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Introduction Over the past 40 years, therapy intensification has continuously contributed to an improvement in the prognosis of children with AML. Hence, the AML-BFM 2004 trial resulted in a 5-year overall survival rate (OS) of 70%. Similar outcomes backing this claim were obtained by other study groups. During the prospective, randomized AML-BFM 2012 trial, purine analogue clofarabine (C) was introduced to the therapy regimen. Prev. synergistic effects of C combined with cytarabine (A) have been observed in relapsed/refractory ped. AML. It was meant to further increase the antileukemic efficacy in the 1st induction of de novo AML. Clofarabine (C), liposomal daunorubicin (Dx; L-DNR), and cytarabine (A) were randomized against to the stand. induction course of cytarabine, etoposide (E), and L-DNR. The implementation of a stand. stem cell transplantation (SCT) indication for patients with HR AML was another progress. The trials' primary obj. was the improvement of event-free survival (EFS) in ped. AML. Patients and Methods AML-BFM 2012 was an open, interventional, multi-center, prospective, randomized clinical trial for patients with de-novo childhood AML (age Results With a 3-yr OS of 82 ± 3% & 3-yr EFS of 69 ± 4%, respectively, children treated by AML-BFM 2012 have an excellent outcome (median FU: 3.03 yrs.), which is superior to previous trials. The outcome did not significantly differ between ADxE and CDxA. In the study n=9 early deaths (EDs; defined as death Two statistical simulations were used to determine the potential significance of the study's primary obj., if 500 patients had been enrolled. In both simulations, the same progress was assumed for the patient outcome, only extrapolated to the required no. of cases. In the 1st simulation, the actual randomization compliance was retained in favor of the stand. arm ("as treated" simulation). In the 2nd calculation, therapy groups were weighted according to the planned intent-to-treat ratio of 1:1 ("intent to treat" simulation). Various simulated case nos. were translated into whole nos. to fulfill the criteria for the Kaplan-Meier analysis. Neither calculation shows a major effect on EFS or OS for either arm. Conclusion The treatment regimen used in AML-BFM 2012 has an excellent overall outcome, which exceeded outcomes from previous trials. The outcome is not only a result of the intro. of C, despite its potential effectivity in ped. AML. The results are closely linked to a better risk group stratification, improvements of allogeneic SCT in HR patients, and better supportive care. Since L-DNR was successfully evaluated in ped. AML in first and second-line treatment (AML-BFM Study 2004 (Creutzig et al. 2013) / Int. Relapsed AML 2001/01 (Kaspers et al. 2013)), incl. a possible reduction of anthracycline-induced cardiomyopathies, the unavailability of L-DNR due to industrial reasons resulted in severe damage in the treatment devel. in children with malignancies. More early clinical trials are vital to further examine other neoadjuvant drug combs. that replace L-DNR. In summary, AML-BFM 2012 showed an improvement of EFS and OS. Forced termination of clinical trials for commercial reasons is ethically dubious. Pharmaceutical companies need to act responsibly regarding clinical trials involving sick children. The introduction of C as the first-line treatment of ped. AML should be considered feasible. Disclosures Reinhardt: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. OffLabel Disclosure: Clofarabine, Etoposide, liposomal Daunorubicine using in AML frontline treatment in children

Introduction:The design of advanced drug delivery systems based on synthetic and supramolecular chemistry has been very successful. Liposomal doxorubicin (Caelyx®), and liposomal daunorubicin (DaunoXome®), estradiol topical emulsion (EstrasorbTM) as well as soluble or erodible polymer systems such as pegaspargase (Oncaspar®) or goserelin acetate (Zoladex®) represent considerable achievements.Discussion:As deliverables have evolved from low molecular weight drugs to biologics (currently representing approximately 30% of the market), so too have the demands made of advanced drug delivery technology. In parallel, the field of membrane trafficking (and endocytosis) has also matured. The trafficking of specific receptors i.e. material to be recycled or destroyed, as well as the trafficking of protein toxins has been well characterized. This, in conjunction with an ability to engineer synthetic, recombinant proteins provides several possibilities.Conclusion:The first is using recombinant proteins as drugs i.e. denileukin diftitox (Ontak®) or agalsidase beta (Fabrazyme®). The second is the opportunity to use protein toxin architecture to reach targets that are not normally accessible. This may be achieved by grafting regulatory domains from multiple species to form synthetic proteins, engineered to do multiple jobs. Examples include access to the nucleocytosolic compartment. Herein, the use of synthetic proteins for drug delivery has been reviewed.

The emergence of coronavirus disease 2019 (COVID-19) has created new challenges in the management of serious diseases. We describe a 41-year-old male who presented with fever, watery diarrhea, and epistaxis. Initial workup revealed pancytopenia with >50% blasts on the peripheral smear raising suspicion of acute myeloid leukemia (AML) (later confirmed by bone marrow biopsy as AML with myelodysplasia-related changes) and a positive polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the extraordinary risk, he was treated with remdesivir and convalescent plasma for COVID-19. On admission day 8, repeat PCR for SARS-CoV-2 returned negative and the patient was deemed stable for chemotherapy. Therefore, induction was done with liposomal daunorubicin and cytarabine. However, he did not respond to the therapy and was started on re-induction therapy with decitabine and venetoclax. In our discussion, we review the current principles of treatment of patients with concurrent COVID-19 and AML.

Survival in children with relapsed/refractory a cute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m²/day x 5 days) and liposomal daunorubicin (40-80 mg/m²/day) were administered with cytarabine (2 g/m²/day x 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), ≥2ⁿd relapse (n=8). Dose level 3 (30 mg/m² clofarabine; 60 mg/m² liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m² clofarabine with 60 mg/m² liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine expo-sure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub)clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880. CA extern

Background: Liposomal daunorubicin/cytarabine (CPX-351) and hypomethylating agent+venetoclax (HMA+V) have shown survival advantage as frontline therapies for older and biologically adverse AML. Although HMA+V is approved for chemotherapy ineligible pts, there is increased use of the combination in older fit pts. with biologically adverse AML. However, clinical outcomes between the two treatments have not been compared and will have a major clinical impact. Our aim was to compare CPX-351 vs HMA+V as upfront treatment for newly diagnosed AML using a multi-center retrospective study. Methods: This is a multicenter retrospective study drawing from 4 large U.S. academic medical centers (Weill Cornell, Northwestern, Moffitt, Memorial Sloan Kettering). Eligibility included pts who received either CPX-351 or HMA+V as frontline therapy for AML. Response was determined using ELN 2017 guidelines. To evaluate the association between treatment type and categorical factors of interest, and the primary outcome variable of treatment response, the chi-square test or Fisher's exact test was used. For the outcome variable of bone marrow response status, multivariable logistic regression analysis was performed. For the relapse free survival (RFS) and overall survival (OS) outcomes, Kaplan-Meier survival analysis was performed, and the log-rank test was employed to compare between categories of treatment-type and prognostic factors of interest. Multivariable cox proportional hazards regression analysis was performed to assess the independent effect of treatment and demographic/prognostic factors of interest on outcomes of RFS/OS. Results: Our study included 211 CPX-351 and 226 HMA+V treated pts. 11 pts were excluded due to missing age or ELN risk. Pt. characteristics and univariate analyses are summarized in Table 1 and 2. Overall CR+CRi rates, median RFS and OS for CPX-351 vs. HMA+V were 57.8% vs. 56.6%, 32.5 vs. 14.1 months (p=0.11) and 17.3 vs. 11.1 months (p=0.007). In multivariable analysis, after adjusting for age, ELN risk, prior myeloid malignancy, and prior HMA therapy, there was no difference between CPX-351 vs. HMA+V in CR+CRi (HR 1.32, p=0.23, 95% CI 0.8-2.1) and RFS (HR 0.92, p=0.75, CI 0.59-1.46). There was a significant difference favoring CPX-351 for OS (HR 0.74, p=0.04, CI 0.55-0.99). When analyses were restricted to pts aged 60-75 years (n= 152 CPX-351, n= 100 HMA+V), rates of CR+CRi were 59.2% vs. 54.0% (p=0.41), and median RFS and OS for CPX-351 vs. HMA+V treated pts was 32.5 vs. 13.3 months (p= 0.80) and OS 17.1 vs. 10.3 months (p=0.12). Multivariable analysis after adjusting for above variables showed no difference in CR+CRi, RFS and OS between CPX-351 vs. HMA+V (CR+CRi: HR 1.28, p=0.55, 95% CI 0.77-2.27, RFS: HR 0.70, p=0.17, CI 0.42-1.17 and OS: HR 0.80, p=0.20, CI 0.57-1.12). Multivariable subgroup analyses demonstrated significant advantage favoring CPX-351 for RFS in TP53 mutated pts (HR 0.37, 95% C.I. 0.14-0.96, p=0.04). Subgroup analyses for OS are summarized in Figure 2. Among patients where minimal residual disease (MRD) data was available (n=93 CPX-351, n=133 HMA+V), MRD negativity by flow was 34.4% (n=32) and 39.1%(n=52) for CPX-351 and HMA+V pts, respectively (p=0.47). Among pts aged 60-75 years, 47.7% and 19% of patients underwent HSCT in CPX-351 and HMA+V groups (p Conclusion: Our analysis demonstrated significant difference in OS favoring CPX-351 in the overall cohort and in several clinical subgroups, while no difference in CR+CRi and RFS was seen. The survival advantage in the CPX-351 group may be due to higher HSCT rates in CPX-351 treated pts. Among pts that did not proceed to HSCT, there was no difference in CR+CRi, RFS and OS between the treatment groups. We suspect that greater HSCT rates in the CPX-351 cohort were due to fewer comorbidities among CPX-351-treated pts or other biases, and comorbidity analyses are pending and will be reported. Figure 1 Figure 1. Disclosures Ritchie: Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; NS Pharma: Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Protaganist: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Speakers Bureau; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau. Lee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Goldberg: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding; Aprea: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; DAVA Oncology: Honoraria; Celularity: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dinner: Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Glaxo SmithKline: Consultancy; Jazz: Consultancy; Astex: Consultancy; Blueprint Medicines: Consultancy; Mesoblast: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Roche/Genentech: Consultancy; Helsinn: Consultancy; Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding. Desai: Agios: Consultancy; Kura Oncology: Consultancy; Takeda: Consultancy; Astex: Research Funding; Bristol Myers Squibb: Consultancy; Janssen R&D: Research Funding.

Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis in the adult population, despite recent advancements in treatment paradigm. Induction with the liposomal formulation of cytarabine and daunorubicin (CPX-351) which has been shown in phase III trials to improve the median overall survival (OS) compared to standard induction (9.6 versus 5.9 months, respectively) and is FDA approved for patients therapy related AML or AML with myelodysplasia-related changes. Hypomethylating agents (HMA) (azacitidine and decitabine) have recently garnered renewed attention in combination with the BCL-2 inhibitor venetoclax (VEN). Azacitidine with venetoclax demonstrated a median overall survival of 16.9 months in those that were deemed ineligible for intensive induction. While these trials were inherently different patient populations, in clinical practice, physicians must often choose between these two therapies in the frontline setting. Thus, we aimed to examine patient characteristics and respective outcomes with these two treatment approaches. Methods: This was a retrospective cohort studies of patients diagnosed with AML and treated at Virginia Commonwealth University/Massey Cancer Center as identified by our data analytics core between June of 2018 and December of 2020. Data was extracted and manually verified from the electronic medical record into an AML database instrument created in RedCap. Statistical analysis was then performed using GraphPad Prism. Descriptive analyses were conducted for demographics and baseline clinical characteristics, and OS rates were evaluated using Kaplan-Meier analyses and compared using log-rank test. Results: A total of 160 patients with AML were identified. Of those, 58 were treated with either HMA/VEN (N = 43) or CPX-351 (N = 15) in the frontline setting. Median age of patients treated with HMA/VEN was 72 (range: 37 - 85) compared to the median age of 69 (range: 44 - 72) for the CPX-351 group, which was statistically significant (p = 0.002). There was no statistical difference in other demographic characteristics such as sex (p = 0.380), race (p = 0.323), Charleston Comorbidity Index (p = 0.097), or ECOG score (p = 0.126). AML risk stratification based on molecular and cytogenetic data per ELN 2017 also did not differ between the two groups (p = 0.230), with both groups having numerically similar adverse-risk patients (86.7% in the CPX-351 cohort and 70.7% in the VEN cohort). Figure 1 demonstrates a Kaplan-Meier analysis, which revealed a median OS in the VEN group of 281 days (9.23 months) compared to a median OS in the CPX-351 group of 713 days (23.4 months), which was not significant (p = 0.109). Additionally, there was no difference in the OS when only the adverse cytogenetic categories were analyzed from each cohort (Figure 2, p = 0.058). There was one (6.7%) death within 30 days in the CPX-351 group and no deaths within 60 days, compared to one (2.3%) death within 30 days and 9 (20.9%) deaths within 60 days in the VEN group, which was not significantly different (p = 0.257). Allogeneic stem cell transplant was more common in the CPX-351 group (40%) than the VEN group (4.7%) (p = 0.0007). Conclusion : Although these regimens were intended for diverging populations of induction versus non-induction candidates, there is clinical overlap in physician discretion regarding both regimens. Our data shows similar baseline characteristics between these two groups, though the VEN cohort was slightly older. Our data demonstrated that in the CPX-351 cohort, the OS was longer, there appeared to be fewer deaths during induction, and more patients proceeded to transplant - though the former approached statistical significance, particularly when matched with adverse cytogenetic risk (p = 0.058). This argues for continued use of intensive regimen for those who are candidates, especially those in whom allogeneic hematopoietic stem cell transplant is being considered. Prospective studies between these regimens is warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Liposomal daunorubicin and cytarabine (CPX-351) was approved based on data which showed improved overall survival (9.56 v 5.95 months; p = .003) and remission rates (47.7% v 33.3%; p = .016) compared to conventional cytarabine and daunorubicin (7+3) chemotherapy in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients receiving CPX-351 had prolonged time to neutrophil and platelet count recovery compared to 7+3, which was not associated with adverse outcomes (Lancet et al, JCO 2018). Based on these data, our center adopted CPX-351 as a first-line agent in this patient population. Considering the significant cost differences and delays in count recovery, we conducted a comparison of outcomes in patients who received CPX-351 versus 7+3 at our center. Methods: The objective of this study was to compare efficacy and safety of CPX-351 versus 7+3 in patients with sAML. Primary outcome was response rate as defined by CR or CRi. Secondary outcomes included duration of neutropenia, incidence of invasive fungal infections (IFIs), and number of patients proceeding to allogeneic hematopoietic cell transplant (HCT). Patients with sAML receiving induction with 7+3 (daunorubicin dosed at 60 or 90 mg/m2 per treating physician's discretion) or CPX-351 from July 2014 to April 2020 were reviewed. Secondary AML was defined as: AML with a history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), AML with myelodysplasia-related changes, or therapy-related AML. Patients with prior myeloproliferative neoplasms, myelofibrosis, or FLT3 mutations were excluded. Patient characteristics were summarized using descriptive statistics (TABLE 1) including mean for continuous measures and proportions and frequencies for categorical measures. The association between continuous variables and patient groups were assessed using ANOVA or Student's t-test. The associations between categorical variables and patient groups were evaluated using Chi-square test. Results: Over the study period, 65 patients with sAML received induction therapy with either CPX-351 (n = 31) or 7+3 (n = 34). Of these, 61 patients had an evaluable bone marrow biopsy at count recovery. The data is summarized in Table 2. The response rates (CR or CRi) were no different (36% 7+3 vs 36% CPX-351, p = 0.958) among the study population. Longer duration of neutropenia was observed with CPX-351 (33 days 7+3 vs 47 days CPX-351, p = 0.026). More patients in the 7+3 arm proceeded to allogeneic HCT; however, this was not statistically significant (59% 7+3 vs 39% CPX-351, p = 0.105). In an efficacy subgroup analysis of patients with TP53 mutation, there was no difference in response rates (33% 7+3 vs 11% CPX-351, p = 0.224). There was no difference in IFI between the groups (38% 7+3 vs 42% CPX-351, p = 0.761). Upon further analysis of IFI characteristics, there was no difference in choice of mold-active vs non mold-active prophylaxis (ppx) and the incidence of IFIs (40% mold ppx vs 39% non-mold ppx, p = 0.91). Patients with baseline neutropenia prior to induction did not have increased risk of IFIs (65% 7+3 vs 74% CPX-351, p = 0.626). Additionally, there were no between group differences in incidence of IFIs in patients who were neutropenic prior to induction. Conclusions: In the evaluable dataset of patients receiving 7+3 or CPX-351, there was no difference in CR/CRi rate between the two subgroups. There was a longer duration of neutropenia in the CPX-351 group without increased incidence of IFI. However, we report a higher incidence of IFI compared to the study population in Lancet et al (18% Lancet vs 40% Miami) despite appropriate anti-fungal prophylaxis, which may be due to patient selection on the clinical trial, demographic differences (e.g., age, ethnicity), or locoregional environmental factors. In our population, a greater percentage of patients who received 7+3 proceeded to allogeneic HCT. While this study was not powered to detect a significant difference between the two regimens and these findings require validation in larger cohorts, they do not support superior outcomes in patients who receive CPX-351. Data on differences in hospital costs will also be presented. Future directions include a larger multi-center real-world analysis to evaluate patient outcomes, safety, and the financial implications of these two regimens. Disclosures Watts: Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptevo Therapeutics: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees.

The "7+3" regimen is recommended for treatment in patients with new diagnosis of acute myeloid leukemia (AML) who are fit for intensive chemotherapy. Patients with secondary AML (sAML) [i.e. AML evolving from antecedent hematologic disorders (AHD-AML) or after previous exposure to chemo/radiation therapy for unrelated cancer (t-AML)], have inferior outcomes with "7+3" regimen. A recent phase 3 study demonstrated superior CR rates and overall survival (OS) with upfront use of CPX-351 compared to "7+3" regimen in older patients (≥60 years) with sAML (Lancet et al JCO 2018). The combination of HMA+Ven is FDA approved for upfront treatment in newly diagnosed AML patients > 75 or those unfit for intensive chemotherapy based on CR+ CRi rates of 67% and median OS of 17.5 months. Herein, we compared the outcomes of older patients with sAML who received upfront treatment with either HMA+Ven or CPX-351 at our institution. Our analysis includes 47 consecutive patients with previously untreated sAML treated between 2018-2020 . Patients were treated with either HMA+Ven (n=27) or CPX-351 (n=20) based on physician preference. WHO criteria were used for the diagnosis AHD-AML and review of medical records for documenting exposure to leukemogenic agent for t-AML. Complete remission (CR) was defined by presence of 1000/µL and platelets ≥100,000/µL) were defined as CRh (hematologic recovery) and CR without blood count recovery as CRi (incomplete blood count recovery). Minimal residual disease (MRD) assessment was done on day-28 BM aspirate using multiparametric flow cytometric assay with lower limit of sensitivity of 0.01%. Patients demographic and disease features are summarized in Table 1. Mean age (p=0.39), mean blast percentage in BM aspirate (P=0.82), high-risk cytogenetics (P=0.37) and high-risk molecular mutations (P=0.737) were similar in both treatment groups. Of the 27 cases of sAML in HMA+Ven group, 8 were t-AML arising after prior chemotherapy (Hodgkin's Disease n=2; paraganglioma, desmoid tumor, breast cancer, NHL, multiple myeloma, ALL: one each) while 19 were AHD-AML. In CPX-351 group, 6 cases were t-AML arising after prior chemotherapy (NHL n=2, breast cancer n=2, T-Lymphoblastic Lymphoma and colon cancer one each) while 14 were secondary to AHD. The mean number of cycles were 3.3 (range 1-18) in HMA+Ven group and 1.45 (1-3) in CPX-351 group. Two-sample t test was used to compare continuous and normally distributed covariates, such as age and BM blasts, between HMA+Ven or CPX-351 arms. Pearson Chi-square or Fisher exact test was used to assess the associations between treatment and clinical outcomes. Kaplan-Meier method and log-rank test were used to assess OS or LFS. A P value of ≤ 0.05 was considered as statistically significant. The CR rate in patients treated on HMA+Ven group was 78% (n=21; 95% CI: 58-91%) vs 50% (n=10; 95% CI: 27-73%) in CPX-351 group (P=0.047). CRi was achieved in 52% (n=14) patients in HMA+Ven group compared to 25%(n=5) patients in CPX-351 group(p=0.064). MRD negative remission was achieved in 52% (n=14) patients in HMA+Ven group and in 25% (n=5) patients in CPX-351 group (p=0.064). In HMA+Ven group, 52% patients (n=14) achieved remission after one cycle of therapy compared to 45% (n=9) patients in CPX-351 arm (p=0.642). With a median follow-up of 6.7 months for all patients, the median leukemia free-survival (LFS) for HMA+Ven vs CPX-351 treatments is 16.2 vs NA months (P = 0.098) and the median OS is 13.2 vs NA months (P = 0.395). Ten patients in each group (37% in HMA+Ven and 50% in CPX-351; p=0.47) underwent allo-HCT. At last follow up, 14 patients (52%) have died in HMA+Ven group from: relapsed AML (n=10), sepsis (n=2), congestive heart failure (n=1) and unknown (UK) in one patient, whereas in CPX-351 group, 8 patients (40%) have died from relapsed AML in (n=5), respiratory failure (n=2) and UK causes in one patient. In patients resistant to initial therapy, the median OS is 3.5 vs 6.0 months between HMA+ Ven and CPX-351 groups (P = 0.224). Conclusion: In patients presenting with sAML, upfront treatment with HMA+Ven is feasible and associated with significantly better CR rates and a favorable trend for higher rates of negative MRD compared to CPX-351. A randomized prospective trial in patients with sAML is warranted to determine the most effective frontline regimen in this high-risk AML subgroup. Disclosures Salhotra: Celgene: Research Funding; Kadmon: Membership on an entity's Board of Directors or advisory committees. Al Malki:Rigel Pharma: Consultancy; Neximmune: Consultancy; Jazz Pharmacuticals, Inc: Consultancy. Aribi:Seattle Genetics: Consultancy. Ali:Incyte Corporation: Consultancy. Budde:Gilead Sciences: Consultancy; Merck: Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Consultancy; Mustang Therapeutics: Research Funding; AstraZeneca: Research Funding; Roche: Consultancy. Dadwal:Ansun Biopharma: Research Funding; Karius: Research Funding; Shire/ Takeda: Research Funding; Gilead: Research Funding; Merck: Consultancy, Honoraria, Other: Advisory board meeting, Research Funding, Speakers Bureau; Chimerix: Research Funding; Janssen: Other: Advisory board meeting; Astellas: Speakers Bureau. Nakamura:NapaJen Pharma: Consultancy; Kadmon Corporation: Other: Advisory board meeting; Viracor: Consultancy; Magenta Therapeutics: Other: Advisory board meeting; Celgene: Other: Support on seminar; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting. Stein:Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Marcucci:Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Merck: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees; Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial). Pullarkat:Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: off label use of HMA+venetoclax in secondary AML

