51 months for both groups. 5-year overall survival (OS) was 54% in the upfront allo-HCT group. While, in the non-upfront group, 5-year OS were 19% (P = 0.013). 5-year progression free survival in the upfront group was higher than that in the non-upfront group (50% versus 20%, P = 0.02). 5-year cumulative incidence relapse rate was significantly higher in non-upfront group (64% vs. 32%, P = 0.006). While, there was no difference in the 5-year non-relapse mortality (NRM) rate (19% versus 16%, P = 0.56). The most common cause of death was disease progression. In multivariable analysis, non-upfront allo-HCT (hazard ratios (HR) 2.14, P = 0.03) and HCT-CI (≥ 2) (HR 6.07, P = 0.002) were identified to be associated with worse OS. Non-upfront allo-HCT and HCT-CI (≥ 2) were also found to be independent risk factors for higher relapse rate. While, haploidentical-HCT was found to be associated with increased NRM. Our study indicated that allo-HCT remains an important curative treatment for adult patients with T-ALL, especially when it was performed in the upfront setting.

Improving outcomes of hematopoietic stem cell transplant for leukemia in children and young adults in resource-limited setting

IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach in patients with relapsed and high-risk leukemia. This retrospective analysis aimed to investigate outcomes and risk factors associated with HSCT in children and young adults with hematological malignancies in a resource-limited setting. MethodsWe retrospectively evaluated 48 pediatric and young adult patients diagnosed with hematological malignancies who underwent HSCT at our institution between April 2017 and Jan 2023. ResultThe median age of the cohort was 10 years (6 months - 21 years), and the majority of patients underwent transplants for acute lymphoblastic leukemia (ALL) (n = 24; 50 %) and acute myeloid leukemia (n = 18; 37.5%). Median time to neutrophil and platelet engraftment were 15 days (range 9–28) and 18 days (range 9–40), respectively. One patient had primary graft failure. Cytomegalovirus reactivation occurred in 21 patients (43.8%). Seventeen patients received escalated donor lymphocyte infusion (DLI). With a median follow-up of 902 days (52–2490), the probability of event free survival and overall survival (OS) was 65.9% and 69.4%. OS for lymphoid and myeloid malignancies were 64.7% and 75.2%, respectively. Kaplan-Meier probabilities of OS for patients in first complete remission (CR), CR2, CR3, or with refractory disease were 80%, 76.2%, 0%, and 40%, respectively (p = 0.02). OS of the patients undergoing matched sibling donor (n = 17) or haploidentical HSCT (n = 31) was 70.6% and 69%, respectively (p = 0.989). ConclusionsOur study demonstrates excellent outcomes of patients with hematological malignancies undergoing allogeneic HSCT with similar outcomes in HLA-identical sibling donors and haploidentical first-degree family donors. Prophylactic DLI might be considered in patients with high-risk leukemia to prevent relapse, including ALL.

Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT Acute Leukemia Working Party.

Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m2 (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m2. We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.

Association between Molecular Profile and Outcome after Intensive Chemotherapy in Patients &amp;gt; 60 Years with Adverse Cytogenetic Risk and/or Secondary Acute Myeloid Leukemia - a Filo Study

