Advances in Llm

LLM ADVANCES IN LLM Current Developments in the Management of Leukemia, Lymphoma, and Myeloma Section Editor: Susan O’Brien, MD Recently Approved Drugs Herald a New Era in Therapy for Diffuse Large B-Cell Lymphoma Grzegorz S. Nowakowski, MD Consultant, Division of Hematology Department of Internal Medicine Professor of Medicine Professor of Oncology Lymphoma Group Mayo Clinic Rochester Rochester, Minnesota H&O What are the standard treatments for been considered largely incurable. This outcome could diffuse large B-cell lymphoma (DLBCL)? be changed with some of the new therapies. For these patients, the current standard is treatment with palliative GN For nearly 20 years, rituximab plus cyclophosphamide, chemotherapy or a recently approved agent. In contrast doxorubicin, vincristine, and prednisone (R-CHOP) has to frontline treatment, which has remained constant for been the standard frontline treatment for DLBCL. Some the past 20 years, there are exciting new treatments in the elderly patients, including those with a poor performance relapsed/refractory setting. This field is changing quickly. status or other comorbidities, may not be eligible for full- dose R-CHOP. These patients will often receive a reduced- H&O What are the unmet needs in DLBCL? dose version of R-CHOP (so-called mini R-CHOP) in the frontline setting. R-CHOP leads to a long-term cure in GN The best chance of achieving a successful outcome in approximately 60% of patients. Patients who relapse do DLBCL is during first-line treatment. There is an unmet so relatively quickly following the initial treatment. Most need to improve frontline treatment with R-CHOP, and patients with relapsed or refractory DLBCL will succumb there have been many attempts to do so throughout the to the disease. There has been much interest in the devel- past 20 years. No new treatments have emerged, primarily opment of treatments for these patients. owing to issues with the design of clinical trials. Another The current standard of treatment is primarily based unmet need is to develop therapies for patients who are on the eligibility of patients for high-dose chemotherapy not eligible for treatment with full-dose R-CHOP. This and autologous stem cell transplant. Approximately half group includes elderly patients with organ dysfunction. of patients who relapse after R-CHOP are eligible for There is a huge unmet need for treatments of relapsed intensive salvage chemotherapy. Among these patients, disease, despite the recently approved therapies in this set- approximately half will have a response that is good ting. Although there is a lot of excitement about chimeric enough for them to proceed to high-dose chemotherapy antigen receptor (CAR) T-cell therapies, limited efficacy, and autologous transplant. These treatments will lead to a toxicity, and access remain problems. Many patients long-term cure in about half of patients. Ongoing clinical treated in the relapsed/refractory setting will require addi- trials are comparing this treatment strategy with different tional therapies or will need to switch from treatment to novel treatments. treatment. Patients who decline to undergo transplant or who are Another unmet need is for patients who relapse after ineligible for the procedure—whether based on age, poor CAR T-cell therapy. This population is particularly chal- performance status, or comorbidities—historically have lenging. These patients frequently have very aggressive 284 Clinical Advances in Hematology & Oncology Volume 19, Issue 5 May 2021 LLM disease. In addition, they often have toxicity from the arm because patients in the control arm had a much better CAR T-cell therapy, primarily hematologic toxicities such outcome than expected. These studies provided important as cytopenias (eg, neutropenia and thrombocytopenia). information that was used to improve the design of new These toxicities limit their ability to tolerate additional trials of frontline therapies for DLBCL. A new generation therapy or to participate in clinical trials. Several exciting of trials incorporated design changes that will likely result novel agents are being evaluated in clinical trials, but in stronger data that might change the standard of care in many patients with relapsed disease after CAR T-cell the frontline setting. therapy will not meet the standard inclusion criteria. To In the relapsed/refractory setting, several drugs have address this ongoing unmet need, it will be necessary been approved by the US Food and Drug Administration to change inclusion criteria to enroll these patients into (FDA) in the past 3 years. These therapies can improve clinical trials. the response rate and durability of response, while min- imizing toxicity. An interesting area of research in the H&O Are there recent