Not All Patients With Relapsed DLBCL Referred for CAR T in Community Setting

Ajeet Gajra, MD, FACP

Hematologists and oncologists working in the community setting encounter multiple obstacles when prescribing chimeric antigen receptor (CAR) T-cell therapy to patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The challenges involve matters of processes, treatment cost, and access to treatment.

To further understand the issues and the solutions needed for physicians who treat relapsed/refractory DLBCL, researchers at Cardinal Health conducted 2 live survey sessions to collect information from clinicians. A total of 114 oncologists and hematologists from community practices and hospital settings participated in the survey. The population of hematologists/oncologists see roughly 20 patients per day, and the majority have been in practice for 11 to 20 years. Overall, 46% of the clinicians who attended the first live survey session, and 26% of those who attended the second reported that they had not referrer any patient for CAR T-cell therapy, and of those who did refer patients 32% and 22% of patients, respectively had not yet been infused with CAR T cells.¹

The results of the survey revealed that while the use of CAR T-cell therapy increased in community practices over the past year, there remain issues with high cost and toxicity of treatment. It was also reported that the processing of insurance was a barrier to getting patients treated. These challenges continue to limit the number of clinicians who recommend CAR T-cell therapy to their patients.

In an interview with Targeted Oncology, Ajeet Gajra, MD, FACP, vice president, Cardinal Health, discussed the ongoing challenges community oncologists face with prescribing CAR T-cell therapy to patients with relapsed/refractory DLBCL.

TARGETED ONCOLOGY: Can you explain the overall prognosis for patients with DLBCL? What are outcomes generally like with existing standard of care therapy?

Gajra: The outlook for DLBCL improved with the advent of chemoimmunotherapy, better risk stratification, and improved supportive care. Recent studies demonstrate that despite aggressive biology, over 60% of patients with DLBCL treated with chemoimmunotherapy achieve long-term remissions and cures. However, the improvements reached a plateau in the past decade, especially for patients who relapse after initial chemoimmunotherapy. These patients typically have poor prognostic features as defined by the International Prognostic Index (IPI) with high likelihood of relapse and death. Patients with relapsed or refractory disease are typically treated with salvage immunochemotherapy such as rituximab, ifosfamide, carboplatin and etoposide (RICE) or rituximab, cisplatin high dose Ara-C and dexamethasone (RDHAP), and those with chemotherapy-sensitive disease receive autologous stem cell transplant (ASCT). Using this approach, complete response (CR) rates are 35% to 40%, and in a recent study the 3-year event-free survival (EFS) and overall survival (OS) were 31% and 50%, respectively. Outcomes with ASCT are much worse for patients with refractory DLBCL as demonstrated in the SCHOLAR trial wherein the objective response rate was 26% (CR rate, 7%) with a median OS of 6.3 months and only 20% of patients were alive at 2 years.

Thus, prior to 2017 when the first CAR T therapy was approved in DLBCL with progression after 2 prior lines of therapy, there had been a significant unmet need for patients with relapsed DLBCL. The approval of 2 CAR-T therapies, axicabtagene ciloleucel (axi-cel) in October of 2017 and tisagenlecleucel (Kymriah; tisa-cel) in May 2018, in the treatment of large-cell lymphoma (LBCL), has ushered in a new mode of treatment which offers the potential of long-term remission in what was essentially a fatal disease.

TARGETED ONCOLOGY: What has been your observation experience with using CAR T cell therapy in patients with DLBCL by US community oncologists?

Gajra: Axi-cel and tisa-cel are both CD19-directed, genetically modified autologous T cell immunotherapy agents. Since the process of obtaining CAR T therapy for an individual patient is quite complex, we sought to assess the uptake of these agents among United States community oncologists. We conducted a study of community oncologists at two time points to assess perceptions and use of approved CAR T therapies in relapsed DLBCL. At each time point over 50 distinct oncologists participated. At the early timepoint, 46% of participants indicated that they had not referred any patients for CAR T therapy but at the later timepoint, this number decreased to 29% suggesting increasing use over the course of the 10-month interval. Of those participants who had referred patients for CAR T therapy, 32% at the early timepoint reported that none of their patients had yet received the CAR T infusion but the percentage of non-receipt decreased to 22% at the later timepoint again suggesting improved uptake and utilization.

TARGETED ONCLOGY: How do patient characteristics factor into how oncologists select patients to administer CAR T cells to? What are the barriers to CAR-T use?

Gajra: CAR T therapies approved in DLBCL have limitations as defined by the FDA approval and are to be used in adult patients with relapsed or refractory large B-cell lymphoma, including DLBCL, after 2 or more lines of systemic therapy. Neither agent is approved for the use of CNS lymphoma. As with the pivotal trials for the 2 agents, patients must have good ECOG performance status, adequate organ function including marrow, hepatic, cardiac and renal function, no active infection and no CNS involvement. Both agents carry black box warnings for neurotoxicity and cytokine release syndrome (CRS) which can be potentially fatal. Thus, the patients selected need to have good physiologic reserve and be willing to accept risks associated with the therapies. With the approval of a new CD19-directed monoclonal antibody, tafasitamab, it is not clear if patients exposed to that agent can still benefit from CAR T therapies.

