Intermediate-dose Cytarabine Research Articles

Mini‐consolidations or intermediate‐dose cytarabine for the post‐remission therapy of AML patients over 60. A retrospective study from the DATAML and SAL registries

AbstractAccording to current recommendations, older AML patients in first complete remission (CR) after induction chemotherapy should receive consolidation with intermediate‐dose cytarabine (IDAC). However, no study has demonstrated the superiority of IDAC over other regimen. In this retrospective study, we compared the efficacy of mini‐consolidations (idarubicin 8 mg/m2 day 1, cytarabine 50 mg/m2/12 h, day 1–5) and IDAC. Inclusion criteria were newly diagnosed AML, age > 60 years, first CR after induction and at least 1 cycle of consolidation. Of the 796 included patients, 322 patients received mini‐consolidations and 474 patients received IDAC. Mini‐consolidation patients were older, and more often, they had de novo AML and unfavorable risk. The rate of allogeneic transplantation was higher in the IDAC group. The median number of cycles was higher in the mini‐consolidation group (4 vs. 2; p < .0001). Median relapse‐free survival was 18 months with mini‐consolidations and 12 months with IDAC (p = .0064). In multivariate analysis, the risk of relapse or death was significantly higher in the IDAC group (p = .004). Median OS was 36 versus 31 months with mini‐consolidations or IDAC, respectively (p = .46). In multivariate analysis, the consolidation regimen had no significant influence on OS (p = .43). In older AML patients, post‐remission therapy with mini‐consolidations represents an alternative to IDAC.

Venetoclax combined with hypomethylating agents for favorable risk acute myeloid leukemia: A single center experience.

e18514 Background: Favorable risk acute myeloid leukemia (FR-AML) is typically treated with intensive induction chemotherapy followed by high dose consolidative cytarabine. However, a subgroup of FR-AML are not candidates for high intensity induction because of advanced age, comorbidities, or poor performance status. For these patients, hypomethylating agents (HMA) combined with venetoclax (HMA-Ven) is inferred as the standard of care based upon results of the VIALE-A trial; however, that trial enrolled only intermediate or poor risk AML. The efficacy of HMA-Ven in FR-AML is unclear. Here we present a single center experience of this regimen in FR-AML. Methods: In this retrospective single center case series, we collected data from all patients >18 years old with newly diagnosed FR-AML between January 2018 to December 2022 at AdventHealth Orlando who were treated with HMA-Ven. Patient with relapsed/refractory disease or a diagnosis of acute promyelocytic leukemia were excluded. FR-AML was defined using ELN 2022 guidelines based on the results of genomic testing of the initial bone marrow aspirate. The primary endpoints were the complete remission (CR) rate and 1-year overall survival (OS). Statistical analyses were performed using the R survminer package. Results: Newly diagnosed FR-AML who received HMA-Ven were identified (n=12). The median age was 67.5 years. 3 (25%) cases had inversion of chromosome 16 and 9 (75%) had NPM1 mutations without FLT3-ITD mutations. 11 (92%) patients received decitabine and venetoclax. Patients received a median of 2.5 cycles of HMA-Ven, and all 12 patients achieved CR after one cycle of treatment. 6 (50%) patients were consolidated with intermediate-dose cytarabine (IDAC), 3 (25%) continued HMA-Ven, 2 (17%) underwent allogeneic stem cell transplant, and 1 (8%) received enasidenib. The 1-year OS was 80% (CI 0.59-1), and the median OS was not reached. 1 patient died due to chemotherapy toxicity with IDAC, and 1 patient died due to heart complications. 2 patients relapsed, 1 after IDAC and 1 after intolerance to further treatment after 6 cycles of HMA-Ven. Conclusions: Our findings suggest that HMA-Ven is an effective treatment for newly diagnosed favorable risk AML. All patients achieved CR with one cycle of treatment with most surviving more than one year. Large multicenter studies are needed to further validate these promising results.

Serum albumin is associated with the inherent property of acute myeloid leukemia and correlates with patient outcomes.

An accurate prognostic model for acute myeloid leukemia (AML) can guide personalized treatment. In our prospective cohort of 591 patients newly diagnosed with AML, we evaluated the prognostic significance of serum albumin levels. We recognized baseline serum albumin as a prognostic factor by univariate Cox regression analysis (albumin-high vs albumin-low: overall survival [OS]: hazard ratio [HR]: 0.679, 95% confidence interval [CI]: 0.529-0.870, P = .002; cumulative incidence of relapse [CIR]: HR: 0.705, 95% CI: 0.530-0.938, P = .017) and multivariate Cox regression analysis (OS: HR per g/L: 0.966, 95% CI: 0.940-0.993, P = .014; CIR: HR per g/L: 0.959, 95% CI: 0.927-0.993, P = .017). In the subgroup analysis, serum albumin was prognostic significant in patients who received intermediate-dose cytarabine combined with daunorubicin and omacetaxine mepesuccinate induction (albumin-high vs albumin-low: OS: HR: 0.585, 95% CI: 0.397-0.863, P = .007; CIR: HR: 0.551, 95% CI: 0.353-0.861, P = .009) rather than those receiving conventional-dose induction regimens. In addition, the impact of baseline serum albumin level was evident in patients with intermediate European LeukemiaNet risk (albumin-high vs albumin-low: OS: HR: 0.617, 95% CI: 0.424-0.896, P = .011; CIR: HR: 0.617, 95% CI: 0.388-0.979, P = .040). Gene set enrichment analysis revealed that leukemia stem cell signatures were enriched in patients with low serum albumin levels. Our study suggested that baseline serum albumin level was associated with the inherent properties of AML and correlated with patient outcomes.