Background: Recognizing the prognostic importance of genetic characteristics rather than clinical history, secondary acute myeloid leukemia (AML), i.e., arising from prior cytotoxic therapy and/or an antecedent hematologic disorder (AHD), is now considered a diagnostic qualifier rather than a separate disease entity (Döhner, Blood 2022). To assess the relationship between clinical history and/or adverse cytogenetics and outcome, we report herein the molecular profile of AML patients &amp;gt;60 years with secondary AML and/or adverse cytogenetics included in a multicentric prospective trial. Methods: Fit patients &amp;gt;60 years with secondary AML and/or adverse cytogenetics according to the European LeukemiaNet, included in the Rev-5-Aza trial (NCT01301820), received induction therapy with lomustine 200 mg/m 2 day 1, idarubicin 8 mg/m 2 days 1-5, and cytarabine 100 mg/m 2 days 1-7. Patients in complete remission (CR) after one induction cycle received consolidation therapy with 12 cycles of alternating azacitidine 75 mg/m 2 days 1-7 and lenalidomide 10 mg days 1-21 every 28 days (Hunault-Berger M, Blood Cancer J 2017). Mutational profile was determined by targeted sequencing of complete coding regions, including splice sites, of 77 genes recurrently mutated in myeloid malignancies using custom SureSelect QXT capture system (Agilent, Santa Clara, CA, USA) on NextSeq500 platform (Illumina, San Diego, CA, USA). As a validation cohort, we determined the molecular profile of 73 patients with adverse cytogenetic risk and/or secondary AML in first CR after the same induction therapy but who received standard chemotherapy consolidation with 6 cycles of idarubicin 8 mg/m 2 day 1 and cytarabine 50 mg/m 2/12 hours days 1-5. Results: Between March 2011 and February 2013, 117 fit patients &amp;gt;60 years included in the Rev-5-Aza trial received induction therapy with 56% reaching first CR and four patients undergoing allogeneic hematopoietic cell transplantation. The molecular profile could be established in 97 of these patients (83%; median age 70 years, interquartile range (IQR): 65-73; therapy-related AML, 32%; AHD, 46%; adverse cytogenetic risk, 70%). Secondary-type mutations were the most frequently observed (49%; ASXL1, 12%; BCOR, 16%; EZH2, 2%; RUNX1, 18%; SF3B1, 8%; SRSF2, 14%; STAG2, 10%; U2AF1, 8%; and ZRSR2, 0%) followed by TP53 mutations (44% of patients). Patients with TP53 mutations were more likely to have adverse risk cytogenetics (95%) in comparison to patients with secondary-type mutations (64%). No clinical or biological characteristic was associated with the achievement of CR (secondary-type mutations, 51%, TP53 mutation, 49%). Clinical history was not associated with overall survival (OS) as patients with therapy-related AML had the same outcome as other patients (hazard ratio [HR]=1.04, P=0.9) and patients with AHD had a more favorable outcome (HR=0.57, P=0.02). On the other hand, adverse cytogenetics was associated with decreased OS (HR=3.32, P&amp;lt;0.001). Whereas TP53 mutations were associated with decreased OS (HR=3.71, P&amp;lt;0.001), secondary-type mutations were not (HR=0.64, P=0.049; Figure A). After multivariable analysis, both complex karyotype (CK; HR=0.006, P=0.006) and TP53 mutations (HR=2.12, P=0.03) were independently associated with OS. Considering both CK and TP53 mutations identified three groups of patients with differential OS (median 1.57 vs. 0.91 vs. 0.45 years, P&amp;lt;0.001; Figure B). Similar results were observed in the validation cohort. Patients in first CR from both cohorts were then compared to identify molecular subgroups for which a lenalidomide/azacitidine consolidation was associated with improved OS in comparison to standard chemotherapy. No molecular subgroup had increased OS with lenalimomide/azaciditine consolidation while standard chemotherapy was associated with improved outcomes in patients with adverse risk cytogenetics. Conclusion: Together, these data suggest that the clinical history contains limited prognostic value compared to genetics, supporting the most recent approach to use cytogenetic and molecular data to assess disease risk. In this patient population, complex karyotype and TP53 mutations, rather than secondary-type mutations, were associated with outcome. Figure. (A) Overall survival according to secondary-type and TP53 mutations status. (B) Overall survival according to complex karyotype (CK) and T P53 mutation status.

Venetoclax in Combination with Intermediate Doses of Cytarabine in Consolidation Phase for Acute Myeloid Leukemia Patients in First Complete Remission; Results of the Part 1 of the Phase 1/2 Multicentric Covenidac Study

For authors: Please: L Gastaud and P Peterlin: co-primary, H dombret et C Recher: co-last Background: The French ALFA-FILO AML intergroup launched the BIG-1 trial (EudraCT No.: 2014-000699-24) in 2015 to evaluate different intensive chemotherapy (ICT) strategies aiming at improving the survival of younger adults with acute myeloid leukemia (AML). All patients (pts) with previously untreated non-APL and non-CBF AML aged 18-60 years were eligible for this trial. The trial design included several randomization types. Results of the R1 and R2 randomizations, namely idarubicin vs daunorubicin for induction and IDAC vs HDAC for consolidation, will be reported at this meeting. In patients who achieved first complete remission (CR), randomizations R4 consisted of nested randomized Phase 2 or 1/2 studies evaluating the addition of new drugs to the IDAC/HDAC consolidation cycles. The protocol was designed to allow several sequential multicenter R4 evaluations of various new agents over the trial period. Venetoclax (VEN) has proved its efficacy when combined to azacitidine or low dose cytarabine in unfit AML pts (DiNardo et al. 2020; Wei et al. Blood 2020). Its role in fit patients treated with ICT is still under investigation. The COVENIDAC Phase 1/2 R4 sub-study is evaluating the safety and efficacy of VEN added to IDAC during the consolidation cycles of CR pts. We report herein the result of the Phase 1 part. Methods: The primary objective of this Phase 1 study was to determine the maximum tolerated dose (MTD) of VEN in combination with IDAC during the consolidation cycles, which will be the recommended dose for the Phase 2 (RP2D). Dose limiting toxicities (DLTs) were assessed during the first cycle of consolidation (C1) according to a 3+3 design. A maximum of 3 consolidation cycles was planned depending on the AML risk group. Hematological DLT was defined as no peripheral blood count recovery within 56 days from day 1 of the cycle. Non-hematological DLTs were defined as Grade ≥4 toxicities or Grade ≤3 toxicities which have not recovery by day 56 and deemed related to VEN per investigator opinion. VEN was started at dose level (DL) 1: 100 mg/d from day 1 to 8. In the absence of DLTs at DL1, 3 others DL were planned: 200 mg/d from day 1 to 8 (DL2); 400 mg/d from day 1 to 8 (DL3), and 400 mg/d from day 1 to 14 (DL4). IDAC was administrated at 1.5 gr/m² twice daily on day 1/3/5 for DL1, DL2 and DL3 pts, then on day 1/2/3 for DL4 pts after a protocol amendment. Main inclusion criteria were: pts in first CR following 1 or 2 courses of induction chemotherapy fit for further ICT; favorable and intermediate risk AML as defined by the protocol; ECOG PS ≤2; written informed consent. Measurable residual disease (MRD) was assessed by multiparametric flow cytometry (MFC) in all pts as well as NPM1-qPCR in NPM1-mutated pts. Results: Between 06/2021 and 04/2022, 15 pts from 9 centers were screened and enrolled. Pt characteristics were as follows: median age, 42 years (IQR, 30-49); 2 males/7 females; ECOG-PS, 0 in 10 pts and 1 in 5 pts; favorable/intermediate/adverse ELN-2017 risk, 9/2/4. Neutropenia and thrombocytopenia durations are shown in Table 1. Only 1 hematological DLT was observed at DL3 (platelet count of 96 giga/L at day 56 in a patient who was infected by Covid-19). Overall, there were very few non hematological AEs ( Table 2, no grade 4) and only 4 SAEs (1 related to IDAC/VEN during C1, 3 non-related). No non-hematological DLT was observed. No patient died during the DLT observation period, 1 experienced a septic shock (C2, DL2). One pt received only C1 (due to DLT), 7 received 2 cycles, and 7 received 3 cycles. Median time between initiation of subsequent consolidation cycles was 37.5 days (IQR, 35-41) for C1/C2 and 40 days (IQR, 35-43) for C2/C3. One pt had to stop VEN during C3. Six pts received an allogeneic HSCT (5 in CR1, 1 after salvage). With a median follow-up of 13.5 months, 3 pts relapsed and 2 died. MRD results will be presented. Conclusion: VEN/IDAC combination appears to be feasible and safe as consolidation therapy, with expected thrombocytopenia and neutropenia durations. These durations appeared even shorter at DL4, when IDAC was given on 3 consecutive days. VEN at 400 mg/d from day 1 to 14 combined with IDAC on day 1/2/3 was thus retained as RP2D for the randomized Phase 2 with RFS as primary endpoint. This phase 2 has already recruited 29 of the 200 pts planned.

