Patients In Complete Remission Research Articles

Key role of glutamine metabolism in persistence of leukemic cells upon exposition to FLT3 tyrosine kinase inhibitors.

Acute myeloid leukemias are a group of hematological malignancies characterized by a poor prognosis for survival. The discovery of oncogenic mutations in the FLT3 gene has led to the development of tyrosine kinase inhibitors such as Quizartinib. However, achieving complete remission in patients remains challenging because these new TKIs are unable to completely eradicate all leukemic cells. Residual leukemic cells persist during Quizartinib treatment, leading to the rapid emergence of drug-resistant leukemia. Given that mitochondrial oxidative metabolism promotes the survival of leukemic cells after exposure to multiple anticancer drugs, we characterized the metabolism of leukemic cells that persisted during Quizartinib treatment and developed metabolic strategies to eradicate them. In our study, employing biochemical and metabolomics approaches, we confirmed that the survival of leukemic cells treated with FLT3 inhibitors critically depends on maintaining mitochondrial metabolism, specifically through glutamine oxidation. We uncovered a synergistic interaction between the FLT3 inhibitor Quizartinib and L-Asparaginase, operating through anti-metabolic mechanisms. Utilizing various models of persistent leukemia, we demonstrated that leukemic cells resistant to Quizartinib are susceptible to L-Asparaginase. This combined therapeutic strategy shows promise in reducing the development of resistance to FLT3 inhibitors, offering a potential strategy to enhance treatment outcomes.

Relapse Prevention in Acute Myeloid Leukemia: The Role of Immunotherapy with Histamine Dihydrochloride and Low-Dose Interleukin-2.

The treatment and management of acute myeloid leukemia (AML) has improved in recent decennia by targeted therapy for subgroups of patients, expanded indications for allogeneic stem cell transplantation (allo-SCT) and surveillance of residual or arising leukemia. However, hematological relapse among patients who have attained complete remission (CR) after the initial courses of chemotherapy remains a significant cause of morbidity and mortality. Here, we review an immunotherapeutic option using histamine dihydrochloride and low-dose interleukin-2 (HDC/LD-IL-2) for remission maintenance in AML. The treatment is approved in Europe in the post-consolidation phase to avoid relapse among patients in CR who are not candidates for upfront allo-SCT. We present aspects of the purported anti-leukemic mechanism of this regimen, including translation of preclinical results into the clinical setting, along with relapse prevention in subgroups of patients. We consider that HDC/LD-IL-2 is a conceivable option for younger adults, in particular patients with AML of normal karyotype and those with favorable responses to the initial chemotherapy. HDC/LD-IL-2 may form an emerging landscape of remission maintenance in AML.

Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions

AbstractIn the phase 2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560 mg and venetoclax 400 mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival was 30% (95% confidence interval [CI], 14-49; median, 28 months; 95% CI, 13-82) and overall survival was 43% (95% CI, 23-62; median, 32 months; 95% CI, 15 to not evaluable). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95% CI, 37-79), with 4 experiencing disease recurrence. Two of 3 reattained CR on re-treatment. Time-to-treatment failure, which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7 years for responders. Beyond 56 weeks, grade ≥3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. This trial was registered at www.ClinicalTrials.gov as #NCT02471391.

Kuicolong-yu enema decoction retains traditional Chinese medicine enema attenuates inflammatory response ulcerative colitis through TLR4/NF-κB signaling pathway.

Ulcer colitis (UC) is a chronic, nonspecific, and noninfectious inflammatory bowel disease. Recently, Toll-like receptors (TLRs) have been found to be closely associated with clinical inflammatory diseases. Achieving complete remission in patients with intermittent periods of activity followed by dormancy is challenging. Moreover, no study has explored the mechanism by which Kuicolong-yu enema decoction retains traditional Chinese medicine enemas to attenuate the inflammatory response in UC. To explore the mechanism by which Kuicolong-yu enema decoction retains traditional Chinese medicine enemas to attenuate the inflammatory response in UC. This prospective clinical study included patients who met the exclusion criteria in 2020 and 2021. The patients with UC were divided into two groups (control and experimental). The peripheral blood of the experimental and control groups were collected under aseptic conditions. The expression of TLR4 protein, NF-κB, IL-6, and IL-17 was detected in the peripheral blood of patients in the experimental group and control group before and 1 month after taking the drug. Linear correlation analysis was used to analyze the relationship between the expression level of TLR4 protein and the expression levels of downstream signal NF-κB and inflammatory factors IL-6 and IL-17, and P < 0.05 was considered statistically significant. There were no significant differences in the patient characteristics between the control and experimental groups. The results showed that the expression levels of TLR4 and NF-κB in the experimental group were significantly lower than those in the control group (P < 0.05). The levels of IL-6 and IL-17 in the experimental group were significantly lower than those in the control group (P < 0.05). The TLR4 protein expression in the experimental group was positively correlated with the expression level of downstream signal NF-κB and was positively correlated with the levels of downstream inflammatory cytokines IL-6 and IL-17 (r = 0.823, P < 0.05). Kuicolong-yu enema decoction retains traditional Chinese medicine enema attenuates the inflammatory response of UC through the TLR4/NF-κB signaling pathway.

Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome

AbstractIvosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in 8 (42.1%) patients, including a grade 1 QT interval prolongation in 1 (5.3%) patient and grade 2 differentiation syndrome in 2 (10.5%) patients. Rates of CR + PR and objective response (CR + PR + marrow CR) were 38.9% (95% confidence interval [CI], 17.3-64.3) and 83.3% (95% CI, 58.6-96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of ≥5 years, and a median overall survival of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC)- and platelet-transfusion-dependent patients, respectively, became transfusion independent (TI; no transfusion for ≥56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in these patients. This trial was registered at www.ClinicalTrials.gov as #NCT02074839.

Prognostic impact of number of induction courses to attain complete remission in patients with acute myeloid leukemia transplanted with either a matched sibling or human leucocyte antigen 10/10 or 9/10 unrelated donor: An Acute Leukemia Working Party European Society for Blood and Marrow Transplantation study.

For the majority of patients with acute myeloid leukemia (AML) an allogeneic stem cell transplant (SCT) in first complete remission (CR) is preferred. However, whether the number of courses required to achieve CR has a prognostic impact is unclear. It is unknown which factors remain important in patients requiring more than one course of induction to attain remission. This Acute Leukaemia Working Party study from the European Society for Blood and Marrow Transplantation identified adults who received an allograft in first CR from either a fully matched sibling or 10/10 or 9/10 human leucocyte antigen (HLA)-matched unrelated donor (HLA-A, HLA-B, HLA-C, HLA-DR, or HLA-DQ). Univariate and multivariate analyses were undertaken to identify the prognostic impact of one or two courses of induction to attain CR. A total of 4995 patients were included with 3839 (77%) patients attaining a CR following one course of induction chemotherapy (IND1), and 1116 patients requiring two courses (IND2) to attain CR. IND2 as compared to IND1 was a poor prognostic factor in a univariate analysis and remained so in a multivariate Cox model, resulting in an increased hazard ratio of relapse (1.38; 95% confidence interval [CI], 1.16-1.64; p=.0003) and of death (1.27; 95% CI, 1.09-1.47; p=.002). Adverse prognostic factors in a multivariate analysis of the outcomes of patients requiring IND2 included age, FLT3-ITD, adverse cytogenetics, and performance status. Pretransplant measurable residual disease retained a prognostic impact regardless of IND1 or IND2. Initial response to chemotherapy as determined by number of courses to attain CR, retained prognostic relevance even following SCT in CR.

Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial

Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1-3 plus mitoxantrone (10 mg/m2 intravenously) on days 3-5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537. 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI -5·8 to 12·6) for the ITT population and 2·7% (-6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7-64) versus 42 days (27-121, U test p<0·0001), respectively. Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia. DKMS and the Gert and Susanna Mayer Stiftung Foundation.

Allogeneic hematopoietic stem-cell transplantation for patients with Richter transformation: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

Management of Richter transformation (RT) is particularly challenging, with survival estimates <1 year. We report on outcomes of 66 RT patients undergoing allogeneic-HCT (allo-HCT) between 2008 and 2018 registered with the EBMT. Median age at allo-HCT was 56.2 years (interquartile range (IQR), 51.3-63.1). Median time from RT to allo-HCT was 6.9 months (IQR, 4.9-11) and 28 (42.4%) were in complete remission (CR). The majority underwent reduced intensity conditioning (66.2%) using peripheral blood derived stem cells. Eighteen (27.3%) patients had a matched sibling donor, 24 (36.4%) a matched unrelated donor and the remaining were mismatched. Median follow-up was 6.6 years; 1- and 3- year overall and progression free survival (PFS) (95% CI) was 65% (54-77) and 39% (27-51) and 53% (41-65) and 29% (18-40), respectively. Patients in CR at time of allo-HCT had significantly better 3-year PFS (39% vs. 21%, p = 0.032). Cumulative incidences of grade II-IV acute graft versus host disease (GVHD) at day +100 was 41% (95% CI 29-53) and chronic GVHD at 3years was 53% (95% CI 41-65). High rates of non-relapse mortality (NRM) were observed; 38% (95% CI, 26-50) at 3 years. Although potentially curative, approaches to reduce considerable NRM and chronic GVHD rates are required.

Prognostic value of the peripheral blood lymphocyte/monocyte ratio combined with 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma

