Impact of Skeletal Muscle Depletion on Patients with Myelodysplastic Syndrome Treated with Azacitidine.

BACKGROUND: Azacitidine (AZA) is the standard treatment for patients with high-risk myelodysplastic syndromes (MDS). The impact of skeletal muscle depletion (SMD), which is associated with outcomes of hematological malignancies, on the clinical course of MDS patients treated with AZA was investigated. METHODS: This retrospective, observational study included 50 MDS patients treated with AZA. Muscle mass was evaluated using the skeletal muscle index (SMI), which is the area of muscle mass at the third lumbar vertebra on CT images divided by the square of the height. RESULTS: Of the enrolled patients, 39 were males, and their median age was 69.5 years. Twenty-seven (20 male and 7 female) patients showed SMD. The median survival was 13.4 months in the SMD group and 15.2 months in the non-SMD group, with no significant difference and no significant association between the response rate or severe non-hematological toxicities and the presence of SMD. By contrast, grade 3-4 anemia and thrombocytopenia were significantly more frequent in the SMD group than in the non-SMD group. SMD was associated with severe anemia and thrombocytopenia in MDS patients treated with AZA. CONCLUSION: Reduced skeletal muscle mass may predict severe hematological toxicity in MDS patients treated with AZA.

Comparison of the prognostic impact of IPI and PIT in peripheral T-cell lymphoma in real-world practice with a large elderly population.

We compared the predictive ability of the International Prognostic Index (IPI), a frequently used prognostic model for peripheral T-cell lymphoma (PTCL), with that of a type-specific prognostic model, the Prognostic Index for PTCL-U (PIT). We retrospectively analyzed 113 patients diagnosed with PTCL. The median age was 67 years (range, 16-88 years), 75 patients (66%) were male, and the most common disease type was PTCL, not otherwise specified (69%). With a median follow-up of 6.8 years (interquartile range, 2.7-9.9 years), 5-year survival rates for the four groups in IPI were 85%, 62%, 49%, and 13%, respectively. Similarly, 5-year survival rates for the four groups in PIT were 83%, 64%, 49%, and 19%, respectively. The area under the receiving operating characteristic curve for predicting mortality from PIT (0.725) was not significantly different from that from the IPI (0.685, P = 0.134). Multivariable analysis showed that performance status ≥ 2 (P < 0.0001) and extranodal lesions ≥ 2 (P = 0.029) were significantly associated with lower overall survival. The present study found no significant difference in prognostic ability between the IPI and PIT for PTCL, and both models appear useful as predictive models.

A multicenter phase II study of bendamustine, rituximab, and cytarabine (BRAC) for relapsed or refractory patients with follicular lymphoma or mantle cell lymphoma.

This phase II clinical trial aimed to evaluate the efficacy and safety of the combination therapy of bendamustine, cytarabine, and rituximab (BRAC) in patients with relapsed or refractory follicular lymphoma (FL) or mantle cell lymphoma (MCL). Thirteen patients were enrolled and received a median of 4 cycles (range 2-6) of BRAC. The complete response rate was 61.5%, and the overall response rate was 84.6%; the 2-year overall survival was 76.9%, and the 2-year progression-free survival was 69.2%. Although all patients received G-CSF prophylaxis, grade 3 or higher neutropenia was observed in all cycles, and the incidence of febrile neutropenia was 20%. Grade 4 thrombocytopenia was observed in 92.5% of all cycles, and platelet transfusion was performed in 94%. Although hematological toxicity was relatively high, BRAC therapy was effective for relapsed and refractory FL or MCL. Further studies are needed to determine the optimal dose of BRAC therapy.Trial registration The UMIN Clinical Trials Registry, UMIN000009797. Registered 17 January 2013, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000011103.

Prognostic impact of the controlling nutritional status score in patients with peripheral T-cell lymphoma.