Allogeneic Hematopoietic Cell Transplantation for Acute Megakaryocytic Leukemia: A Single Center Study

Introduction Acute megakaryocytic leukemia (AMKL) comprises 4-15% of all acute myeloid leukemia (AML) diagnoses in pediatric patients. Unlike patients with Down syndrome who have a &amp;gt;80% expected survival with dose-reduced chemotherapy, the 5-year overall survival (OS) in patients with de novo AMKL is dismal and ranges between 14-49%. While treatment intensification has marginally improved the outcome of these patients over the last few decades, the role of hematopoietic cell transplantation (HCT) in these patients in first complete remission (CR) is often debated. To better define the role of HCT, we evaluated the outcomes of pediatric patients who underwent their first HCT for AMKL at our institution from October 1990 to January 2021. Methods We conducted a retrospective analysis using patient, disease, and transplant-related data collected during routine clinical care and evaluated these variables for their prognostic value. Kaplan-Meier curves were generated to estimate survival probabilities in pre-specified groups and compared using the log-rank test. Multivariable analysis was performed using Cox proportional hazards models to assess the role of various patient and transplant-related factors on survival. The cumulative incidence of relapse (with death as competing risk) was estimated by the Fine-Gray multivariable models and compared using Gray's test. Results Our study included 53 patients. The median age at HCT was 2.3 (range 0.9-19.7) years. The median time of follow-up was 10.3 (range 0.9-346.6) months. At the time of HCT, 56.6% of patients were in CR1, 5.7% were in CR2 and 37.7% had active/refractory disease. Nine (17%) patients received an HCT from a matched sibling donor, 25 (47.2%) from a matched unrelated donor, and 19 (35.8%) from a haploidentical donor. Twenty-two (41.5%) patients relapsed after HCT at a median duration of 2.8 (range 0.6-10.5) months, and 31 (58.5%) patients died at a median duration of 4.3 (range 0.9-15.9) months. The one-year OS estimates trended higher in patients undergoing transplant in more recent decades (1990-2000: 32%, 2000-2010: 46%, 2010-2020: 67%; P = 0.2). Patients who underwent HCT in CR had a significantly higher 1-year OS (57% versus 30%; P &amp;lt; 0.001) and decreased rate of relapse (24% versus 70%; P &amp;lt; 0.001) compared to those who underwent HCT with active/refractory disease. Similarly, in multivariable analysis, being in CR during HCT was associated with improved OS (Hazard Ratio [HR] 0.17, 95% Confidence Interval [CI] 0.07-0.41) and decreased risk of relapse (HR 0.18, 95% CI 0.07-0.46) after adjusting for other pre-specified variables. Conclusion While the overall outcome of patients who undergo HCT for AMKL has improved in the last few decades, it remains suboptimal. Patients who underwent HCT in CR had superior outcomes. Our data supports the notion that patients with de novo AMKL would benefit from HCT when they first achieve CR while we await novel strategies in treating relapsed or refractory AMKL.

