Genetic and Proteomic Advances Pave the Way for Next-Generation Leukemia Therapies

SAN DIEGO, Dec. 10, 2011 /PRNewswire-USNewswire/ -- Despite major research advances over the last several decades that have helped deliver improved therapeutic options for leukemia, the condition remains deadly. Specialists are in need of new options to help diagnose the condition earlier and new therapies that will extend patients' lives. New research addressing important updates on the diagnosis and treatment of leukemia will be presented today at the 53rd Annual Meeting of the American Society of Hematology. 

"While recent discoveries during the past several decades have paved the way for a much better understanding of how the proteins affecting cancer cells can determine response or resistance to treatment, more progress needs to be made," said Martin S. Tallman, MD, moderator of the press conference and Chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center in New York. "The abstracts discussed today represent important steps toward targeting these proteins with effective therapies that will make a meaningful difference in the lives of leukemia patients."

This press conference will take place on Saturday, December 10, at 9:30 a.m. PST.

Fractionated Doses of Gemtuzumab Ozogamicin (GO) Combined to Standard Chemotherapy (CT) Improve Event-Free and Overall Survival in Newly-Diagnosed De Novo AML Patients Aged 50-70 Years Old: A Prospective Randomized Phase 3 Trial from the Acute Leukemia French Association (ALFA) [Abstract 6]

Results from a Phase III clinical trial of monoclonal antibody gemtuzumab ozogamicin (GO) find that the investigational therapy may be a promising option when used in relatively low, frequently repeated doses in conjunction with standard chemotherapy to treat older adults with acute myeloid leukemia (AML).

Chemotherapy has long been the standard of care for induction in patients with AML, an aggressive leukemia that can be fatal within weeks to months of diagnosis without proper treatment. However, with the recent development of targeted therapies, additional research has focused on improving patient outcomes while reducing toxicity associated with conventional chemotherapy regimens. Monoclonal antibodies, or MABs, attach to the cancer cell surface and, when conjugated to a toxin, release the toxin into the cell. MABs are a relatively new type of targeted therapy and are considered an enhancement to chemotherapy that allows treatment to target specific cells while reducing the toxicity to healthy cells. Because GO binds to CD33, an antigen present on AML cells, but not to normal hematopoietic stem cells, it has been the focus of recent research because of its ability to be directed specifically to AML cells.

To evaluate the efficacy of GO when used with chemotherapy in older AML patients, a team of researchers with the Acute Leukemia French Association designed a Phase III, prospective, open-label, randomized trial. Primary study endpoints focused on event-free survival (EFS); secondary endpoints included response rate, disease-free survival (DFS), overall survival (OS), and safety over a three-year follow-up period. Study participants (adults age 50-70 with previously untreated de novo, or first occurrence of, AML) were randomized into one of two treatment arms – either standard chemotherapy referred to as DA, (daunorubicin, ara-C, n=134) or chemotherapy with the addition of GO (DAGO, n=137). 

The study demonstrated that adding GO to a standard chemotherapy regimen significantly improved EFS and OS in older adult AML patients. At two years of follow-up, the rate of EFS was estimated at 15.6 percent in the DA arm compared with 41.4 percent in the DAGO arm. DFS was estimated at 18.1 percent in the DA arm versus 48.5 percent in the DAGO arm. The benefit in EFS was observed in all age groups and translated into a longer OS (19 months vs. 34 months on average in DA arm vs. DAGO arm).

The treatment protocol had some toxicity, as the rate of fatal adverse events possibly attributable to treatment was 6.7 percent in the DA group and 8.7 percent in the DAGO group. Prolonged grade 3 or greater thrombocytopenia was observed in 19 DAGO patients, and three episodes of veno-occlusive disease or sinusoidal obstructive syndrome (liver vein blockages) were observed in the DAGO arm, two noted as fatal.  There were no differences between the arms in the incidence of severe sepsis or in the rate of intensive care unit admission during the course of therapy.

"Research has demonstrated that GO has very potent anti-cancer properties, and with this study we have identified a dosing regimen that gives patients the therapeutic benefit without some of the toxicities previously reported at higher doses," said lead author Sylvie Castaigne, MD, Professor in the Department of Hematology at Hopital de Versailles in Versailles, France. "Specialists treating AML have not been offered a new therapeutic option for several decades, and with this research we are encouraged that GO may be able to deliver better overall outcomes for these AML patients with limited alternatives."

Dr. Castaigne will present this study during the Plenary Scientific Session on Sunday, December 11, at 3:45 p.m. PST at the San Diego Convention Center in Hall AB.

Novel Chromosomal Rearrangements and Sequence Mutations in High-Risk Ph-Like Acute Lymphoblastic Leukemia [Abstract 67]

A recent study focusing on a unique subtype of high-risk B-cell acute lymphocytic leukemia (ALL) has used advanced genome sequencing to identify new targets for the treatment of this deadly blood cancer.

ALL is the most common pediatric malignancy, representing almost one-third of all childhood cancers. In particular, relapsed B-cell ALL remains a leading cause of cancer death in young patients. There are multiple subtypes of ALL with different genetic abnormalities that influence disease outcome and response to therapy, but most current treatments affect all dividing cells, so new targeted therapies that might be effective against non-dividing cells may be required to improve the outcome of this disease.

