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Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities (MLN-FGFR1 abnormalities) are rare hematologic malignancies associated with chromosome 8p11.2 abnormalities. Translocations of 8p11.2 were detected in 10 of 17,039 (0.06%) unique patient cytogenetic studies performed at nine institutions in Japan. No inversions or insertions of 8p11.2 were detected. Among the 10 patients with 8p11.2 translocations, three patients were diagnosed with MLN-FGFR1 abnormalities, which were confirmed by FISH analysis. Peripheral blood eosinophilia was observed in all three patients, and all progressed to AML or T-lymphoblastic lymphoma/leukemia. The prevalence of 8p11.2 translocations in clinical practice and the proportion of MLN-FGFR1 abnormalities in patients with 8p11.2 translocations in Japan were consistent with those in previous reports from Western countries., (© 2024. The Author(s).)

Secondary central nervous system (CNS) lymphomas typically require CNS-penetrating drugs; however, the available agents are limited with temporary effects and poor outcomes. Chimeric antigen receptor T (CAR-T) cell therapy (lisocabtagene maraleucel; liso-cel) has been used to treat a few cases of isolated secondary CNS lymphoma. Herein, we report the case of a 66-year-old male diagnosed with diffuse large B-cell lymphoma (Ann Arbor grade IV; R-IPI, good risk; CNS IPI: Intermediate risk) who achieved complete remission (CR) after six courses of R-CHOP therapy. Three months later, he presented with ptosis and eye movement disorder. Systemic CT and bone marrow examination revealed no lymphoma. Although cranial-enhanced MRI showed normal findings, an increased number of B-cells (51/μL) with the original lymphoma phenotype (CD19+CD79a+CD5-CD10-CD20-Igλ+) was detected in cerebrospinal fluid (CSF), indicating an isolated CNS relapse. Seven high-dose methotrexate courses led to partial response. Subsequently, the patient received CAR-T cell therapy with tolerable adverse events - cytokine release syndrome treated with tocilizumab, no immune effector cell-associated neurotoxicity syndrome, and bone marrow failure treated with granulocyte-colony stimulating factor and eltrombopag. Sequential flow cytometry revealed a high peak of CAR-T cells and the presence of residual CAR-T cells in the peripheral blood, indicating immune surveillance of CNS lymphoma by CAR-T cells. This treatment led to a second CR. This case is the first to validate the efficacy and safety of CAR-T cell therapy for isolated secondary CNS lymphoma in clinical practice. Future accumulation of evidence on the efficacy and safety of CAR-T cell therapy is essential., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website., (Copyright Ⓒ2024 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)

The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and highrisk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (-4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (-2), and GATA3 (-3).

Recently, the ratio of C-reactive protein to albumin (CAR) is used as an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in solid tumors and hematological malignancy. However, no studies of the CAR have been performed in patients with adult T-cell leukemia-lymphoma (ATL). We retrospectively analyzed the clinical features and outcomes in 68 newly diagnosed acute- and lymphoma-type ATL [(acute-(n=42) or lymphoma-type (n=26)] patients in Miyazaki Prefecture from 2013 to 2017. Furthermore, we investigated correlations between pretreatment CAR levels and clinical features. The median age was 67 years (range, 44 - 87). Patients were initially treated by either palliative therapy (n=14) or chemotherapy [n=54; CHOP therapy (n=37)/ VCAP-AMP-VECP therapy (n=17)], and showed median survival durations of 0.5 months and 7.4 months, respectively. The factors affecting OS by multivariate analysis were age, BUN, and CAR. Importantly, we revealed that the high CAR group (optimal cut-off point; 0.553) was a significant indicator of worse OS by multivariate analysis (p< 0.001, HR; 5.46). The median survival of patients with a CAR< 0.553 was 8.37 months, while patients with a CAR>0.553 had a median survival of 3.94 months. The different clinical features between high CAR and low CAR groups were hypoproteinemia and the implementation of chemotherapy. Furthermore, in the chemotherapy group, but not the palliative therapy group, CAR was a significant prognostic marker. Our study indicated that CAR may be a new simple and significant independent prognostic marker in acute- and lymphoma-type ATL patients.

Secondary malignancies that develop after allogeneic-hematopoietic stem cell transplantation (allo-HSCT) have become serious issues. A 47-year-old man who developed acute myeloid leukemia in 2009 and subsequently underwent allo-HSCT twice: in 2009 and 2011. In 2015, voriconazole for lung aspergillus was started. In 2018, chronic graft-versus-host disease (GVHD) and multiple actinic keratoses manifested at his head. In 2020, some lesions were diagnosed as squamous cell carcinoma, so voriconazole was withdrawn, and subsequent surgery and radiation led to remission. Long-term administration of voriconazole in addition to allo-HSCT and chronic GVHD may be closely related to secondary skin cancer.

A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL.

Although tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), intolerance and resistance to TKIs have been serious problems. Due to a lack of research, the importance of the pharmacokinetics (PK) of TKIs is currently unclear. We examined the PK of the third-generation TKI ponatinib to monitor side effects and efficacy during treatments for one patient with CML-chronic phase (CP-CML) and two who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), one for CML-blastic crisis (BC-CML) and one for Ph + ALL. The patient with CP-CML was intolerant to multiple TKIs (dasatinib, nilotinib, imatinib, and bosutinib) and thus was switched to ponatinib (15 mg/day). The patients who received allo-HSCT for BC-CML and Ph + ALL received ponatinib (15 mg/day) as maintenance therapy. Notably, serial evaluation of the PK of ponatinib showed that the median trough values (ng/ml) were 17.2 (12.2-34.5), 33.1 (21.2-40.3) and 27.7 (13.6-29.9) in patients 1, 2, and 3, respectively. These values were around the target concentration (23 ng/ml). All patients are maintaining complete remission without side effects. In conclusion, serial evaluation of PK of ponatinib may yield meaningful information about its safety and efficacy., (© 2021. Japanese Society of Hematology.)

Background: Although anthracycline-related cardiomyopathy is a life-threatening complication during intensive treatment for hematological malignancies, clinical features and outcomes of this type of cardiomyopathy have been unclear because of limited reports in the literature., Methods: We analyzed three cases of anthracycline-related cardiomyopathy among 996 patients with either acute myelogenous leukemia (285), acute lymphoblastic leukemia (37), or malignant lymphoma (674) at our hospital during the period from 2006 to 2016., Results: All patients showed accumulation of anthracycline within a proper range (< 500 mg/sqm). Two patients (Hodgkin lymphoma and acute lymphoblastic leukemia) showed acute heart failure (AHF) with ejection fraction (EF) of 30 and 40% after 4.5 and 5 years after diagnosis, respectively. For AHF, diuretics and carperitide were administered to control in-out balance. The remaining patient (follicular lymphoma) showed ventricular fibrillation (VF)/ventricular tachycardia (VT) with EF of 40% at 5 years after diagnosis. In this patient, immediate cardioversion made VF/VT to normal sinus rhythm, and then, amiodarone was given. Furthermore, implantable cardioverter defibrillator was set up for VF/VT. In all patients, β blocker and/or angiotensin-converting enzyme inhibitor (ACE-I) were administrated to prevent recurrence of anthracycline-related cardiomyopathy. Consequently, two of three patients showed mild improvement of cardiac function., Conclusion: Our study indicates that late-onset (4 to 5 years) anthracycline-related cardiomyopathy can develop, though range of anthracycline accumulation is in proper range. Thus, a cautious follow-up by ECG and UCG is required. Furthermore, the early treatment after the onset of anthracycline-related cardiomyopathy should be also needed to improve the poor outcome.

