Dose Cytarabine Research Articles

Bloodstream Infections in Childhood Acute Myeloid Leukemia and Machine Learning Models: A Single-Institutional Analysis

Childhood acute myeloid leukemia (AML) requires intensive chemotherapy, which may result in life-threatening bloodstream infections (BSIs). This study evaluated whether machine learning (ML) could predict BSI using electronic medical records. All children treated for AML at Children’s Minnesota between 2005 and 2019 were included. Patients with Down syndrome AML or acute promyelocytic leukemia were excluded. Standard statistics analyzed predictors of BSI, and ML models were trained to predict BSI. Of 95 AML patients, 54.7% had BSI. Of 480 admissions, 19% included BSI. No deaths were related to BSI, and survival of non-Whites was significantly inferior to White patients. Logistic regression revealed that higher cytarabine doses increased the risk of BSI, with an odds ratio (OR) of 1.110 (P < 0.05). Prophylactic levofloxacin-vancomycin reduced the risk of BSI, with OR of 0.495 (P < 0.05). The best-performing ML model was regularized logistic regression with an area under the curve (AUC) of 0.748, improved specificity by 37.5% compared with neutropenia, and 2.6% compared with fever. In conclusion, BSI risk was increased by cytarabine and reduced by levofloxacin-vancomycin prophylaxis. ML predicted BSI with improvement over fever or neutropenia. In clinical practice, ML may offer flexibility by controlling sensitivity and specificity by adjusting BSI diagnosis thresholds.

Feasibility of Azacitidine and Venetoclax Followed by High/Intermediate Dose Cytarabine (HIDAC/IDAC) Consolidation in Previously Untreated Acute Myeloid Leukemia Patients Unfit for Intensive Chemotherapy in a Resource Constraint Low-Middle Income Country: A Pilot Study

Feasibility of Azacitidine and Venetoclax Followed by High/Intermediate Dose Cytarabine (HIDAC/IDAC) Consolidation in Previously Untreated Acute Myeloid Leukemia Patients Unfit for Intensive Chemotherapy in a Resource Constraint Low-Middle Income Country: A Pilot Study

AML-703 Feasibility of Azacitidine and Venetoclax Followed by High/Intermediate Dose Cytarabine (HIDAC/IDAC) Consolidation in Previously Untreated Acute Myeloid Leukemia Patients Unfit for Intensive Chemotherapy in a Resource Constraint Low-Middle Income Country: A Pilot Study

AML-703 Feasibility of Azacitidine and Venetoclax Followed by High/Intermediate Dose Cytarabine (HIDAC/IDAC) Consolidation in Previously Untreated Acute Myeloid Leukemia Patients Unfit for Intensive Chemotherapy in a Resource Constraint Low-Middle Income Country: A Pilot Study

Stem Cell Mobilization Performed with Different Doses of Cytarabine in Plasma Cell Myeloma Patients Relapsing after Previous Autologous Hematopoietic Cell Transplantation-A Multicenter Report by the Polish Myeloma Study Group.

Salvage autologous hematopoietic cell transplantation (auto-HCT) may be used to treat relapse of plasma cell myeloma occurring after previous auto-HCT. When an insufficient number of hematopoietic stem cells have been stored from the initial harvest, remobilization is necessary. Here, we aimed to analyze the efficacy and safety of different doses of cytarabine (total 800 vs. 1600 vs. 2400 mg/m2) for remobilization. Sixty-five patients, 55% male, with a median age at remobilization 63 years, were included. Remobilization was performed with cytarabine_800 in 7, cytarabine_1600 in 36, and cytarabine_2400 in 22 patients. Plerixafor rescue was used in 25% of patients receiving cytarabine_1600 and 27% of those receiving cytarabine_2400. Patients administered cytarabine_800 were not rescued with plerixafor. Remobilization was successful in 80% of patients (57% cytarabine_800; 86% cytarabine_1600; 77% cytarabine_2400; p = 0.199). The yield of collected CD34+ cells did not differ between the different cytarabine doses (p = 0.495). Patients receiving cytarabine_2400 were at the highest risk of developing severe cytopenias, requiring blood product support, or having blood-stream infections. One patient died of septic shock after cytarabine_2400. In summary, remobilization with cytarabine is feasible in most patients. All doses of cytarabine allow for successful remobilization. Cytarabine_2400 is associated with higher toxicity; therefore, lower doses (800 or 1600 mg/m2) seem to be preferable.

