Kazunari Aoki

The Prognostic Impact of Absolute Lymphocyte and Monocyte Counts at Diagnosis of Diffuse Large B-Cell Lymphoma in the Rituximab Era

Background: A recent report showed that the combination of the absolute lymphocyte count (ALC) and the absolute monocyte count (AMC) at diagnosis gave a prognostic score in diffuse large B-cell lymphoma (DLBCL). However, this model requires validation in other patient cohorts. Methods: We retrospectively evaluated the prognostic impact of the combination of the ALC and the AMC at diagnosis in a cohort of 299 DLBCL patients who were treated in the rituximab era at a single institution. Results: In univariate analyses, an ALC ≤1.0 × 109/l [4-year overall survival (OS) rate 47.0 vs. 79.4%; p < 0.001] and an AMC ≥0.63 × 109/l (4-year OS rate 52.4 vs. 75.6%; p < 0.001) were associated with inferior OS, respectively. In multivariate analyses, an ALC ≤1.0 × 109/l and an AMC ≥0.63 × 109/l were significantly associated with inferior OS independently of the International Prognostic Index. Furthermore, the combination of ALC and AMC could identify patients with the dismal prognosis; the 4-year OS rates for patients with ALC ≤1.0 × 109/l and AMC ≥0.63 × 109/l were 18.8%. Conclusions: The combination of ALC and AMC at diagnosis may be useful for the prognostic stratification of patients with DLBCL.

Efficacy and tolerability of reduced-dose 21-day cycle rituximab and cyclophosphamide, doxorubicin, vincristine and prednisolone therapy for elderly patients with diffuse large B-cell lymphoma

Abstract Rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) is regarded as the first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL), but it is often necessary to reduce the dose or prolong the intervals between doses. In our center, dose reduction is performed with elderly patients with DLBCL on an individual basis: for patients in their 70s and 80s, the initial CHOP dose is reduced to 70% and 50%, respectively, and the subsequent doses are adjusted so that the patients receive, at 21-day intervals, the highest dose they can tolerate (reduced-dose R-CHOP21). To verify this practice, a retrospective analysis was performed. Between January 2004 and January 2011, 109 ≥ 70-year-old patients with DLBCL received reduced-dose R-CHOP21 with curative intent. The 2-year overall survival rates of the 70–79- and ≥ 80-year-old patients were 75.2% and 64.6%, respectively. Of 35 deaths, 20 were due to disease progression and five were related to treatment toxicity. Multivariate analysis revealed that an age of 75–79 years and an age of 80 years or older were associated with shorter survival. Given that many patients had poor performance status and comorbidities, reduced-dose R-CHOP21 may provide a reasonable balance between efficacy and tolerability for elderly patients with DLBCL.

Unrelated cord blood transplantation in CML: Japan Cord Blood Bank Network analysis.

We analysed 86 patients with CML who received unrelated cord blood transplantation (UCBT), identified through a registry of the Japan Cord Blood Bank Network. At transplantation, the median patient age was 39 years (range, 1–67 years); 38 patients were in chronic phase (CP), 13 in the accelerated phase (AP) and 35 in blast crisis (BC). Median duration from diagnosis to UCBT was 1.5 years (range, 0.2–14.6 years). A nucleated cell (NC) dose of more than 3.0 × 107 per kg was sufficient to achieve neutrophil (91%) and platelet recovery (86%), whereas the lower dose of NC achieved only 60 and 61%, respectively. The duration and type of pre-transplant treatment did not affect neutrophil or platelet recovery. Results of multivariate analysis indicated that older patients (>50 years) had a higher incidence of transplant-related mortality. Advanced-disease stage and lower doses of NCs were significantly associated with lower leukaemia-free and event-free survival. At 2-year survival for patients in CP, AP and BC was 71, 59 and 32%, respectively (P=0.0004). A pre-transplant European Group for Blood and Marrow Transplantation scoring system was effective in predicting the outcome of UCBT. We conclude that UCBT is a reasonable alternative therapy for patients with CML.

Efficiency of high-dose cytarabine added to CY/TBI in cord blood transplantation for myeloid malignancy

Cord blood transplantation (CBT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen, but posttransplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated. Therefore, we conducted a cohort study to compare the prognosis of HDCA/CY/TBI (n = 617) and CY/TBI (n = 312) in CBT for AML/MDS, using a Japanese transplant registry database. The median age was 40 years, and 86.2% of the patients had AML; high-risk disease was observed in 56.2% of the patients. The median follow-up period after CBT was approximately 3.5 years. Overall survival was significantly superior in the HDCA/CY/TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; P < .01), and tumor-related mortality was lower (HR, 0.50; P < .01). The incidence of grade II to IV acute graft-vs-host disease (aGVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group (HR, 1.33 and 2.30, respectively), but not grade III to IV aGVHD. Incidence of infectious episodes showed no significant difference. Nonrelapse mortality was not increased by the addition of HDCA. Higher-dose CA (12 rather than 8 g/m(2)) was more effective, particularly in patients at high-risk for disease. This study is the first to show the superiority of HDCA/CY/TBI to CY/TBI in CBT for AML/MDS. A large-scale prospective study is warranted to establish new conditioning regimens including HDCA administration.

