Induction Chemotherapy For Acute Myeloid Leukemia Research Articles

Outcomes following hematopoietic stem cell transplantation in patients treated with standard chemotherapy with or without gemtuzumab ozogamicin for acute myeloid leukemia

The phase 3 ALFA-0701 trial demonstrated improved outcomes with fractionated-dose gemtuzumab ozogamicin (GO) combined with standard chemotherapy vs. standard chemotherapy alone in adults with de novo acute myeloid leukemia (AML). We examined post-transplant outcomes and occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients who received hematopoietic stem cell transplantation (HSCT) as follow-up therapy in ALFA-0701. Patients aged 50–70 years were randomized to standard chemotherapy with or without GO (3 mg/m2 on days 1, 4, and 7 of induction and day 1 on each of two consolidation courses). Allogeneic HSCT was recommended for patients in first complete remission with matched (related or unrelated) donor, except those with core-binding factor AML or normal karyotype and either NPM1+/FLT3-ITDwt or CEBPA+ AML. Eighty-five patients (GO: n = 32; control: n = 53) received HSCT in first complete remission or after relapse/primary induction failure. Three patients (GO: n = 2; control: n = 1 [received GO as follow-up therapy]) developed VOD/SOS after HSCT or conditioning. Post-transplant survival, non-relapse mortality, and relapse were not different between arms. Results indicate fractionated-dose GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant VOD/SOS or mortality and thus does not preclude the use of HSCT as consolidation treatment.

742. Breakthrough Invasive Fungal Infections with Isavuconazonium Sulfate versus Voriconazole as Primary Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia (AML) who Received Induction Chemotherapy

BackgroundFungal infections in patients with hematologic malignancies are associated with high mortality. Primary antifungal prophylaxis has been shown to be a more effective strategy than treating a documented infection. This retrospective analysis aims to compare the rates of breakthrough invasive fungal infections in patients with acute myeloid leukemia (AML) who received induction chemotherapy and were prescribed voriconazole (Vori) or isavuconazonium (Isv) for primary antifungal prophylaxis.The European Organization for Research and Treatment of Cancer/ Invasive Fungal Infection Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria was used to categorize incidence of breakthrough invasive fungal infections bIFI into ‘possible’, ‘probable’ or ‘definite’ groups who required treatment with liposomal amphotericin B, echinocandin, and/or different triazole.MethodsThis is a single-center retrospective analysis of patients who underwent induction chemotherapy for newly diagnosed AML. These patients received either Vori or Isv sulfate as the primary antifungal prophylaxis at Moffitt Cancer Center between July 2017 and June 2019. Patients who were over 18 years old and received at least 10 days of uninterrupted primary antifungal prophylaxis with either Vori or Isv sulfate were included in the study. Patients with a history of stem cell or solid organ transplant, Human Immunodeficiency Virus, relapsed AML or who received systematic antifungal, other than fluconazole, therapy within 30 days to induction chemotherapy were excluded.Results250 patients were screened for the study and out of which 118 patients met the above criteria. There was a 20.2% (18/89) break through rate of fungal infections in the Vori arm and 17.2% (5/29) in the Isv arm. In the Vori arm there were 15 possible bIFIs, 3 probable bIFIs and 0 definite bIFIs. In the Isv arm there are 2 possible bIFIs, 2 probable bIFIs and 1 definite bIFIs.ConclusionThere is no significant statistical difference (Using the Fisher Exact test statistic p=1) between the Isv and Vori in patients who received these agents for primary fungal prophylaxis for induction chemotherapy for AML at Moffitt Cancer Center between July 2017 - June 2019.Disclosures Rod Quilitz, Pharm D., Astellas (Advisor or Review Panel member)

Adjunction of a Fish Oil Emulsion to Cytarabine and Daunorubicin Induction Chemotherapy in High-Risk AML. the Famyly Pilot Study from the French Innovative Leukemia Organization (FILO)

Background. Acute myeloid leukemia (AML) with unfavorable cytogenetics remains a therapeutic 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 (Picou et al., Pharmacol Res 2018;136:45-55). Objectives. The FILO group launched a pilot clinical study to evaluate the feasibility, safety and efficacy of the adjunction of a commercial FO emulsion (OMEGAVEN) to 3+7 in untreated AML with unfavorable cytogenetics. Patients and methods. The FAMYLY trial was a multicenter single-arm phase II study. Eligible patients had a diagnosis of untreated AML with unfavorable cytogenetics, 18 years old or above. For patients with WBC < 30 G/L, FO was administered at 2 mL/kg/d IV 2 days before 3+7 induction chemotherapy (daunorubicin 60 mg/m² days 1-3 and cytarabine 200 mg/m²/d as a continuous infusion days 1-7), until day 7 of induction. For patients with WBC >= 30 G/L, FO and 3+7 were started concomitantly, and FO was administered until day 9. The primary objective was complete response (CR) on the BM aspirate at the end of induction. Data from 75 patients with adverse cytogenetics and treated with daunorubicin and cytarabine in LAM2001 study (Lioure et al., Blood 2012) was used as a historical control. Serial blood samples were collected before treatment, and on days 1 and 3 after start of treatment, to evaluate the expression of NRF-2 target genes and antioxidant enzymes by RT-qPCR. Results. Thirty patients were included. The median age was 54 years (range: 30-64 years), and only 3 patients were hyperleukocytic. FO administration raised the plasma levels of EPA and DHA (p<0.05). The Cmax of daunorubicin was 92.2 µg/L (Q1; Q3: 44.8; 105.1), and the AUCꚙ 414.9 ng.h, representing a mean clearance Cl=358.5 mL/h and a half-life T1/2=3.5h. The cytarabine clearance was highly variable with a mean of 1.628 L/h. A historical comparison to the LAM2001 trial found no unexpected toxicity. The CR rate was 76%, similar to the daunorubicin arm of the previous study in patients with unfavorable cytogenetics (72%). No survival improvement was observed in a historical comparison. RT-qPCR analysis of NRF-2 target genes and antioxidant enzymes (particularly HMOX1 and NQO1) in sequential blood samples did not show a significant in vivo response. Conclusions. Altogether, FO emulsion adjunction to 3+7 is feasible and safe. Although CR rate improvement was not shown in this cohort of high-risk patients, further research aiming at finding the sufficient dose to trigger an NRF-2 response in vivo should be considered. ClinicalTrials.gov identifier: NCT01999413. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: OMEGAVEN (fish oil emulsion) in Acute Myeloid Leukemia

