Pharmacokinetics for once-daily modified release formulation of tacrolimus hydrate in unrelated hematopoietic stem cell transplantation.

A once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed in response to the problem of nonadherence. However, there have been no data available about the efficacy of Tac QD conversion from intravenous Tac (Tac i.v.) in allogeneic hematopoietic stem cell transplantation (allo-SCT). We analyzed the pharmacokinetics (PK) of Tac QD in allo-SCT recipients. A total of 10 patients with hematological malignancies who received allo-SCT from unrelated donors were enrolled. Patients received Tac i.v. at 0.03 mg/kg a day before transplantation. Administration of Tac i.v. was converted to Tac QD at a 1:4 ratio when the patients had recovered from regimen-related gastrointestinal toxicity and could tolerate oral medication. After conversion, six out of 10 patients (60 %) showed a sustained decrease in Tac exposure and required dose adjustment. The conversion from Tac i.v. to Tac QD should be performed under close medical supervision. Area under the curve (AUC) and the trough of Tac QD showed a correlation, and the trough should be maintained above 7.5 ng/ml to provide an adequate AUC. Although four patients received bone marrow from an HLA DRB1 1 antigen-mismatched unrelated donor, no patients developed grade III-IV acute graft-versus-host disease (GVHD). The modification of Tac QD to maintain a whole-blood trough concentration above 7.5 ng/ml may be as effective as Tac BID.

Administration schedule of daunorubicin for elderly patients with acute myelogenous leukemia: a single-institute experience.

We evaluated the efficacy of daunorubicin  (40 mg/m(2)/day for 5 days, 200 mg/m(2)/cycle) combined with standard dose of cytarabine (100 mg/m(2)/day for 7 days) for acute myelogenous leukemia patients aged 65-74 years as induction therapy. Complete remission (81.3%) was achieved in 13 of 16 patients following the therapeutic program. The median duration of recovering absolute neutolophilic counts over 1000/µl and platelet counts over 100 000/µl were 33 days and 27 days, respectively. None of the patients had any adverse cardiac complications or died during administration of the induction therapy. Patients achieving complete remission received post-remission therapy consisting of two regimens other than induction therapy. The 3-year disease-free and overall survival rates were 36.9 and 50.0%, respectively. Extending the total period of the daunorubicin therapy might be an alternative to increasing the daily dose of daunorubicin in the induction therapy for elderly patients who were candidates for receiving intensified chemotherapy.

Fractionated administration of gemtuzumab ozogamicin for refractory acute myeloid leukemia.

It is difficult to decide an appropriate treatment strategy for elderly leukemia patients with other complications. We encountered 2 cases of refractory acute myeloid leukemia and safely treated the patients with fractionated administration of gemtuzumab ozogamicin (GO). Standard induction therapies were not effective for these patients. Moreover, they suffered from complications due to which their treatment options were restricted. Fractionated administration of GO (GO 3 mg/m(2) on days 1, 3 and 5) was accomplished safely and alleviated the patients' conditions. After treatment, these patients were followed by outpatient basis. We consider that this is an impressive treatment because fractionated administration of GO is potentially less toxic. Further, it will be helpful to maintain or improve the QOL of patients who are unable to receive intensive chemotherapy. These cases were significant because fractionated GO treatment is potentially less toxic and it will be helpful to maintain or improve the QOL of patients who can not receive intensive chemotherapy.

Clinical significance of cancer-related fatigue in multiple myeloma patients.

Cancer-related fatigue (CRF) is one of the adverse events in multiple myeloma (MM) patients treated with cytotoxic agents, proteasome inhibitors (PIs), and immunomodulatory drugs (IMiDs) such as bortezomib, lenalidomide, and thalidomide. The aims of our study were to prospectively analyze the clinical significance of CRF, and to evaluate the cumulative incidence of CRF and the survival rates of 16 MM patients who were treated with PIs and IMiDs. Reactivation of salivary human herpes virus (HHV)-6 and HHV-7 was analyzed using real-time quantitative polymerase chain reaction (qPCR). CRF was evaluated using a visual analog scale (VAS). Eleven newly diagnosed multiple myeloma (NDMM) and five relapsed or refractory MM patients were enrolled in this study. The cumulative incidence of CRF was 54.9%. The treatment types were not associated with the CRF incidence. The cumulative incidence of reactivation of HHV-6 and HHV-7 was 73.1% and 45.6%, respectively. However, the reactivation of HHV-6 and HHV-7 was not related to CRF. The overall survival (OS) and progression-free survival (PFS) in NDMM patients with CRF was significantly shorter than in those without CRF. In conclusion, CRF was one of the major symptoms in MM patients, and predicted shorter OS and PFS in NDMM patients.

