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Chronic lymphocytic leukemia (CLL) is rare in Japan. We conducted the nationwide, prospective observational study CLLRSG-01 to clarify the current state of CLL in Japan and to make accurate international comparisons by preparing naturally air-dried smears like those used in other countries. Of the 201 untreated patients enrolled and evaluated, 119 were diagnosed with CLL and 82 with non-CLL mature B-cell neoplasms, based on the WHO classification. Of the 119 CLL patients, 90 were classified as typical and 29 as atypical according to FAB classification morphology, with the proportion of atypical CLL consistent with reports from other countries. Immunophenotypic analyses by flow cytometry showed that 55% of Japanese CLL patients had a Matutes score of 4 or higher, which is lower than the rate of about 90% in Europeans. Mutated IGHV was identified in 80% of Japanese CLL patients, which is a higher rate than in Western patients. The most frequent IGHV gene was VH3-30 (15%), followed by VH3-23 (12%) and VH4-34 (10%). VH1-69, the most common gene in Western countries, was identified in only one patient. These results indicate that the pattern of immunophenotypes and IGHV gene usage in Japanese CLL patients differs from that in Western patients., (© 2024. Japanese Society of Hematology.)

A 53-year-old woman was diagnosed with lymphoplasmacytic lymphoma (LPL)/Waldenström's macroglobulinemia (WM) in 2008. Six courses of R-COP (rituximab, cyclophosphamide, vincristine, and prednisolone) resulted in complete remission, but LPL/WM relapsed in 2015. After six courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), the M-peak disappeared, but the patient presented with muscle weakness and sensory disturbance in the lower extremities. No lesions were apparent in the brain parenchyma, but T2-weighted magnetic resonance imaging (MRI) showed a signal-hyperintense area with contrast enhancement in the spinal cord at the C2-4 and Th2-3 levels, and cerebrospinal fluid (CSF) examination showed only a few mononuclear cells. In 2020, the patient started to require walking assistance, and MRI findings worsened. Neurologically, lower limb muscle strength was reduced (manual muscle test score 3), and sensations of touch and pain were about 30% of normal. Vibratory sensation was absent at the knees and medial malleoli, accompanied by dysuria due to neurogenic bladder. CSF cell count was 15/μl (all mononuclear cells). Bing-Neel syndrome (BNS) was diagnosed and tirabrutinib was started. Within 2 months of treatment, lower extremity muscle strength had normalized and MRI findings had improved. Tirabrutinib may offer a promising therapeutic option for BNS., (© 2021. Japanese Society of Hematology.)

A 63-year-old man was diagnosed with Waldenström's macroglobulinemia (WM). Six courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) resulted in complete remission, but WM relapsed three years after R-CHOP. After six courses of BR (bendamustine, rituximab), the serum IgM level and CRP normalized. Four years after BR, the patient presented with muscle weakness, sensory disturbance, and myoclonus of lower limbs. T2-weighted magnetic resonance imaging (MRI) showed areas of signal hyperintensity with contrast enhancement in the right temporal and parietal lobes in brain parenchyma, medulla, bilateral basal ganglia, white matter of occipital lobe, and thoracic spinal cord at the Th2-11 levels. Open brain biopsy revealed diffuse proliferation of small lymphocytes and plasmacytoid lymphocytes on the brain surface and around cerebral blood vessels, resulting in a diagnosis of Bing-Neel syndrome (BNS). Two courses of R-MPV (rituximab, methotrexate, procarbazine, and vincristine) resulted in progressive disease, but the neurological symptoms and MRI findings improved following craniospinal irradiation of 30.6 Gy. Three years after craniospinal irradiation, T2-weighted MRI showed recurrence of BNS with progression of myoclonus of lower limbs and IgM elevation. Tirabrutinib was started for the second recurrence of WM and progression of BNS. Two months after the initiation of treatment with tirabrutinib, the myoclonus of lower limbs disappeared and the MRI findings showed improvement. Serum IgM levels decreased and no adverse events were observed. Tirabrutinib shows promise as a therapeutic option for relapsed BNS.

