Dose Cytarabine Research Articles

Real World Data Venetoclax Based Therapies in a Single Center in Latin America

Introduction: Venetoclax-based therapies have changed the outcomes of acute myeloid leukemia, in combination with hypomethylating agents, low-dose cytarabine or in older patients not eligible for intensive regimens. Combinations with venetoclax with target therapy and with standard chemotherapy are being tested to improve outcomes in specific subgroups. In Latin America, the lack of clinical trials increases prescriptions not yet approved in international guidelines (off-label use). In this paper, we present data from a private reference center in Latin America for the treatment of acute myeloid leukemia and high-risk myelodysplasia. Methods: This is a unicentric, retrospective, and non-interventional cohort study performed at Brazilian Hospital Albert Einstein. Inclusion criteria were adult patients (aged ≥18 years) diagnosed with AML between May 2019 and January 2023, who were treated with a venetoclax-based regimen. Independent variables analyzed were age, gender, prognostic risk according to ELN 2022, indication of bone marrow transplantation, and molecular and cytogenetic risk at diagnosis. Results: Sixty-three (N= 63) patients were included, with a median age of 63.1 years old. Forty-eight patients received a combination of venetoclax and a hypomethylating agent, two were associated with low doses of cytarabine, eight were associated with target therapy (inhibitor of FLT3), and five with intensive chemotherapy. The median follow-up was 303 days, and the median use of venetoclax in those who did not suspend treatment was 352 days. The main cause of suspension was hematological toxicity. In the univariate analysis, the following onco-hematological karyotype variables, age, type of regimen combined with venetoclax, and decision for transplant did not show statistical significance. Conclusion: Real-world data show that venetoclax-based therapies are effective in patients with AML, and their combinations have been increasingly explored.

Induction and Maintenance Therapy in Elderly Patients with Mantle Cell Lymphoma: Double-Randomized MCL R2 Elderly Clinical Trial By the European Mantle Cell Lymphoma Network

Background: Mantle cell lymphoma (MCL) formally remains an incurable disease. Recent trials in younger patients have demonstrated the benefit of a cytarabin-containing induction (Hermine, JCO 2022) and a rituximab (Le Gouill, NEJM 2017) as well as a lenalidomide maintenance (Ladetto, Lancet Haematol 2021). The MCL-R2 elderly trial investigated whether an induction with intermediate dose of cytarabine improves long term outcome over R-CHOP alone in elderly patients (>60 yrs). In addition, responders to induction therapy were randomized between a 2 year maintenance with rituximab-lenalidomide (R2) compared to rituximab alone. Here, we present the results of the 2 randomizations. Methods: Patients >60 yrs not eligible for high dose therapy with stage II-IV MCL were included. Initially, patients were randomized between 8 cycles of 3-weekly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or 6 cycles of alternating 3-weekly R-CHOP and 4-weekly R-HAD (rituximab, cytarabine, Dexamethasone). Subsequently, patients in complete or partial remission (CR, CRunconfirmed or PR) underwent a second randomization between rituximab maintenance every 2 months or R2 (lenalidomide 15 mg d2-22 every 4 weeks plus rituximab). Second randomization was stratified for induction regimen, study group, age, MCL international prognostic index (MIPI) and response (CR/CRu vs PR). Both maintenance regimens were continued for 24 months. The primary endpoint was EFS for the maintenance and overall survival for Induction therapy. Results: Out of 624 patients from 7 countries, 620 were randomized for induction, 492 responded (78 % ORR, CR/CRu 41%) and 495 were randomized for maintenance. Median age was 71 yrs, 69% male, 85% stage IV, 47% intermediate and 46% high risk MIPI. Response rate at the end of induction was similar in the 2 groups (OR 88% and 86% in the R-CHOP and R-CHOP/RHAD arm, respectively; CR 33% in both arms). No major safety difference were observed between the 2 induction arms. So far, PFS and OS were not different between the two induction regimen (70.6% vs. 66.8%; p=0.28 and 83% vs. 83% ; p=0.92 respectively: Figure 1A). After a median follow-up of 4.2 years from maintenance randomization, patients in the R2 maintenance arm had a significantly improved PFS in comparison to R alone. The 4-year PFS was 60.9% in the R2 arm vs. 42.9 % in the R arm (p= 0.0002, figure 1B). Adverse events (AEs) were more pronounced in the R2 maintenance arm. Recurrent (> 5%) AEs grade >3 were: neutropenia (50.8% vs 19.2%), respiratory tract infection (6.3% vs. 0.8%), and skin cancer (5.9% vs 3.2%). In 46% of patients in the R2 arm, the dose of lenalidomide had to be reduced at least once. Overall survival (OS) was not different between the two maintenance arms, (R2: 87.6% and R: 85.1% at 2 years). The majority of relapsed/refractory patients were treated with a BTK inhibitor alone or in combination (67.5%; 63% after R-CHOP and 71% after RHOP/RHAD). Conclusions: While no efficacy or toxicity differences were observed between the two induction regimens (8x R-CHOP vs 6x R-CHOP/HAD), the combined R2 maintenance significantly prolonged PFS compared to rituximab alone. However, no difference in OS was observed, and toxicity was increased in the R2 arm. Figure 1: OS(A) stratified by the CHOP and R-CHOP/RHAD arms and PFS (B) stratified by maintenance with rituximab (R) or rituximab-lenalidomide (R2) stratified by the four groups according to induction and maintenance arms.

Tooth Abnormalities and Their Age-Dependent Occurrence in Leukemia Survivors.