Objective and Method: Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma with poor prognosis. We retrospectively reviewed the medical records of 312 patients with aggressive ATL and analyzed the effect of chemotherapy dose intensity on prognosis in clinical practice., Result: As first-line therapy, 62 patients underwent best supportive care (BSC) or single-agent chemotherapy, and 235 underwent intensive chemotherapy. The median survival time (MST) was 0.58 years in the 312 total patients, and 0.13 years and 0.75 years in the BSC/single-agent chemotherapy group and intensive chemotherapy group, respectively. The median average relative dose intensity (ARDI) of patients who received intensive chemotherapy was 60%. We divided patients into 3 groups according to ARDI. Those in the top tertile of ARDI (ARDI ≥ 75%, n = 82) had better overall survival compared with those in the intermediate tertile (45% ≤ ARDI < 75%, n = 79) (P < .0001), with MSTs of 4.69 and 0.75 years, respectively. The occurrence of organ dysfunction and infectious complications was comparable between the two ARDI groups., Conclusion: Higher ARDI improves prognosis in patients with aggressive ATL in clinical practice., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The prognosis of multiple myeloma (MM) has improved with the introduction of novel agents. These data are largely derived from clinical trials and might not reflect real-world patient outcomes accurately. We surveyed real-world data from 284 patients newly diagnosed with MM between 2010 and 2018 in Miyazaki Prefecture. The median follow-up period was 32.8 months. The median age at diagnosis was 71 years, with 68% of patients aged >65 years. The International Staging System (ISS) stage at diagnosis was I in 18.4% of patients, II in 34.1%, and III in 47.5%. Bortezomib-containing regimens were preferred as initial treatment; they were used in 147 patients (51.8%). In total, 80% of patients were treated with one or more novel agents (thalidomide, lenalidomide, or bortezomib). Among 228 patients who were treated with novel agents as an initial treatment, the overall response rate (partial response (PR) or better) to initial treatment was 78.4%, and the median time to next treatment (TTNT) was 11.6 months. In the multivariate analysis, PR or better responses to initial treatment were independently favorable prognostic factors for TTNT. The median survival time after initial therapy for patients with novel agents was 56.4 months and 3-year overall survival (OS) was 70.4%. In multivariate analysis, ISS stage I/II disease and PR or better response to initial treatment, and autologous stem cell transplantation (ASCT) were identified as independent prognostic factors for overall survival (OS).

The relapse of acute lymphoblastic leukemia (ALL) usually involves the bone marrow, with the central nervous system being the most frequent extramedullary site. The relapse of ALL in the female genital organs, particularly the uterus, is markedly rare. We report such a patient who developed relapse in the bone marrow and uterus. The uterine lesion, which presented as abnormal uterine bleeding, consisted of a mass on MRI and proliferation of ALL cells on histology. MRI revealed a heterogeneous high-intensity mass (T2-WI/D-WI) with a diameter of 6.8 cm, a notable decrease in the apparent diffusion coefficient (ADC), and mild enhancement by contrast enhancement study. Histological findings of the uterine cervix demonstrated the infiltration of ALL. The patient achieved remission by allogeneic haplo-identical hematopoietic stem-cell transplantation, but died of complications of the transplantation. This case suggested that attention should be paid to the uterus as a site of extramedullary relapse. In addition, abnormal uterine bleeding, which is a common sign of hormonal imbalance and hormone replacement therapy after chemotherapy, may be an initial sign of extramedullary recurrence. To confirm uterine relapse as an intractable disease, the accumulation of more cases is required.

Objective To elucidate the clinical impact of humanized CCR4 antibody (mogamulizumab) on adult T-cell leukemia-lymphoma (ATL), we retrospectively analyzed the clinical and pathological features and treatment outcomes of aggressive ATL. Methods Twenty-two patients (median age: 65 years) with aggressive ATL [acute- (n=16) or lymphoma-type (n=6)] had their characteristics analyzed. All cases were treated with mogamulizumab at our institution from 2012 to 2018. In addition, we subjected 14 specimens of ATL to histological, immunological, and genetic analyses. Results Regarding the patient outcomes, the overall response rates were 68.1% and 31.8% after 4 and 8 courses (or after the final courses), respectively. The median overall survival (OS) was 95.5 days, while the OS rates at 6 and 12 months were 31.5% and 21.1%, respectively. Concerning patient pathological characteristics, 6 of the 14 patients examined (42.9%) had CCR4 mutations. Regarding the clinicopathological findings related to the mogamulizumab response, notably, the cases with somatic CCR4 mutation tended to have a poorer response (16.7%) than those with wild-type CCR4 (62.5%) after 4 cycles of mogamulizumab. Furthermore, the CCR4 global score tended to be higher in the responder cases than in the non-responder cases. Conclusion The present findings suggest that the CCR4 expression may be related to the mogamulizumab response, although no other significant predictive markers were identified in this study. Further studies will be needed in order to identify more markers related to the mogamulizumab response.

As opportunistic infections among human T-lymphotrophic virus type 1 (HTLV-1) carriers and patients with adult T-cell leukemia/lymphoma (ATL) pose a serious problem, it is necessary to clarify their clinical characteristics and outcomes in these patients. We retrospectively analyzed the clinical features and outcomes of opportunistic infections in 127 HTLV-1 carriers and 153 ATL patients between 2006 and 2016. The cumulative incidence rates of opportunistic infections among HTLV-1 carriers and ATL patients were 1.5% (2/127) and 6.5% (10/153), respectively. The etiology of opportunistic infections was as follows: fungal infections (3 cases), pneumocystis pneumonia, and cytomegalovirus (CMV) infections. Even after aggressive treatment, the prognosis of opportunistic infections was poor (50% of overall survival at 28 days). Regarding prognostic factors affecting the OS of opportunistic infections, higher SOFA scores (especially the respiratory subscore) and higher LDH values were identified by univariate analysis. Moreover, 3 out of 6 patients achieved spontaneous remission of ATL as the short-term outcome after the development of opportunistic infection. However, 5 out of 6 surviving patients exhibited ATL progression or relapse after a median of 194 days (133-226) after contracting an opportunistic infection as the long-term outcome of ATL. In conclusion, opportunistic infections should be carefully followed among HTLV-1 carriers and ATL patients because of their aggressive clinical course and poor outcomes. Furthermore, early diagnosis and subsequent prompt treatment are necessary in clinical practice.

A new entity, namely early/prefibrotic primary myelofibrosis (PMF), was introduced as a subtype of PMF in the 2016 revised World Health Organization (WHO) criteria for myeloproliferative neoplasms (MPN). It was diagnosed based on histopathological features of bone marrow (BM) biopsy specimens together with clinical parameters [leukocytosis, anemia, elevated lactate dehydrogenase (LDH) values, and splenomegaly]. The aim of this study was to evaluate the prevalence of early/prefibrotic PMF in patients who were previously diagnosed with ET, and to compare clinical features at diagnosis and outcomes between early/prefibrotic PMF and essential thrombocythemia (ET) patients. BM biopsy samples obtained at the time of ET diagnosis were available in 42 patients. Sample reevaluation according to the 2016 revised WHO criteria revealed that early/prefibrotic PMF accounted for 14% of patients who were previously diagnosed with ET, which was comparable to the rates in previous reports. Compared to patients with ET, patients with early/prefibrotic PMF had higher LDH values and higher frequencies of splenomegaly. Overall, myelofibrosis-free and acute myeloid leukemia-free survivals were comparable between the 2 groups. Accurate diagnosis is required to clarify the clinical features of Japanese ET patients.