Objectives: By using data from the CEDMIC trial (n = 413), we conducted a post-hoc analysis of the diagnostic value of biomarker monitoring and chest computed tomography (CT) scans for the early detection of invasive fungal disease (IFD) in neutropenic hematological patients., Methods: IFDs were defined in accordance with the EORTC/MSG definition with some modifications. Biomarkers such as Aspergillus galactomannan (GM) and (1→3)-β-D-glucan (βDG) were measured weekly., Results: The positive predictive value (PPV) of GM and βDG in cases of high-risk treatment were 0.70 and 0.69, while those in low-risk treatment were 0.08 and 0, respectively. All of the positive biomarkers that were measured before the development of fever in low-risk treatment were false positives. The proportion of patients who had abnormal chest CT findings was 19% in persistent fever at 4-6 days, 57% at 7 days or later and 36% in recurrent fever. Sixty-nine percent of the patients who had abnormal findings at 7 days or later did not have abnormalities at 4-6 days., Conclusions: Afebrile screening of biomarkers in low-risk treatment is not useful. Chest CT should be reevaluated in persistent fever lasting for 7 days or longer even in patients who did not have abnormalities within 6 days., Competing Interests: Declaration of Competing Interest Shun-ichi Kimura received honoraria from Astellas Pharma, Pfizer, Sumitomo Dainippon Pharma, Merck Sharp and Dohme, Nippon Kayaku, Kyowa Hakko Kirin, Asahi Kasei, Ono Pharmaceutical, Takeda Pharmaceuticals and Celgene. Yoshinobu Kanda received honoraria from Merck Sharp and Dohme, Pfizer, Astellas Pharma, Janssen, Chugai Pharma, Otsuka, Celgene, Sumitomo Dainippon Pharma, Eisai, Novartis, Kyowa Hakko Kirin, Bristol-Myers Squibb, Takeda Pharmaceuticals, Alexion Pharmaceuticals, Shire, Daiichi Sankyo, Ono Pharmaceutical, Nippon Shinyaku, Mochida Pharmaceutical, Mundipharma, Sanofi and Meiji Seika Kaisha, and research funding from Astellas Pharma, Eisai, Otsuka, Kyowa Hakko Kirin, Sanofi, Shionogi, Taiho Pharmaceutical, Chugai Pharma, Nippon Shinyaku and Pfizer. Tatsuo Oyake received honoraria from Astellas Pharma, Chugai Pharma, Celgene, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Bristol-Myers Squibb Japan and Pfizer, and research funding from Kyowa Hakko Kirin, Chugai Pharma, Sionogi and Bayer. Hiroki Yamaguchi received honoraria from Novartis, and served in a consulting or advisory role for Novartis, and research funding from Astellas Pharma and Bristol-Myers Squibb. Shin-ichiro Fujiwara received honoraria from Astellas Pharma, Chugai, CSL Behring, Janssen, Novartis, Kyowa Hakko Kirin, Nippon Shinyaku, Sanofi and Otsuka. Kazuo Tamura received honoraria from Ono Pharmaceutical and Eisai Co. Ltd. The other authors have nothing to declare., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings., Methods: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy., Results: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2-79.4) and 79.6% (71.0-86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2-80.9%) and 78.0% (65.3-87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups., Conclusions: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human leukocyte antigen (HLA)-G, a non-classical HLA class I molecule, has one of the splicing isoforms, HLA-G2, which lacks one domain (α2) and forms a non-covalent homodimer. HLA-G2 is expressed on placental cells, regulatory T cells, tumor cells, and virus-infected cells, and is involved in immunosuppression. The major isoform of HLA-G, HLA-G1, binds to leukocyte immunoglobulin (Ig)-like receptor (LILR) B1 and LILRB2, on the contrary, HLA-G2 binds to only LILRB2. We previously reported that HLA-G2 bound LILRB2 more strongly than HLA-G1 and also to paired Ig-like receptor (PIR)-B, a mouse homolog of LILRBs. Furthermore, HLA-G2 showed immunosuppressive effects in both collagen-induced arthritis (CIA) and atopic dermatitis-like model mice. In this study, we examine in vivo effects of HLA-G2 in systemic lupus erythematosus (SLE) model mice. HLA-G2 showed the suppression of the typical SLE symptoms such as serum anti-dsDNA antibody level and urinary albumin index. Furthermore, HLA-G2 tended to downregulate B-lymphocyte stimulator (BLyS) production. This is the first observation of the immunosuppressive effects of HLA-G2 isoform in SLE model mice, suggesting that HLA-G2 could be a useful therapeutic agent for SLE., (Copyright © 2019 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Purpose: Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index-guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial., Patients and Methods: We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET., Results: In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (-2.0%; 90% CI, -4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P < .001)., Conclusion: A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.

The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again; all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan-Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in > 100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan.

Toxoplasmic encephalitis is a rare infectious complication in patients with hematological malignancy except for allogeneic hematopoietic stem cell transplantation (HSCT). We herein report a case of possible toxoplasmic encephalitis with untreated hairy cell leukemia variant. Magnetic resonance imaging showed multiple nodules with surrounding edema in the entire cerebrum. A polymerase chain reaction analysis for Toxoplasma gondii was negative. Her signs and symptoms fully recovered by empirical therapy with sulfadiazine and pyrimethamine. Toxoplasmic encephalitis may occur in patients who undergo non-allogeneic HSCT for hematological malignancies, even in those who have not been treated.

Philadelphia chromosome positive (Ph+) mixed phenotype acute leukemia (MPAL) is a rare type of acute leukemia having both myeloid and lymphoid features for which no optimal treatment has yet been established. We herein describe two elderly Ph+MPAL patients who achieved molecular remission without any serious adverse events by treatment with dasatinib and prednisolone. Although dasatinib induction therapy combined with prednisolone is known to be a highly effective treatment for Ph+ acute lymphoblastic leukemia, its efficacy for Ph+MPAL has not been shown. The clinical courses of the present cases suggest that combination therapy with dasatinib and prednisolone is a safe and effective therapeutic modality in elderly Ph+MPAL patients.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes caused by human T-lymphotropic virus type I. Intensive combination chemotherapy and allogeneic hematopoietic stem cell transplantation have been introduced since the previous Japanese nationwide survey was performed in the late 1980s. In this study, we delineated the current features and management of ATL in Japan. The clinical data were collected retrospectively from the medical records of patients diagnosed with ATL between 2000 and 2009, and a total of 1665 patients' records were submitted to the central office from 84 institutions in Japan. Seventy-one patients were excluded; 895, 355, 187, and 157 patients with acute, lymphoma, chronic, and smoldering types, respectively, remained. The median survival times were 8.3, 10.6, 31.5, and 55.0 months, and 4-year overall survival (OS) rates were 11%, 16%, 36%, and 52%, respectively, for acute, lymphoma, chronic, and smoldering types. The number of patients with allogeneic hematopoietic stem cell transplantation was 227, and their median survival time and OS at 4 years after allogeneic hematopoietic stem cell transplantation was 5.9 months and 26%, respectively. This study revealed that the prognoses of the patients with acute and lymphoma types were still unsatisfactory, despite the recent progress in treatment modalities, but an improvement of 4-year OS was observed in comparison with the previous survey. Of note, one-quarter of patients who could undergo transplantation experienced long survival. It is also noted that the prognosis of the smoldering type was worse than expected., (© 2015 by The American Society of Hematology.)

