Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial.

This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044.

Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.

Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

Anticoagulation prophylaxis reduces venous thromboembolism rate in adult acute lymphoblastic leukaemia treated with asparaginase-based therapy.

Venous thromboembolism (VTE) is a well-known complication in adults receiving asparaginase (ASNase)-based intensification chemotherapy for acute lymphoblastic leukaemia (ALL). The optimal preventative strategy is unclear. Our objective is to determine the effects of low-molecular-weight heparin (LMWH) as primary VTE prophylaxis. A single-centred retrospective cohort study of adult patients with Philadelphia chromosome negative (Ph-) ALL who received ASNase-based intensification from 2001 to 2017, with prophylaxis given from 2011 to 2017. In all, 214 patients were included in this study with 99 in the historical control group and 125 in the prophylaxis group. The mean (range) enoxaparin dose was 0·79 (0·39-1·2) mg/kg. Of the 125 patients in the prophylaxis group 17 (13·6%) developed VTE during the intensification phase, while 27/99 patients (27·3%) in the control cohort experienced at least one thrombotic event (odds ratio [OR] 0·42, 95% confidence interval [CI] 0·21-0·83). Overall, the main sites of VTE incidences included deep vein thrombosis in the lower extremity (54·6%), pulmonary embolism (13·6%) and catheter-related thrombosis (22·7%). In addition, we found that after adjusting for age, T-phenotype ALL was associated with VTE development (OR 3·07, 95% CI 1·04-9·08). There was no documented major bleeding in the prophylaxis group. LMWH prophylaxis reduced the incidence of symptomatic VTE in adult patients with ALL receiving intensification chemotherapy with ASNase.

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.

BACKGROUND: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.

A phase II open-label study of aprepitant as anti-emetic prophylaxis in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy.

Despite the widespread use of 5-HT3 antagonists as anti-emetic prophylaxis in patients with acute myeloid leukemia (AML) receiving induction chemotherapy, nausea and vomiting persist in many cases. We performed a Phase II single-arm study evaluating the use of aprepitant on days 1-5, in combination with a 5-HT antagonist on days 1-3, in AML patients undergoing induction chemotherapy with daunorubicin on days 1-3 plus cytarabine, given as a continuous infusion, on days 1-7. This was compared to a retrospective cohort of AML patients that received the same chemotherapy regimen with a 5-HT antagonist but without aprepitant. The cumulative incidence of vomiting/retching by the end of day 5 was significantly lower in the aprepitant vs. the control group (26.3 vs. 52.8%, p = 0.013). The cumulative incidence of nausea by the end of day 5 was 61% in the aprepitant group vs. 75% in the control group. The total use of supplemental anti-emetics on days 2-5 was also significantly lower in the aprepitant group (p = 0.01). In contrast, the cumulative incidence of vomiting/retching by the end of day 8, the incidence of vomiting/retching on days 6-8, and the use of anti-emetics on days 6-8, were not significantly different between the two groups. The results suggest that the use of aprepitant may be associated with a lower rate of emesis during aprepitant dosing days, but not afterward. However, this requires confirmation in a randomized trial.

Predictive value of molecular remissions postconsolidation chemotherapy in patients with Core Binding Factor Acute Myeloid Leukemia (CBF-AML) - a single center analysis.

We analyzed the outcome of 80 sequential patients with core binding factor acute myeloid leukemia and evaluated the influence of molecular monitoring by quantitative reverse transcriptase polymerase chain reaction. With a median follow-up of 5 years, the estimated 5-year relapse-free survival and overall survival were 58% and 66%, respectively. Patients who were in molecular remission at the completion of consolidation chemotherapy had a 21% risk of relapse, while the relapse risk for those in molecular remission at the end of 2 years was 5.5%. Our data indicate that postconsolidation molecular remission does not necessarily preclude disease relapse and further monitoring is required. In contrast, molecular negativity by quantitative reverse transcriptase polymerase chain reaction at the end of 2 years is associated with a low risk of relapse.

Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy.

Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .047). LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856.

Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms.

Leukemic transformation (LT) is a rare but fatal complication of Philadelphia-negative myeloproliferative neoplasms (MPNs) for which optimal treatment strategies are not known. At our center, we have adopted a treatment approach for LT where patients within the transplant age group who have a reasonable fitness level are treated with curative intent and offered induction chemotherapy. Subsequently, those who respond and have a suitable donor are considered for allogeneic hematopoietic cell transplantation (HCT). In this study, we evaluated the clinical outcomes of this treatment approach in 75 patients with LT. The 2-year overall survival (OS) from the time of LT was 15%. A total of 39 patients (52%) were treated with curative intent (induction ± HCT) and had a 2-y OS of 26% compared with 3% in those noncuratively treated (P < .0001). In the curative intent group, 18 individuals (46%) achieved complete remission (CR) or CR with incomplete recovery and 12 (31%) reverted to a chronic MPN phase, with 17 patients undergoing HCT. Survival of patients posttransplant was significantly improved compared with those who responded to induction but were not transplanted (2-y OS of 47% vs 15%; P = .03). Thus, induction chemotherapy followed by HCT has the potential for long-term disease control in select patients with LT preceded by a MPN.

Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for low O(6) -methylguanine DNA methyltransferase expression.

Resistance to temozolomide is largely mediated by the DNA repair enzyme O(6) -methylguanine DNA methyltransferase (MGMT). We conducted a prospective multicentre study of patients with previously untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS) who were not candidates for intensive therapy. Patient selection was based on MGMT expression by Western blot. Patients with MGMT:ACTB (ß-actin) ratio <0·2 were eligible to receive temozolomide 200 mg/m(2) /d ×7 d. Patients achieving a complete response (CR) could receive up to 12 monthly cycles of temozolomide ×5/28 d. Of 166 patients screened, 81 (49%) demonstrated low MGMT expression; 45 of these were treated with temozolomide. The overall response rate was 53%; 36% achieved complete clearance of blasts, with 27% achieving a CR/CR with incomplete platelet recovery (CRp). Factors associated with a trend toward a higher response rate included MDS, methylated MGMT promoter and standard cytogenetic risk group. Induction and post-remission cycles were well-tolerated and most patients were treated on an outpatient basis. Patient who achieved CR/CRp had a superior overall survival compared to partial or non-responders. In conclusion, targeted therapy based on pre-selection for low MGMT expression was associated with a higher response rate to temozolomide compared to previous reports of unselected patients.

Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies.

The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first-in-human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m² oral ciclopirox olamine once daily for five days in 21-day treatment cycles. Pharmacokinetic and pharmacodynamic companion studies were performed in a subset of patients. Following definition of the half-life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m² ciclopirox olamine four times daily. Adverse events and clinical response were monitored throughout the trial. Twenty-three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a short half-life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than those of ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated from patients treated once daily with ciclopirox olamine at doses greater than 10 mg/m², demonstrating biological activity of the drug. Dose-limiting gastrointestinal toxicities were observed in patients receiving 80 mg/m² four times daily, and no dose limiting toxicity was observed at 40 mg/m² once daily. Hematologic improvement was observed in two patients. Once-daily dosing of oral ciclopirox olamine was well tolerated in patients with relapsed or refractory hematologic malignancies, and further optimization of dosing regimens is warranted in this patient population.

A pilot phase II RCT of a home-based exercise intervention for survivors of AML.

