Tumor lysis syndrome in induction therapy for acute myeloid leukemia before the rasburicase era.

Guidelines recommend rasburicase for high-risk patients to prevent tumor lysis syndrome (TLS). However, little information is available on the incidence and outcome of TLS in AML patients. We analyzed 145 patients with AML who underwent induction therapy before the approval of rasburicase to evaluate the incidence of TLS and the necessity of rasburicase as prophylaxis. Three patients had already developed clinical TLS (CTLS) at diagnosis of AML, and another three developed CTLS after the initiation of chemotherapy. In patients without TLS at diagnosis of AML, the risk for developing TLS was classified as high in 44 patients, intermediate in 41 and low in 57, according to the current guidelines. Allopurinol alone was administered to prevent hyperuricemia in all patients. All three patients who developed CTLS after diagnosis of AML were at high risk of TLS, and had elevated serum creatinine levels and a WBC count greater than 200,000 per microliter at diagnosis of AML. Allopurinol may be insufficient to prevent TLS in high-risk patients with renal dysfunction at diagnosis of AML, especially those with a high tumor burden and a WBC count of 200,000 or more, which indicates that prophylactic administration of rasburicase should be considered.

Effects of CD34+ cell dose on engraftment and long-term outcomes after allogeneic bone marrow transplantation.

BACKGROUND: The number of CD34+ cells in the graft is generally associated with time to engraftment and survival in transplantation using cord blood or allogeneic peripheral blood stem cells. However, the significance of abundant CD34+ in bone marrow transplantation (BMT) remained unclear. METHODS: We retrospectively reviewed 207 consecutive adult patients who underwent their first BMT at Jichi Medical University between January 2009 and June 2021. RESULTS: The median nucleated cell count (NCC) and CD34+ cell dose were 2.17 × 108/kg (range .56-8.52) and 1.75 × 106/kg (.21-5.84), respectively. Compared with 104 patients in the low CD34+ group (below the median), 103 patients in the high CD34+ group (above the median) showed faster engraftment at day +28 in terms of neutrophil (84.6% vs. 94.2%; p =  .001), reticulocyte (51.5% vs. 79.6%; p < .001), and platelet (39.4% vs. 72.8%; p < .001). There were no significant differences in overall survival, relapse, nonrelapse mortality, acute or chronic graft-versus-host disease, or infectious complications between the two groups in univariate and multivariate analyses. Low or high NCC had no significant effect on overall survival, nonrelapse mortality, cumulative incidence of relapse and graft-versus-host disease, either. While a positive correlation was observed between NCC and the CD34+ cell dose, a high CD34+ cell dose was associated with rapid hematopoietic recovery, even in patients with NCC below the median. CONCLUSION: Measurement of CD34+ cell dose in addition to NCC was useful for predicting hematopoietic recovery, but seemed to have little influence on the long-term outcome in BMT.

Cytotoxicity and exhaustion markers of chimeric antigen receptor T cells targeting BCMA in multiple myeloma cell lines between patients and healthy donors.

OBJECTIVES: Multiple myeloma (MM) accounts for 10% of hematologic malignancies. However, most of the patients suffered from relapsed/refractory disease. We would like to expand CAR T cell therapy to treat MM using our current platform. METHODS: BCMA CAR T lymphocytes were generated for volunteers or MM patients. The transduction efficiency was detected by the ddPCR technique. Immunophenotyping and exhaustion markers were monitored by flow cytometry. The efficacy of BCMA CAR T cells was tested using coculturing with BCMA CAR or mock, and the positive and negative targets, K562/hBCMA-ECTM and K562, respectively. RESULTS: BCMA CAR T cells were generated from consented volunteers or MM patients and could be detected CAR BCMA expression at a mean of 4.07 ± 1.95 or 4.65 ± 1.21 copies/cell, respectively. Those modified T cells were primarily effector memory T cells. Our BCMA CAR T cells could explicitly eradicate the K562/hBCMA-ECTM cell line while the K562 cell line survived. Interestingly, the BCMA CAR, mock T cells, and peripheral blood mononuclear cells from MM patients expressed similar levels of the exhaustion makers, TIM-3, LAG-3, and PD1. CONCLUSIONS: Our BCMA CAR T cells, mainly effector/effector memory, could eliminate BCMA-expressing cells in vitro and had similar levels of exhaustion markers among different populations.

