The number of targeted therapies approved by the U.S. Food and Drug Administration (FDA) in the treatment of a variety of cancers, especially hematologic malignancies, continues to rise. In 2014 alone, 4 of the 10 new agents directed at discrete molecular targets approved by the FDA were for blood cancers: blinatumomab (Blincyto) for acute lymphoblastic leukemia, belinostat (Beleodaq) for peripheral T-cell lymphoma, and two therapies in the treatment of chronic lymphocytic leukemia (CLL)—idelalisib (Zydelig) and ibrutinib (Imbuvica). (Ibrutinib was initially approved in 2013 in the treatment of mantle cell lymphoma.) The FDA also approved two immunotherapies for newly diagnosed CLL—obinutuzumab (Gazyva) and ofatumumab (Arzerra)—prompting ASCO to name the transformation of treatment for CLL its cancer Advance of the Year.
So far in 2015, the FDA has approved new indications for four drugs in the treatment of hematologic malignancies, including brentuximab vedotin (Adcetris) for Hodgkin lymphoma, carfilzomib (Kyprolis) in combination with lenalidomide (Revlimid) and dexamethasone for relapsed multiple myeloma, panobinostat (Farydak) in combination with bortezomib (Velcade) and dexamethasone for relapsed myeloma, and ibrutinib for Waldenström’s macroglobulinemia.
In the near future, advances in genomic profiling for hematologic cancers, new drug combinations, and chimeric antigen receptor (CAR) T-cell gene therapy all promise to improve clinical outcomes for the more than 162,000 people diagnosed with leukemia, lymphoma, or multiple myeloma each year.1
Just before the 57th American Society of Hematology (ASH) Annual Meeting, to be held December 5–8, in Orlando, Florida, The ASCO Post conducted a roundtable discussion with three leaders in the treatment of leukemia, lymphoma, and multiple myeloma to learn about the current state of progress being made in these blood cancers and what is on the 10-year horizon. Our participants included David A. Williams, MD, Leland Fikes Professor of Pediatrics at Harvard Medical School and President of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Boston, and current President of ASH; Michael E. Williams, MD, ScM, Byrd S. Leavell Professor of Medicine and Chief of the Hematology/Oncology Division at the University of Virginia Health System in Charlottesville; and S. Vincent Rajkumar, MD, Edward W. and Betty Knight Scripps Professor of Medicine, Division of Hematology at the Mayo Clinic in Rochester, Minnesota.
ASH 2015
First, Dr. David Williams, please talk about the areas of clinical advancements you expect to see presented at this year’s ASH meeting.
Dr. D. Williams: This is going to be a huge meeting, with about 25,000 hematologists from around the world in attendance. We have over 6,000 abstracts submitted, so this will be an outstanding basic research meeting as well as an outstanding translational and clinical research meeting. I anticipate seeing presentations that reflect a continued maturation of the field of targeted therapies in the treatment of lymphoma, leukemia, and myeloma. By that I mean we will see an increase in the use of combination-targeted therapies with conventional therapies and also the combination of targeted therapies with new immune therapies.
Of course, we are still learning about the genomic signatures of diseases like leukemia, and I think there will be more science around the importance of mutations in the development and evolution of blood cancers—particularly the evolution of resistance to therapy—and that will allow us to treat patients more precisely in the future.
We are defining the genetic landscape of diseases, and ultimately, that will allow us to better select patients most likely to respond to targeted therapy as well as patients who are not going to respond so we can prescribe alternative therapies. I think these advantages will have the combined effect of improving outcomes and reducing treatment toxicities and long-term side effects.
New Insights
From each of your perspectives, what are you learning about the prevention, detection, diagnosis, and treatment of blood cancers?
Dr. D. Williams: We are learning that certain mutations appear to predispose patients to the evolution of leukemia as well as the complexity of relapse and resistance to therapy.
Dr. M. Williams: Improved diagnostics are providing a deeper understanding of the heterogeneity of blood cancers at both the molecular and cellular levels. This has led to a greater understanding of cancer biomarkers for individual patients that in turn are predictive of their clinical course. A corollary of these advances is the ability to risk-adapt treatment for many blood cancers, including lymphoma, myeloma, or CLL, and to optimally apply either current chemoimmunotherapy approaches or to employ newer agents to achieve better outcomes for our patients.
