Induction Mortality Research Articles

Peripheral Blood Neutrophil Nadir and Time to Platelet Recovery during Induction Chemotherapy: Predictors of Clinical Outcomes and Markers for Optimizing Induction Treatment Intensity in Acute Lymphoblastic Leukemia.

To study the kinetics of blood count nadir and time to recovery and find its association with clinical outcomes in a cohort of Acute Lymphoblastic Leukemia (ALL). Data from 243 cases treated between January 2018 to December 2020 was retrospectively analysed. Along with baseline data, serial measures of peripheral blood counts, nadir, and time to partial and complete recovery of counts during course of induction chemotherapy were recorded. Post-induction Complete Remission (CR) status, Event-Free Survival (EFS) , and Overall Survival (OS) were recorded as clinical outcomes for analysis. Median age was 15 (range,1-62) years. Immunophenotype was B-ALL in 71% (n=172), and T-ALL in 27% (n=66). Good steroid response (D8) was seen in 89%(n=216), CR in 79% (n=192), and induction mortality in 12% (n=29). Median neutrophil nadir was 0.06(0-0.49) *10⁹/L and median day to nadir was D17. Median time to partial and complete platelet recovery was D18 and D25. Late neutrophil nadir (>D15) was independent predictor of refractory disease post-induction [OR=5.43 (95%CI 1.06-27.75)]. Late partial platelet recovery (>D22) was independent predictor of poorer EFS and OS [HR = 1.63 (95%CI 1.07-2.47)] and [HR = 1.5 (95% CI 1-2.4)] respectively. We found that a longer time to neutrophil nadir independently predicts refractory disease post-induction and late partial platelet recovery is an independent factor for poorer EFS and OS. Thus, Blood count kinetics as independent predictors of induction outcomes can provide a simple, easy-to-use tool for balancing toxicity-efficacy during induction therapy for ALL.

Outcomes of Acute Promyelocytic Leukaemia in Paediatric Patients: Insights from a Low-Middle-Income Country.

To describe the prognostic variables and course of paediatric acute promyelocytic leukaemia (APL) in Pakistan. Cohort study. Place and Duration of the Study: Department of Paediatric Oncology, Combined Military Hospital, Rawalpindi, Pakistan, from January 2012 to December 2022. Patients aged 1-15 years, clinically confirmed APL with promyelocytic leukaemia- retinoic acid receptor alpha (PML-RARA) were enrolled. Initial admission included a thorough examination, recording demographic and clinical data, reporting time, prior treatment, and socioeconomic status. Statistical analysis used SPSS 25.0, with significance at p <0.05. This study included 50 cases of APL. Out of which, 32 (64%) were males and 18 (34%) were females. The mean age at diagnosis was 7.02 ± 3.86 years. Pallor (96%) and fever (88%) were common presentations. The average white blood cell count was 28.70 ± 35.39 x109/L. Treatment protocols include 48% International Consortium for Childhood (ICC)-APL, and 52% arsenic trioxide (ATO). High-risk cases were 54%. Neutropenic fever and differentiation syndrome were common induction complications. Delays over one month increased induction deaths (6.7 to 35%, p = 0.011), reducing disease-free survival (DFS), (76.7 to 35%, p = 0.001), and overall survival (OS), (80 to 45%, p = 0.007). After 40.90 ± 45.19 months' follow-up, 10-year OS and DFS were 66.0% and 60.0%, respectively. The best OS and DFS, at 80%, were observed in standard-risk cases treated with ATO. Neutropenic fever and bleeding were the primary causes of mortality in paediatric APL induction. Treatment delay was a key prognostic factor. ATO-based therapy offered safer, improved DFS, and OS suitable for primary healthcare settings. Acute promyelocytic leukaemia, Chemotherapy, Neutropenic fever.

Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia

AbstractThe introduction of all-trans retinoic acid combined with anthracyclines has significantly improved the outcomes for patients diagnosed with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries in which arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly because of high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the International Consortium on Acute Promyelocytic Leukemia study involving 806 patients with APL recruited from 2005 to 2020 in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has notably decreased to 14.6% compared with the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age of ≥40 years, Eastern Cooperative Oncology Group performance status score of 3, high-risk status based on the Programa Español de Tratamiento en Hematologia/Gruppo Italiano Malattie EMatologiche dell'Adulto classification, albumin level of ≤3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival rate is 81%, the 4-year disease-free survival rate is 80%, and the 4-year cumulative incidence of relapse rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.

Treatment of Diffuse Large B-Cell Lymphoma at the Moscow City Clinical Hospital No. 52: A Retrospective Clinical Trial Based on the Single-Center Experience and Analysis of Data from Its In-House Registry

Background. The term diffuse large B-cell lymphoma (DLBCL) defines a heterogeneous group of lymphatic tumors. DLBCL is the most frequent immunomorphological variant among aggressive non-Hodgkin lymphomas (NHLs) in adults. It accounts for 30–40 % of all NHLs. Long-term results of treating newly diagnosed DLBCL have not been reliably evidenced in healthcare practice and, therefore, require further study.&#x0D; Aim. To assess the efficacy of chemotherapy for newly diagnosed DLBCL in terms of the 5-year progression-free survival (PFS) based on the analysis of data from the in-house hematology service registry at the Moscow City Clinical Hospital No. 52.&#x0D; Materials &amp; Methods. The study enrolled 156 patients with newly diagnosed DLBCL in the period from 2015 to 2022. The patients were 35–85 years of age (median 65 years).&#x0D; Results. First-line R-CHOP/R-miniCHOP chemotherapy was administered to 70 % of patients, 28 % of patients received R-DA-EPOCH, and 2 % were treated either with R-B or R-CVP. Complete response was achieved in 100 (65 %) patients: 75 out of them (75 %) received R-CHOP/R-miniCHOP, whereas 25 (25 %) received R-DA-EPOCH. Induction mortality was below 2.5 %. The 5-year PFS was 32 % with the survival median of 20 months. As confirmed by the multivariate analysis, the age over 60 years (p = 0.003), high IPI risk group (p = 0.015), advanced stage of the disease (p = 0.002), and non-GCB subtype of tumor (p = 0.045) can be regarded as independent predictors of early DLBCL progression.&#x0D; Conclusion. DLBCL is an aggressive B-cell lymphoma and one of the most frequent immunomorphological NHL variants in the clinical practice of the Moscow City Clinical Hospital No. 52. Despite the use of generally accepted standard immunochemotherapy regimens, the results attained by the present study illustrate unresolved challenges in chemotherapy for newly diagnosed DLBCL patients. By now, more effective first-line DLBCL therapy methods already exist, which are confirmed by the results of clinical trials. As it is sometimes impossible to further escalate immunochemotherapy for obvious reasons (age restrictions, health status, co-morbidities, etc.), a new promising strategy appears to be the personalized chemotherapy based on the study of genetic DLBCL profile of each particular patient.

