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Hematology and Oncology

Hematology/Oncology Fellowship Programs on a Growth Spurt

Left to right, Katie Metrock, M.D., Hilary Haines, M.D., and Kimberly Whelan, M.D. All are pediatric oncologists at Children’s of Alabama and faculty members in the Division of Pediatric Hematology/Oncology in the University of Alabama at Birmingham Department of Pediatrics.

Every year, two pediatric residents are accepted to Children’s of Alabama’s three-year, ACGME-accredited program. Their first year is a whirlwind of rotations through the inpatient, stem cell transplant, and outpatient clinics, said Kimberly F. Whelan, M.D., who completed the fellowship herself and now directs the program. “I think of it as being a very rewarding but steep learning curve year,” she said. In the second and third years, the fellows develop an area of research or scholarly focus that serves as the foundation for their first faculty position.

“We send our fellows out to institutions all across the country,” Dr. Whelan said. “And as that number has grown, it’s been wonderful to see the opportunities for networking and collaboration and the impact our fellows are having on the field — not only here in Birmingham, but across the country.”

The program typically gets about 40 applicants a year and interviews between 20 and 25. With COVID, of course, interviews have gone virtual, which has pros and cons, Dr. Whelan said. “The upside is it’s more convenient for the applicants since they don’t have to take as much time off to travel. And in the virtual interview you’re able to talk with them and get a good sense of what their interest is, where their passion lies, what they’re looking for in the program.”

The downside, however, “is that we don’t get to show off Birmingham and the beautiful Children’s of Alabama, which is such a wonderful institution.”

Recently, the Hematology/Oncology Program added two additional fellowships for hematology/oncology fellowship graduates who want additional training: one in bone marrow transplantation and one in neuro-oncology.

Bone Marrow Transplant Fellowship

While hematology/oncology fellows receive training in bone marrow transplant, the field has become very subspecialized, requiring specialized education, said Hilary Haines, M.D., who directs the bone marrow transplant fellowship. “The field as a whole is moving away from general hematology/oncology [and] into subspecialities, so the need to have dedicated training in these fields is definitely evolving,” she said.

That’s why the division created the one-year fellowship program focused entirely on bone marrow transplantation. It’s one that interests many hematology/oncology fellows, said Dr. Haines, given the complexity of the field. “You get to care for a variety of patients and be involved with cutting-edge technology and new therapies.”

Indeed, bone marrow transplants are not just for blood cancers. Today they are an option — even a cure — for other blood disorders like sickle cell anemia and severe combined immunodeficiency, bone marrow failure, and some neurological diseases. “We’ve identified more diseases that are curable via bone marrow transplant, and our outcomes have improved for the procedure, so we’re more willing to pursue transplant for diseases that we may not have in the past,” Dr. Haines said.

Several large children’s hospitals already offer bone marrow transplant fellowships, she said, so having the option at Children’s of Alabama serves as a good recruitment tool for hematology/oncology fellows who may eventually want to focus on bone marrow transplantation.

The first participant, who completed her hematology/oncology fellowship at Children’s, should finish her training in May.

Neuro-oncology Fellowship

Like Dr. Haines, Children’s neuro-oncologist Katie Metrock, M.D., points to the continued subspecialization in hematology/oncology as the reason for the new, one-year neuro-oncology fellowship she just launched. “The year is meant to submerge you into the field of neuro-oncology,” she said, which is vastly different from hematology/oncology overall. “Fellows get significant exposure to leukemia and lymphoma and other solid tumors during the general hematology/oncology fellowship, but not as much in-depth experience with neuro-oncology because the program operates slightly differently,” she said.

Since patients often require comprehensive care from multiple medical specialties, the extra year is designed to enhance a fellow’s knowledge of pediatric brain tumors, including diagnosis, biology, clinical course, treatment options, outcomes, and areas of research.

