Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n = 331) or single-unit unrelated cord blood (UCB) (n = 668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P = 0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P = 0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P = 0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P = 0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P < 0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P < 0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P < 0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P < 0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

Canonical BAF complex regulates the oncogenic program in human T-cell acute lymphoblastic leukemia.

ABSTRACT: Acute leukemia cells require bone marrow microenvironments, known as niches, which provide leukemic cells with niche factors that are essential for leukemic cell survival and/or proliferation. However, it remains unclear how the dynamics of the leukemic cell-niche interaction are regulated. Using a genome-wide CRISPR screen, we discovered that canonical BRG1/BRM-associated factor (cBAF), a variant of the switch/sucrose nonfermenting chromatin remodeling complex, regulates the migratory response of human T-cell acute lymphoblastic leukemia (T-ALL) cells to a niche factor CXCL12. Mechanistically, cBAF maintains chromatin accessibility and allows RUNX1 to bind to CXCR4 enhancer regions. cBAF inhibition evicts RUNX1 from the genome, resulting in CXCR4 downregulation and impaired migration activity. In addition, cBAF maintains chromatin accessibility preferentially at RUNX1 binding sites, ensuring RUNX1 binding at these sites, and is required for expression of RUNX1-regulated genes, such as CDK6; therefore, cBAF inhibition negatively impacts cell proliferation and profoundly induces apoptosis. This anticancer effect was also confirmed using T-ALL xenograft models, suggesting cBAF as a promising therapeutic target. Thus, we provide novel evidence that cBAF regulates the RUNX1-driven leukemic program and governs migration activity toward CXCL12 and cell-autonomous growth in human T-ALL.

Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical relatives in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukemia: a propensity score analysis of a nationwide database.

Bone marrow (BM) and granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSC) are used as grafts from HLA-identical-related donors for adults with myelodysplastic syndrome (MDS). To assess the impact of graft sources on post-transplant outcomes in MDS patients, we conducted a retrospective analysis of a nationwide database. A total of 247 and 280 patients underwent transplantation with BM and PBSC, respectively. The inverse probability of treatment weighting (IPTW) methods revealed that overall survival (OS) was comparable between BM and PBSC (P = .129), but PBSC transplantation was associated with worse graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) (hazard rate [HR], 1.24; 95% confidence intervals [CIs], 1.00-1.53; P = 0.049) and chronic GVHD-free and relapse-free survival (CRFS) (HR, 1.29; 95% CIs, 1.13-1.73; P = 0.002) than BM transplantation. In the propensity score matched cohort (BM, n = 216; PBSC, n = 216), no significant differences were observed in OS and relapse; 3-year OS rates were 64.7% and 60.0% (P = 0.107), while 3-year relapse rates were 27.1% and 23.5% (P = 0.255) in BM and PBSC, respectively. Three-year GRFS rates (36.6% vs. 29.2%; P = 0.006), CRFS rate (37.7% vs. 32.5%; P = 0.003), and non-relapse mortality rates (13.9% vs. 21.1%; P = 0.020) were better in BM than in PBSC. The present study showed that BM transplantation provides a comparable survival benefit with PBSC transplantation and did not identify an enhanced graft-versus-MDS effect to reduce the incidence of relapse in PBSC transplantation.

Significance of Omitting Day 11 Mini-Dose Methotrexate for GVHD Prophylaxis After Unrelated Bone Marrow Transplantation.

The combination of calcineurin inhibitors and short-term methotrexate has been used as a standard graft-versus-host-disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation. Mini-dose methotrexate (mini-MTX), consisting of 5 mg/m2/d on days 1, 3, 6, and 11, is occasionally selected as an alternative considering toxicity. The significance of day 11 administration remains unclear. We performed a retrospective study of 135 cases of unrelated bone marrow transplantation at our institute between 2006 and 2019 and compared the outcomes between day 11 MTX dose omitted (n = 72) and full-doses of mini-MTX (n = 63). In total cohort, the 4-year overall survival (OS) was 58.7 %, and the omitted group showed poor GVHD/relapse-free-survival (P = .01) with comparable OS (P = .11) and relapse-free survival (P = .11). Human leukocyte antigen (HLA) mismatch is a major risk factor for severe GVHD. We analyzed the impact of omitting day 11 MTX in 2 cohorts from HLA matched or mismatched donors. In both cohorts, the omitted group had a higher risk of severe acute and chronic GVHD. In conclusion, the omission of day 11 MTX was associated with a higher risk of severe GVHD. Therefore the omission of the day 11 dose is not recommended.

