Low-intensity Regimens Research Articles

Associations of hypothetical early intensive in-hospital rehabilitation with activities of daily living after hip fracture surgery in patients with and without dementia: emulating a randomized controlled trial using medical claims data

ObjectivesTo investigate the impact of early intensive in-hospital rehabilitation, initiated within 2 days of surgery and lasting up to 7 days, on the recovery of activities of daily living in patients with and without dementia. Study Design and SettingMedical claims data from 925 hospitals in Japan were analyzed. We enrolled patients aged ≥50 years who underwent hip fracture surgery within 2 days of admission between April 1, 2018, and December 31, 2019. Low- (20 minutes per day starting on day 2), highest- (60 minutes per day starting on day 1), and gradually increasing (20 minutes on day 1, 40 minutes on days 2–4, and 60 minutes per day thereafter) intensity regimens were used as exposures. The outcomes were Barthel Index (BI) scores at 14 and 30 days postoperatively. For per-protocol analysis, a target trial emulation framework with the sequential doubly robust estimator was used. ResultsAmong patients without dementia (N = 11,461), no significant differences in BI scores were observed at 14 days postoperatively across regimens. At 30 days postoperatively, significant differences in BI scores were noted between highest- and low-intensity regimens and between gradually increasing intensity and low-intensity regimens, with additive BI scores of 15.2 (95% CI, 10.7–19.7) and 14.7 (95% CI, 9.2–20.2), respectively. In patients with dementia (N = 14,302), significant differences in BI scores were noted at 14 days postoperatively between highest- and low-intensity regimens and between gradually increasing intensity and low-intensity regimens, with additive BI scores of 8.7 (95% CI, 5.2–12.2) and 10.7 (95% CI, 5.8–15.6), respectively. At 30 days postoperatively, a significant difference in BI scores was observed between gradually increasing intensity and low-intensity regimens, with an additive BI score of 17.9 (95% CI, 11.3–24.5). ConclusionEarly intensive in-hospital rehabilitation is highly relevant and beneficial for dementia patients.

Outcomes in patients with ETV6::RUNX1 or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies

AbstractChildren with ETV6::RUNX1 or high-hyperdiploid B-cell acute lymphoblastic leukemia (B-ALL) have favorable outcomes. The St. Jude (SJ) classification considers these patients low risk, regardless of their National Cancer Institute (NCI) risk classification, except when there is slow minimal residual disease (MRD) response or central nervous system/testicular involvement. We analyzed outcomes in children (aged, 1-18.99 years) with these genotypes in the SJ Total XV and XVI studies (2000-2017). Patients with ETV6::RUNX1 (n = 222) or high-hyperdiploid (n = 296) B-ALL had 5-year event-free survival (EFS) of 97.7% ± 1.1% and 94.7% ± 1.4%, respectively. For ETV6::RUNX1, EFS was comparable between NCI standard-risk and high-risk patients (97.8% ± 1.2% and 97.5% ± 2.6%, respectively; P = .917) and between SJ low-risk and standard-risk patients (97.4% ± 1.2% and 100.0%; P = .360). Of the 40 NCI high-risk patients who received SJ low-risk therapy, 37 had excellent EFS (97.3% ± 2.8%). For high-hyperdiploid B-ALL, EFS was worse for NCI high-risk patients than for standard-risk patients (87.6% ± 4.5% and 96.4% ± 1.3%; P = .016). EFS was similar for NCI standard-risk and high-risk patients classified as SJ low risk (96.0% ± 1.5% and 96.9% ± 3.2%; P = .719). However, EFS was worse for NCI high-risk patients than for NCI standard-risk patients receiving SJ standard/high-risk therapy (77.4% ± 8.2% and 98.0% ± 2.2%; P = .004). NCI high-risk patients with ETV6::RUNX1 or high-hyperdiploid B-ALL who received SJ low-risk therapy had lower incidences of thrombosis (P = .013) and pancreatitis (P = .011) than those who received SJ standard/high-risk therapy. Contemporary MRD-directed therapy yielded excellent outcomes, except for NCI high-risk high-hyperdiploid B-ALL patients with slow MRD response, who require new treatment approaches. Among NCI high-risk patients, 93% with ETV6::RUNX1 and 54% with high-hyperdiploid B-ALL experienced excellent outcomes with a low-intensity regimen. These trials were registered at www.clinicaltrials.gov as #NCT00137111 and #NCT00549848.

Treatment of Acute Myeloid Leukemia in the Community Setting.

The treatment landscape for acute myeloid leukemia (AML) is rapidly changing. Many new agents and lower-intensity regimens have been approved and can be safely used by hematologists and oncologists in both academic and community settings. The US Food and Drug Administration (FDA) held a virtual symposium on AML treatment in the community in November 2022. Several members of the FDA, along with practicing hematologists and oncologists in both academic and community settings, participated in the symposium. The goal of the symposium was to discuss challenges and opportunities in the treatment of patients with AML in community oncology settings. A summary of these discussions and key considerations are presented here.

Age and dose dependent changes to the bone and bone marrow microenvironment after cytotoxic conditioning with busulfan.

Preparative regimens before Hematopoietic Cell Transplantation (HCT) damage the bone marrow (BM) microenvironment, potentially leading to secondary morbidity and even mortality. The precise effects of cytotoxic preconditioning on bone and BM remodeling, regeneration, and subsequent hematopoietic recovery over time remain unclear. Moreover, the influence of recipient age and cytotoxic dose have not been fully described. In this study, we longitudinally investigated bone and BM remodeling after busulfan treatment with low intensity (LI) and high intensity (HI) regimens as a function of animal age. As expected, higher donor chimerism was observed in young mice in both LI and HI regimens compared to adult mice. Noticeably in adult mice, significant engraftment was only observed in the HI group. The integrity of the blood-bone marrow barrier in calvarial BM blood vessels was lost after busulfan treatment in the young mice and remained altered even 6weeks after HCT. In adult mice, the severity of vascular leakage appeared to be dose-dependent, being more pronounced in HI compared to LI recipients. Interestingly, no noticeable change in blood flow velocity was observed following busulfan treatment. Ex vivo imaging of the long bones revealed a reduction in the frequency and an increase in the diameter and density of the blood vessels shortly after treatment, a phenomenon that largely recovered in young mice but persisted in older mice after 6weeks. Furthermore, analysis of bone remodeling indicated a significant alteration in bone turnover at 6weeks compared to earlier timepoints in both young and adult mice. Overall, our results reveal new aspects of bone and BM remodeling, as well as hematopoietic recovery, which is dependent on the cytotoxic dose and recipient age.

Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?

The advent of molecularly targeted therapeutics has transformed the management of patients with acute myeloid leukemia (AML). Particularly for individuals unfit for intensive chemotherapy, lower intensity therapies (LIT) incorporating small molecules have significantly improved patient outcomes. With BCL2, IDH1, IDH2, and FLT3 inhibitors widely used for relapsed AML, combination regimens are now utilized in the frontline. Expansion of these targeted LIT combinations, along with development of novel agents including menin inhibitors, exemplifies the promise of precision medicine. Further understanding of molecular drivers of leukemic transformation and mechanisms of relapse will continue to advance frontline treatment options for patients with AML.

Progression-free survival after front line, second line and third line in patients with follicular lymphoma treated in clinical practice.

The modern-day therapeutic landscape for follicular lymphoma (FL) includes a number of highly effective therapies. We set out to determine progression-free survival (PFS) after front line, second line, and third line of therapy on the basis of relevant biological characteristics and therapeutic choices. Patients (n = 743, 51% females, median 60 years old) diagnosed with grade 1-2 FL between 1997 and 2016 in nine institutions were included. The median PFS1, PFS2, and PFS3 were 8.1 years (95% confidence interval [CI]: 7-9.3 years), 4.2 years (95% CI: 2.8-5.6 years) and 2.2 years (95% CI 1.7-2.8 years). We found longer PFS1 for (1) females, (2) younger age, (3) lower-risk follicular lymphoma international prognostic index (FLIPI), (4) standard intensity (over low intensity) regimens and (5) immunochemotherapy strategies and (6) maintenance rituximab. We found a shorter PFS2 for patients who received front-line immunochemotherapy. Older age at diagnosis correlated with a shorter PFS3. Intensity of front-line chemotherapy, maintenance, or POD24 status did not correlate with PFS2 or PFS3 in this dataset. With current immunochemotherapy strategies, the natural course of FL is characterized by shorter-lasting remissions after each relapse. It will be interesting to see whether new therapies can alter this pattern.

Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis.

Both venetoclax plus a hypomethylating agent (VEN/HMA) and cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG) are low-intensity regimens for older patients with acute myeloid leukemia (AML) that show good efficacy and safety. It is unknown how VEN/HMA compares with the CAG regimen for the treatment of newly diagnosed AML. The outcomes of patients with newly diagnosed AML treated with VEN/HMA were compared with those of patients treated with a CAG-based regimen. Propensity score matching between these two cohorts at a 1:1 ratio was performed according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, state of fitness, and European LeukemiaNet (ELN) 2022 risk stratification to minimize bias. A total of 84 of 96 patients in the VEN/HMA cohort were matched with 84 of 147 patients in the CAG cohort. VEN/HMA resulted in a better response than the CAG-based regimens, as indicated by a higher composite complete remission (CRc) rate (82.1% vs. 60.7%; p=.002) and minimal residual disease negativity rate (88.2% vs. 68.2%; p=.009). In patients with an ELN adverse risk, VEN/HMA was associated with a higher CRc rate compared to CAG (80.5% vs. 58.3%; p=.006). VEN/HMA was associated with longer event-free survival (EFS) (median EFS, not reached vs. 4.5 months; p=.0004), whereas overall survival (OS) was comparable between the two cohorts (median OS, not reached vs. 18 months; p=.078). The VEN/HMA regimen may result in a better response than CAG-based treatment in older patients with newly diagnosed AML.

Venetoclax Plus Azacitidine as a Bridge Treatment to Allogeneic Stem Cell Transplantation in Unfit Patients with Acute Myeloid Leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely recommended for unfit patients with newly diagnosed acute myeloid leukemia (AML). Patient survival can improve with venetoclax plus azacitidine (VEN plus AZA). However, the long-term outcome of this treatment strategy is still unsatisfactory. The high response and low treatment toxicity rates of patients receiving VEN plus AZA can provide an opportunity for HSCT among unfit patients. Nevertheless, the outcomes and complications of VEN plus AZA, followed by HSCT, remain unclear. This single-center retrospective study aimed to compare patients with newly diagnosed AML receiving VEN plus AZA as induction therapy (n = 27) to those receiving the conventional I3A7 regimen as induction therapy (n = 34). The 1-year overall survival, relapse, and non-relapse mortality rates in the two groups were similar. The cytogenetic risks and the hematopoietic cell transplantation-specific comorbidity index are the most significant predictive factors of overall survival. In older patients unfit for intensive chemotherapy, a low-intensity regimen with VEN plus AZA is a suitable bridge therapy. Furthermore, allo-HSCT is feasible and can be a curative option.