The Outcome of Outpatient Intermediate and High Dose Cytarabine Consolidation Chemotherapy in Patients with Acute Myeloid Leukemia. The Experience of King Fahad Specialist Hospital in Dammam, Saudi Arabia

Background: Adult patients with Acute Myeloid Leukemia (AML) have traditionally been hospitalized for the duration of intensive consolidation chemotherapy until blood count recovery to avoid complications. Recently, there has been a trend to shift the care of AML patients treated with intensive chemotherapy from inpatient to outpatient settings to reduce treatment costs and save beds. Methods and materials: A retrospective study of AML patients who received cytarabine consolidation chemotherapy between the 1st of August 2016 and the 31st of December 2023 at King Fahad Specialist Hospital in Dammam, Saudi Arabia was performed. Results: Over a period of 7 years and 4 months, 62 patients received a total of 127 cycles of intensive consolidation chemotherapy at outpatient setting. At diagnosis: 12 patients had extramedullary disease, and 17 patients had adverse cytogenetic abnormalities. Following the 127 cycles of chemotherapy, 38 episodes of febrile neutropenia were encountered, and 46 hospital admissions were required. No complications were encountered following 62.2% of the cycles of consolidation therapy and no early mortality due to intensive consolidation therapy was reported. Out of 62 patients studied, 36 patients underwent various forms of hematopoietic stem cell transplantation. Disease relapses were encountered in 24 patients and the 5-year incidence of relapse for the entire group of patients was 42%. The 5-year leukemia-free survival for the: entire study patients, transplanted patients, and non-transplanted patients were: 43%, 38%, and 50% respectively. The 5-year overall survival for the: entire study patients, transplanted patients, and non-transplanted patients were: 44%, 34%, and 65% respectively. At the end of follow-up: 37 patients (59.68%) were alive, 24 patients (38.71%) were dead, and the fate of 1 patient (1.61%) was unknown as the patient moved to another hospital. Conclusion: Administration of intensive consolidation chemotherapy for patients with AML at outpatient setting is safe, feasible, and cost-effective. The incidence of infectious complications was relatively low. No early treatment-related mortality due to intensive consolidation therapy was encountered. Outpatient administration of intensive consolidation therapy can save beds, reduce hospital costs, and is associated with short-term and long-term outcomes that are comparable to inpatient administration of consolidation therapy.

Optimized BEAC conditioning regimen improves clinical outcomes of autologous hematopoietic stem cell transplantation in non-Hodgkin lymphomas

The conditioning regimen is an important part of autologous hematopoietic stem cell transplantation (ASCT). We explored the efficacy and safety of an optimized BEAC (adjusted-dose, intermediate-dose cytarabine and reduced-dose cyclophosphamide, AD-BEAC) conditioning regimen for non-Hodgkin lymphoma (NHL). A total of 141 NHL patients received AD-BEAC or a standard-dose BEAC (SD-BEAC) conditioning regimen from January 2007 to December 2017, and 104 patients were included in the study after 1:1 propensity matching. The 5-year overall survival (OS) and progression free survival (PFS) rates were significantly higher with AD-BEAC than with SD-BEAC (82.7% vs. 67.3%, P = 0.039; 76.9% vs. 57.7%, P = 0.039). Transplant-related mortality (TRM) was 3.8% in both the AD-BEAC and SD-BEAC groups. The AD-BEAC group had lower incidence of oral ulcers and cardiotoxicity than the SD-BEAC group. An optimized BEAC conditioning regimen is an effective conditioning regimen for ASCT in NHL with acceptable toxicity, that is more effective and safer than a standard BEAC conditioning regimen.

Microcosting analysis of haematopoietic stem cell transplantation and chemotherapy with intermediate doses of cytarabine in the treatment of acute myeloid leukaemia

BackgroundAcute myeloid leukaemia (AML) is considered a costly disease. Depending on the risk stratification, the patient may receive consolidation with cycles of intermediate doses of cytarabine, auto-HSCT or allo-HSCT according to availability in each service and the availability of a compatible donor. Literature data indicate that safety and effectiveness do not differ between consolidation therapy with intermediate-dose cytarabine or auto-HSCT, and so the cost can help physicians and health managers in their choice. MethodThe cost of the second consolidation was compared in 18 to 60-year-old patients with de novo AML who were included in the International Consortium of Acute Myeloid Leukaemia (ICAML) protocol. Patients treated with auto-HSCT or intermediate doses of cytarabine (IDAC) were analysed during four years using the microcosting methodology. ResultsThe mean costs for auto-HSCT and IDAC were BRL$ 34,900.95 (range: 23,611.36–41,229.59) and 15,231.64 (range: 6,546.36–23,253.53), respectively. The mean duration of in-hospital stay was 88.4 (93–133) and 94 (50–153) days, respectively. The mean cost of the four cycles of treatment was BRL$ 114.212,78 for auto-HSCT and BRL$ 121.980,93 for the chemotherapy group. Regardless of the type of treatment, the input that had the greatest economic impact was hospital admission, mainly due to infections. ConclusionAuto-HSCT had a lower average cost per patient and hospitalization rate than chemotherapy.

Efficacy and safety of intermediate-dose cytarabine in the treatment of children with refractory high risk Langerhans cell histiocytosis

Objective: To analyze the efficacy, safety, and long-term prognosis of intermediate-dose cytarabine (Ara-c) regimen in the treatment of children with refractory risk organ involvement Langerhans cell histiocytosis (LCH). Methods: Clinical data of 17 children with multisystem and risk organ involvement LCH who failed the first-line therapy and were treated with intermediate-dose Ara-c (250 mg/m2, twice daily) regimen in the Hematology Center, Beijing Children's Hospital from January 2013 to December 2016 were analyzed retrospectively. In addition to the basic treatment of vindesine and dexamethasone, the patients received two regimens: regimen A: the intermediate-dose Ara-c combined with cladribine and regimen B: the intermediate-dose Ara-c alone. The efficacy, safety and prognosis of the two regimens were analyzed. Results: Among all 17 patients, there were 11 males and 6 females, with the diagnosis age of 2.1 (1.6, 2.7) years. Ten children received regimen A, all of them achieved active disease-better (AD-B) after 8 courses of induction therapy. The disease activity scores (DAS) decreased from 5.5 (3.0, 9.0) to 1.0 (0, 2.3). Seven children received regimen B, and 6 of them achieved AD-B after 8 courses of induction therapy. The DAS decreased from 4.0 (2.0, 4.0) to 1.0 (0, 2.0). The follow-up time was 6.2 (4.9,7.2) and 5.2 (3.7,5.8) years in group A and B. The 5-year overall survival rate was 100.0% in both groups, and the 5-year event free survival rate was (88.9±10.5)% and (85.7±13.2)% in group A and B. Grade 3 or 4 myelosuppression was observed in 8 patients in group A and 2 patients in group B. Conclusions: The intermediate-dose Ara-c regimen (with or without cladribine) is effective and safe for patients with refractory high-risk LCH, with a good long-term prognosis.

Microcosting Analysis of Hematopoietic Stem Cell Transplantation and Chemotherapy with Intermediate Doses of Cytarabine in the Treatment of Acute Myeloid Leukemia

Adult patients with Acute Myeloid Leukemia (AML) are stratified according to clinical and laboratory features at diagnosis into favorable-, intermediate-, or unfavorable-risk groups and may be treated differently according to risk. The European LeukemiaNet panel of experts' recommendation for the post-induction treatment of the favorable subgroup is either chemotherapy with intermediate doses of cytarabine (IDAC, e.g. 1.5 g/m2 q12h for 3 days) or autologous hematopoietic stem-cell transplantation (auto-HSCT). Both alternatives are costly and few studies have compared health economics aspects, which are particularly relevant in source-restrained regions. Moreover, AML treatment in low- and middle-income countries was associated with a higher frequency of invasive fungal diseases (IFD) and infections by multi-resistant bacteria compared to high-income countries and this may directly affect the treatment cost. Studies comparing IFD incidence in patients with hematological malignancies showed lower rates in patients treated with auto-HSCT compared to intensive chemotherapy. Material & Methods: we performed the micro-costing analysis patients with intermediate-risk AML who received auto-HSCT (n=5) or IDAC (n=4) as post-induction treatment at University of Sao Paulo Hospital, Ribeirao Preto, Brazil. For cost analysis, we collected information about all resources and services consumed by patients such as medicines, materials, laboratory analysis, units of blood transfusion components, apheresis, hospital admissions, and outpatient care, in the period that began on the date of diagnosis until the end of treatment. The two groups had similar clinical and laboratorial characteristics at diagnosis and were treated according to the ICAML2015 protocol, in which induction (ID-1) is based on daunorubicin + standard-dose cytarabine (‘3+7‘), followed by a second cycle (ID-2) with daunorubicin + IDAC and, for those patients that achieved CR, consolidation was done with two cycles of IDAC (CONS-1 and CONS-2) or one cycle of IDAC followed by auto-HSCT (CONS-1 and auto-HSCT). The choice between the two alternatives of post-induction regimens was pre-defined by the participating center of the ICAML2015 study. Results: the mean cost of auto-HSCT and IDAC was US$ 4,188.12 and 2,368.22, respectively. Patients who received auto-HSCT stayed longer in-hospital compared to those in the IDAC group (21.8 versus 12.5 days). When the whole treatment is analyzed, the mean cost of the treatment with four cycles of chemotherapy was US$ 121,980.93 and that with three cycles followed by auto-HSCT was US$ 84,619.16. The most costly phase of treatment was the ID-1 (US$ 9,690.10). Regardless of the type of treatment, we observed that the inputs with the greatest economic impact were hospital admissions, which represented 51.2% of the total costs. . The second input with the greatest economic impact was drugs, and in that regard, treatment of infections played an important role in increasing the use of supplies in general. All patients in the study had febrile neutropenia that required hospital admission. Three patients were treated for IFD episodes, all of them were considered to be probable according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group, and the most frequently used antifungals were amphotericin B (deoxycholate) and voriconazole. All patients received prophylaxis with fluconazole. The frequency of IFD considering the whole treatment was 19.4 % (7/36 episodes of febrile neutropenia) and, there was no significant difference between patients who received auto-HSCT or IDAC. In conclusion, our results show that the cost of the post-induction treatment using auto-HSCT was higher than with IDAC and that cost with hospital stay.

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.

Comparing the Efficacy and Safety of Venetoclax Combined with Decitabine Versus Conventional Chemotherapy As Induction Therapy for Young Adults with Newly Diagnosed Acute Myeloid Leukemia - Interim Analysis of a Multicenter, Randomized, Phase 2b Trial

Introduction: Venetoclax in combination with hypomethylating agents (HMAs) is a first-line induction regimen recommended by NCCN guidelines for older or unfit AML patients. In a phase 2 study (NCT04752527) from our group, venetoclax plus decitabine (VEN-DAC) resulted in a 93% of response rate in young adult patients with newly diagnosed (ND) ELN adverse-risk AML. Currently, there is a lack of data on the VEN-DAC regimen in ND young adults with favorable or intermediate risk AML who are fit for intensive chemotherapy. There are also no studies directly comparing the VEN-DAC regimen with intensive chemotherapy in patients with ND AML. Here, we report the results of an interim analysis of a multicenter, randomized, phase 2b trial (NCT05177731) , which explored the efficacy and safety of VEN-DAC versus intensive chemotherapy (idarubicin and cytarabine) in ND AML patients. Methods: Adult patients with newly diagnosed AML aged between 18 and 59 years were enrolled. The diagnosis was made according to the WHO 2016 criteria. Risk stratification was performed according to the 2017 ELN recommendations. Eligible patients were randomized in a 1:1 ratio to the VEN-DAC group (decitabine 20mg/m 2 on days 1-5 and venetoclax at an escalated dose of 100mg, 200mg and 400mg by day 28) or the IA-12 group (idarubicin 12mg/m 2 on days 1-3 and cytarabine 100mg/m 2 on days 1-7). Patients who did not respond to the treatment were allowed to receive another cycle of the original induction regimen. Intermediate-dose cytarabine (2g/m 2, q12h, days 1-3) were applied as consolidation therapy. The primary endpoint was the composite complete remission (CRc, including complete remission, CR and complete remission with incomplete hematologic recovery, CRi). The secondary endpoints included measurable residual disease (MRD) negative remission (defined as <1×10 -3 by flow cytometry), event-free survival (EFS) , overall survival (OS) and adverse events. Results: Since March, 2022, a total of 163 patients with AML were screened and 116 patients were randomized. Sixty patients received the VEN-DAC regimen and 55 patients received the IA-12 regimen. There were no differences in baseline characteristics between the two groups of patients (Table 1). Bythe cut-off date of July 11, 2023, a total of 102 patients have been evaluated, 55 in the VEN-DAC group and 47 in the IA-12 group. The overall CRc rate in the VEN-DAC group was 85.5%, which was comparable to that of the IA-12 group (78.7%, P=0.37). The MRD-negative CR rate in the VEN-DAC group was 67.3%, which was much higher than that in the IA-12 group (53.2%) ( P=0.147). According to univariate analysis, efficacy of the VEN-DAC regimen did not differ from that of the IA-12 regimen with respect to sex, age, initial bone marrow blast count, genetic risk category, and major molecular markers (Figure 1A). Notably, the CRc rate and MRD-negative CR rate were significantly higher in the VEN-DAC group than in the IA-12 group for intermediate-risk and adverse-risk patients, especially those with adverse risk ( P=0.031 for CRc, P=0.029 for MRD-negative CR) (Figure 1A). At median follow-ups of 7.8 months (range, 0.9-16.6), the EFS and OS were not reached in both groups. The median time for platelets to recovery to 20×10 9/L or above in the VEN-DAC group was 12 days after induction in the VEN-DAC group, which was shorter than that in the IA-12 group (21 days) ( P<0.01). In addition, patients in the VEN-DAC group required fewer platelet (5 U vs 7 U, P<0.01) and red blood cell infusions (3 U vs 5 U, P=0.023) during induction as compared with that in the IA-12 group. In addition, the incidence of grade 3 or higher febrile neutropenia (41.8% vs. 83.0%), infection (27.3% vs. 72.3%) and sepsis (5.5% vs. 31.9%) were all significantly lower in the VEN-DAC group than in the IA-12 group ( P<0.01) (Figure 1B). Conclusion: In newly diagnosed young AML patients, venetoclax in combination with decitabine as an induction regimen had comparable efficacy and a higher safety profile compared to IA-12 regimen. In particular, patients with adverse-risk AML showed higher and deeper remission rate in the venetoclax plus decitabine group as compared with the IA-12 group.