Analysis of acute leukemia complications in children at the disease onset and during induction

Background. Despite the progress achieved in the treatment of acute leukemia (AL) in children, complications, both at the disease onset and those resulting from antitumor therapy, remain the main cause of early mortality, which varies from 3 to 20 %.Aim. To assess the frequency, severity, etiology, risk factors, and outcomes of AL complications in children at the disease onset and during induction chemotherapy (ICT).Results. The study analyzed 92 cases of AL in children aged from 5 months to 17 years. 75 patients had acute lymphoblastic leukemia (ALL), 17 had acute myeloid leukemia (AML). In 1 (1.3 %) patient with ALL and in 5 (29.4 %) with AML, a concomitant diagnosis was Down syndrome. At the AL onset, 34 (36.9 %) patients were diagnosed with infection, of which 27 (36 %) and 7 (41.2 %) patients had ALL and AML, respectively. In both cohorts, febrile neutropenia (55.5 %; n = 15 vs. 14.3 %; n = 1), pneumonia (25.9 %; n = 7 vs. 71.4 %; n = 5), enterocolitis (7.4 %; n = 2 vs. 14.3 %; n = 1) predominated in both cohorts for AML and ALL, respectively. Due to uncontrolled infection in 5 (29.4 %) patients with AML and 13 (17.3 %) with ALL, ICT was delayed until the condition stabilized and the infection was controlled. During ICT, the incidence of infectious complications was 81.3 % (n = 61) and 100 % (n = 17) in patients with ALL and AML, respectively. The most common types were enterocolitis (41.2 %; n = 7 vs. 34.4 %; n = 21), febrile neutropenia (29.4 %; n = 5 vs. 37.7 %; n = 23), pneumonia (47.1 %; n = 8 vs. 29.5 %; n = 18), catheter-associated bloodstream infection (11.8 %; n = 2 vs. 8.2 %; n = 4) in AML and ALL, respectively. By etiology, bacterial infections predominated, accounting for 32 % (n = 8) and 36.8 % (n = 35) in the AML and ALL groups, respectively. More cases of invasive mycoses were reported in AML patients – 23.5 % (n = 4) versus 14.8 % (n = 11). Non-infectious complications were diagnosed in 32.6 % (n = 30) of patients with a predominance in ALL group (34.6 %; n = 26 vs. 23.5 %; n = 4). Hyperleukocytosis at the leukemia onset caused such complications as leukostasis (11.8 %; n = 2) and acute tumor lysis syndrome (11.8 %; n = 2). The most common post-cytostatic complications in ALL were vincristine polyneuropathy (61.5 %; n = 16), hemorrhagic syndrome (15.4 %; n = 4), methotrexate-induced encephalopathy (15.4 %; n = 4), acute tumor lysis syndrome (11.5 %; n = 3). In AML cases, the most common type of non-infectious complications were hemorrhagic (75 %; n = 3). Induction mortality in the ALL group was 2.6 % (n = 2), in the AML group it was higher – 11.8 % (n = 2), however, it should be noted that all deaths were registered in children with Down syndrome. The main cause of mortality in both groups was severe infections secondary to chemotherapy-induced hematopoietic aplasia. There were no deaths associated with non-infectious complications or chemotherapy-induced toxicity.Conclusion. The main type of toxicity in children at the AL onset and during ICT remains infectious complications of various etiologies, while in AML patients a higher frequency of invasive mycoses is registered (23.5 % vs. 14.8 %). Despite the high incidence of chemo-induced toxicity, the mortality rate in ALL remains low, amounting to 2.6 % in our cohort. In the AML group, mortality was higher – 11.8 %, but it should be noted that all cases occurred in patients with Down syndrome. There were no deaths due to non-infectious complications in any of the study cohorts.

Real-World Outcomes with Intensive Chemotherapy in Acute Myeloid Leukemia Patients Deemed “Unfit” for Remission Induction By Landmark Trials' Criteria

Background: Induction mortality rates in acute myeloid leukemia (AML) ranges from 7.1% to 40% across Indian tertiary care centers (Kayal S, ASH 2022) exceeding those in the western countries, possibly due to treatment delay, multidrug resistant infections, and inadequate social support. Furthermore, patients seen in our clinics are not representative of those in landmark clinical trials, as a majority of them would be considered unfit for intensive induction based on the trial criteria. Consequently, these patients are left with treatment options, such as less intensive hypomethylating agents, BCL2 inhibitors, and newer targeted therapies. However, these drugs often remain unfeasible due to high out-of-pocket costs and regulatory approval delays, so a majority of patients receive intensive induction with antibiotics. In this retrospective study, we evaluate the effectiveness and toxicities associated with the utilization of such a strategy in the Indian context. Method: This retrospective study was conducted at a single tertiary care cancer center in India. It included patients aged ≥15 years, with acute myeloid leukemia, who received intensive induction chemotherapy as decided by the multidisciplinary joint clinic between January 01, 2017, and December 31, 2019. Patient data were extracted from the Indian acute leukemia research database [INwARD], which is a prospective registry of multiple centers, maintained and audited by the Clinical Data Management Center [CDMC], Vellore for the Hematology cancer consortium and is compliant with ICH-GCP regulations. Ethical approval was obtained from the institutional ethics committee, and the study was registered in the Clinical Trial Registry - India (CTRI/2020/02/023455). Patients were categorized based on the established criteria for “unfit for intensive chemotherapy” derived from landmark trials (VIALE-A, NCT02203773, VIALE-C), and subsequent analyses were performed. Outcomes assessed included 30-day induction mortality, documented infection at diagnosis (defined as fever with radiological, microbiological, or clinical focus of infection) and fungal infections according to EORTC and MSG classifications. Post-induction bone marrow response was defined as complete response/complete response with incomplete marrow recovery (CR/CRi) with ≤5% BM blasts, platelet count &amp;lt;100 × 10 9/L, and absolute neutrophil count &amp;lt;1.0 × 10 9/L. Kaplan-Meier analyses were conducted to assess event-free survival and overall survival. Results: Among 1326 eligible patients, 385 received intensive chemotherapy during the study period (49 received less intensive therapy, 442 referred outside, 210 on palliative care, 212 lost to follow up and 28 died). Demographic and baseline characteristics are detailed in Table 1. Cytarabine and daunorubicin (98.9%) were the most common first-line treatments. Of the 385 patients receiving intensive chemotherapy, 188 were categorized as unfit according to the study criteria (Refer Table 1). The unfit cohort exhibited higher 30-day induction mortality compared to the fit cohort (20.5% vs. 6%, P&amp;lt;0.0001) with a trend for higher incidence of proven and probable fungal infections (18.4% vs. 11.2%, P=0.054). Complete remission rates (CR+CRi) were lower in the unfit cohort (52.4% vs. 68%, P&amp;lt;0.001), while no difference in documented bloodstream infections was observed (P=0.754). Univariate analysis revealed that induction mortality was most influenced by age&amp;gt;50 (P=0.019), ECOG ≥2 (P=0.002) and infection at diagnosis (P&amp;lt;0.0001). However, upon conducting multivariate analyses, infection at diagnosis emerged as the strongest predictor of induction mortality (OR:2.91, 95%CI, 1.51 to 5.59, P=0.001). The median follow up was 15.7 months (range, 0.2-73.8). The 2-year estimated event-free survival (EFS) and overall survival (OS) of the entire cohort was 42.9% and 69.2% respectively. For the unfit and fit cohort, the 2-year EFS was 42.2% vs 43.9% (P=0.065), and the 2-year OS was 62.5% vs 75.1% (P=0.001) respectively. Conclusion: Unfit patients who received intensive chemotherapy had higher induction mortality and lower overall survival. Furthermore, it underscores the importance of improving accessibility to novel therapies, to provide a safe and viable alternative for nearly half of our AML patient population.