Cost-Effectiveness of Anti-BCMA Chimeric Antigen Receptor T Cell Therapy in Relapsed/Refractory Multiple Myeloma.

Despite its promising outcomes, anti-BCMA chimeric antigen receptor T cell therapy (CAR-T) is the most expensive myeloma treatment developed to date, and its cost-effectiveness is an important issue. This study aimed to assess the cost-effectiveness of anti-BCMA CAR-T compared to standard antimyeloma therapy in patients with relapsed/refractory multiple myeloma. The model included myeloma patients in Japan and the United States who have received ≥3 prior lines of antimyeloma therapy, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. A Markov model was constructed to compare the CAR-T strategy, in which patients receive either idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) followed by 3 lines of multiagent chemotherapy after relapse, and the no CAR-T strategy, in which patients receive only chemotherapy. Data from the LocoMMotion, KarMMa, and CARTITUDE-1 trials were extracted. Several assumptions were made regarding long-term progression-free survival (PFS) with CAR-T. Extensive scenario analyses were made regarding regimens for no CAR-T strategies. The outcome was an incremental cost-effectiveness ratio (ICER) with willingness-to-pay thresholds of ¥7,500,000 in Japan and $150,000 in the United States. When a 5-year PFS of 40% with cilta-cel was assumed, the ICER of the CAR-T strategy versus the no CAR-T strategy was ¥7,603,823 per QALY in Japan and $112,191 per QALY in the United States over a 10-year time horizon. When a 5-year PFS of 15% with ide-cel was assumed, the ICER was ¥20,388,711 per QALY in Japan and $261,678 per QALY in the United States over a 10-year time horizon. The results were highly dependent on the PFS assumption with CAR-T and were robust to changes in most other parameters and scenarios. Although anti-BCMA CAR-T can be cost-effective even under current pricing, a high long-term PFS is necessary.

Early reversal of the lymphocyte-to-monocyte ratio after allogeneic-hematopoietic stem cell transplantation is associated with reduced relapse and improved prognosis.

BACKGROUND: The early recovery of lymphocyte and monocyte cells is associated with a favorable prognosis after allogeneic stem cell transplantation (allo-HSCT); however, it is not clear whether the balance of lymphocyte and monocyte recovery affects the post-transplant prognosis. METHODS: We examined whether the time-point at which the number of lymphocytes exceeded the number of monocytes, which we termed lymphocyte-to-monocyte ratio reversal (LMRR), affected the prognosis after allo-HSCT. We retrospectively evaluated 235 patients who underwent their first allo-HSCT at our institution. RESULTS: The median number of days from HSCT to LMRR was 46 (range, 0-214), and the patients were divided into two groups according to the occurrence of LMRR by day 45 (LMRR45). In a multivariate analysis, early LMRR contributed favorably to overall survival (hazard ratio [HR] .519; 95% confidence interval [CI] .332-.812; p = .004) with fewer post-transplant relapses (HR .462; 95% CI, .274-.777; p = .004). Differences in the timing of LMRR did not affect non-relapse mortality (HR 1.477; 95% CI .779-2.80; p = .23) or the incidence of grade II-IV acute GVHD (LMRR45(+): 25.0% vs. LMRR45(-) 35.2%. p = .111). In subgroup analyses, LMRR45(+) was found to be a favorable factor for survival with less relapse, regardless of the disease risk, stem cell source, or the recovery of either lymphocyte or monocyte counts. CONCLUSIONS: An early LMRR may be a novel factor that is associated with reduced relapse and improved survival after allo-HSCT.

Antibody-mediated pathogenesis of chronic GVHD through DBY/HLA class II complexes and induction of a GVL effect.

