Venetoclax-based Regimens Research Articles

P-2147. Incidence of Invasive Fungal Infection in Venetoclax-based Regimens for AML/MDS Patients on Micafungin Prophylaxis

Abstract Background Combining venetoclax with a hypomethylating agent (HMA) is standard of care in Acute Myeloid Leukemia (AML) ineligible for intensive chemotherapy. However, this agent is associated with prolonged neutropenia, potentially increasing the risk of invasive fungal infections (IFI). The necessity of antifungal prophylaxis in this context remains unclear, particularly in regions like the southeastern United States, where the humid climate may contribute to higher overall rates of IFIs. Methods A retrospective, observational cohort study evaluated patients admitted to Baptist Health Baptist Hospital in Miami, Florida, from January 2019 to January 2023 who received venetoclax and an HMA with/without low-dose cytarabine for AML/MDS. Exclusions included incomplete first cycle, active IFI treatment, absence of antifungal prophylaxis, or initiation of venetoclax at an outside institution. The primary endpoint was 90-day IFI incidence using 2022 EORTC criteria. The secondary endpoints were complete response (CR) per ELN 2022 guidelines, 1-year mortality, and 90-day count recovery. Results Among 102 patients evaluated, the mean±SD age was 73±9 years. Twenty-seven patients (27%) had relapsed refractory disease, and 42 (41%) received prior chemotherapy. Overall, 57% presented with de novo AML/MDS; 13 treated specifically for MDS. Micafungin was the predominant inpatient prophylaxis agent (95%), while posaconazole (40%) and fluconazole (37%) were the predominant prophylaxis agents prescribed at discharge. IFI incidence at 90 days was 7%, consisting mostly of possible IFI (6/7). CR was achieved in 61% of patients, and 1-year mortality was 32%. 90-day neutrophil recovery occurred in 62% (63/102), while platelet recovery occurred in 66% (65/99). Conclusion Our findings suggest that micafungin as primary antifungal prophylaxis in AML/MDS patients receiving venetoclax-based regimens demonstrates a comparable incidence of IFI at 90 days to previous studies reporting similar outcomes. Disclosures Timothy Gauthier, PharmD, BCPS, BCIDP, AbbVie Pharma: Advisor/Consultant|Antimicrobial Therapy, Inc: Advisor/Consultant|Ferring Pharma: Advisor/Consultant|Firstline Mobile Health: Advisor/Consultant|Gilead Pharma: Advisor/Consultant|GoodRx: Advisor/Consultant|GSK Pharma: Advisor/Consultant|Melinta Pharma: Advisor/Consultant|Pattern Biosciences: Advisor/Consultant|Pfizer Pharma: Advisor/Consultant|ProCE: Honoraria|WWW.LearnAntibiotics.com: Ownership Interest

Venetoclax-Based Combination Regimens in Acute Myeloid Leukemia.

In recent years, there has been tremendous interest surrounding the integration of venetoclax into both non-intensive and intensive chemotherapy regimens for AML. However, with this increasing utilization of venetoclax, considerable questions surrounding key issues such as dosing strategies and the practicality of venetoclax administration have arisen. This review highlights the evolution of venetoclax-based regimens in AML and provides a commentary on notable practical considerations when utilizing this agent.

Pneumonia in Patients with Chronic Lymphocytic Leukemia Treated with Venetoclax-Based Regimens: A Real-World Analysis of the Polish Adult Leukemia Group (PALG).