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887., (© 2015 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

We describe a 67-year-old female demonstrating symptomatic multiple myeloma (MM) with anemia and bone lesions initially diagnosed in 2009. Although a partial response was achieved after bortezomib and dexamethasone treatment, MM recurred in 2012. Therefore, treatment with lenalidomide, cyclophosphamide, and dexamethasone was commenced. Coagulation tests conducted prior to the chemotherapy were normal. Lenalidomide was discontinued after 10 days due to exacerbation of renal dysfunction. Simultaneously, activated partial thromboplastin time (APTT) was prolonged to 89.5 seconds. The mixing test showed an inhibitor pattern, with factor VIII at 2% and factor VIII inhibitor at 4.85 BU/ml. A diagnosis of acquired hemophilia A was made, and treatment with prednisolone was started, after which APTT improved to 36.4 seconds and factor VIII inhibitor decreased to 1.09 BU/ml. The factor VIII inhibitor level again increased concomitantly with restarting lenalidomide, which was, therefore, discontinued, while immunosuppressive therapy was administered with the addition of cyclophosphamide. Factor VIII inhibitor gradually disappeared from the patient's blood over the next four months. To the best of our knowledge, this is the first description of lenalidomide as a possible cause of acquired hemophilia A. Our experience indicates that we need to pay attention to acquired hemophilia A after initiating lenalidomide therapy in patients with hematologic malignancies.

A 28-year-old man complained of pain in the oral mucosa and pharynx in March 2011, and then developed fever and generalized swelling of the cheek. In March 2012, a gum biopsy led to a diagnosis of extranodal natural killer/T-cell lymphoma (ENKL). (18)F-FDG-PET revealed significant uptake in the mouth, tonsils, jawbone, shoulder blade, humerus, ilium, femur, and spleen. After two courses of the SMILE (dexamethasone, methotrexate (MTX), ifosfamide, L-asparaginase, etoposide) regimen, the response was stable disease. However, a high-dose MTX/cytarabine (MA) regimen was effective. After three courses of the MA regimen, a partial response was achieved. Then, allogeneic bone marrow transplantation from an unrelated donor was performed. At 10 months after transplantation, there was no sign of recurrence. Although the optimal treatment for ENKL refractory to the SMILE regimen has yet to be established, our case suggests the MA regimen to be a potentially effective treatment option.

High incidences of human herpesvirus (HHV)-6 encephalitis have recently been reported from several Japanese SCT centers. To evaluate the effect of low-dose foscarnet (PFA) in preventing HHV-6 infection among recipients of unrelated BM or cord blood (CB), we examined consecutive cohorts without prophylaxis against HHV-6 (cohort 1, n=51) and with PFA prophylaxis (cohort 2, PFA 50 mg/kg/day for 10 days after engraftment, n=67). Plasma real-time PCR assay was performed weekly. High-level reactivation defined as HHV-6 DNA > or =10(4) copies/mL by day 70 was the primary endpoint. No significant reduction of high-level reactivation was seen in cohort 2 (19.4%) compared with cohort 1 (33.8%, P=0.095). A trend was identified toward fewer high-level HHV-6 reactivations in cohort 2 among recipients of unrelated BM (P=0.067), but no difference in incidence was observed among CB recipients (P=0.75). Breakthrough HHV-6 encephalitis occurred following PFA prophylaxis in three patients, and incidence of HHV-6 encephalitis did not differ between cohort 1 (9.9%) and cohort 2 (4.5%, P=0.24). In conclusion, 50 mg/kg/day of PFA does not effectively suppress HHV-6 reactivation and cannot prevent all cases of HHV-6 encephalitis. To effectively prevent HHV-6 encephalitis, alternative approaches based on the pathogenesis of HHV-6 encephalitis will probably be required.

Understanding how climate warming has an impact on the life cycle schedule of terrestrial organisms is critical to evaluate ecosystem vulnerability to environmental change. Despite recent advances identifying the molecular basis of temperature responses, few studies have incorporated this knowledge into predictive models. Here we develop a method to forecast flowering phenology by modelling regulatory dynamics of key flowering-time genes in perennial life cycles. The model, parameterized by controlled laboratory experiments, accurately reproduces the seasonal changes in gene expression, the corresponding timing of floral initiation and return to vegetative growth after a period of flowering in complex natural environments. A striking scenario forecast by the model under climate warming is that the shift in the return time to vegetative growth is greater than that in floral initiation, which results in a significant reduction of the flowering period. Our study demonstrates the usefulness of gene expression assessment to predict unexplored risks of climate change.

