American Society of Hematology

CAR T-Cell Therapies Show Durable Responses, New Research Also Explores Combination Therapies to Extend and Enhance Treatment Responses

Published on: December 01, 2018

CAR T Infographic

(San Diego, December 1, 2018) — Chimeric antigen receptor (CAR) T-cell therapies have quickly shifted the treatment paradigm for many people with several types of aggressive blood cancers, in whom treatment options have been woefully limited. Five studies being presented today at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition spotlight the long-term effectiveness of these therapies in some patients, analyze how combination therapies might affect treatment responses, and examine if transplantation following CAR T-cell therapy affects remission rate.

CAR T-cell therapies are designed by harvesting a patient’s own T cells (the immune system’s primary cancer-killing cells), reengineering them to target specific proteins on the surface of cancer cells, and reintroducing the modified T cells back into the patient’s immune system.

“These are transformative therapies and we’re seeing their expanding value in terms of giving patients who essentially ran out of options an opportunity to live,” said press briefing moderator, Joseph Alvarnas, MD, of the City of Hope in California. “At the same time, we’re identifying the limitations of these therapies. For example, CAR T cells may stop working in some patients for various reasons, which has prompted researchers to ask what combination therapies could be used to extend the benefits of treatment.”

In two of the studies, longer-term follow-up analyses of the ELIANA and JULIET trials further demonstrate sustained responses to T cells designed to target the CD-19 protein, which is frequently expressed on malignant lymphoma cells. Two other studies investigate combining CAR T-cell therapies with additional treatments — the first leverages a second oncologic agent, ibrutinib, while the other analyzes the addition of a checkpoint inhibitor — to determine whether their use might enhance the effect of and sustained response to CAR T.

In the final study, researchers evaluate  the effect of stem cell transplantation on long-term outcomes after CD19 CAR T-cell therapy for pediatric patients with acute lymphocytic leukemia.

This press conference will take place on Saturday, December 1, at 11:30 a.m. PST in Room 22, San Diego Convention Center.

Tisagenlecleucel Continues to Show Durable Remissions in Kids and Young Adults with Stubborn Form of Leukemia

Updated Analysis of the Efficacy and Safety of Tisagenlecleucel in Pediatric and Young Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia [895]

A single infusion of tisagenlecleucel in pediatric and young adult patients with relapsed or treatment-resistant acute lymphocytic leukemia (ALL) continues to be highly effective in fighting cancer in most people, without the need for additional therapies. This latest analysis of the ELIANA trial results includes four additional patients and another year of follow up.

“These are patients who weren’t eligible for transplant, or who had relapsed after transplant; none were in remission and no other treatments were available at the time they entered the trial,” said lead study author Stephan A. Grupp, MD, PhD, of the Children’s Hospital of Philadelphia. “We’ve shown that not only can we get these patients into remission, but they’re also going into remission with durable responses with CAR-T alone – the majority of patients without any subsequent therapies, and with no minimal residual disease when we tested for evidence of leukemia.”

These most recent data continue to validate the benefits of using this new treatment paradigm in this patient population, Dr. Grupp added. Over the last year, tisagenlecleucel has been approved by the U.S. Food and Drug Administration (FDA), as well as by health authorities in the EU, Switzerland, and Canada for the treatment of pediatric and young adult patients (up to 25 years) with relapsed or refractory B-cell ALL based on results from the multi-center, international ELIANA study.

Ninety-seven patients were enrolled in this single arm, open-label phase II study, which was conducted in 25 centers in 11 countries across North America, Europe, Australia, and Asia. Patients ranged in age from 3-24 and received a median of three prior lines of therapy (e.g., chemotherapy, radiation, or targeted therapy). A majority had undergone a previous hematopoietic stem cell transplant.

Among the 79 patients who were followed for three or more months after being infused with their reprogrammed CAR-T product, 82 percent achieved a complete remission. Researchers also reported that 66 percent of patients who had a complete response to CAR-T were still in remission at 18 months. Additionally, the majority of the infused patients were still alive (overall survival of 70 percent) at 18 months post-infusion. Even in this updated analysis, median overall survival has not been reached. Another success, according to researchers, is that the many centers in the study have been able to safely and consistently administer CAR T-cell therapy.

