Hematopoietic stem cell transplantation (HSCT) is a curative option for children with high-risk acute lymphoblastic leukemia (ALL). This retrospective single-center study analyzed 236 pediatric ALL patients in complete remission who underwent allogeneic HSCT using ex-vivo T cell depletion between 2012 and 2021. The majority received haploidentical grafts (n = 202), while the remainder received matched unrelated donor (MUD) grafts (n = 34). At four years, event-free survival (EFS) and overall survival (OS) were 57

Wiskott-Aldrich syndrome (WAS) is a life-threatening inborn error of immunity associated with bleeding risk due to profound thrombocytopenia. We previously demonstrated that romiplostim is effective for thrombocytopenia treatment in 60% of WAS patients. In this prospective trial, 28 WAS patients (aged 0-17 years) were treated with thrombopoietin receptor agonists (TPO-RAs) to evaluate the comparative efficacy and safety of romiplostim versus eltrombopag and to assess the benefit of switching these molecules in individual subjects. We demonstrate that both drugs are effective, with the probability of achieving an overall platelet response (complete response-platelet count of 100 × 109/L or more and partial response-platelet count increase of 30 × 109/L or higher above baseline) of 73% for romiplostim and 43% for eltrombopag. Switching to an alternative TPO-RA allowed the achievement of a complete platelet response in 33% of patients after switching to eltrombopag and in 43% after romiplostim initiation. The cumulative efficacy of TPO-RAs, taking into account alternative therapy, was 87%. There was a grade 2 adverse event (AE) and a severe grade 4 AE related to eltrombopag-reversible acute liver failure associated with metabolic acidosis and encephalopathy. TPO-RAs proved to be an effective treatment for WAS patients waiting for stem cell transplantation or opting for a conservative treatment.

BACKGROUND:Hematopoietic stem cell transplantation (HSCT) is increasingly used in inborn errors of immunity (IEI). A specific spectrum of disease complications at HSCT affect post-HSCT survival in IEI; however, the risk factors for HSCT are poorly studied. OBJECTIVE:To determine the risk factors for HSCT in IEI. METHODS:In the current study were included 312 patients with various IEI who received a first allogeneic HSCT in our center from 2012 to 2020. Different approaches to HSCT were used. An association of overall survival (OS) and risk factors, such as active infection (n = 73), autoimmunity or inflammation (n = 89), malignancy (n = 15), unknown genetic diagnosis (n = 247), nutritional status determined on body mass index (undernutrition, n = 31, obesity, n = 25), age at HSCT (>12 years, n = 37) and organ damage (n = 92) were studied. RESULTS:Median follow-up after HSCT was 5,2 years (range 1,8-10,5). OS was 74% (95% CI 69-79%). The OS was significantly lower in SCID (n = 43) than other IEI (n = 269): 49 (95% CI 34-64%) versus 78% (95% CI 73-83%), Р < ,0001. The only factor, not affecting survival in IEI was unknown genetic defect, while other factors decreased survival. OS was 43% in active infection (P < ,0001), 61% in autoimmunity or inflammation (P = ,003), 67% in malignancy (P = ,47), 52% in undernutrition and 64% in obesity, (P = ,002), 61% in >12 years old (excluding SCID, P = ,02) and 59% in pre-existing organ damage (P < ,0001). CONCLUSION:The current study showed several important risk factors for HSCT in IEI. New tools are needed to predict post-HSCT survival in pediatric IEI.

BACKGROUND:Functional immune reconstitution (IR) is a key factor in determining the success of hematopoietic stem cell transplantation (HSCT). IR depends on a number of factors and is typically delayed by ex vivo T cell depletion of the graft. αβ T cell depletion (αβ TCD) platform was reported to be associated with improved IR. OBJECTIVE:In this retrospective study, we've focused on a homogeneous cohort of 262 children with acute leukemia first transplanted in complete remission, and investigate whether very early recovery of NK and T cells, as well as αβ and γδ T subsets, is associated with clinical outcomes. STUDY DESIGN:The grafts were obtained from apheresis products and processed by αβ TCD method. IR of lymphocyte subpopulations was measured in peripheral blood (PB) on day +30 after HSCT by flow cytometry. RESULTS:The study suggests that in the early post-HSCT period, higher absolute number of T cells, despite being far below the normal range and having a rather limited T cell receptors repertoire, is associated with radically improved non-relapse mortality (NRM). Multivariate analysis confirmed the independent effect of T-cell IR on NRM. Our results show that each 10-fold increase in T cell PB count is associated with a 2.1-fold reduction in NRM (cause-specific Hazard Ratio (csHR) 0.47), independent from other important factors such as aGVHD or serotherapy use. CONCLUSION:Based on these results we suggest that T cells recovery on day +30 after HSCT can be used in predicting NRM risk in the setting of αβ TCD HSCT. Early intervention for IR improvement can be planned.