Dr. Rajkumar: In multiple myeloma, there is a move toward early diagnosis and the initiation of treatment before organ and bone damage occurs. We have been treating myeloma only when we see end-organ damage. That was okay when we had limited options for therapy, but now that our treatments are very effective and prevent complications, it doesn’t make sense to wait for complications before we initiate therapy, particularly when the complications are so devastating, such as serious bone fractures or kidney failure. So the main area that has changed and will be changing substantially over the next few years is in the use of biomarkers to diagnose myeloma and start therapy early.
We are also going to see clinical trials for patients with smoldering myeloma to investigate how to delay or prevent disease progression.
Genomic Sequencing
What are you learning about these cancers from genomic sequencing, including new mutations, subtypes, and treatment strategies?
Dr. D. Williams: We are finding many new mutations in leukemia, and we are just beginning to understand how to use genes to predict treatment response and disease outcome as well as how to define risk factors for the development of side effects and bad outcomes. Details of these types of findings will be presented at the ASH Annual Meeting.
In terms of new therapy for leukemia, this is a pretty exciting time because there are several aspects of gene therapy that are evolving in the treatment of the disease. One is the growth of the gene therapy platform using hematopoietic stem cells to expand indications. We now have a half-dozen diseases where stem cell gene therapy has been clearly shown to effect what appears to be cure of the disease. As a next step, that modality will likely be applied to treat diseases that we would not have thought about treating in this way—for example, the use of progeny of gene-modified hematopoietic stem cells with blood as a delivery system for cross-correction of diseases that we do not consider to be stem cell diseases.
Another evolving area is the identification of new targets that can generate CAR-modified T-cells to recognize a specific protein on tumor cells. The big success so far is in CAR T-cells targeting CD19 in B-cell leukemias. But many other antigens will be identified and then exploited for immune therapy, and that is what a lot of basic research is currently exploring.
So immunomodulation as an approach to therapy, immune therapy in the form of CAR T cells, and continued unraveling of the molecular landscape of tumors will all allow precision medicine to move forward.
Dr. M. Williams: In lymphoma, we now recognize molecular subtypes that are clinically relevant. A good example is diffuse large B-cell lymphoma. There are at least two major subtypes based on cell of origin: germinal center B-cell, and non–germinal center B-cell, which includes the activated B-cell subtype. Patients appear to have different outcomes whether they are treated with R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) or dose-adjusted EPOCH-R (etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab).
The non–germinal center B-cell subtype, which has a poorer prognosis than germinal center B-cell, can be very responsive to lenalidomide (Revlimid) or ibrutinib (Imbruvica), so there is a rationale for incorporating these drugs into initial treatment to improve patient outcomes in poor-risk settings. Early study results show that adding lenalidomide to R-CHOP abrogates the adverse impact of the non–germinal center B-cell diffuse large B-cell lymphoma.2 That combination may become a standard of care in the treatment of this diffuse large B-cell lymphoma subtype if ongoing studies confirm benefit.
Dr. Rajkumar: Cytogenetically, there are at least six distinct types of myeloma. Many of them have a unique presentation, clinical course, response to therapy, and prognosis. Myeloma is a rare disease, and it has been difficult to do trials in each of the disease subtypes. But we have learned that certain types of myeloma respond better to specific treatment approaches.
For example, high-risk patients with t(4;14) myeloma respond well to bortezomib and require bone marrow transplantation followed by bortezomib maintenance; the overall survival of patients with deletion 17p can be improved with bortezomib-based maintenance therapy; and patients with chromosomal trisomies are exquisitely sensitive to lenalidomide. So we can now tailor treatments depending on the baseline cytogenetic type of myeloma without resorting to genomic sequencing and instead incorporate standard fluorescence in situ hybridization (FISH) studies to inform treatment strategies. We have been using FISH mainly for prognosis, but increasingly, FISH and newer genomic approaches are being used to predict response and select treatments for myeloma.
Through sequencing studies, we are just beginning to understand the extent of genomic abnormalities in myeloma. We have learned that there are many recurrent mutations, but each one is only seen in a small number of patients. Some mutations are not targetable, but some are—for example, the BRAF V600E mutation, which is seen in about 5% of patients with myeloma. There are already patients with the BRAF mutation who have been treated with vemurafenib (Zelboraf) and have had sustained responses. We are trying to get myeloma patients included in the NCI-Molecular Analysis for Therapy Choice (MATCH) clinical trial so we can identify new targeted therapeutic options.
