Treatment landscape promising for relapsed or refractory diffuse large B-cell lymphoma
Nearly 30,000 new cases of diffuse large B-cell lymphoma are diagnosed annually in the United States.
Of these, approximately 70% of cases are likely to be cured with front-line therapy. For the 30% of patients who relapse, cure is possible with subsequent therapy.
“Certain patients may need more lines of therapy than others,” Daniel J. Landsburg, MD, assistant professor of clinical medicine in the division of hematology/oncology of the Perelman School of Medicine at the University of Pennsylvania, told Healio.Between 30% to 40% will never be cured either because they never go into remission with front-line treatment, or they may relapse after achieving remission.”
A substantial amount of research has examined the factors that predict which patients will do well and experience cure.
“For example, patients with DLBCL who demonstrate rearrangement of the MYC are considered a poor prognosis group and those patients are less likely to be cured with front-line therapy,” Landsburg said. “The International Prognostic Index [IPI] helps us to assess other risk factors, such as age and nodal sites, to help determine outcomes after treatment. More advanced molecular testing is available, but its use is not standard. Hopefully, it will become standard soon because it could help us to better understand prognosis and identify opportunities for the use of targeted therapies from the start for these patients.”
Standard of care
Despite attempts to improve standard front-line R-CHOP chemotherapy , it has remained the standard of care for patients with DLBCL for decades. However, for those who do relapse after front-line treatment, new treatment options are needed, according to Landsburg.
“Even the patients who were relatively healthy when first diagnosed may be somewhat sicker at relapse, either because their disease behaves more aggressively at relapse or they experienced toxicity from front-line therapy,” he said. “This can be a challenge, as many of the therapies that we use in the relapse setting tend to be more intensive than what is used as front-line therapy. Not only are these patients more ill, but they need better therapies as standard second-line options are potentially more toxic.”
Not only are certain second-line therapies more toxic, they are also not as effective, Landsburg added.
“We often deal with treating multiple relapses for patients multiple times because second-line therapies do not always result in a long-term response,” he said. “DLBCL eventually becomes a disease that needs to be treated frequently for many patients, which poses another challenge because patients develop toxicities and potentially more aggressive disease when requiring ongoing treatment for their DLBCL and it becomes harder and harder to treat these patients in general.”
Curative-intent treatments for relapsed/refractory disease
Chimeric antigen receptor T-cell therapy and autologous hematopoietic stem cell transplant provide cure for certain patients but are not typically offered to older patients because of their aggressiveness.
“In general, CAR T-cell therapy and autologous HSCT are not considered for patients with DLBCL aged 70 years and older,” Landsburg said. “The problem is that this is a large chunk of the patient population. We are often more hesitant to give some of these more aggressive therapies based on age alone and this is a major problem. We are lucky with this disease in that many patients are cured with front-line therapy, and we do not need to think much about treating them down the road, but there are many older patients for whom there are a lot of challenges if not cured by front-line therapy.”
When selecting which therapies to use for his patients, Landsburg said he first identifies which patients will be good candidates for autologous HSCT or CAR T-cell therapy later.
“If they are good candidates, then I am fairly aggressive about second-line treatment and we offer them salvage chemotherapy in the second-line setting. If they are responding well, then they will go on to receive autologous HSCT, and if they do not respond to that then typically CAR T-cell therapy is offered,” he said.
Some patients who are not in complete remission before a planned autologous HSCT may be offered CAR T-cell therapy instead, as it is believed that will lead to a better outcome.”
However, in a study presented during the ASCO2020 Virtual Scientific Program, Nirav N. Shah, MD, assistant professor of hematology and medical oncology at Medical College of Wisconsin and a HemOnc Today Next Gen Innovator, and colleagues found that autologous HSCT is still a viable option for patients with partially chemosensitive, relapsed or refractory DLBCL. Researchers cautioned against replacing autologous HSCT with CAR T-cell therapy before seeing definitive data that are superior or at least equivalent.
Newer treatments
For patients who are less fit, older or have relapsed/refractory disease following CAR T-cell therapy or autologous HSCT, other therapies can be used, including polatuzumab vedotin (Polivy, Genentech) and (Xpovio, Karyopharm Therapeutics).
Still, there is no standard-of-care treatment for patients who relapsed and are not candidates for autologous HSCT or CAR T-cell therapy.