Because there are limited clinical reports on the impact of human T-lymphotropic virus type 1 (HTLV-1) on organ transplantation, its effects on the development of adult T-cell leukemia-lymphoma (ATL), post-transplantation lymphoproliferative disorder (PTLD) and HTLV-1-associated myelopathy (HAM) or atypical HAM after organ transplantation remain unclear.We retrospectively analyzed the impact of HTLV-1 in 54 allogeneic hematopoietic stem cell transplantation (allo-HSCT) cases and 31 renal transplantation cases between January 2006 and December 2016.Among the 54 allo-HSCT cases, nine recipients with ATL tested positive for HTLV-1, and one was found to be an HTLV-1 carrier. All donors tested negative for HTLV-1. Only one HTLV-1 carrier did not present with ATL or HAM development after allo-HSCT. Among nine ATL cases after allo-HSCT, four eventually relapsed due to proliferation of recipient-derived ATL cells. However, in one ATL case, atypical HAM developed rapidly at 5 months after allo-HSCT.Among the 31 renal transplantation cases, all donors tested negative for HTLV-1, and only recipients tested positive. Only one HTLV-1 carrier recipient did not present with ATL or HAM development after renal transplantation. However, one HTLV-1-negative recipient developed PTLD in the brain 10 years after renal transplantation.In clinical practice, careful follow-up of HTLV-1 infected recipients after organ transplantation is important because atypical HAM can develop in ATL patients after allo-HSCT. Furthermore, to clarify the risk of ATL or HAM development in HTLV-1 infected recipients, we prospectively followed up our cohort.

Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with life-threatening thrombohemorrhagic events, and disease progression and development of non-hematological malignancies also reduce long-term survival. We retrospectively surveyed thrombohemorrhagic events and overall survival (OS) in 62 PV and 117 ET patients. The cumulative incidences of thrombohemorrhagic events in PV and ET patients were 11.3 and 10.3%, and the incidence rates were 2.42 and 1.85 per 100 person-years. The combined incidence rates of disease progression and development of non-hematological malignancies in PV and ET patients were 1.73 and 1.69 per 100 person-years. The incidence rates of thrombohemorrhagic events in our Japanese PV/ET patients were lower than those reported by most Western studies, but were comparable to those in the largest prospective observational study in ET patients. The combined incidence rates of disease progression and development of non-hematological malignancies were similar between Japanese and Western PV/ET patients. In ET patients, the conventional risk stratification model based on the presence of advanced age or history of thrombosis was useful to predict thrombosis risk, and both the conventional model and the International Prognostic Score of thrombosis in ET based on the above 2 risk factors plus increased leukocyte count could predict poor survival.

Adult T-cell leukemia-lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering ATL. We conducted a nationwide retrospective survey on ATL patients, and 248 fully eligible individuals were used in this analysis. In the univariate analysis, sex, performance status, log 10 (soluble interleukin-2 receptor [sIL-2R]), neutrophils count, and lymphadenopathy showed values of P < .05 in training samples. A multivariate analysis was performed on these factors, and only log 10 (sIL-2R) was identified as an independent prognostic factor in training samples. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: indolent ATL-PI (iATL-PI) = 1.51 × log 10 (sIL-2R [U/mL]). The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6 years, 5.5 years, and not reached for patients in the high-, intermediate-, and low-risk groups, respectively ( P < .0001). To make the scoring system clinically practicable, we simplified iATL-PI according to trichotomizing sIL-2R at 1000 and 6000 U/mL, using a quartile point. Patients with more than 6000 U/mL sIL-2R were categorized into the high-risk group, less than and equal to 1000 U/mL into the low-risk group, and the others into the intermediate-risk group, and MSTs were 1.6 years, not reached, and 5.5 years, respectively ( P < .0001). iATL-PI has potential as a novel tool for a risk-adapted therapeutic approach., (© 2017 by The American Society of Hematology.)

Objective: The efficacy of mogamulizumab in adult T-cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study. Compared with patients in clinical trials, however, most patients in real-life settings have demonstrated worse outcomes., Method: We retrospectively analyzed 96 patients with relapsed/refractory ATLL who received mogamulizumab treatment., Results: Relapsed/refractory ATLL patients with a median age of 70 years received a median of five courses of mogamulizumab. Hematologic toxicity and skin rash were the most common adverse events, and both were manageable. Of 96 patients, 87 were evaluable for efficacy. The overall response rate was 36%, and the median progression-free survival (PFS) and overall survival (OS) from the start of mogamulizumab therapy were 1.8 and 4.0 months, respectively. Of the original 96 patients, only 25 fulfilled the inclusion criteria of the phase 2 study. Those who met the criteria demonstrated longer median PFS and OS durations of 2.7 and 8.5 months, respectively. The median OS from diagnosis in relapsed/refractory ATLL patients receiving mogamulizumab was 12 months, longer than the 5.8 months in a historical cohort without mogamulizumab., Conclusion: In clinical practice, mogamulizumab exhibited antitumor activity in patients with relapsed/refractory ATLL, with an acceptable toxicity profile. Mogamulizumab therapy improved the OS of ATLL patients., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although a humanized CCR4 antibody (mogamulizumab) was reported to be effective for refractory adult T-cell leukemia-lymphoma (ATL), several reports regarding the use of mogamulizumab before allo-hematopoietic stem cell transplantation (HSCT) strongly indicated a high incidence of severe acute graft-versus-host-disease (GVHD) and treatment-related mortality (TRM). We retrospectively analyzed nine aggressive-type ATL patients who underwent allo-HSCT at a single institution in Miyazaki from 2006.1.1 to 2015.7.31. Among nine ATL patients, three had used mogamulizumab before treatment with allo-HSCT because of the poor control of refractory ATL. All three patients were treated with four to eight cycles of mogamulizumab. The interval from last administration of mogamulizumab to allo-HSCT was two to five months. All three patients with prior mogamulizumab treatment developed mild-moderate acute GVHD (grade 2) 28, 34, or 40 days after allo-HSCT. Acute GVHD was controlled by prednisolone treatment. Two patients in complete remission before allo-HSCT exhibited relatively prolonged survival (survival rate, 66%). Moreover, one patient developed human T-cell leukemia virus type 1-associated myelopathy-mimicking myelitis at five months after allo-HSCT. In contrast, two of six ATL patients without a history of mogamulizumab use survived (survival rate 33%). Thus, in cases of mogamulizumab use before treatment with allo-HSCT for refractory ATL, an appropriately long interval from the last administration of mogamulizumab to allo-HSCT may be one of factors to reduce TRM by acute GVHD, and to subsequently enhance graft-versus-tumor effects in ATL cases. Furthermore, caution is needed when administering mogamulizumab before allo-HSCT for severe GVHD and TRM.