“We see relatively similar results across study sites — even with centers with no prior experience administering CAR T-cell therapy — so we’ve shown we can roll this out, do it safely, and promulgate appropriate approaches to toxicity management as well,” said Dr. Grupp.

Seventy-seven percent of patients experienced grade 3 or 4 cytokine release syndrome (CRS), which is triggered by an over-reactive immune response. Nearly half of these patients required treatment in the intensive care unit for a median of seven days. All cases were ultimately reversed using the management algorithm developed for this study. The majority of key adverse events occurred in the first eight weeks after infusion and included infection, low white blood cell and platelet counts, and neurological events. No cases of cerebral edema were reported. Twenty-five deaths were reported after CAR-T infusion, mostly due to disease progression and other causes unrelated to CAR T-cell therapy.

Dr. Grupp said the prevalence of adverse events remains unchanged from previous analyses and there is ongoing evidence that CAR-T is benefiting patients well after a year.

Further follow-up of patients is ongoing in the ELIANA trial.

This study was supported by Novartis. 

Stephan Grupp, MD PhD, will present this study during an oral presentation session on Monday, December 3, at 4:30 p.m. PST, Room 6A, San Diego Convention Center.

Longer Term Data Validate Durable Responses with Tisagenlecleucel in Adults with Relapsed and Refractory DLBCL
Sustained Disease Control for Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: An Updated Analysis of Juliet, a Global Pivotal Phase 2 Trial of Tisagenlecleucel [1684]

More than 18 months after patients with relapsed or treatment-resistant diffuse large B-cell lymphoma (DLBCL) were treated with a single dose of tisagenlecleucel, high response rates persist, further demonstrating that this therapy is beneficial for many patients who otherwise wouldn’t have a viable option for treatment.

In this latest follow-up analysis of the international JULIET trial, 19-month results show the overall response rate was 54 percent among 99 patients who were followed for at least three months or discontinued therapy early, with 40 percent achieving a complete response and 16 percent achieving a partial response. Moreover, 64 percent of patients who achieved a complete response earlier in the trial are currently still in remission with no detectable evidence of cancer. Median duration of response and median overall survival in responding patients was not reached. Response rates were consistent across subgroups of patients, including the elderly and those with particularly aggressive lymphoma (double-/triple-hit) or prior stem cell transplantation.

“We’re seeing that the responses are sustained. There are a significant number of patients who are staying free of disease, and none of the patients in remission have proceeded on to transplantation,” said lead study author Richard Thomas Maziarz, MD, of the Oregon Health & Science Knight Cancer Institute, in Portland, Oregon.

DLBCL is the most common form of lymphoma, accounting for roughly one-third of all non-Hodgkin lymphoma cases. While current treatment options are successful for many people with this disease,  primary therapy often fails in about one-third of people with DLBCL, and half of these patients won’t be eligible for stem cell transplantation, which is considered the best second-line treatment approach. Such patients would be candidates for this type of therapy. JULIET trial data were used to justify the U.S. Food and Drug Administration (FDA) approval of tisagenlecleucel for this patient population in May 2018. Additional approvals followed this year in the European Union, Switzerland, and Canada.

This single-arm, open-label Phase II trial is among the largest studies to examine a CAR T-cell therapy exclusively in people with DLBCL. It was conducted at 27 treatment sites spanning 10 countries across North America, Europe, Australia, and Asia. Enrollees had to receive two or more previous treatments with documented disease progression, or failed to respond or were otherwise ineligible for autologous stem cell transplant. A total of 115 patients were successfully infused. Patients ranged in age from 22-76 years old with a median age of 56.

Of note, 54 percent of patients who initially had a partial response ended up having a complete response, which suggests that the cell product persists viably and remains active in vivo over time, according to Dr. Maziarz.

Consistent with previous reports on safety, most of the severe adverse events were seen shortly after infusion and included drop in mature blood cells (34% of patients), CRS (23% of patients), infection (19% of patients), and neurological events (11% of patients). There were no deaths that investigators attributed to the therapy.

Patients in the JULIET trial who responded to therapy will continue to be followed. Dr. Maziarz said that as research evolves, the focus will need to be on approaches for optimizing the outcomes of therapy, such as combination therapy with checkpoint inhibitors or other targeted therapy to enhance, maintain, or stimulate their responses.

“We’re changing the natural history of the disease, and identifying subpopulations of patients who may need therapies in addition to CAR-T will be an important next step,” he said. “This research is really the foundation for the next wave of studies to assess combination therapies.”

