ASH18: RNA Sequencing Identifies More Subtypes of Childhood Leukemia

MedicalResearch.com 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

MedicalResearch.com: 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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Humanized Antibody To Attack Resistant Multiple Myeloma Cells in Bone Marrow

MedicalResearch.com Interview with:

Hans van Eenennaam, Ph.D. Executive vice president antibody research and site head Aduro Biotech Europe

Dr. van Eenennaam

Hans van Eenennaam, Ph.D.
Executive vice president antibody research and site head
Aduro Biotech Europe

MedicalResearch.com: What is the background for this study?

Response: A PRoliferation Inducing Ligand (APRIL) is a member of the tumor necrosis factor superfamily and has been shown to stimulate the proliferation and survival of healthy B-lymphocytes. Malignant B-lymphocytes, such as multiple myeloma, use APRIL primarily in the bone marrow to support its proliferation and survival. Studies have shown that APRIL is overproduced in patients with multiple myeloma and mediates primarily via binding to B-cell maturation antigen (BCMA) to stimulate a wide variety of responses that promote multiple myeloma growth and survival, as well as suppressing the immune system so that the tumor cells are protected and sustained in the bone marrow and can escape current available treatments.

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Children Undergoing Bone Marrow Transplant Remain At Risk For Premature Death

MedicalResearch.com Interview with:

Smita Bhatia, MD, MPH Gay and Bew White Endowed Chair in Pediatric Oncology Professor, Pediatric Oncology Vice Chair for Outcomes Research, Dept of Pediatrics Director, Institute for Cancer Outcomes and Survivorship School of Medicine University of Alabama at Birmingham Associate Director for Outcomes Research UAB Comprehensive Cancer Center 

Dr. Bhatia

Smita Bhatia, MD, MPH
Gay and Bew White Endowed Chair in Pediatric Oncology
Professor, Pediatric Oncology
Vice Chair for Outcomes Research, Dept of Pediatrics
Director, Institute for Cancer Outcomes and Survivorship
School of Medicine
University of Alabama at Birmingham
Associate Director for Outcomes Research
UAB Comprehensive Cancer Center 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Allogeneic bone marrow transplantation BMT is used with a curative intent for life-threatening malignant and non-malignant diseases of childhood.

In this observational study, we describe the late mortality experienced by children undergoing BMT over the past 3 decades. Our cohort included 1388 BMT recipients who had undergone allogeneic BMT between 1974 and 2010 and survived 2 or more years.

We found that, conditional on surviving the first 2 years after bone marrow transplantation, the probability of surviving an additional 20 years approached 80%. Risk of dying from non-relapse-related causes exceeded the risk of dying from relapse-related causes.

The leading non-relapse-related causes of death were infection (with or without graft vs. host disease) and new cancers. Overall, the cohort was at a 14-fold greater risk of dying as compared with the general population (of similar age and sex). Further, this excess risk remained elevated even among those who had survived 25 years.

On a positive note, the risk of late mortality has continued to decline over the past 3 decades. 

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Combination Therapy Could Dramatically Alter CLL Treatment

MedicalResearch.com Interview with:

Dr. Danelle James,

Dr. James

Dr. Danelle James, M.D., M.A.S.
Head of Clinical Science
Pharmacyclics, an AbbVie Company

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: CAPTIVATE is a Phase 2 study investigating IMBRUVICA (ibrutinib) plus VENCLEXTA (venetoclax) for the treatment of Chronic Lymphocytic Leukemia (CLL) in the first-line setting. It was designed to evaluate if remission with undetectable minimal residual disease (MRD) can provide treatment-naïve CLL/SLL patients with treatment holidays (a period of time when a patient is able to stop therapy). The study enrolled 164 patients with previously untreated CLL or SLL.

In preclinical and ongoing clinical studies, we’ve seen complementary activities with this combination. The combination has also previously shown potential for deeper remissions, as well as potential for lower risk of tumor lysis syndrome with ibrutinib as the lead-in therapy.

Early data from CAPTIVATE show promising activity for the combination in this patient population, with 77 percent of the first 30 patients achieving responses with no detectable MRD in the blood after only six cycles of the combination therapy. Approximately nine out of 10 of the first patients achieved undetectable MRD after 12 cycles of combination therapy (which were preceded by three cycles of single agent ibrutinib, for a total of 15 cycles of therapy). Specifically, 86 percent of the first 14 patients achieved undetectable MRD in the marrow and 93 percent in the peripheral blood.

