Liposomal Cytarabine and Daunorubicin (CPX-351) in Combination with Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Acute Myeloid Leukemia (AML) and Post-Hypomethylating Agent (Post-HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)

Rivera, Daniel; Kadia, Tapan M.; Montalban‐Bravo, Guillermo; Faderl, Stefan; Sasaki, Koji; Short, Nicholas J.; Daver, Naval; DiNardo, Courtney D.; Masárová, Lucia; Ferrajoli, Alessandra; Jabbour, Elias; Borthakur, G.; Azzawi, Hind Al; Konopleva, Marina; Andreeff, Michael; Kantarjian, Hagop M.; Ravandi, Farhad; Alvarado, Yesid

doi:10.1182/blood-2021-149840

Cited by 3 publications

(7 citation statements)

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“…61 Combinations of CPX-351 and GO have been tried in patients with R/R AML (n = 23) or post-hypomethylating agent (HMA) failure high-risk MDS (n = 1); ORR was 55%; however, OS was a modest 5 months. 62 Longer follow-up data of full cohort of this study are awaited. Further studies have also shed light on other possible determinants of GO sensitivity in AML cells, important of which is the (rs12459419 C > T) single-nucleotide polymorphism in the splice enhancer region of CD33, which offsets the GO-binding site; data from pediatric AML patients and adult patients with NPM1-mutated AML, but not other patient groups, have shown that patients with CC genotype of CD33 have more GO sensitivity compared with patients with CT or TT CD33 genotype.…”

Section: Go In Mds and Other Settingsmentioning

confidence: 97%

Antibody-Drug Conjugates in Myeloid Leukemias

2022

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Targeted therapy in oncology brings with it the promise to maximize cancer cell cytotoxicity with minimal off-target effects. Antibody-drug conjugates (ADCs), an important group of such targeted agents, consist of a monoclonal antibody conjugated to a potent cytotoxic drug. In the field of leukemia, ADCs form an important component of therapeutic arsenal through the use of gemtuzumab ozogamicin in acute myeloid leukemia and inotuzumab ozogamicin (InO) in B-cell acute lymphoblastic leukemia, 2 approved agents. A recombinant fusion protein, tagraxofusp, which function similar to ADC, has gained approval for therapy in blastic plasmacytic dendritic cell neoplasm. The use of such agents as monotherapy or as part of a combination therapy has led to improved response rates and outcomes in certain specific disease subtypes and has led to further studies to identify novel cellular targets and improved delivery of cytotoxic agents using ADC. In this review, we will discuss about ADCs in myeloid leukemia and understand their development and current use in the field.

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Section: Go In Mds and Other Settingsmentioning

confidence: 97%

Antibody-Drug Conjugates in Myeloid Leukemias

2022

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“…While the introduction of a low-dose chemotherapy strategy has widened the spectrum of treatment options for medically unfit patients, still a paucity of studies exist comparing high- vs. low-intensity approaches. Current investigations are exploring the role of a fixed-dose combination of daunorubicin/cytarabine (CPX-351) in RR-MDS/AML [ 92 , 93 ]. CPX-351 is currently approved only in newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes (AML-MRC).…”

Section: Management Of Patients After Hma Failurementioning

confidence: 99%

“…An early phase one trial of 43 RR-AML patients reported an ORR of 23.3% (21% CR) [ 92 ]. Another study of CPX-351, in combination with Gemtuzumab Ozogamicin (GO) in 24 RR-AML and MDS cases post-HMA failure, resulted in an ORR of 55%, though no patient transitioned to Allo-HCT due to age and comorbidities [ 93 ]. Median OS was 5 months and (95% CI 1.9–8) and median response duration was 7 months (95% CI 0–9) while no grade 3–4 nonhematological toxicities occurred [ 93 ].…”

Section: Management Of Patients After Hma Failurementioning

confidence: 99%

What’s Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach

Awada

Gurnari

Xie

et al. 2023

Cancers

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Hypomethylating agents (HMA) such as azacitidine and decitabine are a mainstay in the current management of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) as either single agents or in multidrug combinations. Resistance to HMA is not uncommon, and it can result due to several tumor cellular adaptations. Several clinical and genomic factors have been identified as predictors of HMA resistance. However, the management of MDS/AML patients after the failure of HMA remains challenging in the absence of standardized guidelines. Indeed, this is an area of active research with several potential therapeutic agents currently under development, some of which have demonstrated therapeutic potential in early clinical trials, especially in cases with particular mutational characteristics. Here, we review the latest findings and give a rational approach for such a challenging scenario.

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“…In patients with R/R AML and post-HMAs failure high-risk MDS, an ongoing trial (NCT03672539) aims to investigate the safety and efficacy of CPX-351 in combination with gemtuzumab ozogamicin (GO). The induction schedule includes CPX-351 (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 ) administered on days 1, 3, and 5 and GO at a dose of 3 mg/m 2 on day 1 [ 48 ]. Patients who achieve CR/CRi could receive up to 2 consolidation cycles with CPX-351 (daunorubicin 29 mg/m 2 and cytarabine 65 mg/m 2 ) on days 1 and 3 and GO at 3 mg/m 2 on day 1.…”

Section: New Combinations and Future Directionsmentioning

confidence: 99%

“…After a median follow-up of 24 months, the median OS was 5 months with a median duration of response of 7 months. Adverse events were predominantly characterized by infectious events and the 30-day mortality was 8% [ 48 ].…”

Section: New Combinations and Future Directionsmentioning

confidence: 99%

CPX-351: An Old Scheme with a New Formulation in the Treatment of High-Risk AML

Molica

Perrone

Mazzone

et al. 2022

Cancers

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Therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent aggressive diseases characterized by a dismal prognosis if compared with de novo acute myeloid leukemia, especially in older patients. In these AML subsets, standard chemotherapy regimens produce poor response rates and unsatisfactory outcomes. Historically, conventional approaches consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the “3+7” regimen. Several attempts have been conducted to ameliorate this combination regimen but inconsistent improvements in response rates and no significant changes in overall survival have been observed, until the recent introduction of targeted molecules. A liposomal formulation of traditional chemotherapy agents cytarabine and daunorubicin, termed CPX-351, enhances pharmacodynamics and synergistic effects through the maintenance of the optimal 5:1 molar ratio, which extends the treatment’s half-life and increases the bone marrow tropism of the drug. The use of CPX-351 in newly diagnosed AML-MRC and t-AML patients aged 60–75 years has demonstrated superior remission rates compared to conventional chemotherapy and improvements in event-free and overall survival. Recently, published data from a 5-year follow-up highlighted evidence that CPX-351 has the ability to produce and contribute to long-term remission and survival in older patients with newly diagnosed high-risk/secondary AML. Future perspectives include evaluation of dose intensification with CPX-351 in high-risk settings, combining this agent with targeted therapies, and better understanding the mechanism of improved responses in t-AML and AML-MRC. In this review, we will examine the role of CPX-351 inside the new AML therapeutic scenario and how its employment could potentially modify the treatment algorithm of high-risk and elderly patients with AML

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Liposomal Cytarabine and Daunorubicin (CPX-351) in Combination with Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Acute Myeloid Leukemia (AML) and Post-Hypomethylating Agent (Post-HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)

Cited by 3 publications

References 0 publications

Antibody-Drug Conjugates in Myeloid Leukemias

Antibody-Drug Conjugates in Myeloid Leukemias

What’s Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach

CPX-351: An Old Scheme with a New Formulation in the Treatment of High-Risk AML

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