Primary bone lymphomas comprise <1 % of all malignant lymphomas, and there have been only a limited number of reports on primary adult T-cell leukemia/lymphoma (ATLL) of bone. Here, we report two cases of primary ATLL of bone. The first case was a 41-year-old woman with multiple bone tumors. She was diagnosed with ATLL of the skull through biopsy and treated with chemotherapy. Although the bone lesions showed transient improvement, the subsequent central nervous system (CNS) invasion of ATLL occurred and she died 7 months after diagnosis. The second case was a 65-year-old man with right coxodynia. He was diagnosed with ATLL through right femoral biopsy, and the lesion improved with chemotherapy. However, CNS invasion of ATLL developed during chemotherapy, and he died 10 months after diagnosis. Both the patients with primary ATLL of the bone reported here experienced CNS invasion. Thus, ATLL treatment should aim to prevent CNS invasion at an early stage.

Although clinical trials of first- and second-generation tyrosine kinase inhibitors (TKIs) have been shown to improve the prognosis of chronic myeloid leukemia (CML), there is still uncertainty about the clinical features, treatment outcomes, adverse effects, and other possible problems of their use in the clinical setting. We retrospectively analyzed 51 CML patients treated with TKIs at a single institution between 2002 and 2014. The patients (median age: 53.8 years) were classified as having chronic (n = 48), accelerated (n = 2), or blastic phase (n = 1) CML. Our treatments included both 1st generation TKIs (60.8%) and 2nd generation TKIs (39.2%). We found that the overall response rates of complete cytogenetic response (CCyR), major molecular response (MMR), and MR4 (molecular response 4) were 90.2%, 78.4%, and 64.7%, respectively. Second line 2nd generation TKIs had response rates equivalent to those of 1st line 1st generation TKIs. Moreover, 1st line 2nd generation TKIs tended to achieve an early response rate. Overall survival (OS) at 5 years was 93.2%. Sudden blastic crisis (BC) occurred in 2 CML patients receiving TKI with CCyR status. Hematopoietic stem cell transplantation was performed for BC (n = 1) and sudden BC (n = 2). Side effects of all grades (1-3) and grade 3 alone were 64.7% and 11.8%, respectively. Dose reduction, replacement with another TKI, or low dose TKI treatment may be useful methods to control side effects. Further reasons of TKI discontinuation were economic problems (n = 3) and pregnancy (n = 1). Consequently, our treatment strategy for CML demonstrated good response rate and OS. Currently, treatment discontinuation due to intolerance, resistance, economic problems, pregnancy, and sudden BC remains a concern in clinical practice.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a serious disorder in which monoclonal growth of T cells infected with EBV and macrophage activation cause pancytopenia, high fever and acute liver failure. Patients with chemotherapy- or immunosuppression-resistant EBV-HLH require allogeneic hematopoietic stem cell transplantation (allo-HSCT), but patients who have no sibling donors may not have time to wait for an unrelated donor. In pediatric patients, there are some reports on allogeneic cord blood transplantation (allo-CBT) for the treatment of EBV-HLH; however, in adult patients, reports of allo-CBT for EBV-HLH are quite limited. The present case of a 20-year-old woman with chemotherapy-resistant EBV-HLH and systemic lupus erythematosus (SLE) who underwent allo-CBT following reduced-intensity conditioning (RIC-CBT). She achieved and maintained a complete donor type and the EBV-DNA load, and the titers of anti-double stranded DNA and antinuclear antibodies became negative. It is therefore considered that RIC-CBT is an effective treatment option for adult onset HLH. However, because the effectiveness of allo-HSCT for SLE remains unclear and transplant-related mortality is high, it is recommended that allo-HSCT for SLE is restricted to patients concomitant with oncohematological disease as with our present case.

Objective We elucidated the effectiveness of a humanized CCR4 antibody (mogamulizumab) on adult T-cell leukemia-lymphoma (ATL), which typically has a poor outcome. Methods We retrospectively analyzed 14 patients with aggressive ATL who had been treated at our institution with weekly cycles of mogamulizumab for eight weeks from 2012-2014. Results The patients (median age: 63 years old) were classified as having acute- (n=10) or lymphoma-type (n=4) ATL. The prior treatment regimens consisted of CHOP, VCAP-AMP-VECP, DeVIC and CHASE, with an average of two courses (range: 1-4). The prior disease responses were partial remission (n=3) and progressive disease (n=11). The treatment was administered in the primary refractory setting (n=8), for relapse (n=2), or as bridging therapy before hematopoietic stem cell transplantation (n=4). The overall response rates were 64% and 43% after four and eight cycles (or after the final cycles), respectively. The median overall survival (OS), OS rate at six months and OS rate at 12 months were 66 days, 41.7% and 20.8%, respectively. All of the patients with acute-type ATL who showed a response to treatment had an early response. Notably, six of the 14 ATL patients showed somewhat prolonged survival (>100 days). However, relapse or disease progression in the peripheral blood, central nervous system, lymph nodes, skin, and/or bone occurred within a relatively short period after treatment. The adverse effects were tolerable, and included lymphopenia, cytomegalovirus infection and skin rash. Conclusion Mogamulizumab therapy resulted in an early and high remission rate and somewhat prolonged survival in patients with refractory ATL. However, the duration of remission was short, and there was early relapse and disease progression. This study may show the current impact of mogamulizumab in clinical practice.

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.)

Although graft failure (GF) is a fatal and life-threatening complication of umbilical cord blood transplantation (CBT), the standard treatment has not been established. We describe the case of a 28-year-old man diagnosed with acute myelogenous leukemia with myelodysplasia-related changes harboring a normal karyotype. This patient underwent 2 courses of idarubicin and cytosine arabinose therapy, and 3 courses of high-dose cytosine arabinose therapy. Subsequently, he underwent high-dose chemotherapy (total body irradiation and cyclophosphamide) followed by first CBT. Primary GF occurred after post-immunological reaction and hemophagocytic lymphohistiocytosis, and was diagnosed on day 27 after the first CBT. Therefore, the patient underwent secondary CBT for GF treated with a modified one-day conditioning regimen consisting of fludarabine (30 mg/m(2), 3 days), cyclophosphamide (2 g/m(2)), and total body irradiation (2 Gy), and graft-versus-host disease prophylaxis consisting of mycophenolate and tacrolimus. Consequently, the patient achieved neutrophil engraftment on day 17 after the second CBT. During the clinical course of the second CBT, the main complications were sepsis, BK virus-associated cystitis, and acute graft-versus-host disease (skin, grade 2, stage 3). After these treatments, the patient was disease-free for 39 months. Our case suggests that these treatments may be feasible, safe, and effective for the treatment of patients with GF. This case study may be helpful to physicians who directly care for GF patients, and may provide a future direction for a more efficient treatment modality.