Runx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells.

In bone marrow, special microenvironments, known as niches, are essential for the maintenance of hematopoietic stem cells (HSCs). A population of mesenchymal stem cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells or leptin receptor-expressing cells are the major cellular component of HSC niches. The molecular regulation of HSC niche properties is not fully understood. The role of Runx transcription factors, Runx1 and Runx2 in HSC cellular niches remains unclear. Here we show that Runx1 is predominantly expressed in CAR cells and that mice lacking both Runx1 and Runx2 in CAR cells display an increase in fibrosis and bone formation with markedly reduced hematopoietic stem and progenitor cells in bone marrow. In vitro, Runx1 is induced by the transcription factor Foxc1 and decreases fibrotic gene expression in CAR cells. Thus, HSC cellular niches require Runx1 or Runx2 to prevent their fibrotic conversion and maintain HSCs and hematopoiesis in adults.

Identification of CXCL12-abundant reticular cells in human adult bone marrow.

A population of mesenchymal stem cells, termed CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells or leptin receptor-expressing cells, are the major cellular component of niches for haematopoietic stem cells (HSCs) in murine bone marrow. CAR cells are characterized by several salient features, including much higher expression of CXCL12, stem cell factor (SCF), forkhead box C1 (FOXC1) and early B-cell factor 3 (EBF3), which are essential for HSC maintenance, than other cells. However, the human counterpart of CAR cells has not been fully described. Here, we show the presence of cells expressing much higher CXCL12 than other cells in human adult bone marrow using a flow cytometry-based in situ technique that enables high-throughput detection of mRNA at single-cell resolution. Most CXCL12hi cells expressed high levels of SCF, FOXC1 and EBF3 and had the potential to differentiate into adipocytes and osteoblasts. Histologically, the nuclei of CXCL12hi cells were identified and quantified by EBF3 expression in fixed marrow sections. CXCL12hi cells sorted from residual bone marrow aspirates of chronic myeloid leukaemia patients expressed reduced levels of CXCL12, SCF, FOXC1 and EBF3 in correlation with increased leukaemic burden. Together, we identified the human counterpart of CAR cells, enabling the evaluation of their alterations in various haematological disorders by flow cytometric and histological analyses.

Increased opportunity for prolonged survival after allogeneic hematopoietic stem cell transplantation in patients aged 60-69 years with myelodysplastic syndrome.

We conducted a nationwide retrospective study to evaluate the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 651 patients aged 60-69 years with de novo myelodysplastic syndrome (MDS). We divided patients into two groups: 152 and 499 patients with an early and advanced disease status, respectively. The 3-year overall survival (OS) rate of patients with an early disease status was 45.9% (95% confidence interval [CI], 37.0 to 54.2%). A multivariate analysis revealed five adverse factors for OS: performance status (PS) 2-4 (hazard ratio [HR] 4.48; P < .001), poor cytogenetic risk group (HR 1.83; P = .041), male recipient (HR 2.58; P = .003), use of HLA-mismatched related grafts (HR 4.75; P = .003), and unrelated cord blood (HR 2.47; P = .023). The 3-year OS rate of patients with an advanced disease status was 37.2% (95% CI 32.4 to 41.9%). Five factors correlated with worse OS: PS 2-4 (HR 1.72; P = .003), poor cytogenetic risk group (HR 1.49; P = .003), use of HLA-mismatched related grafts (HR 1.96; P = .015), unrelated cord blood (HR 2.05; P < .001), and the high number of red blood cell transfusions before transplantation (HR 1.85; P = .018). The present results revealed the more frequent utilization of allo-HSCT for MDS patients aged 60-69 years, which increases the curative potential.

Clinical impact of the loss of chromosome 7q on outcomes of patients with myelodysplastic syndromes treated with allogeneic hematopoietic stem cell transplantation.