Patients with chronic lymphocytic leukemia (CLL) are susceptible to infections that can affect their clinical outcomes. The aims of this study were to assess the following: (1) the incidence of pneumonia in CLL patients treated with venetoclax-based regimens in a real-world setting, (2) the risk factors for event-free survival (EFS), and (3) overall survival (OS). This multicenter study included 322 patients from eight centers. Univariable and multivariable analyses (MVA) were performed, with the development of pneumonia during venetoclax-based treatment and OS as outcomes. The most common complication was neutropenia (59%). During treatment with venetoclax-based regimens, 66 (20%) patients developed pneumonia-50 (23%) patients in the rituximab-plus-venetoclax (R-VEN) group and 13 (16%) patients in the obinutuzumab-plus-venetoclax (O-VEN) group (p = 0.15). Chronic obstructive pulmonary disease (COPD)/asthma, splenomegaly, elevated creatinine, and anemia < 8 g/dL were the risk factors for EFS in MVA (HR = 2.08, 95%CI 1.16-3.74, p = 0.014; HR 1.73, 95%CI 1.08-2.78, p = 0.02; HR 2.13, 95%CI 1.10-4.11, p = 0.03, HR 3.58, 95%CI 2.18-5.89, p < 0.001, respectively). Relapsed/refractory (R/R) CLL patients treated with R-VEN with pneumonia had worse OS than those without (p < 0.001). In patients treated with O-VEN, median OS did not differ between patients with and without pneumonia (p = 0.45). Our real-world study showed that pneumonia during venetoclax treatment occurs more frequently than reported in registration trials and has a negative impact on OS, especially in patients with R/R CLL who are treated with R-VEN. Neutropenia is not a risk factor for pneumonia.

Treatment of minimal residual disease in myeloid malignancies after allo-HSCT with venetoclax-based regimens in patients ineligible for or failed in the immunotherapy

ABSTRACT Background: Relapse was the major cause of treatment failure in patients with myeloid malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients who still suffer from the disease while cannot be detected by morphological analysis can be identified by the minimal residual disease (MRD) monitoring. The most used first-line regimens for MRD are immunotherapies. However, for patients who were ineligible for or failed in first-line immunotherapies, options were limited. Methods: A total of 20 patients with myeloid malignancies with recurrent MRD after allo-HSCT were included in this study. The safety and efficacy of venetoclax-based regimens were analyzed. Results: There were 13 patients (65%) treated with venetoclax combined with hypomethylating agents concomitantly and seven patients (35%) treated with venetoclax monotherapy. After venetoclax-based regimens, MRD was eliminated in 11 patients (55%) with 6 subsequently developing recurrent MRD and 5 remaining in molecular remission. MRD declined in two patients (10%), and no responses in seven patients (35%). Among the two patients with declined MRD, one patient finally eliminated MRD after two cycles of the venetoclax-based regimen, and the other patient’s MRD further declined after the second regimen. The objective response rate (ORR) was 65%. The median duration of response was 103 (12–313) days. The incidences of grades 3–4 neutropenia, anemia, and thrombocytopenia independently of pretreatment status were 30%, 20% and 20%, respectively. Conclusion: Venetoclax-based regimens are efficient and safe for MRD in patients with myeloid malignancies ineligible for or failed in the first-line immunotherapies after allo-HSCT.

Real-World Treatment Patterns, Resource Utilization, and Cost of Care in Medicare Beneficiaries Newly Diagnosed with Acute Myeloid Leukemia and Treated with Venetoclax-Based Regimens

Real-World Treatment Patterns, Resource Utilization, and Cost of Care in Medicare Beneficiaries Newly Diagnosed with Acute Myeloid Leukemia and Treated with Venetoclax-Based Regimens

Pneumonia in patients with chronic lymphocytic leukemia treated with venetoclax-based regimens: A real-world analysis of Polish Adult Leukemia Group (PALG).

Patients with chronic lymphocytic leukemia (CLL) are susceptible to infections that can affect their clinical outcomes. To assess: (1) the incidence of pneumonia in CLL patients treated with venetoclax-based regimens in a real-world setting, (2) the risk factors for event-free survival (EFS), and (3) overall survival (OS). This multicenter study included 322 patients from eight centers. Univariable and multivariable analyses (MVA) were performed, having the development of pneumonia during venetoclax-based treatment and OS as outcomes. The most common complication was neutropenia (59%). During treatment with venetoclax-based regimens, 66 (20%) of patients developed pneumonia: 50 (23%) patients in the rituximab plus venetoclax (R-VEN) group, 13 (16%) patients in the obinutuzumab plus venetoclax (O-VEN) group (p=0.15). Chronic obstructive pulmonary disease (COPD)/asthma, splenomegaly, elevated creatinine, and anemia <8g/dL were the risk factors for EFS in MVA (hazard ratio [HR]=2.08, 95% confidence interval [CI], 1.16-3.74, p=0.014; HR 1.73, 95% CI, 1.08-2.78, p=0.02; HR 2.13, 95% CI, 1.10-4.11, p=0.03, HR 3.58, 95% CI, 2.18-5.89, p<0.001, respectively). Relapsed/refractory (R/R) CLL patients treated with R-VEN with pneumonia had worse OS than those without (p<0.001). In patients treated with O-VEN, median OS did not differ between patients with and without pneumonia (p=0.45). Our real-world study showed that pneumonia during venetoclax treatment occurs more frequently than reported in registration trials and has a negative impact on OS, especially in patients with R/R CLL treated with R-VEN. Neutropenia is not a risk factor for pneumonia.