ObjectiveTo explore the prognostic value of the peripheral blood lymphocyte/monocyte ratio (LMR) combined with 18F-FDG PET/CT for diffuse large B-cell lymphoma (DLBCL). MethodsThe clinical data of 203 patients with primary DLBCL who were hospitalized to the First People's Hospital of Lianyungang between January 2017 and December 2022 were retrospectively analyzed. Before and after three courses of treatment, PET/CT was performed on forty DLBCL patients. The subject operating characteristic (ROC) curve has been employed to determine the most effective LMR cutoff points. According to the criteria for assessing the efficacy of Lugano lymphoma, the PET/CT findings after 3 courses of treatment were specified as complete remission (CR), partial remission (PR), stable disease (SD) and disease progression (PD). The CR group, PR+SD group, and PD group were the three groups created from the four outcomes. Results were analyzed using the Cox proportional risk model, the Kaplan-Meier method (K-M), and the log-rank test. ResultsAn optimal cutoff point of 3.00 for the LMR in 203 patients was determined by the SPSS 26 software ROC curve. When LMR≥3.00, the 1-year, 3-year, and 5-year OS (Overall Survival) rates are 98%, 88%, and 64% respectively, and the PFS (Progression-free Survival) rates are 90%, 75%, and 56% respectively. When LMR <3.00, the 1-year, 3-year, and 5-year OS rates are 96%, 72%, and 28% respectively, and the PFS rates are 83%, 60%, and 28% respectively. A lower LMR was substantially related with shorter OS, and PFS, according to a K-M survival analysis (P<0.005). LMR<3.00 was an independent predictor of OS, based on a multifactorial Cox analysis (P=0.037). K-M survival analysis of the 18F-FDG PET/CT results of 40 patients revealed that both OS and PFS were statistically significant (P<0.001). Patients were separated into 3 groups combining LMR and 18F-FDG PET/CT: PET/CT CR patients with LMR≥3.00, PET/CT PD patients with LMR<3.00, and others. The Kaplan-Meier analysis revealed that there were significant differences in OS and PFS for each of the three groups (P<0.001). ROC curves showed that the area under the curve (AUC) of the combined testing of the two was 0.735, and the combined testing of the two was better compared to testing alone (PET/CT AUC=0.535, LMR AUC=0.567). This indicates that combining both PET/CT and LMR is a favorable prediction for DLBCL. ConclusionA decreased LMR at initial diagnosis suggests an unfavorable prognosis for DLBCL patients; For patients with DLBCL, combining 18F-FDG PET/CT and the LMR has a better predictive value.

Effects of Combinatory In Vitro Treatment with Immune Checkpoint Inhibitors and Cytarabine on the Anti-Cancer Immune Microenvironment in De Novo AML Patients.

Despite substantial progress in the diagnostic and therapeutic procedures, acute myeloid leukaemia (AML) still constitutes a significant problem for patients suffering from its relapses. A comprehensive knowledge of the disease's molecular background has led to the development of targeted therapies, including immune checkpoint inhibitors, and demonstrated beneficial effects on several types of cancer. Here, we aimed to assess in vitro the potential of the immune checkpoint blockage for supporting anti-cancer responses to the AML backbone therapy with cytarabine. PBMCs of AML patients were collected at admission and, following the therapy, eight complete remission (CR) and eight non-responders (NR) subjects were selected. We assessed the effects of the in vitro treatment of the cells with cytarabine and the immune checkpoint inhibitors: anti-CTLA-4, anti-PD-1, anti-PD-L1. The study protocol allowed us to evaluate the viability of the cancer and the immune cells, proliferation status, phenotype, and cytokine release. Anti-PD-L1 antibodies were found to exert the most beneficial effect on the activation of T cells, with a concomitant regulation of the immune balance through Treg induction. There was no direct influence on the blast cells; however, the modulation of the PD-1/PD-L1 axis supported the expansion of lymphocytes. Changes in the response between CR and NR patients might result from the differential expression of PD-1 and PD-L1, with lower levels in the latter group. The tested blockers appear to support the anti-cancer immune responses rather than directly improve the effects of cytarabine. In conclusion, checkpoint proteins' modulators might improve the anti-cancer responses in the tumour environment.

Equivalent prognosis with no lymph node metastasis to pathological complete remission in patients with localized advanced esophageal cancer after neoadjuvant triplet chemotherapy with docetaxel, cisplatin, and 5-fluorouracil followed by curative surgery: a single-center retrospective cohort study.

Adjuvant nivolumab therapy has become the standard therapy for patients with localized advanced esophageal cancer with non-pathological complete response after neoadjuvant chemoradiotherapy followed by curative surgery. However, the necessity of this therapy for patients after neoadjuvant chemotherapy (NAC) with docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen followed by surgery is unclear, and the prognosis of grouping based on the presence or absence of pathological tumor and lymph node findings has not been analyzed. Therefore, our study aimed to address these questions. This retrospective cohort study included patients with cT1N1-3M0 and cT2-3N0-3M0 esophageal cancer according to the Japanese Classification of Esophageal Cancer, 11th edition, who received NAC with DCF followed by curative surgery between 2008 and 2020 at Jichi Medical University Hospital. We divided patients with ypT0-3N0-3M0 into four histological groups, namely ypT0N0, ypT+N0, ypT0N+, and ypT+N+, and we evaluated overall survival as the primary outcome and the prognostic relationship of lymph node metastasis as the secondary outcome. A total of 101 patients were included in this study. Kaplan-Meier analysis showed that the curves of the ypT0N0 and ypT+N0 groups were almost identical, while they differed from the other two groups. The hazard ratio of ypN+ was 4.44 (95% confidence interval: 2.03-9.71; P<0.001). The prognosis of the ypT+N0 group after NAC with DCF followed by surgery was similar to that of pathological complete remission. Grouping patients according to pathological lymph node status is a reasonable predictor of prognosis.

Menin Inhibitors Trigger Leukemia Remissions

Abstract Menin inhibitors have proven effective in patients with acute leukemias. A phase II study of revumenib yielded a response rate of 63% in patients with relapsed or refractory disease and KMT2A rearrangements; a phase I trial combining the drug with three chemotherapies also yielded complete remissions in patients with acute myeloid leukemia. A phase I study of a different menin inhibitor detected responses in 63% of patients with acute leukemia and certain gene alterations.

Long-term disease-free survival following comprehensive involved site radiotherapy for oligometastases.