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

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

Antifungal prophylaxis during 7 + 3 induction chemotherapy for acute myeloid leukemia is associated with improved survival, in a setting with low incidence of invasive mold infections.

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in patients undergoing induction chemotherapy for acute myeloid leukemia (AML). In this patient population, antifungal prophylaxis (AP) has been associated with decreased incidence of IFIs and better survival. However, some centers have not adopted AP during induction chemotherapy for AML, as it is unclear whether AP improves outcomes in settings where the incidence of invasive mold infections is low. We retrospectively assessed the differences in clinical outcomes and resource utilization in patients undergoing 7 + 3 induction chemotherapy for AML, after implementing a policy of AP as part of a dedicated inpatient malignant hematology service (HS) at Rhode Island Hospital. Between January 1, 2007 and April 1, 2019, 56 patients with AML received AP during 7 + 3 induction chemotherapy and 52 patients did not, without significant differences in their baseline characteristics. Use of AP was associated with less proven or probable IFI (0% vs. 6%, P = 0.1) and lower all-cause in-hospital mortality (7% vs. 21%, P < 0.05), without significant increases in resource utilization or toxicities. Empiric and targeted antifungal therapies were more frequently started in the non-AP group (69%) than changed in the AP group (41%, P < 0.005). Having a dedicated inpatient malignant hematology service was also associated with improved outcomes. However, use of AP was associated with better survival (30-day post-induction survival log-rank P < 0.05), prior to the implementation of this clinical service as well, which is suggestive of an independent benefit from AP.

Optimum Induction Chemotherapy for Pediatric Acute Myeloid Leukemia: Experience From A Developing Country.

Treatment outcome in children with acute myeloid leukemia (AML) has improved in the developed world but remains poor in developing countries. We assessed the role of etoposide in induction chemotherapy in pediatric AML. This analysis retrospectively compared 2 induction chemotherapy regimens consisting of daunorubicin and cytarabine with etoposide (ADE) and without etoposide (AD). All newly diagnosed cases of AML younger than 18 years from January 1, 2012, onwards who completed their treatment before January 31, 2019, were included. Data of 186 cases, including 117 males (62.9%) and 69 females (37.1%), were analyzed. Demographic, initial presentation blood counts, and AML subtypes were almost identical in both groups. Complete remission rates were almost identical for the ADE versus the AD group (78.8% vs 80.0%, p = 0.980). Treatment-related mortality was higher, albeit not significantly, in the ADE (25 of 105; 23.8%) versus the AD (16 of 81; 19.8%) group (p = 0.508). Overall survival was 32 of 105 (30.5%) in the ADE and 43 of 81 (53.1%) in the AD group (p = 0.079), and disease-free survival was 29 of 105 (27.6%) and 39 of 81 (48.1%) in ADE and AD groups (p = 0.056), respectively. Etoposide in induction treatment of pediatric AML is associated with increased episodes of bacterial and fungal infections and high treatment-related mortality. Moreover, it does not offer any survival benefit. In low- and middle-income countries like Pakistan, it should not be used in the induction treatment protocol.

Survival Benefits from Antifungal Prophylaxis and a Dedicated Inpatient Malignant Hematology Service during Induction Chemotherapy for Acute Myeloid Leukemia

