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Should patients with ALL undergo HSCT after CAR T-cell therapy?
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Yes.
CAR T-cell therapies for ALL hold great promise, yielding remission rates of up to 90% for relapsed/refractory patients. However, the durability of these responses remains uncertain, particularly in adults, as follow-up data are limited for most patients. Further, a substantial number of those patients with durable remissions after CAR T-cell treatment have undergone subsequent allogeneic HSCT to consolidate their responses. In fact, leukemia-free survival appears to be significantly higher among patients who received HSCT following CAR T-cell therapy.
Moreover, there are limitations that temper the impressive results of CAR T cells in ALL. Antigen escape by the leukemic cells and eventual disappearance of the CAR T cells have emerged as significant mechanisms of resistance. It remains to be seen whether the use of combined targets (eg, CD19 and CD22) may overcome antigen escape and whether newer platforms may enhance the persistence of CAR T cells. Also, all available CAR T cell therapies for ALL are directed against normal B-cell antigens, rather than leukemia-specific targets. Consequently, these treatments induce B-cell aplasia and hypogammaglobulinemia for as long as the CAR T cells persist. Somewhat counterintuitively, full immune reconstitution may therefore be superior after HSCT.
Despite the enormous potential of CAR T cells for the treatment of ALL, HSCT still provides the most reliable chance of durable remission. Newer generations of CAR T cells may ultimately offer better outcomes. Similarly, moving CAR T-cell therapy earlier in treatment may also improve efficacy, as results have been best among those patients with the lowest disease burdens. However, additional, preferably leukemia-specific targets are needed, especially against T-cell ALL and against those B-cell cases that have undergone antigen escape. As such, at least for now, the recommendation would still be to pursue allogeneic HSCT, when possible, for those patients who achieve remission after CAR T-cell therapy.
Jonathan M. Gerber, MD, is director of the leukemia division and medical director of hematology at Levine Cancer Institute of Carolinas HealthCare System and a HemOnc Today Editorial Board Member. He can be reached at jonathan.gerber@carolinashealthcare.org. Disclosure: Gerber reports no relevant financial disclosures.
It depends.
Immunotherapies have transformed the therapeutic landscape for children and adults with relapsed and refractory ALL. Traditionally, these patients are treated with intensive cytotoxic chemotherapy followed by HSCT if they achieve a durable remission. In addition, many adults and some children with poor biologic features, such as persistent minimal residual disease (MRD), low hypodiploidy and t(17;19), are offered HSCT in first complete remission. The decision to offer HSCT is often not based on results of randomized clinical trials, but on historical data demonstrating poor OS with cytotoxic chemotherapy alone. The few randomized trials that exist comparing cytotoxic chemotherapy with HSCT were largely performed before modern improvements in supportive care, the ability to monitor and intervene post-HSCT based on MRD and donor chimerism, and the availability of immunotherapies that induce “deeper” and potentially more durable MRD-negative remissions.
A key benefit of HSCT — is the graft-versus-leukemia effect, which is likely tied to a number of factors, including blast biology, KIR genotype and the bone marrow microenvironment. There are likely some ALL patients who are currently not offered HSCT because of excellent outcome with chemotherapy alone who could have even better outcomes with HSCT. In contrast, there are patient groups for whom HSCT is considered standard of care based on poor outcomes with cytotoxic chemotherapy, yet who have no demonstrated survival benefit with HSCT. HSCT carries high rates of short- and long-term morbidity and mortality, including secondary malignancies, infertility, chronic graft-versus-host disease and neurologic impairment. In 2018, one could easily argue in many circumstances we do not have robust or compelling data defining which patients with ALL clearly benefit from HSCT.
It is difficult to justify changing the paradigm without definitive data from randomized trials. The situation is less clear with CAR T cells directed at CD19. Over 200 patients with relapsed/reffractory B-ALL have received tisagenlecleucel. The complete response rates (> 80%) are outstanding. The best available data demonstrate a 2-year OS of about 60%, which is superior to published data using HSCT as definitive therapy in similar populations. There are now patients who have been treated with tisagenlecleucel without HSCT and have maintained a durable remission for over 5 years. Most patients getting CTL019 maintain B-cell aplasia (ie, functional persistence) for years. Although the long-term consequences of prolonged B-call aplasia are unknown, the late effects after CAR T are expected to be far less morbid than those seen after HSCT.
Based on high rates of durable remission and low rates of long-term side effects with tisagenlecleucel, it begs the question of whether it should be used as a definitive therapy or a bridge to HSCT. The risk of using CAR T as definitive therapy is the potential inability to salvage and get to HSCT after relapse. With the advent of additional immunotherapies, including those targeting CD22, salvage rates have improved substantially, lowering this concern. The risks of using CAR as a bridge to transplant are the significant risks for morbidity and mortality of HSCT and potentially increased risk for relapse because conditioning used for HSCT eliminates the therapy (ie, the CAR T cells) that induced and maintain the remission.
The answer to this complicated question is often that it depends on the patient. Patients who are MRD positive after tisagenlecleucel should be offered HSCT. Patients who have poor CAR T persistence, (ie, those who have no detectable CAR T cells or who develop B-cell recovery within 3 to 6 months of therapy) should be considered for HSCT, or can be offered reinfusion on an experimental basis. Patients who have expected poor outcomes with HSCT — such as patients who have already relapsed after HSCT, who have poor biology, who have early medullary relapse (< 18 months) and are MRD positive (> 0.01%) after reinduction chemotherapy, who are persistently MRD positive after 3+ months of intensive chemotherapy, and who have significant comorbidities — should strongly consider CAR T as definitive therapy. If the best HSCT can offer is 40% or lower OS, wiping out the CAR T cells for a transplant seems unwise. For other patients, where survival after HSCT is greater, the best approach is an informed conversation with the patient and his or her family detailing the risks and benefits of HSCT after CAR T cells.
David T. Teachey, MD, is associate professor of pediatrics in the division of oncology at Children’s Hospital of Philadelphia and Perelman School of Medicine at University of Pennsylvania. He can be reached at teacheyd@email.chop.edu. Disclosure: Teachey reports no relevant financial disclosures.