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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Patients above 60 years of age account for approximately 75% of all newly diagnosed AML, and although about 60% are able to achieve a CR with standard remission induction, the relapse rates are very high, and event-free survival (EFS) is about 20% at 2 years. There has been some, but not major, improvement in these results following the use of risk scoring systems. Low-dose cytarabine has been historically used with CR rates of about 15% but dismal survival. It is possible that some of the recently approved AML drugs may improve the outcomes of older patients. As an illustration, gemtuzumab ozogamicin (GO), which has had a complicated clinical development history, was found to confer a survival benefit in older patients with favorable or intermediate-risk cytogenetics; in contrast, a large study found survival to be shorter in those aged 70 to 75 years due to early mortality. GO is approved for the treatment of adults with newly diagnosed CD33+ AML and for patients aged 2 years and older with CD33+ AML who have experienced a relapse or who have not responded to initial therapy. Vyxeos has also been found to result in a survival benefit for older patients with high-risk disease, and further studies are in progress. Venetoclax, an oral BCL-2 inhibitor, was licensed in 2018 in the United States for previously untreated older AML patients not eligible for intensive chemotherapy, in combination with low-dose cytarabine or an HMA. In randomized studies assessing therapy with HMAs, both decitabine and azacytidine have also been found to improve OS, particularly in patients with high-risk cytogenetics; patients experienced clinical benefits, such as a reduction in red cell transfusions and improved quality of life (QoL).24 Ivosidenib is also approved for older patients with IDH1-mutated untreated AML.
Acute Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
It is of interest that despite the extensive genomic and epigenetic data collated from patients with AML, until spring 2017, there was just one genotypic selective therapy, ATRA-ATO, licensed for patients with APL. Since then, several targeted drugs have received US Food and Drug Administration (FDA) approval for selected patients with AML. In April 2017, midostaurin, an N-benzoyl staurosporine analog derived from Streptomyces staurosporeus, was licensed for the treatment of adults with newly diagnosed FLT3ITD AML, in combination with standard chemotherapy, followed in July 2017, by venetoclax, for use in combination with low-dose cytarabine in newly diagnosed older patients with AML. In August 2017, enasidenib, an IDH2 inhibitor, was licensed for adult patients with IDH2R140 or IDH2R172 relapsed or refractory AML, and vyxeos (CPX-351), a novel liposomal cytarabine-daunorubicin formulation, for adult patients with newly diagnosed t-AML or AML with MDS-related changes. This was followed, in September 2017, by an approval for gemtuzumab ozagamicin (mylotarg; GO), and then in July 2018, of ivosidenib, an IDH1 inhibitor, both for patients with relapsed/refractory AML. Clearly these approvals will impact the therapy of AML, and we must continue to use the accumulated enormous genetic data in concert with the new risk stratification tools, such as the ELN 2017 AML Risk Score, to inform the development of rationally designed clinical trials targeting specific mutations and co-mutations to improve the survival of all patients with AML. Notably enasidenib is conceptually novel and is associated with a differentiation syndrome, akin to that observed with ATRA in APL. And since IDH2 and FLT3ITD are expressed in diverse myeloid malignancies, we can anticipate that these drugs may well have activity in other myeloid disorders, such as MDS.
Novel precision therapies for cholangiocarcinoma: an overview of clinical trials
Published in Expert Opinion on Investigational Drugs, 2023
Pedro Luiz Serrano Uson Junior, Jeremiah Bearss, Hani M Babiker, Mitesh J Borad
The IDH1 inhibitor ivosidenib was initially evaluated in advanced iCCA with mutant IDH1 in a phase I dose-escalation trial [28]. In the trial, no dose-limiting toxicities were reported. The median PFS of the 73 patients treated with ivosidenib was 3.8 months and the median OS was 13.8 months. In the phase III trial ClarIDHy, a total of 126 patients with advanced IDH1 mutant iCCA were randomized to ivosidenib 500 mg once daily or placebo. Patients were treated until disease progression or unacceptable toxicity. Every patient in the trial was previously treated and presented with disease progression or intolerance to chemotherapy [29,30]. Ivosidenib improved PFS, 2.7 months versus 1.4 months (HR 0.37; one-sided p < 0.0001) and improvements in OS were also observed, median OS was 10.3 months for ivosidenib and 7.5 months for the placebo arm (one-sided p = 0.093). However, 70% of placebo patients crossed over to ivosidenib on progression. After adjustments for the crossover effect, the rank-preserving structural failure time model-adjusted median OS was 5.1 months for placebo (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common treatment-related adverse effects with ivosidenib included nausea, diarrhea, fatigue, cough, abdominal pain, decreased appetite, ascites, vomiting, anemia and constipation [29,30].
Ivosidenib: an investigational drug for the treatment of biliary tract cancers
Published in Expert Opinion on Investigational Drugs, 2021
Angelos Angelakas, Angela Lamarca, Richard a Hubner, Mairéad G McNamara, Juan W. Valle
The FDA has previously approved ivosidenib for use in patients with IDH1-mutated AML. It has also shown good tolerability and safety as well as improved PFS in patients with advanced iCCA [27,28]. The magnitude of benefit in patients with iCCA warrants further discussion; at first glance, the improvement in median PFS is very modest (2.7 vs. 1.4 months for ivosidenib and placebo, respectively – an additional 1.3 months). Closer inspection of the Kaplan-Meier survival curves for PFS reveals very little separation of the curves within the first 2 months; therefore, the cumulative benefit over the whole time course is more relevant, represented by the hazard ratio which translates to a 63% reduction in risk of disease progression (HR 0.37 (95% CI 0.25–0.54); p < 0 · 0001) [30]. Moreover, there were no placebo-treated patients free of progression at either 6- or 12-months, which was seen in 32% and 22% of ivosidenib-treated patients, respectively. Although PFS was the primary end-point of the ClarIDHy study, it is important to understand how this translates into a survival benefit for patients. The recent presentation of the mature survival data (after adjusting for cross-over from placebo to ivosidenib, using the RPSFT model) shows that there is a clinically meaningful improvement in median OS (10.3 vs. 5.1 months) with an approximately 50% reduction in risk of death at any time as shown by the hazard ratio [31].
Cholangiocarcinoma: shedding light on the most promising drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2021
Amir A. Rahnemai-Azar, Timothy M. Pawlik
In a phase-I study (NCT02073994) of 73 patients with IDH1-mutant advanced CCA, administration of AG-120 (Ivosidenib), an IDH-1 inhibitor, was associated with PR in 5% (n = 4) and stable disease in 56% (n = 40) of patients. Median overall survival (OS) was 13.8 months (95% CI 11.1–29.3) [30]. The result of a multi-center, randomized phase 3 study (ClarIDHy) demonstrated encouraging clinical outcomes [31]. Ivosidenib significantly improved PFS compared with placebo (median 2.7 months [95% CI 1.6–4.2] vs. 1.4 months [1.4–1.6]; hazard ratio 0.37; 95% CI 0.25–0.54; one-sided p < 0.0001) [31]. Serious adverse events were reported in 36 (30%) of 121 patients receiving Ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. The efficacy of AG-221 (Enasidenib, a selective IDH-2 inhibitor) and other IDH1 and IDH2 inhibitors are now being assessed in several ongoing clinical trials (NCT02273739, NCT02273739, NCT02381886, and NCT02481154).