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
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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MedicalResearch.com Interview with:Luciano J. Costa, MD, PhD
Associate Professor
Department of Medicine and UAB-CCC
Bone Marrow Transplantation and Cell Therapy Program
Birmingham, AL 35294
MedicalResearch.com: What is the background for this study? What are the main findings?Response: Even though expected survival for multiple myeloma patients has increased over the last two decades, that improvement has not been much more pronounced among White than among patients of racial/ethnic minorities. It is possible that such discrepancy results from unequal access to care, particularly as treatment becomes more complex and expensive. We used a large dataset of patients with multiple myeloma to explore how socioeconomic factors, specifically marital status, income and insurance affect outcome and how these factors relate to race/ethnicity.
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MedicalResearch.com Interview with: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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MedicalResearch.com Interview with: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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MedicalResearch.com Interview with: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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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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MedicalResearch.com Interview with: Torsten Dahlén MD
Centre for Hematology
Karolinska University Hospital Solna
Stockholm Sweden
MedicalResearch.com: What is the background for this study? Dr. Dahlén: Patients diagnosed with CML have had a dramatic increase in life-expectancy since the widespread introduction of tyrosine kinase inhibitors (TKI) in 2001. However, treatment is today regarded as life-long. We thus need to observe for late-effects of continuous TKI exposure. Recent reports have demonstrated a linkage between TKI treatment, especially more potent 2nd and 3rd generation drugs, and to the occurrence of peripheral arterial occlusive disease (PAOD). This study aimed to use real-world data utilizing Swedish population based registries together with the dedicated Swedish CML registry which contains data and follow-up on more than 98% of all CML patients diagnosed in Sweden since 2002.
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MedicalResearch.com Interview with:Dr. Iris Z Uras and Univ.-Prof. Dr. Veronika 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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MedicalResearch.com Interview with:
PD Dr. Mathias Buttmann
Senior Consultant Neurologist and Head of the Multiple Sclerosis Outpatient Clinic
University of Wuerzburg
Wuerzburg, GermanyMedicalResearch.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.
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MedicalResearch.com Interview with:
Prof Jeffrey H Lipton, PhD, MD, FRCPC
Princess Margaret Cancer Centre
Toronto, ON Canada
MedicalResearch.com: What is the background and purpose for this study?
Dr. Lipton: Ponatinib is a third generation tyrosine kinase inhibitor that has been shown to be extremely effective in treating patients with chronic myeloid leukemia resistant to other drugs. Because of this, it was decided to look at it in newly diagnosed patients in a randomized study against imatinib. The study was terminated prematurely because of evidence of vascular toxicity that became evident in the phase 1 and 2 studies of ponatinib in previously treated patients with resistant disease. (more…)
MedicalResearch.com Interview with:
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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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.
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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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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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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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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MedicalResearch.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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MedicalResearch.com Interview with:
Angelica Loskog, PhD
Professor of Immunotherapy (adjunct)
Dept of Immunology, Genetics and Pathology
Uppsala University
Uppsala Sweden
Medical Research: What is the background for this study? What are the main findings?
Dr. Loskog: CAR T cells have shown remarkable effect in patients with B cell malignancy in the US using 2nd generation CAR T cells. Acute leukemia (ALL) seems easier to treat than lymphomas and one of the reasons may be difficulties for CAR T cells to penetrate a solid lesion or due to a higher local presence of immunosuppressive cells within a lesion. As one of the first centers outside US we are evaluating 3rd generation CAR T cells in both lymphoma and ALL aiming to compare the responses and investigating biological reasons for the different responses. So far we have treated 11 patients and 6 of them had initial complete responses. Unfortunately, some progressed later.
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MedicalResearch.com Interview with:
Prof David C Currow
Discipline of Palliative and Supportive Services
Flinders University
Adelaide, SA, Australia
Medical Research: What is the background for this study? Prof. Currow: This study grew out of a desire to better understand the symptom burden experienced by people with hematological malignancies at the end of life. This has been very poorly documented and although there are lots of strong opinions, there are very few data at a population level.
