Momelotinib versus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: an efficacy/safety analysis in the Japanese subgroup of the phase 3 randomized SIMPLIFY-1 trial.

Momelotinib, an oral Janus kinase (JAK) 1/2 and activin A receptor type 1 inhibitor, improved symptoms, splenomegaly, and anemia in patients with myelofibrosis (MF). This sub-analysis of SIMPLIFY-1 evaluated the efficacy and safety of momelotinib versus ruxolitinib in Japanese patients with JAK inhibitor (JAKi)-naïve MF. Patients were randomized 1:1 to receive momelotinib 200 mg once daily or ruxolitinib 20 mg twice daily (or modified based on label) for 24 weeks, after which patients could receive open-label momelotinib. The primary endpoint was splenic response rate (SRR; ≥ 35% reduction in spleen volume) at 24 weeks; main secondary endpoints were total symptom score (TSS) response (≥ 50% reduction) and transfusion independence (TI) rates. Fifteen Japanese patients (momelotinib, n = 6; ruxolitinib, n = 9) were enrolled; all completed treatment. At Week 24, SRR was 50.0% with momelotinib and 44.4% with ruxolitinib. TSS response rates were 33.3% and 0%, and TI rates were 83.3% and 44.4%. Any-grade treatment-related adverse event (TRAE) rates were 83.3% with momelotinib and 88.9% with ruxolitinib. Grade 3/4 TRAE rates were 0% and 55.6%, with specific events being anemia (55.6%) and vertigo (11.1%) with ruxolitinib. Momelotinib was well tolerated, improved spleen and symptom responses, and reduced transfusion requirements in Japanese patients with JAKi-naïve MF.

Prospects and Potential for Chimerism Analysis after Allogeneic Hematopoietic Stem Cell Transplantation.

Chimerism analysis after allogeneic hematopoietic stem cell transplantation serves to confirm engraftment, indicate relapse of hematologic malignancy, and attribute graft failure to either immune rejection or poor graft function. Short tandem repeat PCR (STR-PCR) is the prevailing method, followed by quantitative real-time PCR (qPCR), with detection limits of 1-5% and 0.1%, respectively. Chimerism assays using digital PCR or next-generation sequencing, both of which are more sensitive than STR-PCR, are increasingly used. Stable mixed chimerism is usually not associated with poor outcomes in non-malignant diseases, but recipient chimerism may foretell relapse of hematologic malignancies, so higher detection sensitivity may be beneficial in such cases. Thus, the need for and the type of intervention, e.g., immunosuppression regimen, donor lymphocyte infusion, and/or salvage second transplantation, should be guided by donor chimerism in the context of the feature and/or residual malignant cells of the disease to be treated.

Cellular carcinogenesis in preleukemic conditions:drivers and defenses.

Acute myeloid leukemia (AML) arises from preleukemic conditions. We have investigated the pathogenesis of typical preleukemia, myeloproliferative neoplasms, and clonal hematopoiesis. Hematopoietic stem cells in both preleukemic conditions harbor recurrent driver mutations; additional mutation provokes further malignant transformation, leading to AML onset. Although genetic alterations are defined as the main cause of malignant transformation, non-genetic factors are also involved in disease progression. In this review, we focus on a non-histone chromatin protein, high mobility group AT-hook2 (HMGA2), and a physiological p53 inhibitor, murine double minute X (MDMX). HMGA2 is mainly overexpressed by dysregulation of microRNAs or mutations in polycomb components, and provokes expansion of preleukemic clones through stem cell signature disruption. MDMX is overexpressed by altered splicing balance in myeloid malignancies. MDMX induces leukemic transformation from preleukemia via suppression of p53 and p53-independent activation of WNT/ß-catenin signaling. We also discuss how these non-genetic factors can be targeted for leukemia prevention therapy.

Impaired Repopulating Ability of Uhrf2-/- Hematopoietic Progenitor Cells in Mice.

UHRF proteins catalyze the ubiquitination of target proteins and are involved in regulating gene expression. Some studies reported a reduced expression of UHRF2 in acute leukemia cells, but the role of UHRF2 in hematopoiesis remains unknown. Here, we generated Uhrf2-/- mice to clarify the role of UHRF2 deletion in hematopoiesis. Compared to Uhrf2+/+ mice, Uhrf2-/- mice showed no differences in complete blood counts, as well as bone marrow (BM) findings and spleen weights. Proportions of cells in progenitor fractions in BM were comparable between Uhrf2+/+ mice and Uhrf2-/- mice. However, in competitive repopulation assays with BM transplants (BMT), the proportions of Uhrf2-/- cells were decreased relative to Uhrf2+/+ cells in all lineages. After the second BMT, Uhrf2-/- neutrophils were few, while 20-30% of Uhrf2-/- T cells and B cells were still detected. RNA sequencing showed downregulation of some genes associated with stem-cell function in Uhrf2-/- hematopoietic stem/progenitor cells (HSPCs). Interestingly, trimethylated histone H3 lysine 9 was increased in Uhrf2-/- HSPCs in a cleavage under targets and tagmentation assay. While UHRF2 deletion did not cause hematologic malignancy or confer a growth advantage of HSPCs, our results suggest that UHRF2 may play a role in the regulation of hematopoiesis.

T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation for a Patient With Tcf3-Hlf-Positive Acute Lymphoblastic Leukemia Extramedullary Relapse After Unrelated Bone Marrow Transplantation.

TCF3-HLF-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has an extremely poor prognosis. A 2-year-old boy with TCF3-HLF-positive BCP-ALL had an isolated extramedullary relapse in multiple bones after allogeneic hematopoietic stem cells transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor. In this study, he received a T-cell-replete haploidentical HSCT (TCR-haplo-HSCT) from his father when in nonremission state, which resulted in a sustained complete remission for over 3 years. Immune therapies for patients with an extramedullary relapse of TCF3-HLF-positive BCP-ALL have been attempted; however, long-term efficacies of these therapies remain unknown. Our TCR-haplo-HSCT may be an effective therapeutic option for such patients.

Clonal hematopoiesis and cardiovascular diseases: role of JAK2V617F.

Bone marrow-derived hematopoietic and immune cells play important roles in the onset and progression of cardiovascular diseases. Recent genetic analyses have discovered that clonal expansion of bone marrow hematopoietic stem/progenitor cells carrying somatic gene mutations is common and is increasing with age in healthy individuals who do not show any hematologic disorders, termed as clonal hematopoiesis. It is emergingly recognized that clonal hematopoiesis is a significant risk factor for cardiovascular diseases rather than a cumulative incidence risk of blood cancers. JAK2V617F, a gain-of-function mutation, has been identified as one of the most important mutations in clonal hematopoiesis as well as the most frequent driver mutation in myeloproliferative neoplasms. Hematopoietic cell clones harboring JAK2V617F are causally associated with the pathogenesis of cardiovascular diseases. Here, we will review the key of JAK2V617F-mediated clonal hematopoiesis including identification, prevalence, and biological impacts, linking to cardiovascular diseases and the related mechanisms. Clonal hematopoiesis with JAK2V617F may be a novel therapeutic target for cardiovascular diseases, connected to precision medicines by detecting its presence.

Evaluation of a quantitative PCR-based method for chimerism analysis of Japanese donor/recipient pairs.

Chimerism analysis is a surrogate indicator of graft rejection or relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Although short tandem repeat PCR (STR-PCR) is the usual method, limited sensitivity and technical variability are matters of concern. Quantitative PCR-based methods to detect single nucleotide polymorphisms (SNP-qPCR) are more sensitive, but their informativity and quantitative accuracy are highly variable. For accurate and sensitive chimerism analysis, a set of KMR kits (GenDx, Utrecht, Netherlands), based on detection of insertions/deletions (indels) by qPCR, have been developed. Here, we investigated informativity and validated the accuracy of KMR kits in Japanese donor/recipient pairs and virtual samples of DNA mixtures representative of Japanese genetic diversity. We found that at least one recipient-specific marker among 39 KMR-kit markers was informative in all of 65 Japanese donor/recipient pairs. Moreover, the percentage of recipient chimerism estimated by KMRtrack correlated well with ratios of mixed DNA in virtual samples and with the percentage of chimerism in HSCT recipients estimated by STR-PCR/in-house SNP-qPCR. Moreover, KMRtrack showed better sensitivity with high specificity when compared to STR-PCR to detect recipient chimerism. Chimerism analysis with KMR kits can be a standardized, sensitive, and highly informative method to evaluate the graft status of HSCT recipients.

