Lymphoma Highlights from the 2018 American Society of Hematology, with Michael E. Williams, MD, ScM

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In this podcast, Cancer.Net Associate Editor Dr. Michael Williams will discuss some of the new research in lymphoma that was presented at the 2018 American Society of Hematology Annual Meeting, held December first through fourth in San Diego, California. Dr. Williams is the Chief of the Hematology/Oncology Division and Director of the Hematologic Malignancies Program at the UVA Cancer Center, and Byrd S. Leavell Professor of Medicine and Professor of Pathology at the University of Virginia School of Medicine. ASCO would like to thank Dr. Williams for discussing this topic. Dr. Williams: Hello. This is Michael Williams. I'm a professor at the University of Virginia Health System in Charlottesville, Virginia, and I'm reporting today on some exciting advances in lymphoma that were presented at the Annual Meeting of the American Society of Hematology, which was held in San Diego, California in early December 2018. Well, there were a number of areas of lymphoma that had important reports, and I'm going to just give you a small sampling of these today. We'll start with a new treatment option for patients with follicular lymphoma. Traditionally, this type of lymphoma, when it's symptomatic and needs therapy, the treatment of choice has been chemotherapy combined with a monoclonal antibody such as rituximab or obinutuzumab. But investigators, in a multicentered trial, decided to test whether you could use a chemotherapy-free treatment approach for patients like this by using rituximab combined with lenalidomide, which is also known as Revlimid, as a substitute for chemotherapy. And this is based on the fact that Revlimid plus rituximab has synergistic activity in patients with relapsed disease, so maybe we could see acceptable, high responses when it would be compared directly with rituximab plus chemotherapy. So the way the trial worked is this. Patients who needed therapy, who had advanced-stage follicular lymphoma—they had never had any therapy before—were randomized to either the rituximab-lenalidomide combination or a rituximab-chemotherapy combination that could include the regimens CVP or cyclophosphamide, vincristine, prednisone, the same combination given with daunorubicin, or the CHOP regimen, or rituximab combined with bendamustine. So over 1,000 patients were treated in this multinational study and the goal of the treatment, of the study was to prove that, actually, the ritux-lenalidomide was superior to the chemotherapy regimens. So the results showed, not superiority, but comparability. The complete remission rate between rituximab-len and ritux-chemotherapy were really identical, 48 and 53 percent, and the 3-year likelihood that the patients were progression-free, so had had no recurrence of their disease, was identical as well: 77 to 78 percent. There was no difference in survival which was 94% at 3 years in both arms. The toxicities differed, however. There was more rash with the lenalidomide combination, whereas low blood counts and the need for growth factor support such as G-CSF was greater with chemotherapy. And it was also interesting that some of the traditional risk factors didn't seem to apply, as much, for lenalidomide. So what would be considered higher risk patients treated with chemotherapy, seemed to do somewhat better with the lenalidomide combination. The importance for a patient with untreated follicular lymphoma who needs therapy is that a chemotherapy-free approach with rituximab plus lenalidomide can be considered equivalent to rituximab-chemotherapy. It’s worth discussing this with your oncologist when you're considering what treatment to use initially. The next subtype of lymphoma that I want to discuss is diffuse large B-cell lymphoma, and there's 2 presentations that I'm going to summarize. One, in patients with advanced stage disease, meaning stage III or IV. This identifies patients who have disease both above and below the diaphragm, to make it stage III, or stage IV means they've got bone marrow or other sites of involvement such as liver or bone. And the question being asked in this trial, which was part of the International GOYA trial, will take just a moment to explain. So the original GOYA trial compared whether a newer form of anti-CD20 monoclonal, namely obinutuzumab, which is also called Gazyva, how that would compare with the standard established monoclonal antibody, rituximab. And the initial findings of this study found that there was no benefit for the newer antibodies. So rituximab and CHOP chemotherapy was equivalent to obinutuzumab and CHOP chemotherapy in overall outcomes. But there was an opportunity with this trial to answer a question that's been out there for many years, and that is how many cycles of treatment does one need? So the investigators took advantage of this large study which included 712 patients who were randomized to rituximab plus CHOP. Just over 