Combination of Venetoclax and Azacytidine As First-Line Induction Therapy for Acute Myeloid Leukemia in Patients Younger Than 60 Years: A Tertiary Care Center Experience from Our Low Middle Income Country

INTRODUCTION: Anthracycline- and cytarabine-based “7+3” induction chemotherapy has been the frontline treatment option for acute myeloid leukemia (AML) in the non-elderly and fit patient population. Sixty percent of these patients (pts) achieve Complete remission (CR). However, an estimated 30-40% of pts relapse (Tara L. Lin &amp; Livio Pagano et al., Expert Review of Hematology, 2021). In addition, based on a large US database study and studies from India, the “7+3” regimen is associated with high rates of induction mortality, intensive care unit (ICU) admission, and duration of hospital stay. BCL2 inhibition with venetoclax has been a new paradigm for the treatment of AML. Herein, we present our institutional experience in treating AML in pts younger than 60 years (yrs) old with a combination of venetoclax (ven) and azacytidine (aza). METHODS: We conducted a retrospective review of patients aged 18-60 who were newly diagnosed with AML between May 2020 and May 2023, and in this study, we included all pts, who met the WHO criteria for AML, did not have APML, had no prior history of treatment for other malignancies, and had not received prior induction treatment. Pts received aza 75 mg/m2 on days 1-7 and ven, which escalated from 100 to 200 to 400 mg on days 1-3. Ven continued at 400 mg without posaconazole or 100 mg with posaconazole from days 4-28, and bone marrow aspiration and biopsy were performed after day 28. Patients who achieved morphological remission without count recovery had up to 14 days off therapy before subsequent cycles. Non-responders received up to 1-2 additional cycles. Post-response (defined as a complete remission [CR] ), and patients with measurable residual disease (MRD) negative by multiparameter flow cytometry (MFC) with the residual blast cutoff being &amp;lt; 0.1% proceeded to further cycles. The primary objective of the study is to focus on the induction mortality rate and complete remission in younger, newly diagnosed AML pts who received aza and ven in the induction period. Responses to induction and subsequent post-remission therapy were recorded. RESULTS: A total of 17 patients with AML aged ≥ 18 years and ≤60 years were treated with a combination of aza and ven from May 2020 to May 2023. The median patient age was 47 yrs (interquartile range [IQR]: 30-56 yrs, 52.9% age &amp;lt;50 yrs ), and 52.9% of the pts were males. According to the European Leukemia Network (ELN) guidelines for 2022, using FISH and next-generation sequencing (NGS), 5 out of 17 pts (41.2%) were categorized as having favorable risk, 3 out of 17 patients (17.6%) were categorized as having intermediate risk, and 9 out of 17 pts (41.2%) were categorized as having adverse risk. During their inpatient stay, none of the pts required renal replacement therapy (RRT), and 1 out of 17 (5.8%) pts required mechanical ventilation. The dose of ven was 400 mg in 8 out of 17 patients (47%). One pt was on sertraline and received 200mg of ven. The remaining pts (8/17) received 100 mg of ven with posaconazole, which reduced the cost of the treatment to 50%. The median pretreatment white cell count (WCC) was 11.49 x 10^9/L (IQR: 6.25 to 39.74 x 10^9/L). The platelet count took a median of 31 days to recover above 50 x 10^9/L (IQR: 28-43 days), while the median time for the absolute neutrophil count (ANC) to recover above 1 x 10^9/L was 52 days (IQR: 47-60 days). 11 out of 17 (64%) of our patients achieved complete remission (CR1) after the first cycle. Additionally, 5 out of 17 (29.4%) were MRD-negative when compared to a large US study database and an Indian study (see table1). The median duration of hospital stay was 16 days (IQR: 10-20 days), and the induction mortality rate was 1/17 (5.8%) (see table1). This death occurred in a patient with adverse risk. CONCLUSIONS: The response to induction therapy with venetoclax and azacytidine in young adults with AML was similar to the standard “7+3” induction therapy, with around 64% of pts achieving CR after the first cycle. The median duration of hospital stay, frequency of ICU admission, and especially induction mortality have been lower than the “7+3” regimen. BCL2 inhibition has indeed resulted in a paradigm shift in the treatment of AML. Therefore, it may be the right time to consider the combination of ven and aza as the standard first-line induction therapy for all pts with AML.

Phase 2 Study of CPX-351 in Combination with Venetoclax in Patients with Newly Diagnosed, High Risk Acute Myeloid Leukemia

Background CPX-351 is a nanoscale liposome of a fixed 5:1 molar ratio of cytarabine and daunorubicin which has improved survival of secondary acute myeloid leukemia (AML) 1. Venetoclax (ven) is a BCL2 inhibitor which, in combination with azacitidine or cytarabine, has become the standard of care for elderly AML. Ven has shown synergism with chemotherapy, with high complete remission (CR) rates in newly diagnosed (ND) and relapsed / refractory (RR) AML 2. In this study, we aim to assess the efficacy and safety of CPX-351 and ven (CPX-ven) in RR and ND AML. Methods This was a phase 2 study with a lead-in safety phase. Enrolment was allowed if the blasts were ≥10%. Patients (pts) age ≥18 with RR AML were eligible for the safety lead-in phase (LIP) or arm A. Arm B enrolled pts age 18 - 69 with ND AML. Other inclusion criteria included adequate liver, renal and cardiac function, and ECOG performance status ≤2. Pts with CNS involvement or prior CPX-351 were excluded. The recommend phase 2 dose was CPX-351 (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 IV on D1, 3 and 5 of induction, and daunorubicin 22 mg/m2 IV on D1 and 3 during consolidation) combined with ven on D2-8 of each cycle. Ven was dosed at 300mg daily and reduced to 150mg or 50mg daily for pts on a moderate or strong CYP3A inhibitors, respectively. The primary outcome measure was complete remission (CR) or CR with incomplete count recovery (CRi). Here, we report the outcomes of arm B including pts with ND AML. Results 14 pts were enrolled on arm B. One pt withdrew and one was too early in treatment, therefore 12 were evaluable. Baseline characteristics are shown in Table 1. The median age was 59.5 years (range, 44 - 69); Four (33.3%) were female. All 12 (100%) pts were classified as adverse risk per the 2017 European Leukemia Net Guidelines. Two (16.7%) pts had treatment for a prior non-myeloid malignancy (therapy-related AML). Eight (66.7%) had an antecedent haematological disorder (secondary AML), of whom seven had treatment (median 1 line, range 1 - 2). Four (33.3%) pts had a complex karyotype, of whom three harbored a TP53 mutation. Nine (75.0%) pts achieved a response, including four CR (33.3%), five CRi (41.6%), and one induction mortality (8.3%) prior to disease assessment. 3/4 (75.0%) pts with complex cytogenetics (including 2/3 (66.7%) with a TP53 mutation) achieved a CR/CRi. Of the secondary AML pts with an evaluable response, 5/7 (71.4%) achieved a CR/CRi. Of the nine pts achieving CR/CRi, five (55.5%) were negative for minimal residual disease (MRD) by flow cytometry. The median number of cycles to CR/CRi was one (range 1 - 2). The median overall survival (OS) was 12.9 months (95% CI, 3.1 - not reached, NR, Figure 1). The median relapse-free survival (RFS) was 8.7 months (95% CI, 3.1 -NR). 7/9 (77.8%) of responding pts underwent an allogeneic stem cell transplant (SCT) after attaining CR/CRi. There were 90 adverse events (AE) in 10 (83.3%) pts. 80 (88.9%) were grade 1 or 2, 10 (11.1%) were grade ≥3. The most common AE was gastrointestinal with seven (7.8%) occurrences. Four (33.3%) pts developed grade ≥3 infections; of these, one (8.3%) died. The cause of death was neutropenic septic shock due to pneumonia. Conclusion CPX-ven is a feasible option for remission induction in pts with high-risk, newly diagnosed AML. The combination produced high rates of response and MRD negativity in a cohort of pts with adverse risk features, including pts with adverse karyotype and AML following prior HMA-based treatment, allowing them to proceed with SCT. Toxicities are as expected for an intensive chemotherapy regimen. Further studies are needed to confirm the efficacy of this combination.