Introduction Liposomal daunorubicin/cytarabine (Vyxeos® or lipo-CD) is a dual drug liposomal encapsulation, delivering these drugs at a fixed 1:5 synergistic ratio for a longer therapeutic period. Compared to standard 7+3, lipo-CD pts had improved survival and remission rates in a pivotal phase III study, with more reaching allogeneic transplantation (HCT), with lower post-HCT mortality and improved survival. With its enhanced pharmacokinetics, lipo-CD may provide a potent bridge to second transplant for early relapses after HCT. Here, we report our experience. Methods We retrospectively reviewed recipients of lipo-CD at our institution since FDA approval 8/2017. Of 23 pts, 8 relapsed Results Median age was 60 yrs. They received 1-4 lines of therapy (median 2) prior to first HCT with 5/8 pts having received 7+3 (cytarabine 100-200mg/m2 × 7 days + dauno 60-90mg/m2 × 3 days). 6 had adverse cytogenetics/genomic profiles. 7/8 had AML and 1 high grade MDS. Pts relapsed at 2 to 7 mo (median 4 mo) after first HCT, and all 8 received full lipo-CD induction (dauno 44 mg/m2 and cytarabine 100 mg/m2 on Days 1, 3, and 5) as outpatient therapy. [Table] 7/8 had Day 14 bone marrow biopsies: 3 were clear, 2 had >80% cytoreduction, and 2 had similar blast count. 3 with persistent disease underwent re-induction with lipo-CD (Days 1 and 3). All successfully proceeded to second transplant at 15-70 days after lipo-CD: 7 with same donor after melphalan 140mg/m2, and 1 from a different donor after busulfan/fludarabine. Tacrolimus was started on day + 7 and discontinued at day + 28 if no GVHD. 4/8 remain alive. 2 relapsed at 3 and 6 months post-HCT and are remarkably in CR at 19 and 16 mo after second transplant despite isolated CNS relapses, which were successfully treated. The other two relapsed at 2 and 3 mo post-HCT and are alive after second transplant. Conclusion Outpatient lipo-CD as a bridge to second transplant is feasible and effective in treating AML/MDS with early relapse after first HCT. While preliminary, survival appears favorable to that reported (14-23% at 1 year) in this very poor risk group, including those with adverse cytogenetics. Prospective multi-center trials are planned.

The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.

Background Liposomal formulation of anthracyclines provide better systemic and organ-specific tolerance, with potential for less local tissue damage during extravasation. Several small series have reported that most liposomal anthracycline extravasations are consistent with irritant injury without tissue necrosis. There have been no reports published regarding the clinical effects of extravasation of liposomal cytarabine-daunorubicin (CPX-351). Case report The patient received CPX-351 for relapsed acute myelogenous leukemia via a left chest wall port-a-catheter. The catheter became dislodged. Once symptoms developed, the infusion was discontinued, with observations demonstrating an 8-cm region of edema, warmth, no erythema, and no drainage. Limited supportive management was performed. Physical examination the following day demonstrated no evidence of necrosis, and erythema resolved completely without additional intervention. Conclusion CPX-351 extravasation behaving as an irritant is consistent with the reports of other liposomal anthracyclines.

Introduction: Liposomal daunorubicin/cytarabine (Vyxeos®) is a dual drug liposomal encapsulation of cytarabine and daunorubicin, delivering drugs at a fixed 5:1 synergistic ratio for a longer therapeutic period. Compared to standard 7+3, liposomal cytarabine/daunorubicin (lipo-cytara/dauno) patients had improved survival and remission rates in a pivotal phase III study of elder adults with high-risk acute myelogenous leukemia (AML). Furthermore, more lipo-cytara/dauno patients went to allogeneic stem cell transplantation (HCT), with lower mortality and improved survival compared to those induced with 7+3. With its enhanced pharmacokinetics, lipo-cytara/dauno may provide a potent bridge to transplant. We report our experience using lipo-cytara/dauno as a bridge to same donor lymphocyte infusion (DLI) or different donor HCT in high-risk AML. Methods: We retrospectively reviewed all patients who received lipo-cytara/dauno at our institution since the FDA approval in August 2017. Of the 21 patients who have been treated, 9 received it as a bridge to cell therapy. All patients received the drug by usual means under the FDA label. Results: The median age of the 9 patients who received lipo-cytara/dauno as a bridge to cell therapy was 59 years. Seven were male, and two were female. Patients had had 1-4 prior lines of chemotherapy (median 2) with 7 of 9 patients having received prior standard 7+3 induction (cytarabine 100-200 mg/m2 x 7 days infusion and daunorubicin 60-90 mg/m2 x 3 days). Most had adverse cytogenetics, and all 9 patients received full lipo-cytara/dauno induction (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on Days 1, 3, and 5) as outpatient therapy [Table]. Of the 9 patients, 6 had AML with very early relapse after HCT, with median time to relapse of 4 months (range 3 to 7 months). All 6 successfully proceeded to their planned cell infusion: 5 received same donor DLI after melphalan at 140 mg/m2, and 1 underwent second HCT from a different donor with busulfan/fludarabine conditioning at Days 15-40 after lipo-cytara/dauno. Of the remaining 3, two had relapsed AML after an initial remission (one was in first complete remission (CR1) for 3 months after 7+3/midostaurin induction and the other was in CR1 for 7 months after 7+3 induction/high dose cytarabine consolidation) and one had primary refractory disease (PREF) after 7+3 and azacitidine/venetoclax induction regimens. All 3 successfully underwent first HCT at Days 15-100 days after lipo-cytara/dauno bridge. The PREF patient received fludarabine/cyclophosphamide/TBI conditioning followed by matched unrelated donor transplant. Of the 2 with relapsed AML after initial remission, one received busulfan/fludarabine/thiotepa conditioning followed by umbilical cord stem cell transplantation and the other patient received fludarabine/cyclophosphamide/TBI conditioning prior to matched related donor transplant. Six of 9 had Day 14 bone marrow biopsies after lipo-cytara/dauno: 2 were in CR, 2 had >80% cytoreduction, and 2 had similar blast count. Three with persistent disease underwent reinduction with lipo-cytara/dauno (Days 1 and 3) and proceeded straight to cell therapy after. Median days to hospitalization after outpatient lipo-cytara/dauno was 6 days (range 3 to 14 days). Four out of 9 patients remain alive. Two were very early post HCT relapses (relapsed at 3 and 6 months post-HCT), both of which are remarkably in CR at 14 and 17 months after second cell therapy. Interestingly, both had CNS relapse, which were successfully treated, and both remain alive and in remission today. The other two had relapsed AML and PREF AML and underwent first HCT after lipo-cytara/dauno bridge. They remain alive and in remission at 1 and 8 months. Conclusion: In this retrospective study, outpatient lipo-cytara/dauno as a bridge to cell therapy is feasible and effective in very high-risk AML with no other viable options. While preliminary, survival appears favorable to that reported elsewhere at 14-23% at 1 year in this poor risk group, including those with adverse cytogenetic and/or very early post-HCT relapse. Prospective multi-center trials are planned to further evaluate lipo-cytara/dauno as a bridge to DLI/HCT in those with early relapse post-HCT and in those with refractory disease, with therapy to include CNS prophylaxis. Disclosures Stiff: Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding. Tsai:Jazz pharmaceuticals: Speakers Bureau; Jazz pharmaceuticals: Consultancy.