“In addition,” Dr. Metrock said, “the field is rapidly evolving as we learn more and more information about these tumors. This gives the fellow extra time to learn the details of the complex care required to help these children succeed.”

Brain tumors are the most common pediatric tumors and the one with the highest mortality rate. In brain tumors, the neuro-oncologist coordinates the team of specialists required to care for these children, including neurosurgeons, neuropathologists, radiation-oncologists, neurologists, ophthalmologists, and others. The fellow will start by watching the neurosurgeon operate, then follow the tissue sample in the pathology lab, learn to discuss a neuro-ophthalmology exam with the ophthalmologist, understand the dosage and design behind radiation-oncology plans, and meet with palliative care, among other rotations — a deep dive they don’t get during their hematology/oncology fellowship.

That experience is different from just meeting the patient and family after the surgery and diagnosis. “We feel we can better understand what’s going on with them — to the extent that’s possible — by following them from the beginning,” Dr. Metrock said.

“My favorite year in all my training was my neuro-oncology fellowship,” she said. “It was a year when I was able to do what I loved most and ask every question I wanted to ask. I’m excited to offer that to other people.”

The first neuro-oncology fellow starts in July 2022.

February 15, 2022 by childrensal

Children’s of Alabama Welcomes Pediatric Neuropsychologist Specializing in Neuro-Oncology

Emily A. H. Warren, Ph.D., is a pediatric neuropsychologist at Children’s of Alabama and an assistant professor in the Division of Pediatric Hematology/Oncology in the University of Alabama at Birmingham Department of Pediatrics.

With or without cancer, childhood is a very important time for brain development. Yet the experience of cancer itself, as well as the cognitive effects of many cancer treatments, can derail that development, leaving kids at risk for long-lasting social, psychological, and cognitive challenges.

“The great thing is that with the wonderful advancements in medical treatments and the comprehensive care these children receive, most will survive,” said Emily A.H. Warren, Ph.D., who came to Children’s of Alabama in the fall of 2021 as its first neuropsychologist dedicated specifically to caring for pediatric brain tumor patients. “Now there can be much more attention focused on quality of life, neurocognitive development, and long-term outcomes like educational attainment.”

Children’s diagnoses and treats more than 60 new central nervous system tumors a year. Dr. Warren uses her expertise in brain development and neuroanatomy to evaluate cognitive development in children with brain tumors. “My main goal is to provide families with a high-quality neuropsychological evaluation, so I can help them understand the potential impact of their child’s brain tumor diagnosis and treatments on cognitive and psychosocial outcomes and support their child in pursuing their goals,” she said.

Her work begins with a comprehensive neuropsychological assessment covering everything from intellectual functioning to learning, memory, attention, executive functioning, processing speed, visual motor skills, and psychosocial adjustment.

“With that data, I can help families understand how a diagnosis like a brain tumor and treatments like surgical resection, radiation, and chemotherapy can affect brain development and cognitive abilities,” she said. The goal of the assessment is to carefully evaluate a child’s cognitive strengths and weaknesses to promote the development of age-appropriate skills. Once she knows each child’s unique cognitive profile, Dr. Warren helps families identify ways to support their child. Supports could include developing an individualized education program (IEP) and other school-based or community interventions such as physical therapy, social skills training, or psychological therapies.

“These children are going through so many complex challenges,” she said. “There are the social and emotional aspects of the diagnosis and treatment, which can be very hard on families. We also need to support their school reintegration because some of these children have been out of school for a while.” Additionally, children may have new functional deficits. They might be in a wheelchair, have visual or hearing impairment, “or just feel that their thinking is slower than it used to be, or they are having trouble getting their words out,” Dr. Warren added.

“I like to spend a lot of time helping families understand the relationship between their child’s cognitive abilities and their academic achievements and social interactions. It is also important to help families understand the social and emotional impact of being a cancer survivor.”

