Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis

Abstract

Abstract Introduction: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are two of the most common hematological disorders in adults with a variable prognosis. The TP53 mutation confers a poorer prognosis in these disorders. After decades of relatively stagnant growth, numerous novel therapies have recently emerged. We explore their outcomes in the management of AML/MDS, with a subgroup analysis for TP-53 mutated AML/MDS. Methods: A comprehensive literature search was conducted in accordance with the PRISMA guidelines on PubMed, Cochrane Central, Google Scholar, and ClinicalTrials.gov. MeSH terms and keywords for ‘Acute Myeloid Leukemia’ AND/OR ‘Myelodysplastic Syndrome’ AND ‘Investigational Drugs’ were used. A total of 1,162 articles were identified. After screening and exclusion of irrelevant and review articles, 45 studies were included. Pooled proportions with 95% confidence intervals were calculated using the DerSimonian–Laird estimator and analyzed with the ‘meta’ package in R (version 4.16-2). Results: A total of 45 studies, comprising 17 Phase I, 7 Phase I/II, 16 Phase II, and 5 Phase III studies, with 2776 patients, were included. The median age was 69 (19-100) years for the AML and 73 (23-90) years for the MDS group. In AML patients, ELN Risk was favorable (5%, n = 68/1270), intermediate (48%, n = 613/1270), and adverse (47%, n = 589/1270). In the MDS group, 18% (n = 102/561) were treatment-naïve, and 91% (n = 309/341) had previously failed HMA (Hypo-methylating agent) therapy. Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib. The most commonly used conventional agent was azacitidine (n = 545, 20%). The pooled rates of overall response (OR), and complete response (CR), were 50.8% (95% CI 0.471-0.544, I2=80%, p<0.01, n=764), 29% (95% CI 0.272-0.319, I2=89%, p<0.01, n=1626), respectively in the AML group, and 44.7% (95% CI 0.389-0.507, I2=87%, p<0.01, n=293), 2.4% (95% CI 0.012-0.039, I2=92%, p<0.01, n=737), respectively in the MDS group. The cumulative complete response with incomplete count recovery (CRi), stable disease (SD), and progressive disease (PD) were 9.5% (95% CI 0.076-0.116, I2=58%, p<0.01, n=962), 34.7% (95%CI 0.310-0.385, I2=79%, p<0.01, n=649), and 7.8% (95%CI 0.061-0.097, I2=89%, p<0.01, n=931), respectively for AML patients. In the MDS group, pooled rates for bone marrow complete response (mCR), SD, and PD were 12.6% (95% CI 0.098-0.155, I2=86%, p<0.01, n=603), 36% (95%CI 0.315-0.415, I2=49%, p=0.07, n=379), and 19% (95%CI 0.150-0.233, I2=69%, p<0.01, n=379), respectively. The median overall survival (mOS) was 9.1 (0.5-NR) months in the AML group and 18.5 (1.5-NE) months in the MDS group. In AML patients, Alvocidib showed an ORR of 80% (n = 8/10), CR of 70% (n = 7/10), and Ivosidenib monotherapy showed an 83% ORR (n = 15/18) (CR 39%, mCR 44%) in MDS patients. In subgroup analysis of combination of novel agents with a conventional drug, the pooled OR and CR were 61% (95% CI 0.557-0.655, I2=66%, p<0.01, n=409), 57% (95% CI 0.536-0.612, I2=93%, p<0.01, n=714), respectively in AML patients and 53% (95% CI 0.457-0.610, I2=48%, p = 0.01, n=171), 15.6% (95% CI 0.103-0.217, I2=42%, p=0.14, n=171), respectively in MDS patients. Four studies with 194 patients were included in the TP53-mutation subgroup. The median age was 73 (31-89) years; 70% (n = 134/195) had AML, and newer agents included Eprenetapopt, Magrolimab, and Entospletinib. All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%). The pooled rates for OR and CR were 49% (95% CI 0.409-0.572, I2=56%, p=0.10, n=149) and 28.6% (95% CI 0.223-0.352, I2=74%, p<0.01, n=194), respectively.The mOS was 11 (3.7-NR) months. The most common adverse events among all groups were hematological, including neutropenia (30%, n = 491/1662) and anemia (28%, n = 428/1555). Conclusions: This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further.