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Children with genetic disorders disease free following novel stem cell transplant

Bellicum Pharmaceuticals, Inc., a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, has announced the presentation of interim data from the lead site in the ongoing BP-004 Phase 1/2 clinical trial during the 57th Annual Meeting of the American Society of Hematology (ASH) in Orlando, Florida. Pediatric patients in the study with a variety of genetic diseases achieved disease-free outcomes following a haploidentical, T cell-depleted hematopoietic stem cell transplant (HSCT) followed by an add-back of BPX-501 donor T cells. The study is designed to evaluate whether this regimen is safe and improves immune reconstitution, infection control and overall outcomes.

Initial outcomes were reported from the 39 pediatric patients who have received the BPX-501 product (of a total of 49 enrolled) at the European trial site as of November 30. Twenty of these children had non-malignant genetic diseases including Fanconi anemia (5), beta thalassemia (4), severe combined immunodeficiency (SCID or "bubble boy" disease) (5), Wiskott-Aldrich Syndrome (3) and others. Nineteen additional patients had blood cancers, with acute lymphoblastic leukemia being the most common. (The cohort with blood cancers requires longer-term endpoints and will be reported on in more detail at a later date.)

"These interim results present strong evidence that the addition of BPX-501 modified donor T cells provides important immune support and improves outcomes in patients undergoing a T-depleted haploidentical stem cell transplant," said lead investigator Dr. Franco Locatelli, Director, Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù. "Historically, haplo-transplants had to be given without T cells to avoid Graft versus Host Disease, increasing the risk of deadly infections and delayed immune recovery, and relapse in patients with malignant disease. An approach that addresses these risks without elevating the GvHD risk could shift the standard of care, making haplo-sourced transplants - almost always available from a family member - an attractive option for patients. I am very happy for the patients and the families who have benefited from participation in this BPX-501 clinical trial."

The presented data show that treatment with BPX-501 is safe and well tolerated for patients with non-malignant and malignant diseases, and provides several important immune benefits compared to the clinical site's historical controls. Highlights include:

Safety: No adverse events associated with infusion of BPX-501 were reported. The occurrence and severity of GvHD in study subjects was generally consistent with the historical control group. There were seven instances of Grade 1 or 2 GvHD which all resolved without requiring activation of the CaspaCIDe® safety switch with rimiducid. Survival: There was no transplant-related mortality (TRM) in the 37 study patients with a minimum of 30 days follow-up. In particular, for non-malignant patients, this lack of TRM (0/18) compares favorably with 9% TRM in the historical non-malignant control patients (3/33). TRM, when it occurs, typically happens early in the post-transplant period in non-malignant transplant patients, primarily due to infection. Immune Reconstitution: Non-malignant patients in the trial achieved a mean improvement of approximately 40 fewer days to reach a T-cell count of 500 cells/ul, showing immune recovery was significantly faster than historical controls. Time in Hospital: Non-malignant patients in the trial were discharged significantly faster from the hospital, 21 days sooner on average following HSCT, compared to historical controls. The number of patients re-hospitalized was also substantially reduced.

"It's exciting to see the progress and outcomes from this BPX-501 study that we initiated just a year ago," said Annemarie Moseley, Ph.D., M.D. Chief Operating Officer and Executive Vice President of Clinical Development at Bellicum. "We are making preparations for dialogue with the regulators in Europe and the U.S. in the first half of 2016, with the goal of defining the path to regulatory approval initially for non-malignant pediatric diseases. We look forward to the further evaluation of BPX-501 in different transplant settings, and in accumulating longer-term data to assess relevant clinical outcomes in the malignant setting."

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Ibrutinib improves survival in untreated chronic leukemia better than chemo

Ibrutinib, a kinase inhibitor, is a significantly more effective frontline treatment for older patients with chronic lymphocytic leukemia or small lymphocytic lymphoma than traditional chemotherapy with chlorambucil.
white blood cells
CLL, a cancer of white blood cells, accounts for 0.9% of all new cancer cases among Americans.

