- New potential treatments for lymphoma were discussed by cancer experts at the annual American Society of Hematology conference.
- They included new therapies that can possibly be used when CAR T-cell immunotherapy isn’t effective.
- There were also developments announced in treatments that use “natural killer” cells and therapies that target cancers associated with the Epstein-Barr virus.
In fall 2005, Kevin Rakszawski had just begun his sophomore year at the University of Pennsylvania when he received a diagnosis of stage 4 Hodgkin’s lymphoma.
Rakszawski, who was studying bioengineering and was a member of the school band, had already decided in high school that he wanted to be an oncologist.
After undergoing treatment and being declared cancer-free, he resumed his academic career. The diagnosis cemented his resolve to be a cancer specialist, and it convinced him to focus specifically on lymphomas.
Fast-forward 14 years to the annual American Society of Hematology (ASH) conference that concluded last week in Orlando, Florida.
That’s where Rakszawski was one of more than 30,000 blood cancer and other blood disease experts from 25 countries in attendance.
Rakszawski, now a medical doctor and assistant professor of medicine in the division of hematology/oncology at Penn State Milton S. Hershey Medical Center, says that attending ASH reminds him just how far lymphoma research has come since he received his diagnosis.
“My main takeaway from the conference this year in the field of lymphoma is that we continue to aim for cures and long-term remissions,” Rakszawski told Healthline. “But with lymphoma patients living longer, we’re also looking to reduce toxicities associated with therapy and maximize the value of treatment.”
The hottest topic at ASH, once again, was CAR T-cell immunotherapy, where a person’s T cells are removed from the body, engineered in the lab so they can find and destroy cancer cells, and reinfused in the patient.
CAR T-cell therapy has been the talk of the blood cancer world for several years now.
First-generation CAR T-cell therapies, two of which were approved by the Food and Drug Administration (FDA) 2 years ago, primarily target CD19, a protein on the surface of most tumor cells in B-cell cancers, such as non-Hodgkin’s lymphoma.
These therapies have produced long-term remissions in about one-third of cases of B-cell lymphomas that haven’t responded to prior therapy.
Kymriah, a CAR T-cell product from Novartis, works at least as well in the real world as it does in scientific studies, Novartis officials announced during the conference.
They said that for people with diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin’s lymphoma, Kymriah’s efficacy matched what was seen in studies conducted before it was approved by the FDA in 2017.
In adults with relapsed/refractory DLBCL, Kymriah achieved an overall response rate of 58 percent, including 40 percent having a complete response.
Novartis announced that side effects from CAR T-cell therapy, including cytokine release syndrome (CRS) and neurotoxicity, were seen at a lower rate.
The rate of severe CRS and neurotoxicity was around 4 percent and 5 percent, respectively.
Yescarta, the other CAR T-cell product from Gilead Kite, is also producing positive responses in people with relapsed or refractory large B-cell lymphoma, according to company officials.
With a minimum follow-up of 3 years after a single infusion of Yescarta, approximately half of people with refractory large B-cell lymphoma in the trial were alive, and the median overall survival was about 25 months.
Christi Shaw, the CEO of Kite, said in a press release that the company is “delivering towards our goal of potentially life-saving therapy for many patients who previously faced limited treatment options and a poor prognosis prior to the introduction of CAR T therapy.”
Max S. Topp, MD, a Yescarta trial investigator and professor and head of hematology at the University Hospital of Wuerzburg in Germany, noted in the press release that earlier steroid intervention during treatment has the potential to “reduce the rate of severe CRS and neurologic events while appearing to maintain comparably impressive efficacy.”
Despite CAR T-cell therapy’s ongoing success, much of the talk at ASH focused on an even newer generation of treatments that may work even better than CAR T-cell therapy and with less toxicity.
Only about two-thirds of people enrolled in clinical trials of CAR T-cell therapy will receive the treatment. Often the disease will progress during the time it takes to produce the cells in the lab.
Several study results announced at ASH are treatments that don’t have to be custom-made for each person.
“We are already seeing the potential migration of the first-generation CAR-T treatments to the newer so-called ‘off-the-shelf’ CAR-T and NK [natural killer] treatments, and the emergence of bi-specific antibodies,” said Robert Alan Brodsky, MD, the ASH secretary and professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, in a press release from the conference.
The experimental off-the-shelf treatment that received the most attention at ASH was mosunetuzumab, a bispecific antibody from Roche that’s designed to bind to two specific receptors on tumor cells.
