Executive editor of CancerConnect and Women magazine oncologist Charles Weaver, MD describes highlights of current blood cancer research from 2015 and the American Society of Hematology (ASH) annual meeting.
In your view, what are some of the most exciting advances in blood cancer research that patients and families affected by a blood cancer should know about today?
In 2015 there were significant advances in the management of several blood cancers, highlighting how far we have progressed in cancer care. Major innovations in immunotherapy and targeted therapy led to a record number of new drug approvals, which have transformed patient outcomes and offer hope that continuing research in these areas will deliver new treatment options in the coming years. Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma were among the biggest beneficiaries of progress in cancer treatment in 2015.
Chronic Lymphocytic Leukemia
The US Food and Drug Administration (FDA) approved new treatments for both untreated and previously treated CLL. These new therapies have fewer side effects and attack CLL in a novel way, creating potential combination treatment options to be evaluated in 2016 and beyond.
- Gazyva® (obinutuzumab) and Arzerra® (ofatumumab) are monoclonal antibodies that target a molecule known as CD20, which is found on the surface of CLL cells. Arzerra produced a near doubling of survival compared to standard CLL treatment of Leukeran® (chlorambucil) and Rituxan® (rituximab) in previously untreated patients; Gazyva combined with Leukeran nearly tripled response rates and prolonged survival of people with previously untreated CLL by nearly a year without a worsening of disease compared with the standard CLL treatment.
- While the approvals for both Gazyva and Arzerra stand to benefit patients with untreated CLL, there is also important progress for patients with previously treated CLL. Two biological therapies that block the growth of cancer—Imbruvica® (ibrutinib) and Zydelig® (idelalisib)—demonstrated important survival improvements for these more advanced patients. Researchers also discovered that ACP-196, a Bruton’s Tysine Kinase Inhibitor was safe and effective. Clinical results published in the New England Journal of Medicine show that another new drug, acalabrutinib (ACP-196), is well tolerated and yields high response rates that are durable in patients with CLL.1
Collaboration among doctors, pharmaceutical companies, and patients over the past five to seven years has resulted in the most significant expansion in treatment options for individuals with multiple myeloma in history. The new proteasome inhibitor Kyprolis® (carfilzomib) appears superior to Velcade® (bortezomib), and several new immunomodulatry drugs have greatly expanded the potential combinations of drugs with fewer side effects available to optimally manage this disease.
“Triplet,” or three-drug combinations, will become the new standard of care for patients who aren’t candidates for stem cell transplant. Researchers found that the addition of the proteasome inhibitor Velcade to the standard two-drug treatment combination of Revlimid® (lenalidomide) plus dexamethasone improved survival when used as initial therapy in multiple myeloma among patients who do not intend to immediately undergo a stem cell transplant.2
Triplet therapy incorporating Velcade is the new standard of care; however, studies also revealed that another proteasome inhibitor Kyprolis appears more effective than Velcade. Results from a worldwide multicenter study found that patients with relapsed multiple myeloma treated with Kyprolis lived twice as long without a worsening of disease compared with those treated with Velcade.3
Additional clinical studies reported in 2015 led the FDA to approve three additional novel treatments for patients with multiple myeloma who have received prior therapies.
- Empliciti® (elotuzumab) is an immuno-stimulatory monoclonal antibody that is targeted against the Signaling Lymphocyte Activation Molecule Family 7 (SLAMF7). Empliciti binds to SLAMF7, which is found on myeloma cells, and results in the cells’ destruction through various processes, including stimulation of the immune system to fight the cancer cells.4
- Ninlaro® (ixazomib) is a proteasome inhibitor approved by the FDA in late 2015 after studies demonstrated it improved the survival of myeloma patients with advanced disease.5
- Darzalex® (daratumumab) is a monoclonal antibody that works by helping certain cells in the immune system attack cancer cells. Researchers designed Darzalex to specifically target and bind to multiple myeloma cells that overexpress the protein called CD38. When Darzalex binds to these myeloma cells they are killed.6
Acute Lymphoblastic Leukemia
There have been few advances in the treatment of B-cell acute lymphoblastic leukemia (ALL)—the most common type of ALL—in recent years; however, 2015 witnessed the breakthrough of two potentially game-changing immunotherapy treatments.
- CAR T-cell therapy is a novel immunotherapy showing promise in ALL, CLL, and other B-cell malignancies. In CAR T-cell therapy, T cells (a type of immune cell) are collected from the patient’s blood and are then genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARs). CARs are proteins that allow the T cells to recognize a specific protein (antigen) on tumor cells. These engineered CAR T cells are then grown in the laboratory until they number in the billions. The expanded population of CAR T cells is then infused into the patient. The T cells are in essence a “living drug”; they multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that possess the antigen.
- Two studies have produced favorable results in the treatment of relapsed ALL: In one trial 88 percent of participants experience a complete cancer remission. In another, which tested a different form of CD19-directed CAR T-cell therapy, 14 of the first 20 patients treated in the study experienced complete remission of the disease.7
- BLINCYTO® (blinatumomab) is another form of immunotherapy. It is an antibody that binds to both a T cell and a specific marker on ALL B cells. These antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BLINCYTO helps place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die. In a comparative clinical trial, BLINCYTO improved overall survival in patients with relapsed and refractory ALL compared to standard chemotherapy.
