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The standard of care for diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, its ideal dose intensity varies among cases.This review provides the latest insights on the dose intensity of R-CHOP for DLBCL patients. Specifically, we discussed the optimal dose intensity for elderly patients, the optimal number of treatment cycles for limited or advanced-stage diseases, and the role of dose-intensified therapies or adding targeted inhibitors.Performing a comprehensive or simplified geriatric assessment can distinguish elderly DLBCL patients who will likely benefit from curative R-CHOP. Very elderly or medically unfit patients may need dose reduction in R-CHOP; the Age, Comorbidities, and Albumin index may aid decision-making. Four cycles of R-CHOP followed by two rituximab cycles comprise a new standard for low-risk, limited-stage DLBCL patients. Compared to eight cycles, six cycles of R-CHOP have similar efficacy and fewer toxicities for advanced-stage DLBCL. Dose-intensified therapy is not recommended in most DLBCL cases but may be considered for patients with double (or triple)-hit lymphoma. Applying targeted inhibitors and not merely escalating R-CHOP dose intensity through molecular subtyping will improve the treatment outcome for DLBCL.Diffuse large B-cell lymphoma (DLBCL) is one of the most common blood cancers. Patients with DLBCL are usually treated with a standard (immuno-) chemotherapy called R-CHOP, which stands for rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin, and prednisone. Of these, cyclophosphamide and doxorubicin are particularly toxic but effective. Therefore, the dosages of these drugs are adjusted according to the patient’s body size. However, the ideal amounts of these drugs (dose intensity) can vary from case to case. For instance, the regular dose intensity of R-CHOP is too toxic for some people, such as very older patients. Furthermore, ideal total amounts of these drugs, that is, ideal cycle numbers of R-CHOP, are also different between patients with limited disease and advanced disease. Therefore, oncology/hematology researchers have been seeking the optimal dose intensity of R-CHOP in each patient with DLBCL for years. The goal of this review is to provide the latest insights on the ideal dose intensity of R-CHOP in DLBCL treatment. In this article, we discuss: how R-CHOP was established as the standard of care for DLBCL, how to identify candidates for standard R-CHOP among older patients, how to adjust the dose intensity of R-CHOP for patients who are not candidates for standard R-CHOP, optimal cycle number of R-CHOP for limited-disease DLBCL, optimal cycle number of R-CHOP for advanced DLBCL, how to treat patients with a large mass, and the role of more intensive therapies other than R-CHOP in DLBCL treatment. Finally, we demonstrate how experts determined the dose intensity of R-CHOP for some example cases with DLBCL.

Key Points Dasatinib-based 2-step induction resulted in a 100% CR rate with minimal toxicities and 53% MRD negativity.This protocol treatment increased the number of HSCTs in CR1, thereby improving 3-year EFS., Visual Abstract, The standard treatment for adults with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

Background Infusion-related reactions (IRRs) during rituximab administration are occasionally severe and remain problematic in oncology practice. Aim To establish a safer, risk-stratified rituximab protocol for patients with B-cell lymphoma. Method We stratified patients into low-, moderate-, and high-risk groups according to the number of risk factors for IRRs, specifically, low-grade histology and bulky tumors ( 10 cm): Then, the administrating schedule of rituximab (375 mg/m

Background: Some chemotherapeutic agents cause carnitine deficiency, which causes general fatigue. However, there is no study on carnitine deficiency in patients with chronic myeloid leukemia (CML) during tyrosine kinase inhibitor (TKI) therapy. Objective: In this study, we investigated carnitine concentrations in patients with CML receiving TKI therapy. Method: This study included patients with well-controlled CML. Total carnitine and free carnitine concentrations were evaluated using the enzyme cycling method. The brief fatigue inventory (BFI) and cancer fatigue scale (CFS) were used to assess general fatigue developed during TKI therapy. Results: Fifty-five patients on TKI therapy were included. Of these, 12 (21.8%) patients had low free carnitine concentrations. Free carnitine concentrations were higher in men than in women. Younger age was closely associated with lower free carnitine concentrations. TKI type, TKI dose, treatment response, or therapy duration were not associated with free carnitine concentrations. None of the scores (the global fatigue score with the BFI and CFS score) correlated with carnitine concentrations. Concentrations of free carnitine in patients in the treatment-free remission group were slightly higher than those in the TKI group, with only 9.1% having a low concentration of free carnitine. Conclusion: Carnitine deficiency is probably not a major cause of general fatigue but may occur in patients with CML receiving TKI therapy.

Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved for the treatment of chronic primary immune thrombocytopenia (ITP) in the United States, Canada and some European countries. We conducted a phase 3, placebo-controlled, double-blind, parallel-group study to evaluate the efficacy and safety of fostamatinib in Japanese patients with primary ITP. Thirty-four patients were randomised to fostamatinib (n = 22) or placebo (n = 12) at 100-150 mg twice a day for 24 weeks. Stable responses (platelet ≥50 000/μl at ≥4 of the 6 visits from weeks 14 to 24) were observed in eight (36%) patients on fostamatinib and in none of the patients on placebo (p = 0.030). Overall responses (platelet ≥50 000/μl at ≥1 of the 6 visits from weeks 2 to 12) were seen in 10 (45%) patients on fostamatinib and in none of the patients on placebo (p = 0.006). Patients on fostamatinib required rescue medication less often and experienced fewer bleeding symptoms than patients on placebo. Adverse events observed were mild or moderate and were manageable. No new safety signals were identified in Japanese patients with ITP.

We investigated the incidence, risk factors, and clinical outcomes of cytomegalovirus (CMV) disease in patients with B-cell lymphoma treated with a bendamustine-containing regimen. The incidence of CMV disease was analyzed after starting treatment with 139 regimens in 126 patients. Clinically significant CMV disease was observed in seven patients. The median duration between bendamustine initiation and the diagnosis of CMV disease was 69 d (range, 40-233), and the median of cycles completed at onset was 2 (range, 1-6). Furthermore, the incidence of CMV disease was significantly higher in the elderly patients than that in the younger patients. The target organs of CMV disease were the liver, gastrointestinal tract, lungs, and retinas. Antiviral therapy was administered to all patients. However, the recurrence of CMV disease was observed in two patients. This study provides information that could contribute to clinicians' decision-making on lymphoma therapy using bendamustine.

Background/Aim: We assessed the prognosis of patients with refractory or relapsed multiple myeloma (RRMM) by focusing on the change in absolute lymphocyte counts (ALCs) after lenalidomide and dexamethasone (Ld) initiation. Patients and Methods: In total, 72 patients with RRMM were treated with Ld. ALCs were evaluated before treatment and at 1, 2, and 3 months after Ld initiation. The median ALCs in the entire cohort before and at 1, 2, 3 months after Ld initiation were 1,131, 1,059, 1,222, and 1,162/μl, respectively. Results: ALCs before Ld initiation did not affect time to next treatment (TNT) or overall survival (OS). However, the patients with ALCs equal to or greater than the median at 3 months showed relatively better TNT than those with lower lymphocyte counts, with a significant difference. OS was also significantly longer in patients with higher ALCs. Conclusion: Immunomodulation by lenalidomide may improve prognosis in patients with RRMM.

This study aimed to evaluate the impact of standard-dose dipeptidyl peptidase-4 inhibitors (DPP-4i) on the incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated 207 diabetes mellitus patients undergoing allogeneic HCT between 2010 and 2019. The 100-day cumulative incidences (CI) of grade II–IV acute GVHD (aGVHD) in patients who took DPP-4i from day − 1 to 14, those who did not, and those who discontinued DPP-4i within 10 days after HCT because of difficulty taking the medicine were 33.9%, 32.8%, and 60.0% (P = 0.063), respectively. With regard to chronic GVHD (cGVHD), taking DPP-4i between days 21 and 60 was associated with a trend toward lower incidence of cGVHD (1-year CI: 25.4% vs. 35.6%, P = 0.094). In a multivariate analysis, the administration of DPP-4i between days 21 and 60 was significantly associated with lower incidence of cGVHD (hazard ratio 0.53, 95% confidence interval 0.30–0.96, P = 0.035). It was difficult to interpret the impact of standard-dose DPP-4i on the development of aGVHD since an inability to continue oral medication was significantly associated with higher incidence of aGVHD. On the other hand, taking DPP-4i over days 21–60 may suppress the development of cGVHD.

von Willebrand factor ristocetin cofactor (vWF activity) and platelet count (PLT) are negatively correlated in patients with polycythemia vera (PV) and essential thrombocythemia (ET). However, vWF activity does not always normalize upon controlling PLT in those patients. To address this issue, we investigated the correlation between vWF activity and PLT in PV and ET patients. The negative correlation between vWF activity and PLT was stronger in calreticulin mutation-positive (CALR+) ET than in Janus kinase 2 mutation-positive (JAK2+) PV or ET groups. When PLT were maintained at a certain level (600 × 10

Whereas most patients with aggressive hematological malignancies can achieve disease remission after receiving current standard first-line chemotherapies, the prognosis of those with primary refrac...