Patients with Down Syndrome and High-Risk B-Acute Lymphoblastic Leukemia Demonstrate Improved Outcomes on a Modified Chemotherapy Regimen: A Report from Children's Oncology Group Study AALL1131

Introduction: Children with Down syndrome (DS) have a 20-fold increased risk of developing B-acute lymphoblastic leukemia (B-ALL), and demonstrate an increased risk of both relapse and treatment-related mortality (TRM). The Children's Oncology Group (COG) High-Risk (HR) B-ALL trial AALL0232 was permanently closed to DS HR patients due to excessive TRM, primarily due to overwhelming sepsis during times of severe neutropenia. On the successor HR B-ALL trial AALL1131, a primary objective for DS patients was therefore to reduce TRM by enhancing supportive care and modifying some elements of therapy. Methods: DS HR patients were treated on a single non-randomized stratum, with several modifications compared to non-DS HR patients. The majority of DS HR patients received a three-drug Induction, with only slow early responders (M2/M3 marrow at Induction day 15) receiving a single dose of anthracycline (daunorubicin 50 mg/m 2). Interim Maintenance 1 (IM-1) consisted of four IV courses of intermediate dose (ID; 2,000 mg/m 2) rather than high-dose methotrexate (HD MTX; 5,000 mg/m 2), with leucovorin rescue beginning earlier, at hour 30 and advancing if tolerated to hour 36, rather than at hour 42. Maintenance modifications included administration of vincristine/steroid pulses every 12 instead of every 4 weeks, and equal duration of therapy for boys and girls. Results: Patient characteristics (Table 1) were similar among the 280 DS HR patients and 5,612 non-DS HR patients except for more frequent bone marrow minimal residual disease (BM MRD) &amp;gt;0.01% in DS vs non-DS patients both at end of Induction (EOI; 54.1% vs 34.9%, p &amp;lt;0.0001) and at end of consolidation (EOC; 23.9% vs 12.0%, p=0.001). DS HR patients were also less likely to have favorable or unfavorable cytogenetics (p &amp;lt;0.0001). In terms of tolerability of the modified IM-1 phase, the duration was significantly longer in DS vs non-DS patients (mean 80.0 ± 16.6 days vs 74.0 ± 14 days, p &amp;lt;0.0001), and delays over 14 days were significantly more frequent (9.7% vs 4.7%, p=0.001). Nevertheless severe toxicities during IM-1 were low, with only 2 DS HR cases of grade 4 mucositis, 2 grade 4 infections, and 1 grade 5 event (sudden death, not otherwise specified). AALL1131 successfully achieved an induction death rate &amp;lt;10% in DS HR patients, although the rate remained significantly higher than in non-DS patients (3.6% vs 1.7%, p=0.035). Event-free survival (EFS) and overall survival (OS) in DS HR patients were improved compared to outcomes on older trials but remained significantly lower than non-DS patients (Figure 1), with 5-year EFS 69.1 ± 3.1% vs 79.5 ± 0.6% (p &amp;lt;0.0001), and 5-year OS 83.3 ± 2.5% vs 88.4 ± 0.5% (p=0.0005). Among DS HR patients, outcomes were particularly poor among those with EOC MRD &amp;gt;0.01% compared to those with EOC MRD &amp;lt;0.01% (5-year EFS 25.8 + 9.9% vs 62.2 + 6.6%, p &amp;lt;0.0021; 5-year OS 54.0 + 12.2% vs 88.1 + 4.5%, p &amp;lt;0.0003). Conclusion: AALL1131 achieved the goal of decreasing induction mortality for DS HR patients, and the modified IM-1 phase utilizing ID MTX with early leucovorin rescue was well-tolerated, with minimal grade 4-5 toxicities, despite a longer mean duration and more frequent treatment delays compared to non-DS patients receiving HD MTX. DS HR patients continued to demonstrate disparities in EOI and EOC MRD levels, as well as in 5-year EFS and OS. Innovative strategies utilizing targeted therapies and immunotherapy are needed to further improve outcomes for patients with DS HR ALL.

Mixed Phenotypic Acute Leukemia -Clinical Presentation, Prognosis and Outcomes of Patients Treated with Acute Lymphoblastic Leukemia like Protocols a Multi-Institutional Study from India

Mixed phenotypic acute leukemia (MPAL) is a rare and difficult to treat type of acute leukemia. Broad consensus favour use of acute lymphoblastic leukemia (ALL) like treatment protocols in the management of MPAL. Data regarding this rare diagnosis is limited mainly to retrospective studies and limited data available from low middle income countries (LMIC). We report epidemiology and real-world outcome data of MPAL patients treated with ALL like protocols among the multi-institutional data base set up by hematology cancer consortium (HCC) in India. In this retrospective multicentric study of a prospectively maintained data set, we collected data from eleven member centers of HCC using an electronic database. Patients who fulfilled the WHO 2016 classification criteria for MPAL were included. Patients diagnosed between January 2018 and March 2022 were included in the study. The data included demographic details, performance status (ECOG), comorbidities, CNS involvement, testicular involvement, presence of mediastinal mass, phenotype of MPAL (B+M, T+M, T+B), karyotype, FISH, PCR and NGS abnormalities. If treatment was not received by patients the reasons were also captured. We also evaluated the treatment protocol used and use of tyrosine kinase inhibitors. The primary objective was to evaluate event-free survival (EFS) and overall survival (OS) at 1year. The impact of the treatment protocol used, age, baseline WBC count, LDH, performance status, CNS involvement on EFS and OS were studied. A total of 114 patients were diagnosed to have MPAL during the study period. The baseline epidemiological features are tabulated in table-1. Sixty-six (58%) patients were treated with ALL like treatment protocols and 48(42%) patients did not receive any treatment due to various reasons at HCC centers. 49(74%) patients received paediatric inspired protocols and 17(26%) patients received adult-type of protocols. Forty three (65%) patients achieved a complete remission after induction. Ten(15%) patients died during induction. Six(9%) patients died after achieving CR of which 3 died due to infection,3 died due to progressive disease and rest were lost to follow up. Minimal residual disease (MRD) done using either flowcytometry or PCR was available in 37 patients. MRD negative status was achieved in 17(46%) patients post phase II of induction. After a median follow up of 12 months, EFS was 61% and OS was 67%(figure1). Estimated EFS and OS at 24 months were 42% and 55% respectively. There were no significant differences in EFS and OS between different MPAL phenotypes. Allogeneic stem cell transplant (ASCT) was performed only in 3 patients. Negative MRD status at the end of second phase of induction was significantly associated with improved EFS with a Hazard ratio of 0.349(CI-0.117-1.036). Age, cytogenetic profile, LDH, baseline WBC count and CNS involvement were analyzed by univariate analysis for effect on treatment outcomes. There was no significant effect of these variables on both EFS and OS. Our study is one of the largest studies conducted on MPAL patients in a resource limited setting. If patients received treatment, the outcomes were encouraging despite poor access to allogeneic stem cell transplant in first complete remission, when compared with similar real world multi-institutional analysis. Induction mortality of 10% was comparable to other similar studies. However, the worse 2-year EFS and OS may be explained by poor rates of allogeneic stem cell transplant (Allo-HSCT). The abandonment of treatment and limited use of Allo-HSCT in first complete remission were major limitations in improving overall outcomes in our patients.

