Breast Cancer Survivors More Likely To Develop Subsequent Blood Cancers Interview with:
medicalresearch.comDr. Marie Joelle Jabagi, PharmD, MPH

University of Paris Sud, Paris-Saclay University, Paris
Health Product Epidemiology Department
French National Agency for Medicines and Health Products Safety
Saint-Denis, France What is the background for this study?

Response: Secondary hematologic malignant neoplasms that develop months or years after the diagnosis of breast cancer may be a consequence of genetic predisposition, environmental factors, previous cancer treatments or a combination of all those factors. These secondary malignant neoplasms are increasingly becoming a concern given that the population of breast cancer survivors is growing substantially. However, their frequency in real life has been poorly investigated to date.

The aims of our research were to estimate the frequency of various types of hematologic malignant neoplasm following a diagnosis of primary breast cancer among women aged 20 to 85 years in France during the past decade, and to compare it to the corresponding frequency in women of the French general population.

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ASH18: RNA Sequencing Identifies More Subtypes of Childhood Leukemia Interview with:

Charles G. Mullighan, MBBS (Hons), MSc, MD Member, St. Jude Faculty Co-Leader, Hematological Malignancies Program Medical Director, St. Jude Biorepository William E. Evans Endowed Chair St. Judes Children’s Research Hospital Memphis, TN

Dr. Mullighan

Charles G. Mullighan, MBBS (Hons), MSc, MD
Member, St. Jude Faculty
Co-Leader, Hematological Malignancies Program
Medical Director, St. Jude Biorepository
William E. Evans Endowed Chair
St. Judes Children’s Research Hospital
Memphis, TN What is the background for this study?


Response: B-lineage acute lymphoblastic leukemia (B-ALL) is the commonest form of ALL, and the commonest childhood tumor. It is a leading cause of childhood cancer death. It consists of multiple subtypes defined by genetic alterations. These are often chromosomal translocations that deregulate oncogenes or form fusion proteins. These alterations are disease initiating events and are associated with distinct patterns of leukemic cell gene expression. Most subtypes also have additional mutations that are important for cells to become fully leukemic.

Identifying these initiating genetic changes is very important to identify patients that are likely to respond or do poorly with conventional therapy (multiagent chemotherapy). Also, some identify new opportunities for targeted therapy. However, using standard genetic testing approaches such as chromosomal cytogenetics, about 30% of B-ALL patients don’t have a subtype classifying alteration.

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Inotuzumab Plus Low-Intensity Chemo Effective in Resistant ALL Interview with:

Elias Jabbour, MD Associate Professor Leukemia Department MD Anderson Cancer Center

Dr. Jabbour

Elias Jabbour, MD
Associate Professor
Leukemia Department
MD Anderson Cancer Center What is the background for this study? What are the main findings?

Response: Inotuzumab is active in relapsed or refractory (R/R) acute lymphoblastic leukemia  (R/R ALL). The addition of low intensity chemotherapy may further improve outcome.

ORR around 80%. Median survival 11 months. Better results obtained in Savage 1. Superior outcome when compared to historical cohort treated with inotuzumab monotherapy

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Intermittent Fasting Inhibits Cancer Cells in Childhood Leukemia ALL Interview with:

Chengcheng (Alec) Zhang, Ph.D. Associate Professor Hortense L. and Morton H. Sanger Professorship in Oncology Michael L. Rosenberg Scholar for Medical Research Department of Physiology  UT Southwestern Medical Center

Dr. Alec Zhang

Chengcheng (Alec) Zhang, Ph.D.
Associate Professor
Hortense L. and Morton H. Sanger Professorship in Oncology
Michael L. Rosenberg Scholar for Medical Research
Department of Physiology
UT Southwestern Medical Center What is the background for this study?

Response: New therapeutic targets and approaches are needed to effectively treat leukemia. Acute myeloid leukemia (AML) is the most common form of adult acute leukemia whereas acute lymphoblastic leukemia (ALL) is the most common form of cancer in children; ALL also occurs in adults. Although treatment of pediatric ALL is highly effective, a sizeable number of patients are non-responders who succumb to this disease. The outcome of ALL in adults is significantly worse than for pediatric ALL. Additionally, some types of ALL have a much poorer prognosis than others.

Dietary restriction, including fasting, delays aging and has prolonged effects in a wide range of organisms and has been considered for cancer prevention. In certain types of solid tumor,_ENREF_1 dietary restriction regimens are able to promote T cell-mediated tumor cytotoxicity and enhance anticancer immunosurveillance, and coordinate with chemotherapy to promote the anti-cancer effects. However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown. Furthermore, whether dietary restriction alone can inhibit cancer development is not clear.

