Klaus Metzeler, MD, from the University Hospital Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany, describes his talk on the persistence of mutations in preleukemic clones during complete remission (CR) in acute myeloid leukemia (AML) at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany. He explains that preleukemic clones are a group of cells that have some mutations that leukemia has, but which are still capable of normal differentiation. If AML is treated with chemotherapy and the patient goes into remission, these preleukemic clones can persist in the bone marrow and make up a substantial amount of hematopoiesis in remission. Dr Metzeler investigated whether these preleukemic clones are associated with clinical characteristics and treatment outcomes by looking at driver mutations in leukemia diagnosis and determining whether these mutations are still found when the patient is in remission. He explains that in around 40% of patients, some mutations are still found in morphologically normal remission bone marrow. These patients had a higher rate of relapse and decreased overall survival (OS) than those who cleared all mutations. In general, the patients with persisting preleukemic clones are older than those who clear all mutations, which is interesting as in apparently healthy older people there is also a high incidence of clonal hematopoiesis. He concludes that leukemias from preleukemic clones may be biologically distinct and more difficult to treat. Regarding treatment options for patients with persisting clones, Dr Metzeler explains that those who do not receive an allogenic stem cell transplant have a high rate of relapse, while those who do receive a transplant have a lower relapse rate. He suggests that the detection of preleukemic clones in remission may be a tentative indication that an allogenic stem cell transplant should be given if the patient is able to receive this. However, because many of these patients are older, some may not be fit enough to receive transplants, and so new strategies to eradicate persistent clones are required.

The classification of acute myeloid leukemias is done according to the FAB classification. The FAB classification system is based on tumor cell morphology under the microscope. As there are many different cell lines with discrete morphological features, the FAB classification system for the myeloid malignancies differentiates more subtypes than for the malignancies of lymphoid origin.

Outline:
00:00 - Introduction
00:30 - AML
02:49 - ALL
05:12 - AML vs. ALL
07:27 - Lymphoma
11:42 - Summary

Philipp Greif, MD, from the University Hospital Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany, discusses the evolution acute myeloid leukemia (AML) relapse at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany, and describes the challenge of finding the drivers of disease progression. Sequencing of AML patient samples is used to look at clonal architecture and to identify different competing clones. Dr Greif explains that by following patients over time, changes in clonal architecture can be seen, which are partly due to the selective pressure of therapy. Evolutionary patterns correlate with the clinical course of patients. When mutations are gained during the course of disease, this correlates with a later relapse, suggesting that leukemia cells need to acquire additional mutations to become therapy resistant. Two main clinical implications of this are that firstly, some of the gained mutations are responsible for chemotherapy resistance, such as in the histone demethylase gene family. Secondly, relapse drivers can sometimes be detected at a low level at diagnosis, indicating that if certain subclones are detected at diagnosis, the patient is unlikely to respond to standard therapy alone, and other options, such as allogeneic bone marrow transplantation, should be explored.

Victoria Prassek, MD, from Ludwig-Maximilians-University (LMU), Munich, Germany, discusses whether gene mutations impact clinical outcome in very old, intensively treated acute myeloid leukemia (AML) patients enrolled in AML Cooperative Group (AMLCG) 1999 and 2008 trials (NCT00266136, NCT01382147) at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany. She describes the aim of this study, which was to validate existing risk classifications and identify genetic markers associated with clinical outcome in this subset of patients. AML is a disease of the elderly, with a median age of diagnosis of 68 years, and the outcome of elderly patients is very poor, partly because patients may not be fit enough for intensive chemotherapy. Dr Prassek argues that there is a need to be able to predict positive outcomes of intensive chemotherapy in these patients. She summarizes results indicating that even in very old, intensively treated AML patients, molecular factors and adverse cytogenetics play an important role and can predict inferior survival. On the other hand, patients in the favorable and intermediate groups according to the ELN and MRC risk classifications may benefit from intensive chemotherapy, indicating that if there are no medical counterindications for such an intensive therapy, it may be beneficial to treat these patients with intensive induction therapy. Dr Prassek also highlights that IDH-1 mutated patients do not reach complete remission (CR) after intensive induction therapy, suggesting that IDH-1 may be a novel marker for inferior prognosis and chemorefractory disease in elderly AML patients. This raises the need to consider whether patients with IDH-1 mutations should be treated with intensive chemotherapy, or a less severe therapy with a greater focus on quality of life.

The panelists, Ruben A. Mesa, MD, FACP; Rami Komrokji, MD; Rafael Bejar, MD, PhD; and Elias Jabbour, MD, explain the genetic alterations and microenvironment involved in the pathobiology of acute myeloid leukemias (AML).

Peter discusses his journey to being diagnosed with AML, his stem cell transplant, and recovery in the hospital.