We conducted a nationwide retrospective study to evaluate the prognostic influence of +1, der(1;7)(q10;p10) [hereafter der(1;7)] and -7/del(7q) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for de novo myelodysplastic syndromes (MDS). In this database, 69 MDS patients with der(1;7), 75 with -7/del(7q), and 511 with normal karyotype (NK) underwent allo-HSCT at advanced disease status. The 3-year overall survival (OS) and cumulative incidence of relapse (CIR) were 50.4 and 19.4% for those with der(1;7), 36.2 and 38.4% for -7/del(7q), and 51.1 and 20.7% for NK, respectively. In the multivariate analysis, the presence of -7/del(7q) correlated with a significantly shorter OS (HR [95% CI], 1.38 [1.00-1.89]; P = 0.048) and higher CIR (HR, 2.11 [1.36-3.28]; P = 0.001) than those with NK. There were 23 patients with der(1;7), 29 with -7/del(7q), and 347 with NK who underwent allo-HSCT at early disease status. The 3-year OS and CIR were as follows: 47.3 and 9.5% for the der(1;7) group, 70.5 and 13.8% for -7/del(7q), and 70.9 and 5.6% for NK, respectively. No significant differences were observed in OS and CIR among three groups. The impact of the loss of chromosome 7q on OS and CIR may differ based on its type and disease status after allo-HSCT for MDS.

Prognostic Impact of Donor Source on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Adults with Chronic Myelomonocytic Leukemia: A Nationwide Retrospective Analysis in Japan.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for patients with chronic myelomonocytic leukemia (CMML). We retrospectively compared the post-transplantation outcomes of 159 patients with CMML who underwent allo-HSCT using 4 types of donor sources: HLA-matched related donor graft, unrelated bone marrow (U-BM), unrelated cord blood (U-CB), and HLA-mismatched related donor graft. The median patient age at allo-HSCT was 54 years (range, 16 to 75 years). In multivariate analyses, the use of HLA-matched related donor grafts correlated with better overall survival than U-BM (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.21 to 3.48; P = .008), U-CB (HR, 3.80; 95% CI, 2.07 to 6.95; P < .001), or HLA-mismatched related donor grafts (HR, 6.18; 95% CI, 2.70 to 14.15; P < .001). Mortality after the relapse or progression of CMML did not significantly differ among the 4 types of donor source. Transplantation-related mortality was highest in recipients of U-CB (HR, 3.32; 95% CI, 1.33 to 8.26; P = .010). In patients with CMML, allo-HSCT using an alternative donor may contribute to durable remission; however, further improvements in transplantation-related mortality are required for this type of transplantation.

Outcome differences between children and adolescents and young adults with non-Hodgkin lymphoma following stem cell transplantation.

Several studies of patients with acute lymphoblastic leukemia and acute myeloid leukemia who received stem cell transplantation (SCT) have reported that adolescents and young adults (AYAs) experience higher transplant-related mortality than that in younger children. However, to the best of our knowledge, there have been no reports of a similar comparison of non-Hodgkin lymphoma (NHL) patients who received SCT. We analyzed 918 patients aged 30 years and younger who received their first stem cell transplantation for NHL. Of the allogeneic transplant patients, children and AYAs did not significantly differ in survival rate, event-free survival rate, relapse rate, or transplant-related mortality. However, 5-year transplant-related mortality after autologous transplantation was significantly higher in children than in AYAs (5.1% in children vs. 0.8% in AYAs, P = 0.0043). The cause of transplant-related death in three of four children was interstitial pneumonitis. In NHL patients, transplantation results in AYAs were not inferior than those in children.

Impacts of graft-versus-host disease on outcomes after allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: A nationwide retrospective study.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic option that may lead to improved outcomes in patients with chronic myelomonocytic leukemia (CMML). However, few studies have examined the impact of the grade of graft-versus-host disease (GVHD) on post-transplant outcomes for CMML. We retrospectively analyzed the outcomes of 141 patients with CMML who underwent allo-HSCT between 1987 and 2010, and achieved neutrophil engraftment. The effects of acute GVHD (aGVHD) or chronic GVHD (cGVHD) on overall survival (OS), leukemia-associated mortality (LAM), and transplant-related mortality were evaluated by hazards regression models, in which the onset date of aGVHD or cGVHD was treated as a time-dependent covariate. Grade I aGVHD was associated with better OS and lower LAM (P=0.042, P=0.033, respectively) than no GVHD in univariate analyses, but not in the multivariate analyses. The multivariate analyses demonstrated that extensive cGVHD significantly associated with better OS (Hazard Ratio [HR] 0.35 [95% confidence intervals (CI), 0.16-0.74]; P=0.007) and lower LAM (HR 0.36 [95% CI, 0.14-0.92]; P=0.033) in patients who were not in complete remission at transplantation. In conclusion, the occurrence of cGVHD may be an important factor affecting the outcomes of CMML patients who received transplantation.