The technique of ab T cell depletion (abTCD) is a well-established method of hematopoietic stem cell transplantation (HSCT) for children with acute leukemia owing to the low rates of graft-versus-host disease and nonrelapse mortality (NRM). The graft-versus-leukemia effect is generally ascribed to natural killer (NK) cells conserved within the graft. It is not known whether NK-related factors affect the outcome of abTCD HSCT, however. The aim of this retrospective study was to explore the impact of NK alloreactivity (based on donor-recipient killer immunoglobulin-like receptor [KIR] mismatch), graft NK cell dose, and blood NK cell recovery on day +30 post-HSCT on the incidences of leukemia relapse and NRM. The pediatric acute leukemia cohort comprised 295 patients who underwent their first HSCT from a haploidentical donor in complete remission. During post hoc analysis, the total cohort was divided into subcohorts by diagnosis (acute lymphoblastic leukemia [ALL]/acute myeloid leukemia [AML]), NK alloreactivity prediction (KIR match/KIR mismatch), graft NK cell dose (less than versus greater than the median value), and blood NK cell recovery on day +30 post-HSCT (less than versus greater than the median value). We also investigated the influence of serotherapy (antithymocyte globulin [ATG] group) versus abatacept + tocilizumab combination [aba+toci] group) on relapse risk in the

PURPOSE Midline low-grade gliomas (mLGGs) of early childhood have a poorer prognosis compared with tumors of other localizations and in older patients. LGGs are associated with aberrant activation of RAS-RAF-MEK pathway, and pharmacological inhibition of the pathway has therapeutic promise. The aim of this study was clinical and molecular characterization of infantile mLGGs, with emphasis on the efficacy of targeted kinase inhibition. PATIENTS AND METHODS This study enrolled 40 patients with mLGG age <3 years. The majority of the patients (30/40) received first-line chemotherapy (CT) as per International Society of Paediatric Oncology LGG 2004 guidelines. In all patients, molecular genetic investigation of tumor tissue by polymerase chain reaction and RNA sequencing was performed. The median follow-up was 3.5 years. RESULTS First-line CT failed in 24 of 30 recipients. The identified molecular profiles included KIAA1549::BRAF fusions in 26 patients, BRAF V600E in six patients, FGFR1::TACC1 fusions in two patients, and rare fusion transcripts in four patients. At disease progression, targeted therapy (TT) was initiated in 27 patients (22 patients received trametinib) on the basis of molecular findings. TT was administered for a median of 16 months, with partial response achieved in 12 of 26 (46%) patients in which response was evaluated. Severe adverse events were detected only on trametinib monotherapy: acute damage of GI or urinary mucosa complicated by hemorrhage and development of transfusion-dependent anemia in four patients and grade 3 skin toxicity in three patients. CONCLUSION mLGGs of early childhood are often aggressive tumors, resistant to CT, and frequently require alternative treatment. The majority of patients harbor druggable molecular targets and respond to molecular TT.

