Different risk factors related to adenovirus- or BK virus-associated hemorrhagic cystitis following allogeneic stem cell transplantation.

Virus-associated hemorrhagic cystitis (HC) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Although numerous studies have attempted to identify factors that predispose patients to viral HC, its causes remain controversial. We analyzed retrospectively the results of 266 allogeneic HSCTs to identify factors associated with HC. Of this group, 42 patients (15.8%) were diagnosed with viral HC, because of either adenovirus (ADV; n = 26; 9.8%) or BK virus (BKV; n = 16; 6.0%). ADV-HC was frequently associated with T cell purging, and was less common in patients with acute graft-versus-host-disease (GVHD). Conversely, BKV-HC was more frequently observed in patients with excessive immune reactions such as GVHD, preengraftment immune reaction, and hemophagocytic syndrome. These observations indicate that ADV- and BKV-HC may differ significantly in their risk factors and pathogenesis. Profound immune deficiency is more likely to be associated with ADV-HC, whereas immune hyperactivity might play a key role in BKV-HC.

JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation.

The acquired JAK2 V617F mutation is observed in the majority of patients with BCR-ABL1 negative chronic myeloproliferative neoplasms (MPN). BCR-ABL1 negative MPN displays myeloproliferation with an elevated leucocyte alkaline phosphatase (LAP) activity, a neutrophil activation marker. We tried to separate the downstream signalling of JAK2 V617F to stimulate myeloproliferation and LAP activity. NB4, a myeloid lineage cell line, was transduced with Jak2 V617F mutation or wild-type Jak2. We found that Jak2 V617F mutation, but not wild-type Jak2 enhanced LAP expression in NB4-derived neutrophils and proliferation of NB4 cells. JAK2 V617F induces constitutive phosphorylation of STAT3 and STAT5, and uses signalling targets such as Ras/MEK/ERK and PI3K/Akt pathways. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, and STAT3 or STAT5 siRNAs, JAK2 V617F was found to specifically use the STAT3 pathway to enhance LAP expression, while STAT5, Ras/MEK/ERK and PI3K/Akt, but not STAT3 pathways, were able to stimulate cell proliferation. These data strongly suggest that JAK2 V617F uses distinct signalling pathways to induce typical pathological features of MPN, such as high LAP activity and enhanced cell proliferation.

Haploidentical hematopoietic stem cell transplantation with one-day posttransplant cyclophosphamide and anti-thymocyte globulin for graft failure.

Patients with myelofibrosis usually have poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy, which has graft failure as a life-threatening complication. However, no consensus is available with regard to therapeutic options for patients with graft failure. Here we report a patient with myelofibrosis who underwent successful salvage haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with one-day posttransplant cyclophosphamide (PTCy) and low-dose anti-thymocyte globulin (ATG) for graft failure. A 39-year-old Japanese male patient with rapidly progressing primary myelofibrosis underwent cord blood transplantation (CBT). Unfortunately, both the first and second CBT resulted in primary graft failures. Therefore, emergent haplo-HSCT from a sibling donor was performed with one-day PTCy (50 mg/kg on day ＋3) after conditioning with etoposide (60 mg/m2 on days -3 and -2) and rabbit anti-human thymocyte globulin (1 mg/kg on days -2 and -1). Neutrophil engraftment was achieved on day ＋13 after haplo-HSCT, and no severe infection or regimen-related toxicity was observed. Skin stage 3, gut stage 1 total grade II acute graft-versus-host disease developed. His posttransplant course had been uneventful with cutaneous chronic graft-versus-host disease (NIH score 2) and suppressed relapse. We believe that haplo-HSCT with one-day PTCy and low-dose ATG is one of the successful therapeutic options for graft failure.

The consequences of tacrolimus blood concentrations during the four weeks following marrow transplantation from an unrelated donor: a single-center experience.

In our institute, tacrolimus was started at a dose of 0.03 mg/kg/day and adjusted to maintain a blood concentration between 10 and 20 ng/mL combined with short term methotrexate after bone marrow transplantation from an unrelated donor. Dose adjustment was performed strictly, in order to prevent grade II-IV acute graft-versus-host disease (GVHD)while avoiding renal toxicity of tacrolimus. Then, in this study, we retrospectively evaluated the tacrolimus blood concentration during the first 4 weeks after transplantation. The mean tacrolimus concentration of the eligible 52 patients was 17.41+/-4.84(range, 9.5-33.4)ng/mL in the 1st week after transplantation, but declined to 13.7+/- 4.0(range, 8.1-25.6)ng/mL in the 2nd week. The dose of tacrolimus was decreased as follows: 0.022+/-0.005 mg/ kg/day(range 0.011-0.039)in the 1st week, and 0.018+/-0.007 mg/kg/day(range 0.004-0.040)in the 2nd week. The incidence of grade II-IV GVHD was 63.0% and grade III-IV was 13.9%. The individual variations of tacrolimus blood concentration did not affect the incidence of grade II-IV acute GVHD, as far as the concentration being maintained in the range of 14.82+/-4.22 ng/mL during the first 4 weeks after transplantation. In addition, the variations of tacrolimus concentration didn?t associate statistically with renal toxicity.