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Engineered Single Cell ‘Cured’ Patient of CLL

MedicalResearch.com Interview with:

Dr. J Joseph Melenhorst, PhD Director, Product Development & Correlative Sciences laboratories (PDCS) Adjunct Associate Professor Penn Medicine Center for Cellular Immunotherapies University of Pennsylvania

Dr. Melenhorst

Dr. J Joseph Melenhorst, PhD
Director, Product Development & Correlative Sciences laboratories (PDCS)
Adjunct Associate Professor
Penn Medicine
Center for Cellular Immunotherapies
University of Pennsylvania

MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by CLL and CAR T cells? 

Response: We started treating patients with a form of blood cancer called CLL (chronic lymphocytic leukemia) using a form of gene therapy wherein we engineer the patient’s own immune cells – T cells – with a tumor targeting molecule: The CAR, which stands for chimeric antigen receptor. When we engineer the patient’s immune cells we use a vehicle, in this case virus, that inserts the payload – the CAR – into the patient’s DNA. The virus disappears, and the CAR stays. Where this CAR inserts itself is unpredictable, but we always get stably engineered cells.  Continue reading

Pre-Emptive Therapy of CMV in Allogeneic Hematopoietic Cell Transplant

MedicalResearch.com Interview with:

 Dr-Roy F. Chemaly

Dr. Chemaly

Roy F. Chemaly, MD, MPH F.A.C.P., F.I.D.S.A.
Department of Infectious Diseases
Infection Control and Employee Health
Division of Internal Medicine
MD Anderson Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: CytomegalovirusCMV infection is a common cause of morbidity and mortality in allo-HCT recipients. Evidence suggests that CMV infection has not only an enormous clinical burden, but a substantial economic burden as well.

We conducted this study at MD Anderson to determine the economic and clinical burden of preemptive therapy (PET) for CMV infection. Between 2012 and 2015, 100 consecutive patients hospitalized at our institution for allo-HCT who experienced reactivation of CMV and were treated pre-emptively, were enrolled.

The majority of patients were men (55%), who had underlying leukemia (73%), and underwent matched unrelated donor transplant (59%). At the time of hospitalization, most patients had acute GvHD (62%), and were on steroids (58%) within 30 days of CMV reactivation which occurred at a median of 32 days post-HCT (2 -174). A total of 192 episodes of PET occurred in the 100 allo-HCT recipients within 1 year post-HCT. PET consisted of ganciclovir (41%), foscarnet (40%), and valganciclovir (38%). IVIG was also used as adjunct therapy in 20% of episodes.

Progression to Cytomegalovirus disease occurred in 4 patients (4%) and mainly affected the GI tract. Mean length of stay for patients treated with ganciclovir or foscarnet was 32 days (2-141) and 41 days (1-177), respectively. The average direct cost per patient admitted for PET was $126,038 ($7,866-$641,841) and the mean cost of CMV antiviral drug per hospitalization was $6,096 for IVIG, $2,410 for foscarnet, $836 for ganciclovir, and $780 for valganciclovir.

Serious side effects from PET were observed in 35% of patients on ganciclovir and 12% of patients on foscarnet. Total direct cost per encounter was significantly higher in patients who had serious side effects from foscarnet. All-cause mortality was 59% at 1 year post-transplant.

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Cost and Side Effects Influence Patients’ Preferences for Leukemia Medications

MedicalResearch.com Interview with:

Carol Mansfield, PhD, Senior Research Economist Health Preference Assessment RTI Health Solutions www.rtihs.org

Dr. Mansfield

Carol Mansfield, PhD,
Senior Research Economist

Health Preference Assessment
RTI Health Solutions
www.rtihs.org 

MedicalResearch.com: What is the background for this study?

Response: As the most prevalent form of leukemia, chronic lymphocytic leukemia (CLL) affects approximately 130,000 people in the United States. More than 20,000 new cases are diagnosed each year. In recent years, more treatment options–each with its own associated benefits, side effects, and price tag–have been approved. This leaves patients and physicians with a variety of factors they must consider when choosing a treatment plan.