500 of them received 6 cycles, and the remaining 186 received 8 cycles. Even the patients who got 6 cycles of CHOP chemotherapy also got an additional 2 doses of rituximab, so the immunotherapy monoclonal antibody was equivalent between the 2 arms. And the results of this showed that there was really no difference at all with a followup of about 3 years. Response rates were equivalent and there was no difference in the patients staying in remission. It didn't matter in terms of survival which was excellent in both arms. There was, however, more toxicity in patients who received 8 cycles, including cardiac problems, infections, etc. These results showed that, I think we can finally put to rest the use of 8 cycles of rituximab-CHOP chemotherapy for advanced-stage large cell lymphoma. It's been an unknown entity because we never had a direct comparison of these. So we can now say that 6 cycles plus the additional 2 doses of rituximab is a standard for advanced-stage diffuse large B-cell lymphoma. Now, what about patients who have limited-stage, so stage I or II diffuse large cell lymphoma? That means just a single lymph node area's involved or 2 adjacent lymph node areas. In the past, these were treated either with 6 cycles of rituximab-CHOP or sometimes cycles of R-CHOP plus local radiation therapy. And in this study, which took a long time to complete; it began in 2005, but it enrolled 592 patients who were then randomized to either 4 cycles or 6 cycles of treatment. Radiation therapy was not planned for any of these patients except for very specific locations of involvement such as testicular DLBCL where radiation therapy is a standard. So the take-home message after over 5 years of follow-up for patients on this study showed that 4 versus 6 were identical. So 89% of patients were still in remission at 3 years after completing treatment, and the overall survival was really impressive, 98 to 99 percent in the 2 arms. So there was no benefit with limited-stage favorable disease. Now, who are these patients? So younger than age 60, stage I or II disease, and normal LDH. They did not have bulky disease, meaning there was no nodal mass more than 7 and a half centimeters. So if you fit those criteria, then you can benefit from a de-escalation of treatment and be spared the additional 2 cycles of R-CHOP. Now, sticking with the topic of diffuse large B-cell lymphoma, a challenging problem in our field is for patients who relapse after their initial therapy, or in some cases, fail to respond to a treatment like rituximab-CHOP or an equivalent immuno-chemotherapy regimen. And a very exciting advance in the field, over the past few years, has been the development of chimeric antigen receptor T cells or CAR Ts. Traditionally, what we've done with patients who relapse or have resistant diffuse large cell lymphoma is to give them a second-line, high-dose chemotherapy regimen, and if they showed a good response to that, they could then go to a dose-intensive treatment with a follow-up consolidation by autologous stem cell transplantation. And with that, you can cure, overall, about 40% or so of patients. The CAR T-cell approach takes a very novel immunotherapy effort, and that is that a patient's own T-cells are removed from the peripheral blood, and then in the laboratory, they're modified and reprogrammed so they can attack the patient’s diffuse large B-cell lymphoma cells that are resistant to chemotherapy. So there were 2 important follow-up studies, each of them involved 1 of the agents, the CAR T-cell products, that are approved by the Food and Drug Administration for patients with relapsed or refractory diffuse large cell lymphoma. The first used the CAR T known as axicabtagene ciloleucel. It's quite a complex name, but it goes by the abbreviation of axi-cel or the trade name is Yescarta. So in this study, the investigators wanted to show that this is a treatment that can be extended to many centers with the product, the CAR T being made in a central facility by the pharmaceutical company. So it was a retrospective study of 295 patients at 17 international centers: a lot of patients across a broad spectrum of sites in North America and Europe. Virtually all the patients were able to develop and obtain a CAR T product. It included patients with some of the higher risk forms of the DLBCL such as double and triple-hit lymphoma. About 3% of patients died during the treatment, although only 1% of these were felt to be related to the treatment itself. The response rates were quite good, with about 80% of people responding. The complete remission rates at 30 days after the CAR T infusion were 47%. So it proved that you can use this centrally manufactured product. So the patients T-cells are collected at the local center, they're shipped to the manufacturing facility, the CAR Ts are generated, sent back to the home institution, and then infused. And I'll say a word in a moment, after I introduce the next paper, to explain some of the side effects of this treatment. So the second study