The multidrug nature of anticancer treatment and different treatment protocols used in the studies are likely to be a major limitation in establishing real risk factors determining the occurrence of dental abnormalities. The authors aimed to establish a relationship between the duration and the dose of chemotherapy and the number of tooth adverse effects in the group receiving the same treatment. Of the 40 anticancer therapy recipients who attended the outpatient dental clinic, 7 leukemia survivors receiving the treatment according to the ALL IC-BFM 2002 protocol were selected. The study group consisted of four females and three males aged 92 to 207 months at the time of dental examination and 29 to 91 months at leukemia diagnosis. As a result of the clinical and radiological examination, dental abnormalities such as agenesis, tooth size reduction, root abnormalities, and taurodontia were identified, and the medical records of all survivors were reviewed in terms of drugs administered, their doses, and treatment schedules. No correlation was observed between the treatment duration of an intensive therapy, the entire therapy, and the number of tooth abnormalities. No relationship was also found between the number of dental abnormalities and the cumulative dose of vincristine, L-asparaginase, methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine. The age at the onset of antineoplastic therapy is likely to be the strongest risk factor for toxic injury during tooth development.

Venetoclax Plus High-Dose Cytarabine and Mitoxantrone (HAM-Ven) As Salvage Treatment for Relapsed/Refractory AML: Updated Results of the Phase-I/II SAL Relax Trial

Background Primary refractory disease and relapse remain the main obstacles for cure in AML. In fit patients, several salvage cytostatic options based on higher doses of cytarabine have been published, with complete remission (CR) rates ranging from 40-55%. The BCL2 inhibitor venetoclax has demonstrated impressive antileukemic activity when combined with hypomethylating agents or low-dose cytarabine in newly diagnosed unfit AML patients. In the phase-I part of the RELAX trial of the Study Alliance Leukemia (SAL), we demonstrated the feasibility of combining venetoclax with higher-dose cytarabine plus mitoxantrone (HAM) in relapsed AML, resulting in a CR/CRi rate of 92%. Here, we report the updated results from the phase-I and additional patients from the phase-II dose expansion in relapsed or refractory (r/r) AML patients. Methods Patients with r/r AML fit for intensive salvage treatment were eligible. Based on the safety results from the phase-I part, patients were treated with the recommended phase-II dose combination of 400 mg venetoclax PO QD (d1-14) including a 2-day ramp-up, followed by cytarabine 1000 mg/m 2 IV BID (d3-5) in combination with mitoxantrone 10 mg/m 2 IV QD (d5-7). Concomitant CYP3A inhibitors were allowed with the appropriate dose adjustments, patients did not receive G-CSF. Patients achieving a CR could enter a maintenance phase with 400 mg venetoclax PO QD over twelve 28-day cycles. This research was supported by a grant from AbbVie Inc. The trial is registered under NCT04330820. Results Between April 2020 and June 2023, 12 patients were enrolled in the dose-escalation part and 40 patients in the expansion part, of whom 38 were evaluable for response by the time of writing. Median follow-up was 6.7 months. Among the 12 patients in the dose-escalation part, 3 received 200 mg/m 2 cytarabine QD over seven days, 3 received 500 mg/m 2 BID over three days and 3 received 1000 mg/m 2 BID over three days, each with identical doses of venetoclax (400 mg PO QD d1-14) and mitoxantrone (10 mg/m 2 IV QD d5-7). Of all 38 evaluable patients, 17 (44.7%) had adverse genetic risk according to ELN2022, and 1 (2.6%) had progressed from antecedent MDS. Median age was 56 years (range, 26-74 years). All patients experienced CTCAE grade ≥3 cytopenias. A median number of two non-hematologic grade 3 and 4 adverse events (AEs) in 32 patients with sufficient data were recorded. Grade 3 and 4 AEs occurring in ≥ 10% of patients included febrile neutropenia, pneumonia, sepsis and gastrointestinal disorders. The 30- and 60-day mortality was 2.6% and 5.2%. Remission assessment showed CR/CRi in 31/38 patients (81.6%). Among the seven patients with no CR/CRi, six showed refractory disease and one died in aplasia before response assessment. CR/CRi rate was 100% (8/8), 81,8% (9/11) and 70.6% (12/17) in patients with favorable, intermediate, and adverse risk, respectively. Utilizing LAIP-based DFN MRD approach, 7/32 (21.9%) evaluable patients were classified as MRD negative (CR/CRi MRD-). In 7/25 (28%) CR/CRi MRD+ patients, the MRD burden was below 0.1% CD45 + events. Of all 31 CR/CRi patients, 26 are in ongoing CR/CRi, 16 received allogeneic HCT as postremission treatment. Three patients died in CR from infectious complications after allogeneic HCT or post-remission treatment and two relapsed and succumbed to progressive disease. Six patients commenced maintenance treatment, of whom four are in ongoing remission. Discussion The combination of venetoclax with higher doses of cytarabine and mitoxantrone (HAM-Ven) is a well-tolerated and very efficacious treatment option leading to complete remissions in 81.6% of patients with r/r AML studied in the RELAX trial. Safety and efficacy compare favorably with published results from the FLAG-Ida-Ven regimen, thereby providing a less dose-intense, fludarabin-free approach for the treatment of fit r/r AML patients. Enrollment into the RELAX trial is currently ongoing. Updated results will be presented at the meeting.