Cytarabine dose intensification improves survival in older patients with secondary/high-risk acute myeloid leukemia in matched real-world versus clinical trial data

Since 1980’s, the established/standard treatment of acute myeloid leukemia (AML) is cytarabine infusion with anthracycline (7 + 3 regimen). We compared the 7 + 3 regimen in older secondary/high-risk AML patients from a clinical trial with a matched population from the Swedish AML Registry treated with an increased cytarabine dose in induction and consolidation as recommended in the Swedish National Guidelines since 2005. After successful propensity score matching, 104 patients per group were included. The primary outcome was overall survival (OS), and standard dosed patients had a median OS of 6.4 versus 10.7 months with increased dose intensity (hazard ratio: 0.69, p = 0.012), with 5-year OS of 8.7% and 18.1%, and remission rates of 36% and 60%, respectively (p < 0.001). Median OS after allogeneic hematopoietic cell transplantation (in 27.9% per group) was 10.4 and 20.7 months, respectively. We conclude that the more intensive cytarabine schedule seems to provide improved outcomes inthe investigated AML patient group.

Medium-cumulative dose of cytarabine in consolidation therapy shows the greatest benefit in AML patients

BackgroundHigh-dose cytarabine (HDAC) is commonly used for consolidation therapy in young acute myeloid leukemia (AML) patients, but the dosage of cytarabine is still controversial in the clinic due to its obvious post-chemotherapy adverse effects. The aim of this study was to contrast the efficacy in different dose groups of cytarabine after consolidation therapy in Chinese AML patients.MethodsAML patients treated with cytarabine consolidation at Qilu Hospital, Shandong University from January 2010 to September 2022 were retrospectively analyzed, from which 346 AML patients with relatively complete follow-up data were selected for this study. We compared the patients’ overall survival (OS) rate, relapse-free survival (RFS) rate, and hematologic adverse events in terms of their general characteristics, cytarabine consolidation therapy dose, consolidation course, 2022 European Leukemia Net (ELN) risk stratification, and transplantation.ResultsIn AML patients under 60 years of age, the 5-year RFS rate with high-dose cytarabine consolidation therapy was superior to that of small-dose cytarabine (P = 0.024), while the 5-year RFS rate was comparable in the high-dose and intermediate-dose groups, and there was no obvious difference among the three groups in the 5-year OS rate (P > 0.05). OS and RFS of those given more than 3 courses of cytarabine consolidation therapy were better than those in the 1–2 courses group (P = 0.060, P = 0.040). OS and RFS were better in patients with cumulative dose of cytarabine ≥ 36g than in patients with cumulative dose < 36g (P < 0.05), but cumulative dose ≥ 54g was comparable in OS and RFS with ≥ 36–< 54g group (P > 0.05). There was no significant difference in hematologic adverse effects among the three treatment groups.In the latest ELN risk stratification favorable-risk group, the cumulative dose of cytarabine ≥ 36g had a better 5-year RFS rate than the < 36g group (P = 0.038), and in the intermediate-risk group the 5-year OS rate and RFS rate were better in the ≥ 36g group than the < 36g group (P = 0.012, 0.025). In addition, the prognosis of transplanted patients was better than that of non-transplanted patients, whereas in non-transplanted patients, consolidation therapy with ≥ 36g cytarabine can effectively improve outcomes. Multivariate analysis indicated that age, fibrinogen (FIB) and the cumulative dose of cytarabine of ≥ 36–< 54g were predictors of OS, while age, white blood cell (WBC) and HDAC were predictors of RFS.ConclusionThe results of the study showed that consolidation therapy with cytarabine up to a cumulative dose of ≥ 36–< 54g in AML patients who did not undergo transplantation significantly improved patient prognosis. In the latest ELN risk stratification, cumulative doses of cytarabine ≥ 36g had a better prognosis in favorable and intermediate-risk patients.

Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells.

Acute myeloid leukemia is the second most frequent type of leukemia in adults. Due to a high risk of development of chemoresistance to first-line chemotherapy, the survival rate of patients in a 5-year period is below 30%. One of the reasons is that the AML population is heterogeneous, with cell populations partly composed of very primitive CD34+CD38- hematopoietic stem/progenitor cells, which are often resistant to chemotherapy. First-line treatment with cytarabine and idarubicin fails to inhibit the proliferation of CD34+CD38- cells. In this study, we investigated Metformin's effect with or without first-line conventional chemotherapy, or with other drugs like venetoclax and S63845, on primitive and undifferentiated CD34+ AML cells in order to explore the potential of Metformin or S63845 to serve as adjuvant therapy for AML. We found that first-line conventional chemotherapy treatment inhibited the growth of cells and arrested the cells in the S phase of the cell cycle; however, metformin affected the accumulation of cells in the G2/M phase. We observed that CD34+ KG1a cells respond better to lower doses of cytarabine or idarubicin in combination with metformin. Also, we determined that treatment with cytarabine, venetoclax, and S63845 downregulated the strong tendency of CD34+ KG1a cells to form cell aggregates in culture due to the downregulation of leukemic stem cell markers like CD34 and CD44, as well as adhesion markers. Also, we found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells. Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.