Successful stem cell transplantation without cryopreservation from a microchimeric haploidentical sibling for refractory acute myeloid leukemia complicated with critical thrombophlebitis and cellulitis.

We describe the case of a 38-year-old male patient who had acute myeloid leukemia and developed prolonged neutropenia after induction chemotherapy. He developed thrombotic complications at multiple sites. Thrombophlebitis of the hemorrhoidal plexus became exacerbated and developed into critical cellulitis. Because the patient had no human leukocyte antigen-identical sibling, we considered an alternative donor. Because of the necessity for early neutrophil recovery to resolve the critical infection, we proceeded with allogeneic peripheral blood stem cell transplantation (PBSCT) from a microchimeric haploidentical sibling donor. We infused peripheral blood mononuclear cells directly into the patient without cryopreservation and thawing procedures. We aimed for the contaminating granulocytes to act as a granulocyte transfusion. Actually, the neutrophils increased to 1.6 x 10(9)/L on day 1, when the patient showed a temporary resolution of infection. Engraftment was achieved shortly after neutropenic nadir, and acute graft-versus-host disease (GVHD) has been well controlled. Although the patient experiences extensive chronic GVHD, he has been well as an outpatient with a 90% Karnofsky performance status score. The leukemia has been in complete remission for more than 1 year. These findings suggest the clinical utility of a salvage therapy with allogeneic PBSCT from a microchimeric haploidentical donor to treat refractory leukemia concurrent with life-threatening infection.

Successful treatment of adult Langerhans cell histiocytosis with intensified chemotherapy.

Langerhans cell histiocytosis (LCH) is a rare disease in adults. The treatment strategy for this condition remains controversial. Intensified systemic chemotherapy is required in pediatric patients with the multiple system form of LCH (MS-LCH) for aggressive forms of the disease. Recent clinical trials have shown that intensified chemotherapy for pediatric patients diagnosed with MS-LCH results in improved outcomes. However, whether the feasibility and efficacy of an intensified systemic chemotherapy regimen are also beneficial for adult patients with MS-LCH remains unclear. Here, we report two cases of adult MS-LCH that were successfully treated with an intensified treatment protocol as used in pediatric patients. One patient fully completed the protocol, and has since maintained a complete response (CR) for 2 years following completion of the treatment. The other patient also achieved CR after induction therapy, and is now undergoing maintenance therapy in an outpatient clinic. The cases presented in this study suggest that intensified systemic chemotherapy as used for pediatric patients with MS-LCH is well tolerated and effective for adult patients as well.

The use of oral beclomethasone dipropionate in the treatment of gastrointestinal graft-versus-host disease: the experience of the Fukuoka blood and marrow transplantation (BMT) group.

OBJECTIVE: We examined the therapeutic strategies for treating mild gastrointestinal (GI) graft-versus-host disease (GVHD) using oral beclomethasone dipropionate (BDP) in 15 Japanese patients based on the donor source. The primary objective was to determine the efficacy and toxicity of oral BDP combined with/without low-dose prednisone (PSL). METHODS: Oral BDP was administered with 1 mg/kg/d of PSL in patients undergoing bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT; n=11), and the dose of PSL was tapered off after 22 days. Oral BDP alone was administered in patients undergoing cord blood stem cell transplantation (CBSCT; n=4). The primary endpoint was the rate of treatment success on day 49, as measured according to the improvement or complete resolution of GI symptoms without additional treatment. The secondary endpoints included treatment-related toxicity according to the National Cancer Institute Common Toxicity Criteria version 3.0, the rate of treatment discontinuation due to toxicity, the rate of relapse of acute GVHD by day 100 and the incidence of bacterial, fungal or viral infection, including cytomegalovirus (CMV) antigenemia. RESULTS: Treatment success was achieved in seven of the 11 (64%) patients undergoing BMT or PBSCT and in all four patients (100%) undergoing CBSCT. Subsequent adverse events included herpes zoster infection, catheter-associated sepsis and CMV enteritis; all affected patients responded well to treatment. CONCLUSION: The use of a risk-stratified treatment strategy with oral BDP depending on the stem cell source is effective in patients with mild GI-GVHD.

Successful treatment of invasive zygomycosis based on a prompt diagnosis using molecular methods in a patient with acute myelogenous leukemia.

Zygomycosis is a lethal and invasive mold infection that is often associated with hematological malignancies. The keys for successful treatment include making a rapid diagnosis and appropriately administering antifungal agents. We herein report the early diagnosis of a case of zygomycosis in a patient with acute myeloid leukemia using a deoxyribonucleic acid sequence analysis. We successfully performed allogeneic hematopoietic stem cell transplantation with the use of high-dose liposomal amphotericin B and granulocyte transfusion.

Reduced-intensity conditioning followed by cord blood transplantation in a patient with refractory folliculotropic mycosis fungoides.

Advanced-stage mycosis fungoides (MF) has a generally poor prognosis. Allogeneic hematopoietic stem cell transplantation improves the outcome of advanced-stage MF. Recently, cord blood has been used as an alternative stem cell source; however, there are few reports of MF patients treated using cord blood transplantation. Here, we report a rare case of refractory folliculotropic MF, which was treated with reduced-intensity conditioning followed by cord blood transplantation.