Germ line DDX41 mutations define a unique subtype of myeloid neoplasms.

Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.

PD-1 expression on tumour-infiltrating cells is a prognostic factor for relapsed or refractory diffuse large B-cell lymphoma.

BACKGROUND: The tumour microenvironment (TME), which is modulated after immune-chemotherapy, is involved in tumour growth and metastasis. Programmed cell death 1 (PD-1) expressed on tumour-infiltrating non-malignant cells plays an important role in the TME through the PD-1/programmed cell death ligand 1 (PD-L1) signalling pathway. However, its impact in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains unclear. METHODS: We conducted a retrospective study using tissue samples at relapse for patients with R/R DLBCL (n = 45) and evaluated the clinical impact of PD-1 expression on tumour-infiltrating non-malignant cells (microenvironmental PD-1, mPD-1). In addition, corresponding 27 samples at diagnosis were analysed to evaluate the changes in PD-1/PD-L1 expression in the TME after chemotherapy. RESULTS: Patients with mPD-1+ DLBCL showed significantly better overall survival compared with patients with mPD-1- DLBCL (hazard ratio, 0.30, p = 0.03). Among patients with mPD-1- DLBCL, those positive for neoplastic or microenvironmental PD-L1 (nPD-L1+ or mPD-L1+ ) showed significantly worse outcomes. Microenvironmental PD-1 and PD-L1 expression has high correlation at relapse, although none was found at diagnosis. CONCLUSION: We determined the clinical impact of microenvironmental PD-1 expression and its relationship with neoplastic or microenvironmental expression of PD-L1 in patients with R/R DLBCL. The expression of PD-1 and PD-L1 in the TME dramatically changes during the chemotherapy. Therefore, evaluating TME at relapse, not at diagnosis is useful to predict the outcomes of R/R DLBCL patients.

Sequential cellular and humoral responses after repetitive COVID-19 vaccination in patients treated with anti-CD20 antibodies.

Patients treated with anti-CD20 antibodies for haematological disorders have insufficient immune responses to mRNA COVID-19 vaccines; however, relevant sequential data are lacking. We sequentially evaluated the humoral and cellular immune responses in 22 patients who had received anti-CD20 antibodies within 12 months before the first vaccination, before and after the third and fourth vaccinations. Humoral responses improved gradually, along with the resolution of B-cell depletion. A steady increase was noted in cellular responses, regardless of the B-cell status. Our findings suggest the potential benefit of repeated vaccinations in these patients until B-cell recovery is confirmed while enhancing cellular responses.

Clinical impact and characteristics of erythroid dysplasia in adult aplastic anaemia: Results from a multicentre registry.

Morphological dysplasia in haematopoietic cells, defined by a 10% threshold in each lineage, is one of the diagnostic criteria for myelodysplastic neoplasms. Dysplasia limited to the erythroid lineage has also been reported in some cases of aplastic anaemia (AA); however, its significance remains unclear. We herein examined the impact of erythroid dysplasia on immunosuppressive therapy responses and survival in AA patients. The present study included 100 eligible AA patients without ring sideroblasts. Among them, 32 had dysplasia in the erythroid lineage (AA with minimal dysplasia [mini-D]). No significant sex or age differences were observed between AA groups with and without erythroid dysplasia. In severe/very severe AA and non-severe AA patients, a response to anti-thymocyte globulin + ciclosporin within 12 months was observed in 80.0% and 60.0% of AA with mini-D and 42.9% and 90.0% of those without dysplasia, with no significant difference (p = 0.29 and p = 0.24 respectively). Overall survival and leukaemia-free survival did not significantly differ between the groups. Collectively, the present results indicate that the presence of erythroid dysplasia did not significantly affect clinical characteristics or outcomes in AA patients, suggesting that its presence in AA is acceptable. Therefore, erythroid dysplasia should not exclude an AA diagnosis.

Safety and blood levels of daratumumab after switching from intravenous to subcutaneous administration in patients with multiple myeloma.