Introduction Most children with acute myeloid leukaemia (AML) harbour fusion genes which are ideal targets for molecular minimal residual disease (MRD) monitoring. However, evidence of prognostic significance is currently lacking and consequently most current paediatric AML treatment protocols rely on flow cytometric (FCM) evaluation to allocate treatment. Molecular MRD techniques provide significantly greater sensitivity and specificity and could allow more accurate outcome prediction, and consequently more personalised therapy, which is highly relevant in a disease where treatment related mortality, morbidity and relapse remain significant. Methods Between June 2016 and February 2019, MyeChild01 enrolled 170 children aged 0-18y with newly diagnosed AML who were randomly assigned to induction therapy with liposomal daunorubicin or mitoxantrone with cytarabine with or without gemtuzumab ozogamicin. Consolidation treatment was determined by karyotype, mutational profile and MRD status. Comprehensive centralised diagnostic assessment consisted of: Karyotype and fluorescence in-situ hybridisation (FISH) using a custom panel of probes to detect paediatric AML-associated gene fusions.PCR based screening for mutations in FLT3, NPM1 and CEPBA.Targeted capture of known fusion loci and paired end sequencing.RNA-seq using the Illumina TruSight fusion panel. Where a fusion gene was identified, RT-qPCR assays were designed and optimised for each patient. NPM1 mutation was also used as an MRD target if present. Paired PB and BM samples were requested after each cycle of treatment. Patients could have sequential monitoring after completion of therapy although this was not mandated. For this analysis, patients with core-binding factor (CBF) leukaemias i.e. inv(16)(p13q22) or t(8;21)(q22q22) with transcript levels above previously defined thresholds (Yin et al, 2012) were considered MRD positive. For all other targets, amplification in at least 2/3 replicates at For patients with CBF or NPM1 mutation, both molecular and FCM MRD status contributed to treatment allocation. Otherwise, FCM MRD was used unless there was no FCM target. Allogeneic stem cell transplantation (HSCT) was recommended for all patients with poor risk cytogenetics, those with intermediate risk cytogenetics who were MRD positive after cycle 2, and those with favourable risk cytogenetics who were MRD positive at the end of cycle 3. After completion of treatment, no specific advice was given regarding management of positive MRD results. Results We identified fusion genes in 126/170 patients (74%). We designed 55 unique RT-qPCR assays to specifically amplify 27 fusions with calculated sensitivity between 1:104 and 1:106. 62/126 children provided a complete set of samples: 31 (60%) with favourable, 18 (29%) with intermediate and 13 (21%) with high risk cytogenetic / molecular profiles. We analysed the effect of molecular MRD status at the end of protocol specified treatment, which included SCT in 17/62 (27%). One year event-free survival from diagnosis was 70% (95% confidence interval 52-82%) in patients who tested MRD negative compared to 11% (1-39%) in patients who tested MRD positive at the end of treatment (p Four patients received non-protocol specified SCT due to physician / family preference based on persistently positive or serially rising transcript levels after completion of treatment. At last follow up 4/4 were alive in complete remission. Rising transcript levels were observed in a further 8 patients to whom no pre-emptive treatment was given due to individual preference or lack of appropriate therapy. Haematological relapse subsequently occurred in 8/8. Conclusion Molecular MRD monitoring is feasible in the majority of children with AML, permitting refinement of response-adapted therapy. Molecular MRD status at the end of treatment is highly predictive of outcome, identifying molecular complete remission as a treatment goal for these children. Serially rising MRD levels reliably predict relapse in the absence of therapeutic intervention. Disclosures Dillon: Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TEVA: Consultancy, Honoraria. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Forty Seven, Inc.: Research Funding; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau. Amrolia:UCLB: Patents & Royalties. Baruchel:Bellicum: Consultancy; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Method: A query was generated to retrieve all cases treated with CPX-351 at Beaumont Health System. SPSS software was used to perform descriptive statistics. Results: We found 11 cases treated with CPX-351 from 2017 to 2019. Six patients were male and 5 females. The median age at diagnosis was 67. Eight patients were Caucasian, two African American and one Asian. The median body mass index (BMI) was 27.1 and median body surface area (BSA) was ! treated with CPX-351 after a diagnosis of AML-MRC and 4 patients (36.3%) with t-AML. The median hospital stay was 35 days. The median units of red blood cells transfusion during hospital stay were 9 units and the median number of transfused platelet units was 6. Only 2 patients (18.1%) achieved complete response (CR) and 2 patients (18.1%) achieved complete response with incomplete blood count recovery (CRi). Three patients developed allergic reactions presented as a rash, 2 patients had significant bleeding and all 11 patients developed neutropenic fever. Three patients died during induction therapy and 2 patients underwent allogeneic hematopoietic stem cell transplant. Six patients (54.5%) died within 90 days of starting induction therapy. Conclusion: t-AML and AML-MRC remain to have dismal prognosis. Our study highlights the high early mortality rate associated with induction therapy with CPX-351. The most common cause of death was refractory or relapsed leukemia. The high incidence of neutropenic fever was also more prevalent to what has been reported. Disclosures No relevant conflicts of interest to declare.

Background Acquired Immune Deficiency Syndrome (AIDS)—related Kaposi's sarcoma (KS) is a rare aggressive tumor. The benefits of drug therapy are established by clinical trials but it has been a challenge to draw comparisons between the different advanced AIDS-KS pharmacotherapy available. This review aims to evaluate the currently approved chemotherapy drugs for the treatment of AIDS-related advanced KS as well as the economic burden and impact on the quality of life of patients. Material and methods Relevant articles were identified through a systematic review of the literature via a search of the National Center for Biotechnology Information (NCBI) PubMed database and the Internet (clinicaltrials.gov) using relevant medical subject heading (MESH) terms. Results A total of 7 phase II and 4 phase III trials of liposomal anthracyclines (liposomal doxorubicin [PLD] and/or liposomal daunorubicin [DNX]) were identified. An evaluation of the trials comparing PLD to a competitor showed statistical difference p ;0.01. DNX phase III trials were also evaluated and showed no statistical differences ( p = 0.64). For paclitaxel, 6 clinical trials were selected (5 phase II and 1 phase III); however heterogeneity was not evaluated. 4 cost-effectiveness studies were compared and 3 concluded that PLD is more cost-effective than the competitor. 4 quality of life studies were analyzed. Conclusion AIDS-KS impacts the patient's life physical, emotional and economic well being. In this work we compared studies of liposomal anthracyclines, still; further research among all the approved drugs for KS is warranted to evaluate efficacy as well as its economic burden worldwide.

Folate polyethylene glycol-cholesterol hemisuccinate (folate-PEG-CHEMS) is a novel folate ligand firstly synthesized by our group and demonstrated good stability and potential targeting results on KB cells in vitro. The current study further explored endocytosis mechanisms of liposomes via folate receptor on L1210JF cells and assessed targeted therapeutic efficacy of folate-PEG-CHEMS anchored liposomes loading daunorubicin (F-L-DNR) in vivo. Folate-PEG-CHEMS was synthesized by a modified method. The liposome properties, cell cytotoxicity, intracellular and intratumoral localization, and therapeutic efficacy on a murine tumor model bearing L1210JF cells were evaluated. High encapsulation efficiency (95.1% ± 1.5%) and appropriate particle size (76.0 ± 35.5 nm) and zeta potential (−12.83 ± 1.36 mV) were achieved for F-L-DNR. IC50 of F-L-DNR on L1210JF cells was 2–3-folds lower than that of non-targeted liposomal daunorubicin (L-DNR). Anticancer efficacy on L1210JF tumor model indicated that mice survival time of F-L-DNR group at doses of 5 mg/kg and 10 mg/kg was significantly longer than that of L-DNR or free DNR. Confocal fluorescence photographs of F-L-DNR indicated enhanced endocytosis of liposomes via folate receptor on L1210JF cells, prolonged retaining time in tumors and improved drug release in the tumor site at 24 h post intravenous injection of F-L-DNR. In conclusion, folate-PEG-CHEMS is an effective ligand for folate-targeted daunorubicin liposomes to achieve increased drug release in tumor and therapeutic efficacy.

Introduction: Liposomal daunorubicin and cytarabine (Vyxeos®) improves overall survival and remission rates compared to conventional daunorubicin and cytarabine (7+3) induction in older patients with secondary acute myeloid leukemia (AML). The safety profiles are similar, despite prolonged time to neutrophil and platelet count recovery with liposomal daunorubicin and cytarabine (Lancet et al, JCO 2018). There are other potential benefits of the liposomal combination, such as the feasibility of outpatient (OP) administration which can improve patient satisfaction and healthcare costs. Herein we show preliminary results of a pilot program based on OP liposomal daunorubicin and cytarabine administration to safely decrease inpatient (IP) days, with close OP monitoring throughout treatment phase until recovery. Methods: The objective of this study is to compare the IP hospital days between patients induced with liposomal daunorubicin and cytarabine in the Inpatient/Outpatient (IPOP) program vs. IP setting. The IPOP program involves administration of chemotherapy and close monitoring of patients in the OP setting who receive traditionally IP chemotherapy regimens. All patients received liposomal daunorubicin and cytarabine induction at a dose of daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 via intravenous infusion over 90 minutes on days 1, 3 and 5. Patients were excluded for IPOP liposomal daunorubicin and cytarabine if they had signs or symptoms of active infection, cardiopulmonary disease, at risk for tumor lysis syndrome, ECOG > 2 or did not have an appropriate caregiver or transportation to the cancer center. Eligible patients received liposomal daunorubicin and cytarabine in the IPOP program and were monitored at least every other day until count recovery. Patients who developed complications such as febrile neutropenia were hospitalized with the goal of de-escalating antibiotic therapy and when appropriate, discharged to IPOP for continued care. Ineligible patients for IPOP treatment received IP liposomal daunorubicin and cytarabine induction and discharged to OP care prior to count recovery if clinically appropriate. A t-test of unequal variance was utilized to determine statistical significance between number of IP days between IPOP and IP groups. Results: Over the study period, 12 patients received induction therapy with liposomal daunorubicin and cytarabine. Seven patients (58%) received IPOP induction and 5 received IP induction (Median age: 72, 67 respectively). One patient was admitted prior to completing the third induction dose, the other six IPOP patients (86%) tolerated OP treatment well. All IPOP patients were eventually admitted, with median of 9 OP days prior to admission (range 4-17 days). All admissions were due to infectious complications: 5 were febrile neutropenia and one was due to a complicated skin/soft tissue abscess. Overall, the IPOP patients were only hospitalized for 46% of total days from start of induction until remission (CR, CRi, PR), progression, or recovery of neutrophils (≥500/µL) and platelets (≥50,000/µL). Mean cumulative days of IP and OP care were 19 and 22 days, respectively. Patients induced in the IP setting were hospitalized for 82% of their induction course with cumulative mean of 31 IP and 7 OP days. Mean cumulative IP hospital days was significantly less in the IPOP group as compared to the IP group (19 vs. 31 days, p=0.034). The overall response rate among the entire cohort was 75% (CR + CRi 50%) and was similar between the IPOP and IP groups. The median time to recover counts in patients who achieved CR + CRi was 36 days for both groups. The overall safety profile was similar between both groups. No patient died during the induction period and two patients successfully underwent hematopoietic stem cell transplantation. Two patients did not respond to therapy and both were eventually discharged with hospice care. Conclusions: In this pilot program, IPOP liposomal daunorubicin and cytarabine induction and management appears to be safe and to significantly reduce the length of hospitalization in patients with secondary AML. Future analyses with larger samples of patients are needed to further evaluate patient outcomes, safety and financial implications based on decreased inpatient hospital utilization. Disclosures No relevant conflicts of interest to declare.