The controlling nutritional status (CONUT) score is a simplified nutritional index calculated from serum albumin, total cholesterol, and total lymphocyte count. This study evaluated the prognostic impact of the CONUT score on overall survival (OS) in patients with peripheral T-cell lymphoma (PTCL). A multicenter, retrospective cohort study including 99 patients with PTCL was conducted. The CONUT score was significantly higher in the non-survivor group (median 5, range 0-12) than in the survivor group (median 3, range 0-11; p = 0.026). The CONUT score was an independent prognostic factor in a multivariable Cox proportional hazards model (hazard ratio 1.119, 95% confidence interval 1.021-1.227, p = 0.017). No significant effect-modification by the International Prognostic Index (IPI) was observed, and the CONUT score affected the prognosis of PTCL regardless of the IPI (P for interaction = 0.208). In conclusion, the CONUT score is an independent prognostic factor for PTCL irrespective of IPI category.

R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial.

Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracyclin with less cardiotoxicity than doxorubicin (DOX). We previously reported the efficacy and safety of R-THP-COP consisting of rituximab (R), THP, cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL) for diffuse large B cell lymphoma (DLBCL) in phase 2 studies. Here, we prospectively compared the efficacy and safety of the R-THP-COP and standard R-CHOP regimen (consisting of R, CPA, DOX, VCR, and PSL) in a noninferiority phase 3 trial. This prospective, randomized phase 3 study included patients younger than 70 years of age with previously untreated DLBCL. The regimen consisted of R (day 1), DOX, or THP (day 3), CPA (day 3), VCR (day 3), and PSL for 5 days every 3 weeks for 6 to 8 cycles. Between July 5, 2006 and June 11, 2013, 81 patients were randomly assigned to the treatment groups (R-CHOP group, 40 patients; R-THP-COP group, 41 patients). R-THP-COP was noninferior to R-CHOP, as assessed by the primary endpoint of complete response rate (85% vs 85% respectively). With a median follow-up of 75.2 months, the 5-year overall survival was 87% in the R-CHOP group and 82% in the R-THP-COP group (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.31-2.49; P = .82). The 5-year progression-free survival was 74% in the R-CHOP group and 79% in the R-THP-COP group (HR: 1.37, 95% CI: 0.56-3.55; P = .49). No grade 3 cardiac side effects were observed in either group. No serious late adverse reactions were observed in either group, with the exception of therapy-related acute myeloid leukemia in the R-THP-COP group. These data indicate that R-THP-COP is noninferior to R-CHOP with regard to clinical response, and has an acceptable safety profile. Thus, this regimen may be an alternative therapy to R-CHOP.

Expression of indoleamine 2,3-dioxygenase in leukemic cells indicates an unfavorable prognosis in acute myeloid leukemia patients with intermediate-risk cytogenetics.

The immunomodulatory effects of indoleamine 2,3-dioxygenase (IDO) are ascribed to its ability to catalyze breakdown of the essential amino acid L-tryptophan. We applied reverse transcription-polymerase chain reaction (RT-PCR) to examine IDO mRNA expression in acute myeloid leukemia (AML) blasts, and investigated its clinical significance. We enrolled 62 patients with AML between April 2005 and March 2013. Bone marrow-derived mononuclear fractions were separated and extracted mRNA was amplified by PCR. RT-PCR showed that the bone marrow of 23 patients expressed IDO mRNA but not in 39. IDO mRNA expression did not significantly differ among cytogenetic risk profiles. The 3-year overall survival rates for patients with and without IDO mRNA expression were 39% and 74%, respectively (p < 0.005). The rates for patients with intermediate-risk cytogenetics with and without IDO mRNA expression were 16% and 70%, respectively (p < 0.005). The expression of IDO mRNA was associated with a poor prognosis of AML.

A phase II study of rituximab combined with pirarubicin-cyclophosphamide, vincristine and prednisolone regimen as first-line therapy for patients with indolent B-cell lymphoma.