The intravenous administration (IV) of daratumumab sometimes causes an infusion reaction and needs a long infusion time. Recently, a subcutaneous formulation (SC) of daratumumab, which has fewer infusion reactions and shorter administration time, was approved. However, because SC has a fixed dose, overdosing is a concern for patients with low body weights. In this study, we investigated the safety and blood levels of daratumumab after switching from IV to SC in patients with multiple myeloma (MM). Patients who switched from IV to SC of daratumumab between June 2021 and May 2022 at Kobe City Medical Center General Hospital were included in the study. Blood daratumumab levels were measured using liquid chromatography-tandem mass spectrometry. Safety after switching from IV to SC was evaluated for six months and graded according to the Common Terminology Criteria for Adverse Events, version 5.0. The median body weight of ten patients included in the analysis was 57.4 kg (range: 45.0-74.4). Blood daratumumab levels were significantly increased after switching to SC (p = 0.002); median through concentration at the last IV dose was 403.6 µg/mL (range: 96.3-776.3) and that at the third SC dose was 557.1 µg/mL (range: 288.3-997.2). Grade 1-2 injection site reactions were observed in six patients (60.0%) after switching to SC. A new grade 3 adverse event was observed in only one patient (neutropenia). The blood levels of daratumumab were significantly increased after switching from IV to SC in patients with MM; however, the dosage was tolerable.

Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan.

Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1 mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1 year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).

Trajectories of the SARS-CoV-2 RNA load in patients with hematological malignancy.

OBJECTIVES: The higher risk of prolonged viral shedding in coronavirus disease (COVID-19) patients with hematological malignancies (HM) necessitates test-based de-isolation strategies. However, evidence to establish their appropriate isolation period is insufficient. This study investigated the factors affecting prolonged viral shedding and the requisite isolation period in these patients. METHODS: We retrospectively reviewed 14 COVID-19 patients with HM between January and April 2022, who were subjected to our test-based de-isolation strategy, followed by analysis of the viral load trajectory. The viral loads of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were evaluated using the cycle threshold (Ct ) of the reverse-transcription quantitative polymerase chain reaction. The trajectories were classified according to the time-interval from COVID-19 onset to the attainment of Ct values >30. RESULTS: The median interval between onset and attainment of a Ct value >30 was 22 days. Five patients with mild or moderate COVID-19 without intense treatment histories achieved Ct values >30 within 20 days. The other nine patients needed more than 20 days, including three patients who did not meet this criterion during the observation period. CONCLUSIONS: The SARS-CoV-2 viral load trajectories in patients with HM can be stratified by treatment history for the underlying HM and severity of COVID-19.

Humoral response and safety of the BNT162b2 and mRNA-1273 COVID-19 vaccines in allogeneic hematopoietic stem cell transplant recipients: An observational study.

BACKGROUND: The effectiveness of mRNA COVID-19 vaccines and the optimal timing of vaccine administration in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) recipients remains inadequately investigated. We examine the effectiveness and safety of mRNA COVID-19 vaccines in allo-HSCT recipients. METHOD: This prospective observational study included 44 allo-HSCT recipients and 38 healthy volunteers. The proportion of subjects acquiring anti-S1 IgG antibodies were considered as the primary endpoint. The occurrence of adverse events after vaccination and objective deterioration of chronic graft-versus-host disease (GVHD) were defined as secondary endpoints. In addition, we compared the geometric mean titers (GMT) of anti-S1 antibody titers in subgroups based on time interval between transplantation and vaccination. RESULTS: A humoral response to the vaccine was evident in 40 (91%) patients and all 38 healthy controls. The GMT of anti-S1 titers in patients and healthy controls were 277 (95% confidence interval [CI]: 120-643) BAU/mL and 532 (95% CI 400-708) BAU/mL, respectively. (p = 0.603). A short time interval between transplantation and vaccination (≤6 months) was associated with low anti-S1 IgG antibody titers. No serious adverse events and deterioration of chronic GVHD were observed. Only one case of new development of mild chronic GVHD was recorded. CONCLUSION: Messenger RNA COVID-19 vaccines induce humoral responses in allo-HSCT recipients and can be administered safely.