Chronic graft-versus-host disease (cGVHD) is a multiorgan syndrome with clinical features resembling those of autoimmune diseases. Thus, understanding commonalities in the pathophysiology of cGVHD and autoimmune diseases, such as the presence of disease-risk HLA alleles, is imperative for developing novel therapies against cGVHD. Alloantibodies against H-Y antigens encoded on the Y-chromosome are well-described risk factors for cGVHD in female-to-male transplantation. However, because H-Y antigens generally localize intracellularly in the male reproductive organs, how they emerge at affected organ levels remains elusive. Here, by analyzing nationwide registry data stratified per donor-recipient sex, we identified specific HLA class II alleles that contributed to susceptibility to male cGVHD after transplantation from HLA-identical female siblings (HLA-DRB1∗15:02: hazard ratio, 1.28; 95% confidence interval, 1.03-1.58; P = .025). Coexpression of HLA-DRB1∗15:02 efficiently transported full-length H-Y antigens, especially DBY, to the surface. The presence of alloantibodies against DBY/HLA class II complexes significantly predicted the occurrence of cGVHD (68.8% vs 31.7% at 1 year; P = .002). Notably, the ability of HLA class II molecules to transport and present DBY to alloantibodies was closely associated with the susceptibility of HLA class II alleles to cGVHD. DBY specifically colocalized with HLA class II molecules on the dermal vascular endothelium in cGVHD and provoked complement-dependent cytotoxicity. Moreover, these complexes were observed in some male leukemic cells. Altogether, these findings suggest that vascular endothelial cells facilitate alloantibody-mediated cGVHD and highlight that alloantibodies against DBY/HLA class II complexes could be common targets for cGVHD and a graft-versus-leukemia effect.

Relapsed and refractory multiple myeloma: A systematic review and network meta-analysis of the efficacy of novel therapies.

The prognosis of multiple myeloma (MM) has dramatically improved with the development of new drugs, and it has become important to determine the appropriate combinations of these novel agents. This study was a systematic review and network meta-analysis (NMA) of randomized trials in patients with relapsed and/or refractory (RR) MM. The PubMed, Cochrane, and Embase databases were searched for randomized trials from 1 January 2002 to 28 February 2022 of patients treated for MM. The primary end-point was progression-free survival (PFS), evaluated as a hazard ratio (HR) with a 95% confidence interval (95% CI) compared to dexamethasone (DEX). The p-score was used to rank treatments. Of a total of 1136 abstracts screened, 37 studies were selected, including 34 treatment options for RRMM. Daratumumab, lenalidomide and DEX was found to be the best treatment for RRMM, with the best HR compared to DEX (HR, 0.13; 95% CI, 0.08-0.20; p-score 0.9796). There was no evidence of significant heterogeneity (I2 , 41.3%; p = 0.146). The current NMA confirmed the excellent efficacy of three-drug regimens including anti-CD38 antibodies to treat RRMM and provides background data to evaluate the efficacy of chimeric antigen receptor T-cell treatments and bispecific T-cell engager therapies.

Effect of cumulative daunorubicin dose on cardiotoxicity after allogeneic stem cell transplantation.

Cardiotoxicity after allogeneic stem cell transplantation (SCT) is associated with a high rate of mortality and worsening quality of life. The relation between daunorubicin dose and post- allogeneic stem cell transplantation (SCT) cardiotoxicity remains unclear. We retrospectively evaluated 171 patients with acute myeloid leukemia (AML) who underwent their first allogeneic SCT at our institution between 2005 and 2021. High-dose daunorubicin (50 mg/m2/day for 5 days) and cytarabine were usually used as induction therapy for AML. The median cumulative daunorubicin dose was 310 mg/m2 (range, 0-950 mg/m2), and 43 patients received two courses of induction therapy with high-dose daunorubicin (daunorubicin doses of ≥500 mg/m2). Cardiotoxicity developed in 12 patients, and the cumulative incidence at 2 years after SCT was 7.1%. Univariable analysis revealed that female sex, left ventricular ejection fraction (LVEF) of < 60% before SCT, and daunorubicin doses of ≥ 500 mg/m2 were associated with cardiotoxicity. Multivariable analysis showed that a daunorubicin dose of ≥ 500 mg/m2 was an independent risk factor for cardiotoxicity. LVEF decline during the study was observed with an increase in the daunorubicin dose, and only a daunorubicin dose of ≥ 500 mg/m2 was associated with a pre-SCT decreased LVEF. Second induction therapy with high-dose daunorubicin is a risk factor for cardiotoxicity after SCT. This should be taken into consideration when determining reinduction therapies for SCT-eligible patients with relapsed or refractory AML.

Daratumumab in first-line therapy is cost-effective in transplant-eligible patients with newly diagnosed myeloma.