Comparison of Autologous, Matched Sibling, and Alternative Donor Stem Cell Transplant Outcomes for Acute Myeloid Leukemia Patients in First Remission: A Propensity Score Matching Study

Introduction Autologous hematopoietic stem cell transplantation (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and alternative donor HSCT (AD-HSCT) are viable post-remission treatment options for acute myeloid leukemia (AML). Auto-HSCT is more commonly administered in favorable- and intermediate-risk AML with good remission, while MSD-HSCT and AD-HSCT are suggested for patients with high-risk factors. In the present study, we aim to retrospectively compared auto-HSCT with MSD-HSCT and AD-HSCT in de novo AML patients who are in first complete remission (CR1) with favorable or intermediate risk, according to 2022 ELN criteria. Methods We conducted a single-center retrospective comparative analysis, comparing auto-HSCT and allo-HSCT for favorable and intermediate-risk de novo AML in CR1. Patients with secondary AML, acute promyelocytic leukemia, poor-risk AML, those receiving syngeneic HSCT, those not in CR1 before HSCT, or those who achieved CR1 with ≥ 3 cycles of induction chemotherapy were excluded from the study. A total of 283 de novo favorable- and intermediate-risk AML patients, based on the ELN 2022 criteria, in first complete remission were initially included for propensity score matching. Persistent undetectable MRD (uMRD) was defined as uMRD after one course of chemotherapy without recurrent positive MRD before HSCT, while non-persistent uMRD was characterized by the presence of detectable MRD at least once before HSCT. The variables used for propensity score matching included induction chemotherapy cycles, consolidation chemotherapy cycles, and measurable residual disease (MRD) measurement by flow cytometer before HSCT. A caliper width of 0.2 was used. Following the matching process, 126 patients were selected for further analysis, with 42 patients in each of the auto-HSCT, MSD-HSCT, and AD-HSCT groups. Results After applying propensity score matching, a final cohort of 126 patients was available for analysis. This cohort consisted of 42 patients in each group: auto-HSCT, MSD-HSCT, and AD-HSCT. Among the AD-HSCT group, 38 of 42 (90.5%) patients received haploidentical HSCT (haplo-HSCT). All patients received myeloablative conditioning regimen. There were no significant differences observed in the 3-year overall survival (OS) and disease-free survival (DFS) among the auto-HSCT, MSD-HSCT, and AD-HSCT groups [3-year OS: 79.5% (95% CI, 67.8-93.3%), 83.0% (95% CI, 72.2-95.3%), and 65.7% (95% CI, 50.5-85.5%), respectively; P=0.21. 3-year DFS: 72.6% (95% CI, 59.9-87.9%), 83.0% (95% CI, 72.2-95.3%), and 67.5% (95% CI, 54.2-84.1%), respectively; P=0.32]. The cumulative incidence of 3-year NRM was 2.7% (95% CI, 2.0-12.5%), 7.3% (95% CI, 1.8-17.9%), and 21.9% (95% CI, 10.7-35.6%), respectively (P=0.008). The 1-year probability of OS after relapse was higher in the auto-HSCT group (44.4%; 95% CI, 21.4-92.3%) compared with MSD-HSCT (0.0%) and AD-HSCT (37.5%; 95% CI, 8.4-99.9%) (P=0.0017). The MRD status before HSCT had an impact on DFS (persistent uMRD versus non-persistent uMRD: HR=0.29; 95% CI 0.09-0.94, P=0.04) and relapse (persistent uMRD versus non-persistent uMRD: HR=0.17; 95% CI 0.05-0.66, P=0.01) following auto-HSCT. The subgroup analysis was then performed based on MRD status before HSCT. In patients with uMRD before transplant (n=83), OS was similar across the groups. However, auto-HSCT showed a trend of increased DFS compared to AD-HSCT (HR 2.85, P=0.09), resulting in a 3-year DFS and OS of 79.1% and 82.8%, respectively. In the non-persistent uMRD group (n=38), auto-HSCT exhibited a tendency to increase the risk of relapse, particularly when compared to AD-HSCT (HR 0.24, P=0.07), but this did not result in inferior OS. The monthly direct medical cost per patient within the first two years after HSCT was significantly lower in auto-HSCT compared to MSD-HSCT (P=0.015) and AD-HSCT (P&amp;lt;0.001). Conclusions Our results provide evidence for the use of auto-HSCT as a viable therapeutic option for favorable- and intermediate-risk de novo AML patients in first complete remission with persistent uMRD. Additionally, our findings demonstrated a notable cost advantage associated with auto-HSCT compared to MSD-HSCT and AD-HSCT.

Vaccination Using an Allogeneic Leukemia-Derived Dendritic Cell Vaccine, Maintains and Improves Frequencies of Circulating Antigen Presenting Dendritic Cells Correlating with Relapse Free and Overall Survival in AML Patients