Introduction: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in patients undergoing induction chemotherapy for acute myeloid leukemia (AML). During induction chemotherapy for AML patients, antifungal prophylaxis (AP) has been associated with a decreased incidence of IFIs and increased survival. However, some centers do not use AP, as it is unclear whether it improves outcomes in settings where the incidence of IFIs is low (&amp;lt;8% of mold infections), as at our center. We retrospectively assessed the differences in clinical outcomes and resource utilization in patients undergoing induction chemotherapy for AML before and after implementation of an AP policy and a dedicated inpatient malignant hematology service at our institution. Methods: AML patients ≥18 years of age who underwent induction chemotherapy between 1/1/07 and 4/1/19 were identified by pharmacy records. Data was verified and extracted by two members of the research team. Primary endpoints were in-hospital mortality during induction chemotherapy and rates of fungal infections within 90-days after induction. Secondary endpoints were 30-day post induction and 90-day post-discharge survival, rates of proven/probable IFI by application of the Mycoses Study Group definitions, diagnostic resource utilization and tolerability. Categorical variables were compared with x2 or Fisher's exact tests and continuous variables with independent samples t-test or the non-parametric Mann-Whitney test as appropriate. Post-induction survival was also analyzed with Kaplan-Meier (KM) curves. Results: 108 adult AML patients were retrospectively reviewed. Fifty-six received AP during induction and 52 did not, without significant differences in demographic or leukemia-specific factors. AP was associated with numerically less fungal infections (9/56 (16%) vs. 14/52 (27%), P=0.169) and proven/probable IFIs (3/52 (6%) vs. 0/56, P=0.1). AP was also associated with lower in-hospital (11/52 (21%) vs. 4/56 (7%), P=0.035) mortality. Clinicians obtained more electrocardiograms (median 4 vs. 1.5, P&amp;lt;0.001) in the AP group; otherwise, there were no significant differences in the number of imaging studies, bronchoscopies, blood cultures, β-D-glucan and Aspergillus galactomannan tests, or adverse events, specifically clinically significant QT prolongation, nephrotoxicity or hepatotoxicity. Antifungals were more likely to be started in the non-prophylaxis group (36/52 (69%)) than changed in the prophylaxis group (23/56 (41%), P=0.003). Implementation of a dedicated inpatient malignant hematology service led to standardization of practices including AP (24/76 (32%) vs. 32/32 (100%), P&amp;lt;0.001) and was associated with significantly lower in-hospital (14/76 (18%) vs. 1/32 (3%), P=0.036) and 90-day post-discharge (16/71 (23%) vs. 1/29 (3%), P=0.021) mortality. Before implementation of this service, AP was associated with numerically lower in-hospital mortality during induction (3/24 (13%) vs. 11/52 (21%), P=0.366), and significantly improved 30-day post-induction survival (Fig. 1, log-rank P=0.042). Conclusions: In a setting where mold infections are rare, AP in patients undergoing induction chemotherapy for AML was associated with improved survival, empiric or targeted antifungal treatment, and a signal for decreased frequency of fungal infections, without substantial increases in utilization of diagnostic resources. This study is limited in its single-center retrospective study design, the overall small number of patients, and is confounded by simultaneous changes in practice, especially with the implementation of a dedicated malignant hematology service. Notably however there was improved 30-day mortality in patients on AP versus those not on AP prior to the implementation of the malignant hematology service. Our findings indicate that outcomes are optimized when adult patients with AML receive their care by a dedicated malignant hematology team, with implications for low-volume institutions and community practices, where AML inductions are not always performed under the care of malignant hematology specialists. Our results suggest that AP and admitting or transferring adult AML patients to a center with a dedicated malignant hematology service, when feasible, may lead to better outcomes. Figure 1 Disclosures Farmakiotis: Astellas: Research Funding; Viracor-Eurofins: Consultancy, Research Funding.

Changes in Gut Microbial Diversity and Correlations with Clinical Outcomes in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Receiving Intensive Chemotherapy

Changes in Gut Microbial Diversity and Correlations with Clinical Outcomes in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Receiving Intensive Chemotherapy

Comparative Analysis of Patterns of Infectious Complications of Outpatient Vs. Inpatient Care Following Intensive Induction Chemotherapy for Adults with Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasms

Comparative Analysis of Patterns of Infectious Complications of Outpatient Vs. Inpatient Care Following Intensive Induction Chemotherapy for Adults with Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasms

Acute Myeloid Leukemia and Cirrhosis: Trends in Utilization of Induction Chemotherapy, Rate of Hospitalizations and Mortality

Introduction: The presence of underlying cirrhosis poses a serious challenge in treatment of newly diagnosed acute myeloid leukemia (AML) patients. In current practice, patients with significant hyperbilirubinemia are precluded from optimal induction and consolidation therapy. Allogenic stem cell transplant is also not a viable option for these patients. This is the first study aimed at evaluating the safety and trends of utilization of chemotherapy in subset of patients with newly diagnosed AML and comorbid cirrhosis, using the Nationwide Inpatient Sample. Methods: We designed a retrospective study using the Nationwide Inpatient Sample (NIS) data, the largest US inpatient database which includes approximately 76 million patients from 2005 to 2014. The authors identified hospitalizations for induction chemotherapy using the primary discharge diagnosis of 'encounter for chemotherapy' (ICD-9 codes -V58.1, V58.11 and V58.12) or procedure codes for 'administration of antineoplastic agent' (0010, 0015, 9925, 9928) and a secondary diagnosis of acute myeloid leukemia, myeloid sarcoma or acute monocytic leukemia. We excluded patients with relapsed disease or in remission. Amongst this population, patients with a diagnosis of cirrhosis including alcoholic, non-alcoholic and biliary cirrhosis were examined to find the differences in baseline characteristics, annual trends in the number of hospitalizations for chemotherapy and total hospitalization charges. We used logistic regression to calculate the adjusted odds ratios (aOR) for in-hospital mortality among these patients. Results: Between 2005 and 2014, a total of 514,032 admissions were identified with a primary diagnosis of chemotherapy for AML. A total of 1,310 (0.25%) admissions had an underlying diagnosis of cirrhosis. The number of hospitalizations for induction chemotherapy in patients with cirrhosis and AML had a statistically significant increase from 62 in 2005 to 195 in 2014. Interestingly, hospitalization for AML patients without cirrhosis has remained largely constant with 52,673 AML patients admitted in 2005 and 55,925 in 2014 (5.8% increase). In-hospital mortality in patients with cirrhosis and undergoing induction chemotherapy for AML was 14.5% (n=9) in 2005, decreasing to almost half at 7.1% in 2014 (n=14). In-patient mortality for AML patients without cirrhosis undergoing chemotherapy has also decreased, from 4.18% (n=2,205) in 2005 to 3.91% (n=2,190) in 2014. Patients with AML and cirrhosis were less likely to undergo treatment at academic centers (81.8%) than those without cirrhosis (87.1%, p=0.046), and they were less likely to possess private insurance (39.3% vs 33.3%, p=0.000). Mortality rate was higher in patients with AML and cirrhosis (12.2%, n=161) than in those without cirrhosis (4.5%, n=23369). The adjusted odds ratio for mortality in patients with cirrhosis was 2.01 (p=0.001), with older age (p=0.00) and caucasian race (p=0.01) being significant confounders. Average hospital cost for each admission for patients with AML and cirrhosis was ($223,723.6±$16,169), significantly higher than for those without cirrhosis ($129,383). Conclusions: Our study highlights the fact that the management of patients with AML and cirrhosis continues to be a dilemma. With the advances in chemotherapy over the last decade, there has been a positive trend with an increase in the number of hospitalizations for induction chemotherapy in patients with AML and cirrhosis as well as a decrease in mortality. However, the pace of improvement remains slow. Moreover, since cirrhosis is more prevalent in the lower socioeconomic strata, these patients are less likely to have private insurance or receive treatment at an academic center, which may contribute to suboptimal care. The increase in mortality in patients with AML and cirrhosis compared to those without cirrhosis can be explained by a compounding effect of AML on pre-existing complications of cirrhosis, such as coagulopathy, thrombocytopenia, encephalopathy, malnutrition and perturbed drug metabolism. Besides, hepatic dysfunction and hyperbilirubinemia often require chemotherapy dose reduction with preclusion of curative options. Further research is needed to develop standard guidelines and non hepatotoxic chemotherapeutic agents. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding.

