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The current World Health Organization (WHO) classification defines a new disease entity of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, making fluorescence in situ hybridization (FISH) screening for these genes mandatory. In addition, the prognostic significance of MYC expression was reported, with a cut-off value of 40%. However, interobserver discrepancies arise due to the heterogeneous intensity of MYC expression by immunohistochemistry. Moreover, a cut-off value of positivity for MYC protein in diffuse large B-cell lymphoma (DLBCL) varies among studies at present. Here, we applied a high-sensitivity semiquantitative immunohistochemical technique using fluorescent nanoparticles called phosphor-integrated dots (PID) to evaluate the MYC expression in 50 de novo DLBCL cases, and compared it with the conventional diaminobenzidine (DAB)-developing system. The high MYC expression detected by the PID-mediated system predicted poor overall survival in DLBCL patients. However, we found no prognostic value of MYC protein expression for any cut-off value by the DAB-developing system, even if the intensity was considered. These results indicate that the precise evaluation of MYC protein expression can clarify the prognostic values in DLBCL, irrespective of MYC rearrangement.

The European Treatment and Outcome Study (EUTOS) long‐term survival (ELTS) score predicts disease‐specific death in patients with chronic myeloid leukemia (CML) being treated with imatinib during the chronic phase (CP) of the disease. However, it is unclear whether the ELTS score predicts CML‐related events or treatment responses. This study evaluated the predictive value of the ELTS score regarding prognosis and treatment response in patients with CML‐CP. Clinical data were retrospectively obtained from patients enrolled in the CML Cooperative Study Group (CML‐CSG), which included patients diagnosed with CML‐CP from April 2001 to January 2016, and treated with any tyrosine kinase inhibitor (TKI) as first‐line therapy. Among 342 eligible patients, the ELTS scores indicated low‐, intermediate‐, and high‐risk in 74%, 21%, and 5% of patients, respectively. Patients with high ELTS scores had significantly higher disease‐specific mortality and worse event‐free survival, progression‐free survival, and overall survival. Among four risk scores, including the Sokal, Hasford, EUTOS, and ELTS scores, risk stratification by the ELTS score had the highest predictive value in assessing patient prognosis, and also in treatment responses. In fact, the EUTOS and ELTS scores were able to predict the major molecular response within 12 months. Most importantly, the ELTS score was the only scoring system that predicted deep molecular response at any time, regardless of risk level (65.0%, 43.7%, and 23.5% in low‐, intermediate‐, and high‐risk groups, respectively). Compared to other risk scores, the ELTS score was the most sensitive risk classification tool for the four endpoints of interest in this study, as well as molecular responses in patients with CML‐CP., In this real‐world TKIs treated CML‐CP patients cohort, the EUTOS long‐term survival (ELTS) score was the most sensitive risk classification tool to predict CML‐specific deaths, EFS, PFS, and OS compared to the Sokal, Hasford, and EUTOS scoring systems. Notably, the ELTS score was the only scoring system that predicted cumulative incidence of deep molecular response.

The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high‐risk DLBCL patients having an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R‐CHOP‐14 (arm A) or 3 cycles of R‐CHOP‐14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2‐y progression‐free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow‐up of 40.3 mo, 2‐y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%‐81.2%) and 66.7% (95% CI: 48.8%‐79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%‐85.7%) and 83.3% (95% CI: 66.6%‐92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non‐hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN‐CTR, UMIN000003823)., The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in patients with high‐risk DLBCL who had an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations.

MYC-associated factor X (MAX) is a protein in the basic helix-loop-helix leucine zipper family, which is ubiquitously and constitutively expressed in various normal tissues and tumors. MAX protein mediates various cellular functions such as proliferation, differentiation, and apoptosis through the MYC-MAX protein complex. Recently, it has been reported that MYC regulates the proliferation of anaplastic large cell lymphoma. However, the expression and function of MAX in anaplastic large cell lymphoma remain to be elucidated. We herein investigated MAX expression in anaplastic large cell lymphoma (ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and found 11 of 37 patients (30%) with ALCL lacked MAX expression, whereas 15 of 15 patients (100%) with PTCL-NOS expressed MAX protein. ALCL patients lacking MAX expression had a significantly inferior prognosis compared with patients having MAX expression. Moreover, patients without MAX expression significantly had histological non-common variants, which were mainly detected in aggressive ALCL cases. Immunohistochemical analysis showed that MAX expression was related to the expression of MYC and cytotoxic molecules. These findings demonstrate that lack of MAX expression is a potential poor prognostic biomarker in ALCL and a candidate marker for differential diagnosis of ALCL and PTCL-NOS.

Regressive lymphoproliferative disorders (R-LPD) after methotrexate (MTX) withdrawal are one of the specific features of methotrexate - associated lymphoproliferative disorders (MTX-LPD). Although the impact of the absolute lymphocyte count (ALC) on the pathogenesis of R-LPD has been recently emphasized, understanding relapse/regrowth events (RRE) and differences among LPD subtypes is necessary. In this study, we confirmed ALC recovery in the regressive group (R-G; R-LPD without RRE) and relapse/regrowth group (R/R-G; R-LPD with RRE). The increase in ALC lasted at least 2 years in R-G, whereas it decreased within 3 years in R/R-G, supporting the better overall survival (OS) in R-G, as previously reported. In addition, our study suggested that an ALC of 1000/µL at the time of development of LPD is a significant predictor for treatment-free survival (TFS). Furthermore, an ALC of 1000/µL at 6 months after MTX withdrawal was found to be a significant indicator of TFS and OS for R-G and R/R-G. The ALC decreased gradually before LPD development in R/R-G, whereas it decreased 6 months before LPD development in R-G, confirming the important role of ALC in the pathogenesis of MTX-LPD such as regressive events and RRE. In addition to ALC, other predictive factors, such as serum C-reactive protein and soluble interleukin-2 receptors, may be helpful in the management of MTX-LPD, including the decision making for an additional chemotherapy for regressive LPD after MTX withdrawal.

Intravascular large B-cell lymphoma (IVLBCL) is a rare lymphoma characterized by the selective growth of lymphoma cells within the lumen of vessels. We describe the case of a 69-year-old male who presented with marked pain in the left facial region. Gadolinium-enhanced magnetic resonance imaging revealed a swollen left trigeminal nerve (TN) and positron emission tomography/computed tomography demonstrated fluorodeoxyglucose-only uptake at the same site. The patient had high serum lactate dehydrogenase and soluble interleukin-2 receptor levels. As random skin biopsy and bone marrow biopsy detected no abnormal pathogenesis, open biopsy of the TN was performed, revealing diffuse large B-cell lymphoma (DLBCL). However, ground glass opacities rapidly developed in both lung fields with severe respiratory failure. The patient died of progressive disease before the initiation of chemotherapy. Postmortem examination revealed widespread lymphoma cells in the lumen of vessels in multiple organs, including the lungs, excluding the bone marrow and skin. Lymphoma cells formed a mass in the TN and left lumbar plexus. A diagnosis of IVLBCL was made based on the postmortem pathological analysis. DLBCL of abnormal sites, such as the peripheral nervous system, should be considered in cases of IVLBCL as a differential diagnosis.