BACKGROUND: Fatigue is the most common and disabling symptom affecting quality of life (QOL) and daily function in patients who have completed treatment for acute myeloid leukemia (AML). Although trials in patients with various solid tumors have reported improved fatigue and QOL following exercise interventions, there have been no studies in AML patients post treatment. METHODS: Forty patients aged ≥ 40 years who had completed treatment for AML were enrolled in a 12-week randomized phase II exercise intervention to determine feasibility (recruitment, retention, and adherence), efficacy, and safety of the intervention. Patients assigned to the exercise group received an individualized, moderate-intensity, 12-week home-based exercise program with weekly telephone support from a certified exercise physiologist. QOL, fatigue, and fitness outcomes were measured at baseline, 6 weeks, and 12 weeks. Between-group differences in 12-week change scores were calculated using linear regression adjusting for age and baseline function. RESULTS: Recruitment and retention rates were 38% and 91%, respectively. Adherence was low at 28%. Analyses did not suggest statistically significant or clinically important benefits in QOL, fatigue, or physical fitness with the intervention. The level of adherence did not appear to impact outcomes. There were no adverse events. CONCLUSION: A home-based exercise program for post-treatment AML patients age 40 years or older can be safely delivered with reasonable recruitment and high retention. However, feasibility was hampered by low adherence. Further research and program modification are needed to better understand and overcome barriers to exercise delivery and adherence in AML survivors.

Serum voriconazole level variability in patients with hematological malignancies receiving voriconazole therapy.

INTRODUCTION: Voriconazole plasma concentrations have been correlated with oral dosing in healthy subjects, but have been poorly characterized in ill patients with hematological malignancies receiving intensive chemotherapy. METHODS: The relationship between orally administered voriconazole, plasma concentrations and liver toxicity was examined in a cohort of 69 primarily acute leukemia patients undergoing intensive chemotherapy. RESULTS: Oral administration of voriconazole was associated with significant interpatient variability, with voriconazole steady-state concentrations ranging from 0 µg/mL to 16.6 µg/mL. Approximately 20% of patients achieved steady-state concentrations <1 µg/mL. When adjusted for weight, patients receiving higher voriconazole doses tended toward higher plasma concentrations; however, there was no significant relationship between the plasma concentration and genotype, age, sex or use of concomitant proton pump inhibitors. Voriconazole concentrations were correlated with higher serum alkaline phosphatase levels at day 6 to 8, and with higher bilirubin and aspartate aminotransferase levels at day 14 to 16, but not with other liver enzyme levels. CONCLUSION: In ill patients with acute leukemia and related disorders undergoing treatment with oral voriconazole, there is a poor correlation between the voriconazole dose and plasma concentrations, and many patients achieve levels that are considered to be subtherapeutic. The findings support the routine use of therapeutic drug monitoring in these patients.

INTRODUCTION: Les concentrations plasmatiques de voriconazole sont corrélées avec les doses orales chez les sujets en santé, mais sont mal caractérisées chez les patients malades atteints d'une hémopathie maligne sous chimiothérapie intensive. MÉTHODOLOGIE: Les chercheurs ont examiné le lien entre le voriconazole administré par voie orale et la toxicité hépatique dans une cohorte de 69 patients atteints surtout de leucémie aiguë sous chimiothérapie intensive. RÉSULTATS: L'administration de voriconazole par voie orale s'associait à une importante variabilité interpatient, les concentrations à l'état stable oscillant entre 0 µg/mL et 16,6 µg/mL. Environ 20 % des patients ont obtenu des concentrations à l'état stable de moins de 1 µg/mL. Après rajustement selon le poids, les patients qui receviaent des doses plus élevées de voriconazole avaient tendance à présenter des concentrations plasmatiques plus élevées. Cependant, on ne constatait aucun lien significatif entre la concentration plasmatique et le géno-type, l'âge, le sexe ou l'utilisation concomitante d'inhibiteurs de la pompe à protons. Les concentrations de voriconazole étaient corrélées avec des taux de phosphatase alcaline sérique plus élevés les jours 6 à 8 et à des taux de bilirubine et d'aspartate aminotransférase plus élevés les jours 14 à 16, mais pas à d'autres taux d'enzymes hépatiques. CONCLUSION: Chez les patients malades atteints d'une leucémie aiguë et de troubles connexes qui suivent un traitement au voriconazole par voie orale, la corrélation entre la dose de voriconazole et les concentrations plasmatiques est faible, et de nombreux patients obtiennent des taux considérés comme subthérapeutiques. Les observations soutiennent une pharmacovigilance systématique chez ces patients.

Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial.