“When looking at the individual patient, we need to try to plan ahead and see what each patient’s preferences are. For example, do they want to receive an infusion or a pill, how close do they live to a cancer center and how often are they willing to travel to the center?” Landsburg said. “Treatment is definitely an individualized decision, but it ultimately rests on whether or not the patient is going to be a good candidate for curative therapy, which takes us down one path, and if they are not good candidates for or their disease has not been cured by those therapies, then we are taken down a different path. The latter path is not well-defined right now, but fortunately there are a lot of options available today and in the pipeline.”
Lisocabtagene maraleucel (Bristol Myers Squibb) — an autologous CAR T-cell therapy that targets the CD19 antigen expressed on the surface of cancer cells — was recently approved for patients with relapsed or refractory DLBCL.
Results of the TRANSCEND NHL 001 trial published in 2020 in The Lancet showed that 73% of patients who received the agent achieved an objective response and 53% achieved complete response.
“Lisocabtagene appears to have low rates of toxicity and appears similar to tisagenlecleucel [Kymriah, Novartis], which targets the same CD19 antigen,” Landsburg said. “It is hard to be the third agent ‘on the block’ because many clinicians are comfortable using one of the other two previously-approved CART products. It is difficult to convince clinicians and patients to take a therapy that has not been used commercially across cancer centers as opposed to what we have been using for years now.”
However, there are certain cases where tisagenlecleucel cannot be used, such as patients who are HIV-positive, for which lisocabtagene can fill this role, Landsburg added.
“Still, we are very pleased with the results we are seeing with tisagenlecleucel at our center and we will continue to use it,” he said. “There may be issues with access to these newer treatments for certain areas of the country, but this is something that will hopefully improve over time. In terms of cost, these therapies are typically covered by insurance and my patients rarely see out-of-pocket costs. However, the overall cost is high and reimbursements from certain insurers are not always favorable.”
Regarding toxicities associated with these treatments, Landsburg said it is now easy to determine upfront which patients will fare better.
“We sort of know now more about who is likely to experience toxicities and so we either monitor them differently, or we treat them differently beforehand to get their disease under better control so that they are less likely to experience toxicities,” he said. “It is a concern, but we have a very good system for monitoring toxicity when patients are in the hospital or outpatient, so we have a good handle on it. We still have some patients that may experience severe toxicity from CAR T-cell therapy, which is unfortunate, but they are few and far between. Most of our patients have come through with few, if any, long-term side effects from these therapies.”
Looking ahead
In addition to new CAR T-cell therapies, researchers are looking at bispecific antibodies, which are not yet FDA-approved.
“They are promising and have similar toxicities as CAR T-cell therapies but are ‘off-the-shelf’ and can be administered at cancer centers where they do not have the ability to offer CAR T-cell therapy,” Landsburg said. “But we do not know if they are curative because of a lack significant long-term follow up at this time.”
Small molecule inhibitors have also shown promise in this patient population.
“One of my interests is in small molecule inhibitors that target different active pathways,” Landsburg said. “Those agents alone in the relapse setting may not be adequate as monotherapy to treat aggressive disease, although some patients do respond well. The addition of those oral agents to standard front-line therapy for patients whose lymphomas demonstrate specific pathologic features may help cure more patients upfront and then obviate the need for treatment for relapse down the road.”
“I don’t think we are at the point where we are giving the best front-line treatments to our patients,” Landsburg said.
“We are still missing opportunities to cure patients at the time of their initial diagnosis,” he said. “If 60% to 70% of patients are cured, that is great and certainly better than a lot of other newly diagnosed cancers. But we are missing something at the beginning. While a lot of current research is focused on the relapsed and refractory setting, there is progress still to be made in curing more patients in the beginning of the disease course by identifying the driver mutations or pathways of their individual lymphomas and then using therapies that match those drivers to treat them. This is where our focus should be.”
References:
- Abramson JS, et al. Abstract LBA4. Presented at: TCT | Transplantation & Cellular Therapy Meetings; Feb. 19-23, 2020; Orlando.
- Shah NN, et al. Abstract 8000. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
For more information:
Daniel J. Landsburg, MD, can be reached at daniel.landsburg@pennmedicine.upenn.edu.
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