Key Considerations for Medical Monitoring in CAR T Clinical Trials During the COVID-19 Pandemic and Beyond

The following blog is an adaptation of a conference presentation in September 2020 that was also re-recorded and available here

Background: Medical monitoring supports the correct determination of patient eligibility for CAR T-cell therapy and plays a key role in monitoring quality patient care throughout CAR T clinical trials (see Figure 1 below). The COVID-19 pandemic presents multiple additional challenges to the safe conduct of medical monitoring in these types of trials:

Transportation issues – impacts both patients and staff, whilst also disrupting cellular therapy products/technical resources shipments to and from labs and hospitals
Staff shortages – either due to COVID-19 exposure or nursing/medical staff being redirected to specialist COVID-19 units
Clinical resource shortages – PPE, mechanical ventilation and hospital beds may be reallocated to the crisis

Figure1. Medical monitoring plays a role throughout CAR T-cell therapy

New guidelines from the CAR T-cell Consortium present an aligned approach to addressing these challenges to deliver optimum care for patients on CAR T therapy and in CAR T therapy clinical trials.¹

Should CAR T treatments continue during the COVID-19 pandemic?

CAR T-cell therapies have provided unprecedented durable responses in patients with previously dismal prognoses. For most of these patients, delaying treatment is not a realistic option, due to otherwise dismal prognosis and the fife saving option represented by CAR T-cell therapies. Healthcare providers need to expertly triage patients who are most in need of urgent treatment – other noncellular therapies are unlikely to result in a durable response and are still associated with significant adverse events.

What considerations need to be made to safely administer CAR T-cell therapy during COVID-19?

Recommendations aim to limit direct patient contact and reduce risk to patients when they at their most immunodeficient. Treatments like lymphodepleting chemotherapy should begin only after the receipt of cell products, with patient housing support provided for at least 4 weeks after the procedure to spare travel needs, particularly during the pandemic. Where possible visitors should be restricted, and early interventions used to limit CRS (cytokine release syndrome)/neurotoxicity and prevent infection. Recommendations also call for telemedicine, reduced non-essential lab work/radiology appointments, oral medications over parenteral and outpatient rather than inpatient visits where appropriate.

Do recommendations for CAR T clinical trials differ depending on trial phase or context?

Although individual patient treatment lies with the treating physician, guidelines around continuing clinical trials aim to optimise use of resources, without compromising patient care. Recommendations therefore depend on specific patients, phase and context:

Phase I trials – in principle should be limited or place on hold, as they are primarily designed to demonstrate safety
Phase II trials – should be continued, as these could offer long-term benefit and possibility of cure
Phase III trials or first-line therapy trials – should be placed on hold, as benefit is yet unproven vs. the standard of care

Enrolment should continue in trials aimed to test novel CRS and neurotoxicity prevention strategies, which might offer life-saving treatment whilst potentially minimizing toxicities and use of resources (such as tocilizumab, the availability of which could alter during the pandemic).

Overall CAR T-cell therapy should only be continued at expert treatment centers on optimal therapeutic candidates.

How do you approach selecting NHL or ALL patients for CAR T-cell therapy during COVID-19?

For patients with adult relapsed/refractory (R/R) aggressive B cell non-Hodgkin’s lymphoma (B-NHL) treatment continuation is contingent on patient type. Guidelines suggest deferring patients at high risk of CAR T-cell therapy failure, as indicated by surrogates of rapid tumor growth: elevated LDH and performance status (ECOG>2). Advanced age alone has not been associated with worse outcomes following CAR T, so treatment should continue in patients over 65 years. Otherwise CAR T-cell therapy should be offered in R/R aggressive B-NHL patients after failure in 2 or more prior lines, as per the label.

For patients with R/R B cell acute lymphoblastic leukemia (B-ALL) up to 25 years, CAR T-cell therapy is lifesaving, and treatment should proceed. Overall ICU admission has also been lower since therapy approval, likely due to improved management of toxicities like CRS, further supporting the use of CAR T in these patients.