Patients with polycythemia vera (PV) experience significant symptoms characterized by fatigue, itching, night sweats, bone pain, fever, and undesired weight loss; these symptoms contribute to a poor quality of life, which is often under appreciated by family and providers. Until recently, PV patients’ only treatment options were phlebotomy and hydroxyurea (HU). However, the development and approval of the JAK2 inhibitor Jakafi® (ruxolitinib) has led to an effective alleviation of these symptoms in many patients.
Jakafi has mainly been used to reduce symptoms in individuals with severe PV who have three or more of these debilitating symptoms. An international study was presented at the American Society of Hematology demonstrating that many PV symptoms remain severe independent of the total number of features present.8 The results of this study demonstrate that the symptom burden in patients with PV is substantial, independent of whether a patient has used HU, has received phlebotomy, or has splenomegaly.
A phase III prospective Randomized Study of Efficacy and Safety in Polycythemia Vera with JAK Inhibitor INCB018424 versus Best Supportive Care (RESPONSE) has previously demonstrated that Jakafi effectively alleviated symptoms and controlled hematocrit in PV patients with at least three debilitating features.9 This current study suggests that PV patients who have only one or two features may also benefit from treatment with a JAK2 inhibitor.
The study demonstrated that the presence of each feature of PV was individually associated with a moderately high symptom burden and that symptoms incrementally increased in severity with the addition of the other features. Based on these findings, PV patients with any of these three features might benefit from more aggressive therapy and should discuss the role of a JAK2 inhibitor in controlling their symptoms.
How do these advances, and others reflect specific trends in treatment or paths of inquiry related to blood cancer research?
A great deal of progress has been made in the advancement of precision personalized cancer treatment, and this trend will continue. There is no longer a “one-size-fits-all” approach to cancer treatment. Even among patients with the same type of cancer, the behavior of the cancer and its response to treatment can vary widely. By exploring the reasons for this variation, researchers have begun to pave the way for more precise and personalized cancer treatment.
It is becoming increasingly clear that specific characteristics of cancer cells and cancer patients can have a profound impact on prognosis and treatment outcome. Although factoring these characteristics into treatment decisions makes cancer care more complex, it also offers the promise of improved outcomes.
Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. By defining the consequences of these genetic abnormalities, doctors can identify specific treatments directed against each genetic abnormality for each individual patient’s unique DNA profile.
Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of cells. Standard chemotherapy typically destroys both normal and cancerous rapidly dividing cells in a wide range of tissues, often causing side effects by damaging normal cells. Precision cancer medicine uses targeted therapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Which advances in treatment do you feel will have the most immediate impact on patients’ treatment?
The most immediate impact will come from the new drugs approved by the FDA and CAR T-cell therapy. The FDA-approved drugs are already available to cancer patients. Although these newly approved drugs are better than previous treatments, there is always room for continued improvement until all patients can be cured. Patients should always discuss the role of clinical trials with their treating physician because these new drugs will continue to be evaluated both with other existing drugs and experimental treatments to further improve patient outcomes. CAR T-cell therapy is being utilized and refined in several major cancer centers with the support of industry and is currently being utilized in B-cell leukemias and non-Hodgkin’s lymphoma.
Are there questions patients should ask their oncologist about how any of these advances might affect their treatment plan?
Patients should always ask about what new therapies are available and what their potential role will be in the overall management of their cancer. Developing an overall treatment plan that considers what next steps will be taken should the initial treatment fail is always prudent. Patients should also inquire what role clinical trials might play in the management of their condition. All treatment advances start in clinical trials, and patients should always consider them as a treatment option.
- Byrd J, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. New England Journal of Medicine. December 7, 2015DOI: 10.1056/NEJMoa1509981.
- Durie B, Hoering A, Rajkumar V, et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): results of the randomized phase III trial SWOG SO777. Proceedings from the 2015 annual meeting of the American Society of Hematology. Abstract #25.
- Amgen press release. FDA Approves New Kyprolis® (Carfilzomib) Combination Therapy For The Treatment Of Patients With Relapsed Or Refractory Multiple Myeloma. Available at: [http://www.amgen.com/media/ news-releases/2016/01/fda-approves-new-kyprolis-carfilzomib-combination-therapy-for-the-treatment-of-patients-with-relapsed-or-refractory-multiple-myeloma/](http://www.amgen.com/media/ news-releases/2016/01/fda-approves-new-kyprolis-carfilzomib-combination-therapy-for-the-treatment-of-patients-with-relapsed-or-refractory-multiple-myeloma/). Accessed January 22, 2016.
- United States Food and Drug Administration (FDA). FDA news release. FDA approves Empliciti, a new immune-stimulating therapy to treat multiple myeloma. Accessed November 30, 2015. Available at: [http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm474684.htm](http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm474684.htm).
- United States Food and Drug Administration (FDA). FDA news release. FDA approves Ninlaro, new oral medication to treat multiple myeloma. Available at: . Accessed November 20, 2015.
- Lokhohrst H, Plesner T, Laubach J, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. New England Journal of Medicine. 2015; August 26, 2015DOI: 10.1056/NEJMoa1506348.
- Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Science Translational Medicine. 2014;6(224):224ra25. doi: 10.1126/ scitranslmed.3008226.
- Geyer H, Scherber R, Kosiorek H, et al. Symptomatic profiles of patients with polycythemia vera: Implications of inadequately controlled disease. Journal of Clinical Oncology. Published online before print November 23, 2015, doi:10.1200/JCO.2015.62.9337
- Vannucchi A, Kiladjian J, Grieshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. The New England Journal of Medicine. 2015; 372:426-435. January 29, 2015DOI: 10.1056/NEJMoa1409002
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