Two-year outcomes of tirabrutinib monotherapy in Waldenström's macroglobulinemia.

The phase II study of tirabrutinib monotherapy at a daily dose of 480 mg under fasting conditions for treatment-naïve and relapsed/refractory Waldenström's macroglobulinemia (ONO-4059-05 study) demonstrated a promising efficacy and tolerable safety profile. We conducted an unplanned analysis with a median follow-up of 24.8 months to update the efficacy and safety results and to report patient-reported quality of life. Of 27 enrolled patients, 22 patients continued receiving the study drug. The major response assessed by an independent review committee was observed in 25 patients (93%), including one and five patients who newly achieved complete response and very good partial response, respectively, after the primary analysis. The progression-free and overall survival rates at 24 months were 92.6% and 100%, respectively. Serum IgM levels in all patients except one declined and were maintained at low levels, although transient increases occurred after temporal interruption of the study drug. The disease-related symptoms including recurrent fever and hyperviscosity mostly disappeared. Health-related quality of life, assessed by cancer-specific questionnaires, was mostly maintained. Grade 3-4 neutropenia, lymphopenia, and leukopenia were newly recognized in three, two, and one patient, respectively. Grade 3 treatment-related hypertriglyceridemia was also recognized. Nine patients experienced grade 1-2 bleeding events (33%), one patient experienced grade 2 treatment-related atrial fibrillation, and one patient experienced grade 1 treatment-related hypertension. Treatment-related skin adverse events were observed in 14 patients (52%). Taken together, tirabrutinib has durable efficacy with an acceptable safety profile for treatment-naïve and refractory/relapsed Waldenström's macroglobulinemia.

Use of liquid chromatography-tandem mass spectrometry for foscarnet quantification in human serum and cerebrospinal fluid.

RATIONALE: Foscarnet (FCV) is used to treat cytomegalovirus, human herpesvirus, and human immunodeficiency virus infections. It is a low-molecular-weight compound containing carboxylate and phosphate groups. There are no reports on the use of liquid chromatography-tandem mass spectrometry (LC/MS/MS) to analyze FCV via bioanalysis. In the present study, we developed the ion-pair LC/MS/MS method to analyze FCV in human serum and cerebrospinal fluid (CSF). METHODS: FCV was extracted from human serum and CSF by weak anion exchange (WAX) solid-phase extraction. The LC/MS/MS systems were coated with 0.1% phosphoric acid in methanol to avoid nonspecific absorption. FCV was detected using ion-pair LC/MS/MS with dibutylammonium acetate. Selected reaction monitoring transition of FCV in the negative ion mode was selected at m/z 125.1 → 62.9. RESULTS: FCV was selectively detected in human serum and CSF, and the liner range was 5-1000 µM (R2 = 0.99). The intraday and interday accuracy and precision were within ±15%. FCV was constantly extracted from human serum and CSF by WAX solid-phase extraction (recovery ratio = 76.0-77.9%). No matrix effect was observed. CONCLUSIONS: A robust LC/MS/MS method to analyze FCV was successfully developed. FCV was selectively measured using LC/MS/MS in very low extract volumes (20 µL). The method will be useful in evaluating the FCV level in human serum and CSF.

Extramedullary relapse of acute myeloid leukemia in brachial plexus after allogeneic stem cell transplantation: a case report.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment for acute myeloid leukemia. However, extramedullary relapse of acute myeloid leukemia can occur after hematopoietic stem cell transplantation, causing treatment failure. Extramedullary relapse rarely involves the peripheral nerves, and it is not influenced by the effect of the graft on leukemia. CASE PRESENTATION: We report a case of extramedullary relapse of acute myeloid leukemia in the brachial plexus of a 41-year-old woman treated with allogeneic hematopoietic stem cell transplantation (HSCT). Complete hematological remission was confirmed by bone marrow examination 1 month after HSCT, and she developed no major complications immediately after HSCT. The immunosuppressant was discontinued 5 months later. However, 2 weeks after immunosuppressant withdrawal, the patient developed left arm pain and paresthesia, with subsequent development of a mass in the left brachial plexus. She was initially diagnosed with brachial plexus neuropathy because of concomitant graft-versus-host disease. Despite the administration of immunosuppressive agents, the mass continued to enlarge. The biopsy of the lesion revealed leukemic relapse. Thus, the patient was diagnosed with extramedullary relapse and underwent radiotherapy, resulting in tumor shrinkage. CONCLUSION: Extramedullary relapse should be considered a differential diagnosis in post-transplant patients with leukemia presenting with paresthesia.