For patients with Philadelphia chromosome (Ph)-positive leukemia, there is no consensus regarding how long tyrosine kinase inhibitors (TKI) should be given or whether TKI could be stopped if TKI is administrated after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed relapse-free survival (RFS) in 92 allo-HCT patients who received TKI for >3 months after allo-HCT, and aimed to develop a novel indicator, called as current TKI- & relapse-free (cTRFree) achievement. TKI after allo-HCT was started as planned in 39 patients, based on measurable residual disease (MRD) in 53 at a median of 152 days after allo-HCT. There was no difference in post-TKI RFS between the planned and MRD-based starting groups (P = 0.69). Second-generation TKIs were associated with superior RFS in Ph-positive acute leukemia (HR 2.71, P = 0.031). TKI was stopped before relapse in 48 patients. Stopping TKI as a time-dependent covariate was not associated with subsequent hematological relapse (HR 1.18, P = 0.72). In the TKI-stop group, TKI administration for >6 months tended to be associated with superior RFS (HR = 0.30, P = 0.08). As an indicator of transplant success, cTRFree was 35% 5 years after starting TKI. TKI could be stopped for recipients with sustained undetectable MRD. However, further prospective studies will be required to establish clinical recommendations.

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.

Bendamustine and rituximab (BR) are widely used in patients with follicular lymphoma (FL) previously treated with conventional immunochemotherapy, but the role of consolidation radioimmunotherapy in these patients is unknown. This study evaluated the efficacy and safety of consolidation with 90 Yttrium-ibritumomab tiuxetan (90 Y-IT) after re-induction therapy with BR in patients with previously treated FL. This study included adult patients with relapsed FL who had undergone one or two prior therapies. Re-induction therapy with BR was administered every 4 weeks up to 4-6 cycles. If patients achieved at least partial response, 90 Y-IT was administered as consolidation therapy. The primary endpoint was 2-year progression-free survival (PFS) after consolidation. A total of 24 FL patients (median age 60 years) who had undergone one (n = 17) or two (n = 7) prior treatments received BR. After BR therapy, 22 patients proceeded to consolidation with 90 Y-IT, resulting in an overall 88% response rate to the protocol treatment. Within a median observation period of 46.8 months, the estimated 2-year PFS rate after the consolidation among the 22 patients receiving 90 Y-IT was 59% (95% confidence interval [CI], 38%-77%). Patients whose remission after previous treatment had lasted ≥2 years had a significantly higher 2-year PFS rate than patients whose remission after previous treatment had been

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of B-cell lymphoma characterized by aggressive disease progression with a high incidence of central nervous system (CNS) involvement. We retrospectively analyzed 16 patients with de novo IVLBCL treated at our hospital between 2004 and 2018 with either standard therapy plus CNS-directed therapy or standard therapy alone. CNS-directed therapy was associated with a significantly better 2-year CNS-free survival (100% vs. 63%

Background Rituximab is widely used as a key component of immunochemotherapy to treat B-cell non-Hodgkin lymphoma (B-NHL). However, infusion-related reactions (IRRs) during drug administration are occasionally severe or even life-threatening and thus remain problematic for patients and healthcare providers. Aim To minimize IRRs to rituximab in patients with various types of B-NHL. Method: We stratified patients into low- (n = 39), moderate- (n = 35), and high-risk (n = 7) groups according to the number of risk factors, specifically, an indolent histology and the presence of bulky tumors (> 10 cm). For the first rituximab cycle, the low- and moderate-risk groups underwent conventional infusion #1 (~ 4.3 h), and the high-risk group underwent long infusion (6.8 h). Patients in the low-, moderate-, and high-risk groups without IRRs in the first cycle underwent short infusion (2.3 h), conventional infusion #2 (3.5 h), and conventional infusion #1, respectively. Patients with IRRs in the first cycle received a second rituximab cycle with the same schedule as that in the first cycle. The procedure for the third cycle was at the attending physician’s discretion. Results Among 81 B-NHL patients, the incidences of IRRs in the low-, moderate-, and high-risk groups were 31%, 20%, and 57%, respectively, without any grade ≥ 3 IRRs. The overall conversion rate to short infusion in the third cycle was 54%, without any IRRs. Conclusion Our step-by-step protocol provided safe and comfortable rituximab administration for both patients and practitioners (UMIN-CTR; UMIN000032309, registered on 19th April 2018).

Background/Aim: Here, we investigated whether bortezomib as a maintenance therapy affected outcomes in transplant-ineligible patients with multiple myeloma (MM). Patients and Methods: Following induction therapy with bortezomib, maintenance therapy with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) was administered once or twice every 4 weeks until disease progression. The endpoints of this study were time to next treatment and overall survival. Results: Seventy-six newly diagnosed, transplant-ineligible patients were treated with a bortezomib-based regimen; 28 discontinued induction therapy, 27 did not receive maintenance therapy after induction therapy (the non-maintenance group), and 21 did (the maintenance group). In the three groups, the median times to the next required treatment were 3, 14, and 37 months, respectively. The 3-year overall survival rates were 55%, 69%, and 85%, respectively. There were no significant differences in patient characteristics between the non-maintenance and maintenance groups, except for poorer estimated glomerular filtration rates in the maintenance group. Conclusion: Bortezomib maintenance therapy may be a useful option for transplant-ineligible patients with MM.

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph−) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL.

Molecular relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has been thought to predict clinical relapse in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (PhALL). Tyrosine kinase inhibitor (TKI) administration after allo-HCT may dynamically change the status from molecular relapse to molecular remission, but these state changes cannot be accurately represented by conventional survival indicators such as relapse-free survival, where events are usually considered irreversible. We aimed to develop novel indicators of transplant outcomes for allo-HCT recipients with PhALL and to visualize current molecular-relapse-free survival (CMRFS) and current on-TKI status (CTKI), treating molecular relapse or TKI administration after allo-HCT as a reversible event. We retrospectively analyzed 286 patients with PhALL who received allo-HCT between 2000 and 2016 in order to develop the indicators. CMRFS was defined as the probability of molecular remission without clinical relapse or death at any time after allo-HCT. Similarly, CTKI was defined as the probability of TKI administration without clinical relapse or death at any time after allo-HCT. The 1- and 5-year CMRFS rates were 67% and 59%, respectively, whereas the 1- and 5-year conventional molecular relapse-free survival rates were 42% and 37%. The 1- and 5-year CTKI rates were 14% and 8%, respectively. In a post hoc analysis focusing on patients who had achieved a molecular complete remission within 6 weeks (n = 201), the 5-year CMRFS rate (71%) was similar to the 5-year conventional molecular relapse-free survival (molRFS) rate (70%) in the non-TKI group. On the other hand, the 5-year CMRFS rate in the TKI group was 61%, whereas the 5-year conventional molRFS rate was only 38%. CMRFS and CTKI might become useful indicators of transplant success in terms of survival, leukemia-free status, and treatment-free status at any time point. Future extension of these survival models to other clinical situations is warranted.

In 2018, two novel antibody therapies, inotuzumab ozogamicin (InO) and blinatumomab, against relapsed or refractory acute lymphoblastic leukemia were approved in Japan. In InO, the antitumor drug ozogamicin is conjugated to the anti-CD22 antibody. Blinatumomab is a bispecific T cell engager antibody comprising the variable regions of the anti-CD19 and the anti-CD3 antibodies. The remission rate of InO is about 75%; however, the frequency of sinusoidal obstruction syndrome is increased when allogeneic hematopoietic cell transplantation is performed after InO treatment. Blinatumomab has a remission rate of 45-70%. The management of cytokine release syndrome during blinatumomab treatment is required in certain cases. Although both the treatments have higher remission and negativity of minimal residual disease rates compared to those in conventional chemotherapy, it is difficult to maintain remission in the long term. Allogeneic hematopoietic stem cell transplantation should be performed as commonly as possible.

This phase 1/2 study aimed to identify the maximum tolerated dose, the recommended phase 2 dose (RP2D), and efficacy of the clofarabine, etoposide, and cyclophosphamide combination regimen in adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients aged ≥ 15 years with relapsed/refractory ALL were enrolled. Escalating doses of clofarabine (20–30 mg/m2/day × 5 days), etoposide (50–100 mg/m2/day × 5 days), and cyclophosphamide (200–440 mg/m2/day × 5 days) were administered. Dose-limiting toxicity was defined as Grade 3 or more non-hematological toxicities and others. A total of 18 patients (B-ALL; n = 13, T-ALL; n = 5) were recruited in phase 1; however, the protocol was amended to close study without proceeding to phase 2. Three patients were enrolled in cohort 1, three in cohort 2, six in cohort 3, and six in cohort 4. The RP2D of clofarabine, etoposide, and cyclophosphamide was 30, 100, and 440 mg/m2 daily, respectively. Complete remission (CR) was achieved in four patients (22%) and CR without platelet recovery in four patients (22%), with an overall response rate of 44%. The RP2D of the combination therapy was successfully determined in this study.

Bendamustine and rituximab (BR) are widely used in patients with follicular lymphoma (FL) previously treated with conventional immunochemotherapy, but the role of consolidation radioimmunotherapy in these patients is unknown. This study evaluated the efficacy and safety of consolidation with

Nodal marginal zone lymphoma (NMZL) is a form of nodal B-cell lymphoma exhibiting proliferation of abnormal lymphocytes at the circumference of the mantle zone in the lymph nodes. Although the outcome of patients with this disease is often favorable, we recently encountered a patient with a CD5-positive NMZL who was resistant to chemotherapy. A 67-year-old woman complaining of systemic lymph node swelling was referred to our hospital. After biopsy of the neck lymph node, she was diagnosed with CD5-positive NMZL. Disease progression was revealed after 16 months, and she was initially treated with chemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP). However, this therapy was ineffective. Subsequent therapy with rituximab and bendamustine also failed to induce remission. A rebiopsy revealed that the NMZL had transformed into a diffuse large B-cell lymphoma. This patient died after 2 years from the initial diagnosis due to lymphoma progression. Cases of CD5-positive NMZL are rare; thus, it is difficult to study the clinical implications of CD5 expression in this disease. Here we describe the current understanding of CD5 expression in NMZL.

Portable, on-site blood typing methods will help provide life-saving blood transfusions to patients during an emergency or natural calamity, such as significant earthquakes. We have previously developed waveguide-mode (WM) sensors for forward ABO and Rh(D) blood typing and detection of antibodies against hepatitis B virus and hepatitis C virus. In this study, we evaluated a WM-sensor for reverse ABO blood typing. Since reverse ABO blood typing is a method for detection of antibodies against type A and type B oligosaccharide antigens on the surface of red blood cells (RBCs), we fixed a synthetic type A or type B trisaccharide antigen on the sensor chip of the WM sensor. We obtained significant changes in the reflectance spectra from a WM sensor on type A antigen with type B plasma and type O plasma and on type B antigen with type A plasma and type O plasma, and no spectrum changes on type A antigen or type B antigen with type AB plasma. Signal enhancement with the addition of a peroxidase reaction failed to increase the sensitivity for detection on oligosaccharide chips. By utilizing hemagglutination detection using regent type A and type B RBCs, we successfully determined reverse ABO blood groups with higher sensitivity compared to a method using oligosaccharide antigens. Thus, functionality of a portable device utilizing a WM sensor can be expanded to include reverse ABO blood typing and, in combination with forward ABO typing and antivirus antibody detection, may be useful for on-site blood testing in emergency settings.

Although it is well known that platelet depletion is one of the major adverse events related to tyrosine kinase inhibitor (TKI) therapy, the effect of TKIs on thrombopoietin (TPO), a stimulating factor for thrombopoiesis, has not been examined to date. In this study, we investigated the effect of TKIs on the levels of plasma TPO concentration in patients with well-controlled chronic myeloid leukemia receiving imatinib or dasatinib and those in treatment-free remission (TFR). Blood samples for blood cell counts and plasma TPO levels were obtained from 23 dasatinib-treated patients before and 1 h after intake, 11 patients treated with imatinib before and 2 h after intake, and nine TFR patients. Levels of plasma TPO were determined by using enzyme-linked immunosorbent assays. Levels of TPO were significantly inversely correlated with platelet counts in the entire cohort (r = − 0.568, p

We investigated the effects of dasatinib on natural killer (NK) cell-induced signaling protein and perforin expression as well as plasma cytokine levels by analyzing blood samples from patients with well-controlled chronic myeloid leukemia receiving tyrosine kinase inhibitor (TKI) therapy. Perforin expression and phosphorylation of signal transducer and activator of transcription (STAT) 1, STAT3, Janus kinase (JAK) 1, and JAK2 in NK cells were evaluated by flow cytometry, and the levels of plasma cytokines, including interferon (IFN)-γ and interleukin (IL)-2, were determined by enzyme-linked immunosorbent assays in 40 patients (dasatinib, n = 23; imatinib, n = 11; and nilotinib, n = 6). Perforin levels in NK cells were higher in dasatinib-treated patients before TKI treatment; phospho (p)-STAT1 levels were closely correlated with pJAK1 and perforin levels, and pSTAT3 levels were correlated with pJAK2 and perforin levels. The correlation between pJAK1 and pSTAT1 was apparent in dasatinib-treated patients but not in other TKI-treated patients, and the correlation between pJAK2 and pSTAT3 was apparent in patients treated with other TKIs. Constitutive expression of IFN-γ was higher in patients treated with dasatinib or with other TKIs than in those who were in treatment-free remission (TFR). In contrast, constitutive expression of IL-2 was lower in patients treated with other TKIs than in those treated with dasatinib or in those who were in TFR. These results provided insights into the effects of dasatinib on JAK/STAT signaling in NK cells in vivo and the mechanisms underlying NK cell activation induced by dasatinib therapy.

