- [Show abstract] [Hide abstract] ABSTRACT: Background Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. Methods An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. Results Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was −33.61 mg h/dL, and the 95 % confidence interval was −70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. Conclusion Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. Trial registry http:// www. clinicaltrials. jp; Identifier: JapicCTI-132398.
- [Show abstract] [Hide abstract] ABSTRACT: To evaluate the efficacy and feasibility of upfront high-dose chemotherapy (HDCT) and rituximab (R) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) in patients with newly diagnosed high-intermediate(HI)-, and high(H)-risk diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter prospective phase II trial. In 15-60-year-old patients with H- or HI-risk DLBCL, after three courses of (R-)CHOP14, high-dose etoposide was given prior to peripheral blood stem cell harvesting. After an additional three courses of (R-)CHOP14, auto-PBSCT was performed following HDCT. The primary endpoint of the study is progression-free survival (PFS) at 2 years after registration in eligible patients. The expected PFS and the threshold PFS were estimated to be 70 and 50 %, respectively. Among 40 eligible patients registered, 30 patients completed treatment. With a median observation period in surviving eligible patients of 63 months, the 2- and 4-year PFS after registration were 79.9 and 72.0 %, respectively. The 2- and 4-year overall survival (OS) were 92.5 and 84.6 %, respectively. In 30 patients who completed treatment, the 4-year PFS and OS after auto-PBSCT were 79.2 and 85.9 %, respectively. In conclusion, the results of our study suggest that upfront HDCT and auto-PBSCT combined with rituximab is highly effective as an initial treatment for HI-, and H-risk DLBCL.
- [Show abstract] [Hide abstract] ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-SCT) using posttransplant cyclophosphamide (PTCy) has been increasingly performed. We conducted a multicenter phase II study to evaluate the safety and efficacy of PTCy-based HLA-haploidentical peripheral blood stem cell transplantation (PTCy-haploPBSCT) following busulfan (BU)-containing reduced-intensity conditioning. Thirty-one patients were enrolled; 61% patients were not in remission and 42% patients had a history of prior allo-SCT. Neutrophil engraftment was achieved in 87% patients with a median of 19 days. The cumulative incidence of grades II-IV, III-IV acute graft-versus-host disease (GVHD), and chronic GVHD at 1 year were 23%, 3%, 15%, respectively. No patients developed severe chronic GVHD. Day 100 non-relapse mortality (NRM) were 19.4%. Overall survival (OS), relapse, disease free survival were 45%, 45%, 34%, respectively, at 1 year. Subgroup analysis showed that patients who had a history of piror allo-SCT had lower engraftment, higher NRM, and lower OS than those not receiving a prior allo-SCT. Our results suggest that PTCy-haploPBSCT after BU containing reduced-intensity conditioning achieved low incidence of acute and chronic GVHD and NRM, and stable donor engraftment and low NRM particularly in patients without a history of prior allo-SCT. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: AimsTo analyse the clinicopathological characteristics and prognosis of 40 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B-cell lymphoproliferative disorders (MTX-BLPD).Materials and resultsSoluble interleukin 2 receptor titres (median 1500 U/ml) in 40 patients with MTX-BLPD were lower than those of 24 RA patients with non-MTX- associated (non-MTX) BLPD (5731 U/ml) and 15 with control diffuse large B-cell lymphoma (DLBCL, 5918 U/ml) (P<0.01). By in situ hybridisation, Epstein-Barr virus (EBV) was detected in tumour cells of 25 in 40 RA patients with MTX-BLPD (63%). Immunohistologically, BCL2 expression was detected in 35% of patients with MTX-BLPD, which was lower than 93% of control DLBCL patients (P<0.01). Eleven patients with EBV-positive MTX-BLPD (44%) showed remission after MTX withdrawal. In RA patients with clinical stage III/IV BLPD, 15 with rituximab (R)-plus cytotoxic therapies pursued better prognosis than 10 with R-minus cytotoxic therapies (P<0.05). Among the 15 patients, seven with MTX-BLPD showed better overall survival than nine control DLBCL patients (P<0.01).Conclusions In RA patients with MTX-BLPD, immunosuppression by MTX, EBV infection and low BCL2 expression in tumour cells may play roles in tumourigenesis and tumour regression. R-plus cytotoxic therapies as well as MTX withdrawal were highly effective in these patients.