Purpose: The prognosis of acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL) is poor, but there is marked diversity in survival outcomes. The aim of this study was to develop a prognostic index (PI) for acute- and lymphoma-type ATL (ATL-PI)., Patients and Methods: In a retrospective review, data from 807 patients newly diagnosed with acute- and lymphoma-type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed a PI using a multivariable fractional polynomial model., Results: Median overall survival time (MST) for the 807 patients was 7.7 months. The Ann Arbor stage (I and II v III and IV), performance status (0 to 1 v 2 to 4), and three continuous variables (age, serum albumin, and soluble interleukin-2 receptor [sIL-2R]) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (P < .001; χ(2) = 89.7, 2 df; log-rank test). We also simplified the original ATL-PI according to dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and developed an easily calculable PI with prognostic discrimination power (P < .001; χ(2) = 74.2, 2 df; log-rank test)., Conclusion: The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks.

Angioimmunoblastic T-cell lymphoma (AITL) is a major type of peripheral T-cell lymphoma (PTCL). To elucidate the clinicopathologic characteristics and prognosis of AITL in Japan, we retrospectively analyzed 207 patients with AITL. The median patient age was 67 years (range, 34-91 years), with 73% of patients older than 60 years. With a median follow-up of 42 months in surviving patients, 3-year overall survival (OS) was 54% and progression-free survival (PFS) was 38%. The International Prognostic Index (IPI) and the prognostic index for PTCL, not otherwise specified (PIT) were predictive for OS in this analysis. Multivariate analysis found that age older than 60 years, elevated white blood cell (WBC) and IgA levels, the presence of anemia and thrombocytopenia, and extranodal involvement at > 1 site were significant prognostic factors for OS, and IgA, anemia, and mediastinal lymphadenopathy were significant prognostic factors for PFS. A novel prognostic model consisting of the prognostic factors for OS was successfully constructed. In conclusion, IPI and PIT were still useful for prognostication of AITL, and other factors, including those not used in IPI, such as IgA, anemia, WBC count, thrombocytopenia, and mediastinal lymphadenopathy, also significantly affected prognosis. Future investigations for IgA as a unique prognostic factor are warranted.

Purpose: Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL., Patients and Methods: A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg., Results: Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 ± 147 hours (± standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases., Conclusion: KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted.

The TARGET system is an online database that can be easily accessed by physicians. The registration of one's own chronic myeloid leukemia (CML) patients in the TARGET system makes it possible to share experiences among physicians, and, thus, may facilitate appropriate treatment for patients. Patients were registered in the TARGET system from October 2003 to March 2010 in Japan. A total of 1236 patients from 176 hospitals were registered in Japan. We analyzed data from 639 CML chronic phase patients not receiving prior therapy registered in this system. After 90 months follow-up, high survival rates were demonstrated for imatinib-treated newly diagnosed CML patients, with event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) rates of 79.1, 94.8, and 95.1%, respectively. A landmark analysis of 296 patients who showed a complete cytogenetic response (CCyR) at 12 months after the initiation of imatinib treatment revealed that, at 90 months, 99% of patients (95% CI, 98-100) had not progressed to accelerated phase (AP) or blastic crisis (BC). The patients showing a CCyR and a reduction of at least 3log levels of BCR-ABL transcripts after 18 months of treatment had an estimated survival rate without CML progression of 100% at 84 months. The probability of achieving undetectable BCR-ABL in patients by 72 months with an major molecular response (MMR) at 12 months was 86.5%, compared with 64.7% for those without an MMR (p < 0.0001). There were no new safety issues. In summary, based on this 7-year TARGET analysis, imatinib showed a continual clinical benefit as first-line therapy for newly diagnosed CML. The TARGET system may represent a more practical and general feature compared with the IRIS study., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The etiology of cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), and Epstein-Barr virus (EBV) reactivation and the potential for complications following cytotoxic chemotherapy in the absence of allogeneic transplantation are not clearly understood. Patients with adult T cell leukemia (ATL) are susceptible to opportunistic infections. In this study, the incidence, kinetics and clinical significance of reactivation of CMV, HHV-6, and EBV in ATL patients were investigated. Viral DNA in a total of 468 plasma samples from 34 patients was quantified using real-time PCR. The probability of CMV, HHV-6, and EBV reactivation by 100 days after the start of chemotherapy was 50.6%, 52.3%, and 21.6%, respectively. Although most CMV reactivations were self-limited, plasma CMV DNA tended to persist or increase if the CMV DNA levels in plasma reached ≥ 10(4) copies/ml. CMV reactivation was negatively associated with survival, but the P-value for this association was near the borderline of statistical significance (P=0.052). One patient developed fatal interstitial pneumonia concomitant with peak CMV DNA accumulation (1.6 × 10(6)  copies/ml plasma). Most HHV-6 and EBV reactivations were self-limited, and no disease resulting from HHV-6 or EBV was confirmed. HHV-6 and EBV reactivation were not associated with reduced survival (P=0.35 and 0.11, respectively). These findings demonstrated that subclinical reactivation of CMV, HHV-6, and EBV were common in ATL patients receiving chemotherapy. There were differences in the viral reactivation patterns among the three viruses. A CMV load ≥ 10(4) copies/ml plasma was indicative of subsequent exacerbation of CMV reactivation and developing serious clinical course., (Copyright © 2011 Wiley-Liss, Inc.)

