PER Pulse™ Recap
Medical Writer: David Lee, PhD
The 19th Annual International Congress on Hematologic Malignancies®, which was held February 20-21, 2015, featured internationally recognized experts in hematology/oncology. These experts, along with representatives from community practice, discussed best practices and key advances for the treatment of patients with leukemia, lymphoma, and myeloma. This first of 3 PER Pulse™ Recaps from the International Congress on Hematologic Malignancies® focuses on multiple myeloma (MM), including therapeutic advances in the first-line setting and for patients with previously treated disease, as presented by C. Ola Landgren, MD, PhD, Sundar Jagannath, MD, and Jonathan Kaufman, MD.
Dr. Landgren addressed therapy for previously untreated patients. He described the importance of depth of response, and that improved overall survival correlated with the elimination of minimal residual disease. For patients not eligible for autologous stem cell transplant, a melphalan-based combination has long been a standard approach; however, the phase III FIRST trial confirmed that the non-melphalan–based regimen of lenalidomide/dexamethasone yielded superior progression-free survival (PFS) compared with a previous standard regimen of melphalan/prednisone/thalidomide (MPT; 25.5 months vs 21.2 months; HR = 0.72; P <.001).
Dr. Jagannath summarized phase III advances for patients with previously treated MM. The ASPIRE trial compared the triplet of carfilzomib/lenalidomide/dexamethasone to lenalidomide/dexamethasone in previously treated patients who were not refractory to bortezomib nor intolerant to lenalidomide. The primary endpoint of median PFS was significantly increased in the triplet arm (26.3 months vs 17.6 months; HR = 0.69; P =.0001). The PANORAMA 1 trial evaluated bortezomib/dexamethasone with either panobinostat or placebo in patients with relapsed/refractory MM. In this trial, median PFS was 12.0 months in the panobinostat arm and 8.1 months in the placebo arm (HR = 0.63; P <.0001).
Monoclonal antibodies are a rapidly emerging new class of agents in MM. Dr. Kaufman described CD38 and SLAMF7, which are molecules that can differentiate MM cells from normal cells, and are therefore rational therapeutic targets for antibodies. Daratumumab and SAR650984 are both antibodies targeting CD38, whereas elotuzumab targets the SLAMF7 molecule (also known as CS1). Encouraging activity has been observed with these new antibodies in both newly diagnosed patients and those with relapsed/refractory disease, and phase III trials of anti-CD38 and anti-SLAMF7 antibodies are ongoing.
The 19th Annual International Congress on Hematologic Malignancies®, which was held February 20-21, 2015, featured internationally recognized experts in hematology/oncology. These experts, along with representatives from community practice, discussed best practices and key advances for the treatment of patients with leukemia, lymphoma, and myeloma. This second of 3 PER Pulse™ Recaps from the International Congress on Hematologic Malignancies® focuses on chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), including standards of care and new targeted agents, as presented by William G. Wierda, MD, PhD, Myron S. Czuczman, MD, Thomas E. Witzig, MD, and Andre Goy, MD, MS.
Anti-CD20 antibodies have become a part of the standard of care for patients with CLL. Dr. Wierda described how agents targeting intracellular signaling are now rapidly becoming established, as well. Ibrutinib, which targets Bruton’s tyrosine kinase (BTK), is approved in patients with previously treated disease, and has also been approved specifically for patients with the unfavorable chromosome 17p deletion. In a phase II study enrolling 144 patients with del(17p), the overall response rate (ORR) by independent review was 65%, and the median overall survival (OS) had not been reached with a median follow-up of 11.5 months. Idelalisib, which inhibits the delta isoform of phosphatidylinositol 3-kinase, has also shown activity in patients with del(17p). A subgroup analysis of 110 patients showed similar progression-free survival (PFS) with idelalisib plus rituximab in patients with (16.6 months) or without (20.3 months; P = .94) the 17p deletion.
Dr. Czuczman discussed 2 emerging themes in therapy for patients with follicular lymphoma (FL). The first is that therapeutic goals are shifting from palliative approaches to more-aggressive therapy, with the goal of inducing durable complete responses (CRs) in patients with advanced disease. With the development of numerous targeted agents that have the potential for improving patient outcomes and increasing cure rates, Dr. Czuczman stressed the need for new approaches for clinical trial design. Adaptive trials, such as the I-SPY approach in breast cancer, would allow for the identification of the most active agents within months, rather than years.
