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Instructor of Medicine
Division of Oncology
Department of Internal Medicine
Harvard Medical School
Hematopoietic Cell Transplant and Cellular Therapy Program
Massachusetts General Hospital Cancer Center
Matthew J. Frigault, MD, has disclosed that he has received consulting fees from Arcellx, Celgene, Foundation, Kite/Gilead Sciences, Nkarta, Novartis, and Xenetic.
Now that the FDA has approved the CAR T-cell therapies tisagenlecleucel and axicabtagene ciloleucel for relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL) and large B-cell lymphoma, how should clinicians identify the patients most likely to benefit? In the “real world,” I have found that the best approach is to optimize each patient and their disease state to maximize their probability of successful therapy while minimizing their risk of toxicity, rather than enforcing strict eligibility requirements. In this commentary, I share my perspective on identifying and optimizing patient eligibility for CAR T-cells.
Patients need sufficient functional reserve to tolerate the risk of cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome (ICANS). The goal of the initial pretreatment evaluation is to optimize patients with an emphasis on multidisciplinary evaluation to minimize potential toxicities and tailor intervention to patient-specific risk factors. The evaluation includes testing of baseline renal and hepatic function, assessment of sufficient hematologic reserve for optimal leukapheresis, and general cardiac screening.
Pediatric and young adult patients generally tolerate CAR T-cells well, despite having been through multiple lines of prior therapy, including stem cell transplant (SCT). Younger patients typically have sufficient cardiac, renal, hepatic, and pulmonary reserve to tolerate potential CAR T-cell–related toxicities; however, we recommend repeating screening just before moving forward with CAR T-cell treatment. When considering tisagenlecleucel or axicabtagene ciloleucel for adult and older patients with diffuse large B-cell lymphoma (DLBCL), we evaluate each on a case-by-case basis out of concern for cardiac, pulmonary, and renal dysfunction that could limit tolerability.
The registrational studies for these agents required an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1, which excludes many patients who may benefit from CAR T-cells. However, real-world data presented at ASH 2018 by both Jacobson and Nastoupil indicated that patients with an ECOG PS ≥ 1 can benefit from axicabtagene ciloleucel. Regarding age, Sano and colleagues reported similar outcomes between patients aged younger than 65 years vs 65 years or older who received axicabtagene ciloleucel after FDA approval. Ultimately, the decision to treat should be made by the patient in collaboration with a physician experienced in CAR T-cells.
Comorbidities and Patient History
In the real-world analysis by Jacobson and colleagues, 60% of patients would have been ineligible for the pivotal ZUMA‑1 study based on use of bridging chemotherapy or clinical factors such as prior allogeneic SCT or cardiac and renal dysfunction. Nonetheless, this real-world cohort showed favorable outcomes, including a CR rate of 44% and a safety profile comparable to that of the ZUMA-1 cohort.
These data support using CAR T-cells in a broader patient population. Below, I highlight key clinical factors when considering CAR T-cells for real-world patients:
Cardiac dysfunction and arrhythmias: Most CAR T-cell trials have required a minimum cardiac ejection fraction (EF) of ≥ 45%. However, decreased cardiac function is common in our patients who received anthracycline-based regimens, which are associated with dose-dependent reductions in EF. Furthermore, many patients have preexisting vascular disease as well as underlying cardiac arrythmias (eg, atrial fibrillation/flutter).
When treating patients with cardiac issues, clinicians should consider the use of extensive hydration before and after lymphodepleting chemotherapy; the patient’s risk of cytokine-release syndrome and need for volume resuscitation; and, in the event of CAR T-cell–associated toxicities, the possibility of exacerbating underlying arrythmias. In these cases, close collaboration with cardiology for appropriate risk stratification, cardiac optimization before CAR T-cell infusion, and early intervention in the event of toxicity is recommended.