Epstein-Barr Virus-associated Lymphoproliferative Disorder with Encephalitis Following Anti-thymocyte Globulin for Aplastic Anemia Resolved with Rituximab Therapy: A Case Report and Literature Review.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) sometimes occur following Anti-thymocyte globulin (ATG) administration for allogenic stem cell transplantation but are rare in aplastic anemia (AA) patients. A 55-year-old woman with AA following ATG developed refractory fever and was diagnosed with EBV-LPD. She was successfully treated with weekly rituximab monotherapy; however, she developed EBV encephalitis. She was admitted to the intensive care unit and finally recovered from unconsciousness. EBV-LPD should be considered after ATG for AA when symptoms appear. Because EBV-LPD following ATG for AA can rapidly progress, weekly monitoring of EBV-DNA and early intervention may be necessary.

Successful treatment of myeloma cast nephropathy using bortezomib-based chemotherapy plus selective plasma exchange.

Myeloma cast nephropathy is a major complication of multiple myeloma. Recent evidence has demonstrated that the earlier induction of bortezomib-based chemotherapy with plasma exchange (PE) provides better results for kidney function and patient survival. Due to its non-selectivity, PE with albumin replacement carries the risk of fibrinogen loss, leading to bleeding. We herein report a case of successful treatment of myeloma cast nephropathy using bortezomib-based chemotherapy and selective PE. A 61-year-old woman who had a 20-year history of type II diabetes mellitus was admitted to our hospital for the evaluation of hypercalcemia, severe kidney dysfunction, and anemia. Subsequent bone marrow evaluation and renal biopsy revealed that she had multiple myeloma (IgG-κ) and myeloma cast nephropathy. Ten days after admission, bortezomib-based chemotherapy with selective PE achieved rapid and thorough free light-chain (FLC) reduction; within a month, her kidney function had been recovered (creatinine level, 1.2 mg/dl). Her serum fibrinogen level was not reduced, and no bleeding complication occurred. Five months later, autologous hematopoietic stem-cell transplantation was performed successfully, and the patient's kidney function was stable (creatinine level, 1.1 mg/dl) thereafter. This case report demonstrates the importance of early induction therapy with bortezomib-based chemotherapy and PE in a patient with myeloma cast nephropathy, which is especially applicable in patients aged <65 years. In addition, it shows that selective PE is a safe and effective method of FLC removal.

Clinical significance of granule-containing myeloma cells in patients with newly diagnosed multiple myeloma.

The clinical features and prognostic significance of myeloma cells containing granules remain unclear. The purpose of this retrospective study was to investigate the clinical significance of granule-containing myeloma cells in patients with newly diagnosed multiple myeloma (NDMM). We retrospectively analyzed the records of 122 patients diagnosed with NDMM between January 2007 and December 2013. Granule-containing myeloma cells were defined as myeloma cells that exhibited three or more granules in their cytoplasm by May-Giemsa staining. The patients were classified into two groups, the granule-containing myeloma (GM) and nongranule-containing myeloma (non-GM) groups, depending on the proportion of myeloma cells that contained granules (cut-off value: 10%). There were 25 (20.5%) patients in the GM group. Patients in the GM group displayed significantly higher CD56 and CD49e expression than those in the non-GM group (t-test, P = 0.027 and 0.042). None of the patient characteristics differed significantly between the two groups. There was no significant difference in the chemotherapy profiles of the two groups, and the overall response rates of the two groups were similar. During the median follow-up period of 33.9 months, the overall survival (OS) in the GM group was similar to that in the non-GM group; 4-year OS of the GM and non-GM groups were 78.5% and 51.9%, respectively (P = 0.126). We concluded that cases of NDMM involving granule-containing myeloma cells are not infrequent. Moreover, CD56 and CD49e expression was significantly higher in the presence of myeloma cell populations, and the presence of granules did not affect survival.

Long-term follow-up high-dose chemotherapy (drug-only program) followed by autologous stem cell transplantation for aggressive non-Hodgkin's lymphomas.

