Intensive Chemotherapy Research Articles

NEWS, NEWS2, and qSOFA accuracy in predicting sepsis-related mortality in acute myeloid leukemia: a retrospective single-center analysis.

Acute myeloid leukemia (AML) treated with intensive chemotherapy carries a high risk of severe infection. The development of reliable assessment tools to promptly identify patients at risk of developing critical illness is essential to prevent delays in intensive care unit (ICU) admission. This study evaluated the accuracy of quick Sequential Organ Failure Assessment (qSOFA) score, National Early Warning Score (NEWS), and NEWS2 score in predicting ICU admission and sepsis-related mortality in this population. A retrospective analysis was conducted, including 365 episodes of febrile neutropenia in 126 patients. The results showed that all three scores-qSOFA, NEWS, and NEWS2-demonstrated good accuracy for all outcomes, with area under the receiver-operating characteristic curve values for sepsis-related mortality of 0.812, 0.858, and 0.848, respectively. In addition, the scores exhibited excellent accuracy in predicting ICU admission and the composite outcome of ICU admission or sepsis-related mortality. To our knowledge, this is the first study to evaluate the accuracy of NEWS in a population of patients with AML who did not undergo stem cell transplantation. These findings suggest that NEWS and NEWS2 are effective tools for identifying patients with AML at high risk of clinical deterioration during febrile neutropenia, supporting their use in clinical practice.

Prognostic significance and treatment strategies for IKZF1 deletion in pediatric B-cell precursor acute lymphoblastic leukemia

BackgroundThe predictive importance of IKZF1del in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has shown variability across different studies. Thus, the optimal treatment approach for children with IKZF1del BCP-ALL remains contentious, with the ongoing debate surrounding the use of IKZF1del-based high-risk stratification versus a minimal residual disease (MRD)-guided protocol.MethodsIKZF1 status was reliably determined in 804 patients using multiplex ligation-dependent probe amplification (MLPA) data obtained from four hospitals in Fujian, a province of China. In the Chinese Children Leukemia Group (CCLG)-ALL 2008 cohort, IKZF1 status was included in the risk assignment, with all IKZF1del patients receiving a high-risk regimen. Conversely, in the Chinese Children’s Cancer Group (CCCG)-ALL 2015 cohort, IKZF1del was not incorporated into the risk assignment, and patients were treated based on an MRD-guided risk stratification protocol.ResultsIKZF1del was found in 86 patients (86/804, 10.7%) overall and in 30 (30/46, 65.2%) BCR::ABL1-positive patients. Overall, IKZF1del was a poor prognostic predictor for patients, though the significance diminished upon age adjustment, white blood cell (WBC) count at diagnosis, treatment group, and MRD status. In the CCLG-ALL 2008 cohort, IKZF1del conferred a notably lower 5-year overall survival (OS) and event-free survival (EFS) and a significantly higher 5-year cumulative incidence of relapse (CIR) than IKZF1wt. In the CCLG-ALL 2015 cohort, IKZF1del conferred a lower 5-year OS and EFS and a higher 5-year CIR than IKZF1wt, but the differences were insignificant. The IKZF1del patients treated with higher intensity chemotherapy (CCLG-ALL 2008 high-risk regimen) had a markedly lower 5-year OS and EFS compared with those treated with the MRD-guided protocol (CCCG-ALL 2015 protocol). Furthermore, patients treated with the CCLG-ALL 2008 high-risk regimen experienced a higher frequency of serious adverse events (SAEs), especially infection-related SAEs, compared with those treated with the CCCG-ALL 2015 MRD-guided protocol.ConclusionsThe prognostic effect of IKZF1del may vary in different protocols. Compared with higher intensity chemotherapy, the MRD-guided protocol may be a more effective approach to treating BCP-ALL with IKZF1del in children.