Evaluation of efficacy and safety in the use of cytarabine for mobilization of hematopoietic stem cells in a reference hospital in northeastern Brazil

Autologous hematopoietic stem cell transplantation (Auto-HSCT) is widely used in the treatment of patients with hematological neoplasms. Since these cells circulate in small quantities in the periphery, the use of regimens that promote their mobilization is essential. In this study, we retrospectively evaluated the efficacy and safety of using intermediate doses of cytarabine (1.6 g/m²) + filgrastim (10 mcg/kg/day) in the mobilization of stem cells in 157 patients treated by the Unified Health System at the Hematology and Bone Marrow Transplant Service of the Hospital Real Português de Beneficência, in Recife, Pernambuco. The sample included patients with multiple myeloma (MM) (58.6 %), lymphomas (29.9 %), and other neoplasms (11.5 %). The target of 2.0 × 10 6 CD34+ cells/kg was achieved by 148 (94.3 %) patients, in most cases (84.1 %) in a single apheresis and the median number of cells collected was 9.5 × 10 6 CD34+ cells/kg. No episode of febrile neutropenia was observed, however, 79 patients (50.3 %) required platelet transfusion (no cases attributed to bleeding). The median engraftment time was 11 days. Given these results, we suggest that the use of intermediate doses of cytarabine, combined with filgrastim, is safe and effective in mobilizing hematopoietic stem cells (HSCs).

Bone marrow stromal cells reduce low-dose cytarabine-induced differentiation of acute myeloid leukemia.

Low-dose cytarabine (LDAC) is a standard therapy for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. While high doses of cytarabine induce cytotoxicity, the precise mechanism of action of LDAC in AML remains elusive. In vitro studies have demonstrated LDAC-induced differentiation; however, such differentiation is seldom observed in vivo. We hypothesize that this discrepancy may be attributed to the influence of bone marrow (BM) stromal cells on AML cells. Thus, this study aimed to investigate the impact of BM stromal cells on LDAC-induced differentiation of AML cell lines and primary samples. Our results demonstrate that the presence of MS-5 stromal cells prevented LDAC-induced cell cycle arrest, DNA damage signaling and differentiation of U937 and MOLM-13 cell lines. Although transcriptomic analysis revealed that the stroma reduces the expression of genes involved in cytokine signaling and oxidative stress, data obtained with pharmacological inhibitors and neutralizing antibodies did not support the role for CXCL12, TGF-β1 or reactive oxygen species. The presence of stromal cells reduces LDAC-induced differentiation in primary samples from AML-M4 and myelodysplastic syndrome/AML patients. In conclusion, our study demonstrates that BM stroma reduces differentiation of AML induced by LDAC. These findings provide insights into the limited occurrence of terminal differentiation observed in AML patients, and suggest a potential explanation for this observation.

Measurable residual disease conversion rate with consolidation chemotherapy in acute myeloid leukemia

The rate of MRD clearance in AML with standard consolidation chemotherapy is not well defined. A multi-institution retrospective analysis was performed on 107 consecutively treated AML patients in morphologic complete remission with detectable MRD post-induction therapy who received standard chemotherapy consolidation. In response to standard intermediate/high-dose cytarabine consolidation therapy, 26 of 60 patients (43.3%) with MRD threshold of detection of at least 0.1% converted to MRD-negative status (undetectable with assay used), and 6 of 47 patients (12.8%) with MRD threshold of detection > 0.1% converted to MRD-negative status. Multivariable logistic regression for patients with MRD threshold of detection of at least 0.1% showed that, when controlling for age, ELN risk category, dose of cytarabine, and use of a combination agent, treatment with 1 cycle of consolidation cytarabine versus ≥2 cycles decreased the odds of conversion of AML to MRD-negative (OR = 0.24, 95% CI 0.07–0.85, p = 0.03).

Up-Front ASCT Overcomes the Survival Benefit Provided by HDAC-Based Induction Regimens in Mantle Cell Lymphoma: Data from a Real-Life and Long-Term Cohort.

Mantle cell lymphoma (MCL) is a rare malignancy with heterogeneous behavior. Despite the therapeutic advances recently achieved, MCL remains incurable. Currently, the standard of care for young and fit patients involves induction immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). However, the role of more intensive induction regimens, such as those based on high doses of cytarabine (HDAC), remains controversial in the management of ASCT-eligible patients. This retrospective, observational, and single-center study involved 165 MCL patients treated at the largest oncology center in Latin America from 2010 to 2022. We aimed to assess outcomes, determine survival predictors, and compare responses between different primary therapeutic strategies, with a focus on assessing the impact of HDAC-based regimens on outcomes in ASCT-eligible patients. The median age at diagnosis was 65 years (38-89 years), and 73.9% were male. More than 90% of the cases had a classic nodal form (cnMCL), 76.4% had BM infiltration, and 56.4% presented splenomegaly. Bulky ≥ 7 cm, B-symptoms, ECOG ≥ 2, and advanced-stage III/IV were observed in 32.7%, 64.8%, 32.1%, and 95.8%, respectively. Sixty-four percent of patients were categorized as having high-risk MIPI. With a median follow-up of 71.1 months, the estimated 2-year OS and EFS were 64.1% and 31.8%, respectively. Patients treated with (R)-HDAC-based regimens had a higher ORR (85.9% vs. 65.7%, p = 0.007) compared to those receiving (R)-CHOP, as well as lower POD-24 rates (61.9% vs. 80.4%, p = 0.043) and lower mortality (43.9% vs. 68.6%, p = 0.004). However, intensified induction regimens with (R)-HDAC were not associated with a real OS benefit in MCL patients undergoing up-front consolidation with ASCT (2-year OS: 88.7% vs. 78.8%, p = 0.289). Up-front ASCT was independently associated with increased OS (p < 0.001), EFS (p = 0.005), and lower POD-24 rates (p < 0.001) in MCL. Additionally, CNS infiltration, TLS, hypoalbuminemia, and the absence of remission after induction were predictors of poor OS. In the largest Latin American cohort of MCL patients, we confirmed the OS benefit promoted by up-front consolidation with ASCT in young and fit patients, regardless of the intensity of the immunochemotherapy regimen used in the pre-ASCT induction. Although HDAC-based regimens were not associated with an unequivocal increase in OS for ASCT-eligible patients, it was associated with higher ORR and lower rates of early relapses for the whole cohort.

Comparison of efficacy and toxicity according to etoposide and cytarabine dosing in BEAM conditioning followed by autologous stem cell transplantation in Hodgkin lymphoma

The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell transplantation (ASCT) is a commonly used intensification regimen for patients with Hodgkin lymphoma. As etoposide and cytarabine dosing are not defined, we conducted a retrospective, multicenter study, to compare efficacy and toxicity in 130 patients with Hodgkin lymphoma receiving etoposide and cytarabine at either 200 mg/m2/d (n = 50), 400 mg/m2/d (n = 35), or etoposide 200 mg/m2/d and cytarabine 400 mg/m2/d (n = 45). Progression-free survival and overall survival were not associated with the intensity of conditioning. Increased conditioning intensity was associated with longer duration of thrombocytopenia, a higher number of transfused RBC and platelet units and a higher frequency of mucositis, but serious adverse events or infectious complications were not increased. The intensity of BEAM regimen was not associated with survival but with the rate of cytopenia and mucositis advocating for the use of lower dosing in frail patients.

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.

Toxicity Profile According to Etoposide and Cytarabine Dosing in Patients with Lymphoma Receiving Autologous Stem Cell Transplantation Following BEAM Conditioning.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is part of the treatment strategy for some patients with high-risk lymphoma by improving survival with an acceptable toxicity profile. Although the BEAM (BCNU, etoposide, cytarabine, and melphalan) intensification regimen is the most used, the optimal dosing for each drug is unclear. Here, we retrospectively compared the outcome of 110 patients receiving higher (400mg/m2, n = 69) or lower (200mg/m2, n = 41) etoposide and cytarabine doses in our institution between 2012 and 2019. Patients in the BEAM 200 group experienced less toxicity with reduced fever duration (P < 0.001), number of platelet transfusions (P = 0.008), antibiotic duration (P < 0.001), antifungal therapy (P < 0.001), and mucositis (P < 0.001) whereas length of stay, admission to the intensive care unit, and in-hospital mortality were not different between groups. Progression-free survival (PFS) was non-significantly lower in the BEAM 200 group (36-month PFS, 68% vs. 80%, P = 0.053) whereas OS was similar between the two groups (36-month OS, 87% vs. 91%, respectively, P = 0.12). Albeit a non-significant reduction in PFS, BEAM 200 conditioning intensity was associated with a reduced toxicity profile.

Intensified conditioning regimen with fludarabine combined with post-transplantation cyclophosphamide for haploidentical allogeneic hematopoietic stem cell transplantation in children with high-risk acute leukemia

ABSTRACTObjective:Post-transplantation cyclophosphamide (PTCy) can reduce the incidence of graft versus host disease (GVHD) and this intervention is often applied on adults with hematologic malignancy. However, the high relapse rate hinders the development of the intervention and data of PTCy used on children with hematologic malignancy remains limited. In order to overcome issue of high relapse rate in PTCy treatment, we used fludarabine (Flu), enhanced dose of cytarabine (Ara-C, 9 g/m2), busulfan (Bu), Cy, anti-thymocyte globulin (ATG) combined with PTCy for an intensified conditioning regimen.Methods:A total of 22 children with acute leukemia received intensified PTCy conditioning regimen (PTCy intensified group). We matched with 18 children who received modified Bu-Cy and ATG conditioning regimen in the same period (ATG group).Results:The two-year cumulative incidences of grade II–IV acute GVHD was significantly lower in PTCy intensified group (13.6 ± 7.7% vs 38.9 ± 11.5%, P = 0.048). Two-year GVHD-free relapse free survival (GRFS) in PTCy seems to be better among the increment group despite not being significant (63.3 ± 10.3% vs 35.4 ± 11.9%, P = 0.092). The positive rate of minimal residual disease after transplantation was significantly lower than that before transplantation (20.0% vs 2.5%, P = 0.029).Conclusion:In conclusion, ATG and PTCy combined with Flu-based increased intensity conditioning regimen is effective for acute leukemia in children. It could reduce GVHD rate significantly and potentially improve GRFS.

