Center for Lymphoma Announces the Formation of Adolescent and Young Adult Lymphoma Program

Lisa Roth, MD
Lisa Roth, MD

Recently the Center for Lymphoma announced the formation of the Adolescent and Young Adult (AYA) Lymphoma Program at Weill Cornell Medical College. The program is a collaborative effort between the Departments of Medicine and Pediatrics, and will be lead by Dr. Lisa Roth, a pediatric oncologist and new member of the Lymphoma Center.

Lymphoma is the most common malignancy in adolescents and young adults age 18-30y. While there has been remarkable progress in the treatment of children and older adults, improvements among adolescents and young adults have lagged behind. The reasons for this discrepancy are multifactorial, but include low enrollment in clinical trials, poor access to healthcare services, and a deficit in clinical and translational research in this area. The AYA Lymphoma Program seeks to advance the treatment of lymphoma in the AYA age group through the following missions:

1) Optimize medical care for AYA patients with lymphoma.

2) Provide psycho-social support tailored to AYA patients.

3) Lead clinical and translational studies aimed at improving outcomes in this age group.

Weill Cornell Medical College is in a unique position to treat AYA patients with lymphoma given the strengths of the Center for Lymphoma and the Division of Pediatric Oncology. Dr. Roth has been a Weill Cornell faculty member since joining the Department of Pediatrics in 2012. She is the Charles, Lillian, and Betty Neuwirth Clinical Scholar in Pediatric Hematology/Oncology and has been awarded fellowships from the Lymphoma Research Foundation and the Empire Clinical Research Investigator Program. Dr. Roth will work closely with a team of doctors, physician assistants, social workers, and researchers all with the common goal of improving outcomes for adolescents and young adults with lymphoma.

Ibrutinib and the Improvement in CLL Patient Care

Furman Face By Dr. Richard Furman MD

Ibrutinib is a first in line of new treatments, known as tyrosine kinase inhibitors that display promise in promoting improved response rates in refractory CLL patients. Unlike chemotherapy which cannot differentiate between healthy and cancerous cells, ibrutinib specifically inhibits the Bruton’s tyrosine kinase (BTK) enzyme in the body’s cancerous B-cells. By inhibiting the enzyme, ibrutinib deprives B-cells of their activating chemical signal. This enzyme is expressed only in B-cells, allowing ibrutinib to exclusively target B-cells, affording a tremendous amount of specificity. This specificity allows for an excellent tolerability of ibrutinib in CLL patients, thus increasing quality of life.

This is significant for CLL patients as chemotherapy treatment often comes with disadvantages. A patient achieving a complete recovery will experience marrow toxicity, and be at risk of developing secondary acute myeloid leukemia and/or myelodysplastic syndrome. Even common CLL regimens like FCR (fludarabine + cyclophosphamide + rituximab), expose patients to major risks.

These initial disadvantages are exacerbated by patient relapse and further chemotherapy. For example a patient, who at diagnosis exhibits a very good response to their first line of chemotherapy treatment and another positive response in their second line of chemotherapy, would ultimately be given a 7-9 year median survival rate from their initial chemotherapy. Unfortunately, survival past that 9 year rate is unlikely, as increased chemotherapy leads to a corresponding decrease in longevity. Any increase in longevity beyond that 9 year mark would require treatment besides standard chemotherapy agents. Accordingly, length of survival is the long term promise and improvement held by tyrosine kinase inhibitors like ibrutinib. The side effects associated with chemotherapy regimens are non-existent for ibrutinib.

Due to the nature of currently available chemotherapy treatment, successful benchmarks are increasingly focused on complete response and partial response rates with chemotherapy, and not on overall survival. Chemotherapy focuses on the complete response, partial response, and minimal residual disease status of patients. Conversely, ibrutinib and other similar treatments display significant improvements towards progression free survival and overall survival, even when accounting for patients who develop resistance and require additional therapy.

Increasingly, the avoidance of chemotherapy is the most important aspect of CLL therapy. My hope is to begin using tyrosine kinase inhibitors like ibrutinib earlier in treatment, and avoid chemotherapy. This would lead to vast improvements in patient quality of life and the important metrics of long term survival.

Novel Therapeutic Strategies for Targeting the Lymphoma Microenvironment

Ruan Face By Jia Ruan, MD, PhD

Although conventional chemotherapy is primarily aimed at tumor cells, we now know of the importance of neighborhood cells, included within the tumor mass. These include endothelial cells and pericytes that form blood vessels, macrophages that mediate inflammation, and fibroblasts and extracellular matrix proteins that build matrix and scar tissues. The interaction between the tumor cells and their neighborhood is collectively known as the tumor microenvironment. Given the importance of the tumor microenvironment in maintaining tumor growth and developing resistance to conventional chemotherapy, novel strategies that target the microenvironment are under active investigation. Clinical researchers led by, Dr. Jia Ruan, have recently published 2 important studies on developing novel therapeutic strategies that target lymphoma angiogenesis (blood vessel formation) and lymphangiogenesis (lymphatic vessel formation) within the tumor microenvironment.

The first study was published in the leading hematology journal Blood in collaboration with Dr. Leandro Cerchietti, a lymphoma biologist, and Dr. Katherine Hajjar, a vascular biology expert, both at Weill Cornell Medical College. The study found that pericytes, the vascular accessory cells surrounding the endothelial cells, are important players in lymphoma tumor angiogenesis, and represent potentially novel therapeutic targets for anti-lymphoma therapy. Specifically, the Weill Cornell lymphoma researchers treated human diffuse large B-cell lymphoma (DLBCL) growing in mouse models with an oral drug called imatinib. This incapacitated a critical cell surface receptor within the pericytes, namely platelet-derived growth factor receptor β (PDGFRβ), which is important for the survival of the pericytes and its communication with the endothelial cells. As a result, lymphoma-associated microvascular blood vessel formation was reduced due to programmed-cell death of both pericytes and endothelial cells. This ultimately translated into therapeutic effect of lymphoma growth impairment. This study provided proof of principal that targeting non-tumor vascular cells within the lymphoma microenvironment can result in significant inhibition of lymphoma growth, providing the basis for more refined consideration of anti-angiogenesis as a treatment strategy for lymphoma patients.

The second study published in Cancer Research, in collaboration with Dr. Lijun Xia, a glycoprotein and vascular biology expert at the Oklahoma Research Foundation. The researchers found that 1) lymphatic vessels, which form the vascular network known as lymphangiogenesis, contributed to the growth and spreading of lymphomas in an experimental model of mantle cell lymphoma (MCL), and 2) treatment with the immunomodulatory drug lenalidomide potently inhibited the growth and spreading of MCL by disabling tumor lymphangiogenesis. Mechanistically the researchers demonstrated that treatment with lenalidomide reduced the number of MCL-associated macrophages and their production of a growth factor important for the formation of lymphatic vessels, namely vascular endothelial growth factor-C (VEGF-C). This is the first study to address the potential importance of lymphangiogenesis in lymphoma growth, and provided a novel perspective of the mechanisms of action of lenalidomide in lymphoma therapy. This pre-clinical study synergizes with our recent clinical data displaying high response rates and durable remissions with the biologic combination of lenalidomide + rituximab in patients with previously untreated MCL.

Both studies open potentially new novel paths to treating lymphoma, exemplifying the Lymphoma Program’s commitment to the bench-to-bedside translational research that brings cutting-edge science to patient care.

References

1. Blood. 2013 Jun 27:121(26):5192-202. Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes.

2. Cancer Res. 2013 Dec 15:73(24):7254-64. Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma.