AFFILIATIONS

Department of Pediatrics (Division of Pediatric Hematology and Oncology)

Experimental Therapeutics Cancer Center Program

High Risk Leukemia and Lymphoma Program, Primary Children’s Hospital (Medical Director)

Member, Hematologic Malignancies DOT

Data and Safety Monitoring Committee (Chair)

Medical Director, Research Compliance Office

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Research

I am a clinical researcher with a special interest in developing clinical trials with targeted agents in pediatric patients with high risk and relapsed leukemia and investigating predictors for common toxicities associated with ALL treatment. In addition to my involvement in clinical research within the COG ALL Disease Committee, I have been involved in projects assessing the risk for treatment-related bone toxicity and the development of clinical trials for relapsed/refractory ALL through projects funded by the Leukemia and Lymphoma Society (LLS).

Clinical Trials Development in Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood tumor, and while the cure rate for children has improved markedly over the past four to five decades, ALL remains a leading cause of death in children. Using high throughput genomic approaches, there have been recent discoveries regarding the underlying biological pathways that mediate transformation and relapse, and this has led to development of several new targeted therapies. Over the past 10 years I have served as the study chair for the following national cooperative group or consortium clinical trials:

  • “Classification of Acute Lymphoblastic Leukemia” (COG AALL03B1): Over 11,000 children with newly diagnosed ALL were uniformly classified based on clinic features, genetic blast features and early treatment response and their risk assignment was used for treatment allocation. Diagnostic marrow and germline samples were also banked as a part of this study.
  • “Intensive Induction Therapy for Children with Acute Lymphoblastic Leukemia who Experience a Bone Marrow Relapse” (COG AALL01P2): This trial piloted a three block re-induction regimen for children with relapsed ALL, with the goal of establishing a uniform platform for future combination studies with novel agents.
  • “A Feasibility Pilot and Phase 2 Study of Chemoimmunotherapy with Epratuzumab for Children with Relapsed CD22-Positive Acute Lymphoblastic Leukemia (ALL)” (COG ADVL04P2): This trial tested the combination of the anti-CD22 monoclonal antibody, epratuzumab, with the COG ALLL01P2 platform chemotherapy regimen in children with relapsed ALL.
  • “A Phase I Study Evaluating the Safety, Tolerability and Biological Activity of EZN-3042, a Survivin mRNA Antagonist, Administered with Re-induction Chemotherapy in Children with Relapsed Acute Lymphoblastic Leukemia (ALL)” T2009-007: In studies comparing paired diagnosis and relapse samples from children with ALL, the expression of the gene survivin was shown to rise dramatically at relapse. Survivin functions as an anti-apoptotic protein and plays a role in cell division. Based on these observations, we developed a clinical trial within the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium, using an anti-sense survivin oligonucleotide in combination with conventional chemotherapy for children with relapsed ALL.

Presently, I am involved in the development of a clinical trial, which will test CDK4/6 inhibition in children with relapsed/refractory ALL. Preclinical studies performed in Dr. Iannis Aifantis’s laboratory at NYU have demonstrated that Cycle D3 is essential for differentiation of lymphocyte progenitors. Based on these observations, targeting of the CDK4/6 complex was pursued preclinically. Subsequent studies demonstrated that treatment with a CDK4/6 inhibitor targets the G1-S phase transition machinery and leads to cell cycle arrest and further that treatment with the inhibitor blocks disease progression and induces apoptosis in T-ALL models of disease. Dr. Aifantis and I are co-investigators for a project testing pharmacologic inhibition of CDK4/6 in combination with chemotherapy in children with ALL and a clinical trial testing this strategy is in development. This project is currently funded through a LLS Specialized Center of Research Program (SCOR) grant (PI, William Carroll).

Biological Predictors of Osteonecrosis in Acute Lymphoblastic Leukemia

As noted, ALL is the most common childhood malignancy and also one of the most curable. Significant improvements in outcome have been achieved over recent decades, but this has come at the cost of unwanted side effects for many children and young adults. High cures rates have now afforded an opportunity to assess ways to lessen the burden of treatment-related side effects.

One of the most common and significant side effects of ALL therapy is osteonecrosis (ON), or bone death. ON results from a reduction in the blood supply to an area of bone; frequently in the regions of the hip and knee joints. ON often results in permanent long-term side effects, including joint pain, impairment in physical functioning and the need for orthopedic surgical intervention. This toxicity increases with age and occurs in a significant number (up to one quarter) of adolescents and young adults greater than 10 years of age receiving ALL therapy. This toxicity has been closely linked to steroid treatment, which is a highly effective element of ALL therapy. The potent steroid dexamethasone, despite its superior anti-leukemia properties, is more likely to cause this bone toxicity than the other commonly used steroid formulation in ALL, prednisone. There is also a suggestion that other drugs that are routinely used to treat ALL, including asparaginase and methotrexate, may increase the risk for development of this complication.

In collaboration with Dr. Mary Relling at St. Jude Children’s Research Hospital, we are seeking discover biological mechanisms and risk factors that predispose individuals to ON so that effective preventative strategies can be developed. Another goal of this project is to assess the role of other common chemotherapeutic agents by measuring individual drug levels and correlating them with the incidence of ON. The overall goal of these studies is to identify risk factors for ON early in therapy, so that modifications in treatment and enhanced surveillance to detect bone toxicity could potentially be instituted to avoid later complications. This work is currently supported by a Translational Research Award from the LLS.