A phase 2 study of the combination of decitabine (DAC), venetoclax (VEN), and ponatinib in patients (Pts) with chronic myeloid leukemia (CML) in accelerated phase (AP)/myeloid blast phase (MBP) or Philadelphia-chromosome positive (Ph+) acute myeloid leukemia (AML).

e19044 Background: CML-AP/MBP and Ph+ AML are therapeutic challenges. Based on published pre-clinical data of synergism (Leonard et.al., Sci Transl Med 2016), we hypothesized that combining ponatinib with DAC and VEN might lead to high rates of response and facilitate allogeneic stem cell transplantation (SCT). Methods: The study (NCT04188405) enrolled pts ≥ 18 years of age with CML-AP, CML-MBP or Ph+ AML with ECOG PS ≤ 3 and adequate liver/renal function. Pts with significant uncontrolled cardiovascular comorbidities were excluded. Therapy was with DAC (20 mg/m2/day) x 5 days, VEN (400 mg equivalent dose/day) x 21 days, and ponatinib (45mg/day) x 21 days in cycle 1 and then continuously in cycles 2-24. Each cycle was for 28 days. Ponatinib was reduced to 30mg/day for pts in CR/CRi and to 15 mg/day for pts in CMR. Intrathecal prophylaxis with 4 doses of cytarabine was recommended. The primary objective was to determine the overall response rate (ORR) with the regimen. Results: From Jul 2020 to Jan 2023, 15 pts were treated, 4 with CML-AP, 10 with CML-MBP and 1 with Ph+ AML (Table). 11 pts (73%) had prior TKI exposure, including 4 pts with prior ponatinib. 5 of 13 tested pts (38%) had an ABL1 kinase domain mutation (T315I, Q252H, L384M in 1 pt each and E255K in 2 pts). The median number of cycles received was 3 (range, 1-7). 11 pts (73%) responded; 6 pts (40%) with CR/CRi and 5 (33%) with MLFS. Best response was achieved after cycle 1 in 9 of 11 (82%) responders. All 4 pts with CML-AP responded, and 9 of 11 pts (82%) with prior TKI exposure responded. Four pts underwent subsequent SCT. At a median follow-up of 9.8 months, the median overall survival (OS) was 11.0 months, and the estimated 10-month OS was 63%. The median relapse-free survival was 5.7 months. Among the 11 responders, 5 relapsed (one after SCT), and 6 are in ongoing response (3 after SCT). One pt had a related grade 3 mucositis. No grade 4-5 related non-hematological adverse events were observed. Of the 10 pts who received &gt; 1 cycle of therapy, 5 pts had delay (&gt;1 week) in initiation of subsequent cycles due to cytopenias. The 60-day mortality rate was 0%. Two pts died on study, one from leukemia and one from infection while in MLFS. Conclusions: A triplet combination of DAC, VEN and ponatinib was well-tolerated and resulted in an ORR of 73% in this poor-risk population of pts with advanced Ph+ leukemias. Clinical trial information: NCT04188405 . [Table: see text]

Identification of factors to predict low risk febrile neutropenia admissions in patients with acute myeloid leukemia (AML) following intensive chemotherapy.

7031 Background: Febrile neutropenia (FN) is the most common reason for hospital readmission following chemotherapy for AML. Standard practice for FN in AML is hospitalization for rapid administration of IV antibiotics, thus FN is a major driver of healthcare resource utilization and cost. Whether this approach is justified in all situations is unknown. While FN risk models have been developed focusing on solid tumors, factors predicting uncomplicated courses of FN in AML, which may allow identification of patients suitable for outpatient management, have not been studied. We therefore examined whether baseline clinical characteristics could predict which AML patients with FN have a lower risk of progression to severe illness. Methods: We retrospectively reviewed medical records from 7/29/2014-12/24/2022 to identify adults with FN (fever &gt;38.3C and white blood count &lt;1000/µL). Included were patients with high-grade myeloid neoplasm (&gt;10% blasts in blood/marrow) who received intensive chemotherapy (cytarabine dose &gt;=100 2 /day) within 8 weeks. We collected baseline clinical and disease variables. Outcomes were: infections identified, hospital length of stay (LOS), intensive care unit (ICU) admission, and survival. A “low-risk [LR]” outcome was defined as a LOS &lt;72hrs without ICU admission or inpatient death. Univariate and multivariable (MV) logistic regression models were used to assess covariate associations with outcomes. Results: We identified 350 FN admissions in 198 patients with a median age 62 (range: 21-87) yrs. 63% were newly diagnosed and 37% relapsed/refractory. 12% had prior transplant. Median duration of neutropenia prior to fever was 12 (1-287) days. 46% had transfusion &lt;24 hours prior to fever. The median LOS was 5 (1-56) days. 9% of patients went to ICU and 6% died inpatient.Overall, 15% of admissions were classified as LR. 57% had an infection identified. The table shows factors in MV analysis that predicted an infection identified or high-risk (HR) admission. Conclusions: Only 15% of AML admissions for FN were LR. Factors that predict HR outcomes in standard FN models such the MASCC score—e.g. age, prior fungal infection —were not predictive of HR outcomes in AML. As a next step, we will compare our model to other published models used to predict poor outcomes after FN, which have not been developed or validated in AML. [Table: see text]

Outcomes of 3- versus 5-day administration schedule of consolidation cytarabine in adults with acute myeloid leukemia (AML).