Funding for this study was provided by Novartis. 

Richard Maziarz, MD, will present this study during a poster presentation session on Saturday, December 1, at 6:15. p.m. PST, Hall GH, San Diego Convention Center.

Concurrent Ibrutinib May Improve Outcomes, Reduce Toxicity of CAR T-Cell Therapy with JCAR014 for CLL

Comparison of Efficacy and Toxicity of CD19-Specific Chimeric Antigen Receptor T-Cells Alone or in Combination with Ibrutinib for Relapsed and/or Refractory CLL [299]

For patients with difficult-to-treat chronic lymphocytic leukemia (CLL), continuing to take the targeted oral agent ibrutinib before, during, and after receiving CAR T-cell therapy may be associated with less severe adverse effects and better responses, compared with outcomes for a similar group of patients who received the same CAR T-cell therapy without ibrutinib.

“These results suggest that combining ibrutinib with CAR T-cell therapy may lead to better outcomes by improving efficacy and reducing toxicity,” said lead study author Jordan Gauthier, MD, of the Fred Hutchinson Cancer Research Center in Seattle.

The study was small, involving a total of 43 patients, and was not a randomized controlled trial, so the findings should be confirmed in a larger, prospective trial, he said.

Ibrutinib is approved by the FDA as both an initial treatment for CLL and as a treatment for difficult-to-treat CLL. The drug works by blocking the activity of a protein that helps leukemia cells grow and survive; interrupting this treatment can cause a rapid tumor flare, making the disease even more difficult to treat.

Prior to this study, Dr. Gauthier’s colleagues had conducted an early-phase study of CAR T cells as a single therapy in 24 patients with CLL who had previously been treated with ibrutinib. Ibrutinib had been discontinued before CAR T-cell therapy began, in most cases because the patients’ CLL seemed to be getting worse. Other preliminary studies have suggested, however, that continuing ibrutinib treatment before, during, and after CAR T-cell immunotherapy may prevent tumors from worsening, boost the effectiveness of the CAR T cells, and help to prevent CRS.

In this study, researchers enrolled a second group of 19 patients with difficult-to-treat CLL who were similar in age and disease characteristics to the earlier group. This second group remained on ibrutinib before, during, and for at least three months after receiving the same CAR T-cell therapy. Dr. Gauthier and his colleagues then compared this group’s outcomes with the earlier group of patients who had discontinued ibrutinib before receiving CAR-T.

Eighty-three percent of patients in the ibrutinib cohort had either a complete or partial response to treatment compared with 65 percent of those not receiving ibrutinib. Patients receiving ibrutinib were also more likely to achieve a deep molecular response, meaning that highly sensitive methods detected no malignant DNA sequences in the bone marrow.

The researchers observed that CRS occurred less frequently among those receiving ibrutinib. No patients in this cohort developed severe symptoms of CRS, compared with 25 percent of those not receiving ibrutinib. Two early deaths were reported: one patient who was receiving ibrutinib (sudden death from presumed cardiac arrhythmia in the context of CRS) and one patient who was not (severe CRS and neurotoxicity).

“To our knowledge, these are the most encouraging results that have been seen to date in humans with a combination of CAR T cells and a targeted agent,” said Gauthier. “While the CAR T cells expanded robustly in both groups and led to high rates of response, we did not observe a single case of severe CRS in patients receiving ibrutinib during CAR T therapy.”

Because those who received ibrutinib and CAR-T concurrently were treated more recently than those who did not, this cohort may have also benefited from improvements in the management of patients receiving CAR T-cell therapy that have occurred over time, Dr. Gauthier said.

The next step will be to prospectively study the effects of ibrutinib combined with CAR T-cell immunotherapy in a larger cohort.

This study was supported by Juno Therapeutics, Inc., a Celgene Company.

Jordan Gauthier, MD, Fred Hutchinson Cancer Research Center, will present this study during an oral presentation session on Sunday, December 2, at 7:30 a.m. PST, Pacific Ballroom 20, Marriott Marquis San Diego.