BACKGROUND: In previous studies of frontline therapy for adult acute lymphoblastic leukemia (ALL), early treatment with higher doses of anthracyclines has been reported to improve outcome. The current study was conducted to evaluate whether addition of anthracycline-based consolidation chemotherapy (Course 2) with liposomal daunorubicin (150 mg/m2 intravenously [IV] on Days 1 and 2) and cytarabine (1.5 g/m2 IV on Days 1 and 2) to the standard hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and cytarabine) would improve outcome. METHODS: Sixty-eight consecutive adults with de novo ALL or lymphoblastic lymphoma were treated with this modified hyper-CVAD regimen inclusive of rituximab for CD20 expression ≥20%. RESULTS: Sixty-three (93%) patients achieved complete response (CR). With a median follow-up of 90 months, the 5-year CR duration (CRD) and overall survival (OS) rates were 46% and 44%, respectively. Compared with 208 patients treated with standard hyper-CVAD (rates of 45% and 47%, respectively; P = not significant), outcome with the modified hyper-CVAD regimen was not improved overall. Outcome was improved by the addition of rituximab for the CD20-positive subset (rates of CRD and OS of 50% and 53%, respectively), whereas anthracycline intensification worsened outcome for the CD20-negative subset (rates of CRD and OS of 41% and 35%, respectively; P = .01) compared with standard hyper-CVAD. A high mortality rate related to infections in CR was noted among patients aged 60 years or older. CONCLUSIONS: In the context of the hyper-CVAD regimen, early anthracycline intensification did not improve outcome for adults with de novo ALL or lymphoblastic lymphoma. Cancer 2010. © 2010 American Cancer Society.

The treatment of relapsed acute myeloid leukemia (AML) remains unsatisfactory. We conducted a phase II randomized trial where patients received intermediate-dose cytarabine for four days followed by gemtuzumab ozogamicin on day 5 (Arm A), or combined with liposomal daunorubicin for three days (Arm B), or cytarabine given for five days combined with cyclophosphamide for three days and topotecan by continuous infusion for 5 days (Arm C). Eligible patients had primary refractory AML, a first relapse after a remission of less than one year, or a second or greater relapse. The primary objective of this trial was attainment of a conventional complete remission (CR) or a CR without platelet recovery (CRp) in at least 40% of patients. The CR/CRp rates for the 82 eligible patients were 3/26 (12%) in Arm A, 2/29 (7%) in Arm B, and 1/27 (4%) in Arm C. No patients who had relapsed within six months of initial CR or who had suffered multiple relapses responded. More than 95% of patients subsequently died of AML. No unexpected toxicities were encountered. We conclude that none of these three regimens were effective enough in the treatment of high-risk relapsed or refractory AML to warrant further study. This trial was registered at http://www.clinicaltrials.gov as #NCT00005962.

Kaposi’s sarcoma is a vascular tumor of skin and viscera first described in 1872. Prior to the 1980s, this disease was rarely seen in the Western world, but was quite prevalent in Sub-Saharan African countries. Since the onset of the HIV pandemic in the 1980s, the incidence of Kaposi’s sarcoma has increased markedly in Africa and continues to be a significant problem in association with AIDS in Western countries. Many therapies have been demonstrated to be effective in the treatment of HIV-related Kaposi’s sarcoma, including alitretinoin gel, interferon alpha, and various forms of cytotoxic chemotherapy. Antiretroviral therapy combined with cytotoxic agents has yielded significantly greater efficacy than chemotherapy alone. However, as reviewed in this report, pegylated liposomal doxorubicin has been established as the treatment of choice for patients with AIDS-associated Kaposi’s sarcoma in Western countries. Compelling preclinical and clinical evidence, reviewed herein, has demonstrated that the nanoparticle (pegylated liposome) delivery system of this formulation leads to greater tumor localization of doxorubicin and consequent improved efficacy, as well as reduced toxicity.

Despite a decreased incidence of AIDS-related Kaposi's sarcoma (KS) due to the advent of highly active antiretroviral therapy, approximately 15% of AIDS patients still develop AIDS-related KS. This study evaluated the clinical benefit, tumor response, and safety of pegylated liposomal doxorubicin for the treatment of AIDS-related KS.This was a double-blind, multicenter study that randomized patients with AIDS-related KS to six cycles of pegylated liposomal doxorubicin (20 mg/m2; n = 60) or liposomal daunorubicin (40 mg/m2; n = 19) every 2 weeks. Clinical benefit was assessed using patient questionnaires and monitoring of KS-associated symptoms. Tumor responses were assessed using imaging techniques, direct measurement of skin lesions, and photographs, when possible.Clinical benefit was observed in 48/60 patients (80%) receiving pegylated liposomal doxorubicin and was maintained for a median of 62 days (range, 28-107 days). Clinical benefit was achieved by 12/19 patients (63.2%) receiving liposomal daunorubicin and was maintained for a median of 55 days (range, 28-84 +days). Clinical benefit correlated with tumor response. Tumor responses were achieved by 55.0% of patients receiving pegylated liposomal doxorubicin and 31.6% of patients receiving liposomal daunorubicin. Response rates were similar within each treatment group when only those patients without changes in antiretroviral therapy during treatment were considered. Adverse events associated with pegylated liposomal doxorubicin were neutropenia (30%), nausea (28.3%), and asthenia (16.7%).Pegylated liposomal doxorubicin is safe and effective for the treatment of AIDS-related KS, with most patients experiencing clinical benefit, tumor response, or both.

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, 'DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m(-2) for Group A and 100 mg m(-2) for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

Thirty four patients with advanced soft tissue sarcoma not previously treated with an anthracycline were treated with DaunoXome 100mg/m2 every 3 weeks. Thirty-three patients were evaluable for toxicity. Grade 3-4 neutropenia was seen in 20 patients (60.6%), complicated by febrile neutropenia in 2 (6.1%). Other grade 3 toxicities were rare. Among 32 patients assessable for response, one patient had a partial response, giving a response rate of 3.13% (95% confidence interval, 0.08–16.22%). Seven patients (21.9%) had stable disease, and 24 patients (75.0%) had disease progression. The median time to progression for all patients was 42 days (95% CI, 39–49) and the progression-free rate at 3 months was 12.5%. In conclusion, DaunoXome at this dose and schedule is well tolerated in patients with advanced soft tissue sarcoma, but is not associated with significant activity. Further studies at this dose and schedule cannot be recommended in this disease.

Sixty-two patients with high-risk acute leukemia were treated with the FLAD regimen [3 days of treatment with fludarabine 30 mg/m(2), cytarabine (AraC) 2 g/m(2), and liposomal daunorubicin 80 mg/m(2)]. The acute myeloid leukemia (AML) patients were either refractory to standard induction regimens (8), were in first or second relapse (13), or received therapy as first-line treatment [21 patients, 16 were above 60 years of age and 5 had post-myelodysplastic syndrome (MDS) AML]. The acute lymphoblastic leukemia (ALL) patients were treated for relapsed (7) or refractory disease (10). Three patients had chronic myeloid leukemia (CML) in the blastic phase. FLAD was well tolerated by most patients. Ten major infectious complications were recorded while no signs of cardiac toxicity were observed. Five patients (8%) died before day 28 with hypocellular marrow, mainly of infection or hemorrhage, and response could not be evaluated. Complete response rate was 62% and 69% among AML patients treated at diagnosis or for relapsed disease, respectively, and 59% among the ALL patients. Furthermore, FLAD managed to overcome the negative impact of poor prognosis karyotype in ALL patients, since five of the seven patients with t(9;22) or complex karyotype achieved complete remission (CR). Nine patients underwent bone marrow transplantation (BMT). Among the AML patients who were treated at diagnosis or for relapse, the median duration of CR was 7 months (range: 2-18) and 8 months (range: 2-26), respectively. Median survival among these patients was 8 (range: 1-40) and 12 (range: 1-30) months, respectively. Similar values were found in ALL patients. In conclusion, FLAD may be an effective alternative treatment for patients with relapsed AML and for patients with ALL who failed first-line therapy.

Aims To investigate the population pharmacokinetics of daunorubicin in children after administration of liposomal daunorubicin (Daunoxome®). Methods Plasma samples from 19 children with relapsed acute myeloic leukaemia and five children with other malignancies were collected. Daunoxome® was administered as a 1- to 2.5 h infusion with doses ranging from 30 to 60 mg m−2. Overall, 214 samples were analysed for daunorubicin using capillary electrophoresis, and population pharmacokinetic modelling was performed using NONMEM. Results The data were best described by a one compartment model. Inclusion of interoccasion variability in the model (16.7% for clearance) improved strongly the precision of the estimates. The inclusion of body surface area or height as a covariate decreased interindividual variability. However, the best fit was obtained using the absolute dose, and when weight was included as a covariate for clearance (CL) and volume of distribution (V ). The final parameter estimates were: CL 6.41 ml h−1 kg−1± 0.5 51% and V 65.4 ml kg−1 ± 0.5 27% (population mean ± 0.5 interindividual variability). The area under the curve at a dose of 60 mg m−2 was 231 mg l −1h. Conclusions In comparison with free daunorubicin, Daunoxome® shows a low volume of distribution, a lower clearance and a lower interindividual variability in these parameters. This might be advantageous in reducing the variability in exposure to the drug.

