Induction Of Myeloid Leukemia Research Articles

The Occurrence of Infection and TP53 Mutation Are Risk Factors for Cardiovascular Toxicity of Acute Myeloid Leukemia Induction Therapy

Introduction: For almost 50 years,induction therapy (IT) is the standard of care for acute myeloid leukemia (AML) patients. Nevertheless, little is known about cardiovascular (CV) toxicity during IT. We aimed to describe CV events (CVE)occurring during IT and to identify clinical, hematological and molecular risk factors of such events. Methods: Two hundred and twenty-four patients of 18 years or more (median age 61 (51;67) years, 58% males), treated with ITbetween 2014 and 2021 were enrolled in this study. Two hundred and one (90%) received an anthracycline-based IT, the others received gemtuzumab ozogamicin as part of a clinical protocol research. Survival from the time from initiation of IT until death or until the initiation of the second course of therapy (either salvage regimen in case of primary refractory or relapsed AML, or intensive consolidation therapy in case of response) was considered. The primary endpoint was the time to occurrence of the first CVE after IT initiation, with death as a competing event. Multivariate analysis included significant covariate, identified by univariate models among initial characteristics and occurrence of infection (coded as time dependent covariate). Results: Hematological characteristics were as follows: European LeukemiaNet (ELN) 2022 risk of myelodysplastic neoplasm (MDS)/AML was low, intermediate and adverse in 13%, 29% and 58% of patients respectively. Main mutations encounters were: DNMT3A, FLT3, NPM1, TET2, NRAS, RUNX1, ASXL1, IDH2, PTPN11, BCOR, SRSF2, WT1 and TP53. Main CV risk factors were tobacco (36%), arterial hypertension (35%), obesity (24%), hyperlipidemia (22%), diabetes mellitus (11%). Baseline left ventricular ejection fraction (assessed by transthoracic echocardiography) was >45% in all patients, >55% in 95% of patients. Seventy-five patients (33%) presented a CVE during IT. Eighty-six percent of CVE were severe (grade 3 or more). Patients presenting CVE during IT were significantly older (p=0.02) and presented more often a past history of dilated cardiomyopathy (p=0.04), arterial hypertension (p=0.005) or dyslipidemia (p=0.005). At baseline, CVE patients presented a greater left auricle volume (p=0.005), higher tricuspid regurgitation grade (p=0.01), and more often a right ventricular dilatation or a significative valvopathy (respectively p=0.01 and p=0.03). There was no difference in CVE occurrence between patients treated with and without anthracyclin (p=0.2). Competing risk models identified the following adverse characteristic for the risk of first CVE, namely the occurrence of the first infectious event (Hazard ratio [HR]= 2.43, p=0.005), TP53 mutation (HR=1.79, p=0.04). No other clinical characteristics nor mutation (including TET2 and DNMT3A) were identified. Multivariate analyses demonstrated that TP53 mutation (HR=1.78, p=0.04) and occurrence of infection (HR=2.29, p=0.008) retained independent prognostic value, see Table 1. In a response stratified model, only TP53 mutation was a risk factor of first CVE (HR=2.46, p=0.008). Conclusions: CVE occurred in 33% of patients during IT and were severe. The major adverse role of onset of infection for CVE occurrence after IT could overcome the prognostic value of mutations usually associated with CV risk in the healthy population (i.e. TET2, DNMT3A, ASXL1, ...). TP53 mutation was the only molecular abnormality associated with CVE, in agreement with the increased risk of doxorubicin-induced cardiac toxicity in a mouse model of TP53 clonal hematopoiesis developed by Sano et al. These results suggest that TP53 mutated patients could benefit from careful CV monitoring and optimization of primary prevention treatment.

A Prospective Study to Evaluate the Effect of Therapeutic Drug Monitoring-Based Posaconazole Prophylaxis on Invasive Fungal Infection Rate During Acute Myeloid Leukemia Induction Therapy.

The online version contains supplementary material available at 10.1007/s12288-023-01709-3.

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

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

Acute myeloid leukemia induction in the age of novel therapeutic agents

Acute myeloid leukemia (AML) is a malignant neoplasm of the myeloid lineage characterized by the uncontrolled proliferation of immature myeloid blasts in the bone marrow and peripheral blood. AML is a heterogenous disease which occurs across the age spectrum, although with an increasing incidence with age. For decades, first-line, curative-intent therapy has been based on intensive therapy with anthracycline (typically daunorubicin or idarubicin) plus cytarabine (3+7), followed by additional consolidative chemotherapy and/or allogeneic stem cell transplantation. While improvements over the decades in overall survival have been observed, until recently this has been driven largely by advancements in supportive care leading to reduction in treatment-related mortality and allowing a greater proportion of patients (particularly older individuals) to safely undergo intensive therapy induction and consolidation. Despite this, five-year overall survival (OS) rates in older individuals are as low as 5% (age > 70). Although OS for patients age 15-39 is now in the range of 50%-60%, a large portion of patients still succumb to their disease. Cytogenetic and molecular profiling has led to defined risk categories, and complete risk stratification for all patients eligible for intensive therapy is crucial to aiding in the selection of optimal induction and post- remission therapy. In recent years, an improved understanding of AML biology and genetics has led to the approval of a number of novel therapies for patients deemed fit and unfit for intensive therapy, which may finally be moving the needle beyond 3+7. This article will review a current approach to AML induction patients eligible for intensive therapy, with a focus on the utilization of available novel agents.

