Neelapu Discusses Toxicities Associated With CAR T Cells in Large B-Cell Lymphomas

Sattva S. Neelapu, MD

Sattva S. Neelapu, MD

Two chimeric antigen receptor (CAR) T-cell therapies have been approved for the treatment of patients with large B-cell lymphoma, including axicabtagene ciloleucel (axi-cel; Yescarta) and tisagenlecleucel (Kymriah). These options are available in the third-line setting following at least 2 prior lines of systemic therapy.

“Currently, these products are indicated in the third-line setting and beyond,” said Sattva S. Neelapu, MD. “After patients have failed on frontline therapy like R-CHOP [Rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone] for aggressive B-cell lymphomas, the second-line therapy usually involves autologous SCT [stem cell transplant] for patients who are transplant-eligible or have stage II disease. Now, we have a third-line option.”

Axi-cel was approved by the FDA in October 2017, for the treatment of adult patients with relapsed/refractory large B-cell lymphoma; the agent is indicated for the treatment of patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma (TFL) following 2 or more prior lines of therapy. The approval was based on findings from the phase II ZUMA-1 trial which demonstrated an objective response rate (ORR) of 72%.

According to updated data presented at the 2018 ASH Annual Meeting,2-year findings from the ZUMA-1 trial further supported the approvalof axi-cel in this patient population. Data showed an overall survival (OS) rate of more than 50% from treatment with the CD19-targeted CAR T-cell therapy. The 2-year progression-free survival rate after a median follow-up of 27.1 months was 39%. Median duration of response and median OS had not yet been reached.

Tisagenlecleucel received its approval from the FDAin May 2018 for the treatment of patients with relapsed/refractory DLBCL, high-grade B-cell lymphoma, and TFL following 2 or more prior lines of therapy; the indication was based on results from the phase II JULIET trial, in which the CAR T-cell therapy reached an ORR of 50% in adult patients with relapsed/refractory DLBCL.

Updated findings from this trial were also presented at the 2018 ASH Annual Meeting, demonstrating an ORR of 54% and a complete remission rate of 40%, andthe median OS in patients who achieved a complete responsehad not been reached. Data also showed that 57% of patients experienced cytokine release syndrome (CRS), an adverse event (AE) commonly associated with CAR-T cell therapies. Other AEs noted in this trial included prolonged cytopenias (45%), infection (37%), febrile neutropenia (15%), and tumor lysis syndrome (2%).

CRS also occurred in 13% of patients treated with axi-cel in the ZUMA-1 trial. Other common grade ≥3 AEs included anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%). These patients received tocilizumab (Actemra) and corticosteroids to treat CRS and related events.

In an interview withTargeted Oncology, Neelapu, a professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center in Houston, discussed the evolving role for CAR T-cell therapy in patients with B-cell lymphomas. He also highlighted the toxicities commonly associated with these therapies and how physicians can treat these AEs as they arise.

TARGETED ONCOLOGY: What is the current role in the treatment paradigm for CAR T-cell therapy in lymphoma?

Neelapu:The 2 CAR T-cell products that are approved in the United States, Europe, Canada, and a few other countries are axi-cel and tisagenlecleucel. These are approved for patients with relapsed/refractory large B-cell lymphoma who have failed at least 2 or more lines of systemic therapy. The histologies that are included are DLBCL, high-grade B-cell lymphoma including double-hit and triple-hit lymphomas and TFL. In addition, axi-cel is also approved for primary maintenance of B-cell lymphoma.

Currently, these products are indicated in the third-line setting and beyond. After patients have failed the frontline therapy like R-CHOP for aggressive B-cell lymphomas, the second-line therapy usually involves autologous SCT for patients who are transplant-eligible or if they have stage II disease. Now, we have a third-line option, which is the CAR T-cell therapy. Previously, the outcomes in these patients have been dismal with a median survival of only 6 months. Now with CAR T-cell therapy, there are 2-year data [that have been] presented for both axi-cel and tisagenlecleucel. What they show is that these products can induce durable remissions in about 35% to 40% of the patients lasting beyond 2 years.

TARGETED ONCOLOGY: What does the future of CAR T-cell therapy look like in terms of sequencing?

Neelapu: [Because of the data] that have been observed in the third-line setting, it is now being explored in earlier stages of the disease process, including patients in the second-line setting for B-cell lymphomas. There are randomized trials ongoing comparing head-to-head with autologous SCT, and we will probably have those results in about a year or 2.

