Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial

Burd, Amy; Levine, Ross L.; Ruppert, Amy S.; Mims, Alice S.; Borate, Uma; Stein, Eytan M.; Patel, Prapti A.; Baer, Maria R.; Stock, Wendy; Deininger, Michael; Blum, William; Schiller, Gary J.; Olin, Rebecca L.; Litzow, Mark R.; Foran, James M.; Lin, Tara L.; Ball, Brian; Boyiadzis, Michael; Traer, Elie; Odenike, Olatoyosi; Arellano, Martha; Walker, Alison; Duong, Vu H.; Kovacsovics, Tibor; Collins, Robert H.; Shoben, Abigail B.; Heerema, Nyla A.; Foster, Matthew C.; Vergilio, Jo Anne; Brennan, Timothy J.; Vietz, Christine; Severson, Eric Allan; Miller, Molly; Rosenberg, Leonard; Marcus, Sonja; Yocum, Ashley O.; Chen, Timothy; Stefanos, Mona; Druker, Brian J.; Byrd, John C.

doi:10.1038/s41591-020-1089-8

Cited by 120 publications

(131 citation statements)

References 30 publications

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“…These data add to the accumulating evidence for utilizing NGS at diagnosis in AML to inform not only prognosis but also treatment regimen and intensity of therapy. Awaiting full molecular and cytogenetic results prior to initiating induction chemotherapy has been shown to be feasible and is currently being utilized in clinical trials such as BEAT AML to guide therapeutic decisions 34 . This strategy may become the standard of care as rapid NGS panels are becoming more available and more molecularly targeted agents are evaluated during induction 35‐37 .…”

Section: Discussionmentioning

confidence: 99%

Genomic characteristics and prognostic significance of co‐mutatedASXL1/SRSF2acute myeloid leukemia

et al. 2021

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The ASXL1 and SRSF2 mutations in AML are frequently found in patients with preexisting myeloid malignancies and are individually associated with poor outcomes. In this multi‐institutional retrospective analysis, we assessed the genetic features and clinical outcomes of 43 patients with ASXL1mutSRSF2mut AML and compared outcomes to patients with either ASXL1 (n = 57) or SRSF2 (n = 70) mutations. Twenty‐six (60%) had secondary‐AML (s‐AML). Variant allele fractions suggested that SRSF2 mutations preceded ASXL1 mutational events. Median overall survival (OS) was 7.0 months (95% CI:3.8,15.3) and was significantly longer in patients with de novo vs s‐AML (15.3 vs 6.4 months, respectively; P = .04 on adjusted analysis). Compared to ASXL1mutSRSF2wt and ASXL1wtSRSF2mut, co‐mutated patients had a 1.4 and 1.6 times increase in the probability of death, respectively (P = .049), with a trend towards inferior OS (median OS = 7.0 vs 11.5 vs 10.9 months, respectively; P = .10). Multivariable analysis suggests this difference in OS is attributable to the high proportion of s‐AML patients in the co‐mutated cohort (60% vs 32% and 23%, respectively). Although this study is limited by the retrospective data collection and the relatively small sample size, these data suggest that ASXL1mutSRSF2mut AML is a distinct subgroup of AML frequently associated with s‐AML and differs from ASXL1mutSRSF2wt/ASXL1wtSRSF2mut with respect to etiology and leukemogenesis.

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Section: Discussionmentioning

confidence: 99%

Genomic characteristics and prognostic significance of co‐mutatedASXL1/SRSF2acute myeloid leukemia

et al. 2021

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“…Increasingly mutational information is available for patients as a result of next generation sequencing (NGS) technology assaying panels of commonly affected myeloid genes ( 33 ). This is of further importance as these genetic markers are now commonly used as both therapeutic targets ( 50 , 51 ) and as prognostic markers of response to therapies ( 52 ). The results of these large scale sequencing efforts of AML samples at diagnosis, in combination with data relating to treatment use and clinical outcome will likely refine these risk categories.…”

Section: Introductionmentioning

confidence: 99%

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: Who, When, and How?

2021

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Although the majority of patients with acute myeloid leukemia (AML) treated with intensive chemotherapy achieve a complete remission (CR), many are destined to relapse if treated with intensive chemotherapy alone. Allogeneic stem cell transplant (allo-SCT) represents a pivotally important treatment strategy in fit adults with AML because of its augmented anti-leukemic activity consequent upon dose intensification and the genesis of a potent graft-versus-leukemia effect. Increased donor availability coupled with the advent of reduced intensity conditioning (RIC) regimens has dramatically increased transplant access and consequently allo-SCT is now a key component of the treatment algorithm in both patients with AML in first CR (CR1) and advanced disease. Although transplant related mortality has fallen steadily over recent decades there has been no real progress in reducing the risk of disease relapse which remains the major cause of transplant failure and represents a major area of unmet need. A number of therapeutic approaches with the potential to reduce disease relapse, including advances in induction chemotherapy, the development of novel conditioning regimens and the emergence of the concept of post-transplant maintenance, are currently under development. Furthermore, the use of genetics and measurable residual disease technology in disease assessment has improved the identification of patients who are likely to benefit from an allo-SCT which now represents an increasingly personalized therapy. Future progress in optimizing transplant outcome will be dependent on the successful delivery by the international transplant community of randomized prospective clinical trials which permit examination of current and future transplant therapies with the same degree of rigor as is routinely adopted for non-transplant therapies.

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“…The drugs being tested may change during the trial, as new targets and new drugs are found. Umbrella trials may allow new drugs to be tested and approved more quickly than traditional clinical trials and in world of AML potentially replace slower ‘Pick‐a‐Winner’ concept [67]. One example is BEAT AML trial (NCT03013998) where precision medicine therapy strategy in AML is feasible within 7 days from the date of diagnosis allowing patients and physicians to rapidly incorporate genomic data into treatment decisions.…”

Section: Precision‐based Therapymentioning

confidence: 99%

Acute myeloid leukaemia in patients we judge as being older and/or unfit

Lazarevic

2021

J Intern Med

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Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial

Cited by 120 publications

References 30 publications

Genomic characteristics and prognostic significance of co‐mutatedASXL1/SRSF2acute myeloid leukemia

Genomic characteristics and prognostic significance of co‐mutatedASXL1/SRSF2acute myeloid leukemia

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: Who, When, and How?

Acute myeloid leukaemia in patients we judge as being older and/or unfit

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