Yachiyo Kuwatsuka

Low absolute lymphocyte count is a poor prognostic marker in patients with diffuse large B-cell lymphoma and suggests patients’ survival benefit from rituximab

Objectives:  To evaluate the prognostic value of absolute lymphocyte count (ALC) at diagnosis in patients with diffuse large B‐cell lymphoma (DLBCL).

Hematopoietic stem cell transplantation for core binding factor acute myeloid leukemia: t(8;21) and inv(16) represent different clinical outcomes

We analyzed 338 adult patients with acute myeloid leukemia (AML) with t(8;21) and inv(16) undergoing stem cell transplantation (SCT) who were registered in the Japan Society for Hematopoietic Cell Transplantation database. At 3 years, overall survival (OS) of patients with t(8;21) and inv(16) was 50% and 72%, respectively (P= .002). Although no difference was observed when restricted to allogeneic SCT in first complete remission (CR; 84% and 74%), OS of patients with t(8;21) and inv(16) undergoing allogeneic SCT in second or third CR (45% and 86% at 3 years; P= .008) was different. OS was not different between patients in first CR who received allogeneic SCT and those who received autologous SCT for both t(8;21) AML (84% vs 77%; P= .49) and inv(16) AML (74% vs 59%; P= .86). Patients with inv(16) not in CR did better after allogeneic SCT than those with t(8;21) (70% and 18%; P= .03). Patients with t(8;21) and inv(16) should be managed differently as to the application of SCT. SCT in first CR is not necessarily recommended for inv(16). For t(8;21) patients in first CR, a prospective trial is needed to clarify the significance of autologous SCT and allogeneic SCT over chemotherapy.

Long-term survival following autologous and allogeneic stem cell transplantation for blastic plasmacytoid dendritic cell neoplasm

We sought to clarify the role of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN). We retrospectively identified 25 BPDCN patients (allo-HSCT, n = 14; auto-HSCT, n = 11) from registry data of the Japan Society for Hematopoietic Cell Transplantation and analyzed clinicopathologic data and clinical outcomes after transplantation. The median age at HSCT was 58 years (range, 17-67 years). All 11 patients who underwent auto-HSCT were in the first complete remission (CR1). With a median follow-up of 53.5 months, the overall survival rates at 4 years for patients who underwent auto-HSCT and allo-HSCT were 82% and 53% (P = .11), respectively, and progression-free survival rates were 73% and 48% (P = .14), respectively. Auto-HSCT for BPDCN in CR1 appears to provide promising results and deserves further evaluation in the setting of prospective trials.

Donor Lymphocyte Infusion for the Treatment of Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Analysis by the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation

Because the efficacy of donor lymphocyte infusion (DLI) for acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) remains uncertain, especially in the Asian population, a nationwide registry study was retrospectively performed by the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation to identify the factors affecting the patient survival after DLI. Among 143 adult AML patients who received DLI for the treatment of first hematological relapse after HSCT, the overall survival rates at 1 year, 2 years, and 5 years were 32% ± 4%, 17% ± 3%, and 7% ± 3%, respectively. Complete remission (CR) at the time of DLI, which was obtained in 8% of the patients, was the strongest predictive factor for survival after DLI. Therefore, long-term survival after DLI was achieved almost exclusively in patients who successfully achieved a CR before DLI, indicating the limited efficacy of DLI in a minority of patients.

Decreased risk of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with the 5,10-methylenetetrahydrofolate reductase 677TT genotype

Polymorphism in 5,10-methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism, has been shown to affect the sensitivity of patients to folate-based drugs such as methotrexate. In this study, we investigated whether a common single nucleotide polymorphism at position 677 in the donor or recipient’s MTHFR gene affects the risk for acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling donors when the recipient receives prophylactic treatment with methotrexate for GVHD. MTHFR genotypes were determined in 159 recipients with a hematological disease and their donors using polymerase chain reaction–restriction fragment length polymorphism analysis of genomic DNA. The 677TT genotype, which encodes an enzyme with approximately 30% of the activity of the wild-type (677CC), was observed in 13% of patients and in 8% of normal donors. Multivariate analyses demonstrated a significant association between 677TT genotype in patients and a lower incidence of grade I–IV acute GVHD (relative risk, 0.35; 95% confidence interval, 0.13–0.95; P = 0.040). There was no association between the incidence of acute GVHD and the donor MTHFR genotypes. These results suggest that greater immunosuppression by methotrexate due to low MTHFR enzyme activity decreases the risk of acute GVHD in recipients of allogeneic HSCT.

Prognostic value of serum soluble interleukin-2 receptor level in patients with diffuse large B cell lymphoma, treated with CHOP-or RCHOP-based therapy

The emergence of rituximab has changed the clinical outcome of patients with B-cell lymphoma, which necessitates reassessment of previously determined prognostic factors. Thus, we evaluated the prognostic significance of serum soluble interleukin-2 receptor (sIL2R) levels in patients with diffuse large B cell lymphoma (DLBCL), treated with CHOP (n = 108) or RCHOP (n = 94). Serum sIL2R level ranged from 316 to 23 800 U/mL (median 1064 U/mL) and levels were generally higher in higher IPI risk group. Multivariate analyses revealed that sIL2R ≥1000 U/mL was associated with shorter progression free survival [hazard ratio (HR) = 2.52, p = 0.011] and overall survival (HR = 2.34, p = 0.037) independent of IPI risk group or rituximab use. Further subgroup analyses revealed that the impact of sIL2R was most apparent in patients with IPI low risk, both in CHOP alone and RCHOP group. Our study confirmed the prognostic value of sIL2R in patients with DLBCL with low International Prognostic Index (IPI) risk, also in the era of rituximab.