Recently, CAR T-cell therapy trials have also been initiated in the frontline setting in patients with more aggressive B-cell lymphomas who are at high-risk and have high-risk factors such as double-hit and triple-hit lymphomas, as well as those who have [scored] high on the international prognostic index. Besides this, CAR T-cell therapies are also being investigated in patients with relapsed/refractory indolent B-cell lymphomas as well as mantle cell lymphoma (MCL). There are some early data that has been presented from small numbers of patients, and it looks promising for patients with both indolent lymphomas as well as MCL.

TARGETED ONCOLOGY: What are some of the largest safety concerns that need to be taken into consideration with CAR T-cell therapy?

Neelapu:CAR T-cell therapy can cause both acute toxicities as well as late toxicities. There has been a lot of attention here for acute toxicities. The 2 common acute toxicities that can occur with CAR T-cell therapies are CRS and neurological toxicity, which is now called immune effector cell—associated neurotoxicity syndrome (ICANS). CRS is the most common toxicity that typically starts out in patients who have fever or constitutional symptoms such as loss of appetite or fatigue, but it can affect every organ system in the body; it can cause irreversible organ disfunction if it is managed inappropriately.

Neurological toxicity starts off with the [the patient experiencing] difficulty, impaired handwriting, or confusion. In more severe cases, it can also lead to seizures, motor weakness, or even cerebral edema in patients. These toxicities, if not managed appropriately, can lead to death, which is why it is important to be aware of these toxicities. Typically, they occur within the first 2 weeks after the infusion.

There can also be late toxicities after CAR T-cell therapy. There are at least 2 common late toxicities, including prolonged cytopenias, that are observed in almost all CAR T-cell products and presents in about 30% of patients in pivotal trials. Beyond the 30%, some can have grade 3 or 4 cytopenias and these patients are typically managed with transfusions or growth factor support as needed. Eventually, most of those cytopenias resolve, unless the patient has myelodysplastic syndrome.

Besides the prolonged cytopenias, there can also be an on-target/off-tumor effect of the CAR T-cell therapy. In the case of CD19 CAR T-cell therapy with the approved products, B-cell aplasia is an expected on-target/off-tumor effect. That can lead to hypogammaglobulinemia in these patients. In adults, patients typically receive immunological replacement therapy only if they have both hypogammaglobulinemia and recurrent infections.

TARGETED ONCOLOGY: How is CRS treated when it occurs in patients receiving CAR T-cell therapy?

Initially, it was not clear what the exact mechanism of CRS was, but now we have more information. It appears that 1 of the primary mediators of CRS is interleukin 6 (IL-6). There were IL-6 therapies that were instituted. In fact, tocilizumab, which is an anti—IL-6 receptor antibody, has been approved for the management of CRS. If somebody does not respond to tocilizumab, there is also an option to use corticosteroids, which can cause global immune suppression to mitigate or suppress multiple immune cells as well as down regulate multiple cytokines. For neurological toxicity, this is managed with supportive care; but in more severe cases, we use corticosteroids as well to dampen that for the CAR T cells.

TARGETED ONCOLOGY: Are there any other toxicity concerns physicians should be aware of?

There is also some concern that CAR T-cell therapy can put patients at risk for therapy-related malignancies due to insertion or mutagenesis, but so far that has not been observed. We have also seen an abstract where it was shown that immune reconstitution, especially for CAR T cells, is also delayed in these patients. The CD4 count is delayed with at least a third of patients having CD4 counts of less than 100 at the 1-year time point, and at least 15% of patients having CD4 counts of less than 200 at the 2-year time point. In order to predict these patients, they need to form options for infections and they need to have prophylaxis. We typically give prophylaxis to these patients for at least 1 year. We check the CD4 count and if the CD4 count is more than 200 at the 1-year time point, we stop the prophylaxis.

TARGETED ONCOLOGY: What challenges still exist surrounding the incorporation of CAR T-cell therapy into this space?

Neelapu:One of the biggest hurdles with CAR T-cell therapy at this point is an autologous T-cell therapy. There is a correction time that is required to make a product for each of our patients, which makes the process commercial as well as expensive. The current turnaround time is at least 3 to 4 weeks for autologous CAR T-cell products. In the future, [we aim to] develop allogenic off-the-shelf CAR T-cell therapies in order to both make these therapies more readily available as well as bring down the cost.