[Myeloproliferative neoplasms and vascular diseases].

Vascular diseases are a feature of myeloproliferative neoplasms (MPNs) with a driver mutation, such as JAK2V617F. There is growing evidence that clonal hematopoiesis with JAK2V617F (JAK2V617F-CH) is often complicated with vascular diseases, even in the absence of MPN onset. Such vascular diseases associated with the MPN driver mutation include arterial/venous thrombosis, atherosclerotic coronary artery disease and aortic aneurysm, and pulmonary hypertension. Murine studies have recently revealed mechanisms by which hematopoietic cells activated by the MPN driver mutation may promote thrombosis and vascular remodeling in deep vein stenosis, atherosclerosis, and pulmonary hypertension models. Furthermore, MPN driver mutations mediate various downstream molecules of JAK-STAT activation in neutrophils and macrophages, such as inflammatory cytokines, which may be candidates for preventing and treating vascular diseases in MPNs and JAK2V617F-CH.

Comparison of cryoprotectants in hematopoietic cell infusion-related adverse events.

BACKGROUND: The standard cryoprotectant for human cellular products is dimethyl sulfoxide (DMSO), which is associated with hematopoietic cell infusion-related adverse events (HCI-AEs) in hematopoietic stem cell transplantation including peripheral blood stem cell (PBSC) transplantation (PBSCT). DMSO is often used with hydroxyethyl starch (HES), which reduces DMSO concentration while maintaining the postthaw cell recovery. The cryoprotectant medium CP-1 (Kyokuto Pharmaceutical Industrial) is widely used in Japan. After mixture of a product with CP-1, DMSO and HES concentrations are 5% and 6%, respectively. However, the safety profile of CP-1 in association with HCI-AEs has not been investigated. STUDY DESIGN AND METHODS: To compare CP-1 with other cryoprotectants, we conducted a subgroup analysis of PBSCT recipients in a prospective surveillance study for HCI-AEs. Moreover, we validated the toxicity of CP-1 in 90 rats following various dose administration. RESULTS: The PBSC products cryopreserved with CP-1 (CP-1 group) and those with other cryoprotectants, mainly 10% DMSO (non-CP-1 group), were infused into 418 and 58 recipients, respectively. The rate of ≥grade 2 HCI-AEs was higher in the CP-1 group, but that of overall or ≥grade 3 HCI-AEs was not significantly different, compared to the non-CP-1 group. Similarly, after propensity score matching, ≥grade 2 HCI-AEs were more frequent in the CP-1 group, but the ≥grade 3 HCI-AE rate did not differ significantly between the groups. No significant toxicity was detected regardless of the CP-1 dose in the 90 rats. CONCLUSIONS: Infusion of a CP-1-containing PBSC product is feasible with the respect of HCI-AEs.

Effects of second transplantation with T-cell-replete haploidentical graft using low-dose anti-thymocyte globulin on long-term overall survival in pediatric patients with relapse of leukemia after first allogeneic transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the preferred treatment for children with high-risk hematologic malignancies, but post-allo-HSCT relapse has a poor prognosis and limited treatment options. We evaluated the feasibility, outcome, and risk factors influencing survival after T-cell-replete haploidentical HSCT with low-dose anti-thymocyte globulin (ATG) in 30 patients with post-allo-HSCT relapse of acute lymphoblastic leukemia and acute myeloid leukemia. Overall, 50% of the patients had complete remission (CR) before the second transplant and the overall survival (OS) rate was 52%. In surviving patients (median follow-up 614 days), Kaplan-Meier analysis revealed estimated 2-year leukemia-free survival and OS rates of 48.1% and 61.1%, respectively. Cumulative incidences of 2-year non-relapse mortality and relapse were 24.7% and 36.3%, respectively. Achieving CR before the second allo-HSCT was a predominant independent prognostic factor identified in the multivariate analysis, with a significantly improved 2-year OS rate of 86.7%. T-cell-replete haplo-HSCT with low-dose ATG for second allo-HSCT may benefit a selected patient population.

T-cell replete haploidentical stem cell transplantation with low dose anti-thymocyte globulin for relapsed/refractory Ewing sarcoma family tumors.