Clinical impact and predisposing factors of delayed-onset neutropenia after autologous hematopoietic stem-cell transplantation for B-cell non-Hodgkin lymphoma: association with an incremental risk of infectious events

BACKGROUND Clinical significance of delayed-onset neutropenia (DON) after autologous hematopoietic stem-cell transplantation (ASCT) has not been well described. We conducted a retrospective cohort study to examine risk factors and clinical impact of DON. DESIGN AND METHODS Subjects were consecutive 108 patients with B-cell lymphoma receiving ASCT. We defined DON as absolute neutrophil counts <1.0 x 10(9)/l at any point from 30 days onward after ASCT without apparent causes of neutropenia. Documented infectious events were reviewed from 1 to 18 months after ASCT. RESULTS Fifty-two percent of patients received rituximab. Cumulative incidence of DON was 50% at 1 year. Rituximab usage was identified as an independent risk factor of DON. A total of 117 infectious events were documented, of which 24 events occurred during DON period. Cumulative incidence of total infectious events was 75% and 42% in the groups with and without DON, respectively (P = 0.001). Varicella-zoster virus (P = 0.033) and upper respiratory infection (P = 0.016) were frequent in the patients experiencing DON. In a multivariable analysis, DON remained a significant factor for total infectious events and upper respiratory infection. CONCLUSIONS Rituximab usage is an independent risk factor of DON. DON correlates with increased occurrence of infectious events. Careful follow-up would be needed after the onset of DON.

Graft-Versus-Host Disease and Survival after Cord Blood Transplantation for Acute Leukemia: A Comparison of Japanese versus White Populations

An earlier report identified higher risks of acute and chronic graft-versus-host disease (GVHD) in White children compared with the Japanese after HLA-matched sibling transplantations. The current analysis explored whether racial differences are associated with GVHD risks after unrelated umbilical cord blood transplantation. Included are patients of Japanese descent (n = 257) and Whites (n = 260; 168 of 260 received antithymocyte globulin [ATG]). Transplants were performed in the United States or Japan between 2000 and 2009; patients were aged 16 years or younger, had acute leukemia, were in complete remission, and received a myeloablative conditioning regimen. The median ages of the Japanese and Whites who received ATG were younger at 5 years compared with 8 years for Whites who did not receive ATG. In all groups most transplants were mismatched at 1 or 2 HLA loci. Multivariate analysis found no differences in risks of acute GVHD between the Japanese and Whites. However, chronic GVHD was higher in Whites who did not receive ATG compared with the Japanese (hazard ratio, 2.16; P < .001), and treatment-related mortality was higher in Whites who received ATG compared with the Japanese (relative risk, 1.81; P = .01). Nevertheless, there were no significant differences in overall survival between the 3 groups.

Stable Engraftment after a Conditioning Regimen with Fludarabine and Melphalan for Bone Marrow Transplantation from an Unrelated Donor

Graft failure and nonrelapse mortality (NRM) are major obstacles after the first unrelated-donor bone marrow transplantation (UD-BMT) with reduced-intensity conditioning. We evaluated UD-BMT with fludarabine (5 × 25 mg/m2) and melphalan (2 × 90 mg/m2) treatment combined with short-term methotrexate and tacrolimus (n = 20) or cyclosporine (n = 2) therapy for 22 patients with hematologic malignancies who were ineligible for conventional conditioning. Only 9 patients were in remission at transplantation. Seventeen patients underwent HLA-matched or DRB1 allele—mismatched transplantation, and 5 patients underwent HLA-A allele—mismatched or serologically HLA-DR—mismatched transplantation. Regimen-related toxicities were tolerable, although transient oral mucositis, hepatobiliary enzyme elevation, and diarrhea were observed frequently. All evaluable patients achieved sustained neutrophil engraftment, and all patients tested showed complete donor chimerism on day 28. With a median follow-up of 16 months, NRM and overall survival rates at 1 year were 19% and 81%, respectively, among the patients who underwent HLA-matched or DRB1 allele-mismatched transplantation. Acute graft-versus-host disease (GVHD) of grades II to IV occurred in 26% of the patients. The cumulative incidence of chronic GVHD was 44%. Despite the small number of patients and the short follow-up period, this reduced-intensity regimen enabled satisfactory engraftment and achievement of rapid complete donor chimerism with tolerable toxicities in the patients, including those who underwent HLA-mismatched UD-BMT.

Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells.

Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF‐04449913 (PF‐913) is a selective, small‐molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof‐of‐concept and mechanism of action of PF‐913 following administration to patients with acute myeloid leukemia (AML) are unclear. This study examined the role of the Hedgehog signaling pathway in AML cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF‐913. In primary AML cells, activation of the Hedgehog signaling pathway was more pronounced in CD34+ cells than CD34− cells. In vitro treatment with PF‐913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF‐913 attenuated the leukemia‐initiation potential of AML cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF‐913 modulated self‐renewal signatures and cell cycle progression. Furthermore, PF‐913 sensitized AML cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in AML cells cocultured with HS‐5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia‐initiation potential, and also enhanced AML therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment.