Ponatinib Currently Not Indicated As First Line CML Chronic Phase Therapy

MedicalResearch.com Interview with:

Prof Jeffrey H Lipton, PhD, MD, FRCPC  Princess Margaret Cancer Centre Toronto, ON Canada

Prof. Jeffrey Lipton

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.   Continue reading

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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Third Generation CAR T cells For Relapsed Lymphoma and Leukemia

Angelica Loskog, PhD Professor of Immunotherapy (adjunct) Dept of Immunology, Genetics and Pathology Uppsala University Uppsala SwedenMedicalResearch.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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Patients With Blood Cancers May Need More Support At End Of Life

Prof David C Currow Discipline of Palliative and Supportive Services Flinders University Adelaide, SA, AustraliaMedicalResearch.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. Continue reading

Occupational Exposure To Low Dose Radiation Linked To Leukemia

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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Bone Marrow Receptor Opens Door To New Therapy For a Pediatric Leukemia

Susan Schwab, PhD Assistant professor at NYU Langone Skirball Institute of Biomolecular Medicine 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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Breastfeeding May Be Linked To Lower Risk of Childhood Leukemia

Efrat Amitay, PhD, MPH School of Public Health University of Haifa Mount Carmel, Haifa, IsraelMedicalResearch.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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Personalized Medicine: Gene Predicts Neuropathy from Vincristine Chemotherapy

William E. Evans, Pharm.D. Member, Pharmaceutical Sciences St. Jude Children’s Research HospitalMedicalResearch.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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Order of Mutations Affects Disease Pattern in Chronic Blood Disorders

David G. Kent, Ph.D From the Cambridge Institute for Medical Research and Wellcome Trust–Medical Research Council Stem Cell Institute University of CambridgeMedicalResearch.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. Continue reading

Genetic Basis For Acute Lymphoblastic Leukemia Drug Toxicity Identified

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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Socioeconomic Status Affects Long Term Childhood Leukemia Survival

Professor Eleni Petridou Preventive Medicine & Epidemiology, Department of Hygiene Epidemiology and Medical Statistics, Athens University Medical School Athens GreeceMedicalResearch.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. Continue reading

Increased Risk Of Leukemia After Breast Cancer Treatment

MedicalResearch.com Interview with:
Dr. Judy Karp, Dr. Antonio Wolff and  Dr. Kala Visvanathan
Breast 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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Hematologic Cancers: Umbilical Cord Transplantation – One vs Two Units

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 55455MedicalResearch.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 55455

Medical 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.

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Novel Susceptibility Variants at 10p12.31-12.2 for Childhood Acute Lymphoblastic Leukemia in Ethnically Diverse Populations

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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Chemotherapy Proves Life-Saving for Some Leukemia Patients Who Fail Induction Therapy

Newswise — (MEMPHIS, Tenn. – April 11, 2012) An international study found that bone marrow transplants are not the best option for some young patients with acute lymphoblastic leukemia (ALL) who fail to attain clinical remission after the initial weeks of intense chemotherapy known as induction therapy.

The largest study ever of such pediatric ALL patients identified a subset of young children who achieved 10-year survival rates of 72 percent after additional chemotherapy rather than bone marrow transplantation. The patients are among the estimated 85 percent of children with ALL whose cancer begins in white blood cells destined to become B cells.

The results appear in the April 12 edition of the New England Journal of Medicine. The study involved researchers from 14 research groups in the U.S., Europe and Asia.

“Induction failure is a rare event, affecting just 2 to 3 percent of all pediatric ALL patients. But these children are at very high risk for a bad outcome and were always considered candidates for bone marrow transplantation,” said Ching-Hon Pui, M.D., chair of the St. Jude Children’s Research Hospital Department of Oncology. “These results tell us that induction failure should no longer be considered an automatic indication for a transplant.” Pui is the study’s corresponding author.

Improvements in both chemotherapy and transplantation prompted investigators to revisit the question of optimal care for these patients. But no single institution or nation had enough patients to answer it. “This study shows the importance of international collaboration to advance the treatment outcome for these patients,” said first author Martin Schrappe, M.D., University Medical Center Schleswig-Holstein, Kiel, Germany.

Investigators evaluated the outcomes of 44,017 ALL patients age 17 and younger whose cancer was discovered during a 15-year period ending in December 2000. Each was treated on a clinical trial at one of the centers participating in this international collaborative analysis. St. Jude patients were part of the study. Researchers tracked 1,041 patients whose cancer did not go into remission following four to six weeks of induction therapy.

Historically, the prognosis has been grim for patients who fail induction therapy. While overall long-term survival for childhood ALL patients climbed to 80 percent during the 15 years covered in this study, it was just 32 percent for patients who did not enter remission after the first intense weeks of treatment. The definition of induction failure differed slightly among the clinical trials included in this analysis.

The study found long-term survival rates of 72 percent among some young patients with B-lineage ALL treated with additional chemotherapy following induction therapy failure. The patients were ages 1 through 5 when their cancer was found and many had more than 50 chromosomes in their leukemia cells, rather than the normal number of 46 chromosomes. Together they accounted for about 25 percent of patients whose disease did not go into remission following induction therapy.

The children who benefited from additional chemotherapy also had no other markers of high risk, including high white blood cell counts or chromosomal rearrangements involving the MLL gene.

The study found transplants remain the best hope for many other young ALL patients who fail induction therapy. The patients included those whose cancer originated in white blood cells known as T cells. T cell ALL accounts for 12 to 15 percent of childhood ALL, but about 38 percent of patients in this study. The transplants involve killing the patient’s own diseased bone marrow and replacing it with blood-producing stem cells from a genetically matched donor. The procedure leaves patients at risk for a variety of immediate and chronic health problems.

Patients with a chromosomal rearrangement known as the Philadelphia chromosome were not included in the analysis because new drugs have led to a dramatic improvement in their outcome. About 13 percent of ALL induction treatment failures involved patients with the genetic alteration.

The other authors are Stephen Hunger, University of Colorado School of Medicine; Vaskar Saha, University of Manchester, U.K.; Paul Gaynon, Children’s Hospital Los Angeles; Andre Baruchel, Hospital Robert Debre, Paris; Valentino Conter, University of Milan-Bicocca, Italy; Jacques Otten, Brussels University Hospital, Belgium; Akira Ohara, Toho University, Tokyo; Anne Birgitta Versluys, University Medical Center Utrecht, the Netherlands; Gabriele Escherich, University Medical Center Eppendorf, Germany; Mats Heyman, Astrid Lindgren Children’s Hospital, Sweden; Lewis Silverman, Dana-Farber Cancer Institute, Boston; Keizo Horibe, Nagoya Medical Center, Japan; Georg Mann, St. Anna Children’s Hospital, Vienna; Bruce Camitta, Medical College of Wisconsin, Milwaukee; Jochen Harbott, Justus-Liebig-University, Giessen, Germany; Hansjorg Riehm and Martin Zimmermann, both of Medical School Hannover, Hannover, Germany; Sue Richards, University of Oxford, England; and Meenakshi Devidas, University of Florida, Gainesville.

In the U.S., the work was supported in part by National Cancer Institute grants to the Children’s Cancer Group, Pediatric Oncology Group and ALSAC.

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.

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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