Comparison of Decitabine with Venetoclax versus Intensive Chemotherapy Using Propensity Score Matching and Treatment-related Mortality Risk Scoring - European Medical Journal

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Comparison of Decitabine with Venetoclax versus Intensive Chemotherapy Using Propensity Score Matching and Treatment-related Mortality Risk Scoring

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Hematology
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Authors:
Abhishek Maiti,1 Courtney D. DiNardo,1 Farhad Ravandi,1 Tapan M. Kadia,1 Elias J. Jabbour,1 Naval G. Daver,1 Gautam Borthakur,1 Guillermo Garcia-Manero,1 Wei Qiao,4 Sherry A. Pierce,1 Naveen Pemmaraju,1 Kiran Naqvi,1 Maro Ohanian,1 Nicholas J. Short,1 Yesid Alvarado,1 Koichi Takahashi,1 Musa Yilmaz,1 Nitin Jain,1 Steven Kornblau,1 Koji Sasaki,1 Michael Andreeff,1 Prithviraj Bose,1 Alessandra Ferrajoli,1 Ghayas C. Issa,1 Lucia Masarova,1 Philip A. Thompson,1 Caitlin R. Rausch,3 Jing Ning,4 Hagop M. Kantarjian,1 *Marina Y. Konopleva 1

1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3. Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
*Correspondence to [email protected]

Disclosure:

All of the following disclosures are outside of the submitted work. Dr Maiti has received research funding from Celgene. Dr Pemmaraju has received consultancy fees or honorarium from Celgene, Stemline, Incyte, Novartis, MustangBio, Roche Diagnostics, and LFB; research funding or clinical trials support from Stemline, Novartis, AbbVie, Samus, Cellectis, Plexxikon, Daiichi-Sankyo, and Affymetrix; and grants or funding from Affymetrix and the SagerStrong Foundation. Dr Daver has received consultancy fees from Sunesis Pharmaceuticals, Karyopharm, Pfizer, Bristol-Myers Squibb, Novartis, Otsuka America Pharmaceutical, Inc., and Jazz Pharmaceuticals; research funding from Sunesis Pharmaceuticals, Karyopharm, Immunogen, Pfizer, Incyte, Bristol-Myers Squibb, Daiichi-Sankyo, and Kiromi; and honoraria from Incyte. Dr Ravandi has received research funding from Amgen, Bristol-Myers Squibb, Merck, Seattle Genetics, and Sunesis Pharmaceuticals; honoraria from Amgen, Pfizer, Seattle Genetics, and Sunesis Pharmaceuticals; and had a consulting or advisory role for Amgen, Seattle Genetics, and Sunesis Pharmaceuticals. Dr Borthakur has received research funding from AbbVie, Incyte, Janssen, GlaxoSmithKline, Cyclacel, BioLine Rx, and Oncoceutics, Inc; and consultancy fees from BioLine Rx, NKarta, and PTC Therapeutics. Dr Short has received research funding from Takeda Oncology; consultancy fees from Takeda Oncology and AstraZeneca; and honoraria from Amgen. Dr Alvarado has received research funding from Jazz Pharmaceuticals; and honoraria from Abbott. Dr Takahashi has received consultancy fees from Symbio Pharmaceuticals. Dr Jain has received consultancy fees from AbbVie, Pharmacyclics, an AbbVie company, Janssen, Genentech, Pfizer, ADC Therapeutics, AstraZeneca, Servier, Verastem, Precision Biosciences, and Adaptive Biotechnologies; research funding from AbbVie, Pharmacyclics, an AbbVie company, Genentech, BMS, Pfizer, ADC Therapeutics, Incyte, AstraZeneca, Servier, Cellectis, Verastem, Precision Biosciences, and Adaptive Biotechnologies; honoraria from and held membership on an entity’s Board of Directors or advisory committees at AbbVie, Pharmacyclics, an AbbVie company, Janssen, Genentech, Pfizer, ADC Therapeutics, AstraZeneca, Servier, Verastem, Precision Biosciences, and Adaptive Biotechnologiess. Dr Sasaki has received consultancy fees from Pfizer; and honoraria from Otsuka. Dr Andreeff has received consultancy fees from Daiichi Sankyo, Jazz Pharmaceuticals, Celgene, Amgen, AstaZeneca, and 6 Dimensions Capital; patents and royalties, with patents licensed and royalty bearing from Daiichi Sankyo; research funding from Daiichi Sankyo, Breast Cancer Research Foundation, CPRIT, and NIH/NCI; equity ownership from Reata, Aptose, Eutropics, Senti Bio, Oncoceutics, and Oncolyze; and membership on an entity’s Board of Directors or advisory committees at Senti Bio, Center for Drug Research & Development, Cancer UK, NCI-CTEP, German Research Council, Leukemia Lymphoma Society, NCI-RDCRN (Rare Disease Clinical Research Network), CLL Foundation, and BiolineRx. Dr Bose has received consultancy fees from Incyte, Celgene, and Blueprint Medicines; research funding from Incyte, Celgene, Blueprint Medicines, Kartos Therapeutics, Constellation Pharmaceuticals, Pfizer, Astellas, NS Pharma, Promedior, and CTI BioPharma; and speakers bureau involvement at Incyte. Dr Jabbour has received consultancy fees and research funding from Takeda, BMS, Adaptive, Amgen, AbbVie, Pfizer, and Cyclacel LTD. Dr DiNardo has received honoraria from AbbVie, Agios, Novartis, Celgene, Daiichi-Sankyo, Jazz Pharmaceuticals, and Notable Laboratories; research funding from AbbVie, Agios, Novartis, Celgene, Daiichi-Sankyo, and Calithera Biosciences; and has had a role as a scientific advisory board member at Notable Laboratories.  Dr Kantarjian has received research funding from Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Pfizer, Immunogen, Jazz Pharmaceuticals, and Novartis; and honoraria from Pfizer, Immunogen, Actinium, and Takeda. Dr Konopleva has received research funding from Calithera, Stemline, Eli Lilly, AbbVie, Cellectis, F. Hoffman La-Roche, Genentech, Ascentage, Ablynx, AstraZeneca, and Agios; consultancy fees from Stemline, Forty-Seven, AbbVie, Amgen, F. Hoffman La-Roche, and Kisoji; honoraria from Stemline, Forty-Seven, AbbVie, Amgen, F. Hoffman La-Roche, Genentech, and Kisoji; equity ownership, patents, and royalties from Reata.