Dr. Warren’s research focuses on cognitive and social outcomes following radiation therapies for brain tumor survivors. “With advances in radiation technology, such as proton radiation, children tend to have better neurocognitive and developmental outcomes than we saw in the past,” she said. “Even so, we still routinely see challenges with skills such as attention, executive functions, and processing speed. Children who receive more intensive therapies might be at greater risk for cognitive challenges. This is why it’s important to individually tailor each neuropsychological evaluation to meet the needs of each child.”

Dr. Warren hopes to collaborate with her colleagues in pediatric oncology and radiation oncology to continue this research and is currently a co-investigator for a clinical trial exploring whether memantine, a drug used in Alzheimer’s disease, is neuroprotective in children receiving brain radiation.

February 15, 2022 by childrensal

Hematology and Oncology, Inside Pediatrics

Bench-to-Bedside: Translational Focus Moves Sickle Cell Research into Clinic Faster

Jeffrey Lebensburger, D.O., is a pediatric hematologist at Children’s of Alabama and an associate professor in the Division of Hematology/Oncology in the Department of Pediatrics at the University of Alabama at Birmingham.

Basic research is conducted in labs and on animal models, and clinical research is conducted in humans. Traditionally, the two don’t mix, with the basic happening before the clinical. Translational research, a mix of the two, is designed to get new discoveries and treatments to patients faster. “Translational research is a vital component to making breakthroughs in clinical care,” said Jeffrey D. Lebensburger, D.O., who directs the pediatric hematology section of Children’s of Alabama’s Department of Hematology and Oncology.

Dr. Lebensburger and his research partner, University of Alabama at Birmingham assistant professor Malgorzata Kasztan, Ph.D., are using this approach to find better ways to prevent early kidney disease in children with sickle cell disease. Between 20 percent and 30 percent of children with the disease already demonstrate kidney injury before they hit their teens, and up to 70 percent will develop chronic kidney disease by the time they’re middle-aged. Many will require dialysis or transplantation, often beginning in their 20s. However, the most commonly used test for kidney problems rarely identifies early signs.

“While we may think that the kidneys are doing okay in childhood based on the tests, there may be severe damage that leads to this early dialysis, which is why we greatly need this bench-to-bedside approach to prevent progression early in adulthood,” Dr. Lebensburger said.

“We are particularly interested in looking at which patients are at risk for kidney disease and if there is a way to identify those patients early in the process, so they can get better care,” said Dr. Kasztan.

Tracking the progression from childhood through adulthood, however, would take too long and cost too much. Yet mice genetically engineered to have sickle cell disease fully mature in just a few months, making them a perfect model for exploring kidney disease progression.

Using these mice, coupled with a biobank of patient blood and urine samples and a sophisticated assay for kidney damage available only in the research setting, Drs. Lebensburger and Kasztan identified high levels of the protein endothelin-1 (ET), which binds to two receptors, ETA and ETB, as a key contributor to early kidney damage. Blocking the ETA receptors with an already-FDA-approved drug, however, protected the mouse kidneys.

“That allows us to bring back to the patient what we’re seeing in the mouse model and understand if it will continue into adulthood,” Dr. Kasztan said. “Then we could potentially intervene earlier.”

At the same time, biomarkers of early damage they find in the human blood and urine samples can be “mirrored” in the mouse model to confirm the results, she said. Then interventions that work in the animal model can be tested in patients.

This type of bidirectional work provides the foundation for clinical trials in humans, said Dr. Lebensburger. “That’s an example of this bench-to-bedside approach: It works in the mouse model of sickle cell, so we can lobby the FDA to start a clinical trial in humans.”

February 15, 2022 by childrensal

Hematology and Oncology, Inside Pediatrics

Bringing Groundbreaking Cancer Trials to Alabama Children

Left, Elizabeth Alva, M.D., and right, Katie Metrock, M.D.

