Management Strategies for Hematologic Malignancies

Minneapolis—With the introduction of novel agents, healthcare professionals and managed care organizations are determining how to evaluate the new therapies and incorporate them into effective benefit designs. The agents are becoming more common in multiple myeloma (MM), chronic myeloid leukemia (CML), and non-Hodgkin lymphoma (NHL). Those disease states and the importance of understanding and evaluating differences among clinical end points were topics discussed during a satellite symposium at the AMCP meeting titled The Evolving Role of Outcomes and End Points in Evaluating Therapy for Hematologic Malignancies: Value-Driven Benefit Design and Utilization Management Strategies. Gary C. Yee, PharmD, FCCP, BCOP, professor and associate dean for academic affairs at the University of Nebraska Medical Center’s college of pharmacy, began with an overview of MM, which affects approximately 61,000 individuals in the United States. Dr. Yee cited statistics from the American Cancer Society that indicate there were 20,180 MM cases diagnosed and 10,650 MM-related deaths in the United States in 2010. With the US Food and Drug Administration (FDA) approving several drugs in recent years to treat MM, the 5-year survival rates have increased, according to Dr. Yee: from 12% in 1963 to 28% in 1975 to 35% in 1995 to 40% in 2007. The 2011 National Comprehensive Cancer Network (NCCN) MM guidelines suggest that patients who are not candidates for transplant should be treated with melphalan, prednisone, and thalidomide; bortezomib, melphalan, and prednisone; or lenalidomide and low-dose dexamethasone. Patients who are candidates for a transplant should undergo an induction treatment of bortezomib or lenalidomide plus lowdose dexamethasone, followed by a stem cell harvest, and an autologous hematopoietic stem cell transplantation. Michael J. Mauro, MD, professor of medicine in Oregon Health and Science University’s division of hematology and medical oncology, followed by discussing how tyrosine kinase inhibitors (TKIs) have helped treat patients with CML. In 2001, imatinib became the first FDA-approved TKI. In recent years, dasatinib and nilotinib have gained FDA approval as a first- and second-line treatment. In January 2011, the NCCN issued guidelines indicating that the primary treatment for CML should be 300 mg of nilotinib twice daily or 100 mg of dasatinib once daily. Dr. Mauro cited several trials involving TKIs, including results from the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) and DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML-CP Patients) studies. ENESTnd is a global, multicenter, randomized phase 3 trial involving 846 patients with chronicphase CML within 6 months of diagnosis and comparing 300 mg and 400 mg of nilotinib taken twice daily with 400 mg of imatinib taken once daily. After a 24-month follow-up period, nilotinib was superior as a first-line treatment. The trial is scheduled to last 5 years. DASISION is a phase 3 trial in 108 centers in 26 countries involving patients with treatment-naïve Philadelphia chromosome-positive CML and compares 100 mg of dasatinib with 400 mg of imatinib, both taken once daily. At 18 months, dasatinib was superior in several measures, including superior rates of complete cytogenetic response and major molecular response. The study is scheduled to last 5 years. Dr. Mauro said TKIs have potential comorbidities and toxicities, including cardiovascular or cardiopulmonary risk, myelosuppression, and pancreatic, hepatic, dermatologic, and hemorrhagic toxicity. He also mentioned that tolerability is inversely proportional to the number of therapy options. In addition, he suggested that dosage should not be interrupted or reduced below the target level, particularly early in the treatment phase. Dr. Yee then discussed NHL, the most common hematologic malignancy in the United States. NHL represents approximately 89% of all lymphomas, and as of January 1, 2007, there were 438,000 people in the United States with NHL. The World Health Organization classifies NHLs based on the cell of origin, morphology, immunophenotype, and genetic and clinical features. Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma are the most common NHL subtypes, accounting for 31% and 22% of all NHLs, respectively. In the past decade, the FDA has approved several drugs to treat NHL, among them denileukin diftitox, vorinostat, romidepsin, pralatrexate, ibritumomab tiuxetan, tositumomab, bendamustine, and bortezomib. Dr. Yee cited a 2007 article from the Journal of Clinical Oncology that recommended end points to use in NHL trials. According to Dr. Yee, the end points should reflect the histologic, clinical situation, and objectives of the study and should be defined consistently throughout the trial. He said that overall and complete response rates can be assessed accurately in single-arm and randomized trials, although response rates are not as important as other end points, other than in phase 2 trials involving new agents. Important primary end points in NHL studies include overall survival and progression-free survival, whereas secondary end points include event-free survival, failure-free survival, time to progression, disease-free survival, and duration of response. When treating DLBCL, providers should focus on long-term survival and cure, although the approach varies depending on the disease stage, according to Dr. Yee. Patients with stage I or II nonbulky DLBCL are advised to take 3 cycles of cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisone (CHOP) or 6 cycles of CHOP with or without radiation therapy. Patients with stage III or IV disease should take 6 cycles of CHOP. Dr. Yee also discussed several trials involving patients with B-cell lymphoma that found rituximab plus CHOP (R-CHOP) was superior to chemotherapy alone. In addition, he spoke about a randomized, phase 3 trial comparing bendamustine and rituximab (B-R) with R-CHOP as first-line therapy in 513 patients with advanced indolent NHL. The study found that there was a noninferiority with B-R compared with R-CHOP, while B-R was significantly superior to R-CHOP for median progression-free survival (54.9 months vs 34.8 months; P<.001). B-R was also superior to R-CHOP in terms of complete remission rate (40% vs 30%), although the difference was not statistically significant (P=.26). The time to next treatment was superior in B-R compared with R-CHOP (not reached vs 37.5 months; P=.001). The FDA originally approved rituximab in November 1997 as a single agent to treat relapsed or refractory low-grade or follicular, B-cell NHL. In subsequent years, the FDA approved rituximab for other indications. Most recently, the drug was approved in January 2011 as a single-agent maintenance therapy in patients with previously untreated follicular B-lymphocyte antigen CD20, B-cell NHL who have achieved a response to rituximab in combination with chemotherapy. The session concluded with James T. Kenney, Jr., RPh, MBA, pharmacy operations manager for Harvard Pilgrim Health Care, discussing how managed care organizations can make better informed decisions. Dr. Kenney said some recent challenges include evaluating diverse clinical trial data, applying appropriate utilization management criteria, achieving cost-effective outcomes, implementing value-based benefit designs, achieving compliance for complex regimens, and managing direct drug and medical costs. To determine the best value of novel agents, Dr. Kenney said healthcare professionals should use and examine the following end points: progression-free survival, overall survival, objective response rate, disease-free survival, time to progression, and complete response.