Learn about the latest innovations in hematologic oncology.
The FDA will assess two CAR T-cell drugs that appear highly effective as second-line therapy for relapsed or refractory large B-cell lymphoma, according to Geoffrey Hill, MD, SCCA, Fred Hutch, and UW director of hematopoietic stem cell transplantation.
SCCA, Fred Hutch and UW physicians helped test one of the drugs, which represent an important advancement in care. Clinical trial results were presented at the annual meeting of the American Society of Hematology (ASH).
“Our work at SCCA, Fred Hutch, and UW is at the leading edge of science,” says Dr. Hill. “Each year, the ASH meeting reminds us of the progress we’re making in treating hematological cancers and how this is improving clinical care and patient outcomes.”
Dr. Hill and more than 20 other SCCA, Fred Hutch, and UW physicians joined hematology-oncology experts from around the world at the December conference. They unveiled findings from the latest research into promising new treatments for hematological malignancies, such as lymphoma, leukemia and myeloma.
SCCA, Fred Hutch, and UW’s key findings presented at the annual ASH meeting ranged from CAR T-cell therapies and other cancer treatments to stem cell transplants. Highlights from the conference featured news that:
1. Two of three head-to-head comparisons find CAR T-cell therapy more effective than autologous stem cell transplant as second-line therapy in patients with large B-cell Lymphoma
For patients with large B-cell lymphoma (LBCL) who are refractory to or relapse within 12 months of initial CHOP therapy, the standard second-line treatment is additional chemotherapy followed by autologous stem cell transplant (ASCT). However, the outcome of these patients remains poor.
Three multisite clinical trials presented at the annual ASH meeting offered the first direct comparisons of CAR T-cell therapy vs. standard-of-care (SOC) as second-line therapy. Two of the three studies showed significant improvements in patient outcomes with CAR T-cell therapy with no new safety signals.
“These results pave the way for the FDA to potentially bump CAR T-cell therapy up as a second-line treatment. This is good news for patients with large B-cell lymphoma who are not responding to first line therapy,” says Dr. Hill.
All three studies were Phase 3 randomized trials. They compared different CAR T-cell therapies (administered after lymphodepleting chemotherapy) with SOC (platinum-based chemotherapy followed by ASCT for patients who showed complete or partial response). Study participants were patients with relapsed or refractory LBCL.
ZUMA-7 study: Axicabtagene ciloleucel (axi-cel)
In this study, patients were randomized to receive axi-cel (n=180) or SOC (n=179). The study allowed steroids as bridging treatment during CAR T-cell production. Patients in the SOC arm who did not respond to chemotherapy received off protocol axi-cel.
Compared with SOC arm, axi-cel therapy resulted in a:
- 4.1-fold increase in median event-free survival (8.2 months vs. 2 months)
- 2-fold increase in complete response (65% vs. 32%)
- 2.6-fold increase in the percentage of patients who were able to receive CAR T-cell therapy vs. ASCT (94% vs. 36%)
Transform study: Lisocabtagene maraleucel (liso-cel)
In the Transform Study, patients were randomized to receive liso-cel (n=92) or SOC (n=91). Bridging chemotherapy was allowed during CAR T-cell production. Patients in the SOC arm could cross over to liso-cel if they:
- Did not respond to three cycles of chemotherapy
- Did not show complete response after ASCT
- Showed any evidence of progressive disease
Improvements in outcomes were similar to the axi-cel study. Liso-cel resulted in a:
- 4.4-fold increase in median event-free survival (10.1 months vs. 2.3 months)
- 1.7-fold increase in complete response (66% vs. 39%)
- .6-fold increase in the percentage of patients who were able to receive definitive CAR T-cell therapy vs. ASCT (98% vs. 63%)
Belinda study: Tisagenlecleucel (tisa-cel)
Tisa-cel is approved for use as a third-line treatment for B cell acute lymphoblastic leukemia and LBCL. Researchers conducting this study did not find any significant improvements in event-free survival or complete response with tisa-cel.
It's unclear why these results were negative, especially given the success of the axi-cel and liso-cel studies, says Dr. Hill, adding that it may be because tisa-cel is a different type of CAR T-cell product. More likely, this study allowed participants to receive more chemotherapy as a bridge in the tisa-cel arm and more cycles in the SOC arm, which could have affected the outcomes.
The results may also be related to the design of the study. Researchers in the tisa-cel study tried to make a more direct comparison of transplant vs. CAR T-cell therapy. In contrast, the axi-cel and liso-cel studies compared initial reinduction chemotherapy to CAR T-cell therapy.
2. Replacement of vincristine with polatuzumab vedotin in the R-CHOP regimen improves progression-free survival in patients with untreated diffuse large B-cell lymphoma
The phase 3 POLARIX trial found a 6.5% improvement in progression-free survival at 2 years with this regimen. This likely represents the first significant advance in initial therapy for untreated diffuse large B-cell lymphoma since the addition of rituximab. As important, the use of polatuzumab did not appear to increase toxicity.
The lymphoma research team from SCCA, Fred Hutch, and UW contributed to this study. Team members noted the key limitation of POLARIX was that more intensified regimens that R-CHOP are used for those with the most aggressive B-cell lymphomas. As a result, Ryan Lynch, MD, of SCCA, Fred Hutch, and UW initiated a trial to evaluate polatuzumab vedotin as part of the intensive DA-R-EPOCH regimen. Data is expected to be presented this year.
“The use of the antibody-drug conjugate polatuzumab vedotin as part of initial therapy for aggressive B-NHL has the potential to improve cure rates and reduce the need for complex downstream options such as a CAR-T and transplant for patients suffering with these diagnoses,” says Ajay Gopal, MD, the clinical research director and medical director for hematology and hematologic malignancies at SCCA, Fred Hutch, and UW.
