FROM ASPHO 2017
MONTREAL (FRONTLINE MEDICAL NEWS) – Daratumumab may do for patients with T-cell acute lymphoblastic leukemia (T-ALL) what it has done for those with multiple myeloma. That, at least, is the hope of a team of investigators who are conducting preclinical studies and planning human trials of the CD38 inhibitor in leukemia.
“We believe daratumumab significantly inhibits disease progression as shown in our different [patient-derived xenograft] models,” said Karen L. Bride, MD , of Children’s Hospital of Philadelphia.
Daratumumab’s primary target, the CD38 receptor, was found to be expressed at high levels in all but 1 of 15 T-ALL samples, and the drug significantly inhibited disease progression in mice with human tumor xenografts, she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.
The Food and Drug Administration approved daratumumab (Darzalex) in November 2015 for the treatment of patients with multiple myeloma who had received at least three prior lines of therapy. They then amended the approval last fall to “at least one prior medicine.”
When added to a standard regimen of bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma in the phase III CASTOR trial , daratumumab reduced the risk of disease progression or death by 61% with little increase in toxicity.
The drug is believed to work against multiple myeloma through both an on-target (anti-CD38) mechanism, and through off-target promotion of increases in T-helper cells, cytotoxic T-lymphocytes, T-cell function response, and T-cell receptor clonality (Blood. 2016 Jan. doi: 10.1182/blood-2015-12-687749 ).
CD38 in T-ALL
Dr. Bride and her colleagues hope to bring daratumumab’s anti-CD38 action to bear on relapsed or refractory T-ALL.
“One of the reasons this is particularly challenging is that we find T-ALL is clinically and genetically heterogeneous,” she said. “With a number of different genetic mutations that have been identified, there are certainly some potentially targetable pathways. However, finding an appropriate target that can be broadly applicable is still needed.”
CD38 may be one such target. It is expressed at relatively high levels on both T-ALL and B-precursor ALL blasts but at only low levels on normal immune cells.
The investigators first used flow cytometry to measure CD38 levels in samples from 10 patients with early T-cell precursor (ETP) T-ALL and 11 with non-ETP disease, both at diagnosis and after 1 month of induction chemotherapy. CD38 expression was detectable in all of the samples and did not change significantly after chemotherapy, suggesting that CD38 was indeed a valid target in T-ALL.
They then grafted primary ALL blasts from patients with ETP-ALL and non-ETP-ALL into mice and randomly assigned them to be treated for 3 to 5 weeks with daratumumab or to serve as controls. The mice were initially treated after they developed more than 1% of peripheral blood blasts.
Daratumumab-treated models had significant reductions in disease burden as measured by blasts in both peripheral blood (P = .0112) and spleen (P = .0003).
There were six responses to daratumumab in the seven treated mice grafted with ETP-ALL and no cases of toxicity. Among the eight mice with non-ETP ALL, however, there was only one response, and five animals became moribund roughly 1 hour after injection.
The investigators could not find an explanation for these reactions either on necropsy or pathology studies.
“We hypothesized that there was potentially massive tumor lysis syndrome being experienced by the mice, and, as a consequence, they were becoming moribund,” Dr. Bride said.
In subsequent experiments, they have begun introducing the drug within 5 days of adoptive transfer, prior to full engraftment. This is akin to treating during a minimal residual disease phase, she said.
Despite the observed but unexplained toxicities in some animals, “our data are promising enough that we’re hopeful that we will open a phase I/II trial of daratumumab starting next year,” Dr. Bride said.
Not so fast
However, a pediatric hematologist/oncologist who was not involved in the study said in an interview that Dr. Bride and her colleagues would be wise not to proceed too quickly into human trials, at least until the potential toxicities of daratumumab in T-ALL have been more fully elucidated.
“I found it very striking that the mice responded the way they did, and that was just from receiving the drug. So, there is something else that’s going on, and I think it behooves them to investigate further. It’s not that I’m skeptical about the activity of the drug; I just don’t want studies to be shut down because the investigators didn’t have the best trial design,” said Valerie I. Brown, MD .
Dr. Brown, director of experimental therapeutics at Penn State Health Milton S. Hershey (Penn.) Medical Center, was a comoderator of the session where Dr. Bride presented the study findings.
Asked about her response to Dr. Brown’s comments in an interview, Dr. Bride said that “because of the success of daratumumab in humans already, I think I’m a bit less worried about this agent. You can’t necessarily translate exactly across diseases, but I do think it’s very promising, and I don’t think [the toxicity] is a reason to pull back.”
The study was supported by grants from the Leukemia and Lymphoma Society and the National Institutes of Health. Janssen donated the daratumumab. Dr. Bride and Dr. Brown reported no conflicts of interest to disclose.