Impacts of graft-versus-host disease on outcomes after allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: A nationwide retrospective study

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic option that may lead to improved outcomes in patients with chronic myelomonocytic leukemia (CMML). However, few studies have examined the impact of the grade of graft-versus-host disease (GVHD) on post-transplant outcomes for CMML. We retrospectively analyzed the outcomes of 141 patients with CMML who underwent allo-HSCT between 1987 and 2010, and achieved neutrophil engraftment. The effects of acute GVHD (aGVHD) or chronic GVHD (cGVHD) on overall survival (OS), leukemia-associated mortality (LAM), and transplant-related mortality were evaluated by hazards regression models, in which the onset date of aGVHD or cGVHD was treated as a time-dependent covariate. Grade I aGVHD was associated with better OS and lower LAM (P=0.042, P=0.033, respectively) than no GVHD in univariate analyses, but not in the multivariate analyses. The multivariate analyses demonstrated that extensive cGVHD significantly associated with better OS (Hazard Ratio [HR] 0.35 [95% confidence intervals (CI), 0.16-0.74]; P=0.007) and lower LAM (HR 0.36 [95% CI, 0.14-0.92]; P=0.033) in patients who were not in complete remission at transplantation. In conclusion, the occurrence of cGVHD may be an important factor affecting the outcomes of CMML patients who received transplantation.

Blastic Plasmacytoid Dendritic Cell Neoplasm Expressing the CD13 Myeloid Antigen

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), currently considered to originate from immature plasmacytoid dendritic cells (DC), is a rare and aggressive CD4+CD56+ neoplasm that frequently involves the skin and bone marrow. We present a case of an 80-year-old man with a CD4+CD56+ BPDCN that affected the orbital cavity and bone marrow. Although BPDCN has not been reported to express any lineage-specific markers, the neoplastic cells strongly expressed the CD13 antigen. Therefore, in addition to pathological examination, we attempted to induce in vitro morphological and surface marker changes with IL-3 and CD40 ligand. After treatment with these cytokines, the tumor cells enlarged markedly, acquired many fine dendrites, similar to mature DC, and showed enhanced expression of antigens specific to DC or antigen-presenting cells, such as CD40, CD80, CD83 and CD86. To the best of our knowledge, this is the first report of BPDCN expressing a myeloid antigen, CD13, although CD33 expression has been described in some cases. The present patient received 2 courses of combination chemotherapy consisting of cytarabine and etoposide, which resulted in complete remission. Given that the cellular origin of plasmacytoid DC is still controversial, myeloid antigen expression involving CD13 may not exclude a diagnosis of BPDCN.

Allogeneic haematopoietic cell transplantation with reduced-intensity conditioning for elderly patients with advanced myelodysplastic syndromes: a nationwide study

Japanese subjects. Cancer Epidemiology Biomarkers and Prevention, 15, 1009–1013. Tamakoshi, A., Hamajima, N., Kawase, H., Wakai, K., Katsuda, N., Saito, T., Ito, H., Hirose, K., Takezaki, T. & Tajima, K. (2003) Duplex polymerase chain reaction with confronting two-pair primers (PCR-CTPP) for genotyping alcohol dehydrogenase beta subunit (ADH2) and aldehyde dehydrogenase 2 (ALDH2). Alcohol and Alcoholism, 38, 407–410. Wang, Y., Yagasaki, H., Hama, A., Nishio, N., Takahashi, Y. & Kojima, S. (2007) Mutation of SBDS and SH2D1A is not associated with aplastic anemia in Japanese children. Haematologica, 92, 1573.