- [Show abstract] [Hide abstract] ABSTRACT: We retrospectively analyzed in 54 consecutively enrolled Japanese patients with rheumatoid arthritis (RA) and lymphoproliferative disease (LPD) relevant clinicopathological characteristics, in particular paying attention to treatment with methotrexate (MTX). Between the 28 patients treated with MTX (MTX-treated group) and the 26 who were not (non-MTX group), there was no difference in age, interval between onset of RA and LPD, and lymphoma stage. Immunohistochemical analysis showed that in the MTX-treated group, 15 (53 %) patients had mature B-cell LPD, eight (29 %) mature T/NK-cell LPD, and five (18 %) had Hodgkin lymphoma. In the non-MTX group, 22 (84 %) had mature B-cell LPD, 2 (8 %) had mature T/NK-cell LPD, and 2 (8 %) had Hodgkin lymphoma. The frequency of mature T/NK-cell LPD was significantly higher in the MTX-treated group (p < 0.05). Of the eight patients in the MTX-treated group with mature T/NK-cell LPD, two had large granular lymphocytic leukemia and the other six had a variety of different histological types with frequent CD8 but not CD56 expression. Epstein-Barr virus (EBV) infection was significantly higher in the MTX-treated group (p < 0.05); evidence of latent type II EBV infection was found in four of the eight patients with mature T/NK-cell LPD. Withdrawal of MTX led to complete remission in seven patients with mature T/NK-cell LPD irrespective of EBV infection. Our findings highlight that mature T/NK-cell LPD is a frequent complication in RA patients treated with MTX. EBV infection may play a role in the pathogenesis of T/NK-cell LPD, as well as B-cell LPD and Hodgkin lymphoma in MTX-treated RA patients.
- [Show abstract] [Hide abstract] ABSTRACT: A high dose of melphalan followed by autologous stem cell transplantation (ASCT) is considered as the standard therapy for multiple myeloma. For induction therapy, 78 patients received conventional regimens (control group) and 32 patients received bortezomib-containing regimens (bortezomib group). We retrospectively compared the yield of harvested CD34+ cells between the two groups. In order to mobilize CD34+ cells, 83% of the control group and 63% of the bortezomib group received a high dose of cyclophosphamide followed by G-CSF, and 12% of the control group received a high dose of etoposide instead of cyclophosphamide. Furthermore, 5% of the control group and 38% of the bortezomib group received G-CSF alone for CD34+ cell mobilization. Overall, the yield of CD34+ cells was higher in the control group than in the bortezomib group (7.4 vs. 5.2×10(6)/kg, P=0.004). Regarding the patients mobilized by a high dose of cyclophosphamide followed by G-CSF, the rate of achieving CD34+ cells >2.0×10(6) cells/kg was similar. Bortezomib did not significantly affect the successful collection of at least CD34+ cells > 2.0×10(6) cells/kg after mobilization with a high dose of cyclophosphamide followed by G-CSF.