A real-world evaluation of treatment (Tx) patterns and outcomes of acute myeloid leukemia (AML) induction therapies in the community setting.

e19006 Background: AML is an aggressive hematologic malignancy of older adults (median age at diagnosis: 68 y); median overall survival (mOS) is low, even with Tx. The VIALE-A study changed the standard of care by combining venetoclax (VEN) with a hypomethylating agent (HMA), extending mOS from 9 to 14 mo. With the evolving Tx landscape and growing availability of less-intensive induction chemotherapy (IC), it is important to understand the impact of these Tx in the real world. This study evaluated Tx patterns and clinical outcomes for patients (pts) with AML who received intensive IC, VEN-based Tx (eg, VEN + azacitidine), or non-VEN-based low-intensity (NVB-LI) Tx (eg, a single HMA) in the first-line (1L) setting. Methods: A retrospective, observational, US-based, cohort study was conducted utilizing electronic health record data from adults with AML who initiated 1L IC between 01/01/2016 and 12/31/2019, or 1L VEN-based Tx or 1L NVB-LI Tx between 01/01/2019 and 12/31/2020. Eligible pts had ≥6 mo of follow-up after 1L initiation (or <6 mo due to death). Pts who received AML Tx as part of clinical trials were excluded. Remission was defined as a physician-reported best response of complete remission (CR), CR with incomplete hematologic improvement, or CR with no measurable residual disease. Time-to-event outcomes were assessed using the Kaplan–Meier method; all other data were summarized using descriptive statistics. Results: A total of 451 pts were included; 54% were male, 70% were White. Median follow-up was 17 mos. Mean age at 1L initiation was 52, 73, and 76 y in the IC, VEN, and NVB-LI cohorts, respectively. Among the 207 pts in the IC cohort, 99% discontinued Tx during follow-up, 85% of whom discontinued due to completion of Tx. Among the 152 pts in the VEN cohort and 92 in the NVB-LI cohort, 72% and 75% discontinued Tx, respectively, primarily due to disease progression (59% and 68% of discontinuing pts, respectively). Median duration of 1L Tx was 2, 11, and 7 mo in the IC, VEN and NVB-LI cohorts, respectively. In the IC, VEN, and NVB-LI cohorts, 80%, 45%, and 20% of pts achieved remission during 1L Tx; median time to remission was 1, 3, and 3 mo, respectively. Median relapse-free survival was not reached during follow-up in any of the cohorts. In the IC cohort mOS was not reached; mOS was 17 mo in the VEN cohort, and 9 mo in the NVB-LI cohort. Conclusions: Pts receiving 1L IC had the highest rate of remission, the shortest time to remission, and the most favorable mOS among all Tx cohorts, supporting continued intensive chemotherapeutic approaches with curative intent in eligible pts. mOS favored combination VEN-based Tx over NVB-LI, suggesting that VEN-based therapies may provide more benefit for pts ineligible for IC. Further research is warranted to determine the most appropriate Tx approach for pts with AML based on Tx effectiveness, pt medical history, and IC eligibility.

Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma.

Chromothripsis is a catastrophic event of chromosomal instability that involves intensive fragmentation and rearrangements within localized chromosomal regions. However, its cause remains unclear. Here, we show that reduction and inactivation of Ran GTPase-activating protein 1 (RanGAP1) commonly occur in human osteosarcoma, which is associated with a high rate of chromothripsis. In rapidly expanding mouse osteoprogenitors, RanGAP1 deficiency causes chromothripsis in chr1q, instant inactivation of Rb1 and degradation of p53, consequent failure in DNA damage repair, and ultrafast osteosarcoma tumorigenesis. During mitosis, RanGAP1 anchors to the kinetochore, where it recruits PP1-γ to counteract the activity of the spindle-assembly checkpoint (SAC) and prevents TOP2A degradation, thus safeguarding chromatid decatenation. Loss of RanGAP1 causes SAC hyperactivation and chromatid decatenation failure. These findings demonstrate that RanGAP1 maintains mitotic chromosome integrity and that RanGAP1 loss drives tumorigenesis through its direct effects on SAC and decatenation and secondary effects on DNA damage surveillance.

Real-World (RW) Evaluation of Acute Myeloid Leukemia (AML) Induction Therapies in the Community Setting: A Retrospective Evaluation of Outcomes of Intensive Chemotherapy, Venetoclax-Based Regimens, and Non-IC-Based Treatments

Real-World (RW) Evaluation of Acute Myeloid Leukemia (AML) Induction Therapies in the Community Setting: A Retrospective Evaluation of Outcomes of Intensive Chemotherapy, Venetoclax-Based Regimens, and Non-IC-Based Treatments

Characteristics, Treatment Complexity, and Outcome of Mixed-Phenotype Acute Leukemia in Children in a Low-Middle-Income Country.

