Immune Escape of Relapsed AML Cells after Allogeneic Transplantation

Christopher, Matthew; Petti, Allegra A.; Rettig, Michael P.; Miller, Christopher A.; Chendamarai, Ezhilarasi; Duncavage, Eric J.; Klco, Jeffery M.; Helton, Nicole M.; O’Laughlin, Michelle; Fronick, Catrina C.; Fulton, Robert S.; Wilson, Richard K.; Wartman, Lukas D.; Welch, John S.; Heath, Sharon E.; Baty, Jack; Payton, Jacqueline E.; Graubert, Timothy A.; Link, Daniel C.; Walter, Matthew J.; Westervelt, Peter; Ley, Timothy J.; DiPersio, John F.

doi:10.1056/nejmoa1808777

Cited by 330 publications

(314 citation statements)

References 32 publications

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“…Recently, it was reported that in AML cells after allogeneic stem cell transplantation (SCT), no relapse-specific mutational patterns were observed. 62 In contrast, other studies found an enrichment of WT1 mutations in AML relapse after chemotherapy as well as after SCT. 41,63 Although the gain of WT1 mutations were not significant in any of the studies, combined analysis of two independent cohorts showed a significant association of WT1 mutations with relapse after SCT suggesting a common evolutionary pattern (Figure 3).…”

Section: Aml Relapse After Allogeneic Stem Cell Transplantationmentioning

confidence: 88%

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

Vosberg

Greif

2019

Genes Chromosomes & Cancer

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Based on the individual genetic profile, acute myeloid leukemia (AML) patients are classified into clinically meaningful molecular subtypes. However, the mutational profile within these groups is highly heterogeneous and multiple AML subclones may exist in a single patient in parallel. Distinct alterations of single cells may be key factors in providing the fitness to survive in this highly competitive environment. Although the majority of AML patients initially respond to induction chemotherapy and achieve a complete remission, most patients will eventually relapse. These points toward an evolutionary process transforming treatment‐sensitive cells into treatment‐resistant cells. As described by Charles Darwin, evolution by natural selection is the selection of individuals that are optimally adapted to their environment, based on the random acquisition of heritable changes. By changing their mutational profile, AML cell populations are able to adapt to the new environment defined by chemotherapy treatment, ultimately leading to cell survival and regrowth. In this review, we will summarize the current knowledge about clonal evolution in AML, describe different models of clonal evolution, and provide the methodological background that allows the detection of clonal evolution in individual AML patients. During the last years, numerous studies have focused on delineating the molecular patterns that are associated with AML relapse, each focusing on a particular genetic subgroup of AML. Finally, we will review the results of these studies in the light of Darwinian evolution and discuss open questions regarding the molecular background of relapse development.

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Section: Aml Relapse After Allogeneic Stem Cell Transplantationmentioning

confidence: 88%

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

Vosberg

Greif

2019

Genes Chromosomes & Cancer

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“…Additionally, genome‐wide approaches can identify cases where the HLA loci are themselves altered by the disease. For example, Christopher et al used RNA‐seq to identify AML patients with the downregulation of HLA loci genes at relapse after transplantation, suggesting that dysregulation of immune function was involved in this relapse and potentially reversible.…”

Section: What Is the Potential Value Added By Genome‐wide Testing?mentioning

confidence: 99%

Genomic testing in myeloid malignancy

Docking

Karsan

2019

Int J Lab Hematology

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Clinical genetic testing in the myeloid malignancies is undergoing a rapid transition from the era of cytogenetics and single‐gene testing to an era dominated by next‐generation sequencing (NGS). This transition promises to better reveal the genetic alterations underlying disease, but there are distinct risks and benefits associated with different NGS testing platforms. NGS offers the potential benefit of being able to survey alterations across a wider set of genes, but analytic and clinical challenges associated with incidental findings, germ line variation, turnaround time, and limits of detection must be addressed. Additionally, transcriptome‐based testing may offer several distinct benefits beyond traditional DNA‐based methods. In addition to testing at disease diagnosis, research indicates potential benefits of genetic testing both prior to disease onset and at remission. In this review, we discuss the transition from the era of cytogenetics and single‐gene tests to the era of NGS panels and genome‐wide sequencing—highlighting both the potential and drawbacks of these novel technologies.

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“…AML relapse after allogeneic HSCT is associated with a dysregulation in immune function pathways such as HLA expression by AML blasts that may help AML cells evade donor immune responses. 27 Immunologic consolidation can be effective when newly infused donor immune cells that are naive with regard to the patient's AML elicit a GvL response independent of HLA-related antigen presentation, for example, to targets that are expressed on the membrane of AML blasts. 28,29 Thus, as also suggested by other studies, immunological consolidation is of importance for survival in this setting.…”

Section: Discussionmentioning

confidence: 99%

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Jong

Janssen

Biemond

et al. 2019

European J of Haematology

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Objective: Relapse of AML after allogeneic hematopoietic stem cell transplantation (HSCT) has a poor prognosis, and standard of care therapy is lacking. Early (<6 months) relapse is associated with dismal outcome, while the majority of relapses occur early after transplantation. A more precise indication which patients could benefit from reinduction therapy is warranted. Methods:We retrospectively analyzed outcomes of 83 patients with postallogeneic HSCT relapse. Patients were divided based on intention to treat (curative vs supportive care). Results:Of the 50 patients treated with curative intent, 44% reached complete remission (CR) upon reinduction chemotherapy, and of these patients, 50% survived.Two survivors reached CR after immunotherapy (donor lymphocyte infusion (DLI), without reinduction chemotherapy). Sixty-nine percent of the survivors had received high-intensity cytarabine treatment, followed by immunologic consolidation. Relapse <3 months after transplantation was predictive for adverse survival (P = .004), but relapse <6 months was not. In fact, >50% of the survivors had a relapse <6 months. Conclusion:We confirmed the dismal prognosis of postallogeneic HSCT relapse.Importantly, our data demonstrate that patients fit enough to receive high-dose chemotherapy, even when relapse occurred <6 months, had the best chance to obtain durable remissions, in particular when immunologic consolidation was performed after reaching CR. K E Y W O R D S acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation, graft-versusleukemia, outcome Allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred treatment for patients with (MRD positive) intermediate-risk or poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). While transplant related mortality has decreased, the risk for relapse has not. Disease relapse is a common and important cause of the poor long-term survival of allogeneic HSCT recipients with AML. Relapse accounts for 30%-40% of deaths after allogeneic HSCT, depending on the type of the donor and disease status at transplant. 1,2 Prognosis of postallogeneic HSCT AML relapse is poor 3,4 and has hardly improved in the past decades. There is no standard of care for patients who relapse after allogeneic HSCT. Age (<37 year) and a longer time (>5 months) between allogeneic HSCT and relapse have been identified as favorable prognostic factors. 3,5,6 Other factors such as clinical condition and personal considerations of the patient may be weighed in the decision to either give supportive care, offer low-dose chemotherapy, or attempt high-dose reinduction chemotherapy. In reality, curative treatment options are often limited, and in many cases, it can be more appropriate to refrain from intensive treatment regimens and opt for best supportive care. Most AML relapses occur in the first 6 months after allogeneic HSCT, a period during which many patients still receive immunosuppressive therapy. Rapid tapering of immunosuppression can potentially lead ...

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Immune Escape of Relapsed AML Cells after Allogeneic Transplantation

Cited by 330 publications

References 32 publications

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

Genomic testing in myeloid malignancy

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

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