Author Interviews, Genetic Research, Leukemia, NYU/NYMC / 11.12.2016
Novel Relapse Markers Identified in Pediatric ALL
MedicalResearch.com Interview with:
Jason Saliba PhD
Perlmutter Cancer Center
New York University Langone Medical Center
New York, NY
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically over the last four decades, but the prognosis for those who relapse remains dismal, especially for those who relapse while on therapy. In fact, relapsed disease remains a leading cause of cancer related mortality in children. To date, various studies have discovered a number of somatic alterations that contribute to driving relapse and have provided profound insight into the selective forces that lead to clonal outgrowth of drug resistant populations. However, the timing of the initial emergence of the driving mutations along with the speed of clonal outgrowth is unknown.
Whole exome sequencing (WES) was run on available diagnosis, germline (remission), and relapse samples collected from thirteen pediatric ALL patients treated according to Nordic NOPHO ALL protocols. Analyses were then performed to find somatic missense mutations enriched in the relapse samples versus their patient matched diagnosis and/or germline samples. Candidate relapse driving missense mutations were identified as present at high levels (>20%) in the relapse sample, but were undetectable in germline or low to absent in the diagnosis sample. Eight of the thirteen patients contained mutations in genes previously reported to be enriched at relapse. Interestingly, a majority of the patients contained novel candidate relapse specific genes involved in a wide array of cellular processes such as cell adhesion/migration, RNA polymerase II/transcription, circadian rhythm, the unfolded protein response, RNA transport, epigenetic regulation, DNA methylation, and kinases.
Dr. Uras[/caption]
Dr. Iris Z Uras and Univ.-Prof. Dr. Veronika Sexl
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Dr. Sexl[/caption]
Institute of Pharmacology and Toxicology
University of Veterinary Medicine
Vienna
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Patients suffering from AML have poor prognosis and high mortality rate despite considerable advances in chemotherapy and hematopoietic stem cell transplantations. Up to 30% of patients with AML harbor an activating mutation in the FLT3 receptor tyrosine kinase (FLT3-ITD). Such mutations are associated with a high predisposition to relapse after remission. In a simplified way we can say that these tumor cells depend on FLT3: Is FLT3 blocked, cells die. Hence, FLT3 inhibitors are being developed as targeted therapy for FLT3-mutant AML; however, clinical responses are short-lived and their use is complicated by rapid development of resistance. This emphasizes the need for additional therapeutic targets.
Our study represents a novel therapeutic window to specifically target and kill AML cells with FLT3-ITD mutations. We found that the tumor-promoting enzyme CDK6 but not its close relative CDK4 directly regulates and initiates the production/transcription of FLT3 and thus lead to disease. The FDA-approved kinase inhibitor Palbociclib not only blocks the activity of CDK6 but in turn impairs FLT3 expression: Mutant AML cells die immediately. The treatment does not affect cells without the mutation.
The power of CDK6 inhibition in AML cells goes beyond FLT3: Palbociclib also stops production of the PIM1 kinase and thus overcomes the potential activation of survival pathways counteracting the effects of FLT3 inhibition.
Dr. Mathias Buttmann[/caption]
PD Dr. Mathias Buttmann
Senior Consultant Neurologist and Head of the Multiple Sclerosis Outpatient Clinic
University of Wuerzburg
Wuerzburg, Germany
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Buttmann: The synthetic anthracenedione mitoxantrone is approved for disease-modifying treatment of patients with aggressive forms of relapsing or secondary progressive multiple sclerosis (MS). It has been known for years that this DNA-intercalating agent increases the risk of acute myeloid leukemia. We performed a retrospective cohort study to investigate whether mitoxantrone also increases the risk for other types of malignancies. We included all 677 mitoxantrone-treated multiple sclerosis patients who were seen at our large German academic MS centre between 1994 and 2007 and collected follow-up information on the occurrence of malignancies, death and causes of death as of 2011. Follow-up was complete in 676 patients. The median age at mitoxantrone initiation was 41 years and the median follow-up duration was 8.7 years. We identified 37 patients with a malignancy after mitoxantrone initiation, among them 4 cases of acute myeloic leukemia and 7 cases of colorectal cancer.