Monocentric experience of venetoclax-based regimen in paediatric refractory and relapsed AML/MDS.

BCL-2 inhibitor venetoclax demonstrates promising efficacy in paediatric relapsed/refractory acute myeloid leukaemia (r/r AML). This retrospective analysis evaluated 12 patients treated with venetoclax-based regimens under compassionate use forr/r myeloid malignancies. The overall response rate (ORR) was 41.6%, with complete response (CR) achieved in 33% of patients. Three patients successfully underwent allogeneic haematopoietic scell transplantation (HSCT) after venetoclax bridging therapy. Venetoclax demonstrated a favourable safety profile with manageable side effects. These findings suggest venetoclax's potential as a valuable therapeutic option for paediatric r/r AML, particularly for heavily pretreated patients. Further investigation in larger multicentre trials is warranted to refine treatment strategy.

Treatment selection and influencing factors for chronic lymphocytic leukemia: a physician survey in Japan

BackgroundChronic lymphocytic leukemia (CLL) is a rare form of lymphoma in Japan. This study aimed to explore hematologists’ motivations and considerations in making treatment decisions for CLL.MethodsResponses from hematologists treating CLL, obtained through an online survey, were descriptively analyzed. Subgroup analyses by preferred first-line (1L) treatment, years of clinical experience, and level of interest in CLL were conducted.ResultsOut of 107 hematologists surveyed, 82.2% identified Bruton tyrosine kinase inhibitors (BTKi) as their primary choice for 1L treatment; the reasons included established clinical evidence (61.4%) and oral administration convenience (56.8%). Key factors influencing 1L treatment selection among those favoring BTKi included the presence of 17p deletion, TP53 mutation, and patient’s fitness status. BTKi was favored by 92.6% of hematologists with < 10 years of clinical experience and by 78.8% with more experience. The main reasons for choosing BTKi included safety (50.0%) and tolerance (46.7%) among hematologists who stated they had a specific interest in CLL and the oral administration route (62.1%) among hematologists with lower interest. When BTKi was used as 1L therapy, venetoclax-based regimens were preferred for second-line treatment. The most common concern about BTKi was substantial out-of-pocket costs.ConclusionAlthough many Japanese hematologists select their treatment based on clinical evidence, variations exist in treatment strategies, possibly associated with hematologists’ experience and interest in CLL. These findings underscore the importance of further promoting evidence-based treatments to ensure that all physicians can make informed decisions. Future research should explore additional factors that influence CLL treatment decisions.

Mega-dose decitabine conditioning and prophylactic donor lymphocyte infusion for patients with relapsed/refractory AML with active disease at the time of allogeneic haematopoietic cell transplantation: A multicenter prospective phase II study.