Benzo[a]pyrene (BaP) is an environmental pollutant found in cigarette smoke and is implicated as a causative agent of tobacco-related diseases, such as arteriosclerosis. In contrast, vitamin D signaling, which is principally mediated by conversion of vitamin D to the active form, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], decreases cardiovascular disease risk. However, combined treatment with BaP and 1,25(OH)2D3 enhances BaP toxicity, including BaP-DNA adduct formation. We further investigated the cross-talk between BaP and 1,25(OH)2D3 signaling pathways, and found that combined treatment with these compounds induces mRNA and protein expression of plasminogen activator inhibitor 1 (PAI-1) in monocyte/macrophage-derived THP-1 and U937 cells. Protein synthesis inhibitor treatment did not inhibit induction of the PAI-1 gene (SERPINE1) in these cells. BaP plus 1,25(OH)2D3 induced differentiation markers, inhibited cellular proliferation, and induced apoptosis and oxidative stress in these cells. Reactive oxygen species scavenger treatment suppressed apoptosis but not SERPINE1 induction in cells treated with BaP plus 1,25(OH)2D3. Thus, combined treatment with BaP and 1,25(OH)2D3 induced SERPINE1 mRNA expression in these cells through a mechanism that does not require de novo protein synthesis or reactive oxygen species production. These findings suggest that induction of the proinflammatory factor PAI-1 plays a role in BaP toxicity. Interestingly, PAI-1 knockdown decreased expression of the cell surface antigen CD14, a monocytic differentiation marker, in THP-1 cells treated with BaP plus 1,25(OH)2D3. PAI-1 induction may also be related to a function of monocytes/macrophages in response to xenobiotic and vitamin D signaling.

Background: Although introduction of pediatric-type Berlin-Frankfurt-Munster (BFM) chemotherapy has markedly improved the prognosis of adolescent and young adult (AYA) patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-negative ALL), their higher toxicity has become an emerging issue with an increased post-remission mortality in AYA patients than pediatric patients. Allogeneic stem cell transplantation (allo-SCT) with myeloablative conditioning (MAC) regimens containing total body irradiation (TBI) is recognized as an important treatment option for patients with higher risk diseases. However, safety and efficacy of allo-SCT with TBI-MAC have not been fully investigated among AYA patients who received pediatric-type chemotherapy. Patients and methods: AYA was defined as 16 to 39 years old. Of the 143 AYA patients with Ph-negative ALL who underwent the first allo-SCT in the first remission between 2007 and 2016 at the 20 institutions, 106 patients who were treated with one BFM chemotherapy regimen before transplant and were conditioned with MAC regimens containing more than or equal to 8 Gy of TBI dose. The reasons for the transplant were surveyed with a multi-answer questionnaire. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p < 0.20) in univariate analyses were subjected to multivariate analysis. The Fine-Gray and Cox proportional hazard model were used for multivariate analysis of risk factors and prognostic factors, respectively. Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 106 patients included in this study, 61 were male, and 45 were female. The median age at transplant was 29 years (range, 16-39 years). Donor types were related, unrelated, and cord blood in 47 (44%), 47 (44%), and 12 (12%) patients, respectively. The difficulty of continuing chemotherapy due to side effects as the reason for transplant was included in 13 patients (12%). As chemotherapy before transplant, pediatric-type and adult-type regimens were used in 56 (53%) and 50 patients (47%), respectively. There was no significant difference in baseline characteristics and transplant procedures between the pediatric-type group and the adult-type group, except for proportion of patients over 30 years (14% vs. 64%, respectively; p < 0.01), those with more than or equal to 2 of hematopoietic cell transplant comorbidity index (13% vs. 36%, respectively; p < 0.01), and transplant between 2007 and 2011 (36% vs. 64%, respectively; p < 0.01). The CI of NRM, the OS rates, and the CI of relapse were not significantly different between two groups (NRM: 4% vs. 12% at three years after transplant, respectively; p = 0.26), (OS: 86% vs. 70%, respectively; p = 0.14), and (relapse: 16% vs. 24%, respectively; p = 0.32), respectively. Multivariate analysis for NRM revealed that more than or equal to 1 of performance status at transplant (hazard ratio [HR] = 4.8; p < 0.01) and transplant due to side effects of chemotherapy (HR = 3.5; p = 0.04) were identified as independent risk factors, but not pediatric-type chemotherapy (HR = 0.48; p = 0.23). The proportions of transplant due to side effects of chemotherapy were similar between two groups (13% vs. 12%, respectively; p = 1). No independent prognostic factor for OS was found, while transplant between 2007 and 2011 (HR = 2.5; p = 0.04) was extracted as an independent risk factor of relapse. Regarding transplant complications, significant differences were not shown in CI of grade II to IV acute graft-versus-host disease (GVHD), chronic GVHD, bacteremia, cytomegalovirus reactivation, hemorrhagic cystitis, and avascular necrosis between two groups. No characteristic cause of NRM was found in the pediatric-type group. Conclusion: These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric-type chemotherapy. Disclosures Kimura: MSD: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Kyowa Kirin: Honoraria; Chugai Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Eisai: Honoraria; Nippon Kayaku: Honoraria; Takeda Pharmaceutical: Honoraria; SymBio Pharmaceutical: Honoraria. Usuki: MSD: Speakers Bureau; Alexion: Speakers Bureau; Pfizer: Research Funding; Kyowa Kirin: Research Funding, Speakers Bureau; Eisai: Speakers Bureau; Nippon shinyaku: Research Funding, Speakers Bureau; Astellas-Amgen-Biopharma: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Astellas: Research Funding, Speakers Bureau; Mundipharma: Research Funding; Yakult: Speakers Bureau; PharmaEssentia: Speakers Bureau. Sakaida: Bristol Myers Squibb: Research Funding; Chugai: Research Funding; Ono: Research Funding; Kyowa Kirin: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Handa: Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Sanofi: Honoraria, Research Funding; Ono: Honoraria; BMS: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding. Hatta: Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding; Sanofi: Research Funding; MSD: Honoraria.

