Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy.

Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035.

Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition.

Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.

A uniform conditioning regimen of busulfan, fludarabine, and antithymocyte globulin for allogeneic haematopoietic cell transplantation from haploidentical family, matched sibling, or unrelated donors-A single-centre, prospective, explorative study.

In a prospective, explorative study, the donor-source difference of haploidentical family (HF), matched sibling (MS), and unrelated donors (UD) was evaluated for the outcome of haematopoietic cell transplantations (HCT) in 101 patients with acute myeloid leukaemia (AML) in complete remission (CR). To eliminate compounding effects, a uniform conditioning regimen containing antithymocyte globulin (ATG) was used. After transplantation, there was a significantly higher cumulative incidence of acute graft-versus-host disease (GVHD) in HF-HCT patients (49%, 7%, and 16% for HF-, MS- and UD-HCT respectively; p < 0.001). A quarter of acute GVHD cases observed in HF-HCT patients occurred within three days of engraftment and were characterized by diffuse skin rash, fever, weight gain, and hypoalbuminaemia. This peri-engraftment acute GVHD was not observed in MS-HCT or UD-HCT patients. Additionally, a significantly higher proportion of HF-HCT patients achieved complete donor chimaerism in the peripheral mononuclear cells at one month (88%, 46%, and 69% for HF-, MS- and UD-HCT respectively; p = 0.001). There was no significant difference in engraftment, chronic GVHD, leukaemia recurrence, non-relapse mortality, and patient survival. In patients with AML in CR who received HCT using ATG-containing conditioning, stronger donor-patient alloreactivity was observed in HF-HCT, in terms of increased acute GVHD and higher likelihood of complete donor chimaerism.

Natural Killer Cell Activity Test Helps to Suspect Aggressive Natural Killer Cell Leukemia - Diagnostic Challenge.

Aggressive natural killer cell leukemia (ANKL) is a rare disease with an aggressive clinical course. We aimed to assess the clinicopathological characteristics of the difficult to diagnose ANKL. During ten years, nine patients with ANKL were diagnosed. All the patients exhibited aggressive clinical course and underwent the BM study to rule out lymphoma and hemophagocytic lymphohistiocytosis (HLH). BM examination showed varying degrees of infiltration of neoplastic cells, which were mainly positive for CD2, CD56, cytoplasmic CD3 and EBV in situ hybridization. Five BM aspirates showed histiocytic proliferation with active heomphagocytosis. Normal or increased NK cell activity test results were obtained from 3 patients who were available for testing. Four had multiple BM studies until diagnosis. An aggressive clinical course and positive EBV in situ hybridization, often with associated secondary HLH, should raise the suspicion of an ANKL. Conducting additional supplementary tests such as NK cell activity and NK cell proportion would be helpful for the diagnosis of ANKL.

Real-World Treatment Patterns and Clinical Outcomes in Korean Patients With AML Ineligible for First-Line Intensive Chemotherapy: A Subanalysis of the CURRENT Study, a Non-Interventional, Retrospective Chart Review.

BACKGROUND: Although most elderly patients with acute myeloid leukemia (AML) are ineligible for intensive chemotherapy (ICT), treatment options remain limited. CURRENT (UMIN000037786), a real-world, non-interventional, retrospective chart review, evaluated clinical outcomes, clinicopathologic characteristics, and treatment patterns in these patients. We present results from a subanalysis of Korean patients in this study. METHODS: Patients were aged ≥ 18 years with primary or secondary AML ineligible for ICT who initiated first-line systemic therapy or best supportive care (BSC) between 2015 and 2018 across four centers in Korea. Primary endpoint was overall survival (OS) from diagnosis. Secondary endpoints included progression-free survival (PFS), time to treatment failure, and response rates. Data analyses were primarily descriptive, with time-to-event outcomes estimated using the Kaplan-Meier method, and Cox regression used to determine prognostic factors for survival. RESULTS: Among 194 patients enrolled, 84.0% received systemic therapy and 16.0% received BSC. Median age at diagnosis was 74 and 78 years, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 was reported in 73.0% and 48.4% of patients, respectively; poor cytogenetic risk was reported in 30.1% and 16.1% of patients. Median OS was 7.83 vs. 4.50 months, and median PFS was 6.73 vs. 4.50 months in the systemic therapy vs. BSC groups. Prognostic factors affecting OS included secondary AML (hazard ratio, 1.67 [95% confidence interval, 1.13-2.45]), ECOG performance status ≥ 2 (2.41 [1.51-3.83]), poor cytogenetic risk (2.10 [1.36-3.24]), and Charlson comorbidity index ≥ 1 (2.26 [1.43-3.58]). CONCLUSION: Clinical outcomes are poor in Korean patients with AML ineligible for ICT who are prescribed current systemic therapies or BSC. There is a substantial unmet need for novel agents (monotherapy or in combination) to improve clinical outcomes in this patient population.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. METHODS: This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled. RESULTS: At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. CONCLUSION: These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

