World-renowned thought leaders discussed important clinical advances and new guidelines in the diagnosis and treatment of hematologic malignancies, at the first annual National Comprehensive Cancer Network (NCCN) Hematologic Malignancies Congress.
NEW YORKWorld-renowned thought leaders discussed important clinical advances and new guidelines in the diagnosis and treatment of hematologic malignancies, at the first annual National Comprehensive Cancer Network (NCCN) Hematologic Malignancies Congress. Highlights were presented in a media briefing.
Key changes, which have been included in updated NCCN Clinical Practice Guidelines in Oncology, include incorporation of recently FDA-approved dasatinib (Sprycel) into treatment of chronic myelogenous leukemia (CML), of lenalidomide (Revlimid) into treatment of multiple myeloma and myelo-dysplastic syndromes (MDS), and of 5-azacitidine (Vidaza) or decitabine (Dacogen) into treatment of MDS.
Hematologic cancer is not uncommon, NCCN noted in a news release, with more than 100,000 new cases diagnosed in the United States in 2006 alone. Indeed, commented media briefing moderator Christopher E. Desch, MD, national medical director of NCCN, "In addition to my position with NCCN, I care for patients in rural Virginia, and many of them have chronic leukemias, myeloma, or MDS."
Panelists at the briefing included Steven D. Gore, MD, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Paul G. Richardson, MD, of Dana-Farber Cancer Institute; and Stephen D. Nimer, MD, of Memorial Sloan-Kettering Cancer Center, all of whom have worked on developing NCCN guidelines for hematologic cancers.
"Now that we've started recognizing that many people with chronic anemia actually have chronic leukemia, it is thought that MDS may represent the most common hematologic malignancy," with some patients developing MDS secondarily as a result of effective chemotherapy for more common cancers such as breast cancer, lymphoma, or multiple myeloma, Dr. Gore commented.
Critical advances in MDS began in 1993, he said, when a team of oncologists led by Peter L. Greenberg, MD, of Stanford University, developed a prognostic scoring system for stratifying risk levels in MDS, which improved clinicians' ability to evaluate the benefit of various treatment regimens. In 2000, Bruce Cheson, MD, then with the Cancer Therapy Evaluation Program (CTEP) at NCI, spearheaded development of uniform clinical response criteria in MDS, he added.
These key changes, combined with technological advances such as polymerase chain reaction (PCR) and research into bone marrow physiology in MDS, fueled significant advances in the quality and validity of clinical research in MDS, Dr. Gore said.
While stem cell transplant remains the only curative treatment for MDS, there are now three new effective therapies that are FDA-approved for MDS-5-azacitidine, decitabine, and lenalidomide, he noted, "and two of these drugs prolong the duration of stable disease and may improve survival, although we don't know that for sure."
Notably, these newly approved drugs "are not conventional chemotherapy drugs," he added. "Two of the drugs, 5-azacitidine and decitabine, are members of a totally new class of drugs [hypomethylating agents] that we think work by impacting gene expression. . . . They are much lower dosed, less toxic, and chronically administered, compared with the traditional treatments for leukemia."
Lenalidomide is well tolerated and particularly effective in MDS patients with chromosome 5q deletions, Drs. Gore and Nimer noted, and lenalidomide might be considered a targeted agent in this population, Dr. Nimer added.
Important to accelerating testing of new treatments for MDS, commented Dr. Nimer, is that, as of 2004, there are now three mouse models of MDS, "each of which mimics some aspect of MDS."
NCCN guidelines on MDS, he added, evolve continuously: In versions 1 and 2 of the MDS guidelines, "there was not much for physicians to do but put patients on a clinical trial; there was no standard treatment. But since December 2004, we've met repeatedly to revise the guidelines, because now there are actually drugs that work, and more knowledge is being gained all the time."
Integrating New Myeloma Agents
As with MDS, there are now multiple treatment options in multiple myeloma, noted Dr. Richardson, with bortezomib (Velcade), lenalidomide, and thalidomide (Thalomid) considered potentially new "backbones" of therapy. The question for clinicians is how to integrate "a veritable soup" of treatments into induction/first-line therapy; transplant/maintenance therapy to control the disease; and single-agent or combination therapy for patients with relapsed/refractory disease, "which is the hallmark of myeloma," he added.
With better understanding of the biology of myeloma and other hematologic cancers in the last few years, he said, there has been a new focus on treatment strategies that target the bone marrow microenvironment, which "is absolutely vital to tumor growth, resistance, and survival, and these strategies have yielded tremendous rewards in terms of therapeutic benefit to patients."
There is a growing trend toward tailored, risk-adapted treatments for myeloma, Dr. Richardson said, with some patients stratified to watch-and-wait groups, some identified as candidates for clinical trials of specific agents, and some with symptomatic myeloma assessed as potential candidates for transplant, which is not curative in myeloma. Gene-expression profiling and proteomics have the promise of being used to assist in tailoring therapy or stratifying patients according to risk, he said. Currently, risk stratification is based on cytogenetics (eg, deletions of chromosomes 13 and 17) and clinical features such as high beta-2 microglobulin levels.
Noting that "it is a very exciting time for us to be hematologists," Dr. Nimer commented that gene amplification made possible by the advent of PCR has driven advances in treating hematologic cancers, by enabling identification of specific types of molecular abnormalities that can occur in certain patient subsets, allowing clinicians to then match appropriate treatments and patients.
For example, he said, "in the acute leukemias, trying to distinguish between acute myelogenous leukemia [AML] and acute lymphocytic leukemia [ALL] used to be done morphologically and visually. This would never be [used as a basis for treatment] today."
He noted that for one type of AML, acute promyelocytic leukemia, there is not only a specific clinical syndrome identified but also a specific molecular abnormality detected by PCR. At Memorial Sloan-Kettering, patients with this abnormality receive a different treatment regimen than other AML patients, and the cure rate for this subpopulation is about 85% in adults vs about 20% in AML patients without the abnormality.
"The new paradigm is not thinking about cancers based upon where they occur in the body, but in terms of what drives themwhat is the fuel that feeds a particular cancer," he emphasized.