BackgroundMixed-phenotype acute leukemia (MPAL) in children is an uncommon subtype of acute leukemia that cannot be definitively assigned to a specific lineage. There is no consensus on the best approach to therapy. Management is more complex in low–middle-income countries (LMICs).AimTo evaluate the clinicopathological characteristics and outcomes of patients with MPAL in a developing country.Patients and MethodsA retrospective descriptive study of 42 pediatric patients newly diagnosed with MPAL from July 2007 until December 2017.ResultsThe immunophenotyping was T/Myeloid in 24 patients (57.1%) and B/Myeloid in 16 (38.1%). Three subjects had MLL gene rearrangement, two had Philadelphia-positive chromosomes, and eight had FMS-like tyrosine kinase 3 (FLT3-ITD) internal tandem duplication (FLT3-ITD) with a ratio >0.4. Two subjects died before starting chemotherapy. Ten patients (25%) received acute lymphoblastic leukemia (ALL) induction, and all achieved complete remission (CR) with no induction deaths and no shift of therapy. Thirty patients (75%) started therapy with acute myeloid leukemia (AML) induction: five (16.6%) died during induction, 17 (56.7%) achieved CR, and 10 patients received maintenance ALL therapy after ending AML treatment. Four of the eight patients with induction failure were switched to ALL therapy. The 5-year event-free survival (EFS) and overall survival (OS) rates were 56.7% [standard error (SE): 8.1%] and 61% (SE: 8%), while the cumulative incidence of relapse was 21.7% (SE: 6.7%), with a median follow-up duration of 5.8 years. Patients treated with ALL-directed therapy had a 5-year EFS rate of 111 70% (SE: 14%) and OS rate of 78.8% (SE: 13%). Patients treated with ALL-directed therapy had a 5-year EFS rate of 70% (SE: 14.5%) and OS rate of 78.8% (SE: 13%). FLT3-ITD mutation showed a significantly lower 5-year EFS rate of 28.6% (SE: 17%) vs. 75% (SE: 9%) for the wild type, p = 0.032. Undernourished patients with a body mass index (BMI) z-score ≤-2 at presentation had a significantly lower 5-year EFS rate of 20% (SE: 17%) compared to 61.8% (SE: 8%) for patients with BMI z-score >-2, p = 0.015.ConclusionThis study supports ALL-directed therapy for pediatric MPAL in a setting of LMIC. Given the poor outcome of FLT3-ITD, the role of FLT3 inhibitor needs to be explored in this subset of cases.

Blast cells surviving acute myeloid leukemia induction therapy are in cycle with a signature of FOXM1 activity

BackgroundDisease relapse remains common following treatment of acute myeloid leukemia (AML) and is due to chemoresistance of leukemia cells with disease repopulating potential. To date, attempts to define the characteristics of in vivo resistant blasts have focused on comparisons between leukemic cells at presentation and relapse. However, further treatment responses are often seen following relapse, suggesting that most blasts remain chemosensitive. We sought to characterise in vivo chemoresistant blasts by studying the transcriptional and genetic features of blasts from before and shortly after induction chemotherapy using paired samples from six patients with primary refractory AML.MethodsLeukemic blasts were isolated by fluorescence-activated cell sorting. Fluorescence in situ hybridization (FISH), targeted genetic sequencing and detailed immunophenotypic analysis were used to confirm that sorted cells were leukemic. Sorted blasts were subjected to RNA sequencing. Lentiviral vectors expressing short hairpin RNAs were used to assess the effect of FOXM1 knockdown on colony forming capacity, proliferative capacity and apoptosis in cell lines, primary AML cells and CD34+ cells from healthy donors.ResultsMolecular genetic analysis revealed early clonal selection occurring after induction chemotherapy. Immunophenotypic characterisation found leukemia-associated immunophenotypes in all cases that persisted following treatment. Despite the genetic heterogeneity of the leukemias studied, transcriptional analysis found concerted changes in gene expression in resistant blasts. Remarkably, the gene expression signature suggested that post-chemotherapy blasts were more proliferative than those at presentation. Resistant blasts also appeared less differentiated and expressed leukemia stem cell (LSC) maintenance genes. However, the proportion of immunophenotypically defined LSCs appeared to decrease following treatment, with implications for the targeting of these cells on the basis of cell surface antigen expression. The refractory gene signature was highly enriched with targets of the transcription factor FOXM1. shRNA knockdown experiments demonstrated that the viability of primary AML cells, but not normal CD34+ cells, depended on FOXM1 expression.ConclusionsWe found that chemorefractory blasts from leukemias with varied genetic backgrounds expressed a common transcriptional program. In contrast to the notion that LSC quiescence confers resistance to chemotherapy we find that refractory blasts are both actively proliferating and enriched with LSC maintenance genes. Using primary patient material from a relevant clinical context we also provide further support for the role of FOXM1 in chemotherapy resistance, proliferation and stem cell function in AML.

Incidence and Predictors of Left Ventricular Dysfunction Among Acute Myeloid Leukemia Patients

Background: Patients with acute myeloid leukemia (AML) induction treatment are at risk for cardiovascular dysfunction. Left ventricular (LV) dysfunction may be a result of chemotherapy or the cytokine crisis resulting from leukemic cells lysis. We sought to investigate the effects age and chemotherapy dosage have on the left ventricular function in leukemia patients undergoing induction.Methods: We performed a retrospective chart review on patients diagnosed with AML including acute promyelocytic leukemia, who received chemotherapy between January 1, 2013 and December 31, 2015 at the Emory University Winship Cancer Center. Baseline and follow up EFs were recorded by echocardiography. We evaluated patients who had a drop in EF after the first or subsequent inductions. A logistic regression model was performed to evaluate the effect of increasing chemotherapy dosage and age on the risk of LV dysfunction.Results: A total of 144 consecutive AML patients with normal ejection fraction at diagnosis were evaluated, of whom 101 patients had Echocardiographic baseline and follow up data. 81 patients received Idarubicin and 20 patients received Daunorubicin. A total of 12 patients (11.8%) demonstrated a decrease in EF (to ≤45%) (range 25-45). The median age of patients with LV dysfunction was 51 years (range 27-69) compared to the median age of 47 (range 18-76) for those who didn't experience a drop in their EF. The median months from the start of treatment to the observed drop were 4 months (1-12). Reduction in EF (range 25-45) was mild to moderate (35-45%) among 90% of patients. 2 out of 12 patients recovered their LV function on repeat echocardiography. In a logistic regression model adjusted for prior LV dysfunction among Idarubicin recipient, LV dysfunction odds increased with increasing age (p value = 0.054), higher Idarubicin dosage (P value = 0.51 and their interaction (p value= 0.052).Conclusions: Patients undergoing induction chemotherapy treatment for AML may experience left ventricular dysfunction. In our sample, the overall incidence of LV dysfunction was 11.8% and the severity was mostly mild to moderate (EF= 35-45%). The risk was higher among older patients who received higher chemotherapy dosages. AML patients undergoing induction chemotherapy, especially older patients and those who receive higher dosages, may benefit from enhanced cardiac surveillance to monitor their LV function. DisclosuresArellano:Cephalon Oncology: Research Funding. Kota:Leukemia Lymphoma Society: Research Funding; Takeda Pharmaceuticals: Consultancy; Novartis: Consultancy; Xcenda: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