The response criteria proposed by European Leukemia Net are useful to predict the prognosis of de novo chronic myeloid leukemia (CML) patients in the chronic phase (CP) treated with imatinib. However, the clinical significance of late suboptimal response, which is defined as the achievement of CCgR without MMR after 18 months, is controversial. In this study, we retrospectively analyzed the clinical courses of 16 CML-CP patients, who satisfied the criteria for late suboptimal response. The median duration of imatinib treatment was 62 (25∼87) months. The median starting dose of imatinib was 400 mg/day. Imatinib dose was escalated to 600∼800 mg/day in 10 patients for various reasons. Among 4 patients who continued high-dose imatinib for late suboptimal response, 2 patients subsequently achieved MMR, and BCR-ABL mRNA transcript levels were decreasing in 2 patients. However, imatinib was kept at 300 or 400 mg/day in 6 patients. Among these six patients, 4 patients achieved MMR, while 2 failed to achieve MMR. None of 16 patients progressed to the acute phase or blast phase. Imatinib dose escalation was effective for late suboptimal response. Furthermore, a second tyrosine kinase inhibitor such as nilotinib may be more potent to reduce the risk of disease progression by achieving earlier MMR.

Definitive risk factors for the development of adult T-cell leukemia (ATL) among asymptomatic human T-cell leukemia virus type I (HTLV-1) carriers remain unclear. Recently, HTLV-1 proviral loads have been evaluated as important predictors of ATL, but a few small prospective studies have been conducted. We prospectively evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002 to 2008. The proviral load at enrollment was significantly higher in males than females (median, 2.10 vs 1.39 copies/100 peripheral blood mononuclear cells [PBMCs]; P < .001), in those 40 to 49 and 50 to 59 years of age than that of those 40 years of age and younger (P = .02 and .007, respectively), and in those with a family history of ATL than those without the history (median, 2.32 vs 1.33 copies/100 PBMCs; P = .005). During follow-up, 14 participants progressed to overt ATL. Their baseline proviral load was high (range, 4.17-28.58 copies/100 PBMCs). None developed ATL among those with a baseline proviral load lower than approximately 4 copies. Multivariate Cox analyses indicated that not only a higher proviral load, advanced age, family history of ATL, and first opportunity for HTLV-1 testing during treatment for other diseases were independent risk factors for progression of ATL.

Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity with a high incidence of central nervous system (CNS) involvement at diagnosis. To evaluate CNS involvement, particularly recurrence including progression on therapy and relapse of IVLBCL, we retrospectively analyzed 109 patients with IVLBCL receiving chemotherapies with or without rituximab. In 82 patients (75%) without CNS involvement at initial diagnosis, risk of CNS recurrence at 3 years was 25% with a median follow-up in survivors of 39 months (range, 2-158 months). In 27 patients (25%) with CNS involvement at initial diagnosis, risk of CNS recurrence at 1 year was 25% with a median follow-up in survivors of 18 months (range, 10-77 months). Duration from diagnosis to CNS recurrence tended to be short in patients with CNS involvement at diagnosis. No significant difference in risk of CNS recurrence was found between patients receiving chemotherapies with or without rituximab. On multivariate analysis skin involvement at initial diagnosis was identified as a predictive factor for CNS recurrence in patients without CNS involvement at diagnosis (hazard ratio, 5.27; 95% confidence interval, 1.59-17.4; P = 0.007). Survival rate after CNS recurrence at 2 years was 12% in patients without CNS involvement at diagnosis. Central nervous system recurrence is a serious complication in IVLBCL patients and optimal strategies for CNS involvement should be established to obtain further improvements to clinical outcomes in the rituximab era.

Thalidomide is now recognized as an important agent for multiple myeloma. In this study, we retrospectively analyzed the effect of thalidomide therapy in 52 patients with relapsed/refractory multiple myeloma. Median age was 70 years. Eight patients were treated with thalidomide alone, 36 with dexamethasone, and 8 with chemotherapy. The maintenance dose of thalidomide was 100 mg/day in 42 cases. The probability of overall survival and progression-free survival one year after the start of thalidomide were 76.2% and 70.9%, respectively. Complete or partial response was obtained in 16 patients (31%). The probability of survival was better in patients who obtained a partial or complete response than in non-responders (P=0.04). Adverse effects (CTCAE criteria Grade 3-4) were somnolence (n=3), constipation (n=5), peripheral neuropathy (n=1), deep vein thrombosis (n=1), anemia (n=10), leukocytopenia (n=10), and thrombocytopenia (n=3). The high incidence of cytopenia in this study suggests that the Japanese population tends to display bone marrow suppression after thalidomide therapy. Some patients developed peripheral neuropathy at the early stage of administration and attention was necessary. In conclusion, thalidomide therapy is safe and effective in patients with refractory multiple myeloma.

A 65-year-old woman presented with a 6-month history of abdominal pain and watery diarrhea. Type II enteropathy-associated T-cell lymphoma (EATL) was diagnosed based on the clinical presentation and pathological examination of the tumor. The patient received combination chemotherapy but did not achieve remission. Subsequently, high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) were performed. After these therapies, she achieved complete remission, which has been sustained for 18 months. Although the role of HDT-ASCT for EATL is still controversial, the clinical course of this patient suggests that ASCT can improve the prognosis in some patients with EATL.

