Vyxeos (cytarabine/daunorubicin liposomal formulation)

FLT3 inhibitors, gemtuzumab ozogamicin, and CPX-351 have been shown to improve outcomes for specific subsets of patients. Venetoclax (VEN) with a hypomethylating agent (HMA) is the standard-of-care frontline regimen for most older patients, except perhaps for those with an IDH1 mutation where ivosidenib with azacitidine may also be considered...This article focuses on recent updates and ongoing challenges in the management of AML, with a particular focus on the ongoing challenge of secondary AML and considerations regarding the selection of initial therapy in younger patients. An overview of common side effects and toxicities associated with targeted therapies is also presented here, along with recommended strategies to mitigate these risks.

P1/2, N=47, Recruiting, Ohio State University Comprehensive Cancer Center | Suspended --> Recruiting

There has been import of the IDH1 inhibitor ivosidenib, initially approved for AML; the Bcl-2 inhibitor venetoclax and liposomal daunorubicin/cytarabine (CPX-351) are under active investigation as well. Unfortunately, effective treatment of TP53-mutated disease remains elusive, though preliminary evidence suggests improved outcomes with oral decitabine/cedazuridine over parenteral hypomethylating agent monotherapy. Investigational agents with novel mechanisms of action may help expand the repertoire of treatment options for HR-MDS and trials continue to offer a hopeful therapeutic avenue for suitable patients.

P=N/A, N=100, Recruiting, Centre Hospitalier Universitaire de Nice

P2, N=30, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P3, N=1400, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

P1, N=38, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=30, Completed, Weill Medical College of Cornell University | Active, not recruiting --> Completed

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 RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

P1/2, N=47, Suspended, Ohio State University Comprehensive Cancer Center | Recruiting --> Suspended | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=0, Withdrawn, Uwe Platzbecker | N=108 --> 0 | Not yet recruiting --> Withdrawn

Mechanistically, the protective effect of CPX-351 occurred through pathways involving both the host and the intestinal microbiota, namely via the activation of the aryl hydrocarbon receptor-IL-22-IL-10 host pathway and the production of immunomodulatory metabolites by anaerobes. This study reveals how the gut microbiota may contribute to the good safety profile, with a low infection-related mortality, of CPX-351 and highlights how a better understanding of the host-microbiota dialogue may contribute to pave the way for precision medicine in AML.

P2, N=12, Recruiting, Roswell Park Cancer Institute | N=46 --> 12

P2, N=78, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P3, N=882, Recruiting, University of Ulm

P=N/A, N=108, Recruiting, Jazz Pharmaceuticals | Not yet recruiting --> Recruiting

Here, we review the current in vitro, clinical, and real-world evidence on the use of CPX-351 in patients with AML and mutations in FLT3. Additionally, we review preliminary data from clinical trials and patient case reports that suggest the combination of CPX-351 with FLT3 inhibitors may represent another treatment option for patients with FLT3 mutation-positive AML.

As in AML, FL kinetic profile predicts response and survival in HR-MDS/CMML. A FLD kinetic profile was the only factor independently associated with higher CR/CRi rates and better EFS. These results have to be confirmed on larger cohorts.

The use of CPX-351 demonstrated efficacy across subgroups, especially in t-AML and pts without prior HMA exposure, as shown in larger studies. In pts <60 years, even though CRc rates were lower, CPX-351 led to longer mOS in those who achieved CRc and in those who underwent alloSCT compared to pts ≥60 years, although it didn't reach statistical significance in this small cohort. Induction therapy outcomes and treatment-related complications in our study corroborate the data for prior CPX-351 studies.

CPX-351 is able to induce good quality remission with high CR rate and MRD negativity, regardless of mutational burden, allowing a high number of elderly AML patients to undergo to HSCT. MRD evaluation has proven to be a strong prognostic tool also in the setting of elderly s-AML and t-AML patients receiving CPX-351. The prognostic value of high risk mutation seems to be less relevant in CPX-351 treated patients.

Concomitant midostaurin (days 8-21) was allowed for patients with FLT3 mutations (Patients #1 and #8)...ConclusionThis 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.

Four pts (33%) were refractory to venetoclax (VEN)-based therapy and 3 pts (25%) had previous alloHCT (Table 1)... Combination of cladribine with standard dose of CPX-351 is well tolerated. Cladribine dose 5 mg/m 2 was selected as RP2D. Safety profile does not indicate any significant additional myelosuppression.

Among patients with AML treated with CPX-351, PTPN11 and IDH2 mutations were independently associated with inferior overall survival compared to those without these mutations. The PTPN11 gene is involved in RAS pathway regulation and has also been associated with shorter survival in AML in other studies. Here, mutated SRSF2 was associated with improved survival after CPX-351 induction.

Traditionally, patients who are eligible for allogenic stem cell transplant (SCT) with AML-MRC/AML-MR are given high intensity chemotherapy (IC), such as daunorubicin and cytarabine (“7+3”), liposomal 7+3 or fludarabine+cytarabine+idarubicin (FLAG-IDA) whereas patients who are not transplant-eligible were treated with hypomethylating agents (i...Treatment with a “7+3” backbone or FLAG-IDA were considered ‘intensive’ regimens; treatment with azacitidine with or without venetoclax, and low dose cytarabine (LDAC), with or without venetoclax were considered ‘non-intensive... Aza/Ven is an effective treatment regimen for AML-MRC/AML-MR, with 14/21 patients achieving CR/CRi after firstline treatment compared to 6/14 patients after IC. 4/4 patients achieved CR/CRi with salvage aza/ven after failing to respond to IC. Our study suggests that aza/ven should be considered as a firstline treatment option even in patients who are fit for intensive therapy as a means to achieve adequate responses to bridge to allogenic stem cell transplant without attendant toxicities associated with IC.

