CAR T-cell therapy effective for chronic lymphocytic leukemia
CD19-specific chimeric antigen receptor-modified T-cell therapy induced durable molecular remissions in patients with high-risk chronic lymphocytic leukemia who had previous treatment failure with ibrutinib, according to results from a phase 1/phase 2 study published in Journal of Clinical Oncology.
“CLL is the most common adult leukemia,” Cameron Turtle, MBBS, PhD, FRACP, FRCPA, associate member of the clinical research division at Fred Hutchinson Cancer Research Center, and colleagues wrote. “Patients with high-risk disease manifest by del17(p13.1), p53 mutation, complex karyotype or unmutated immunoglobulin variable regions require earlier therapy and have shorter survival.”
Ibrutinib (Imbruvica; Pharmacyclics, Janssen), a Bruton tyrosine kinase inhibitor, has demonstrated a high overall response rate in patients with relapsed or refractory disease. However, complete response rates remain low, and survival is poor after progression with ibrutinib.
Anti-CD19 chimeric antigen receptor (CAR) T cells have demonstrated high response rates in patients with refractory B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma, as well as in a small subset of patients with CLL.
Turtle and colleagues conducted a phase 1/phase 2 open-label clinical trial to evaluate the efficacy and safety of anti-CD19 CAR T-cell therapy after lymphodepletion chemotherapy in 24 patients (median age, 61 years) with CLL who previously received ibrutinib (median duration, 13 months). Nineteen patients had experienced disease progression on ibrutinib and three patients were ibrutinib intolerant. All patients discontinued ibrutinib prior to CAR T-cell therapy — including two patients who had not experienced progression — because the safety of concurrent CAR T-cell and ibrutinib therapy is unknown.
The researchers administered anti-CD19 CAR T cells at three dose levels: 2 x 10 CAR T cells/kg (n = 4), 2 x 10 CAR T cells/kg (n = 19), or 2 x 10 CAR T cells/kg (n = 1).
Researchers noted most patients developed toxicities associated with lymphodepletion chemotherapy.
Twenty patients developed cytokine release syndrome — including one grade 4 and one grade 5 case — eight of whom also developed neurotoxicity. Two patients required ICU management, one of whom developed fatal neurotoxicity. Researchers reversed all other cases of neurotoxicity.
Researchers defined the maximum tolerated dose as 2 x 10 CAR-T cells/kg or less.
Four weeks after CAR T-cell infusion, 17 patients achieved a complete or partial response for an ORR of 71%.
Nineteen patients underwent restaging. Fourteen of these patients (74%; 95% CI, 49-91) achieved lymph node responses defined by International Workshop on CLL criteria, which included four complete and 10 partial responses.
Four weeks after treatment, researchers evaluated 21 of 22 patients with baseline marrow disease.
Seventeen of these patients had no marrow disease detected by high-resolution flow cytometry, fifteen of whom (88%; 95% CI, 64-99) showed eliminated CLL from marrow by flow cytometry.
In addition, seven of 12 patients who cleared marrow by flow cytometry but also had clonal malignant IGH sequence had no detectable malignant IGH sequences in marrow 4 weeks after CAR T-cell infusion.
Researchers noted achieving a malignant IGH-negative status correlated with better PFS than by International Workshop on CLL criteria, which requires all lymph nodes be 15 mm or smaller.
“These data indicate that early restaging by tumor size criteria alone, 4 weeks after CAR T-cell administration, may not be the optimal determinant of prognosis, as suggested after immune checkpoint blockade in other malignancies,” Turtle and colleagues wrote. “Additional studies will be required to determine whether strategies such as IGH sequencing, PET imaging or delayed restaging after CAR T-cell immunotherapy of CLL can identify patients who might benefit from additional CAR T-cell infusions to improve outcomes.”
Absence of the malignant IGH clone in the marrow of patients with CLL who responded by International Workshop on CLL criteria led to 100% PFS and OS rates after a median follow-up of 6.6 months.
PFS appeared similar in patients with partial or complete lymph node responses.
“This approach can achieve sustained molecular remissions and improve the poor prognosis of ibrutinib-refractory CLL,” Turtle and colleagues wrote. “Future studies in patients who are likely to become refractory to ibrutinib on the basis of high-risk cytogenetics or early detection of mutations before relapse that confer ibrutinib resistance are warranted.” – by Kristie L. Kahl
Disclosures: Turtle reports he is a consultant/adviser for Adaptive Biotechnologies, Bluebird Bio, Celgene, Juno Therapeutics, Precision Biosciences and Seattle Genetics; and receives research funding from Juno Therapeutics. Please see the full study for a list of all other researchers’ relevant financial disclosures.