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Minimal residual disease (MRD) is a surrogate marker for survival in multiple myeloma (MM), while the lymphocyte-to-monocyte ratio (LMR) is a prognostic factor associated with the patients' immunological status. We retrospectively evaluated the clinical impact of MRD negativity and LMR. MRD was analyzed by multicolor flowcytometry (threshold, 1 × 10-5). Fifty-eight patients (median age 70 years) who achieved complete response were included in this study. Twenty-two patients received autologous stem cell transplantation, 14 received daratumumab-based chemotherapy, and 22 received another treatment. Forty-one (70.7%) patients achieved MRD negativity. Over the median follow-up time of 15.1 months, PFS in MRD-negative patients was significantly longer than in MRD-positive patients (P = 0.020). In addition, a high LMR at MRD assessment was associated with MRD negativity (P = 0.019) and long PFS (P = 0.009). Finally, neither MRD negativity nor high LMR at MRD assessment was associated with significantly shorter PFS compared with MRD positivity or low LMR (P = 0.002). In conclusion, high LMR was associated with MRD negativity and can be used as a predictor of long PFS. Change of treatment strategy might be essential for patients with MRD positivity and high LMR at MRD assessment due to their short PFS.

The alkylating agent busulfan is commonly used as conditioning in allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). However, a consensus has not yet been reached regarding the optimal busulfan dose in cord blood transplantation (CBT). Therefore, we conducted this large nationwide cohort study to retrospectively analyze the outcomes of CBT in patients with AML receiving busulfan at intermediate (6.4 mg/kg i.v.; BU2) or higher (12.8 mg/kg i.v.; BU4) doses within a fludarabine/i.v. busulfan (FLU/BU) regimen. Among 475 patients who underwent their first CBT following FLU/BU conditioning between 2007 and 2018, 162 received BU2 and 313 received BU4. Multivariate analysis identified BU4 as a significant factor for longer disease-free survival (hazard ratio [HR], .85; 95% confidence interval [CI], .75 to .97; P = .014) and a lower relapse rate (HR, .84; 95% CI, .72 to .98; P = .030). No significant differences were observed in non-relapse mortality between BU4 and BU2 (HR, 1.05; 95% CI, .88-1.26; P = .57). Subgroup analyses showed that BU4 provided significant benefits for patients who underwent transplantation while not in complete remission (CR) and those age

Background We have reported an extremely rare case of a frontal convexity tumor diagnosed as IgG4-related disease (IgG4-RD) with unique neuroradiological images. Case Description A 64-year-old man with a history of monoclonal gammopathy of undetermined significance and conservative treatment had presented with a left facial spasm. Computed tomography showed a high-density round tumor with perifocal edema in the right frontal convexity. Magnetic resonance imaging demonstrated unique findings, including low signal intensity on T1- and T2-weighted, fluid-attenuated inversion recovery, and diffusion-weighted images, with slight gadolinium enhancement. The tumor was totally removed via right frontal craniotomy. It had been located in the subdural space, was not adherent to the dura, and was less vascular than meningiomas. Histological investigation demonstrated plasma cells that were strongly positive for IgG4 and contained κ and λ light chains at a ratio of 1.5:1. The serum IgG4 level was elevated. The tumor met the diagnostic criteria for IgG4-RD. The patient was followed up for 3 years during postoperative adjuvant steroid therapy. The steroid therapy was discontinued, and during the next 4 years, neither tumor recurrence nor symptoms were observed. Conclusion Intracranial IgG4-RD with smoldering monoclonal gammopathy of undetermined significance is extremely rare. We reviewed the differential diagnosis of plasma cell granuloma and plasmacytoma, therapeutic implications, and clinical outcomes. Complete resection of a conspicuous and solitary IgG4-RD lesion in the frontal convexity is simple and could provide a cure with less-aggressive adjuvant therapy.

For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open‐label, multicenter study to investigate an intrapatient nilotinib dose‐escalation strategy for patients with newly diagnosed chronic‐phase (CP) CML based on early MR4.5 achievement. The primary study endpoint was achievement of MR4.5 by 24 months following the initiation of nilotinib 300 mg BID. Fifty‐three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207‐736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR4.5. The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non‐AE related reasons. Four of these patients achieved MR4.5. The MR4.5 rate by 24 months was 45.7%. The progression‐free, overall and event‐free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML‐CP., The N‐Road study aimed to determine the optimal treatment strategy for nilotinib use in patients with newly diagnosed CML‐CP based on early achievement of deep molecular response. Most patients received nilotinib at a dose of 300 mg BID and were able to achieve an early deep molecular response. Together with the finding that none of the patients whose dose was escalated to 400 mg BID achieved MR4.5, we consider that continuous nilotinib at a dose of 300 mg BID may be the optimal treatment strategy for newly diagnosed patients with CML‐CP.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase1,2. ABL1-selective tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML3–7. The ultimate goal of CML treatment is likely to be TKI-free maintenance of deep molecular response (DMR), which is defined by quantitative measurement of BCR-ABL1 transcripts on the international scale (IS)8, and durable DMR is a prerequisite to reach this goal9. Thus, an algorithm to enable the early prediction of DMR achievement on TKI therapy is quite valuable. Here, we show that our mathematical framework based on a clinical trial dataset10 can accurately predict the response to frontline nilotinib. We found that our simple dynamical model can predict nilotinib response by using two common laboratory findings (observation values): IS11,12 and white blood cell (WBC) count. Furthermore, our proposed method identified patients who failed to achieve DMR with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs in clinical practice.Significance StatementChronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. The goal of this treatment is the sequential achievement of deep molecular response (DMR). Tyrosine kinase inhibitors (TKIs) are effective in the reduction because they inhibit CML cell proliferation. However, because of individual differences in the TKI efficacy, some patients are unable to achieve DMR, so that early prediction of DMR reachability is necessary for personalized medicine. By combining time series analysis and mathematical modeling, we developed a mathematical method that accurately predicts patients who do not achieve DMR in the early stages of TKI administration. Our prediction method gives a basis of effective personalized treatments for CML patients.

