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Liso-cel: ASH 2022 Jeremy Abramson vs. SOC SCT and ASCT in RR LBCL

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Liso-cel: ASH 2022 Jeremy Abramson vs. SOC SCT and ASCT in RR LBCL

By Jeremy Abramson, MD

What did the phase 3 Transform study show in patients with relapsed or refractory large B-cell lymphoma (LBCL)? So with this ASH (American Society of Hematology) meeting, I was honored to present the primary analysis of the Transform trial, which is a randomized phase 3 trial comparing Lisocabtagene Maraleucel (liso-cel), an anti CD19 CAR T-cell product, with the standard of care as second line therapy in patients with relapsed or refractory large B-cell lymphomas.

We specifically looked at patients with primary refractory disease or disease progressing within one year of frontline chemoimmunotherapy who have a particularly poor expected outcome with a historic standard of care. Liso-cel is a CD19-directed 4-1BB costimulated CAR T-cell, administered at equal target doses of CD4 and CD8 CAR T-cells. This was compared with platinum-based chemotherapy followed by BEAM which is high dose chemotherapy and autologous stem cell transplant for patients with chemotherapy sensitive disease. We randomized 92 patients to each arm. The vast majority of patients had diffuse large B-cell lymphoma and had primary refractory disease to frontline chemoimmunotherapy.

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In our study, we had built-in crossover allowed so patients on the standard of care arm who were failed by second-line chemotherapy could cross over to receive Liso-cel. And in fact, two-thirds of patients assigned to the standard of care arm did indeed cross over at the time of this analysis. What we found was a significant superiority for Liso-cel over the standard of care.

Our primary endpoint was event free survival. The median event free survival was not reached for Liso-cel and was 2 months with the standard of care. At 18 months, this corresponded to 53% of Liso-cel patients remaining event free compared to only 21% of patients on the standard of care. We also saw improvements in progression-free survival (PFS).

With a 60% reduction in the risk of progression or death favoring Liso-cel over standard of care, complete responses were also better. With 74% of patients having a complete response to Liso-cel compared to only 43% on standard of care (SOC), and among patients who achieved a complete response, the duration of complete response was better on the Liso-cel arm.

 

So complete responses were more durable in patients who received Liso-cel. Of course, we also looked at safety, and overall, we found Liso-cel to be very well managed. The most common side effect was cytopenias in both arms. But these were reversible and recovered in the vast majority of patients.

 

There were more prolonged cytopenias in the Liso-cel arm. But most of these did indeed recover by day 62, and there was no increased risk of grade 3 or higher infections. When we looked at cytokine release syndrome (CRS), a common side effect related to CAR T-cell therapy, we found that 49% of patients on Liso-cel did have any grade of cytokine release syndrome (CRS).

 

But it was almost entirely low grade with only 1% of patients having grade 3 or higher CRS (cytokine release syndrome). And in fact, that was just a single case of grade 3 CRS (cytokine release syndrome), and there were no grade 4 or 5 events. Neurotoxicity was also quite low at 11%, 4 patients had grade 3 CRS (cytokine release syndrome). There were no grade 4 or 5 events.

So overall, we conclude that Liso-cel significantly improved event-free survival (EFS), progression-free survival (PFS), and complete response rate (CRS) over standard of care. We also numerically saw an improved overall survival that did not reach statistical significance, but we hypothesized that this is maybe impacted by the fact that two-thirds of patients on their standard of care arm crossed over to receive Liso-cel.

As such, we performed a supportive overall survival analysis, adjusting for the impact of crossover. And when we do that, we did find a significant improvement in overall survival favoring Liso-cel with a hazard ratio of 0.43. And so we think that Liso-cel is an effective and safe option, and now a preferred second line treatment option for patients with early relapsed or primary refractory large B-cell lymphoma.

Lisocabtagene Maraleucel Key Statistics:

 

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What are the most common questions for this research?

The most common question I get asked is, “Who’s actually a candidate for CAR T-cell therapy in the second line setting?” And the answer as of today is actually the majority of patients with relapsed large B-cell lymphoma after frontline chemoimmunotherapy. We now have 2 randomized trials, both ZUMA-7, and Transform, which compared CAR T-cells compared with standard of care of high-dose chemotherapy as a second line treatment for patients with primary refractory or early relapsed large B-cell lymphoma. Now, it turns out that in the modern era, patients who are treated with R-CHOP in the frontline setting and relapse that the majority of relapsing patients occur within 1 year of frontline chemoimmunotherapy.

And that means that in that context, Liso-cel and Axi-cel are better than the standard of care we have used for decades. So as of today, any patient who has primary refractory disease or disease progressing within 1 year should be referred for consideration of CAR T-cells, such as Liso-cel in the second line setting.

 

The next question becomes, “What about patients I otherwise would not take to transplant?” What do we do for those patients in the second line setting? Previously, patients who relapsed and were not considered a candidate for high-dose chemotherapy, did not have a curative treatment option available in the second line setting.

 

That is no longer the case, the pilot trial specifically looked at Lisocabtagene Maraleucel (liso-cel) as a second line treatment for non-transplant eligible patients. These include patients who are older, patients who have medical comorbidities that may preclude them from receiving high dose chemotherapy. The pilot trial clearly showed high rates of complete and durable responses for patients in the second line setting, which led to FDA approval for Liso-cel as a second line therapy for non-transplant eligible patients, independent of their duration of initial remission.