Inhibiting the Immune System’s Natural Response May Boost Benefits and Sustainability of CAR T Therapy

Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia [556]

CD19-directed CAR T-cell therapy has been shown to be effective in patients with relapsed B-cell acute lymphocytic leukemia (B-ALL). Many patients will have durable or long-term responses with long-lasting CAR T cells. For some patients however, the anti-tumor effects of CAR T-cell treatment are shortlived. This may, in part, be caused by a reaction of the patient’s immune system against their very own CAR T-cells. This may occur through the immune system’s checkpoint pathways.

In the first study of its kind in this patient population, researchers at Children’s Hospital of Philadelphia (CHOP) investigated whether adding another immunotherapy agent to the CAR T-cell therapy regimen to prevent this effect could extend treatment response and improve outcomes for children with relapsed B-ALL.

“We see excellent responses to CAR T cells, but unfortunately some patients relapse due to early loss of these cells,” said senior study author Shannon Maude, MD, PhD, of CHOP. “We wondered whether the loss of CAR T-cell activity might be mediated, in part, by naturally occurring checkpoint mechanisms in the body’s immune system and whether interrupting or inhibiting these checkpoints could prolong the CAR T cells’ effect.”

This small, single-center study included a total of 14 children ranging in age from 4-17 years — 13 with heavily pretreated relapsed B-ALL and one with lymphocytic lymphoma (previous treatments included bone marrow transplant and one or two types of CAR-T). All received CD19-directed CAR T-cell therapy and an immunotherapy called a checkpoint inhibitor, intended to inhibit the immune checkpoint PD-1 (programmed cell death 1). Patients in the study were given either pembrolizumab or nivolumab. Researchers administered checkpoint inhibitors no sooner than 14 days after patients received their CAR T-cell infusion, as levels of CAR T cells often decline 14 days following infusion of the CAR T-cell therapy, and because CRS is typically experienced within the same window.  

Half of patients maintained either partial or complete disease responses. Patients were followed for a median of 13.3 months following additional treatment with a checkpoint inhibitor. Half of the patients (3 of 6) treated for early B-cell recovery re-established B-cell aplasia (a sign that the CAR T-cell therapy is working). Four patients started pembrolizumab for bulky extramedullary disease that either returned after CAR T-cell therapy or did not respond to the treatment at all, and demonstrated two partial and two complete responses. Among four patients who failed to achieve disease remission with initial CAR T-cell infusion, no complete responses were achieved with the addition of pembrolizumab, although partial responses were observed.

“When we give a checkpoint inhibitor, it seems to release the immune blockade on the T cell, removing the restriction that’s holding it in check and, in turn, allowing the T cell to have greater activity,” Dr. Maude said. “So in the context of CAR T cells, this combination therapy could overcome that resistance in some patients. These are children who would otherwise have no other therapeutic options, so efforts to maximize their response is critical.”

Mild CRS symptoms and fever typical of CAR T-cell proliferative responses were seen in three of 14 patients within two days of starting pembrolizumab. Other early and delayed adverse effects associated with PD-1 inhibition were tolerable or reversible upon discontinuation.

Dr. Maude and her team will continue following these patients and exploring combination strategies to improve outcomes with CAR T-cell therapy.

This study was supported, in part, by a grant from the V Foundation.

Amanda Li, MD, British Columbia Children’s Hospital, will present this study during an oral presentation session on Monday, December 3, at 7:00 a.m. PST, Ballroom 20A, San Diego Convention Center

A First Stem Cell Transplant After CAR T-Cell Therapy Reduces Relapses in ALL

Long Term Follow-up after SCRI-CAR19v1 Reveals Late Recurrences As Well As a Survival Advantage to Consolidation with HCT after CAR-T Cell Induced Remission [967]

In a new study, patients with ALL who received a first stem cell transplant after CD19 CAR T-cell therapy were less likely to experience a relapse of their cancer when compared to similar patients who didn’t undergo transplantation.

This is one of the first studies to evaluate the potential role stem cell transplantation plays in long-term outcomes after CD19 CAR T-cell therapy for pediatric patients, said lead study author Corinne Summers, MD, of the Seattle Children's Hospital and Fred Hutchinson Cancer Research Center.

“We see a trend toward improved leukemia-free survival in pediatric patients who receive their first stem cell transplant following CAR T-cell therapy,” Dr. Summers said.

In addition, either a first or a repeat stem cell transplant after CAR T-cell therapy reduced the risk of relapse in a subset of patients who were at elevated risk of having their cancer come back.

