New drug combination promises deeper remission in chronic leukemia

Researchers leading the SWOG S1712 clinical trial have found that adding ruxolitinib to standard tyrosine kinase inhibitor (TKI) treatment in patients with chronic phase chronic myeloid leukemia (CP-CML) significantly increases the percentage of patients whose molecular response is strong enough to justify discontinuing treatment.

The results will be presented at the 26th Annual John Goldman Conference on Chronic Myeloid Leukaemia of the European School of Haematology, which will be held in Prague from 27 to 29 September.

Kendra L. Sweet, MD, a SWOG investigator at Moffitt Cancer Center who was principal investigator of the S1712 study, will announce the results on Friday, September 27, as an oral presentation in the conference's first scientific session, which is devoted to the meeting's highest-scoring abstracts..

Treatment-free remission has become a common therapeutic goal for patients with CP-CML. Yet only about 40 to 50 percent of CP-CML patients achieve a molecular response deep enough to qualify them for an attempt to stop TKI therapy.”

Kendra L. Sweet, SWOG researcher, Moffitt Cancer Center

“In this study, adding ruxolitinib to TKIs resulted in durable, deep molecular responses in significantly more patients. Ultimately, this could lead to more patients successfully discontinuing treatment, which has been shown to significantly reduce healthcare costs and improve health-related quality of life.”

CML is often treated with a class of drugs known as tyrosine kinase inhibitors. However, leukemic stem cells in a patient's bone marrow can hide from TKIs. Preclinical data suggests that a drug called ruxolitinib can alter the bone marrow microenvironment to sensitize these stem cells to TKIs.

Researchers from the SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute (NCI), hypothesized that adding ruxolitinib to TKI treatment would increase the efficacy of TKIs against leukemic stem cells, thereby eliminating measurable residual disease in more patients.

In the S1712 clinical trial, they randomized 75 eligible patients with CML whose disease was still molecularly detectable on current therapy and who had been treated with a TKI for at least one year. All patients continued their TKI treatment, but in half of the patients the drug ruxolitinib was added to the treatment.

After 12 months of study treatment, all patients' blood was tested for molecular response (MR), a highly sensitive test for RNA from a gene specific to leukemia cells. A value of MR4.0 – considered a deep molecular response – indicates a reduction in this RNA to 0.01 percent or less of baseline. A value of MR4.5 means no such RNA was detected and is considered a complete molecular response.

The proportion of S1712 patients achieving MR4.0 at 12 months was significantly higher in the ruxolitinib arm – 46 percent versus 26 percent in the TKI arm. The proportion of patients achieving MR4.5 at 12 months was also significantly higher in the ruxolitinib arm – 14 percent versus 3 percent in the control arm.

The additional administration of ruxolitinib also resulted in more patients achieving a sufficiently deep remission to be able to stop treatment. Two years after randomization, the proportion of patients who met the criteria of the National Comprehensive Cancer Network (NCCN) guidelines for discontinuing treatment was 29 percent in the study group compared to 11 percent in the control group.

Toxicity was similar in both arms. Two patients in the ruxolitinib arm had grade 3 treatment-related adverse events (side effects). In the TKI arm, three patients had grade 3 treatment-related adverse events and one patient had a grade 4 adverse event. Grade 1 or 2 anemia was more common in patients in the ruxolitinib arm of the study.

Sweet's team is currently working to determine which CML patients will benefit most from adding ruxolitinib to their TKI regimen. The authors conclude that further studies are needed to examine whether this combination can increase the percentage of these patients who achieve treatment-free remission.

Study S1712 is supported by the NCI, part of the National Institutes of Health (NIH), led by SWOG, and conducted by the NIH-funded NCI National Clinical Trials Network (NCTN).

S1712 is funded by the NIH/NCI through grants U10CA180888 and U10CA180819 and supported in part by Incyte, which supplied ruxolitinib.