The tumor microenvironment (TME) is a critical regulator of the development of malignant lymphoma. Therapeutics targeting the TME, especially immune checkpoint molecules, are changing the treatment strategy for lymphoma. However, the overall response to these therapeutics for diffuse large B-cell lymphoma (DLBCL) is modest and new targets of immunotherapy are needed. To find critical immune checkpoint molecules for DLBCL, we explored the prognostic impact of immune checkpoint molecules and their ligands using publicly available datasets of gene expression profiles. In silico analysis of three independent datasets (GSE117556, GSE10846, and GSE181063) revealed that DLBCL expressing CD24 had a poor prognosis and had a high frequency of MYC aberrations. Moreover, gene set enrichment analysis showed that the 'MYC-targets-hallmark' (false discovery rate [FDR] = 0.024) and 'inflammatory-response-hallmark' (FDR = 0.001) were enriched in CD24-high and CD24-low DLBCL, respectively. In addition, the expression of cell-specific markers of various immune cells was higher in CD24-low DLBCL than in CD24-high DLBCL. CIBERSORT analysis of the datasets showed fewer macrophages in CD24-high DLBCL than in CD24-low DLBCL. Additionally, immunohistochemical analysis of 335 cases of DLBCL showed that few TME cells were found in CD24-high DLBCL, although statistical differences were not observed. These data indicate that CD24 expression suppresses immune cell components of the TME in DLBCL, suggesting that CD24 may be a target for cancer immunotherapy in aggressive large B-cell lymphoma.

Methotrexate (MTX) is one of the potent drugs for autoimmune diseases (ADs), especially for rheumatoid arthritis. Recent studies suggest that MTX should be immediately withdrawn when patients with AD develop lymphoproliferative disorder (LPD). However, biopsy cannot be performed for diagnosis because LPD regresses quickly after MTX withdrawal, thus making clinical MTX-LPD (c-MTX-LPD) challenging to diagnose. In this study, among the 28 patients with c-MTX-LPD, seven developed a proven LPD (p-LPD) after suspicious LPD (s-LPD) regression, six of which were Hodgkin lymphoma. Four of seven patients with p-LPD + died, whereas all patients with p-LPD- survived. The clinical manifestations indicative of p-LPD include fever, elevated serum C-reactive protein level, and soluble interleukin-2 receptor level. Anti-AD drugs did not appear to affect the pathogenesis of p-LPD development. P-LPD was not observed after 3 years from the time of s-LPD regression.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD), a category of immunodeficiency-associated LPD according to the World Health Organization classification, is associated with immunosuppressive drugs (ISDs). Several factors, including autoimmune disease (AID) activity, Epstein-Barr virus (EBV) infection, ISD usage, and aging, influence the development of OIIA-LPD, resulting in complicated clinical courses and outcomes. Most OIIA-LPD develops in patients with rheumatoid arthritis using methotrexate (MTX-LPD). The management of MTX-LPD is based on the clinical course, i.e., with/without regression, with/without relapse/regrowth event (RRE), LPD subtype, and ISDs for AIDs after LPD development. There are three clinical courses after ISD withdrawal: regressive LPD without relapse/regrowth (R-G), regressive LPD with RRE (R/R-G), and persistent LPD (P-G). The majority of EBV+ diffuse large B-cell lymphomas are classified in R-G, whereas classic Hodgkin lymphoma is generally classified in R/R-G. Polymorphic LPD (P-LPD) in MTX-LPD develops with heterogeneous pathological features similar to monomorphic LPD. Chemotherapy for MTX-LPD is selected according to that for de novo LPD, although the strategy for aggressive P-LPD and non-specific LPD is not well established. The absolute lymphocyte count in the peripheral blood has been suggested as a candidate marker for MTX-LPD development and RRE. Several clinical issues, including correct diagnosis among overlapping clinicopathological features in MTX-LPD and clinical management of LPD by ISDs other than MTX, require further investigation.

The purpose of this trial was to evaluate the efficacy of 2-year consolidation therapy with nilotinib, at a dose of 300 mg twice daily, for achieving treatment-free remission in chronic myeloid leukemia patients with a deep molecular response (BCR-ABL1IS ≤0.0032%). Successful treatment-free remission was defined as no confirmed loss of deep molecular response. We recruited 96 Japanese patients, of whom 78 sustained a deep molecular response during the consolidation phase and were therefore eligible to discontinue nilotinib in the treatment-free remission phase; of these, 53 patients (67.9%; 95% confidence interval: 56.4–78.1%) remained free from molecular recurrence in the first 12 months. The estimated 3-year treatment-free survival was 62.8%. Nilotinib was readministered to all patients (n=29) who experienced a molecular recurrence during the treatment-free remission phase. After restarting treatment, rapid deep molecular response returned in 25 patients (86.2%), with 50% of patients achieving a deep molecular response within 3.5 months. Tyrosine kinase inhibitor withdrawal syndrome was reported in 11/78 patients during the early treatment-free remission phase. The treatment-free survival curve was significantly better in patients with undetectable molecular residual disease than in patients without (3-year treatment-free survival, 75.6 versus 48.6%, respectively; P=0.0126 by the log-rank test). There were no significant differences in treatment-free survival between subgroups based on tyrosine kinase inhibitor treatment before the nilotinib consolidation phase, tyrosine kinase inhibitor-withdrawal syndrome, or absolute number of natural killer cells. The results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904).

Our study aims to highlight the critical role of the introduction of second generation tyrosine kinase inhibitors (2nd TKIs) on the prognosis of patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP), as determined by European Treatment and Outcome Study (EUTOS) system. Patients who were diagnosed with CML-CP before March 2009 were classified into the imatinib group, and those diagnosed after April 2009 were classified into the 2nd TKI group. EUTOS high-risk patients exhibited significantly worse outcomes in terms of event-free survival (EFS), progression-free survival (PFS), and CML-associated death than those considered to be low-risk. Risk stratification by EUTOS score was predictive of risk-associated clinical outcomes in patients classified into the imatinib group; however, the EUTOS score failed to predict the outcomes of patients classified into the 2nd TKI group. Our data suggest that the introduction of 2nd TKIs might have improved treatment outcomes, particularly in EUTOS high-risk patients.

This study was performed to investigate the features and outcome of patients with therapy-related chronic myeloid leukemia (TR-CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 308 patients with CML in the chronic phase who were extracted from the CML Cooperative Study Group database. Of these patients, 11 (3.6%) were identified as having TR-CML. No differences in age, sex, white blood cell count, hemoglobin level, platelet count, or European Treatment and Outcome Study risk were observed between patients with TR-CML vs. de novo CML. However, the responses of TR-CML patients to TKIs (6, 3, and 2 received imatinib, nilotinib, and dasatinib, respectively) were excellent; all achieved major or deep molecular response. Furthermore, the outcomes of TR-CML patients were relatively favorable; the 3-year event-free survival rates in the TR-CML and de novo CML patients were 100% and 94%, respectively; the difference was not statistically significant. In conclusion, our study showed that TR-CML patients could achieve a good clinical course with TKI therapy. Detailed investigations of TR-CML may provide new insights into CML biology.