While every patient wants the most effective drug with the fewest side effects, most people don’t have that option available. By asking patients to make tradeoffs and rank their preferences, we can form an understanding of how patients approach their treatment.

This study showed that patients with CLL value medicines that provide the longest progression-free survival, but are willing to trade some benefits for a lower risk of serious adverse events. Additionally, we found that cost clearly has an impact on which treatment a patient would choose. When patients get prescribed something they can’t afford, they are forced to make very difficult choices.

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Microtransplantation Can Be Safe and Effective For Older AML Patients

MedicalResearch.com Interview with:
Huisheng Ai, MD, Director

Department of Hematology and Transplantation,
Affiliated Hospital of the Academy  of Military Medical Sciences,
Beijing, China 

MedicalResearch.com: Which of these results did you find most interesting or surprising?

Response: First, we must stress that microtransplant dramatically improved the outcome of older patients with AML.

As we know, older AML patients often possess unfavorable prognostic factors, organ dysfunction, and slow post-chemotherapy hematopoietic recovery. Therefore, the general treatment outcome is unsatisfactory even though the incidence is increasing by age with low complete remission (CR) rates (34% to 65%) and poor short-term survival (Two years overall survival was about 11% to 25%).

This study involved cases from multiple centers of China, USA and Spain, and found that microtransplant could not only significantly improve complete remission rate in older AML patients among all age groups from 60 to 85, but also improve 1-year and 2-year overall survival and disease free survival especially in patients aged 60 to 75. Second, microtransplant completely overcomes the restriction of HLA typing. The donor could be the patient’s haploidentical family member, or unrelated and fully mismatched one. The incidence of graft-versus-host disease (GVHD) was only 1.1%, even if no any GVHD prevention was given. Other treatment related complications and mortality were also decreased.

These results are much better than those of traditional chemotherapy, myeloablative and non-myeloablative transplant, which provides a more safe and effective treatment choice. We are looking forward to seeing the revision of NCCN guideline for older AML to make microtransplant benefit more older patients.

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Intermittent Fasting Inhibits Cancer Cells in Childhood Leukemia ALL

MedicalResearch.com 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

MedicalResearch.com: 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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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.

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Germline Genetic Variation in IKZF1 and Predisposition to Childhood ALL

MedicalResearch.com 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

MedicalResearch.com: 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

MedicalResearch.com 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

MedicalResearch.com: 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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Cord Blood Transplant in Leukemia With Minimal Residual Disease

MedicalResearch.com Interview with:

Dr. Filippo Milano, MD, PhD Assistant Member, Clinical Research Division Associate Director Cord Blood Transplantation Cord Blood Program Assistant Professor, University of Washington Fred Hutchinson Cancer Research Center

Dr. Filippo Milano

Dr. Filippo Milano, MD, PhD
Assistant Member, Clinical Research Division
Associate Director Cord Blood Transplantation
Cord Blood Program
Assistant Professor, University of Washington
Fred Hutchinson Cancer Research Center

MedicalResearch.com: What is the background for this study?

Response: When first introduced, cord blood (CB) graft was used only as a last resort when no suitable conventional donor could be identified, largely due to the limiting cell doses available in a cord blood graft. A CB graft, however, is attractive due to the increased level of HLA disparity that can be tolerated, without increased risk of graft versus host disease, allowing nearly all patients to find such a donor.

The main intent of the study was to evaluate whether or not, at our Institution, cord blood SHOULD STILL BE considered only AS an alternative DONOR or IF instead outcomes were comparable to those obtained with more “conventional” types of transplants from matched and mismatched unrelated donors.

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Phase 3 Trial of Iomab-B as an Induction and Conditioning Agent Prior to Bone Marrow or Stem Cell Transplant in Relapsed or Refractory AML

MedicalResearch.com Interview with:

Felix Garzon, MD, PhD Senior Vice President Head of Clinical Development Actinium Pharmaceuticals, Inc. New York, NY 10016

Felix Garzon

Felix Garzon, MD, PhD
Senior Vice President
Head of Clinical Development
Actinium Pharmaceuticals, Inc.
New York, NY 10016

MedicalResearch.com: What is the background for this study? What is goal of this Study?