Venetoclax and Azacitidine for Molecular Relapse during First Line Intensive Chemotherapy in Patients with NPM1 Mutated or Core Binding Factor (CBF) AML. a Study from the Dataml Registry

Introduction: Molecular follow-up (FU) for AML patients (pts) with NPM1 mutation, RUNX1::RUNX1T1 or CBFB::MYH11 fusion transcripts has been established over the last ten years. Real-time quantitative PCR (qPCR) is the gold standard for the evaluation of measurable residual disease (MRD) in pts undergoing intensive chemotherapy (IC). Failure to achieve a deep molecular response is a strong predictive factor of relapse and survival and may guide post remission therapy (Ivey A, NEJM 2016). Moreover, the ELN MRD working party recommended a schedule for molecular FU and recently established a definition of molecular relapse (Heuser M, Blood 2021). However, there is no therapeutic consensus for pts with molecular relapse before overt clinical relapse. Frontline allogeneic hematopoietic cell transplantation (alloHCT), salvage IC or even waiting for morphological relapse in order to screen molecular characteristics of the relapsing disease or propose a clinical trial, may be discussed with pts. Venetoclax with azacitidine (VEN/AZA) was recently approved in unfit AML pts and demonstrated a particular efficacy in NPM1-mutated AML. In this study, we thought to describe the safety and efficacy of VEN/AZA in pts with NPM1 mutated or CBF AML in molecular relapse after first line IC. Methods: Pts of the DATAML registry with the following criteria were included in this study : AML with NPM1 mutation, RUNX1::RUNX1T1 or CBFB::MYH11 transcripts, first line IC, morphological complete remission (CR), no alloHCT in first line, regular monitoring of MRD by qPCR in bone marrow (BM) and/or blood, molecular relapse defined according to ELN2021 guidelines on two successive samples, at least one cycle of VEN/AZA. Pts with molecular relapse followed by morphological relapse before VEN/AZA or those who relapsed after alloHCT were not included. Treatment: First line IC was cytarabine 200 mg/m² d1-7 with idarubicin 9mg/m²/d1-5 or daunorubicin 90mg/m²/d1-3 in pts 18-60y or cytarabine 100 mg/m² d1-7 with idarubicin 8mg/m²/d1-5 and lomustine 200 mg/m²/d1 in pts > 60y. Post remission therapy was intermediate or high dose cytarabine or mini-consolidations according to age and performance status. Midostaurin was added in FLT3-mutated pts. At time of molecular relapse, pts received off label venetoclax 400 mg/d (d1-14, d1-21 or d1-28 according to centers) with no ramp-up and azacitidine 75 mg/m²/d subcutaneously (d1-5, d8-9). Antifungal/antibiotic prophylaxis and G-CSF use were not systematically recommended. Results: Twenty-two pts treated with VEN/AZAfrom 21/09/2020 to30/03/2023 were included. Their characteristics at diagnosis were: female (n= 14), median age 55y (range 27-71), de novo AML (n=21), median WBC (68 giga/L, range 2.32-339.7), NPM1 mutation (n=20), CBFB::MYH11 (n=2), FLT3 mutation (n=13). All pts achieved first CR after one cycle of induction chemotherapy. Pts received a median of three consolidation cycles. All but three pts had negative MRD or low level MRD (LL-MRD) in blood and/or BM at the end of consolidation. The median time between CR1 and molecular relapse was 9.5 months (range, 1-50). The median time between molecular relapse and first VEN/AZA cycle was 51 days. During first cycle of VEN/AZA, 12, 5 and 5 pts received 14, 21 or 28 days venetoclax, respectively; 19 were treated as out-pts, 4 received posaconazole and GCSF was used in 11 pts. 12 and 3 pts had grade 3-4 neutropenia or febrile neutropenia (FN), respectively. Only 3 pts (14%) were hospitalized for FN. The median number of VEN/AZA cycles was 2 (range 1-12). After C1+/-C2, 10 (45%) and 11 pts (55%) had undetectable or LL MRD in blood, respectively (Fig1). 20 pts were bridged to alloHCT in morphological CR after a median of 2 cycles (range, 1-4). Only one pt had a molecular progression before transplantation after 2 cycles. Two pts died, one had a molecular relapse after 7 cycles and progress rapidly to frank relapse, the other one died of post-transplant complication while in CR with undetectable MRD. All other pts remained in CR at date of last news. With a median FU from D1C1 of 13.5 months, median OS wat not reached and 1y-OS was 86% (Fig2). Conclusion: In the setting of molecular relapse, VEN/AZA is safe, prevent overt relapse, and induce a high rate of molecular response before alloHCT. Molecular relapse becomes a major therapeutic challenge. Clinical trial endpoints should include the treatment of molecular relapse as an event for RFS and EFS estimation.

Ongoing Phase III Randomized Trial of Salvage DFP-10917 Vs. Non-Intensive Reinduction or Intensive Reinduction for Acute Myelogenous Leukemia (AML)