Cold agglutinin anti-I antibodies in two patients with COVID-19.

BACKGROUND: Cold agglutinin syndrome (CAS) is associated with various diseases. Several studies of CAS associated with coronavirus disease 2019 (COVID-19) reported hemolytic anemia and thrombosis; however, the clinical significance of cold agglutinins (CA) in patients with COVID-19 is unclear. Here, we present two cases of CA identified in the context of COVID-19 without hemolytic anemia and clotting. CASE REPORT AND DISCUSSION: Two patients with no known risk factors for CA were diagnosed with COVID-19; peripheral blood smears reveal red blood cells (RBCs) agglutination. These patients showed a high CA titer. We confirmed retrospectively that the CA was an anti-I antibody. The two COVID-19 cases with a high CA titer showed no hemolysis or thrombosis. Mycoplasma pneumoniae is known to cause CAS, but not all patients who have a high CA titer show hemolysis. Coagulation abnormalities are documented in severe COVID-19 cases. Although CA increases the risk of thrombosis in those with lymphoproliferative diseases, the role of anti-I antibodies in COVID-19 is unclear. The impact of CAS on clinical presentations in COVID-19 remains a matter of verification. CONCLUSIONS: A high CA titer was identified in COVID-19 patients without hemolytic anemia and clotting. Anti-I antibodies were identified. Further studies are required to clarify the pathophysiology of CA in COVID-19.

Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma.

E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single-arm phase II study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T-cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression-free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.

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.

CD38 expression is an important prognostic marker in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases with variable outcomes. Although several prognostic markers have been developed, specific biomarkers for stratifying treatment strategies have not been fully investigated. This study aimed to analyze the clinical impact of the expression of cluster of differentiation (CD) 38, which is associated with cellular proliferation and disease progression, in patients with de-novo DLBCL. Using flow cytometry analysis, 137 cases with DLBCL were investigated for surface expression of CD38. Based on the cut-off value by the survival classification and regression tree analysis, the patients were categorized into a CD38HIGH group (n = 37) and CD38LOW group (n = 100). The 4-years progression-free survival (PFS) was 31.6% in the CD38HIGH group and 60.7% in the CD38LOW group (p < 0.001). Multivariate analysis showed the CD38HIGH group to be associated with significantly worse PFS (adjusted hazard ratio [aHR], 2.15, 95% CI: 1.26-3.68, p = 0.005) and poor overall survival (OS) (aHR, 2.54, 95% CI: 1.25-5.19, p = 0.010) than the CD38LOW group. In conclusion, we demonstrated that high CD38 expression is an independent adverse prognostic factor associated with poor clinical outcomes compared to low CD38 expression. CD38 expression in DLBCL cells might be useful for predicting outcomes and designing risk-adapted therapies for patients with de-novo DLBCL.

Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study.

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03-185.00%) and 148.02% (90% CI, 113.32-193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105.

Associated characteristics and treatment outcomes of medication-related osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases.