Learning Objectives After completing this course, the reader will be able to: Differentiate liposomal anthracycline formulations. Describe the efficacies and tolerabilities of liposomal anthracyclines as single agents and in combination therapy in the treatment of metastatic breast cancer. Compare the efficacies and tolerabilities of liposomal anthracyclines with those of conventional anthracyclines. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Anthracyclines are a mainstay of therapy for patients with metastatic breast cancer. However, their use has been limited by associated toxicities, including myelosuppression, alopecia, nausea and vomiting, stomatitis, and most importantly, cardiotoxicity. Liposomal anthracyclines were developed to increase the therapeutic index of conventional anthracyclines by maintaining antitumor efficacy while improving the safety profile. There are currently three liposomal formulations: liposomal daunorubicin, liposomal doxorubicin (D-99), and pegylated liposomal doxorubicin. Only one phase I study has been conducted with liposomal daunorubicin for metastatic breast cancer. Liposomal doxorubicin has shown comparable efficacy with conventional doxorubicin and less toxicity. Pegylated liposomal doxorubicin is the most widely studied of the liposomal anthracyclines and has demonstrated similar efficacy to conventional doxorubicin and a better safety profile, including significantly less cardiotoxicity, in patients with metastatic breast cancer. Pegylated liposomal doxorubicin has shown efficacy as a single agent and in combination with many agents, including cyclophosphamide, paclitaxel, docetaxel, and gemcitabine, with response rates ranging from 33%-75%. Growing evidence supports the use of pegylated liposomal doxorubicin as first-line treatment for patients with metastatic breast cancer, owing to its antitumor activity in both anthracycline-naïve patients and in patients with previous anthracycline exposure.

We have conducted a phase I/II trial to determine the maximum tolerated dose, early safety and efficacy of single-agent liposomal daunorubicin in relapsed or refractory acute myeloid leukaemia (AML). Successive cohorts of six patients received escalated doses of 75, 100, 125 or 150 mg/m2 of DaunoXome for three consecutive days. Responding patients received a further consolidation cycle of DaunoXome at a dose identical to the one inducing complete or partial remission at the various dose levels. Twenty-eight patients with a median age of 50.5 years were enrolled. A maximum tolerated dose was determined at 150 mg/m2. Twelve patients received the second cycle. DaunoXome was well tolerated at all administered levels; dose-limiting toxicities included nausea and vomiting, mucositis and two episodes of cardiotoxicity resulting in the death of two patients. The overall response rate was 46% with a median duration of response of 180 d and a median duration of survival of 208 d. Ten patients demonstrated a complete response following cycle 1, and a further four entered partial response with the first cycle (marrow blasts between 5% and 10%). Of these, three attained complete response with the second cycle (total complete response 13/28). Our results indicate that DaunoXome at a dose of 150 mg/m2 displays acceptable toxicity in a 3-d regimen followed by a 3-d consolidation course at 100 mg/m2/d. At this dose schedule, interestingly high remission rates were achieved, justifying further evaluation of DaunoXome for the treatment of relapsed or refractory AML patients.

According to the results of the international study Relapsed AML 2001/01 response was better after re-induction with L-DNR/FLAG (liposomal daunorubicin, fludarabine, cytarabine, G-CSF) compared to FLAG only but survival rate was not improved. However, the findings might be group-specific.Patient characteristics, actual therapy given and long-term course of the disease in 155 pediatric patients (including non-randomized) with first relapse and 10 primary nonresponders treated in Germany were analyzed.Overall 4-year survival rates after relapse were similar in the 2 treatment groups L-DNR/FLAG and FLAG (0.43 ± 0.05 vs. 0.47 ± 0.06, p(log-rank)=0.47). The rate of randomization was low (65%) and 5% of the 101 randomized patients changed the treatment arm. Therefore, induction was based in 40% patients on an individual decision with preference for L-DNR/FLAG. There were less patients with favorable cytogenetics and morphology in the L-DNR/FLAG-group (p0.04). Response to the first re-induction course at day 28 tended to be more unfavorable with FLAG only. In this patient group protocol intensifications were more frequent as compared to the L-DNR/FLAG-group (p=0.07), and late CR could be achieved after intensification in 9/18 poor responding patients.The initial selection bias of relapse patients with unfavorable risk factors to the disadvantage of the L-DNR/FLAG-group and the more drug- and time-intensive treatment after 1(st) re-induction given in the FLAG-group may have nullified the initial beneficial effect of L-DNR containing re-induction therapy and led to similar and relatively favorable survival rates in both treatment groups in Germany.

Summary Purpose To assess the efficacy and toxicity of liposomal daunorubicin administered as a two-hour intravenous infusion to patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) Patients and methods Eligible patients had relapsed or refractory NHL with measurable or evaluable disease, and low grade, select intermediate grade, or mantle cell pathologic types. Prior exposure to an anthracycline or anthracenedione was allowed. Liposomal daunorubicin at a dose of 100 mg/m2 was given intravenously over a minimum of 120 minutes every 3 weeks, as a single agent Results Thirty-three patients were accrued twenty-three (70%) had low-grade histologies, six (18%) had intermediate-grade histologies (follicular large-cell and diffuse small cleaved), and four (12%) patients had mantle-cell lymphoma Eighteen (55%) had received two or more prior regimens, fourteen (42%) received a prior anthracycline A median of six cycles of liposomal daunorubicin were administered (range 1–15) Of 31 patients evaluable for response, 2 complete and 10 partial remissions were documented for a major response rate of 39% (95% confidence interval (CI) 22%–58%). The median duration of response was 195 months (range 4.3–41.1 +) Six responders (50%) had received a prior anthracycline, one responder had mantle-cell histology The major toxicities were grade 3 or 4 neutropenia in 26 patients (79%), mild to moderate nausea in 22 (67%), and fatigue in 16 (48%) Conclusions Liposomal daunorubicin at 100 mg/m2 every three weeks has activity in patients with relapsed or refractory NHL, including patients with prior exposure to an anthracycline Further studies of liposomal daunorubicin in combination with other agents are warranted

The possibility that Daunoxome (DNX), a combination of daunorubicin (DNR) with a liposomal targeting system, escapes PGP was tested. Two pairs of leukaemic cell lines, each consisting of the parental non-multidrug resistance (MDR) line and of a MDR variant, were studied for cytotoxicity (MTT test) and for cellular DNR kinetic and accumulation (flow cytometry). DNX and free DNR were equally toxic against non-MDR cells, whereas the liposomal anthracycline was more toxic than the free drug against the MDR variant. Non-MDR cells accumulated DNR more rapidly when they were exposed to free DNR than to DNX, but MDR cells accumulated more DNR when they were exposed to DNX. The kinetics of DNX and free DNR were also studied in the blast cells of 41 cases of acute leukaemia and they were found to be related to blast cell PGP expression. In 15 cases with a low PGP expression intracellular DNR accumulation was faster and higher with free DNR than with DNX. In 26 cases with a high PGP expression the area under the curve was similar with DNX and free DNR, but the kinetics of intracellular DNR accumulation showed an early low plateau with free DNR and a slow and continuous increase with DNX. In MDR cell lines the ratio was more favourable to DNX than to free DNR. We conclude that liposome encapsulated DNR is partially protected from PGP and that it is worth testing for the treatment of PGP-positive acute leukaemia.

Liposomal formulations have been shown to alter the efficacy and toxicity profiles of anthracylines for patients with HIV-related advanced Kaposi's sarcoma (KS). Using decision-analysis models, the costs and cost-effectiveness of the two U.S. Food and Drug Administration (FDA)-approved liposomal formulations of these agents were estimated. Estimates of costs, effectiveness, and cost-effectiveness were derived from clinical trial data of separate, randomized phase III trials of pegylated liposomal doxorubicin (20 mg/m2 every 3 weeks) and liposomal daunorubicin (40 mg/m2 every 2 weeks). Clinical response rates were 59% for pegylated liposomal doxorubicin and 25% for liposomal daunorubicin. Despite higher acquisition costs for pegylated liposomal doxorubicin, total estimated costs of treatment for KS and chemotherapy-related hematologic toxicities were similar ($7,066 U.S. compared with $6,621 U.S. for liposomal daunorubicin). Cost-effectiveness profiles, defined as average costs per responder, favored pegylated liposomal doxorubicin ($11,976 U.S./responder versus $26,483 U.S./responder for liposomal daunorubicin), reflecting the higher reported response rate in the phase III trial. Sensitivity analyses suggested that the costs and cost-effectiveness results would not differ markedly when evaluated over a range of assumptions, including response rate, neutropenia rate, and dosage variations.

In general, de novo solid tumors are composed of phenotypically and functionally heterogeneous malignant cells. This heterogeneity interferes with the effectiveness of targeted molecular cancer therapies. Even if most of the tumor is killed by a targeted treatment, recurrences are common and can be lethal. In this study, a mixed tumor model, which is predominantly a population of epidermal growth factor receptor (EGFR)-positive A431 cells combined with a smaller population of EGFR-negative Balb3T3/DsRed cells, was established. This mixed tumor was then treated with photoimmunotherapy, a newly developed target-cell–selective cancer therapy using a monoclonal antibody (mAb)–photosensitizer (IR700 fluorescence dye) conjugate and exposure of near-infrared light. Although photoimmunotherapy successfully treated EGFR-positive A431 cells in the mixed tumor, EGFR-negative Balb/DsRed cells were not responsive. However, photoimmunotherapy also induced a large increase in tumor permeability, known as the super-enhanced permeability and retention (SUPR) effect, which allowed a 5-fold increase in the accumulation of a liposomal chemotherapy (DaunoXome) and resulted in more effective therapy than either photoimmunotherapy or liposomal daunorubicin alone. The liposomal daunorubicin, administered 1 hour after EGFR-targeted photoimmunotherapy, was homogeneously distributed, allowing delivery to tiny surviving nests of EGFR-negative Balb3T3/DsRed cells, resulting in prolonged survival of mice. Mol Cancer Ther; 13(2); 426–32. ©2013 AACR.

