Liposomal Cytarabine Research Articles

MDB-05. PERSONALIZED, RISK ADAPTED THERAPY FOR PEDIATRIC PATIENTS WITH MEDULLOBLASTOMA – A SINGLE CENTER 8-YEAR RETROSPECTIVE REVIEW

Abstract BACKGROUND Clinically relevant risk stratification and optimal therapies for pediatric medulloblastoma molecular subgroups are still being investigated. METHODS We reviewed host/disease characteristics, patient/tumor specific risk adapted therapy and outcomes of patients treated for medulloblastoma at UC Davis since 2016. RESULTS Fifteen patients (age 1-19 years, 12 male, 3 with Li Fraumeni Syndrome (LFS), 2 with spinal cord disease) were included in our review. Tumor histologies included: Classic (n=8), Desmoplastic-Nodular (n=6), Anaplastic (n=1). Tumor genomic profiles were SHHP53WT(n=5), SHHP53 mutated (n=4), Group4 (n=3), NWNSHH (n=2), WNT (n=1). Gross total resection was achieved in 9 patients. Patients with post resection residual tumor, high risk genomic features or disseminated disease were stratified as high risk. We treated all radiation eligible patients (n=13) per COG ACNS0332 maintenance chemotherapy regardless of risk group with 12/13 receiving radiosensitization (Vincristine/Carboplatin) and either 23.4 Gy/36 Gy CSI (two patients treated per Headstart3D2 and ACNS0334 respectively). 2 patients with spinal cord disease were treated with intrathecal topotecan and liposomal cytarabine respectively. During ACNS0332 maintenance bacteremia, weight loss and hypomagnesemia were frequent complications. 5 patients required chemotherapy dose reductions (4 Vincristine/1 Cisplatin). Two patients with LFS developed glioblastoma/undifferentiated pleomorphic sarcoma following ACNS0332 therapy. Two patients (with WNT and NWNSHH subgroup tumors) experienced medulloblastoma relapse. These patients were treated using LITT/Intrathecal chemotherapy and ACNS0821 chemotherapy. Both are alive and one patient is NED off therapy. All patients who have not developed secondary malignancies (n=13) are alive. (follow up 7-72 months). All attend school with support, 10 have hearing impairment and 5 receive endocrine supplements. CONCLUSIONS Utilizing patient specific risk adapted therapy we have achieved favorable clinical outcomes in our patient cohort. Therapy deintensification for patients with WNT medulloblastomas should be approached with caution. Patients with LFS might require radiation sparing therapeutic protocols for longer term benefit.

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNAsplicing factormutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

IELSG30 phase 2 trial: intravenous and intrathecal CNS prophylaxis in primary testicular diffuse large B-cell lymphoma

AbstractPrimary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724.

Cardiotoxicity of CPX-351 in children and adolescents with relapsed AML: a Children's Oncology Group report.

Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421. Subjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%. Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF. In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).

Multicenter Pilot Trial of Intrathecal Liposomal Cytarabine Combined with FAB Chemoimmunotherapy with Reduced Doxorubicin in CAYA with Mature De-Novo B-NHL

Background: Children, adolescents, and young adults (C-AYA) with newly diagnosed advanced Mature B Non-Hodgkin Lymphoma (MB-NHL), specifically Burkitt Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBCL), have achieved ≥ 90% overall survival with multi-agent chemotherapy and intrathecal chemotherapy (IT) without central nervous system (CNS) radiation (Cairo et al., Blood 2007; Goldman/Cairo et al., BJH 2014; Frazier/Cairo, et al., BJH 2014; Minard-Colin, et al., NEJM 2020). Standard therapy includes short but intensive courses of multiagent chemotherapy including CNS-penetrating high dose methotrexate and cytarabine for CNS penetration as well as vincristine, prednisone, doxorubicin, and cyclophosphamide with or without etoposide. Patients also receive 9, 10 and 13 IT doses of intrathecal chemotherapy when treated according to FAB Group B, FAB Group C (CNS -) and FAB Group C (CNS +) protocols, respectively. While this approach has effectively eliminated need for CNS radiation for disease control, the need for sedation of patients during these procedures results in the need for repeated episodes of patient fasting, increased healthcare costs, and most importantly, general anesthesia is associated with long-term late effects in cognitive development (Banerjee et al., JAMA Oncol, 2019). Liposomal cytarabine (LC) is a formulation of cytarabine encapsulated in spherical multivesicular, biodegradable particles known as DepoCyt® which has a maximum-tolerated intrathecal dose of 35 mg in patients between the ages of 3 and 21 years (Bomgaars et al., JCO, 2004). This liposomal formulation has a half-life of 100-263 hours compared with only 3.4 hours of standard cytarabine. As an s-phase specific agent, prolonged exposure may increase its efficacy in controlling CNS disease while decreasing the total number of intraventricular doses required for treatment. Objective: To determine the safety and efficacy of reduction of IT therapy and substitution of LC within modified FAB group B and C backbones of systemic immunochemotherapy. Methods: LC was incorporated into the multiagent chemotherapy regimen in a unique manner to mitigate the risk of possible CNS toxicity. A total of 2 doses of LC were administered as part of the prophylaxis IT therapy for Group B and CNS negative group C patients. A total of 4 doses of LC were administered as part of the treatment of Group C CNS + patients (Table 1). The LC was given only in phases of therapy in which no systemic cytarabine was administered. When Methotrexate was given, the LC was only given after clearance. Dexamethasone replaced prednisone for all patients to mitigate potential CNS toxicities from LC. Results: This trial enrolled 33 patients with newly diagnosed MB-NHL (25 Group B, 8 Group C with 7 CNS+). Median age was 12 (Range 3-25). Males comprised 64% of patients and 52% had Burkitt Lymphoma/Leukemia. The CNS was involved in 21% of patients, and a total of 78 doses of LC was given. Twenty-six patients received 2 prophylactic doses (25 Group B and 1 Group C CNS negative). Six of seven CNS + patients received all 4 planned doses of LC. The median days from the start of the induction cycles until LC administration (post methotrexate clearance) was 3 days. Of the 33 patients, only 1 (3%) had a transient Grade 3 adverse event (facial nerve palsy). With dexamethasone prophylaxis, there were minimal adverse events and no toxic deaths reported. There were no other serious adverse events, such as seizure, headaches, nausea, vomiting, fever, somnolence, confusion, or asthenia that have been previously reported. The 2-year EFS and OS of LC when added to an FAB backbone for MB-NHL, was 94.5% and 97.2%, respectively (Figure 1). Conclusions: By utilizing dexamethasone prophylaxis and waiting for systemic methotrexate clearance, we were able to demonstrate that IT LC in C-AYAs with MB-NHL who received FAB chemoimmunotherapy with HD MTX was feasible, safe, and did not compromise event free and overall survival. We were also able to reduce the total number of IT injections without apparent compromise to CNS prophylaxis and treatment.

