An Integrated Analysis of Darbepoetin Alfa (DAR) in the Treatment of Anemia in Patients with Low- or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS)

Background : Although erythropoiesis-stimulating agents (ESAs) are recommended for anemia in lower-risk MDS, ESAs have not yet been globally approved for this use.

Aim : To evaluate darbepoetin alfa (DAR) for anemia in patients with IPSS low/int-1 risk MDS in 2 DAR trials.

Methods : Safety data were pooled from a phase 2 single-arm, open-label trial stratified by past ESA use (NCT00095264, Gabrilove BJH 2008) and a phase 3, randomized, placebo (PBO)-controlled trial (NCT01362140, Platzbecker Leukemia 2017), both of DAR in low/int-1 MDS. Efficacy data were not pooled due to differing trial designs (Figure). Red blood cell (RBC) transfusions were measured from week 5 on, to allow sufficient time for DAR's effects to be seen. Unless noted, data are from the primary period (phase 2: to week 28, phase 3: to week 24, ie, blinded period).

Results : Of the 352 patients (48 receiving PBO) in these 2 trials, 52% were male and 91% white; 30% of the phase 2 patients had prior ESA use (prior ESA use not allowed in the phase 3 trial). Baseline endogenous EPO levels were similar in the 2 trials, with ~60-65% of patients having EPO <100 mU/mL. Compared with the phase 2 trial, in the phase 3 trial, more patients were int-1 risk (49% vs 28%), and mean (SD) hemoglobin (Hgb) was lower [9.2 (0.8) vs 9.8 (1.0) g/dL]. Median MDS duration for phase 3 (n=147) was 4.3 months; phase 2 ESA-naïve (n=144), <1 month; and phase 2 prior ESA (n=62), 8 months. The most common WHO categories were RA (40%), RARS (27%), RCMD (18%), and RAEB-1 (10%) (no patients were RAEB-2).

RBC transfusion incidence was decreased with DAR in the phase 3 trial (weeks 5-24, 36% vs 59%, P=0.008) with transfusion rates similar to that seen in ESA-treated patients in the phase 2 trial (ESA-naïve: 16%, ESA-treated: 30%) (Table). DAR patients were transfused at a median (min-max) Hgb of 8.6 (5-13) g/dL and PBO patients at a Hgb of 8.4 (5-11) g/dL. In the 48-week active treatment period of the phase 3 trial, 60% of the patients had a transfusion; transfusion rates over the 52 weeks of the phase 2 trial were 28% for ESA-naïve and 42% for ESA-treated patients. The IWG 2006 response rate increased with DAR in the phase 3 trial (DAR: 15%, PBO: 0%, P=0.016) and increased further in the active treatment period to 35% (81% of patients increased to Q2W dosing then). Post hoc blinded review by an external panel of 3 MDS experts also found an increased erythroid response rate with DAR in the phase 3 trial (24% vs 4%); there were 22 patients (18 DAR, 4 PBO) now considered responders and 2 DAR patients no longer considered responders. The experts considered clinical features such as drug discontinuation due to Hgb >12 g/dL, response in the active treatment period, and change in transfusion needs. These phase 3 results were also assessed per IWG 2000 criteria for major response (DAR: 19%, PBO: 3%) and minor response (DAR: 39%, PBO: 6%). In the phase 2 trial, IWG 2000 response rates were 58% major and 15% minor for ESA-naïve patients and 31% major and 19% minor for those with prior ESA treatment.

In the primary period, the dose was reduced in 119 (39%) DAR patients and held for high Hgb in 69 (23%) DAR patients; no PBO patients had the dose reduced or withheld. The dose was reduced at a median (min-max) Hgb of 11.6 (8-13) g/dL and withheld at a Hgb of 12.8 (10-15) g/dL. In the extended treatment period, all patients received DAR; the dose was reduced in 69 (21%) patients and withheld due to high Hgb in 86 (26%) patients. In the phase 2 trial, 44% of patients changed to Q2W dosing (increased frequency allowed after 6 weeks); in the phase 3 trial, 81% of patients changed to Q2W dosing in the active treatment period (increased frequency allowed from week 31 on). Safety results from these trials (Table) did not show any new safety signals, with similar incidence of serious adverse events (SAEs) and AEs leading to discontinuation of investigational product both by treatment and DAR dosing regimen (Q3W vs Q2W). Specific AEs, such as thrombotic and embolic events, did not appear to be increased with DAR or more frequent dosing.

Conclusion/Summary : In phase 2 and phase 3 darbepoetin alfa trials of 352 patients with lower-risk MDS, increased erythroid response and reduction in RBC transfusions were seen, with no new safety signals. Increased response rates with Q2W dosing suggest that Q3W dosing was not always adequate. Erythroid response rates differed by response criteria, indicating that IWG 2006 criteria may not comprehensively capture all important clinical endpoints.

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