Despite recent advances in drug development, durable complete remissions with systemic therapy alone for metastatic cancers remain infrequent. With the development of advanced radiation technologies capable of selectively sparing normal tissues, patients with oligometastases are often amenable to comprehensive involved site radiotherapy with curative intent. This study reports the long-term outcomes and patterns of failure for patients treated with total metastatic ablation often in combination with systemic therapy. Consecutive adult patients with oligometastases from solid tumor malignancy treated by a single high volume radiation oncologist between 2014 and 2021 were retrospectively analyzed. Oligometastases were defined as 5 or fewer metastatic lesions where all sites of active disease are amenable to local treatment. Comprehensive involved site radiotherapy consisted of stereotactic radiotherapy to a median dose of 27 Gy in 3 fractions and intensity modulated radiation therapy to a median dose of 50 Gy in 15 fractions. This study analyzed overall survival, progression-free survival, patterns of failure and toxicity. A total of 130 patients with 209 treated distant metastases were treated with a median follow-up of 36 months. The 4-year overall survival, progression-free survival, local control and distant control was 41%, 23%, 86% and 29%. Patterns of failure include 23% alive and free of disease (NED), 52% distant failure only, 9% NED but death from comorbid illness, 7% both local and distant failure, 4% NED but lost to follow-up, 4% referred to hospice before restaging, 1% local only failure, 1% alive with second primary cancer. Late grade 3+ toxicities occurred in 4% of patients, most commonly radionecrosis. Involved site radiotherapy to all areas of known disease can safely achieve durable complete remissions in patients with oligometastases treated in the real world setting. Distant failures account for the majority of treatment failures and isolated local failures are exceedingly uncommon. Oligometastases represents a promising setting to investigate novel therapeutics targeting minimal residual disease.

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.

Single-Cell Proteomic Analysis Reveals Menin Inhibition-Induced Proteomic Alterations in AML Patients Treated with Revumenib

Menin inhibition is a promising therapeutic approach for acute myeloid leukemia (AML) with certain genetic alterations including KMT2A rearrangements or NPM1 mutations. The first-in-human Phase 1 clinical trial of revumenib (SNDX-5613) in patients with R/R AML showed promising results and induced complete remission in patients who refractory to multiple lines to therapy. These findings suggest that revumenib could provide a new therapeutic option for patients with AML with KMT2A and NPM1 genetic alterations. AML is characterized by the existence of distinct differentiation hierarchies, a phenomenon substantially contributing to disease heterogeneity. AML hierarchies exhibit distinct expressions of phenotypic profiles, apoptotic networks, signaling pathways, and metabolic profiles, leading to varying sensitivity towards targeted therapies, resulting in differential sensitivity to targeted therapies. Revumenib induces AML differentiation and thus shift the balance between AML hierarchies, resulting in drastic alterations in the overall AML proteomic profiles and enrichment of distinct leukemia phenotypes with differential sensitivity to targeted therapies. Detailed interrogation of revumenib-induced proteomic alterations could permit precise targeting of persistent cells and development of data-driven combinatorial approaches to achieve higher response rates. Moreover, the distinct combinations of genetic alterations can impact the efficacy of revumenib-induced differentiation and therapeutic outcomes. Thus, to better understand these complexities we performed multimodal single-cell (sc) analysis of AML landscape in R/R AML treated with revumenib (n=4) in Phase 1. We utilized two leukemia-focused 51-parameter CyTOF panels to analyze pre and post-treatment samples from R/R AML patients treated with revumenib. Sc proteogenomic profiling was performed using MissionBio platform using a panel covering 37 genes with recurrent AML-relevant mutations. UMAP and clustering analyses of CyTOF data identified AML blasts, unveiled quantitative changes in cell composition, and delineated proteomic shifts induced under revumenib therapy pressure. We observed enrichment of CD11b+/-CD68+, more differentiated monocytic cells situated at close proximity to AML blasts and depletion of immature AML blasts. Through unsupervised analysis, we discovered discrete AML differentiation hierarchies, delineated by a differentiation continuum that initiates with immature AML blasts (CD34+/-c-Kit+/-), progresses through intermediate AML blasts (CD68+/CD11b-/CD14-), and culminates with more differentiated monocytic cells (CD68++/CD11b+/CD14+/-). Notably, intermediate AML blasts and monocytic cells were enriched in post-treatment samples. Simultaneous ScDNA+protein analysis showed enrichment of differentiated AML blasts with monocytic/dendritic cell phenotype and harboring AML mutations. Differentiated AML blasts expressed higher levels of MCL1 and BCL-xL and upon differentiation we observed gradual downregulation of BCL2. Importantly, intermediate and more differentiated AML blasts under revumenib therapy expressed high levels of p53 protein, a feature that can partly attributed to NPM1 mutations. Sc proteomic analysis delineated proteomic shifts elicited by revumenib and identified potential therapeutic partners, by targeting MCL1, BCL-xL and MDM2, that could be used in combination with revumenib to improve therapeutic efficacy. We next performed differential expression analysis by comparing the proteomic profiles of pre- and post-therapy samples. We observed suppression of less differentiated AML phenotypic profiles (c-Kit, CD123, CD34) along with MEIS1 and PBX3. Importantly, we also observed significant alterations in immune landscape, suggesting that revumenib could rewire Myeloid-to-T and NK cell interaction/communication by inducing proteomic shifts and driving AML blast differentiation. Further analysis of an expanded cohort of R/R AML patients is currently underway. In conclusion, multimodal sc analysis revealed profound proteomic alterations induced by revumenib and identified potential therapeutic targets. These findings present new avenues for optimizing combinatorial treatment regimens, enhancing revumenib's efficacy, and illuminating survival mechanisms in persistent, differentiated AML blasts.