This was the conclusion of the phase 3 RESONATE-2 study presented at the 2015 Annual Meeting of the American Society of Hematology (ASH) in Orlando, FL, on Monday.

The multi-center, international randomized study followed 269 patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The results showed the 24-month overall survival rate for patients taking ibrutinib was 97.8% versus 85.3% for those on chlorambucil.

The study, led by Jan Burger, an associate professor in leukemia at the University of Texas MD Anderson Cancer Center in Houston, is published in the New England Journal of Medicine.

Prof. Burger says the study shows ibrutinib was superior to chlorambucil in patients who had received no prior treatments, as "measured by progression-free survival, overall survival, and response," and it "also revealed significant improvements in hemoglobin and platelet levels."

Ibrutinib is marketed as Imbruvica by its developer, Pharmacyclics, who part-funded the trial. The drug is approved in the US for use in patients with previously treated mantle cell lymphoma and CLL, and also for the treatment of Waldenström's macroglobulinemia (WM), a rare form of cancer that begins in the body's immune system.

Ibrutinib blocks key enzyme of leukemia cell receptor

CLL and SLL are types of non-Hodgkin lymphoma. They both affect a type of white blood cell called B-lymphocytes (B-cells), causing them to grow out of control. The only difference between CLL and SLL is where the cancer starts, so they are often lumped together as CLL.

In CLL/SLL, cancer growth is driven by the B cell receptor (BCR), a molecule that sits on the surface of the leukemia cell and sends signals into the cell using enzymes, including Bruton's tyrosine kinase (BTK).

Ibrutinib works by attaching to and blocking BTK, shutting down its signals and eventually triggering death of the leukemia cell. The drug also disables tissue anchor signals on the leukemia cells, so they are no longer attached to their nurturing environment and starve.

According to National Cancer Institute estimates, there will be 14,620 new cases of CLL in the US in 2015, and 4,650 deaths to the disease. CLL represents 0.9% of all new cancer cases among Americans and 0.8% of all cancer deaths.

Risk of death was 84% lower with ibrutinib than chemo

For the trial, the 269 previously untreated older patients with CLL or SLL were randomly assigned to receive either ibrutinib or chlorambucil, both orally. The patients were aged 65 years or older, and 44% had advanced stage disease.

Over a median follow-up of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil. Also, note the authors:

"The relative risk of progression was 84% lower and the relative risk of death was also 84% lower with ibrutinib than with chlorambucil."

Of the patients receiving ibrutinib, 1 in 5 experienced side effects, including diarrhea, fatigue, cough and nausea.

"CLL is the most common adult leukemia in Western countries, and primarily affects older patients with a median age of 72 years at diagnosis," Prof. Burger explains, as he sums up the significance of the study:

"In many countries, chlorambucil has remained the standard first-line therapy for such patients since the 1960s. This study paves the way for the use of ibrutinib in the front-line therapy setting."

Earlier this year, Medical News Today learned how, following the discovery of a rare human antibody, researchers stumbled upon a way to make leukemia cells kill each other. Under lab conditions, they found 15% of cells were killed in 24 hours.

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Early gene therapy results in Wiskott-Aldrich syndrome promising

Four children treated in US trial show improvements, will continue to be monitored for long-term outcomes.

Researchers reported promising preliminary outcomes for the first four children enrolled in a U.S. gene therapy trial for Wiskott-Aldrich syndrome (WAS), a life-threatening genetic blood and immune disorder, at the 57th annual meeting of the American Society of Hematology (abstract #260).

All four boys are alive and have improved between nine and 24 months following treatment, according to study principal investigator Sung-Yun Pai, MD, a pediatric hematologist-oncologist from Dana-Farber/Boston Children's Cancer and Blood Disorders Center. Since undergoing treatment, none of the boys of have experienced bleeding events or severe WAS-related infections. In addition, all four have experienced improvements in immunologic symptoms and variable improvements in platelet count. The two patients who had required medication to stimulate platelet production prior to undergoing gene therapy are no longer on those medicines.