A Retrospective Comparative Analysis of Intensive Vs. Non-Intensive Chemotherapy in Treatment Naïve Acute Myeloid Leukemia (AML) Patients in India

Background &amp; Significance: Acute Myeloid Leukemia (AML) is a hematological malignancy characterized by the rapid proliferation of abnormal myeloid cells. Intensive chemotherapy has been the main stay of therapy in young adults whereas Azacytidine and Venetoclax based therapy is preferred in older and unfit patients of AML. As per Indian Acute Leukemia Research Database of (INwARD) of the Hematology Cancer Consortium, 3+7 is the most commonly used intensive chemotherapy in India induction mortality (n=392) is 16.9% (range 6.1 - 43%). (1) Another Indian Study of acute leukemia (n=268), highlighted that 54% had baseline infections. Only 40% of infected patients received induction therapy as compared to 93% of non-infected patients. Venetoclax has improved outcomes in AML. There is an unmet need for protocols for younger patients who are unfit for 3+7 due to multi drug resistant baseline infections or ECOG ≥2 or organ dysfunction. Poor risk cytogenetics and mutations are associated poor response to intensive therapies. We did retrospective comparative analysis of overall outcomes in patients receiving intensive chemotherapy versus non-intensive chemotherapy in a tertiary care centre of North India Material &amp; Methods: We did a retrospective comparison of intensive chemotherapy 3+7/ FLAG based therapy versus Azacytidine and Venetoclax based therapy since 2019. Institutional electronic medical record software (PARAS) was utilized to identify patients. Type of therapy was decided as per physician discretion. Patients who were elderly (age &amp;gt;60 years), ECOG PS 2 or more, or clinic-radiological evidence of infection. Intensive therapy included received Inj. Daunorubicin 60 mg/m2 IV once daily for 3 days and Inj. Cytarabine 100 mg/m2 IV as a continuous infusion for 7 days. Or FLAG/VEN based therapy Inj. Fludarabine 30 mg/m2 IV once daily for 4 days, Cytarabine 1500 mg/m2 IV once daily for 4 days. Inj. Filgrastim (biosimilar)5 mcg/kg s/c once daily from day 1 to ANC &amp;gt; 500 cells/ μL. Non-Intensive therapy arm received Inj. Azacytidine @75mg/m2 for 7 days with Tab Venetoclax 100mg once a day for 7-14 days as per patient tolerance. Posaconazole was used as a anti-fungal prophylaxis. We recorded baseline characteristics, type of therapy, compared the tolerability and efficacy of both the regimens. We did survival analysis using Kaplan Meier Curves and statistical analysis using SPSS version 25. Results: Baseline Data is presented in Table 1, 69 patients received intensive chemotherapy and 58 patients received non-intensive therapy. Patient in the intensive therapy arm were younger and fit whereas patients were older in the non-intensive therapy arm. Post Induction bone marrow evaluation was done between day 28 to day 35 post therapy. CR rate was 78.2 per cent in Intensive therapy arm v/s 51.7 per cent in non-intensive therapy arm. Patients were stratified as per ELN risk category. Patients in the standard risk and intermediate risk groups did better in the intensive therapy arm but outcome did not differ in patients of poor risk ELN category patients. Fig:1 Non- intensive therapy was better tolerated with fewer grade 3 or more febrile neutropenia and fewer 3 rd line antibiotics lesser duration of stay. The decision between intensive and non-intensive chemotherapy should be carefully individualized, considering patient age, performance status, cytogenetic risk, and comorbidities. Conclusion: Our study re-affirms the role of intensive chemotherapy in younger and fitter patients, however in adverse risk ELN patients non-intensive therapy appears non inferior to intensive therapy

Current Results of Intensive Therapy in Younger Adults with Acute Myeloid Leukemia (AML): The Large Randomized French Backbone Intergroup (BIG)-1 Study on Behalf of the Filo, ALFA, and SFGM-TC Study Groups

Introduction. This multicenter study randomly explored various standard intensive chemotherapy (ICT) strategies in adults with AML, namely higher-dose idarubicin (IDA) vs high-dose daunorubicin (DNR) and intermediate-dose (IDAC) vs high-dose (HDAC) cytarabine. The study was planned large enough to allow patient subgroup analysis. Treatments. Eligible patients (pts) were randomized (R1) to receive an induction course with either DNR at 90 mg/m 2/d for 3 days or IDA at 9 mg/m 2/d for 5 days combined with cytarabine at 200 mg/m 2/d CIV for 7 days. Since 09/2018, FLT3-mutated AML pts may also receive midostaurin 100 mg/d d8-21. Then, all pts alive without contra-indication for further ICT were randomized (R2) to receive a first consolidation (C1, if in CR/CRp/CRi) or salvage (if induction failure) with either HDAC (3g/m 2/12h) or IDAC (1.5g/m 2/12h) cytarabine at day 1, 3 and 5. Pts in CR/CRp/CRi after C1/salvage received two additional HDAC/IDAC cycles (C2, C3), according to R2 arm. In intermediate (int) or adverse (adv) risk AML pts as defined in the protocol, allogeneic HSCT from sibling or 10/10 (or even 9/10 if adv-risk) matched donors was offered after C1 (adv-risk) or C2 (int-risk). Conditioning regimens were myeloablative (MAC; Bu-Cy ± ATG) if age&amp;lt;45y or reduced-intensity (RIC; Bu-Flu-ATG) if age≥ 45y or HCTCI&amp;gt; 2 in int-risk pts, and sequential FLAMSA/Bu-Cy-ATG in adv-risk pts. Fav-risk pts were also eligible for HSCT if late CR/CRp/CRi or suboptimal NPM1 MRD response. Alternative stem cells sources and conditioning regimens might also be offered to adv-risk pts. Patients &amp; Methods. Pts aged 18-60y with de novo, post-MDS or therapy-related AML (CBF, APL, Ph+, and post-MPN excluded) were eligible if ECOG-PS ≤3, no active infection or neoplasia, no organ contra-indication, and a health insurance. Patient characteristics are shown in Table 1. Between 01/2015 and 05/2019, 1405 pts were enrolled and 1357 were evaluable. Among them, 1159 were randomized in R1 with the primary objective to increase 3-year OS from 45% in the DNR to 55% in the IDA arm. A total of 1221 pts were randomized in R2, including 198 pts after the end of the R1 inclusion period (they received DNR or IDA according to centers' preferences). Primary R2 objective was to show OS non-inferiority after IDAC vs HDAC in a per protocol (PP) set, defined as pts who received the planned HDAC/IDAC dose ± 20% during C1/salvage. The non-inferiority boundary was an upper limit of the hazard ratio [HR] CI below 1.25. Analysis of R1 and R2 effects was adjusted on ELN-2022 risk groups, the other randomization/treatment arms, and time-dependent HSCT in first remission. Median follow-up was 5.4 years. Results. Overall, 1148 (84.6%) pts achieved CR/CRp/CRi and 564 (41.6%) received HSCT in first remission ( Table 1). At 6 years, OS was estimated at 53.4% (95% CI, 50.6-56.2). In the R1 population, IDA did not prolong OS (adjusted HR, 1.04 [0.88-1.23]; p=0.67). This lack of effect was observed in the three ELN-2022 risk groups. During induction, IDA was associated with longer neutropenia and antibiotic administration durations, more RBC/platelet transfusions, more mucositis and fungal infections. Remission and induction death rates were similar in both arms. In the R2-PP set that excluded 39 R2 pts, OS was significantly non inferior in the IDAC as compared to the HDAC arm (adjusted p-value, 0.004) and this was observed in the three ELN-2022 groups ( Figure 1). During the first C1/salvage cycle, IDAC was associated with less CNS toxicity and less RBC/platelet transfusions. Only 2 pts died during this cycle. Neither responses, HSCT rates, relapse incidence, nor RFS were significantly impacted by R1 or R2. With respect to the OS endpoint, no interactions were found between induction anthracycline and R2. In pts in induction failure at R2, the salvage rate was 51.6% after HDAC vs 39.5% after IDAC (adjusted p-value, 0.081). As expected, time-dependent HSCT in first remission significantly prolonged RFS (adjusted HR, 0.41 [0.32-0.52]; p&amp;lt;0.0001) and OS from remission (adjusted HR, 0.65 [0.50-0.83]; p=0.001) in int/adv-risk AML pts. In these pts, no interaction was found between the effect of HSCT and the R2 arm (HDAC or IDAC). Conclusions. In younger adults with non-CBF AML, benefit/risk analysis favors high-dose DNR vs IDA for remission induction and confirms IDAC as the standard for consolidation. The high overall transplant rate may have contributed to the good results of this study.

Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with Ph/BCR::ABL Negative B-Precursor Adult Lymphoblastic Leukemia (ALL): Preliminary Results of the GMALL Bold Trial

Older patients (pts) with newly diagnosed ALL are ineligible for unmodified pediatric-based therapies. Although results are improved with age-adapted, dose-reduced regimens including MRD-based treatment modification, there is much space for further improvement.Therefore, the GMALL study group developed a trial to evaluate Blinatumomab, a CD19 directed bi-specific T-cell engager, in sequence with chemotherapy in this patient population with high medical need (NCT 03480438). Importantly, Blinatumomab replaced three cycles of standard consolidation chemotherapy.Pts aged 56 - 76 years (yrs) with CD19-positive, Ph-neg B-precursor ALL wereeligible. The primary endpoint was complete hematologic remission (CR) afterinduction (1 cycle chemo, 1 cycle Blinatumomab) and the key secondary endpoint was molecular response (table 1). The efficacy population included pts treated with dose reduced and shortened induction I (IP1) and Blinatumomab 1 or early death (ED). Induction was followed by 3 further Blinatumomab cycles alternating with age adapted consolidation cycles (HDMTX/ASP, HDAC, reinduction and maintenance) according to GMALL protocols for older pts (Gökbuget et al, ASH 2021). The median age was 66 (56-76) yrs. 21% had pro-B-ALL and 79% c/preB subtype. 40% had comorbidities according to the Charlson Score; most frequent were diabetes (13%) myocardial infarction (10%) or vascular diseases (10%). 50 pts were evaluable for IP1: 76% achieved CR/CRu and 2 pts (4%) died due to infections. 33% (N=11) had a molecular response and 18% MolCR (table 1). 47 pts were evaluable for the primary endpoint after Blinatumomab 1: CR/CRu was observed in 85%; 2 experienced ED (4%; those mentioned above; no additional ED). 88% of the CR pts had a molecular response (82% MolCR). The median follow-up is 757 (61-1584) days. Overall Survival (OS) after 1 and 3 yrs was 80% and 67% for the efficacy population (figure 1). The resp results for the total population were 82% and 65%. The 3y OS was 69% for c/pre-B-ALL and 58% for pro-B-ALL (p&amp;gt;.05). 3y OS was 81% for pts aged 55-65 yrs and 53% for those older than 65 yrs (p=.025). Only three pts received an allogeneic stem cell transplantation in CR1. 6 pts relapsed, 2 pt developed a secondary malignancy (Colon Ca, MDS) and 3 pts died in CR (1 HLH, 1 arterial disease, 1 Covid19). EFS was 60% at 3 yrs. We compared the results with those of the current GMALL standard therapy for older pts with B-precursor ALL (N=186) (Gökbuget et al, ASH 2022). Patient characteristics were similar. CR rates after induction were 85% vs 78% for BOLD vs standard (p&amp;gt;.05). Molecular CR rates in pts with hematologic CR were 82% vs 55% (p=.006). OS at 3 yrs was 67% and 49% (p=0.08) and Remission Duration (RD) was 83% vs 58% (p=0.055). Overall tolerability and efficacy of the regimen was very promising with a high hematologic and molecular response rate; mortality in induction and consolidation was low. In comparison with the current standard therapy the MRD response rates were significantly better. OS and RD was superior despite the omission of several chemotherapy cycles in contrast to other trials with unmodified chemotherapy but additional cycles of Blinatumomab. An ongoing randomized trial (NCT04994717) compares an even more dose reduced combination of Blina and chemotherapy with standard of care. This is an independent academic trial initiated by the GMALL Study Group which received free supply of Blinatumomab and financial support by Amgen.

Multicenter Retrospective Evaluation of Treatment of High-Risk Acute Promyelocytic Leukemia (APL): Results from the Hematology Research Outcomes (HERO) Consortium