Olutasidenib Alone or in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Myelodysplastic Syndromes/Neoplasms (MDS)

Introduction Olutasidenib is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Olutasidenib is approved in the US for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) based on the pivotal cohort (n=153) of a registrational Phase 1/2 trial (NCT02719574), which demonstrated a rate of complete remission (CR) or CR with partial hematologic recovery (CRh) of 35%, with a duration of response of 25.9 months. The Phase 1/2 study also enrolled patients with mIDH1 myelodysplastic syndromes/neoplasms (MDS), and here we report results from this subset of 22 patients. Methods The Phase 1/2 open-label study enrolled 332 adult patients with mIDH1 AML or intermediate-, high-, or very high-risk MDSfrom 57 centers in 9 countries. Inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate liver and renal function. Patients were R/R to prior therapy or, if treatment-naïve (TN), had to be eligible for azacitidine therapy (to be enrolled in a combination therapy cohort). Olutasidenib was administered at 150 mg BID (n=3) or 100-150 QD (n=3) as monotherapy or in combination with azacitidine (n=16), given at 75 mg/mm 2 daily for 7 consecutive days, in 28-day cycles. The primary efficacy endpoint for MDS was the CR rate, based on response criteria of the International Working Group in MDS. Secondary efficacy endpoints included overall response (CR/PR/marrow CR), time to response, duration of response and safety. Results Twenty-two patients with MDS were enrolled, including 6 who received monotherapy (4 R/R and 2 TN) and 16 who received combination therapy (11 R/R and 5 TN). Baseline demographics and disease characteristics are shown in Table 1. The age ranged from 59-87 years, and 59% of the study population were male. Seven patients were treatment-naïve and 15 were R/R with 1-4 prior treatment regimens. For the pooled Phase 1 and 2 data (n=22), 6 (27%) patients achieved CR and 7 (32%) patients achieved marrow CR with no PRs, generating a 59% overall response rate. The median time to response was 2.0 months. The median duration of response was not reached (NR) at 30.1+ months ( Table 2). The overall response rate was 2/6 (33%) for monotherapy and 11/16 (69%) for combination therapy. Three of 6 patients received monotherapy at a lower dose (100-150 QD) than the approved dose level, and none responded. Of the 3 patients who received monotherapy at the approved dose level (150mg BID), 2 (66%) responded. In the 7 TN patients, the overall response rate was 86%. In the 15 R/R patients, the overall response rate was 47%. All patients with MDS experienced at least 1 treatment-emergent adverse event (TEAE). The most frequent TEAEs in the study were nausea, constipation, vomiting, thrombocytopenia, neutropenia, diarrhea, and fatigue. Grade 3 TEAEs occurred in 19/22 (86%) patients, and Grade 4 TEAEs in 9/22 (41%). The most frequent Grade 3/4 TEAEs reported were cytopenias. Grade 3 transaminitis occurred in 4 patients. Grade 3 differentiation syndrome was reported in 1 patient, who discontinued treatment after 23 days due to pneumonia, which lead to respiratory failure and death. TEAEs resulting in death occurred in 5 patients and included disease progression (3), pneumonia (1, mentioned above) and chest fungal infection (1). The overall safety profile in patients with MDS was consistent with what has been reported in patients with AML in this study (Watts, et al., Lancet Hematol, 2022; de Botton et al., Blood Adv, 2023). Conclusions Olutasidenib, both as monotherapy and in combination with azacitidine, induced durable remissions in patients with intermediate-, high-, or very high-risk MDS. Patients had varying treatment backgrounds, including treatment-naïve and up to four prior regimens. This treatment had a tolerable and manageable safety profile. These encouraging results, which warrant further investigation with a larger number of patients, show that olutasidenib has clinically meaningful activity in patients with mIDH1 MDS.

Olutasidenib for the Treatment of mIDH1 Acute Myeloid Leukemia in Patients Relapsed or Refractory to Hematopoietic Stem Cell Transplant, Prior mIDH1 Inhibitor, or Venetoclax