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Germline Genetic Variation in IKZF1 and Predisposition to Childhood ALL Interview with:

Michelle Churchman, PhD Scientific Manager of Charles Mullighan's laboratory Department of Pathology St Jude Children's Research Hospital

Dr. Michelle Churchman

Michelle Churchman, PhD
Scientific Manager of Charles Mullighan’s laboratory
Department of Pathology
St Jude Children’s Research Hospital What is the background for this study? What are the main findings?

Response: The role of IKZF1 alterations in the development of B-progenitor acute lymphoblastic leukemia (B-ALL) and their role in determining poor outcome of treatment has been a long-term focus of our groups. We had previously identified somatic (tumor-acquired) IKZF1 deletions and mutations in high-risk leukemia, and identified several mechanisms by which these mutations drive high-risk leukemia. We also have a long-standing interest in studying inherited genetic risk factors of childhood ALL. In this latest study, our research team identified a family in Germany with a history of B-cell deficiency and B-ALL that had a germline IKZF1 mutation, prompting us to investigate whether inherited IKZF1 variants are related to predisposition to ALL in general. To investigate this, the IKZF1 gene was sequenced from the germline DNA of nearly 5000 patients enrolled on St. Jude Children’s Research Hospital and Children’s Oncology Group front-line ALL trials. We identified 27 unique inherited (germline) IKZF1 variants in 44 patients and found that most of them perturbed the normal functions of the encoded Ikaros transcription factor. Particularly, several of the variants lost the ability to bind DNA and regulate expression of transcriptional targets.

We know from previous studies that genes involved in differentiation and adhesion are overexpressed in IKZF1-altered leukemic cells, which results in abnormal adhesion between cells and components of the bone marrow.

Many of the variants resulted in increased adhesion. We show that several of these germline variants caused leukemic cells to be less sensitive to drugs.

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Leukoencephalopathy As Marker of Cognitive Impairment After Chemotherapy For Childhood ALL Interview with:
Yin Ting Cheung, PhD

Department of Epidemiology and Cancer Control and
Noah D Sabin, MD
Department of Diagnostic Imaging
St Jude Children’s Research Hospital
Memphis, TN What is the background for this study? What are the main findings?

Response: Long-term survivors of childhood acute lymphoblastic leukemia (ALL) who are treated with high-dose intravenous methotrexate or intrathecal chemotherapy are at risk for neurocognitive impairment, particularly in cognitive processes such as processing speed, attention and executive function. However, many children who receive these therapies do not experience significant impairments, suggesting the need for biomarkers to identify patients at greatest risk. Prior research from our team demonstrated that, during chemotherapy, patients were at risk for white matter changes in the brain, also known as leukoencephalopathy. No studies documented the persistence or impact of brain leukoencephalopathy in long-term survivors of childhood ALL treated on contemporary chemotherapy-only protocols.

In this study, we included prospective neuroimaging from active therapy to long-term follow-up, and comprehensive assessment of brain structural and functional outcomes in long-term survivors of ALL treated with contemporary risk-adapted chemotherapy. We demonstrated that survivors who developed leukoencephalopathy during therapy displayed more neurobehavioral problems at more than 5 years post-diagnosis. Moreover, these survivors also had reduced white matter integrity at long-term follow-up, and these structural abnormalities were concurrently associated with the neurobehavioral problems.

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Acute Lymphoblastic Leukemia: Tyrosine Kinase Inhibitors Target Resistant Variant

Department of Pathology St. Jude Children's Research Hospital Memphis, TN 38105

St. Jude Children’s Research Hospital Interview with:
Dr. Charles Mullighan, M.D., MBBS(Hons), MSc
Department of Pathology
St. Jude Children’s Research Hospital
Memphis, TN 38105

MedicalResearch: What are the most important take home points from this study for practicing clinicians and their patients?

Dr. Mullighan: Acute lymphoblastic leukemia (ALL) remains a leading cause of cancer death in children, and the prognosis worsens with increasing age. Current therapies are inadequate for many patients. This study has defined the genetic basis of a recently described subtype of Acute lymphoblastic leukemia called Ph-like ALL. We show that the prevalence increases with rising age, and that in both children and young adults the disease is driven by a diverse range of genetic changes that activate kinase signaling, which fuels the growth of leukemia cells. Ph-like Acute lymphoblastic leukemia currently has a poor outcome. The activated kinases may be inhibited by currently approved tyrosine kinase inhibitors (TKIs). We have shown efficacy of these inhibitors in cell lines and experimental models, and in a series of patients with Ph-like Acute lymphoblastic leukemia treated with TKIs.
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Novel Susceptibility Variants at 10p12.31-12.2 for Childhood Acute Lymphoblastic Leukemia in Ethnically Diverse Populations Author Interview: Jun J. Yang, Ph.D.

