New CAR T Cell for Adult ALL, 'Game Changer' in Pediatric ALL

Alexander M. Castellino, PhD

February 01, 2018

Chimeric antigen receptor (CAR) T-cell therapy has been hailed as the clinical cancer advance of the year; the first of these products to be approved was tisagenlecleucel (Kymriah, Novartis), for the treatment treat children and young adults with acute lymphoblastic leukemia (ALL).

Details of the landmark trial that led to that approval were published online Februray 1 in the New England Journal of Medicine.

"Previously, for patients who relapsed after transplant or did not respond to treatment, there wasn't much else we had to offer them, and often, they went to hospice," commented coauthor Michael A. Pulsipher, MD, of Children's Hospital Los Angeles (CHLA), in a statement. "Now, instead of sending them to hospice, we treat them with CAR T cells, make them better, then send them home."

"CAR-T therapy is truly a game changer for pediatric leukemia," commented coauthor Alan S. Wayne, MD, director of the Children's Center for Cancer and Blood Diseases at CHLA.

New Product in Adult ALL

Now another CAR T cell, dubbed 19-28z, has shown activity in adult patients with relapsed or refractory B-cell ALL in a clinical trial reported in the same issue of the New England Journal of Medicine. This product was developed at the Memorial Sloan Kettering (MSK) Cancer Center, New York City. The study was partly supported by Juno Therapeutics.

The MSK researchers report that treatment with a single infusion of 19-28z CAR T cells led to a high remission rate — 44 of 54 patients (83%) experienced complete remission. What sets this study apart from others is that some of these patients had been followed for as long as 5.5 years. The results offer insights into who may benefit the most from this therapy, say the researchers.

"This is the longest follow-up study of people with ALL treated with CAR therapy," principal investigator Jae Park, MD, medical oncologist at MSK, told Medscape Medical News. "It confirms the power of CAR T cells as an effective cancer therapy in adults with ALL, and patients with low or high disease burden show immediate remission," he added.

"However, with the longest follow-up, we are able to demonstrate for the first time that patients with lower disease burden [less than 5% bone marrow blasts] benefited the most from CAR therapy, with significantly improved survival and reduced toxicity," he said.

"Among all the clinical and disease factors we examined, pretreatment disease burden was the strongest predictor of long-term outcome after CAR therapy," Dr Park said in an MSK release. "Our data support incorporation of CAR therapy in earlier treatment setting in ALL when the disease volume is small so as to achieve the greatest long-term efficacy and lowest toxicity," he added.

"In recent years, we have witnessed many clinical studies that primarily focused on early response rates and toxicities in patients treated with CAR T cells. With the results of this study, we can begin to appreciate the long-term benefit and outcomes of this therapy," corresponding author Michel Sadelain, MD, PhD, who is director of MSK's Cell Engineering Center, said in the MSK statement.

These data...predict better outcomes when used earlier in the course of disease Dr Michel Sadelain

"These data strongly support the use of this CAR therapy for adults with relapsed ALL and predict better outcomes when used earlier in the course of disease," Dr Sadelain added.

New Product Is Different

The study used 19-28z CAR T cells, which express a chimeric receptor containing an anti-CD19 antibody binding site and the intracellular domains from the T-cell coactivating receptors, CD28 and CD3-zeta chain.

The product is different from the two CAR T-cell therapies that have been launched commercially, Dr Park noted.

Tisagenlecleucel also contains an anti-CD19 antibody binding site, but its intracellular domains come from the T-cell coactivating receptors, 4-1BB and CD3 zeta.

Although the other approved CAR T-cell product, axicabtagene ciloleucel (Yescarta, Kite Pharma), for adult patients with non-Hodgkin's lymphoma, also uses 19-28z CAR T cells, the constructs that produce the MSK cells are unique, Dr Park said.

The biology of these molecules is different and will dictate whether persistence of CAR T cells is required to affect outcomes, Dr Park noted. In the MSK study, persistence of CAR T cells is not required for durability of response. "This is because 19-28z CAR T cells grow exponentially. Critical numbers of cells have a benefit, but they do not have to stay there," he said.

Dr Park also noted that the clinical study conducted with 19-28z CAR T cells was independent of studies of similar technology licensed to Juno Therapeutics.