Adoptive Immunotherapy with Cord Blood (CB) Grafts Targeting Shared Inherited Paternal Antigens (IPA) and/or Non-Inherited Maternal Antigens (NIMA) during Induction Treatment for High Risk Myeloid Malignancies: Safety and Preliminary Results

BackgroundSeveral groups have reported use of haploidentical peripheral blood donor cells as adjunct to chemotherapy in remission induction of myeloid leukemia (Colvin et al, BBMT 2009, Gue et al, Blood 2011). Moreover, CB grafts have been associated with greater disease control and enhanced graft-versus-leukemia responses, as a consequence of the fetal-maternal interactions during pregnancy (van Rood et al, PNAS 2009 and PNAS 2012).We evaluated prospectively the feasibility and tolerability of infusing partially HLA matched cord blood units (CBUs) with specific alloreactive properties after salvage chemotherapy to patients (pts) with refractory myeloid leukemia.Patients and MethodsPts with confirmed diagnosis of AML or MDS, according to WHO classification (excluding acute promyelocytic leukemia) who had received two or more previous induction/re-induction regimens were eligible. All pts were treated at NYPH and all CBUs were obtained from the NCBP. The study was performed under FDA IND and was approved by the IRBs of both institutions. Pts received induction chemotherapy followed by CBU infusion (1-3 days later) without any immunosuppression.CBUs eligible for the study contained a pre-cryopreservation Total Nucleated Cell (TNC) dose of 0.5-2.5x107/kg. They were HLA matched at 4-6/6, HLA-A, -B intermediate resolution, -DRB1 high resolution. CBUs had undergone HLA typing of the mother, thus allowing determination of the paternal and maternal antigens. CBUs with shared IPA targets and/or NIMA match were selected for cell therapy.ResultsA total of 34 patients underwent CBU search. Mean CBU number per search was 134 (range: 7-250) with 58% potentially eligible CBUs per pt (range: 5-159). A total of 143 CBUs underwent testing including HLA confirmatory typing. At least one eligible CBU was identified for each pt. Higher HLA allele level match was preferred in the final selection.Of the 34 pts, 23 did not receive treatment because of progressive disease and death (n=8); other clinical trials/treatments (n=6); hematopoietic stem cell transplants (HSCT) (n=9); while one is currently undergoing evaluation. Ten pts have been treated (Table); 8 had AML, 7 with primary induction failure (PIF); one had myeloid blast phase CML and one with high risk MDS. Nine pts had poor risk karyotype and 4 had prior allografts. Median age was 52 years (range: 34-67); median number of prior treatments was 11 (2-15) and median HSCT-CI was 3 (0-7).Of the CBUs infused, six were 5/6 and four were 4/6 HLA matched. The allele level compatibility and presence of shared IPA targets and/or NIMA matches are shown in the Table. CBU median TNC was 90x107 (range: 63-151) and they tended to be “older” with a median cryopreservation time of 10 years. CBUs provided a mean cell dose of 1.66 x 107 TNC/kg (range: 1.1-2.4). Mean post-thaw CD34+ and CD3+ cell doses were 52x103/kg (range: 20-90) and 0.34x107/kg (range: 0.24-0.52; SD: 0.08), respectively, with excellent post-thaw CD34+ viability (93.5%-98.3%).No CBU infusion reactions or cytokine release syndrome were observed. One pt, recipient of a prior allograft with no history of GVHD, experienced skin rash 1 week after CBU infusion. The skin biopsy was consistent with GVHD. No GVHD was observed in the other 9 pts. One pt died of disseminated adenovirus infection early after treatment; viremia was present at the initiation of chemotherapy.Transient CBU chimerism was detected in 5 of the 10 pts as early as one week and as late as 6 months after CBU infusion. Four pts with median pre-treatment BM blast counts of 56% (range 13-94) had objective hematologic responses (Cheson B JCO 2003) with median post-treatment blast counts of 0% (range 0-12), 3 with morphologic leukemia free state and one with a partial response. One patient had aplastic marrow but with flow cytometry evidence of persistent leukemia; while 4 pts recovered with morphologic persistent leukemia. Six pts went on to receive HSCT. Two subsequently relapsed and one died of disseminated adenovirus, while 3 pts remain in remission.ConclusionUse of CBUs as adoptive immunotherapy for pts with refractory myeloid leukemia represents a safe, well tolerated treatment, in which the potential for alloreactivity can be enhanced through the selection of CBUs by targeting shared IPA and NIMA present in the patients. Further, smaller CBUs, unlikely to be adequate grafts for adult transplantation, can be utilized for cell therapy. [Display omitted] DisclosuresRoboz:Cellectis: Research Funding; AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy. Ritchie:Celgene: Consultancy, Other: Travel, Speakers Bureau; Pfizer: Consultancy, Other: Research funding to my institution; Incyte: Consultancy, Speakers Bureau; Astellas Pharma: Other: Research funding to my institution; NS Pharma: Other: Research funding to my institution; Bristol-Myers Squibb: Other: Research funding to my institution; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau. Lee:Amgen: Consultancy; Baxalta: Consultancy; Clinipace: Consultancy; Alexion Pharmaceuticals: Consultancy.

