Andre Goy, MD
A few weeks ago, physicians and scientists from around the globe gathered in San Francisco for the 2014 American Society of Hematology (ASH) Annual Meeting. While it is well beyond the scope of this column to examine all of the significant data presented at ASH, let’s review some trends, since there were key developments across the board.
The most striking results presented were those involving immune-based therapies, particularly with the definite entrance of PD-1 inhibitors into hematology (ie, unleashing the immune system by blocking PD-1 T-cell induced exhaustion). Two PD-1 inhibitors showed dramatic activity in heavily pretreated Hodgkin lymphoma: pembrolizumab (objective response rate [ORR] = 67%) and nivolumab (ORR = 87%).
Other immune-based therapies were also very impressive, with confirmation of the activity of bispecific antibodies (linking CD3 and CD19), such as blinatumomab, in acute lymphocyctic leukemia (ALL), and CAR T-cells showing durable complete remissions in 92% of pediatric patients with relapsed/refractory ALL.
The second obvious trend at ASH involved small molecules, particularly BCR-targeted agents (ibrutinib, idelalisib, duvelisib), with more mature data confirming activity in high-risk patients, such as those carrying a del17p, who typically have very poor outcomes with standard chemotherapy. In a study of 140 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with del 17p, the ORR with ibrutinib was >80% and at 12 months, 79% of patients had not progressed, which is completely unexpected in that population.
Another development reported with small molecules involved the BCL2 inhibitor ABT-199 (venetoclax), with data confirming impressive activity across the board in B-cell malignancies. Also, for the first time, a benefit was shown with an IDH2 inhibitor (AG-221) in acute myeloid leukemia.
In another area, a number of new monoclonal antibodies are currently being tested in B-cell non-Hodgkin lymphoma (NHL), particularly naked anti-CD20 (obinutuzumab, ublituximab, and ofatumumab, among others) or antibody-drug conjugates. For example, brentuximab vedotin significantly reduced the risk of relapse and extended progression-free survival (PFS) following autologous stem cell transplant for relapsed/refractory Hodgkin lymphoma (AETHERA trial). Brentuximab was also used as salvage therapy pre-transplant, either as a single agent or in combination (with bendamustine, particularly), and showed very impressive results, including a high complete remission rate. This will definitely change the landscape of Hodgkin lymphoma, including emerging data supporting replacement of chemotherapy in elderly patients in the frontline setting.
The momentum seen toward combinations of biological agents continues to expand in multiple myeloma (MM), typically including the proteasome inhibitor bortezomib (and now carfilzomib, or ixazomib [an oral compound]), lenalidomide (and now also pomalidomide) plus dexamethasone, providing unprecedented responses in the frontline setting.
The true breakthrough in MM, however, is likely the emergence for the first time of Mab candidates in myeloma, particularly those targeting CD38, such as elotuzumab or daratumumab, which have shown activity as single agents in relapsed/refractory MM, offering an option beyond the triplets backbone therapies (as we did with chemoimmunotherapy in lymphoma).
Beyond this brief highlight of some specific developments from the meeting, a number of themes emerged from ASH that reflect the ongoing changes occurring in oncology.1.
Logically, combinations of small molecules are being explored to replace chemotherapy with already promising results, including in high-risk patients with CLL, MCL, and indolent NHL.2.
Though such regimens appear to be potentially less toxic than standard cytotoxic chemotherapy (to some degree debatable), they are associated with extreme costs, particularly for new regimens given for prolonged periods. On the other hand—for example—6 cycles of chemoimmunotherapy can definitely either cure or give very long remissions to subsets of patients with B-cell lymphomas. This issue is definitely—and should be—part of an honest debate moving forward with the development of novel strategies for cancer patients.3.
ASH joined the Choosing Wisely
effort, which encourages physicians and patients to discuss the necessity of common medical tests and treatments (eg, there is no need for extensive coagulopathy workup in patients who have a deep vein thrombosis or pulmonary embolism in the setting of a transient major risk factor). Without any doubt, this list will continue to grow as we engage physicians more toward cost/quality awareness.