The Role of NK Cells in Allogeneic Hematopoietic Stem Cell Micro-Transplantation for Acute Myeloid leukemia

To explore the role of NK cells in allogeneic hematopoietic stem cell micro-transplantation(MST) in the treatment of patients with acute myeloid leukemia(AML). Data from 93 AML patients treated with MST at our center from 2013-2018 were retrospectively analyzed. The induction regimen was anthracycline and cytarabine combined with peripheral blood stem cells transplantation mobilization by granulocyte colony stimulating factor (GPBSC), followed by 2-4 courses of intensive treatment with medium to high doses of cytarabine combined with GPBSC after achieving complete remission (CR). The therapeutic effects of one and two courses of MST induction therapy on 42 patients who did not reach CR before transplantation were evaluated. Cox proportional hazards regression analysis was used to analyze the impact of donor NK cell dose and KIR genotype, including KIR ligand mismatch, 2DS1, haplotype, and HLA-Cw ligands on survival prognosis of patients. Forty-two patients received MST induction therapy, and the CR rate was 57.1% after 1 course and 73.7% after 2 courses. Multivariate analysis showed that, medium and high doses of NK cells was significantly associated with improved disease-free survival (DFS) of patients (HR=0.27, P =0.005; HR=0.21, P =0.001), and high doses of NK cells was significantly associated with improved overall survival (OS) of patients (HR=0.15, P =0.000). Donor 2DS1 positive significantly increases OS of patients (HR=0.25, P =0.011). For high-risk patients under 60 years old, patients of the donor-recipient KIR ligand mismatch group had longer DFS compared to the nonmismatch group (P =0.036); donor 2DS1 positive significantly prolonged OS of patients (P =0.009). NK cell dose, KIR ligand mismatch and 2DS1 influence the therapeutic effect of MST, improve the survival of AML patients.

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

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

Assessment of Measurable Residual Disease on Day 28 of First Induction Chemotherapy in Acute Myeloid Leukaemia Patients

Background: Measurable residual disease (MRD) is an independent, strong, prognostic marker in acute myeloid leukaemia (AML) that is important for risk stratification and treatment planning. This study assessed the MRD on day-28 after first induction chemotherapy in AML patients. Objective: To assess measurable residual disease status on day 28 after the first induction chemotherapy in newly diagnosed acute myeloid leukaemia patients. Methodology: This cross-sectional study was conducted at the Department of Haematology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from April 2021 to March 2022 among a total of 25 newly diagnosed AML patients who were admitted and received induction chemotherapy with DA (7+3). On Day-28, bone marrow aspiration was done with standard procedure and first pull of 2ml bone marrow sample was sent to a laboratory for MRD evaluation by multiparameter flow cytometry. MRD was considered positive when value was ?0.1%. Results: On day 28 of post induction chemotherapy most of the patients (92%) achieved morphological remission and among them more than half (52.2%) were MRD positive. The presence of CD14 myeloid marker and baseline higher serum uric acid level was significant in MRD positive patients and cytarabine dose 150 mg/m2 was found significant in MRD negative patients. Conclusion: More than half of the Acute Myeloid Leukaemia patients, treated with standard induction chemotherapy and achieved morphological remission on day 28 of chemotherapy, had positive measurable residual disease assessed by multiparameter flow cytometry. Positive MRD indicates relatively poorer prognosis and may necessitate more cycles of induction followed by more intensive consolidation which may include haematopoietic stem cell transplantation.

IELSG30 phase 2 trial: intravenous and intrathecal CNS prophylaxis in primary testicular diffuse large B-cell lymphoma

AbstractPrimary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724.

Budget impact analysis of venetoclax for the management of acute myeloid leukemia from the perspective of the social security and the private sector in Argentina.

This study aimed to estimate the budget impact of the incorporation of venetoclax for the treatment of patients with Acute Myeloid Leukemia (AML) over 75 years of age or those with comorbidities and contraindications for the use of intensive chemotherapy, from the perspective of the social security and the private third-party payers in Argentina. A budget impact model was adapted to estimate the cost difference between the current scenario (azacitidine, decitabine and low doses of cytarabine) and the new scenario (incorporation of venetoclax) for a third-party payer over a time horizon of three years. Input parameters were obtained from a literature review, validated or complemented by expert opinion using a modified Panel Delphi approach. All direct medical costs were estimated by the micro-costing approach and were expressed in US dollars (USD) as of September 2020 (1 USD = 76.18 Argentine pesos). For a third-party payer with a cohort of 1,000,000 individuals covered, incorporating venetoclax was associated with an average budget impact per-member per-month (PMPM) of $0.11 USD for the social security sector and $0.07 USD for the private sector. The duration of treatment with venetoclax was the most influential parameter in the budget impact results. The introduction of venetoclax was associated with a positive and slight budget impact. These findings are informative to support policy decisions aimed to expand the current treatment landscape of AML.