Early Minimal Residual Disease Assessment after Acute Myeloid Leukemia Induction with Fludarabine Cytarabine and Idarubicin (FLAI) Provides the Most Useful Prognostic Information

Despite the achievement of hematological remission (CR), acute myeloid leukemia (AML) patients with persistence of detectable disease assessed with high sensitivity techniques (multicolor-flow-cytometry, MFC, or PCR-based molecular analysis) show a poor outcome. The aim of our study was to evaluate the prognostic impact of MFC and molecular minimal residual disease (MRD) assessment in a cohort of AML patients who had received a fludarabine-high dose cytarabine containing induction (FLAI) as front-line treatment by identifying optimal time-points (TPs) and MFC and molecular MRD cut-off values.One hundred and ten consecutive AML patients treated in our center between 2004 and 2014 were retrospectively analyzed. Median age was 47 years. Median follow up was 59 months. MRD was assessed at 3 TPs during treatment; TP1, after induction I; TP2, after induction II; TP3, after consolidation therapy for patients who did not undergo hematopoietic stem cells transplantation (HSCT) or prior transplantation.Two thresholds of MFC-MRD were evaluated; MFC-MRD undetectable (MFC-MRD <0.025%) and low MFC-MRD burden (MFC-MRD <0.1%). A sub-analysis for patients carrying NPM1 mutation was performed analyzing NPM1 expression levels on bone marrow (BM) samples . A reduction >3.5 log of NPM1 transcript at TP1 was considered optimal as per our published experience.For patients presenting WT1 over-expression at diagnosis WT1-MRD was evaluated at TP1, with a cut-off of for negativity of WT1 copies/104 ABL lower than 250 on BM samples.Following FLAI, 103/120 patients achieved CR (86%). Out of 103 patients in CR after FLAI MFC-MRD data were available for 88 patients at TP1 (85%) and for 77 at TP2 and TP3 (75%). At TP1, 30/88 (34%) patients had undetectable disease. This percentage remained substantially unchanged at TP2. Patients with MFC-MRD <0.1% were 41/88 (47%) at TP1; this percentage increased to 62% at TP2. At TP3 the percentage of patients with undetectable MFC-MRD or with MFC-MRD <0.1% was comparable to what was observed at TP2.After a median follow-up of 60 months, out of 103 CR patients 26 relapsed. Patients undergoing HSCT in first CR were censored at the time of transplant for CI of relapse evaluation.In competitive risk analysis, the 3-year CI of relapse was 42.2%. In univariate analysis a higher CI of relapse was significantly associated with secondary disease, high risk group according to ELN 2017, time from hematological recovery following induction 1 to start of induction 2 (i.e. >20 days), detectable MFC-MRD and MFC-MRD ≥0.1% both at TP1 and TP2 and positive WT1-MRD at TP1.Multivariate analysis revealed MFC-MRD ≥0.025% at TP1 as the strongest factor affecting the CI of relapse (p<0.0001, Fig. 1a). Interestingly, the combination of MFC-MRD with the most stringent sensitivity cut off (0.025%) and WT1-MRD at TP1 led to the identification of 3 groups of patients having a significantly different CI of relapse. Patients for whom both methods gave positive results displayed the worst outcome (p<0.0001, Fig. 1b). Patients with MFC-MRD ≥0.1% at TP2 had the highest CI of relapse (p<0.001, Fig. 1c).Patients with undetectable MFC-MRD at TP1 had the best 3-year overall survival (OS) (92.5%, p< 0.001). Multivariate analysis showed that risk group according to ELN 2017 and MFC MRD ≥0.1% at TP1 were the only factors that significantly impacted on OS.Our study included 42 AML with mutated NPM1. Thirty-five achieved CR and had available NPM MRD data. At TP1 18/35 (51%) patients achieved >3.5 log reduction of NPM1 transcript. At TP2 27/35 (77%) patients obtained NPM1 negativity. Three-year OS for patients showing more or less than 3.5 log transcript reduction at TP1 was 94.1% vs 48.6%, respectively (p<0.03). Three-year OS for patients achieving NPM-MRD negativity at TP2 was 90.5% compared to 21.4% for those who remained positive (p<0.001). Multivariate analysis showed that >3.5 log reduction of NPM- MRD at TP1 was the strongest predictor for OS (p<0.05).Our study is the first report analyzing the prognostic impact of longitudinal MRD assessment for AML patients receiving a fludarabine-containing induction regimen. Early (post induction) MRD assessment is the strongest factor affecting CI of relapse and survival. This observation is probably linked to the strong anti-leukemic activity of FLAI and may allow planning of alternative therapeutic interventions in patients with suboptimal response. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognosis and Application of Day 14 Bone Marrow Results in Acute Myeloid Leukemia Induction