In terms of new therapies, there are many in development, and some are close to being FDA-approved. At least three new proteasome inhibitors have shown activity in myeloma: ixazomib (MLN9708), oprozomib (ONX-0912), and marizomib (NPI-0052). We are also going to have improved immunomodulatory agents. Although we welcome new proteasome inhibitors and immunomodulatory agents, merely having more drugs in the same class is not going to be a major advance. It is more important to identify new drugs that have a different mechanism of action than the ones we already know work in myeloma.
In that regard, we are poised for at least two monoclonal antibodies to be approved by the FDA within the next few months. One is elotuzumab, which, in combination with lenalidomide and dexamethasone, has produced significant improvement in response rate and progression-free survival in relapsed/refractory myeloma in a phase III trial.3 The other is daratumumab, which binds to CD38 and has shown single-agent activity against relapsed/refractory disease in about one-third of myeloma patients studied. (Editor's Note: Daratumumab was approved shortly before this issue of The ASCO Post went to press.)
Close on the heels of these two agents is another monoclonal antibody against CD38—SAR650984—which is also highly active in myeloma, and we will see how it fits in as a therapeutic option for patients. Then there is dinaciclib, a novel cyclin-dependent kinase inhibitor, which has shown single-agent activity in relapsed disease; venetoclax, a Bcl-2 selective inhibitor, which has shown responses as a single agent in some types of myeloma; LGH447, a Pan-Pim kinase inhibitor that has also shown single-agent activity in myeloma; and finally, there is filanensib, which is a kinesin spindle protein inhibitor that has shown single-agent activity in myeloma as well.
Many drugs in myeloma have shown synergistic activity when used in combination with known active drugs. But the drugs that I have mentioned are of particular interest because, with the exception of elotuzumab, they all have single-agent activity in relapsed/refractory disease. Thus, they are likely to become very powerful tools for us in the near future.
There is also a great deal of interest in immunotherapy with either CAR T cells or checkpoint inhibitors. CAR T cells directed against B-cell maturation antigen are going to be tested in many centers. There are also trials investigating checkpoint inhibitors in this setting. Time will tell how immunotherapy fits in as a viable treatment for myeloma.
Stem Cell Transplant
With so many effective therapies available for hematologic cancers, what is the role of stem cell transplantation in these diseases?
Dr. M. Williams: Autologous stem cell transplantation remains a very important aspect of management for patients with relapsed diffuse large B-cell lymphoma and Hodgkin lymphoma, as well as some cases of relapsed follicular lymphoma. Autologous stem cell transplantation is also important in treating younger and medically fit patients with mantle cell lymphoma as consolidation after first-line therapy. I think as we go forward we are going to see more selective use of stem cell transplantation for the non-ALL lymphoid malignancies as regimens improve to provide deep remissions, as assessed by minimal residual disease markers or circulating tumor DNA, and as consolidation or maintenance strategies are developed via immunotherapeutics and targeted agents.
Dr. Rajkumar: I agree; stem cell transplant will continue to play a role in blood cancers. As long as myeloma remains incurable, stem cell transplant, particularly autologous transplants, will play a huge role in the treatment of this disease.
Mantle Cell Lymphoma
Although there has been a lot of progress in the treatment of non-Hodgkin lymphoma, mantle cell lymphoma remains clinically challenging. What are you learning about the biology of this disease, and what progress has been made in its treatment?
Dr. M. Williams: Survival rates are improving well beyond 5 years for many patients with mantle cell lymphoma given the many effective agents and regimens for the disease, including bortezomib, lenalidomide, and ibrutinib. The clinical spectrum of the disease is also being better appreciated in recent years. About 20% of patients with mantle cell have a very indolent clinical course. These patients often present with a CLL-like pattern, including lymphocytosis and splenomegaly but little adenopathy, and many can be observed for months or years in some cases before treatment.
At the other end of that spectrum are patients with blastoid variants or very advanced disease who require active treatment right up front. The molecular underpinnings of this spectrum of clinical behavior are now better understood, and identify pathways that can be therapeutically targeted.
Indolent Disease
What is the current strategy for treating indolent forms of lymphoma and CLL?