PURPOSE: To investigate the feasibility of high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) for aggressive non-Hodgkin's lymphoma (NHL), we conducted HDCT with ASCT using a drug-only protocol without total body irradiation. Previously untreated and treated adult patients with aggressive lymphoma were enrolled onto this study. For the HDCT protocol, we developed the AECC regimen, a drug-only regimen consisting of etoposide, carboplatin, cyclophosphamide, and nimustine (ie, ACNU). Mobilized peripheral blood stem cells were used mainly as a source for ASCT and were used based on collection rates of CD34 cells. PATIENTS AND METHODS: Fifty-six patients were enrolled and assessed for this study. The median length of follow-up was 6.5 years, with a range of 0.2-12.5 years. Retrospective immunophenotypic examination indicated that the majority of the patients were diagnosed with B-cell lymphoma. RESULTS: Before HDCT, 37 patients still had disease (26 partial responses [PRs] and 11 cases of no response), and 19 patients exhibited a complete response (CR) before HDCT with ASCT. Among 56 patients, 37 (66%) exhibited a CR, including patients continuing their first CR and those experiencing a second or further CR, and 11 patients (19.6%) exhibited PR on HDCT with ASCT. Outcomes of patients without CR were significantly poorer than those of the patients with CR, and 7-year overall survival rates of patients with and without CR were 63% and 27.2%, respectively. No patients developed a second malignancy, including leukemia or myelodysplastic syndrome. CONCLUSIONS: High-dose chemotherapy followed by ASCT is one of the available consolidation therapies for aggressive NHL, and additional involved-field irradiation could play a role in the management of patients with NHL who do not exhibit a CR after treatment with HDCT containing a drug-only program.

Toxicity and outcome of intensive chemotherapy for acute lymphoblastic leukemia complicated with Turner's syndrome.

A 17-year-old woman was diagnosed as acute lymphoblastic leukemia (ALL). As she had chromosomal abnormalities of 44, XO, der(9)t(3;9)(q11;p13), der(10;19)(q10;p10), del(15)(q15), -16, -19, +22 with the presence of ovarian dysplasia and abnormal physical features, a diagnosis of Turner's syndrome was made. She received an induction chemotherapy, which consisted of daunorubicin, cyclophosphamide, vincristine, L-asparaginase and prednisolone. Although, severe liver dysfunction was observed, the patient achieved a complete remission (CR) on day 31 following chemotherapy and has maintained CR for more than five years. The recording of such cases may well be of value to clarify toxicity and outcome after chemotherapy for patients with ALL complicated with Turner's syndrome.

Intensified daunorubicin in induction therapy and autologous peripheral blood stem cell transplantation in postremission therapy (Double-7 protocol) for adult acute myeloid leukemia.

To investigate whether an intensified dose of daunorubicin (DNR) in induction therapy and autologous peripheral blood stem cell transplantation (PBSCT) in the postremission period are effective treatments, we used a Double-7 protocol to treat adult patients with de novo acute myeloid leukemia (excluding M0 and M3). Induction therapy consisted of 40 mg/m2 of DNR intravenous drip infusion for 7 days and 200 mg/m2 of ara-C by continuous infusion for 7 days (7 + 7 DC regimen). Patients who achieved complete remission (CR) were given high-dose chemotherapy with autologous PBSCT in postremission therapy. Of the 22 assessable patients, 16 attained CR (73%). Disease-free survival (DFS) and overall survival (OS) at 3 years were 61.2% and 48.1%, respectively. Nine of the CR patients underwent PBSCT without therapy-related mortality. Patients in a favorable cytogenetic group (n = 7) attained 100% CR and long-term survival (71.4% DFS and 85.7% OS at 3 years). Thus, intensified DNR administration of 280 mg/m2 (40 mg/m2 per day for 7 days) in induction therapy for adult patients younger than 60 years of age might be optimal or at least comparable with the new anthracyclines such as idarubicin. In addition, autologous PBSCT in postremission therapy might improve DFS and OS, at least for patients in a favorable cytogenetic group, such as those with a t(8;21) abnormality.

Successful combination therapy with trastuzumab and Paclitaxel for adriamycin- and docetaxel-resistant inflammatory breast cancer.

We present a case of adriamycin-and docetaxel-resistant inflammatory breast cancer (IBC) in which partial response was achieved with combination therapy using trastuzumab and paclitaxel. A 48-year old woman noticed a lump in her right breast. She was diagnosed with IBC and the disease was staged as T4d N1 M0, stage III B. The patient was started on neoadjuvant chemotherapy with adriamycin (50 mg/m2) and docetaxel (60 mg/m2) administered every three weeks. Six courses were performed and the response was evaluated as no change. After one month, contralateral breast swelling indicated bilateral IBC. Bilatera1 mastectomy using the Halsted method was performed. The immunohistochemical results of the Hercep Test was strongly positive (3+). After the mastectomy, right pleural effusion appeared, and cytological examination revealed the cells to be classV(adenocarcinoma). To treat the clinically advanced breast cancer, combination therapy with trastuzumab (initially 4 mg/kg followed by two or more cycles of 2 mg/kg) and paclitaxel (80 mg/m2) were given intravenously every week for eight cycles and then every two weeks thereafter. A total of 32 courses of therapy were performed, the pleural effusion completely disappeared and partial response was maintained for a duration of 482 days. The adverse reactions were mild, and it was possible for her to be treated as an outpatient with high quality of life. This report suggests that weekly combination therapy of trastuzumab and paclitaxel was useful for treatment of adriamycin-and docetaxel-resistant metastatic breast cancer.

[Successful induction of complete cytogenetic response with high-dose imatinib mesylate and subsequent allogeneic stem cell transplantation for CML blastic crisis].

A 29-year-old man was referred to our hospital with leukocytosis on March 7th, 2002. The white blood cell count was 132.9 x 10(3)/microliter with 42.0% blast cells. We diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in a blast crisis and started imatinib mesylate therapy at a dose of 800 mg/day on March 9th, 2002. The patient's peripheral blood blasts had disappeared by March 22nd, 2002, and the percentage of blasts in the bone marrow was 0.6% on May 2nd, 2002. The patient achieved a complete cytogenetic response on May 13th, 2002, and underwent allogeneic peripheral blood stem cell transplantation from his HLA-identical sibling donor on May 30th, 2002. Although adverse reactions such as grade 3/4 of hematological events (leukopenia, anemia, thrombocytopenia and neutropenia) and grade 1/2 of non-hematological events (hyperbilirubinemia, dermatitis and edema) were observed, these adverse reactions were clinically managed. This case suggested the usefulness of imatinib mesylate in the management of the CML-associated blast crisis.

Antigen-independent IFN-γ production by human naïve CD4 T cells activated by IL-12 plus IL-18.

The role of T cells in innate immunity is not well defined. In this report, we show that a subset of human peripheral blood CD4(+) T cells responds to IL-12 plus IL-18, but not to IL-12 or IL-18 alone, by producing IFN-γ in the absence of any antigenic stimulation or cell proliferation. Intracellular staining reveals a small percentage of resting CD4(+) T cells (0.5 to 1.5%) capable of producing IFN-γ in response to IL-12 plus IL-18. Interestingly, both naïve (CD45RA(+)) and memory (CD45RO(+)) CD4(+) populations were responsive to IL-12 plus IL-18 stimulation in producing IFN-γ. The expression of IFN-γinduced by IL-12 and IL-18 is sensitive to rapamycin and SB203580, indicating the possible involvement of mTOR and p38 MAP kinase, respectively, in this synergistic pathway. While p38MAP kinase is involved in transcription, mTOR is involved in message stabilization. We have also shown that NFκB family member, cRel, but not GADD45ß and GADD45γ, plays an important role in IL-12 plus IL-18-induced IFN-γ transcription. Thus, the present study suggests that naïve CD4(+) T cells may participate in innate immunity or amplify adaptive immune responses through cytokine-induced antigen-independent cytokine production.

Rapid progression and unusual premortal diagnosis of mucormycosis in patients with hematologic malignancies: analysis of eight patients.

