Effectiveness of hyperbaric oxygen therapy for virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Although some studies have suggested the effectiveness of hyperbaric oxygen (HBO) therapy for hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT), the role of HBO has not been established. We compared the treatment outcomes of 8 patients with viral HC (adenovirus [ADV], n = 2; BK virus [BKV], n = 6) treated with HBO (HBO[+]) and 8 patients (ADV, n = 2; BKV, n = 6) treated with conventional therapy (HBO[-]), such as urinary catheterization and intravenous cidofovir. HBO therapy was performed at 2.1 atmospheres for 90 min/day until clinical improvement was achieved. The median number of HBO treatments was 10 (range 8-12). The median duration of HBO treatment was 19.5 days (range 10-23 days). All 8 HBO(+) patients achieved complete remission (CR) at a median of 14.5 days (range 5-25 days). Of the 8 HBO(-) patients, 5 (62.5%) obtained CR and 3 remained symptomatic for 2-6 months. The cumulative incidence of transplant-related mortality at day 100 after allogeneic HSCT was significantly higher in the HBO(-) patients than in the HBO(+) patients (14.2 vs. 0%, P < 0.05). No severe HBO-related adverse effects were observed. In conclusion, HBO is a feasible option for treating viral HC after allogeneic HSCT.

DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.).

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.

Adenovirus pneumonia presenting with nodular shadows on chest X-ray in two unrelated allogeneic bone marrow transplant recipients.

Adenoviruses are increasingly recognized as important pathogens following allogeneic stem cell transplantation. We herein report two cases of disseminated adenovirus infection that presented with nodular shadows on chest X-ray after allogeneic bone marrow transplantation from unrelated donors. Both patients died of respiratory failure. Autopsies revealed adenovirus infection of multiple organs. Adenovirus infection should be suspected when nodular lung lesions of unknown origin appear in allogeneic stem cell transplant recipients.

Detection of minimal residual disease in patients with multiple myeloma using clonotype-specific PCR primers designed from DNA extracted from archival bone marrow slides.

Polymerase chain reaction (PCR)-negative molecular complete remission (mCR) can be induced by stem cell transplantation in some patients with multiple myeloma (MM) and is associated with long-term progression-free survival (PFS). The detection of molecular minimal residual disease (MRD), however, requires fresh or frozen materials for designing clone-specific primers, which are not always readily available. In this study, we used DNA extracted from archival bone marrow (BM) slides for PCR to detect MRD in 50 patients with MM who received various induction therapies and autologous peripheral blood stem cell transplantation (ASCT). Clonotype-specific immunoglobulin (Ig) H PCR primers were prepared for 32 of 50 cases (64%) using BM slides, and for 9 of 14 cases (64%) using fresh BM cells. DNA in peripheral blood stem cell autografts of the 22 patients who achieved at least a partial response after ASCT was subjected to PCR to amplify clonotype-specific rearranged IgH gene sequences. The median PFS of the eight patients with MRD-positive autografts was 18 months, whereas that of 14 patients with MRD-negative autografts was not reached at a median follow-up of 27 months (p = 0.012). Post-ASCT PFS of the four patients who achieved mCR was 100% at a median follow-up of 47 months. These results indicate that archival BM slides can serve as a source of DNA for preparing clonotype-specific primers for MRD monitoring in patients with MM whose cryopreserved myeloma cells are not available for DNA preparation. Our results also suggest that patients with MM who received MRD-negative autografts and achieved mCR have a long PFS.

Late response to low-dose imatinib in patients with chronic phase chronic myeloid leukemia.

Imatinib was the first BCR-ABL tyrosine kinase inhibitor to become clinically available. In this study, we retrospectively evaluated the long-term efficacy of low-dose imatinib (final maintenance dose <300 mg per day) due to intolerance, in comparison to optimal-dose imatinib (≥300 mg per day) in patients with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase. The Kaplan-Meier estimates of the median time to complete cytogenetic response, major molecular response, and complete molecular response were longer for 31 patients receiving low-dose imatinib (360, 1360, and 1420 days, respectively) than 74 patients receiving optimal-dose imatinib (170, 420, and 720 days, respectively). However, the differences in response shrank over time and progression-free survival were comparable between the two groups. These findings suggest that long-term treatment with low-dose imatinib is an acceptable alternative for patients with intolerance to the optimal dose.

An Epstein-Barr virus-associated leukemic lymphoma in a patient treated with rabbit antithymocyte globulin and cyclosporine for hepatitis-associated aplastic anemia.

Lymphoproliferative disorders (LPDs) are generally caused by uncontrolled B-cell proliferation induced by the Epstein-Barr virus (EBV) in the setting of impaired EBV-specific T-cell immunity, particularly when there is pharmacological immunosuppression including antithymocyte globulin. We herein present an unusual case of EBV associated with LPD (EBV-LPD) in which LPD occurred 3 weeks after the use of rabbit antithymocyte globulin administered for severe hepatitis-associated aplastic anemia; the patient died of fulminant leukemic lymphoma 5 days after the onset. We also review the pertinent literature on EBV-LPD after immunosuppressive therapy and document the efficacy of EBV viral load monitoring and the need for preemptive therapy.