The revised WHO classification newly defined the entities “High‐grade B‐cell lymphoma with MYC and BCL2, and/or BCL6 rearrangements (HGBL‐DH/TH)” and “HGBL, NOS.” Standard immunochemotherapy for diffuse large B‐cell lymphoma (DLBCL), R‐CHOP, is insufficient for HGBL patients, and there are currently no optimized therapeutic regimens for HGBL. We previously reported that CCND3, which encodes cyclin D3, harbored high mutation rates in Burkitt lymphoma (BL), HGBL and a subset of DLBCL. Furthermore, the knockdown of cyclin D3 expression was toxic to germinal center (GC)‐derived B‐cell lymphomas. Thus, the fundamental function of cyclin D3 is important for the pathogenesis of GC‐derived B‐cell lymphoma. We herein used two structurally different CDK4/6 inhibitors, palbociclib and abemaciclib, and examined their suppressive effects on cell proliferation and their ability to induce apoptosis in various aggressive B‐cell lymphoma cell lines. The results obtained demonstrated that abemaciclib more strongly suppressed cell proliferation and induced apoptosis in GC‐derived B‐cell lymphoma cell lines than the control, but only slightly inhibited those features in activated B‐cell (ABC)‐like DLBCL cell lines. Palbociclib exerted partial or incomplete effects compared with the control and the effect was intermediate between abemaciclib and the control. Moreover, the effects of abemaciclib appeared to depend on cyclin D3 expression levels based on the results of the expression analysis of primary aggressive B‐cell lymphoma samples. Therefore, abemaciclib has potential as a therapeutic agent for aggressive GC‐derived B‐cell lymphomas., The effects of CDK4/6 inhibitors on cell proliferation in aggressive B‐cell lymphoma cell lines were investigated. Abemaciclib completely suppressed cell growth irrespective of the CCND3 mutation status in GCB‐like DLBCL cell lines. Abemaciclib has potential as a therapeutic agent for aggressive GC‐derived B‐cell lymphomas, including high‐grade B‐cell lymphomas.

Methotrexate-associated lymphoproliferative disorders (MTX-LPD) is categorized into other iatrogenic immunodeficiency-associated lymphoproliferative disorders, developing LPD in patients with autoimmune diseases (AIDs) under low dose MTX administration. Two-thirds of MTX-LPDs regresses after MTX withdrawal with the higher incidence in Japanese patients, MTX-LPDs consist of various subtypes of LPDs, the feature of each LPD such as the regressive rate, relapse/regrowth rate, and prognosis, widely varies. The absolute lymphocyte count (ALC) in peripheral blood is suggested to influence LPD development, regression, and relapse/regrowth events. Because various factors might effect the pathogenesis and clinical features of MTX-LPD, careful attention should be paid to assess MTX-LPD.

Methotrexate (MTX) carries a risk of lymphoproliferative disorders (LPDs), but MTX-associated LPDs (MTX-LPDs) can resolve spontaneously after MTX withdrawal. However, the precise clinicopathologic features of MTX-LPD remain unclear. We aimed to investigate the clinicopathologic characteristics, outcomes, and prognostic factors for histologic types of MTX-LPD. Paraffin-embedded tissue samples of 219 patients with MTX-LPD were analyzed. In total, 30,33,106, and 26 had reactive lymphoid hyperplasia (RH), polymorphic-LPD (Poly-LPD), diffuse large B-cell lymphomas (DLBCLs), and classic Hodgkin lymphoma (CHL), respectively. The clinicopathologic features of RH, Poly-LPD, DLBCLs, and CHL were as follows: extranodal involvement: 13.8% (4/29), 36.4% (12/33), 69.5% (73/105), and 15.4% (4/26); Epstein-Barr virus encoded RNA positivity: 55.2% (16/29), 71.9% (23/32), 45.3% (48/106), and 76.9% (20/26); necrosis: 0% (0/29), 51.5% (17/33), 34.3% (36/105), and 12.0% (3/25); and Hodgkin Reed-Sternberg-like cells: 17.2% (5/29), 50% (14/28), and 19.8% (21/106). The median duration from MTX withdrawal to the time of disease regression was 10.4, 3.0, 4.2, and 2.7 months for RH, Poly-LPD, DLBCLs, and CHL. After MTX withdrawal, progression-free survival was the greatest for RH, followed by for Poly-LPD, DLBCL, and CHL (all P

Tyrosine kinase inhibitor (TKI) treatment is the standard of care for patients with chronic myeloid leukemia (CML). Even in the imatinib era, the presence of 'clonal chromosomal abnormalities' in the Philadelphia chromosome (CCA/Ph+) at diagnosis reportedly increased the risk of disease progression and predicted shorter survival. However, it remains unclear whether CCA/Ph+ is a poor prognostic marker in the era of new‑generation TKIs. The data of patients with CML in the chronic phase (CP) that were extracted from the CML Cooperative Study Group database were retrospectively analyzed. Of the 328 eligible patients, 33 (10.1%) had CCA/Ph+, including 9 major route and 24 minor route aberrations. The characteristics of patients with and without CCA/Ph+ were similar; however, the proportion of blasts was higher among patients with CCA/Ph+. Notably, the survival rate of patients with CCA/Ph+ was not inferior to that of patients without CCA/Ph+, and there were no differences in responses to TKIs. All 9 patients with major route CCA/Ph+ attained a major molecular response (MMR) with no disease progression, and 8 ultimately achieved a deep molecular response. In particular, the median interval between TKI initiation and achievement of MMR was shorter in patients initially treated with a second‑generation TKI than in those treated with imatinib (5 vs. 10 months). The present retrospective study, thus, revealed favorable treatment outcomes in CML‑CP patients with CCA/Ph+ treated with second‑generation TKIs. The data indicated that administering second‑generation TKIs as first‑line treatments is preferable in CML‑CP patients with CCA/Ph+.

Recently, attention has been focused on methotrexate-induced lymphoproliferative disease (MTX-LPD), and atypical phenotypes are occasionally documented. We encountered two patients with rheumatoid arthritis (RA) who were diagnosed with non-specific LPD (LPD-nos). Biopsy samples were not obtained during the initial examination when the LPD development was discovered, and the patients achieved a complete response after MTX cessation (case 1) or steroid pulse therapy (case 2). However, the tumors flared up 1.5 years later, and LPD-nos was determined following biopsies of the lymph node (LN, case 1) and liver (case 2). Prednisolone was subsequently administered instead of chemotherapy; however, multiple masses, including in the spine (case 1), and severe icterus with liver dysfunction (case 2) were exacerbated within a few months. Although the re-biopsy of LN proved the presence of HL and radiation followed by aggressive chemotherapy rescued the patient (case 1), the superficially accessible biopsy site was not found, and autopsy finally revealed HL (case 2). In both cases, the underlying pathogenesis along with the B symptoms and laboratory abnormalities suggested MTX-LPD, HL in particular. Therefore, even if the pathological diagnosis does not confirm the specific LPD subtype, the administration of aggressive chemotherapy should be considered if the LPD activity flares severely.

Thrombopoietin receptor (TPO-R) agonists have been shown to be effective in refractory chronic immune thrombocytopenia (ITP); however, their efficacy in patients under critical care is not known. We report the case of a female patient with a newly diagnosed ITP who experienced severe bleeding from an external wound. The patient was administered the standard treatments for ITP, which are high-dose intravenous immunoglobulin (IVIg) and corticosteroids. However, following failure of these treatments, we administered romiplostim on day 6 after the onset of ITP. On day 6 after the initiation of romiplostim, there was improvement in platelet count and bleeding tendency. We were subsequently able to perform a splenectomy successfully. The efficacy of TPO-R agonists in ITP has been reported in several situations, including before surgery in an ITP patient; however, the use of TPO-R for arterial bleeding with shock has not been reported. To our knowledge, the present article is a rare case report of the use of a TPO-R agonist in a patient with critical artery injury. Our data suggest that the early use of romiplostim is effective in emergency cases of newly diagnosed ITP with life-threatening bleeding, which is refractory to standard treatment.