The achievement of clinical and hematological remission at the end of induction therapy is one of the key treatment response parameters in pediatric acute myeloid leukemia (AML). Besides conventional cytomorphological evaluation of bone marrow (BM) blast count, minimal residual disease (MRD) measurement has been widely applied in routine clinical practice in recent years. The aim of the study was to compare the results of flow cytometric MRD evaluation with the results of cytomorphological BM investigation when assessing the achievement of remission at the end of induction in children with AML. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. We analyzed BM samples obtained from 402 children with AML, who had been treated according to the AML-MRD-2018 protocol and undergone simultaneous cytometric and cytomorphological BM investigation at the end of induction. A myelogram count was performed on 500 nucleated cells per BM smear. MRD was measured by 10-color flow cytometry with the 0.1 % cut-off for reliable MRD-positivity. The threshold of 5 % blasts was used as the criterion of complete remission (CR). Overall concordance of the two methods was 83.3 % for the CR status confirmation: in 335 out of 402 patients, the presence or absence of CR was stated using both techniques. Half of the 67 discordant samples were obtained from patients with a significant monocytic component of the leukemic population: 14 (20.9 %) with AML M4 and 20 (29.9 %) with AML M5. Among all FAB subtypes, the highest concordance rate was noted in patients with M1 variant (91.7 %), while the worst comparability – in children with megakarioblastic leukemia (M7 type, 72.7 %). Failure to achieve CR by cytomorphology did not influence the outcome of the patients who achieved CR as confirmed by immunophenotyping. At the same time, for flow cytometric BM investigation, achieving MRD negativity (< 0.1%) was the most significant favorable outcome predictor even at this rather early stage. Moreover, relapse incidence in children who were in CR but MRD positive (≥ 0.1 %) was higher than in patients who did not achieve CR at the end of induction according to flow cytometry (MRD ≥ 5 %), especially in the intermediate-risk group. This difference can be explained by more intensive chemotherapy (FLAI instead of HAM cycle) given to patients who did not achieve CR at the end of induction, and patients in the intermediate-risk group were additionally re-stratified to a high-risk group with subsequent hematopoietic stem cell transplantation. Flow cytometric and cytomorphological BM examination for the CR status confirmation at the end of induction in children with AML demonstrated a relatively high concordance rate (83.3 %). CR achievement by cytomorphology does not influence final outcome, although for the flow cytometry conventional threshold of 5 % also seems inadequate. We can assume that the modification of therapy is also required for patients with MRD ≥ 0,1 % at this stage of treatment.

In children, therapy-related hematologic neoplasms (t-HN) are uncommon. Many are driven by genetic events independent of clonal hematopoiesis. We sought to understand the clinical and genetic factors of pediatric t-HN in a large independent cohort. Fifty-six t-HN were retrospectively identified. Chromosome microarray, next-generation and/or RNA sequencing were performed. Patients had primary hematologic, solid, or central nervous system tumors. t-HN included myeloid (t-MN) and lymphoblastic (t-ALL) phenotypes. Approximately half of the cases harbored KMTA2A rearrangement (KMT2Ar). Among t-HN without KMT2Ar, genetic drivers were heterogeneous, including diverse fusions or aneuploidy. Approximately 18% harbored 17p deletions and/or TP53 mutations. EFS/OS was not associated with t-HN lineage or KMT2Ar, but HSCT was associated with improved EFS and OS. We detail one of the largest cohorts to date of pediatric t-HN, confirming frequent KMT2Ar and t-ALL.

The aim of our study is to evaluate the prognostic value of the morphological types of ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) in children. We performed a retrospective analysis of data on 81 cases of pediatric ALK+ ALCL which had been diagnosed in 2011–2022. All patients and/or their legal representatives signed voluntary informed consent for participation in the study, as well as for biological material testing. The analysis of medical records was carried out in accordance with the internal rules of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthсare of the Russian Federation, developed and approved by the Independent Ethics Committee of the Center. The patients received treatment according to the standard protocol. We assessed overall (OS) and event-free (EFS) survival depending on the morphological type of the tumor. The median follow-up was 55.6 months. Three-year and 5-year OS rates were 81.9% and 79.8%, respectively. Three-year and 5-year EFS rates were 59.6% and 56.0%, respectively. There were no statistically significant differences in OS and EFS between the common and non-common morphological types of ALK+ ALCL. Better survival rates were observed in the patients with a lymphohistiocytic variant. We found statistically significant differences in OS (p = 0.031) and EFS (p = 0.002) between the cases with a small cell component and without it. The results suggest that ALK+ ALCL with small cell morphology has a more aggressive course in children. Validation in larger patient cohorts and further study of the biology of different morphological types are needed to develop stratified treatment approaches.

