Induction Chemotherapy For Acute Myeloid Leukemia Research Articles

Myeloid Sarcoma: Novel Advances Regarding Molecular Pathogenesis, Presentation and Therapeutic Options

Myeloid sarcoma (MS), an extramedullary form of acute myeloid leukemia (AML) is a rare tumor mass of myeloid blasts. It can disseminate to any one or multiple anatomical sites, with (synchronous MS) or without (isolated MS) bone marrow (BM) involvement. The aim of this review is to describe the most recent advances in MS regarding diagnosis, molecular background, various clinical manifestations from several organs, and treatment approaches. Due to the lack of prospective, randomized clinical trials, therapeutic decisions are a challenge for the clinician. In the era of novel targeted AML treatments, a critical analysis of how to decide the best option for individual patients, also covering the possible central nervous system (CNS) prophylaxis is provided. For the majority of the patients, AML induction chemotherapy, followed by hematopoietic stem cell transplantation (HSCT) is generally recommended. This paper discusses the role of radiotherapy, the treatment of refractory and relapsed disease, along with the therapeutic approach of difficult-to-treat patients, due to specific problems related to different anatomical sites of MS.

Impact of Chemotherapy Educational Videos for Patients with Acute Myeloid Leukemia.

Patient education in acute myeloid leukemia (AML) has become increasingly complex with the introduction of new treatments and chemotherapy regimens. Video education presents an opportunity to supplement traditional patient education and address some of the gaps associated with standard methods. This single-center study sought to assess the potential impact of supplemental video education on patients receiving induction chemotherapy for AML. Participants were consented to be randomized to receive their education with or without a supplemental video designed for their treatment regimen. We then provided a survey to each participant to assess knowledge retention, anxiety, and overall satisfaction with their care. Patients that received video education were found to have significantly improved knowledge retention compared to those that did not. There were no differences detected in anxiety or patient satisfaction. Video education appears to be an effective supplemental method for patient education in AML. Limitations include the single-center nature of the study at an urban academic medical center with a relatively well-educated, primarily Caucasian, younger population. Future research is warranted to assess the video in a diverse set of languages and to explore its broader benefits.

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

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

Defective Necroptosis Mediates Chemotherapy Resistance in AML

Acute myeloid leukemia (AML) is a hematopoietic malignancy that can affect individuals of any age and, if left untreated, is always fatal. Standard induction chemotherapy, known as “7+3,” using drugs like cytarabine (Ara-C) and an anthracycline (daunorubicin or idarubicin), is typically given to young and fit older patients. While this treatment regimen has shown positive outcomes in patients who respond to it, relapse and refractory disease remain the primary causes of death. Prognostic classification, which combines cytogenetic and mutational status, can estimate overall and event-free survival but is not effective in predicting induction failure. Despite decades of research and treatment with 7+3 chemotherapy, the reasons behind variable treatment responses in AML patients remain unclear, especially for those who experience induction failure. Understanding these mechanisms could aid in risk-adapted treatment decisions and the identification of new therapeutic targets. Recent research has investigated gene expression and signaling patterns in leukemic cells at the time of diagnosis to categorize patients according to their response to chemotherapy. Notably, increased NF-kB signaling at diagnosis has been linked to chemotherapy resistance. NF-kB is a family of transcription factors involved in regulating genes linked to cancer cell survival, proliferation, and therapy resistance. However, the exact mechanism by which NF-kB activation contributes to chemotherapy failure and resistance in AML is yet to be determined. Using publicly available datasets, we found that AML patients undergoing induction failure exhibited elevated expression of TNFAIP3/A20, which is driven by NF-kB signaling and leads to a worse prognosis for patients undergoing 7+3 chemotherapy. In experiments with primary AML samples, it was observed that A20-High AML are resistant to Doxorubicin treatment, whereas A20-Low AML samples are sensitive to Doxorubicin. Knockdown of A20 in A20-High AML samples resulted in increased cell sensitivity to Doxorubicin, suggesting that elevated A20 expression reduces AML cells' response to the Doxorubicin both in vitro and in vivo. To understand why A20 is overexpressed in AML, we investigated its requirement on AML cell function in various models, including human AML cell lines, patient-derived samples, and mouse models of AML. Deletion or knockdown of A20 led to reduced leukemic progenitor function, cell viability, and AML development in vitro and in vivo. A20 is a dual ubiquitin-editing protein that regulates signaling pathways by acting either as a deubiquitinase to modulate NF-kB signaling or as an E3 ligase to control necroptosis. Further analyses revealed that A20 prevents necroptosis by targeting the necroptosis effector, RIPK1, for degradation through the proteasome in AML. Preventing necroptosis, either pharmacologically or genetically, restored the viability and clonogenicity of A20-deficient AML cells in vitro and in vivo. Notably, Doxorubicin, but not AraC, induced necroptosis in AML cells, which is suppressed in leukemic clones expressing A20. Examination of single-cell RNA-sequencing data from AML patients before and after Doxorubicin treatment confirmed the persistence of A20-expressing clones during treatment. These findings demonstrate that NF-kB-driven overexpression of A20 contributes to failed induction chemotherapy in AML, highlighting the therapeutic potential of targeting an alternative cell death pathway in AML.