Response: Iomab-B (“Iomab”) was developed at the Fred Hutchinson Cancer Research Center (“the Hutch”) in Seattle, Washington. The Hutch is a pioneer in the field of bone marrow transplantation (BMT) having 3 Nobel Prizes and doctors there performed some of the first transplants for leukemia patients. Iomab-B is intended to be an induction and conditioning agent prior to a BMT for patients with relapsed or refractory Acute Myeloid Leukemia (AML) who are over the age of 55. BMT is the only potentially curative option for AML i.e. for this patient population that currently has a survival prognosis of 2-6 months which means that if Iomab-B is successful it would create a new market segment and offer patients a great clinical benefit and a hope for a cure. Actinium Pharmaceuticals licensed Iomab from the Hutch in 2012 and prior to us licensing Iomab, it had been studied in almost 300 patients in several phase 1 and phase 2 clinical trials in an array of blood cancers, both leukemias and lymphomas. Actinium is now the sponsor of a pivotal phase 3 trial for Iomab-B to study its use as an induction and conditioning agent prior to a bone marrow transplantation in patients with relapsed or refractory AML who are over the age of 55. This trial, which we have named the SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) trial, started at the end of June 2016 and we expect to enroll 150 patients by the end of 2017.

The primary endpoint of the SIERRA trial is durable complete remissions (dCR) of 6 months. The study arm will consist of Iomab-B administration followed by a  bone marrow transplantation, patients will be evaluated for dCR at 6 months after engraftment, which will be assessed at day 28 or day 56. The control arm of the study will be physician’s choice of chemotherapy and if the patient is able to achieve a complete remission (CR) they may receive a BMT or some other form of treatment with curative intent. The study is designed to evaluate if the study arm of Iomab-B and a BMT can double the dCR rate of the control arm, which is designed to replicate the current treatment regimen prior to a bone marrow transplantation .

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Biomarker May Predict Response to Common Leukemia Treatment

MedicalResearch.com Interview with:

Dr Laura Eadie PhD Post Doctoral Researcher Affiliate Lecturer Discipline of Medicine University of Adelaide

Dr. Laura Eadie

Dr Laura Eadie PhD
Post Doctoral Researcher
Affiliate Lecturer Discipline of Medicine
University of Adelaide

Summary: Researchers based at SAHMRI (South Australian Health and Medical Research Institute) in Adelaide, South Australia have recently demonstrated the significance of early increases in the expression of ABCB1 in predicting long-term response to imatinib therapy. Lead researcher, Dr Laura Eadie, has recently had these findings published in the journal Leukemia and says that she hopes “the evidence provided by the study could be used to inform better patient treatment in the future”.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: ABCB1 (p-glycoprotein) is a membrane transporter known to be involved in the efflux of the tyrosine kinase inhibitors (TKIs) that are used to treat chronic myeloid leukaemia (CML). Overexpression of ABCB1 has also been demonstrated to cause resistance to the TKIs imatinib, nilotinib and dasatinib in vitro. Although studied previously in CML patients, the predictive value of ABCB1 in determining a patient’s long-term response to imatinib had not been realized … until now.

Previous studies investigating ABCB1 as a predictive biomarker focused on expression levels of ABCB1 at one time point in isolation. For our study, we have measured the levels of ABCB1 at two separate time points specified in the TIDEL II trial protocol: day 1 (prior to the start of imatinib therapy) and day 22 (three weeks on imatinib). We then calculated the fold rise in ABCB1 expression levels at day 22 compared with day 1 and grouped patients about the median into high and low fold rise. When we compared molecular outcomes for patients within these two ABCB1 expression groups we noticed a striking difference in outcome to imatinib therapy.

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Multikinase Inhibitor Midostaurin Improved Symptoms and Survival in Most Advanced Forms of Blood Cancer Mastocytosis

MedicalResearch.com Interview with:

Jason R. Gotlib, MD The Clinical Investigator Pathway Hematology Division at Stanford University Medical Cent