TP53-Mutated Acute Myeloid Leukemia Patients Treated with Intensive Therapies Have Superior Outcomes: A Single Institution, Retrospective Study

Background: Mutations in TP53, found in 5-20% of acute myeloid leukemia (AML), confer poor prognosis and are associated with high rates of therapy resistance, high relapse rates, and dismal overall survival (OS). Recent advances have provided a variety of options for up-front AML therapy including a liposomal preparation of standard-of-care chemotherapy (CPX-351) and venetoclax-based combinations. Due to known poor outcomes with intensive chemotherapy, many providers are favoring less intense strategies for patients with TP53 mutant AML, but these approaches have not been directly compared for this patient subgroup. Strategies for treating TP53 mutant AML are highly heterogeneous and optimal treatment strategies have not been defined in this setting. We performed a retrospective study to compare the clinical outcomes of TP53 mutant AML patients treated at our center. Methods: The study was a single-center, retrospective cohort analysis conducted at the University of Minnesota. Adult patients (age ≥18 years) with the diagnosis of AML or myeloid sarcoma between January 1, 2014 and July 31, 2022 who have next-generation sequencing panel confirming a pathogenic TP53 mutation and received front-line therapy for AML at our center were included in this study. Kaplan-Meier analysis was used to estimate the probabilities of OS, defined as the date of treatment initiation to the date of death from any cause or last follow-up. Results: Our study includes 88 patients with TP53 mutant AML with available clinical data in an AML registry at our institution. Baseline demographic and clinical characteristics are summarized in Table 1. The median age at diagnosis was 67 years (range 28-87) with male predominance (65.9%). Among this, 15/88 patients (17.1%) had therapy-related AML and 40/88 patients (45.5%) had secondary AML. The median bone marrow blast percentage at diagnosis was 31% and peripheral blast percentage was 9%. The majority of patients have high variant allelic frequency (VAF, 71.9% with VAF &amp;gt; 0.4 for patients with available VAF data) and ASXL1 was the most frequent co-mutation identified followed by KRAS and NRAS. Treatment regimens were classified as intensive or nonintensive. Intensive treatment regimens included infusional cytarabine with either daunorubicin or idarubicin (7+3), liposomal cytarabine and daunorubicin (CPX-351), and mitoxantrone, etoposide and cytarabine (MEC). Nonintensive regimens included hypomethylating agents (decitabine or azacitidine) with or without venetoclax and clofarabine with low-dose subcutaneous cytarabine. A total of 66 patients were included in the survival analysis. There was no significant difference in OS between patients aged &amp;lt; 65 years and ≥ 65 years at diagnosis (2-year OS, 11% versus 5%, P=0.76). Superior 2-year OS was observed in patients who received front-line intensive (n = 31) versus nonintensive (n = 35) induction chemotherapy (2-year OS, 13% versus 3%, P=0.01, Figure 1). Patients who received intensive therapy for any line of treatment also demonstrated superior OS compared to those who never received intensive therapy (2-year OS, 12% versus 3%, P=0.02). The rate of achieving complete remission (CR) was higher in patients who received intensive treatment compared to non-intensive therapy in the first-line (51.6% versus 25.7%, P=0.03). Rate of CR at any time was also higher for patients who received intensive treatment for any line of treatment (50% versus 18.2%, P&amp;lt;0.01). Among the intensive first-line treatment group, 7+3 (n = 18) showed superior OS relative to CPX-351 (n = 12) (2-year OS, 22% versus 0%, P=0.03) although there was no significant difference in CR rate (55.6% versus 50%, P=0.77). Furthermore, significant survival benefit was shown in patients who underwent allogeneic hematopoietic cell transplantation compared to patients who had not (2-year OS, 21% versus 4%, P&amp;lt;0.01]). Conclusions: In our cohort, TP53 mutant AML patients treated with intensive chemotherapy and transplant have superior outcomes to those who do not. Since this was a retrospective study, we cannot rule out the possibility that these results are confounded by providers favoring more intensive therapies for fitter patients. However, these data imply that TP53 mutant patients may benefit from more intensive therapy and suggests that future work to define optimal therapy regimens in this patient population may incorporate intensive strategies.

A Phase 1b/2 Trial of Liposomal Cytarabine and Daunorubicin (CPX-351) in Intermediate to High-Risk Acute Myeloid Leukemia for Patients Who Have Failed an Initial Cycle of Induction Chemotherapy

Introduction Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with a high rate of recurrence following standard chemotherapy that continues to have a poor prognosis. While there have been numerous recent advances in the treatment of AML, seven days of continuous infusion cytarabine combined with three doses of an anthracycline medication (7+3) remains the most common backbone treatment for younger (&amp;lt;60) patients. Following 7+3 treatment, patients are typically assessed by a bone marrow biopsy 14-21 days after initial treatment, and 20%-30% of patients will have persistent disease at this time. This residual disease is typically treated with an additional round of the same induction treatment at a full or slightly reduced dose. Unfortunately, a complete response (CR) following re-induction is infrequent in intermediate and high-risk AML patients (CR rates of 35% and 18%, respectively). We have performed mass cytometry studies of AML cell cycle state and find that in patients with residual disease at day 14-21 of induction, leukemia stem and progenitor cells have a low proliferative fraction. We hypothesize that this low rate of proliferation reduces the effectiveness of re-induction therapy and could be countered using CPX-351, which is FDA-approved for treatment of therapy-related AML and AML with myelodysplasia-related changes. CPX-351 is a formulation of cytarabine and daunorubicin in a liposomal structure at an optimal 5:1 molar ratio that has been shown to be preferentially absorbed by hematopoietic cells and to persist in serum and bone marrow for significantly longer than traditional 7+3 chemotherapy. We hypothesize that the unique properties of CPX-351 will better target quiescent leukemia stem and progenitor cells and we thus designed a phase 1b/2 study to determine the safety and efficacy of CPX-351 as re-induction treatment for patients with intermediate and high-risk AML with residual disease after a first round of induction. Patients and Methods Eight patients with intermediate or high-risk AML who had failed to achieve hypocellular marrow 14-21 days following initial treatment with traditional 7+3 cytarabine and daunorubicin were treated with CPX-351 re-induction in the phase 1b portion of the study with a CPX-351 dose of daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 given two or three times every 48 hours. Concomitant midostaurin (days 8-21) was allowed for patients with FLT3 mutations (Patients #1 and #8). Four patients were ELN intermediate-risk and four adverse-risk; mean blast count before re-induction was 45%. Patients were assessed weekly for signs of toxicity and for treatment response. Samples were collected from bone marrow biopsies performed before and after treatment for correlative mass cytometry studies using a 50-antibody panel to determine cell cycle state, intracellular signaling markers, and DNA damage response. Results Of the eight patients treated to date, six received two doses of CPX-351 and two received three doses. Of the six patients receiving two doses, five achieved a morphologic CR (two with residual genetic alterations), and one patient achieved a CRi. Two patients received three doses of CPX-351, with one achieving a PR and the other MLFS. Five of the eight patients were able to proceed to an allogeneic stem cell transplant. Consistent with previous studies of CPX-351, treatment was well-tolerated, almost all grade 3 or 4 toxicities were due to cytopenias (including two DLTs for delayed count recovery) and the only significant drug-related non-hematologic toxicity was a decrease in cardiac ejection fraction in patient #1. All treated patients survived &amp;gt;150 days and all were able to receive additional AML-directed therapy or HSCT after CPX-351 treatment. Due to slow accrual, hematologic toxicity, and the 100% CR/CRi rate in the two-dose group, the trial was amended to use two doses for the phase 2 portion, and an additional study site was opened. Study accrual is ongoing with a target of 20 additional patients in the phase 2 portion. Conclusion This ongoing phase 1b/2 trial of CPX-351 (liposomal cytarabine and daunorubicin) as re-induction treatment for intermediate and high-risk AML has been safe and tolerable with early treatment outcomes that appear to be much better than reported historical controls. Correlative studies by mass cytometry will further establish the mechanistic reasons for the observed responses.