Background: DFP-10917 is a deoxycytidine analogue with a novel structure. It contains a side chain cyanide (CN) group at the 2 carbon of deoxyribose that induces DNA damage in a manner unique from structurally related nucleoside analogues (eg, cytarabine, decitabine, or gemcitabine). When administered at high doses, DFP-10917 inactivates deoxyribonucleic acid (DNA) polymerase leading to S-phase arrest similar to cytarabine. When administered at low concentrations by continuous infusion, it displays an alternative, potentially advantageous, mechanism of action - DNA strand breakage leading to G2/M phase arrest and ultimately cell apoptosis. The strand breakage occurs via a spontaneous beta elimination reaction that requires no additional enzymatic activity. There is no current standard treatment for patients with relapsed/refractory (R/R) AML. Results of a completed Phase I/II study in R/R AML (D11-11002; NCT01702155) demonstrated preliminary efficacy of DFP-10917 in this indication, with a ~50% complete response (CR) rate in Phase II. Five of 14 patients who achieved CR proceeded to stem cell transplantation. Based on completed studies, risks associated with DFP-10917 are predominantly hematological (eg, neutropenia, anemia, febrile neutropenia, leukopenia, lymphopenia, thrombocytopenia). Study Design and Methods: Based on promising Phase II results, the Sponsor initiated Study D18-11141 (NCT03926624), a Phase III, randomized, controlled study to compare the rate and duration of CR in patients with AML R/R to 2-4 prior induction regimens. Patients receive either DFP-10917 or non-intensive reinduction (low-dose cytarabine [LoDAC], azacitidine, decitabine, venetoclax + LoDAC or azacitidine or decitabine) or intensive reinduction (high and intermediate dose cytarabine regimens). Patients assigned to DFP-10917 receive 6 mg/m 2/day by continuous infusion for 14 days followed by a 14-day rest period. Control treatment is administered per physician's decision. Adults aged ≥18 years with histologically or pathologically confirmed diagnosis of AML based on World Health Organization classification and adequate performance status (≤2) and organ function are eligible. Study Status: The study is ongoing at 34 study centers in the United States. As of July 2023, 162 patients were enrolled, with 82 assigned to DFP-10917. A majority of the patients are male (57.4%) and aged <75 years (83.3%). Overall, 44% have AML with myelodysplasia-related changes; 36% have AML not otherwise specified; and <20% have AML with recurrent genetic abnormalities or therapy-related myeloid neoplasms. Enrollment and management of patients were affected from 2020 to 2021 by COVID-19 restrictions. A prospectively-planned interim analysis will occur after the 150 th patient randomized is followed for >2 months. Based on recruitment projections, this analysis is scheduled for 09/2023. At that time, the Data Safety Monitoring Board will review an unblinded estimate of the treatment effect for the primary endpoint of CR, with the study either stopped for superiority or futility or continuing to a final analysis. If continued, the number of patients required for the final analysis will range from 300 to 450, in increments of 50, with the number determined based on the size of the interim treatment effect for the primary endpoint of CR or the secondary endpoint of overall survival.

Venetoclax Plus ‘2 + 5‘ Modified Intensive Chemotherapy with Daunorubicin and Cytarabine in Fit Elderly Patients with Untreated De Novo Acute Myeloid Leukaemia: A Single-Centre Retrospective Analysis

Background: The treatment options for elderly patients with acute myeloid leukemia (AML) have been limited considering the poor tolerability of intensive standard chemotherapy. Recently, we report promising clinical outcomes in 13 untreated fit elderly patients with AML who received modified intensive induction of venetoclax in combination with ‘2 + 5‘ (daunorubicin and cytarabine) chemotherapy (modified DAV regimen), followed by venetoclax plus modified intermediate-dose cytarabine consolidation. Building on this foundation, we expanded the sample size and included 11 more patients who treated with modified DAV regimen and extended follow-up time to further explore the efficacy and safety of the modified DAV regimen for induction therapy in elderly AML patients. Method: 24 elderly AML patients (aged ≥55 years) who were received induction chemotherapy that included daunorubicin (60mg/m2 days 1-2, intravenously), cytarabine (100 mg/m 2 days 1-5, intravenously), and venetoclax (100 mg day 3, 200 mg day 4, 400 mg days 5-10, orally) from March 2021 to May 2023 were retrospectively analyzed. After induction, patients received three cycles of venetoclax (400 mg days 1-14, orally) in combination with intermediate- dose cytarabine (1 g/m 2 days 1-3, intravenously) as consolidation treatment. Overall response rate, composite complete response (CRc) rate, overall survival (OS), duration of remission (DOR), and adverse events were analyzed. Results: 24 de nove elderly patients with AML were were divided into favourable- (6), intermediate- (13), and adverse-risk groups (5) according to European LeukemiaNet (ELN) risk stratification. The cohort was consisted of 9 males (37.5%) and 15 females (62.5%) and the median (range) age of which was 64 (57-71) years. The last follow-up date was 15 July 2023, with 313 days of median follow-up. After one cycle of induction, 20 patients (83.3%) achieved CR, 2 patients (8.33%) who achieved PR after one cycle of induction attained CR after receiving a second modified DAV induction. Thus, the CR rate was 91.7% after 2-cycle induction. 2 patients (8.33%) failed to achieve remission after induction therapy. In responders, 20 of the patients were measurable residual disease (MRD) negative after 2-cycle induction, detected by multi-parameter flow cytometry (MFC). Among 22 CR patients, 20 have completed the first consolidation cycle (one patient received consolidation regimen without venetoclax due to economic pressures, and another one did not receive consoliation treatment yet), 18 patients have completed the second consolidation cycle, and 16 patients have completed all cycles of consolidation chemotherapy. Of these, 3 patients relapsed during consolidation therapy and 4 patients relapsed after completion of consolidation therapy. For the total of 24 patients, the median follow-up was 313 days. The median OS was not achieved and the median EFS was 384 days. Among the 16 patients who completed three courses of consolidation therapy, the median follow-up time was 314 days, and there were no deaths to date. The median OS was not achieved and the median EFS was 398 days. The adverse events observed during the induction therapy in most patients were Grade 3-4 neutropenia (100%), anemia (100%), and thrombocytopenia (100%). For responders in the first induction cycle, the median (interquartile range [IQR]) time to blood cell count recovery (absolute neutrophil count ≥1 ×10 9/L and platelet count ≥50×10 9/L) in patients who had a response following induction therapy was 20.0 (18.75-22.0) days. The most common non-haematological grade 3-4 adverse events observed during induction included febrile neutropenia (65.2%), pneumonia (34.8%), and constipation (15.4%). Conclusions: Our study demonstrated promising response and safety of modified DAV therapy in elderly fit de novo AML patients.