Outcomes of patients with acute myeloid leukemia (AML) improve significantly by intensification of induction. To further intensify anthracycline dosage without increasing cardiotoxicity, we compared potentially less cardiotoxic liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 vs 12 mg/m(2) per day for 3 days) during induction. In the multicenter therapy-optimization trial AML-BFM 2004, 521 of 611 pediatric patients (85%) were randomly assigned to L-DNR or idarubicin induction. Five-year results in both treatment arms were similar (overall survival 76% ± 3% [L-DNR] vs 75% ± 3% [idarubicin], Plogrank = .65; event-free survival [EFS] 59% ± 3% vs 53% ± 3%, Plogrank = .25; cumulative incidence of relapse 29% ± 3% vs 31% ± 3%, P(Gray) = .75), as were EFS results for standard (72% ± 5% vs 68% ± 5%, Plogrank = .47) and high-risk (51% ± 4% vs 46% ± 4%, Plogrank = .45) patients. L-DNR resulted in significantly better probability of EFS in patients with t(8;21). Overall, treatment-related mortality was lower with L-DNR than idarubicin (2/257 vs 10/264 patients, P = .04). Grade 3/4 cardiotoxicity was rare after induction (4 L-DNR vs 5 idarubicin). Only 1 L-DNR and 3 idarubicin patients presented with subclinical or mild cardiomyopathy during follow-up. In conclusion, at the given dose, L-DNR has overall antileukemic activity comparable to idarubicin, promises to be more active in subgroups, and causes less treatment-related mortality. This trial was registered at www.clinicaltrials.gov as #NCT00111345.

Background Extravasation of cytostatic agents is one of the major complications in cancer treatment with anthracyclines. There is a lot of information about the management of extravasations with ‘classical’ anthracyclines but liposomal anthracyclines have distinctive pharmacokinetics and a different toxic-effect profile. Currently, dexrazoxane is only licensed to treat extravasation with ‘classical’ anthracyclines. However, the efficacy of desrazoxane has been reported in some cases reports. This review collects all extravasation cases that have been published with liposomal and pegylated liposomal anthracyclines, with special emphasis on the use of dexrazoxane. Purpose To review the scientific literature on the development and managenement of anthracycline extravasation injuries, including clinical evidence for desrazoxane. Material and methods A bibliographic review was conducted using the Pubmed database with the following keywords: antracyclines, extravasations and chemotherapy. The period covered was from database inception to September 2015, inclusive. Articles about clinical cases and literature in English or Spanish were included. Practice guidelines and expert consensus were also analysed. Results Practice guidelines and expert consensus were not found. 7 articles fulfilled the inclusion criteria: 5 cases reports (including 6 patients) and 2 series of cases (each series treated in the same way). Extravasated drugs: 3 liposomal doxorubicin, 1 liposomal daunorubicin and 4 pegylated liposomal doxorubicin. General therapy: local cold packs, topical and subcutaneous corticosteroids, painkillers, subcutaneous lidocaine and low weight molecular heparin. Desrazoxane was administered in 3 cases but only 1 article reported the dosage. Symptoms: local oedema, pain, burning, erythema and haematoma. Outcome: only 1 patient treated with local cold packs and washing had necrotic areas and scars; the rest of the cases completely resolved in 2 or 3 months with no skin injury. Since 2006, the date of approval of desrazoxane, 3 of 4 reported cases have been treated with this medicine. Conclusion There is a lack of consensus in the management of extravasations with liposomal anthracyclines, and desrazoxane could be used to treat severe extravasations of liposomal anthracyclines. Therefore, the introduction of this antidote for this medicine needs further study to ensure its efficacy and safety. Hence all oncology services should make a protocol including general interventions and the off-label use of this medicine. No conflict of interest.

A 34-year-old man presented to the hospital with a productive cough, dyspnea, subjective fever, chills, and myalgias. Fever, tachycardia, tachypnea, and severe hypoxemia were noted on arrival. Examination revealed a frail, diaphoretic man in considerable respiratory distress, with diffuse bilateral rales and rhonchi; a violaceous, raised rash over the limbs and trunk was also noted. Findings on chest radiography were suggestive of multilobar pneumonia. A rapid oral antibody test for human immunodeficiency virus (HIV) returned a positive result. Computed tomography of the chest showed striking flame-shaped opacities and spicular thickening of the bronchovascular bundles in all lobes (panels A, B, and C, arrows). These findings are characteristic of pulmonary Kaposi sarcoma (KS).1 In our patient, the diagnosis was confirmed by bronchoscopy and skin biopsy. Computed tomographic features of KS are extremely helpful in guiding the initial management of HIV-infected patients presenting with symptoms of pneumonia. Kaposi sarcoma in HIV-infected patients is diagnostic of AIDS. The goals of therapy in AIDS-associated pulmonary KS are prevention of progression and reduction of tumor burden. Initial management consists of highly active antiretroviral therapy, as this is associated with lesion regression and prolonged survival.2 After optimizing highly active antiretroviral therapy, systemic chemotherapy can be initiated for pulmonary KS. Single-agent chemotherapy can include liposomal doxorubicin, liposomal daunorubicin, paclitaxel, or etoposide. Various combination chemotherapy regimens have been studied and may provide higher response rates compared with single agents.3 Immunosuppression remains a major concern with the use of these agents in patients with AIDS-associated KS. Antiviral therapy directed against human herpesvirus 8 have shown variable success.4 Agents such as interleukin 12 and a variety of angiogenesis inhibitors are under investigation as potential therapies. Our patient initially received noninvasive positive pressure ventilation. He subsequently had worsening respiratory failure and required endotracheal intubation. Until the diagnosis of KS was confirmed, the patient was treated with broad-spectrum antibiotics for severe community-acquired pneumonia as well as coverage for Pneumocystis jirovecii pneumonia. Highly active antiretroviral therapy, in the form of emtricitabine, tenofovir, and efavirenz was administered after stabilization. The patient's respiratory status improved over the following days, and he was successfully extubated and transferred to the medical floor. He experienced a prolonged hospital course that was complicated by suspected immune reconstitution inflammatory syndrome and hospital-acquired pneumonia. Eventually, he was given valganciclovir, doxorubicin, and vinblastine for treatment of KS, but he died after developing overwhelming sepsis.

Summary Background To assess the response rate, toxicity and survival in patients with malignant pleural mesothelioma treated with liposomal daunorubicin. The study design allowed for dose escalation pending toxicity Patients and methods Liposomal daunorubicin (Dauno-Xome, Nexstar, USA) 120 mg/m2 was administered every 21 days to a maximum of 6 cycles Patients had to have histologically-proven malignant pleural mesothelioma Patients were all chemotherapy-naive with ECOG performance status 0–2 Results Fourteen patients were enrolled There were no objective or symptomatic responses though nine patients (64%) had stable disease on therapy Myelosuppression was the major toxicity with 9 of 11 patients evaluable for toxicity experiencing grade 3 or 4 neutropenia Other toxicities seen in at least 30% of patients included grade 3 infection and grade 2 nausea and vomiting The median overall survival by intention-to-treat analysis was 6 1 months from the time of first treatment. The median duration of stable disease from time of first treatment for patients not progressing on therapy was 5 1 months Conclusions Liposomal daunorubicin 120 mg/m2 has no useful clinical activity in patients with malignant pleural mesothelioma Toxicity was substantial with most patients experiencing at least one episode of grade 3 or 4 neutropenia Liposomal daunorubicin cannot be recommended for patients with malignant pleural mesothelioma

PURPOSE: The cancer stem cells play an important role in the invasion, metastasis and relapse of cancers as they are resistant to regular chemotherapy. In the present study, stealth liposomal daunorubicin plus tamoxifen was developed for eradicating breast cancer cells together with cancer stem cells. METHODS: Inhibitory effects were performed on the bulk human breast cancer cells (MCF-7), the sorted MCF-7 cancer stem-like cells (side population, SP), and the sorted MCF-7 cancer cells (NSP), respectively. Antitumor activity and TUNEL analysis were evaluated on the MCF-7 xenografts in nude mice. RESULTS: The encapsulation efficiencies of daunorubicin and tamoxifen were 95% and 90%, respectively. The mean particle size of the stealth liposomes was about 100 nm. Breast cancer stem cells were identified by the specific markers CD44+/CD24-, and isolated from bulk MCF-7 cells. When applying stealth liposomal daunorubicin plus tamoxifen, the inhibitory effects on both the breast cancer cells and the cancer stem cells were significantly increased in vitro, respectively. In the MCF-7 xenografts in mice, stealth liposomal daunorubicin plus tamoxifen showed the most favorable antitumor activity due to the passive targeting the tumor tissue and the synergistic effects in eliminating breast cancer cells and cancer stem cells. CONCLUSION: Stealth liposomal daunorubicin plus tamoxifen could have the potentials in eliminating both breast cancer cells and cancer stem cells.

This randomized phase III clinical trial explored the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) in acute myeloid leukaemia (AML) patients aged >60 years. Three hundred and one AML patients were randomized to receive DNR (45 mg/m(2) days 1-3) or DNX (80 mg/m(2) days 1-3) plus cytarabine (AraC; 100 mg/m(2) days 1-7). Patients in complete remission (CR) received a course of the same drugs as consolidation and then were randomized for maintenance with AraC+ all trans retinoic acid or no further treatment. Among 153 patients in the DNR arm, 78 (51.0%) achieved CR, 55 (35.9%) were resistant and 20 (13.1%) died during induction. Among 148 patients in the DNX arm, 73 (49.3%) achieved CR, 47 (31.8%) were resistant and 28 (18.9%) died during induction. Univariate analysis showed no difference as to induction results. After CR, DNX showed a higher incidence of early deaths (12.5% vs. 2.6% at 6 months, P = 0.053) but a lower incidence of relapse beyond 6 months (59% vs. 78% at 24 months, P = 0.064), with a cross in overall survival (OS) and disease-free survival (DFS) curves and a later advantage for DNX arm after 12 months from diagnosis. DNX seems to improve OS and DFS in the long-term follow-up, because of a reduction in late relapses.

Kaposi’s sarcoma is a vascular tumor of skin and viscera first described in 1872. Prior to the 1980s, this disease was rarely seen in the Western world, but was quite prevalent in Sub-Saharan African countries. Since the onset of the HIV pandemic in the 1980s, the incidence of Kaposi’s sarcoma has increased markedly in Africa and continues to be a significant problem in association with AIDS in Western countries. Many therapies have been demonstrated to be effective in the treatment of HIV-related Kaposi’s sarcoma, including alitretinoin gel, interferon alpha, and various forms of cytotoxic chemotherapy. Antiretroviral therapy combined with cytotoxic agents has yielded significantly greater efficacy than chemotherapy alone. However, as reviewed in this report, pegylated liposomal doxorubicin has been established as the treatment of choice for patients with AIDS-associated Kaposi’s sarcoma in Western countries. Compelling preclinical and clinical evidence, reviewed herein, has demonstrated that the nanoparticle (pegylated liposome) delivery system of this formulation leads to greater tumor localization of doxorubicin and consequent improved efficacy, as well as reduced toxicity.