BACKGROUND: Despite intensive multimodal therapies, the prognosis of relapsed/ refractory Ewing sarcoma family tumors (RR-ESFTs) is dismal. Some case reports using allogeneic stem cell transplantation (allo SCT) for RR-ESFTs have been reported, however, the efficacy of allo SCT is yet to be established. AIM: The purpose of this study was to evaluate the response and toxicity of T-cell replete haploidentical SCT (TCR-haplo-SCT) in RR-ESFTs. METHODS AND RESULTS: In this study, we retrospectively analyzed six patients with RR-ESFTs who received TCR-haplo-SCT. Four patients had relapsed and two patients had refractory Ewing sarcoma. Before the TCR-haplo-SCT, all patients received a reduced intensity-conditioning regimen containing fludarabine, melphalan, and low-dose rabbit anti-thymocyte globulin (2.5 mg/kg), as well as graft-versus-host disease (GVHD) prophylaxis, which consisted of tacrolimus, methotrexate, and prednisolone. Primary neutrophil engraftment was achieved in all the patients. Four patients developed acute GVHD (aGVHD) (grade I, 1; grade II, 1; grade III, 2), and two patients developed chronic GVHD (cGVHD). Among the four that developed aGVHD, three survived for 14, 116, and 129 months without relapse, while one died due to a transplant-related complication. In contrast, the two patients who did not develop aGVHD experienced relapse early after TCR-haplo-SCT. CONCLUSIONS: In this study, three of the six patients with RR-ESFTs survived for more than one year without relapse, and the treatment toxicity was considered acceptable even for patients who underwent high-intensity pretreatment. TCR-haplo-SCT could be a potential therapeutic option for patients with RR-ESFTs.

Effectiveness of T-Cell Replete Haploidentical Hematopoietic Stem Cell Transplantation for Refractory/Relapsed B Cell Acute Lymphoblastic Leukemia in Children and Adolescents.

Background: The prognosis of refractory/relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains dismal owing to acquired resistance to chemotherapeutic agents. This study aimed to evaluate the efficacy of T-cell replete HLA haploidentical hematopoietic stem cell transplantation (TCR-haplo-HSCT) for pediatric refractory/relapsed BCP-ALL (RR-BCP-ALL). Methods: Nineteen pediatric patients with RR-BCP-ALL underwent TCR-haplo-HSCT between 2010 and 2019 at the Fukushima Medical University Hospital. The disease status at TCR-haplo-HSCT included complete remission (CR) in eight patients and non-CR with active disease in 11 patients. Total body irradiation-based, busulfan-based, and reduced-intensity conditioning regimens were employed in 11, 6, and 2 patients, respectively. Low-dose anti-thymocyte globulin (thymoglobulin, 2.5 mg/kg) was used in all patients. Graft-vs.-host disease (GVHD) prophylaxis was administered with tacrolimus, methotrexate, and prednisolone. Results: All patients received peripheral blood stem cells as the stem cell source. The HLA disparities in graft vs. host directions were 2/8 in one, 3/8 in five, and 4/8 in 13 patients. Among 18 patients who achieved primary engraftment, acute GVHD occurred in all 18 evaluable patients (grade II, 9; grade III, 8; grade IV, 1), and chronic GVHD was observed in 10 out of 15 evaluable patients. Three patients died because of transplant-related mortality. The 3-year overall survival (OS) and leukemia-free survival rates were 57.4 and 42.1%, respectively. Compared to patients older than 10 years in age (N = 10), those younger than 10 years in age (N = 9) showed an excellent OS rate (3-year OS rate: patients < 10 years old, 100%; patients > 10 years old, 20% [95% confidence interval, 3.1-47.5]; p = 0.002). Conclusions: We suggest that TCR haplo-HSCT with low-dose ATG conditioning has the potential to improve the transplantation outcomes in patients with RR-BCP.

Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary arterial remodeling. Clonal somatic mutations including JAK2V617F, the most frequent driver mutation among myeloproliferative neoplasms, have recently been identified in healthy individuals without hematological disorders. Here, we reveal that clonal hematopoiesis with JAK2V617F exacerbates PH and pulmonary arterial remodeling in mice. JAK2V617F-expressing neutrophils specifically accumulate in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines in chronic hypoxia-exposed JAK2V617F transgenic (JAK2V617F) mice, as well as recipient mice transplanted with JAK2V617F bone marrow cells. JAK2V617F progressively upregulates Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions. JAK2V617F-mediated STAT3 phosphorylation upregulates ALK1-Smad1/5/8 signaling. ALK1/2 inhibition completely prevents the development of PH in JAK2V617F mice. Finally, our prospective clinical study identified JAK2V617F-positive clonal hematopoiesis is more common in PH patients than in healthy subjects. These findings indicate that clonal hematopoiesis with JAK2V617F causally leads to PH development associated with ALK1 upregulation.

Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice.

Frameshifts in the Calreticulin (CALR) exon 9 provide a recurrent driver mutation of essential thrombocythemia (ET) and primary myelofibrosis among myeloproliferative neoplasms (MPNs). Here, we generated knock-in mice with murine Calr exon 9 mimicking the human CALR mutations, using the CRISPR-Cas9 method. Knock-in mice with del10 [Calrdel10/WT (wild-type) mice] exhibited an ET phenotype with increases of peripheral blood (PB) platelets and leukocytes, and accumulation of megakaryocytes in bone marrow (BM), while those with ins2 (Calrins2/WT mice) showed a slight splenic enlargement. Phosphorylated STAT3 (pSTAT3) was upregulated in BM cells of both knock-in mice. In BM transplantation (BMT) recipients from Calrdel10/WT mice, although PB cell counts were not different from those in BMT recipients from CalrWT/WT mice, Calrdel10/WT BM-derived macrophages exhibited elevations of pSTAT3 and Endothelin-1 levels. Strikingly, BMT recipients from Calrdel10/WT mice developed more severe pulmonary hypertension (PH)-which often arises as a comorbidity in patients with MPNs-than BMT recipients from CalrWT/WT mice, with pulmonary arterial remodeling accompanied by an accumulation of donor-derived macrophages in response to chronic hypoxia. In conclusion, our murine model with the frameshifted murine Calr presented an ET phenotype analogous to human MPNs in molecular mechanisms and cardiovascular complications such as PH.

Crucial role of hematopoietic JAK2 V617F in the development of aortic aneurysms.

JAK2V617F is the most frequent driver mutation in myeloproliferative neoplasms (MPNs) and is associated with vascular complications. However, the impact of hematopoietic JAK2V617F on the aortic aneurysms (AAs) remains unknown. Our cross-sectional study indicated that 9 (23%) out of 39 MPN patients with JAK2V617F exhibited the presence of AAs. Next, to clarify whether the hematopoietic JAK2V617F contributes to the AAs, we applied a bone marrow transplantation (BMT) with the donor cells from Jak2V617F transgenic (JAK2V617F) mice or control wild-type (WT) mice into lethally irradiated apolipoprotein E-deficient mice. Five weeks after BMT, the JAK2V617F-BMT mice and WT-BMT mice were subjected to continuous angiotensin II infusion to induce AA formation. Four weeks after angiotensin II infusion, the abdominal aorta diameter in JAK2V617F-BMT mice was significantly enlarged compared to that in the WT-BMT mice. Additionally, the abdominal AA-free survival rate was significantly lower in the JAK2V617F-BMT mice. Hematopoietic JAK2V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of infiltrated macrophages were significantly upregulated in the abdominal aorta of the JAK2V617F-BMT mice accompanied by STAT3 phosphorylation. The accumulation of BM-derived hematopoietic cells carrying JAK2V617F in the abdominal aorta was confirmed by use of reporter GFP-transgene. BM-derived macrophages carrying JAK2V617F showed increases in mRNA expression levels of Mmp2, Mmp9, and Mmp13. Ruxolitinib decreased the abdominal aorta diameter and the incidence of abdominal AA in the JAK2V617F-BMT mice. Our findings provide a novel feature of vascular complications of AAs in MPNs with JAK2V617F.

Decline of serum albumin precedes severe acute GVHD after haploidentical HSCT.