Additional Cytotoxic Chemotherapy Is Unlikely to Eliminate Measurable Residual Acute Myeloid Leukemia (AML)

Additional Cytotoxic Chemotherapy Is Unlikely to Eliminate Measurable Residual Acute Myeloid Leukemia (AML)

1735. Epidemiology of Invasive Fungal Infections During Induction Chemotherapy in Adults With Newly Diagnosed Acute Myeloid Leukemia Without Antifungal Prophylaxis: A Retrospective Cohort Study

BackgroundWhile invasive fungal infections (IFIs) are common in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy, little current data exist on the epidemiology of IFIs in this patient population given widespread use of antifungal prophylaxis. Because our institution does not administer antifungal prophylaxis, we are in a unique position to study the natural history of IFIs in these patients.MethodsWe evaluated the incidence of IFIs using established definitions in adults with AML undergoing induction chemotherapy at Stanford Health Care from 2012 to 2017. We also analyzed incidence of antifungal treatment, impact of IFI diagnosis on survival, and risk factors for IFI development. Patients were followed for up to 12 weeks after beginning induction chemotherapy.ResultsOf 488 patients analyzed, 243 were eligible for inclusion. The median age was 57 (interquartile range 45–65). Men composed 134 (55%) of the patients and 157 (65%) where white. Fifty-four (22%) had antecedent myelodysplastic syndrome; most received a “7 + 3” regimen involving cytarabine and an anthracycline. Thirty-one (13%) developed a proven or probable IFI; 104 (43%) developed a proven, probable, or possible IFI. Most IFIs were due to lower respiratory tract disease. Eighteen identified organisms were Candida, including six C. albicans. Eight organisms were mold, including four Aspergillus isolates (all but one A. fumigatus) and one isolate each of Fusarium solani, Rhizomucor, Rhizopus, and Scedosporium apiospermum/Pseudallescheria boydii. One hundred ninety patients (78%) received antifungals during their initial admission and 99 (46%) of patients surviving their initial admission were discharged on antifungals. Only 66.7% of patients with a proven or probable IFI survived through 12 weeks, compared with 92.2% of those without (P = 0.007). Baseline absolute neutrophil count ≤500 cells/μL and longer duration of neutropenia were significantly associated with development of proven or probable IFIs.ConclusionAmong patients receiving induction chemotherapy for AML, IFIs due to Candida and mold remain frequent absent antifungal prophylaxis and are associated with worse survival. Our findings support the use of antifungal prophylaxis in this patient population.Disclosures All authors: No reported disclosures.

Gut Microbiome Signatures Are Predictive of Infectious Risk Following Induction Therapy for Acute Myeloid Leukemia.

The majority of studies that provide insights into the influence of the microbiome on the health of hematologic malignancy patients have concentrated on the transplant setting. Here, we sought to assess the predictive capacity of the gastrointestinal microbiome and its relationship to infectious outcomes in patients with acute myeloid leukemia (AML). 16s rRNA-based analysis was performed on oral swabs and stool samples obtained biweekly from baseline until neutrophil recovery following induction chemotherapy (IC) in 97 AML patients. Microbiome characteristics were correlated with clinical outcomes both during and after IC completion. At the start of IC, higher stool Shannon diversity (hazard ratio [HR], 0.36; 95% confidence interval [CI], .18-.74) and higher relative abundance of Porphyromonadaceae (HR, 0.36; 95% CI, .18-.73) were associated with increased probability of remaining infection-free during neutropenia. A baseline stool Shannon diversity cutoff of <2 had optimal operating characteristics for predicting infectious complications during neutropenia. Although 56 patients received therapy >72 hours with a carbapenem, none of the patients had an infection with an extended spectrum β-lactamase-producing organism. Patients who received carbapenems for >72 hours had significantly lower α-diversity at neutrophil recovery (P = .001) and were approximately 4 times more likely to have infection in the 90 days following neutrophil recovery (HR, 4.55; 95% CI, 1.73-11.93). Our results suggest that gut microbiome evaluation could assist with infectious risk stratification and that improved targeting of antibiotic administration during IC could decrease subsequent infectious complications in AML patients.Baseline microbiome diversity is a strong independent predictor of infection during acute myeloid leukemia induction chemotherapy (IC) among clinical and microbiome covariates. Higher baseline levels of Porphyromonadaceae appear protective against infection, while carbapenem use is associated with consequences to the microbiome and infection susceptibility post-IC.