Introduction: Rituximab is widely used as the standard treatment for most types of B-cell non-Hodgkin lymphomas (B-NHL). However, infusion-related reactions (IRRs), such as fever, chills, nausea, rashes, rigors, or hypotension, are a significant burden to patients and oncology practitioners. Thus, we developed a novel protocol on the rituximab administration to avoid severe IRRs during a short-time infusion in the outpatient chemotherapy center of Nihon University Itabashi Hospital. Methods: This observational study aimed to establish an effective dosing schedule for safely administering rituximab within a short time for patients with various B-NHL types. Rituximab was diluted to a concentration of 1 mg/mL and intravenously administered to patients at a dose of 375 mg/m 2. Before the rituximab administration, prophylactic premedications were given per guidelines. We stratified patients into low (n = 0), moderate (n = 1), or high risk (n = 2) groups according to the observed number of risk factors for IRRs identified in our previous study, i.e., indolent histology and presence of bulky disease (>10cm) (Hayama et al. 2017, PMID: 28144804). In the low- and moderate-risk groups, the infusion rate of rituximab was set at 25 mg/h (first 1h), 100 mg/h (next 1h), and a maximum of 200 mg/h thereafter (conventional infusion #1, approx. 4.3h). In the high-risk group, the infusion rate of rituximab was set at 25 mg/h (first 1h) and a maximum of 100 mg/h thereafter (long infusion, approx. 6.8h). The second infusion of rituximab was dependent on the occurrence of IRRs in the first cycle. If a patient in the low-risk group did not have IRRs in the first cycle, the infusion rate of rituximab in the second cycle was then started at 100 mg/h for the first 30min and increased by 100 mg/h every 30min to a maximum of 400 mg/h thereafter (short infusion, approx. 2.3h). Also, for a patient in the moderate-risk group without any grade of IRRs in the first cycle, the infusion rates of second rituximab was set at 100 mg/h (first 1h) and a maximum of 200 mg/h thereafter (conventional infusion #2, approx. 3.5h). Finally, a patient in the high-risk group without IRRs in the first cycle received the second rituximab as per the conventional infusion #1. If patients experienced any grades of IRR in the first cycle, the next rituximab was administered on the same schedule as the first cycle. The infusion procedure for the third cycle was at the discretion of attending physicians (Figure). The primary endpoint was the incidence of IRRs during the first and second doses of rituximab in each risk group. The secondary endpoints were; overall incidence of IRRs in the first and second doses of rituximab; infusion rates of rituximab at the IRRs; conversion rate of the short infusion at the third cycle in each group; overall conversion rate of the short infusion at the third cycle. Results: A total of 81 B-NHL patients treated with rituximab in 2018 and 2019 at Nihon University Itabashi Hospital was evaluated. The incidence of IRRs during the first and second cycles in each risk group was 31%, 20%, and 57% in the low- (n = 39), moderate- (n = 35), and high-risk (n = 7) groups, respectively, with no significant difference among the three risk groups (p = 0.1407). The overall incidence of IRRs was 28% without grade 3 or higher severity. The IRRs occurred most frequently at the infusion rate of 100 mg/h (n = 16). Conversion rates to the short infusion at the third cycle of rituximab were 82%, 29%, and 29%, in the low-, moderate-, and high-risk groups, respectively, with a significant imbalance between the groups (p Conclusions: Our step-by-step infusion protocol of rituximab provided a safe and comfortable drug administration for both patients and oncology practitioners. In addition, the protocol can reduce unexpected, severe adverse reactions to rituximab that typically require hospital admission and medical expenses (UMIN-CTR, UMIN000032309). Figure 1 Figure 1. Disclosures Miura: Chugai: Honoraria; Kyowa Kirin: Honoraria. Hatta: Pfizer Japan Inc.: Honoraria; Novartis KK: Honoraria; Bristol-Myers Squibb: Honoraria; Otsuka Pharmaceutical.: Honoraria.