7014 Background: Consolidation therapy with intermediate to high-dose cytarabine is critical to prevent relapse in AML. Cytarabine is typically administered every 12 hours on days 1, 3, 5. Two large studies have examined a condensed 3-day administration schedule in patients &lt;60 years and demonstrated a shorter time to absolute neutrophil count (ANC) recovery without compromising long term outcomes. However, use of this regimen in patients ≥60 years has not been evaluated. Here we report our experience with the condensed administration schedule compared with the standard schedule in patients over and under 60 years. Methods: All patients with AML in first complete remission (CR) following intensive induction chemotherapy receiving consolidation at our institution between 1/1/2020 to 12/31/2021 were included in the study. Patients received cytarabine every 12 hours on days 1, 3, 5 (AC135) from 1/1/2020 – 12/31/2020 and cytarabine every 12 hours on days 1, 2, 3 (AC123) from 1/1/2021 – 12/31/2021. All patients received peg-filgrastim support. Data was collected to determine time to ANC recovery &gt;1,000/µL, hemoglobin (Hb) &gt;8g/dL, and platelets &gt;75,000/µL. Comparison of continuous variables between two groups was done using multiple t-tests. Results: Between 1/1/2020 - 12/31/2021, 91 patients received at least one cycle of consolidation with 212 individual encounters. 38 patients received all cycles with AC135, 45 received AC123, and 8 received at least one cycle each of AC123 and AC135. Median age of the AC123 cohort was 50.2 years (range 19-72 years) and 54.3 years for the AC135 cohort (range 22-72 years). For patients ≥60 years of age, 33% (71/213) of the encounters were in the AC123 cohort and the rest in AC135 cohort. Median dose of cytarabine was 5,100 mg/dose in AC123 and 4,600 mg /dose in AC135 (p=0.02). Median time to ANC recovery, hemoglobin, and platelets as well as hospital-related outcomes are described in the table. In patients ≥60 years, median time to ANC recovery was 16.5 vs. 18.6 days (p = 0.03) and platelet recovery was 17.4 vs. 19.7 (p = 0.0008) in AC123 vs AC135 respectively. No neurotoxicity events were noted. Complication rates were similar in both arms. Conclusions: Our study demonstrates that AC123, as compared to AC135, is safe and leads to earlier hematopoietic recovery in adults under and over 60 years. AC123 should be considered the preferred schedule of consolidation therapy administration. [Table: see text]

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.

Exploiting the DNA Damaging Activity of Liposomal Low Dose Cytarabine for Cancer Immunotherapy.

Perhaps the greatest limitation for the continually advancing developments in cancer immunotherapy remains the immunosuppressive tumor microenvironment (TME). The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis is an emerging immunotherapy target, with the resulting type I interferons and transcription factors acting at several levels in both tumor and immune cells for the generation of adaptive T cell responses. The cGAS-STING axis activation by therapeutic agents that induce DNA damage, such as certain chemotherapies, continues to be reported, highlighting the importance of the interplay of this signaling pathway and the DNA damage response in cancer immunity/immunotherapy. We have developed a multi-targeted mannosylated cationic liposomal immunomodulatory system (DS) which contains low doses of the chemotherapeutic cytarabine (Ara-C). In this work, we show that entrapment of non-cytotoxic doses of Ara-C within the DS improves its ability to induce DNA double strand breaks in human ovarian and colorectal cancer cell lines, as well as in various immune cells. Importantly, for the first time we demonstrate that the DNA damage induced by Ara-C/DS translates into cGAS-STING axis activation. We further demonstrate that Ara-C/DS-mediated DNA damage leads to upregulation of surface expression of immune ligands on cancer cells, coinciding with priming of cytotoxic lymphocytes as assessed using an ex vivo model of peripheral blood mononuclear cells from colorectal cancer patients, as well as an in vitro NK cell model. Overall, the results highlight a broad immunotherapeutic potential for Ara-C/DS by enhancing tumor-directed inflammatory responses.

A Phase II Study of the Combination of Decitabine, Venetoclax and Ponatinib in Patients with Chronic Myeloid Leukemia (CML) in Myeloid Blast Phase (MBP) or Philadelphia-Chromosome Positive (Ph+) Acute Myeloid Leukemia (AML)