Intensive chemotherapy after hypomethylating agent and venetoclax in adult acute myeloid leukemia

AbstractThe combination of a hypomethylating agent (HMA) and venetoclax (VEN) is approved for adults aged >75 years with newly diagnosed acute myeloid leukemia (AML) as well as those ineligible for intensive chemotherapy (IC). HMA/VEN is increasingly substituted for IC in adults with AML aged <75 years, particularly in those with adverse cytogenetic and molecular features. When patients fail to respond or relapse after HMA/VEN, the utility of salvage IC is largely unknown. We performed a retrospective single-institution study and identified 46 patients who received IC after HMA/VEN, including 24 patients who received HMA/VEN as their first treatment for AML. This population had complete remission (CR)/CR with incomplete count recovery (CRi)/morphologic leukemia-free state rate of 37%, CR/CRi rate of 28%, and a median overall survival (mOS) of 7.2 months (95% confidence interval, 5.0-10.3). Patients who relapsed after an initial response to HMA/VEN and subsequently received IC were more likely to achieve a CR/CRi than those refractory to HMA/VEN (50% vs 19%; P = .04), although there was no statistically significant difference in survival (mOS, 8.8 vs 5.4 months; P = .64). Age >65 years predicted poorer survival (mOS, 4.3 vs 10.6 months; P < .001). IC after HMA/VEN should be further studied and chosen with caution.

Clinical relevance of NFYA splice variants in patients with acute myeloid leukaemia undergoing intensive chemotherapy.

Aberrant alternative splicing (AS) contributes to leukemogenesis, but reports on the clinical and biological implications of aberrant AS in acute myeloid leukaemia (AML) remain limited. Here, we used RNA-seq to analyse AS in AML cells from 341 patients, comparing them to healthy CD34+ haematopoietic stem cells (HSCs). Our findings highlight distinct AS patterns in the nuclear transcription factor Y subunit alpha (NFYA) gene, with two main isoforms: NFYA-L (Long) and NFYA-S (Short), differing in exon 3 inclusion. Patients with lower NFYA-L but higher NFYA-S expression, termed NFYA-S predominance, displayed more favourable characteristics and better outcomes following intensive chemotherapy, regardless of age and European LeukemiaNet risk classification, compared to those with higher NFYA-L but lower NFYA-S expression, termed NFYA-L predominance. The prognostic effects were validated using The Cancer Genome Atlas cohort. Transcriptome analysis revealed upregulated cell cycle genes in NFYA-S predominant cases, resembling those of active HSCs, demonstrating relative chemosensitivity. Conversely, NFYA-L predominant cases, as observed in KMT2A-rearranged leukaemia, were associated with relative chemoresistance. NFYA-S overexpression in OCI-AML3 cells promoted cell proliferation, S-phase entry and increased cytarabine sensitivity, suggesting its clinical and therapeutic relevance in AML. Our study underscores NFYA AS as a potential prognostic biomarker in AML.

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

Characteristics and outcomes of children, adolescent, and young adult patients with myelodysplastic neoplasms: A single-center retrospective analysis

Myelodysplastic syndrome, or myelodysplastic neoplasms, are a rare finding in pediatric, adolescent, and young adult (AYA) patients. More literature is needed to highlight trends of survival or treatment resistance in subpopulations to improve treatment. Here we report a single center retrospective analysis of pediatric and AYA patients from 2000 to 2022 including molecular and cytogenetic data. Using the IPSS-R and IPSS-M, which have been reported exclusively in adults, and excluding patients with bone marrow failure syndromes, we analyzed 119 pediatric and AYA patients with myelodysplastic neoplasms. Therapy-related myelodysplastic neoplasms were present in 36 % of patients, and 31 % of patients developed acute myeloid leukemia. The 5-year overall survival (OS) rate for the entire cohort was 45 %. Contrary to young adults and older adults, mutations were not common in pediatrics. Those who underwent stem cell transplant (SCT)(at any time) had significantly longer median OS. Although SCT at any time improved OS in the de novo myelodysplastic neoplasm group, the choice of the initial treatment with intensive chemotherapy, hypomethylating agents, or SCT did not significantly alter OS. Median OS was shorter in the pediatric group (<18 years old) and longer for those with isolated deletion of 5q or TET2 mutation, but these were not significant findings. Median OS was significantly shorter in those with monosomy 7 or 7q deletion and those with therapy-related myelodysplastic neoplasms. These findings build on previously reported findings and encourage the use of SCT along with molecular and cytogenetic analysis.