Although there have been great strides in treating pediatric cancer, it remains the leading cause of death by disease among children. In addition, more than 95 percent of childhood cancer survivors have significant health-related issues because of the toxicity of current treatment options. Yet just 4 percent of government spending on cancer goes to pediatric cancer.¹

That’s why the Sunshine Project is so important. The project, part of the National Pediatric Cancer Foundation, brings together more than 20 children’s hospitals, including Children’s of Alabama, with the goal of streamlining the process required to bring new, less toxic, more effective pediatric oncology drugs to clinical practice.

Children’s joined the consortium in 2020 and is already participating in several novel studies for some of the worst pediatric cancers. The ultimate goal is to “provide hope to families,” said Children’s oncologist Elizabeth Alva, M.D.

One such trial is for patients newly diagnosed with metastatic fusion-positive rhabdomyosarcoma, which has a three-year, event-free survival rate of just 6 percent. “Traditionally, we inundate these patients with very intensive therapy,” said pediatric oncologist Katie Metrock, M.D., but outcomes are still dismal. Research has traditionally focused on intensifying that therapy, but sometimes that just leads to greater toxicity without improving outcomes, said Dr. Alva.

This uniquely designed study, called the EVOLUTION trial, is based on evolutionary theories around adaptation and resistance. Patients will be enrolled into one of four arms based on shared decision-making between the family and clinicians—not randomization. The first arm is standard of care. The second arm is “first strike therapy,” which Dr. Alva compares to a “meteor hitting the Earth and killing all the dinosaurs.” This approach addresses the hypothesis that children relapse because once the chemo-sensitive cells are gone, a more resistant population emerges. “So the first-strike theory is to get rid of everything,” she said.

A third arm focuses on maintenance, or a “second strike”: providing the standard of care until the patient is in remission and then switching to a less-intense maintenance therapy to keep those resistant cells at bay while restoring quality of life.

The fourth arm provides adaptive therapy. This means starting with standard chemotherapy that starts and stops based on response and adaptive timing of therapy, with a goal of increased time to progression rather than complete remission.

Children’s is also participating in a phase 2 study evaluating the use of digoxin, a decades-old drug typically used in patients with heart failure, for patients with recurrent/refractory medulloblastoma. The drug was identified as potentially beneficial in laboratory and animal studies.

“It is exciting to think that there are well-known drugs that can be repurposed to help treat various cancers,” said Dr. Metrock. “Our hope is that the tumors will show response to digoxin, and it could potentially be added to other up-front regimens in the future.” While the drug is well tolerated in children,” she said, “we haven’t used it in this heavily pretreated population, so we need to see how our patients do with it.”

Two other trials are exploring immunotherapy. One is testing the immunotherapy nivolumab in combination with azacitidine for children with recurrent, refractory osteosarcoma. The other is exploring a vaccine made from the patient’s own cancer cells designed to trigger the immune system to target the cancer for destruction in children with high-grade gliomas. Trials such as these are coordinated by the Clinical Trials Office at Children’s of Alabama, which was established in 2019 to increase access to new therapies for Alabama children, thanks to a lead gift from the Hugh Kaul Foundation.

Projects like the Sunshine Project are desperately needed, said Dr. Alva. “Unfortunately, pediatric cancer doesn’t get the same degree of funding as adult cancer. It’s rare, but when it strikes in a pediatric population, so many more years of life are lost.”

¹ National Pediatric Cancer Foundation. Facts about Childhood Cancer. Available at: https://nationalpcf.org/facts-about-childhood-cancer/.

August 27, 2021 by childrensal

Hematology and Oncology, Inside Pediatrics

Asthma, Sickle Cell Disease and Trauma – Connecting the Dots

BrandiPernell-Asthma-SickleCell_Research-Resized

Brandi M. Pernell, DNP, assistant professor of Pediatric Hematology and Oncology

Take a child with sickle cell disease who is already at a significantly higher risk for asthma, pain and acute chest syndrome—the leading cause of death in these children—and mix in adverse childhood experiences (ACEs) such as violence, racism, abuse, parental death or divorce. The result: sicker children who, due to toxic stress exposures, are more likely to experience poorer health outcomes.