Venetoclax Combined with HMA Versus CAG Based Chemotherapy in Acute Myeloid Leukemia: A Propensity Score Matched Analysis

Abstract Background: Venetoclax(VEN) combination with hypomethylating agent(HMA) are lower-intensity regimens with safety which are widely used for older patients with newly diagnosed acute myeloid leukemia (AML). On the other hand, regimen of cytarabine, aclarubicin and G-CSF (CAG) with or without HMA is also of low-intensity usually applied to older AML patients. The comparison of outcomes of these two regimens has not been reported. In this study, we performed a multicenter, retrospective propensity score-matched study to compare the therapeutic responses and survival outcomes of newly diagnosed AML patients with induction of HMA-VEN to those with CAG based treatment. Methods: Newly diagnosed AML patients treated either VEN/HMA or CAG with or without HMA between January 2013 and April 2023 were compared. Age at diagnosis, sex, ECOG performance status, state of fitness for intensive chemotherapy according to Ferrara criteria and ELN2017 risk group were used to construct the propensity score using logistic regression. Propensity score matching was performed in a 1:1 ratio with a calliper value of 0.02. The treatment response, relapse rate, duration of remission, overall survival (OS) were compared between the two groups. Results: A total of 98 out of 109 newly diagnosed patients treated with VEN/HMA were matched to 98 out of 159 newly diagnosed patients treated with CAG based therapy. The patients in VEN/HMA cohort were treated between February 25, 2021 and April 30, 2023. The CAG based treatment recipients were treated from January 25, 2013 to November 12, 2021. The CAG based treatment cohort which was termed as “CAG cohort” below matched closely with the VEN/HMA cohort in terms of baseline characteristics and propensity scores (Table1). The median age was 62 years (range, 52-67) in VEN/HMA cohort and 63 years (range,52-68) in CAG cohort, and the median follow-up period was 6.3 months (range,3.2-14.0) in VEN/HMA cohort and 12 months (range,3.8-28.3) in CAG cohort. Patients treated with VEN/HMA achieved a significantly higher rate of CRc (82.4% vs 60.6%, P=0.002) compared to CAG cohort, with 36.5% in CR, 45.9% in CRi in VEN/HMA cohort and 30.3% in CR, 30.3% in CRi in CAG cohort. There was no statistic difference of the CRc rate between CAG versus CAG plus HMA(35.7%，n=14 vs 60.5%,n=76, p=0.085). CRc in the VEN/HMA and CAG cohort were 100% vs 85.7(p=0.483), 75.9% vs 46.9%(p=0.021), 64.3% vs 45.2%(p=0.079) in the ELN2017 favorable, intermediate and adverse risk group, respectively. The MRD-negative remission rate was higher in VEN/HMA cohort compared to CAG cohort (85.5% vs 61.2%, p= 0.003). The MRD-negative remission rate in the VEN/HMA and CAG cohort were 91.6% vs 80.0%(p=0.571), 88.0% vs 66.6%(p=0.188), 83.9% vs 45%(p=0.003) in the ELN2017 favorable, intermediate and adverse risk group, respectively(Table2). Responses of patients with different mutations were analyzed and ASXL1 predicted higher CRc rate with VEN/HMA treatment compared to CAG based treatment (92.3% vs. 40%, p= 0.019). The median OS was not reached in VEN/HMA cohort and 18 months in CAG cohort(p=0.16). Patients who achieved CRc had longer survival than those without CRc (not reached vs 6.4m, p<0.001). Patients who got MRD negative remission had better survival than those only with MRD positive remission (not reached vs 11.8m, p=0.0002). Patients who underwent allogeneic HSCT had longer survival than those didn't receive transplantation (not reached vs 12.3m, p<0.001). Conclusions: With propensity score-matched analysis, our data show that VEN/HMA demonstrates better treatment response than CAG regimen in patients with newly diagnosed AML. The survival outcome benefits from MRD negative response and allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

Real World Data on Treatment of Acute Myeloid Leukemia (AML) in a Private Healthcare Institution in Brazil, a Low-Middle Income Country - Importance of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Introduction: Treatment of patients with AML has evolved in the past decade, with development of novel drugs and increased knowledge about the genetic basis of disease. However, results of therapy in AML in LMICs have lagged those seen in more developed countries. A recently published paper highlighted the worse outcome of pts with AML treated in two public healthcare hospitals in Brazil compared with pts treated at an academic center at Oxford, UK, with lower overall survival (OS), lower rates of HSCT and a longer time to HSCT. 1 We hypothesized, however, that better outcomes could be seen in private healthcare institutions in Brazil with a higher rate of HSCT in first remission. Methods: We reviewed medical records of 122 patients with a diagnosis AML treated at Hospital Israelita Albert Einstein in São Paulo, Brazil, from 2010 until 2023. OS was defined as time from diagnosis until death from any cause and estimated by the Kaplan-Meier method. Risk was evaluated by the ELN 2022 risk classification. Results: A total of 122 consecutive patients were included. Median age was 63 years (range 24-91 years), and 45% were female. Per the ELN 2022 risk classification, 17% of patients were low risk, 33% were intermediate risk and 50% were considered high risk cases. Intensive chemotherapy was used in 62.5% of cases, while low-intensity regimens were employed in 37.5% of cases, including venetoclax in 21.4% of patients. After a median follow-up of 36 months, median OS of the whole cohort is 25.2 months (95% CI 19.2-83.8 months), and 3-years OS is 44% (95% CI 34-55%). As expected, patients in the high 2022 ELN risk category had lower 3-years OS probability (15.6% vs. 47.3%/91.6% for intermediate- and low-risk, respectively). Eighty-two patients (67.2% of the cohort) underwent HSCT, and 59% were in MRD-negative complete remission (CR) prior to HSCT. We next analyzed outcomes in patients younger than 60 years of age who received intensive chemotherapy, the subset of patients analyzed by Silveira et al. 1 Results are summarized in Table 1 and figure 1. The outcomes of our patients compare favorable to what has been reported here in Brazil and, like the data from the UK center, has a high rate of HSCT with a low time to transplant. Conclusion: Our results demonstrate that it is feasible to obtain favorable outcomes in patients with AML in a LMIC with a high rate of HSCT in first CR. It is also important to mention that our results also reflect the reality of a private healthcare institution in Brazil. However, even after considering this, our results carry an important message. There is limited availability of clinical trials and novel medications for AML in LMICs compared to the developed world, and options in the salvage setting are usually limited to intensive chemotherapeutic regimes. Allogeneic HSCT is a technique that is readily available in most countries and has the potential to cure AML, particularly when employed in first CR. We believe that physicians and institutions treating patients with AML in a LMIC should primarily focus on strategies that improve access to HSCT in first CR for these patients.