What Is the Optimal Treatment Modality in Molecularly Defined Secondary AML? a Multicenter Cohort Study

Introduction Secondary ontogeny acute myeloid leukemia (AML), defined by the presence of mutations in ASXL1, BCOR, EZH2, SF2B1, SRSF2, STAG2, U2AF1 or ZRSR2 was recently integrated into both the ICC and WHO diagnostic criteria, as well as into the ELN 2022 risk classification as adverse risk. However, it is unknown whether cytarabine + anthracycline (7+3), liposomal cytarabine and daunorubicin (CPX-351) or hypomethylating agent + venetoclax (HMA+VEN) is the optimal frontline treatment for these patients (pts). We performed the largest multicenter retrospective cohort study to date, dedicated to pts with molecular-defined secondary ontogeny AML, comparing treatment modalities and assessing the impact of clinical and molecular characteristics on response and survival. Methods We included pts with newly diagnosed (ND) AML who were treated at 4 large academical centers with 7+3, CPX-351 or HMA+VEN. Secondary ontogeny was defined as absence of TP53 mutation and presence of at least one of the aforementioned mutations. Composite complete response (cCR) was defined as complete response (CR) + CR with incomplete count recovery (CRi). Logistic regression was fitted to evaluate odds ratio (OR) for cCR. Overall survival (OS) was compared between groups by log-rank test. COX regression for OS were fitted to evaluate effect of secondary/co-mutations within each treatment group, as well as the effect of treatment and allogeneic stem cell transplantation (SCT) as a time-varying covariate. Results Out of 1132 ND AML pts in the entire cohort, 401 (35%) were molecularly defined as secondary ontogeny and included in the final analysis. Initial treatment was 7+3 in 173 (43%), HMA+VEN in 162 (40%) and CPX-351 in 66 pts (17%). Pts in the HMA+VEN group were older (median age 74 years[yrs]; CPX351 66 yrs; 7+3 63 yrs, p&amp;lt;0.001), while pts in the CPX351 group were more likely to have prior myeloid neoplasm (n=52 [79%]; HMA+VEN n=72 [44%]; 7+3 n=48 [28%], p&amp;lt;0.001) and prior HMA exposure (n=27 [41%]; HMA+VEN n=23 [14%]; 7+3 n=28 [16%], p&amp;lt;0.001). The cCR rates were 56% (97/173), 56% (90/162) and 44% (29/66) in 7+3, HMA+VEN and CPX-351, respectively (p=0.21). In the 7+3 group, the presence of RUNX1 co-mutation was associated with lower cCR rate (OR 0.8, 95% confidence interval [CI] 0.7-0.95, p=0.01), while PTPN11 was associated with higher cCR rate (OR 1.4, 95% CI 1.1-1.8, p=0.011). In the HMA+VEN group, monosomal karyotype (OR 0.7, 95% CI 0.5-0.9, p=0.002), NRAS co-mutation (OR 0.6, 95% CI 0.5-0.8, p&amp;lt;.001) and SF3B1 mutation (OR 0.76, 95% CI 0.6-0.9, p=0.008) were associated with lower cCR rate and FLT3-TKD with higher cCR rate (OR 1.5, 95% CI 1.1-2.1, p=0.01). In the CPX-351 group, NRAS co-mutation was associated with lower cCR rate (OR 0.65, 95% CI 0.5-0.9, p=0.005). As most younger pts (aged ≤ 60 yrs, n=85) were treated with 7+3 (n=64) or CPX-351 (n=13) and almost exclusively older pts (age &amp;gt;75, n=78) were treated with HMA+VEN (n=74), we performed age-group based analyses. In pts aged &amp;gt; 60 yrs (n=318), the median OS (mOS) was comparable between groups (7+3: 16 months [mo], 95% CI 13-27; HMA+VEN 15 mo, 95% CI 13-19; CPX-351 11 mo, 95% CI 9-28 p=0.57). Similar results were seen in pts 60-75 yrs (n=238): 7+3 mOS 16 mo, 95% CI 13-27; HMA+VEN mOS 16 mo, 95% CI 13-26; CPX-351 mOS 10 mo, 95% CI 8-28, p=0.74. The effect of secondary/co-mutations on survival differ between groups: For 7+3 splicing mutations were associated with worse OS, whereas IDH1/2 were associated with improved OS ( Figure). Conversely, in HMA+VEN and CPX351 groups K/NRAS co-mutations were associated with worse survival. NPM1 co-mutation did not affect survival in any treatment group. In multivariable analysis, age, prior myeloid disease, K/NRAS co-mutations and monosomal karyotype were associated with worse OS ( Table). Conversely, BCOR mutation, IDH1/2 co-mutation and SCT were associated with improved OS. Treatment with HMA+VEN or CPX351 were not statistically different vs 7+3, although there was a trend for better OS with HMA+VEN vs 7+3 (HR 0.68, 95% CI 0.44-1.03, p=0.069). Conclusion In pts with ND secondary ontogeny AML the OS with HMA+VEN was at least comparable to 7+3 or CPX351 when adjusted for multiple covariates. The effect of co-mutations on response and OS differed between treatment modalities and may aid in optimal treatment selection in this population. Prospective trials should evaluate the potential superiority of HMA+VEN and effect of co-mutations in secondary ontogeny AML.

Intrathecal Therapy Options for Meningeal Carcinomatosis.

Around 5 percent of all patients with metastatic breast cancer go on to develop distant metastases in the meninges, also known as meningeal carcinomatosis. The median survival of these patients is between 3.5 and 4.5 months. Current treatment approaches are based on radiotherapy, systemic and intrathecal therapy. Methotrexate, liposomal cytarabine and trastuzumab are the most common substances used for intrathecal therapy. The aim of this review was to provide an overview of these intrathecal therapy options for meningeal carcinomatosis. A systematic search of the literature was carried out in PubMed using the following search terms: "meningeal metastases", "meningeal carcinomatosis", "leptomeningeal metastasis", "leptomeningeal carcinomatosis", "leptomeningeal disease", "breast cancer", "MTX", "methotrexate", "DepoCyte", "liposomal cytarabine", "trastuzumab" and "anti-HER2". This search resulted in 75 potentially relevant studies, 11 of which were included in this review after meeting the previously determined inclusion and exclusion criteria. The studies differ considerably with regards to study design, cohort size, and dosages of administered drugs. In principle, intrathecal therapy has a tolerable side-effects profile and offers promising results in terms of the median overall survival following treatment with trastuzumab for HER2-positive primary tumors. The focus when treating meningeal carcinomatosis must be on providing a multimodal individual therapeutic approach. However, comprehensive studies which compare the efficacy and side effects of individual pharmaceuticals are lacking. Because of the poor prognosis associated with meningeal carcinomatosis, an approach which treats only the symptoms (best supportive care) should always be considered and discussed with affected patients.