BACKGROUND AND AIMS The prognosis of Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) patients has improved since the introduction of tyrosine kinase inhibitors (TKI). The inclusion of TKIs in standard ALL protocols allows a great increase in complete molecular responses, but at the price of non negligible toxicities and high rates of toxic deaths. On the other and TKI monotherapy as induction treatment allows to rapidly achieve complete hematologic remission (CR) but only a minority of patients achieve a complete molecular response with high risk of relapse. On the other hand, In the last years we tested a combination of Fludarabine, Cytarabine, Daunoxome (FLAD) with or without TKIs (mainly Dasatinib) as salvage regimen in relapsed-refractory ALL, with acceptable toxicity and good efficacy. We decided to apply the same schedule in newly diagnosed Ph+ ALL as consolidation treatment after a two months TKI (Dasatinib) monotherapy induction on a minimal residual disease condition. MATERIALS AND METHODS FLAD regimen consisted with a three-days administration of Fludarabine 30 mg/sqm followed four hours later by Cytarabine 2000 mg/sqm and Daunoxome 100 mg/sqm. TKI were suspended during chemotherapy administration and were re-administrated starting from day 5. G-CSF was given to all patients from day 4 to complete hematological recovery. FLAD was administrated for up to two cycles; all patients with available donor proceeded to allogeneic bone marrow transplantation (allo-BMT) after FLAD. Minimal residual disease (MRD) was evaluated in all patients after each FLAD either by RQ-PCR for VDJ rearrangements, multicolor flow cytometry (MFC) and RQ-PCR for BCR/Abl. Ten Ph+ ALL have been treated with FLAD + TKIs from January 2008 to December 2014: six patients received FLAD as salvage regimen, two of them in post allo-BMT setting, whereas four patients were treated frontline, after hematological CR was obtained with Dasatinib + steroids induction. All frontline patients proceeded to allo-BMT after two FLAD. Median age for frontline patients was 50 years (range 29-58), median follow-up was 20 months. RESULTS As salvage regimen, 5/6 patients achieved hematological CR after FLAD, with three patients achieving also MFC MRD negativity and clearance of VDJ and BCR/Abl transcript. All patients who did not receive subsequent BMT relapsed, whereas of the two transplanted patients one is still in CR after a follow-up of 38 months. In the frontline setting, all patients received 70 days induction of Dasatinib + Steroids and achieved CR with complete hematological recovery. BCR/Abl transcript could be detected in all patients on BM samples on day 33 and on day 70 (Fig. 1), two patientshad MFC MRD positivity both on day 33 and on day 70, whereas two patients achieved MFC MRD negativity on day 33. FLAD was very well tolerated, with negligible non hematological toxicity, with a median duration of ANC Two patients achieved BCR/Abl negativity after first FLAD. All patients achieved molecular complete response after the second course (Fig. 1). No patient experienced relapse, whereas one patient died in CR on day +289 after allo-BMT due to myocardial viral infection. CONCLUSIONS FLAD has a very good efficacy in adult Ph+ ALL, with an acceptable toxicity profile. Deep responses have been observed in relapsed patients, and all newly diagnosed patients who received FLAD as consolidation regimen had achieved molecular CR before allo-BMT. Achieving complete hematological response with Dasatinib + steroids allowed us to safely administer two FLAD courses. Figure 1. BCR/abl on bone marrow samples at different timepoints for each of the four patients receiving FLAD as consolidation therapy Figure 1. BCR/abl on bone marrow samples at different timepoints for each of the four patients receiving FLAD as consolidation therapy Disclosures Off Label Use: Use of liposomal daunorubicin in the treatment of ALL.

Visceral leishmaniasis (VL) in patients with HIV co-infection presents a significant therapeutic challenge due to the lessened chance of achieving long-term cure. We report a case of VL in a 60-year-old man with HIV infection who became refractory to anti-leishmania treatment due to multi-drug resistance. In the face of a worsening clinical situation, and with no other options available, he was treated with an experimental regimen of liposomal daunorubicin, which has previously been shown to have in vitro activity against Leishmania donovani and to be effective treatment of VL in animal studies. To our knowledge, he was the first patient with VL and HIV co-infection to have this treatment evaluated. We report on the lack of response to this treatment and possible causes for its failure., Author Summary In areas where leishmaniasis is endemic, visceral leishmaniasis (VL) is a potentially incurable AIDS illness in HIV infected people. Co-infection with HIV and any of the Leishmania species that cause VL can result in failure of the CD4 lymphocyte count to rise above 200 cells/mm3 despite sustained, effective suppression of HIV infection, and this failure of CD4 recovery then commonly prevents immune mediated eradication of VL despite aggressive, prolonged anti-Leishmania treatment. The situation is made more challenging by the limited number of agents active against VL and their high rate of adverse effects. We report the first evaluation of liposomal daunorubicin used to treat VL in a patient with HIV and L. infantum co-infection. We selected this drug on the basis of the proven activity of anthracyclines against Leishmania species both in vitro and in animal models and the well tolerated use of daunorubicin in HIV infected patients with Kaposi’s sarcoma. This treatment proved unsuccessful in our patient, probably because resistance of L. infantum to liposomal daunorubicin had been induced by previous treatment with another anti-leishmania drug, miltefosine.

The treatment of relapsed adult acute lymphoblastic leukaemia (ALL) is frequently unsuccessful with current chemotherapy regimens, and often there is an overexpression of multidrug resistance (MDR)-related proteins. Liposomal encapsulation makes daunorubicin (DNR) less sensitive to the efflux effect of P-glycoprotein (PGP), and in vitro data indicate that liposomal-encapsulated DNR (Daunoxome-DNX) is more toxic than DNR against ALL cell lines. In this study, we assessed the in vivo and in vitro efficacy and toxicity of DNX plus cytarabine (Ara-C) as reinduction chemotherapy in 25 relapsed ALL patients (pts). The expression of MDR-related proteins (PGP, MRP1 and LRP) was also analysed. Of the 25 pts, 12 were males and 13 females; median age was 32 yr (range 18-58). Six cases were ALL T and 19 ALL B; eight pts were Ph+ (32%), and nine Bcr-Abl+ (36%). The expression of MDR-related proteins, and DNR and DNX retention and induction of apoptosis in leukaemic cells were evaluated in all cases. Seventeen of 25 (68%) pts were at first relapse and eight (32%) at second or subsequent relapse. The DNX was given in a dose of 80 mg/m(2)/d (days 1-3) in 11/25 pts (44%) and in a dose of 100 mg/m(2)/d (days 1-3) in 14/25 pts (66%). In all pts, Ara-C was administered in a dose of 2 g/m(2) (days 1-5). Twenty pts (80%) achieved a complete remission (CR) and two (8%) entered a partial remission (PR) for an overall response (OR) rate of 88% (22/25), with a tolerable toxicity and without significant cardiotoxicity. Before the start of DNX therapy, 18/25 (72%) cases overexpressed at least one MDR-related protein compared with 9/25 (36%) cases with MDR overexpression at diagnosis (P = 0.01). Taking into account the small number of cases, the response rate was not affected by MDR expression and the in vitro results also showed a higher uptake and apoptotic cell death by DNX compared with DNR. Twelve pts subsequently underwent allogeneic bone marrow transplantation (11 unrelated donor BMT, and one sibling BMT). The overall survival was 39% after 12 months. These data show the efficacy (OR rate 88% and CR rate 80%) of DNX plus Ara-C as reinduction therapy in very poor-risk ALL pts and the response rate seems not to be affected by MDR overexpression. Moreover, the high rate of remissions and the good clinical tolerance in heavily pretreated pts suggest a promising role of DNX in ALL chemotherapy regimens.

Pyrogenic contaminations of some classes of injectable drugs, e.g. toxic or immunomodulatory as well as false-positive drugs, represent a major risk which cannot yet be excluded due to the limitations of current tests. Here we describe a modification of the In vitro Pyrogen Test termed AWIPT (Adsorb, Wash, In vitro Pyrogen Test), which addresses this problem by introducing a pre-incubation step in which pyrogenic contaminations in the test sample are adsorbed to albumin-coated beads. After rinsing, the beads are incubated with human whole blood and the release of the endogenous pyrogen interleukin-1beta is measured as a marker of pyrogenic activity. Intentional contaminations with lipopolysaccharide were retrieved from the chemotherapeutic agents paclitaxel, cisplatin and liposomal daunorubicin, the antibiotic gentamicin, the antifungal agent liposomal amphotericin B, and the corticosteroid prednisolone at lower dilutions than in the standard in vitro pyrogen test. This represents a promising new approach for the detection of pyrogenic contamination in drugs or in drugs containing interfering additives and should lead to improved safety levels.

BACKGROUND The anthracycline/ifosfamide combination is the most effective chemotherapy in soft tissue sarcoma. To improve the tolerability and potential efficacy of this combination, the authors combined a moderate dose of continuous infusion ifosfamide with liposomal daunorubicin (L-Dauno). METHODS In a single-arm, Phase II study, 40 patients with a median age of 57 years (range, 19–78 years) were enrolled. Of these, 35 patients were treated with first-line chemotherapy. The treatment regimen was comprised of ifosfamide at a dose of 5 g/m2 over 24 hours and L-Dauno at a dose of 100 mg/m2 every 4 weeks with granulocyte–colony-stimulating factor support. RESULTS Eleven (31%) of 35 anthracycline/ifosfamide-naive patients achieved a partial/complete response, 6 patients (17%) had stable disease, and 13 patients (37%) had disease progression. Three patients were not evaluable, and there were two intermittent deaths. The median time to disease progression was 6 months, the median overall survival was 14 months, and the median time to treatment failure was 15 months. Toxicity was tolerable. CONCLUSIONS The combination of Ifosfamide and L-Dauno was found to be a highly active chemotherapy regimen for first-line treatment of soft tissue sarcoma. Therefore, we believe randomized studies with this regimen are warranted. Cancer 2005. © 2005 American Cancer Society.