Characteristics and outcomes of therapy-related myeloid neoplasms after peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) for metastatic neuroendocrine neoplasia: a single-institution series.

Peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) is an effective therapy for metastatic neuroendocrine neoplasia (NEN), but therapy-related myeloid neoplasms (t-MN) remain of concern. The study reviewed the clinicopathological features and outcomes of patients who developed t-MN. Retrospective analysis of all patients diagnosed with t-MN by 2016 WHO classification, from a cohort of 521 patients who received PRRT/PRCRT over a 12-year period. Molecular next-generation sequencing using an in-house 26-gene panel was performed. Twenty-five of 521 (4.8%) patients were diagnosed with t-MN, including six acute myeloid leukaemia (AML) and 19 myelodysplastic syndrome (MDS). The median time from first cycle PRRT/PRCRT to diagnosis of t-MN was 26months (range 4-91). Twenty-two of 25 (88%) patients had grade 1-2 pancreatic or small bowel NEN with moderate metastatic liver burden. Six patients (24%) had prior chemotherapy. Median number of PRRT cycles = 5 (22/25 (88%) with concomitant radiosensitising chemotherapy). All 25 patients achieved disease stabilisation (68%) or partial response (32%) on RECIST 1.1 at 3months post-PRRT. At t-MN diagnosis, all patients presented with thrombocytopenia (median nadir 33 × 109/L, range 3-75) and 17 (68%) remained NEN progression-free. Marrow genetic analysis revealed unfavourable karyotype in 16/25 (66%) patients with tumour protein 53 (TP53) mutation in nine (36%). Azacitidine therapy was utilised in ten eligible patients, while four received induction chemotherapy for AML. The median overall survival from first PRRT was 62months (19-94), but from t-MN diagnosis was only 13months (1-56), with death due primarily to haematological disease progression. The diagnosis of t-MN after PRRT/PRCRT is an infrequent but serious complication with poor overall survival. Most patients present with thrombocytopenia; unfavourable genetic mutations have a poor response to t-MN treatment. Prospective data are needed to explore potential pre-existing genetic factors and predictive biomarkers to minimise the risk of t-MN.

Comparison of PEG-rhG-CSF and common rhG-CSF after induction chemotherapy in patients with newly diagnosed acute myeloid leukemia.

e18507 Background: To compare the PEG-rhG-CSF (brand name:jinyouli) with ordinary rhG-CSF in the myelosuppressive phase after induction chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients promotes the recovery of neutrophils. At the same time, the effects of the two drugs on the incidence of infection and hospitalization were compared. Methods: A prospective randomized controlled trial was conducted in which patients with newly diagnosed AML who met the enrollment criteria were randomized into 1:1 groups: 1. PEG-rhG-CSF group: patients ≥45 kg for 6 mg/time, &lt;45 kg for 3 mg/time, subcutaneous injection once on the 5th day after stopping chemotherapy; 2. rhG-CSF group: 5 μg/kg/day until neutrophils count ≥0.5×109/L and/or leukocytes count ≥1.0×109/L. The neutrophil recovery time (duration from day 1 of chemotherapy to neutrophils count ≥0.5×109/L and/or leukocytes count ≥1.0×109/L), infection rate and hospitalization time were collected from the two groups, and the two groups were analyzed and compared using SAS 9.4. Results: From August 2014 to December 2017, 60 patients with newly diagnosed AML were enrolled: 30 patients in the PEG-rhG-CSF group and 30 patients in the rhG-CSF group. Except for the gender composition (P=0.018), there were no significant differences in age, chemotherapy regimen, neutrophils count before chemotherapy, leukocytes count before chemotherapy, and induction efficacy between the two groups. The median time (range) of neutrophils recovery in patients with PEG-rhG-CSF and rhG-CSF was 19 (14-35) days and 19 (15-26) days, P=0.36. The number of patients (ratio) with infection during neutropenia in the PEG-rhG-CSF group and the rhG-CSF group were 27 (90.0%) and 28 (93.3%), P=1. The median length of hospitalization (range) was 20.5 (17-49) days and 21 (19-43) days, P=0.53. Conclusions: In patients with AML induction chemotherapy, there was no significant difference between the application of PEG-rhG-CSF and daily rhG-CSF in neutrophil recovery time, infection incidence and hospitalization time.