Comparative Analysis of Clinical Outcomes and Healthcare Resource Utilization (HRU) in Patients (Pts) with Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Unfit for High-Intensity Chemotherapy Treated with Venetoclax (VEN) Vs Other Therapies: Results from the AML Real World Evidence (ARC) Initiative

Introduction: The BCL-2 inhibitor VEN is approved in combination with hypomethylating agents or low-dose cytarabine for adults with ND AML. The ARC Initiative is a multicenter chart review study of adult pts with AML. This abstract presents real-world clinical outcomes and hospitalizations among ND AML VEN treated pts ineligible for intensive chemotherapy (IC) and their matched controls. Methods: This multicenter chart review study included adult pts (≥18 years) with ND AML who received VEN in combination with HMA on or after April 2016, or non-VEN regimens on or after May 2015, from 15 international academic sites (US: 11; Israel: 4). Pts ineligible for IC (i.e., ≥75 years or ≥1 comorbidity based on the Ferrara criteria) and treated with VEN (VEN cohort) were matched 1:1 to control pts who received non-VEN-based regimens (CON cohort). Pts were matched based on age (<60, 60-74, ≥75 years) and European LeukemiaNet (ELN 2017) risk. All analyses are based on the May 2023 data cutoff; data collection is ongoing. Clinical outcomes include composite complete remission (CRc; i.e., CR, CR with partial hematologic recovery [CRh], or CR with incomplete marrow recovery [CRi]) and overall survival (OS; assessed using Kaplan-Meier analysis). Hospitalizations were assessed overall and among pts who achieved CRc. Results were separately reported overall and among the respective subsets of VEN pts matched to CON pts treated with high-intensity regimens (CON-H) or low-intensity regimens (CON-L). Results: A total of 142 IC-ineligible VEN pts and 142 matched CON pts were included in the analysis, including 80 VEN pts matched to CON-H pts (56.3%) and 62 VEN pts matched to CON-L pts (43.7%) ( Table 1). Overall, VEN pts received VEN-azacitidine (75.4%) or VEN-decitabine (24.6%). A total of 68.3% of all pts were classified as ELN adverse risk, and 24.6% of VEN pts and 20.4% of CON pts were classified as Eastern Cooperative Oncology Group (ECOG) Grade ³2. Among pts with genetic mutations tested (96.5% of VEN pts and 94.4% of CON pts), 22.6% of VEN pts and 14.2% of CON pts had TP53 mutations and 21.9% and 19.4%, respectively, had IDH1/2 mutations. VEN pts had a mean of 11.6 months of follow-up, and CON pts had a mean of 15.0 months of follow-up. VEN pts were significantly more likely to achieve CRc than CON pts (64.7% vs 44.3%, p=0.001). This difference was more pronounced for VEN pts matched to CON-L pts (62.1% vs 18.0%, p<0.001). The 6-month OS rates were not statistically different between VEN pts and matched CON pts (74.7% vs 67.6%; p=0.20), despite the majority of CON pts receiving high-intensity regimens, but improved among VEN pts matched to CON-L pts (73.5% vs 55.3%; p<0.05). VEN pts had fewer days of hospitalization per pt per month (PPPM; mean 6.3 days vs 8.9 days, p=0.045) and shorter mean duration of hospitalization (13.7 days vs 18.2 days, p<0.001) compared with CON pts. A larger difference was seen in the amount of time (days) (6.5 vs 10.5 PPPM, p=0.006) and mean length of hospital stay (13.9 vs 22.4 days, p<0.001) for VEN pts matched to CON-H pts. Among pts with ≥1 all-cause hospitalization, 69.2% of VEN pts and 74.8% of CON pts were hospitalized for treatment administration (p=0.42). Among pts who achieved CRc, VEN pts had fewer days of hospitalization PPPM than CON pts (mean 4.3 days vs 6.8 days, p=0.002). This difference was more pronounced for VEN pts compared to CON-H pts (4.3 days vs 7.7 days, p=0.001). Mean duration of hospitalization was also shorter for VEN vs CON pts (13.6 days vs 20.4 days, p<0.001). Both VEN and CON pts experienced more hospitalizations before CRc was achieved, with statistically fewer hospitalizations for VEN pts compared with CON pts (days of hospitalization PPPM: 10.1 vs 17.4, p=0.001; duration of hospitalization: 16.4 vs 28.2, p<0.001). In the 60 days after CRc was achieved, VEN pts still had fewer days of hospitalization PPPM than CON pts (1.4 vs 5.2, p<0.001). Conclusions: Pts with ND AML who were ineligible for IC and received VEN had significantly higher rates of CRc than matched pts who received non-VEN-based regimens. Although pts treated with VEN-based regimens achieved similar rates of CRc compared to matched control pts treated with high-intensity therapy, pts treated with VEN-based regimens required a significantly lower burden of hospitalizations compared with matched pts on non-VEN-based regimens.