Background and Aim: Treatment with a tyrosine kinase inhibitor (TKI) is the standard of care for patients with chronic myeloid leukemia (CML). Based on the results of the ENESTnd and DASISION studies, the European LeukemiaNet 2013 guidelines now recommend the use of TKIs, imatinib (400 mg once daily), nilotinib (300 mg twice daily), and dasatinib (100 mg once daily) as first-line treatment for patients with CML in the chronic phase (CML-CP). Compared to imatinib, the new generation TKIs, nilotinib and dasatinib, were found to have deeper and faster treatment response rates with acceptable toxicities. However, a direct comparison between nilotinib and dasatinib has never been reported previously. Our study aims to compare the outcomes and molecular responses achieved following the first-line use of these two agents in patients with CML-CP. Patients and Methods: The database of the CML Cooperative Study Group, which includes patients who were initially diagnosed with CML after the introduction of imatinib (April 2001), was reviewed, and patients who were given nilotinib or dasatinib as first-line therapy were identified. The event-free survival (EFS, defined as the loss of treatment efficacy, disease progression, or any cause of death), and rates of cumulative major molecular response (MMR), and deep molecular response (DMR, defined as the depth of MR 4.5) were compared between the nilotinib and dasatinib groups. Further, the predictive ability of the Sokal, Hasford, and European Treatment and Outcome Study (EUTOS) scoring systems for the achievement of molecular responses was also evaluated. For the analysis of molecular responses, patients who switched from their initial treatment agent to another TKI before achievement of MMR or DMR were considered to have no MMR or DMR. Results and Discussion: Out of 361 patients with CML-CP enrolled in our database, 58 and 63 were treated with conventional doses of nilotinib (300 mg twice daily) and dasatinib (100 mg once daily), respectively, as first-line therapy. Patients who had been started on a low dose TKI therapy were excluded from this analysis. The patient demographics, including age, sex, observation periods, and the Sokal, Hasford, and EUTOS scores did not show significant differences between the groups. In total, there were five events during the observation period (1 in the nilotinib group and 4 in the dasatinib group), and all events were deaths unrelated to CML, except for one in a patient in the dasatinib group who showed loss of complete cytogenetic response. The disease did not progress to the accelerated or blastic phase in any of the cases. The EFS did not differ between these two groups (p = 0.214). The MMR rates by 6, 12, 18, and 24 months were 59%, 72%, 74%, and 81%, respectively, in the nilotinib group and 52%, 73%, 81%, and 86%, respectively, in the dasatinib group. The DMR rates by 6, 12, 18, and 24 months was 7%, 17%, 24%, and 28%, respectively, in the nilotinib group and 3%, 16%, 25%, and 29%, respectively, in the dasatinib group. During the first 24 months of treatment, 4 (7%) patients in the nilotinib group and 11 (17%) in the dasatinib group had been switched to other TKIs (p = 0.0983). Among the three scoring systems, only the Hasford score could predict the achievement of DMR, and all of them failed to predict the achievement of MMR in the entire cohort. Our data suggest that both nilotinib and dasatinib have comparable efficacies, with high molecular response rates and promising outcomes. The validity of our findings should be tested in a randomized study, which is currently underway in Japan. Disclosures Takaku: Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis Pharma K.K.: Honoraria, Speakers Bureau. Tokuhira:Mitsubishi Tanabe Pharma Corporation: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; AYUMI Pharmaceutical Corporation: Speakers Bureau; Chugai: Speakers Bureau. Asou:Eisai Co., Ltd.: Research Funding; SRL Inc.: Consultancy; Yakult Honsha Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Asahi Kasei Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Kizaki:Nippon Shinyaku,: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Speakers Bureau. Kawaguchi:Novartis Pharma K.K.: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau.

Human parvovirus B19 (HPV-B19) causes hemophagocytic lymphohistiocytosis (HLH). Here we describe a 35-year-old female with hereditary spherocytosis (HS) who developed HLH due to HPV-B19 infection. Upon admission, she had high fever and diarrhea. Laboratory findings included severe pancytopenia and elevated serum triglyceride and ferritin levels. Moreover, high HPV-B19 levels in the peripheral blood and increased reactive lymphocytosis in the bone marrow led to a diagnosis of HLH due to HPV-B19 infection. With supportive therapy and a blood transfusion, HLH symptoms, including fever and myelosuppression, improved in 1 week. However, symptoms of heart failure (HF) suddenly developed, and an echocardiography revealed diffuse systolic dysfunction, suggesting viral myocarditis due to HPV-B19 infection. Conservative management with diuretics gradually improved HF symptoms over a period of 2 weeks. HPV-B19 infection in adult patients with HS rarely results in severe HLH, but conservative therapy may improve the symptoms. Nonetheless, a careful follow-up is required after HLH improves because viral myocarditis can develop, as was seen in our patient.

We performed a retrospective study to evaluate the incidence of second malignancies (SMs) in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). We analyzed data from 339 patients with CML who were extracted from the CML Cooperative Study Group database. The standardized incidence ratio (SIR) was calculated to assess the risk of SMs using data from the Cancer Registries in Japan. The median follow-up was 65 months. SMs developed in 14 patients (4.1%, 10 men, 4 women) after the start of TKIs. The median age was 69 years at the time of the CML diagnosis and 72.5 years at the time of the SM diagnosis. Ten patients were treated with imatinib, three with dasatinib, and one with nilotinib as the initial treatment. The SIR for all malignancies was 1.05 (95% CI 0.50–1.93) for men and 1.08 (95% CI 0.29–2.76) for women. The difference in the overall survival (OS) of patients with or without SMs was not statistically significant (5-year OS: 82.5% vs. 92.9%; p = 0.343). A subgroup analysis of 166 patients treated with second-generation TKIs (92 dasatinib, 74 nilotinib) showed that the SIRs for all malignancies were 1.33 (95% CI 0.36–3.41) for men and 0 for women. In conclusion, the incidence of SMs in CML patients during TKI treatment was the same as that in the general Japanese population. There was no evidence of an increase in the incidence of SMs during second-generation TKI treatment. Furthermore, the occurrence of SMs during TKI treatment did not affect the survival or mortality in our cohort.

This study investigated the incidence rate and features of vascular adverse events (VAEs) in Japanese patients with chronic myeloid leukemia (CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 369 CML patients in the chronic or accelerated phases, selected from the CML Cooperative Study Group database; 25 events in 23 (6.2%) of these patients were VAEs. At the time of VAE incidence, nine patients were on treatment with imatinib, 12 with nilotinib, three with dasatinib, and one with bosutinib. VAE incidence comprised 13 cases of ischemic heart disease (IHD), eight of cerebral infarction (CI), and four of peripheral arterial occlusive disease (PAOD). IHD incidence rate in the study population was higher than that in the age-matched general population, particularly in nilotinib-treated patients, while CI incidence rate was almost equivalent. Compared with the Suita score, the SCORE chart and the Framingham score risk assessment tools detected more patients with high or very high risk of VAEs. In conclusion, incidence of IHD requires closer monitoring in nilotinib-treated patients. More detailed investigations for determining the most useful tool to predict VAE incidence and long-term analysis of therapy-related VAE cases are needed for improving safety during TKI therapy.