It is too early, however, to draw conclusions about long-term outcomes. The study protocol calls for the children to be monitored for 15 years in order to assess the treatment's safety and efficacy.

WAS is caused by mutations that lead to the loss or dysfunction of the WAS gene, which is found on the X chromosome. The condition, which occurs only in boys, affects the development and function of T-cells and platelets, leaving patients vulnerable to bleeding, eczema and infections. The only curative treatment is a hematopoietic (blood-forming) stem cell transplant from a compatible donor. However, it is often difficult to identify an appropriate match.

The trial centers on a viral vector, which is used to insert functional copies of the WAS gene into a patient's hematopoietic (blood-forming) stem and progenitor cells, which give rise to all cell types found in the blood and the immune system. These cells are collected from the patient, exposed to the vector in the laboratory and, once the vector inserts the gene and doctors have eradicated the patient's own blood system with chemotherapy, are returned to the patient via intravenous transfusion. The vector is a self-inactivating lentivirus -- a member of a family of viruses that can insert genes into mammalian cells and drive expression of those genes -- that has been engineered to avoid triggering the development of leukemia, a complication seen in previous gene therapy trials for immunodeficiency syndromes, including WAS.

The study's variable results to date raise questions about which factor is most important to the success of gene therapy for any given individual with WAS: the number of WAS gene copies the vector inserts into the patient's cells, the number of modified cells given to a patient, or how effectively the patient's native blood system is eliminated before the modified cells are infused.

"Putting the data that we have together, we get the sense that these factors all matter," said Pai, who presented the data on behalf of a team of investigators from the U.S., Turkey, Japan and Chile. "We suspect that infusing a few cells that each have two or three copies of the WAS gene may be better than infusing many cells with only one copy of the gene each. But with the very small number of patients we've treated to date, our data are only suggestive."

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Transfusion with red blood cells stored longer shows similar outcomes for treating condition caused by severe anemia

Among children in Uganda with lactic acidosis due to severe anemia, transfusion of longer-storage red blood cells, compared with shorter-storage, resulted in a similar reduction of elevated blood lactate levels, a measure of tissue oxygenation, according to a study published by JAMA. The study is being released to coincide with its presentation at the American Society of Hematology annual meeting.

During storage, red blood cells (RBCs) undergo changes that might impair the capacity for tissue oxygenation by transfused RBCs. Although millions of transfusions are given annually worldwide, the effect of RBC unit storage duration on oxygen delivery is uncertain. Walter H. Dzik, M.D., of Harvard Medical School and Massachusetts General Hospital, Boston, and colleagues randomly assigned 290 children (age 6-60 months) with elevated blood lactate levels due to severe anemia to receive RBC units stored 25 to 35 days (longer-storage group; n = 145) vs 1 to10 days (shorter-storage group; n = 145). The study included children who presented to a university-affiliated national referral hospital in Kampala, Uganda.

The researchers found that RBC units maintained under standard storage conditions for 25 to 35 days were not inferior to RBC units stored for up to 10 days as measured either by resolution of lactic acidosis at 8 hours or by secondary outcomes defined by improvement in clinical symptoms, normalization of vital signs, correction of laboratory abnormalities, and improvement in cerebral tissue (brain) oxygen saturation. Average lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours, and analysis indicated no statistical difference in lactate reduction between the 2 groups. Adverse events, survival, and 30-day recovery were also not significantly different between the groups.

"This study provides biological evidence that longer-storage RBCs correct lactic acidosis and increase cerebral tissue oxygenation as effectively as shorter-storage RBCs," the authors write.

"More complete data throughout the continuum from donation to transfusion are needed to improve outcomes for patients requiring transfusions," write Philip C. Spinella, M.D., F.C.C.M., of Washington University in St. Louis, and Jason Acker, M.B.A., Ph.D., of the University of Alberta, Edmonton, Canada, in an accompanying editorial.