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

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

Impact of Outpatient Administration of Cytarabine Consolidation Chemotherapy on Hospital Length of Stay in Adults with Acute Myeloid Leukemia

Background: Administration of 3-4 cycles of high/intermediate dose cytarabine (H/IDAC) reduces relapse of acute myeloid leukemia (AML) and bridges patients (pts) to allograft. There is no accepted standard model of safely delivering H/IDAC in these pts. To reduce reliance on inpatient (inpt) chemotherapy administration and safely avoid or forestall hospitalization during cycles, we developed an outpatient (outpt) protocol to deliver H/IDAC. Pts were assigned outpt or inpt treatment at their hematologist's discretion. We aimed to evaluate the benefits and safety of our model in this retrospective observational study. Methods: Pts diagnosed with AML and treated with intensive induction chemotherapy between 2015 and 2020 were identified; included pts received ≥1 consolidation cycle of 1-3g/m² cytarabine over 3 hours BID, dose adjusted for age and renal function, on days 1, 3 &amp; 5 of a planned 28-day cycle. Outpts received H/IDAC via computerized ambulatory delivery device (CADD) pump and central venous access device (CVAD), attended days 1-6, then 3 times a week for blood product support until count recovery; elective readmission was not mandated. Pts were educated to present to hospital if unwell. Inpts were admitted for H/IDAC but could be discharged prior to count recovery. Antimicrobial prophylaxis consisted of antifungal agents and valaciclovir. The primary endpoint was mean duration of hospital admission (LOS) per consolidation cycle. As pts may have been treated on an inpt and/or outpt basis, generalized estimating equations were used to compare LOS clustered by pt. Secondary outcomes included death during H/IDAC; intensive care unit (ICU) admission; time to admission; blood product use; cycle length; bacteremia; time to count recovery; relapse free survival (RFS) and overall survival (OS). Results: Of 109 pts identified, 62 pts were included and 47 pts excluded (not AML=3; induction death=7; refractory leukemia=14; alternative=13; no consolidation=10). Median age was 55.2 years (range 18.2-70.3); 31 (50%) males; ELN 2010 fav=23 (37.1%), Int-2/3 = 30 (48.4%), Adv=8 (12.9%); denovo AML in 60 (96.7%); and therapy related in 2 (3.2%). FLT3-ITD, NPM1 and bi-allelic CEBPA mutations detected in 11 (17.7%), 27 (43.5%) and 2 (3.2%) pts, respectively. Fifty-nine pts (95.1%) received 7+3 idarubicin induction and 7 (11.3%) received midostaurin. A total of 131 cycles of H/IDAC were administered; 81 (61.8%) were commenced as outpt and 50 (38.2%) as inpt. Twenty-seven (43.6%) pts commenced all cycles as an outpt. Those commencing consolidation as an outpt spent, on average, 10.3 fewer days in hospital per cycle. The mean (SD) LOS for outpt and inpt was 11 (8.3) versus 21.3 (8) days (p&amp;lt;0.001), respectively. For each consolidation cycle, outpts spent less time in hospital (mean, [SD]): cycle 1, 12.6 (10.3) vs 20.7 (8.0) days (RR 1.6, p=0.007); cycle 2, 11.6 (7.2) vs 21.4 (8.3) days (RR 1.8, p=0.001); cycle 3, 8.4 (5.8) vs 24.6 (7.4) days (RR 2.9, p&amp;lt;0.001). There were no deaths among inpts and one death in outpts (septic shock). ICU admission occurred in 8/81 (9.9%) cycles in outpts vs 1/50 cycles (2%) in inpts (p=0.12). Mean ICU LOS for outpts vs inpts in cycle 1 was 17.6 days vs 1.6; cycle 2, 5.1 vs 0 days; and cycle 3, 4.2 vs 0 days. Bacteremia was detected in 41 cycles (31.3%), with 38 isolates (gram pos=17, gram neg=21) in 31 outpt cycles (38.2%) and 15 isolates (gram pos=6, gram neg=9) in 10 inpt cycles (20%). Median time to admission in outpts was 14 days (IQR, 3-21); 15 (18.5%) cycles did not result in pt admission. There were no differences in timing of admissions by cycle number nor time-point to prompt elective admission (Fig.1). There was no difference in packed cell or platelet transfusion requirement between inpts and outpts. Time to blood count recovery was similar. No improvement was seen in cycle length. The proportion undergoing allogeneic transplant in first remission was 37.1%, and at any time, 59.7%. Over a median follow up of 3.3 years, median RFS was 2 years and OS, not reached. Conclusion: In selected pts, outpt based AML H/IDAC consolidation therapy significantly reduced hospital length of stay compared with inpts. There was no impact on cycle length. Bacteremia and ICU admission rates were higher in outpts, and strategies such as remote monitoring or pre-emptive hospitalization could be considered. Our findings suggest outpt consolidation should be considered in a supported clinical setting.