 

As of today CAR T-cell such as Liso-cel or Axi-cel should be considered for any patient who’s transplant eligible, relapsing or progressing within 1 year of initial therapy, or for any second line patient who’s not considered transplant eligible. That’s the vast majority of patients with relapsed large B-cell lymphoma in the modern era.

 

What is Breyanzi (Lisocabtagene Maraleucel) approved for?

The FDA authorized lisocabtagene maraleucel with a Risk Evaluation and Mitigation Strategy due to the possibility of catastrophic or life-threatening cytokine release syndrome (CRS) and neurologic toxicities. CRS occurred in 45 percent of patients receiving lisocabtagene maraleucel as second-line therapy for LBCL (Grade 3 or higher, 1.3 percent), while neurologic toxicities occurred in 27 percent of patients (Grade 3, 7 percent ). In 33% to 38% of the people, serious adverse events occurred.

For second-line therapy, the recommended dose of lisocabtagene maraleucel is 90 to 110 106 CAR-positive T cells with a CD4:CD8 ratio of 1:1.

 

Hematopoietic Cell Transplantation Types

There are two forms of hematopoietic cell transplantation: autologous and allogeneic.

Autologous transplantation: In autologous transplantation, your own hematopoietic stem cells are harvested and stored for future use prior to the administration of high-dose chemotherapy or radiation. After your chemotherapy or radiation treatment, the harvested cells are frozen and returned to you.

Allogeneic transplantation requires getting hematopoietic stem cells from a donor, preferably a sibling with an identical genetic makeup. In the absence of a genetically compatible sibling, a non-relative may be substituted. In rare instances, it is possible to use a parent or child who is only half-matched; this is known as a haploidentical transplant. In some instances, umbilical cord blood can also be used in umbilical cord blood transplants.

Prior to the transplantation of autologous or allogeneic hematopoietic stem cells, a myeloablative transplant requires the administration of extremely high doses of chemotherapy or radiation.

Non-myeloablative transplant: A non-myeloablative transplant, also known as a reduced intensity transplant, allows you to undergo less intensive chemotherapy prior to getting an allogeneic hematopoietic stem cell transplant. This method may be recommended for a variety of reasons, including your age, disease kind, other medical issues, or prior treatments.

What type of hematopoietic stem cell transplantation is the most effective? Your doctor will choose whether allogeneic or autologous transplantation is best for you based on a number of factors, including your underlying illness, age, general health, and the availability of a compatible donor. Due to the variable risks associated with various types of transplantation, this is a complex decision that frequently integrates your opinions. Due to the use of one’s own cells, autologous transplantation is associated with fewer serious side effects. Autologous transplants may be less effective than allogeneic transplants in the treatment of some forms of cancer.

 

What are the key takeaways from this research and data? 

Key takeaways are that the standard of care has squarely shifted for the management of relapsed and refractory large B-cell lymphoma. As of today, frontline therapy for patients with large B-cell lymphoma is still R-CHOP for the vast majority of patients, with dose adjusted EPOCH-R considered for select subgroups such as double hit lymphomas and primary mediastinal B-cell lymphomas.

 

But patients relapsing after frontline therapy now can be, can have transformational curative intent second line therapy, which is far better than the historic standard of platinum-based chemotherapy and high dose chemotherapy and stem cell transplant for chemosensitive patients relapsing after their frontline setting should quickly be referred to a center that has CAR T-cell therapy available to be considered for a second line curative intent CAR T cell. Such as Lisocabtagene Maraleucel (liso-cel), or Axicabtagene ciloleucel (axi-cel) for really any second line patient in that setting. There’s still a very small subset of patients who I would describe as young fit patients with a rate late relapse of DLBCL. Who should still be considered for platinum-based chemotherapy and high dose chemotherapy.

But for those patients, if they relapse or progress on that second line therapy would go to CAR T-cell in a third line setting. So as of today, the majority of patients are now gonna receive a CD19-directed CAR T-cell for relapse to refractory large B-cell lymphoma.

 

Jeremy Abramson, MD – About The Author, Credentials, and Affiliations

Dr. Jeremy Abramson is the Jon and Jo Ann Hagler Chair in Lymphoma and the Director of the Lymphoma Program at Massachusetts General Hospital Cancer Center. He also holds the position of Associate Professor of Medicine at Harvard Medical School. Dr. Abramson received his medical degree from New York City’s Mount Sinai School of Medicine and a Masters Degree in Medical Sciences from Harvard Medical School. He did an internal medicine residency at Massachusetts General Hospital in Boston before moving on to a fellowship in hematology and oncology at the Dana-Farber Cancer Institute. Dr. Abramson is a Medical Oncology board certified physician.

 

Dr. Abramson’s clinical and scientific interests include lymphoid malignancies such as non-Hodgkin lymphomas, Hodgkin lymphoma, and chronic lymphoid leukemias. His research focuses on identifying new therapeutic targets in lymphomas and lymphoid leukemias, as well as the design and implementation of clinical trials for new cancer medicines and cellular immunotherapies in these illnesses. He is a Fellow of the American College of Physicians and a member of the American Society of Hematology and the American Society of Clinical Oncology. Dr. Abramson is the author of numerous publications and book chapters on lymphoma and frequently lectures on the subject.

 

References

  1. UpToDate – Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics). UpToDate Article, May 6, 2022

  2. FDA – FDA approves Lisocabtagene Maraleucel for second-line treatment of large B-cell lymphoma –FDA Resources for Information | Approved Drugs, May 27, 2022

 

 

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