BACKGROUND: Haploidentical hematopoietic stem cell transplantation (HSCT) is a useful therapy for relapsed/refractory acute leukemia or lymphoma because of the strong graft-vs-leukemia (GVL) effect. However, it is often accompanied by severe acute graft-versus-host disease (aGVHD), which is the most serious complication after haploidentical HSCT. Thus, it is important to control the severity of aGVHD while maintaining the GVL effect. In our experience of pediatric haploidentical HSCT, it takes several days for aGVHD to become severe after the appearance of initial symptoms, mostly skin rashes. In this study, we aimed to identify useful biomarkers at the onset of aGVHD that predict subsequent development of severe aGVHD. METHODS: Forty-five consecutive children with relapsed/refractory acute leukemia or lymphoma who developed aGVHD after haploidentical HSCT were enrolled. We analyzed possible biomarkers from samples collected at the onset of acute GVHD. RESULTS: Nineteen patients developed grade 1-2 aGVHD, and 26 patients developed grade 3-4 aGVHD. There was no significant difference in patient characteristics between the two groups. Transplant-related mortality occurred only in the grade 3-4 aGVHD group (34.5%). Multivariate analysis revealed that serum albumin was an independent biomarker for predicting the severity of aGVHD (P = 0.009). The area under the receiver operating characteristic curve of serum albumin was 0.864. CONCLUSIONS: The serum albumin level at the onset of aGvHD could be a useful biomarker for the development of subsequent severe aGVHD in pediatric patients after haploidentical HSCT.

Differences among hemoglobin thresholds for red blood cell transfusions in patients with hematological diseases in teaching hospitals: a real world data in Japan.

A hemoglobin (Hb) threshold level of 7 g/dL has been proposed for red blood cell (RBC) transfusion in patients with chronic anemia in the Japanese guideline since 2005. However, Hb thresholds for hematological diseases in clinical practice and factors responsible for higher Hb thresholds remain unclear. Hb thresholds were collected for patients with hematological diseases from 32 Japanese teaching hospitals. Uni- and multivariate analyses were used to analyze relationships between Hb threshold level and various patient and hospital factors. In total, 4996 units of RBC were transfused to 1054 patients with hematological diseases in 2421 transfusions. Median age was 68 years. Myelodysplastic syndrome was the most frequent diagnosis. Overall median Hb threshold level was 6.9 g/dL. Multivariate linear regression analysis detected the following variables associated with Hb threshold level: hospital; cardiovascular disease; symptomatic anemia; and hematopoietic stem cell transplantation. Hospital was the most significant factor. Collectively, median Hb threshold level in clinical practice in Japan was similar to the guidelines. Higher Hb threshold level depended on the hospitals at which the transfusions were performed as well as patient condition. Educational approaches directed toward hospitals may be useful to promote transfusion guidelines.

Hematopoietic cell infusion-related adverse events in pediatric/small recipients in a prospective/multicenter study.

BACKGROUND: Hematopoietic cell infusion-related adverse events (HCI-AEs) in hematopoietic stem cell transplantations (HSCTs) have been largely attributed to toxicity of dimethyl sulfoxide (DMSO) for cryopreservation, but HSC products also contain various cells and plasma components. Our recent prospective study of 1125 HSCT recipients revealed the highest overall HCI-AE rate in bone marrow transplantation (BMT) using fresh/noncryopreserved products, although products of peripheral blood stem cell transplantation and cord blood transplantation (CBT) are generally cryopreserved with DMSO containing smaller plasma volumes. We aimed to clarify if product volume and component effects are more substantial in small recipients including children. STUDY DESIGN AND METHODS: We performed subgroup analysis on 219 recipients of 45 kg or less body weight (whole small recipients), including 90 children (pediatric recipients), from the original cohort (general recipients). RESULTS: Whereas overall HCI-AE rates did not differ among hematopoietic stem cell sources in the general recipients, bradycardia most often occurred after CBT in whole small recipients. Conversely, whole small and general recipients shared the same trend of having the highest rate of hypertension in BMT. The overall HCI-AE rate was higher in allogeneic HSCT compared with autologous HSCT. Notably, pediatric recipients showed a 10-fold higher incidence of nausea and vomiting in allogeneic HSCT compared with autologous HSCT, suggesting a possible role of allogeneic antigens. Multivariate analysis identified a relatively large infusion volume per body weight as a significant factor correlating with HCI-AE in whole small recipients. CONCLUSIONS: We should be aware of product volume and specific HCI-AEs such as nausea and vomiting in small patients including children.