Background. Active immunotherapy relies on the patient's immune system for induction of an effective immune response. Not only the frequency, number and exhaustion or activation status of CD8 T cells is important for an efficacious tumor cell lysis, but the quality, number and distribution of different antigen presenting cells is of equal importance. Vididencel is an allogeneic leukemia-derived dendritic cell vaccine used in AML patients in first complete remission (CR1/CRi), but with MRD positivity, to mount an immune response through intradermal vaccination (ADVANCE-II, Clintrials.gov: NCT03697707). Intradermal vaccination is known to induce a specific immune response, by recruitment of skin and blood derived dendritic cells, which process antigen and present them to the immune system (Zuo et al., 2021). In this study circulating dendritic cells and monocytes have been investigated before and during vaccination to investigate the effect of vididencel treatment on the composition of antigen presenting cells in relation to clinical responses. Methods. A total of 20 evaluable AML patients, in CR1/CRi, with measurable residual disease (MRD +) and ineligible for HSCT at inclusion, received 4 biweekly doses of vididencel, followed by 2 booster doses at week 14 and 18. Peripheral blood mononuclear cells were taken at baseline, week 6, 11, 14, 18, 20 and 32, ficoll isolated and cryopreserved in liquid nitrogen. Analysis of immune cell composition was performed by spectral flow cytometry, using a single 40-marker panel. Immune subset analysis of dendritic (live, single, CD45+, Lin-(CD3, 56, 19), CD16-, CD15-) cells was performed and correlated to clinical response, relapse free and overall survival, by high dimensional analysis using FlowSOM. Results. Dendritic cell subsets increased upon vaccination, with levels before and during vaccination being the highest in patients remaining in CR. Gating of the dendritic cell subsets by spectral flow cytometry analyses could be hampered by presence of leukemic blasts in the peripheral blood, expressing for example CD123, a marker required for gating of pDCs. Using gating on the lineage negative, CD15-, CD16- and HLA-DR+ cells, a deep immunophenotyping was performed on dendritic cells in peripheral blood. Baseline analysis showed a significantly higher frequency of CD45RA+, HLA-DR+ cells in patients who remain in CR. Using tSNE and UMAP plots generated to analyse changes in the Lin-, CD14-, CD15-, CD16- and CD11b-, HLA-DR+ population; changes and increases in several subsets were observed, most notably in subsets with cDC1, cDC2 and pDC characteristics, like expression of CD141, CLEC9A, CD1c and CD123. Higher frequencies at baseline of dendritic cells (cDC1 and cDC2) correlated positively with both relapse-free and overall survival. In patients remaining in CR, vaccination further increased or maintained dendritic cell subset frequencies, of which classical cDC1 and cDC2 correlated with longer overall survival (p&amp;lt;0.05). Conclusion: Patients who remain in CR after vididencel treatment had highest baseline levels of HLA-DR+ CD45RA+ cells, which could be myeloid cells able to differentiate into dendritic cell subsets, as in general CD45RA+ is lost during maturation from precursor to matured dendritic cells. Vaccination might improve and induce maturation of dendritic cell subsets, such as cDC1, cDC2 and pDC, which enhance antigen capturing, processing and presentation to tumor-reactive T cells, ultimately leading to improved survival.

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.

We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML.

Comparison of autologous, matched sibling, and alternative donor stem cell transplant outcomes for acute myeloid leukemia patients in first remission: A propensity score matching study.

Autologous hematopoietic stem cell transplantation (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and alternative donor HSCT (AD-HSCT) are viable post-remission treatment options for acute myeloid leukemia (AML). A total of 283 de novo favorable- and intermediate-risk AML patients, based on the ELN 2022 criteria, in first complete remission were initially included for propensity score matching. Following the matching process, 126 patients were selected for further analysis, with 42 patients in each of the auto-HSCT, MSD-HSCT, and AD-HSCT groups. Among the AD-HSCT group, 38 of 42 (90.5%) patients received haploidentical HSCT. In patients with persistent undetectable measurable residual disease (uMRD) before transplant (n=83), overall survival (OS) was similar across the groups. However, auto-HSCT showed a trend of increased disease-free survival (DFS) compared to AD-HSCT (HR 2.85, P=0.09), resulting in a 3-year DFS and OS of 79.1% and 82.8%, respectively. In the non-persistent uMRD group (n=38), auto-HSCT exhibited a tendency to increase the risk of relapse, particularly when compared to AD-HSCT (HR 0.24, P=0.07), but this did not result in inferior OS. The monthly direct medical cost per patient within the first 2years after HSCT was significantly lower in auto-HSCT compared to MSD-HSCT (P=0.015) and AD-HSCT (P<0.001). Our results provide evidence for the use of auto-HSCT as a viable therapeutic option for favorable- and intermediate-risk de novo AML patients in first complete remission with persistent uMRD. Additionally, our findings demonstrated a notable cost advantage associated with auto-HSCT compared to MSD-HSCT and AD-HSCT.

Naxitamab Combined with Granulocyte-Macrophage Colony-Stimulating Factor as Consolidation for High-Risk Neuroblastoma Patients in First Complete Remission under Compassionate Use-Updated Outcome Report.