Compared to the general population matched for sex, age and year of occurrence, we calculated an 1.5-fold increased incidence of any type of malignancy, a tenfold increased incidence of acute myeloic leukemia and a threefold increased incidence of colorectal cancer, while the incidence of other types of malignancies was not increased. Higher age at mitoxantrone initiation but neither higher cumulative mitoxantrone dose nor treatment with other immuosuppressive agents was identified as a malignancy risk factor. Fifty-five patients had died, among them 12 from a malignancy. Our study confirmed previous reports on an increased incidence of acute myeloic leukemia after mitoxantrone treatment and newly described an association between mitoxantrone therapy and an increased incidence of colorectal cancer.
Dr. Odejide[/caption]
MedicalResearch.com Interview with:
Oreofe O. Odejide, MD
Instructor in Medicine, Harvard Medical School
Dana-Farber Cancer Institute
Medical Research: What is the background for this study? What are the main findings?
Dr. Odejide: The care that patients with hematologic cancers receive near the end of life is distinct from patients with solid tumors. For instance, previous research has shown that patients with blood cancers are more likely to receive intensive care at the end of life such as chemotherapy within 14 days of death, intensive care unit admission within 30 days of death, and they are less likely to enroll in hospice. My colleagues and I hypothesized that timing of discussions regarding end-of-life preferences with patients may contribute to these findings, and we wanted to examine hematologic oncologists’ perspectives regarding end-of-life discussions with this patient population.
We conducted a survey of a national sample of hematologic oncologists obtained from the publicly available clinical directory of the American Society of Hematology. We received responses from 349 hematologic oncologists, giving us a response rate of 57.3%. In our survey, we asked hematologic oncologists about the typical timing of EOL discussions in general, and also about the timing of the first discussion regarding resuscitation status, hospice care, and preferred site of death for patients. Three main findings emerged:
Dr. Manali Patel[/caption]
MedicalResearch.com Interview with:
Manali Patel, MD, MPH
Instructor in the Division of Oncology
Department of Medicine
Stanford University School of Medicine
Researcher at the Clinical Excellence Research Center and the Primary Care and Outcomes Research Group at Stanford
Staff oncologist at the Veterans Administration and a researcher in the Palo Alto Veterans Administration Health Services & Research Development group.
Medical Research: What is the background for this study?
Dr. Patel: Racial and ethnic disparities in Acute Leukemia are well documented in the literature but the reasons underlying the disparities remain largely unknown. In our previous work, we demonstrated mortality disparities for minorities with Acute Myeloid Leukemia despite favorable prognostic demographic and molecular factors. We have also shown that differences in receipt of treatment may partially explain a large component of these disparities. The purpose of this study is to determine how socioeconomic status factors influence mortality from Acute Leukemia using a population-based novel linked dataset of the Surveillance Epidemiology and End Results Database and the National Longitudinal Mortality Study.
Medical Research: What are the main findings?
Dr. Patel: We found a total of 121 patients with Acute Lymphoid Leukemia and 438 patients with Acute Myeloid Leukemia in the linked dataset. After adjusting for socioeconomic status factors, there were increased risk of mortality among Hispanic and decreased risk of mortality among Asian Pacific Islander patients as compared with non-Hispanic white patients in Acute Lymphocytic Leukemia. Among patients with Acute Myeloid Leukemia, we found no associations of mortality by race/ethnicity and socioeconomic status.
Dr. Röllig[/caption]
MedicalResearch.com Interview with:
Dr. Christoph Röllig
Medizinische Klinik und Poliklinik I
Universitätsklinikum der Technischen Universitä
Dresden, Germany
Medical Research: What is the background for this study? What are the main findings?
Dr. Röllig: When this trial began in 2009, standard treatment for Acute Myelogenous Leukemia (AML) consisted of a combination of cytarabine plus anthracyclin/anthracendion and the need for improvement was obvious in the light of only around 50% long-term survivors even amongst younger patients. Although a promising approach, the use of kinase inhibitors in AML had not been shown to be beneficial and was not widely used. Sorafenib had been shown to be tolerable as single agent and in combination with commonly used chemotherapeutic agents. The results of the trial show that the addition of sorafenib to standard chemotherapy for newly diagnosed AML patients up to the age of 60 years is associated with significant prolongation of event-free survival and relapse-free survival compared to placebo plus standard chemotherapy. That means that patient who took sorafenib had less AML relapses.
To our knowledge, this is the first randomized-controlled showing that integrating a kinase inhibitor into standard intensive chemotherapy of younger patients with AML is associated with significant improvement of relapse-free survival, with no increase in treatment-related mortality. After a decade of evaluating the potential of kinase inhibitors in 