Medical Research: What are the main findings?Prof. Currow: The main finding is that community-dwelling people with hematological malignancies at the end of life have a burden of symptoms that looked almost identical to people with solid tumours. Given much lower rates of access to the hospice and palliative care, this suggests that these people and their family caregivers are missing out on opportunities for better symptom control and better support. (more…)
MedicalResearch.com Interview with: Dr Klervi Leuraud, Epidemiologist
Institute for Radiological Protection and Nuclear Safety
Cedex, France
MedicalResearch: What is the background for this study? What are the main findings?Dr. Leuraud: INWORKS was performed to quantify the risk of cancer mortality associated to protracted low doses of ionizing radiation typical of occupational or environmental exposures, as well as of diagnostic medical exposures. While such risks are well known for acute exposures as those experienced by the Japanese survivors of the A-bombs, there is still a lack of information for exposures experienced by the workers and the public. Our study confirms the existence of an association between leukemia mortality and chronic exposure to low doses received by nuclear workers.
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MedicalResearch.com Interview with:Susan Schwab, PhD
Assistant professor at NYU Langone
Skirball Institute of Biomolecular Medicine
Medical Research: What is the background for this study? What are the main findings?Dr. Schwab: T cell acute lymphoblastic leukemia (T-ALL) remains a devastating pediatric disease. Roughly 20% of children do not respond to current therapies. Furthermore, metastasis to the central nervous system is common in T-ALL, and intrathecal chemotherapy, even when successful at eradicating the cancer, causes serious long-term cognitive side-effects.
Here we report that the chemokine receptor CXCR4 is essential for T cell acute lymphoblastic leukemia progression in both mouse and human xenograft models of disease. Consistent with sustained disease remission in the absence of CXCR4, loss of CXCR4 signaling results in decreased levels of c-Myc, which is required for leukemia initiating cell activity. T-ALL cells reside near cells generating the CXCR4 ligand CXCL12 in the bone marrow, and our data suggest that vascular endothelial cells may be an important part of the T-ALL niche.
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MedicalResearch.com Interview with:
Efrat Amitay, PhD, MPH
School of Public Health
University of Haifa
Mount Carmel, Haifa, Israel
Medical Research: What is the background for this study?
Dr. Amitay: Although childhood cancer is still rare, we are seeing an increase of around 0.9% annually in the incidence rate in the western world. In spite of advancements in treatment technologies, childhood cancer is a leading cause of death among children and adolescents in the western world – accounting for about 12.3% of all deaths among children age 1-14 years in the US. Childhood cancer is also emerging as a major cause of death in other parts of the world where death rates from communicable diseases are declining. Leukemia is the most common type of childhood cancer and accounts for about 30% of all childhood and adolescent cancers.
Medical Research: What are the main findings?
Dr. Amitay: The meta-analysis of all 18 studies indicated that compared with no or shorter duration of breastfeeding, breastfeeding for 6 months or longer was associated with a 19% lower risk for childhood leukemia (OR=0.81, 95% CI, 0.73-0.89). A separate analysis of 15 of those studies indicated that ever being breastfed compared with never being breastfed was associated with an 11% lower risk for childhood leukemia (OR=0.89, 95% CI, 0.84-0.94). All meta-analyses of other sub groups of studies have shown similar associations, indicating that 14%-19% of all childhood leukemia cases may be prevented by breastfeeding for 6 months or more.
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MedicalResearch.com Interview with:William E. Evans, Pharm.D.
Member, Pharmaceutical Sciences
St. Jude Children’s Research Hospital
MedicalResearch: What is the background for this study? What are the main findings?Dr. Evans: We are currently curing over 85 percent of children with acute lymphoblastic leukemia (ALL), the most common cancer in children. While we continue to focus on pushing cure rates closer to 100 percent through the development of new treatments, we are also increasingly focused on reducing the acute and chronic side effects of treatment. This is important to improve the quality of life for patients during treatment and as they become adults after being cured, because some side effects can persist for decades after treatment is completed.
