Clinical trials that lay the groundwork for novel leukemia and lymphoma treatments will be among the highlights of the annual meeting of the American Society of Hematology (ASH) getting under way this week in Orlando. The trials, presented by researchers and physicians from City of Hope, could ultimately lead to innovative therapeutic approaches that improve survival and quality of life for patients with those and other diseases.
The ASH meeting, which will host more than 20,000 investigators working on blood diseases, including cancers, encourages clinicians and scientists working both ends of the bench-to-bedside translational research spectrum to discuss the latest results in marathon talks and poster sessions, often sharing the latest available research. This year, more than 2,000 presentations will address leukemia-related topics alone, and more than 130 will include City of Hope speakers or co-authors.
"Our researchers always anticipate the ASH meeting as a tremendous opportunity to share their successes and learn from those of colleagues," said Stephen J. Forman, M.D., director of City of Hope's Hematologic Malignancies and Stem Cell Transplantation Institute and the Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation. "Ultimately, patients around the world benefit from the important findings presented at ASH."
Among the research presented by City of Hope scientists will be results of three phase 1 clinical trials that lay the groundwork for novel leukemia or lymphoma treatments. Those studies address:
Safety of targeted radiation in acute leukemia. Led by City of Hope hematologist Anthony S. Stein, M.D., researchers evaluated safety of a radiation procedure called total marrow and lymphoid irradiation (TMLI) in patients who had relapsed or failed therapy for acute myeloid (AML) or acute lymphoblastic (ALL) leukemia. TMLI is a new technology that, compared to more uniform total body irradiation (TBI), allows highly targeted or "sculpted" delivery of cell-killing radiation to regions harboring tumor cells prior to bone marrow transplant. The theory is that radiation doses high enough to kill tumor cells could be directed at bone marrow, where disease burden is greatest, and away from organs less populated by cancer cells, minimizing side effects.
Stein will report that in a phase 1 trial of TMLI combined with two chemotherapy drugs, most of the 51 transplant patients undergoing the procedure tolerated the regime pre-transplant. Although the trial was designed to test how safely radiation doses can be escalated, many patients treated with the highest doses showed disease remission at the trial's end, supporting the idea that the procedure is effective. These findings have already informed the development of a phase 2 trial underway now to measure both safety and efficacy.
Novel antibody therapy against AML. Most AML tumor cells express a protein called CD33 on their surface. Previously, cancer researchers engineered a dual-purpose monoclonal antibody that first latches onto CD33 expressed on a tumor cell and then drags a potent cytotoxic drug (called SGN) tethered to it inside, killing the tumor cell. City of Hope's Stein will give a talk reporting the safety and appropriate dose of that drug conjugate, called SGN-CD33A, as determined in a phase 1 trial conducted in AML patients.
The overall results are encouraging. Adverse drug reactions, which were fully expected for a drug that kills bone marrow cells, were minimal and tolerated by most of the 87 patients tested. And although the trial's primary goal was to test drug safety, about a third of the patients who received high SGN-CD33A doses showed an anti-leukemic effect, as evidenced by clearance of immature leukemic cells called blasts from their bone marrow. Bolstered by these findings, doctors at City of Hope have already begun a new trial administering SGN-CD33A at the effective dose to patients newly diagnosed with CD33-positive AML.
Combining CAR-T immunotherapy with transplant for non-Hodgkin lymphoma. Many patients with recurrent non-Hodgkin lymphoma can be effectively treated by transplantation of blood stem cells, but they often relapse. A multi-institutional team co-led by City of Hope's Leslie Popplewell, M.D., and Xiuli Wang, Ph.D., has conducted phase 1 trials to assess whether standard cell transplant strategies could be supplemented with an immunotherapy procedure designed to rally an anti-tumor immune response in patients with diffuse large B cell or mantle cell lymphoma.
The team tested slightly different infusions of patients' own T cells genetically engineered to express receptor proteins called CAR constructs, which enhance T cell recognition of a tumor cell. Popplewell will report that both variations proved safe overall, and that most patients did not show signs of toxicity with increasing T cell doses. The study's authors conclude that immunotherapy treatment is safe in high-risk transplant patients and are currently modifying both the CAR construct and T cell populations in hopes of achieving a more long-lasting effect.
Also at the meeting, the 5th edition of the textbook Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation will be unveiled. Edited by Forman, along with Robert S. Negrin, M.D., of Stanford, Joseph H. Antin, M.D., of Dana Farber Cancer Institute in Boston, and Frederick R. Appelbaum, M.D., of the Fred Hutchinson Cancer Research Center in Seattle, this resource is considered the bible of the hematopoietic cell transplantation field. Its first editor and namesake, E. Donnall Thomas, won the 1990 Nobel Prize for Physiology or Medicine for work in cell and organ transplant to treat human diseases.