The FMS-related tyrosine kinase 3 (FLT3) internal tandem duplication mutations (FLT3-ITD) positive acute myeloid leukemia (AML) is a disease with a dismal outcome. Gilteritinib is a second-generation FLT3 inhibitor with activity against ITD and high affinity toward the FLT3 receptor, thereby showing therapeutic potential for relapsed/refractory FLT3-mutated AML. Bone marrow transplantation (BMT) from a human leukocyte antigen (HLA) identical sibling donor was performed in a 38-year-old Japanese male with FLT3-ITD positive AML. Neutrophil engraftment (>0.5 × 109/L) was achieved on day 16, and bone marrow remission was revealed on day 32. The patient's AML relapsed hematologically four months after BMT and was resistant to salvage chemotherapy. Gilteritinib was administered and the patient achieved non-remission but ‘stable disease’ status according to the response criteria. During administration, liver damage was observed but controllable. The patient received cord blood transplantation (CBT) as the second hematopoietic stem cell transplantation (HSCT) three months after relapse and achieved second remission. There was no evidence of recurrence of AML four months after CBT. This case demonstrates that gilteritinib can control FLT3-ITD positive AML that relapsed early after initial HSCT and can bridge to second HSCT.

Case Acute compartment syndrome (ACS) with acquired hemophilia A (AHA) is rare and has no established treatment strategy. A 64-year-old woman presented with a giant hematoma in the rectus abdominis. Laboratory findings included decreased hemoglobin and increased activated partial thromboplastin time. Arterial embolization was performed for hemostasis. After catheter removal, she developed severe arm pain and numbness with blistering. Fasciotomy was performed to decrease intracompartmental pressure. Laboratory investigations revealed decreased factor VIII (FVIII) activity and increased FVIII inhibitor. AHA was diagnosed and treated with immunosuppressive and FVIII inhibitor-bypassing agents. Conclusions Fasciotomy should be performed promptly if ACS with AHA is suspected.

Summary Background BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase. Methods DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0–2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period. Findings Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5–83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48–71), with a median follow-up of 366 days (IQR 353–372). Grade 3–4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3–4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed. Interpretation Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population. Funding Bristol-Myers Squibb.

Simple Summary Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). An improved immunological environment may be useful for maintaining MRD negativity. Whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies and expected immunotherapies via improvement of the immunological environment and maintenance of MRD negativity. Abstract Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). Immunomodulatory drugs (IMiDs), monoclonal antibody drugs (MoAbs), and autologous grafts for autologous stem cell transplantation (ASCT) can improve the immunological microenvironment. ASCT, MoAbs, and proteasome inhibitors (PIs) may be important for the achievement of MRD negativity. An improved immunological environment may be useful for maintaining MRD negativity, although the specific treatment for persistent MRD negativity is unknown. However, whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies, including IMiDs, PIs, MoAbs, and ASCT, and expected immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, via improvement of the immunological environment and maintenance of MRD negativity.

The combination of bortezomib, lenalidomide, and dexamethasone (VRD) is used as induction treatment in multiple myeloma; however, the optimum schedule for this regimen remains controversial. In this retrospective study, we compared the efficacy and tolerability of twice-weekly VRD (twVRD) and modified VRD-lite in transplant-eligible myeloma patients. Fifty-five patients (median age 61 years) were included; 22 received twVRD (bortezomib [1.3 mg/m2 on days 1, 4, 8, and 11] and lenalidomide [25 mg/body on days 1–14] over 21-day cycles) and 33 received modified VRD-lite (bortezomib [1.3 mg/m2 on days 1, 8, 15, and 22) and lenalidomide [15 mg/body on days 2–7, 9–14, 16–21] over 28-day cycles). Overall response, very good partial response, and complete response rates after VRD were 96.4%, 45.5%, and 20.0%, respectively (median follow-up period, 17.7 months). The 1-year progression-free survival (PFS) and overall survival rates were 95.8% and 98.2%, respectively. The response rate and PFS were similar between the groups, regardless of cytogenetic risk and age. The incidence of peripheral neuropathy ≥ grade 2 and thrombocytopenia ≥ grade 3 was higher in the twVRD group (27.2% vs. 0.0%, P = 0.003 and 27.2% vs. 0.0%, P = 0.003). In conclusion, modified VRD-lite had similar efficacy with, but better tolerability than, twVRD in transplant-eligible patients.

A 68-year-old male presented with appetite loss and abdominal distention. The whole-body computed tomography scan revealed an ileocecal mass with a large amount of ascites, which was consistent with malignant lymphoma. Due to the worsening of his general condition following admission, he was intubated and admitted to the intensive care unit (ICU). In the ICU, we performed a core-needle biopsy (CNB) on the left peritoneal mass, the findings of which showed a pathological diffuse infiltration of CD20+ middle-sized lymphoid cells. After chemotherapy was initiated, the patient showed complete response, suggesting that CNB can be performed immediately and safely even on a critically ill patient.

Simple Summary Multiple myeloma is an uncurable hematological malignancy, although the prognosis of myeloma patients is getting better using proteasome inhibitors (PIs), immune modulatory drugs (IMiDs), monoclonal antibodies (MoAbs), and cytotoxic agents. Drug resistance makes myeloma difficult to treat and it can be subdivided into two broad categories: de novo and acquired. De novo drug resistance is associated with the bone marrow microenvironment including bone marrow stromal cells, the vascular niche and endosteal niche. Acquired drug resistance is related to clonal evolution and non-genetic diversity. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAbs, and autologous stem cell transplantation because these treatments improve the bone marrow microenvironment and might prevent clonal evolution via sustained deep response including minimal residual disease negativity. Abstract Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow stromal cells, and soluble factor-mediated drug resistance, which is induced by cytokines and growth factors, are two types of de novo drug resistance. The microenvironment, including conditions such as hypoxia, vascular and endosteal niches, contributes toward de novo drug resistance. Clonal evolution was associated with acquired drug resistance and classified as branching, linear, and neutral evolutions. The branching evolution is dependent on the microenvironment and escape of immunological surveillance while the linear and neutral evolution is independent of the microenvironment and associated with aggressive recurrence and poor prognosis. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibody agents (MoAbs), and autologous stem cell transplantation (ASCT) have improved prognosis of myeloma via improvement of the microenvironment. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAb and ASCT. This review summarizes the role of anti-myeloma agents for microenvironment and clonal evolution and treatment strategies to overcome drug resistance.

This is the rare case report that bilateral vagus nerve paralysis was emerged as the initial symptom of acute myelogenous leukemia (AML). An 83-year-old man admitted to our hospital because of dysphagia. His dysphagia progressed two months prior to admission. Although physical examination revealed no abnormality, videoendoscopy and videofluorography examination clearly revealed bilateral vagus nerve palsy. Brain MRI showed hypointense signals at the bilateral clivus on T1 weighted images, suggesting tumor infiltration to bilateral petroclivus. He was diagnosed as AML by blood samples and bone marrow biopsy. After initiation of the treatment including radiation therapy, dysphagia shows mild improvement. Although bilateral cranial nerve palsy due to malignant tumor involving at the clivus is very uncommon, we should pay attention to the symptom.

This study presents the final report of the multicenter, prospective tyrosine kinase inhibitor discontinuation study, D‐STOP, after a 3‐year follow‐up of 54 patients with chronic CML who discontinued dasatinib after a sustained deep molecular response (DMR) for ≥2 years with dasatinib treatment. Estimated treatment‐free remission (TFR) rates at 12 and 36 months were 63.0% [95% confidence interval (CI): 48.7‐74.3] and 59.3% (95% CI: 45.0‐71.0), respectively. CD3−CD56+ NK, CD16+CD56+ NK, and CD57+CD56+ NK large granular lymphocyte (NK‐LGL), CD8+CD4– cytotoxic T cell, and CD57+CD3+ T‐LGL cell numbers were relatively elevated throughout the 24‐month consolidation only in failed patients who molecularly relapsed within 12 months. In successful patients, these subsets elevated transiently after 12 months, but returned to basal levels after 24‐month consolidation. Therefore, smaller changes in NK/T, particularly the NK subset throughout consolidation, reflected higher TFR rates. TFR rates of those patients exhibiting elevation in CD3−CD56+ NK >376 cells/μL, CD16+CD56+ NK > 241 cells/μL, or CD57+CD56+ NK‐LGL >242 cells/μL during consolidation compared with others were 26.7% (8.3%‐49.6%) vs 78.3% (55.4%‐90.3%), HR 0.032 (0.0027‐0.38; P = .0064), 31.2% (11.4%‐53.6%) vs 85.0% (60.4%‐94.9%), HR 0.039 (0.0031‐0.48; P = .011), or 36.8% (16.5%‐57.5%) vs 77.3% (53.7%‐89.8%), HR 0.21 (0.065‐0.69; P = .010), respectively. Therefore, silent responses of T/NK subsets to dasatinib throughout consolidation were significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, may be immunologically insufficient to maintain TFR. Their decline, subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR, might be immunologically significant. (D‐STOP, NCT01627132)., The figure shows that silent NK/T cell reactions against dasatinib, particularly that of NK cells, during sustained DMR before dasatinib discontinuation are significant for longer treatment‐free remission.

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).

Introduction: Tyrosine kinase inhibitors (TKIs) dramatically improved the prognosis of chronic myelogenous leukemia (CML), as nearly half of CML patients presenting with a deep molecular response (DMR) over several years could achieve treatment-free remission. DASISION study reported dasatinib (DAS), a second-generation TKI was superior to imatinib to achieve faster and deeper response in treating newly-diagnosed chronic CML. However, standard initial dosage of 100 mg DAS/day might be too potent for patients aged >70 years with CML, possibly owing to the presence of other health conditions that threaten the life spans (e.g., lung and cardiovascular disease), thereby preventing TKI continuation. In this open-label, multicenter, single-arm, phase 2 study (DAVLEC), we evaluated the efficacy and safety of a reduced initial dose of DAS (20 mg/day) in the elderly with chronic CML. Patients and Methods: We included CML patients aged >70 years with an ECOG performance status of 0-2 and adequate organ function. After diagnosis, they began orally taking 20 mg of DAS per day. BCR-ABL mRNA values were measured and aligned to an international scale at a central laboratory to evaluate the drug's efficacy at 3, 6, 9, and 12 mo of therapy, per recommendations by European LeukemiaNet. The dosage was maintained in case of the optimal, increased by 20 mg/day when the warning appeared and could be decreased when an adverse event (AE) > grade 3 appeared. Patients were excluded if the respond was the failure or disease progression was detected. Primary endpoint was the cumulative major molecular response (MMR) rate at 12 mo. Secondary endpoints included the rates of the cumulative DMR, treatment discontinuation due to AEs, and failure to DAS treatment or disease progression. The non-inferiority of primary endpoint MMR (non-inferiority limit of 38%) was evaluated by binomial test with normal approximation. Other differences were investigated by Mann-Whitney tests, with p < 0.05 indicating significance. Results: Among the 56 patients enrolled from 25 centers, 4 declined participation, and so 52 (median age, 77.5 years) began taking 20 mg/day of DAS. In total, 73.1% of the patients had comorbidities. Median BCR-ABL values at 3, 6, and 12 mo were 1.47%, 0.23%, and 0.03%, respectively; cumulative MMR rate at 3, 6, 9, and 12 mo were 11.5%, 36.5%, 40.4%, and 59.6%, respectively. Calculated MMR at 12 mo was higher than 38%, a value selected based upon findings from the DASISION trial, accounting for a non-inferiority margin of 10% (p=0.047). At 12 mo, among the 31 patients achieving MMR, 23 were only given 20 mg DAS/day, and 14 and 7 respectively achieved MR4.0 and 4.5. Patients discontinued the study due to treatment failure (n=3), content withdrawal (n=2), drug-related AEs (Long QT Syndrome; n=1), or others (n=2). No patient discontinued it due to disease progression. Treatment-related AEs of all grades were noted in 96.2%and that of grade 3 or 4 events in 23.1% of the patients. Median dose interruptions for a median of 7 days (range: 5-36) were respectively noted in 3 and 2 patients due to hematological and non-hematological AEs. Furthermore, 4 patients experienced pleural effusion < grade 2, and 1 had lymphocytosis. Patients who achieved MMR at 12 mo (n=31) had a significantly lower BCR-ABL value at 3 mo (0.41% vs. 4.26%, p=0.0020) and a lower halving time from diagnosis to 3 mo (11.35 vs. 18.34 days, p=0.0050) than those who did not (n=21). Patients who achieved MMR by 12 mo with only 20 mg/day of DAS (n=23) had lower BCR-ABL values at 1 and 3 mo (25.51 vs. 63.63 %, p=0.00028; 0.33 vs. 5.89%, p Patients who achieved MMR at 12 mo (n=31) had higher plasma DAS concentration (23.5 vs. 8.0 ng/mL, p Conclusion: This study discovered that prescribing a starting very-low dose DAS (20 mg/day) while monitoring IS and AEs was a successful initial therapeutic strategy for the elderly with chronic CML comparable to previous studies using standard-dose. Notably, rapid BCR-ABL downregulation, early molecular responses at 1 and 3 mo, a shortened halving time from diagnosis to 3 mo, and sufficient increase in plasma DAS concentrations 2 h post-intake after 12 mo of treatment were key indicators for successful low-dose therapy. Disclosures Kumagai: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria, Speakers Bureau. Murai: Bristol Myers Squibb: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria; CHUGAI Pharmaceutical Co., Ltd.: Honoraria; TAKEDA Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Asahi Kasei Pharma Corporation.: Honoraria. Tanaka: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria. Nishiwaki: Kyowa-Kirin: Research Funding; Alexion: Honoraria. Inokuchi: Bristol-Myers Squibb: Research Funding. Yoshida: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis KK,: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria; AbbVie GK: Honoraria; Janssen Pharmaceutical KK: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Uoshima: Janssen: Honoraria; Eisai: Honoraria. Usuki: MSD K.K.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Amgen-Astellas Biopharma K.K.: Research Funding; Mundipharma K.K.: Research Funding; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Celgene K.K.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Kuroda: Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Ono: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Celgene: Honoraria, Research Funding. Fujimaki: CSL Behring K.K.: Honoraria; Mundipharma K.K.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Janssen Pharmaceutical KK: Honoraria; AbbVie GK: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Shibayama: Chugai: Research Funding; Eizai: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Kyowa Kirin: Speakers Bureau; AbbVie: Research Funding; Celgene: Research Funding; Novartis: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Mundi Pharma: Speakers Bureau; Otsuka: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; AstraZeneca: Research Funding, Speakers Bureau; Takeda: Speakers Bureau. Kondo: Abbvie: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Pfizer: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding. Kimura: Eisai: Speakers Bureau; Kyowa-Kirin: Research Funding, Speakers Bureau; PharmaEssentia: Speakers Bureau; Astellas: Speakers Bureau; Sanifi: Speakers Bureau; Gilead: Research Funding; Nippon-Boehringer-Ingelheim: Research Funding; Celgene: Research Funding, Speakers Bureau; Sumitomo-Dainippon: Research Funding; Chugai: Research Funding, Speakers Bureau; Mundi: Research Funding; Yakult: Research Funding, Speakers Bureau; MSD: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; SymBio: Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding, Speakers Bureau; Janssen: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Takeda: Research Funding, Speakers Bureau; Nippon-Shinyaku: Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion: Research Funding, Speakers Bureau; Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ohara Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; AbbVie: Research Funding, Speakers Bureau; Apellis: Research Funding.

Tyrosine kinase inhibitors (TKIs) improve the prognosis of patients with chronic myelogenous leukemia (CML) by inducing substantial deep molecular responses (DMRs); some patients could successfully discontinue TKI therapy after maintaining DMR for ≥1 year. In this cessation study, we investigated the optimal conditions for dasatinib discontinuation in patients who maintained DMR for ≥2 years. This study included 54 patients with CML who were enrolled in D-STOP multicenter prospective trial, had achieved DMR, and had discontinued dasatinib after 2-year consolidation. Peripheral lymphocyte profiles were analyzed by flow cytometry. The estimated 12-month treatment-free survival (TFS) was 62·9% (95% confidence interval: 48·5%–74·2%). During dasatinib consolidation, the percentage of total lymphocytes and numbers of CD3-CD56+ natural killer (NK) cells, CD16+CD56+ NK cells, and CD56+CD57+ NK-large granular lymphocytes (LGL) were significantly higher in patients with molecular relapse after discontinuation but remained unchanged in patients without molecular relapse for >7 months. At the end of consolidation, patients whose total lymphocytes comprised

To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/μL was significantly better in the MMF+ group (relative risk (RR), 1.55; P

LR11 (also called SorLA or SORL1) is a type I membrane protein, originally identified as a biomarker for atherosclerosis and Alzheimer's disease. We recently found that LR11 was specifically expressed in Diffuse Large B-cell lymphoma (DLBCL) cells, and high serum sLR11 concentrations in retrospective cohort indicated inferior survival. In this study, we prospectively validated the clinical impact of serum sLR11 in 97 patients with newly-diagnosed, untreated DLBCL.Serum sLR11 concentrations were increased in DLBCL patients compared to normal controls (mean±SD: 21.2±27.6 vs. 8.8±1.8ng/ml, P0.0001), and significantly reduced at remission (mean±SD: 17.4±16.4 vs. 10.9±4.5ng/ml, P=0.02). Increased serum sLR11 concentrations were affected by tumor burden and bone marrow invasion. The 2-y OS and PFS were significantly lower in patients with high sLR11 concentrations (≤18.1ng/ml vs.18.1ng/ml; 2-y OS: 89.0% vs. 56.4%, P0.0001; 2-y PFS: 85.8% vs. 56.9%, P0.0001).Serum sLR11 is a tumor-derived biomarker for predicting the survival of newly diagnosed patients with DLBCL.

Lenalidomide is an immunomodulatory drug that is administered commonly in patients with relapsed or refractory multiple myeloma (RRMM). Eosinophils have immunological functions, for instance, in allergic diseases and asthma. The purpose of this study was to investigate the clinical significance of elevated eosinophil levels in patients with RRMM treated with lenalidomide. A total of 59 patients were included. Elevated eosinophil level was defined as an increase in the eosinophil count of ≥250/µL from the eosinophil count on day 1 during the first cycle. The percentage of patients with elevated eosinophil levels was 22.0%. The overall response ratio in the elevated eosinophil group and nonelevated eosinophil group was 84.6% and 63.0% (P = .189), respectively. The median time to next treatment (TTNT) in the elevated eosinophil group was significantly longer than that in the nonelevated group (40.3 months vs 8.4 months; P = .017). Additionally, TTNT in the elevated eosinophil group with partial response (PR) or better was significantly longer than that in the nonelevated eosinophil group with PR or better (40.3 months vs 11.9 months; P = .021). We concluded that elevated eosinophil levels were frequently observed and might predict a longer TTNT in patients with RRMM treated with lenalidomide., Elevated eosinophils predicted significantly long time to next treatment in relapsed or refractory multiple myeloma patients treated with lenalidomide. Elevated eosinophils might show an immunological effect of lenalidomide. We considered that NKG2D and IL‐2 were associated with elevated eosinophils according to the literature review.

The clinical features and prognostic significance of myeloma cells containing granules remain unclear. The purpose of this retrospective study was to investigate the clinical significance of granule‐containing myeloma cells in patients with newly diagnosed multiple myeloma (NDMM). We retrospectively analyzed the records of 122 patients diagnosed with NDMM between January 2007 and December 2013. Granule‐containing myeloma cells were defined as myeloma cells that exhibited three or more granules in their cytoplasm by May‐Giemsa staining. The patients were classified into two groups, the granule‐containing myeloma (GM) and nongranule‐containing myeloma (non‐GM) groups, depending on the proportion of myeloma cells that contained granules (cut‐off value: 10%). There were 25 (20.5%) patients in the GM group. Patients in the GM group displayed significantly higher CD56 and CD49e expression than those in the non‐GM group (t‐test, P = 0.027 and 0.042). None of the patient characteristics differed significantly between the two groups. There was no significant difference in the chemotherapy profiles of the two groups, and the overall response rates of the two groups were similar. During the median follow‐up period of 33.9 months, the overall survival (OS) in the GM group was similar to that in the non‐GM group; 4‐year OS of the GM and non‐GM groups were 78.5% and 51.9%, respectively (P = 0.126). We concluded that cases of NDMM involving granule‐containing myeloma cells are not infrequent. Moreover, CD56 and CD49e expression was significantly higher in the presence of myeloma cell populations, and the presence of granules did not affect survival.

Data characterizing the safety and effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) are limited. We describe the safety and effectiveness of eculizumab in PNH patients enrolled in a post-marketing surveillance study. Types and frequencies of observed adverse events were similar to those reported in previous clinical trials and no meningococcal infection was reported. Effectiveness outcomes included the reduction of intravascular hemolysis, the change in hemoglobin (Hb) level, the withdrawal of transfusion and corticosteroids, the change of renal function, and overall survival. The effect of eculizumab on intravascular hemolysis was demonstrated by a reduction in lactate dehydrogenase levels at all measurements after baseline. Significant increases in Hb levels from baseline were also observed after 1 month’s treatment with eculizumab (p < 0.01). Of those who were transfusion-dependent at baseline, the median number of transfusions decreased significantly from 18 to 0 unit/year after 1 year of treatment with eculizumab (p < 0.001). An increase in Hb and a high rate of transfusion independence were observed, especially in patients with platelet count ≥150 × 109/L. Approximately 97 % of patients showed maintenance or improvement of renal function. Overall survival rate was about 90 % (median follow-up 1.9 years). These results suggest an acceptable safety profile and favorable prognosis after eculizumab intervention.

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.

Allogeneic hematopoietic stem cell transplantation is recommended as a curative treatment option for fulminant aplastic anemia with no neutrophil despite the administration of granulocyte-colony stimulating factor. In the absence of an HLA-matched donor, unrelated cord blood transplantation (UCBT) is a treatment option that can be performed quickly. However, the optimal conditioning regimen of UCBT is yet to be established. We report two cases of fulminant aplastic anemia in adult patients who received UCBT. The first patient was a 52-year-old woman and the second was a 26-year-old man, both of whom received a conditioning regimen of total body irradiation (TBI; 2-4 Gy), fludarabine (Flu; 120 mg/kg), and cyclophosphamide (CY; 100 mg/kg) before UCBT. Short-term methotrexate and tacrolimus were used for prophylaxis of acute graft-versus-host disease (GVHD). Engraftments were achieved on days 26 and 19, and they exhibited complete donor chimerism by days 28 and 34. There was no evidence of acute GVHD, and therefore, the immunosuppressant drugs were discontinued. Reduced-intensity UCBT using a low-dose TBI/Flu/CY conditioning regimen could be an effective treatment option for fulminant aplastic anemia in the absence of a suitable donor.

Background With the introduction of imatinib, a first-generation tyrosine kinase inhibitor (TKI) to inhibit BCR-ABL1 kinase, the outcome of chronic-phase chronic myeloid leukemia (CP-CML) has improved dramatically. However, only a small proportion of CP-CML patients subsequently achieve a deep molecular response (DMR) with imatinib. Dasatinib, a second-generation TKI, is more potent than imatinib in the inhibition of BCR-ABL1 tyrosine kinase in vitro and more effective in CP-CML patients who do not achieve an optimal response with imatinib treatment. Methods In the present study, we attempted to investigate whether switching the treatment from imatinib to dasatinib can induce DMR in 16 CP-CML patients treated with imatinib for at least two years who achieved a major molecular response (MMR) with detectable levels of BCR-ABL1 transcripts. Results The rates of achievement of DMR at 1, 3, 6 and 12 months after switching to dasatinib treatment in the 16 patients were 44% (7/16), 56% (9/16), 63% (10/16) and 75% (12/16), respectively. The cumulative rate of achieving DMR at 12 months from initiation of dasatinib therapy was 93.8% (15/16). The proportion of natural killer cells and cytotoxic T cells in peripheral lymphocytes increased after switching to dasatinib. In contrast, the proportion of regulatory T cells decreased during treatment. The safety profile of dasatinib was consistent with previous studies. Conclusion Switching to dasatinib would be a therapeutic option for CP-CML patients who achieved MMR but not DMR by imatinib, especially for patients who wish to discontinue TKI therapy.

We herein report the case of a 68-year-old man with a history of allogeneic hematopoietic stem cell transplantation for acute myelocytic leukemia in whom graft-versus-host disease (GVHD) developed in the gastrointestinal tract and liver five months after transplantation. In that same period, chest computed tomography showed infiltration in both upper lungs. We performed bronchoscopy to clarify the GVHD and pulmonary infection. Nocardia nova was identified in the bronchoalveolar lavage fluid, and we diagnosed the patient as having pulmonary nocardiosis. Because the differential diagnosis is important for the medical management of GVHD and pulmonary infection, performing bronchoscopy is essential for making an appropriate and rapid diagnosis.