Background: T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 10-15% or 25% of cases of pediatric or adolescent and young adult (AYA) ALL, respectively. The use of pediatric protocols can improve outcomes in AYA T-ALL. Furthermore, nelarabine (NEL) has been shown to be effective for patients with relapsed or refractory T-ALL. This nationwide, multicenter, prospective, phase II trial for T-ALL was conducted to assess the feasibility and efficacy of NEL, intensive L-asparaginase (L-asp), and protracted intrathecal therapy (IT) when incorporated in the AIEOP-BFM-ALL 2000 based pediatric treatment for patients Patients & Methods: From December 2011 to November 2017, 364 patients with newly diagnosed T-ALL, age 0-24 (median 9.6 years), were enrolled in the JPLSG ALL-T11/JALSG T-ALL-211-U (ALL-T11) trial conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group and the Japan Adult Leukemia Study Group. Patients were stratified into three groups according to their prednisone (PSL) response, initial central nervous system (CNS) status, and PCR-based minimal residual disease (MRD) at the end of induction consolidation protocol IB (TP2). Good or poor PSL responses were defined as Results: Fifteen patients were excluded having not meeting inclusion criteria. Of 349 evaluable patients, 238 (68.2%) were male, the median white blood cell count was 45 × 10 9/L (range 0.4-1375), and 73.4% were HR by NCI criteria. Twenty-eight patients (8.0%) had CNS3 status. PCR-MRD could be evaluated in 208 patients. Among 310 stratified patients, 168 (54.2%), 103 (33.2%), and 39 (12.6%) were SR, HR, and VHR, respectively. HSCT was performed in 35 patients (10.0%). The composite CR (CR+CR in suppression) rate after IA, and the CR rate after IB were 85.4% and 90.5%, respectively. With a median follow-up of 5 years 2 months, the 3-year event-free survival (EFS) and overall survival (OS) of the whole cohort was 85.6% (95% CI: 81.5-89.9) and 91.4% (87.9-93.9), respectively (Figure 1), and the 3-year cumulative incidence of relapse was 8.9% (5.9-12.1). Induction death was seen in 14 patients (4.0%), and 3-year non-relapse mortality of the whole cohort was 0.6% (0.1-2.1). Three-year EFS and OS for each risk group were 90.4% (84.9-94.0) and 95.8% (91.4-98.0) in SR, 91.3% (83.9-95.4) and 95.1% (88.6-97.9) in HR, and 87.2% (71.9-94.5) and 87.2% (71.9-94.5) in VHR respectively. Three-year EFS and OS were 90.1% (86.1-93.0) and 95.7% (92.7-97.5), and 55.6% (30.5-74.8) and 66.7% (40.4-83.4) in MRD-negative and MRD-positive patients (p < 0.001 and p < 0.001), respectively. Grade 3 or higher peripheral motor and sensory neuropathies were seen in 9 (8.7%) and 6 (5.8%) in HR and 2 (5.1%) and 0 in VHR, respectively. Clinical allergic reaction, anaphylaxis, and pancreatitis were reported in 10 (2.9%), 16 (4.6%), and 31 (8.9%) patients, respectively. Conclusions: The addition of NEL, intensified L-asp, and protracted IT in AIEOP-BFM-ALL 2000 based treatment showed encouraging outcomes with acceptable toxicities despite the limited use of CRT and HSCT. Figure 1 Figure 1. Disclosures Hatta: Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Imai: Juno Therapeutics: Patents & Royalties: chimeric receptor with 4-1BB signaling domain. Saito: Toshiba corporation: Research Funding. Kiyoi: Astellas: Honoraria; celgene: Honoraria; Daiichi Sankyo: Honoraria; Dainippon Sumitomo: Honoraria; Eisai: Honoraria; Fijifilm: Honoraria; Kyowa Kirin: Honoraria; Otsuka: Honoraria; Perseus Proteomics: Honoraria; Pfizer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Zenyaku Kogyo: Honoraria. Matsumura: Nippon Shinyaku: Research Funding; Ono: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Chugai: Research Funding; Asahi Kasei: Research Funding; Japan Blood Products Organization: Research Funding; Mundipharma: Research Funding; Amgen: Speakers Bureau; AYUMI Pharmaceutical: Research Funding; Eli Lilly Japan: Research Funding; Sumitomo Dainippon: Research Funding; Takeda: Research Funding; Astellas: Speakers Bureau; Kyowa Kirin: Research Funding; Taiho: Research Funding; Nihon Pharmaceutical: Research Funding; Janssen: Speakers Bureau; Mitsubishi Tanabe: Research Funding; Eisai: Research Funding; Otsuka: Consultancy, Research Funding, Speakers Bureau; MSD: Research Funding; Shionogi: Research Funding; Addvie: Research Funding. Miyazaki: Chugai: Honoraria; Kyowa-Kirin: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Sumitomo-Dainippon: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Nippon-Shinyaku: Honoraria; Takeda: Honoraria; Sanofi: Honoraria.