Mycophenolic acid inhibits natural killer cell proliferation and cytotoxic function: a possible disadvantage of including mycophenolate mofetil in the graft-versus-host disease prophylaxis regimen.

To determine how immunosuppressant agents used for graft-versus-host disease (GVHD) prophylaxis affect natural killer (NK) cells, we examined the effects of cyclosporine (CSP), tacrolimus (TAC), mycophenolic acid (MPA, an active form of mycophenolate mofetil), and methotrexate (MTX) on the proliferation and cytotoxicity of NK cells. The proliferation of NK cells from healthy individuals in the presence of interleukin (IL)-2 and IL-15 was suppressed to 51% ± 16% of that of the controls with CSP, to 31% ± 19% with TAC, to 14% ± 6% with MPA, and to 87% ± 18% with MTX. Both CSP and TAC increased the proportion of CD16(-)CD56(bright) cells, a NK cell subset capable of secreting high amount of cytokines, and also enhanced NKp30 expression, whereas MPA markedly decreased the proportion of CD16(-)CD56(bright) cells and reduced the expression of all activating NK cell receptors, including NKG2D, NKp30, NKp44, and NKp46. MPA also reduced the cytotoxicity against K562 cells from 61% ± 15% to 17% ± 7% and that against Daudi cells from 44% ± 4% to 4% ± 4%, whereas the other 3 drugs did not diminish these cytotoxicities. The inhibition of NK cell proliferation and cytotoxicity against leukemic cell lines by MPA was partially abolished by the inclusion of guanosine in the culture. Similar to the effect of MPA on T cells, MPA inhibited the down-regulation of p27 on NK cells induced by the incubation of NK cells in the presence of IL-2. These results suggest that MPA is a potent inhibitor of NK cells, and that its inclusion in the GVHD prophylaxis regimen might diminish the graft-versus-leukemia effect of NK cells.

Hydroxyurea upregulates NKG2D ligand expression in myeloid leukemia cells synergistically with valproic acid and potentially enhances susceptibility of leukemic cells to natural killer cell-mediated cytolysis.

Valproic acid (VPA), a histone deacetylase inhibitor, upregulates NKG2D ligands (NKG2DLs) on some monocytic and lymphoid leukemic cells. However, its effect on myeloid leukemia cells and synergistic agents that can augment the effect of VPA remains unknown. Of the various myeloid cell lines examined, OUN-1, a chronic myelogenous leukemia cell line, showed the most prominent upregulation of MICA/B and ULBP2 in response to VPA. The NKG2DL upregulation was observed only in leukemic cells without apoptosis and the effect was abrogated by pretreatment of cells with caffeine, an inhibitor of ATM/ATR. Several activators of ATM/ATR were screened for their effect on NKG2DL expression, but only hydroxyurea (HU) efficiently upregulated both MICA/B and ULPB2 expression on the cell line. VPA and HU synergistically upregulated the NKG2DLs on OUN-1 cells as well as primary leukemic cells from some patients with acute myeloid leukemia. The upregulation of NKG2DLs by VPA and/or HU was associated with increased transcription of each NKG2DL gene. OUN-1 cells treated with VPA + HU were more susceptible to killing by natural killer (NK) cells than untreated cells and the enhanced cytotoxicity of NK cells was blocked by the treatment of NK cells with anti-NKG2D monoclonal antibodies. The same concentrations of VPA and HU did not affect the cytotoxicity of NK cells against OUN-1 cells. These data suggest that VPA and HU might enhance the NK cell-mediated antileukemia effect by increasing the susceptibility of myeloid leukemic cells to NK cells.

CD16+ CD56- NK cells in the peripheral blood of cord blood transplant recipients: a unique subset of NK cells possibly associated with graft-versus-leukemia effect.

A marked increase in CD16+ CD56- NK cells in the peripheral blood (PB) was observed in a cord blood transplant (CBT) recipient with refractory acute myeloid leukaemia (AML) in association with attaining molecular remission. CD16+ CD56- NK cells isolated from the patient became CD16+CD56+NKG2D+ when they were cultured in the presence of IL-2. Although cultured CD16+CD56- NK cells retained the killer-cell immunoglobulin receptor (KIR)-ligand (KIR-L) specificity and the patient's leukemic cells expressed corresponding KIR ligands, they killed patient's leukemic cells expressing ULBP2. The cytotoxicity by cultured CD16+CD56- NK cells was abrogated by anti-ULBP2 antibodies. When leukemic cells obtained at relapse after CBT were examined, both the ULBP2 expression and susceptibility to the cultured NK cells decreased in comparison to leukemic cells obtained before CBT. An increase in the CD16+CD56- NK cell count (0.5 x 10(9)/L or more) in PB was observed in seven of 11 (64%) CBT recipients but in none of 13 bone marrow (BM) and eight peripheral blood stem cell (PBSC) transplant recipients examined during the similar period after transplantation. These findings suggest an increase in CD16+CD56- NK cells to be a phenomenon unique to CBT recipients and that mature NK cells derived from this NK cell subset may contribute to the killing of leukemic cells expressing NKG2D ligands in vivo.