Characteristics and Outcomes of Therapy-Related Myeloid Neoplasms after Peptide Receptor Radionuclide/Chemoradionuclide Therapy (PRRT/PRCRT) for Metastatic Neuroendocrine Neoplasia: A Single Institutional Series

Background: Peptide receptor radionuclide/chemoradionuclide therapy(PRRT/PRCRT) is an emerging therapy in patients with metastatic neuroendocrine neoplasia (NEN). However, therapy-related myeloid neoplasms (t-MN) remain a potential complication with substantial adverse outcomes. The study reviewed our PRRT/PRCRT patients who developed t-MN, with regard to their clinicopathological features and outcomes. Methods: Retrospective analysis of all patients diagnosed with t-MN, defined as per revised 2016 WHO classification, from this single centre cohort of 521 patients who received PRRT/PRCRT over a 12-year period. Molecular next generation sequencing using an in-house 26 gene panel were performed. Findings: Twenty-five (4.8%) patients were diagnosed with t-MN, including six acute myeloid leukaemia (AML) and 19 myelodysplastic syndrome (MDS). The median time from first cycle PRRT/PRCRT to diagnosis of t-MN was 26 months (range 4 - 91). Twenty-two of 25 (88%) patients had Grade 1-2 pancreatic or small bowel NEN with moderate metastatic liver burden. The majority, 22 of 25 (88%) received concomitant radiosensitising chemotherapy. All 25 patients achieved disease stabilisation (68%) or at least a partial response (32%) on RECIST 1.1 assessment at 3 months post-PRRT. At t-MN diagnosis, all patients presented with thrombocytopenia (median nadir 33 x 109/L, range 3 - 75) and 17 (68%) were NEN progression free. Marrow genetic analysis revealed unfavourable karyotype in 16/25 (66%) patients and tumour protein 53 (TP53) mutations in nine (36%). Azacitidine therapy was utilised in ten eligible patients, while four received induction chemotherapy for AML. The median overall survival from the time of t-MN diagnosis was 13 months (range 1 - 56), with cause of death due largely to haematological disease progression. Interpretation: The diagnosis of t-MN after PRRT/PRCRT is uncommon but a serious complication with poor overall survival. Most patients present with thrombocytopenia, unfavourable genetic mutations and poor response to t-MN treatment. Funding: No funding source involved. Declaration of Interest: RJH holds shares in Telix Pharmaceuticals on behalf of the Peter MacCallum Cancer Centre. MSH reports personal fees and non-financial support from Ipsen and Sanofi Genzyme, personal fees and other from Endocyte, outside the submitted work. All remaining authors declare no competing interests. Ethical Approval: The study was approved by the hospital’s medical ethics committee as a retrospective audit with approval of waiver for patient consent (HREC Project number 18/61R). All patients had provided written, informed consent for PRRT/PRCRT.

Evaluation of Prognostic Factors after Induction Chemotherapy for Acute Myeloid Leukemia

Purpose: Recent studies have shown that dose escalation of daunorubicin from 45mg/m2 to 90mg/m2 during acute myeloid leukemia (AML) induction showed response benefit and overall survival in patients <=65 years. Yet, the further management of patients with persistent disease based on the evaluation of D14 bone marrow has often been questioned due to lack of data. The primary purpose of this study is to evaluate the overall remission rates of patients with a positive D14 bone marrow compared with those who had a negative D14 results, and to determine if blast % on the D14 bone marrow aspirate is a prognostic indicator for remission and survival in acute leukemia patients who underwent induction chemotherapy. We aim to investigate the relevance of the D14 bone marrow result by dividing the result into blast percent categories and investigate if the there is a correlation between D14 blast % and CR.Patients/Methods: This was an IRB approved retrospective chart review conducted at North Shore University Hospital. Adult patients with AML who received standard induction 7 + 3 Daunorubicin and Cytarabine from 2010 to 2015 were included. 150 patients were reviewed and those that were eligible were evaluated for various factors (D14 blast %, initial marrow blast %, gender, age, cytogenetic risk profile, initial WBC, initial hemoglobin, initial platelets and initial LDH levels, along with those lab values at D14) for tests of association with CR. These patients' D14 blast % biopsies were divided into blast percent categories as followed: (Chemotherapeutic/<1%, 1-10%, 10-30%, 30-60% and > 60%). Complete remission (CR) was defined as patients having <5% blasts on their day 28 bone marrow or day 63 and corresponding neutrophil count >1,000 and platelet count >100 k. Fisher's exact test was used to compare the proportion of patients who reached CR among the D14 blast % categories, and on other categorical data. The Wilcoxon test was utilized to compare CR on continuous variables. Results were considered statistically significant if p < 0.05.Results: 115 patients were analyzed and we found no significant association between D14 blast % and CR status. However, initial blast % was found to be significantly associated with CR status (p=0.009), specifically, those with >60% initially had the greatest CR rate. D14 hemoglobin, D14 platelets or D14 LDH levels were not significantly associated with CR status (p=0.67, p=0.33, and p=0.13, respectively). Similarly, initial WBC, hemoglobin, platelets and LDH levels were each not significantly associated with CR (p=0.99, p=0.51, p=0.47 and p=0.36, respectively). Results did provide evidence to suggest that D14 WBC was significantly associated with CR (p=0.02), but when both D14 WBC and initial blasts % were included in a multiple logistic model, WBC was no longer a significant predictor of outcome. As such, only initial blast percent (at time of diagnosis or initial visit) was deemed predictive of CR response day at D63 (p=0.0142); patients with initial blast >60% had the greatest rate of CR compared with <20% blasts initially.Conclusion: The data suggests that there is no statistical difference between the blast % on the D14 bone marrow and the achievement of CR during induction chemotherapy for AML. Secondary outcomes showed that the initial blast % was associated with CR especially in patients with an initial blast % >60%. Also, D14 WBC might be associated with remission. Prospective studies are required to confirm these findings. DisclosuresNo relevant conflicts of interest to declare.