Introduction. Olutasidenib is a small molecule, oral, mutated-IDH1 (mIDH1) inhibitor approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). In the pivotal cohort of the registrational phase 1/2 trial, 51/147 (35%) patients achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) to olutasidenib, with a duration of response of 25.9 months and an overall response rate (ORR) of 48%. The phase 1/2 study included 10 cohorts for a total of 335 patients, and there were patient subsets that were R/R to previous hematopoietic stem cell transplant (HSCT), ivosidenib (IVO) or venetoclax (VEN). We conducted post hoc analyses to better understand the response to olutasidenib in these poor-prognosis subgroups of mIDH1 AML. Methods. This Phase 1/2, open-label, multi-center study enrolled patients with confirmed AML or intermediate, high-, or very high-risk myelodysplastic syndromes/neoplasms (MDS). Patients received olutasidenib 100mg QD, 150mg QD or 150mg BID monotherapy or the combination of olutasidenib 150mg BID plus azacitidine. Patients were grouped by prior therapy. Baseline demographics and disease characteristics are shown in Table 1. The study was not powered to statistically evaluate subpopulations; descriptive statistics are provided. Data cutoff date is June 2021. Results. The post-HSCT group (n=31) had a relatively high median baseline bone marrow blast count (58%) and a median of 4 prior treatment regimens ( Table 1). Six (19%) of these patients had a CR (including the 1 patient with MDS), and 3 (10%) patients had a CR with incomplete count recovery (CRi) resulting in a 29% composite complete remission (CRc) rate. One patient had a morphologic leukemia-free status, resulting in a 32% ORR. Half the responders received monotherapy, and half received a combination of olutasidenib and azacitidine. Two patients were enrolled in the monotherapy maintenance cohort while in CR to prior HSCT; one of these patients maintained a CR for 13 months before progressing, and the other patient progressed and discontinued due to a new central nervous system disease ( Table 2). For the 10 patients with responses (ORR), the median duration of response was 7.1 months (range 1-23.4+). At data cutoff, 2 patients were ongoing responders, 3 patients proceeded to a second HSCT, and 3 to donor lymphocyte infusion (DLI). The post-IVO group (n=9) had a high median baseline bone marrow blast count (83%) and a median of 4 prior treatment regimens ( Table 1). Two patients (22%) achieved a CR; both CRc and ORR were 22% ( Table 2). Both responders had received olutasidenib in combination with azacitidine. One responder proceeded to HSCT after 3.1 months, and one responded for 5.6 months and then had disease progression. Response rates in the post-VEN group (n=20) included CR in 6 patients (30%), CRh in 1 (5%), and CRi in 2 (10%) resulting in a CRc of 9 (45%) and an ORR of 45% ( Tables 1 and 2). One responder received combination olutasidenib and azacitidine. Two patients were enrolled in the monotherapy maintenance cohort while in CRi to prior treatment; both improved their response to a CR. Median duration of response was not reached and ongoing at 28.5 months. At data cutoff, 5 patients continued treatment, and 15 had discontinued. Conclusions. This descriptive analysis suggests that olutasidenib alone or in combination with azacitidine may induce complete remissions in patients with mIDH1 AML or MDS that is R/R to VEN, IVO or even HSCT. Further investigation of these difficult-to-treat subpopulations is needed. Although only a small number of patients receiving maintenance therapy were included in this analysis, the data show that maintenance of a CR and even improvement of response from CRi to CR is possible with olutasidenib.

Long-Term Real-World Experience of CPX-351 in Combined French-Italian Cohorts Identified High Rate of Negative Measurable Residual Disease (MRD) and Prolonged Overall Survival

Introduction CPX-351 is a liposomal formulation of cytarabine and daunorubicin packaged at a 5:1 molar ratio. This drug has been approved by the FDA and EMEA for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML) according to the WHO 2016 AML classification. Real world experience from several countries (France, Italy, Germany, UK and US) showed similar results of phase 3 clinical registration but with short follow-up. Lancet et al. published a long-term update of phase 3 clinical trial and confirmed long-term remission and improvement of overall survival (OS) ( Lancet Haematology 2021). Thus, the primary objective of this study was to analyze the efficacy of CPX-351 in a real-life setting with a longer follow-up, evaluating the impact of measurable residual disease (MRD) in responding patients. Methods We retrospectively collected data from patients treated with CPX-351 in thirty-six centers in France and Italy. Overall response rate (ORR) was defined by complete remission (CR) and CR with incomplete hematological recovery (CRi). Among the patients in CR or CRi, 62 (61%) had MRD evaluation assessed by next-generation sequencing (NGS) or flow cytometry. OS was calculated from the date of AML diagnosis to the date of death or last follow-up. All statistical analysis were performed using SPSS v.22 software (IBM SPSS Statistics). Results Between April 2018 and October 2019, 170 patients treated with CPX-351 were included in this study. The sex ratio male/female was 80/90 and the median age was 66 years (range 20-83). AML subtypes were MRC-AML in 117 (69%) and t-AML 48 (28%) patients. According to the European LeukemiaNet (ELN) 2017 classification, genetic risk was favorable, intermediate, and adverse in 8 (5%), 61 (36%), and 98 (58%) (missing for 3 patients), respectively. According to the ELN 2022 classification, genetic risk was favorable, intermediate, and adverse in 8 (5%), 16 (9%) and 143 (84%), respectively. Thirty percent and 19% of patients had complex and monosomal karyotypes, respectively. Assessed by NGS the most frequent mutated genes were: TP53 (n=35, 21%), RUNX1 (n=30, 18%), ASXL1 (n=22, 13%) and TET2 (n=18, 11%) among the XX were NGS was available (sinon ca fait des % qui ne tombe pas juste sur les 170 pts). According to a genetic ontogeny-based classifier (Lindsley et al., Blood 2015), 28 %, 39% and 33% had de novo/pan-AML, secondary type mutations AML, and TP53 mutated AML, respectively. The ORR was 102/170 (60%) after one (n=91) or two (n=11) inductions including 53% CR and 6% CRi. Among the 102 CR/CRi patients, 62 (61%) were evaluable for MRD after induction or after first consolidation. Forty (65%) patients had MRD below the threshold of 10 -3. ELN2017 and ELN2022 were identified as factors predicting CR/CRi rate ( P=0.032 and P=0.043, respectivelyà but the Lindsley classifier did not predict response ( P= 0.060). After 3-years of follow-up, in a univariate analysis, only MRD &amp;gt;10 -3 ( P=0.031); ELN 2017 classification ( P=0.027) and presence of TP53 mutation ( P=0.017) but not ELN 2022 or the Lindsley classifier; were associated with a significantly poorer median OS. In a multivariate analysis, only MRD &amp;gt;10 -3 was associated with a poorer OS (hazard ratio [HR]=2.6, 95% CI 1.2-5.5, P=0.013). Median OS was 40.9 months vs. 10.6 months for patients with MRD &amp;lt;10 -3 vs. ≥10 -3, respectively ( P=0.006). Sixty (35%) patients underwent an allogeneic hematopoietic stem cell transplant (HSCT) with an improved median OS compared to non-transplanted patients (not-reached vs. 9.1 months, P&amp;lt;0.0001). We also observed a trend towards a better median OS in transplanted patients who underwent an HSCT with MRD &amp;lt;10 -3 (not reached vs. 26.0 months, P=0.06). Conclusion After 3 years of follow-up, the improved OS with CPX-351 was confirmed in the real- life setting. Achievement of MRD negativity contributed to improvement of OS in the overall population and, maybe, in transplanted patients. These data provide the rationale for the ongoing ALFA-2101 phase III clinical trial evaluating CPX-351 vs. 3+7 (daunorubicin and cytarabine) in non-MRC-AML and non-t-AML using MRD as the primary endpoint.