Real World Outcomes of CPX-351 Compared to Traditional Chemotherapy with Cytarabine Consolidation for Treatment of Secondary Acute Myeloid Leukemia

Introduction: Outcomes in patients with secondary AML (sAML) are inferior to those with de novo AML which has led investigators to seek alternatives to traditional treatment. Liposomal daunorubicin and cytarabine, or CPX-351, for the treatment of sAML has shown superior complete remission/complete remission with incomplete count recovery (CR/CRi), event-free survival (EFS), and overall survival (OS) compared to the traditional non-liposomal formulations of daunorubicin and cytarabine (“7+3”). However, this agent was originally studied in combination with a suboptimal consolidation regimen which did not include standard of care high dose cytarabine (HiDAC). This is often cited as a limitation of the study and may have contributed to the significantly lower response rates reported when compared to historical data. Here we present a real-world comparison of the efficacy and safety of patients with sAML receiving CPX-351 versus traditional 7+3 with HiDAC consolidation. Methods: Patients were at least 18 years of age with sAML, defined as: t-AML, AML-with Myelodysplasia-Related Changes (MRC), or AML with a history of chronic myelomonocytic leukemia (CMML). Patients were included if they had received induction (and consolidation, if applicable) with CPX-351 or induction with 7+3 (daunorubicin 60 mg/m 2 for 3 days and cytarabine 100 mg/m 2 for 7 days), followed by consolidation with cytarabine (≥1000 mg/m 2 x 6 doses). Nominal data were analyzed using chi squared tests or Fisher's exact tests. Continuous data were analyzed using the Mann-Whitney U test. A Kaplan Meier estimator was used for survival outcomes. Results: Overall, 58 patients with sAML were included, with 36 (62%) receiving CPX-351 and 22 (38%) receiving 7+3 followed by cytarabine-based consolidation between April 2013 and June 2022. Patients in the CPX-351 were older (67.5 vs 62 years, p=0.04) and had a higher prevalence of poor-risk cytogenetics (p=0.22). Other baseline characteristics were similar (Table 1). The rate of CR/CRi following induction was significantly higher in patients who received 7+3-based induction vs patients who received CPX-351 (81.8% vs 44.4%, p=0.01). Twenty-five percent of patients achieved CR/CRi in the CPX-351 arm with one induction cycle, compared to 95.5% in the 7+3 group. Median progression-free survival (PFS) was 3 vs 6.1 months (p=0.67) and median OS was 18.3 vs 9.3 months (p=0.73) in the CPX-351 and 7+3 cohorts, respectively (Figure 1). Thirty-nine percent of patients in the 7+3 cohort proceeded to allogeneic stem cell transplant compared to 81% in the CPX-351 cohort, however median OS in patients who underwent transplant was similar between the two cohorts (16.8 vs 15.8 months). Median OS was longer in the CPX-351 cohort however this was not statistically significant (Figure 1). Rates of both febrile neutropenia (94.3% vs 95.5%; P&amp;gt;0.99) and confirmed infections (54.3% vs 50%) were similar amongst those treated with CPX-351 and 7+3. Bacteremia and pneumonia were the most common infections in both cohorts. Median duration of neutropenia was significantly longer in the CPX-351 cohort (43 days vs. 27 days, p=0.002) with no major difference in duration of thrombocytopenia. In the 7+3 cohort, 11 deaths were directly attributed to progression, while 5 were associated with infection. In the CPX-351 cohort, 6 deaths were directly attributed to progression, while 8 were attributed to infection. At day 60, two deaths were observed in the CPX-351 cohort and there were no deaths in the 7+3 cohort. Conclusion: These findings suggest use of traditional 7+3 induction followed by HiDAC consolidation may be an alternative to CPX-351 for patients with sAML. Although median PFS was longer in the 7+3 cohort, this did not translate into longer median OS, likely due to the low rate of patients proceeding to transplant. Similar rates of overall survival in patients undergoing allogeneic stem cell transplantation support the hypothesis that transplant should be the goal for most patients with sAML. The retrospective nature of the study may limit broader application of this data.

CPX-351 Versus FLAG-IDA with or without Venetoclax in Previously Untreated and Relapsed or Refractory Acute Myeloid Leukemia

1. Introduction A recent randomized comparison of liposomal daunorubicin and cytarabine (CPX-351) did not improve response rates or overall survival compared with FLAG-IDA in newly diagnosed acute myeloid leukemia (AML) - although subgroup analyses appeared to show some benefit with CPX-351. The real-world outcomes of these cohorts are unknown. Additionally, there is little data on the relative outcomes of these cohorts in the relapsed or refractory (RR) setting. We aimed to explore the efficacy of CPX-351 and FLAG-IDA with or without venetoclax in newly diagnosed and RR AML outside of clinical trials. 2. Methods We analyzed 142 patients from the Project ERIS database with newly diagnosed or relapsed or refractory (RR) AML treated with CPX-351 or FLAG-IDA from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. We recorded baseline patient-related and disease characteristics, including age, ECOG, Charlson comorbidity index (CCI) scores, molecular profiling and ELN 2022 cytogenetic risk, dates of regimen initiation, and survival. We used the D'Agostino &amp; Pearson method for normality testing and the t-test or Mann-Whitney (as applicable) tests for between-group comparisons. Categorical comparisons used Fischer's exact test. We applied the Bonferroni correction if multiple comparisons were made. The Wilson-Brown method was used for 95% confidence intervals. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results First, we analyzed 43 (30.3%) patients with newly diagnosed AML fit for intensive chemotherapy: 33 (76.7%) received CPX-351 and 10 (23.3%) received FLAG-IDA. In the FLAG-IDA cohort, three (30.0%) patients received concurrent venetoclax. There were no significant differences in baseline characteristics, including age, sex, race, or CCI scores, shown in Table A. However, patients in the CPX-351 cohort had significantly worse ECOG performance status compared with the FLAG-IDA cohort (median, 1 vs 0, p = 0.007). There were no significant differences in the proportion of patients that had ELN 2022 adverse risk cytogenetics between the CPX-351 and FLAG-IDA cohorts (65.6% vs 55.6%, p = 0.701). The composite complete response rate (CRc; CR + CRi + CRh) was 53.6% (95% CI: 35.8-70.5) in the CPX-351 cohort and 62.5% (95% CI: 30.6-86.3) for FLAG-IDA (p = 0.709). The rate of MRD negativity was 33.3% for CPX-351 (95% CI: 5.9-70.0) and 50.0% (95% CI: 2.6-97.4) for FLAG-IDA. A similar proportion of patients proceeded to allogeneic stem cell transplant (alloSCT; 39.4% vs 40.0%, p &amp;gt; 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (16.1 m. vs 11.4 m., p = 0.129, Figure B). Next, we analyzed 96 (90.7%) patients that received FLAG-IDA and ten (9.3%) that received CPX-351 for RR AML in any subsequent line; three (2.1%) patients in the overall cohort received either CPX-351 or FLAG-IDA in the first-line setting, then crossed over to the other arm at disease progression. Sixteen (16.7%) patients received venetoclax with FLAG-IDA. There were no significant baseline differences between cohorts, as shown in Table A. The CRc for CPX-351 was 33.3% (95% CI, 5.9-70.0) compared with 47.7% (95% CI, 37.6-58.0, p = 0.681) for FLAG-IDA. The rate of MRD negativity was 50.0% (95% CI, 2.6-97.4) for CPX-351 and 66.7% for FLAG-IDA (95% CI, 39.1-86.2, p &amp;gt; 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (12.7 m. vs 14.5 m., p = 0.561). 4. Discussion There was no significant difference in the rates of CRc, MRD negativity, or overall survival in patients that received CPX-351 or FLAG-IDA with or without venetoclax in the first-line setting or at the time of disease progression. Both approaches appear to be viable in carefully selected cohorts of patients. A comprehensive toxicity analysis and exploratory molecular subgroup analysis are ongoing.