The anthracycline drug pirarubicin (tetrahydropyranyl-adriamycin [THP]) apparently has been reported to show fewer cardiotoxic effects than doxorubicin. We have previously described the effectiveness of the R-THP-COP regimen comprising rituximab, cyclophosphamide, pirarubicin, vincristine and prednisolone in patients with diffuse large B-cell lymphoma. We conducted a phase II study to determine the effectiveness of a regimen incorporating rituximab (R-THP-COP) for patients with previously untreated advanced-stage indolent CD20-positive B-cell lymphoma according to the Working Formulation and World Health Organization classification. Four to six courses of the regimen were administered every 3 weeks in 50 patients. The complete remission rate was 57%, while the 3-year overall survival rate was 92%. Regimen-related death was not observed. The R-THP-COP regimen appears very effective for patients with previously untreated advanced-stage indolent CD20-positive B-cell lymphoma. The present results indicate the need for randomized trials of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) and R-THP-COP among patients with CD20-positive indolent lymphoma.

Serum soluble interleukin-2 receptor (sIL-2R) level is associated with the outcome of patients with diffuse large B cell lymphoma treated with R-CHOP regimens.

Serum concentration of soluble interleukin-2 receptor (sIL-2R) predicts the clinical outcome of patients with aggressive non-Hodgkin's lymphoma treated with the cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen without rituximab. In the present study, we aim to re-assess the prognostic significance of serum sIL-2R for diffuse large B cell lymphoma (DLBCL) patients treated with CHOP plus rituximab and to assess sIL-2R with subtype of DLBCL, such as GCB type and non-GCB type. Two hundred and thirty-three patients with DLBCL were enrolled between December 2002 and March 2008. To evaluate serum levels of sIL-2R, venous blood samples were drawn from patients immediately before initiation of treatment. Serum sIL-2R was determined by sandwich enzyme-linked immunosorbent assay. The 5-year overall survival (OS) rates for patients with sIL-2R levels of ≥2,000 (110 cases) and <2,000 U/mL (123 cases) were 54.2% and 89.0% (P < 0.0001), respectively. Multivariate analysis using the proportional-hazards model revealed that serum sIL-2R (P = 0.0099) and extranodal involvement sites (P = 0.0392) were independent prognostic factors for OS and that clinical stage (P = 0.0168), performance status (P = 0.0181), sIL-2R (P = 0.0232), and LDH (P = 0.0316) were independent prognostic factors for progression-free survival in sIL-2R and every factor of the International Prognostic Index. Serum sIL-2R might be a useful prognostic factor for DLBCL patients in the rituximab era.

Phase II study of the tetrahydropyranyl adriamycin-cyclophosphamide, vincristine, and prednisolone regimen combined with rituximab as first-line treatment for elderly patients with diffuse large B-cell lymphoma.

The anthracycline drug pirarubicin (tetrahydropyranyl adriamycin; THP) apparently has fewer cardiotoxic effects than doxorubicin. We previously described the benefit of the THP-COP regimen comprising cyclophosphamide, THP, vincristine, and prednisolone for elderly patients with diffuse large B-cell lymphoma (DLBCL). However, that study was completed before rituximab (R) was introduced into clinical practice. Here we report a phase II study of the THP-COP regimen combined with R (R-THP-COP) every 3 weeks. The complete response and 3-year overall survival rates was 63% and 53%, respectively, and no deaths were related to the regimen. We conclude that the R-THP-COP regimen is safe and effective for patients with DLBCL. Based on these results, a randomized controlled trial of rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and R-THP-COP as a phase III study is ongoing.

IgG type multiple myeloma and concurrent IgA type monoclonal gammopathy of undetermined significance complicated by necrotizing skin ulcers due to type I cryoglobulinemia.