Objective: Despite the remarkable advances in chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), adult T-cell leukemia-lymphoma (ATL) is still associated with a high mortality rate. It is therefore essential to elucidate the current features of ATL., Methods: We retrospectively analyzed 81 patients with aggressive type ATL at our institution over a 7-year period based on Shimoyama's diagnostic criteria., Results: Eighty-one patients with a median age of 67.5 years were classified as having acute (n=47), lymphoma (n=32), or chronic type (n=2) ATL. They were initially treated by either palliative therapy (n=25) or systemic chemotherapy [n=56; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (n=25)/vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP)-doxorubicin, ranimustine, and prednisone (AMP)-vindesine, etoposide, carboplatin, and prednisone (VECP) therapy (VCAP-AMP-VECP) or CHOP-VMMV therapy (n=31)], and showed median survival durations of 16 and 277 days, respectively. Subsequent to the initial treatment, HSCT (n=6) was performed for certain patients, thus revealing that two-thirds (n=4) relapsed, and one-third (n=2) survived for 131 days and 203 days, respectively. The relapsed ATL patients were treated with conventional salvage therapy (n=29) or anti-CC chemokine receptor 4 antibody (mogamulizumab) (n=3). The patients treated with mogamulizumab demonstrated complete response (2) and partical response (1) with short duration periods of 82 days, 83 days, and 192 days, respectively. Among the five long-term survivors (>5 years) who received chemotherapy, most showed a low and intermediate risk according to the ATL prognostic index., Conclusion: In our study, the overall survival of ATL remains poor due to the advanced age of the patients at diagnosis, a high proportion of patients receiving palliative therapy, and a small proportion of long-term survivors receiving chemotherapy and undergoing HSCT. This study illustrates the current clinical features, treatment strategies, and outcomes in clinical practice.

Malignancy is a fatal complication of end-stage renal disease (ESRD) requiring haemodialysis. However, the successful treatment of haematological malignancies has been rarely reported. We describe the case of a 63-year-old man who presented with IgA-type multiple myeloma (MM; Durie-Salmon stage IIIB) derived from monoclonal gammopathy of undetermined significance concomitant with ESRD due to diabetic nephropathy. First, haemodialysis was initiated before chemotherapy, and bortezomib and dexamethasone were found to be ineffective. Subsequently, 8 courses of dose-adjusted lenalidomide therapy were administered according to the degree of haematological and renal functions. The patient remained in partial remission without disease progression for 21 months. Thus, lenalidomide therapy is effective for bortezomib-refractory MM concomitant with ESRD.

Objective: Disseminated intravascular coagulation (DIC) is a clinical condition with high mortality that is characterized by the systemic activation of coagulation pathways resulting in multiple organ failure. Although no standard treatment for DIC has been established, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC., Methods: To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 92 DIC patients who were treated with rTM at Miyazaki Prefectural Hospital over a 4-year period (62 patients had infectious diseases and 30 patients had hematological diseases). A diagnosis of DIC was made based on the diagnostic criteria of the Japanese Association for Acute Medicine (JAAM) and Japanese Ministry of Health and Welfare (JMHW) for infectious diseases and hematological diseases, respectively. In addition to treating the underlying disease, rTM was administered for six consecutive days., Results: In this study, 49 of the 92 DIC patients (53.3%) experienced resolution of DIC seven days after administration (46.8% patients with infectious disease and 66.7% with hematological disease). A higher survival rate was observed after a 28-day observation period in 69 of the 92 patients (75.0%) (72.6% of the patients with infectious disease and 80.0% of the patients with hematological disease). A lower DIC score at the initiation of rTM treatment was closely related to a higher rate of resolution of DIC., Conclusion: Our findings indicate that rTM therapy is an effective, safe and feasible treatment for DIC patients. Furthermore, making an accurate and early diagnosis of DIC and providing subsequent immediate treatment with rTM may improve the resolution of DIC.

Immunodeficiency-associated lymphoproliferative disorders (LPD) represent a rare life-threatening clinical entity characterized by heterogeneous histological findings that range from polymorphic to monomorphic proliferated abnormal lymphocytes. Currently, there is no standard treatment for LPD. To elucidate the clinical features and treatment outcomes of immunodeficiency-associated LPD patients with rheumatoid arthritis (RA), we retrospectively evaluated 9 cases observed over a 5-year period. The diagnoses of these patients included 5 diffuse large B-cell lymphomas, 3 LPD, and 1 mucosa-associated lymphoid tissue lymphoma. At initial diagnosis, 6 patients had advanced-stage RA, and half of these underwent total knee arthroplasty. All patients with RA received methotrexate (MTX) and low-dose prednisolone. Biologics were administered to 4 of 9 patients. After the development of immunodeficiency-associated LPD, MTX discontinuation resulted in 5 complete remissions (CR), 1 partial remission, and 3 cases of stable disease. Relapse was observed in 3 of 5 CR patients in the MTX-withdrawal remission group. Subsequently, conventional chemotherapy, rituximab, and radiation were administered to 4, 3, and 1 patient, respectively. These treatments induced a second CR. In the chemotherapy group, 1 patient developed acute myocardial infarction and another experienced ileus and pulmonary abscess. In the rituximab group, no severe complications were observed. Consequently, all patients remained disease-free during the median 23-month follow-up period. Our results indicate that, depending on the RA disease stage, performance status, and extent of treatment response, less intensive treatments than those commonly indicated for non-Hodgkin lymphoma, involving MTX discontinuation and subsequent therapy containing rituximab, might be an efficient therapeutic strategy for immunodeficiency-associated LPD.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is a complication of hematopoietic stem cell transplantation (HSCT). Standard initial treatment of patients with EBV-PTLD includes administration of rituximab or dose reduction of a calcineurin inhibitor. We report successful chemotherapeutic treatment of rituximab-resistant EBV-PTLD after HSCT in a patient with severe aplastic anemia (AA). A 38-year-old woman with antithymocyte globulin (ATG)-resistant severe AA received bone marrow transplantation from an unrelated donor (human leukocyte antigen-DR single-locus mismatch). The conditioning regimen included fludarabine, cyclophosphamide, ATG, and total body irradiation, and prophylaxis for graft-versus-host disease consisted of short methotrexate and tacrolimus. Neutrophil engraftment occurred on day 21. Left cervical lymph node swelling was observed after day 45, and analysis of a biopsy specimen revealed EBV-PTLD and a high blood EBV load (56,000 copies). The patient was treated with rituximab 4 times per week, but the lymphadenopathy continued and the blood EBV load increased to 96,000 copies. Half-dose treatment with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) was initiated on day 71. After 32 days of treatment with R-CHOP, the patient's neutrophil level was restored to > 0.5 × 10(9)/L and both the lymphadenopathy and the blood EBV load (< 100 copies) were rapidly reduced. Although chemotherapy is not preferred soon after HSCT, it may be an effective strategy for treating patients with rituximab-resistant EBV-PTLD.

Objective: Pure red cell aplasia (PRCA) is a rare clinical entity characterized by anemia due to severe suppression of erythroid precursors, where the other cell lineages in the bone marrow remain morphologically normal. A standard treatment has not yet been established for PRCA due to the rarity of this condition. Recently, however, the administration of either cyclosporine (CSP) or prednisolone (PSL) has been reported to be an effective treatment for PRCA., Methods: To clarify the clinical characteristics of PRCA, 11 PRCA cases were retrospectively analyzed over a 13-year period at our institution. Since acute PRCA was found to be self-limiting, we administered the immunosuppressive treatment of CSP or PSL after providing supportive care for 4 weeks., Results: The causes of PRCA were as follows: idiopathic (3), acute parvovirus infection (1), chronic parvovirus infection (3), thymic tumor (3), and end-stage renal disease with hemodialysis (1). Complete remission (CR) was achieved for 4 of the 5 patients treated with CSP, for 2 of the 3 patients with chronic parvovirus infection treated by immunoglobulin (Ig), and for all 3 patients treated with PSL. During the follow-up periods, 4 of the 11 patients relapsed. Complete remission was achieved a second time in all 4 cases by therapies that were more intensive and had longer administration periods than those provided during initial treatment. Consequently, 9 of the 11 patients were still alive (80%) after 5 years., Conclusion: Depending on the cause of the PRCA, treatment with CSP, PSL, or Ig was found to be effective in most PRCA cases.