Efficacy Analysis of Ixazomib-Based Regimens Based on Dynamic Frailty Assessment in Elderly and Frail Patients with Newly Diagnosed Multiple Myeloma

Background: Elderly frail MM patients often lack evidence-based basis due to many comorbidities and poor treatment tolerance, and are often excluded by new drug clinical trials. There are many unsolved problems in clinical practice.There is still variation in the prognosis of frail patients identified using current frailty assessment tools. A potential treatment approach to improve outcomes in this heterogeneous population could involve starting with a well-tolerated low-intensity regimen and adjusting treatment based on ongoing dynamic frailty assessments.Therefore, our center conducted a retrospective study to explore the efficacy and safety of real-world isazomib-based two-drug regimen in the treatment of newly diagnosed elderly frail MM patients by adjusting treatment intensity based on dynamic frailty assessment. Methods: Patients with NDMM who received 2 or more courses of ixazomib-based regimens at the Department of Hematology, Affiliated Hospital of Hebei University from January 1, 2018 to April 1, 2023. All patients were assessed for frailty using the IMWG Geriatric Assessment (IMWG-GA) tool, and a total of 21 patients with frailty assessed as Frail were included, including 11 patients (52.4%) aged 75 years and older and 17 patients (81.0%) with ECOG score ≥ 2.A two-drug regimen of ixazomib combined with dexamethasone (ID) was initiated, and dynamic frailty assessment and efficacy evaluation were performed during the 3-4 courses of treatment. After the frailty status improved, the third drug was used in the following cases: 1) R-ISS high-risk group, and 2) R-ISS intermediate-low risk group with efficacy < PR. The combination of the two drugs was continued in the following cases: 1) R-ISS intermediate-low risk group with improved frailty status with efficacy ≥ PR, and 2) no improvement in frailty status with efficacy ≥ SD. The effectiveness of treatment, discontinuation rate, early death and related adverse effects were assessed. Results: A total of 21 patients were included in this study, of whom 12 patients increased the intensity of treatment after improvement of frail status , the third drug was added with Cyclophosphamide (8 patients) or Lenalidomide (3 patients) or Daratumumab (1 patient) in courses 3-4. 9 patients continued to be treated with ID regimen. The median duration of treatment was 10 (2-19).The ORR was 85.7% (18/21), and the efficacy above MR was 95.2% (20/21). Two patients died, both over 80 years of age, with many underlying complications, including one patient who abandoned treatment and died (17 months), one patient who died (24 months) due to gastrointestinal bleeding, without early death. Four patients experienced disease progression after self-interruption of treatment, 15 patients were still using ixazomib-based therapy, and none discontinued due to adverse reactions. After a follow-up time of 9.0 (2.6-37.0) months, the PFS and OS were not reached. All patients overall tolerated well, mainly grade 1-2 adverse reactions (CTCAE 5.0). Conclusion: This study is a single-center retrospective study that included 21 frail patients with newly diagnosed multiple myeloma and achieved good efficacy with a low discontinuation rate, no serious adverse effects, and no early deaths. This study confirmed that the frail state of the patient was dynamically altered over time and treatment during the remedy period. For elderly frail patients, the two-drug regimen for ID was initiated, the treatment regimen was dynamically adjusted based on frailty assessment, cytogenetic-based stratification (R-ISS) was introduced after frailty assessment was improved, the treatment intensity was increased in patients, and the third drug was added to make up for the lack of treatment; for intermediate-low risk patients with better efficacy, continuous two-drug treatment was performed to avoid adverse reactions caused by excessive treatment, early drug withdrawal and early death. For the heterogeneous population of frail MM in the elderly, the treatment was dynamically adjusted according to frailty assessment and an individualized treatment plan was developed, which achieved the combination of efficacy and safety. However, the benefit of dynamically adjusting treatment regimens according to frailty stratification and the optimal regimen suitable for frailty MM in the elderly still need to be confirmed by evidence-based medical data.

Evaluating the Effectiveness of Risk Adjustment Using Dynamic Frailty Assessment in Treating Newly Diagnosed Multiple Myeloma in Elderly Patients

Background: The treatment of newly diagnosed multiple myeloma (NDMM) in elderly patients is challenging due to various problems. To address these challenges, the European Myeloma Network (EMN) recommends conducting a frailty assessment before NDMM treatment in elderly patients. If the assessment identifies an intermediate fit or frail group, dosage reduction is recommended to avoid excessive treatment. However, as frailty status improves, there may be a risk of insufficient treatment leading to poor outcomes. In order to explore the optimal treatment approach for elderly NDMM patients in real-world settings, a retrospective analysis was conducted on the effectiveness of dynamically adjusting treatments based on frailty assessment in intermediate-fit and frail groups of elderly NDMM patients. Methods: Patients who were initially diagnosed with multiple myeloma and assessed as intermediate fit or frail patients by IMWG-GA frailty assessment at the Department of Hematology, Affiliated Hospital of Hebei University from January 1, 2018 to April 1, 2023 were included in this study.The initial treatment regimen for all patients in this group consisted of a combination of Bortezomib with dexamethasone (BD) or Ixazomib with dexamethasone (ID) .Frailty assessment and efficacy evaluation were conducted every 2-3 courses during the treatment period. In the frail group, treatment in those frailty status improved was adjusted based on prognosis stratification by adding a third drug to high-risk R-ISS patients and subsequently adjusting it according to efficacy evaluation; additionally, a third drug was added to patients who did not reach partial response (<PR). For the intermediate fit group, sequential addition of a third drug occurred during courses 2-3.The options for the third drug included cyclophosphamide, lenalidomide, and thalidomide，and common regimens used were ICD, IRD, VRD, VCD, and VTD.The response rate, discontinuation rate, early death, and adverse drug reactions were observed. Results: A total of 45 patients with newly diagnosed NDMM were included in this study. Among them, 37 patients were assessed as frail .24 /45 patients were treated with the BD regimen and 21/45 patients with the ID regimen. During treatment, dynamic frailty assessment showed significant improvement in frail status during courses 3-4 (see Table 1). Following dynamically adjusted principles, additional drugs were administered to certain patients: 24 /37 frail patients received a third drug; among the intermediate fit patients, all received a third drug. The best ORR achieved throughout the study was at an impressive rate of 82.2% (37/45), with a corresponding best efficacy above VGPR seen in 51.1% (23/45) of cases. Twenty-one patients experienced disease progression for various reasons during treatment, with a median PFS of 14.0 (3.0-96.0) months. During the follow-up period, a total of 17 patients died, while none died within 6 months. The median overall survival (OS) was found to be 18.0 months (ranging from 3.0 to 115.5 months). Safety evaluation was conducted on all 45 patients within the first year and they tolerated the treatment well. Most adverse reactions reported were of grade 1-2 according to CTCAE version 5.0. Conclusion: This study is a retrospective study that the initial treatment involved administering a low-intensity regimen consisting of either BD or ID two-drug combination. Serious adverse reactions, drug withdrawal, and early death decreased in both groups. The treatment intensity was increased for high-risk patients or those with poor efficacy in the frail group after the improvement of frailty status. This new therapeutic strategy which integrates dynamic changes of frailty status, cytogenetic risk factors, efficacy evaluation and dynamic adjustment of treatment, has shown improved efficacy for patients with two different levels of frailty. Additionally, it has been found to reduce early mortality rates. These promising results warrant further investigation through prospective studies.