That’s what Brandi M. Pernell, DNP, an assistant professor of pediatric hematology and oncology who works at the Children’s of Alabama dedicated pediatric sickle cell clinic, found in her research.

“The literature shows that those who experience ACEs early in life have a higher risk of chronic conditions like asthma, cardiovascular disease, and obesity”—even cancer, Dr. Pernell said. But until her work, there was limited documentation in the sickle cell literature about ACEs. What is known is that acute stress is a common trigger for pain episodes in children with sickle cell disease. Pernell is now connecting the dots to show that ACEs increase asthma risk in these children which, in turn, leads to an increased risk for pain and acute chest syndrome.

Her findings highlight the need to screen children with sickle cell disease, particularly adolescents, for ACEs and, if found, implement protective factors and buffering mechanisms to address the physiologic sequelae from these toxic exposures.

She’s already begun that process, teaming with the local chapter of the Sickle Cell Foundation to promote social and emotional competence and resilience among affected adolescents. That community-based approach is important, she said. “I believe we need to meet families and patients where they are,” she said. And the Foundation has a different relationship with patients and families than the clinic staff. “We address the medical side, but ACEs are things happening in the home and neighborhood,” said Dr. Pernell.

For Dr. Pernell, the work is more than a scientific endeavor; it’s personal. She felt called to this research, she said, both as a Black woman (sickle cell primarily affects Black people) and as a healthcare provider, particularly given the events of 2020. “In the wake of COVID and the social and racial uprising prior to and throughout 2020, it just spoke to me,” she said. So when she joined the University of Alabama at Birmingham faculty in 2016, this is where she focused her research. “I can relate to my patients in a way that some others can’t,” she said. “I’ve experienced some of the same things they have.”

“If not me, then who?” she asked, quoting the late congressman and civil rights leader John Lewis. “If not now, then when?”

August 27, 2021 by childrensal

Hematology and Oncology, Inside Pediatrics

Oncolytic Herpes Virus Immunotherapy Shows Early Promise in Pediatric Patients with High-Grade Glioma

Gregory Friedman, M.D., professor of pediatrics at the University of Alabama at Birmingham (UAB), director of developmental therapeutics for the Alabama Center for Childhood Cancer and Blood Disorders at UAB and Children’s of Alabama

It’s a pretty big deal when your research is published in the New England Journal of Medicine. But it’s just as rewarding when your research holds promise for treating one of the most deadly cancers seen in children: high-grade gliomas.

“Unfortunately, outcomes are very poor for children with progressive gliomas, and we have not seen a significant improvement in outcomes for this dreadful disease in the last 30 years,” said Gregory Friedman, M.D ., professor of pediatrics at the University of Alabama at Birmingham (UAB), director of developmental therapeutics for the Alabama Center for Childhood Cancer and Blood Disorders at UAB and Children’s of Alabama and lead author of the paper, “Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas.” Dr. Friedman also presented the findings from the phase 1 trial during the virtual American Association for Cancer Research Annual Meeting in April 2021.

“The toxicities associated with the current standard therapies are unacceptably high,” Dr. Friedman said. “There is, therefore, a great need for effective and less toxic targeted therapies for these children.”

Dr. Friedman’s team used a genetically engineered cold-sore virus, a herpes simplex virus type-1 (HSV-1), which naturally infects cells of the peripheral and central nervous system. While the modified virus, called “G207,” can’t infect and harm normal cells, it can target tumor cells by directly killing the cells and stimulating the child’s own immune system to attack the tumor.

Twelve patients between 7 and 18 years old with high-grade gliomas that had progressed on prior treatments received an infusion of G207 through intratumor catheters. Within 24 hours, some also received a single, small radiation dose directed to their tumors, which was designed to enhance virus replication and spread throughout the tumor.

