Arjan A. van de Loosdrecht, MD, PhD
Results from the randomized phase II HOVON89 trial showed that nearly 40% of patients with low intermediate-1 risk myelodysplastic syndrome (MDS) who were refractory to erythropoietin and granulocyte-colony stimulating factor (EPO/G-CSF) experienced hematologic improvement with erythroid response (HI-E) after being treated with lenalidomide (Revlimid) monotherapy. These results were reported at the 2016 American Society of Hematology Annual Meeting in San Diego.
The overall HI-E rate included a third of patients without a 5q deletion (non-del[5q]). The addition of EPO/G-CSF did not significantly improve the HI-E rate overall or in the non-del5q subgroup. Improvement in HI-E had a significant association with better 12-month survival rates.
“Lenalidomide yielded sustained HI-E in 34% of patients with non-5q deletion low or intermediate-1 risk MDS that was refractory or unlikely to respond to EPO with or without G-CSF,” said Arjan A. van de Loosdrecht, MD, PhD, a professor of Hematology at VU University Medical Center in Amsterdam, The Netherlands. “Use of erythropoietin, or WHO [World Health Organization] or IPSS [International Prognostic Scoring System] criteria, did not predict HI-E in lenalidomide-treated patients.”
Moreover, the researchers identified patients who may not benefit from lenalidomide in EPO-refractory and transfusion-dependent low/intermediate-1 risk MDS with the use of mutational profiling and flow cytometry, said van de Loosdrecht.
Several lines of evidence provided a rationale for investigating lenalidomide in low-risk MDS. Laboratory studies have suggested that lenalidomide promotes erythroid lineage expansion of primitive erythroid precursors and may restore erythropoietin responsiveness in MDS progenitors buy interfering with JAK2/EPO signal transduction, van de Loosdrecht said. As an immunodulatory agent, lenalidomide may interfere with the altered inflammatory microenvironment in low-risk MDS.
Treatment with lenalidomide has been shown to improve erythropoiesis, including restoration of red blood cell transfusion independence to patients with non-del(5q) MDS, he continued. Some clinical evidence has suggested that the addition of EPO to lenalidomide might improve HI-E and transfusion independence rates, compared with lenalidomide alone.
Investigators performed a phase II trial to examine the safety and efficacy of lenalidomide in low/intermediate-1 risk MDS that was refractory or unlikely to respond to EPO/G-CSF. All patients started treatment with lenalidomide, and those who did not attain HI-E after 4 cycles received EPO, with or without G-CSF, in addition to lenalidomide.
Patients who attained HI-E with lenalidomide continued treatment for 6 months, and those who received EPO/G-CSF continued for 12 months, or until loss of response or disease progression. Data analysis comprised 184 patients, 84% of whom had non-del(5q) MDS.
The 2 groups had no substantive differences in demographic or clinical characteristics. The patients had received a median of 13 units of red blood cells, including 4 units in the 8 weeks prior to enrollment.
Overall, 41% of the patients achieved HI-E: 38% of patients treated with lenalidomide alone and 42% of those who received lenalidomide plus EPO/G-CSF. HI-E rates were 34% among patients with non-del(5q) MDS versus 79% for those with a 5q deletion and did not differ between treatment groups. The median time to HI-E was 3.1 months in both arms, and the median duration of HI-E was 10.6 months.
Grade 3/4 adverse events occurred in 65% of patients treated with lenalidomide and 72% for the group that received lenalidomide and EPO/G-CSF. Rates of grade 3/4 toxicity during the first 4 cycles of therapy was 51% and 56% with lenalidomide versus lenalidomide/Epo/G-CSF.
Other comparisons of the 2 treatment groups showed that a similar proportion received the planned full dose of treatment (57% vs 59%), required dose reductions >10% (30%), and had dose reduction/delay (7% vs 8%). Hematologic toxicity was the most common reason for dose reduction/delay in both arms (52% vs 59%).
The median progression-free survival (PFS) was virtually identical in the 2 groups (~15 months). Overall survival (OS) exhibited a trend in favor of the patients who received only lenalidomide (45.1 vs 37.7 months; P
The incidence of leukemia progression at 2 years was 16% and did not differ significantly between treatment groups.
Analysis of survival by del(5q) status showed no significant differences by treatment arm for PFS. However, patients with non-del(5q) MDS had significantly better overall survival with lenalidomide alone (P
= .04). OS did not differ by treatment for patients with a 5q deletion.
An evaluation of potential predictors of response to treatment showed that endogenous EPO level, pretreatment with EPO/G-CSF, and MDS classification by WHO criteria did not predict HI-E, PFS, or OS. IPSS score did not predict HI-E or PFS, but was predictive for OS (P