Prognostic factors and outcome of relapsed/progressive pediatric Ewing sarcoma: single-center 10-year experience

BackgroundEwing sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Despite more intensive chemotherapy regimens and improved local control therapy, there is still a considerable rate of recurrent/progressive disease.MethodsA retrospective study of 50 relapsed/progressive ES patients who were treated at the National Cancer Institute (NCI), Cairo University, during the period from 1st of January 2008 to the end of December 2018, to assess different prognostic variables and disease outcomes.ResultsOut of fifty eligible cases, 32 patients (64%) had disease recurrence, and 18 (36%) developed disease progression on treatment. The median follow-up period was 7.4 months. The median overall survival (OS) was 7.5 months, and the cumulative OS was 64% at 6 months and 32.6% at 1 year. The cumulative event-free survival (EFS) was 41.3% at 6 months and 22.3% at 1 year. Patients with disease recurrence had better OS and EFS than patients with disease progression (p = 0.019). Patients who underwent local control at relapse/progression had a significantly better outcome than patients who received chemotherapy only (p < 0.001). Recurrence > 2 years from initial diagnosis was the only independent predictor of better survival outcome.ConclusionsPatients with relapsing/progressive ES portended a poor outcome, with disease progression on treatment faring worse than relapse. Better outcome was observed in patients who experienced recurrence > 2 years after diagnosis, patients with disease recurrence rather than disease progression on treatment, and patients who underwent local control along with intensive chemotherapy.

A systematic review of venetoclax for the treatment of unfit AML patients in real-world: is all thatglitters gold?

Acute myeloid leukemia (AML) is an aggressive hematological disease that mainly affects elderly patients. Following the randomized VIALE-A trial, current standard treatment in patients who are not candidates for intensive chemotherapy consists of the combination of venetoclax (VEN), a selective inhibitor of the anti-apoptotic protein BCL-2, with azacitidine (AZA) or decitabine (DEC). We performed a systematic review to critically assess the growing existing evidence regarding the effectiveness of the VEN-based combinations in unfit adult patients with newly diagnosed AML in the real-world setting. Following PRISMA guidelines, a systematic search of published manuscripts and conference abstracts (European Hematology Association and American Society of Hematology) was conducted (updated March 2024). Primary outcomes were composite complete remission (CRc) and median overall survival (mOS). A total of 73 studies fulfilled inclusion criteria, with a median age of 73years old. The weighted mean mOS was 10.3months among 7 138 patients, significantly lower than expected according to the VIALE-A trial (14.7months), while the weighted mean CRc rate was 58.2% among 5 831 patients, slightly lower to that reported in the VIALE-A (66.4%). Early death rates at 30 and 60days were 5% and 13%, respectively. The weighted mean percentage of subsequent allogeneic transplant was 15.4%. In conclusion, breakthrough mOS reported in the VIALE-A trial using VEN-AZA was not well reproduced in real world for unfit newly diagnosed AML patients, while CRc rates were more consistent. Strategies to optimize patient selection, dosing regimens, and supportive care are crucial to improve outcomes in real-world.

Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations

AbstractThe European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population.

Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine

AbstractThe European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine–treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most patients as adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). Although outcomes with venetoclax-azacitidine improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine. The mutational status of TP53, FLT3 internal tandem duplication (FLT3-ITD), NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% confidence interval (CI), 20.2-32.7]; 12.1 months [95% CI, 7.3-15.2]; and 5.5 months [95% CI, 2.8-7.6], respectively). ELN prognostic classifiers did not provide clinically meaningful risk stratification of OS outcomes in patients treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows the classification of these patients into 3 risk groups with distinct differences in median OS. These trials were registered at www.clinicaltrials.gov as #NCT02993523 and #NCT02203773.