Background: Advanced phases of CML and Ph+ AML are therapeutic challenges. Preclinical and early clinical data have shown that combining venetoclax (VEN) with a tyrosine kinase inhibitor (TKI) works synergistically in Ph+ myeloid leukemias (Leonard et. al., Sci Transl Med 2016 and Maiti et. al., Acta Haematologica 2020). We hypothesized that combining a potent TKI (ponatinib) with a hypomethylating agent plus VEN backbone might lead to high rates of response that could facilitate potentially curative allogeneic stem cell transplantation (SCT). Methods: This is a single-arm phase II study (NCT04188405) that enrolled patients (pts) ≥ 18 years (yrs) of age with newly diagnosed or relapsed/refractory advanced phase CML [CML in accelerated phase (CML-AP) or CML-MBP] or Ph+ AML. Pts were required to have an ECOG PS ≤ 3 and adequate liver and renal function. Pts with clinically significant cardiovascular comorbidities, including recent or active myocardial infarction, heart failure, clinically significant arrhythmias, cerebrovascular accident, venous thromboembolism or uncontrolled hypertension were excluded. Pts were treated with a combination of decitabine (DAC) (20 mg/m2/day) x 5 days, VEN (400 mg equivalent dose/day) x 21 days, and ponatinib (45mg/day) x 21 days in cycle 1 and then continuously in cycle 2+ (Fig. 1A). Ponatinib was reduced to 30mg/day for pts in CR/CRi and to 15 mg/day for pts in CMR. For C1 only, pts who had not received ponatinib prior to trial initiation had a lead-in phase of ponatinib monotherapy for 7 days before the initiation of DAC and VEN. Cycles were repeated every 28 days, as permitted by peripheral blood count recovery, and pts could receive a maximum of 24 cycles. Intrathecal prophylaxis with 4 doses of cytarabine was recommended. The primary objective was to determine the overall response rate of the regimen. Results: From July 2020 to May 2022, 12 pts were treated, 1 pt with de novo Ph+ AML and 11 pts with advanced phase CML (2 pts with CML-AP and 9 pts with CML-MBP). The median age of the pts was 45 yrs (range, 28-71 yrs). Three pts (25%) had received no prior therapy (1 each with Ph+ AML, CML-AP and CML-MBP). Nine pts (75%) had prior TKI exposure (including prior ponatinib exposure in 4 pts) and 3 pts (25%) had received prior chemotherapy. Eleven pts (92%) had the p210 transcript of BCR::ABL1. Eight pts (67%) had additional cytogenetic abnormalities, including 5 pts with complex karyotype and 2 pts with a MECOM rearrangement. 4 of 11 tested pts (36%) had an ABL1 kinase domain mutation detected at enrollment (T315I, Q252H, L384M and E255K in 1 pt each). The median number of cycles received was 2 (range, 1-7). Nine pts (75%) responded, including 1 with CR, 3 with CRi and 5 with MLFS as best response. The CR/CRi rate was 33%. Best response was achieved after cycle 1 in 7 of 9 responders. Both pts with CML-AP responded, and 2 of 3 pts without prior TKI exposure responded. One of the responders achieved an MMR. After a median follow-up of 9.1 months, the median overall survival (OS) is 9.5 months, and the estimated 9-month OS is 64%. The median relapse-free survival 5.1 months. Among the 9 responders, 3 pts are in continuous response without SCT, 1 pt proceeded to SCT and is still alive, 3 pts did not undergo SCT and relapsed (2 of whom had a complex karyotype), 1 pt died in MLFS, and 1 pt was lost to follow-up (Fig. 1B). The one pt who proceeded to SCT achieved MLFS as best response pre-SCT and remains in MRD-negative CR 22 months post-SCT. The toxicity profile of the regimen was similar to historical expectations with DAC plus VEN. One pt developed grade 3 mucositis, which was considered related to study therapy. No grade 4-5 related non-hematological adverse events were observed. Related grade 1-2 non-hematological adverse events included rash in 2 pts, and transaminitis, creatinine elevation and mucositis in 1 pt each. Of the 8 pts who received > 1 cycle of study therapy, 4 pts had delay (>1 week) in initiation of a subsequent treatment cycle due to cytopenias; for 2 of these pts the duration of VEN was reduced. The 60-day mortality rate was 0%. Two pts died on the study, one from leukemia and one from infection while in MLFS. Conclusion: The triplet combination of DAC, VEN and ponatinib was well-tolerated in pts with advanced Ph+ myeloid leukemias. In this poor-risk population, a marrow remission rate of 75% was achieved, although durations of remission were modest in the absence of consolidative SCT. This study continues to accrue pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase I/II Study of Combination of ASTX727, Gilteritinib and Venetoclax in Patients with Relapsed/Refractory FLT3 Mutated Acute Myeloid Leukemia (AML) and Frontline FLT3 Mutated AML Patients Unfit for Chemotherapy

Background:FLT3 gene mutations occur in approximately 30% of patients (pts) with AML and are associated with worse survival and higher relapse risk. Gilteritinib, a selective potent oral FLT3 tyrosine kinase inhibitor (FLT3i), improves survival in pts with relapsed FLT3 mutated AML. ASTX727 is an oral fixed-dose combination of decitabine (35 mg) and cedazuridine (a cytidine deaminase inhibitor; 100 mg) approved for treating pts with myelodysplastic syndrome (MDS). We are evaluating the safety and efficacy of the combination of ASTX727, gilteritinib, and venetoclax (VEN) in pts with relapsed or refractory FLT3-mutated AML and older/unfit pts unable to receive chemotherapy. Methods: In the phase I, pts with R/R FLT3-mutated AML or high-risk (HR) MDS or chronic myelomonocytic leukemia (CMML) are eligible. FLT3-ITD and/or FLT3-TKD mutations were allowed. In the phase II, the study will also enroll newly diagnosed pts with FLT3-mutated AML ineligible for induction therapy. Pts are required to have an ECOG performance status ≤3, total bilirubin ≤2.5 x upper limit of normal (ULN), ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. Hydroxyurea or 1 dose of cytarabine up to 1000 mg was allowed in pts with proliferative disease to lower white blood count to ≤ 25 x 109/L before initiation of study therapy. In the phase 1, we evaluated two dose levels of gilteritinib (80 mg and 120 mg daily) continuously with fixed dosages of ASTX727 (35/100 mg daily on days 1-5) and VEN (400 mg daily, dose adjusted for concomitant azoles, for up to 28 days). Cycles are repeated every 28 days for up to 24 cycles, followed by indefinite therapy with gilteritinib as maintenance. During cycle 1, VEN was given at a dose of 100 mg on day 1, 200 mg on day 2, and 400 mg daily onwards. Bone marrow (BM) aspiration was performed on day 21, and VEN was held in pts with BM blasts <5% or aplasia. During cycles 2-24, VEN was given at 400 mg daily (dose adjusted for concomitant azoles) on days 1-21 but dose reductions depending on tolerance were permitted. Gilteritinib continued at the enrolled dose in cycles 2-24. Results: Between 11/2021 and 6/2022, 8 patients (7 AML and 1 HR-CMML) have been enrolled in the phase 1 portion of the trial (Table 1). Their median age was 57 years (range, 38-83). Median number of prior lines of therapy was 1 (range, 1-10). Four pts (50%) had a previous allogeneic hematopoietic stem cell transplant (HSCT), 6 pts (75%) had prior treatment with hypomethylating agent (HMA)+VEN, and 3 pts (27%) received prior FLT3i. None received prior gilteritinib. Cytogenetics was diploid in 4 pts, complex in 3 pts, and miscellaneous in 1 pt. The median FLT3-ITD allelic ratio (AR) was 0.4 (range, 0.11-10.60), with 50% having a high AR (≥0.5). All pts had a FLT3-ITD mutation and no pt had a FLT3-TKD mutation. NPM1 co-mutation was present in 4 pts (50%), followed by DNMT3A (37%) and IDH2 (37%). Six pts have been enrolled on dose level 1 (gilteritinib 80 mg) and 2 pt on dose level 2 (gilteritinib 120 mg). No DLTs have been observed in either dose level. Myelosuppression was frequent, requiring dose adjustment of ASTX727 and/or VEN in cycle 2 onward in 5 pts. Grade 3 non-hematologic adverse events included: sepsis (25%), bacteremia (25%), pneumonia (13%), and other infection (25%). No tumor lysis syndrome, differentiation syndrome, or QTc prolongation was observed. The 30-day and 60-day mortality rates were 0% and 13%, respectively. The overall response rate (ORR) was 87% with 4 (50%) pts achieving CR/CRi (1 CR, 3 CRi) and 3 (37%) pts achieving MLFS. One pt withdrew from the study in cycle 1 and was not evaluable for response. The ORR in pts with prior HMA+VEN was 83% (3 CRi, 2 MLFS). Five of 7 responders (71%) achieved the best response within 1 cycle and 2 (29%) within 2 cycles. Pts received a median of 2 cycles of therapy (range, 1-6). With a median follow-up of 6 months, median overall survival was not reached (range, 1.2-8+ months), and the estimated 6-month overall survival is 70%. One responding pt proceeded to HSCT. Two pts have died, 1 in CRi due to an unknown cause, and 1 due to disease progression and sepsis. Conclusion: The combination therapy with ASTX727, VEN, and gilteritinib appears to be effective and safe in R/R FLT3 mutated AML and HR-MDS. Myelosuppression was frequent but manageable. Continued accrual is anticipated to define the optimal triplet regimen in both R/R and newly diagnosed FLT3-mutated AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Double-Blind, Placebo Controlled, Randomized, Multicenter, Phase II Study to Assess the Efficacy of the High Affinity CXCR4 Inhibitor BL-8040 As Addition to Consolidation Therapy in AML By the SAL and OSHO Leukemia Study Groups