▪Introduction:The 2017 National Comprehensive Cancer Network (NCCN) guidelines for Acute Myeloid Leukemia (AML) recommend performing a bone marrow aspirate (BMA) and trephine biopsy (BMTB) 14-21 days after starting induction therapy (commonly referred to as a “Day 14 [D14] marrow”). Those who do not achieve a hypoplastic marrow, with cellularity <10-20% and blasts <5-10%, are recommended to undergo a second induction cycle (IC). We performed a retrospective analysis to determine the impact of day 14 bone marrow (D14 BM) characteristics in predicting remission, association with overall survival (OS) and the impact of a second IC based on D14 BM results.Methods:Patients with AML aged 18-70 years undergoing induction therapy with standard “7+3” regimens at Vancouver General Hospital or University of Alberta Hospital from 2007-2015 and 2005-2015 respectively were included. D14 cellularity was determined on BMTB and blast percentage (blast %) was assessed by morphology on BMA and BMTB. We examined outcomes by three D14 risk categories: 1. blast % (<5/≥5%), 2. cellularity (<20%/≥20%) or 3. blast % and cellularity (< 5% blasts or <20% cellularity/ ≥5% blasts and ≥20% cellularity). Overall response rate was determined at peripheral count recovery and defined as complete remission (CR) or CR with incomplete count recovery (CRi), (Cheson B J Clin Onc 2003; 21(24):4642-9). Differences in categorical variables were determined using Mantel-Haenszel tests. Binary logistic regression was used to determine association between D14 BM and other covariates on CR/CRi rate. Cox regression was used to determine association between covariates with OS.Results:546 patients were identified with 486 (89.0%) undergoing a D14 BM (Table 1). On the D14 BM, 190 patients had blasts ≥5%, 96 had cellularity ≥20% (with 12 patients also having blasts <5%) and 84 had both blasts ≥5% and cellularity ≥20%. The CR/CRi rate stratified by D14 categories was: 87% vs. 56%, p<0.001 (< 5% vs. ≥ 5% blasts), 79% vs. 57%, p<0.001 (< 20% vs. ≥20% cellularity) and 79% vs. 54%, p<0.001 (<5% blasts or <20% cellularity vs. ≥5% blasts and ≥20% cellularity).In univariate analysis, D14 low-risk categories were associated with higher CR/CRi rates (D14 blasts <5%, OR 5.4, 95% CI 3.5-8.4, p<0.001, D14 cellularity <20%, OR 2.9, 95% CI 1.8-4.6, p<0.001 and D14 blasts <5% or cellularity <20%, OR 3.4, 95% CI 2.1-5.5, p<0.001) and improved OS (D14 blasts <5%, HR 0.66, 95% CI 0.51-0.84, p<0.001, D14 cellularity <20% ,HR 0.55, 95% CI 0.42-0.73, p<0.001 and D14 blasts <5% or D14 cellularity<20% ,HR 0.52, 95% CI 0.39-0.70, p<0.001). In multivariate analysis, the diagnostic cytogenetics and D14 blasts <5% predicted CR/CRi at count recovery whereas age, cytogenetics and D14 blasts <5% were significantly associated with improved OS (Table 2). The risk category using both blast % and cellularity was not included in the multivariate model due to multicollinearity with D14 blast % and cellularity.131 patients (27%) underwent a second IC, most commonly with etoposide/cyclophosphamide (n=48) or mitoxantrone/etoposide (n=48) regimens based upon the results of the D14 BM. CR/CRi rates for patients receiving 1 vs. 2 ICs in high risk D14 groups were: 43% vs. 62%, p=0.01 (D14 blasts ≥ 5%), 67% vs. 55%, p=0.33 (D14 cellularity >20%) and 38% vs. 55%, p=0.35 (D14 blasts ≥5% and cellularity ≥20%). In patients with ≥5% residual blasts on D14 marrow but <20% cellularity there was significant variation in use of D14 BM results with only 49/106 (46.2%) patients undergoing a second IC. In this group, a second IC improved CR/CRi (43.9% vs. 72.0%, P=0.004) but there was no difference in OS (HR 1.08, 95% CI 0.63-1.86, p=0.77). Furthermore, in this group leukemia free survival following CR/CRi was worse in patients that received a second IC (HR 2.24, 95% CI 1.00-4.98, p=0.05).Conclusion:D14 BM results are prognostic for achievement of CR/CRi following induction therapy for AML. D14 blasts <5% predicted CR/CRi in multivariate analysis, despite possible confounding of this analysis by the use of second IC based on D14 BM results. In addition, D14 blasts <5% are prognostic for OS in multivariate analysis including other recognized prognostic factors. For patients with residual blasts but hypocellular marrow on D14 BM, second IC was associated with greater CR/CRi rates but no difference in OS. This finding suggests that for this subset of patients, treatment decisions based on D14 BM may not significantly improve OS. [Display omitted] DisclosuresHogge:Novartis, Roche, and Sanofi: Consultancy.

Financial Implications of Early Hospital Discharge After AML-Like Induction Chemotherapy: A 4-Year Retrospective Analysis.