Mucormycosis is a rare but emerging group of life-threatening opportunistic mycoses. We described experience of eight patients who developed mucormycosis. These patients had developed hematologic malignancies, and none achieved complete remission. Six of the eight patients presented with neutropenia, five received corticosteroid, and four had concomitant hyperglycemia. The most frequent physical finding was fever, and five patients complained of facial pain, headache, or chest pain. Four patients presented with concomitant bacterial infection, pulmonary aspergillosis, or intestinal candidiasis. Premortal diagnosis of mucormycosis was made in only one patient. Postmortem biopsy or autopsy was the diagnostic tool for the other patients. Although patients who were treated with amphotericin B survived longer than those treated with micafungin or voriconazole, all patients died due to the progression of mucormycosis. Estimated median survival was 23 days. Premortal diagnosis was rarely achieved as biopsy of infected tissues was the only diagnostic tool, and four patients who revealed dual infection were diagnosed with aspergillosis or bacterial infections. In patients with a high risk of mucormycosis presenting with pain and uncontrollable fever, mucormycosis should be included in the differential diagnosis. High dosages of liposomal amphotericin B should be given and surgical debridement should be performed promptly in cases highly suggestive of mucormycosis.

Irinotecan hydrochloride for the treatment of recurrent and refractory non-Hodgkin lymphoma: a single institution experience.

BACKGROUND: Irinotecan hydrochloride (CPT-11) has a broad range of antitumor activity and has demonstrated little cross-resistance with doxorubicin or vincristine. In the current study, the authors investigated the efficacy and adverse effects of irinotecan in the treatment of recurrent and refractory non-Hodgkin lymphoma, for which current therapies appear to be unsatisfactory. METHODS: Irinotecan was administered by intravenous infusion at a dose of 40 mg/m(2)/day for 3 days, and this regimen was repeated 2-3 times at weekly intervals, followed by 2 weeks off therapy. The subjects were 48 patients with recurrent or refractory non-Hodgkin lymphoma. The histologic classification (Working Formulation) was low grade in 8 patients, intermediate grade in 36 patients, high grade in 1 patient, and other (angiocentric lymphoma, Ki-1 lymphoma, and unidentified) in 3 patients. RESULTS: Forty-five patients were determined to be evaluable. Therapy resulted in a complete disease remission in 2 patients and a partial remission in 15 patients. The response rate was 37.8%. The median duration of response was 64 days and the median time to disease progression was 77 days. The median survival time was 422 days. Major adverse reactions included myelosuppression and gastrointestinal toxicity. Leukopenia, anemia, and thrombocytopenia of Grade 3 or 4 (according to the National Cancer Institute Common Toxicity Criteria) was observed in 63.0%, 30.4%, and 6.5% of the patients, respectively, and Grade 3 or 4 diarrhea occurred in 30.4% of patients. Treatment was withdrawn because of diarrhea in three patients. Because of myelosuppression and diarrhea, approximately 67% of the patients required changes to the regimen, including dose reduction, prolongation of the interval between treatments, and reducing the number of days of consecutive treatment. CONCLUSIONS: The results of the current study suggest the activity of irinotecan as salvage therapy for patients with recurrent and refractory non-Hodgkin lymphoma. However, the optimum dosing schedule remains to be determined.

Early cytomegalovirus (CMV) gastrointestinal disease that developed 19 days after bone marrow transplantation, with a high-level of CMV antigenemia, of up to 1120 cells/slide.

We report a 19-year-old male with acute myeloid leukemia who developed an early cytomegalovirus gastrointestinal disease with a high level of cytomegalovirus antigenemia after bone marrow transplantation. He underwent bone marrow transplantation from HLA-matched related donor. He developed acute graft-versus-host disease on day 15, and he immediately went on prednisolone. The graft-versus-host disease disappeared immediately, but he developed a severe epigastralgia on day 23. Although absolute neutrophil count was 0.5 x 10(9)/l, the pp65 cytomegalovirus antigenemia increased up to 1120 cells/slide. The endoscope examination was performed on day 29 and it showed erosive gastritis, and microscopical examination revealed nuclear inclusion bodies and positive cells of cytomegalovirus antigen. Ganciclovir treatment was started, and it continued until negative cytomegalovirus antigenemia was confirmed. He consequently discharged to outpatient without late phase CMV diseases or recurrence of AML. We assessed that the patient had two risk factors. First, he was the cytomegalovirus seropositive patient and received bone marrow from seronegative donor. Second, he was treated with prednisolone for acute graft-versus-host disease. The ganciclovir treatment turned out to be successful, but the cytomegalovirus disease developed too early to start the antigenemia guided preemptive treatment. The high-risk patients could develop the early cytomegalovirus disease even though under the status of myelosuppression after bone marrow transplantation.