Hematopoietic Stem Cell Transplantation for Children with Neurological Diseases Improves the Outcomes and Not Leads to Significant Late Effects — Report from Russian Group

Strong evidence of safety, tolerability, efficacy and low rate of late effects presence after hematopoietic stem cell transplantation (HSCT) required for children with severe refractory cases of neurological diseases.

We aimed to analyze the effectiveness of both allogenic and autologous hematopoietic stem cell transplantation for all cohorts of patients with neurological diseases based on safety, tolerability and late effects rate.

Sixty three patients enrolled to the analysis transplanted 2004 - 2017. Diagnosis: Hurler syndrome (HS) - 40 patients, multiple sclerosis (MS) - 13 patients, metochromatic leukodystrophy (ML) - 4 patients, neuromyelitis optica (NMO) - 3 patients. Median of age 11,8 years old (3 months - 17,4 years old). Most of the patients were girls (n=39, 61,8%). All patients were with confirmed diagnosis by clinical and laboratory testing, imagining. Patients with autoimmune disorders (AD) were treated with different immunosuppressive drugs without effect. MS patients received autologous hematopoietic stem cell transplantation (HSCT) with peripheral blood stem cells (PBSC), other patients - allogenic HSCT both from related and unrelated donors. For allogenic HSCT bone marrow (BM) was used in 32 cases, PBSC - in 13 and cord blood (CB) - in 2 cases (for HS only). In 34 cases HSCT from unrelated donor were done. MS patients received Cyclophosphamide and ATG based chemotherapy before autologous HSCT, NMO and ML patients received Treosulfan, Fludarabine, Rituximab and ATG (if unrelated donor). In case of HS myeloablative conditioning (MAC) regimen was used for 29 patients and reduced intensity conditioning (RIC) - for 11 patients. RIC: Fludarabine, Melphalan, ATG. MAC: Busulfan/Treosulfan, Fludarabine, Thiotepa/Melphalan and ATG with Rituximab (in case of unrelated donors). Patients received CsA/Tacro-based with MMF/MTX GvHD prophylaxis for all allogenic cases. In 3 RIC HSCT for HS immunomagnetic СD3/СD19+ depletion of PBSC was used.

All MS patients improved fast. Median follow-up of MS pts. 48,7±2,4 months (10-84 months). Two MS patients relapsed (clinical and MRI). Median of engraftment day - +10. No severe complications registered. All patients after allogenic HSCT engrafted (full donor chimerism on day +30). Median of engraftment day - 21 (11-30 days). Thirty nine patients after allogenic HSCT survived. Reasons of death: infections - 4 pts., TRALI - 1 pt., aGvHD - 1 pt. TRM improved, over the years, with improving of supportive care and donor selection as well as pre-transplant screening. No early severe toxicity revealed. GvHD: grade II - 17 patients, grade III-IV - 3 patients, local cGVHD - 3 patients. No patients had extensive cGvHD. All 5 rejected patients were with HS (MAC and RIC rejection rate was same). At median follow up of 60 months (8-160 months), the estimated probability of 5 years OS is 87%. All patients with complete donor's chimerism have good neurological response (best response correlated with early HSCT for all patients). Better status before HSCT correlated with better outcome. Cardio-vascular effects (EF decreasing) were most common for MS patients (n=7), progressive skeletal deformation - for HS patients (totally 17 cases), in one of them operative reconstitution was performed, endocrine (thyroid dysfunction, growth hormone deficiency) - for MS, NMO and HS patients (n=8), late immune reconstitution - for 1 case (NMO patient). Median period of late effects arising after HSCT was 21 month (12-27 months). All survived patients (MS, HS, ML, NMO) improved deficit in neurocognitive sphere in different grade but needed in special rehabilitation.

Thus, this is the first analysis of outcomes and late effects of a group of children received HSCT for neurological diseases, especially for AD. HSCT is successful approach for patients with such diseases. In-time HSCT can significantly improve the outcome. Most of the patients remain in remission during the long time of follow-up. Long-time follow-up showed that these patients require the special observational protocol including estimation of cardio-vascular, skeletal, endocrine and neurocognitive risks. Better neurocognitive response correlated with intensive rehabilitation using computer model. Russian Joint study showed effective cooperation for treatment of such patients in the national setting.