Objective: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disease with pathological features that are termed thrombotic microangiopathies. Since the discovery of the von Willebrand factor-cleaving protease [a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13)], it is widely known that approximately two-thirds of TTP patients have a severe deficiency of ADAMTS13 activity due to gene mutations or acquired autoantibodies to this enzyme. However, the remaining one-third of TTP patients have only moderately reduced or almost normal ADAMTS13 activity. To elucidate the clinical characteristics and outcomes of these two types of TTP, we have retrospectively analyzed the cases of acquired TTP patients treated in a single institution from 2000 to 2011., Methods: Our case studies include 11 TTP patients, of which 5 were considered idiopathic and 6 had cases of TTP associated with underlying diseases such as non-Hodgkin lymphoma or connective tissue diseases., Results: These patients were treated with a combination therapy of plasma exchange and steroids and with several adjunctive therapeutic regimens including the on-label use of cyclophosphamide and cyclosporine and the off-label use of high-dose steroid or immunoglobulin with rituximab. Splenectomies were not performed. As a result of these treatments, 6 out of the 7 patients with ADAMTS13 activity deficient TTP achieved a complete remission without relapse, but the remaining 4 patients with non-ADAMTS13 activity deficient TTP all died without complete remission., Conclusion: We present herein the detailed clinical courses of 11 patients with TTP and address our experiences with the efficacy of various therapeutic regimens. This case-oriented study should be helpful to the physicians who directly care for TTP patients, and may provide a future direction for developing a more efficient treatment modality.

Objective: Acute promyelocytic leukemia (APL) is characterized by the proliferation of blasts with distinct morphology and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) transcripts. Although the treatment outcome is dramatically improved by all-trans retinoic acid (ATRA), life-threatening bleeding from enhanced fibrinolytic-type disseminated intravascular coagulation (DIC) remains a serious clinical problem, and a standard treatment has not been established. However, recent reports indicate that recombinant human soluble thrombomodulin (rTM) is effective against DIC., Methods: To elucidate the clinical characteristics and outcomes of DIC resulting from APL, we retrospectively analyzed 10 patients with DIC resulting from APL at our institution over a six year period. Of the 10 patients, four were treated with serine protease inhibitors (SPI) and six were treated with rTM. The diagnosis of DIC was based on the diagnostic criteria of the Japanese Ministry of Health and Welfare. In addition to treating APL with ATRA, rTM was administered for six consecutive days., Results: The DIC was resolved within seven days after initiating treatment in 25.0% (1/4) of the patients in the SPI group and 66.6% (4/6) of the patients in the rTM group. Although the rTM group consisted of patients with life-threatening bleeding who required RCC transfusion, a prompt resolution rate and reduced DIC score without progression of bleeding was achieved in this group. All patients were alive after the 28-day observation period., Conclusion: Based on the present findings, rTM administration may be an effective, safe, and feasible therapeutic modality, producing a rapid resolution without progression of hemorrahage.

Crystal-storing histiocytosis is a rare clinical entity characterized by an increase in the number of abnormal histiocytes accompanied by accumulation of crystallized immunoglobulins. We describe the case of an 80-year-old man who presented with crystal-storing histiocytosis of the lung 13 years after receiving a diagnosis of gastric non-Hodgkin lymphoma (NHL ; clinical stage, Lugano IA). After wedge resection of the left upper lobe, the histological findings showed crystal-storing histiocytosis with CD68(+), some small to medium lymphoid cells with CD79a(+) with κ(+(weekly)) and λ(-), and some plasma cells with CD138(+), and rearrangement of the immunoglobulin heavy chain. Based on the nonrecurrent gastric NHL, small B-cell population, and failure to detect the same clone by polymerase chain reaction analysis, our case was classified as pulmonary localized crystal-storing histiocytosis without underlying lymphoproliferative or plasma cell disorder. The findings of minor B-cell populations harboring a heavy chain rearrangement with slight light-chain restriction (κ > λ) may be related to the pathogenesis of crystallogenesis and crystal-storing histiocytosis. Moreover, surgical treatment may be an effective therapeutic option for solitary crystal-storing histiocytosis.

Portal vein thrombosis is a rare, aggressive and life-threatening complication of liver cirrhosis (LC). Eltrombopag is effective for the treatment of chronic hepatitis with thrombocytopenia, and portal vein thrombosis at this time has rarely been reported. We describe the case of a 78-year-old woman who suffered from LC due to hepatitis C viral infection. The patient developed immune thrombocytopenic purpura (ITP) that was diagnosed on the basis of nasal bleeding, progressive severe thrombocytopenia, elevation of platelet-associated IgG (PAIgG), no response to the transfusion of platelets and no abnormal findings on bone marrow biopsy. Although we first administered prednisolone (0.5 mg/kg/day), there was no recovery of platelet function and the nasal bleeding persisted. Subsequently, we administered eltrombopag for refractory ITP at a dose of 12.5 mg/day, and the thrombocytopenia gradually improved. Fifty-four days after the start of eltrombopag therapy, she developed portal vein thrombosis. Eltrombopag was stopped immediately, and antithrombin III was administered for prophylaxis against further portal vein thrombosis. Despite these treatments, there were subsequent deep vein and pulmonary artery thromboses. We then administered heparin for recanalization of the thrombi. One month after the initiation of heparin, there was recanalization as well as improvements of the portal vein, deep vein and pulmonary artery thromboses. There was no further thrombosis progression after switching from heparin to warfarin therapy. Our case suggests that eltrombopag may increase the risk of portal vein thrombosis ; therefore, this drug must be used carefully in the treatment of ITP in patients with LC due to hepatitis C viral infection.

We performed a retrospective population-based cohort study of acute myeloid leukemia (AML) in Miyazaki Prefecture, Japan. Over 6 years, we diagnosed 221 patients (211 adults and 10 children) with AML, indicating an incidence of AML in Miyazaki Prefecture of 3.2 per 100,000 per year. In 193 adult patients with non-acute promyelocytic leukemia (APL), the proportion of patients with myelodysplasia, unfavorable risk karyotypes, antecedent hematologic diseases, prior chemotherapy for other malignancies, and small proportion of blasts in the marrow was higher in patients ≥65 years, and patients with poor performance status (PS) and higher WBC counts at diagnosis were more prevalent among patients ≥75 years. One-third of the adult non-APL patients met the inclusion criteria usually applied in clinical trials: de novo AML, age ≤64 years with PS 0-2 and no key organ dysfunction. The 5-year overall survival (OS) rate of adult non-APL patients was 21.1 % (patients ≤64 years, 33.8 %; 65-74 years, 21.6 %; ≥75 years, 0 %). Multivariate analysis revealed that French-American-British subtypes M0, M6, and M7, poor PS (3, 4), unfavorable risk karyotypes, and higher WBC counts at diagnosis were independent adverse prognostic factors associated with OS. This analysis provides real world data.