"Blood collection centers and hospital blood banks need to collect and share information on donor characteristics and quality metrics from the RBCs donated. Hospitals should collect data on patients receiving transfusions, the indications for transfusion, the timing and dose of each blood product transfused, and the physiologic response to transfusion. Administrative data sets need to be linked to each of these data sets to allow cost-effective analyses to be performed. Only with better data can future studies determine which therapies or strategies are optimal to improve outcomes for patients requiring transfusions."

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Prenatal maternal iron intake shown to affect the neonatal brain

In the first study of its kind, researchers have shown that inadequate maternal iron intake during pregnancy exerts subtle effects on infant brain development. Their findings have been published online by the journal Pediatric Research.

The research--led by principal investigators Bradley S. Peterson, MD, director of the Institute for the Developing Mind at The Saban Research Institute of Children's Hospital Los Angeles and Catherine Monk, PhD, of Columbia University Medical Center-- indicates the potential significance for the child of even modest changes in maternal dietary health.

Dietary iron is required for normal growth and development, and for optimal brain growth in utero. But 35 to 58 percent of healthy women have some degree of iron deficiency, especially in pregnancy. Worldwide, nearly half of pregnant women are anemic, and this severe maternal iron deficiency can have adverse consequences for the developing fetus.

Past animal studies have shown that prenatal brain iron deficiency leads to impaired functioning of the hippocampus, adversely affecting learning and memory, and with delayed maturation of white matter in the brain. Consistent with these findings, it has been shown that newborns with a low iron profile lagged in general motor and neurocognitive development.

In this study, the researchers looked at the organization of newborn brain tissue using Diffusion Tensor Imaging (DTI), a magnetic resonance imaging (MRI) technique. The DTI images - taken at an average of 20 days after birth-- were used to associate maternal iron intake during pregnancy to differences in cortical gray matter and, to a lesser extent, in major axonal pathways within the underlying white matter of the brain.

The scientists found that maternal iron intake correlated inversely with fractional anisotropy (FA) - a unit of measurement in DTI that is a useful measurement of tissue organization in the brain--at locations scattered throughout the gray matter of the brain. This suggests that higher dietary iron intake is associated with greater complexity and therefore greater maturity of cortical gray matter and, conversely, that lower dietary iron is associated with lesser complexity and more immaturity of the developing gray matter shortly after birth.

"These findings are consistent with our expectations," said Peterson, who is also a professor of professor of pediatrics and psychiatry at Keck School of Medicine of the University of Southern California. "Neurons become increasingly more complex in their extensions and connections as the brain matures, and the maturational delays reported previously in animal models and human behavioral studies of iron deficiency would predict that lower iron intake would produce neurons in cortical gray matter that are structurally less complex and more immature. That is what our DTI findings suggest is the case.'"

These correlations were detected in the newborn infants of a sample of 40 healthy adolescent mothers who were adhering to prenatal care and across a range of iron intake. Despite their prenatal care, 14 percent still met clinical criteria for mild anemia, underscoring the health risks in adolescent mothers and their newborn children.

Peterson says that the technical nature of MRI brain assessments limited the number of adolescent women and their infants who could be studied, the findings bear further investigation. "Our imaging findings add brain-based assessments to the growing evidence that common inadequacies in maternal nutrition influence a child's development, even before birth."

Additional contributors to the study include Michael K. Georgieff, University of Minnesota Medical School; Dongrong Xu and Xuejun Hao, New York State Psychiatric Institute; Ravi Bansal, Children's Hospital Los Angeles and the University of Southern California; and Hanna Gustafsson and Julie Spicer, Columbia University Medical Center.

The research was supported by the National Institute of Mental Health grant # MH093677.

Newborn Brain Images
Newborn brain images show total maternal prenatal iron intake (purple) correlates with measures of local tissue organization (FA values).
Credit: Bradley Peterson, MD, Children's Hospital Los Angeles
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