Triplet regimens, such as lenalidomide, bortezomib, and dexamethasone (RVd) or thalidomide, bortezomib, and dexamethasone (VTd), are standard induction therapies for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to RVd and VTd has been investigated in the GRIFFIN and CASSIOPEIA trials, respectively, resulting in improvement in the rate of minimal residual disease (MRD) negativity. In this study, we conducted a cost-effectiveness analysis with a 10-year time horizon to compare first-line and second-line use of daratumumab for transplant-eligible patients with NDMM. Because long-term follow-up data for these clinical trials are not yet available, we developed a Markov model that uses MRD status to predict progression-free survival. Daratumumab was used either in the first-line setting in combination with RVd or VTd or in the second-line setting with carfilzomib plus dexamethasone (Kd). Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were calculated from a Japanese and US payer perspective. In the Japanese analysis, D-RVd showed higher QALYs (5.43 vs 5.18) and lower costs (¥64 479,793 vs ¥71 287 569) compared with RVd, and D-VTd showed higher QALYs (5.67 vs 5.42) and lower costs (¥43 600 310 vs ¥49 471,941) compared with VTd. Similarly, the US analysis demonstrated dominance of a strategy incorporating daratumumab in first-line treatment regimens. Given that overall costs are reduced and outcomes are improved when daratumumab is used as part of a first-line regimen, the economic analysis indicates that addition of daratumumab to first-line RVd and VTd regimens is a dominant strategy compared with reserving its use for the second-line setting.

Novel immunotherapies in multiple myeloma.

For a substantial period, options for the treatment of multiple myeloma (MM) were limited; however, the advent of novel therapies into clinical practice in the 1990s resulted in dramatic changes in the prognosis of the disease. Subsequently, new proteasome inhibitors and immunomodulators with innovations in efficacy and toxicity were introduced; yet there remains a spectrum of patients with poor outcomes with current treatment strategies. One of the causes of disease progression in MM is the loss of the ability of the dysfunctional immune environment to control virulent cell clones. In recent years, therapies to overcome the immunosuppressive tumor microenvironment and activate the host immune system have shown promise in MM, especially in relapsed and refractory disease. Clinical use of this approach has been approved for several immunotherapies, and a number of studies are currently underway in clinical trials. This review outlines three of the newest and most promising approaches being investigated to enhance the immune system against MM: (1) overcoming immunosuppression with checkpoint inhibitors, (2) boosting immunity against tumors with vaccines, and (3) enhancing immune effectors with adoptive cell therapy. Information on the latest clinical trials in each class will be provided, and further developments will be discussed.

Urine Xanthine Crystals in Hematologic Malignancies with Tumor Lysis Syndrome.

Tumor lysis syndrome (TLS) is a metabolic disorder caused by massive tumor lysis. Hypouricemic agents are administered to prevent TLS-related hyperuricemia and renal failure. We experienced three cases of urine xanthine crystals during TLS in patients with hematologic malignancies who received prophylactic febuxostat. Yellowish and pinkish deposits were observed in urinary tract catheters and urinary bags. Urine microscopy revealed that the deposits were xanthine crystals. In rapid tumor lysis, inhibition of xanthine oxidase can cause xanthine accumulation and urine xanthine crystallization. During TLS, urine xanthine crystals may be overlooked, so careful observation and management are required to avoid xanthine nephropathy.

Clinical interaction between dexamethasone and aprepitant in chemotherapy for lymphoma.

Aprepitant (Apr) is an effective antiemetic agent for chemotherapy-induced nausea and vomiting (CINV). Current CINV guidelines recommend the antiemetic combination of a 5-HT3 receptor antagonist, Apr, and dexamethasone (Dex) for highly emetogenic chemotherapies. Apr inhibits CYP3A4 dose-dependently. Since Dex is metabolized by CYP3A4, the combined use of Apr and Dex inhibits Dex metabolism. CINV guidelines therefore recommend dose-reduction of Dex when Apr and Dex are used together. However, there is some controversy over whether or not Dex should be reduced when administered as an antitumor agent for lymphoid malignancies. We retrospectively compared the antitumor effect of Dex-containing chemotherapy in which Dex is administered at the usual dose without Apr (group A) or administered at a half-dose in combination with Apr (group B). We analyzed 62 consecutive patients with refractory or relapsed CD20 + B cell lymphoma who received R-DHAP therapy in our hospital, including 29 and 33 cases in groups A and B, respectively. The response rate at the end of the first course of R-DHAP was 62.1% and 54.5%, respectively (P = 0.61). As another endpoint to evaluate the effect of Dex, group B tended to show greater suppression of the lymphocyte count (P = 0.05). Therefore, decreasing the dose of Dex by half appeared to be reasonable when combined with Apr.

Elimination of plasma soluble antigen in cynomolgus monkeys by combining pH-dependent antigen binding and novel Fc engineering.

A conventional antibody targeting a soluble antigen in circulation typically requires a huge dosage and frequent intravenous administration to neutralize the antigen. This is because antigen degradation is reduced by the formation of antigen-antibody immune complexes, which escape from lysosomal degradation using neonatal Fc receptor (FcRn)-mediated recycling. To address this, we developed an antigen-sweeping antibody that combines pH-dependent antigen binding and Fc engineering to enhance Fc receptor binding. The sweeping antibody actively eliminates the plasma antigens by increasing the cellular uptake of the immune complex and dissociating the antigens in the acidic endosome for degradation. Strong antigen sweeping can reduce the dosage, potentially achieve higher efficacy, and expand the scope of antigen space available for targeting by antibodies. In this study, to further improve the sweeping efficacy, we developed a novel antibody Fc variant by enhancing Fcγ receptor IIb (FcγRIIb) binding and modulating charge characteristics for increased cellular uptake of the immune complex, together with enhancing FcRn binding for efficient salvage of the antigen-free antibodies. Our Fc variant achieved strong antigen sweeping in cynomolgus monkeys with antibody pharmacokinetics comparable to a wild-type human IgG1 antibody. The positive-charge substitutions enhanced uptake of the immune complex by FcγRIIb-expressing cells in vitro, which was completely inhibited by an anti-FcγRIIb antibody. This suggests that the strong in vivo sweeping efficacy improved by the charge engineering is more likely achieved by FcγRIIb-dependent uptake of the immune complex rather than nonspecific uptake. We expect this novel Fc engineering can maximize the antigen sweeping efficacy even in humans and create novel therapeutic antibodies that meet unmet medical needs for patients.

Impact of muscle mass loss assessed by computed tomography on the outcome of allogeneic stem cell transplantation.

The definition of sarcopenia assessed by computed tomography (CT) varies among different reports, and few studies have examined the effect of muscle mass loss on the prognosis of post-hematopoietic cell transplantation (HCT). We retrospectively evaluated 172 patients who underwent an initial allogeneic HCT for acute leukemia at our institution. They were divided into 3 groups according to muscle mass measured at the third lumbar vertebra as assessed by CT. Patients with low muscle mass had a worse performance status, higher comorbidity index and higher disease risk. There was a significant difference in 2-year overall survival between the 3 groups, and worse overall survival (OS) was associated with lower muscle mass (p = 0.005). Muscle mass loss did not affect non-relapse mortality (p = 0.238) but was significantly associated with relapse (p = 0.067). Pre-transplant muscle mass loss may therefore reflect a poor prognosis for the primary disease.

Nilotinib vs. imatinib in Japanese patients with newly diagnosed chronic myeloid leukemia in chronic phase: 10-year follow­up of the Japanese subgroup of the randomized ENESTnd trial.

In the 10-year analysis of Japanese patients with newly diagnosed CML-CP in the ENESTnd trial, nilotinib yielded higher cumulative response rates. There were no new occurrences of disease progression or deaths since the 5-year analysis. Cumulative 10-year rates of MMR and MR4.5 were higher in the nilotinib arms [300 mg twice daily (BID), 86.2% and 69.0%, respectively; 400 mg BID, 78.3% and 69.6%, respectively] than the imatinib arm (400 mg once daily, 60.0% and 48.0%, respectively). Nasopharyngitis (85.7%, 77.3%, 79.2%), rash (50.0%, 68.2%, 37.5%), headache (39.3%, 45.5%, 25.0%), and back pain (39.3%, 50.0%, 29.2%) were the most frequently reported all-grade adverse events (AEs) for nilotinib 300 and 400 mg BID and imatinib, respectively. Cardiovascular AEs were more common with nilotinib than with imatinib. More patients on nilotinib had pre-diabetic and diabetic levels of HbA1c (300 mg BID, 17.9% and 10.7%, respectively; 400 mg BID, 22.7% and 18.2%, respectively) compared with imatinib (4.2% each). Overall, 10-year results from the Japanese cohort are consistent with prior results from the full ENESTnd cohort and the Japanese subgroup, and continue to support the long-term use of nilotinib in Japanese patients with newly diagnosed CML-CP, but with proper monitoring and management of comorbidities.