- [Show abstract] [Hide abstract] ABSTRACT: Background Allogeneic hematopoietic stem cell transplantation (HSCT) for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is much more intensive than multi-agent combined chemotherapy, although allogeneic HSCT is associated with increased morbidity and mortality when compared with such chemotherapy. Minimal residual disease (MRD) status has been proven to be a strong prognostic factor for adult patients with Ph-negative ALL. Methods We investigated whether MRD status in adult patients with ALL is useful to decide clinical indications for allogeneic HSCT. We prospectively monitored MRD after induction and consolidation therapy in adult patients with Ph-negative ALL. Results Of 110 adult ALL patients enrolled between July 2002 and August 2008, 101 were eligible, including 59 Ph-negative patients. MRD status was assessed in 43 patients by the detection of major rearrangements in TCR and Ig and the presence of chimeric mRNA. Thirty-nine patients achieved CR1, and their probabilities of 3-year overall survival and disease-free survival (DFS) were 74% and 56%, respectively. Patients who were MRD-negative after induction therapy (n = 26) had a significantly better 3-year DFS compared with those who were MRD-positive (n = 13; 69% vs. 31%, p = 0.004). All of 3 patients who were MRD-positive following consolidation chemotherapy and did not undergo allogeneic HSCT, relapsed and died within 3 years after CR. Conclusions These results indicate that MRD monitoring is useful for determining the clinical indications for allogeneic HSCT in the treatment of ALL in CR1.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: The feasibility and efficacy of high-dose melphalan (HD-MEL) followed by autologous hematopoietic stem cell transplantation (auto-SCT) in elderly patients with multiple myeloma (MM) are discussed. Methods: We retrospectively analyzed and compared the results of 25 elderly patients (aged 65-76 years, elderly group) and 63 control patients (aged 51-64 years, control group). Many patients received a vincristine and doxorubicin combined with dexamethasone (VAD) regimen (elderly group: 92%, control group: 78%) with autologous peripheral blood stem cells being harvested after the administration of chemotherapy with high-dose cyclophosphamide (elderly group: 72%, control group: 87%). Ten elderly patients received MEL at a dose of 100-120 mg/m(2), while 15 patients received MEL at a dose of 180-200 mg/m(2). Results: Treatment-related deaths occurred in one elderly patient and two younger patients due to infections. The rate of achieving complete response (CR) or very good partial response (VGPR) was 60% in the elderly group and 83% in the control group. Progression-free survival from auto-SCT in the elderly group was similar to that observed in the control group (median 17.1 vs. 20.8 months, p=0.26), with the median overall survival (OS) from auto-SCT being 40.8 months in the former and 72.5 months in the latter group (p=0.07). When calculated from the beginning of induction treatment, the median OS of the elderly group was 47.0 months and the 3-year OS rate was 81%. Conclusion: The current study provides evidence for the efficacy of auto-SCT in elderly MM patients. A prospective study of auto-SCT in elderly patients using strict eligibility criteria is required to evaluate the prolongation of survival in the era of novel agents.
- [Show abstract] [Hide abstract] ABSTRACT: A 76-year-old man suffered from swelling stoma for several weeks. A biopsy sample revealed the diffuse infiltration of large lymphoid cells which were positive for CD20, bcl-6, and MUM1. The patient was diagnosed with diffuse large B-cell lymphoma, with a non-germinal center B-cell pattern. A whole-body PET-CT scan revealed that the lymphoma was restricted to the stomal site. Bladder reconstruction was undertaken using the ileal conduit: this is the first reported case of lymphoma that developed primarily at the stoma. During the long-term maintenance after bladder reconstruction, clinicians should consider the possibility of lymphoma at the stomal site.
- [Show abstract] [Hide abstract] ABSTRACT: A 67-year-old man developed a diffuse large B-cell lymphoma, and was simultaneously diagnosed as myelodysplastic syndrome(refractory cytopenia with multilineage dysplasia). Acute lung injury was complicated after the 6th course of rituximab injection, but was recovered by steroid pulse therapy. At that moment, marked leucocytosis was prominent due to the disease progression of myelodysplastic syndrome. Two months later, he relapsed into lymphoma systematically. During salvage chemotherapy without rituximab, the patient deteriorated into lethal respiratory failure. Autopsy findings revealed the diffuse alveolar damage with microscopic evidence of an adenovirus infection. His bone marrow showed the transformation of myelodysplastic syndrome into acute myeloid leukemia. The coincidence of myeloproliferative and lymphoproliferative diseases in the same patient is a rare phenomenon. We should be cautious when acute lung injury occurs during such a condition.