Introduction Tyrosine kinase inhibitors (TKIs) markedly enhance the prognosis of chronic myelogenous leukemia (CML), potentially enabling the attainment of deep molecular response (DMR). Subsequently, the discontinuation of TKI became imperative to evade adverse events and financial burden of TKI therapy. In several studies, beginning with the STIM1 (Lancet Oncol 2010;11:1029), nearly 40%-60% of patients with chronic CML who sustained long DMR could discontinue TKI and attain long-term treatment-free remission (TFR). Remarkably, initial dasatinib specifically induces the elevation in lymphocytes, including large granular lymphocytes (LGL), NK cells, and cytotoxic T cells, as well as the decline in regulatory T cells (Tregs) in the early phase of treatment, related to early clinical responses.(Int J Hematol 2014;99:41) Nevertheless, lymphocyte variations by dasatinib during sustained DMR before cessation is an area of growing interest. In the Japanese multicenter prospective D-STOP trial (NCT01627132), we discontinued dasatinib following 2-year consolidation to sustain DMR in chronic CML to assess the TFR rate. We here present the final results of the D-STOP trial, including the peripheral NK/T cell change during dasatinib consolidation associated with successful TFR. Methods: Chronic phase CML patients treated with TKIs who had undetectable BCR-ABL1 mRNA were enrolled. After confirmation of undetectable BCR-ABL1 mRNA (International Scale Results: Sixty-five patients received consolidation therapy, and 54 discontinued dasatinib treatment after maintenance of DMR for 2 years. Estimated treatment-free remission (TFR) rates at 12 and 36 months were 63.0% [95% confidence interval (CI): 48.7-74.3] and 59.3% (95% CI: 45.0-71.0), respectively.(Figure 1) CD3-CD56+NK, CD16+CD56+NK, CD57+CD56+NK large granular lymphocytes (NK-LGL), CD8+CD4- cytotoxic T, and CD57+CD3+T-LGL cell numbers were relatively elevated throughout 24-month consolidation only in failed patients who molecularly relapsed within 12 months. In successful patients (TFR >12-months), these subsets elevated transiently after 12 months but returned to basal levels after 24-month consolidation. (Figure 2)There were no differences in CD8-CD4+ helper T and Treg. cell numbers during consolidation between 2 groups. Therefore, smaller changes in the NK/T sebsets, particularly NK subset throughout consolidation, exhibited higher TFR rates. TFR rates of those exhibiting elevation in CD3-CD56+NK > 376 cells/mL, CD16+CD56+NK > 241 cells/mL,CD57+CD56+NK-LGL > 242 cells/mL or CD8+CD4- cytotoxic T cells > 212 cells/mL during consolidation compared with others were 26.7% (8.3%-49.6%) versus 78.3% (55.4%-90.3%), HR 0.032 (0.0027-0.38; P = 0.0064) (Figure 3), 31.2% (11.4%-53.6%) versus 85.0% (60.4%-94.9%), HR 0.039 (0.0031-0.48; P = 0.011), 36.8% (16.5%-57.5%) versus 77.3% (53.7%-89.8%), HR 0.21 (0.065-0.69; P = 0.010), or 41.2% (18.6%-62.6%) versus 76.5% (48.8%-84.9%), HR 0.18 (0.019-1.77; P = 0.14), respectively. Conclusion Silent responses of the T/NK subsets to dasatinib throughout consolidation was significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, could be immature cells with little immunosurveillance; their decline subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR might be immunologically significant. Disclosures Kumagai: Pfizer: Honoraria; Otsuka pharmacology: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Nakaseko:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria. Nishiwaki:Novartis: Research Funding. Yoshida:Otsuka: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Matsue:Janssen Pharmaceutical K.K.: Honoraria; Novartis Pharma K.K: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Celgene: Honoraria; Ono Pharmaceutical: Honoraria. Morita:Bristol-Myers Squibb: Honoraria. Sakamoto,:Yakult Honsha Co. Ltd: Other: remuneration. Inokuchi:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria.

Lymphocytosis in response to dasatinib for chronic myelogenous leukemia (CML) may be associated with favorable response. However, it occurs at varying times and in a limited subset of patients. To identify early clinical markers for favorable responses applicable to all patients with or without lymphocytosis, we prospectively analyzed lymphocyte profiles of 50 Japanese CML patients treated with dasatinib after intolerance/resistance to imatinib. Although absolute lymphocyte counts did not differ significantly until 3 months between patients with complete molecular response (CMR) at 12 months and those without it, relative increases in lymphocyte compared with baselines differed significantly from 1 month. Patients with relative lymphocyte counts150 % at 1 month or200 % at 3 months had higher CMR rates at 12 months than others (57.9 vs. 23.3 %, P = 0.015, and 76.5 vs. 16.1 %, P0.0001, respectively). A relative increase in lymphocyte subset of CD57(+)CD14(-), CD8(+)T, or NK cells200 % at 1 month was also significantly associated with a higher CMR rate. There were significant negative correlations between relative lymphocyte increases and BCR/ABL transcript levels. CD57(+)CD14(-) cells were a highly specific focus of proliferation. Relative increases in lymphocyte count and its subsets from 1 month are reliable early markers of favorable responses to dasatinib.

Autologous hematopoietic stem cell transplantation (auto-HCT) is considered a standard therapy for transplant-eligible patients with multiple myeloma, while allogeneic HCT (allo-HCT) is controversial. We retrospectively analyzed 765 patients with myeloma who underwent tandem transplantation between 1998 and 2012 using Japanese registry data. We evaluated the clinical outcomes of tandem auto-HCT (n = 676) and auto/allo-HCT (n = 89). To adjust for a selection bias, we compared overall survival (OS) between the two groups by a propensity score analysis. The probability of OS at six years was 58.5% for the tandem auto-HCT group and 54.4% for the tandem auto/allo-HCT group (p = 0.47). In a matched-pair analysis based on the propensity score, the difference in survival between the two groups was not statistically significant, although the survival curve appeared to reach a plateau beyond five years in the auto/allo group. Further strategies to reduce treatment-related mortality and enhance a graft-versus-myeloma effect are necessary to improve OS.

Human T-cell lymphotropic virus type-1 (HTLV-1)-associated bronchioloalveolar disorder (HABA) is a specific state with chronic and progressive respiratory symptoms caused by bronchiolar or alveolar disorder characterized by smoldering adult T-cell leukemia or the HTLV-I carrier state. We herein report a rare case of HABA with an initial presentation of mosaic perfusion in the lung. The diagnosis was made according to the results of a flow cytometry analysis of the bronchoalveolar lavage fluid and pathological findings. Clinicians must be careful to recognize that mosaic perfusion may be a radiological finding of HABA.

Tumor-lysis syndrome (TLS) describes a group of metabolic disturbances caused by the massive and abrupt release of cellular components into the blood after the rapid lysis of malignant cells. TLS is a potentially life-threatening complication in rapidly proliferating, bulky tumor, or highly chemo-radiosensitive cancers. In contrast, TLS is the rare complication among patients with multiple myeloma (MM). TLS seems to occur more frequently in MM patients receiving bortezomib (BOR) and carfilzomib (CFZ) than in those receiving other cytotoxic agents. We retrospectively investigated the frequency, risk factors, and clinical outcome among the relapsed or refractory MM (RRMM) patients treated with proteasome inhibitors (PI), such as BOR, CFZ, and ixazomib (IXA), in our institute. Between November 2005 and December 2017, seventy-two RRMM myeloma patients treated with BOR, CFZ, or IXA, in our institute. The number of patients treated PI was defined as below. Relapse or refractory disease and response criteria were defined according to the International Myeloma Working Group criteria. Patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and primary plasma cell leukemia were excluded. We evaluated TLS by the Cario-Bishop grading classification. After starting of PI, the following parameters were recorded and evaluated for prognosis: serum hemoglobin concentration (Hb), serum level of lactate dehydrogenase (LDH), creatinine (Cr), uric acid (UA). The cutoff levels of LDH, Cr, and UA were the upper normal limit. Anemia was defined by the CRAB criteria. Hepatosplenomegaly and plasmacytoma were evaluated using computed tomography. We analyze these two groups in terms of patient characteristics, laboratory findings, response, and survival. Fisher's exact tests were used to compare differences between the two groups. We analyzed prognostic factors for survival in significant poor predictors of laboratory parameters and well-established prognostic factors by Cox regression analysis. Overall survival (OS) and time to next treatment (TTNT) were analyzed by the Kaplan-Meier method. Median age of the patients was 71 years (range, 41-86) at the time of PI treatment. Median number of prior treatments was 2 (range, 1-8). The number of patients treated 53 of BOR, 10 of IXA, 4 of BOR + CFZ, 3 of CFZ + IXA, 1 of BOR + IXA, and 1of BOR + CFZ + IXA, respectively. TLS occurred in 13 patients (18.1%); such as 8 of BOR (13.3%), 4 of CFZ (40.0%), and 1 of IXA (6.7%). TLS occurred more frequently in the patients treated with twice weekly CFZ plus dexamethasone (CFZ 56mg/m2) than twice weekly CFZ, lenalidomide, plus dexamethasone (CFZ 27mg/m2); 50% and 25%, respectively. Median day of TLS after PI was 8 (range, 4-21). Median day of TLS in BOR, CFZ, and IXA were 7.5, 5.5, and 13 days, respectively. Two patients received rasbricase after TLS occurred. There was no patient who underwent hemodialysis for TLS. The mortality related with TLS was none. The significant factors associated TLS were anemia, high LDH level, prior treatments of 2 or more and hepatosplenomegaly according to univariate analysis. In multivariate analysis, high LDH level (Odds ratio; 12.9, P=0.027) and hepatosplenomegaly (Odds ratio; 13.4, P=0.035) was related with TLS significantly. There was no significant difference between overall response rate in the TLS group and non-TLS group (46.4% vs 64.8%, P=0.117). In median follow-up was 12.9 months, the median TTNT of the TLS group was significantly shorter than that of the non-TLS group (1.9 vs 7.0 months, P = 0.009, Figure 1a). The median OS of the TLS group was significantly shorter than that of the non-TLS group as well (5.8 vs 46.4 months, P = 0.017, Figure 1b). Our analysis revealed that 18.1% of RRMM patients treated with PI developed TLS although TLS was manageable by prophylaxis.gh LDH level and hepatosplenomegaly were identified with significant risk factors for TLS. TLS was not associated with good response of treatment. The TTNT and OS in the TLS group was significantly shorter than those in the non-TLS group. We considered that TLS might be related with progressive disease without activity of treatment in RRMM patients treated with PI. Among the RRMM patients with high LDH level, TLS is one of common adverse events in first cycle of PI but tolerable. Disclosures No relevant conflicts of interest to declare.

Hemophagocytic syndrome (HPS) presents with fever, pancytopenia, liver dysfunction and increase in hemophagocytic histiocytes in various organs. Although there are two major classifications of HPS in adults, malignant and reactive histiocytosis, it is often very difficult to distinguish between these disorders. We analyzed the laboratory data of patients with HPS to evaluate prognostic factors. Of 34 patients, 14 survived, and 20 died. The median age of survivors was 29.6+/-11.5 yr significantly younger than those who died (54.7+/-17.8 yr). Twenty patients had no obvious underlying disease, the other 13 had hematological malignancies or viral infections. Comparison of laboratory data revealed that nonsurvivors had significantly lower Hb and platelet values on admission. During treatment, worsening of anemia and thrombocytopenia, increase of transaminase and biliary enzymes were similarly more prominent. Risk factors associated with death were: age over 30 yr, presence of disseminated intravascular coagulation, increased ferritin and beta2-microglobulin, anemia accompanied by thrombocytopenia and jaundice. Our data suggests that patients with HPS and any of these risk factors should be treated aggressively with sufficient chemotherapy and supportive care.

Pregnancy with paroxysmal nocturnal hemoglobinuria (PNH) is associated with significant risk of complications, such as life-threatening thrombosis. Recently, eculizumab has come into clinical use and revolutionized the treatment of PNH. However, clinical information regarding eculizumab use for PNH during pregnancy is limited. The present report describes pregnancies with PNH treated with eculizumab that were registered with the Japan PNH study group and reviews the literature. In case 1, the patient received eculizumab throughout pregnancy and delivered a healthy neonate at term, although breakthrough hemolysis occurred at 20 weeks of gestation. In case 2, the patient discontinued eculizumab before pregnancy and developed preeclampsia at 27 weeks of gestation. She received eculizumab and delivered a preterm, but healthy, neonate by cesarean section. In case 3, the patient received eculizumab from 18 weeks of gestation and delivered a healthy neonate at term without any complications. Reports of 11 pregnant women treated with eculizumab were identified in the literature. Of 14 pregnancies, including our own cases, breakthrough hemolysis and preeclampsia occurred in five and two cases, respectively. There were no thrombotic complications, maternal or neonatal deaths, or fetal structural abnormalities. Thus, eculizumab appears to be safe and effective for managing PNH during pregnancy.