Early hospital discharge (EHD) after intensive acute myeloid leukemia (AML) induction chemotherapy has become routine at the University of Washington/Seattle Cancer Care Alliance over the past several years. We assessed the financial implications of EHD over the first 4 years after its broad adoption for patients with AML and other high-grade myeloid neoplasms undergoing AML-like induction chemotherapy. We retrospectively compared charges between 189 patients with EHD who received all postinduction inpatient/outpatient care within our care system between August 2014 and July 2018 and 139 medically matched control patients who remained hospitalized for logistical reasons. Charges from the day of initial discharge (patients with EHD) or end of chemotherapy (control patients) until blood count recovery, additional chemotherapy or care transition, hospital discharge (for control patients only), an elapse of 42 days, or death were extracted from financial databases and separated into categories: facility/provider, emergency department, transfusions, laboratory, imaging, pharmacy, and miscellaneous. Combined charges averaged $4,157/day (range, $905-$13,119/day) for patients with EHD versus $9,248/day (range, $4,363-$48,522/day) for control patients (P<.001). The EHD cohort had lower mean facility/provider, transfusion, laboratory, and pharmacy charges but not imaging or miscellaneous charges. During readmissions, there was no statistically significant difference in daily inpatient charges between the EHD and control cohorts. After multivariable adjustment, average charges were $3,837/day lower for patients with EHD (P<.001). Together with previous data from our center showing that EHD is safe and associated with reduced healthcare resource utilization, this study further supports this care approach for AML and other high-grade myeloid neoplasms if infrastructure is available to enable close outpatient follow-up.

Efficacy and cost-benefit of filgrastim administered after early assessment bone marrow biopsy during induction therapy for acute myeloid leukemia

The role of filgrastim during acute myeloid leukemia (AML) induction therapy remains controversial. At our institution, newly diagnosed AML patients from 2003 through 2019 were retrospectively evaluated. Patients were stratified on whether they received filgrastim within 5 days after early assessment bone marrow (BMBx) and divided into early GCSF group (eGCSF) and no-eGCSF group. A total of 121 patients were included. We found significantly shorter hospital stay (median 24 vs 26 days, p < .01), absolute neutrophil count recovery days (median 23 vs 25 days, p = .03), and intravenous antibiotics days (mean 18.5 vs 21.4 days, p = .01) in patients with eGCSF comparing with no-eGCSF. There was no significant difference regarding complete response rates; however, for those failed to achieve remission, eGCSF was associated with higher blast count. There was no significant difference regarding overall survival or progression-free survival. The use of eGCSF was associated with cost savings of $5199 per patient over no-eGCSF.

The utility of day 14 bone marrow response assessment in patients undergoing acute myeloid leukemia induction: A single institution retrospective experience

The utility of day 14 bone marrow response assessment in patients undergoing acute myeloid leukemia induction: A single institution retrospective experience

Resistance of osteosarcoma cells to the proapoptotic effects of carfilzomib involves activation of mitogen activated protein kinase pathways.

What is the central question of this study? Carfilzomib, a second-generation proteasome inhibitor approved for the treatment of multiple myeloma, shows efficacy against osteosarcoma. However, drug resistance remains a major challenge. What is the role of carfilzomib-induced changes in mitogen-activated protein kinase (MAPK) pathways in the sensitivity of osteosarcoma cells to the proapoptotic effects of the drug? What is the main finding and its importance? The dose-dependent antiapoptotic effects in osteosarcoma are associated with activation of MAPK signalling. Combinational targeting of MAPK signalling pathways can synergistically enhance carfilzomib-induced cell apoptosis, suggesting that MAPK inhibitors in combination with proteasome inhibitors can serve as a novel therapeutic tool for osteosarcoma. Osteosarcoma is the most common primary bone malignancy. Despite efforts to improve outcomes, the overall survival rates for osteosarcoma have remained unchanged over the past three decades. In this study, we assessed the proapoptotic effects of the second-generation proteasome inhibitor carfilzomib on osteosarcoma and investigated the potential mechanisms underlying the synergistic proapoptotic action when combined with mitogen-activated protein kinase (MAPK) inhibitors. We found that carfilzomib alone significantly inhibited cell proliferation and induced apoptosis in a dose-dependent manner, characterized by the induction of cleaved caspase 3 and poly (ADP-ribose) polymerase. More importantly, focusing on the changes of antiapoptotic B-cell lymphoma 2 (Bcl-2) family members and signalling pathways, we found a striking induction of myeloid cell leukaemia 1 (Mcl-1) and the activation of MAPK pathways. Furthermore, we observed that combinational targeting of the MAPK pathways using the specific inhibitors U0126, SP600125 or SB203580 synergistically enhanced carfilzomib-induced cell apoptosis. Notably, we found that the combinational inhibition of extracellular signal-regulated kinase or c-Jun N-terminal kinase MAPK pathways significantly decreased the expression of the three antiapoptotic Bcl-2 family proteins, and in particular this reversed induction of Mcl-1 by carfilzomib. Collectively, our findings show that activation of the MAPK pathways contributes to the mechanisms of drug resistance to carfilzomib. In addition, the synergistic proapoptotic action of MAPK and proteasome inhibitors in osteosarcoma cells suggests that combinational therapy with both drug types may serve as a novel strategy for the clinical management of osteosarcoma.

Evaluating Acute Myeloid Leukemia Induction Regimens in Elderly Patients with Unfavorable Risk Cytogenetics That Are Candidates for Intensive Remission Therapy