A randomized comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: the UK NCRI AML19 trial

AbstractLiposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia (AML); to date, there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). A total of 189 patients were randomized (median age, 56 years). Per clinical criteria, 49% of patients had de novo AML, 20% had secondary AML, and 30% had high-risk MDS. MDS-related cytogenetics were present in 73% of the patients, with a complex karyotype in 49%. TP53 was the most common mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 (44%) patients. The overall response rate (CR + CRi) after course 2 was 64% and 76% for CPX-351 and FLAG-Ida, respectively. There was no difference in OS (13.3 months vs 11.4 months) or event-free survival in multivariable analysis. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months). There was no difference between the treatment arms in patients with clinically defined secondary AML or those with MDS-related cytogenetic abnormalities; however, an exploratory subgroup of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months). In conclusion, the OS of younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.

Exploiting the DNA Damaging Activity of Liposomal Low Dose Cytarabine for Cancer Immunotherapy.

Perhaps the greatest limitation for the continually advancing developments in cancer immunotherapy remains the immunosuppressive tumor microenvironment (TME). The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis is an emerging immunotherapy target, with the resulting type I interferons and transcription factors acting at several levels in both tumor and immune cells for the generation of adaptive T cell responses. The cGAS-STING axis activation by therapeutic agents that induce DNA damage, such as certain chemotherapies, continues to be reported, highlighting the importance of the interplay of this signaling pathway and the DNA damage response in cancer immunity/immunotherapy. We have developed a multi-targeted mannosylated cationic liposomal immunomodulatory system (DS) which contains low doses of the chemotherapeutic cytarabine (Ara-C). In this work, we show that entrapment of non-cytotoxic doses of Ara-C within the DS improves its ability to induce DNA double strand breaks in human ovarian and colorectal cancer cell lines, as well as in various immune cells. Importantly, for the first time we demonstrate that the DNA damage induced by Ara-C/DS translates into cGAS-STING axis activation. We further demonstrate that Ara-C/DS-mediated DNA damage leads to upregulation of surface expression of immune ligands on cancer cells, coinciding with priming of cytotoxic lymphocytes as assessed using an ex vivo model of peripheral blood mononuclear cells from colorectal cancer patients, as well as an in vitro NK cell model. Overall, the results highlight a broad immunotherapeutic potential for Ara-C/DS by enhancing tumor-directed inflammatory responses.

A Phase 2 Randomized Study Comparing Venetoclax and Azacitidine to Conventional Induction Chemotherapy for Newly Diagnosed Fit Adults with Acute Myeloid Leukemia

Background: The standard therapy for acute myeloid leukemia (AML) for younger, functionally fit patients has not substantially changed in the last 40 years. Intensive induction chemotherapy (IC), with various schedules of cytarabine and an anthracycline, remains the mainstay of therapy. Conventional IC results in complete remission rates of 60-75% of younger and 40-60% of older adults. Despite this, rates of long-term survival and cure remain sub-optimal. These regimens are also associated with significant risk and burden of morbidity, including substantial marrow suppression, mucosal toxicity, high rates of infectious and bleeding complications, potential cardiac injury, prolonged hospitalization, and long-term risk of secondary malignancies. Recently, a placebo-controlled randomized phase 3 trial of older AML patients, and those with comorbidities precluding intensive IC, compared azacitidine and venetoclax to azacitidine and revealed a significant overall survival (OS) advantage for the combination, impressive tolerability, with a markedly higher remission rate at 66% and median OS of 14.7 months, and improvements in other outcome parameters. These recent data compare favorably to outcomes expected from conventional IC, particularly considering their evaluation to date in older, frailer patients, in whom outcomes would be expected to be poorer than younger patients. Based on these considerations, the current randomized phase 2 study seeks to test the hypothesis that treatment with venetoclax and azacitidine will lead to an improved event-free survival (EFS) among fit patients with newly diagnosed AML, when compared to IC. We hypothesized that rates of composite remission for azacitidine and venetoclax will be similar to conventional IC, with an improved safety profile, fewer and less prolonged hospitalizations, lower cost of care, improved candidacy for stem cell transplantation (SCT), and fewer post-SCT complications. Study Design and Methods: This is an open-label, multicenter, phase II randomized clinical trial comparing the therapeutic activity of conventional IC (7+3 regimen or liposomal daunorubicin and cytarabine) to the combination of venetoclax and azacitidine among IC-eligible patients, excluding those with protocol-defined favorable risk genetics or FLT3 mutations. The primary outcome is EFS, where an event is defined as progressive disease (>50% increase in marrow blasts, >50% increase in peripheral blasts, new extramedullary disease), change in therapy due to persistent leukemic disease, relapse after remission, transition to hospice, or death. This study randomizes, in 1:1 fashion, to conventional IC (SOC) or venetoclax plus azacitidine (investigational). Patients will be stratified by age (≥ 65 versus < 65 years old). There is a preselection prior to randomization for either 7+3 or liposomal daunorubicin and cytarabine, to apply to those who are subsequently assigned to the SOC arm. With 172 patients, 86 allocated per arm, the study will achieve 85% power to detect a treatment difference at the one-sided 10% type I error rate, assuming the true hazard ratio is 0.635, based on assumptions of 1-year EFS of 55% on the investigational arm (azacitidine-venetoclax) and 39% on SOC (IC). Before study completion, futility analysis will be trigged after accruing 50% of the subjects and observing 40% of required EFS events. Assuming a failure rate of 30% on the SOC arm and 50% on the investigational arm, if 43 or more events are seen in the latter group, the trial will be stopped for futility. O'Brien-Fleming boundaries set on the p-value due to interim analysis are handled with the Lan-DeMets procedure with the interim p-value = 0.693, and the final p-value = 0.1. Assessments of differences in EFS between the arms will be made with the log rank test; modeling will employ the Cox proportional hazards regression. Differences in EFS at 1-year will also be estimated using the Kaplan Meier method, with standard deviations calculated by Greenwood's formula. Secondary endpoints include composite remission rates, OS, toxicity, rate of measurable residual disease, number and duration of hospitalizations, cost and quality of life measures. Accrual is assumed to be 24 months with a minimum follow up of 15 months, yielding an estimated study duration of 39 months. The study is currently enrolling patients and will be open to accrue at seven hospitals across the United States.