Just as CAR T-cell therapies in lymphoma target a receptor called CD19, mosunetuzumab binds to CD20 on B cells and malignant B cells, and CD3 on T cells.
A multicenter trial of people whose B-cell non-Hodgkin’s lymphoma had relapsed or is refractory, including those who had done CAR T-cell therapy, found that almost half of people with slow-growing lymphomas had complete responses to the treatment.
Stephen J. Schuster, MD, director of the Lymphoma Program at the Abramson Cancer Center at Penn and lead investigator of the trial, said at the conference that among people in the study whose lymphoma progressed after CAR T-cell therapy, 22 percent went into complete remission when treated with the drug.
More than 270 people in seven countries in North America, Europe, Asia, and Australia have received the experimental therapy.
All of them had B-cell lymphomas that had relapsed or hadn’t responded to prior therapies.
Of that group, 193 people were evaluable. This included 124 cases (65 percent) of aggressive lymphomas and 67 cases (35 percent) of slow-growing cancers.
The overall cohort included people whose disease had progressed after stem cell transplant as well as those whose disease didn’t respond to or relapsed after CAR T-cell therapy.
Among the group with aggressive lymphomas, 46 participants (37 percent) saw the amount of cancer in their body decrease while 24 participants (19 percent) achieved complete remission.
Among people with slower-growing lymphomas, 42 participants (63 percent) saw a decrease in cancer and 29 participants (43 percent) achieved complete remission.
For the participants who saw their disease entirely disappear, the remissions appear to be long lasting.
At a median follow-up of 6 months, 24 of the 29 participants (83 percent) with slow-growing lymphoma and 17 of the 24 participants (71 percent) with aggressive lymphoma were still disease-free.
In four people whose disease came back after remission, three saw a response when they started treatment again.
This includes one person who went back into a remission that has now been ongoing for 13 months.
Molecular testing of some of the people who had previously received CAR T-cell therapy showed the CAR T-cells in their bodies increased in number in their blood after treatment with mosunetuzumab.
“This could mean that not only does mosunetuzumab have the ability to kill cancer, but also that it may help re-engage CAR T cells and boost the effect of the prior CAR treatment,” Schuster said in a press release.
CRS was reported in 29 percent of participants in this study, but only 3 percent required treatment with Actemra, which is used for the treatment of severe or life threatening CRS.
“There is still a large need for new treatments in relapsed or refractory cases, since some patients fail CAR T and others are too sick to wait for cell manufacturing,” Schuster said.
As Healthline reported last year, natural killer therapies are another treatment for lymphomas that are getting a lot of attention.
Dan S. Kaufman, MD, PhD, professor of medicine and director of cell therapy at the University of California, San Diego School of Medicine, told Healthline that one trial from the MD Anderson Cancer Center in Ohio has engineered cord blood–derived natural killer cells “with an anti-CD19 CAR with early results showing promising efficacy against B-cell lymphomas.”
Another trial will soon be starting from Fate Therapeutics, a company with whom Kaufman consults and collaborates, using natural killer cells derived from human-induced pluripotent stem cells (iPSCs).
Kaufman, who has 20 years of clinical experience in hematology and leads a research group studying blood cell development and production of new cell-based therapies for cancer, says these iPSC-derived cells are engineered “with both a novel anti-CD19 CAR that is optimized for function in NK cells, as well as a stabilized version of CD16 that leads to improved anti-tumor activity when combined with anti-CD20 antibodies.”
“Therefore, these iPSC-derived [natural killer] cells will utilize multiple different mechanisms to better treat lymphoma and be available as an ‘off-the-shelf’ therapy that are manufactured, stored, and ready to treat patients without delays that occur in current CAR T-cell-based treatments,” he said.
Despite all the advances, virtually every scientist interviewed by Healthline at ASH agreed that the first-generation CAR T-cell treatments will stay on the market for multiple reasons.
But they soon will have company. The more treatment options the better, seemed to be the mantra at ASH.
In addition to CAR T-cell and off-the-shelf treatments as well as targeted therapies, another trend in lymphoma treatment seen at this year’s ASH conference is the deployment of a combination of therapies at once.
Sometimes two, three, and even four different drugs for one person.
Combination therapies can extend survival and perhaps even provide a cure, several experts told Healthline. They can also bring together drug companies that were once rivals.
The ongoing trend in lymphoma research is toward removing or reducing standard chemotherapy agents from the frontline setting and using immunotherapy or targeted therapies, says Danelle James, head of clinical science at Pharmacyclics, an AbbVie company.
At Pharmacyclics, she told Healthline, the number of options that involve more than one drug continue to mount.