Background/purpose: Standard acute myeloid leukemia (AML) induction regimens have reduced response in elderly patients. As an alternative, hypomethylating agents have better tolerability, but poorer response rates. Venetoclax, an oral anti-apoptotic protein BCL-2 inhibitor, was approved in combination for the treatment of newly-diagnosed AML adults 75 years or older and is supported by NCCN guidelines in combination with hypomethylating agents or low dose cytarabine for special patient populations. This study evaluated the outcomes of AML induction regimens in unfavorable risk patients 60 years old or older that were candidates for intensive remission induction therapy. Methodology: This was an IRB-approved retrospective chart review of AML patients with unfavorable risk cytogenetics aged 60 or older admitted to the Baptist Hospital of Miami Oncology Unit between February 1st, 2018 and August 1st, 2019, an 18-month period. Patients were included if they received one of the following AML induction regimens: daunorubicin + cytarabine (7+3), liposomal daunorubicin/cytarabine (CPX-351), venetoclax + decitabine (VEN +DEC), venetoclax + azacitidine (VEN+ AZA), or venetoclax + low dose cytarabine (VEN + LoDAC). For the purpose of the study, the 7+3 and CPX-351 regimens were classified as high intensity, while the VEN+ DEC, VEN+AZA, and VEN+LoDAC regimens were classified as low intensity. The primary outcome assessed was the rate of complete morphologic remission (CR) and complete morphologic remission with incomplete count recovery (CRi). Additional secondary outcomes included rate of induction failure, relapse free survival (RFS), time to complete remission, transplant status and eligibility, length of stay (LOS), and incidence of any-grade treatment-related toxicities. Results: A total of 20 patients were identified. Of the 20 patients, 9 (45%) received induction with 7+3, 3 (15%) received CPX-351, 5 (20%) received VEN+DEC, and 3 (15%) received VEN +AZA, thus 12 (60%) received high intensity regimens, while 8 (40%) received low intensity. The primary outcome of CR/CRi rate was 75% in the high intensity group vs. 63% in the low intensity group (P=0.0922). Furthermore, the rate of induction failure, median time to CR/CRi, median LOS, and transplant eligibility were similar between the high and low intensity groups. The median RFS was 272 days in the high intensity groups vs. 223 days in the low intensity groups (P=0.1496). The median duration of neutropenia was 30 days in the high intensity group vs. 34 days in the low intensity group while the median duration of thrombocytopenia was 31 days in the high intensity groups vs. 32 days in the low intensity group. Finally, the rate of grade 3 and 4 toxicities was 100% in the high intensity group vs. 88% in the low intensity group (P=0.0003), with higher incidences of grade 3 febrile neutropenia, grade 4 thrombocytopenia, and grade 1 and 2 liver enzyme elevations noted in the high intensity group. Conclusion: There were no statistically significant differences between the CR/CRi rates and median RFS of the high and low intensity groups, while there were significantly less grade 3 and 4 toxicities noted in the low intensity group. Venetoclax-based regimens are an acceptable alternative to intensive induction therapy in unfavorable risk patients over the age of 60 due to similar outcomes and less toxicity. Disclosures No relevant conflicts of interest to declare.

Adult Langerhans cell histiocytosis presenting with multisystem involvement and sarcomatoid features: a case report

BackgroundLangerhans cell tumors are rare clonal disorders characterized by neoplastic proliferation of dendritic cells that can be further classified into the subtypes Langerhans cell histiocytosis and Langerhans cell sarcoma, which are rare neoplasms exhibiting aggressive features and a poor prognosis. In addition to illustrating the refractoriness and poor outcomes of multisystem Langerhans cell histiocytosis in adults, specific events in this case highlight important characteristics of disease biology that warrant detailed discussion and exposition to a wider audience.Case presentationWe describe the case of a 42-year-old Caucasian man with Langerhans cell histiocytosis diagnosed from a lesion on the left arm that presented with constitutional symptoms, early satiety, and weight loss. Esophagogastroduodenoscopy showed extensive esophageal and duodenal involvement by Langerhans cell histiocytosis with features of Langerhans cell sarcoma. He was initially treated for Langerhans cell histiocytosis with low doses of cytarabine until he eventually presented clear transformation to acute monoblastic leukemia with complex karyotype that could not be properly controlled, leading eventually to death.ConclusionsLangerhans cell histiocytosis remains an exceedingly rare entity in adults, frequently presenting as multisystem disease with risk organ involvement. Langerhans cell sarcoma represents an aggressive subtype with extremely poor prognosis for which intensive acute myeloid leukemia induction should be strongly considered.

Day 14 Bone Marrow Evaluation During Acute Myeloid Leukemia Induction in a Real-world Canadian Cohort

IntroductionThe 2017 National Comprehensive Cancer Network guidelines for acute myeloid leukemia have recommended performing bone marrow (BM) aspiration and BM trephine biopsy (BMTB) 14 to 21 days after starting induction therapy (commonly referred to as “day 14 [D14] marrow”). Those who do not achieve a hypoplastic marrow, with cellularity < 20% and blasts < 5%, are recommended to undergo 2-cycle induction (2CI). We performed a retrospective analysis to determine the impact of D14 BM characteristics in predicting for remission, association with overall survival (OS), and the effect of 2CI according to the D14 BM results. Patients and MethodsPatients aged 18 to 70 years undergoing induction therapy with standard “7 + 3” regimens were included. D14 cellularity was determined from BMTB samples and the blast percentage was assessed by morphology on BM aspiration and BMTB samples. The outcomes evaluated included the rates of complete remission (CR) and OS. ResultsA total of 486 patients with results from D14 BM evaluation were included in the present study. On multivariate analysis, cytogenetic risk and D14 blasts < 5% were predictive of CR/CR with incomplete count recovery (P < .001). Cytogenetic risk (P < .001), age < 60 years (P = .001), and D14 blasts < 5% (P = .045) predicted for OS. 2CI was performed in 131 patients (27%). Patients with hypocellular D14 BM but residual blasts (n = 106) underwent 2CI in 46% of cases, with improved remission rates (43.9% vs. 72.0%; P = .004) but no difference in OS. ConclusionsThe results from D14 BM evaluations are predictive of subsequent remission and OS. Our findings did not show a survival benefit with D14 BM-driven 2CI.