Idarubicin Versus Daunorubicin Versus Mitoxantrone for Induction Chemotherapy in Acute Myeloid Leukemia: Patient Registration Study of Turkish Society of Hematology-Acute Myeloid Leukemia Working Group

Introduction: Standard induction chemotherapy in newly diagnosed acute myeloid leukemia (AML) includes a combination of standard-dose cytarabine and an anthracycline (idarubicin [IDA], daunorubicin [DNR], or mitoxantrone [MXR]). Anthracycline selection is still not standardized, and the impact of anthracycline selection on survival and response in patients with adverse genetic risk is of interest. The study aimed to retrospectively compare the effectiveness of induction regimens with respect to anthracycline preference. Methods: The study population was recruited from the Turkish AML Registry project database based on documentation of newly diagnosed AML and induction chemotherapy with IDA, DAU, or MXR in combination with cytarabine. Patients diagnosed before 31 August 2022 were received typical “7 + 3” induction chemotherapy containing 3 days of IDA, DAU, or MXR. Results: The study included 317 newly diagnosed AML patients (median age 51; range, 18 - 79; 55.2% male). Of the patients, IDA was administered in 266 (83.9%), DNR in 42 (13.2%), and MXR in 9 (2.8%). The three anthracycline treatment groups were similar between age, gender, type of AML by the World Health Organization (WHO), and risk classification by 2017 European LeukemiaNet (ELN) when evaluated according to the baseline disease characteristics. At the time of diagnosis, although the median white blood cell levels were 19 x 10 9/L (0.4 - 355) in the IDA, 7.8 x 10 9/L (0.7 - 357.2) in the DAU, and 5.5 x 10 9/L (0.6 - 34) in the MXR therapy group (p = 0.019); the hemoglobin and platelet levels and bone marrow blast percentage were similar between the treatment groups. FMS-like tyrosine kinase-3 internal tandem duplication ( FLT3-ITD) (p = 0.561) and Nucleophosmin 1 gene ( NPM1) (p = 0.430) mutation frequencies were also similar between treatment groups. Morphological complete remission (CR) was documented in 65% of all evaluable patients. Among the patient groups, CR was 67.7% for IDA, 50% for DNR, and 55.6% for MXR (p = 0.081). In univariate analysis (Table 1), significant predictors of overall survival (OS) were age ≥60 years (p <0.001), acute leukemias of ambiguous lineage (p <0.001), presence of disseminated intravascular coagulation (DIC) (p = 0.012), and FLT3-ITD mutation (p = 0.018); no significant interaction was noted between NPM1 mutation and OS (p = 0.059). Additionally, when idarubicin was taken as a reference, there was no meaningful relationship between anthracycline type and OS (p values for daunorubicin and mitoxantrone were 0.145 and 0.356, respectively). In multivariate analysis (Table 1), age ≥60 years (p = 0.001), acute leukemias of ambiguous lineage (p = 0.007), and the presence of DIC (p = 0.040) remained significant. After a median follow-up of 29.8 months, 32.5% relapse cases were documented and similarly distributed among IDA (33.1%), DNR (31%), and MXR (22.2%) therapy groups (p = 0.771). During the same period, allogeneic hematopoietic stem cell transplantation (AHSCT) was documented in 10.9% and 26.2% of patients treated for IDA and DNR, respectively. No patient progressed to AHSCT in the MXR arm (p <0.001). In the study, 142 (44.8%) deaths were reported, and there was a 48.5%, 26.2%, and 22.2% mortality rate between the IDA, DNR, and MXR treatment groups, respectively. There was no significant difference in OS by anthracycline type in both the study cohort and age group <60 years (Figures 1A and 1B). There was also no significant difference in OS in patients with the adverse genetic risk group and <60 years age group with adverse genetic risk, according to 2017ELN (Figures 1C and 1D). The results may have been influenced by the number of patients in the treatment groups of the retrospective study and by differences in fitness levels that needed to be measured systematically. Conclusions: We are encouraged that our findings mostly agree with previously published studies and that IDA, DNR, and MXR offer comparable survival values in the research and the younger patient groups. In the future, the ever-changing treatment environment in patient groups with targetable mutations makes choosing the optimal anthracycline for induction chemotherapy in AML much more difficult.

First-in-human trial of tocilizumab in combination with a standard induction chemotherapy in newly diagnosed acute myeloid leukemia patients: The phase 1 TOCILAM study.

7028 Background: Numerous studies have pointed out the pathological role of deregulated expression of Interleukin-6 (IL-6) in cancers. In acute myeloid leukemia (AML), IL-6 promotes chemo-resistance and correlates with poor prognosis. One explanation is that AML cells express IL-6 receptor (R) and self-produce IL-6 at once, favouring blast proliferation and survival. Therefore, IL-6 blockade may represent a new promising therapeutic strategy for AML. Here, we have tested Tocilizumab (Toci), an anti-IL-6R antibody, in combination with a standard AML induction chemotherapy. Methods: This was a monocentric Phase 1 study testing three escalating doses of Toci (4, 6 and 8 mg/kg) administered at day (d) 8 of a standard AML induction chemotherapy (Idarubicine 8 mg/m² d1 to d5 + cytarabine 100 mg/m² d1 to d7). All adults ( > = 18 yo) with a newly diagnosed (excluding patients (pts) with a favorable risk according to ELN-2017 classification if < 60 yo) or a relapsed/refractory AML were eligible. The main objective was to determine the maximum tolerated dose of Toci for further phase 2/3 studies. Patients had to be included 2 by 2, according to a continual reassessment method while targeting a related-experimental drug toxicity level < 30%. A maximum of 12 pts had to be included. Toxicity was evaluated using NCI version5 criteria. Responses were evaluated according to ELN-2017 criteria between d30/d45 of induction. Also, IL-6 and Toci plasma levels were assessed. All pts gave informed consent and the trial was registered at Clinical trials under NCT04547062. Results: Between Dec/2020 and Dec/2022, 12 pts were treated, including 2 pts at 4 mg/Kg, 2 at 6 mg/kg and 8 at 8 mg/kg of Toci. The median age was 66 yo (range: 56-73), all pts had a newly diagnosed AML, ELN risk was intermediate: 25%; unfavorable: 75%. No dose limiting toxicity related to Toci was documented. Two pts died during induction, 1 of infection and 1 of cerebral haemorrhage. Complete remission (CR) rate for evaluable pts was 90% (n = 9/10). After induction, 7 received a consolidation and 7 were allo-transplanted. With a median follow-up of 600d, 4 patients have relapsed and 7 have died, 1-y OS and LFS were estimated at 43% (21-88%) and 39% (19-82%), respectively. Dosages of IL-6 (pg/mL) showed a significant increase after Toci injection (median 23,2 (2.6-53.5) vs 202,9 (21.1-6189.2) after 8d and 481,5 (53.8-7327.4) after 15d), suggesting a good saturation of the targets (IL6-R) on AML cells and a potential anti-leukemic effect. Median dosages of Toci (µg/ml) were higher 8d and 15d after injection at L2 (34.8; 17.2) and L3 (38.5; 12.9) compared to L 1 (10.9; 1.4). Conclusions: The combination of Toci to a standard AML intensive induction appears to be very safe providing both high CR rate and the expected biological effect. We now recommend a dose of 8 mg/kg of Toci given at d8 of induction for further phase 2/3 studies. Clinical trial information: NCT04547062 .