Orthotopic Heart Transplantation Followed By Autologous Stem Cell Transplantation in Patients with Cardiac AL Amyloidosis: Results from a Single Centre Prospective Study

Background: Patients with advanced cardiac AL amyloidosis have a dismal prognosis, with an overall survival (OS) of only 5 months for Stage IIIb patients (Palladini et al, 2023). Induction chemotherapy followed by high dose chemotherapy and autologous stem cell transplantation (HDT and ASCT) has been widely used as treatment for AL amyloidosis. However, patients with advanced cardiac AL amyloidosis are often not suitable for HDT and ASCT due to high transplant related mortality (TRM). Orthotopic cardiac transplantation (OHT) following induction treatment may improve patient fitness and thus allow HDT and ASCT to deepen and prolong responses. We present our single centre, prospective study of patients with Stage IIIa and Stage IIIb cardiac AL amyloidosis who received OHT followed by sequential HDT and ASCT. Aims: The primary outcomes were 3 year OS and progression-free survival (PFS). Efficacy and safety were assessed as secondary outcomes. Efficacy was evaluated by light chain and cardiac response after ASCT. Safety was assessed by rate of TRM, cardiac rejection, opportunistic infections, and cytopenia related complications. Methods: During 2015 to 2021, patients with Stage IIIa or Stage IIIb AL amyloidosis aged under 65 years underwent OHT followed by HDT and ASCT. Patients with multiple myeloma were excluded. At approximately 6 months following OHT, patients underwent stem cell mobilization with granulocyte colony-stimulating factor alone followed by peripheral blood apheresis stem cell collection. Mycophenolate immunosuppression was temporarily withheld during stem cell mobilization and collection. Patients then received a high dose melphalan ASCT followed by 3-6 monthly assessments. Results: Nine patients (median age of 53 years, range 47-60 years) completed both OHT and ASCT. Seven other patients were screened but did not proceed with OHT. The cohort included both stage IIIa (55%) and stage IIIb (44%) patients. Most patients received cyclophosphamide-bortezomib-dexamethasone induction therapy (89%) and one patient received lenalidomide-bortezomib-dexamethasone. The median time from diagnosis of AL amyloidosis to OHT was 11 months (range 5-57 months) and median time from OHT to ASCT was 7 months (range 5-8 months). 3 year OS was 83% and PFS was 56% (Figure 1). At a median follow up of 37 months (range 17-69 months), 89% of patients remain alive. One patient with Stage IIIa disease who underwent HDT and ASCT with progressive disease (PD) died 28 months following ASCT due to PD. Subgroup analysis demonstrated 3 year OS in Stage IIIa patients of 75% compared to 100% in Stage IIIb (p=0.48). 3 year PFS was 53% in Stage IIIa patients and 66% in Stage IIIb (p=0.8). Patients in complete remission (CR) prior to ASCT had an improved 3 year OS of 100% compared to 66% for those in partial remission (PR) or with PD (p=0.32). 3 year PFS was significantly improved at 100% when ASCT occurred in CR compared to 0% in those in PR or with PD (p=0.01) (Figure 2). All patients either maintained a CR or achieved an improved haematological response following HDT and ASCT, with 89% of patients in CR at 6 months post ASCT. At the median follow up of 37 months, 78% were in CR and 22% had PD. At last follow up, there has been no documented amyloid recurrence in a cardiac allograft. There was no TRM noted in this study. All patients had cardiac rejection with 66% developing Grade 3A/2R rejection requiring methylprednisone. The most common infective complication was CMV reactivation (44%). Other infective complications included cryptococcal infection (11%), aspergillus and MAC infection (11%) and HSV reactivation requiring hospitalization (11%). During admission for HDT and ASCT, 89% had febrile neutropenia and there were no bleeding complications. Conclusions: We have demonstrated, in a prospective design, that sequential OHT/ASCT following induction therapy is safe in patients with Stage IIIa/b cardiac AL amyloidosis without an increase in TRM. This approach was associated with excellent survival outcomes compared with historical cohorts. Given the deep and prolonged responses seen with daratumumab based induction, a risk adapted strategy may be more appropriate moving forward, with only those not achieving a haematological CR undergoing consolidation ASCT following OHT.

