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Combination induces remission in advanced MM


 

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m2), reinfusion of autologous stem cells (≥2.1×106 cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

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