This study investigated factors associated with the development of human herpesvirus (HHV)-6 encephalitis. Among 111 enrolled subjects, 12 patients developed central nervous system (CNS) dysfunction. CNS dysfunction in four patients was found to have no association with HHV-6. The remaining eight patients displayed HHV-6 encephalitis (n=3), limbic encephalitis (HHV-6 DNA in cerebrospinal fluid was not examined; n=3) or CNS dysfunction because of an unidentified cause (n=2). Real-time PCR showed CNS dysfunction in the latter eight patients, which developed concomitant with the appearance of high plasma levels of HHV-6 DNA (> or =10(4) copies/ml). Overall, eight of the 24 patients with high-level HHV-6 DNA developed CNS dysfunction, whereas no patients developed CNS dysfunction potentially associated with HHV-6 infection if peak HHV-6 DNA was <10(4) copies/ml. We next analyzed plasma concentrations of IL-6, IL-10 and tumor necrosis factor-alpha among patients who displayed high-level plasma HHV-6 DNA and found elevated IL-6 concentrations preceding HHV-6 infection in patients who developed CNS dysfunction. (Mean+/-s.d.: 865.7+/-1036.3 pg/ml in patients with CNS dysfunction; 56.5+/-192.9 pg/ml in others; P=0.01). These results suggest that high-level HHV-6 load is necessary for the development of HHV-6 encephalitis, and systemic inflammatory conditions before HHV-6 infection form the preparatory conditions for progression to encephalopathy.

The efficacy and safety of high-dose chemotherapy with tandem autologous peripheral blood stem cell transplantation (auto-PBSCT) were evaluated in a multicenter clinical study of patients with advanced multiple myeloma. Eligible patients (n = 40) were consecutively enrolled in the phase I/II study and received 2-4 cycles of vincristine-adriamycin-dexamethasone regimen. The responding patients underwent PBSC harvesting following high-dose cyclophosphamide and filgrastim administration. The first auto-PBSCT (n = 32) following high-dose melphalan (200 mg/m(2)) was performed within 2 months of PBSC harvesting; the second auto-PBSCT (n = 28) was scheduled 3-6 months later. Treatment-related mortality was 2.5% (n = 1) throughout the protocol. Grade 4 nonhematologic toxicity occurred in 12.5 and 14.3% of the first and second auto-PBSCT patients, respectively. All but one patient (who died) achieved hematopoietic recovery. For the 28 patients completing the second auto-PBSCT, the results were favorable with a response rate of 65% (complete response rate = 27.5%, n = 11); the five-year progression-free survival and overall survival were 20.3 and 66.5%, respectively. In conclusion, high-dose chemotherapy with tandem auto-PBSCT is feasible and safe with a favorable response rate in treating advanced multiple myeloma in Japan.

Since hematology is a highly specialized field, an individual physician may not have much direct treatment experience with a given disease. Therefore, the Japanese Society of Hematology (JSH) has discussed establishing a registry of hematologic disorders, in order to contribute to improving the quality of treatments and clinical outcomes in this field. As a first step, the Timely and Appropriate Registration System for GLIVEC Therapy (TARGET), a registration system for chronic myeloid leukemia (CML) patients treated with imatinib, was established in October 2003. We present the preliminary results of the first 4 years' experience with this system. CML patients treated with imatinib in Japan were registered through the website and the patient's clinical course, including parameters and events like imatinib dose, blood counts, adverse events, and efficacy were recorded in months 1, 3, 6, 9, and 12 and then every 6 months thereafter. By September 2007, 862 patients from 176 hospitals were registered. Follow-up period was 0-54 months, and 127 patients were followed-up for more than 36 months. Based on these cumulative data, present imatinib treatment trends were analyzed and safety and efficacy were compared with international trial data.

Purpose: To evaluate the safety and efficacy of rituximab-containing chemotherapies for intravascular large B-cell lymphoma (IVLBCL)., Patients and Methods: We retrospectively analyzed 106 patients (59 men, 47 women) with IVLBCL who received chemotherapy either with rituximab (R-chemotherapy, n = 49) or without rituximab (chemotherapy, n = 57) between 1994 and 2007 in Japan. The median patient age was 67 years (range, 34 to 84 years). The International Prognostic Index was high-intermediate/high in 97% of patients., Results: The complete response rate was higher for patients in the R-chemotherapy group (82%) than for those in the chemotherapy group (51%; P = .001). The median duration of follow-up for surviving patients was 18 months (range, 1 to 95 months). Progression-free survival (PFS) and overall survival (OS) rates at 2 years after diagnosis were significantly higher for patients in the R-chemotherapy group (PFS, 56%; OS, 66%) than for patients in the chemotherapy group (PFS, 27% with P = .001; OS, 46% with P = 0.01). Multivariate analysis revealed that the use of rituximab was favorably associated with PFS (hazard ratio [HR], 0.45; 95% CI, 0.25 to 0.80; P = .006) and OS (HR, 0.42; 95% CI, 0.21 to 0.85; P = .016). Treatment-related death was observed in three patients (6%) who received R-chemotherapy and in five patients (9%) who received chemotherapy., Conclusion: Our data suggest improved clinical outcomes for patients with IVLBCL in the rituximab era. Future prospective studies of rituximab-containing chemotherapies are warranted.

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATLL), but shows high mortality. We evaluated the feasibility of reduced-intensity transplantation using fludarabine and busulfan, with particular focus on the clinical impact of antithymocyte globulin (ATG) in the conditioning regimen. Fourteen elderly patients with aggressive ATLL were enrolled in the current study without ATG, and were compared to those in 15 patients who were treated similarly, but with ATG, in our previous study. Engraftment was prompt, and treatment was tolerable. Overall (OS) and progression-free survival (PFS) at 3 years were 36% and 31%, respectively. HTVL-1 proviral load became undetectable by the polymerase chain reaction in 62% of patients. Compared to the previous study with ATG, complete donor chimera was significantly delayed. Although early relapse tended to be decreased, OS or PFS was not improved significantly. Analysis of combined data from both our current and previous studies disclosed that grade I-II acute GVHD was the only factor that favorably affected OS and PFS. These data suggested the presence of a graft-versus-ATLL effect and the feasibility of a transplant procedure without ATG in elderly ATLL patients, but could not demonstrate the clinical benefit of incorporating ATG.