A 61-year-old male who worked as a frozen chicken processor was referred to us with necrotizing skin ulcers on his hands and feet. Serum IgG and IgA levels were 4,355 mg/dl and 605 mg/dl, respectively. Serum immunoelectrophoresis demonstrated M-bows for anti-IgGlambda and anti-IgAkappa. Bone marrow aspirate revealed approximately 31% atypical plasma cells. Cryoglobulin was identified in his serum. Cryoglobulin immunoelectrophoresis revealed monoclonal IgGlambda paraproteins. The diagnosis was IgGlambda type multiple myeloma and concurrent IgAkappa type monoclonal gammopathy of undetermined significance with type I cryoglobulinemia. A skin biopsy taken from an involved site showed amorphous eosinophilic material occluding small vessel lumens. There was a good response after one cycle of chemotherapy consisting of vincristine, adriamycin and dexamethasone (VAD). There was a concurrent decrease in serum cryoglobulin levels ; this was associated with re-epithelialization of skin ulcers. Two years later, multiple myeloma progressed during a maintenance therapy of melphalan and prednisolone. Treatment with bortezomib following VAD resulted in a transient response. Serum IgG levels increased to 7,200 mg/dl, in contrast to a decrease in IgA levels to 7 mg/dl. The increase corresponded with the reappearance of skin ulcers. Shortly thereafter, the patient died of multiple myeloma.

Phase II study of Rituximab combined with THP-COP as first-line therapy for patients younger than 70 years with diffuse large B cell lymphoma.

INTRODUCTION: We previously described the effectiveness of the THP-COP regimen comprising cyclophosphamide, pirarubicin (tetrahydropyranyl adriamycin; THP), vincristine and prednisolone in patients with diffuse large B-cell lymphoma (DLBCL). The anthracycline drug THP was apparently less cardiotoxic than doxorubicin. However, that study was completed before rituximab was introduced into clinical practice. We conducted a phase II study to determine the effectiveness of a regimen incorporating rituximab (R-THP-COP) against DLBCL. PATIENTS: Six to 8 courses of the regimen were administered every 2 weeks in 48 patients who were younger than 70 years. RESULTS: The complete remission rate was 92%, the 3-year overall survival rate was 83% and 3-year progression free survival rate was 74%. No deaths were associated with the treatment regimen. CONCLUSION: We conclude that R-THP-COP regimen is very effective against DLBCL. The results of our study urge randomized trials of R-CHOP and R-THP-COP among patients with CD20+ DLBCL.

Serum soluble Fas level determines clinical outcome of patients with diffuse large B-cell lymphoma treated with CHOP and R-CHOP.

INTRODUCTION: We previously reported that serum concentrations of soluble Fas (sFas) predict the clinical outcome of patients with diffuse large B cell lymphoma (DLBCL) after treatment with CHOP but without rituximab (R). Here, we investigated whether the role of sFas as a prognostic factor remains valid in the R-CHOP era. PATIENTS: We treated 132 patients with DLBCL between October 1995 and September 2002 (group A: without rituximab), and 75 between December 2002 and March 2007 (group B: with rituximab). The patients received eight cycles of CHOP or THP (tetrahydropyranyl-adriamycin)-COP before September 2002, and R-CHOP or R-THP-COP after October 2002. The distribution of patients according to the International Prognostic Index did not significantly differ between the groups. RESULTS: The 5-year overall survival (OS) rates for patients with sFas levels of > or = 3.0 and <3.0 ng/ml in group A were 19.8 and 61.9% (P < 0.0001), whereas the 3-year OS rates in group B were 54.7 and 92.2% (P < 0.01), respectively. Multivariate analysis using the proportional hazards model revealed that sFas most significantly correlated with overall survival (P < 0.05). CONCLUSION: Serum sFas is thus a useful tool for selecting the appropriate therapeutic strategy for DLBCL.

Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen.

We studied the clinical outcomes of 171 adults with hematologic malignancies who received unrelated cord blood transplantation (CBT) as a primary unrelated stem-cell source (n=100), or bone marrow transplant (BMT) or peripheral blood stem-cell transplant (PBSCT) from related donors (n=71, 55 BMT and 16 PBSCT). All patients received myeloablative regimens including 12 Gy total body irradiation. We analyzed the hematologic recovery, and risks of graft-versus-host disease (GVHD), transplantation-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. Significant delays in engraftment occurred after cord blood transplantation; however, overall engraftment rates were almost the same for both grafts. The cumulative incidences of grades III to IV acute and extensive-type chronic GVHDs among CBT recipients were significantly lower than those among BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent differences in TRM (9% in CBT and 13% in BMT/PBSCT recipients), relapse (17% in CBT and 26% in BMT/PBSCT recipients), and DFS (70% in CBT and 60% in BMT/PBSCT recipients) between both groups. These data suggest that unrelated cord blood could be as safe and effective a stem-cell source as related bone marrow or mobilized peripheral blood for adult patients when it is used as a primary unrelated stem-cell source.