Impact of rhG-CSF on Clinical Efficacy and Immune Cell Subsets after Initial Induction Chemotherapy in AML.

The impact of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in acute myeloid leukemia (AML) is still controversial. The purpose of this study is to explore the impact of rhG-CSF administration on clinical efficacy and immune cell subsets after initial induction chemotherapy in AML. The clinical efficacy and immune cell subsets were compared in the newly diagnosed patients with AML according to whether rhG-CSF was used after initial induction chemotherapy. Next, rhG-CSF stimulation experi-ments on leukemia cell lines and primary leukemia blasts were performed in vitro. There was no statistical difference between control group and rhG-CSF therapy group in complete remission rate and relapse free survival. The duration of agranulocytosis was significantly shortened in rhG-CSF therapy group compared with control group. The percentage of circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) were significantly increased after the administration of rhG-CSF. Furthermore, it was found that rhG-CSF did not promote the proliferation of leukemia cell lines and primary leukemia blasts, but increased the proportion of M-MDSCs and Tregs in vitro. Administration of rhG-CSF after initial induction therapy of AML does not affect the clinical remission and relapse rate, but reduces the duration of agranulocytosis and increases the proportion of M-MDSCs and Tregs.

Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Introduction: Outcome in acute myeloid leukemia (AML) for patients aged >60 years is poor with a median survival of approximately 11 months. Targeting the proteasome in AML is attractive, since leukemia stem cells demonstrate sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB or MCL-1 through stabilizing effects on NOXA. AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the recommended phase II dose (RP2D) of ixazomib in combination with intensive induction and consolidation chemotherapy for AML. A secondary objective was to determine if the level of CD74 in blasts correlated with response, since prior studies showed that CD74 may be a poor prognostic indicator, but its effect might be diminished with proteasome inhibition. Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent (HMA) therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidation or transplant in this phase was at the discretion of the treating physician. In the second phase (B), induction was administered with the established RP2D of ixazomib in phase A. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A classical 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). Secondary objectives included rate of complete remission (CR), disease-free survival (DFS), overall survival (OS), and outcome relationship with CD74. Results: Thirty-nine patients were enrolled, including 15 (38%) patients with secondary AML, either with antecedent myeloid malignancy or therapy-related AML. Twenty-six patients (67%) were male, and the median age was 68 years (range 61-80 years). There were no grade 5 toxicities attributed to study drug. Four patients died before day 30 with persistent leukemia, 3 of whom were replaced for assessment of the MTD. Three other patients were not evaluable and were replaced. Nearly all grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There were no grade 3 or 4 neurotoxicity events attributable to ixazomib. Among the 38 patients evaluable for response, 26 achieved CR, and 2 achieved CR with incomplete count recovery (CRi), for a composite remission rate (CCR) of 74%. Among the 15 patients with secondary AML, 9 achieved CR and 2 achieved CRi, for a CCR of 73%. The median OS for the 39 patients is 40.8 months [95% CI, 17.6, Inf]. The 18-month OS estimate was 63% [95% CI, 49-80%]. Of note, 30 patients underwent stem cell transplantation. There was no significant association between level of CD74 expression on blasts at baseline and response. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction and consolidation in this trial has been reached safely and is the recommended phase 2 dose for both. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate for this regimen in this older adult population appears favorable. With ixazomib added in treatment, we saw no association of response rate with level of CD74 in blasts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Measures of Structural Racism Predict ICU Admission Following Intensive Chemotherapy for AML

INTRODUCTION: Recent observational studies have revealed that real-world complications of intensive chemotherapy for frontline treatment of acute myeloid leukemia (AML) far exceed those reported in clinical trials. A 2017 analysis of over 40,000 AML patients found that 26% of patients who received induction chemotherapy were admitted to the intensive care unit (ICU), with increased mortality for non-white patients (Halpern, JAMA Oncology 2016). In a newly created Chicago AML registry (Abraham, Blood 2022), higher ICU admission rate was noted following induction chemotherapy for non-white patients. The current study aims to i) describe treatment complications based on race/ethnicity and ii) examine structural racism (SR) measures as risk factors for ICU admission following intensive chemotherapy in a diverse real-world patient population. METHODS: Using the Chicago AML registry, we compared ethnoracial differences in treatment complications including infections, thrombosis, renal or liver dysfunction (defined as peak creatinine >1.5 g/dL or peak bilirubin >1.2 mg/dL), respiratory failure requiring ventilatory support and hemodynamic instability needing pressor support. We then examined associations of race/ethnicity and previously published measures of census tract disadvantage, affluence, and segregation (referred to as SR measures) with ICU admission. These structural barriers were examined alongside known predictors of treatment mortality including disease characteristics and comorbidities. Additional outcomes included duration of ICU stay and mortality. RESULTS: In this cohort of 573 patients who underwent intensive induction chemotherapy for AML, 30-day complications differed based on race/ethnicity. Renal dysfunction was highest in non-Hispanic black (NHB) patients with an incidence of 27.8% with 6% initiating dialysis compared to 17.6% of non-Hispanic white (NHW) and 11.3% of Hispanic patients with 2% needing dialysis. Hepatotoxicity was highest in Hispanic patients (64%) vs. NHB (51%) and NHW (47%). Infectious complications were highest in NHB with microbiologically documented infections in 50.6% compared to 39.7% in NHW and 32.6% in Hispanic. Venous thrombosis occurred in 14.5% of NHB patients, compared to 14.7% of NHW and 13.3% Hispanic patients. In total, 141 (24.6%) patients required ICU admission during intensive induction with rates differing significantly by race and ethnicity (p = 0.014). Average length of stay in the ICU was 7.8 days for NHB patients, 6.7 days for NHW and 6.0 days for Hispanics. Due to low 30-day mortality, we were unable to detect differences between ethnoracial groups. Mechanical ventilation was utilized in 32% of NHB compared to 26% of NHW and 20% of Hispanic patients admitted to the ICU. Vasopressor were required in 31% of NHB patients vs. 27% of NHW patients. Predictors of ICU admission in our dataset included non-white race, unmarried status, living in a neighborhood with lower % of NHW residents, and WBC > 50,000/µL at diagnosis. Additional census tract variables including higher disadvantage and lower affluence conferred nonsignificant risk. Interestingly, comorbidities, ELN Score and baseline creatinine > 1.5 g/dL were not predictors of ICU admission. CONCLUSIONS: In a real-world population of AML patients, we show variation in the spectrum of treatment complications based on race/ethnicity. Moreover, with detailed individual and neighborhood socioeconomic position (SEP) data, measures of SR predicted ICU admission following induction chemotherapy. Other significant predictors include marital status - an individual measure of SEP, and hyperleukocytosis, which may indicate delay in medical presentation. High comorbidity index did not predict increased rate of ICU admission similar to prior studies (Tawfik, J Geriatr Oncol, 2016), while renal dysfunction was a non-significant predictor. Collectively our results suggest that there is a need to incorporate individual and neighborhood SR measures to identify patients at risk of clinical decline when stressed with intensive therapies. An algorithmic approach to identify 'high risk’ patients based on clinical/molecular and structural factors could prompt more detailed assessment of fitness prior to initiation of chemotherapy and directly influence leukemia outcome disparities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Outcomes in Acute Myeloid Leukemia Patients Receiving 7+3 Induction By Using Protocolized Antifungal Prophylaxis in a Community Setting