Frontline Aspacytarabine with Venetoclax for Older/Unfit Patients with Acute Myeloid Leukemia: Preliminary Results of a Phase 1 Study

Introduction: Venetoclax (VEN), a selective BCL2 inhibitor, in combination with hypomethylating agents (HMA) or low-dose cytarabine is currently the standard of care for first line treatment of older/unfit patients with acute myeloid leukemia (AML). This, however, requires indefinite cycles of treatment and results in prolonged cytopenias. Aspacytarabine (ASPA, formerly BST-236), a novel pyrimidine antagonist, is a cytarabine prodrug designed to enable high cytarabine dose treatment with reduced systemic toxicity, that was previously proven safe and effective for the treatment of AML in adults unfit for intensive chemotherapy. Given excellent outcomes with intensive chemotherapy with VEN, we hypothesized that higher cytarabine dose using ASPA and VEN followed by a limited consolidation with ASPA may provide superior outcomes than the current standard. Aims: To assess the safety and efficacy of VEN plus ASPA induction treatment regimen in older/unfit AML patients followed by limited consolidation course(s) with ASPA alone. Methods: A phase I/II dose escalation and expansion study using 1 or 2 induction courses with intravenous (IV) ASPA 2.3 or 4.5 g/m 2 daily for 6 consecutive days plus VEN at a dose of 200 mg or 400 mg for 7 days without azole antifungals. Followed by up to 3 consolidation courses with single agent ASPA 2.3/4.5 g/m 2/day for 6 days, in patients with newly diagnosed AML unfit for intensive chemotherapy. Patients with secondary AML are allowed. MRD was evaluated centrally by flow cytometry at Dr. Wood's laboratory, with a sensitivity of 0.1%. Results: Two cohorts are completed with 7 patients enrolled. Table 1 details the cohort treatment. Baseline characteristics and outcome are provided in Table 2. To date, the combination is well-tolerated. As expected, all patients had cytopenia (16% grade 4, and 84% grade 3 and lower), following the induction treatment and non-hematological grade ≥3 reported in more than 1 patient were pneumonia and sepsis both reported in 2 patients). One death occurred in cohort 1: an 80 year-old patient with a cardiac medical history died at home on day 27 of induction, prior to bone marrow analysis, but with full count recovery; death was deemed unrelated to study treatment. One 79-year-old patient from cohort 2 discontinued the study following the 1 st consolidation, while in CR MRD-, due to prolonged laryngitis. In the first, cohort, 1 patient attained a CR MRD- after 1 induction course, and this response is still maintained 6 months from study entry (after 3 consolidation courses of ASPA monotherapy). In the second cohort, all 3 patients' disease entered a CR after 1 course of ASPA and VEN Two achieved CR MRD-, and the 3 rd patient is currently receiving a second induction course, as per protocol. All responding patients had a full count recovery within 35 days and disease continues to be in CR. Conclusions: The combination induction regimen of ASPA and VEN followed by consolidation with ASPA alone, is a promising therapy. The regimen is tolerable, and all patients in cohort 2 have attained a CR with 2/3 MRDneg and the third with treatment ongoing. This treatment may overcome the limitations of prolonged cytopenia and indefinite therapy with HMA/VEN along with a high CR rate. This study is ongoing, and updates will be provided at the conference.

Acute Non-Lymphoblastic Leukemias Presenting with Gingival Hyperplasia: Diagnosis and Management Updates