Patients with relapsed/refractory acute myeloid leukaemia (R/R AML), especially those who failed in novel target agents are related to dismal survival. We developed a multi-institutional, single-arm, prospective phase II trial, to investigate intensified conditioning with 'Mega-Dose' decitabine (MegaDAC) following allogeneic haematopoietic cell transplantation (allo-HCT) for R/R AML. From 2019 to 2023, 70 heavily treated R/R AML patients in active disease were consecutively enrolled. Significantly, every patient (n = 18) harbouring specific mutations exhibited no response to their best available target agents (BATs). Moreover, 74.3% of the enrolled patients did not reach remission following venetoclax-based regimens. All patients underwent intravenous decitabine (400 mg/m2) along with busulfan and cyclophosphamide. Median follow-up was 26 months (8-65) after HCT. All engrafted patients achieved MRD negativity post-HCT, with a median 3.3-log reduction in recurrent genetic abnormalities. The regimen was well tolerated, without irreversible grades III-IV toxicity peri-engraftment. The estimated 2-year CIR was 29.6% (18.4%-41.7%) and the est-2-year NRM was 15.5% (7.8%-25.5%). The est-2-year LFS, OS, and GRFS were 55.0% (43.5%-69.4%), 58.6% (47.0%-73.0%), and 42.9% (31.9%-57.6%), respectively. Multivariate analysis showed that pre-HCT drug exposures had no significant impact on primary outcomes. MegaDAC is highlighted as an effective and safe option for R/R AML in the new era of targeted therapies.

Safety, Efficacy, and Predictive Factors of Venetoclax-Based Regimens in Older Patients With Acute Myeloid Leukemia: A Meta-Analysis

Safety, Efficacy, and Predictive Factors of Venetoclax-Based Regimens in Older Patients With Acute Myeloid Leukemia: A Meta-Analysis

Targeting Acute Myeloid Leukemia Stem Cells through Perturbation of Mitochondrial Calcium.

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. Although venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and nonresponsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate an active metabolic (i.e., OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance. Significance: We identify increased utilization of mitochondrial calcium as a distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.

Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies

To our knowledge, venetoclax is the first example of personalized medicine for multiple myeloma (MM), with meaningful clinical activity as a monotherapy and in combination in patients with myeloma harboring the t(11:14) translocation. However, despite the high response rates and prolonged progression-free survival, a significant proportion of patients eventually relapse. Here, we aim to study adaptive molecular responses after the acquisition of venetoclax resistance in sensitive t(11:14) MM cell models. We therefore generated single-cell venetoclax-resistant t(11:14) MM cell lines and investigated the mechanisms contributing to resistance as well as the cells' sensitivity to other treatments. Our data suggest that acquired resistance to venetoclax is characterized by reduced mitochondrial priming and changes in B-cell lymphoma-2 (BCL-2) family proteins' expression in MM cells, conferring broad resistance to standard-of-care antimyeloma drugs. However, our results show that the resistant cells are still sensitive to immunotherapeutic treatments, highlighting the need to consider appropriate sequencing of these treatments after venetoclax-based regimens.

Exploring the prognostic role of complex karyotype in chronic lymphocytic leukaemia patients treated with venetoclax-based regimens.

Although the unfavourable prognostic role of complex karyotype (CK) in chronic lymphocytic leukaemia (CLL) patients treated with chemoimmunotherapy has been clarified, its impact on the outcome of patients being treated with novel targeted agents, and especially with venetoclax-based regimens, remains to be resolved. In fact, only few studies, utilizing data derived from clinical trials (e.g. MURANO, CLL14, GAIA-CLL13), specifically focus on this topic while real-word evidence is missing. In our real-life retrospective study conducted on 61 patients with CLL and treated with venetoclax-based regimens in any therapeutic line, we documented a remarkable lower progression-free survival in patients harbouring both CK and high CK, while overall response rate (including complete remissions and partial remissions) and overall survival are not affected by CK in our population.

Time from diagnosis to treatment has no impact on survival in newly diagnosed acute myeloid leukemia treated with venetoclax-based regimens.

In newly diagnosed acute myeloid leukemia (AML), immediate initiation of treatment is standard of care. However, deferral of antileukemic therapy may be indicated to assess comorbidities or pretherapeutic risk factors. We explored the impact of time from diagnosis to treatment on outcomes in newly diagnosed AML undergoing venetoclax-based therapy in two distinct cohorts. By querying the Study Alliance Leukemia database and the global health network TriNetX, we identified 138 and 717 patients respectively with an average age of 76 and 72 years who received venetoclax-based first-line therapy. When comparing patients who started treatment earlier or later than 10 days after initial diagnosis, no significant difference in median overall survival was observed - neither in the SAL cohort (7.7 vs. 9.6 months; P=0.42) nor in the TriNetX cohort (7.5 vs. 7.2 months; P=0.41). Similarly, severe infections, bleeding, and thromboembolic events were equally observed between early and later treatments, both in the overall patient groups and specific subgroups (age ≥75 years or leukocytes ≥20x109/L). This retrospective analysis indicates that delaying the start of venetoclax-based therapy in newly diagnosed AML might be a safe option for selected patients, provided that close clinical monitoring is performed.

