NCCN Meeting Addresses Issues in Hematologic Malignancies

The National Comprehensive Cancer Network (NCCN) 6th Annual Congress on Hematologic Malignancies, held recently in New York, included reviews of the management of hematologic diseases as well as discussions of outstanding issues in the field. The following is a synopsis of some of the important highlights from the meeting.

Follicular Lymphoma

• Delays in initiating upfront therapy and maintenance therapy are advised in asymptomatic patients with follicular lymphoma, said Andrew D. Zelenetz, MD, of Memorial Sloan-Kettering Cancer Center, New York, and Chair of the meeting.
• Asymptomatic patients with low disease burden have a similar quality of life to that of patients in remission.
• Routine treatment of every newly diagnosed patient is ill-advised. Patients with signs and symptoms, including those with a tumor burden greater than 3 cm and compromised end-organ function, should be treated.
• The decision to initiate therapy in an asymptomatic patient should be guided by patient preference. Some patients want treatment for a disease they know they have, whereas others prefer to wait until they become symptomatic before starting treatment.
• Disease proliferation, assessed by image analysis of MIB-1/Li-67 staining, holds promise as a marker for deciding when to initiate therapy.

Chronic Lymphocytic Leukemia

• Fluorescence in situ hybridization (FISH) testing for 13q, 11q, and 17p deletions can guide therapy selection for patients with chronic lymphocytic leukemia, said Susan M. O’Brien, MD, of The University of Texas MD Anderson Cancer Center, Houston.
• Deletion of the long arm of chromosome 13 (del 13q) is a marker of good prognosis, and standard NCCN guidelines should be followed for these patients.
• The 11q deletion is associated with extensive lymph node involvement, disease progression, and shortened survival. Most patients will experience disease progression within 2 years. Treatment with an alkylating agent is recommended, and FCR (fludarabine, cyclophosphamide, rituximab) is the preferred regimen. FCR is the only regimen to show an improvement in overall survival.
• The 17p deletion signals the worst prognosis of these three cytogenetic abnormalities. Currently available therapies are much less effective in this group. Alemtuzumab (Campath) is an option for nonbulky disease. Patients with 17p deletions should be enrolled in a clinical trial.
• Older patients with good performance status can be treated with reduced-dose FCR or enrolled in a clinical trial. Those with poor performance status should receive palliative care.
• Two novel inhibitors of B-cell signaling (PCI-32765 and CAL-101) are in early stages of development and, thus far, have shown promising results. Both agents appear to be effective in patients with poor-prognosis cytogenetics. Dr. O’Brien estimated that if studies continue to be positive, these drugs will be on the market within 5 years.

Acute Myeloid Leukemia

• In addition to conventional prognostic markers such as age, performance status, and cytogenetics for acute myeloid leukemia, testing for three mutations is being used to predict prognosis and risk of relapse, said Jerald Radich, MD, of Fred Hutchinson Cancer Research Center, Seattle.
• Mutations in FLT3 and NPM1 have been shown in several studies to be associated with survival and relapse risk. Internal tandem mutations in FLT3 (FLT3-ITD) are associated with a poorer outcome compared to patients with wild-type FLT3. In addition, measuring the proportion of mutant gene to wild type (the allelic ratio) strengthens the prognostic power.
• Conversely, mutations of the NPM1 gene have an improved survival compared to wild-type NPM1. Thus, the best prognosis is in the group with NPM1 mutation and FLT3 wild type; the worst in NPM1 wild type with an FLT3-ITD mutation.
• Likewise, there is increasing evidence that mutations in the CEPBA gene are associated with an improved outcome.
• The detection of minimal residual disease, usually by flow cytometry, is highly associated with subsequent relapse.
• The field is moving toward developing better markers to guide therapy selection in patients with disease progression and to select therapy at diagnosis.

Multiple Myeloma Treatment

• “Novel agents have revolutionized the treatment of multiple myeloma and improved survival,” said Kenneth Anderson, MD, of Dana-Farber Cancer Institute, Boston.
• Combinations of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone, as well as other novel agents, are being studied to improve outcomes further.
• “We are learning how to give bortezomib,” Dr. Anderson said. Bortezomib should be given once weekly (not twice weekly), and subcutaneous administration is superior to intravenous delivery in reducing the incidence of peripheral neuropathy.
• Newer promising drugs in phase III testing for multiple myeloma include elotuzumab, pomalidomide, and carfilzomib.
• Oncogenomic studies are being used to identify novel mutations and potential therapeutic targets at diagnosis and again when mutations change during relapse.

Multiple Myeloma and Maintenance Therapy

• Maintenance therapy with thalidomide (Thalomid), lenalidomide, and bortezomib is of value in multiple myeloma, including those who are elderly and those who have undergone autologous stem cell transplant, said Steven Devine, MD, of Ohio State University Comprehensive Cancer Center in Columbus.
• Thalidomide improves progression-free survival and overall survival as maintenance therapy after autologous stem cell transplant, but can be associated with unacceptable toxicity, whereas lenalidomide is also effective and has less toxicity. Data are less mature for bortezomib as maintenance therapy, but thus far, the drug appears to achieve good responses in patients with poor-risk cytogenetics.
• The possibility that the risk of secondary malignancies are increased with lenalidomide maintenance has been raised, but this issue is unresolved. Patients on lenalidomide maintenance should be monitored closely.

Multiple Myeloma and Bone Disease

• Bone disease, which occurs in 84% of multiple myeloma patients, should not be taken lightly, stated Asher Chanan-Khan, MD, who recently moved to the Mayo Clinic in Jacksonville, Florida.
• Dr. Chanan-Khan prefers kyphoplasty to vertebroplasty as surgical intervention for vertebral fractures. Kyphoplasty is able to restore up to 54% of vertebral height and improves quality of life compared with vertebroplasty, he said. Also, kyphoplasty can be performed on two or three vertebrae grouped together.
• The optimal duration of bisphosphonate therapy remains to be defined. ■

Disclosure: Dr. Anderson has received research support and/or served on an Advisory Board/Speakers Bureau, or as a Consultant/Expert Witness, for Bristol-Myers Squibb Company; Celgene Corporation, Merck & Co., Inc; Millennium Pharmaceuticals, Inc; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals, Inc; and Acetylon Pharmaceuticals, Inc. Dr. Anderson also reported Patent, Equity, or Royalty, from Acetylon Pharmaceuticals, Inc.

Dr. Chanan-Khan has received research support and served on an Advisory Board/Speakers Bureau, or as a Consultant/Expert Witness, for Celgene Corporation and Millennium Pharmacuticals, Inc.

Dr. Devine has received research support from Genzyme and honoraria from Genzyme and Millennium.

Dr. O’Brien has received research support from Gilead and Pharmacyclics.

Dr. Zelenetz is an investigator for and receives research support from Amgen Inc., GlaxoSmithKline, and Genentech, Inc./Roche. Dr. Zelenetz is on an advisory board for Genentech, Inc./Roche, and GlaxoSmithKline.

Dr. Radich reported no potential conflicts of interest.