Introduction. Relapse of acute myeloid leukemia (AML) develops in children who received intensive chemotherapy and achieved the first complete remission (CR1). Only intensive anti-relapse chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HSCT) may lead to cure. Aim - to present the results of treatment of children with AML who relapsed after completion of treatment or while on therapy according to the AML-MM-2006 protocol. Materials and methods. The study included children with AML who relapsed after completion of treatment of the first-line therapy according to the AML-MM-2006 protocol. During the follow-up period (median - 4.6 years), 68 relapses were registered among 187 patients who reached CR1 (early - 36, late - 26; with a change of phenotype to ALL-6). The cumulative probability of relapse was 40 %. Four (6 %) patients with relapsed AML initially belonged to the group of standard, 33 (54 %) - of intermediate risk of relapse of AML and 25 (40 %) - to the group of high risk. Eleven (18 %) were patients with "CBF-leukemia", 19 (31 %) - with rearrangements of the 11q23 (KMT2A gene). Fludarabine, high doses of cytarabine and idarubicin in 33 (80 %) or mitoxantrone in 8 (20 %) patients were used to induce the second complete remission (CR2) in 41 patients (66 %). Results. Out of 53 patients who received chemotherapy as a second induction therapy, CR2 was achieved in 30 patients (57 %) (in 9 - with early, in 21 - with late relapse) after chemotherapy courses; 2 patients died within 30 days of the start of CT; 21 patients were refractory to chemotherapy. HSCT after relapse was performed in 51 patients, mainly from a haploidentical donor. Twenty-five patients underwent HSCT in CR2, 26 - in the status of "active disease". Among patients transplanted into CR2, the probability of relapse was 20 %, and the overall survival rate was 80 %. Among patients transplanted outside of CR2, the probability of achieving CR2 was 77 %, the probability of relapse was 50 % and overall survival (OS) 58 %. The probability of OS in the group as a whole reached 52 %. The most significant prognostic factors of an unfavorable outcome were early relapse, refractory course of relapse, M7 variant of AML, complex karyotype and rearrangements of the ETV6 gene, combined ("bone marrow + CNS damage + non-hematopoietic tissue") relapse and relapse after HSCT performed in CR1. Conclusion. About 50 % of patients with relapses of AML can be cured with the help of high-dose chemotherapy and alloHSCT.

Infants of the first year of life represent a unique group of patients with acute myeloid leukemia (AML). Materials and methods of the research: the characteristics of 492 patients with newly diagnosed AML aged 10 DoL-18 y/o who received intensive chemotherapy according to the AML-MM-2006 and AML-MRD-2018 guidelines in Apr. 2007-Apr. 2021 were analyzed. The analysis was carried out separately for infants (<1 y/o, 58/12%), young children (1-3 y/o, 99/20%) and children aged 3-18 y/o (335/68%). Results: the infant group was characterized by a higher incidence of hyperleukocytosis, extramedullary lesions, the predominance of monoblast/monocytic (63%) and megakaryoblast (24%) subvariants and chromosomal aberrations involving the 11q23 locus (KMT2A gene) (53%). “CBF leukemias” were virtually non-existent in infants (0% for t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 and 2% for inv(16)(p13.1q22)/CBF::MYH11) and the rates increased with age. Activating mutations in the FLT3 gene were extremely rare (2% vs. 13.5% in patients >/=3 y/o). Patients of the 1-3 y/o group were similar in morphological and cytogenetic characteristics to the infants’ group but had a smaller tumor mass and higher survival rates. The 5-year overall survival of infants was statistically significantly lower than in older patients, 52% vs. 67% (p<0.001), primarily due to high mortality prior to remission, which in its turn was caused by complications associated with hyperleukocytosis. Conclusions: given the vulnerability of this category of patients, it is reasonable to transfer them to larger medical facilities with extensive experience in the field in order to conduct the remission induction stage (especially cytoreduction) within the intensive care unit.