Background: Leukemias represent a heterogeneous group of hematological malignancies, which are characterized by the disordered proliferation of neoplastic hematopoietic cells, with the diffuse bone marrow involvement. Most frequent oral findings in leukemias are cyanotic or erythematous gingival hyperplasia with or without necrosis, petechiae, ecchymoses, mucosal ulcers and hemorrhage. Gingival hyperplasia is reported as a consistent symptom, which forwards patients for a dentistry consultation, that may lead to an early diagnosis of acute leukemias. The recognition of gingival enlargement as an initial oral manifestation of leukemic involvement assumes major practical significance, especially for the early diagnosis of non-lymphoblastic leukemias. Objectives: The aims of researches were the evaluation of diagnosis and management of hyperplastic gingivitis in acute leukemias. Material and Methods: The patients' follow-up and treatment were realized at the comprehensive cancer center. Our observational, analytical and descriptive study enrolled 8 patients with acute leukemias, who were treated at the Institute of Oncology from Moldova between 2012-2023. The diagnosis was asserted by the bone marrow aspiration with cytochemical reactions, tissue biopsy, buccal swab, or fine needle aspiration cytology. The immunophenotyping was performed in selected cases. The types of acute leukemias were assessed and distinguished according to the 2017 Revision of WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. This prospective study was related to the hospitalized and outpatient care. Results: Hyperplastic gingivitis developed in cases with myelomonocytic and monocytic acute leukemias. The leukemia patients were admitted to the Institute of Oncology with a history of fatigue, fever, bone pain, gingival bleeding and enlargement detected by dentistry and family doctors from the consulting centers. ECOG-WHO performance score was 2-3. The intra-oral examination revealed generalized gingival hyperplasia. There were the amounts of plaque and calculus, which did not justify the enlargement degree. The gingiva was spongy and painless on palpation, with solitary sectors of necrosis and mucosal bleeding. Multiple soft and tender lymph nodes ranging from 0.8-1.5 cm in diameter were palpable bilaterally in the cervical and axillary regions. Splenomegaly of various degree was revealed by ultrasound scan in all patients. Complete blood count values ranged between: Hb 66-104 g/l, RBC 2.3-3.7 x 10 12/l, WBC 11.3-47.2 x 10 9/l, PLT 17.0-115.0 x 10 9/l, blast cells 17-65%. The bone marrow aspiration detected hypercellularity, myeloid and monocytic blast cells (31.0-58.0%), as well as monocytes (9.0-14.0%). The studied cases were not suggestive of presence of FLT3 mutations. Hyperplastic gingivitis regressed in 5 (62.5%) cases after the achievement of complete (4 patients) and partial (1 patient) hematological responses under the first-line combined chemotherapy with conventional doses of cytarabine, anthracyclines and etoposide (2 patients). Local treatment included daily administration of oral steroids, antiseptic and hemostatic drugs. The narrative review of the recent references revealed that 37-53% of patients with monocytic and myelomonocytic leukemias were reported to develop gingival hyperplasia. Conclusions: Hyperplastic gingivitis emerges in acute leukemias mostly due to the gingival infiltration with neoplastic blast cells. Gingival hyperplasia may regress under the combined chemotherapy and local treatment in patients with complete or partial hematological responses. Early diagnosis and treatment, thus, can increase the leukemia patients' prospects for complete hematological and local responses.

Venetoclax in Combination with Intermediate Doses of Cytarabine in Consolidation Phase for Acute Myeloid Leukemia Patients in First Complete Remission; Results of the Part 1 of the Phase 1/2 Multicentric Covenidac Study

For authors: Please: L Gastaud and P Peterlin: co-primary, H dombret et C Recher: co-last Background: The French ALFA-FILO AML intergroup launched the BIG-1 trial (EudraCT No.: 2014-000699-24) in 2015 to evaluate different intensive chemotherapy (ICT) strategies aiming at improving the survival of younger adults with acute myeloid leukemia (AML). All patients (pts) with previously untreated non-APL and non-CBF AML aged 18-60 years were eligible for this trial. The trial design included several randomization types. Results of the R1 and R2 randomizations, namely idarubicin vs daunorubicin for induction and IDAC vs HDAC for consolidation, will be reported at this meeting. In patients who achieved first complete remission (CR), randomizations R4 consisted of nested randomized Phase 2 or 1/2 studies evaluating the addition of new drugs to the IDAC/HDAC consolidation cycles. The protocol was designed to allow several sequential multicenter R4 evaluations of various new agents over the trial period. Venetoclax (VEN) has proved its efficacy when combined to azacitidine or low dose cytarabine in unfit AML pts (DiNardo et al. 2020; Wei et al. Blood 2020). Its role in fit patients treated with ICT is still under investigation. The COVENIDAC Phase 1/2 R4 sub-study is evaluating the safety and efficacy of VEN added to IDAC during the consolidation cycles of CR pts. We report herein the result of the Phase 1 part. Methods: The primary objective of this Phase 1 study was to determine the maximum tolerated dose (MTD) of VEN in combination with IDAC during the consolidation cycles, which will be the recommended dose for the Phase 2 (RP2D). Dose limiting toxicities (DLTs) were assessed during the first cycle of consolidation (C1) according to a 3+3 design. A maximum of 3 consolidation cycles was planned depending on the AML risk group. Hematological DLT was defined as no peripheral blood count recovery within 56 days from day 1 of the cycle. Non-hematological DLTs were defined as Grade ≥4 toxicities or Grade ≤3 toxicities which have not recovery by day 56 and deemed related to VEN per investigator opinion. VEN was started at dose level (DL) 1: 100 mg/d from day 1 to 8. In the absence of DLTs at DL1, 3 others DL were planned: 200 mg/d from day 1 to 8 (DL2); 400 mg/d from day 1 to 8 (DL3), and 400 mg/d from day 1 to 14 (DL4). IDAC was administrated at 1.5 gr/m² twice daily on day 1/3/5 for DL1, DL2 and DL3 pts, then on day 1/2/3 for DL4 pts after a protocol amendment. Main inclusion criteria were: pts in first CR following 1 or 2 courses of induction chemotherapy fit for further ICT; favorable and intermediate risk AML as defined by the protocol; ECOG PS ≤2; written informed consent. Measurable residual disease (MRD) was assessed by multiparametric flow cytometry (MFC) in all pts as well as NPM1-qPCR in NPM1-mutated pts. Results: Between 06/2021 and 04/2022, 15 pts from 9 centers were screened and enrolled. Pt characteristics were as follows: median age, 42 years (IQR, 30-49); 2 males/7 females; ECOG-PS, 0 in 10 pts and 1 in 5 pts; favorable/intermediate/adverse ELN-2017 risk, 9/2/4. Neutropenia and thrombocytopenia durations are shown in Table 1. Only 1 hematological DLT was observed at DL3 (platelet count of 96 giga/L at day 56 in a patient who was infected by Covid-19). Overall, there were very few non hematological AEs ( Table 2, no grade 4) and only 4 SAEs (1 related to IDAC/VEN during C1, 3 non-related). No non-hematological DLT was observed. No patient died during the DLT observation period, 1 experienced a septic shock (C2, DL2). One pt received only C1 (due to DLT), 7 received 2 cycles, and 7 received 3 cycles. Median time between initiation of subsequent consolidation cycles was 37.5 days (IQR, 35-41) for C1/C2 and 40 days (IQR, 35-43) for C2/C3. One pt had to stop VEN during C3. Six pts received an allogeneic HSCT (5 in CR1, 1 after salvage). With a median follow-up of 13.5 months, 3 pts relapsed and 2 died. MRD results will be presented. Conclusion: VEN/IDAC combination appears to be feasible and safe as consolidation therapy, with expected thrombocytopenia and neutropenia durations. These durations appeared even shorter at DL4, when IDAC was given on 3 consecutive days. VEN at 400 mg/d from day 1 to 14 combined with IDAC on day 1/2/3 was thus retained as RP2D for the randomized Phase 2 with RFS as primary endpoint. This phase 2 has already recruited 29 of the 200 pts planned.

