The pharmaceutical arsenal for the treatment of patients with leukemias or myelodysplastic syndromes (MDS) currently in the pipeline continues to grow, with some drugs showing particularly promising results. Updates on many studies for drugs that are currently in development were presented at ASH 2013.
Chronic Lymphocytic Leukemia
Several new, targeted therapies show promise to expand the treatment options for chronic lymphocytic leukemia (CLL) and are more effective and better tolerated than standard chemotherapy.
Phase 3 studies of idelalisib demonstrated impressive progression-free survival in previously treated patients with CLL.
An orally bioavailable selective inhibitor of the Bcl-2 protein, known as ABT-199, induced remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma in an early-phase, open-label, dose-escalation trial. Overall, 67 (88%) patients had at least a 50% reduction in the sum product of diameters of nodal masses. The median time to achieve a 50% reduction was 6 weeks (the time of the first computed tomography scan stipulated per protocol). “Forty-one patients had achieved at least a partial remission at that 6-week scan, indicating that cytoreduction is rapid,” said lead investigator John Seymour, MBBS, PhD, Director, Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Australia.
A total of 89% of patients had at least a 50% reduction in bone marrow infiltrate at the first bone marrow biopsy at week 25, with a median reduction of approximately 95%.
The small-molecule inhibitor IPI-145, which blocks the activity of the enzyme phosphoinositide-3-kinase (that is responsible for CLL signaling), was investigated in an early-phase trial of 193 patients, including 52 patients with CLL that is treatment resistant or has relapsed, and 15 patients with untreated CLL. It is important to note that IPI-145 demonstrated activity in approximately 50% of the enrolled patients who had a mutation in the tumor suppressor gene p53. A 25-mg twice-daily dose of IPI-145 will be further evaluated in a randomized phase 3 clinical trial.
A phase 2 clinical trial of otlertuzumab in combination with bendamustine (Treanda) in patients with relapsed CLL showed superior response rates compared with bendamustine alone. This randomized trial included 65 patients with relapsed CLL who had received 1 to 3 previous regimens. The overall response rates were 68% (International Workshop on CLL criteria) and 81% (National Cancer Institute Working Group response criteria) in the group receiving otlertuzumab plus bendamustine versus 32% and 64%, respectively, in the patients randomized to bendamustine alone.
Acute Myeloid Leukemia
In a new study, the monoclonal antibody gemtuzumab ozogamicin (Mylotarg)—which had been withdrawn from the market in 2010—when added to standard chemotherapy improved event-free survival without causing excessive toxicity and mortality in children with acute myeloid leukemia. In a phase 3 clinical trial, more than 1000 children (average age, 10 years) received gemtuzumab or a standard treatment regimen, followed by additional chemotherapy for low-risk patients and stem-cell transplants for high-risk patients. Compared with standard regimens, the addition of gemtuzumab was associated with better disease-free survival (55% vs 61%, respectively) and reduced risk of relapse (33% vs 41%, respectively). No significant difference was found between the gemtuzumab and standard treatment groups with respect to overall survival (74% vs 70%, respectively).
“The therapy seemed to have a particularly lasting effect among those patients who achieved remission in the course of treatment,” said lead investigator Alan S. Gamis, MD, MPH, Associate Division Director of Oncology, Children’s Mercy Hospitals and Clinics in Kansas City, MO. “Although gemtuzumab was previously removed from the market due to lack of clinical value in earlier trials, this growing body of positive data in populations of critical need may be sufficient to bring it back as a commercial treatment option.”
In patients with MDS refractory to hypomethylating agents, treatment with sapacitabine was associated with a 1-year survival rate of up to 38% in a phase 2 clinical study. Sapacitabine is an oral nucleoside analog prodrug that interferes with DNA synthesis by introducing single-strand DNA leading to the arrest of the cell division cycle at the G2 phase. The study included 63 patients with MDS refractory to azacitidine and/or decitabine who were randomized to 1 of 3 dosage arms of sapacitabine. The overall 1-year survival rate was 32%, with greater survival seen in the 2 higher-dosage arms. Of the 63 patients in the study, 23 had stable disease at ≥16 weeks.
Oral rigosertib (Estybon) induced responses and transfusion independence in lower-risk patients with MDS in a phase 2 clinical trial presented by Azra Raza, MD, Director, Myelodysplastic Syndrome Center, Columbia University, New York City. Rigosertib is an inhibitor of the cellular-signaling pathways PI3K and PLK. A combined response rate of 53% (International Working Group criteria) was observed in 36 evaluable patients receiving an intermittent dosing schedule. Overall, transfusion independence was observed in 39% of patients who received at least 8 weeks of intermittent rigosertib.
In patients with high-risk MDS who were previously treated with hypomethylating agents, a phase 1/2 study of rigosertib demonstrated either a reduction in or a stabilization of bone marrow blasts or improvement in peripheral blood counts in 53% of the 19 evaluable patients. The median overall survival of responders was 9.6 months versus 1.7 months in the nonresponders.