Dr. M. Williams: These diseases are very important testing grounds for newer immunotherapeutics and targeted drugs, such as tyrosine kinase inhibitors and proapoptotic agents. We have the opportunity to start moving away from traditional chemotherapy-based treatment to regimens that use very minimal or lower intensity cytotoxics complemented by newer monoclonal antibody and cell signaling or apoptosis targeted agents either alone or incorporated into a backbone anti-CD20/chemotherapy-based regimen.
Obstacles to Improved Care
What is the biggest obstacle to advancing care for hematologic cancers over the next 5 years?
Dr. D. Williams: I’m a pediatrician, and almost all of the diseases I take care of are considered rare. In pediatrics, we recognized a long time ago that we have to do things collaboratively across many centers to have enough patients to conduct informative clinical trials. That is a paradigm that will have to be used in adult diseases as we get more personalized in our approaches to treatment.
Dr. M. Williams: I would answer that in two ways. The biggest obstacle from a scientific and clinical standpoint of so many promising new agents is finding the resources and patient base to test new regimens, and creating well-designed clinical trials to clearly establish where they fit into current treatment algorithms. For example, if you are going to combine two targeted drugs, how do you rationally select the agents? How do you dose, schedule, and sequence them?
The other obstacle is establishing the value, not just the cost, of care. The cumulative cost for individual patients and for society is not sustainable at the current levels, thus creating an oncologic, economic, and societal mandate to justify approaches to the management of hematologic malignancies and, indeed, all cancers.
Dr. Rajkumar: For me, the biggest obstacle is the lack of large randomized trials that test treatment strategies—not just one regimen vs another, but overall strategies. For example, trials might test combination vs sequential approaches, ie, cure vs control. Such trials are very difficult to design because the sample sizes have to be huge, and we need to improve patient accrual in order to achieve those goals.
I agree with Dr. [Michael] Williams that cost of care is another huge obstacle. The cost of a triplet combination of VRD (bortezomib, lenalidomide, and dexamethasone) is already nearly $200,000 a year, and if you add in a couple of antibodies, treatment is going to be prohibitively expensive, especially for patients on continuous therapy.
Another obstacle is in the treatment of high-risk myeloma. Almost all of the progress in this disease is happening in low-risk patients. Patients with high-risk translocations, high-risk gene-expression profiling, or early relapse after first-line therapy still do not do well. We need to design specialty trials for them.
Future Progress
What progress do you predict in the treatment of hematologic cancers over the next decade?
Dr. D. Williams: We will increase our understanding of the aberrant pathways that drive both the transformation of normal cells and the initiation of the cancer as well as resistance to therapy. Along with the continued development of work to harness the immune system in the treatment of these malignancies, these are major advances I anticipate in both pediatric and adult oncology.
It is a great time to be a hematologist/oncologist, and I am very excited to see the fruits of the research done over the past 20 years come to the clinic. We have many more therapies to offer our patients than we did just 5 years ago.
Dr. M. Williams: I agree, this is a remarkable time to be working on these diseases. Over the next 10 years I anticipate patients living longer, having higher cure rates, and enjoying improved quality of life both during and after treatment. We will see a movement away from reliance on traditional chemotherapy and radiation therapy to more effective, less toxic regimens.
Dr. Rajkumar: We are going to see more risk-adapted therapy for myeloma. We cannot continue to treat every patient with a one-size-fits-all approach. We will be using a surrogate marker like minimal residual disease as the goal of therapy, allowing at least some patients to stop therapy once that goal is achieved. We will see the incorporation of immunotherapy in the myeloma treatment paradigm to maintain responses long term.
Finally, if we are lucky, we will cure this disease. ■
Disclosure: Dr. David Williams has done sponsored research from Bluebird Bio (for non–cancer-related studies and received licensing fees from Bluebird Bio (for non–cancer-related gene therapy technology). Dr. Michael Williams has been a consultant or advisor for Celgene and Takeda and has received research support from Celgene, Jansen, Pharmacyclics, and Takeda. Dr Rajkumar reported no potential conflicts of interest.
References
1. American Cancer Society: Cancer Facts & Figures 2015. Available at cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015. Accessed November 3, 2015.
2. Nowakowski GS, LaPlant B, Macon WR, et al: Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large b-cell lymphoma: A phase II study. J Clin Oncol 33:251-257, 2015.
3. Lonial S, Dimopoulos MA, Palumbo A, et al: ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients with relapsed/refractory myeloma (RRMM). 2015 ASCO Annual Meeting. Abstract 8508. Presented June 2, 2015.