Background: Secondary central nervous system lymphoma (SCNSL) without extra-central nervous system (CNS) involvement is characterized by isolated secondary CNS relapse in malignant lymphoma patients. SCNSL is a rare disease, and no standard treatment has yet been established., Patients and Methods: To elucidate the clinical characteristics and outcomes of SCNSL, we retrospectively analyzed 12 patients (median age 67 years) in Miyazaki prefecture for the last 5 years., Results: The initial histological diagnoses of the patients were diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma, and adult T-cell lymphoma in 9, 2, and 1 patient, respectively. We focused on analysis of the 9 SCNSL cases originating from DLBCL. The locations of CNS relapse were the cerebral hemisphere, basal ganglia, and cerebellum in 7, 1, and 1 patient, respectively. Three patients were treated with high-dose methotrexate (HD-MTX) therapy; 4 with whole-brain radiation therapy (WBRTX); and 1 with both HD-MTX and WBRTX. The remaining patients were treated with rituximab. Partial remission was achieved in 6 out of 9 patients (67%); the other 3 patients (33%) did not respond to therapy. Median survival of the 9 patients with CNS relapse was 253 days; 6 of the 9 patients survived for more than 6 months. As of March 2011, 2 HD-MTX group patients but none of the WBRTX group patients were alive., Conclusions: In this retrospective study, 6 of 9 patients with SCNSL originating from DLBCL survived for more than 6 months. Both HD-MTX and WBRTX had clinical benefits in the treatment of SCNSL.

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.

Immunodeficiency-associated lymphoproliferative disorders (LPD) in rheumatoid arthritis are a rare, aggressive, and life-threatening clinical entity. We describe a 60-year-old man who had rheumatoid arthritis that was treated with methotrexate. Eight months after the treatment, the case was diagnosed as Epstein-Barr virus-negative LPD (diffuse large B-cell lymphoma) with abdominal bulky mass and clinical stage IVB at high risk in the international prognostic index. Immediate withdrawal of methotrexate led the patient to achieve complete remission, and 8 subsequent courses of rituximab treatment for the prevention of relapse kept the patient disease-free for 29 months. Our case suggests that these treatments may be an effective, safe, and feasible strategy for immunodeficiency-associated LPD in rheumatoid arthritis.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome. Although the major BCR/ABL transcript is present in majority of CML patients, the minor BCR/ABL transcript is rarely reported as an additional chromosomal abnormality related to the progression of CML. We describe the case of a 37-year-old woman who had CML and pain in the extremities. She was diagnosed with lymphoid blast crisis of CML on the basis of the following findings: presence of promyelocytes, myelocytes, and metamyelocytes in peripheral blood smear; detection of major and minor BCR/ABL transcripts by polymerase chain reaction analysis; proliferation of lymphoblastic cells with abnormal B-cell phenotype; and aberrant expression of myeloid antigens in the bone marrow. The patient underwent one course of idarubicin and cytosine arabinose therapy combined with imatinib followed by daunorubicin/cyclophosphamide plus vincristine and prednisone/L: -asparaginase (DNR/COP/L: -ASP) therapy, high-dose cytosine arabinose, and CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone). Subsequently, the patient underwent high-dose chemotherapy (total body irradiation and cyclophosphamide) followed by allogeneic bone marrow stem cell transplantation from a human leukocyte antigen (HLA)-matched unrelated donor. After these treatments, the patient was disease-free for 19 months. Our case suggests that these treatments may be feasible, safe, and effective for the treatment of patients with blast crisis CML expressing the minor BCR/ABL transcript.

Disseminated intravascular coagulation (DIC) is a clinical entity with high mortality and is characterized by multiple organ failure caused by activation of systemic intravascular coagulation. Although a standard treatment for DIC has not been established owing to the absence of randomized controlled trials, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 35 DIC patients treated with rTM at our institution over a 2-year period (infectious disease: 21 cases; hematological disease: 14 cases). Diagnosis of DIC was based on the diagnostic criteria for DIC of the Japanese Ministry of Health and Welfare. In addition to the treatment of underlying diseases, we administered rTM for 6 consecutive days. Twenty-one (60.0%) of the DIC patients attained resolution of DIC at 7 days after administration (infectious disease: 61.9%; hematological disease: 57.1%). Furthermore, 7 of the remaining 14 DIC patients (who did not attain resolution at 7 days) attained resolution at an average of 12.1 days. Consequently, 28 (80.0%) of the 35 patients were alive with resolution of DIC after a 28-day observation period (infectious disease: 76.2%; hematological disease: 85.7%). Among them, for 7 (70%) of the 10 DIC patients with severe life-threatening bleeding symptoms without hemorrhagic shock, treatment with heparin was contraindicated; these patients were successfully treated with rTM without the progression of hemorrhage. In the majority of DIC patients, rTM administration may be an effective, safe, and feasible therapeutic modality producing a good outcome.

Waldenström's macroglobulinemia (WM) is a slowly progressive, low-grade B cell lymphoproliferative disorder. In contrast to the indolent progression, the development of cryoglobulinemic glomerulonephritis associated with WM is a rare, aggressive, and life-threatening complication. We describe the case of a 53-year-old man who suffered from WM, which was accompanied by cryoglobulinemic glomerulonephritis. WM was diagnosed on the basis of an increase in monoclonal IgM kappa and infiltration of abnormal lymphoplasmacytic cells in the bone marrow. Moreover, the case was complicated by increase in the levels of urinary protein, serum creatinine, and serum cryoglobulin. Histological findings showed endocapillary glomerulonephritis with hyaline plugs. Electron microscopy demonstrated the accumulation of electron-dense deposits in the subepithelial, subendothelial, intramembranous, and mesangial areas, which revealed cryoglobulinemic proliferative glomerulonephritis. The patient received four courses of rituximab therapy followed by four courses of R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) in combination with cryofiltration. Subsequently, the patient underwent high-dose chemotherapy (melphalan [L-PAM]) followed by tandem autologous peripheral blood stem cell transplantation. After these treatments, the patient remained disease-free for 26 months. Histological findings of cryoglobulinemic glomerulonephritis were markedly improved after these treatments. Our case suggests that these treatments may be a feasible, safe, and effective strategy for critical cryoglobulinemic glomerulonephritis derived from WM.

Human T-lymphotropic virus 1 (HTLV-1) causes an aggressive malignancy of T lymphocytes called adult T-cell leukemia/lymphoma (ATLL), and expression of HTLV-1 Tax influences cell survival, proliferation, and genomic stability in the infected T lymphocytes. Cyclin-dependent kinase inhibitor 1A (CDKN1A/p21(waf1/Cip1)) is upregulated by Tax, without perturbation of cell cycle control. During an analysis of the gene expression profiles of ATLL cells, we found very low expression of CDKN1A in ATLL-derived cell lines and ATLL cells from patient samples, and epigenetic abnormalities including promoter methylation are one of the mechanisms for the low CDKN1A expression in ATLL cells. Three HTLV-1-infected cell lines showed high levels of expression of both CDKN1A and Tax, but expression of CDKN1A was detected in only two of six ATLL-derived cell lines. In both the HTLV-1-infected and ATLL cell lines, we found that activated Akt phosphorylates CDKN1A at threonine 145 (T145), leading to cytoplasmic localization of CDKNIA. In HTLV-1-infected cell lines, cytoplasmic CDKN1A did not inhibit the cell cycle after UV irradiation; however, following treatment with LY294002, a PI3K inhibitor, CDKN1A was dephosphorylated and relocalized to the nucleus, resulting in suppression of the cell cycle. In the ATLL cell lines, treatment with LY294002 did not inhibit the cell cycle but induced apoptosis with the cytoplasmic localization. Therefore, the low CDKN1A expression in ATLL cells may be a key player in ATLL leukemogenesis, and the abnormal genomic methylation may influence the expression of not only HTLV-1 Tax but also CDKN1A during long-term development of ATLL from the HTLV-1-infected T lymphocytes.