One of the medications that every child with acute lymphoblastic leukemia received 30-40 times during their 2+ years of treatment is vincristine. The major side effect of vincristine is peripheral neuropathy (about 25 percent of patients develop this side effect), which can cause loss of sensation, numbness, neuropathic pain and alter their motor skills including manual dexterity, balance and ability to walk properly. This can have very practical consequences, such as writing, using a smart phone, and the use of eating utensils. It can also alter their gait.
Our main finding is we discovered that an inherited variant of the CEP72 gene enhanced the risk and severity of vincristine neuropathy in two groups of patients we studied. Those children who inherited two copies of the high-risk CEP72 gene (one from each parent, about 16 percent of patients) had a significantly higher likelihood (about 3.5-fold) of developing vincristine neuropathy and had a more severe form of neuropathy (about 2.5-fold higher severity).
The CEP72 gene encodes a protein essential for normal microtubule formation in cells—a critical process for cell division. Vincristine inhibits this same cellular process. The inherited form of CEP72 that increases the risk and severity of vincristine neuropathy is associated with lower expression of the CEP72 protein. When coupled with vincristine treatment, CEP72 increases a cell’s sensitivity to vincristine. We were able to reproduce this in the laboratory by lowering CEP72 expression in human neurons made from induced pluripotent stem cells and in human leukemia cells, increasing the sensitivity of both to vincristine. We also showed that the leukemia cells from patients who inherited two copies of the CEP72 risk allele were more sensitive to vincristine, suggesting it may be possible to treat these patients with a lower dose of vincristine to reduce their neuropathy without compromising the treatment of their leukemia—a possibility we plan to test in our next clinical trial at St. Jude.
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MedicalResearch.com Interview with:
David G. Kent, Ph.D
From the Cambridge Institute for Medical Research and Wellcome Trust–Medical Research Council Stem Cell Institute University of Cambridge
Medical Research: What is the background for this study? What are the main findings?
Dr. Kent: Cancers are the result of the sequential acquisition of errors in the genetic code. Most studies have focused on the sum of these mutations (e.g., A+B+C = cancer) but no study in patients has asked the question of whether or not the order of genetic mutations impacts the disease (e.g., does A to AB equal B to BA). We studied patients with chronic blood disorders (known as myeloproliferative neoplasms, or MPNs) that are precursors to cancer to access the earliest stages of tumour development and studied whether or not the order of mutation acquisition impacted disease. We studied patients with mutations in two genes (JAK2 and TET2) and showed that the order of acquisition of these mutations impacted timing of clinical presentation, disease subtype, frequency of thrombotic events, and differed in their response to targeted therapy in the lab. (more…)
MedicalResearch.com Interview with:
Jun J. Yang Ph.D.
Assistant Member Dept. of Pharm. Sci.
St. Jude Children's Research Hospital
Memphis, TN 38105
Medical Research: What is the background for this study? What are the main findings?
Dr. Yang: Mercaptopurine is highly effective in acute lymphoblastic leukemia (ALL) and essential for the cure of this aggressive cancer. However, it also has a narrow therapeutic index with common toxicities. Identifying genetic risk factors for mercaptopurine toxicity will help us better understand how this drug works and also potentially enable clinicians to individualize therapy based on patients’ genetic make-up (precision medicine).
In addition to confirming the role of TPMT, we have identified another important genetic risk factor (a genetic variation in a gene called NUDT15) for mercaptopurine intolerance. Patients carrying the variant version of NUDT15 are exquisitely sensitive and required up to 90% reduction of the normal dose of this drug. TPMT variants are more common in individuals of African and European ancestry, whereas NUDT15 variants are important in East Asians and Hispanics.
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MedicalResearch.com Interview with:
Professor Eleni Petridou
Preventive Medicine & Epidemiology, Department of Hygiene
Epidemiology and Medical Statistics,
Athens University Medical School Athens Greece
Medical Research: What is the background for this study? What are the main findings?