As this is largely a pediatric group the treatment considerations are slightly different:

ICU bed availability may be an issue, especially for 18-25 age group in adult centers – transferring these patients to a pediatric center with more resources may be an option
Tocilizumab availability – tocilizumab may be redirected for use in COVID-19 patients, therefore shortage could occur and availability should be confirmed upfront
General bed availability is mostly unaffected in pediatrics, however there may be rather shortages of pediatric staff, due to infection or allocation to COVID units

How does COVID-19 testing fit into the CAR T-cell therapy treatment pathway?

Patients should be tested for COVID-19 at initial evaluation and 24-72 hours before they are scheduled to begin lymphodepleting chemotherapy. If RT-PCR tests come back positive, CAR T-cell procedures should be deferred until the patient is asymptomatic and has at least two consecutive negative PCR tests one week apart.

Usual quarantine procedures should be followed for CAR T candidates who have come into close contact with infected individuals, with CAR T-cell therapy should be delayed for the 14-day period. Any patients who develop COVID-19 during their hospitalization for CAR T-cell therapy administration should be managed according to their present symptoms and most recent treatment guidelines.

How can CAR T-cell patients at risk for COVID-19 best be supported and managed?

Managing COVID-19 risk prior to CAR T-cell therapy involves appropriate screening measures and testing at the relevant time points (including before apheresis, before lymphodepleting chemotherapy, and before and after CAR T-cell infusion) and preventative measures such as telemedicine and personal protective equipment, like face masks.

To support patients post CAR T-cell therapy, physicians should work with caregivers to limit in-person visits whilst maintaining close monitoring via telemedicine. Post CAR T-cell therapy supportive treatment should be adapted per standard of care, including infection prophylaxis and in line with COVID-19 recommendations.

More detailed recommendations of pre- and post-CAR T-cell therapy can be found here.

Conclusion

For the patients who are in need, delaying CAR T-cell treatments would be detrimental, unless justified by Covid-19 infection or higher risk for toxicity or poor outcome. By following regularly updated guidelines which adapt to reflect the most relevant information, treatment should continue safely for both patients and physicians. We are committed to learning from these expert recommendations and implement them across ongoing clinical research activity in the CAR T-cell field.

References:

Bachanova V, Bishop MR, Dahi P, Dholaria B, Grupp SA, Hayes-Lattin B, Janakiram M, Maziarz RT, McGuirk JP, Nastoupil LJ, Oluwole OO, Perales MA, Porter DL, Riedell PA; CAR T-cell Consortium. Chimeric Antigen Receptor T Cell Therapy During the COVID-19 Pandemic. Biol Blood Marrow Transplant. 2020 Jul;26(7):1239-1246.

Key Considerations for Medical Monitoring in CAR T Clinical Trials During the COVID-19 Pandemic and Beyond

Should CAR T treatments continue during the COVID-19 pandemic?

What considerations need to be made to safely administer CAR T-cell therapy during COVID-19?

Do recommendations for CAR T clinical trials differ depending on trial phase or context?

How do you approach selecting NHL or ALL patients for CAR T-cell therapy during COVID-19?

How does COVID-19 testing fit into the CAR T-cell therapy treatment pathway?

How can CAR T-cell patients at risk for COVID-19 best be supported and managed?

Conclusion

References:

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Should CAR T treatments continue during the COVID-19 pandemic?

What considerations need to be made to safely administer CAR T-cell therapy during COVID-19?

Do recommendations for CAR T clinical trials differ depending on trial phase or context?

How do you approach selecting NHL or ALL patients for CAR T-cell therapy during COVID-19?

How does COVID-19 testing fit into the CAR T-cell therapy treatment pathway?

How can CAR T-cell patients at risk for COVID-19 best be supported and managed?

Conclusion

References:

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