Study Finds IWG 2006 Response Criteria Valid in Patients With Higher-Risk MDS

Complete response (CR) to first-line therapy, as determined by the International Working Group (IWG) 2006 response criteria, can be used as a surrogate end point for overall survival (OS) in higher-risk patients with myelodysplastic syndromes (MDS), according to a study published in Cancer Medicine. Results also showed any response that was associated with restoration of effective hematopoiesis was associated with better outcomes among these patients.

Improvement in OS and delayed evolution to acute myeloid leukemia (AML) are the primary goals when treating higher-risk patients with MDS. To assess patient response after MDS therapy, an IWG of experts proposed criteria based on available data and consensus opinions in 2000. The criteria were later modified in 2006.

However, health regulatory agencies have yet to accept the IWG 2006 response criteria as surrogate endpoints “that clearly translate to clinically meaningful benefits,” authors wrote, while there is currently not widespread use of the criteria to determine patient benefit in clinical practice.

Patients over age 18 with higher-risk MDS, who had received treatment, and for whom details of response and outcomes were available, were recruited from MDS Clinical Research Consortium (MDSCRC) centers to take part in the study. To assess response, follow-up bone marrow evaluations were obtained within 4 to 6 months of therapy initiation, researchers wrote. “The best response to treatment was categorized per the published IWG 2006 response criteria as CR, partial response (PR), marrow CR (mCR), hematological improvement (HI), stable disease (SD) or progressive disease (PD).”

To validate results, a separate group of 539 higher-risk MDS patients who received first line hypomethylating agent (HMA) therapy were assessed. Study end points included median OS and AML transformation which were both measured from time start of therapy. In addition, the majority of first line treatments taken by the study group were hypomethylating agents azacitidine or decitabine, alone or in combination with other drugs, authors said.

A total of 646 treated International Prognostic Scoring System (IPSS) higher-risk patients with MDS were identified from the MDSCRC with a median age of 68.

Analyses revealed:

• The best overall response rate (ORR) by IWG 2006 criteria to first line therapy among 597 evaluable patients was 38% and included CR 16%, mCR 2%, PR 10%, HI 10%, SD 33%, and PD 24%
• CR was associated with a better overall survival (OS) compared to all other response groups (P < .001)
• Among 470 patients treated with HMA as first-line therapy, the ORR, defined as HI or better, was 39%
• Median OS from time of best response was 21 months (mo), 8 mo, 14 mo, 12 mo, 13 mo, and 8 mo for CR, mCR, PR, HI, SD, and PD, respectively (P< .001)

In the comparison cohort researchers found “mCR alone without HI, SD, and PD outcomes were inferior to CR, PR, mCR+HI, and HI.”

The retrospective nature of the study and lack of central review mark limitations. Authors also acknowledged the challenges of assessing mCR, HI, and SD outside of clinical trials. However, the ORR and outcomes reported aligned with 2 of the largest studies ever conducted in patients with higher-risk MDS.

“CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher-risk MDS patients in randomized phase II studies determining comparison arms of phase III trials, and for regulatory purposes,” researchers concluded.

Reference

Komrokji RS, Al Ali NH, Sallman D, et al. Validation of international working group response criteria in higher-risk myelodysplastic syndromes: a report on behalf of the MDS clinical research consortium. Cancer Med. Published online December 22, 2020. doi:10.1002/cam4.3608