PURPOSE: This study aimed to evaluate the association between clinical characteristics and development of medication-related osteonecrosis of the jaw (MRONJ) in patients who underwent dental examinations before the initiation of treatment with denosumab or zoledronic acid, which are bone-modifying agents (BMAs), for bone metastases. Additionally, the clinical outcomes of patients who developed MRONJ were evaluated along with the time to resolution of MRONJ. METHODS: The medical charts of patients with cancer who received denosumab or zoledronic acid for bone metastases between January 2012 and September 2016 were retrospectively reviewed. Patients were excluded if they did not undergo a dental examination at baseline. RESULTS: Among the 374 included patients, 34 (9.1%) developed MRONJ. The incidence of MRONJ was significantly higher in the denosumab group than in the zoledronic acid (27/215 [12.6%] vs 7/159 [4.4%], P = 0.006) group. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment, older age, and tooth extraction before and after starting BMA treatments were significantly associated with developing MRONJ. The time to resolution of MRONJ was significantly shorter for patients who received denosumab (median 26.8 months) than for those who received zoledronic acid (median not reached; P = 0.024). CONCLUSION: The results of this study suggest that treatment with denosumab, age > 65 years, and tooth extraction before and after starting BMA treatments are significantly associated with developing MRONJ in patients undergoing treatment for bone metastases. However, MRONJ caused by denosumab resolves faster than that caused by zoledronic acid.

Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia.

BACKGROUND: Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001). METHODS: We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. RESULTS: Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). CONCLUSION: Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

Reversible renal-limited thrombotic microangiopathy due to gemcitabine-dexamethasone-cisplatin therapy: a case report.

BACKGROUND: Gemcitabine and cisplatin are chemotherapeutic agents used for treating multiple cancers, and these agents are sometimes used in combination. Drug-induced thrombotic microangiopathy (TMA) is a rare but potentially fatal complication. It typically presents as a systemic disease with the classical triad of hemolytic anemia, thrombocytopenia, and organ damage. In contrast to systemic TMA, cases of renal-limited TMA, defined as biopsy-proven renal TMA without the classical triad, have been reported with relatively good prognosis. Most cases of renal-limited TMA are associated with calcineurin inhibitors, and cases of drug-induced renal-limited TMA due to gemcitabine-dexamethasone-cisplatin therapy have been rarely reported. CASE PRESENTATION: A 43-year-old woman with lymphoma developed acute kidney injury with marked proteinuria, microhematuria, and abnormal urinary casts after receiving one cycle of gemcitabine-dexamethasone-cisplatin therapy. Although she did not show hemolytic anemia and thrombocytopenia, renal biopsy showed diffuse injury to the glomerular endothelial cells, supporting the diagnosis of renal-limited TMA. Her condition improved only with the cessation of gemcitabine and cisplatin treatment. She received another chemotherapy without gemcitabine and platinum agents, and no recurrence of renal-limited TMA was observed. CONCLUSIONS: Drug-induced TMA occurs early after gemcitabine and cisplatin use in renal-limited form and is reversible when detected and managed in a timely manner. Urinalysis, which is simple and inexpensive and can be easily performed, is a beneficial screening tool for early-onset drug-induced TMA among patients who receive gemcitabine-dexamethasone-cisplatin therapy.

Population pharmacokinetics of tacrolimus in umbilical cord blood transplant patients focusing on the variation in red blood cell counts.

WHAT IS KNOWN AND OBJECTIVE: The distribution of tacrolimus (TAC), an immunosuppressant used during cord blood transplantation (CBT)-one of the haematopoietic stem cell transplantations, to red blood cell (RBC) is approximately 90% in whole blood. In CBT patients, the total RBC count shows dramatic fluctuation due to conditioning before transplantation, including anticancer agents and total body irradiation, as well as RBC transfusions during the treatment period. Therefore, the amount of TAC in whole blood may show wide variation. However, therapeutic drug monitoring (TDM) of TAC has been performed based on the whole blood concentration. In this study, to contribute to TDM of TAC in CBT, we performed the population pharmacokinetic (PPK) analysis of TAC in 56 CBT patients and investigated the factors that affected the concentration of TAC, focusing the variation of RBC count. METHOD: A one-compartment model was applied to the observed whole blood TAC concentrations, and a PPK analysis was conducted with a non-linear mixed effect model. RESULTS AND DISCUSSION: Our final PPK model indicated good robustness and accuracy. In addition, haemoglobin (Hb) level was an influential covariate on Vd, which was expressed as Vd(L) = 91.4 × (Hb/8.2)(-1.07) . WHAT IS NEW AND CONCLUSION: In this study, our results showed the necessity for the Hb level monitoring during TDM of TAC in CBT patients and provided useful information for improving TDM strategy of TAC.