Many patients go into remission following CAR T-cell therapy, Dr. Summers said, but there are also relapses beyond one year following treatment. The goal of the study was to evaluate whether stem cell transplantation could make remissions last.

In this phase I/II trial, researchers analyzed 64 ALL patients who had received an infusion of their own T cells that had been reprogrammed to recognize and target the CD19    protein found on the surface of most leukemia cells. Patients had previously relapsed or had not responded to other treatment. Follow-up monitoring occurred for at least one year.

Fourteen patients relapsed, died, or did not respond to the CAR T-cell therapy. Of the 50 patients who achieved a sustained remission after CAR T-cell therapy, 34 had a history of previous stem cell transplant.

There were several cohorts observed:

  • Of 24 patients who had a previous stem cell transplant but did not undergo a second one following CAR T-cell therapy, seven remain in remission.
  • Among the 10 patients who had their second stem cell transplant following CAR T-cell therapy, five remain alive and in remission after at least 24 months of follow-up.
  • Among the 16 patients who had not had a previous stem cell transplant, 13 had one after receiving CAR T-cell therapy. One of these patients relapsed following the stem cell transplant.
  • Of the three patients who did not have a stem cell transplant after CAR T-cell therapy, two relapsed and the third remains in remission after 28 months of follow-up.

One of the expected effects of CAR T-cell therapy is a decrease in B cells following the procedure. This effect, known as B-cell aplasia, occurs because CAR T-cell therapy kills both normal and cancerous B cells. Continued B-cell aplasia is regarded as an indicator that the CAR T cells are still actively preventing the patient’s cancer from coming back. By contrast, short B-cell aplasia — that is, when B-cell counts begin to increase after CAR T-cell therapy — indicates that the CAR T-cells may no longer be working.

In the current analysis of patients who had been followed for at least a year, those with short B-cell aplasia who had a stem cell transplant after CAR T-cell therapy were less likely to relapse, regardless of whether the transplant was their first or their second. In this group of eight patients, one died of transplant-related complications and two relapsed. By contrast, all six patients with short B-cell aplasia who did not undergo stem cell transplant after CAR T-cell therapy relapsed.

Among patients who had a stem cell transplant after CAR T-cell therapy, all relapses thus far have occurred within two years, said Dr. Summers. However, among patients who did not have a stem cell transplant following CAR T-cell therapy, relapses continue to occur two or more years after treatment.

“For pediatric patients who achieve remission after CAR T-cell therapy, undergoing a first stem cell transplant following CD19 CAR T-cell therapy appears to be beneficial,” said Dr. Summers. “For patients who achieve remission, but have a higher risk of relapse because of short B-cell aplasia, a stem cell transplant after CAR T-cell therapy appears to be beneficial whether or not they have had one previously.”

For patients with a previous stem cell transplant, the benefit of a second one after CAR T-cell therapy is unclear; it may be that among this group of patients, only those with short B-cell aplasia benefit from a second transplant, according to the authors.  

Longer follow-up is needed to understand the reasons for long-term relapse after CD19 CAR T-cell therapy and whether patients with a prior stem cell transplant can benefit from receiving a second one following CAR T-cell therapy. Phase II of the trial, now underway, is testing the anti-CD19 CAR T-cell therapy in a larger group of patients with acute leukemia or lymphoma that has relapsed or been unresponsive to other therapy. 

This study was supported by Stand up to Cancer, St. Baldrick’s Foundation, Alex’s Lemonade Stand, and Juno Therapeutics.

Corinne Summers, MD, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center will present this study during an oral presentation session on Monday, December 3, at 4:30 p.m. PST, Seaport Ballroom A, Manchester Grand Hyatt San Diego.


The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on improved sickle cell disease outcomes, large-scale practice-changing clinical trials, and and looking to the future in the era of personalized medicine. For the complete annual meeting program and abstracts, visit http://www.hematology.org/annual-meeting. Follow @ASH_hematology and #ASH18 on Twitter and Instagram, and like ASH on Facebook for the most up-to-date information about the 2018 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The Society publishes Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, as well as the newly launched, online, open-access journal, Blood Advances.

CONTACTS:
Adam Silverstein, FleishmanHillard
917-697-9313; Adam.Silverstein@fleishman.com

Stephen Fitzmaurice, ASH
561-506-6890; SFitzmaurice@hematology.org

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