Successful rechallenge with azacytidine and venetoclax after sustained treatment-free remission in a relapsed acute myeloid leukemia patient: a case report
Edoardo TamelliniClaudia SimioAndrea BernardelliI. FerrariniA VatteroniAlessia MoioliV. MacalusoEnrico MarchettiIlaria Tanasi
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Abstract Combined therapy with venetoclax and hypomethylating agents has significantly improved the outcome of unfit patients ineligible for intensive chemotherapy. A recently published exploratory analysis of the VIALE-A trial reported that up to 51% of patients achieving remission survived more than 2 years. These data along with those from reallife settings, lead to questioning how long it is appropriate to continue treatment in long-term survivors. Accordingly, recent retrospective studies suggested the feasibility of suspending therapy in selected patients while maintaining prolonged responses. Also, these studies showed that retreatment may induce a second remission in almost a third of patients. We report the case of a patient who received salvage therapy with venetoclax and azacytidine, that was discontinued few cycles after blasts clearance because of severe hematological toxicity. Despite suspension, he maintained a sustained response lasting almost one year and was successfully retreated with the same combination when a second relapse occurred.Keywords:
Venetoclax
Azacitidine
Hematology
Salvage therapy
<p>Figure S6. Flowcytometric analysis for ROS detection following 48 h vehicle treated (cont), 0.1 μM of azacitidine treated (A 0.1), 1.0 μM of azacitidine treated (A 1.0), 0.1 μM of venetoclax treated (V 0.1), 0.5 μM of venetoclax treated (V 0.5), 0.1 μM of azacitidine and 0.1 μM of venetoclax (A 0.1+V 0.1), 1.0 μM of azacitidine and 0.1 μM of venetoclax (A 1.0 + V 0.1), 0.1 μM of azacitidine and 0.5 μM of venetoclax (A 0.1 + V 0.5) and 1.0 μM of azacitidine and 0.5 μM of venetoclax (A 1.0 + V 0.5).</p>
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<p>Figure S6. Flowcytometric analysis for ROS detection following 48 h vehicle treated (cont), 0.1 μM of azacitidine treated (A 0.1), 1.0 μM of azacitidine treated (A 1.0), 0.1 μM of venetoclax treated (V 0.1), 0.5 μM of venetoclax treated (V 0.5), 0.1 μM of azacitidine and 0.1 μM of venetoclax (A 0.1+V 0.1), 1.0 μM of azacitidine and 0.1 μM of venetoclax (A 1.0 + V 0.1), 0.1 μM of azacitidine and 0.5 μM of venetoclax (A 0.1 + V 0.5) and 1.0 μM of azacitidine and 0.5 μM of venetoclax (A 1.0 + V 0.5).</p>
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The phase 3 VIALE-A trial reported that venetoclax in combination with azacitidine significantly improved response rates and overall survival compared with azacitidine alone in older, unfit patients with previously untreated acute myeloid leukemia (AML). However, the cost-effectiveness of azacitidine-venetoclax in this clinical setting is unknown. In this study, we constructed a partitioned survival model to compare the cost and effectiveness of azacitidine-venetoclax with azacitidine alone in previously untreated AML. Event-free and overall survival curves for each treatment strategy were derived from the VIALE-A trial using parametric survival modeling. We calculated the incremental cost-effectiveness ratio (ICER) of azacitidine-venetoclax from a US-payer perspective. Azacitidine-venetoclax was associated with an improvement of 0.61 quality-adjusted life-years (QALYs) compared with azacitidine alone. However, the combination led to significantly higher lifetime health care costs (incremental cost, $159 595), resulting in an ICER of $260 343 per QALY gained. The price of venetoclax would need to decrease by 60% for azacitidine-venetoclax to be cost-effective at a willingness-to-pay threshold of $150 000 per QALY. These data suggest that use of azacitidine-venetoclax for previously untreated AML patients who are ineligible for intensive chemotherapy is unlikely to be cost-effective under current pricing. Significant price reduction of venetoclax would be required to reduce the ICER to a more widely acceptable value.
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Abstract Venetoclax/azacitidine combination therapy is effective in acute myeloid leukemia (AML) and tolerable for older, multimorbid patients. Despite promising response rates, many patients do not achieve sustained remission or are upfront refractory. Identification of resistance mechanisms and additional therapeutic targets represent unmet clinical needs. By using a genome-wide CRISPR/Cas9 library screen targeting 18,053 protein- coding genes in a human AML cell line, various genes conferring resistance to combined venetoclax/azacitidine treatment were identified. The ribosomal protein S6 kinase A1 (RPS6KA1) was among the most significantly depleted sgRNA-genes in venetoclax/azacitidine- treated AML cells. Addition of the RPS6KA1 inhibitor BI-D1870 to venetoclax/azacitidine decreased proliferation and colony forming potential compared to venetoclax/azacitidine alone. Furthermore, BI-D1870 was able to completely restore the sensitivity of OCI-AML2 cells with acquired resistance to venetoclax/azacitidine. Analysis of cell surface markers revealed that RPS6KA1 inhibition efficiently targeted monocytic blast subclones as a potential source of relapse upon venetoclax/azacitidine treatment. Taken together, our results suggest RPS6KA1 as mediator of resistance towards venetoclax/azacitidine and additional RPS6KA1 inhibition as strategy to prevent or overcome resistance.
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There are currently limited objective criteria to help assist physicians in determining whether an individual patient with acute myeloid leukemia (AML) is likely to do better with induction with either standard 7 + 3 chemotherapy or targeted therapy with venetoclax plus azacitidine. The study goal was to address this need by developing exploratory clinical decision support methods.Univariable and multivariable analysis as well as comparison of a range of machine learning (ML) predictors were performed using cohorts of 120 newly diagnosed 7 + 3-treated AML patients compared with 101 venetoclax plus azacitidine-treated patients.A variety of features in the two patient cohorts were identified that may potentially correlate with short- and long-term outcomes, toxicities, and other considerations. A subset of these diagnostic features was then used to develop ML-based predictors with relatively high areas under the curve of short- and long-term outcomes, hospital stays, transfusion requirements, and toxicities for individual patients treated with either venetoclax/azacitidine or 7 + 3.Potential ML-based approaches to clinical decision support to help guide individual patients with newly diagnosed AML to either 7 + 3 or venetoclax plus azacitidine induction therapy were identified. Larger cohorts with separate test and validation studies are necessary to confirm these initial findings.
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Abstract Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML). Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle). Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut. See related commentary by Perl and Vyas, p. 2719
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