Outpatient Low-Dose Venetoclax Plus Azacitidine Vs. Intensive Chemotherapy for Newly Diagnosed Fit Patients with Acute Myeloid Leukemia in a Limited Resource Setting

Introduction: venetoclax plus azacitidine (Ven/Aza) is the standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are unsuitable candidates for intensive chemotherapy (IC), prompting questions related to whether it should be used for candidates fit for IC (FIT). Access to novel agents in low- and middle-income countries (LMIC) is limited, however, in a previous phase 2 study (NCT05048615), we demonstrated that using venetoclax concomitantly with strong CYP3A4 inhibitors like itraconazole could be a practical approach to reduce the venetoclax dose and diminish treatment-related costs without compromising treatment response. We sought to compare FIT patients for IC with newly diagnosed AML who received either low-dose Ven/Aza or traditional IC as first-line treatment to evaluate survival outcomes in LMIC. Methods: we retrospectively included all newly diagnosed adult patients with AML suitable for IC treated in our center from August 2016 to March 2023. Since the COVID-19 pandemic, we have used Ven/Aza as a standard first-line therapy in an effort to reduce early mortality and to allow outpatient induction for all patients with AML. Low-dose Ven/Aza was administered as follows: venetoclax 100 mg QD fixed dose plus itraconazole 100 mg BID for 21 days per cycle, and azacitidine 100 mg SC fixed dose QD or 7 days, 1-2 cycles. IC patients received 7+3 or intermediate dose cytarabine plus 3 days of mitoxantrone. Consolidation with intermediate dose cytarabine was given following remission in both groups. Baseline characteristics were registered and compared. We evaluated induction complications, complete response (CR/CRi), 30 and 60-day early death (ED), allogeneic hematopoietic stem cell transplantation (HCT), event-free survival (EFS), and overall survival (OS). Multivariate Cox regression for OS was performed. Results: 83 patients were included, the median age at diagnosis was 44 years (IQR, 32-56), 27 received Ven/Aza (56% received 2 cycles), and 56 IC. Patients who received Ven/Aza were older, had a higher risk disease, and had a longer time between diagnosis and treatment. Patients who received Ven/Aza had a lower incidence of febrile neutropenia, need for transfusions, and less than half required hospitalization during induction; 30- and 60-day mortality was reduced 2.4 and 3-fold in Ven/Aza vs IC although statistical significance was not reached. There were no differences in the rate of CR/CRi between groups (Table 1). After achieving CR/CRi, the IC group had a higher incidence of being relapsed however the median EFS was not different with 7.7 months (95% CI 5.9-9.6) for Ven/Aza vs. 8.5 months (95% CI 6.6-10.5) for IC (p=0.53). Median OS was 10 months (95% CI 5.8-14.1) for Ven/Aza vs 9 months for IC (95% CI 6.6-11.3) (p=0.33) (Figure 1). Patients who received Ven/Aza followed by HCT had the best outcomes with a 2-year OS of 80% vs. 35.5% of those who received IC plus HCT. An OS landmark analysis for patients alive at or beyond 5 months (median time from diagnosis to HCT) showed prolonged survival in HCT vs. not transplanted patients (16 vs 11 months, p=0.035), irrespective of their induction arm. In the multivariate analysis, HCT (HR 0.05, 95% CI 0.007-0.5) and a need for cytoreduction (HR 8.7, 95% CI 1.2-59.6) were the only predictors of OS. Conclusion: in this single-center study, AML patients treated in a limited resource setting with low-dose Ven/Aza had similar complete response and survival to IC with reduced complications and shorter hospital stay, despite being older with higher risk disease. This induction treatment is a low-cost but effective option in a LMIC environment and could be considered an alternative option, even in suitable candidates for IC, especially with access to HCT.

Real-World Treatment Patterns and Clinical Outcomes in Newly Diagnosed Acute Myeloid Leukemia with and without mIDH1 Treated with Intensive Chemotherapy from an International Real-World Database (REAL-IDH)

Introduction Intensive chemotherapy (IC) remains the main backbone therapy in fit, newly diagnosed, acute myeloid leukemia (AML) patients. Clinical trials assessing the efficacy of IC under-represent select subgroups of patients, such as those with certain comorbidities, unique characteristics, or rare genomic abnormalities. Real-world data provides additional insights into treatment patterns and clinical outcomes in patients with AML receiving first-line IC. REAL-IDH is an international network that generates evidence to improve real-world understanding of AML, including patients with a mutation in the gene encoding isocitrate dehydrogenase 1 (m IDH1). This abstract presents data from the REAL-IDH study, specifically on treatment patterns and outcomes in newly diagnosed AML patients who were treated with IC, including those with or without m IDH1 disease. Methods This retrospective, longitudinal, observational study was conducted using databases from the USA (Cancer Outcomes Tracking and Analysis [COTA]), UK (Cancer Analysis System [CAS]), and France (DATAML registry). Data were collected on adult patients with newly diagnosed AML between 2013-2020 (USA and UK) and 2017-2021 (France).Similar inclusion/exclusion criteria were applied across countries. Here we report treatment patterns, efficacy and safety outcomes, including complete (CR) and partial response (PR), CR with incomplete count recovery (CRi), minimal residual disease (MRD), morphological leukemia-free state (MLFS), time to treatment response (TTR), objective response rate (ORR; defined as rate of CR, CRi, PR and MLFS in the total treated population), mortality rate, and overall survival (OS) in patients receiving first-line IC. Results 13,013 patients with AML were included in the REAL-IDH study, with 7406 eligible patients receiving IC as first-line treatment (USA: n=1145; France: n=800; UK: n=5461). In the IC population, of those tested for the IDH mutation, m IDH1 was detected in 70 (6.1%), 84 (10.5%), and 15 (9.3%) patients in the USA, France, and UK, respectively. The most frequent first-line IC, in all three databases, was cytarabine + anthracycline (7+3 regimen) in the total populations and in the m IDH1 and wild-type subgroups. In France, lomustine was added to 7+3 in patients >60 years. The most frequent second-line therapy in the whole IC population was salvage chemotherapy with high-dose or intermediate-dose cytarabine or a combination of either of these with anthracycline (daunorubicin, idarubicin, or amsacrine) in France and decitabine or the combination of cytarabine, etoposide and mitoxantrone in the USA. Azacitidine/venetoclax combination was used in second and third line in France and USA and it was the most frequent third-line therapy (35.8%) in France. Patients received IC in combination with targeted therapies (mainly midostaurin) in 18% of the IC population in France and 12.4% of the IC population in the USA. Rates of CR, MLFS, TTR and ORR were similar in the USA and France ( Table 1). Mortality rates were similar across all three countries ( Table 1). Adverse events (AE) were reported in 43.7% of patients (500; N=1145) in the USA and 76.3% (610; N=800) in France with a reported infection in 13% (149; N=1145; CTCAE coded infection AE) and 43.1% (345; N=800; fungal/bacterial at induction or during treatment; septic shock/pneumopathy at induction or during first 3 months of treatment leading to admission to an intensive care unit; or infection leading to death) of patients in the USA and France, respectively. Conclusion This large-scale population-based study provides insight into treatment patterns and clinical outcomes in patients with AML who received first-line IC in the real-world setting, including patients with or without m IDH1 disease. Intensive treatment combinations have not significantly changed over the past decade with the exception of the addition of targeted therapies. Despite the lack of a common standard IC regimen and protocol across countries, and different healthcare systems, mortality rates were similar with IC across each country. In the REAL-IDH study we observed that treatment patterns in m IDH1 or wild type patients were similar. More specific data is needed regarding the sequencing of treatment regimens and overall outcomes in m IDH1 AML patients.