Clinical Characteristics of GNB1 and GNAS Mutations in an Unselected Cohort of 6,343 Patients with Hematologic Abnormalities

Genes encoding the alpha (GNAS) and beta (GNB1) subunits of the heterotrimeric G-protein complex are recurrently mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Alterations in G-protein coupled receptors can affect signaling via the PI3K/AKT/mTOR and RAS/MAPK pathways, suggesting that GNB1/GNAS mutations may function similarly to mutations in RAS and tyrosine kinases in myeloid disease progression. However, unlike RAS mutations, GNB1/GNAS mutations are among the most commonly affected genes in clonal hematopoiesis of indeterminate potential (CHIP), suggestive of a distinct functional role in myeloid disease initiation.We evaluated 6343 unique patients who received gene panel sequencing at our institution as part of a diagnostic evaluation of known or suspected hematologic malignancy. We identified 68 patients that had at least 1 sample with a mutation in GNB1 (N =42), GNAS (N=24) or both (N=2) (Figure 1). Twenty-six patients had multiple samples (range 2-10) obtained at serial timepoints during the course of progression and treatment. GNB1 mutations affected codon 57 (K57E/M/N/T) in 38 out of 42 cases; the remaining were G53E, D76G, I81V, and K89R. GNAS mutations affected codon 201 (R201H/C) in 23 out of 24 cases.Forty patients had active myeloid neoplasms [AML (N=10), MDS (N=13), MPN (N=11), MDS/MPN (N=5), BPDCN (N=1)]. The distribution of myeloid diagnoses was similar among patients with GNB1 or GNAS mutations. Analysis of serial samples showed that GNB1/GNAS mutations were frequently acquired at the time of leukemic transformation and clinical progression. Among 5 patients with secondary AML, 2 patients acquired GNB1/GNAS mutations at the time of transformation from MDS to AML, and 3 patients were found to have GNB1/GNAS mutations in high-risk MDS prior to subsequent transformation to AML. After induction chemotherapy for AML, two patients had expanded or newly acquired GNB1 mutations at time of treatment failure.Notably, 15 out of the 40 (37.5%) patients with active myeloid disease had co-mutations in the MPN-associated genes JAK2, CALR, and MPL. Eleven of these patients had a clinical diagnosis of MPN, including myelofibrosis (n=5), essential thrombocytosis (n=3), polycythemia vera (n=2), and systemic mastocytosis (n=1). In the context of underlying oncogenic kinase alterations including JAK2 V617F, GNB1 mutations have been shown to promote resistance to kinase inhibitors in vitro. Fourteen out of fifteen patients had no history of ruxolitinib therapy, suggesting that these mutations arise during the course of disease progression in the absence of therapeutic selection pressures. The impact of GNB1/GNAS mutations on the clinical response to JAK inhibitors has not been evaluated.Twenty-eight patients in the cohort (41%) had no evidence of active myeloid disease, including 14 patients with a lymphoid malignancy [mature B-cell neoplasms (n=8), mature T cell neoplasms (n=3), plasma cell neoplasms (n=2), acute lymphoblastic leukemia (n=1)], 6 patients with AML in complete remission, and 8 patients without a clinical diagnosis of hematologic malignancy. Four of the AML patients had a GNAS or GNB1 mutation that was newly acquired or persistent at the time of complete remission following induction chemotherapy. All 4 patients underwent allogeneic stem cell transplant (HSCT) based on disease risk at diagnosis and are alive with median follow up of 2.5 years. In 1 patient, a new GNB1 mutation was identified immediately after HSCT in the context of 100% donor chimerism, suggesting donor-engrafted CHIP. All 8 patients without hematologic malignancy were evaluated for cytopenias or cytoses at the time of the identification of the GNB1/GNAS mutation.GNB1 and GNAS are recurrently mutated in diverse clinical and genetic contexts. In patients with active myeloid disease, MPN-associated mutations were common and GNB1/GNAS mutations were newly acquired at the time of clinical progression, suggesting a functional role similar to other gene mutations that activate mitogenic signaling pathways. However, many GNB1 and GNAS mutations are seen as sole mutations in the absence of active myeloid disease, suggesting that unlike other signaling mutations they can drive initiation of clonal hematopoiesis. The diverse clinical spectrum of patients with GNB1/GNAS mutations suggests that these mutations have distinct, context dependent effects in hematopoietic cells. [Display omitted] DisclosuresKim:Aushon Biosciences: Consultancy; LabCorp, Inc.: Consultancy; Papgene, Inc: Consultancy. Lane:N-of-one: Consultancy; Stemline Therapeutics: Research Funding.

Vascular Access Device Complications during Induction Chemotherapy for AML: A Single Institutional Analysis