Introduction: Invasive fungal infections (IFI) are a leading cause of mortality in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy including "7+3” regimen of cytarabine and daunorubicin.1 Posaconazole improves survival and reduces IFI rates in comparison with fluconazole.2 The aim of our study was to compare outcomes of patients receiving induction chemotherapy for AML at our institution before and after implementation of a priority matrix (PM) including standardized antifungal prophylaxis. Our primary endpoint was incidence of IFI, and our secondary endpoints were mortality at 30 days and 1 year. Methods: All patients admitted with AML and receiving 7+3 induction chemotherapy at Gundersen Health System between January 2013 and January 2022 were included in our study. Patients were assigned either to Pre-PM or Post-PM group (whether induction was started before or after January 1, 2019, respectively). The priority matrix (Figure) included mandatory treatment with appropriate prophylaxis (posaconazole /voriconazole), patient education, electronic health record (EHR) updates, standardized work up for refractory fevers, and other optimization practices. Antifungal agent was given starting on day 8 after initiation of induction until resolution of neutropenia, defined as an absolute neutrophil count >500/uL. Treatment-related mortality rates (TRMR) and Charlson Comorbidity Index (CCI) were calculated at time of diagnosis. Statistical analyses using chi-square, Fisher exact, Wilcoxon rank sum tests, and Cox proportional hazards were done in SAS version 9.4. Results: The study population consisted of 37 patients: 23 in the Pre-PM group (prior to Jan 1, 2019) and 14 in the Post-PM group. The population was predominantly white, non-Hispanic with a median age 63 years, and was 60% male. Groups were similar with regard to median age, sex, TRMR, and CCI. Of the 23 Pre-PM patients, 6 received fluconazole. All patients in the Post-PM group received prophylaxis-1 with voriconazole, and 13 with posaconazole. Six Pre-PM patients (26%) developed IFI, compared with 1 Post-PM patient (7%; p=0.22). Five of the 6 Pre-PM patients who received fluconazole developed IFI, as did 1 Post-PM patient who received posaconazole (p<0.001). Four (17%) Pre-PM patients, none of whom received fluconazole died within 30 days, and there were no deaths in the Post-PM group (p=NS). Fifteen (65%) Pre-PM patients died within 1 year (5 had received fluconazole prophylaxis), compared with 3 (21%) Post-PM patients. Mortality rates were not significantly different between groups at 30 days (p=0.22)); however, mortality at 1 year was significantly higher in the Pre-PM group (log rank p=0.004), including in those receiving fluconazole (log rank p=0.0005). Conclusions: Our study shows significantly improved outcomes with use of a standardized protocol in AML patients receiving 7+3 induction by using posaconazole over fluconazole per our PM intervention. We reduced IFI rates to our goal of <10% in AML patients and improved 30-day and 1 -year survival at our institution, rates comparable to national averages. Because community health care facilities are increasingly treating patients with AML, we share our protocol to help improve care in this setting. References 1Hsu A. et al. Supportive Care in Cancer, . 2021;29(2):707-712. 2Cornely OA, et al. N Engl J Med. 2007;356:348-359 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adjunction of a fish oil emulsion to cytarabine and daunorubicin induction chemotherapy in high-risk AML

The treatment of acute myeloid leukemia (AML) with unfavorable cytogenetics treatment remains a challenge. We previously established that ex vivo exposure of AML blasts to eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or fish oil emulsion (FO) induces Nrf2 pathway activation, metabolic switch, and cell death. The FILO group launched a pilot clinical study to evaluate the feasibility, safety, and efficacy of the adjunction of a commercial FO emulsion to 3 + 7 in untreated AML with unfavorable cytogenetics. The primary objective was complete response (CR). Thirty patients were included. FO administration raised the plasma levels of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids (p < 0.001). The pharmacokinetics of cytarabine and daunorubicin were unaffected. A historical comparison to the LAM2001 trial (Lioure et al. Blood 2012) found a higher frequency of grade 3 serious adverse events, with no drug-related unexpected toxicity. The CR rate was 77%, and the partial response (PR) 10%, not significantly superior to that of the previous study (CR 72%, PR 1%). RT-qPCR analysis of Nrf2 target genes and antioxidant enzymes did not show a significant in vivo response. Overall, FO emulsion adjunction to 3 + 7 is feasible. An improvement in CR was not shown in this cohort of high-risk patients. The present data does not support the use of FO in adjunction with 3 + 7 in high-risk AML patients.ClinicalTrials.gov identifier: NCT01999413.