Healthcare Resource Utilization in Acute Myeloid Leukemia Treatments: Hypomethylating Agent + Venetoclax Vs. High Intensity Regimens

Background Treatment of acute myeloid leukemia (AML) leads to significant healthcare resource utilization (HRU), including extended hospitalization and transfusions. Standard treatment regimens include the high intensity "7+3” (anthracycline + cytosine arabinoside) and CPX-351 (daunorubicin + cytarabine liposome) used in younger, fit patients, and the lower intensity hypomethylating agent + venetoclax (HMA-Ven) used in patients deemed ineligible for intensive induction. Previous reports show comparable remission rates between regimens. Studies have shown no significant difference in HRU between 7+3 and CPX-351, but there have yet to be reports on HRU for HMA-Ven compared to high intensity regimens. Methods We retrospectively analyzed patients with newly diagnosed AML treated at UC Davis Medical Center from 5/2012 to 5/2021 with HMA-Ven, 7+3, or CPX-351, identified using pharmacy and EMR reports. Patients met criteria if they achieved first complete remission with (CR) or without (CRi) count recovery as per ELN 2017 criteria. The date of CR1 was defined as date of first bone marrow biopsy following induction with evidence of CR/CRi. Primary outcomes assessed were number of packed red blood cell (pRBC) units transfused, platelet (Plt) units transfused, and hospital days (HDs) from start of treatment to CR1. Secondary outcomes assessed were HRU in 60 and 90 days post-CR1, time to count recovery, and time to CR/CRi. Survival outcomes included relapse-free survival (RFS), overall survival (OS), and estimated 12- and 24-month survival. Data were analyzed with SPSS; pairwise comparisons of medians were performed using Wilcox Sum Rank test, and time to event analyses were performed via the Kaplan-Meier method. Results We identified 68 patients treated with HMA-Ven, 49 of which achieved CR/CRi (53% CR, 19% CRi). 60 of 113 patients (53%) treated with 7+3 achieved CR1 without re-induction, as well as 7 of 14 patients (50%) treated with CPX-351. No patients were enrolled in clinical trials. Of the 7+3 patients who achieved CR1, 14 received additional agents: midostaurin or gemtuzumab. Initial analyses revealed no significant difference between 7+3 and CPX-351 patients in all three primary HRU outcomes (p>0.05). Thus, those patients were analyzed as a single high-intensity treatment group and compared with the lower-intensity HMA-Ven group. Median age for HMA-Ven patients was 72 years, significantly higher than 56 years for the 7+3/CPX group (p<0.001, Table 1). The median days to CR1/CRi was 31 days for the HMA-Ven group and 34 days for the high-intensity group. Patients treated with HMA-Ven required significantly fewer pRBC and Plt units and hospital days than the 7+3/CPX group from start of treatment to CR1 (p<0.001, Table 1). At 60 and 90 days post-CR1, these results were maintained (p≤0.01). Similar results for all three primary outcomes were seen amongst the non-responders of each group with an endpoint of 30 days post-treatment start (p<0.01). Of the HMA-Ven and 7+3/CPX patients, 24% and 63%, respectively, proceeded to HCT. The high-intensity patients who did not receive HCT were placed on midostaurin maintenance or surveillance. There were no significant differences between survival outcomes before adjusting for HCT (p>0.05). The median RFS was 31 months [95% confidence interval (CI), 14-48] for HMA-Ven and 18.1 months [CI, 8.4-28] for 7+3/CPX. Median OS was 33.7 months [CI, 13-55] for HMA-Ven and 74.2 months [CI, 57-85] for 7+3/CPX. Estimated 12- and 24-month RFS was 67% and 60% respectively for HMA-Ven and 67% and 46% for 7+3/CPX. Estimated 12- and 24-month OS was 77% and 62% respectively for the HMA-Ven group and 85% and 70% for 7+3/CPX. After adjusting for HCT, no significant difference was also seen (p>0.05). Conclusion To our knowledge, this is the first assessment of HRU in AML patients treated with HMA-Ven. We found that they required significantly fewer pRBC and Plt transfusions and significantly shorter hospitalizations compared with 7+3 or CPX-351 treated patients, despite a significantly higher median age. These differences were maintained 60- and 90-days post-CR. RFS and OS were not statistically significantly different between treatment regimens. Limitations include the retrospective and single center study design. Our data suggest that HRU should be prospectively evaluated in AML and may be relevant to consider when recommending treatment options. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Defining Primary Vs Secondary AML: Correlation between Pathology and NGS/FISH

Introduction: The treatment of acute myelogenous leukemia (AML) is often determined by factors that include an antecedent dysplasia. At presentation it is often unknown whether a patient has had dysplastic bone marrow features or not. We opted to look back at our leukemia patients to determine the frequency of antecedent dysplasia and to determine if next generation sequencing (NGS) or Florescent in situ hybridization (FISH) findings correlate with the pathologic review. Methods: We chart reviewed 43 charts from a period of 9/21/2021 to current from Orlando Health records. We focused on 29 charts that we could gather complete information from. We reviewed initial bone marrow biopsies and NGS/ FISH findings. We determined if a patient had a known history of myelodysplasia from previous records. If there was no known history of myelodysplastic syndrome (MDS) but dysplasia was seen on the bone marrow biopsy, we looked at NGS/FISH. While there can be overlap with AML, findings that suggest MDS are as follows: NGS: TET2, NRAS, U2AF1, RUNX1, TP53, SF3B1 FISH: 5q-, -5 (5p15, 5q31, 5q33), 7q-, -7 (Cen 7, 7q22, 7q31), Trisomy 8 (Cen 8), MLL (11q23), 20q- (20q12, 20qter) We then examined what treatments were used based on these findings. Results: Overall: 11/29 patients had dysplasia mentioned in their initial pathology report. 4/11 had a known preexistent dysplasia. Of the 7 who didn't have known dysplasia, 6/7 had an NGS or FISH suggesting MDS. Age: Of the patient who had dysplastic findings as well as NGS/FISH to support those findings, the patients had an average age of 57. The one patient without MDS/FISH findings has an age of 69. The average age of all patients with dysplastic findings on their bone marrow was 60. Of the patients who did not have any dysplastic findings on the bone marrow, the average age was 58. Treatment: Vyexos (liposomal daunorubicin and cytarabine), a therapy generally used for secondary leukemias was only used in two patients. Age and performance status was cited as a reason to use alternative therapy. Although one patient did receive 7+3 (idarubicin and cytarabine) instead of Vyxeos. One patient also had severe COVID pneumonia at diagnosis as the reason for not getting induction with Vyexos and instead getting venetoclax/azacitidine. Four patients were either treated with hypomethylating agent of either azacitidine or decitabine, again this was normally chosen due to performance status, age, or active COVID pneumonia as above. Conclusion: These results show that pathology findings of underlying dysplastic changes seem to correlate with NGS or FISH findings. Of the 7 patients with these bone marrow changes but no known MDS, 6 of them had NGS or FISH to support an underlying disease. Factors such as age did not help to predict antecedent MDS. Based on this information it may be appropriate to start with induction therapies such as Vyxeos when dysplastic changes are seen on the bone marrow while FISH and NGS are still pending, if their performance status and age allow to do so. Further larger retrospective studies to compare underlying dysplastic findings versus FISH/NGS findings should be done to further support this concept.