- [Show abstract] [Hide abstract] ABSTRACT: There is evidence of a slight increase in malignant lymphoma among rheumatoid arthritis(RA)patients receiving methotrexate( MTX). Increased rates of lymphoma have been attributed to reactivation of the Epstein-Barr virus(EBV). A 72-yearold woman was admitted to our hospital for generalized lymph adenopathy. She suffered from RA and has been treated with MTX for 7 years; the total amount of MTX received was around 2, 700 mg. The cervical lymph node revealed a diffuse proliferation of large atypical lymphocytes. An immunophenotype revealed CD10+, CD19+, CD20+, and k+. The chromosome analysis showed a complex abnormality containing t(14;18)(q32;q21). The tumor cells were positive for EBV sequences by in situ hybridization(ISH). A rituximab containing regimen was effective, but a systemic relapse occurred 4 years later. The biopsied sample was diagnosed as diffuse large B-cell lymphoma. FISH analysis revealed positive for t(14;18)(q32;q21), however, EBV was negative using ISH. In general, the concurrence of t(14;18)(q32;q21)and EBV in the B-cell lymphoma is rare. In addition, the negative change in EBV in the relapsed lymphoma cells revealed a quite rare phenomenon.
- [Show abstract] [Hide abstract] ABSTRACT: We retrospectively analyzed the outcomes of 26 patients with acute promyelocytic leukemia (APL) in the first CR (CR1) or second CR (CR2), who underwent autologous PBSCT (auto-PBSCT) between 1992 and 2008. All patients received all-trans retinoic acid-based induction therapy. After two courses of consolidation chemotherapy, upfront auto-PBSCT was performed in 20 patients in the CR1. Five patients had a high WBC count of more than 10 × 10(9)/L (high risk), while 15 patients had a count of less than 10 × 10(9)/L (low risk) at initial presentation. In addition, six patients, who were considered as low-risk patients at presentation, had a relapse after three cycles of consolidation and 2 years of maintenance therapy, but gained the molecular remission after re-induction and consolidation, and underwent auto-PBSCT in the CR2. In 26 recipients, engraftment was rapid and no TRM was documented. All 20 patients autotransplanted in CR1 were still in CR at a median of 133 months (73-193 months), and six patients who underwent auto-PBSCT in CR2 were also still in CR at a median of 41 months (2-187 months) without maintenance therapy. PML/RARα chimeric mRNA was undetectable in PBSC or BM samples examined before auto-PBSCT. Despite a small number of cases studied, our retrospective observations suggest that auto-PBSCT may be an effective treatment option to continue durable CR in the treatment of high-risk APL. We review previous reports and discuss the role of autotransplantation in the treatment of APL patients in CR.
- [Show abstract] [Hide abstract] ABSTRACT: Recently, the safety and effectiveness of bortezomib for patients with multiple myeloma and renal failure has been reported. In this study, we retrospectively analyzed the 8 myeloma patients with renal failure who have received bortezomib in our hospital.One patient had already required constant hemodialysis before bortezomib.Bortezomib treatment was performed for 229 days, during which time it was injected 30 times.The other 2 patients with chronic renal failure also showed no further renal impairment due to bortezomib.In the remaining 5 patients, serum creatinine levels decreased through 2 cycles(total: 8 injection)of bortezomib treatment.Two patients were complicated with herpes zoster, and 2 patients were complicated with neuropathy in grade 3.We showed the safety and efficacy of bortezomib in Japanese patients with multiple myeloma complicated with renal failure.We should positively consider the therapeutic choice of bortezomib for the refractory myeloma with renal failure.
- [Show abstract] [Hide abstract] ABSTRACT: We report a case of a 46-year-old female demonstrating general fatigue and visual disturbances with retinal bleeding. She had a white blood cell count of 419,300/mm. Thereafter, she developed vomiting associated with vertigo caused by cerebellar hemorrhage, deteriorating to acute hydrocephalus secondary to obstruction of the cerebral aqueduct. Emergency procedures for cerebral protection, such as hyperventilation, administration of mannitol, and barbiturate coma, were performed. Bone marrow examination showed a positive BCR-ABL/t(9;22)(q34;q11) chromosomal translocation detected by FISH and RT-PCR (masked Ph) and she was diagnosed as having chronic myeloid leukemia (CML) in the chronic phase (CP). She was administered Ara-C, together with imatinib 600 mg/d through a nasogastric tube. Eight days later, she underwent successful extubation and recovered without any neurological defect. She was maintained on imatinib 400 mg/d and demonstrated a major molecular response at 15 months. Physicians need to be aware that brain hemorrhage may develop as an initial symptom of CML patients in CP.