Real-World Health Care Resource Use and Costs Among Patients With Chronic Lymphocytic Leukemia Treated With Venetoclax-Based and Bruton Tyrosine Kinase Inhibitor-Based Regimens in the Second-Line Setting.

Real-world evidence comparing health care resource use (HRU) and costs between novel targeted therapies among patients with chronic lymphocytic leukemia (CLL) is lacking. We compared all-cause and CLL-specific HRU and costs between patients initiated on B-cell lymphoma 2 inhibitor (venetoclax)- or Bruton tyrosine kinase inhibitor (BTKi)-based regimens in the second-line (2L) setting. This is a retrospective observational study using Optum Clinformatics Data Mart of adult patients with CLL/small lymphocytic lymphoma who received 2L venetoclax- or BTKi-based regimens (January 2018-December 2021) for the first time and had ≥one CLL diagnostic claim after 2L initiation and ≥two claims for venetoclax or BTKi. Baseline characteristics were balanced using stabilized inverse probability of treatment weights. Mean monthly cost difference (MMCD) between cohorts for all-cause and CLL-specific per patient per month (PPPM) costs was estimated. Rates of PPPM-HRU were compared between cohorts using rate ratios (RRs). Of 280 patients, median age 75.5 years, 64.6% and 35.4% received BTKi- versus venetoclax-based regimens, respectively. Most BTKi-treated patients received monotherapy (88.4%), whereas 62.3% of venetoclax-treated patients received combination therapy with anti-CD20 agents. The median duration of 2L therapy was 11.6 and 11.0 months for BTKi versus venetoclax cohorts, respectively. All-cause total costs were lower for venetoclax versus BTKi (MMCD [SE], $-2,497.64 [$1,006.77] in US dollars (USD); P = .01), driven by lower medication costs offsetting medical costs; trends were similar for CLL-specific estimates. Outpatient HRU was higher for venetoclax versus BTKi (RR all-cause: 1.22 versus CLL-specific: 1.64). Venetoclax was associated with total monthly cost savings versus BTKis, illustrating the economic value of time-limited venetoclax-based regimens in the 2L setting.

Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients.

Over the past two decades, the prognosis in adolescents and young adults (AYAs) diagnosed with acute myeloid leukemia (AML) has significantly improved. The standard intensive cytotoxic treatment approach for AYAs with AML, consisting of induction chemotherapy with anthracycline/cytarabine combination followed by consolidation chemotherapy or stem cell transplantation, has lately been shifting toward novel targeted therapies, mostly in the fields of clinical trials. One of the most recent advances in treating AML is the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax with hypomethylating agents, which has been studied in elderly populations and was approved by the Food and Drug Administration (FDA) for patients over 75 years of age or patients excluded from intensive chemotherapy induction schemas due to comorbidities. Regarding the AYA population, venetoclax combination therapy could be a therapeutic option for patients with refractory/relapsed (R/R) AML, although data from real-world studies are currently limited. Venetoclax is frequently used by AYAs diagnosed with advanced hematologic malignancies, mainly acute lymphoblastic leukemia and myelodysplastic syndromes, as a salvage therapeutic option with considerable efficacy and safety. Herein, we aim to summarize the evidence obtained from clinical trials and observational studies on venetoclax use in AYAs with AML. Based on the available evidence, venetoclax is a safe and effective therapeutic option for R/R AML AYA patients. However, further research in larger cohorts is needed to confirm these data, establishing the benefits of a venetoclax-based regimen for this special population.