Consolidation with Ponatinib Plus Sequential Blinatumomab and Chemotherapy after Low Intensity Dasatinib-Based Induction in Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Outcomes from a Single Institution

Introduction: Dasatinib plus prednisone is a standard induction approach for adults with Philadelphia Chromosome positive (Ph+) ALL known to result in high remission rates with minimal toxicity, however optimal post-remission therapy has not been determined. Given the excellent outcomes observed in recent clinical studies using ponatinib in adult Ph+ ALL, we explored a strategy of switching the TKI to ponatinib and consolidating with sequential blinatumomab (blina) and chemotherapy after dasatinib + prednisone induction. In contrast to recent studies of blina + TKI wherein patients have received up to 3-5 cycles of blina, we limited the number of blina cycles to 2 to minimize cost and logistical burden. We also administered systemic chemotherapy after blina with the goal of decreasing risk of extramedullary relapse, which has been observed in studies of blina-based “chemotherapy-free” regimens. Methods: Since June 2021, all adult patients with Ph+ ALL (n=14) at our institution were switched to ponatinib (30mg/d then 15mg/d once complete molecular remission [CMR] achieved) after dasatinib + prednisone induction. Concurrent with TKI, patients could also receive blina for one or two cycles (at discretion of treating clinician), followed by up to four cycles of consolidative chemotherapy alternating between high-dose methotrexate (1.5g/m 2) and intermediate-dose cytarabine (1g/m 2 x 6 doses). Patients not proceeding to stem cell transplant continue ponatinib monotherapy for up to 5 years, and 12 doses of intrathecal methotrexate 15mg are given throughout the total course of treatment. Prior to June 2021, our institutional approach was to recommend allogeneic SCT in CR1 for all transplant candidates immediately after dasatinib + prednisone induction. We reviewed charts of patients with newly diagnosed Ph+ ALL at University of Colorado Hospital from 2014-2023 to compare outcomes of patients treated before 06/2021 (“dasatinib/SCT” cohort) and after 06/2021 (“ponatinib” cohort). Results: From 6/2021-02/2023, 14 patients (median age 54) with newly diagnosed Ph+ ALL were switched to ponatinib after dasatinib + prednisone induction. After induction, 12 patients received blina (median 1 cycle; range 1-2) and consolidation chemotherapy (median 4 cycles; range 3-4). Blina could not be obtained for 2 patients who instead received chemotherapy only for 6 cycles. 3 patients (21%) underwent allogeneic SCT in CR1 due to persistent detectable bcr/abl transcripts by qPCR, and all 3 continued ponatinib as maintenance after SCT. With a median follow-up of 15 months (range: 4-24 months) no relapses have occurred and all patients remain alive at last follow-up. No patients have discontinued ponatinib due to intolerance. Chemotherapy plus ponatinib was well-tolerated after blina, with all except for one patient having received all intended cycles (one patient stopped chemotherapy after 3 cycles due to excessive hematologic toxicity). Between 11/2014-03/2021, 36 patients (median age 50) with Ph+ ALL were treated with dasatinib + prednisone induction, after which 31 (86%) underwent allogeneic SCT in CR1. All non-transplant candidates continued TKI alone. With a median follow-up of 37 months (range: 4-102 months), 11 relapses have occurred, 9 of which occurred after SCT. Among 13 patients who died during follow-up, 7 deaths were due to relapsed/refractory ALL and 6 were due to treatment-related mortality. Comparing outcomes between the two cohorts, relapse-free survival is improved in the more recent (ponatinib) cohort compared to the earlier (dasatinib/SCT) cohort (p=0.044, log-rank test) (Figure 1) despite a lower rate of allogeneic SCT in CR1 (21% vs 86%). No difference in overall survival (p=0.12) has been observed (not shown). Conclusions: For adults with Ph+ ALL, switching to ponatinib after dasatinib-based induction and consolidating with blina and chemotherapy is a safe and potentially effective strategy. The optimal number of blina cycles given post-remission is unclear, though we observed favorable outcomes in patients receiving a median of only 1 cycle, and maximum of 2 cycles. Favorable outcomes despite the low rate of allogeneic SCT (21%) seen in our cohort suggest that SCT may be safely avoided for some patients who receive ponatinib plus blina and chemotherapy-based consolidation.

Outpatient consolidation chemotherapy with intermediate dose cytarabine has similar survival and relapses rates in acute myeloid leukemia as compared to high dose cytarabine: A single center analysis.

The last decade has seen advances in delivering outpatient consolidation therapy for acute myeloid leukemia (AML). The standard of care involves high-dose cytarabine or intermediate-dose cytarabine, given twice daily for three alternating days. At the London Regional Cancer Program, we have transitioned the administration of outpatient cytarabine to a once-daily regimen over six consecutive days. The outcomes of a longer duration interval of high-dose cytarabine and intermediate-dose cytarabine is currently unknown. This study aims to assess the feasibility of administering a continuous 6-day protocol of high-dose (HDAC-16) and intermediate-dose cytarabine (IDAC-16) consolidation therapy in the outpatient setting. This is a retrospective chart review to analyze AML patients treated with outpatient high-dose or intermediate-dose cytarabine consolidation therapy at the London Regional Cancer Program from January 1, 2019, through November 1, 2022. The primary objective was to determine the outcomes of the 6-day outpatient administration of once daily high-dose cytarabine or intermediate-dose cytarabine. Forty-five patients received 89 cycles of cytarabine as outpatients; males were 55.6% of the total population, with a median age of ~57 years. Our overall 2-year survival of HDAC-16 (57.1%) and IDAC-16 (83.3%) is consistent with the reported literature. There was no difference in delays, relapse rates, and nonrelapse mortality between both HDAC and IDAC groups. The 2-year relapse free survival was 57.1% for HDAC-16 and 66.7% for IDAC-16. Outpatient administration of intermediate-dose cytarabine once daily over six consecutive days results in similar overall survival and relapse rates as compared to high dose cytarabine consolidation chemotherapy. Moving to a once daily administration schedule can alleviate logistical and/or accessibility hurdles for outpatient oncology clinics. Prospective randomized trials are needed in this setting to validate our results.

AML consolidation therapy: timing matters.