Molecular Ontogeny in AML Is Both Prognostic and Predictive in Patients Treated with Hypomethylating Agents Plus Venetoclax

Introduction The prognostic value of secondary ontogeny in newly diagnosed acute myeloid leukemia (AML) is based on data from patients (pts) treated with intensive chemotherapy. Secondary ontogeny-defining mutations have been integrated into recently revised diagnostic and prognostic criteria, irrespective of initial therapy. We conducted a retrospective cohort study of pts treated with hypomethylating agents (HMA) +/- venetoclax (VEN) in order to determine the prognostic value of molecular ontogeny in AML treated with low-intensity regimens and evaluate whether the observed benefit of VEN is distinct for each ontogeny. Methods We included all pts with newly diagnosed AML who were treated with either HMA (HMA monotherapy or HMA+non-VEN drug) or HMA+VEN at Dana Farber Cancer Institute between 2014 and 2022. We defined three ontogeny groups in hierarchical order (Lindsley, Blood 2015) based on the presence of a TP53 mutation (“ TP53 group”), the presence of ≥1 secondary ontogeny mutation without concurrent TP53 mutation (“secondary group”), and all others (“de novo” group). Overall 314 pts were included: 111 (35%) in the TP53 group (60 with HMA+VEN, 51 with HMA); 115 (37%) in the secondary group (68 with HMA+VEN, 47 with HMA); 88 (28%) in the de novo group (38 with HMA+VEN, 50 with HMA). No significant differences in baseline characteristics were observed between pts treated with HMA+VEN vs HMA. Composite complete response (cCR) was defined as Complete response (CR) plus CR with incomplete recovery (CRi) and was evaluable in 252/314 (80%). Overall survival (OS) was compared by a log-rank test. Univariate and multivariable Cox regression models were fitted to assess the effect of covariates on OS with allogeneic hematopoietic cell transplant (HCT) as a time-varying covariate. Results Overall, the cCR rate (49% vs 28%, p=0.001), HCT rate (17% vs 8%, p=0.018), and OS (median OS 9.9 [95% confidence interval (CI) 8-13] vs 7.4 [95% CI 6-10], p=0.018) were significantly better in pts treated with HMA+VEN compared with those treated with HMA. To determine whether the benefit of VEN was different based on molecular ontogeny, we assessed outcomes in each group separately. In patients with TP53 mutations, there was no difference in cCR rate between pts treated with HMA+VEN (30%) vs HMA (25%), p=0.82. Conversely, the cCR rates were significantly higher with HMA+VEN vs HMA in those in the secondary (50% vs13%, p<0.001) and de novo groups (50% vs 22%, p=0.034). The HCT rates between HMA+VEN vs HMA were higher in the secondary group (24% vs. 6%, p=0.02) and were similar in the TP53 and de novo groups (15% vs 8%, p=0.38 and 11% vs 10%, p> 0.99, respectively). In the TP53 group, OS was similar in those treated with HMA+VEN vs HMA (median OS 5.7 months [95% CI 4-8] vs 6.1 [95% CI 4-10], respectively, p=0.93). In contrast, pts in the secondary group treated with HMA+VEN vs HMA had significantly better OS (median OS 14.1 months [95% CI 10- 20] vs 6.9 [95% CI 5-11], p=0.0054, Figure). In the de novo group, OS was not significantly different between HMA+VEN ( median OS 13.2 months [95% CI 8-23]) vs HMA (median OS 10.3 [95% CI 6-14]), p=0.12. To verify the prognostic significance of VEN in each ontogeny and adjust for potential confounders, we performed regression models for each ontogeny separately. HMA+VEN vs HMA was associated with significantly improved survival only in the secondary group (secondary: hazard ratio [HR] 0.59, 95% CI 0.38-0.94, p=0.025; TP53: HR 1.19, 95% CI 0.78-1.81, p=0.42; de novo: HR 0.67, 95% CI 0.40-1.12, p=0.13). HCT was associated with improved OS across all groups ( TP53: HR 0.17, 95% CI 0.07-0.42, p<0.001; secondary: HR 0.40, 95% CI 0.18-0.89, p=0.026; de novo: HR 0.14, 95% CI 0.03-0.58, p=0.0067). Among all pts treated with HMA+VEN (n=166), the OS was similar between de novo and secondary groups (p=0.92); and both groups had better OS compared to the TP53 group (comparison vs de novo p=0.007; comparison vs secondary p<0.001). These results were verified in a regression analysis, adjusting for age, HCT, and disease characteristics. Conclusion In newly diagnosed AML patients, treatment with HMA+VEN had a particular benefit in those with secondary mutations, with better response and HCT rates, and prolonged OS compared with HMA. Consequently, outcomes were similar in pts with genetically defined secondary and de novo disease. In pts with TP53 mutations, treatment with HMA+VEN did not improve any clinical outcomes compared with HMA.