Dr. Jason R. Gotlib

Jason R. Gotlib, MD
The Clinical Investigator Pathway
Hematology Division
Stanford University Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The background is that advanced forms of systemic mastocytosis, which are blood cancers characterized by accumulation of abnormal mast cells in the bone marrow and additional organs, represent a group of orphan diseases with a large unmet need. Approximately 90% of patients harbor the acquired KIT D816V mutation, a mutated receptor tyrosine kinase on the surface of mast cells which a primary driver of disease pathogenesis. Only 1 drug is approved for patients with one form of advanced systemic mastocytosis, termed ‘aggressive systemic mastocytosis, or ‘ASM’. This therapy is imatinib (Gleevec), but it is only approved for patients without the KIT D816V mutation, or with KIT mutation status unknown because the KIT D816V mutation is resistant to imatinib. Therefore, this drug may only be useful for approximately 10% of patients. Other drugs that have been used off-label for systemic mastocytosis (but are not approved for this indication) include interferon-alpha or cladribine, which show some activity, but their evaluation to date has been primarily limited to small case series which are usually retrospective in nature, and include mixed populations of systemic mastocytosis patients who have both early stage disease without organ damage (e.g. indolent systemic mastocytosis) and and advanced stage patients, as included in this trial, who have one or more findings of organ damage. Also, those trials employed differing response criteria and no central adjudication of eligibility and response assessments was undertaken.

Midostaurin is a multikinase inhibitor with activity against both wild-type KIT, but most importantly, KIT D816V (in contrast to imatinib). Prior work demonstrated that cell lines transformed with the KIT D816V mutation can be inhibited at relatively low concentrations of midostaurin. These concentrations could also be achieved in vivo (e.g. at concentrations achievable in the blood of patients). Cell lines transformed by KIT D816V could not be inhibited by imatinib.

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Life Expectancy Greatly Improved for Patients Diagnosed with CML

MedicalResearch.com Interview with:
Hannah Bower, MSc
Department of Medical Epidemiology and Biostatistics
Karolinska Institutet
Stockholm, Sweden

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Previously, if left untreated or with symptomatic treatment (up to the 1970’s), the median survival time of patients with chronic myeloid leukemia (CML) ranged between two and three years. Later, interferon alpha and allogeneic stem cell transplantation were introduced. However, improvements in survival were mainly seen in younger patients. Treatment with the tyrosine-kinase inhibitor (TKI) imatinib-mesylate (Glivec®, Gleevec®) began in Sweden in the early 2000 resulting in major survival improvements, with the exception of the old/very elderly.

We investigated if these improvements continued to 2013 and if improvements are now observed in the elderly via the life expectancy and the loss in expectation of life; the latter of these quantifies the change in the life expectancy due to a diagnosis of CML. The great improvements in life expectancy, especially in the youngest patients, translate into great reductions in the loss in expectation of life. The major factor contributing to the improvement in the elderly is likely the increasing use of TKIs.

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Breast Cancer Drug May Also Treat Aggressive Leukemia

MedicalResearch.com Interview with:

Dr. Iris Z Uras

Dr. Uras

Dr. Iris Z Uras and Univ.-Prof. Dr. Veronika Sexl

Univ.-Prof. Dr. Veronika Sexl

Dr. Sexl

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.

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Cesarean Section May Increase Risk of Childhood Leukemia

MedicalResearch.com Interview with:

Erin Marcotte, Ph.D. Assistant Professor Division of Epidemiology and Clinical Research Department of Pediatrics University of Minnesota

Dr. Erin Marcotte

Erin Marcotte, Ph.D.
Assistant Professor
Division of Epidemiology and Clinical Research
Department of Pediatrics
University of Minnesota

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Marcotte: Recently there have been several studies that indicate a higher risk of immune-related disorders, such as type-I diabetes, asthma, and allergies, among children born by cesarean delivery. Our analysis used pooled data from 13 independent studies of childhood leukemia that were conducted in 9 different countries. We used data on over 33,000 children to investigate the relationship between birth by cesarean delivery and risk of childhood leukemia. We did not find an association between cesarean delivery overall and childhood leukemia. However, when we looked at emergency cesarean deliveries and pre-labor (planned) cesarean deliveries separately, we found a 23% increase in risk of acute lymphoblastic leukemia among children born by pre-labor cesarean delivery.

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End Of Life Discussions Occur Late in Blood Cancer Patients’ Disease

Oreofe O. Odejide, MD Instructor in Medicine, Harvard Medical School Dana-Farber Cancer Institute

Dr. Odejide

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:

  • First, the majority of hematologic oncologists (56%) reported that typical EOL discussions occur “too late.”
  • Second, hematologic oncologists practicing primarily in tertiary care settings were more likely to report late discussions compared to those in community settings.
  • Third, a substantial proportion of respondents reported that they typically conduct the initial discussions regarding resuscitation status, hospice care, and preferred site of death at less optimal times.