Background Choroid plexus carcinomas (CPCs) are rare aggressive pediatric tumors of the brain with no treatment standards. Genetic profiling of CPCs is often confined to possible association with Li-Fraumeni syndrome, though only about a half of CPCs develop from syndromic predispositions. Whole-chromosome gains and losses typical of CPCs reflect genomic instability of these tumors, but only partially explain the aggressive clinical course. Methods This retrospective study enrolled 25 pediatric patients with CPC, receiving treatment between January 2009 and June 2022. Molecular-genetic testing was performed for 20 cases with available tumor tissue and encompassed mutational status, chromosomal aberrations, and gene expression profiles. We analyzed several factors presumably influencing the outcomes, including molecular profiles and clinical parameters. The median follow-up constituted 5.2 years (absolute range 2.8-12.6 years). Results All studied CPCs had smooth mutational profiles with the only recurrent event being TP53 variants, either germline or somatic, encountered in 13 cases. Unbalanced whole-chromosome aberrations, \nnotably multiple monosomies, were highly typical. In 7 tumors, chromosome losses were combined with complex genomic rearrangements: segmental gains and losses or signs of chromothripsis. This phenomenon was associated with extremely low 5-year survival: 20.0 +/- 17.9% vs 85.7 +/- 13.2%; P = .009. Transcriptomically, the cohort split into 2 polar clusters Ped_CPC1 and Ped_CPC2 differing by survival: 31.3 +/- 17.8% vs 100%; P = .012. Conclusion CPCs split into at least 2 molecular subtypes distinguished both genomically and transcriptomically. Clusterization of the tumors into Ped_CPC1 and Ped_CPC2 significantly correlates with survival. The distinction may prove relevant in clinical trials for dedicated and patient-oriented optimization of clinical protocols for these rare tumors.

This article presents an analysis of genotype and phenotype correlations in a pediatric cohort with Langerhans cell histiocytosis (LCH). Approximately 60% of LCH patients carry BRAF V600E somatic point mutation. Numerous studies have demonstrated that the presence of this mutation is associated with a more severe course of the disease and a higher risk of relapse. Apart from BRAF V600E mutation, other mutations in genes involved in the RAS/RAF/MEK/ERK signaling pathway have been identified in LCH. Next generation sequencing of DNA with high coverage of target regions is considered an optimal approach to detect somatic mutations other than BRAF V600E. The identification of somatic driver mutations holds great potential for enhancing our understanding of the phenotypic heterogeneity of LCH and developing targeted therapeutic strategies. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology.

Langerhans cell histiocytosis (LCH) is a disorder with a variety of clinical signs. The most severe forms affect risk organs (RO). The established role of the BRAF V600E mutation in LCH led to a targeted approach. However, targeted therapy cannot cure the disease, and cessation leads to quick relapses. Here, we combined cytosine-arabinoside (Ara-C) and 2'-chlorodeoxyadenosine (2-CdA) with targeted therapy to achieve stable remission. Nineteen children were enrolled in the study: 13 were RO-positive (RO+) and 6 RO-negative (RO-). Five patients received the therapy upfront, whereas the other 14 received it as a second or third line. The protocol starts with 28 days of vemurafenib (20 mg/kg), which is followed by 3 courses of Ara-C and 2-CdA (100 mg/m2 every 12 h, 6 mg/m2 per day, days 1-5) with concomitant vemurafenib therapy. After that, vemurafenib therapy was stopped, and 3 courses of mono 2-CdA followed. All patients rapidly responded to vemurafenib: the median disease activity score decreased from 13 to 2 points in the RO+ group and from 4.5 to 0 points in the RO- group on day 28. All patients except 1 received complete protocol treatment, and 15 of them did not have disease progression. The 2-year reactivation/progression-free survival (RFS) for RO+ was 76.9% with a median follow-up of 21 months and 83.3% with a median follow-up of 29 months for RO-. Overall survival is 100%. Importantly, 1 patient experienced secondary myelodysplastic syndrome after 14 months from vemurafenib cessation. Our study demonstrates that combined vemurafenib plus 2-CdA and Ara-C is effective in a cohort of children with LCH, and the toxicity is manageable. This trial is registered at www.clinicaltrials.gov as NCT03585686.