For example, Venclexta is one of Abbvie’s most successful treatments for a growing list of lymphomas and other cancers, often in combination with Imbruvica and other drugs.
A trial of people with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) showed that those who received up to 12 cycles of Venclexta and Imbruvica, the combination regimen of these two oral drugs, achieved high rates of undetectable minimal residual disease.
“This is our mission, to move away from chemotherapy,” James said.
Constantine Tam, MD, a hematologist and disease group leader of the low grade lymphoma and chronic lymphocytic leukemia programs at Peter MacCallum Cancer Centre in Victoria, Australia, said at the conference that the oral regimen of Imbruvica followed by combined Imbruvica and Venclexta delivered a promising rate of disease clearance in previously untreated cases.
Imbruvica is a first in class Bruton’s tyrosine kinase inhibitor that’s administered orally.
Venclexta is a first in class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. It’s also an oral medication.
Kura Oncology, a pharmaceutical company focused on precision medicines for cancer, has resurrected a treatment for angioimmunoblastic T-cell lymphoma (AITL), a rare, often aggressive form of peripheral T-cell lymphoma (PTCL).
The treatment, tipifarnib, originally showed durable anticancer activity in both blood cancers and solid tumors.
But the drug was ultimately scrapped because scientists couldn’t determine the molecular mechanism of action that could explain the promising clinical activity.
But thanks to advances in next-generation sequencing and emerging information about cancer genetics and tumor biology, Kura CEO Troy Wilson told Healthline this activity is now better understood and can be explained.
Wilson says he was determined to finish what other scientists started and bring the drug back to life.
He says he was convinced he could solve the tipifarnib puzzle, learn why the treatment worked so well for some cases and not others, and give this treatment another shot.
The untangling of the human genome has led to all kinds of landmark discoveries of focused, precision medicines.
And tipifarnib is now showing positive results in trials.
At ASH, Wilson announced clinical and regulatory updates for tipifarnib in AITL, including data from Kura’s ongoing phase II clinical trial of tipifarnib in relapsed or refractory peripheral T-cell lymphoma (PTCL).
Kura will initiate a single-arm, phase II trial next year of its treatment in angioimmunoblastic T-cell lymphoma.
“Tipifarnib continues to demonstrate clinically meaningful activity in advanced PTCL, including patients with AITL for whom there are few treatment options,” said Thomas E. Witzig, MD, a hematologist at the Mayo Clinic in Minnesota and principal investigator in the trial, in a press release.
“The high level of clinical activity of tipifarnib, including complete responses, in third- and fourth-line patients, coupled with the fact that tipifarnib is an oral medication means it could be another treatment option for a patient population with high unmet need,” Witzig said.
“Based on our growing body of data, we believe CXCL12 pathway biomarkers may have the potential to unlock the therapeutic value of tipifarnib across multiple hematologic and solid tumor indications, including diffuse large B-cell lymphoma, acute myeloid leukemia, cutaneous T-cell lymphoma and pancreatic cancer,” Wilson added.
“We will continue our efforts to identify these patient subsets and to bring this important drug candidate to patients in need,” he said.
Meanwhile, Viracta, whose approach to lymphomas that are caused by the Epstein-Barr virus was the subject of a Healthline story in June, also shared positive new trial results at ASH.
Pierluigi Porcu, MD, a physician at the Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University in Pennsylvania, presented data from the company’s phase 1b/2a clinical trial of the orally administered combination of nanatinostat (Nstat) in combination with the antiviral valganciclovir for the treatment of Epstein-Barr–associated relapsed/refractory lymphomas.
“There is a clear unmet medical need for effective and well-tolerated treatment options for EBV-positive lymphomas, and EBV positivity is very often correlated with poor prognosis. The overall objective response rate, complete response rate, and clinical benefit rate observed for heavily pretreated relapsed/refractory EBV-positive lymphoma patients in this dose ranging Phase 1b study are very encouraging,” Porcu said in a press release.
“These data underscore the potential for Nstat and valganciclovir as a novel therapeutic approach for the treatment of relapsed/refractory EBV-positive lymphomas,” added Ivor Royston, MD, president and CEO of Viracta, in the company’s press release.
Royston said he hopes awareness of this treatment will lead to increased screening of relapsed/refractory lymphomas for the presence of the Epstein-Barr virus.
“We expect to complete the Phase 2 portion of the Phase 1b/2 study in the first half of 2020, initiate a registration study in the second half of the year, and expand our treatment approach into EBV-positive solid tumor indications,” he said.