BACKGROUND: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies. PATIENTS AND METHODS: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle. RESULTS: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

Treatment of elderly patients with acute lymphoblastic leukaemia using a paediatric-based protocol.

All newly diagnosed patients aged 60-79 years with acute lymphoblastic leukaemia (ALL) receiving induction chemotherapy with a modified paediatric-based regimen over a 7-year period were retrospectively analysed (n = 51, median age 65 years). The treatment regimen consisted of induction, central nervous system prophylaxis, seven cycles of intensification and 24 cycles of maintenance. BCR-ABL1 negative patients received weekly asparaginase during intensification, while BCR-ABL1+ patients received daily imatinib. Post-remission therapy was given in an outpatient setting. The complete response rate was 75%, with an induction mortality of 20%; 6% of patients had resistant disease. 37% of patients who achieved a complete remission relapsed. The estimated 5-year overall survival was 40% for BCR-ABL1 negative and 47% for BCR-ABL1+ patients (P = not significant); the 5-year disease-free survival was 57% and 39%, respectively (P = NS). The post-induction phase was generally well tolerated, with 81% able to complete the intensification phase and proceed to maintenance. In conclusion, administration of this modified paediatric-based protocol is feasible and active for elderly patients with ALL. Survival is superior to most previously reported series in this age group, but remains worse compared to younger patients. Further improvement of the toxicity profile, particularly during induction, is required to improve outcomes.

Ambulatory consolidation chemotherapy for acute myeloid leukemia with antibacterial prophylaxis is associated with frequent bacteremia and the emergence of fluoroquinolone resistant E. Coli.

BACKGROUND: Ambulatory consolidation chemotherapy for acute myeloid leukemia (AML) is frequently associated with bloodstream infections but the spectrum of bacterial pathogens in this setting has not been well-described. METHODS: We evaluated the emergence of bacteremias and their respective antibiotic susceptibility patterns in AML patients receiving ambulatory-based consolidation therapy. Following achievement of complete remission, 207 patients received the first cycle (C1), and 195 the second cycle (C2), of consolidation on an ambulatory basis. Antimicrobial prophylaxis consisted of ciprofloxacin, amoxicillin and fluconazole. RESULTS: There were significantly more positive blood cultures for E. coli in C2 as compared to C1 (10 vs. 1, p=0.0045); all E. coli strains for which susceptibility testing was performed demonstrated resistance to ciprofloxacin. In patients under age 60 there was a significantly higher rate of Streptococccus spp. bacteremia in C2 vs. C1; despite amoxicillin prophylaxis all Streptococcus isolates in C2 were sensitive to penicillin. Patients with Staphylococcus bacteremia in C1 had significantly higher rates of Staphylococcus bacteremia in C2 (p=0.009, OR=8.6). CONCLUSIONS: For AML patients undergoing outpatient-based intensive consolidation chemotherapy with antibiotic prophylaxis, the second cycle is associated with higher rates of ciprofloxacin resistant E. coli, penicillin-sensitive Streptococcus bacteremias and recurrent Staphylococcus infections.

Changing frontline AML treatment patterns from 2013 to 2022.

The treatment patterns for patients with newly diagnosed acute myeloid leukemia (AML) were compared between 2013 and 16 and 2021-22 in a real-world setting. A significantly higher proportion of patients age 70 and over received non-intensive therapy (NIT) in 2021-22 as compared with 2013-16 (65 % vs 44 %, p = 0.014), with a corresponding reduction in the proportion receiving either intensive therapy or no antileukemic treatment. Treatment patterns among patients < age 70 were unchanged. The complete response rate in the NIT group was 69 % in 2021-22 vs. 24 % in 2013-16 (p < 0.001); the overall survival (OS) of NIT patients was 11.5 months in 2021-22 vs. 7.8 months in 2013-16. Older patients from rural areas were more likely to decline therapy than those from urban regions. The increase in the proportion of patients opting for NIT may be related to the availability of more effective treatment options. Although outcomes are improving, the OS with NIT remains suboptimal.