Background: Leukemia-cell-stroma interactions are an attractive therapy target in AML. The CXC chemokine receptor 4 (CXCR4) and its ligand CXCL12 (SDF-1) are expressed and secreted by myeloid leukemia blasts and play an essential role in the migration, homing, differentiation, proliferation, and retention of myeloid blasts within the protective bone marrow (BM) niche. The high-affinity CXCR4 antagonist BL-8040 is directly toxic for AML blasts and interrupts the interaction between blasts and the protective BM microenvironment. Objective: The aim of this clinical trial was to evaluate the impact of BL-8040 in combination with standard consolidation therapy on relapse free survival (RFS) in patients with acute myeloid leukemia (AML) in first complete remission (CR, CRp, CRi). Methods: Adult patients ≥ 18 years with documented 1st CR/CRi/CRp, after induction therapy with cytarabine and an anthracycline, and not scheduled for allogeneic stem cell transplantation were randomized in a 1:1 ratio to receive two cycles (≥ 60 years) or three cycles (<60 years) of high-dose cytarabine plus BL-8040 or placebo as consolidation therapy. The dosage of cytarabine was 1g/m² per dose for subjects older than 60 years and 3 g/m² per dose for subjects younger than 60 years. Results: Between November 2015 and November 2019, 134 patients of the originally planned number of 202 were recruited at 29 trial sites, 6 patients violated inclusion and/or exclusion criteria and were excluded. Considering the results of the interim analysis, the data monitoring committee recommended to stop recruitment. Thus, no further patients were enrolled. One hundred and twenty-eight patients were randomized (63 placebo; 65 BL-8040). Baseline characteristics were balanced between treatment arms: median age 61 vs 63 years; 2010 ELN favorable or intermediate-risk 95% vs 98%; CXCR4 expression 38% vs 30% in the BL-8040 and standard arm, respectively. Overall median follow-up time was 25.4 months. Median RFS was similar between arms 10.3 months [95% CI 8.0,12.0] for the BL-8040 arm and 11.5 months [95% CI 8.6,24.1] for the placebo arm (two-sided p=0.98 by log-rank test).The median OS was not reached at the time point of the analysis. Intention to treat (ITT) analyses revealed no difference between placebo and BL-8040, neither for the total cohort, nor for the subset of patients with expression of CXCR4 with respect to RFS (Hazard ratio (HR) 1.0, 95% CI 0.7,1.6, p =0.9, and HR 0.9, 95% CI 0.1,2.9, p =0.9,respectively) or overall survival (OS; HR 1.1, 95% CI 0.6,2.0, p = 0.8, and HR 2.5, 95% CI 0.4,13.8, p = 0.3, respectively). Regarding safety endpoints, overall, 739 and 576 adverse events were documented in the BL-8040 and placebo arm, respectively. Serious adverse events were similar between therapies. Conclusion: The addition of BL-8040 to intensive consolidation therapy did not improve RFS or OS. Although more side effects were noted, no differences in serious adverse events were observed.