Targeting S100A9 protein affects mTOR-ER stress signaling and increases venetoclax sensitivity in Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is a heterogeneous disease with limited treatment options and a high demand for novel targeted therapies. Since myeloid-related protein S100A9 is abundantly expressed in AML, we aimed to unravel the therapeutic impact and underlying mechanisms of targeting both intracellular and extracellular S100A9 protein in AML cell lines and primary patient samples. S100A9 silencing in AML cell lines resulted in increased apoptosis and reduced AML cell viability and proliferation. These therapeutic effects were associated with a decrease in mTOR and endoplasmic reticulum stress signaling. Comparable results on AML cell proliferation and mTOR signaling could be observed using the clinically available S100A9 inhibitor tasquinimod. Interestingly, while siRNA-mediated targeting of S100A9 affected both extracellular acidification and mitochondrial metabolism, tasquinimod only affected the mitochondrial function of AML cells. Finally, we found that S100A9-targeting approaches could significantly increase venetoclax sensitivity in AML cells, which was associated with a downregulation of BCL-2 and c-MYC in the combination group compared to single agent therapy. This study identifies S100A9 as a novel molecular target to treat AML and supports the therapeutic evaluation of tasquinimod in venetoclax-based regimens for AML patients.

Selinexor and Chidamide in Patients with Relapsed/Refractory Acute Myeloid Leukemia Exposed to Venetoclax: A Single-Arm, Phase 2 Study

Background: Novel therapies for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are imperative, particularly those who have experienced relapse or resistance to multiline chemotherapies or venetoclax-based regimens, thereby underscoring the need for more innovative therapies that are both effective and well-tolerated. Chidamide and Selinexor have shown potential synergistic anti-leukemia effects by targeting NF-Κb /c-FLIP signaling via suppressing HDAC1/XPO1 activity. Therefore, the aim of this study was to investigate the activity and tolerability of chidamide combined with selinexor regimen for R/R AML. Methods: We report the findings of a phase 2 study in patients with relapsed/refractory AML that combined chidamide with selinexor. Selinexor was administered orally twice weekly for 4 weeks at a dose of 40/60 mg, depending on the patent's weight (over or under 70 kg). Chidamide was taken orally once a day at a dose of 10mg for 28 days. The primary endpoint was composite complete remission rate [CRc, complete response (CR) plus complete response with incomplete blood count recovery (CRi)] after 1 cycles of treatment. The secondary endpoints include safety and survival. Results: Between December 2022 and April 2023, a total of 11 patients, median age 40 years (range, 22-54) were enrolled in the trail (ClinicalTrials.gov number, NCT05951855.). 8 out of 11 (72.7%) patients with R/R AML had received more than three prior lines of treatment. All of patients were previously exposed to venetoclax or hypomethylating agents (HMAs). Key baseline and clinical characteristics are summarized in Table 1. 10(90.9%) patients received the initial dose of 40 mg of selinexor twice a week, while one (9.1%) received 60 mg. Chidamide was administered to all patients at a daily dose of 10 mg daily. Five (45.5%) patients achieved a CRc (with 3 CR and 2 CRi), two (18.1%) achieved Partial remission (PR), and 5 (45.5%) had progressive disease for an overall response rate (ORR) of 63.6%. With a median follow-up of 147 days（range 59-234）, the median event-free survival (EFS) was 75 days and median overall survival (OS) was not yet reached (Figure 1). Among the seven patients who achieved CRc or PR, all proceeded to transplant after responding. One relapsed on day 56 following response and died 20 days later. Another patient died from an infection during the allogeneic hematopoietic stem cell transplantation (allo-HSCT). The remaining 5 patients are currently alive as of July 2023. No dose-limiting toxicities were observed. Common adverse events included neutropenia (72.7%), thrombocytopenia (63.6%), nausea/vomiting (63.6%), fatigue (45.5%), diarrhea (18.1%), bacteremia (9%). Conclusion: In this study, the combination of Selinexor and chidamide was administered as salvage treatment for R/R AML patients, resulting a high response rate and favorable safety profile. This offers a potential way for patients to bridge to transplantation. However, future studies with larger sample sizes and longer follow-up periods are needed to further validate its efficacy.