Assistant Member Dept. of Pharm. Sci.
St. Jude Children’s Research Hospital
262 Danny Thomas Pl., MS313 Memphis, TN 38105 What are the main findings of the study?

Dr. Yang: We performed a comprehensive survey of inherited genetic variations for their contribution to the susceptibility of acute lymphoblastic leukemia (ALL), the most common cancer in children. This is by far the largest study of its kind (in terms of the number of subjects involved), and also the first one to include multi-ethnic populations. We identified 4 genomic loci related to the predisposition to ALL, 2 of which contributed to racial differences in the incidence of ALL.  This study provided unequivocal evidence for inherited susceptibility of childhood ALL and pointed to novel biology of the pathogenesis of this disease.
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Gene responsible for relapses in young leukemia patients

One of the causes of resistance to cancer treatment in children is now beginning to be elucidated. Acute lymphoblastic leukemia patients with a particular form of the ATF5 gene are at higher risk of having a relapse when treated with E. coli asparaginase, a key chemotherapy drug for this type of leukemia. This is what a study by Dr. Maja Krajinovic published in the Blood, the journal of the American Society of Hematology, reveals Dr. Krajinovic is an investigator at the Sainte-Justine University Hospital Research Center, which is affiliated with the University of Montreal.

Dr. Krajinovic’s team focused on asparaginase, one of the drugs in a chemotherapy “cocktail” administered to young patients during the intensification phase of their treatment.

They observed that E. coli asparaginase therapy was associated with an increase in relapses when administered to patients who had particular polymorphism (special form) of the ATF5 gene. In fact, this gene regulates asparagine synthetase, an enzyme that produces asparagine, which in turn feeds cancer cells.

“In the presence of this polymorphism that, as we demonstrated, modifies the transcription rate of the ATF5 gene, it is possible that the medication, rather than preventing the proliferation of leukemia cells by reducing the rate of asparagine, does just the opposite by creating feedback that triggers cancer cells to produce asparagine themselves,” explains Dr. Krajinovic.

The discovery of a form of gene associated with high rates of relapse during treatment with E.coli asparaginase opens the door to the possibility of selecting a type of pharmacological treatment based on a patient’s genetic profile, an approach that reflects the shift toward personalized medicine. “If a DNA test detects the implicated polymorphisms in children, it will be possible to predict the risk of relapse or side effects,” exclaimed Dr. Krajinovic. “The clinician can then propose an alternative treatment or adjust the dose accordingly.”

Since the introduction of combination chemotherapy, the rate of pediatric survival without relapse has skyrocketed to about 80%. Yet some patients still resist treatment or present side effects. Pharmacogenetic research strategies involve studying the reaction to each drug used for combined chemotherapy based on various patient genetic profiles so as to design treatment plans that increase efficacy and reduce side effects in patients. Dr. Krajinovic has published a number of similar studies that focus on antifolate, another drug used in combination regimens to treat acute lymphoblastic leukemia.


Study Details

The study, led by Dr. Maja Krajinovic, an investigator in the Viral and Immune Disorders and Cancers research axis at the Sainte-Justine University Hospital Research Center and the Departments of Pediatrics and Pharmacology at the University of Montreal, was published online on the Oct. 4, 2011 in the scientific journal Blood. Dr. Daniel Sinnett, an investigator working in the same research axis, conducted with Dr. Krajinovic polymorphism-related functional assays. Dr. Sinnett is also an author of many studies on the genetic determinants of acute lymphoblastic leukemia, including a recent study on natural killer cells published in collaboration with Dr. Ali Ahmad as principal author. The study was published in the August 4, 2011, issue of Blood and was reviewed in an editorial that underscored the originality of the work.

The study was funded by the Canadian Institutes of Health Research (CIHR), the Leukemia and Lymphoma Society of Canada, the Charles Bruneau Foundation and the Fondation des Gouverneurs de l’espoir. Drs. Maja Krajinovic and Daniel Sinnett also held National researcher career award from the Fonds de recherche en santé du Québec (FRSQ) in conjunction with this work. The functional studies were conducted in part within the context of one of the projects of Genome Quebec and Genome Canada.

EurekAlert Public release date: 26-Oct-2011