Outcome of Cerebral Vasculopathy and Cognitive Performances 10 Years Post-Enrollment in the Drepagreffe Trial Comparing Allogeneic Stem Cell Transplantation to Standard-Care in Children with Sickle Cell Anemia and History of Abnormal Cerebral Velocities

DREPAGREFFE-1 (NCT01340404), was the first prospective trial comparing allogeneic stem cell transplantation (alloSCT) to standard-of-care (SoC) in children with sickle cell anemia (SCA). This French multicenter trial was defined by the random-availability of a matched-sibling donor (MSD). Inclusion criteria were SS/Sb0 children (5-15yr) placed on long-term chronic-transfusion (CT) for a history of abnormal cerebral arterial velocities (TAMMV≥200 cm/sec), with at least one non-SCA sibling, and parents accepting HLA-typing and alloSCT if an MSD was available.

Sixty-seven children (35F/32M), including 7 with stroke-history, were enrolled (Dec-2010/June-2013). Children with MSD (n=32) were transplanted, while those without (n=35) were maintained on CT for at least one year and then switched to hydroxyurea (HU) if normalized TAMMVs and no stenosis. Results at 1 and 3 years were reported (Bernaudin et al JAMA. 2019;321(3); Verlhac et al Br J Haematol. 2021;193(1)). As a reminder, comparing alloSCT vs. SoC at 1 yr, the highest TAMMVs (primary outcome) were significantly lower after alloSCT than under SoC (difference -40.8 cm/s; [95%CI:-62.9;-18.6]; P<.001). At 3 years, the highest TAMMVs were lower, the proportion of patients with normalized-TAMMVs was higher, the stenosis score in stroke-free patients was lower, and the quality of life (QoL) was better for physical and school functioning. Nevertheless, no significant difference in ischemic lesions and cognitive performance was observed.

DREPAGREFFE-2 trial (NCT 05053932), supported by ABM and Pfizer, aimed to reevaluate at 10yr the 67 SCA-children (Sept-2022/Aug-2024) to test whether the differences in cognitive performance and ischemic lesions had changed significantly. Events and treatment changes since Year 3 were routinely recorded. Clinical evaluation, routine biological check-up, Intracranial and cervical-color Doppler-ultrasound, cerebral MRI/MRA/neck-MRA were performed. Non-opposition consent was required for cognitive testing (WISC-V and WAIS-IV), biological research, and QoL (PedsQL^TM) assessment. Death and stroke did not occur in either arm.

In the alloSCT arm (n=32), follow-up ended at 7.0 and 7.9 years for 2 children with full donor-chimerism and no chGvHD, due to return to Africa and UK. At 10yr, median (range) donor-chimerism was 92.5% (19%-100%) and no chGvHD was observed.

In the SoC arm (n=35), 23 patients with normalized velocities and no stenosis under CT were switched to HU. At 10yr, 17 are still on HU, 15 are on CT, and 3 had related haploIdentical-SCT at 6.7, 7.2 and 9.3yr post-enrollment. They are well, one having only mild chGvHD. Two patients still on CT for stroke-history did not give consent for research analyses.

Including the 3 haplo-SCT with the alloSCT-arm for analysis at 10yr, Hb and HbA% were higher while HbS%, Retic., WBC, neutro, bilirubin, LDH, and ferritin were lower in the alloSCT vs. SoC arm (P<.001 for all).

Available mean (SD) QoL at 10yr in alloSCT (n=25) vs. SoC (n=28) was not different for emotional but higher for physical (84.0 (16.3) vs 76.4 (11.2); P=.013), school (72.6 (17.2) vs 61.4 (14.7);P=.016) and even social functioning (93.8 (10.7) vs. 86.4 (12.9); P=.003).

MRI/MRA and cognitive performance data were only analyzed in stroke-free patients. At enrollment (T0), silent cerebral infarcts (SCI) were present in 6/31 in the SoC-arm and 12/28 in the alloSCT arm. At 10yr, 5 additional patients had developed SCI in the SoC arm, but none did in the alloSCT, while SCI were either no more visible or <3mm in 1 (SoC) and 4 patients (alloSCT) (P=.010). Comparing alloSCT (n=24) to SoC (n=21), cognitive testing showed no difference in verbal comprehension and perceptual reasoning index, while the mean (SD) working memory index (WMI) was higher (89.6 (11.8) vs 80.5 (10.8); P=.021) with a digit span of 8.4 (1.9) vs. 6.7 (1.8)(P=.005), the processing speed index (PSI) was higher (96.5 (21.9) vs. 83.7 (14.4);P=.035) with a symbol search of 9.3 (2.0) vs. 7.3 (2.9)(P=.021), respectively. Compared to T0, mean (SD) WMI and PSI at 10yr improved, although not significantly, in transplanted patients [+5.8 (15.6) vs. +9.0 (25.4)] but not in the SoC arm [-2.0 (15.7) and +0.6 (19.7)].

Thus, this first prospective comparative trial demonstrates that differences between alloSCT and SoC changed significantly at 10yr with alloSCT providing better primary prevention of SCI, social QoL, working memory and processing speed