The purpose of this clinical trial was to evaluate the efficacy of 2-year consolidation therapy using nilotinib (NIL) for achieving a molecular response (MR4.5, BCR-ABL1IS ≤ 0.0032% on the International Scale) in patients with chronic myeloid leukemia in the chronic phase (CML-CP) who had achieved a major molecular response (MMR, BCR-ABL1IS ≤ 0.1%) with imatinib (IM). We recruited 76 Japanese patients for this trial. Nilotinib 300 mg, twice daily, was administered for 2 years, and 74 patients were evaluated in the study. The median age was 55.0 years. The median duration of IM treatment was 69.0 months. All patients showed MMR at the time of entry into the study; the median time to MMR on IM therapy was 20.4 months. The proportion of patients who achieved MR4.5 increased over time. The rates of MR4.5 in the 74 evaluable patients were 27.0% [90% confidence interval (CI) (18.7–36.8%)] and 44.6% [90% CI (34.7–54.8%)] at 12 and 24 months, respectively. The frequency of ABCG2 421C/A + A/A was an independent predictive biomarker for achieving a 24-month MR4.5. Switching to NIL led to safer, deeper molecular responses in patients with MMR on long-term IM therapy for future treatment-free remission.

ABL1-tyrosine kinase inhibitors (TKIs) have led to dramatic changes in treatment strategies for chronic myeloid leukemia in the chronic phase (CML-CP). However, clinical studies have highlighted increasing numbers of adverse events (AE) with TKIs. Although TKI modification plays a key role in AE management, this process is poorly understood, particularly in terms of the TKI nilotinib. In the present study, we retrospectively analyzed the records of 70 patients with newly diagnosed (ND)-CML-CP who were treated with nilotinib to investigate the drug potency of nilotinib and treatment management. During a median observation period of 3.4 years, 76% of patients continued nilotinib as a first-line treatment. The 1-year and overall major molecular response (MMR) rates and the overall molecular response (MR) 4.5 rate for all patients receiving first-line nilotinib therapy were 70, 84.2, and 50%, respectively. No case progressed to the accelerated or blast phase during the study. To avoid AEs during the early phase, nilotinib doses were reduced to

Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein-Barr virus (EBV) infection (p = .00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors.

Background Lympho-proliferative disorder (LPD) is known as a relatively rare but life-threatening complication in RA patients under MTX administration. Spontaneous regression of LPD after MTX withdrawal is regarded as a distinct character of LPD under MTX administration. Previous study from our institution [1] and others [2] reported the link between decreased lymphocyte counts at LPD diagnosis and restoration after MTX cessation and the regression of LPD. Objectives To investigate the immunological factors including lymphocyte subsets which involved in spontaneous regression of LPD following MTX withdrawal. Methods We studied 35 RA patients complicated with LPD under MTX administration in our institution. Age, sex, RA disease duration matched control MTX-treated patients (N=35) were selected. LPD patients were divided into two groups regarding to the status of LPD after MTX cessation; regressive group (N=22) and persistent group (N=13). Clinical features were compared among 3 groups. Flowcytometric analysis of the whole blood sample and measurement of cytokine concentration in ELISA were conducted in a part of the LPD patients (N=10, 7 regressive, and 3 persistent LPD) and controls (N=10). The time of MTX cessation, which was simultaneous with LPD diagnosis, was defined as week 0, and blood sample was collected at week 0, 4 and 12. Results At week 0, number of peripheral lymphocytes was significantly decreased in regressive group, compared to persistent group and control group. Flowcytometric analysis revealed significant decrease in proportion of effector memory CD8+ T cells (EMCD8+T), Epstein Barr Virus specific CD8+ T cells (EBV specific CD8+) and T helper 1 cells (Th1 cells) subset in regressive group compared to control group. Following MTX cessation, significant increase in proportion and absolute number of these subsets were observed only in the regressive group, but not in persistent group. Expansion of Th1 cells and EMCD8+ T cells significantly correlated with increase of serum IFN-γ, and expansion of EMCD8+ T cells inversely correlated with change of serum IL-15. Conclusions Restoration in proportion and absolute number of Th1 cells, EMCD8+T cells and EBV specific CD8+ T cells coincided with increase of IFN-γ, and associated with regression of LPD developed under MTX administration. Since changes of those immunological factors were not observed in persistent LPD, this study would be the first report to demonstrate the difference of immune status between regressive and persistent LPDs developed under MTX administration. References Saito S, et al. Rheumatology. 2017; in press. Inui Y, et al. Leuk Lymphoma. 2015; 56(11):3045–3051. Acknowledgements None. Disclosure of Interest S. Saito: None declared, K. Suzuki: None declared, K. Yamaoka Speakers bureau: Pfizer, Chugai Pharma, Mitsubishi-Tanabe Pharma, Takeda Industrial Pharma, GlaxoSmithKline, Nippon Shinyaku, Eli Lilly, Janssen Pharma, Eisai Pharma, Astellas Pharma and Actelion Pharmaceuticals, K. Amano: None declared, M. Tokuhira Speakers bureau: Eisai Co., T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co.,Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.,Ltd., Teijin Pharma Ltd., AbbVie GK, 2,Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K.

The development of novel therapeutic agents over the past decade, including the proteasome inhibitor, bortezomib, and the immunomodulatory drugs, lenalidomide and thalidomide, has resulted in improved outcomes for patients with multiple myeloma. However, there is still considerable controversy as to which regimen should be used as first-line therapy, which patients should be considered for autologous or allogeneic transplantation, and how consolidation or maintenance therapy is used in patients that have a good response to first-line therapy. The present paper will review clinical evidence from previous and ongoing studies to explore issues related to these questions.

Objective To clarify the characteristics of lymphoproliferative disorder (LPD) in patients with RA treated with MTX. Methods Among 33 patients developing LPD during MTX treatment, 20 LPDs regressed spontaneously within 12 weeks after MTX cessation (regressive LPD), and 13 did not regress and most of them died or needed chemotherapy (persistent LPD). The control group consisted of 66 clinically matched MTX-treated RA patients without LPD. The clinical characteristics were compared between these three groups. Results While no significant differences were found in clinical RA and LPD features among the three groups, the absolute lymphocyte number of the two LPD groups at LPD diagnosis was significantly lower than the control group (497/µl in the regressive vs 680/µl in the persistent vs 1400/µl in the control, P < 0.05). After MTX withdrawal, the lymphocyte number in the regressive group rapidly recovered to 1214/µl (P < 0.01) by week 2 and was thereafter maintained at an equivalent level to the control group. In contrast, lymphocyte level in the persistent group did not show significant increase throughout 12 weeks (620/µl at week 2, P = 0.57). Changes in lymphocyte number following MTX withdrawal clearly distinguished the regressive LPD from the persistent LPD. Conclusion A significant decrease in lymphocyte count at the LPD diagnosis and its restoration after MTX withdrawal were markedly associated with spontaneous regression of LPD developing during MTX treatment.