In addition to patient specific factors, CAR T therapy represents a complex manufacturing process that is unlike traditional drug therapy or stem cell transplant. After identification of a potential patient with relapsed LBCL who has received at least two prior systemic therapies, a benefits verification and referral to a designated CAR T-cell therapy center is required. If deemed appropriate by the CAR T center, the patient undergoes apheresis for T-cell collection. The cells are then transported to the manufacturer’s facility where they are isolated, activated and undergo gene transfer, creating the chimeric cells which go through a process of expansion to generate the numbers needed for therapeutic effect. This process takes from 10 days to a few weeks. The CAR T cells are then cryopreserved and transferred back to the CAR T facility and reinfused into the patient. Thus, it is critical to maintain “vein to vein” integrity. Thus, unlike traditional cytotoxic or monoclonal antibody products, these agents are patient specific, living cell products that have a complex process for their manufacture, storage and shipping, leading to high costs to the healthcare system and the patient.

Given this information, not surprisingly, the oncologists surveyed identified the high cost of therapy as a major barrier to uptake and utilization at both time points respectively. Over half the participants identified cumbersome logistics of administering therapy and following patients as another major barrier. Further exploration of logistical issues identified barriers encountered during the referral process could be attributed to the payer or the CAR T center.

The payer specific challenges identified include slow approval process by 27% of payers (and high rates of denials by in 13% of payers. The challenges specific to the CAR-T center include slow intake process by 23% of CAR T centers lack of a CAR T center in geographic vicinity in 13%. CAR T center choosing stem cell transplant rather than CAR T for the patient was also seen 10% of the time. Other commonly encountered clinical challenges reported by the participants included deterioration of the patient prior to CAR T administration, and the need to administer bridging chemotherapy while awaiting manufacture of CAR T therapy. The lack of communication from the CAR T center during the process was identified by a minority as an impediment to recommending CAR T therapies, including lack of instructions to the primary oncologist and the patient.

TARGETED ONCOLOGY: Can you discuss the toxicities observed with CAR T cell therapy in this patient population? Do you haveany insight into toxicities observed in the real-world setting?

Gajra: As stated, both approved products carry black box warnings for CRS and neurotoxicity, now called Immune Effector Cell Associated Neurologic Syndrome (ICANS). CRS is an acute systemic inflammatory syndrome characterized by fever, hypotension, tachycardia, hypoxia and multiple organ dysfunction. ICANS is a neuropsychiatric complex manifested by encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia and anxiety. The treating team needs to maintain a high index of suspicion for these potentially life-threatening agents and patients need to have access to facilities with advanced critical care. Tumor debulking ahead of CAR T infusion and prophylactic use of tocilizumab may reduce the risk of CRS. Use of corticosteroids early can alleviate the severity and duration of ICANS.

The scientific team at Cardinal Health has studied the real-world adverse events (AEs) to CAR T agents in DLBCL.2 We analyzed the postmarketing case reports from the FDA, AEs reporting system involving axicel and tisa-cel for large B-cell lymphomas were analyzed. Of 804 AE cases identified 67% of axi-cel cases and 26% of tisa-cel cases reported neurological AEs. Compared with cases without neurological AEs, significant associations were observed between neurological AEs and use of axi-cel, age ≥ 65 years, CRS and the outcome of hospitalization. These findings and those of other investigators suggest that there may be differences in neurological toxicity based on the agent used.

TARGETED ONCOLOGY: Can you provide background on how this web-based survey can about at Cardinal Health Specialty Solutions? What is the overall goal with it?

Gajra: We are continuously engaged in research with healthcare providers, including medical oncologists/hematologists, to assess their perspectives on issues they face in their day-to-day practice, including the impact of new therapies on patient care. We share our research findings with healthcare stakeholders through peer-reviewed manuscripts and abstracts, as well as through our Oncology Insights report, which is published twice a year.

TARGETED ONCOLOGY:How can the information obtained from this survey impact practice? Where are you in the process of response collect and obtaining results?

Gajra: Our research on CAR-T therapy, collected via web-based and in-person surveys, has helped us identify the challenges to the use of these therapies encountered by community oncologists. Given that over 50% of cancer care is rendered in the community setting, it is important to identify these barriers with a goal of mitigating them and facilitating timely access to these potentially life-saving therapies for patients. With a new CAR-T approval in mantle cell lymphoma this year and other potential approvals in newer indications on the horizon, streamlining access to CAR-T therapies will continue to be a priority.

We have a follow-up to this paper that will be presented at ASH 2020 where additional research with community oncologists in early 2020 has revealed that the rate of non-receipt of CAR-T therapies in DLBCL is relatively constant at around 30%. In addition, we are exploring interest and uptake of CAR-T therapies in the outpatient setting as oncologists gain more confidence in preventing, minimizing and managing the toxicity of CAR-T therapies.

_References:

_{1. Gajra A, Jeune-Smith Y, Yeh T, et al. Perceptions of community hematologists/oncologists on barriers to chimeric antigen receptor T-cell therapy for the treatment of diffuse large B-cell lymphoma. Immunotherapy. 2020 12(10); 725-732. doi: 10.2217/imt-2020-0118}

_{2. Gajra A, Zettler ME, Phillips EG Jr, Klink AJ, Jonathan K Kish, Fortier S, Mehta S, Feinberg BA. Neurological adverse events following CAR T-cell therapy: a real-world analysis. Immunotherapy. 2020 Oct;12(14):1077-1082. doi: 10.2217/imt-2020-0161}