Naxitamab is an anti-GD2 antibody approved for the treatment of relapsed/refractory HR-NB. We report the survival, safety, and relapse pattern of a unique set of HR-NB patients consolidated with naxitamab after having achieved first CR. Eighty-two patients were treated with 5 cycles of GM-CSF for 5 days at 250 μg/m2/day (-4 to 0), followed by GM-CSF for 5 days at 500 μg/m2/day (1-5) and naxitamab at 3 mg/kg/day (1, 3, 5), on an outpatient basis. All patients but one were older than 18 months at diagnosis and had stage M; 21 (25.6%) pts had MYCN-amplified (A) NB; and 12 (14.6%) detectable MRD in the BM. Eleven (13.4%) pts had received high-dose chemotherapy and ASCT and 26 (31.7%) radiotherapy before immunotherapy. With a median follow-up of 37.4 months, 31 (37.8%) pts have relapsed. The pattern of relapse was predominantly (77.4%) an isolated organ. Five-year EFS and OS were 57.9% (71.4% for MYCN A) 95% CI = (47.2, 70.9%); and 78.6% (81% for MYCN A) 95% CI = (68.7%, 89.8%), respectively. EFS showed significant differences for patients having received ASCT (p = 0.037) and pre-immunotherapy MRD (p = 0.0011). Cox models showed only MRD as a predictor of EFS. In conclusion, consolidation with naxitamab resulted in reassuring survival rates for HR-NB patients after end-induction CR.

Total Body Irradiation Versus Chemotherapy Conditioning in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis.

Allogeneic hematopoietic stem cell transplant (HSCT) is indicated in pediatric patients with acute lymphoblastic leukemia (ALL) who have relapsed or are at a very high risk of relapse during first complete remission. Two types of myeloablative conditioning are employed before allogeneic HSCT: total body irradiation (TBI)-based regimens and chemotherapy (CHT) alone. This study compares the efficacy and safety of TBI-based regimens and CHT-based conditioning in pediatric, adolescent, and young adult patients with ALL (0-24 years old). TBI-based and CHT-conditioning regimens were evaluated in 4262 and 1367 patients, respectively, from 15 studies. Compared to CHT alone, TBI-based regimens were associated with better overall survival (OS), relative risk (RR) 1.21, better event-free survival (RR 1.34), and a reduced risk of relapse (RR 0.69). Both approaches had comparable risk of acute graft-versus-host disease (GVHD), grades 3 to 4 acute GVHD, chronic GVHD, and nonrelapse mortality (NRM). In the subgroup analysis for patients in first complete remission, TBI-based regimens and CHT alone had comparable OS and NRM. Our results demonstrate the superiority of TBI-based regimens compared to CHT alone in pediatric patients with ALL.

Use of an Allogeneic Leukemia-Derived Dendritic Cell Vaccine in MRD+ AML-Patients Results in MRD Conversion, Improved Relapse-Free Survival and Vaccine Induced Immune Responses to Tumor Antigens

Background. Maintenance therapy in AML patients with measurable residual disease (MRD) remains challenging. Immunotherapy could be an effective way to induce durable disease control. This phase II study aims to show efficacy of priming the immune system, using an allogenic leukemia-derived dendritic cell vaccine (DCP-001), to induce an effective anti-leukemic response to control or kill remaining malignant cells (ADVANCE-II, Clintrials.gov: NCT03697707). Methods. A total of 20 evaluable AML patients in first complete remission (CR1) with MRD positivity and ineligible for HSCT received 4 biweekly doses of 25e6 or 50e6 cells per intradermal vaccination (cells/vc) and 2 doses as boosts at week 14 and 18 of 10e6 cells/vc. MRD, as primary endpoint, was assessed at baseline, week 14, 20 and 32 by flow cytometry and/or molecular analyses. Evaluation of secondary endpoints relapse-free (RFS) and overall survival (OS) was done at data cut-off (18th July 2022). Peripheral blood samples were taken before and during treatment for analysis of vaccine induced responses as measured by IFNγ ELISPOT and general immune profiles by flow cytometry using a 40-marker panel. Results. Patients aged 34-79 (median 60y) had a cytogenetic risk status assessed of 4 better, 15 intermediate and 1 poor-risk, with mutations in NPM1 (n=10), CBFB-MYH11 (n=4), IDH2 (n=2), RUNX1-RUNX1T1 (n=2), TP53 (n=1) and CEBPA (n=1). All 20 patients have received 4 initial vaccinations, 17 patients received all booster vaccinations and 1 patient received one booster. No serious adverse events (AE) or severe AE (grade 3 or higher) related to the treatment have been reported. Related AEs are mainly injection site reactions, such as redness, warmth and swelling, occurring within 48 hours after intradermal administration. To date, median RFS and OS have not yet been reached (Figure 1), with a median follow up period of 15.4 (range 6.6- 16.8) months for the entire study population. Estimated RFS and OS at 6 months is 83.9% (range 64-94%) and 97% (range 79-99%), respectively. Estimated RFS and OS at 12 months is 70% (range 48-85%) and 87% (67-95%), respectively. MRD response (conversion or >10-fold decrease of MRD) was observed in 7 patients: 5 patients converted to negative and 2 showed a MRD decrease. Responses were observed within 14-20 weeks and durable in 4 out of 5 patients, remaining MRD negative up to week 32. Seven patients remained in CR with stable MRD levels and 6 patients relapsed before week 32. Three patients with stable MRD became eligible for HSCT during study and were transplanted successfully. Immune responses were observed to tumor associated antigens expressed by DCP-001; WT1, RHAMM and PRAME, with specific vaccine induced responses (VIR) in the majority of patients (17/20) and highest number of VIR per antigen observed in patients with MRD responses (Figure 2). Differences in immune profiles at baseline were observed; relapsed patients had a high number of CD8RO+ cells, in particular CD8 CM. On the contrary, MRD responders had the highest level of CD8RA+ cells at baseline, with CD8 EMRA cells at the highest level. Patients with stable MRD had comparable, but slightly lower CD8RO+ levels than MRD responders. Conclusion/discussion. Vaccination with DCP-001 resulted in durable MRD responses with five patients converting to MRD negativity, remaining relapse-free and alive during follow up. This translates in promising survival data with the median RFS for the full patient population not reached to date, at a median FU time of 15.4 months. Highest level of vaccine-induced T-cell responses to leukemia specific antigens were detected in MRD responders. Baseline levels of CD8 memory profiles were markedly different in MRD responders, which might be indicative that lower number of memory cells, and thus especially higher number of CD8 EMRA could reflect the ability to induce a tumor specific cytotoxic T-cell response after vaccination. Relapse on study was limited, with an estimated RFS at 6 months of 83.7%, which is higher than expected for this MRD+ AML patient population, which would be around 45% as shown for placebo-treated patients from a recent phase III study in a similar patient population (Quazar AML001). Immunotherapy with DCP-001 as AML maintenance therapy is safe and effective in triggering immune responses and converting patients from MRD positive to MRD negative, leading to promising relapse-free survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