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment. Novel treatments such as proteasome inhibitors and immunomodulatory agents significantly prolong both progression free survival and overall survival (OS) in patients with MM. However, recent clinical data have indicated that it is difficult to eradicate all MM clones even with the administration of such novel agents. To overcome drug resistance (DR), further investigation of the mechanism underlying DR is required, and strategies to up-regulate, maintain, and restore drug sensitivity will become increasingly important in the clinical setting. The findings from basic research focusing on the microenvironment, genetic abnormalities, and signal transduction disturbances related to MM pathogenesis are excellent strategies for developing new agents. In addition, based on the improved OS over 10 years and the low continuation rate of standard therapy in frail patients, a stratified strategy has the potential to provide total therapy.

Background: According to VISTA study, the prognosis of elderly multiple myeloma (MM) patients has been improved with VMP therapy. However, intensive chemotherapy has induced severe adverse events (AEs), resulting in highly discontinued rate, especially often seen in unfit or frail patients. Several studies have demonstrated the potent of weekly bortezomib administration in induction therapy (GIMEMA, GEM2005MAS65), and maintenance therapy with bortezomib. Based on these fact, we designed phase 2 clinical study, BoRtezomib-based Optimized therapy Aiming Disease control in Japan (BROAD-J study), based on a weekly VMP as induction therapy followed by maintenance therapy with bortezomib (Bor-MT) with every two weeks administration for newly-diagnosed (ND) symptomatic non-transplant eligible MM patients. (UMIN 00007335) Method: From August 2011 to June 2016, according to the International Myeloma Working Group (IMWG) criteria, 87 patients older than 65 years with symptomatic MM were eligible for this trial (Table 1). The primary objectives were included maximum response and time to progression duration. Secondary objective was the continued treatment duration and adverse event rate. The induction phase consisted of VMP treatment: Melpharan: on days 1-4 (6 mg/m2), every 35-day cycle; prednisolone: on days 1-4 (40mg/d, every 35-day cycle; Bortezomib: 1.3mg/m2, d1, 8, 15, 22 every 35-day cycle. After 9 cycles of VMP therapy, the maintenance therapy starts. The maintenance phase was consisted of twice a month bortezomib administration (1.3 mg/m2) without dexamethasone until progressive disease. Dose reductions of bortezomib were allowed according to instructorfs recommendation. Patients could receive supportive therapy including bisphosphonates and transfusions as necessary. AEs were graded according to NCI-CTCAE v4.0. Response was assessed prior to every treatment cycle. Response categories were based on the International Myeloma Working Group uniform response criteria. Results: Mean age was 75 years (66-88), sex ratio was 44:43 (M: F), and ISS stage was I 12%, II 43%, III 43%. High risk cytogenetics abnormalities (i.e. del17p, t(14;16)) were observed in 13 patients (15%). Overall response rate was 87% and complete response was obtained in 22 patients (25%) (Table 1). Median progression free survival (PFS) was 36 months (Figure 1a) and median overall survival was 57 months (Figure 1b). Median PFS (Kaplan-Meier estimate) was significantly higher with patients who obtained CR or VGPR than PR or SD (P Discussion: This trial reveals that VMP regimen with weekly bortezomib administration is effective and tolerablefor unfit or frail elderly MM patients. In addition, maintenance therapy of twice a month bortezomib administration was effective in patients who obtained VGPR or more better. These results are no way inferior to results of VISTA trial. However, high R-ISS stage patients or poor treatment responders did not obtain the benefit of this setting, so, another setting with anti-myeloma antibody (i.e. elotuzumab or daratumumab) may be warranted in the future for such patients. Conclusion: BROAD-J study is conducted to yield the possibility of a careful treatment toward at least PR state and the efficacy of VMP followed by bortezomib maintenance in unfit or frail MM patients. The excellent results we demonstrated such as a good OS, PFS, and a low incidence of AEs might be suggested a superiority of this strategy. Download : Download high-res image (64KB) Download : Download full-size image Disclosures Tokuhira: Bristol Myers Squibb Co., Ltd: Honoraria; Eizai Co., Ltd: Honoraria; Pfizer Co., Ltd: Honoraria.

Introduction: Deferasirox is an oral iron chelator, approved worldwide for the treatment of chronic iron overload due to transfusion. Deferasirox was permitted two years ago in Japan, but there is little known regarding its efficacy and tolerability in clinical practice. Methods: We conducted a retrospective study of 18 patients with transfusion-dependent anemias treated by deferasirox at our institution. The starting dose was individualized and ranged from 6.4 to 26.3 mg/kg/day. Routine clinical laboratory data were followed, and serum ferritin was assessed every 4 weeks. Results: The mean serum ferritin level of 18 patients at the time of deferasirox induction was 3162 ng/ml. Ten of 18 patients could sustain deferasirox treatment for at least 6 months, at an average maintenance dose of 10.8 mg/kg/day. Serum ferritin reduction was observed in 4 patients, at doses less than 20 mg/kg/day. Eighty-nine percent of the patients had adverse events, and 13 of them in all ultimately discontinued. Myelodysplastic syndrome (MDS) patients showed poor tolerability. Severe infections of grade 3 or more were documented in 6 patients, and 2 of them were fatal. Conclusions: The potential for beneficial iron chelation of deferasirox at less than the recommended 20 mg/kg dose was demonstrated. On the contrary, poor tolerability was documented, with adverse events such as severe infections, especially in MDS patients. Although it was not clearly demonstrated that deferasirox was responsible for impaired immunity, careful watching is required to administrate deferasirox.