insights into the relapsed/refractory space is how to sequence the available pathogenesis of DLBCL that might impact therapies. For example, CD19 is a target for several differ- treatment? ent compounds, which must be sequenced in some way. This question is a focus of ongoing research and represents GN Traditionally, DLBCL has been divided into 2 sub- an unmet need. types: activated B-cell (ABC) and germinal center B-cell Relapse after CAR T-cell therapy is a challenging area (GCB). The ABC subtype has been associated with a of DLBCL. It is necessary to develop therapies that are worse outcome. Many treatments for the ABC subtype act less myelosuppressive. Enrollment criteria for clinical trials primarily via B-cell receptor signaling. We now know that should encompass patients with cytopenias, which are fre- the pathogenesis of DLBCL is more complex, involving quently seen at the time of relapse after CAR T-cell therapy. the driver mutations as well as different molecular clusters. Ongoing research is evaluating whether these clusters H&O What are some of the recently approved could benefit from targeted therapies in the frontline and treatments for relapsed/refractory DLBCL? relapsed/refractory settings. There are 2 different broad approaches. One is trying to identify molecular drivers GN The field is changing rapidly. The major breakthrough to develop the best targeted therapy. The other approach, has been in cellular therapies. There are 3 different CAR which has recently gained traction, is agnostic to the T-cell products approved in this space: axicabtagene molecular pathogenesis of DLBCL and targets common ciloleucel (Yescarta, Kite), tisagenlecleucel (Kymriah, antigens that appear in all of the subtypes. CAR T-cell Novartis), and lisocabtagene maraleucel (Breyanzi, Bristol therapies, as well as other treatments that target surface Myers Squibb). These treatments have similar efficacy. At markers such as CD19, are rapidly being developed. An 6 months after treatment, approximately 40% of patients advantage to these therapies is that they work regardless of are in a durable remission. the molecular pathogenesis of DLBCL. There are novel antibodies and antibody-drug conjugates. In April 2021, the FDA approved loncastuximab H&O What are the challenges and/or tesirine-lpyl (Zynlonta, ADC Therapeutics), which targets opportunities in devising new treatment CD19. Tafasitamab-cxix (Monjuvi, MorphoSys/Incyte), strategies for DLBCL? which also targets CD19, is approved for use in combination with lenalidomide (Revlimid, Celgene/Bristol Myers GN The challenges and opportunities vary according Squibb). Polatuzumab vedotin-piiq (Polivy, Genentech), to the line of therapy. In the frontline setting, the major which targets CD79b, is approved in combination with challenge has been to select the right patients for clinical bendamustine and a rituximab product. Both of these trials. In the past, hundreds of millions of dollars were drugs received accelerated approval, and they are fre- spent on large trials enrolling thousands of patients in quently used in this setting. Another agent that received the frontline setting. Unfortunately, the results from accelerated approval for relapsed/refractory DLBCL is these trials did not lead to new treatment options, and the nuclear transport inhibitor selinexor (Xpovio, Karyo- R-CHOP remains the standard of care. We now recognize pharm Therapeutics). some deficiencies in the original designs of those studies. There were issues regarding patient selection; the enroll- H&O What are some promising novel ment criteria frequently selected patients with a better treatments? performance status. Therefore, it was difficult to show a difference between the experimental arm and the control GN There are additional antibody-drug conjugates in Clinical Advances in Hematology & Oncology Volume 19, Issue 5 May 2021 285 LLM clinical trials that appear promising. There are drugs that with the doublet to show that the combination is better. are similar to polatuzumab vedotin-piiq but that target Moving forward, there will be more approvals using this different surface molecules. Bispecific antibodies bind the approach. The approval of tafasitamab-cxix plus lenalido- antigen on the surface of lymphoma cells on one side and mide provides proof of concept that it is possible to use the receptor on the effector T cell on the other side. These real-world data to move drugs to patients faster and more antibodies are essentially CAR T cells in a vial. The usual efficiently. process of preparing the CAR T-cell product involves Another development pertains to clinical trials in the collection of cells from patients via apheresis. The cells frontline setting, such as PHOENIX, ROBUST, and

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