Treatment response was assessed by imaging, tumor pathology and the patient’s performance status. Eleven of the 12 patients demonstrated a response, with a median overall survival of 12.2 months; a 120 percent increase over the typical overall survival of 5.6 months in this population. To date, 36 percent of patients have survived longer than 18 months, surpassing the median overall survival for newly diagnosed pediatric high-grade glioma.

To date, immunotherapies have failed to improve outcomes in pediatric brain tumors because the tumors are “cold,” with very few immune cells needed to attack the tumor, Dr. Friedman said. “Importantly, when examining matched pre- and post-treatment tissue from patients, we showed something that has not been seen before with any other therapy: that G207 dramatically increased immune cell trafficking to the tumors and turned the ‘cold’ tumors to ‘hot’ ones. This is a critical step in the development of an effective immunotherapy for children with brain tumors,” he said.

G207 alone or in combination with radiation therapy was well tolerated, with no dose-limiting toxicities, grade 3/4 treatment-related adverse events, or evidence of virus shedding into the bloodstream, saliva, or conjunctiva.

“While further investigation in a phase 2 clinical trial is needed, our findings suggest that oncolytic immunovirotherapy using a modified cold-sore virus is a safe and potentially efficacious approach to target pediatric high-grade glioma,” Dr. Friedman said.

August 27, 2021 by childrensal

Hematology and Oncology, Inside Pediatrics

ICOS Research Advances to Benefit Survivors, Improve Outcomes

By numbers alone, the Institute for Cancer Outcomes and Survivorship at the University of Alabama School of Medicine has posted an impressive list of accomplishments: Just six years after its founding, ICOS has received funding or commitments for $40 million, up $30 million since 2019. Additionally, faculty members have published approximately 500 journal papers, 167 of those in just the last year.

But the mission of ICOS far transcends those numbers. In their quest to study cancer outcomes long-term and identify issues survivors face, institute members – who include epidemiologists, physician-scientists, behavioral scientists, molecular biologists and nurse-scientists – have aggressively pursued research questions aiming to help survivors prevent and manage long-term complications from cancer and its treatment.

“Institute members are asking some terrific, clinically pertinent questions and going after them like a dog after a bone,” said ICOS Director Smita Bhatia, M.D., M.P.H., who’s also the Gay and Bew White Endowed Chair in Pediatric Oncology at the University of Alabama at Birmingham (UAB). “Really changing practice to improve clinical outcomes – that’s our goal.”

Over the past two years, notable ICOS studies have produced clinically useful results as well as spawned new and related research. Bhatia offered updates on several key efforts:

Examining the molecular basis of long-term complications in pediatric cancer survivors: Boosted by a sizable 7-year grant from the National Institutes of Health, ICOS researchers have “unearthed some very interesting genes associated with chemotherapy that cause heart failure,” Bhatia reported. “They’ve also developed a risk prediction model that allows us to say, ‘If you have this genetic makeup, we can predict whether you’ll develop heart failure or not.’”
Testing strategies to improve adherence to oral chemotherapy among adolescents with acute lymphoblastic leukemia (ALL): Physicians texted patients each night to remind them to take their chemotherapy, with a duplicate text sent to parents. Parents were instructed to watch their children take the medication. Families also watched educational videos on the topic. “Among adolescents at baseline who were non-adherers, they benefited most with this intervention,” Bhatia said. “Those findings were published and we’re now taking this to the next level in a 2,000-patient trial.”
Understanding how to treat older cancer patients without undue toxicity: Geriatric assessment surveys were given to older adults with colorectal cancer, multiple myeloma and other malignancies that are pinpointing how a patient’s total fat and muscle tissue may be linked to treatment toxicity levels. “This is like a gold mine in terms of giving us so many good findings we can apply in clinic,” Bhatia said.