In our country, the use of emicizumab in children with hemophilia A without inhibitors (HA) in the real-world clinical setting is limited and is available only as few individual case reports. Our aim was to evaluate the effectiveness and safety of the prophylactic use of emicizumab in children with severe HA in the real-world clinical setting. We conducted a retrospective analysis of medical records of children with HA who had received emicizumab at 9 centers based in the Russian Federation. We assessed the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (ASBR), annualized joint bleeding rate (AJBR), annualized bleeding rate for bleeding episodes that required additional treatment with FVIII concentrate (ABRRT) and the number of hospital admissions for bleeding both before and after the treatment with emicizumab, as well as the occurrence and severity of adverse events during the therapy. Ethics committee approval was not required for this study because it involved the use of aggregated retrospective data from routine clinical practice that were fully anonymized. Two emicizumab administration regimens were compared with regard to their effectiveness. Before the treatment with emicizumab, ABR was 5.38 (95% confidence interval (CI) 3.90–7.64), ASBR – 4.16 (95% CI 2.99–5.94), AJBR – 2.7 (95% CI 1.87–4.03), and ABRRT – 4.8 (95% CI 3.37–7.08). After the initiation of the treatment with emicizumab, the bleeding rate plummeted: ABR decreased by 93.9% (95% CI 88.8–96.7), ASBR – by 96.9% (95% CI 93.1–98.6), AJBR – by 96.1% (95% CI 90.4–98.4%) and ABRRT – by 95.1% (95% CI 90.0–97.6). During the treatment with emicizumab, the rate of bleeding episodes that required hospital admission decreased from 1.58 (95% CI 0.98–2.68) to 0.04 (0.01–0.10), which amounted to 97.6% (95% CI 91.1–99.4). The median follow-up time for the patients treated with emicizumab was 15.5 months (range 9–29 months). When comparing the annualized bleeding rates in the groups of the patients who were preventively treated with emicizumab at doses of 3 mg/kg (administered once every 2 weeks) and 1.5 mg/kg (once per week), we didn't find any statistically significant differences. In the real-world clinical setting, the use of emicizumab in the children with HA led to a significant reduction in all bleeding episodes (by more than 90%), regardless of the administration regimen.

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder caused by WAS gene mutations resulting in haematopoietic/immune cell defects. Recent studies report accelerated death of WAS platelets and lymphocytes. Data on megakaryocyte (MK) maturation, viability and their possible role in thrombocytopenia development in WAS are limited. In this study we evaluate the MK viability and morphology in untreated, romiplostim-treated WAS patients compared with normal controls. The study included 32 WAS patients and 17 healthy donors. MKs were captured from bone marrow aspirates by surface-immobilized anti-GPIIb-IIIa antibody. Viability (by phosphatidylserine [PS] externalization), distribution by maturation stages and size of MK were determined by light microscopy. MK distribution by maturation stages in patients differed from controls. 40 ± 22% of WAS MKs versus 23 ± 11% of normal MKs were at maturation stage 3 (p = 0.02), whereas 24 ± 20% in WAS and 39 ± 14% in controls had megakaryoblast morphology (p = 0.05). Romiplostim treatment changed the MK maturation stages distribution close to normal. PS-positive (PS+) MK in WAS was significantly higher (21 ± 21%) than in healthy controls (2 ± 4%, p < 0.01). WAS patients with more damaging truncating mutations and higher disease score had higher PS+ MK fraction (Spearman r = 0.6, p < 0.003). We conclude that WAS MKs have increased cell death tendency and changes in maturation pattern. Both could contribute to thrombocytopenia in WAS patients.

We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naive children with severe (SAA) and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin (hATG) and cyclosporin A (CsA) with (n = 49) or without (n = 49) ELTR. The primary endpoint was the overall response rate (ORR) at 4 months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR + IST and IST groups was similar (65% vs 53%; P = .218); however, the complete response (CR) rate was significantly higher in the ELTR + IST group (31% vs 12%; P = .027). In severity subgroups, the ORR was 89% vs 57% (P = .028) in favor of IST + ELTR in SAA, but it did not differ in patients with vSAA (52% vs 50%; P = .902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared with 17% of initial ELTR(+) patients (P = .016). No significant difference in ELTR + IST and IST groups was observed in the 3-year overall survival (OS) (89% vs 91%; P = .673) or the 3-year event-free survival (EFS) (53% vs 41%; P = .326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. This trial was registered at Clinicaltrials.gov as #NCT03413306.