Molecular and clinical predictors of venous thromboembolism in acute myeloid leukemia and myelodysplastic syndrome.

e19008 Background: Malignancy is a well-described risk factor for venous thromboembolism (VTE). Although widely recognized and studied in solid tumors, VTE is also an appreciable cause of morbidity in patients with hematologic malignancies. Many validated scoring systems exist to predict risk of VTE based on cancer type and other clinical characteristics. However, hematologic malignancies are poorly represented in these models. The purpose of this study was to determine risk factors for the development of VTE in a large cohort of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with the goal of creating a risk stratification model to predict VTE risk in this patient population. Methods: Patients presenting to the University of Wisconsin-Madison with newly-diagnosed AML or MDS from 1/1/2010 through 12/31/2021 were included. Data were collected retrospectively, including patient demographics, clinical characteristics, molecular data, treatment, and complications. Univariate and multivariable logistic and log-binomial regression was used to assess whether variables of interest had any association with VTE. Poisson regression was used to estimate the mortality rate. Results: 547 patients were included in the analysis, including 304 patients with AML and 243 patients with MDS. The overall prevalence of VTE was 14% (95% CI 11.4-17.2%). Those with AML were more likely to experience VTE compared to those with MDS (19.1% vs. 7.8%, RR = 2.4, 95% CI 1.5-4.1, p &lt; 0.001). Higher body mass index (BMI, p = 0.022), induction chemotherapy (p = 0.001), and younger age (p = 0.001) were also associated with development of VTE. Within a subgroup of patients with molecular data available (154 patients), 18.2% experienced VTE. Harboring a mutation in a chromatin modification gene ( ASXL1/2, EED, EZH2, KMT2A) was associated with an 87% reduction in the risk of developing VTE (RR = 0.13, 95% CI 0.01-0.58, p = 0.002). When adjusted for diagnosis and age, the mortality rate for those who experienced VTE was only half the rate of those who never experienced VTE (95% CI 35-69%, p &lt; 0.001). Conclusions: At our institution, the total incidence of VTE was higher than previously described, which underscores the importance of elucidating risk factors of VTE in order to prevent this complication. AML diagnosis, elevated BMI, younger age, and induction chemotherapy were associated with increased risk of VTE, while mutations in chromatin modification genes were associated with a reduction in risk. Surprisingly, the development of VTE was associated with decreased mortality, perhaps reflecting the association of curative-type chemotherapy regimens with VTE in this cohort. In summary, this study demonstrates interesting associations that can ultimately be used to create a risk prediction model of VTE in myeloid malignancies in order to provide optimal supportive care for this patient population.

Induction mortality (IM) of acute myeloid leukemia (AML) patients treated with purine analogues-cytarabine-anthracycline at a general hospital.

e19019 Background: Cytarabine-anthracyclines (7+3) induction chemotherapy (IC)) has been the mainstay therapy for over four decades and it remains the standard AML IC regimen internationally. Triplet IC using purine analogues (fludarabine/cladribine) in combination with cytarabine and idarubicin (FIA/CLIA) is superior to the standard 7+3 regimen, but challenging to administer in general hospital settings due to myelosuppression. We reviewed AML IM rate in patients induced with (fludarabine/cladribine) combined with cytarabine and idarubicin (FIA/CLIA) at Memorial Hermann Hospital, Texas Medical Center (MHH at TMC). Patients and Methods: Of 44 AML reviewed records from January 2013 to January 2022, 40 received 5 days FIA/CLIA IC, and four 3-4 days due to age and comorbidities. For clinical characteristics see Table. Results: Median age was 51.5 years (range: 18-68). Three died before assessment. After 1 cycle the composite CR (CR+ CR i) was 82.9% (34/41) and 87.8% (36/41) after 2 cycles. MRD negative composite CR was 92%. Four patients had adverse risk cytogenetics and primary induction failure (modified FIA). 37% had febrile neutropenia. 25% had bacteremia with 15% requiring ICU admission and 4% mechanical ventilation. The 30-day induction mortality was 9%. Conclusions: FIA/CLIA has a higher CR rate than ‘3+7’ (which historically is 60%). The 30-day induction mortality in non-academic centers is about 30%. Given the fact that in AML achieving a CR is the most important factor to improve survival, with adequate treatment expertise, triplet IC regimen can be safely administered with a low induction mortality. [Table: see text]

Clinical Characteristics and Contemporary Outcomes of Acute Myeloid Leukemia Evolving from Chronic Myelomonocytic Leukemia

Clinical Characteristics and Contemporary Outcomes of Acute Myeloid Leukemia Evolving from Chronic Myelomonocytic Leukemia

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow.

Despite the great success of immune-checkpoint inhibitor (ICI) treatment for multiple cancers, evidence for the clinical use of ICIs in acute myeloid leukemia (AML) remains inadequate. Further exploration of the causes of immune evasion in the bone marrow (BM) environment, the primary leukemia site, and peripheral blood (PB) and understanding how T cells are affected by AML induction chemotherapy or the influence of age may help to select patients who may benefit from ICI treatment. In this study, we comprehensively compared the distribution of PD-1 and TIGIT, two of the most well-studied IC proteins, in PB and BM T cells from AML patients at the stages of initial diagnosis, complete remission (CR), and relapse-refractory (R/R) disease after chemotherapy. Our results show that PD-1 was generally expressed higher in PB and BM T cells from de novo (DN) and R/R patients, while it was partially recovered in CR patients. The expression of TIGIT was increased in the BM of CD8+ T cells from DN and R/R patients, but it did not recover with CR. In addition, according to age correlation analysis, we found that elderly AML patients possess an even higher percentage of PD-1 and TIGIT single-positive CD8+ T cells in PB and BM, which indicate greater impairment of T cell function in elderly patients. In addition, we found that both DN and R/R patients accumulate a higher frequency of PD-1+ and TIGIT+ CD8+ T cells in BM than in corresponding PB, indicating that a more immunosuppressive microenvironment in leukemia BM may promote disease progression. Collectively, our study may help guide the combined use of anti-PD-1 and anti-TIGIT antibodies for treating elderly AML patients and pave the way for the exploration of strategies for reviving the immunosuppressive BM microenvironment to improve the survival of AML patients.