February 26, 2021 by childrensal

Hematology and Oncology, Inside Pediatrics

Robust LLH Program Continues Expanding, Raising Profile

With an overarching goal of improving cure rates while decreasing treatment toxicity and side effects, the Leukemia, Lymphoma and Histiocytosis (LLH) program at Children’s of Alabama has nearly doubled in size over the past decade as faculty members continue raising its national and international profile and spearheading innovative clinical trials and research.

The LLH program includes five physicians and four nurse practitioners within the Division of Pediatric Hematology and Oncology, which includes more than 25 faculty. LLH clinicians consult on about half of the new cancer diagnoses seen each year at Children’s, said Director Matthew Kutny, M.D., also an associate professor of pediatric hematology and oncology at the University of Alabama at Birmingham (UAB).

LLH faculty members published 34 research articles in peer-reviewed journals over the last two years and presented more than 30 times at national oncology meetings. Additionally, several members sit on national steering committees or review boards that develop pediatric cancer treatment guidelines, Kutny said. The LLH program also participates in several key clinical trial consortiums, such as the National Cancer Institute’s Children’s Oncology Group, including selected membership in a network studying the newest oncology treatments in children.

“Our faculty has expanded, but we’ve also gained greatly in our expertise,” Kutny explained. “When children come here with a particular diagnosis, they’re not just treated by a general hematologist or oncologist, but rather, through our disease-specific teams.”

“We have providers who really understand that disease and are involved at a national level in developing the best treatments for that disease,” he added.

Kutny’s own research efforts include leading several national trials in myeloid leukemias as well as focusing on central nervous system disease in acute myeloid leukemia. Other notable faculty research efforts include:

Aman Wadhwa, M.D., M.S.P.H.: Working with Smita Bhatia, M.D., M.P.H., Wadhwa is examining how body composition affects childhood cancer outcomes in lymphomas, with an eye toward predicting and modifying toxicities.
Wayne Liang, M.D., M.S.: With a dual appointment in bioinformatics, Liang is harnessing the power of big data via electronic health records to better match patients to appropriate clinical trials, among other efforts.
Julie Wolfson, M.D., M.S.H.S.: Involved in many local and national projects, Wolfson is concentrating on outcomes disparities in adolescents and young adults with cancer, an at-risk group not often incorporated into clinical trials.
Ana Xavier, M.D.: Leading several national trials in difficult-to-treat lymphomas, Xavier is also focusing on reducing the burden of chemotherapy and radiation exposure in lymphoma patients.

February 26, 2021 by childrensal

Hematology and Oncology, Inside Pediatrics

Membership in Elite Consortium Offers Many Benefits to Researchers, Patients

MEMBERSHIP IN ELITE CONSORTIUM OFFERS MANY BENEFITS TO RESEARCHERS, PATIENTS

Children’s of Alabama has become the only institution in the state – and among an elite group nationally and internationally – to be accepted into a unique clinical trials consortium focusing on personalized therapy approaches for children with malignant brain tumors.

Accepted into the Pacific Pediatric Neuro-Oncology Consortium (PNOC) in December 2020, Children’s membership in this distinguished group offers many advantages to researchers, clinicians, and ultimately to young patients, said Girish Dhall, M.D., director of the Division of Pediatric Hematology, Oncology, and Blood & Marrow Transplantation.

The consortium is comprised of about two dozen sites across the United States, Canada, Europe and Australia. Unlike other consortia, PNOC’s clinical trial portfolio includes neurosurgery trials with techniques such as convection-enhanced delivery, fluorescent agents and advanced imaging compounds.

“The only way to get access to certain cutting-edge or state-of-the-art clinical trials is to be invited by a drug company working on a multi-institution trial or in trials run by these consortia,” Dhall explained. “This means we have access to a multitude of open trials and our patients don’t have to go out of state to be enrolled in trials testing promising experimental drugs that are not yet FDA-approved.”