Background: Regimens employing all-trans retinoid acid and arsenic (ATRA+ATO) are the backbone of high-risk APL treatment. The APML4 regimen consists of a three-phase treatment approach: induction with ATRA, ATO, and idarubicin; two cycles of consolidation with ATRA+ATO; and maintenance with ATRA, methotrexate, and mercaptopurine. 1 MD Anderson Cancer Center (MDACC) developed a regimen incorporating gemtuzumab ozogamicin (GO) in addition to ATRA+ATO. 2 Differences in tolerability and efficacy between these two approaches are unknown as no comparative data exists. We aimed to describe real-world treatment outcomes for high-risk APL, comparing toxicity between APML4 and ATRA+ATO+GO. Methods We conducted a multicenter, retrospective cohort study including patients treated among six US centers participating in the pharmacist-led collaborative research consortium, HERO. Adults (&amp;gt;18 years) with newly diagnosed high-risk APL (t(15;17)(q24.1;q21.2)) according to the Sanz risk model 3 between April 2014 and June 2022, who received at least one dose of an induction regimen under the institution's high-risk protocol were compared based on induction regimen received. Patients with incomplete records were excluded. The primary endpoint was a composite of mortality, ICU admission, or confirmed infection during induction. Secondary endpoints included individual components of the primary endpoint, other induction-related toxicities, and complete response (CR) rate after induction. Analyses were performed as intent-to-treat which included all patients who received APML4 and ATRA+ATO+GO inductions regardless of consolidation strategies. Chi-square or Fisher's exact tests were utilized to evaluate dichotomous variables. Continuous variables were analyzed via Student's t-test or Mann-Whitney U test. Kaplan-Meier analysis with log-rank test was performed to estimate progression-free survival (PFS) and overall survival (OS). Results Fifty-seven patients with high-risk APL who started either APML4 (n=41) or ATRA+ATO+GO (n=16) as induction treatment met inclusion criteria. Baseline characteristics were balanced (Table 1) except for race and ethnicity, with a higher percentage of non-Hispanic white patients in the APML4 cohort (p=0.020) and a higher percentage of Hispanic/LatinX in the ATRA+ATO+GO cohort (p=0.011). Of evaluated molecular abnormalities, FLT3-ITD was most common (76%). Steroid prophylaxis was more common in the ATRA+ATO+GO cohort (p=0.015). Additional cytoreductive therapy was frequent in both arms: hydroxyurea used more often in the APML4 cohort (p=0.033) and idarubicin in the ATRA+ATO+GO cohort (p&amp;lt;0.001) (Table 1). Induction mortality was 7%, including 3 deaths in the APML4 cohort and 1 in the ATRA+ATO+GO (Table 2; p=1.000). Time to platelet recovery was longer with APML4 than ATRA+ATO+GO (median 27 vs 23 days, p=0.021) as was time to ANC recovery (median 38 vs. 29 days, p=0.020). No additional significant differences in individual safety outcomes were observed. Of note, there was no difference in differentiation syndrome that required dose changes or holds between the two cohorts. There were no detectable differences in treatment effectiveness, with 92.7% of patients in the APML4 arm and 93.8% of patients in the ATRA+ATO/GO arm achieving a CR at end of induction (Table 2). With a median follow-up of 35 months, neither group reached the median for overall survival and the estimated 36-month survival was similar between cohorts; 92.5% (95%CI 84.3-100) for APML4 and 94.1% (95%CI 83.1-100) for ATRA+ATO+GO. Conclusion ATRA+ATO-based regimens yield similar short- and long-term efficacy in a high-risk APL population, though hematologic recovery occurred earlier in the ATRA+ATO+GO cohort. No clinically significant differences in acute toxicities exist between APML4 and ATRA+ATO+GO induction strategies as demonstrated by this real-world multicenter analysis.

Venetoclax Combined with “7+3” Induction Chemotherapy Induces High Rates of MRD-Negative Remission in Newly Diagnosed AML Patients Fit for Intensive Chemotherapy Irrespective of Age

Introduction: Approximately 70% of patients (pts) with acute myeloid leukemia (AML) treated with the “7+3” regimen achieve complete remission (CR), with 30-50% of those attaining measurable residual disease (MRD) negative state by multiparameter flow cytometry (MFC). However, despite initial responses, the majority of pts eventually relapse. Venetoclax (Ven) added to intensive chemotherapy (IC) facilitates apoptosis of leukemic stem cells (LSC), and may result in deeper, more durable remissions. Moreover, IC induces MCL-1 downregulation and may overcome Ven resistance. We present safety and efficacy results from a phase 1b study of escalating cumulative Ven doses combined with daunorubicin (Dauno)+cytarabine (AraC) followed by high-dose cytarabine (HiDAC) chemotherapy in pts with newly diagnosed AML (NCT05342584). Objectives: The primary objective of this study is to determine the optimal dose of Ven in combination with Dauno &amp; AraC and HiDAC chemotherapy. Secondary objectives are response per 2022 ELN, survival (OS), event-free survival (EFS) and duration of response (DoR). A key exploratory objective is to assess rates of LSC eradication by means of MFC and single cell DNA (Tapestri, Mission Bio) and RNA sequencing (“high-resolution MRD assay”). Methods: Eligible pts must have a new diagnosis of AML, be 18-75 yrs of age and deemed fit for intensive chemotherapy. In a 3+3 design, Ven in escalating duration (400 mg D1-8 or -11 or -14, including 2-day ramp-up) is combined with AraC 100mg/m2 (D2-8) and Dauno 60mg/m2 (D2-4) in 2 separate age groups (&amp;lt;60 and ≥60yrs); Dauno 90mg/m2 was initially studied in pts &amp;lt; 60yrs, but since 04/2023 the dose is no longer explored. During consolidation, fixed dose Ven (200 mg x7days) is used in combination with age-adjusted HiDAC (1.5g/m2 in &amp;lt;60yrs and 1g/m2 in ≥60yrs, every 12hrs on days 1,3,5). In the expansion phase, additional pts in each age group will undergo 1:1 randomization between the starting and highest tolerated dose determined during dose escalation, for a total of 20 pts per dose cohort in both phases. Results: Twenty-seven AML pts enrolled and 25 completed the induction phase to date, 2 are actively treated. Median age was 59yrs, 44% were females and 67% ethnic or racial minorities. Fourteen (52%) pts had poor-risk genotypes by ELN 2022. Fourteen pts were treated with Ven x 8d, 11 in Dauno60 and 3 in Dauno90 cohorts, 7 pts with Ven x11d and 6 pts with Ven x14d. No DLTs were observed, and the toxicity profile was similar to historical experience with the “7+3” regimen. There were no induction mortality deaths. Twenty pts (20/25, 80%) achieved a composite complete remission (CRc) with single induction (19 CRs and 1 CRi), 10/13 in &amp;lt;60 and 10/12 in ≥60yr groups. Median time to ANC≥0.5K/uL and PLT≥50K/uL was 26 days and time to CR was 32 days. Of those in CRc, all except three pts &amp;lt; 60yrs were MFC-MRD negative (17/20, 85%). Among 8 patients with available MRD PCR testing, 6 achieved molecular MRD-negative and 2 low-level molecular MRD CRs. With a median 5.6-month follow-up time, median EFS or OS have not been reached, 25/27 (93%) patients are alive (10/12 ≥60yrs), 12 pts have completed the protocol, 5 continue on therapy and 5 underwent allogeneic transplantation. From those in CRc, 7 younger and 8 older pts (75%) remain in remission without evidence of hematologic or molecular relapse. Of 5 pts with complex karyotype plus TP53 mutated AML, 3 did not respond and 2 had an early treatment failure. Table 1 summarizes patient characteristics, toxicity and outcomes. Conclusions: Ven 400mg in combination with “7+3” induction chemotherapy is safe and highly effective in achieving MRD negative remissions in the vast majority of patients. Responses were low in TP53 mutated pts, suggesting no benefit of the addition of venetoclax to intensive chemotherapy, similar to what has been observed when venetoclax is added to standard dose hypomethylating agents in those pts, for whom non-cytotoxic approaches are being explored. The study is completing enrollment in the Dauno60 + Ven x14d cohorts and is entering the expansion phase in order to better explore the optimal Ven dose to combine with the “7+3” regimen. Updated results, as well as rates of LSC elimination post-induction will be presented at the meeting.

Prophylactic Use Of Levofloxacin During Induction Of Acute Lymphoblastic Leukaemia In Children-Experience From Pakistan.

To assess whether prophylactic use of Levofloxacin would reduce the number of febrile neutropenia episodes during the induction phase, a single-centre, case-control study was carried out. Data was collected prospectively of patients who received Levofloxacin prophylaxis during the induction chemotherapy from September 2019 till October 2020. The cases were compared with historical controls who did not receive antibiotics prophylaxis. A total of 121 patients were enrolled, among which 61 patients were cases, whereas 60 patients were controls. The patients who received Levofloxacin prophylaxis had lower rate of febrile neutropenia episodes than patients who did not receive any prophylaxis (p≤0.01) (odds ratio [OR]:0.23, CI 95%). No significant difference in induction mortality was seen between the two groups (p≤0.14). Levofloxacin prophylaxis reduced the rate of febrile neutropenia episodes among patients, but it did not affect the infection related mortality.