We performed a retrospective analysis of patients with diffuse large B cell lymphoma treated with rituximab plus CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) as a first-line therapy at 22 hospitals of the Kyushu Lymphoma Study Group. During the period 1996-2005, 1,057 patients (aged 22-90 years) were analyzed. Of these, 678 were treated with CHOP, and 379 were treated with rituximab plus CHOP (R-CHOP). The complete response rate was 59.9% in the CHOP group and 67.0% in the R-CHOP group (P < 0.001). Three-year progression-free survival (PFS) and overall survival (OS) rates were significantly higher in the R-CHOP group than in the CHOP group (61.3 vs. 45.6% for PFS, P < 0.001; 68.3 vs. 54.5% for OS, P < 0.001). The International Prognostic Index was a good prognostic marker for both groups; a survival benefit of rituximab addition was found for each risk subgroup and also for both age groups (60 years). Among 345 patients who received localized radiation therapy, the adding rituximab to CHOP attenuated the survival difference between CHOP and R-CHOP groups (P = 0.104), compared with no radiation group (P < 0.001). Results of this large-scale, multicenter study confirm that rituximab plus CHOP provided a greater survival benefit than CHOP alone.

We evaluated the usefulness of prognostic markers in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) +/- rituximab (R-CHOP) in Japan. We studied 730 patients with DLBCL; 451 received CHOP and 279 R-CHOP. We analyzed biopsy samples immunohistochemically for markers of germinal center B cells (CD10, Bcl-6), postgerminal center B cells (Multiple myeloma-1), and apoptosis (Bcl-2). The median follow-up period for surviving patients was 56.4 months for the CHOP group and 25.2 months for the R-CHOP group. DLBCL were categorized as germinal center B (GCB) subtype (352/730; 48.2%) or non-GCB subtype (378/730; 51.8%). In the CHOP group, the high expression of CD10 (P = 0.022) or Bcl-6 (P = 0.021), or GCB subtype (P = 0.05) was associated with better overall survival, whereas the high expression of Bcl-2 (P = 0.001) or MUM1 (P = 0.011), or non-GCB subtype (P = 0.05) was associated with worse overall survival. In the R-CHOP group, however, these biomarkers except Bcl-6 were not significant prognostic factors. The patients with non-GCB subtype showed improved survival in the R-CHOP group (P = 0.756). The International Prognostic Index was a useful clinical marker of survival in the CHOP group (P < 0.001) and also in the R-CHOP group (P < 0.001). Results of improved survival with rituximab addition indicate that the relevance of previously recognized prognostic factors should be re-evaluated.

Adult T-cell leukemia (ATL) is a fatal malignancy caused by infection with human T lymphotropic virus type-1 (HTLV-1). To search for a new biomarker of ATL, we analyzed sera from ATL patients using ProteinChip arrays. The spectral comparison of ATL patients with HTLV-1 carriers and healthy volunteers showed that the intensities of five peaks (1779, 1866, 2022, 4467, and 8930 m/z) were significantly increased in ATL, while those of four peaks (4067, 4151, 8130, and 8597 m/z) were decreased. From these differentially expressed peaks, we chose peaks of 1779, 1866, and 2022 m/z as biomarker candidates of ATL. MS/MS ion search using tandem mass spectrometry and immunoprecipitation assay using anti-C3 antibody showed that factors derived from these candidate peaks were identified as C3f, which is a component of the complement system and a fragment of complement C3. These results indicate that the complement system was activated in ATL. Further analysis of markers specific to the activation pathways (classical, alternative, and lectin pathways) in the complement system showed that the serum concentration of the marker of the lectin pathway was significantly higher in ATL patients. These results suggest that activation of the complement system in ATL occurs mainly through the lectin pathway.

Adult T-cell leukemia/lymphoma (ATLL) is caused by latent human T-lymphotropic virus-1 (HTLV-1) infection. To clarify the molecular mechanism underlying leukemogenesis after viral infection, we precisely mapped 605 chromosomal breakpoints in 61 ATLL cases by spectral karyotyping and identified frequent chromosomal breakpoints in 10p11, 14q11, and 14q32. Single nucleotide polymorphism (SNP) array-comparative genomic hybridization (CGH), genetic, and expression analyses of the genes mapped within a common breakpoint cluster region in 10p11.2 revealed that in ATLL cells, transcription factor 8 (TCF8) was frequently disrupted by several mechanisms, including mainly epigenetic dysregulation. TCF8 mutant mice frequently developed invasive CD4(+) T-cell lymphomas in the thymus or in ascitic fluid in vivo. Down-regulation of TCF8 expression in ATLL cells in vitro was associated with resistance to transforming growth factor beta1 (TGF-beta1), a well-known characteristic of ATLL cells, suggesting that escape from TGF-beta1-mediated growth inhibition is important in the pathogenesis of ATLL. These findings indicate that TCF8 has a tumor suppressor role in ATLL.

We previously reported that monotherapy with carbapenem or cefepime exhibited efficacy equivalent to cefepime plus an aminoglycoside as initial therapy for febrile neutropenia (FN), achieving an adequate response in two-thirds of the patients. However, only one-third of the remaining poor responders to monotherapy became afebrile after an aminoglycoside was added to the initial carbapenem or cefepime. The present study was designed to evaluate the benefit of intravenous ciprofloxacin for neutropenic patients with fever who were refractory to initial therapy given for the first 3 days. Patients with FN--as defined by an axillary temperature >or=37.5 degrees C and a neutrophil count <1,000/microL-who had no response to initial therapy with carbapenem or cefepime for 72 hours were to receive additional ciprofloxacin 600 mg/day. They were otherwise managed according to the Japanese guidelines for FN. An adequate response was defined as a decline of temperature to <37.5 degrees C within 7 days after initiation of ciprofloxacin treatment. Thirty-one patients with FN (seventeen male and fourteen female; mean age 53.1 +/- 14.8 years) were entered in the study. The initial antibiotics were cefepime (2 - 4 g/day) in twenty and carbapenem (1 - 2 g/day) in eleven. Three patients were excluded from analysis, leaving 28 patients for evaluation of efficacy. The response rate was 16/31 patients (51.6%),with four patients judged non-assessable due to adverse effects, protocol violation or early change to other agents. Adverse events occurred in seventeen patients, but all were mild and reversible. Only three patients had adverse events (skin rash, hepatic dysfunction and elevation of alkaline phosphatase in one patient, respectively) considered related to ciprofloxacin. These findings indicate that addition of intravenous ciprofloxacin is effective against FN refractory to initial antibiotic therapy and has acceptable toxicity.