Picalm::MLLT10 can Identify a New Subgroup of Acute Leukemias of Ambiguous Lineage with Unique Extramedullary Disease and Treatment Response

Background: Mixed-phenotype acute leukemias (MPAL), which is included in acute leukemias of ambiguous lineage (ALAL), can be classified as four different subtypes based on recurring genetic alterations including BCR::ABL, KMT2A and ZNF384 gene rearrangement as well as BCL11B activation. The 2022 WHO classification has already mentioned PICALM::MLLT10 fusions are also enriched in MPAL but need more data. In 2022 ELN classification, PICALM::MLLT10 was identified as acute myeloid leukemia (AML) with other rare recurring translocations but not ALAL. In addition, there is no separate classification for PICALM::MLLT10 in the new ICC classification. Therefore, it is still confused whether PICALM::MLLT10 corresponds to AML or acute lymphoblastic leukemia (ALL) or ALAL. Methods: Fourteen PICALM::MLLT10 positive patients of 390 AL patients (14/390, 3.6%) were identified by RNA sequencing (RNA-seq) in our center from 2020-2022, including 8 female and 6 male, with a median age of 33 years (16-50 years). These patients were newly diagnosed AL according to bone marrow morphology and immunology including 5 ALAL, 5 T-ALL [ 4 early T-cell precursor ALL (ETP-ALL), 1 cortical T-ALL], 2 AML, 1 B-ALL with aberrant expression of myeloid antigen, and 1 B/T MPAL. Results: The mean white blood cell counts of these patients was 8.25×10 9/L (2.34-51×10 9/L) and platelet counts was 168.5×10 12/L (39-429×10 12/L) individually. It should be mentioned that extramedullary disease (EMD) was found in 7 cases (7/14), including mediastinum, tonsil, and skin. In terms of immunotyping, CD7 was identified in all patients (14/14) and CD33 in 71.4% (10/14) patients. The major concurrence mutations were PHF6 mutation (8/14), JAK3 mutation (5/14), and SUZ12 mutation (4/14). Characteristic cytogenetic abnormality t(10;11)(p12.3;q14.2) was only found in three cases (3/14) (Table 1). The PICALM breakpoints are mainly concentrated in exon 17 (n=6) and exon 19 (n=8). Exon 4 (n=8), exon 6 (n=2), exon 9 (n=2) and exon 10 (n=2) are the most commonbreakpointsof MLLT10. To our knowledge, this is the first report about the breakpoints and fusion gene forms of PICALM::MLLT10. For initial treatment, these patients individually received standard ALL induction chemotherapy (VDPCP, vincristine, idarubicin, pegaspargase, cyclophosphamide, prednisone) and AML induction chemotherapy (3+7 IA regimen including idarubicin, cytarabine). The initial complete remission (CR) rate was only 35.7% (5/14), and 9 patients showing no remission (NR). These NR patients subsequently received salvage chemotherapy. It is worth mentioning that 6 of them received combined chemotherapy regimen including low doses of cytarabine (LDAC), granulocyte colony-stimulating factor (G-CSF) and anthracyclines such as aclarubicin or idarubicin or homoharringtonine (CAG or IAG or HAG), and 2 of 6 patients also further received combination therapy with venetoclax (CAG or IAG +VEN). Finally, 5 of them dramatically achieved CR (5/6). In the other 3 patients, 1 patient who was failure to initial Hyper-CVAD A/B regimen also dramatically achieved CR after the more Hyper-CVAD A regimen combined with venetoclax, and 1 patient achieved CR while another still NR with both receiving CLAG (cladribine, cytarabine, G-CSF) regimen. Subsequently 11 patients (9 CR, 2 with refractory disease) received allogenic hematopoietic stem cell transplantation (allo-HSCT), and all the CR patients survived well after HSCT (follow up 3-24 months, median 15 months) without relapse, while 2 NR patients died soon after transplantation because of severe complications (Table 2). Conclusions: Our data suggested PICALM::MLLT10 positive AL should be more appropriately recognized as an independent ALAL entity and may benefit from LDAC, G-CSF and anthracyclines combination chemotherapy as well as venetoclax. Sequential HSCT after chemotherapy combined with venetoclax may further improve long-term survival in AL patients with CR even MRD positive.