Clinical significance of high-dose cytarabine added to cyclophosphamide/total-body irradiation in bone marrow or peripheral blood stem cell transplantation for myeloid malignancy.

BACKGROUND: Addition of high-dose cytarabine (HDCA) to the conventional cyclophosphamide/total-body irradiation (CY/TBI) regimen significantly improved prognosis after cord blood transplantation (CBT) for adult acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The efficacy of HDCA in bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT), however, has not yet been elucidated. FINDINGS: We conducted a cohort study to compare the prognosis of HDCA/CY/TBI (N = 435) and CY/TBI (N = 1667) in BMT/PBSCT for AML/MDS using a Japanese transplant registry database. The median age was 38 years, and 86.0% of the patients had AML. Unrelated donors comprised 54.6%, and 63.9% of donors were human leukocyte antigen (HLA)-matched. Overall survival (OS) was not improved in the HDCA/CY/TBI group (adjusted hazard ratio (HR), 1.14; p = 0.13). Neutrophil engraftment was inferior (HR, 0.80; p < 0.01), and the incidence of hemorrhagic cystitis and thrombotic microangiopathy increased in HDCA/CY/TBI (HR, 1.47 and 1.60; p = 0.06 and 0.04, respectively), leading to significantly higher non-relapse mortality (NRM; HR, 1.48; p < 0.01). Post-transplant relapse and tumor-related mortality were not suppressed by the addition of HDCA. CONCLUSIONS: This study indicated the inefficacy of HDCA/CY/TBI in BMT/PBSCT for AML/MDS. Our results should be validated in large-scale prospective studies.

CXCR4/CXCL12 signaling impacts enamel progenitor cell proliferation and motility in the dental stem cell niche.

Dental stem cells are located at the proximal ends of rodent incisors. These stem cells reside in the dental epithelial stem cell niche, termed the apical bud. We focused on identifying critical features of a chemotactic signal in the niche. Here, we report that CXCR4/CXCL12 signaling impacts enamel progenitor cell proliferation and motility in dental stem cell niche cells. We report cells in the apical bud express CXCR4 mRNA at high levels while expression is restricted in the basal epithelium (BE) and transit-amplifying (TA) cell regions. Furthermore, the CXCL12 ligand is present in mesenchymal cells adjacent to the apical bud. We then performed gain- and loss-of-function analyses to better elucidate the role of CXCR4 and CXCL12. CXCR4-deficient mice contain epithelial cell aggregates, while cell proliferation in mutant incisors was also significantly reduced. We demonstrate in vitro that dental epithelial cells migrate toward sources of CXCL12, whereas knocking down CXCR4 impaired motility and resulted in formation of dense cell colonies. These results suggest that CXCR4 expression may be critical for activation of enamel progenitor cell division and that CXCR4/CXCL12 signaling may control movement of epithelial progenitors from the dental stem cell niche.

Efficiency of high-dose cytarabine added to CY/TBI in cord blood transplantation for myeloid malignancy.

Cord blood transplantation (CBT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen, but posttransplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated. Therefore, we conducted a cohort study to compare the prognosis of HDCA/CY/TBI (n = 617) and CY/TBI (n = 312) in CBT for AML/MDS, using a Japanese transplant registry database. The median age was 40 years, and 86.2% of the patients had AML; high-risk disease was observed in 56.2% of the patients. The median follow-up period after CBT was approximately 3.5 years. Overall survival was significantly superior in the HDCA/CY/TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; P < .01), and tumor-related mortality was lower (HR, 0.50; P < .01). The incidence of grade II to IV acute graft-vs-host disease (aGVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group (HR, 1.33 and 2.30, respectively), but not grade III to IV aGVHD. Incidence of infectious episodes showed no significant difference. Nonrelapse mortality was not increased by the addition of HDCA. Higher-dose CA (12 rather than 8 g/m(2)) was more effective, particularly in patients at high-risk for disease. This study is the first to show the superiority of HDCA/CY/TBI to CY/TBI in CBT for AML/MDS. A large-scale prospective study is warranted to establish new conditioning regimens including HDCA administration.