BackgroundThe role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K).MethodsGenomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate.ResultsAmong 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002).ConclusionIn this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.

Acute Myeloid Leukemia - Update 2022

The suspicion of acute myeloid leukemia (AML) is a haematological emergency that requires a rapid diagnostic workup. Symptoms are usually caused by cytopenias of all blood cell lines. The differentiation of acute promyelocytic leukemia (APL) is important because of the early death rate caused by thrombembolic and bleeding events. Rapid immunophenotypic and genetic characterization is necessary for risk stratification and therapy selection. For this purpose, a center with appropriate expertise should be contacted. Therapy has become more complex due to numerous new approvals. For certain patients, the established intensive induction therapy with cytarabine and anthracycline is now combined with targeted agents, like the antibody conjugate Gemtuzumab-Ozogamicin or the FLT3 inhibitor Midostaurin. Patients with secondary AML benefit from the liposomal chemotherapy combination CPX-351. Therapy with the hypomethylating agent Azacitidine and the BCL2-inhibitor Venetoclax (Aza/Ven) represents the standard for patients who are not fit for intensive therapy. Here, it is important to consider interactions with CYP3A4-effective drugs.In most cases, APL is treated "chemotherapy-free" with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In high-risk patients, the combination of chemotherapy and ATRA is still standard.Moreover, maintenance therapies were (re)established as an important therapeutic element of post-remission therapy. For example, Midostaurin is used in patients with FLT3 mutations, as is the multikinase inhibitor sorafenib after allogeneic stem cell transplantation. In addition, oral azacitidine is available for non-allogeneic transplant eligible patients in first complete remission. These new drugs have improved prognosis and resulted in a more individualized therapy mostly driven by genetic aberrations. This development will continue in the next years and will significantly improve treatment options, especially for older patients.

Post-remission measurable residual disease directs treatment choice and improves outcomes for patients with intermediate-risk acute myeloid leukemia in CR1

ObjectivesThis study retrospectively investigated in which cycle measurable residual disease (MRD) is associated with prognosis in patients in first complete remission (CR1) of intermediate-risk acute myeloid leukemia (AML).MethodsThe study enrolled 235 younger patients with intermediate-risk AML. MRD was evaluated by multiparameter flow cytometry after the 1st, 2nd, and 3rd chemotherapy cycles (MRD1–3, respectively).ResultsNo significant association was detected after the 1st and 2nd cycles. However, the 5-year incidence of relapse was higher in the MRD3-positive group (n = 99) than in the negative group (n = 136) (48.7% vs. 13.7%, P = 0.005), while 5-year disease-free survival (DFS) and overall survival (OS) were lower in the MRD3-positive group than in the negative group (43.2% vs. 81.0% and 45.4% vs. 84.1%; P = 0.003 and 0.005, respectively). Allogeneic hematopoietic stem cell transplantation led to a lower 5-year relapse, and higher DFS and OS rates than chemotherapy in the MRD3-positive group (22.3% vs. 71.5%, 65.9% vs. 23.0%, and 67.1% vs. 23.9%; P < 0.001, 0.002, and 0.022, respectively), but did not affect the MRD-negative group.ConclusionsMRD3 could serve as an indicator for post-remission treatment choice and help improve outcomes for intermediate-risk AML in CR1.

Autologous stem cell transplantation (ASCT) for acute myeloid leukemia in patients in first complete remission after one versus two induction courses: A study from the ALWP of the EBMT.