Central nervous system involvement of primary cutaneous diffuse large B cell lymphoma-leg type diagnosed according to the WHO 2008 classification

Dear Editor,Primary cutaneous large B cell lymphoma-leg type(PCLBCL-LT) is a unique subtype of diffuse large B celllymphoma, which predominantly affects the skin [1, 2].Unlike other types of cutaneous B cell lymphoma,PCLBCL-LT frequently disseminates to extracutaneoussites [1, 2]; however, invasion of the central nervous system(CNS) is quite rare.A 75-year-old Japanese female developed two tumors inher chest wall and was diagnosed with PCLBCL-LT. Shereceived three cycles of R-CHOP (50 % dose) [3] followedby local electron beam radiotherapy and subsequentlyachieved complete remission. However, the lymphoma hassince recurred twice (on the left forehead and in the leftmalar region), and the patient received local electron beamradiotherapy on each occasion. Four years after the initialdiagnosis, she experienced nausea and difficulty in swallow-ing. Upon examination, a left-sided facial paresis and a newcutaneous tumor on the left side of the forehead (with adiameter of 10 mm) were noted. CT scanning of the trunkand a bone marrow aspirate showed no evidence of recurrentlymphoma. Contrast-enhanced T1-weighted MRI images ofthe brain revealed homogeneously enhancing periventricularlesionscrossingthecorpuscallosum(Fig.1a)andsurroundinghyperintensity on fluid-attenuated inversion recovery images(Fig.1b).Theenhancedlesionsshowedrestricteddiffusionondiffusion-weighted images. Lymphoma-like cells were ob-served (13 cells/μl) in the cerebrospinal fluid (CSF) as eval-uated by cytospin preparation. Histologic examination of thecutaneous tumor showed diffuse proliferation of both centro-blasts and immunoblasts, which expressed CD20 and BCL2.PCR analysis of cells from the cutaneous tumor and the CSFshowed monoclonal rearrangement of the immunoglobulinheavy chain gene, with the same-sized PCR products. Fromthese findings, the patient was diagnosed with a CNS relapseof PCLBCL-LT. She received four cycles of high-dose meth-otrexate (2.5 g/m2) plus rituximab (375 mg/m2) and twocycles of R-ESHAP chemotherapy (50 % dose) [4]. Aftertwo cycles of high-dose methotrexate-based treatment, herconsciousness disturbances and neurologic abnormalitiesshowed a marked improvement. After the completion of allscheduledchemotherapies,sheachievedacompleteremissionand was able to eat and walk by herself.At present, four cases of CNS involvement of recur-rent PCLBCL-LT have been reported [5–7]. However, allcases were diagnosed according to the EORTC classifi-cation [5–7]. This article is the first case report describ-ing CNS relapse in a patient with PCLBCL-LTdiagnosed according to the WHO 2008 classification[2]. Furthermore, PCR analysis showed that the skintumor at diagnosis and the abnormal cells in the CSFwere of the same clonal origin.We experienced a rare case of CNS-relapsed PCLBCL-LT. Further investigations are needed to clarify the exactincidence of CNS recurrence in PCLBCL-LT according tothe WHO 2008 classification.

Human herpes virus 6-associated myelitis following allogeneic bone marrow transplantation

Dear Editor,Human herpes virus 6 (HHV6) can be reactivated in recip-ients of hematopoietic stem cell transplantation (HSCT),resulting in a number of clinical manifestations [1].HHV6-associated myelitis is characterized by dysesthesiaof the lower extremities, dysuria, or dyschezia, without anysymptoms of encephalitis [2, 3]. All previously reportedcases of HHV6-associated myelitis occurred in cord bloodtransplantation (CBT) recipients [2, 3]. Here, we report acase of HHV6-associated myelitis developed in a bonemarrow transplantation (BMT) recipient.A 20-year-old Japanese male with Philadelphia-negativeacute lymphoblastic leukemia received myeloablativeallogeneic BMT from a human leukocyte antigen-DRallele single mismatched unrelated donor during a secondremission (Fig. 1). A total of 2.08×10

Acute renal failure associated with systemic polyoma BK virus activation in a patient with peripheral T-cell lymphoma

Renal dysfunction associated with polyoma BK virus (BKV) reactivation usually occurs in the setting of profound immunosuppression related to renal transplantation and hematopoietic stem cell transplantation. However, it has been rarely described as a complication during the course of conventional chemotherapy. Here, we report a case of BKV-associated acute renal failure developed in a patient suffering from refractory peripheral T-cell lymphoma, not otherwise specified. After repetitive cycles of salvage chemotherapy, the patient developed fever and urinary frequency, rapidly followed by anuria that necessitated the emergent institution of hemodialysis. Cytologic examination of the urine revealed the presence of decoy cells and positive immunostaining for polyomavirus simian virus 40 antigen. High levels of BKV were detected in urine and plasma with quantitative real-time polymerase chain reaction, strongly suggesting that his renal failure was due to polyoma virus-associated nephropathy. This rare complication should be kept in mind in case of unexplained renal failure developed in immunodeficient patients undergoing cytotoxic chemotherapy.