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Multi-Kinase Inhibitor Midostaurin Plus Chemo Improves AML Survival

MedicalResearch.com Interview with:
Renaud Capdeville, MD

Global Program Head
Oncology Global Development
Novartis

Medical Research: What is the background for this study? What are the main findings?

Dr. Capdeville: RATIFY (Randomized AML Trial in FLT3 in patients <60 Years Old; CALGB 10603) was a Phase III, international, randomized, placebo-controlled, double-blind group trial of newly-diagnosed (Acute myeloid leukemia, acute myelogenous leukemia) AML patients aged 18 to less than 60 who have a FLT3 mutation.

In the study, patients who received the investigational compound PKC412 (midostaurin) plus standard induction and consolidation chemotherapy experienced a 23% improvement in overall survival (OS) (hazard ratio [HR] = 0.77, P =0.0074) compared with those treated with standard induction and consolidation chemotherapy alone. The median OS for patients in the PKC412 (midostaurin) treatment group was 74.7 months (95% confidence interval [CI]: 31.7, not attained), versus 25.6 months (95% CI: 18.6, 42.9) for patients in the placebo group.

The data, collected and analyzed in partnership with the Alliance for Clinical Trials in Oncology, are from the largest clinical trial in FLT3-mutated AML to date, with 3,279 patients screened and 717 study participants from around the world.

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Disparities in Acute Leukemia Care are Multifactorial

Manali Patel, MD, MPH Instructor in the Division of Oncology Department of Medicine at 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.

Dr. Manali Patel

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.

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AML: Kinase Inhibitor Plus Standard Chemotherapy Reduces Relapse Risk

Dr. Christoph Röllig Medizinische Klinik und Poliklinik I Universitätsklinikum der Technischen Universitä Dresden, Germany

Dr. Röllig

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 AML, their use in combination with standard treatment is becoming an important option for newly diagnosed younger patients.

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Patient Specific Drug Combinations Improve AML Treatment

MedicalResearch.com Interview with:
Jeffrey Tyner, Ph.D.
Assistant Professor in Cell, Developmental and Cancer Biology at the Oregon Health & Science University School of Medicine and researcher and OHSU Knight Cancer Institute
Stephen Kurtz, Ph.D.
Research Assistant Professor at the Oregon Health & Science University School of Medicine Leukemia Center and researcher
OHSU Knight Cancer Institute

What is the background for this study? What are the main findings? 

Dr. Tyner: This study was one of many resulting from the ‘Beat AML’ initiative. Acute myeloid leukemia (AML) is a complex form of leukemia; less than 25 percent of newly diagnosed AML patients survive beyond five years. Led by the Knight Cancer Institute at Oregon Health & Science University and The Leukemia & Lymphoma Society (LLS), Beat AML brings together academic health centers and biopharmaceutical companies to accelerate discoveries to improve outcomes for patients with acute myeloid leukemia.

In this study, by using a unique method to test drugs used together, we identified drug combinations that are active against leukemia cells in a patient-specific manner.

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Cancer Spending and Survival Varies Widely Across Europe

Milena Sant, MD Analytical Epidemiology and Health Impact Unit Department of Preventive and Predictive Medicine Fondazione IRCCS Istituto Nazionale dei Tumori Milan, ItalyMedicalResearch.com Interview with:
Milena Sant, MD
Analytical Epidemiology and Health Impact Unit
Department of Preventive and Predictive Medicine
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, Italy

Medical Research: What is the background for this study? What are the main findings?

Dr. Milena Sant: Effective treatments for haematological malignanacies are available since early 2000, however in previous studies differences in survival by large European region were evidenced. We used the EUROCARE data to investigate survival time trends and differences across countries within large regions.

The study results highlighted a general improvement in 5-year relative survival, most marked for CML (5-year relative survival improved from 30% to 54% from 1997 to 2006-08; and for NHL, particularly follicular type (from 59 to 74%); less variation was seen for Hodgkin survival; Despite this increase,  remarkable differences by country within regions were evident. For instance CML survival varyied from 33% in Eastern European countries to 58%in central and northern European countries

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