A Strategy of Day 14 Bone Marrows and Early Intervention Is Associated with Similar Outcomes Compared to a Strategy of No Day 14 Bone Marrows and Delayed Intervention in Patients with Acute Myeloid Leukemia

INTRODUCTION: Although early clearance of leukemic blasts following induction chemotherapy for acute myeloid leukemia (AML) has been associated with improvement in outcomes (Kern et al. 2003), it remains unclear if a strategy of day 14 marrows with early intervention for residual leukemia (Day14 strategy) is superior to a strategy of no day14 marrows with delayed chemotherapy (noDay14 strategy). To compare these strategies we conducted a single centre retrospective analysis of patients receiving standard ‘3+7‘ induction chemotherapy for AML (APL excluded) treated from 2004-2017. Prior to 2014 all patients were treated with a Day14 strategy, but due to a change in institutional policy all patients thereafter were treated using a noDay14 strategy. Outcomes were assessed using an intention-to-treat approach.RESULTS: Patient characteristics are as in Table 1. Gender, age, WBC and cytogenetic risk category were similar between the Day14 and noDay14 cohorts, but there were more patients with age >60 and secondary AML in the noDay14 cohort. NPM1 and FLT-3 testing were not routinely available prior to 2008.Of patients intended to have a day 14 marrow, 229 (91%) underwent a marrow at a median of 14 days (9-22) with others not receiving one due to induction complications (n=16), death (n=4) or other reasons (n=3). Of these, 59 (25.8%) had residual leukemia (i.e. >5% blasts) and 51 received chemotherapy. Response was not evaluated for 2 patients, there were 3 deaths, 19 had persistent disease and 27 had complete remission (CR) or CR with incomplete count recovery (CRi).An end-of-induction (EOI) marrow (after single induction in the noDay14 cohort and single induction ± intensification in the Day14 cohort) was performed in 331 (91%) patients. Median time to a marrow was longer in the Day14 cohort (p=0.001). At EOI there was no difference within the Day14 and noDay14 cohorts in mortality (8.3 vs. 3.6%, p=0.12), CR/CRi rates (75.4 vs. 83%, p=0.13) or induction failure (14.3 vs. 13.4%, p=0.87). Majority of the patients with induction failure went on to receive reinduction chemotherapy. After all reinductions; mortality and rates of CR/CRi and persistent leukemia were similar between the two cohorts.There was no difference in the allogeneic stem cell transplantation rates for the Day14 and noDay14 cohorts (39.8 vs. 41.2%, p=0.90). Median follow-up for the entire cohort was 509 days. Amongst non-transplanted patients, relapse rates were similar in the Day14 and noDay14 cohorts (62.1 vs. 51.7%, p=0.2) as was relapse free survival (RFS, 378 vs. 381 days, p=0.47). When censored for transplant patients in the Day14 and noDay14 cohorts had similar rates of relapse (37.4 vs. 30.4%, p=0.26) and RFS (443 vs. 395 days, p=0.45, Fig. 1A). RFS was also not different for the two cohorts amongst patients aged>60 (p=0.90), aged <60 (p=0.40) or favourable (p=0.17), intermediate (p=0.69) or unfavourable risk karyotype (p=0.87).The 5 year overall survival (OS) of the entire cohort was 43% and median OS was 856 days with no difference in the Day14 and noDay14 cohorts (758 days vs. not reached, p=0.11, Fig. 1B). There was no difference in the OS amongst the two cohorts when stratified by the diagnostic karyotype (favorable, p=0.24, intermediate, p=0.34 and unfavorable, p=0.50). For patients aged >60, OS was similar in the Day14 and noDay14 cohorts (413 vs. 569 days, p=0.47) but amongst patients aged <60 there was a trend toward better OS with treatment under a noDay14 strategy (median not reached vs. 1215 days, p=0.055). In subgroup analysis, patients treated under the Day14 strategy having residual leukemia at Day14 had worse OS relative to those without leukemia (328 vs. 1507 days, p<0.001).To minimize the impact of changes in care occurring over the duration of the study we evaluated patients treated from 2010 - 2017 during which supportive care and anti-fungal prophylaxis was similar. Overall results were similar to when the entire cohort was considered; however, patients treated using a Day14 strategy had a significantly higher mortality than those treated using a noDay14 strategy at EOI (11.1 vs. 3.6%, p=0.047).CONCLUSIONS: Although patients with residual leukemia at day 14 have worse OS, our data suggest that there is no advantage to performing routine day 14 marrows supplemented by early intensification treatment. Additionally, this approach may be associated with a higher early mortality and, amongst patients aged<60 years old, with worse OS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outpatient Intensive Induction Chemotherapy for Acute Myeloid Leukemia and Advanced Myelodysplastic Syndrome