- [Show abstract] [Hide abstract] ABSTRACT: We performed a retrospective analysis of patients with diffuse large B cell lymphoma treated with rituximab plus CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) as a first-line therapy at 22 hospitals of the Kyushu Lymphoma Study Group. During the period 1996-2005, 1,057 patients (aged 22-90 years) were analyzed. Of these, 678 were treated with CHOP, and 379 were treated with rituximab plus CHOP (R-CHOP). The complete response rate was 59.9% in the CHOP group and 67.0% in the R-CHOP group (P < 0.001). Three-year progression-free survival (PFS) and overall survival (OS) rates were significantly higher in the R-CHOP group than in the CHOP group (61.3 vs. 45.6% for PFS, P < 0.001; 68.3 vs. 54.5% for OS, P < 0.001). The International Prognostic Index was a good prognostic marker for both groups; a survival benefit of rituximab addition was found for each risk subgroup and also for both age groups (<or=60 and >60 years). Among 345 patients who received localized radiation therapy, the adding rituximab to CHOP attenuated the survival difference between CHOP and R-CHOP groups (P = 0.104), compared with no radiation group (P < 0.001). Results of this large-scale, multicenter study confirm that rituximab plus CHOP provided a greater survival benefit than CHOP alone.
- [Show abstract] [Hide abstract] ABSTRACT: A 36-year-old man with underlying systemic lupus erythematosus complicated by autoimmune hemolytic anemia underwent immunosuppressive treatment. After showing a low-grade fever for two days, his fever spiked. He was confirmed to have pandemic (H1N1) 2009 by real-time reverse transcription polymerase chain reaction (PCR). His condition deteriorated to acute respiratory distress syndrome (ARDS), and mechanical ventilation became necessary. The lowest PaO(2)/FIO(2) ratio was 77, and he was placed on extracorporeal membrane oxygenation (ECMO). Based on our observation, the emergency use of ECMO in addition to peramivir might be useful. A noteworthy point is that once ARDS deteriorates due to pandemic (H1N1) 2009, intensive supportive care should be started.
- [Show abstract] [Hide abstract] ABSTRACT: The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G1-S transition by promoting degradation of the cyclin-dependent kinase inhibitor p27(kip1) (p27). Recent evidence has indicated an oncogenic role of Skp2 in not only carcinogenesis but also lymphomagenesis. Materials and methods: Clinicopathologic features and immunohistochemical expression of Skp2 and p27 were studied retrospectively in 671 patients treated with cyclophosphamide, vincristine, doxorubicin and prednisolone (CHOP) or cyclophosphamide, vincristine, doxorubicin and prednisolone plus rituximab (R-CHOP). The median follow-up periods were 43.2 months in the CHOP group (n = 425) and 24.0 months in the R-CHOP group (n = 246). High Skp2 or low p27 expression correlated significantly with poor overall survival (OS) and progression-free survival (P < 0.001) in both treatment groups. The prognostic value of Skp2 or p27 expression was independent of the parameters included in the International Prognostic Index by multivariate analysis. Patients with high Skp2 expression in combination with low p27 expression showed the worst survival. Addition of rituximab to the CHOP regimen did not provide a beneficial outcome to patients with diffuse large B-cell lymphoma with high Skp2 expression and low p27 expression. Skp2 and p27 may be useful prognostic markers in the rituximab era.
Matsuyama Red Cross HospitalMatuyama, Ehime, Japan
Fukuoka-shi, Fukuoka-ken, Japan
- Division of Internal Medicine