Infections due to severe neutropenia are the most common therapy-associated causes of mortality in patients with acute myeloid leukemia (AML). New strategies to lessen the severity and duration of neutropenia are needed. Cytarabine is commonly used for AML consolidation therapy; we compared high- and intermediate-dose cytarabine administration on days 1, 2, and 3 (AC-123) versus days 1, 3, and 5 (AC-135) in consolidation therapy of AML. Recently, clinical trials demonstrated that high-dose AC-123 resulted in a shortened white blood cell (WBC) recovery time compared with high-dose AC-135. Our main hypothesis is that this is also the case for different cytarabine dosage, granulocyte colony-stimulating factor (G-CSF) administration, and cycle lengths. We analyzed 334 treatment schedules on virtual cohorts of digital twins. Comparison of 32,565 simulated consolidation cycles resulted in a reduction in the WBC recovery time for AC-123 in 99.6% of the considered cycles (median reduction 3.5 days) without an increase in the number of leukemic blasts (lower value in 94.2% of all cycles), compared to AC-135. Our numerical study supports the use of AC-123 plus G-CSF as standard conventional AML consolidation therapy to reduce the risk for life-threatening infectious complications.

Identification of a novel NPM1 mutation in acute myeloid leukemia.

e19019 Background: Nucleophosmin (NPM1) is predominant nucleolar localization. NPM1-mutant acute myeloid leukemia (AML) account for 25-35% of adult AML patients, has been defined as a distinct AML entity in the 2022 WHO classification. The majority of NPM1 mutations reported affect exon 12 (classical type A mutation), account for 75-80% of adult NPM1-mutated AML cases, which generate an extra nuclear export signal (NES) in the C-terminal leading to aberrant cytoplasmic localization. Similar aberrant cytoplasmic translocation has also been reported in NPM1 mutants that identified in exons 9 and 11. Identification of novel non-type A mutants is paramount for diagnosis, risk stratification, and prognosis for targeted population. Methods: Somatic mutation analysis is performed on 566 AML patients using next-generation sequencing (NGS). Immunofluorescence and immunohistochemistry were used to identify the cytological localization of mutant NPM1. HEK-293T cells transiently transfected with plasmids for ectopic expression of the GFP-mutated NPM1 fusion proteins were treated with the specific Crm1/XPO1 inhibitor leptomycin B and to evaluate the NES dependence of their subcellular localization. Results: We identified one AML patient with NPM1 mutant located on exon 5. This patient was a 59-year-old female with de novo AML, with an 18-nucletide in-frame insertion at position 405 (c.405_406insGCCCTGGAACTGGGGAAC, named MutSong) in the middle of exon 5 [variant allele fraction (VAF), 11.9%]. It generated a new NPM1 mutant protein (p.135insALELGN), and containing a leucine-rich NES. Notably, different with all NPM1 mutant in other exons reported so far, our exon 5 mutant retained the functional c-terminal but insert one leucine-rich NES, similar finding was recently reported in NPM1 mutants that identified in exon 5 but on different position. This NPM1 mutant in exon 5 resulted in cytoplasmic localization both by confocal and immunohistochemistry in AML patient sample. HEK-293T overexpressing the new GFP-NPM1 exon 5 fusion protein indicated the aberrant localization in the cytoplasm and partially in nucleoli. Moreover, NES-dependent cytoplasmic localization was inhibited by exportin-1 inhibitor leptomycin B, indicated that the novel NES generated by exon 5 mutant is responsible for cytoplasmic localization. This patient carried WT1, IKZF1, JAK2, and NUP98 mutations, and was intravenously treated with daunorubicin plus cytarabine for induction followed by 3 cycles of intermediate-dose cytarabine as consolidation. Then the patient received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, the patient died of severe pulmonary infection and viral encephalitis 14 months after the initial remission, 7 months after allo-HSCT. Conclusions: Our finding of the novel NPM1 mutation in exon 5 supported that beside exon 12, exon 5 mutant is another NPM1 “born to be exported” mutant critical for leukemogenesis.

Prognostication refinement in NPM1-mutated acute myeloid leukemia stratified by FLT3-ITD status with different induction doses of cytarabine.

We aimed to retrospectively discern the heterogeneity of outcomes from clinicopathological characteristics and next-generation sequencing (NGS) data in adult patients with NPM1-mutated (NPM1mut ) acute myeloid leukemia (AML) induced with standard-dose (SD, 100-200 mg/m2 ) and intermediate-dose (ID, 1000-2000 mg/m2 ) cytarabine arabinose (Ara-C). In the entire cohort and FLT3-ITD subgroups, multivariate Logistic and Cox regression analyses were used to analyze the comprehensive complete remission (cCR) rate after one or two induction cycles, event-free survival (EFS), and overall survival (OS). Among a total of 203 NPM1mut patients evaluable for clinical outcome, 144 (70.9%) received a first SD-Ara-C induction and 59 (29.1%) received ID-Ara-C induction. Early death was recorded in seven (3.4%) after one or two cycles of induction. Focusing analysis on the NPM1mut /FLT3-ITD(-) subgroup, independent factors showing inferior outcome were presence of TET2 mutation [cCR rate, OR=12.82 (95%CI 1.93-85.28), p=0.008; EFS, HR=2.92 (95%CI 1.46-5.86), p=0.003], increasing age [EFS, HR=1.49 (95%CI 1.10-2.02), p=0.012 by every 10-years elevation], white blood cell count ≥60 × 109 /L [EFS, HR=3.30 (95%CI 1.63-6.70), p=0.001], and ≥4 mutated genes at initial diagnosis [OS, HR=5.54 (95%CI 1.77-17.33), p=0.003]. In contrast, when focusing on the NPM1mut /FLT3-ITD(+) subgroup, factors showing superior outcome were ID-Ara-C induction [cCR rate, OR=0.20 (95%CI 0.05-0.81), p=0.025; EFS, HR=0.27 (95%CI 0.13-0.60), p=0.001] and allo-transplantation [OS, HR=0.45 (95%CI 0.21-0.94), p=0.033]. Factors showing inferior outcome included CD34(+) [cCR rate, OR=6.22 (95%CI 1.86-20.77), p=0.003; EFS, HR=2.01 (95%CI 1.12-3.61), p=0.020] and ≥5 mutated genes [OS, HR=2.85 (95%CI 1.33-6.10), p=0.007]. We conclude that TET2(+) , age, and white blood cell count convey an outcome risk modulation for AML with NPM1mut /FLT3-ITD(-) , as does CD34 and ID-Ara-C induction for NPM1mut /FLT3-ITD(+) . The findings permit re-stratification of NPM1mut AML into distinct prognostic subsets to guide risk-adapted individualized treatment.