FLT3-ITD Does Not Predict Inferior Prognosis Compared with FLT3-wild Type in Acute Myeloid Leukemia (AML) Patients Age ≥ 60 Years: A Retrospective Cohort Study

IntroductionFLT3 mutations are found in up to 30% of AML patients (pts), with 80% being internal tandem duplications (ITD). Based largely on data in younger pts from an era prior to the use of FLT3 inhibitors or hypomethylating agents (HMA) and venetoclax (Ven), FLT3-ITD mutated (FLT3-ITD+) AML is associated with higher relapse rates and decreased survival compared to FLT3 wild-type (WT) disease. Post hoc analysis from the VIALE-A trial demonstrated comparable outcomes between pts with FLT3-mutated vsFLT3-WT AML treated with HMA+Ven. Further, the AMLSG16-10 trial demonstrated improved survival among pts aged 60-70 with FLT-ITD+ AML treated with "7+3” and midostaurin compared to historical controls. To determine the clinical significance of FLT3-ITD+ in older adults with AML, we assessed the prevalence of FLT3-ITD mutations in pts with AML age ≥ 60 years treated at Dana Farber Cancer Institute (DFCI), evaluated whether FLT3-ITD+ is associated with an inferior prognosis in this age group and identified other specific characteristics affecting survival. Methods We included older (age ≥ 60) pts diagnosed with AML at DFCI between August 2015 and September 2021 and treated with: daunorubicin and cytarabine ("7+3") with or without a third drug; liposomal daunorubicin and cytarabine (CPX351); or HMA-based therapy (HMA+/-Ven). Groups were defined by presence (FLT3-ITD+) or absence (FLT3-ITD-) of FLT3-ITD mutation. We excluded pts in whom diagnostic molecular analysis was not performed, those who had acute promyelocytic leukemia or who received other treatments. Overall survival (OS) was evaluated by the Kaplan-Meier method. Cox regression models were fitted to assess the effect of FLT3-ITD mutations and additional covariates (age, prior myeloid disease, cytogenetics, molecular groups, treatment, and transplant as time-dependent covariate) on OS. Results Of the 380 pts, 53 (14%) were FLT3-ITD+ and 327 (85%) FLT3-ITD-. The median age was 69 years (range 60-89) and was similar between groups (68 [range 60-87] vs 70 [range (60-89], respectively, p=0.18). Intensive chemotherapy (IC) was used in 179 pts: 111 (62%) with "7+3", 20 (11%) with "7+3"+midostaurin (15 [47%] in FLT-ITD+ and 5 [3%] in FLT-ITD- in pts with FLT-TKD mutation), 16 (9%) with "7+3"+other non-FLT3 inhibitor investigational therapy and 32 (18%) with CPX351. HMA+Ven or HMA was used in 111 (29%) and 90 (24%) of pts, respectively. Baseline characteristics in FLT3-ITD+ and FLT3-ITD- pts differed by rates of normal karyotype, monosomal and/or complex karyotype (both p<0.001), and specific molecular co-mutations: (TP53 [p=0.032], secondary type mutations [0.045] and NPM1 [p=0.001]. Table). The median OS of the entire cohort was 13.6 months (CI 95% 11-16) and did not differ between pts with FLT3-ITD+vsFLT3-ITD- (median OS 15.4 [CI 95% 11-28] vs 13.1 [CI 95% 11-16], p=0.33). The median OS was similar between FLT3-ITD+vsFLT3-ITD- pts among those who received IC: 24.8 months (CI 95% 15-NA) vs 19.1 (CI 95% 13-30; p=0.43) and HMA-based-therapy: 9.33 months (CI 95% 6-NA) vs 9.9 (CI 95% 8-14; p=0.95), respectively (Figure). The addition of midostaurin could potentially ameliorate an adverse impact of a FLT3-ITD mutation. Thus, we conducted a sensitivity analysis in IC-treated pts who did not receive midostaurin, which demonstrated similar outcomes in FLT3-ITD+ ( n=17) vsFLT-ITD- (n=142): Median OS 15.4 months (CI 95% 4-NR) vs 17.5 (CI 95% 13-30), respectively, p=0.97. In a multivariable analysis ( MVA), FLT3-ITD status was not associated with OS (HR 1.1 [CI 95% 0.7-1.6] p=0.66). Factors associated with OS in the MVA were: treatment with HMA+Ven vs HMA (HR 0.62 [CI 95% 0.4-0.9], p=0.01), age ≥ 70 years (HR 1.03 [CI 95% 1.003-1.1], p=0.03), monosomal and/or complex karyotype vs normal karyotype (HR 1.67 [CI 95% 1.2-2.4], p=0.009) and TP53 mutations (HR 1.63 [CI 95% 1.1-2.3], p=0.005). Of note, treatment with intensive therapy vs HMA was not associated with OS (0.98 [CI 95% 0.7-1.5], p=0.93). Conclusion In older pts with AML, FLT3-ITD mutations were less common than reported in younger pts and were not associated with an adverse prognosis. Age ≥ 70 years, complex/ monosomal karyotype and presence of TP53 were associated with worse survival. Compared to HMA, therapy with HMA+Ven was associated with improved OS, while treatment with IC was not. The prognostic significance of a FLT3-ITD mutation should be re-evaluated in older pts with AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genomic Correlates of Outcome in a Randomised Comparison of CPX-351 and FLAG-Ida in High-Risk Acute Myeloid Leukaemia and Myelodysplastic Syndrome: Results from the UK NCRI AML19 Trial