Clinical Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation Using Busulfan/Cyclophosphamide and Melphalan or Thiotepa As Conditioning Regimen in 37 Patients with Acute Megakaryoblastic Leukemia

Background Acute megakaryoblastic leukemia (AMKL) is a rare and heterogeneous subtype of acute myeloid leukemia (AML), which accounts for approximately 10% of childhood AML and about 1% of adult AML. Patients with non-Down's syndrome AMKL (non-DS-AMKL) are often associated with a poor prognosis with a 3-year overall survival (OS) rate of less than 40%. Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative therapy for AMKL. However, the long-term survival post-transplant needs to be improved. Here we conducted a single-center study to evaluate the long-term efficacy and safety of allo-HSCT in 37 non-DS-AMKL patients using an innovative conditioning regimen of Busulfan/Cyclophosphamide (Bu/Cy) and Melphalan (MEL) or Thiotepa (TT). Methods From August 2015 to July 2023, a total of 37 non-DS-AMKL patients (M/F 21:16) were treated consecutively in our hospital (Hebei Yanda Lu Daopei Hospital). The median age was 2 years (range 1-9 years). Chromosomal abnormalities were present in 24 cases, with fusion genes as follows CBFA2T3/GLIS2 (5 cases) 13.5%, NUP98-KDM5A (2 cases) 5.4%, MLL-AF10 (3 cases) 8.1%, MLL-AF9 (1 case) 2.7%. Gene mutations: WT1 (10 cases) 27%, JAK2 (7 cases) 18.9%, EVI1 (6 cases) 16.2%, TET2 (4 cases) 10.8%, ASXL1 (4 cases) 10.8%, PTPN11 (4 cases) 10.8%, NRAS (3 cases) 8.1%, GATA1 (2 cases) 5.4%. Before transplantation, in bone marrow (BM), 29 patients were in complete remission (CR), 3 were in partial remission (PR) and the rest 5 were in non-remission (NR). Thirty-three patients received the haploidentical transplantation (donors from parents n=31, siblings n=2) including 1 with the 3 rd transplant, and 4 received matched-unrelated donor transplantation. The stem cell sources were from BM and peripheral blood stem cells (PBSCs) among the 33 related donors, and PBSCs for the 4 unrelated donors. Patients received a median cell number of total mononuclear cells 20.15×10 8/kg (10.7-32.85), CD34+ cells 12×10 6/kg(4.05-27.14) and CD3+ cells 4.66×10 8/kg(1.81-19.38). The conditioning regimens administered were modified Bu/Cy (fludarabine 30 mg/m 2/d×5d; cytarabine 2g/m 2/d×5d; Bu 3.2 mg/kg/d×4d, Cy 1.8g/m 2/d×2d; etoposide 100mg/m 2/d×2d; antithymocyte globulin 1.5mg/kg/d×5d) in 2 patients, Bu/Cy+MEL (MEL 55mg/m 2/d×2d) in 31 patients, and Bu/Cy+TT (TT 2.5mg/kg/d×2d) in the rest 4 patients. Cyclosporine A (CSA)+ mycophenolate mofetil (MMF)+ short methotrexate (sMTX) were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up time was 24 months (2-84 months), and all 37 cases survived the graft, with a median leukocyte engraftment of +13 days (9-21 days), and a median platelet engraftment of +9 days (4-38 days). BM was assessed one month after transplantation, with all grafts fully donor-type. The 5-year OS was 54.1% (Figure 1). There was a significantly higher OS in the CR group (5-year OS 69%) than the PR or NR groups (P&amp;lt;0.001) (Figure 2). Among the CR patients, no significant difference was observed in the 3 different condition regimen groups with modified BU/CY group OS of 50%, BU/CY+MEL group OS of 69.6% and BU/CY+TT group OS of 75% (P=0.869) (Figure 3). After transplantation, 17 patients died including 11 from relapse, 4 from GVHD, 1 from gastrointestinal bleeding and 1from cerebral hemorrhage. The cumulative recurrence rate (CIR) was 29.7%, among which the CIR of the CR group was 17.2%, the PR group of 66.7% and the NR group of 80% (P&amp;lt;0.001). Post-transplant, the incidence of acute GVHD (aGVHD) was 35.13% (Grade II-IV), and severe aGVHD (Grade III-IV) incidence was 18.91%. And 51.35% of patients developed chronic GVHD. Other complication incidences were cystitis at 16.21%, cytomegalovirus at 5.94%, Epstein-Barr viremia at 13.5% and infections at 21.62%. Conclusions Our study indicates that the use of modified Bu/Cy +MEL or +TT conditioning regimens in allo-HSCT procedures presents a feasible and effective approach, demonstrating an improvement in overall survival for non-Down Syndrome AMKL patients. Crucially, it was observed that achieving CR prior to transplantation significantly contributes to better outcomes. Therefore, it is strongly recommended that allo-HSCT is performed in CR status. However, to corroborate these findings, it is essential to conduct long-term, large-scale clinical research across multiple centers.