Human herpesvirus 6 (HHV-6) causes life-threatening encephalopathy in recipients of allogeneic SCT, but no consensus has been reached regarding appropriate preventive methods. This study evaluated a plasma HHV-6 viral load-guided preemptive approach against HHV-6-associated encephalopathy. Plasma real-time PCR assay was performed once a week. Among 29 patients, 19 developed positive plasma HHV-6 DNA. Median maximum plasma HHV-6 DNA was 4593.5 copies/ml plasma (range, 150.0-127 891.0 copies/ml plasma). In one of eight events with low-level HHV-6 DNA (defined as <1000 copies/ml plasma) and four of seven events with mid-level HHV-6 DNA (1000-9999.5 copies/ml plasma), HHV-6 loads in plasma subsequently continued increasing. Ganciclovir was administered against six of nine patients with high-level HHV-6 DNA (> or =10,000 copies/ml plasma). High-level HHV-6 DNA resolved similarly in both groups with or without ganciclovir therapy. Among the nine patients with high-level HHV-6 DNA two developed encephalopathy. As encephalopathy developed before the detection of high-level HHV-6 DNA in plasma, these two patients had not received preemptive ganciclovir therapy. In conclusion, our preemptive approach against HHV-6-associated encephalopathy cannot prevent all cases of HHV-6 encephalopathy in SCT recipients due to the dynamic kinetics of plasma HHV-6 viral load.

Sixteen patients with adult T-cell leukemia/lymphoma (ATL) who were all over 50 years of age underwent allogeneic stem cell transplantation with reduced-conditioning intensity (RIST) from HLA-matched sibling donors after a conditioning regimen consisting of fludarabine (180 mg/m2), busulfan (8 mg/kg), and rabbit antithymocyte globulin (5 mg/kg). The observed regimen-related toxicities and nonhematologic toxicities were all found to be acceptable. Disease relapse was the main cause of treatment failure. Three patients who had a relapse subsequently responded to a rapid discontinuation of the immunosuppressive agent and thereafter achieved another remission. After RIST, the human T-cell leukemia virus type 1 (HTLV-1) proviral load became undetectable in 8 patients. RIST is thus considered to be a feasible treatment for ATL. Our data also suggest the presence of a possible graft-versus-ATL effect; an anti-HTLV-1 activity was also found to be associated with this procedure.

The lignostilbenedioxygenase isozyme I and III genes, lsdA and lsdB, were coexpressed within the same Escherichia coli cells. The lignostilbenedioxygenase isozymes produced were separated on QAE anion-exchange column chromatography. Three parts of active fractions corresponding to alphaalpha, alphabeta, and betabeta dimers were detected. The purified isozyme from second active fractions corresponded to the native heterogeneous isozyme II.

Background: A relationship between Helicobacter pylori infection and idiopathic thrombocytopenic purpura (ITP) has previously been reported. We determined the prevalence of H pylori infection in Japanese patients with chronic ITP and the effect of its eradication on platelet count., Methods: The study population comprised 53 Japanese adults with chronic ITP and a platelet count of less than 100 x 10(3)/ micro L. A (13)C-urea breath test was performed to determine H pylori infection status. Those patients who were H pylori positive gave written informed consent and received eradication therapy. The effect of H pylori eradication on platelet count was evaluated up to 6 months after therapy. Clinical parameters were compared between responders to the therapy (increase in platelet count) and nonresponders, as well as between H pylori-positive and -negative patients., Results: Of the 53 patients with chronic ITP in the study, 39 (74%) were H pylori positive. Of the 32 infected patients who received treatment, H pylori was successfully eradicated in 27 patients (84%). In 10 (37%) of these patients, this resulted in a favorable platelet response. A partial response was seen in 5 additional patients (19%). A significant (P<.001) increase in platelet count was demonstrated in patients in whom H pylori was successfully eradicated but not in patients who were unsuccessfully treated or in untreated patients. Current corticosteroid therapy was reported more often in nonresponders than in responders., Conclusion: Eradication of H pylori may prove effective in increasing platelet count in H pylori-positive patients with chronic ITP.

Cyclosporine (CyA) was administered to 12 patients with myelodysplastic syndrome (MDS), and a response (major erythroid response, according to International Working Group criteria) was observed in 7 patients (58.3%). The median duration of response was 18 months (range, 3-22 months). Two patients are still responding and continuing to take CyA. Three patients stopped because of malignancy complications. To identify variables associated with responsiveness to CyA therapy, we analyzed the treatments of 72 MDS patients, comprising the 12 new patients and 60 patients previously described in the literature. Responses were observed in 44 of the 72 patients (61.1%). Univariate analyses revealed that higher daily dose of CyA (P for trend test, .007) and shorter disease duration (median, 5 months versus 17.5 months, P = .04) were factors significantly associated with response. No significant associations were observed between response and bone marrow features such as erythroid hypoplasia or hypoplastic marrow. Multivariate analysis also demonstrated that high CyA dose (>5 mg/kg per day) was significantly associated with response (P = .02). The present study showed that CyA therapy is useful for MDS patients with any marrow cellularity. Shorter disease duration is a pretreatment variable correlated with response, and a higher CyA dose results in a higher response rate.

