Thalidomide, Hydroxyurea Combination Bests Hydroxyurea Alone for Sickle Cell Anemia

Findings from a recent open-label quasi-experimental clinical trial conducted in India highlight the safety and efficacy of combined thalidomide and hydroxyurea (HU) for treating sickle cell anemia (SCA) versus HU alone.1

Although HU has been proven to safely and effectively mitigate the effects of sickle cell anemia in adults, concerns have emerged regarding its utilization in children. However, recent studies have shown the consistent success presented by the treatment, as well as hypothesizing alternative mixtures for combination therapy.2

“This study provides preliminary evidence supporting the efficacy and safety of combining thalidomide with HU for SCA treatment,” wrote Priyanka Samal, department of clinical hematology, Institute of Medical Sciences & Sum Hospital, and colleagues. “Combination therapy is a promising therapeutic option for patients who do not achieve optimal outcomes with HU alone, highlighting the need for further research to refine and optimize treatment strategies for SCA management.”1

The study enrolled male patients with SCA aged >12 years and postmenopausal female patients with SCA aged ≥45 years for a total of 83 participants. After 8 participants were excluded and 9 opted to discontinue treatment during the follow-up period, the study included a total of 66 participants. 1

Investigators then split participants into 2 groups: Group A would receive a mixture of thalidomide and HU, and Group B, the control cohort, would receive HU alone. Patients were monitored during follow-up visits at 3, 6, 9, and 12 months.1

The study’s 5 primary outcomes included Hb increment, reduction in vaso-occlusive crises (VOCs), decreased transfusion requirement, decreased sickle hemoglobin (HbS)%, and increased HbF%. Samal and colleagues used transfusion independence – defined as a reduction in need for transfusion – as the response criterion.1

Patients whose hemoglobin increased by ≥2 g/dL were considered major responders, and those whose hemoglobin increased by 1-2 g/dL were defined as minor responders. Non-responders exhibited no significant change.1

Samal and colleagues recorded similar baseline characteristics between both groups, marking their baseline packed red blood cell (PRBC) requirement per year at 5.27 and 5.03 respectively (P =.467) and their VOC episodes per year at 11.18 and 10.79, respectively (P =.501).1

The team noted both groups exhibited a decrease in HbS% from baseline, although Group A's decrease was significantly greater, decreasing from 72.5 ± 5.5 to 64.5 ± 5.4 over the course of 12 months (P <.0001). By comparison, Group B's HbS% decreased from 73.3 ± 7.7 to 69.9 ± 6.2 (P <.0001).1

HbF values, however, increased solely in Group A, rising from 18.9 ± 5.1 to 28.4 ± 5.6 (P <.0001) over the course of the trial. Group B did not exhibit a significant rise (P <.115). Patients in Group A also had fewer VOC episodes (3.48 ± 2.81) and PRBC transfusions (3.62 ± 2.19) than Group B, which had 11.36 ± 4.20 VOCs and 13.27 ± 3.70 PRBC transfusions (P =.0001 and .0001, respectively).1

Roughly 85% of Group A were major responders, exhibiting Hb increases ≥2 g/dL. Only 15% of Group B were major responders.1

The team also indicated that Group A outperformed Group B in each of the 5 primary outcomes, all of which were sustained over the 12 month follow-up period. Those receiving the mixture also had a higher mean decline in blood requirement (3.61 ± 2.19 units) versus control (13.27 ± 3.70 units) over the follow-up period.1

The team stated that side effects, including somnolence, constipation, and mild peripheral neuropathy, did arise during testing. However, they were all consistent with previous knowledge of thalidomide’s effects. None of these required discontinuations of treatment or led to complications.1

Although the study’s endpoints were successfully reached, the team cautions that certain aspects of the trial may have missed longer-term effects. To that end, they called for further research into the treatment.

“To further validate the safety and efficacy of thalidomide and HU, future studies should focus on large-scale, multicenter trials with extended follow-up periods,” wrote Samal and colleagues.1

References

1. Samal P, Paul A, Bahirat H, Bishoyi AK, Epari V. Efficacy and safety of thalidomide with hydroxyurea in sickle cell anemia: a quasi-experimental clinical trial. Blood Res. 2025;60(1):21. Published 2025 Apr 1. doi:10.1007/s44313-025-00068-4

2. McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opinion on Drug Safety. 2015;14(11):1749-1758. doi:10.1517/14740338.2015.1088827