[Background] Methotrexate - induced lymphoproliferative disorders (MTX-LPDs) belong to the group of other iatrogenic immunodeficiency-associated LPDs, as defined in the revised 4th edition of the World Health Organization (WHO) classification. The phenomenon of LPD regression after MTX withdrawal is a specific event that develops in patients with autoimmune diseases (ADs), such as rheumatoid arthritis (RA). Although patients with regressive MTX-LPDs have better overall survival (OS), relapse/regrowth (R/R) events after regression are one of the factors of poor prognosis. Recent studies including ours have shown that lymphocytes play an important role in the regressive LPD phenomenon in MTX-LPDs (Rheumatology (Oxford). 2017;56:940-946, Front Immunol. 2018;4;9:621) ; however, little is known of the details regarding differences among the LPD subtypes and the influence of lymphocytes on R/R events. In this study, we analyzed patients with regressive Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL), especially focusing on the influence of the absolute lymphocyte count (ALC) on R/R events and clinical outcomes. [Methods] Data were collected from 25 patients with ADs who developed LPD and had regressive LPD after MTX withdrawal at our institutions. All diagnoses were confirmed based on immunohistochemistry analysis of paraffin-embedded samples. All pathological samples were classified and diagnosed according to the WHO classification. The ALCs were determined at the time of MTX withdrawal due to LPD development (0 M), 1 month after MTX withdrawal (1 M), 6 months after MTX withdrawal (6 M), and at the time of R/R. The OS was calculated between 0 M and the time of the last observation. Statistical analyses were performed using EZR software. [Results] Of 25 patients with regressive MTX-LPDs, the median age at 0 M was 67 years (range: 44ー84). Ten men and 15 women were included. The basal ADs were RA (N = 23), psoriasis vulgaris (N = 1), and systemic lupus erythematosus (N = 1). The median duration of MTX treatment was 5.5 years. Seventeen cases of DLBCL and 8 cases of HL were included. The median ALCs at 0 M and 1 M in all patients were 627/µL and 1364/µL, respectively. The median ALC ratio (ALC at 1 M divided by ALC at 0 M) was 2.3 (0.6-8), and it indicated over 1 in 24 patients, confirming ALC recovery at 1 M. Regarding the ALCs at 0 M and 1 M, significant differences between DLBCL and HL were not detected (p=0.215 and p=0.77, respectively). Of all patients, the median duration from the time of MTX duration to R/R was 12 months (range, 7-41). Thirteen patients remained in the remission state without R/R (Regression group), whereas 12 patients experienced an R/R event (R/R group). In the latter group, the median ALCs at 0 M, 1 M, 6 M, and R/R were 582/µL, 1194/µL, 1158/µL, and 565/µL, respectively. The ALC significantly increased at 1 M from 0 M (p=0.006) and decreased at R/R from 1 M (p=0.05), suggesting that the ALC recovery diminished when the LPD underwent R/R. On the other hand, among 13 patients in the regressive group, the median ALCs at 1 M, 6 M, and at the time of the last observation were over 1500/µL (1732/µL, 1782/µL, and 1574/µL, respectively), although that at 0 M was less than 1000/µL (991/µL). To investigate the influence of ALC on the OS, we analyzed the clinical definition of the ALC cut-off of 1000/µL after the ALC recovery observed at 1 M. The result indicated that patients with ALC greater than or equal to 1000/µL after 6 M had significantly better OS compared to those with ALC less than 1000/µL after 6 M (5-year OS, 100% vs. 43.8%, p=0.00048), considering that the ALC is one of the strong prognostic factors in the clinical outcomes of MTX-LPDs. It is of note that the R/R rate in patients with HL was higher than that in those with DLBCL (100% and 23.4%, respectively), and all 8 patients with HL had an ALC at R/R of less than 1000/µL. [Summary] In this study, we demonstrated that ALC recovery was detected at 1 M, which continued during the clinical course in patients who maintained a remission state, although it decreased to less than 1000/µL after ALC recovery in patients with R/R LPDs. In addition, the ALC of 1000/µL was a critical level affecting the clinical outcomes. Regarding LPD subtypes, the reason for higher R/R rates observed in HL compared to those in DLBCL was thought to be dependent on the rates of lower ALCs. [Conclusion] Our data suggest that the ALC is one of the predictive factors for R/R and OS in patients with regressive MTX-LPDs. Disclosures Tokuhira: Mitsubishi Tanabe Pharma Corporation: Speakers Bureau; AYUMI Pharmaceutical Corporation: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Chugai: Speakers Bureau. Tamaru:Nichirei Bioscience INC.: Research Funding; Takeda Pharmaceutical Company Limited: Speakers Bureau. Kizaki:Nippon Shinyaku,: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Speakers Bureau.

Multiple myeloma (MM) is a hematological malignancy characterized by abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents such as proteasome inhibitors, immunomodulatory drugs, and antibodies that have significantly improved clinical outcomes of the patients of MM, most patients eventually relapse and develop drug resistance. In particular, the prognosis of patients harboring either chromosome TP53 deletion or mutations remains very poor, suggesting the prevalence of TP53 abnormalities increases with disease progression. Therefore, novel therapeutic strategies to overcome this unfavorable feature are urgently needed in clinical settings. WEE1 is a cell-cycle checkpoint kinase and a key regulator of DNA damage surveillance pathways. In response to extrinsically induced DNA damage, WEE1 kinase induces cell cycle arrest, allowing damaged DNA to be repaired before the cell undergoes DNA replication in S phase, and preventing cells harboring unrepaired, damaged DNA from mitotic lethality. Furthermore, WEE1 overexpression has been observed in many types of cancers. In addition, our previous studies revealed that monotherapy with AZD1775, a potent and highly selective inhibitor of WEE1, inhibited the proliferation of various MM cell lines irrespective of TP53 status. (Blood 2016; 128: 3256). On the other hand, one of the defining features of MM cells is the production of large amounts of protein, such as immunoglobulin, that must be processed within the endoplasmic reticulum (ER). Due to the accumulation of abundant immunoglobulin in ER, MM cells are constitutively under conditions of ER stress. The unfolded protein response (UPR)-signaling pathway is a cytoprotective mechanism against ER stress, and is therefore activated in MM cells to survive these conditions. Activation of the UPR has been observed in many types of cancers, and loss of TP53 has shown to enhance the UPR. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is one of three ER transmembrane protein kinases implicated as primary effectors of the UPR. Recent studies have suggested that PERK inhibition resulted in dose-dependent inhibition of tumor growth both in vitro and in vivo. In addition, more recent studies have proposed that PERK induces resistance to cell death elicited by chemotherapy. The combination of WEE1 and PERK inhibitors might thus offer an attractive therapeutic option against this incurable hematological malignancy. Here, we investigated the therapeutic utility of AZD1775 and GSK2606414, a highly selective inhibitor of PERK kinase, alone and in combination in various MM cells including TP53 wild-type (MM1.S) as well as TP53-deficient (KMS-11) and TP53-mutated (U266, RPMI8226, OPM-2) cell lines. AZD1775 and GSK2606414 alone induced dose-dependent cell growth inhibition in all investigated MM cells irrespective of TP53 status. Interestingly, GSK2606414 in combination with AZD1775 inhibited proliferation of all MM cells more effectively than either single agent. Assays for apoptotic cell death demonstrated that AZD1775 in combination with GSK2606414 induced significant and marked apoptotic cell death in MM cells used in this study compared to monotherapy alone. Next, western blotting analysis was performed to address the mechanisms of apoptotic cell death by the treatment of WEE1 and PERK inhibitors in MM cells. GSK2606414 inhibited PERK activation and decreased its downstream substrates (phospho-eIF2a, ATF4, and CHOP). Combination treatment with WEE1 inhibitor and various doses of PERK inhibitor significantly increased PARP and caspase 3 cleavage, CDK1 phosphorylation, and histone H2AX expression. Taken together, these data suggest that combining AZD1775 and GSK2606414 synergistically induced DNA damage and promoted premature mitotic entry, resulting in apoptotic cell death of TP53-deleted or -mutated MM cells. In conclusion, dual targeting of WEE1 and PERK might be a promising therapeutic approach for MM irrespective of TP53 status. Disclosures Tokuhira: Bristol-Myers Squibb: Speakers Bureau; AYUMI Pharmaceutical Corporation: Speakers Bureau; Mitsubishi Tanabe Pharma Corporation: Speakers Bureau; Chugai: Speakers Bureau. Kizaki:Novartis: Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Nippon Shinyaku,: Research Funding, Speakers Bureau.

The expression of YB-1 has been reported to predict poor clinical outcome in many human malignancies, including hematopoietic malignancies. In this study, we investigated the correlations between YB-1 expression and the clinicopathological features of patients with diffuse large B-cell lymphoma (DLBCL) in a single institution. The expression of YB-1 was analyzed in 168 cases by immunohistochemistry. Fifteen out of 168 cases (8.9%) showed cytoplasmic expression of YB-1. The expression of YB-1 was significantly associated with 5-year overall survival (OS) (p = 0.023). Rituximab plus CHOP therapy (n = 94) improved the 5-year survival rate in both YB-1-positive and -negative patients. In conclusion, the data presented in this report provide evidence that the cytoplasmic expression of YB-1 is a poor prognosis factor in DLBCL treated with CHOP therapy, whereas rituximab improves the survival of both YB-1-positive and -negative patients with DLBCL.