Introduction:To improve patients' quality of life and reduce healthcare costs many conditions formerly thought to require inpatient care are now treated in an outpatient setting. With respect to the treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we believe that outpatient induction chemotherapy may confer similar benefits, but, thus far, there has been a paucity of studies exploring the safety and feasibility of this option. The feasibility of outpatient consolidation has been established (Saini L et al Am J Hematol 2012), and we have shown that early discharge after completion of induction does not increase treatment related mortality provided patients are doing well at discharge, live near the treatment center, and have support at home (Vaughn JE et al JAMA Oncol 2015). Here we extend our findings by examining whether intensive inductionchemotherapy for AML and MDS can be safely administered exclusively in an outpatient setting.Methods:We conducted a pilot feasibility study. Eligible patients were ≥ age 18, met inclusion criteria for inpatient induction regimens, were without active infection, and had the following: normal chest x-ray, adequate cardiac function, expected death rate of < 5-10% within 28 days of beginning intensive therapy (Walter RB et al J Clin Oncol 2011), peripheral blast count <10 X 10^9/L, and fibrinogen level >100 mg/dL. Logistical requirements included residence near the treatment center, caregiver support, trained nursing staff, infusion room capacity, and participation in follow-up. Patients received prophylactic antimicrobials such as oral levofloxacin, fluconazole and acyclovir and were admitted to the hospital for predetermined complications of therapy (e.g. temperature > 101F, significant bleeding, severe organ toxicity). Criteria for feasibility for future study were: >50% of patients completed chemotherapy without requiring admission and <5% of treated patients died within 14 days of starting induction.Results:Eighteen patients were consented and 15 patients were treated with a median age 52 (range 19-72) and median TRM score 1.1711 (mean 2.5718, range 0-8.001): 7 received initial induction chemotherapy and 8 received salvage induction chemotherapy. Of those not treated, 2 were limited by scheduling constraints and 1 was found to have bilateral paraspinous extramedullary disease prompting admission. All regimens contained cytarabine at 1.5-2g/m2 per dose. 12 patients completed induction chemotherapy in the outpatient setting (80%; exact 95% CI 51-95%) while 3 patients required inpatient admission: 2 for neutropenic fever and 1 for grade 3 mucositis. All 3 of these patients completed chemotherapy as inpatients without complication. No patients died within 14 days of the initiation of induction chemotherapy (exact 95% CI 0-25%). The logistical issues that arose were largely related to scheduling multiple infusions, hydration, and transfusions at our outpatient infusion center. In addition to chemotherapy, 7 patients received RBC transfusions, 5 patients received platelet transfusions, and 2 patients received IV antibiotics. Significant systems changes had to be implemented to facilitate close clinical follow up and to ensure that the AML patients received education for care of central venous lines, effects of chemotherapy including risk of infection and bleeding, and medication management. Psychosocial support was also essential for the patients and families coping with AML.Conclusions:Our pilot study suggests it is feasible to complete outpatient induction chemotherapy in select AML and high-risk MDS patients. An inter-professional team approach including nurses, social workers, medical providers and pharmacists was key to the successful implementation of outpatient induction. We plan to formally compare resource utilization, quality of life measures, and charges for outpatient vs. inpatient induction therapy. DisclosuresScott:Agios Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Acceleron: Other: Data and Safety Monitoring Board; Incyte: Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Percival:FLXbio: Research Funding. Walter:Celator/Jazz Pharmaceuticals, Inc.: Research Funding. Becker:GlycoMimetics, Inc.: Research Funding.

CD33-Single Nucleotide Polymorphism (CD33-SNP) Score Predicts Gemtuzumab Ozogamicin Response in Childhood Acute Myeloid Leukemia: Report from Children's Oncology Group AAML0531 Trial

Introduction: Gemtuzumab ozogamicin (GO) has re-emerged as a potential agent with promise in acute myeloid leukemia (AML) treatment. GO received accelerated approval in 2000 for treatment of relapsed AML in older patients but was withdrawn from the market due to lack of benefit and increased early mortality in SWOG S0106 trial. Several studies thereafter demonstrated GO improved clinical outcomes with pronounced effects in patients with favorable-risk cytogenetics. In light of new results from several randomized trials, an FDA advisory panel recently determined that GO has a favorable risk/benefit profile as an adjunctive therapy for certain newly-diagnosed AML patients. We recently reported that CD33 splicing polymorphism rs12459419 C>T regulates production of alternatively spliced CD33 isoform lacking exon 2 and hence the IgV domain for CD33(Lamba et al, 2017). Consistent with this, we demonstrated that rs12459419 was significant predictor of cell surface CD33 intensities as well as clinical response in the randomized COG-AAML0531 trial. We now expand our investigation to other potentially significant CD33 SNPs for impact on GO efficacy in de novo AML patients enrolled in the same AAML0531 trial.Methods: We genotyped five CD33 SNPs: rs2455069 (Arg60Gly), rs35112940 (Arg304Gly), rs61736475 (Ser305Pro) and rs1803254 and associated these with CD33 cell surface levels and clinical outcome in AML patients (n=817: 408=No-GO and 409=GO). We further developed a composite CD33 SNP-score ranging from -6 to +2, using genotype information on the 4-CD33 SNPs with significant association with cell surface CD33 levels. A directional genotype score was generated for each SNP by taking into account the direction of association of variant allele with CD33 levels. Genotype score ranged from 0 to -2 for rs12459419, rs1803254 and rs35112940 -with variant alleles associated with lower CD33 intensity. For CD33 SNP rs2455069 -with variant allele associated with high CD33 cell surface intensity, genotype scores ranged from 0 to +2 based on number of variant alleles present. Composite CD33-SNP Score = Σ (individual genotype scores of rs12459419, rs1803254, rs2455069 and rs35112940) followed by grouping into score of ≥0 OR <0.Results: CD33 coding SNPs-rs2455069, rs35112940 and 3'UTR SNP-rs1803254 but not rs61736475 were associated with cell surface CD33 levels on AML blasts and superior response with GO. These SNPs did not show any linkage with each other and the effect seen was independent. The CD33-SNPscore was therefore built using genotype scores for previously reported rs12459419 and the new rs2455069, rs1803254 and rs35112940 CD33 SNPs. Patients with a CD33-SNP score of ≥0 had higher cell surface CD33 levels (Figure 1) and demonstrated improved 5-year disease-free survival of 67±8% vs. 49±9% (hazard ratio [HR]=0.58, [95% confidence interval 0.41-0.84]; p=0.004) as well as reduced risk of relapse (24±7% vs. 48±9%; HR=0.448 [95% CI: 0.30-0.67]; p <0.001, Figure 2) when treated with GO vs. NO-GO. GO did not improve outcomes in patients with a CD33-SNPscore of <0, which was associated with lower CD33 expression levels. Subgroup analyses showed similar results, in low- and intermediate-risk patients, but for high-risk group statistical significance was not reached.Conclusion: In this study to comprehensively evaluate the role of CD33 SNPs on outcome we created a composite CD33-SNP_score using a directional genotype score for these three and our previously reported splicing SNP, rs12459419. Our findings suggest the use of GO with intensive induction chemotherapy in childhood AML should be restricted to patients with CD33-SNP score of ≥0. Although CC genotype for our recently reported splicing SNP rs12459419 was significantly represented in CD33-SNP score of ≥ 0, it is important to realize it occurs with an allele frequency of ~0.3 in European patients but is less frequent in other ethnic groups (ranging from ~0.10-0.15 in African American and Asian and non-existent in Sub-Saharan Africans), whereas rs1803254 is more frequent in black vs. white patient (0.32 vs. 0.15), thus the use of a composite CD33-SNP score would broaden identification of those patients who will benefit from GO or other CD33 targeted agents, in non-European populations. Validation of this CD33-SNP score with GO response remains to be performed and if reproduced, future studies should consider the use of the CD33-SNP score to guide GO therapy. [Display omitted] DisclosuresLoken:Hematologics Inc: Employment, Equity Ownership. Walter:ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding.