Optimal Therapeutic Strategies in Relapsed/Refractory AML with Prior Exposure to Venetoclax Based Therapy

Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from immature myeloid progenitors with notoriously poor outcomes, particularly in the elderly. Venetoclax (Ven) plays an essential role in acute myeloid leukemia (AML) directed therapy as it is approved for frontline therapy in combination with azacitidine (Aza), decitabine (Dec), or low-dose cytarabine (LDAC) for patients aged 75 years and older, or those with significant comorbidities. However, venetoclax-based therapy is not curative, and the ideal salvage regimen is unclear in these patients. We performed a retrospective review that analyzed a single center's venetoclax-based regimens to identify rational subsequent lines of therapy after failing venetoclax. Methods: We conducted a retrospective review of adult patients at Roswell Park Comprehensive Cancer Center who had a confirmed AML diagnosis and received a venetoclax-based regimen as upfront therapy between January 2015-February 2023. Demographics, prior hematological disorders, ELN risk stratification, Eastern Cooperative Oncology Group (ECOG) performance status, treatment received in upfront vs relapsed/refractory settings, date of remission/relapse, disease-specific variables [molecular data, cytogenetics], and outcomes [duration of response, time to progression, MRD status, and overall survival] were collected. Of note, in patients who received upfront venetoclax regimen, the subsequent salvage therapy was grouped by targeted (Gliterinib, Enasidenib, Ivosidenib), low-intensity (single agent hypomethylating therapy, gemtuzumab, ozogamicin), or intensive groups (CLAG-M) and analysis was performed for progression-free survival (PFS). The patient demographics and clinical characteristics were summarized by group (i.e. response, regimens) using the Mann-Whitney U and Fisher's exact test. Survival functions were described by the Kaplan-Meier method and compared with the Log-rank test. Analyses were performed in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: The retrospective study analyzed 97 patients. In the upfront analysis, the median age was 73.4 years (range: 51.4-89.8) and 64 (66.0%) of the patients were male. 65 patients (67.0%) received Aza/Ven, 26 (26.8%) Dec/Ven, and 6 (6.2%) LDAC/Ven. Per ELN 2022 criteria, 13.3% of patients were stratified as favorable,12.2% as intermediate, and 74.4% as adverse risk. Of the adverse risk patients, 67/97 (69.1%) patients received Aza/Ven. Median survival time for all upfront induction regimens was 15.8 months (95% CI: 8.1-22.6), greatest median survival with Aza/Ven of 19.1 months (95% CI:10.4-23.6). Median PFS by all induction regimens was 8.9 months (95% CI: 5.0-13.9) with the greatest median PFS being Aza/Ven at 10.9 months (95% CI: 6.6-20.2); p=0.045). Overall, 29 out of 97 (29.9%) patients received salvage therapy. These included 19 (65.5%) males with 93.1% of patients being Caucasian. The majority of patients (81.5%) had adverse ELN risk stratification (Table 1). Total 1-year survival rate is 0.050 (0.31-0.67), with intensive 0.050 (0.16-0.67), low intensity 0.67 (0.35-0.86), targeted 0.39 (0.18-0.60). Total 3-year survival rate is 0.19 (0.06-0.38) with intensive 0.17 (0.02-0.46), low intensity 0.30 (0.08-0.56), and targeted 0.20 (0.05-0.41). Patients receiving subsequent salvage therapy after upfront venetoclax regimen showed the greatest PFS after receiving low-intensity therapy compared to targeted or intensive regimens with a median survival of 13.9 months (95% CI: 0.0-35.9); p&amp;lt;0.001) (Figure 1). Median survival after intensive therapy was 1.3 months (95% CI:0.5-3.9) and targeted therapy 5.8 months (95% CI: 2.8-10.0). Total OS 14.9 (95% CI: 6.1-22.7) with a low-intensity median survival of 22.7 months (95% CI:1.4-Not Reached (NR)). Conclusion: In this single-center retrospective review, it was found that a low-intensity salvage regimen after the upfront venetoclax regimen showed the greatest PFS compared to targeted or intensive regimens, however, there is no statistically significant difference in OS. Our study results were limited by a small sample size. Further studies are needed to clearly define the ideal salvage regimen for AML patients failing upfront venetoclax-based therapy.