Acknowledgements:

The authors would like to thank all the patients and their caregivers, co-investigators, collaborators, and members of the study teams involved in these trials.

Citation:
EMJ Hematol. ;8[1]:67-70. Abstract Review No: AR7.
Keywords:
10 day, acute myeloid leukemia (AML), decitabine, treatment-related mortality, venetoclax.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIMS

Acute myeloid leukaemia (AML) usually presents in older patients over the age of 65 years.1 A large proportion of such patients are frail or have comorbidities that make them poor candidates for intensive therapies.2 Venetoclax-based lower-intensity regimens are now established as standard therapy for older or unfit patients with AML.3,4 However, initial clinical trials of venetoclax did not incorporate objective methods for delineating patients who are considered ‘unfit’ for intensive chemotherapy. Consequently, the benefit of venetoclax-based regimens in truly unfit patients has been debated, and experts have advocated for randomised controlled trials against intensive chemotherapy.5

The authors conducted a retrospective study to address these questions.6

MATERIALS AND METHODS

The authors compared outcomes of 85 patients with newly diagnosed AML, treated on a prospective Phase II trial of 10-day decitabine and venetoclax (DEC10-VEN), with a historical cohort of patients treated with intensive chemotherapy containing cytarabine of at least 1 g/m2/day.7 The historical cohort of 85 patients was selected from over 1,300 patients using propensity score matching. To better understand outcomes in patients deemed unfit by objective methods, the authors used a previously validated treatment-related mortality scoring that classified patients at low versus high risk of 30-day mortality from intensive chemotherapy.8

RESULTS

The two cohorts of patients treated with DEC10-VEN and intensive chemotherapy were well balanced in terms of baseline characteristics. More than 50% of patients were >70 years, >30% patients had Eastern Cooperative Oncology Group (ECOG) performance status scores of 2 or higher, nearly 30% patients were at high risk of early mortality form intensive chemotherapy, and nearly two-thirds of patients had European LeukemiaNet (ELN) adverse risk disease. The authors found that DEC10-VEN led to significantly higher rates of complete remission compared to intensive chemotherapy (62% versus 42%; p=0.01), lower rates of relapse (34% versus 56%; p=0.01), lower 30-day mortality (1% versus 24%; p<0.01), and longer overall survival (OS) at 12.4 months versus 5.0 months (Figure 1). Patients at both  low risk as well as high risk of early mortality from intensive chemotherapy derived benefit with DEC10-VEN and had significantly longer OS.6 Subgroup analysis for OS showed benefit with DEC10-VEN over intensive therapy in most subgroups and multivariable analysis confirmed improved outcomes with DEC10-VEN over intensive therapy for most outcomes including complete remission rates, early mortality, and OS.

Figure 1: Overall survival in patients with newly diagnosed acute myeloid leukaemia treated with DEC10-VEN, and a propensity score-matched cohort of patients treated with intensive chemotherapy.

CI: confidence interval; DEC10-VEN: 10-day decitabine with venetoclax; HR: hazard ratio; IC: intensive chemotherapy; OS: overall survival.

CONCLUSION

The authors concluded that in this retrospective analysis, DEC10-VEN showed better outcomes compared to intensive chemotherapy in newly diagnosed AML. Patients who were at both low risk as well as high risk of early mortality with intensive chemotherapy appeared to benefit from DEC10-VEN. These results have implications for the design of future clinical trials incorporating venetoclax-based regimens. The authors commented that clinical trials evaluating the role of venetoclax with hypomethylating agents in younger and older ‘fit’ patients are currently ongoing at their institution.

References
Short NJ et al. Acute myeloid leukaemia. Lancet. 2018;392(10147):593-606. Kantarjian H et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116(22):4422-9. DiNardo C et al. A randomized, double-blind, placebo-controlled study of venetoclax with azacitidine vs azacitidine in treatment-naïve patients with acute myeloid leukemia ineligible for intensive therapy-viale-A. Abstract LB2601. EHA 25th Congress, 11-21 June, 2020. Wei AH et al. Venetoclax plus LDAC for patients with untreated AML ineligible for intensive chemotherapy: Phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137-45. Estey E et al. Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse? Leukemia 2020;34(3):671-81. Maiti A et al. 10-day decitabine and venetoclax (dec10-ven) vs. intensive chemotherapy (IC) in acute myeloid leukemia (AML): a propensity score matched analysis stratified by risk of treatment-related mortality. Abstract S141. EHA 25th Congress, 11-21 June, 2020. Maiti A, DiNardo CD, Rausch CR, et al. Ten-day decitabine with venetoclax (DEC10-VEN) in acute myeloid leukemia: updated results of a phase II trial. Blood. 2019;134(Suppl 1):2637. Walter RB et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29(33):4417-23.

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