Risk Factors for Complications Associated with Peripherally Inserted Central Catheters During Induction Chemotherapy for Acute Myeloid Leukemia.

Objective Peripherally inserted central catheters (PICCs) are widely used in patients with hematologic malignancies. However, the risks of PICC-related complications during chemotherapy for acute myeloid leukemia (AML) are not fully understood. Methods We conducted a retrospective review of 128 adult patients with AML who received induction therapy by way of PICC insertion between 2012 and 2019. Results The median duration of PICC insertion was 30 days. The incidence rate of catheter-related bloodstream infection (CRBSI) was 2.4% at 30 days, and women were more likely to suffer from CRBSI than men. Local reactions at the insertion site were observed in 56 patients; however, these events did not predict CRBSI. The incidence rates of catheter-related thrombosis (CRT) were 1.6% at 30 days. Obesity put patients at an increased risk for CRT. Unexpected PICC removal occurred in 59 patients, and women were at a higher risk of catheter removal than men. Conclusion Low PICC-related complication rates, possibly associated with high rates of catheter removal, were observed during intensive chemotherapy for AML. Women and obese patients require careful monitoring of their PICC. Procedures to achieve appropriate PICC removal without increasing the complication rate need to be considered.

Relationship of tumor load parameters before and after autologous stem cell transplantation with clinical prognosis in transplant-eligible patients with multiple myeloma: A retrospective analysis.

We retrospectively examined 57 patients with multiple myeloma who underwent autologous stem cell transplantation (ASCT) at our institution. A receiver-operating characteristic curve (ROC) analysis showed that the reduction rate of quantitative serum monoclonal protein (M-protein) before ASCT and the difference in involved and uninvolved free light chains (dFLC) 30 days after ASCT, respectively, had the greatest predictive value for all patients (area under the curve [AUC] 0.791 and 0.660, respectively). Based on the ROC curve-based cutoff values of tumor burden parameters, progression-free survival (PFS) in the high serum M-protein reduction (≥90 %) group was significantly better than that in the low serum M-protein reduction group (<90 %) (2-year PFS 79.5 % vs. 17.0 %, p < 0.001), but there were no significant differences in PFS between the low (<5.2 mg/L) and high (≥5.2 mg/L) dFLC groups (2-year PFS, 72.0 % vs. 46.0 %; p = 0.149). A multivariate analysis identified the reduction in serum M-protein as an independent predictive factor before ASCT for PFS (hazard ratio [HR] 0.287, p = 0.022) and high dFLC on day 30 after ASCT for PFS (HR 3.902, p = 0.040). These results demonstrate that a good prognosis can be expected with a reduction of serum M-protein before and after ASCT.

A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B-cell lymphoma.

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m2 , rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.

Risk factors for high-dose methotrexate-induced nephrotoxicity.

High-dose methotrexate (MTX) is widely used for the treatment of hematological malignancies. Despite the application of routine supportive care measures, such as intensive fluid hydration and urine alkalinization, nephrotoxicity is still a problem. The present study aimed to evaluate the risk factors for MTX-induced nephrotoxicity. We retrospectively reviewed 88 patients who received a regimen consisting of high-dose MTX (1000 mg/m2) and cytosine arabinoside between 2006 and 2018. Nephrotoxicity (≥ grade 2) was observed in 11 patients. Nephrotoxicity was observed only in patients with a high MTX concentration. Other than the MTX concentration, the serum uric acid level and urine pH at day 1 were associated with nephrotoxicity. A multivariate analysis revealed that urine pH was an independent risk factor for MTX-induced nephrotoxicity. Urine pH < 7.0 at day 1 was a significant risk factor for nephrotoxicity (odds ratio, 8.05; 95% confidence interval 1.95-33.3) and was also a predictor of delayed MTX elimination at 72 h after injection. Among pre-treatment factors, a low serum calcium level predicted urine pH < 7.0 at day 1. In conclusion, the present study suggests that low urine pH at day 1 is an independent risk factor for MTX-induced nephrotoxicity.