Venetoclax-based non-intensive induction followed by allogenic stem-cell transplantation in elderly acute myeloid leukemia patients with adverse cytogenetics.

Elderly acute myeloid leukemia (AML) patients with poor-risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor-risk cytogenetics 60-75 years old patients. We included 60-75-year-old AML patients eligible to allogenic stem cell transplantation (allo-SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019. Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0-103) and 26 days (range, 0-63). The median duration of the first hospitalization was 32 days (ranges, 7-79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo-SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo-SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro-intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06). VEN-based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60-75 with adverse cytogenetics.

Intensive pediatric chemotherapy regimen (PNET HR+5) in adult high-risk medulloblastoma and pinealoblastoma patients

Abstract Background High-risk medulloblastoma (HRMB) is rare in adults. The 5-year overall survival rate is less than 60%. We present here a retrospective analysis of adults treated with an intensive pediatric chemo-radiotherapy regimen PNET HR+5: NCT00936156. Methods 18 patients over the age of 20 (range, 20-33 years) with HRMB (n = 13), pinealoblastoma (n = 4) and central nervous system embryonal tumor (n = 1) were treated with 2 courses of carboplatin-etoposide followed by 2 courses of high-dose thiotepa (HDT) with autologous hematopoietic stem-cell rescue. A craniospinal irradiation (CSI) (36 Gy craniospinal axis then a boost of 18 Gy to the primary tumor site) was then initiated within 150 days of surgery, completed with 6 cycles of temozolomide; the axis irradiation was not mandatory for non-metastatic pinealoblastoma. Results We observed no progression under chemotherapy and no toxic death. Four patients received only 1 HDT. Two non-metastatic pinealoblastoma received only focal irradiation. One medulloblastoma received only 25 Gy on axis. 56% (10/18) received 6 cycles of temozolomide. No long-term toxicity was recorded. Median time between surgery and CSI was 175 days (range, 115-250). With a median follow-up of 6.0 years (range, 2.6-9), the progression-free survival and overall survival rates for medulloblastoma were respectively 65% (95% CI: 31-86%) and 76% (95% CI: 42-91%) at 5 years. Conclusions The PNET HR+5 regimen showed promising results in an adult population, with a meaningful improvement in progression-free survival and overall survival in patients with HRMB.

Cost-effectiveness of treating childhood acute myeloid leukemia at a tertiary care center in North India.

Childhood cancers are a significant global health concern, particularly in low- and middle-income countries (LMICs), where over 80% of childhood cancer patients reside. In India, acute myeloid leukemia (AML) constitutes a significant portion of childhood cancers; however, the data on the cost-effectiveness of childhood AML treatment in India and other LMICs remain limited. The study focused on children (<15years of age) diagnosed with AML at a tertiary care cancer center in North India. Data, including treatment outcome, treatment-related morbidity, mortality, and costs were retrospectively collected from the electronic medical record and hospital database. Cost-effectiveness was assessed using disability-adjusted life years (DALY) averted in relation to the country-specific cost-effectiveness threshold. Among 59 AML patients, treatment-related high mortality rates, abandonment, and limited access to bone marrow transplantation were notable challenges. Intensive chemotherapy resulted in substantial sepsis-related complications, with treatment-related mortality reaching 30%. The 3-year event-free survival and overall survival of the 43 patients who received intensive therapy were 24.5%±7.6% and 27.9%±8.3%, respectively. Despite these challenges, treating childhood AML was still found to be cost-effective. The total cost per newly diagnosed patient treated with curative intent was $4454. Cost per DALY averted accounted for 24% of the gross domestic product (GDP) per capita, rendering the treatment to be cost-effective with a stringent cost-effectiveness threshold utilized. The study underscores the challenges faced while treating childhood AML in LMICs, including treatment-induced high sepsis-related mortality and abandonment. Despite these challenges, it remains cost-effective to treat childhood AML in India. Future efforts should focus on reducing treatment-related morbidity and mortality to further improve outcomes and cost-effectiveness.

