Outcomes for Patients (Pts) with Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) with del5q Aged < 65 Years Treated with Lenalidomide (LEN) in MDS-003 and MDS-004: A Retrospective Combined Analysis
Authors: Fenaux Pierre , Giagounidis Aristoteles , List Alan F. , Nimer Stephen D. , Hellström-Lindberg Eva , Powell Bayard L. , Yu Xujie , Skikne Barry , Shammo Jamile M. , Cañizo Consuelo del 
Published: October 2019

Abstract
Abstract 1723

Background:
Two multicenter studies (MDS-003/-004) found LEN leads to RBC transfusion independence (TI) in > 50% of pts with RBC transfusion dependent Low-/Int-1-risk MDS with del5q (List A et al. NEJM 2006;355: 1456–65; Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). RBC-TI ≥ 8 wks with LEN was associated with significantly reduced risk of AML progression and death (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). Alternative therapy is required for pts failing LEN therapy. Aims: To assess predictive factors of LEN response and long term outcomes (especially after primary or secondary LEN failure) of pts < 65 yrs included in MDS-003/-004; ie, those in whom intensive therapies including allogeneic stem cell transplantation (ASCT) may be considered. Methods: LEN was administered as follows (all 28-d cycles): 5 mg/d on d 1–28 and 10 mg/d on d 1–21 or 1–28. RBC-TI ≥ 26 wks and cytogenetic response (CyR; IWG 2000) are reported. Overall survival (OS) and AML progression were assessed using Kaplan-Meier method. Response rates and outcomes in pts < 65 yrs were retrospectively compared with pts ≥ 65 yrs. Primary failure was defined as lack of RBC-TI with LEN treatment and secondary failure as relapse after achievement of RBC-TI ≥ 26 wks. Cox proportional hazards models were used to evaluate the effect of potential risk factors (ie, age, sex, time since diagnosis, FAB classification, LEN dose, IPSS risk, WPSS risk, cytogenetics, bone marrow blast %, transfusion burden, no. of cytopenias, hemoglobin level, platelet and neutrophil counts, RBC-TI ≥ 26 wks [time-dependent variable] and CyR [categorical variable]) on OS and AML progression. Logistic model was used to evaluate the effect of potential risk factors on achievement of RBC-TI ≥ 26 wks. Results: The trials included 97 (33.9%) pts < 65 yrs. Of these, 73.2% were female; 20.6% were IPSS Low-, 52.6% Int-1-, and 4.1% Int-2-risk; 30.9% had del5q with ≥ 1 additional cytogenetic abnormality (8.2% had complex cytogenetics). At baseline (BL), median time since diagnosis was 2.4 yrs (range 0.2–20.7) and median RBC transfusion requirement was 6 units/8 wks (range 1–15). In pts ≥ 65 yrs (n = 189) most BL characteristics were similar except IPSS risk, which was lower (36.5% Low-, 37.0% Int-1-, 5.8% Int-2-risk; p =.012). RBC-TI ≥ 26 wks was achieved by 54 (55.7%) pts < 65 yrs (vs 49.7% pts ≥ 65 yrs; p =.563). The median duration of RBC-TI ≥ 26 wks in responders was not estimable in pts < 65 yrs or ≥ 65 yrs (log-rank p =.879). None of the potential risk factors assessed was a significant predictor of RBC-TI ≥ 26 wks in pts < 65 yrs, possibly due to small pt number. In pts < 65 yrs with available follow-up cytogenetics (n = 71), CyR was achieved by 32 (45.1%) pts (vs 64.5% pts ≥ 65 yrs; p =.014). At time of data cutoff, 51 (52.6%) pts < 65 yrs were alive (vs 36.0% pts ≥ 65 yrs; p =.008); 29 (29.9%) pts progressed to AML (vs 20.1% pts ≥ 65 yrs; p =.077). The 1-, 2-, and 3-yr AML-progression rates were 9.7%, 15.4%, and 24.0% in pts < 65 yrs; and 6.0%, 17.9%, and 22.3% in pts ≥ 65 yrs (log-rank p =.308). The 1-, 2-, and 3-yr OS rates were 91.7%, 78.1%, and 66.4% in pts < 65 yrs; and 83.1%, 65.2%, and 49.9% in pts ≥ 65 yrs (log-rank p <.001). In pts < 65 yrs, RBC-TI ≥ 26 wks was the only factor associated with longer median OS (4.9 yrs in responders vs 2.0 yrs in non-responders) and lower BL ANC was the only factor associated with a reduced risk of AML-progression. A total of 43 (44.3% of total population) pts < 65 yrs experienced primary LEN failure and 9 (16.7% of responders) secondary failure. In pts < 65 yrs with primary failure after 16 wks (median follow up from primary failure 2.6 yrs), 13 (30.2%) pts progressed to AML (1- and 2-yr cumulative AML rates 7.9% and 16.8%) and median OS was 2.67 yrs. In pts < 65 yrs with secondary failure (median follow up from secondary failure 1.7 yrs), 3 (33.3%) pts progressed to AML and median OS was not reached (1-yr cumulative OS rate was 64.8%). Conclusions: LEN-treated pts < 65 yrs had greater incidence of IPSS Int-1-risk, had similar rates of RBC-TI ≥ 26 wks, but achieved CyR less often and more progressed to AML vs pts ≥ 65 yrs. In pts < 65 yrs, achievement of RBC-TI ≥ 26 wks was the only factor associated with longer OS. After primary or secondary LEN failure, AML progression rates were ∼30% each, and median OS 2.67 yrs and 1-yr OS 64.8%, respectively. Low-/Int-1-risk pts < 65 yrs with del5q and primary or secondary LEN failure have a relatively poor outcome and should be considered potential candidates for ASCT.

Disclosures:
Fenaux: Celgene Corporation: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Johnson & Johnson: Honoraria; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hellström-Lindberg:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yu:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment. Shammo:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. del Cañizo:Celgene Corporation: Spanish advisory committee.