Although the introduction of novel agents, such as proteasome inhibitors, immunomodulatory drugs, and histone deacetylase inhibitors (HDACi) has improved the clinical outcomes of the patients with multiple myeloma (MM), most patients eventually relapse and develop drug resistance. Proteasome inhibitor, bortezomib (BTZ), is a key drug for the treatment of MM, and the prognosis of the patients with BTZ resistance is very poor. Therefore, novel therapeutic approaches to overcome BTZ resistance are urgently needed. WEE1 is a cell cycle checkpoint kinase and a key regulator of DNA damage surveillance pathways. In response to extrinsically induced DNA damage, WEE1 induces cell cycle arrest, allowing for the damaged DNA to be repaired before the cell undergoes DNA replication, and prevents cells from mitotic lethality. WEE1 is overexpressed in various cancers, and relates to poor prognosis. In addition, the inhibition of WEE1 has been shown to induce cancer cells to premature mitotic entry leading to apoptotic cell death, suggesting that combining WEE1 inhibitor with DNA damaging agent is effective in cancer therapy. Resent research has shown that HDACi increase reactive oxygen species production resulting in increased DNA damage and impaired DNA repair. These data suggest that the combination of WEE1 inhibitor and HDACi might be an attractive therapeutic option against this incurable hematological malignancy. In the present study, we investigated the efficacy of WEE1 inhibitor MK-1775, a potent and highly-selective small molecule inhibitor of WEE1, in combination with HDACi in various MM cells. MTS assays showed that single agent MK-1775 inhibited the proliferation of various MM cell lines, including BTZ-resistant cell line, in a dose- (0 to 10 μM) and time- (0 to 72 h) dependent manner. In combination with vorinostat which is a pan-HDACi, MK-1775 inhibited the proliferation of BTZ-resistant MM cells more effectively than single agent. Furthermore, the combination of vorinostat and MK-1775 was able to re-sensitize BTZ-resistant MM cells to BTZ. Assays for apoptotic cell death demonstrated that MK-1775 induces both early and late apoptosis in MM cells. Western blotting analysis was performed to investigate the molecular mechanisms of MK-1775-induced cell death, showing that MK-1775 inhibited the expression of the target molecules of Bcl-2 and MCL1, and CDK1 phosphorylation. Moreover, the marked increase in PARP and Caspase 3 cleavage, and histone H2AX expression was observed following treatment with MK-1775 in combination with vorinostat. These findings suggest that the combination of MK-1775 and vorinostat induces synergistically DNA damage and promotes premature mitotic entry resulting in apoptotic cell death in MM cells. In conclusion, our data suggest that WEE1 in combination with HDACi might be a promising molecular target for the treatment of BTZ-resistant MM. Citation Format: Takayuki Tabayashi, Yuka Tanaka, Yasuyuki Takahashi, Yuta Kimura, Tatsuki Tomikawa, Tomoe Anan, Morihiko Sagawa, Reiko Watanabe, Michihide Tokuhira, Masahiro Kizaki. Dual targeting of cell cycle checkpoint and histone deacetylase overcomes bortezomib resistance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1884.

We here report the case of a young Japanese woman diagnosed with chronic active Epstein-Barr virus (EBV) infection. Intensive therapy with the CHOP regimen was partially able to control virus expansion, but various central nervous system symptoms appeared and gradually progressed. EBV-encoded RNA, detected using in situ hybridization, disclosed the presence of EBV in liver and bone marrow tissue, and real-time PCR revealed the presence of EBV in the cerebrospinal fluid (CSF) and serum. CD3+CD4+CD8-CD56- T-cell expansion in the peripheral blood (PB) and CSF was also observed. Atrophic brain changes were progressive, and the patient died of central nervous system disturbance and pulmonary hemorrhage a year after diagnosis. Autopsy revealed that EBV-infected T lymphocytes with a phenotype similar to those seen in PB and CSF had infiltrated multiple organs: the lymph nodes, bone marrow, endocardium, pericardium, myocardium, spleen, liver, and spinal cord. There have been few previous reports of severe degenerative changes in the myocardium, liver, and spinal cord in patients with EBV infection. Although EBV occasionally infiltrates the central nervous system and brain, atrophic changes mediated by EBV are rare. The autopsy results of this case suggest the possibility of EBV-mediated, severe degenerative changes in multiple organs.

Basophils play an important role in allergic inflammation and are pathologically related to hematological disturbances, such as iron deficiency anemia and myeloproliferative disorders; however, they are only rarely encountered in lymphoid malignancies. Here, we report the case of a 33-year-old man with a bulky mass of the small intestine, multiple paraaortic lymphoadenopathy, pleural effusion, and ascites, who was diagnosed as a case of de novo CD5+ diffuse large B cell lymphoma (DLBCL). This patient showed a marked elevation of the basophil count in the peripheral blood, which appeared to run in parallel with the tumor burden. High dose chemotherapy followed by autologous peripheral blood cell transplantation yielded complete remission, and the patient has remained disease free for 5 years. To the best of our knowledge, this is the first report of a case of de novo CD5+ DLBCL showing marked elevation of the PB basophil count.

In the WHO classification, the majority of Hodgkin-like ALCL cases as defined by the REAL classification are considered to be CHL. However, establishing a histological diagnosis for the gray zone between CHL and ALCL is often confusing. In this study, we re-evaluated such cases by performing immunohistochemistry with antibodies against PAX-5/BSAP, Oct.2, and BOB.1/OBF.1. Expression of PAX-5/BSAP was observed in 88% (76/87) of CHL specimens and none (0/11) of ALK-positive ALCL specimens. Among specimens of Hodgkin-like ALCL and ALK-negative ALCL, expression of PAX-5/BSAP was observed in 77% (20/26) and 18% (3/17), respectively. Most of the PAX-5/BSAP-positive specimens were negative for Oct.2 and/or BOB.1/OBF.1 except for four CHL specimens. Our results may support the WHO classification in which most cases of Hodgkin-like ALCL are classified as CHL. However, the patients with Hodgkin-like ALCL with CHL-immunophenotype (PAX-5/BSAP-positive and negative for Oct.2 and/or BOB.1) did not have a favorable outcome, with a 5-year OS rate of 58%.

The interaction between tumor cells and the tumor microenvironment is essential in the development and progression of diffuse large B-cell lymphoma (DLBCL). Loss of human leukocyte antigen DR (HLA-DR) in DLBCL is a robust adverse prognostic marker. We evaluated the immunohitochemical expression of HLA-DR in lymphoma and the biologic implications of the loss of HLA-DR. The loss of HLA-DR correlated with clinical stage (p < 0.05), International Prognosis Index (p < 0.05), soluble interleukin-2 receptor (p < 0.05) and poor outcome in patients with DLBCL, especially among elderly patients. Flow cytometry analysis of the infiltrating T-cells showed that the mean CD4 + CD25 +/CD8 ratio of the infiltrating T-cells was higher in the HLA-DR positive group than in the HLA-DR negative group (p < 0.05). These data suggest that loss of HLA-DR expression in DLBCL decreases the ratio of helper T-cell within the T-cell population in the tumor microenvironment and might contribute to escape from immunosurveillance.