Introduction: Induction chemotherapy for acute myeloid leukemia (AML) is fraught with complications ranging from minor to life threatening. Central venous access is routinely achieved to administer cytotoxic chemotherapy to avoid damage to peripheral veins. Vascular access devices (VAD), however, are not without complications, ranging from bloodstream infection (BSI) to thrombosis. There is limited data on the safety of VAD, some showing equivalent risk for DVT across devices. In non AML patients, data has shown that risk of complications increase with the number of lumens within the device. We performed a single institutional analysis to investigate the correlation between VAD and infectious and/or thrombotic complications during induction chemotherapy for AML.Method: We retrospectively reviewed medical records of 93 adults [median age 64 (21-89)] with AML at Beaumont Hospital, an academic community center from January 2010 - December 2015. We extracted data regarding type of VAD, thrombosis, and bloodstream infections during the first 60 days of induction chemotherapy.Results: Demographic distribution of the cohort were 52 (56%) white, 4 (4%) African American, 11 (12%) others. Of these patients, 17 (18%) had single lumen mediport, 41 (44%) had peripherally inserted central catheter (PICC), 12 (13%) had tunneled dual lumen catheter (TDL), 23 (25%) had tunneled triple lumen catheter (TDL). Of the patients with PICC, 2 were single lumen, 1 was triple lumen. In the total population, 33 (35%) developed BSI with the following rates per VAD; Mediport 7 (41.8%), PICC 6 (25.6%), TDL 5 (41.7%), TTL 11 (47.8%). Bloodstream infection rate adjusted for skin flora and fungi were as follows; Mediport 6 (35%), PICC 6 (15%), TDL 2 (17%), TTL 6 (23%). Median time to BSI was 11 days (range 5-60) with no difference between type of VAD. Deep vein thrombosis of the upper extremity occurred in 5 of 93 cases, 4 of which were in patients with PICC and 1 with a TDL. Combined BSI and/or upper extremity thrombosis rate were as follows; Mediport 7 (41%), PICC 14 (36%), TDL 5 (42%), TTL 12 (52%). When adjusted for BSI due to skin flora combined with DVT the rates were Mediport 6 (35%), PICC 10 (25.6%), TDL 2 (17%), TTL 7 (30%).Conclusion: In patients undergoing induction chemotherapy for AML, the choice of VAD was associated with different levels of risk of BSI and DVT. The lowest overall BSI rate was with PICC. When adjusted for BSI due to skin flora or fungi, PICC and TDL were similar. The combined risk of BSI and DVT was lowest with PICC, however, if only accounting for BSI due to skin flora or fungi, then TDL was the safest. A lower rate of line associated DVT risk may be achieved with a tunneled VAD compared to PICC. This data suggests that dual lumen PICC or TDL are the optimal VAD for induction chemotherapy in AML patients.Figure 1. Skin flora include S. epidermidis, Acinetobacter, S. aureus, S. viridans.Fungi includeCandida species, R. mucilaginosa. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Response Rate, Event-Free Survival (EFS), and Overall Survival (OS) in Newly-Diagnosed Acute Myeloid Leukemia (AML): U.S. Food and Drug Administration (FDA) Trial-Level and Patient-Level Analyses

Background: Several novel therapeutics are being developed for AML with demonstrable effects on response rates (e.g. complete remission [CR], CR with incomplete hematologic recovery [CRi], CR with incomplete platelet recovery [CRp], overall response rate [ORR = CR+CRi/CRp]), and EFS. Improvement in EFS recently served as the basis of approval of gemtuzumab ozogamicin (GO) for the treatment of newly-diagnosed CD33-positive AML in adults (Jen et al. Clin Cancer Res 2018). The relationship between response rate, EFS, and OS in newly-diagnosed AML has not been conclusively established. Therefore, we conducted trial-level and patient-level meta-analyses of newly-diagnosed AML trials submitted to the FDA.Methods: We searched for trials submitted with Biologics License or New Drug Applications for treatment of newly-diagnosed AML between 2007 and 2017. Criteria for inclusion were randomized, active-controlled, multicenter trials of intensive AML induction and consolidation chemotherapy. The estimated odd ratios (OR - ratio of odds of response in treatment to odds of response in controls) of CR and ORR and hazard ratios (HR - ratio of hazard of treatment versus control) for EFS and OS were calculated for each study. EFS was defined as time from randomization to treatment failure (defined as date of randomization for patients who failed to achieve CR following induction), disease relapse following CR, or death. Associations between treatment effects at the trial-level were evaluated using weighted least square (WLS) regression analyses on the log-scale (weighted by sample size of each randomized comparison). Coefficient of determination (R2) and 95% confidence interval (CI) were calculated to measure the strength of associations. Individual patient data for OS were plotted against EFS to explore their relationship. An exploratory patient-level responder analysis was performed to compare OS between responders and non-responders, regardless of treatment assignment in the pooled dataset. We estimated HRs of OS from Cox proportional hazards models. OS estimates by response were obtained based on the Kaplan-Meier method.Results: We identified 8 trials with a total of 4482 patients and 3 experimental agents (GO, n=5; [daunorubicin and cytarabine] liposome injection, n=2; midostaurin, n=1) for treatment of newly-diagnosed AML. Two trials tested therapy in defined patient populations (FLT3 mutant = 1 and secondary AML = 1). The association between OS HR and CR OR at the trial-level was moderate (R2 = 0.67, 95% CI: 0.16 - 0.94; Figure 1), whereas the association between OS HR and ORR OR was weak (R2 = 0.43, 95% CI: 0.03 - 0.98). For the OS vs. EFS HR analysis, a weaker than expected association was observed (data to be presented at the meeting). Individual patient level data scatter plots suggested that one possible reason for the lack of a strong association between EFS and OS was that early failures and relapses did not always result in worse OS (Figure 2). In the patient-level responder analysis, patients who achieved a CR response had better OS compared with CRi+CRp response and no response (Figure 3).Conclusions: On a trial level, the meta-analysis of randomized, active-controlled trials in newly-diagnosed AML suggests a moderate association between OS and CR rate, but not ORR. A strong association between EFS and OS is not established and may be confounded by improvements in salvage therapy, supportive care, hematopoietic stem cell transplantation, and/or differing censoring across trials. A patient-level responder analysis showed that CR responders have better OS compared with CRi+CRp responders and nonresponders. While our results are limited by the number of trials, they suggest that CR remains the response endpoint associated with greatest long-term benefit and that EFS, while clinically meaningful, is not a surrogate for OS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.