In addition to prestigious trial access, PNOC enables basic and translational scientists at Children’s and University of Alabama at Birmingham (UAB) to propose new trials of candidate drugs or therapies and fosters collaboration among them and researchers at other institutions, said Dhall, who was a founding member of PNOC about eight years ago when based in Los Angeles.

PNOC is unusual because of its focus on personalized therapies for children with brain tumors that aims to improve survival while reducing toxic, treatment-related side effects, he noted.

“Traditionally we use chemotherapy or radiation therapy for these cancers, but both just kill rapidly dividing cells and don’t discriminate between cells inside the cancer and cells that might normally be rapidly dividing inside the body,” he said. “The focus has shifted to understanding specifically what makes these cancer cells grow and divide by studying the DNA, RNA and protein inside the cancer cells to develop therapies that improve the efficacy but reduce toxicity to normal cells at the same time.”

Of PNOC’s current open clinical trials, Children’s will launch its participation in two: One in children with a uniformly fatal tumor called diffuse intrinsic pontine glioma, or DIPG; and another that combines two drugs for children with refractory or recurrent low-grade gliomas, “a population in which this is like a chronic disease and they progress from one therapy to another, so it’s important for them to have multiple options,” Dhall said.

February 25, 2021 by childrensal

Hematology and Oncology, Inside Pediatrics, Neurology & Neurosurgery

Children’s of Alabama Launches Second Groundbreaking Trial of Viral Treatment for Brain Tumors

Children’s of Alabama and the University of Alabama at Birmingham are leading studies using a genetically re-engineered herpes virus to treat pediatric high-grade gliomas.

“A uniformly dismal prognosis.” That’s how Children’s of Alabama neurosurgeon James M. Johnston, Jr., M.D., describes what children with recurrent malignant brain tumors face, with an average lifespan of six months given a lack of effective treatments.

Now Johnston, in collaboration with Greg Friedman, M.D., associate professor of pediatric oncology and director of Developmental Therapeutics at Children’s, is leading groundbreaking studies designed to shift that trajectory. The team recently completed a Phase 1 immunotherapy clinical trial of genetically re-engineered herpes virus G207 to treat pediatric high-grade gliomas. Their work builds on adult research on the viral treatment pioneered by James Markert, M.D., MPH, who chairs the Department of Neurosurgery at the University of Alabama at Birmingham (UAB), as well as Friedman’s laboratory work, which showed the virus was more effective against pediatric brain tumors than adult tumors.

In the past three years, 11 patients with high-grade gliomas have traveled to Children’s from throughout the country, Mexico and Canada to participate in the study. They receive special screening to pinpoint the tumor location, which is then biopsied. Johnston then places three to four catheters in the tumor. The next day, Friedman and his team infuse the genetically-modified virus into the brain through the catheters.

“We think the virus works by directly killing the tumor cells,” Johnston said, as well as activating the immune system to destroy any remaining cells. “Brain tumors have a way to hide from the immune system by making themselves immunologically ‘cold,’” he explained. The herpes virus turns a “cold” tumor into a “hot” tumor and generates the immune response. Indeed, months after the surgery tests show that immune cells have infiltrated the tumor and continue killing tumor cells.

The initial phase 1 trial in patients with high-grade gliomas was designed to demonstrate safety and wasn’t powered to show efficacy. Nonetheless, Johnston said, “our median survival was significantly longer than the historical six months,” with several children now long-term responders.

In late December 2019, the team received a three-year, $750,000 R01 grant from the U.S. Food and Drug Administration for a Phase 1 trial in malignant cerebellar brain tumors, which may be even more sensitive to the virotherapy than the gliomas. At the same time, they are submitting grants for a Phase 2 multicenter trial of the virus therapy for recurrent malignant supratentorial tumors.

Johnston stresses that the research is a team effort, involving basic scientists, oncologists, surgeons, nurses and intensivists. “It’s an ‘all-hands-on-deck’ kind of thing,” he said.

October 26, 2020 by childrensal

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