Advances in Hematologic Malignancies
Issue 11, Fall 2019
— Caron Jacobson, MD
Anti-CD19 chimeric antigen receptor (CAR) T-cells have had a dramatic impact on the natural history of chemotherapy-refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL) and B-cell acute
lymphoblastic leukemia (B-ALL), with durable remissions seen in 40% and 50% of patients, respectively. However, patients who were treated on the pivotal ELIANA and JULIET trials of tisagenecleucel (t-cel) in B-ALL and B-NHL, and the ZUMA-1 trial of
axicabtagene ciloleucel (axi-cel) in B-NHL, were carefully chosen based on performance status, organ function requirements, lack of comorbid disease, and ability to wait for manufacturing of autologous CAR T-cells. As a result, these patients were
not representative of the general population with lymphoid malignancies.
Now, these CAR-T therapies are available in the commercial, non-clinical trial setting, which allows for the liberalization of treatment criteria. The time it takes for insurance approval, coordination of multidisciplinary services, and manufacturing
the final cellular product, coupled with the unique toxicities seen with these therapies, means that eligibility limits must still exist.
We and others have looked at our "real world" experience with commercial axi-cel in aggressive B-NHL and found that although up to 60% of patients would not have been eligible for ZUMA-1, response rates and durability of response, as well as rates of
high-grade cytokine release syndrome (CRS) and neurotoxicity appear to be comparable in trial-ineligible patients compared to those treated on-study. However, poor performance status and increased tumor burden, as well as high pre-treatment inflammatory
markers, were associated with worse outcomes. This suggests that eligibility criteria for ZUMA-1 may be overly strict, but some exclusion criteria are probably reasonable.
For example, treating centers must decide what minimal organ function parameters are advisable, including cardiac ejection fraction, creatinine clearance, bone marrow function, and liver function tests. Patients must be able to withstand CRS and neurotoxicity
and so cannot have severely compromised organ function or underlying neurologic disease that would make it difficult for them to survive such toxicities. Other considerations include the presence of an active autoimmune disease that could be aggravated
by the T cell infusion, and the need for systemic anticoagulation, given the rare instances of intracranial hemorrhage seen during neurotoxicity. Each treating center will weigh these potential contraindications individually.
All centers would agree, however, that early referral of patients who might be CAR-T therapy candidates is of vital importance to
be able to navigate the complexities with insurance companies, scheduling, and T cell manufacturing, especially if a patient's disease is rapidly progressing. We recommend that patients be referred at the time of first relapse, preferably before the
initiation of salvage therapy, as there are not randomized trials of CAR T-cell therapy versus standard of care in the second line setting. This early referral will ensure that a patient’s chances of being well enough to receive CAR T-cells when needed
are optimized, and that more patients will have the opportunity to have this potentially life-saving therapy.
More on our CAR T-cell therapy program
Current CAR T-cell clinical trials