was also presented at the ASH meeting and published simultaneously in the New England Journal of Medicine in early December 2018. So this used the second FDA approved CAR T known as tisagenlecleucel or Kymriah. In this study, there were 93 patients who were able to receive a CAR T-cell infusion, 40% of them achieved a complete remission, and another 12% had a partial response. And that a year after their documented response, two-thirds of these patients were maintaining the response, including 79% of those who achieved a complete remission. So this trial again confirmed across multiple centers that CAR T-cells can be an effective therapy. The side effects of both of these drugs can include something called cytokine release syndrome where the immunologic effects, essentially, release cytokines into the blood that can mediate a capillary leak, respiratory troubles, and low blood pressures, that can, in some cases, require intensive care unit support. This can be managed by other mediators that tamp down the cytokine effect such as an interleukin-6 antagonist. The other toxicity which is less well understood and problematic can be neurologic effects which can include confusion, speech alterations and even coma. But again, approaches and treatments to identify and manage this are being developed. So CAR Ts have become established. They're available at a number of centers, but it's important to consider this as a treatment option in the setting of relapsed or refractory diffuse large cell lymphoma. The long-term curability is still unknown, although it's encouraging that patients with very resistant disease who'd get a good response can maintain that response out to a year and more. So we're going to be very interested to see how the longer-term follow-up comes together. The final topic I wanted to mention today is Waldenstrom macroglobulinemia. So this is a unique form of indolent B-cell lymphoma where the lymphoma cells release a monoclonal immunoglobulin into the blood known as IGM. Now, IGM is a very large antibody, and because of that, when the levels are very high, patients can have problems with high viscosity or thickening of the blood, which can cause confusion, vision changes, sometimes respiratory problems. And these patients also can become anemic or develop enlarged lymph nodes or enlarged spleen. So one of the standard treatments for this disease is, again, the immunotherapy monoclonal antibody rituximab, but the responses are typically incomplete and somewhat short-lived. So it was exciting, a couple of years ago, when the targeted tyrosine kinase inhibitor, ibrutinib, which targets the bruton tyrosine kinase in malignant B-cells. This is an agent that's approved in chronic lymphocytic leukemia, and certain lymphomas such as mantle cell, marginal zone, as well as lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. So here's the study. Investigators had shown that if you combine rituximab with ibrutinib, that the response rates were improved as compared with rituximab by itself. And in a follow-up study that looked at this over a longer period of time, these benefits of the combined therapy were confirmed. These included patients without prior treatment or with prior treatment, with either chemotherapy or rituximab. And there was a confirmed benefit for the ibrutinib-rituximab combination in patients, whether they had had treatment before or not, and regardless of certain genetic markers that we use to assess risk in Waldenstrom. It was also shown that because these treatments continue indefinitely, as long as patients are responding and tolerating therapy, that the response rates improved over time. The side effects of treatment with ibrutinib are well-known, now, after several years of use across a variety of diseases, as mentioned, and include diarrhea, sometimes rash. You can see problems with easy bruising or bleeding, atrial fibrillation, and sometimes skin rash, or muscle and joint aches. But most patients are able to continue therapy and to benefit from it over an extended period of time. So the combination of ibrutinib plus rituximab was shown to add benefit compared with rituximab alone, and again, is a treatment approach and option that you could consider whether you have previously untreated or relapsed Waldenstrom macroglobulinemia. So overall, it was a very exciting meeting. We've had practice-changing data presented, and I've given you just a sampling of those. I think it's important for anyone dealing with lymphoma, or related malignancy, such as CLL or multiple myeloma to be very encouraged by the progress in the field, the opportunity to get much better responses with less toxicity and with minimal or no use of traditional chemotherapy. So we're pleased to be able to offer these treatment approaches for our patients. And I thank you for your taking part in the podcast and hope you found it useful. Thanks again. ASCO: Thank you, Dr. Williams. Learn more about lymphoma at www.cancer.net. 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