FLAG based v/s Standard 3 + 7 induction therapy in treatment naïve Acute Myeloid Leukemia: Time to think “beyond anthracyclines”

Daunorubicin and Cytarabine (DA; 3 + 7) has been the standard frontline Acute Myeloid Leukemia (AML) induction regimen resulting in Complete Remission (CR) rates of 50–70%. It is associated with induction mortality of 15–30%. We report a comparative analysis of DA versus fludarabine, cytarabine, G-CSF (FLAG) + /- Venetoclax in resource constrained settings. We conducted a single center, retrospective analysis of 37 treatment naïve fit AML patients from May 2021 to December 2022 who received either standard DA regimen (Group 1) or FLAG + /- Venetoclax (Group 2). The median patient age was 36.6 years in DA arm (n = 18) as compared to 40.1 years in FLAG arm (n = 19). CR rates at day 28 were 55.5% in group 1 and 89.4% in group 2 (odds ratio [OR], 7.20; 95% confidence interval [CI], 1.274 −40.678; P = 0.012). Patients in FLAG based therapy arm had shorter duration of neutropenia (P = 0.003), fewer episodes of grade 3 febrile neutropenia (P = 0.0228), shorter duration of antibiotic therapy (P = 0.03), lesser need of 3rd line antibiotic therapy (P = 0.0228). Mortality rates were 16.6% (n = 3) in (group 1) and 0% (n = 0) in (group 2) (p = 0.105). Our analysis supports that FLAG based induction regimen is an effective and well-tolerated therapy in treatment naïve fit AML patients.

Early death (ED) in elderly acute promyelocytic leukemia (APL) patients treated with lower induction doses of all-trans retinoic acid (ATRA).

e19012 Background: With the introduction of the differentiating agent ATRA, APL has progressed from being one of the most life-threatening diseases to becoming the most curable subtype of adult AML. However, despite this advancement, death within the first 30 days of treatment amongst elderly patients remains a critical issue with ED rates reportedly as high as 20-50%. There is limited data looking at the elderly population due to often being excluded from clinical trials given age associated with being prominent negative risk factor. Pharmacokinetic studies comparing 25 mg/m2/day and 45 mg/m2/day doses in adult patients have shown similar peak concentrations and mean area under the curve. Notably, low dose ATRA has been offered in pediatric patients in order to reduce incidence of differentiation syndrome. Differentiation syndrome is a key contributor to ED in elderly APL patients causing treatment failure. We propose that lower doses of ATRA in the elderly reduces the impact differentiation syndrome has on induction mortality amongst elderly APL patients and leads to a lower rate of ED. Methods: Fifteen APL patients &gt; 60 years of age were treated. Thirteen received low doses of ATRA (equal to or less than 25mg/m2/day) and two received standard doses of ATRA (45mg/m2/day). Arsenic trioxide was also used in addition to cytoreductive agents, such as cytarabine, hydroxyurea, and idarubicin as needed during induction. Dose reductions and regimens were based on age, comorbidities, and overall clinical judgement. During the course of treatment, further dose reductions and pauses in therapy were made based on clinical course. Results: A total of 15 elderly APL patients were treated between May 2017 and November 2020 at cancer centers within Georgia and South Carolina. The age range was 65-88 years old with a median age of 71 years old. 9/15 (60%) were female and 2/15 (13%) were classified as high risk. 13/15 were Caucasian and the remaining 2 were African American. Amongst the 13 APL patients who received lower doses of ATRA, one ED was noted. This occurred in 81-year-old Caucasian male with low risk APL who had multiple significant comorbidities and elected to halt treatment and pursue hospice. Amongst the 2 low risk APL patients who received standard doses of ATRA, one ED was noted due to differentiation syndrome. This patient also had many significant comorbidities. Conclusions: The ED rate in elderly APL patients treated with low doses of ATRA during induction was noted to be 1/13 (7.7%) which is significantly lower than what has been reported in literature. [Table: see text]

Impact of Delay Prior to Treatment in Ethiopian Children with Acute Lymphoblastic Leukemia.

More than 85% of childhood malignancies occur in developing countries with less than a 30% cure rate as opposed to more than 80% cure rate in developed countries. This disproportionately significant difference might be due to delays in diagnosis, treatment initiation, lack of adequate supportive care, and treatment abandonment. We aimed to determine the impact of overall treatment delay on induction mortality of children with acute lymphoblastic leukemia treated at Tikur Anbessa specialized hospital (TASH). A cross-sectional study was conducted among children who were treated from 2016 to 2019. Children with Down syndrome and relapsed leukemia were excluded from this study. A total of 166 children were included; most patients were males (71.7%). The mean age at diagnosis was 5.9 years. The median time interval from the onset of symptoms to the first TASH visit was 30 days and the median period from TASH's first clinic visit to diagnosis was 11 days. The median time to initiate chemotherapy after diagnosis was 8 days. The total median time from the first onset of symptoms to chemotherapy initiation was 53.5 days. Induction mortality was 31.3%. High-risk ALL and patients with an overall delay between 30 and 90 days were more likely to experience induction mortality. Patient and healthcare system delay is high compared to most studies done and a significant association has been noted with induction mortality. Efforts to expand the pediatric oncology service in the country and efficient diagnostic and treatment approach need to be established to reduce mortality associated with overall delay.

Levofloxacin Prophylaxis Versus no Prophylaxis in Acute Myeloid Leukemia During Post-Induction Aplasia: a Single Center Study.

Acute myeloid leukemia (AML) patients are at high risk of infections during post-induction neutropenia. Recently, the role of antibacterial prophylaxis has been reconsidered due to concerns about the emergence of multi-resistant pathogens. The aim of the present study was to evaluate the impact of avoiding prophylaxis on the rate of induction death (primary endpoint), neutropenic fevers, bloodstream infections (BSIs), resistant pathogens BSIs and septic shocks (secondary endpoints). We performed a retrospective single-center study including 373 AML patients treated with intensive induction chemotherapy, divided into two groups according to levofloxacin prophylaxis given (group A, gA) or not (group B, gB). Neutropenic fever was observed in 91% of patients in gA and 97% in gB (OR 0.35, IC95% 0.08 - 1.52, p=0162). The rate of BSIs was 27% in gA compared to 34% in gB (OR 0.69, 0.38 - 1.25, p=0.222). The induction death rate was 5% in gA and 3% in gB (OR 1.50, 0.34 - 6.70, p=0.284). Fluoroquinolones (FQ) resistant pathogens were responsible for 59% of total BSIs in gA and 22% in gB (OR 5.07, 1.87 - 13.73, p=0.001); gram-negative BSIs due to multi-drug resistant organisms were 31% in gA and 36% in gB (OR 0.75, 0.15 - 3.70, p=0.727). Despite its limitations (retrospective nature, single-center, different cohort size), the present study showed that avoiding levofloxacin prophylaxis was not associated with an increased risk of induction death. The cumulative incidence of neutropenic fever was higher in non-prophylaxis group, while no difference was observed for BSIs. In the prophylaxis group we observed a higher incidence of FQ-resistant organisms.