Adding to the information on clinical trials, Dr. Witzig described a study of 767 patients evaluating event-free survival (EFS) as an endpoint for patients with diffuse large B-cell lymphoma (DLBCL). Patients who were event-free at 24 months from diagnosis (EFS24) had a survival that was similar to that of the general population matched for age and sex (P =.25). These data suggest that EFS24 would be a useful surrogate for OS in future clinical trials. Along different lines, data were presented demonstrating impaired rituximab activity and outcome in patients who were deficient in vitamin D (≤8 ng/mL), suggesting that vitamin D supplementation in patients who are deficient would improve outcomes in those patients. The LS1293 trial is currently recruiting patients to test this hypothesis.
Finally, Dr. Goy described the changing options for patients with mantle-cell lymphoma (MCL). For elderly patients, the addition of targeted agents such as bortezomib is promising, and bortezomib has been approved in the frontline setting, based on a phase III trial that demonstrated improved PFS with the combination of bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) compared with R-CHOP (24.7 mo vs 14 mo; P <.001). The combination of lenalidomide and rituximab (R-squared) in previously untreated MCL yielded a CR in 57% of 30 evaluable patients; the 12-month PFS was 93%. In patients with relapsed MCL, the combination of ibrutinib and rituximab (IR) in 50 patients led to an ORR of 88%, including 40% CR.
The 19th Annual International Congress on Hematologic Malignancies®, held February 20-21, 2015, featured internationally recognized experts in hematology/oncology. These experts, along with representatives from community practice, discussed best practices and key advances for the treatment of patients with leukemia, lymphoma, and myeloma. This third of 3 PER Pulse™ Recaps from the International Congress on Hematologic Malignancies focuses on therapeutic approaches for patients with chronic myeloid leukemia (CML), myelofibrosis (MF), and polycythemia vera (PV), as presented by Michael Mauro, MD, and Moshe Talpaz, MD.
Dr. Mauro discussed issues related to the treatment of patients with CML. For example, with several choices available for frontline therapy of patients with chronic-phase CML, including imatinib, nilotinib, and dasatinib, treatment will depend on several factors, including the presence of comorbidities. For situations where second-generation tyrosine kinase inhibitors nilotinib or dasatinib are being considered, National Comprehensive Cancer Network guidelines describe nilotinib as potentially a better option for patients with a history of lung disease, whereas dasatinib may be better suited for patients with cardiac issues, pancreatitis, or hyperglycemia.Dr. Talpaz addressed treatment of patients with MF and PV. In MF, single-agent ruxolitinib has been approved for patients with intermediate- or high-risk disease. While patients achieve symptom control with ruxolitinib, combinations with other pathway inhibitors are being explored to attack the underlying disease. These include combinations with inhibitors of phosphatidylinositol 3-kinase, such as buparlisib, and with Hedgehog pathway inhibitors, including sonidegib. Other inhibitors of JAK signaling have been investigated. A phase III trial of pacritinib, a selective inhibitor of JAK2 and FLT3, showed activity in terms of a ≥35% reduction in spleen volume at week 24 compared with best available therapy (BAT), although there was no direct comparison with ruxolitinib. Pacritinib was also active in patients with reduced platelet counts (<50,000/ml). Dr. Talpaz also summarized results of the phase III RESPONSE trial in the setting of PV, which led to the approval of ruxolitinib in patients who do not achieve an adequate response with or cannot tolerate hydroxyurea. Compared with BAT, more patients with ruxolitinib achieved the primary endpoint of a combination of hematocrit control through week 32 and a ≥35% reduction in spleen volume at week 32 (21% vs 1%; P <.001).
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Supported by educational grants from Abbvie, Celgene Corporation, Genentech, Gilead, Incyte Corporation, Jazz Pharmaceuticals, Takeda Oncology, Novartis Pharmaceuticals Corporation, Onyx Pharmaceuticals Inc., a subsidiary of Amgen Inc., Pharmacyclics, Sigma-Tau Pharmaceuticals, Inc., and TG Therapeutics, Inc.
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