Renal dysfunction: Due to use of fludarabine-based preconditioning regimens, we strongly consider renal dysfunction when evaluating patients for CAR T-cell therapy. There are limited data supporting use of fludarabine in patients with poor renal function (ie, creatinine clearance < 30 mL/min), and we aggressively dose reduce due to concerns for fludarabine-associated neurotoxicity. Given patient-specific variability in creatinine clearance and isolated serum creatinine, we recommend performing 24-hour urine creatinine testing to better approximate renal function. Unfortunately, we lack sufficient data to support using these regimens—and thus proceeding with CAR T-cell therapy—in patients on dialysis.
Prior allogeneic SCT: Among the pediatric and young adult patients with B-ALL who received tisagenlecleucel through the ELIANA trial, 61% had already undergone allogeneic SCT. The trial excluded those with active graft-vs-host disease (GVHD), and no new cases of GVHD were observed on study. Recently, Jain and colleagues reported no apparent GVHD in 4 adults with relapsed/refractory B-cell non-Hodgkin lymphoma who received axicabtagene ciloleucel developed from T-cells collected after relapse following allogeneic SCT. Taken together, these data support the use of CAR T-cells following allogeneic SCT in patients without active GVHD.
HIV-associated lymphomas: Patients with HIV were excluded from pivotal studies due to technical issues with the use of retroviral and lentiviral-based transduction systems. In 2019, Abramson and colleagues reported successful treatment with axicabtagene ciloleucel in 2 HIV-positive patients with relapsed DLBCL without evidence of viral reactivation. Although the ability to produce CAR T-cells for this population may be manufacturer dependent, these data indicate that patients with HIV can be successfully treated. Treatment should be done in close collaboration with infectious disease specialists.
Active/prior central nervous system (CNS) disease: Another population excluded from key trials and, until recently, from many CAR T-cell centers were those with active or prior CNS disease due to concerns for increased ICANS risk. However, my colleagues and I recently reported that tisagenlecleucel was safe and effective in 8 patients with CNS disease; similar results were reported for the investigational product lisocabtagene maraleucel in 9 patients by Abramson and colleagues at ASCO 2019. Patients with active or prior CNS disease should be managed closely with neurology/neuro-oncology at CAR T-cell centers.
Social and Financial Support
At our center, our goal is to facilitate access to CAR T-cell therapies for all patients despite social and financial barriers. In the initial consult, patients meet with a social worker who helps identify and overcome potential challenges in their support system (such as financial hurdles related to the mandatory 30-day Risk Evaluation and Mitigation Strategy monitoring period) by assisting patients in obtaining local housing and accessing financial support (eg, foundation grants). We also incorporate practice nurse teaching sessions to reinforce posttreatment requirements and to set appropriate expectations.
If patients cannot easily travel to our center, we opt for a virtual consult focusing on local screening and discussion with the patient and referring clinician as to whether an in-person consult is worthwhile. We minimize the number of trips needed through a multidisciplinary approach that involves coordinating consultation for pretreatment screening, social work, CAR T-cell education, and apheresis for T-cell collection all within a period of 5-7 days.
When to Refer Patients for CAR T-Cells
Although it is important to consider patient eligibility, it is even more critical to consider timing. Ideally, potential patients should be referred as soon as possible regardless of perceived barriers. Delays in referral often lead to additional complications, decreased performance status, and/or disease progression, all of which may lead to a suboptimal treatment course. As discussed above, the key to successful treatment is patient optimization and a collaborative, multidisciplinary approach that individualizes care.
Given how rapidly the CAR T-cell field is evolving, we recommend discussing eligibility with an authorized center rather than screening at the referral site. The optimal time to consider eligibility and refer is when a patient is in their first relapse and receiving salvage chemotherapy with hopes for autologous SCT. It is ideal to review these patients during their workup for autologous SCT as most patients will also be eligible for subsequent CAR T-cell treatment in the event of relapse or suboptimal response to salvage therapy.
How do you determine eligibility for CAR T-cell therapy in your practice? Please share your thoughts in the comments box.
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