Details of the Study

Dr Park and colleagues began the study with 83 adult patients with relapsed/refractory B-cell ALL, of whom 78 underwent leukapharesis. The median absolute lymphocyte count was 0.8 x 103 cells per cubic millimeter.

The success rate for producing CAR T cells was 97% (65/67). Fifty-three patients were treated with 19-28z CAR T cells.

All 53 patients had been heavily pretreated: 68% (36/53) received CAR T cells as third or later salvage therapy, 23% (12/53) had refractory disease, 36% (19/53) had received transplants, and 25% (13/53) had received blinatumomab (Blincyto, Amgen).

At the time of CAR T-cell infusion, 60% (32/53) of patients had high disease burden, 28% (15/53) had minimal residual disease (MRD), defined as bone marrow blasts from 0.01% to less than 5%), and 11% (6/53) were MRD-negative (less than 0.01% bone marrow blasts).

This was a phase 1 study, and the primary endpoint was safety. Cytokine release syndrome and neurotoxic effects were the two most common side effects reported. Symptoms of cytokine release syndrome include fever, tachycardia, hypotension, respiratory distress, and hypoxemia. Neurologic adverse events include confusion, disorientation, aphasia, encephalopathy, and seizure.

Cytokine release syndrome occurred in 85% (45/53) of all patients. Events of grade 3 or higher occurred in 26% (14/53) of patients; there was one death.

Patients who experienced cytokine release syndrome were managed with supportive care alone or tocilizumab with or without glucocorticosteroid.

Neurotoxic adverse events of grades 2, 3, and 4 were reported in one (2%) patient, 19 (36%) patients, and three (6%) patients, respectively.

Both of these side effects occurred at a significantly higher rate in patients with high disease burden, the researchers note. Cytokine release syndrome was seen in 41% of patients with high disease burden and in 5% of patients with low disease burden (P = .004). Likewise, neurotoxic adverse events were seen in 59% of patients with high disease burden and in 14% of patients with low disease burden (P = .002).

Response Rates and Survival

The researchers report that 44 of 53 patients treated (83%) experienced complete remission; of 48 patients who were assessed for minimal residual disease, 32 (67%) experienced MRD-negative complete remission.

Median follow-up was 29 months (range: 1 to 65 months). Nedian event-free survival (EFS) was 6.1 months, and median overall survival (OS) was 12.9 months.

EFS and OS were significantly longer for the 32 patients with MRD-negative complete remission, compared with the 21 patients with MRD-positive complete remission or who showed no response after CAR T-cell infusion.

Relapse was also dictated by MRD status after CAR T-cell therapy: all (9/9) patients with MRD-positive complete remission experienced relapse, compared with 50% (16/32) of patients with MRD-negative complete remission.

CAR T-cell dose, Ph-positive status, conditioning regimen, median duration of CAR T-cell detection, and absolute magnitude of peak CAR T-cell expansion were not associated with longer survival.

"The absence of these associations may be investigated in larger cohorts, since our study was not powered to detect moderate effects," the MSK researchers note.

Median EFS was significantly longer for patients with low disease burden before therapy than for those with high disease burden (10.6 months vs 5.3 months; P = .01), as was overall survival (20.1 months vs 12.4 months; P = .02).

The complete remission rate seen with 19-28z CAR T cells is similar to that seen for tisagenlecleucel in children and young adults with B-cell ALL. In the landmark study that has now been published, the complete remission rate in 75 patients within 3 months was 81%. In this study, 1-year EFS and OS rates were 50% and 76%, respectively.

Long-term Effects Explained

Dr Park explained that in their study, unlike other studies, 19-28z CAR T-cell persistence was not required for durable remissions.

His team noted that a higher ratio of peak CAR T-cell expansion to tumor burden significantly correlated with EFS and OS and was a better predictor of either endpoint compared with the absolute magnitude of T-cell expansion or disease burden.

"This...may explain how patients with a low disease burden can have a long-term survival benefit without having high-grade short-term toxic effects and also explains why high peak proliferation alone does not correlate with long-term outcomes," the MSK researchers write.

The study was supported by several cancer charities and in part by Juno Therapeutics.

New Engl J Med. Published online February 1, 2018. Abstract

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