7%) backbone and Azacitidine alone (13... Progression free survival obtained after induction therapy and overall survival were relatively shorter than the ones which were presented by other real-world registries. Lack of early access to the targeted and novel agents, like Flt3 inhibitors, Venetoclax, IDH1 and 2 inhibitors, CPX351 and Glasdegib should be a potential explanation to this relatively short PFS and OS. We have also been aware of un-ideal access to well established and nation wide cytogenetic laboratory service to induce early integration of targeted agents to the treatment and better risk stratification to determine the patients who should obtain the best prolonged survival via allo-HCT.

Background: Hypomethylating agent (HMA) and venetoclax (Ven) frontline therapy for acute myeloid leukemia (AML) is astandard of care for patients (pts) deemed to be poor candidates for intensive induction due to age or fitness...Fifteen pts (65%) had frontline therapy with azacitidine backbone, 6 pts (26%) with decitabine; some pts received both before intensive therapy...Other regimens included 7+3 (n=2, 9%), FLAG-Ida + Ven (n=2, 9%), HiDAC + Mitoxantrone +/- Ven (n=4, 17%) ( Table 1)... Intensive therapy for R/R AML after prior frontline less-intensive therapy was associated with an ORR rate of 27% and median OS of 5. 8 months in our cohort. This approach may be an appropriate strategy for a subset of pts, particularly those eligible for alloHCT.

P2, N=108, Not yet recruiting, Uwe Platzbecker | Initiation date: Oct 2023 --> Jan 2024

P=N/A, N=108, Not yet recruiting, Jazz Pharmaceuticals

P1, N=13, Terminated, Jonsson Comprehensive Cancer Center | Trial completion date: Jul 2025 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2024 --> Oct 2023; slow accrual

P2, N=50, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

GO was administered in combination with daunorubicin and cytarabine (3+7, N = 30; or 2+5, N = 1) at standard dose on days 1, 4, 7 of induction, and on day 1 of consolidation for up to two cycles...Table 1. Patients’ characteristics.

New WHO criteria outline the role of molecular biology in defining MR-AML: further research is needed to identify subgroups that would benefit from CPX-351 and selected pts, such as TP53+, eligible to biological therapies. Figure 1.

The limited number of pts and the high numbers of bias due to the different treatment times of the two groups and the different follow-up may influence the results. Prospective studies are needed to fully address a real comparation between these regimens.

First line therapy was 3+7 or analogues in 81,3% of patients, CPX-351 in one patient, HMA plus venetoclax in one patient...In patients treated with midostaurin as a part of their induction regimen CR rate was 60%, median OS was 18.5 months, and median EFS was 16.7 months...The prognosis of FLT3 mutated AML with associated myeloid sarcoma remains dismal. Gilteritinib could play a role in relapsed setting, and in our series demonstrated activity in CNS disease; this positive effect needs to be validated in a larger series of patients.

Gemtuzumab Ozogamicin (GO), a monoclonal antibody targeting CD33, linked to calicheamicin, is approved in combination with daunorubicin and cytarabine (3+7) for the treatment of patients with previously untreated, de novo CD33-positive non promyelocytic AML...Figura 1. Overall survival of the whole population (34 cases) from the diagnosis.

P2, N=13, Active, not recruiting, Case Comprehensive Cancer Center | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Dec 2023 --> Jun 2024

Venetoclax (ven) is a BCL2 inhibitor which, in combination with azacitidine or cytarabine, has become the standard of care for elderly AML...Toxicities are as expected for an intensive chemotherapy regimen. Further studies are needed to confirm the efficacy of this combination.

Achievement of MRD negativity contributed to improvement of OS in the overall population and, maybe, in transplanted patients. These data provide the rationale for the ongoing ALFA-2101 phase III clinical trial evaluating CPX-351 vs. 3+7 (daunorubicin and cytarabine) in non-MRC-AML and non-t-AML using MRD as the primary endpoint.

In this phase Ib dose escalation study, standard dose CPX-351 combined with 7 days of Ven was found to safe and tolerable in pts with rAML. The combination produced encouraging response rates in a poor risk population, including those with prior Ven treatment, allowing a significant proportion to undergo allo-SCT and extended survival. The RP2D is being studied in pts with newly diagnosed and less heavily pretreated AML.

Patients with good or intermediate-risk AML received intensive chemotherapy such as 7+3 +/- gemtuzumab or midostaurin if determined to be fit...Other patients received low-intensity chemotherapy: azacitidine or decitabine and venetoclax (n=43, 59%), decitabine or azacitidine alone (n=18, 24%) prior to approval of venetoclax, and other (n=5, 7%)... Our model to personalize AML therapy selection represents an innovative approach to precision medicine that incorporates both geriatric assessment for patient profiling and genetic profiling of leukemia cells. Geriatric assessment demonstrated high frequency of impairment in objective physical and cognitive function. Patients were able to start therapy within a median of 1 day following enrollment.

Introduction: The approval of venetoclax (VEN)-based frontline therapy for acute myeloid leukemia (AML) in November 2018 marks a new era of AML care...Among patients who were tested and qualified, no difference was observed in the use of gemtuzumab ozogamicin, CPX-351, FLT3 inhibitors or IDH1/2 inhibitors across race/ethnicity... In this large, real-world dataset, we demonstrate OS improvements in the era of modern AML care, particularly among patients >70 years though their outcomes remain inferior to younger patients. Intriguingly, the largest OS improvement was observed in NHB, where the OS disparity between NHB and NHW in Pre era appears to have been mitigated. Hispanics have not experienced similar OS improvement in modern AML care.