Lenalidomide Shows Activity in Low-Risk MDS

Article

Results from the randomized phase II HOVON89 trial showed that nearly 40% of patients with low intermediate-1 risk myelodysplastic syndrome who were refractory to erythropoietin and granulocyte-colony stimulating factor experienced hematologic improvement with erythroid response after being treated with lenalidomide monotherapy.

Arjan A. van de Loosdrecht, MD, PhD

Arjan A. van de Loosdrecht, MD, PhD

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 = .09).

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 = .006).

A landmark analysis at 12 months showed that attainment of HI-E had a significant association with prolonged OS (>67 months vs 28 months for nonresponders, P <0.001).

An analysis of results of next-generation sequencing and response to lenalidomide showed that the presence of 2 or more mutations was inversely related to HI-E (P = .004), as was the presence of 1 or more splicing-factor mutations (P <.0001). Analysis of the 7 most frequently mutated genes showed that only SRSF2 and SF3B1 had significant associations with lack of response to lenalidomide (P = .021 and P = .004, respectively).

van de Loosdrecht AA, Chitu DA, Cremers EMP, et al. Lenalidomide with or without Erythropoietin and Granulocyte-Colony Stimulating Factor Shows Efficacy in Patients with Low and Intermediate-1 Risk Myelodysplastic Syndrome with or without Del 5q, Refractory or Unlikely to Respond to Erythropoietin. Results of a HOVON89 Phase II Randomized Multicenter Study. Presented at: 58th American Society of Hematology Annual Meeting; December 2-6, 2016; San Diego, CA. Abstract 224.

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