Venetoclax Plus Azacitidine, Low Dose Cytarabine, Aclarubicin and G-CSF (VA-CAG Regimen) for Newly Diagnosed Young Patients with Acute Myeloid Leukemia: A Prospective, Multicenter, Single-Arm Phase 2 Clinical Trial

Background: Venetoclax, in combination with hypomethylating agents or low-dose cytarabine, is approved for newly diagnosed acute myeloid leukemia (AML) patients who are over 75 years of age or not eligible for intensive chemotherapy, while the efficacy of venetoclax-based regimens in young fit AML patients still needs to be further explored. Although the combination of anthracycline and cytarabine has achieved a remission rate of about 70% in these patients, the low complete response rate in adverse-risk patients, strong adverse reactions, and long duration of myelosuppression limited the clinical benefit. We presumed that venetoclax plus azacitidine in combination with low-intensity regimens CAG (G-CSF priming, low dose cytarabine, and aclarubicin) could have a better composite complete remission with an acceptable safety profile. Methods: Patients who were newly diagnosed with AML aged from 18 to 65 years without active infection, bleeding and severe cardiopulmonary insufficiency were enrolled. Participants received induction as azacitidine 75 mg/m 2 subcutaneously once daily on days 1-7, cytarabine 10mg/m 2 subcutaneously q12h on days 1-7, aclacinomycin 12 mg/m 2 on days 1,3,5,7, granulocyte colony-stimulating factor 5µg/kg on days 1-7, and venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-21). Venetoclax dose was adjusted based on concomitant CYP3A inhibitors. The efficacy were evaluated by bone marrow morphology and flow cytometry on day 28 cycle 1. The primary endpoints were safety and the composite complete remission rate. This study was approved for ethical review and registered with ClinicalTrials.gov (NCT05662956). Results: Twenty-six patients from eight sites were enrolled between January 1, 2023, and June 20, 2023. The median age was 52 years (range, 18-63years). Thirteen patients (50.0%) had adverse risk, 7 patients (26.9%) had intermediate risk, and 6 patients (23.1%) had favorable risk. All 26 patients (100%) achieved complete remission after cycle 1, and 21 patients (80.8%) was MRD negative by flow cytometry. Two patients (7.7%) were treated with venetoclax for 14 days due to ineffective platelet transfusion and severe infection during treatment. Twenty-two patients (84%) used azole drugs to prevent fungal infection. The median myelosuppression time was 13 days (range, 5-22days), and the median red blood cell and platelet transfusions were 5.5u (range, 0-11.5u) and 30u (range, 0-170u), respectively. Eleven patients (42.3%) experienced infection (including pulmonary fungal infection, oral cold herpes, novel coronavirus infection, etc.), and two of them (7.7%) had a breakthrough invasive fungal infection, but with good management. The most common grade 3/4 adverse events included bone marrow suppression (92.3%), liver injury (19.2%), gastrointestinal reaction (11.5%) and coagulation dysfunction (3.8%).No treatment-related death occurred. Conclusion: VA-CAG regimen achieved high rates of complete remission and MRD negative in young adult fit patients with newly diagnosed AML. This combined regimen has an acceptable safety profile, with low incidence of infection and transfusion dependence.

R-CODOX-M/R-IVAC versus DA-EPOCH-R in patients with newly diagnosed Burkitt lymphoma (HOVON/SAKK): final results of a multicentre, phase 3, open-label, randomised trial

Patients with newly diagnosed high-risk Burkitt lymphoma are treated with high-intensity immune-chemotherapy regimens such as R-CODOX-M/R-IVAC or with lower-intensity regimens such as DA-EPOCH-R. The aim of this study was to make a formal comparison between these regimens. This multicentre, phase 3, open-label, randomised study was done in 26 clinical centres in the Netherlands, Belgium, and Switzerland. Eligible patients were aged 18-75 years with newly diagnosed high-risk Burkitt lymphoma without CNS involvement. Patients were randomly assigned to two cycles of R-CODOX-M/R-IVAC (R-CODOX-M: rituximab 375 mg/m2 on day 1 and 9, cyclophosphamide 800 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2-5, vincristine 1·5 mg/m2 on days 1 and 8, doxorubicin 40 mg/m2 on day 1, and methotrexate 3000 mg/m2 on day 10; R-IVAC: rituximab 375 mg/m2 on days 3 and 7, iphosphamide 1500 mg/m2 on days 1-5, etoposide 60 mg/m2 on days 1-5, and cytarabin 2000 mg/m2 on day 1 and 2) or six cycles of DA-EPOCH-R (dose-adjusted etoposide 50-124 mg/m2 on days 1-4, prednisolone 120 mg/m2 on days 1-5, vincristine 0·4 mg/m2 on days 1-4, dose-adjusted cyclophosphamide 480-1866 mg/m2 on day 5, dose-adjusted doxorubicin 10-24·8 mg/m2 on days 1-4, rituximab 375 mg/m2 on days 1 and 5). Patients older than 65 years received a dose modified R-CODOX-M/R-IVAC. All drugs were intravenous except for prednisolone, which was oral. Patients also received four intrathecal CNS administrations with cytarabin (70 mg) and four with methotrexate (15 mg). Patients were stratified by centre, leukemic disease, and HIV-positivity. The primary endpoint was progression-fee survival. All analyses were done by modified intention-to-treat, excluding randomly assigned patients who were subsequently found to have CNS involvement or diagnosis other than Burkitt lymphoma at study entry. This study is registered with the European Clinical Trial Register, EudraCT2013-004394-27. Due to a slow accrual, the study was closed prematurely on Nov 15, 2021. Between Aug 4, 2014, and Sept 17, 2021, 89 patients were enrolled and randomly assigned to receive R-CODOX-M/R-IVAC (n=46) or DA-EPOCH-R (n=43). Five patients were excluded after random assignment (three in the R-CODOX-M/R-IVAC group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and two CNS involvement] and two in the DA-EPOCH-R group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and one CNS involvement]. 84 remaining patients were included in the modified intention-to-treat analysis. 73 (87%) of 84 patients were male, 76 (90%) presented with stage III or IV disease, and nine (11%) had HIV-positive Burkitt lymphoma. Median patient age was 52 years (IQR 37-64). With a median follow-up of 28·5 months (IQR 13·2-43·7), 2-year progression-free survival was 76% (95% CI 60-86%) in the R-CODOX-M/R-IVAC group and 70% (54-82%) in the DA-EPOCH-R group (hazard ratio 1·42, 95% CI 0·63-3·18; p=0·40). There were two deaths in the R-CODOX-M/R-IVAC group (one infection [treatment related] and one due to disease progression [not treatment related]) and one death in the DA-EPOCH-R group (COVID-19 infection [treatment related]). In the R-CODOX-M/R-IVAC group, four patients went off-protocol because of toxic effects, versus none in the DA-EPOCH-R group. Patients treated with R-CODOX-M/R-IVAC had more infectious adverse events (24 [56%] of 43 patients had at least one grade 3-5 infection vs 14 [34%] of 41 patients in the DA-EPOCH-R group). The trial stopped early, but the available data suggest that while DA-EPOCH-R did not result in superior progression-free survival compared with R-CODOX-M/R-IVAC, it was associated with fewer toxic effects and need for supportive care. DA-EPOCH-R appears to be an additional valid therapeutic option for patients with high-risk Burkitt lymphoma without CNS involvement. The Dutch Cancer Society and the Schumacher-Kramer Foundation.