Achieving complete remission (CR) is the main goal in AML treatment and a prerequisite for successful autologous stem cell transplantation (ACT). Comparing results of peripheral blood ACT in patients with AML in CR1 attained following 1 versus 2 chemotherapy courses transplanted in 2000-2019. Patients 1532 (84%) with one and 293 (16%) patients with two induction chemotherapies courses (a total of 1825 patients) were included in the study. Follow-up was 7.9 (95% CI: 7.4-8.4) and 7.7 (95% CI: 7.0-8.6) years (p= 0.8). Time from diagnosis to ACT was 4.7 (range, 3.9-5.8) versus 5.7 (range, 4.7-7.1) months (p< 0.001), respectively. Leukemia free survival (LFS) and overall survival (OS) at 5 years were inferior for patients achieving CR1 with 2 versus 1 course of chemotherapy: 26.6% versus 41.7% (HR=1.42 [95% CI: 1.22-1.66], p< 0.001) and 36.2% versus 53.3%, (HR=1.48 [95% CI: 1.25-1.75], p< 0.001), and 5-year relapse incidence (RI) was higher: 67.2% versus 52.3%, (HR=1.46 [95% CI: 1.25-1.72], p< 0.001). Five-year non-relapse mortality (NRM) was 6.2% versus 6.0% for patients with 2 versus 1 chemotherapy courses, and did not differ significantly (HR=1.31 [95% CI: 0.81-2.10], p= 0.27). LFS and OS were inferior and relapse rate was higher in AML patients who received two inductions chemotherapy courses to reach CR1 before being autografted. AML patients who required 2 induction courses to achieve remission, may be offered allogeneic transplantation rather than an autologous one in an attempt to reduce their high RI and improve outcomes.

Neutropenia in the First Cycle of Consolidation Chemotherapy with High-Dose Cytarabine Is Not Associated with the Incidence of Relapse in Adult Acute Myeloid Leukemia Patients in First Complete Remission

Neutropenia in the First Cycle of Consolidation Chemotherapy with High-Dose Cytarabine Is Not Associated with the Incidence of Relapse in Adult Acute Myeloid Leukemia Patients in First Complete Remission

Extramedullary acute myeloid leukemia (eAML): Retrospective single center cohort study on clinico-pathological, molecular analysis and survival outcomes

Introductionextramedullary acute myeloid leukemia (eAML) is characterized by extramedullary tumor formation infiltrated by myeloid blasts, with or without maturation and effaced architecture. The clinical, genetic and molecular aspects and overall outcomes are well defined worldwide, but not well characterized in our region. Purpose and methodsThis is a retrospective single center cohort study on 32 patients, who were identified over 10 years to study the clinical, pathologic and genetic-molecular aspects, and survival outcomes. ResultseAML is rare (1%), occurs at a younger age with male predominance. Central nervous system (CNS) with facial bone invasion is most commonly identified (34.4%). 45.5% were positive for conventional myeloid markers (MPO), CD33, CD117, and 36% positive for CD34 and CD68. 54% with normal karyotype had deleterious mutations on further testing. NGS revealed pathogenic mutations in 76%(N-9/17) and none tested positive for P53, IDH1 or IDH2. At a median follow up time of 43mo (range, 8.6–80mo); 37.5%(N-12) were in complete remission, 62.5%(N-20) relapsed. 28% of relapses were after allotransplant. 31%(N-10) alive and continued in complete remission(CR), and 69%(N-22) of patients have died.Median overall survival (OS) is 18.4 and relapse free survival (RFS) 18.7 months. OS and RFS were significantly better in patients, who attained CR after induction (IC 11.9 mo vs zero; P = 0.0001; IC 12mo vs zero; P = 0.0001) compared to patients with relapsed disease; and in patients who received allo-transplant consolidation with median OS and RFS 42 vs 8.5mo (P = 0.002) and 42months vs 10 mo (P = 0.006). Thus allotransplant may be considered for all eligible patients in first CR. Conclusionachievement of complete remission after induction therapy is associated with improved outcomes in eAML. Allotransplant in first complete remission may be the most effective modality for achieving long-term remissions.

Early detection of WT1 measurable residual disease identifies high-risk patients, independent of transplantation in AML

AbstractWT1 overexpression is frequently identified in acute myeloid leukemia (AML) and has been reported to be a potential marker for monitoring measurable residual disease (MRD). We evaluated the use of postinduction WT1 MRD level as a prognostic factor, as well as the interaction between postinduction WT1 MRD response and the effect of allogeneic stem cell transplantation (allo-SCT) in the first complete remission (CR). In the ALFA-0702 trial, patients with AML, aged 18 to 59, had a prospective quantification of WT1 MRD. The occurrence of a WT1 MRD ratio >2.5% in bone marrow or >0.5% in peripheral blood was defined as MRDhigh, and ratios below these thresholds were defined as MRDlow. The prognostic value of MRD after induction chemotherapy was assessed in 314 patients in first CR by comparing the risk of relapse, the relapse-free survival (RFS), and the overall survival (OS). Interaction between MRD response and the allo-SCT effect was evaluated in patients by comparing the influence of allo-SCT on the outcomes of patients with MRDhigh with those with MRDlow. The results showed that patients with MRDhigh after induction had a higher risk of relapse and a shorter RFS and OS. The MRD response remained of strong prognostic value in the subset of 225 patients with intermediate-/unfavorable-risk AML who were eligible for allo-SCT, because patients with MRDhigh had a significantly higher risk of relapse resulting in worse RFS and OS. The effect of allo-SCT was higher in patients with MRDlow than in those with MRDhigh, but not significantly different. The early WT1 MRD response highlights a population of high-risk patients in need of additional therapy.