Serum IgA level, monocyte count, and international prognostic index are independently associated with overall survival in patients with HTLV-I-negative nodal peripheral T cell lymphoma.

Peripheral T cell lymphomas (PTCL) account for 10-15 % of non-Hodgkin's lymphomas and are associated with poor prognosis. Although many prognostic factors for PTCL have been proposed, the heterogeneity of PTCL seems to be an obstacle in the establishment of clinically useful prognostic system, such as the International Prognostic Index (IPI) in diffuse large B cell lymphoma. PTCL with nodal manifestation include the HTLV-I-negative histologic subtypes of PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL). As PTCL-NOS encompasses a group of similar tumors and mostly shares their clinical pictures, we retrospectively analyzed clinical data from 77 patients diagnosed with ALCL, AITL, and PTCL-NOS at Kobe City Medical Center General Hospital from May 1994 to February 2012 to identify the prognostic factor for nodal PTCL. The median age of patients was 64 years, ranging from 23 to 83 years. With a median follow-up of 50 months, 5-year overall survival (OS) was 43 %. Multivariate analysis identified high-risk IPI (hazard ratio (HR), 4.04; P = 0.015), absolute monocyte count > 0.8 × 10(9)/L (HR, 3.44; P = 0.001), and serum concentration of IgA > 410 mg/dL (HR, 2.31; P = 0.013) as poor prognostic factors for OS. Thus, we have identified novel prognostic factors of monocyte count and serum IgA level for nodal PTCL. Although conventional prognostic models mainly reflect both tumor characteristics and host factors, the present model indicates the importance of host immune response as the unfavorable prognosis.

The prognostic impact of absolute lymphocyte and monocyte counts at diagnosis of diffuse large B-cell lymphoma in the rituximab era.

BACKGROUND: A recent report showed that the combination of the absolute lymphocyte count (ALC) and the absolute monocyte count (AMC) at diagnosis gave a prognostic score in diffuse large B-cell lymphoma (DLBCL). However, this model requires validation in other patient cohorts. METHODS: We retrospectively evaluated the prognostic impact of the combination of the ALC and the AMC at diagnosis in a cohort of 299 DLBCL patients who were treated in the rituximab era at a single institution. RESULTS: In univariate analyses, an ALC ≤1.0 × 10(9)/l [4-year overall survival (OS) rate 47.0 vs. 79.4%; p < 0.001] and an AMC ≥0.63 × 10(9)/l (4-year OS rate 52.4 vs. 75.6%; p < 0.001) were associated with inferior OS, respectively. In multivariate analyses, an ALC ≤1.0 × 10(9)/l and an AMC ≥0.63 × 10(9)/l were significantly associated with inferior OS independently of the International Prognostic Index. Furthermore, the combination of ALC and AMC could identify patients with the dismal prognosis; the 4-year OS rates for patients with ALC ≤1.0 × 10(9)/l and AMC ≥0.63 × 10(9)/l were 18.8%. CONCLUSIONS: The combination of ALC and AMC at diagnosis may be useful for the prognostic stratification of patients with DLBCL.

Therapeutic effects of lenalidomide on hemorrhagic intestinal myeloma-associated AL amyloidosis.

A 74-year-old woman with refractory IgG-κ multiple myeloma developed massive melena caused by hemorrhagic submucosal tumors in the duodenum and middle jejunum. A biopsy revealed the tumor to be marked AL amyloid deposition. Treatment with bortezomib did not improve the melena or the underlying disease. The patient also developed multiple amyloidomas in the bilateral femoral heads, which caused a fracture in the left femoral head. Treatment with lenalidomide, as the final therapeutic option, resolved the intractable melena and improved both the intestinal lesions and myeloma. This case shows that successful treatment of multiple myeloma leads to marked improvement of accompanying AL amyloidosis.