Late-onset neutropenia in patients treated with rituximab for non-Hodgkin's lymphoma.

Late-onset grade 4 neutropenia occurred in 3 (5.6%) of 54 non-Hodgkin's lymphoma patients treated with rituximab between September 2001 and March 2004. Neutropenia appeared 5 to 25 weeks after administration of cytotoxic agents in combination with rituximab and recurred 4 and 17 weeks after the first onset in 2 patients. Five episodes occurred in a total of 332 cycles of rituximab therapy. Bone marrow findings at the time of late-onset neutropenia showed neutrophil maturation arrest with or without reversible myeloid dysplasia in 3 episodes and selective depletion of the myeloid series in 1 episode. Neither circulating immune complexes nor antineutrophil antibodies were detected during the 3 episodes that we evaluated. Bone marrow cells stained CD8- and CD57-. Late-onset neutropenia resolved 5 to 7 days after granulocyte colony-stimulating factor therapy was started. Further studies are needed to determine how rituximab functions and to identify appropriate countermeasures.

Hemorrhagic cystitis in adults after unrelated cord blood transplantation: a single-institution experience in Japan.

Hemorrhagic cystitis (HC) is the main complication after hematopoietic stem cell transplantation (SCT). Adenovirus (AdV) is the leading cause of late-onset HC after SCT in Japan. The incidence and outcome of HC were studied in 77 adults who underwent unrelated cord blood transplantation (CBT). Thirty-two patients developed HC in a median of 19 days (range, 11-170 days) after CBT. The cumulative incidence of HC was 41.8% at 1 year. Ten patients developed gross hematuria. The cumulative incidence of moderate-to-severe HC was 13.2% at 1 year. Only 1 patient developed severe HC; AdV was detected in a urine sample from that patient. AdV was also detected in a urine sample from another patient with moderate HC after CBT. AdV in both patients was identified as AdV type 11. The cumulative incidence of AdV-induced HC was 2.8% at 1 year. The incidence of AdV-induced severe HC after CBT may be relatively low among Japanese adults. The role of other viruses, including BK virus, in the pathogenesis of HC after CBT needs to be examined.

Varicella-zoster virus encephalitis in a patient undergoing unrelated cord blood transplantation for myelodysplastic syndrome-overt leukemia.

Varicella-zoster virus (VZV) infection of the central nervous system (CNS) is rare after hematopoietic stem cell transplantation (SCT). Here, we describe the first patient who developed VZV encephalitis after cord blood transplantation (CBT). A 35-year-old man with myelodysplastic syndrome-overt leukemia underwent CBT. On day +23, a neutrophil count consistently greater than 0.5 x 10(9)/L was achieved. On day +42, 1 mg/kg per day of prednisolone therapy was initiated for grade III acute graft-versus-host disease (GVHD). Then, the dose of prednisolone was slowly reduced. For exacerbation of chronic GVHD, the dose of prednisolone was again increased to 1 mg/kg per day on day +231. On day +265, localized cutaneous zoster in the left thoracic region occurred, but soon resolved after acyclovir therapy. On day +309, he suddenly developed diplopia. Subsequently, right facial palsy and hearing impairment occurred. No skin rash was observed. Magnetic resonance imaging (MRI) scans revealed multifocal abnormal high-signal intensity in the CNS. A high level of VZV DNA was detected in a cerebrospinal fluid specimen. He was diagnosed with VZV encephalitis. Acyclovir was given intravenously for 40 days. Four months after the onset, the neurologic symptoms had incompletely resolved. MRI scans showed substantial resolution but with mild residual lesions. The present report indicates that VZV should be considered as a possible causative agent in patients who develop multifocal neurologic symptoms of the CNS after SCT.