Measurable residual disease monitoring in patients with acute myeloid leukemia treated with lower-intensity therapy: Roadmap from an ELN-DAVID expert panel.

With the availability of effective targeted agents, significant changes have occurred in the management of patients with acute myeloid leukemia (AML) over the past several years, particularly for those considered unfit for intensive chemotherapy. While testing for measurable residual disease (MRD) is now routinely performed in patients treated with intensive chemotherapy to refine prognosis and, possibly, inform treatment decision-making, its value in the context of lower-intensity regimens is unclear. As such regimens have gained in popularity and can be associated with higher response rates, the need to better define the role of MRD assessment and the appropriate time points and assays used for this purpose has increased. This report outlines a roadmap for MRD testing in patients with AML treated with lower-intensity regimens. Experts from the European LeukemiaNet (ELN)-DAVID AML MRD working group reviewed all available data to propose a framework for MRD testing in future trials and clinical practice. A Delphi poll served to optimize consensus. Establishment of uniform standards for MRD assessments in lower-intensity regimens used in treating patients with AML is clinically relevant and important for optimizing testing and, ultimately, improving treatment outcomes of these patients.

Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants.

DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides DDX41 mutation. Patients with myeloid malignancies and DDX41 variants responded well to therapy, with an overall response rate for patients with treatment naïve AML and MDS of 87% and 84%, respectively. The median overall survival (mOS) of patients with treatment-naïve AML or MDS was 49 and 71 months, respectively. Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively.

Impact of Type of Induction Therapy on Outcomes in Older Adults with AML after Allogeneic Stem Cell Transplantation.

Although venetoclax-based lower-intensity regimens have greatly improved outcomes for older adults with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy, the optimal induction for older patients with newly diagnosed AML who are suitable candidates for hematopoietic stem cell transplant (HSCT) is controversial. We retrospectively analyzed post-HSCT outcomes of 127 patients ≥60 years of age who received induction therapy at our institution with intensive chemotherapy (IC, n=44), lower-intensity therapy (LIT) without venetoclax (n=29) or LIT with venetoclax (n=54) and who underwent allogeneic HSCT in first remission. The 2-year relapse-free survival with LIT with venetoclax was 60%, versus 54% with IC and 41% with LIT without venetoclax, and 2-year overall survival for LIT with venetoclax was 72%, versus 58% with IC and 41% with LIT without venetoclax. The benefit to LIT with venetoclax induction was greatest in patients with adverse-risk AML (2-year OS 74%, 46%, and 29%, respectively). Induction with LIT, with or without venetoclax, was associated with the lowest rate of non-relapse mortality (NRM) (2-year NRM 17% versus 27% with IC; P=0.04). By multivariate analysis, type of induction therapy did not significantly impact any of the post-HSCT outcomes evaluated; hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was the only factor that independently predicted for RFS and OS. LIT plus venetoclax followed by HSCT is feasible treatment strategy in older, fit, and HSCT-eligible patients with newly diagnosed AML and may be particularly beneficial in those with adverse-risk disease.

Undetectable measurable residual disease is associated with improved outcomes in AML irrespective of treatment intensity.

Acute myeloid leukemia (AML) can be treated with either high- or low-intensity regimens. Highly sensitive assays for measurable residual disease (MRD) now allow for a more precise assessment of response quality. We hypothesized that treatment (Rx) intensity may not be a key predictor of outcomes, assuming that an optimal response to therapy is achieved. We performed a single-center retrospective study including 635 patients with newly diagnosed AML responding to either intensive cytarabine/anthracycline-based chemotherapy (IA; n=385) or low-intensity venetoclax-based regimens (LOW+ VEN; n= 250) and who had adequate flow cytometry-based MRD testing performed at the time of best response. The median overall survival (OS) was 50.2, 18.2, 13.6, and 8.1months for the IA MRD-, LOW+ VEN MRD-, IA MRD+, and LOW+ VEN MRD+ cohorts, respectively. The 2-year cumulative incidence of relapse (CIR) was 41.1%, 33.5%, 64.2%, and 59.9% for the IA MRD-, LOW+ VEN MRD-, IAMRD+, and LOW+ VEN MRD+ cohorts, respectively. The CIR was similar between patients within MRD categories irrespective of the treatment regimen received. The IA cohort was enriched for younger patients and favorable AML cytogenetic/molecular categories. Using multivariate analysis, age, best response (complete remission [CR]/CR with incomplete hematologic recovery/morphologic leukemia-free state), MRD status, and European LeukemiaNet (ELN) 2017 risk remained significantly associated with OS, whereas best response, MRD status, and ELN 2017 risk were significantly associated with CIR. Treatment intensity was not significantly associated with either OS or CIR. Achievement of MRD- CR should be the key objective of AML therapy in both high- and low-intensity treatment regimens.