The Kyushu Hematology Organization for Treatment Study Group (K-HOT) consisted of 22 institutions specializing in hematology in Kyushu. This study is aimed at reviewing the daily practice of infection control for the treatment of hematological malignancies in our group. Nominal questionnaires were mailed to the hematology department in each institution from November 2001 to April 2002. For the first general surveys, 19 of 22 (86%) institutions responded. The second survey was mailed to the 19 respondents and 17 answered the detailed questionnaires with a response rate of 89%. Prophylactic use of trimethoprim-sulfamethoxazole (ST) against Pneumocystis carinii and anti-mycobacterial drugs in patients who had a history of tuberculosis was routine especially for patients with adult T-cell leukemia/lymphoma (ATL). Furthermore, the neutrophil counts to start a granulocyte-colony stimulating factor appeared to be high in ATL as compared with other hematological malignancies. In the setting of autologous stem cell transplantation (SCT), prophylactic use of acyclovir, immunoglobulin and ST was not routine and was reduced in duration, if used at all, as compared with allogeneic SCT. For allogeneic SCT, the cumulative dose of immunoglobulin significantly varied from institutions to institutions. The benefit of this study is the ability to recognize practical management patterns for infection control.

Objective: The juvenile visceral steatosis (JVS) mouse, a murine model of systemic carnitine deficiency, shows a disorder of fatty acid oxidation and develops cardiac hypertrophy associated with lipid accumulation. Recently, alpha-tocopherol was shown to decrease 1,2-diacylglycerol (DAG) levels. We investigated the involvement of DAG in cardiac hypertrophy due to energy metabolism disorder by evaluating the effects of alpha-tocopherol administration on the hearts of JVS mice., Methods: Both JVS and control mice were fed a high alpha-tocopherol diet or a standard diet from 4 to 8 weeks of age. Myocardial DAG levels and fatty acid composition were assessed at 8 weeks of age., Results: The ventricular to body weight ratio in the JVS mice was significantly higher than that in the control mice [11.2+/-0.1 (mean+/-S.E.M.) versus 3.8+/-0.1 mg/g, P<0.01], and was reduced by alpha-tocopherol treatment (9.7+/-0.2 mg/g, P<0.01 versus JVS mice). However, echocardiographic analysis showed the exaggeration of left ventricular dilatation in the alpha-tocopherol treated JVS mice (P<0.01 versus JVS mice). The myocardial thiobarbituric-acid-reactive substance level was not affected by alpha-tocopherol treatment. The myocardial DAG level was 2.5-fold higher in the JVS mice compared with that in the control mice (2004+/-136 versus 806+/-36 ng/mg dry weight, P<0.01) with a significant increase in 18:1 and 18:2 fatty acids. alpha-Tocopherol treatment reduced myocardial DAG levels in the JVS mice (1443+/-49 ng/mg dry weight, P<0.01 versus JVS mice) without any alteration of the fatty acid composition., Conclusions: alpha-Tocopherol treatment may partially reduce cardiac hypertrophy but it may also depress cardiac function in the JVS mice by decreasing the myocardial DAG level. An increase in DAG might be involved in the development of cardiac hypertrophy and in the maintenance of cardiac function in energy metabolism disorder of the heart.

A common structure of substrates of lignostilbenedioxygenases was investigated using synthesized stilbenes. Cell-free extracts of Sphingomonas paucimobilis TMY1009 degraded only trans-4-hydroxystilbene and trans-4-hydroxy-3-methoxystilbene. Other stilbenes that had no 4-hydroxyl group and had a cis structure were not substrates for lignostilbenedioxygenases. These results indicate that a 4-hydroxyl group and trans-structure is necessary for the common structure for substrates of lignostilbenedioxygenases.

Adult T-cell leukemia-lymphoma (ATL) is a retrovirus-associated T-cell malignancy with an extremely poor prognosis; the median survival time of ATL patients with the acute or lymphoma type is less than 1 year with various combination chemotherapies. Cladribine (2-chlorodeoxyadenosine; 2-CdA), a purine analog resistant to degradation by adenosine deaminase, has shown definitive clinical activity against various lymphoid malignancies, including hairy cell leukemia, indolent lymphoma, and cutaneous T-cell lymphoma. An in vitro study showed the sensitivity of T-lymphoblastoid cell lines to cladribine, and a preceding Japanese phase I study of cladribine showed that 1 refractory patient with ATL achieved an objective response. To evaluate the therapeutic efficacy of cladribine in treating ATL, we conducted a multicenter phase II study. The plan was to administer cladribine to 30 ATL patients as 0.09 mg/kg per day by 7-day continuous intravenous infusion every 4 weeks for up to 3 courses. Before the planned interim analysis, 16 patients with relapsed or refractory ATL were enrolled, 15 of whom were eligible. Only 1 of the 15 eligible patients showed an objective response (overall response rate, 7%; 90% confidence interval, 0% to 28%), and 11 patients (73%) showed progressive disease, mostly during the first course of treatment. Because the upper limit of the 90% confidence interval of the overall response rate did not reach 30% in the interim analysis, the Independent Monitoring Committee advised us to discontinue patient enrollment. In conclusion, cladribine is not worthy of further investigation for the treatment of ATL.