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

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

A Phase II Study of Single Agent Aspacytarabine (BST-236) in Adults Unfit for Intensive Chemotherapy with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) or Higher Risk Myelodysplastic Syndromes (R/R HR MDS)

Background-Common treatment approaches for R/R AML and to some extent HR MDS involve intensive chemotherapy regimens, typically combining high dose cytarabine with other drug(s), but these intensive regimens may not be suitable for unfit or elderly patients. To address this issue, a cytarabine prodrug called BST-236 has been developed, which delivers high doses of cytarabine while reducing systemic toxicity, making it a potential option for intensive chemotherapy in older and frail patients. This Phase II study aimed to assess the efficacy and tolerability of BST-236 in unfit patients with R/R AML or HR MDS previously treated with a non-intensive regimen. Methods-This ongoing Phase 2 trial (NCT 04827719) enrolled HR MDS and AML patients (pts) aged ≥ 75 years or with comorbidities incompatible with intensive chemotherapy. MDS pts were refractory or had relapsed to azacytidine (AZA), and AML pts to AZA, low-dose cytarabine (LDAC) or AZA -venetoclax (VEN), given as a first line regimen. Each BST-236 induction and maintenance course consisted of 6 daily 1-hour intravenous infusions at a dose of 4.5 g/m 2/d (containing 3 g/m 2/d of cytarabine). After completing 1 induction cycle, patients with stable disease (SD) or partial response could undergo a second similar cycle, and patients who achieved complete remission (CR) could receive 2 to 4 maintenance cycles at the same schedule. Inclusion of 20 AML and 20 MDS pts was planned. Results-From August 2021 to May 2023, 16 MDS and 20 AML pts from 9 centers were enrolled, with a median follow up of 3 months. MDS: Median age was 74.8 years [IQR, 71.2-76.4] and ECOG was 0- 1 in all but 1 patient . All pts were previously treated with AZA and 4 (29%) had adverse R-IPSS karyotype. 14/16 were evaluable for response after 1 induction: 1 (7%) CR, 2 (14%) marrow CR, 7 (50%) SD. Hematological improvement was observed in 6 (43%) patients. Two serious treatment related adverse events (SAE) - febrile neutropenia and sepsis - occurred in 2 pts. Median duration of hospitalization for the induction cycle was 29.5 days [IQR 25.5-32.5] and 30-day mortality rate was 0%. AML: Median age was 77.6 years [IQR, 73.8-79.4] and all pts had ECOG 0-1. Two pts were previously treated with AZA, 1 with LDAC, 17 with AZA-VEN and 8 (50%) had adverse ELN score. 17/ 20 pts were evaluable for response after 1 induction cycle : 2 (12%) CR including 1 CR with negative MRD, 1 (6%) CRi, 10 (59%) SD. Three SAE- infections and hepatobiliary disorders- occurred in 2 pts. Median duration of hospitalization for the induction cycle was 26 days [IQR 23.2-30.8] and 30-day mortality rate was 10%. Four MDS pts still need to be enrolled, and follow up is ongoing. An update will be presented at the meeting. Conclusion- Response rates with BST-236, in this pretreated older frail R/R AML and MDS population, were modest. Toxicity, including myelosuppression, however appears lower than with conventional intensive chemotherapy, suggesting this treatment could be interesting earlier in the disease course.