3. BCMA CAR T cells with a gamma secretase inhibitor is safe and increases BCMA surface expression in patients with relapsed or refractory multiple myeloma
BCMA-targeted CAR T cells represent a potential therapeutic option for patients with refractory multiple myeloma (MM). However, a gamma secretase complex cleaves BCMA from the surface of tumor cells, allowing tumors to escape BCMA CAR T cells.
This Phase 1 study led by Andrew Cowan, MD, of SCCA, Fred Hutch, and UW assessed safety and efficacy of a gamma-secretase inhibitor (GSI) in combination with BCMA CAR T cells. Treatment included three doses of a GSI over five days followed by BCMA CAR T-cell therapy three times per week for three weeks.
Among study participants:
- 67% were penta-refractory
- 72% had high risk genetics
Results showed that:
- GSI increased BCMA expression on tumor cells 12-fold
- 78% of patients (14 of 18) achieved very good partial response or better
- 44% of patients (8 of 18) achieved complete response
- Combined GSI and BCMA CAR T cells was safe and tolerable
“Considering that the study participants were heavily pre-treated and high risk, these results are very promising,” says Dr. Hill. “This approach could greatly improve outcomes for patients with multiple myeloma who don’t respond to our usual drugs."
Dr. Cowan, the senior investigator, plans additional studies to fine tune the dosing and timing of doses.
4. Single-cell transcriptomics detect residual disease in acute myelogenous leukemia post allogeneic hematopoietic cell transcription
In patients with acute myelogenous leukemia, physicians make treatment decisions based on the evidence of measurable residual disease, among other factors. Prior to allogenic stem cell transplant, physicians want to see evidence of no disease. Post-transplant, they look for recurrent disease.
Current methods for measuring measurable residual disease include:
- Flow cytometry, in which a leukemia cell-specific antibody is labeled with a fluorochrome. This technology has limitations because it cannot always distinguish malignant leukemia cells from normal cells.
- Next generation molecular techniques that detect leukemia-specific mutations in the leukemia cells. However, mutations are not always present and may evolve over time.
SCCA, Fred Hutch, and UW’s Scott Furlan, MD, reported at the ASH meeting on a new technique that uses single cell RNA sequencing of individual cells and UMAP clustering of transcriptomes. This diagnostic tool can discriminate malignant vs. nonmalignant and donor vs. recipient cells after allogenic stem cell transplant with high sensitivity.
“This is an incredibly powerful technique that also gives us the ability to look at how the residual leukemia cells are actually behaving,” says Dr. Hill.
The initial study evaluated this new technique in one patient. Dr. Furlan plans a subsequent study with a larger cohort of patients.
Other ASH highlights
SCCA, Fred Hutch, and UW physicians presented a variety of new therapies at the ASH meeting. They include a CD20-targeted CAR T-cell therapy, the IL-15 receptor agonist NKTR-255 and pembrolizumab plus AVD:
Third generation CD20-targeted CAR T cells show promising efficacy and safety
This single-institution Phase 1 study, presented by SCCA, Fred Hutch, and UW physician, Mazyar Shadman, MD, evaluated the safety and efficacy of a CD20-targeted CAR T cell. This is a new CAR T cell developed by Brian Till, MD, of SCCA, Fred Hutch, and UW.
Twenty patients with a variety of CD20+ B-cell malignancies participated in the study. It also included patients who previously received CD19 CAR T-cell therapy.
The results were promising, according to Dr. Shadman. They included:
- High response rates, ongoing responses and conversions from partial to complete response
- A favorable safety profile with no incidences of grade 3 or 4 cytokine release syndrome or grade 3 or 4 neurotoxicity
NKTR-255 enhances CD8+ T cells
A Phase 1 study conducted by Alexandre Hirayama, MD, of SCCA, Fred Hutch, and UW evaluated NKTR-255. This new immunotherapy drug is an IL-15 receptor agonist designed to boost CD8+ T cells. Study participants included eight patients with relapsed hematological malignancies after CAR T-cell therapy.
Dr. Hirayama reported enhanced CD8+ T cells in patients with and without detectable CAR T cells. Based on these results, another trial will combine NKTR-255 with CAR T-cell therapy in patients with large B-cell lymphoma.
Pembrolizumab plus AVD chemotherapy improves remission in untreated Hodgkin lymphoma
Pembrolizumab alone is very effective in patients with Hodgkin lymphoma. Many patients achieve complete remission, but not a cure.
Immune checkpoint inhibitors, such as pembrolizumab, have been shown to be highly effective in the relapsed setting, but data are limited in the use of these agents in newly diagnosed patients. In this study, researchers looked at whether pembrolizumab in place of bleomycin plus AVD chemotherapy was safe and effective.
The single-center study led by Dr. Lynch included patients with previously untreated Hodgkin lymphoma. Of 30 patients receiving the dual treatment, more than 90% achieved remission for one year without relapse. The study has been extended with an additional 20 patients.
“I expect that this study from our center will prove to be one of the initial handful of trials that lay the groundwork for the next phase of improvements in initial treatment for Hodgkin Lymphoma,” said Dr. Gopal.
Hematologic cancer care at SCCA
SCCA, Fred Hutch, and UW are national leaders in hematological research that leads to the advancement of new cancer treatments and improved delivery of clinical care. SCCA physicians offer consultations for community oncologists to discuss therapy options and available clinical trials.
Reach SCCA's hematologic cancer team by calling 206.606.1024.