Effectiveness of Supportive Care Measurements to Reduce Infections during Induction for Children with Acute Myeloid Leukemia: A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

BACKGROUNDCurrent intensive chemotherapy for pediatric acute myeloid leukemia (AML) in conjunction with supportive care has increased survival rate up to 70%, and yet infections are still responsible for considerable morbidity and most treatment-related deaths. These factors have led to much interest in supportive care measurements to reduce infections and infectious mortality. The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial AML-05 was a phase 2 study that included children with de novo AML treated with intensive chemotherapy. We surveyed participating JPLSG sites to assess the effect of each supportive care measurements on Induction I infection risk and non-relapse mortality for children in AML-05 study. METHODSBetween November 2006 and December 2010, JPLSG AML-05, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, recruited 447 eligible children (age <18 years) with de novo AML. AML-05 used 5 courses of intensive chemotherapy with Induction I consisting of etoposide 150mg/m2/dose intravenous (IV) every 24 h on day 1-5; cytarabine 200 mg/m2/dose intravenous (IV) every 12 h on days 6-12; mitoxantrone 5 mg/m2/dose IV on days 6-10; triple intrathecal treatment (methotrexate/ cytarabine/ hydrocortisone) (ECM 5+7+5). Data of Infectious complications were collected prospectively and monitored in real-time to optimize reporting accuracy. In this analysis, infectious events were limited to Induction I. Non-relapse mortality was defined as any induction death within 40 days of being taken off study due to non-disease related causes. The survey included questions on implementations in each patient participated in AML-05 study for antibacterial prophylaxis, antifungal prophylaxis, intestinal sterilization, use of HEPA-filter, surveillance culture, and use of G-CSF until count recovery. RESULTSThe survey response rate from the JPLSG sites was 359/447 (80.3%). In multiple regression, anti-bacterial prophylaxis reduced the development of febrile neutropenia during induction chemotherapy (Odds ratio [OR] 0.56, 95% confidence interval [CI] 0.39-0.88; p = 0.013). Sterile site bacterial infections increased in younger age group (OR 2.0, 95% CI, 1.09-3.66; p = 0.025) but decreased in patients who were routinely carried out surveillance culture (OR 0.5, 95% CI, 0.27-0.96; p = 0.038). Fungal infection during induction chemotherapy was associated with intestinal sterilization (OR 0.21, 95% CI, 0.61-0.70; p = 0.011) and the use of G-CSF (OR 3.83, 95% CI, 1.10-13.32; p = 0.035). Prophylactic antifungal agent had a tendency to reduce the frequency and duration of pyrexia, and the peak value of CRP. Nonetheless, routine prophylaxis with these agents did not impact non-relapse mortality. CONCLUSIONSProphylactic use of antibiotics was associated with less development of febrile neutropenia. Routine prophylaxis with these agents may be associated with incidence and severity of infectious complications, but did not impact non-relapse mortality during induction chemotherapy in childhood AML. DisclosuresNo relevant conflicts of interest to declare.

Interim Disease Evaluation Post Induction Chemotherapy for Acute Myeloid Leukemia

Introduction: Interim disease evaluation and its timing during induction chemotherapy (day 14 or day 21) for patients with acute myeloid leukemia (AML) remains controversial. It has been suggested that failure to achieve complete remission (CR) at day 21 is associated with a poor prognosis. Nonetheless, the significance of persistent disease and the need for an early double induction is questionable.Methods: We performed a retrospective single center study at the American University of Beirut Medical Center, Lebanon, approved by the institutional review board, to evaluate the early response to induction chemotherapy in patients with AML, assessing the significance of residual disease at day 21 and its impact on progression free and overall survival (PFS and OS respectively). Consecutive patients with newly diagnosed (N=48) or recurrent AML (N=4), excluding acute promyelocytic leukemia, treated over an 8 year period (2008-2016), with available post induction bone marrow evaluation at day 21 were included (Table 1). Medical records for enrolled patients were reviewed to identify the morphological/molecular assessment of the bone marrow at presentation and then at day 21 post induction, in addition to significant outcomes including mortality and risk of relapse.RESULTS: We identified a total of 52 patients over the specified period. The median age at diagnosis was 49.5 (range 18-74). 26 patients (50%) had an abnormal karyotype, out of which 6 patients had a complex karyotype. 34 patients (65 %) achieved morphological remission at day 21 with <5% blasts on bone marrow evaluation, while 18 patients had residual/progressive disease. All patients did not receive re-induction chemotherapy before day 28. 7 patients or around 39% of those with early residual disease later achieved complete remission by day 28. There was a mild increase in the risk of relapse/progression in those with early residual disease (HR 1.2, p-value<0.05), but no statistically significant increase in terms of in-hospital mortality, taking into account that only 2 patients died during hospitalization for induction therapy, both of whom had residual disease at day 21. Risk of death at last follow up was slightly higher among those with residual disease at day 21 (HR 1.3, p-value <0.05). However, a statistically insignificant improvement in PFS/OS was noted in those achieving early remission.CONCLUSION: Early residual disease post induction chemotherapy for AML does not appear to be a significant prognostic indicator. Disease evaluation should thus be individualized, since many patients with residual blasts ultimately achieve CR by day 28 without the need for re-induction therapy. Larger prospective studies are needed to confirm the need and significance of day 21 marrow evaluation, and those who would benefit from it for prognostic and therapeutic indications. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.