The Total Lifetime Cost of Treating Patients (Pts) with CLL in the United States (US)

Background:CLL is the most common form of leukemia in pts aged ≥ 19 y and accounts for 38% of all new leukemia cases. The CLL treatment (tx) paradigm changed after the introduction of oral targeted therapies (Bruton tyrosine kinase inhibitors [BTKi] and B-cell lymphoma 2 inhibitors). However, relapses after tx are common, and these txs come with a high cost. Limited data exist evaluating the lifetime cost of treating pts with CLL with current therapies. The objective of this study was to estimate the total lifetime cost of treating pts with CLL in the US from the health system perspective. Methods: A semi-Markov model with a lifetime horizon was developed to estimate the per-pt cost of treating CLL. The model consisted of 6 distinct health states, including tx by line of therapy (LOT; first line [1L] through fifth line and later [5L+]) and death. Pts entered the model in the 1L. CLL txs selected for inclusion were those most commonly used according to market share data and recommended by National Comprehensive Cancer Network guidelines. Tx categories included ibrutinib ± anti-CD20 monoclonal antibody (mAb), acalabrutinib ± anti-CD20 mAb, venetoclax-based regimens, chemoimmunotherapy, and phosphatidylinositol 3-kinase inhibitor-based regimens. Transition probabilities and time spent on each LOT were calculated based on data abstracted from digitized time to next tx (TTNT) and OS Kaplan-Meier curves from real-world studies. Tx-specific data were applied for 1L and second-line (2L) txs, and data pooled across txs for each LOT were applied for third line (3L) through 5L+. TTNT and OS data from the literature were extracted for the duration of available follow-up. Best-fitting parametric survival models were used for reasonable extrapolation of TTNT data beyond the limited follow-up. OS beyond the available follow-up was estimated based on survival data from US life tables adjusted for each tx via a calculated tx-specific HR. Costs associated with drug acquisition and administration of CLL txs, inpatient stays, outpatient visits, emergency department (ED) visits, Richter's transformation (RT), end-of-life care, and other health care resource utilization (HCRU) were included in the model. AE management costs were assumed to be captured within inpatient costs and therefore not included separately in the model. Inputs were derived from published literature and publicly available sources. At the point of entry into the model, the study cohort was assumed to be 70 y old and included 64% males, based on median age and sex distribution reported in the literature (Mato et al. Clin Lymphoma Myeloma Leuk 2023). All costs were converted to a health system perspective, discounted 3% per year, and adjusted to 2023 US dollars (USD). Model outcomes included per-pt total expected lifetime cost and total expected lifespan. A scenario analysis was conducted to calculate per-pt-per-year (PPPY) cost of each LOT. A 1-way sensitivity analysis was conducted to identify key drivers of the total lifetime cost. Results: The total expected lifetime cost of treating a pt with CLL in the US was estimated to be $1,142,357. The estimated total time spent in the model was 8.03 y. Drug costs were the largest driver of the total lifetime cost (77%), followed by inpatient and ED costs (20%; Table). The majority of time was spent in 1L and 2L (6 and 1.68 y, respectively). The probability of receiving 2L, 3L, fourth-line (4L), and 5L+ therapy was estimated to be 44%, 16%, 6%, and 4%, respectively. In the scenario analysis, the annual cost in each LOT ranged from $140,867 to $234,807 PPPY, with costs increasing with each subsequent LOT (Figure). The 1-way sensitivity analysis showed that lifetime costs were mainly driven by drug acquisition costs, especially BTKi such as ibrutinib and acalabrutinib, as well as the cost of venetoclax. Other key drivers of the total expected lifetime cost included hospitalization costs and pt starting age. Conclusions:Study results showed that the expected lifetime cost of treating a pt with CLL in the US is high. Drugs (especially oral targeted txs) were the top drivers of lifetime total cost. As expected, scenario analysis showed that the economic burden increased with each LOT. Given the high lifetime economic burden of this disease, there is a need for potentially more effective 1-time-only tx options.