Primary immune thrombocytopenia (ITP) is an autoimmune disease mediated by the production of autoantibody against platelets. Rituximab, an anti-CD20 antibody, is reported to be useful for treatment of ITP. In Japan, however, robust evidence on this treatment has not been accumulated. Hence, we conducted this open-label phase III clinical trial to confirm the efficacy and safety of rituximab, administered at 375 mg/m² once per week at weekly intervals for 4 consecutive weeks in Japanese patients with chronic ITP, who had relapsed and were refractory to conventional therapy. The primary endpoint was defined as the percentage of patients with a platelet count above 50 × 10⁹/L at week 24 after the first dose of rituximab, which was 30.8% of 26 patients (95% confidence interval 14.3-51.8%). Although the lower confidence limit of primary endpoint failed to meet the pre-specified threshold of 20%, the clinical efficacy of rituximab is substantial in consideration of the 2% response rate in the placebo arm in other clinical studies in patients with chronic ITP. We conclude that rituximab is clinically useful and safe in the treatment of Japanese patients with chronic ITP, achieving the goal of maintaining platelet count and reducing risk of bleeding while minimizing treatment-related toxicity.

Summary The T cell-lineage marker CD2 is sometimes expressed in acute promyelocytic leukemia (APL), and CD2 expression is reported to correlate with some clinical characteristics. However, the significance of CD2 expression in APL has not been fully elucidated. We evaluated CD2 expression in APL treated by the same treatment strategy in a single institute, and whether it had any special characteristics. Among 29 APL, 6 were positive for CD2. Patients with CD2+ APL tended to have a higher leukocyte count than CD2− APL (34.5 ± 13.1/l vs. 6.8 ± 2.1 /l), morphological characteristics as variant-APL (50 vs. 0%). They also showed poor clinical prognosis. The CR rate of CD2− APL was 87.0% while that of CD2+ APL was 50 %. The mortality was 13.0 and 66.7%, respectively, and the survival rate was significantly lower in CD2+ APL. CD2 expression was proven to be a risk factor associated with death in addition to the morphological characteristics of variant-APL and leukocytosis. These results indicated that CD2 expression might have a significant impact on the prognosis of APL. Whether CD2+ APL should be characterized as a special clinical entity should be discussed in a larger patient population.

Background Nilotinib (NIL) is a second-generation tyrosine kinase inhibitor (TKI) that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). Superior rates of deeper molecular responses (DMR) were achieved with NIL vs. imatinib (IM) in patients newly diagnosed with CML in chronic phase (CML-CP) in the ENESTnd trial. In addition, the ENESTcmr study demonstrated that switching to NIL after a minimum of 2 years on IM led to increased rates of DMR vs. remaining on IM. Switching to NIL treatment for 2 years safely led to MR4,5 (BCR-ABLIS…0.0032%) in 47.5% of patients with major molecular response (MMR) on long-term IM therapy in our STAT1 trial. Recently, treatment free remission (TFR) was proposed as one of the goals in CML treatment. Indeed, prospective trials suggest that IM therapy may be safely and successfully discontinued in 40% of CML patients with MR4.5. STAT2 is the first study to evaluate the efficacy of two-year consolidation by NIL for successful TFR in patients with CML-CP who had achieved MR4.5. Before enrolling in STAT2, some patients were treated by not only IM but also NIL because of MMR but no MR4.5 after IM therapy, and some patients changed over from STAT1 to STAT2. Here, we present the results of the subgroup analysis from STAT2 based on the prior treatments at the time of entry into the study. Methods In the STAT2 trial, patients who achieved MR4.5 on IM front line therapy (subgroup 1; SG1) or NIL second line therapy after IM therapy (subgroup 2; SG2) were eligible and NIL was given twice daily at the dose of 600 mg/day for 2 years in consolidation phase. The primary endpoint of STAT2 was the proportion of patients with successful TFR, defined as no confirmed loss of MR4.5 (2 consecutive IS RQ-PCR tests), within the first 12 months of TFR phase. Thirty-five institutions in STAT study group participated. The study was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was signed by all patients according to institutional guidelines. The study was approved by all institutional review boards and registered with UMIN-CTR (000005904). Results Between July 2011 and December 2012, 96 patients were enrolled in STAT2. Among 96 patients, 50 patients were treated by IM first line only as prior therapy (SG1). On the other hand, 40 patients were treated by IM first line and NIL second line including 21 patients who changed over from STAT1 to STAT2 because they achieved MR4.5 (SG2). Six patients were excluded in this analysis because second generation TKIs were taken as a first line therapy. Among patients treated by NIL for 2 years in this study, 40/50 (80%; 95% CI, 68.4%-88.7%) in SG1 and 33/40 (82.5%; 95% CI, 69.6%-91.5%) in SG2 entered the TFR phase, respectively. The median age was 54.5 years in SG1 and 56.0 years in SG2. The ratio of men to women was 26:14 in SG1 and 18:15 in SG2. The total duration of TKI treatment was 110 months for the SG1 with a median of 86 months of IM, and 24 months of NIL, and 93 months in SG2 with a median of 62 months of IM, and 31 months of NIL,, respectively. All patients achieved MR4.5 at the time of entry into the study and the median time to MR4.5 was 47 months in SG1 and 60 months in SG2.The proportion of patients who maintained TFR at 12 months after stopping NIL was similar across the 2 subgroups: 25/40 (62.5%; 95% CI, 48.3%-77.3%) in SG1, and 23/33 (69.7%; 95% CI, 54.0%-82.5%) in SG2. The Kaplan-Meier (KM) analysis of TFR survival showed that in the 2 subgroups, the majority of events occurred within the first 6 months after stopping NIL (Figure 1). There were no significant differences between these 2 subgroups. Conclusion After two-year consolidation by NIL of CML-CP patients who achieved MR4.5, the TFR rate was 67.9% (90%CI: 58.2% to 76.6%) at 12 months in the STAT2 trial. In the present analysis looking at the prior TKI exposure, the TFR rate was similar in patients treated with IM first line only or who switched from IM to NIL before entering the study, despite the fact that the treatment duration of switched patients was slightly shorter. These findings suggest that two-year consolidation by NIL is associated with successful TFR in CML with MR4.5 that was achieved with IM alone or after switching to NIL. Figure Kaplan-Meiercurve of TFR survival in the 2 subgroups based onthe prior treatmentsbefore two-year consolidation by NIL, IM first line only as prior therapy (subgroup1) and IM first line and NIL second line (subgroup2). Figure. Kaplan-Meiercurve of TFR survival in the 2 subgroups based onthe prior treatmentsbefore two-year consolidation by NIL, IM first line only as prior therapy (subgroup1) and IM first line and NIL second line (subgroup2). Disclosures Takahashi: PFIZER: Honoraria, Research Funding; BMS: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding. Nakaseko:BMS: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; NOVARTIS: Honoraria. Nishiwaki:Novartis PHARMA: Research Funding.