With the introduction of novel genomic sequencing technologies, researchers can now identify genetic alterations including mutations, chromosomal rearrangements, and structural variations that drive the initiation and progression of leukemia and, importantly, may provide new targets for the development of novel therapies. Prior research had identified a new subtype of B-cell ALL with poor outcome and a gene expression profile similar to that of Philadelphia chromosome (Ph+) ALL (known as Ph-like ALL). Notably, Ph+ ALL is characterized by the expression of BCR-ABL1, which can be effectively treated with tyrosine kinase inhibitors such as imatinib.

To understand the genetic basis underlying Ph-like B-cell ALL, a cooperative research study composed of the Children's Oncology Group, St. Jude Children's Research Hospital, the National Institutes of Health, and British Columbia Genome Sciences Center analyzed the transcriptome (RNA sequence) of 11 Ph-like patients by next-generation sequencing. The team also conducted whole genome sequencing on two of the patients, a process that has become increasingly attractive to understand the full genetic profile of certain types of cancer patients.  

From detailed genetic analysis, new rearrangements, structural changes, and sequence mutations that activate tyrosine kinases and cytokine receptors were identified in 10 of the 11 cases studied. Importantly, these alterations were sensitive to kinase inhibition with existing treatments such as imatinib. The results suggest that the use of genomic sequencing can be used to identify the full spectrum of genetic alterations in ALL, enabling clinicians to identify high-risk patients who may be candidates for more aggressive, targeted treatment regimens.

"Our data support screening patients upon diagnosis to identify those who have specific high-risk ALL, which will help us understand the genetic changes driving this specific type of cancer and determine those patients who may benefit most from specific targeted treatments," said lead author Kathryn G. Roberts, PhD, Postdoctoral Fellow in the Department of Pathology at St. Jude in Memphis, Tenn. "We've been working toward the goal of tailoring therapy to individual patients for years, but with new technologies such as genome sequencing we're getting much closer to the reality of individualized treatments and an improved chance of survival."

Dr. Roberts will present this study in an oral presentation on Sunday, December 11, at 4:30 p.m. PST at the San Diego Convention Center in Room 28 ABCD.

B-Cell Depletion, Remissions of Malignancy, and Cytokine-Associated Toxicity in a Clinical Trial of T-Cells Genetically-Engineered to Express an Anti-CD19 Chimeric Antigen Receptor [Abstract 167]

According to new data, researchers have made important progress in the development of a promising new treatment approach for B-cell malignancies using genetically engineered T-cells.

B-cell malignancies, known to be aggressive and frequently resistant to standard therapeutic regimens, remain a challenge for clinicians and patients. One promising new approach to these cancers is the use of genetically engineered T-cells that express chimeric antigen receptors (CARs), proteins that help T-cells recognize and attack specific tumor-associated targets. Of particular interest is CD19, a common protein found on the surface of lymphoid cancer cells.

Seeking to determine if genetically engineered T-cells could recognize lymphoma and leukemia cells that express the surface protein CD19, a research team from the National Cancer Institute (NCI) and Sunybrook Odette Cancer Center in Toronto conducted a study using gene therapy methodology to induce patient-derived T-cells to express anti-CD19 CAR-encoding genes so that the T-cells could recognize and destroy the B-cell lymphomas and leukemias that express CD19.

A total of eight patients enrolled in the study were infused with autologous T-cells expressing the CAR, designed to specifically target CD19. Researchers treated four chronic lymphocytic leukemia (CLL) and four B-cell lymphoma patients with chemotherapy and then infused them with the genetically engineered T-cells followed by a high dose of IL-2 (interleukin-2, therapy which stimulates growth of T-cells). After this infusion, CAR-expressing T-cells were detected in the blood of all patients.

One CLL patient achieved complete remission that remained ongoing at 15 months after treatment; one CLL patient attained stable disease; and another five patients achieved partial remission. A marked depletion in CD19+ cells, suggesting that the T-cells successfully targeted and reduced the malignant cells, was found in four of the eight patients, an effect that remained at 15 months post treatment. However, patients experienced significant toxicity during the first 10 days after treatment, the most prominent of which was abnormally low blood pressure.

"While this gene technology is in the early stages of development and we need to improve the toxicity profile, our study validates that it has a potent ability to eliminate the specific cells being targeted, an important basis for future research," said lead author James N. Kochenderfer, MD, Assistant Clinical Investigator at the Experimental Transplantation and Immunology Branch at NCI in Bethesda, Md. "We believe that with these positive results we can explore a wide range of opportunities and potential applications for future clinical use."

Dr. Kochenderfer will present this study in an oral presentation on Sunday, December 11, at 5:30 p.m. PST at the Manchester Grand Hyatt in Elizabeth Ballroom DE.

American Society of Hematology 53rd Annual Meeting

The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on new treatment techniques for patients with bleeding and clotting disorders, improving recovery and outcomes in transplantation, emerging treatments for lymphoma and myeloma, and assessing therapeutic strategies for sickle cell disease. For the complete annual meeting program and abstracts, visit www.hematology.org/2011abstracts. Get up-to-date information about the annual meeting by following ASH on Twitter @ASH_hematology.

The American Society of Hematology (www.hematology.org) is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems by promoting research, clinical care, education, training, and advocacy in hematology. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online.

SOURCE American Society of Hematology



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