Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens
Abhishek MaitiCaitlin R. RauschJorgé E. CortesNaveen PemmarajuNaval DaverFarhad RavandiGuillermo Garcia‐ManeroGautam BorthakurKiran NaqviMaro OhanianNicholas J. ShortYesid AlvaradoTapan M. KadiaKoichi TakahashiMusa YılmazNitin JainSteven M. KornblauGuillermo Montalban‐BravoKoji SasakiMichael AndreeffPrithiviraj BoseAlessandra FerrajoliGhayas C. IssaElias JabbourLucia MasárováPhilip A. ThompsonSa WangSergej KonoplevSherry PierceJing NingWei QiaoJohn S. WelchHagop M. KantarjianCourtney D. DiNardoMarina Konopleva
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Outcomes of relapsed or refractory acute myeloid leukemia after front-line hypomethylating agent and venetoclax regimensAcute myeloid leukemia (AML) is the most common acute leukemia in adults.][6] Consequently, VEN+HMA regimens have emerged as a reasonable new standard of care for older patients. 7However, little is known about outcomes of patients after failure of front-line venetoclax-based regimens.We found that patients failing front-line VEN+HMA have high-risk biology, dismal overall survival (OS) despite salvage therapy, and new putative mechanisms of resistance.This knowledge may help guide physicians' expectations, inform discussion with patients, and design clinical trials in patients after venetoclax failure.This was a retrospective study to determine the outcomes of patients after failure of front-line VEN+HMA therapy.Patients with newly diagnosed (ND) AML enrolled on two clinical trials of VEN and HMA at our institute, either with primary refractory disease or relapse (R/R) after initial response were included (Online Supplementary Figure S1).In one trial, patients with ND AML aged 65 years or older received venetoclax 400-1,200 mg daily with decitabine 20 mg/m 2 for 5 days or azacitidine 75 mg/m 2 for 7 days every 4 weeks (clinicaltrials.govidentifier: NCT02203773). 4The other trial enrolled patients with ND AML aged 60 years or older, and patients received venetoclax 400 mg daily or equivalent with decitabine 20 mg/m 2 for 10 days every 4 weeks until response, followed by 5-day decitabine with venetoclax cycles (clinicaltrials.govidentifier: NCT03404193). 5None of the patients included in these analyses received any third agents such as targeted therapies.Responses included complete remission (CR), CR with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) according to the European LeukemiaNet 2017 criteria. 8Primary refractory disease was defined as lack of reduction of bone marrow (BM) blasts to 5% or less by up to cycle 4 of VEN+HMA, as originally defined in these two protocols designed in 2014 and 2017.Relapse was defined as clinically significant progressive disease with increase in BM blasts to more than 5% after achievement of CR/CRi/MLFS.OS was measured from the date of establishment of primary refractory disease or relapse after VEN+HMA therapy, until death or censored at last follow-up.The data cut-off date for this report was July 8 th , 2019.To provide context for this analysis, we compared outcomes, both from initial therapy, and from time of R/R disease, with front-line IC using a historical cohort.We found 278 patients treated with IC who matched for both age and European LeukemiaNet (ELN) 2017 cytogenetic risk status with 88 out of 95 patients treated with VEN+HMA.There were no patients in our historical IC cohort who matched for both age and cytogenetic risk status of seven patients who received VEN+HMA, and hence the comparison was limited to those 88 patients.Two out of those seven unmatched patients had R/R disease after VEN+HMA.The patients in the IC cohort were diagnosed between 2000 and 2018, and received treatment with IC containing at least 1 g/m 2 /day of cytarabineKeywords:
Venetoclax
Hypomethylating agent
Azacitidine
Refractory (planetary science)
<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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