Background Liposomal daunorubicin and cytarabine (CPX-351) improves survival compared to 3+7 chemotherapy in patients aged 60 years with secondary AML defined by clinical or cytogenetic criteria (Lancet JE, JCO 2018). It is increasingly recognised that secondary AML may be better defined by mutational profile than clinical history (Döhner, Blood 2022; Khoury, Leukemia 2022), however patients with molecularly defined secondary AML were not specifically included in previous studies. Moreover, no randomised data for CPX-351 in patients aged <60y were available prior to this study. Previous UK NCRI trials established the FLAG-Ida regimen as a preferred regimen in patients aged <60y with high-risk and secondary AML (Burnett AK, Leukemia 2018). The UK NCRI AML19 trial randomised patients with AML or high grade MDS between induction therapy with CPX-351 and FLAG-Ida. Initial results reporting similar event-free and overall survival (OS) have been previously presented (Russell NH, HemaSphere 2022). Here we present an exploratory analysis of outcomes stratified by genomic, cytogenetic and clinical definitions of secondary AML. Methods AML19 (ISRCTN78449203) enrolled patients with previously untreated AML, MDS-EB2, or MDS-EB1 with IPSS score >3.5, predominantly aged <60 years. Patients known to have an adverse karyotype at diagnosis according to MRC criteria were randomised between CPX-351 and FLAG-Ida. Treatment consisted of up to 4 courses of CPX-351 or 2 courses of FLAG-Ida followed by MACE/MidAC consolidation with allogeneic transplant recommended after 2 cycles if feasible. Of note, patients could also enter the FLAG-IDA vs CPX randomisation if they became high risk at other defined points after induction, the results of which will be reported separately. Cytogenetic testing was performed in local laboratories with results reviewed and coded centrally. Complex karyotype was defined as ≥4 unrelated abnormalities. Following the completion of the trial, banked diagnostic DNA was analysed for variants in 41 recurrently mutated myeloid genes, including the entire coding regions of all myelodysplasia-related genes according to 2022 WHO and ELN criteria (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) (Döhner, Blood 2022; Khoury, Leukemia 2022). Libraries were prepared using the Agilent SureSelect XT HS2 platform and sequenced on an Illumina NextSeq2000 to a depth of >1000x. Results In total, 195 patients entered were randomised at trial entry, and NGS was performed on 173. Of the whole cohort, 49% were classified by clinical features as de novo AML, 20% as secondary AML and 31% as high-risk MDS. Myelodysplasia-related cytogenetic abnormalities were present in 70% of patients, with a complex karyotype in 51%. TP53 was the most commonly mutated gene in 43% of patients, followed by DNMT3A in 19% and ASXL1 in 18% (Figure A). A mutation in at least one myelodysplasia-related gene was present in 75 (43%) patients, of whom 60 (35%) were categorised as secondary AML by mutational status, which by ELN 2022 criteria requires the absence of TP53 variants. As previously reported, OS did not differ between the two randomisation arms (Hazard Ratio [HR] for CPX-351 0.84, 95% confidence interval [95CI] 0.59 - 1.20). In patients with clinically defined secondary AML, there was no OS benefit for CPX-351 (HR 1.1, 95CI 0.53 - 2.30), while high-risk MDS had a trend to benefit (HR 0.54, 95CI 0.28 - 1.00) (Figure B). When secondary disease was defined by the presence of myelodysplasia-related cytogenetic abnormalities, CPX-351 did not provide benefit (HR 1.04, 95CI 0.77 - 1.55). However, in patients with mutationally defined secondary AML, there was an OS benefit from CPX-351 (HR 0.42, 95CI 0.21 - 0.84, p value for heterogeneity 0.05) (Figure B). Patients with TP53 mutations had an adverse prognosis, with median OS of 7 months compared to 28 months in those with wild-type TP53. CPX-351 did not provide benefit compared to FLAG-Ida in this group (HR 0.92, 95CI 0.57 - 1.49). Conclusion In this exploratory subgroup analysis, CPX-351 had a significant survival benefit over FLAG-Ida in young high-risk patients with secondary AML/MDS as defined by the presence of myelodysplasia-related gene mutations, but not by clinical criteria. We observed no significant difference in patients with TP53 mutations. Acknowledgements This study received research support from Cancer Research UK and a research grant from Jazz Pharma Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a "MEMMAT-like" Metronomic Antiangiogenic Approach.

Simple SummaryAbout 30% of patients with medulloblastoma experience recurrence, which is usually incurable despite intensive chemotherapy. The aim of our retrospective study was to evaluate a novel combinatorial metronomic antiangiogenic approach (“MEMMAT-like”) for recurrent medulloblastoma consisting of five oral drugs, an intravenous antibody against vascular endothelial growth factor, and intrathecal therapy. The study, conducted between 2006 and 2016, included 29 consecutive patients with first or multiple recurrences treated according to this “MEMMAT-like” strategy and confirmed a significantly longer median overall survival than in previously reported studies. As of 07/2022, 9/29 patients are alive 86 to 164 months after recurrence. Treatment was primarily out-patient and well-tolerated. Toxicities did occur but were manageable. The novel combination significantly improved overall and progression-free survival for patients with recurrent medulloblastoma. A formal study (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) has been completed and is currently being evaluated.Medulloblastoma (MB) recurrence is usually incurable despite intensive therapy including high-dose chemotherapy. An evolving alternative approach to conventional chemotherapy aims at interfering with tumor angiogenesis at different levels. We report on a novel combinatorial metronomic antiangiogenic approach. The study is a retrospective observational study of 29 consecutive patients with first or multiple recurrences prospectively treated according to the MEMMAT strategy (“MEMMAT-like”) before the formal protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) started. The study period was 11/2006 to 06/2016. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by IV bevacizumab and intraventricular therapy consisting of alternating etoposide and liposomal cytarabine. Median overall survival (OS) after recurrence for the whole group was 29.5 months, OS was 48.3 ± 9.3% at three years and 34.5 ± 8.8% at five years, and progression-free survival was 42.0 ± 9.5% at three years and 29.4 ± 9% at five years. As of 07/2022, 9/29 patients are alive 86 to 164 months after the recurrence that prompted the “MEMMAT-like” therapy. Treatment was primarily out-patient and generally well-tolerated. Toxicities did occur but were manageable. In conclusion, antiangiogenic therapy according to the MEMMAT strategy increased median OS of patients with recurrent MB and may lead to long-term survival. Adherence to the protocol, including intraventricular therapy, appears important.

P11.16.A Questioning convention - is intrathecal chemotherapy (ITC) necessary for patients with newly diagnosed primary central nervous system lymphoma (PCNSL): combined results from three independent cohorts

Abstract Background Despite beguiling responses to initial therapy in many patients, PCNSL remains a therapeutic challenge. Relapse is common, cures are elusive for most patients, and overall response are disappointing compared to other diffuse large B-cell lymphomas. High-dose methotrexate-based therapies have become the standard of care, with many variations, but there is no consensus, and very little data regarding the role of ITC in the initial treatment of patients with PCNSL. Material and Methods We collected study-level and where possible, patient-level data from three independent clinical trials comparing adults with newly diagnosed PCNSL treated with regimens that differed based on the use of ITC. Patient characteristics, overall (OS) and progression-free survival (PFS), and characteristics of relapse were examined. The frequency of lymphomatous meningitis at diagnosis based on the location of CSF sampling - ventricular vs. lumbar - was also investigated. Complete data retrieval for this updated analysis has allowed us to combine data from the three studies and calculate summary statistics using a random effects model and inverse variance technique. In addition, predictors of OS and PFS were modeled using a Cox proportional hazards technique. Results The three cohorts were treated with: HD MTX/rituximab/ifosfamide followed by either HD MTX/cytarabine/ifosfamide (group Ia), or cytarabine/thiotepa and autologous stem cell transplant (group Ib) (n=80); HDMTX/vinca alkaloids/ifosfamide/cytarabine (group II) (n=83); or HD MTX/rituximab (group III) (n=49). ITC consisted of MTX/cytarabine/prednisolone (group Ia only, n=43); MTX/cytarabine/prednisolone (group II, n=65); or liposomal cytarabine (group III, n=21). One- and two-year OS was better in the ITC chemotherapy compared to the no-ITC group (RR 1.25 [1.16-1.34] and 1.20 [1.14-1.26] respectively, p&amp;lt; 0.001 for both comparisons). One-year PFS was also improved in the ITC group (RR 1.12 [1.01-1.25], p=0.031). Two-year PFS was not statistically different between groups (RR 1.20 [0.90-1.59], p=0.220). Relapse involving the CSF was more frequent in the non-IT chemotherapy group (RR 2.31 [2.03-2.62], p&amp;lt; 0.001). CSF cytology was positive in 81% of ventricular specimens vs 14.3% of lumbar specimens (p&amp;lt; 0.001). Conclusion This analysis of three independent cohorts of adults with newly diagnosed PCNSL suggests (when ventricular rather than lumbar CSF is sampled) that lymphomatous meningitis is dramatically more frequent, and perhaps universal. Including ITC as part of the initial treatment regimen increased both OS and PFS substantially. A randomized controlled trial is urgently required.