Beat-AML 2024 ELN–refined risk stratification for older adults with newly diagnosed AML given lower-intensity therapy

AbstractAlthough the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A “mutation score” was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: −1 to 0 points (“Beat-AML intermediate”) vs 1+ points (“Beat-AML adverse”). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined “Beat-AML favorable-risk” group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making.

The clinical implications of BCOR mutations in a large cohort of acute myeloid leukemia patients: a 5-year single-center retrospective study

To elucidate the effect of BCOR mutation (BCOR mut) on clinical outcomes, we included a total of 899 consecutive AML patients in a single-center during July 2016 to December 2021. Fifty cases (5.6%) had BCOR mutations, which co-occurred with mutations of RUNX1, DNMT3A, IDH2, BCORL1, STAG2, SF3B1 and U2AF1, but were exclusive with KIT and CEBPA mutations. BCOR mut was also found to be exclusive with t(8;21)(q22;q22.1) AML in all patients and MLL rearrangements in the European Leukemia Net (ELN) adverse group. In those receiving intensive chemotherapy regimens, BCOR mut was associated with lower complete remission (CR) rates and worse prognosis. Subgroup analysis showed that BCOR mut mainly conferred a poor prognosis in the intermediate and adverse groups of the ELN2017 risk. These results suggest that BCOR mutation is an independent prognostic parameter in AML, implying BCOR mutation as a novel marker for chemorefractory disease and inferior prognosis.

Mucositis-associated bloodstream infections in adult haematology patients with fever during neutropenia: risk factors and the impact of mucositis severity

PurposeHaematology patients with high-risk neutropenia are prone to mucosal-barrier injury-associated laboratory-confirmed bloodstream infections (MBI-LCBI). We assessed risk factors for MBI-LCBI including candidaemia in neutropenic haematology patients with fever.MethodsThis prospective observational study was performed in six dedicated haematology units in the Netherlands. Eligible haematology patients had neutropenia < 500/mL for ≥ 7 days and had fever. MBI-LCBIs were classified according to Centers for Disease Control (CDC) definitions and were followed until the end of neutropenia > 500/mL or discharge.ResultsWe included 416 patients from December 2014 until August 2019. We observed 63 MBI-LCBIs. Neither clinical mucositis scores nor the blood level of citrulline at fever onset was associated with MBI-LCBI. In the multivariable analysis, MASCC-score (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.05 to 1.29 per point decrease), intensive chemotherapy (OR 3·81, 95% CI 2.10 to 6.90) and Pichia kudriavzevii (formerly Candida krusei) colonisation (OR 5.40, 95% CI 1.75 to 16.7) were retained as risk factors for MBI-LCBI, while quinolone use seemed protective (OR 0.42, 95% CI 0.20 to 0.92). Citrulline level (OR 1.57, 95% CI 1.07 to 2.31 per µmol/L decrease), active chronic obstructive pulmonary disease (OR 15.4, 95% CI 1.61 to 14.7) and colonisation with fluconazole-resistant Candida (OR 8.54, 95% CI 1.51 to 48.4) were associated with candidaemia.ConclusionIn haematology patients with fever during neutropenia, hypocitrullinaemia at fever onset was associated with candidaemia, but not with bacterial MBI-LCBI. Patients with intensive chemotherapy with a low MASCC-score and colonisation with Pichia kudriavzevii had the highest risk of MBI-LCBI.Trial registrationClinicalTrials.gov (NCT02149329) at 19-NOV-2014.

Successful rechallenge with azacytidine and venetoclax after sustained treatment-free remission in a relapsed acute myeloid leukemia patient: a case report.