Prof. Petridou: Impressive gains in survival from childhood leukemia have been achieved during the last decades mainly on account of advancements in treatment of the disease. Yet, these big improvements do not seem to be equally shared by all sick children. Disparities in the survival of children suffering leukemia who live in high versus low-income countries, as well as among different racial groups pointed to socio-economic status (SES) of the family as a factor that might adversely affect the outcome. SES, however, is a multifaceted variable comprising economic, social and professional components, which cannot be easily assessed. Therefore, an array of area of residence- and individual family- based proxy indices have been used in order to investigate the association between SES and overall or event-free survival from childhood leukemia. We have intensively searched for published articles around the globe and also analyzed primary data kindly provided by the US National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) for the period 1973-2010 as well as the Nationwide Registry for Childhood Hematological Malignancies (NARECHEM) in Greece for the period 1996-2011. This study is the first meta-analysis summing up the findings of 29 individual studies and quantifying the adverse effect in the survival due to SES differentials among 60 000 afflicted children. According to the findings, lower socio-economic status children suffering, at least, the more common Acute Lymphoblastic Leukemia (ALL) type have nearly two fold higher death rates compared to those of high socio-economic status. Of note, the SEER data show that the survival gap was wider in the USA with increased risk of death from ALL in the lower SES children (by 20-82%) and widening during the last 40 years time period. (more…)
MedicalResearch.com Interview with:
Dr. Judy Karp, Dr. Antonio Wolff and Dr. Kala VisvanathanBreast Cancer Program
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
Baltimore, MD 21287
Medical Research: What is the background for this study? What are the main findings?
Response: The background for this study was the clinical observation from the Johns Hopkins Leukemia Program that a significant number of women with newly diagnosed acute myeloid leukemia had a personal history for breast and/or ovarian cancers. This observation led to our examination of the large NCCN breast cancer database in a multidisciplinary and multi-institutional study. The overarching finding in our study is that the risk of developing some form of leukemia following chemotherapy with or without radiation therapy, while small, continues to increase over at least 10 years without a plateau and is roughly twice what we thought it to be from previous breast cancer studies.
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MedicalResearch.com Interview with:
John E. Wagner, M.D.
Principal Investigator
Professor Director, Division of Blood and Marrow Transplantation Department of Pediatrics McKnight Presidential Endowed Chair Hageboeck Family / Children's Cancer Research Fund Endowed Chair University of Minnesota Minneapolis, MN 55455Medical Research: What is the background for this study? What are the main findings?Dr. Wagner: Earlier studies of umbilical cord blood transplantation (UCB) in children with hematological malignancies demonstrated a survival rate of approximately 50%. While single UCB transplant was very effective despite HLA mismatch, few adults had access to umbilical cord blood as a treatment option due to the cell dose requirement of 2. 5 x 10^6 nucleated cells per kilogram recipient body weight. For this reason, at the University of Minnesota we explored the co-transplantation of two partially HLA matched umbilical cord blood units in adults as a straightforward strategy to achieving the cell dose requirement. Early results were remarkable with survival rates higher than that observed in children. This in turn led to the design of the BMT CTN 0501 study, a randomized trial comparing single versus double umbilical cord blood transplantation in children aged 2-21 years with hematological malignancies. All patients received a uniform conditioning regimen of fludarabine, cyclophosphamide and total body irradiation and GVHD prophylaxis of cyclosporine A and mycophenylate mofetil. 224 patients were randomized.
There were four major findings:
1) survival results overall, regardless of treatment arm, have improved,
2) for children, an adequately dosed single umbilical cord blood unit is sufficient, giving a survival result of 72% at one year,
3) double umbilical cord blood transplant is associated with more GVHD and poorer platelet recovery but survival is comparable to an adequately dosed single unit, and
4) HLA mismatch is well tolerated with potentially better disease free survival in patients transplanted with HLA mismatched umbilical cord blood , a provocative finding that requires further investigation.
MedicalResearch.com 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
MedicalResearch.com: 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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