Combined therapy with venetoclax and hypomethylating agents has significantly improved the outcome of unfit patients ineligible for intensive chemotherapy. A recently published exploratory analysis of the VIALE-A trial reported that up to 51% of patients achieving remission survived more than 2 years. These data along with those from reallife settings, lead to questioning how long it is appropriate to continue treatment in long-term survivors. Accordingly, recent retrospective studies suggested the feasibility of suspending therapy in selected patients while maintaining prolonged responses. Also, these studies showed that retreatment may induce a second remission in almost a third of patients. We report the case of a patient who received salvage therapy with venetoclax and azacytidine, that was discontinued few cycles after blasts clearance because of severe hematological toxicity. Despite suspension, he maintained a sustained response lasting almost one year and was successfully retreated with the same combination when a second relapse occurred.

Inotuzumab ozogamicin in adult acute lymphoblastic leukemia: Development, current status, and future directions.

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low-intensity chemotherapy or other anti-ALL-targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher-risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T-cell therapy, to eliminate measurable residual disease and to prevent post-HSCT relapse. Veno-occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO-related veno-occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use.

Early stoppage of empirical antibiotic therapy at clinical improvement in paediatric leukaemia patients with high-risk febrile neutropenia (ESAT-HR-FN study): Study protocol of a single centre investigator initiated randomised open label non-inferiority trial

Background and rationaleFebrile neutropenia (FN) is one of the major causes of early mortality among children undergoing induction chemotherapy for haematological malignancies. FN occurs in up to 80 % of the children undergoing intensive chemotherapy and FN specific mortality is as high as 10 %. The management of high-risk FN (HR-FN) is by early initiation of broad-spectrum empirical antibiotic therapy (EAT) which is continued till blood count recovery. Adverse effects of prolonged EAT among children without proven infective focus have questioned the rationale behind the duration of EAT. The non inferiority of early stoppage of EAT in patients with low-risk FN (LR-FN) when afebrile for 48 h, irrespective of marrow recovery, is proven among adults and children. However, there is paucity of data regarding the same in children with HR-FN. This study aims to determine whether early discontinuation of EAT in children with HR-FN without proven infective focus who become afebrile and awaiting marrow recovery, would reduce antibiotic duration and their adverse effects without any negative consequences for patients. ObjectiveTo compare the rates of recurrent fever in paediatric patients (2–18 years) with HR-FN when EAT is continued till marrow recovery (control group) versus when stopped early at defervescence irrespective of marrow recovery (study group). MethodologyThis is the study protocol of a phase 3, single centre, randomized, open label, non-inferiority clinical trial. The primary outcome is the rate of fever recurrence among patients with HR-FN, when EAT is stopped early irrespective of marrow recovery (study group) and will be compared to the rate of fever recurrence on continuation of EAT till marrow recovery which is defined as an absolute neutrophil count (ANC) ≥ 500/mm3 (control group). Secondary outcomes include the comparison of duration of antibiotic use, mortality rates, hospital re-admission rates, requirement of multiple broad-spectrum antibiotics, therapeutic anti-fungal usage and need for organ support between the study and the control groups. A total of 280 children with acute leukaemia undergoing EAT for grade 3 or severe FN (ANC <500/μL) without clinico-laboratory evidence of infective foci are being randomized in the ratio of 1:1 between the study and the control group after defervescence for 48 h. The patients will be followed up for primary outcome (fever recurrence) till the end of induction period (day 35) or recovery of ANC ≥500/mm3 whichever is earlier. Expected outcomeESAT-HR FN study is the first large phase 3 randomised study to assess the impact of early stoppage of EAT irrespective of marrow recovery among a homogenous paediatric cohort of HR-FN in the setting of induction chemotherapy for acute leukaemia. This study will be seminal in addressing the duration of EAT in HR-FN among children without infective foci and if proven to be non-inferior this strategy will help to reduce the adverse effects from prolonged antibiotic use, the emergence of drug resistance, decrease hospital stay length and overall health care costs.