Five-day versus 7-day treatment regimen with azacitidine in lower risk myelodysplastic syndrome: A phase 2, multicenter, randomized trial.

BACKGROUND: Low-dose azacitidine (AZA) regimens, primarily 5-day AZA, have been used in lower risk myelodysplastic syndrome (LrMDS) but they have yet to be directly compared to the standard 7-day, uninterrupted dosing schedule. METHOD: In this phase 2, multicenter, randomized trial, 55 patients with adult LrMDS (low and intermediate-1 risk by international prognostic scoring system [IPSS]) were randomly assigned and received either 5-day (n = 26) or 7-day (n = 29) AZA between March 2012 and August 2020. The trial was stopped prematurely because of the slow accrual of patients. The primary end point was the overall response rate (ORR) of the 5-day AZA as compared to that of the 7-day regimen. RESULTS: Median patient age was 59 years, and IPSS intermediate-1 risk comprised the majority (81.8%). The median number of cycles in both arms was six. In the ITT subset (n = 53), in each of the 5-day and 7-day arms, the ORR of 48.0% and 39.3%, hematologic improvement of 44.0% and 39.3%, and RBC transfusion independence of 35.3% and 40.0% were observed respectively, and none of these findings were significantly different between the two arms. A cytogenetic response rate was significantly higher in the 7-day arm (8.3% and 53.8%, p = .027). Survival and adverse events were similar between the groups, although gastrointestinal toxicities, grade ≥3 thrombocytopenia, and febrile neutropenia were less frequent in the 5-day arm. CONCLUSION: The 5-day AZA in LrMDS showed comparable efficacy to a 7-day regimen in terms of similar overall response and other outcomes, despite significantly higher rates of cytogenetic responses in the 7-day regimen. LAY SUMMARY: Azacitidine (75 mg/m2 /day for 7 consecutive days per 28-day cycle) has shown survival benefit in patients with higher risk myelodysplastic syndrome (MDS). Although the use of azacitidine is less-well studied for lower risk MDS, it is generally accepted as a feasible option for lower risk MDS (LrMDS).

Clinical implications and genetic features of clonal cytopenia of undetermined significance compared to lower-risk myelodysplastic syndrome.

Clonal cytopenia of undetermined significance (CCUS) is characterized by persistent cytopenias with genetic aberrations, which do not meet the diagnostic criteria for myelodysplastic syndrome (MDS). We aimed to compare the clinical and genetic characteristics of CCUS with lower-risk MDS and identify patients with CCUS with a high risk of progression. We performed targeted sequencing of bone marrow (BM) samples from patients with idiopathic cytopenia of undetermined significance (ICUS) (n = 139) and MDS (n = 226). Overall survival (OS) of patients with CCUS (n = 78) was worse than non-clonal ICUS (n = 61) and superior to lower-risk MDS (n = 99). Patients with CCUS showed similar characteristics to those with lower-risk MDS, except for higher haemoglobin, lower BM cellularity, and less frequent SF3B1 mutations. Lower haemoglobin, DDX41 (biallelic germline and somatic), ETV6, and RUNX1 mutations were independent prognostic factors for worse OS. Lower haemoglobin and DDX41 mutations were also associated with lower progression-free survival. Patients with CCUS with high-risk features showed similar or worse OS than patients with lower-risk MDS. Our findings suggest that patients with CCUS having certain clinical or genetic features should be regarded and treated as lower-risk MDS despite lacking significant dysplasia or MDS-associated chromosomal abnormalities.

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). CONCLUSIONS: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).

Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia.

DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the incidence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). Germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients in whom germline-based testing was performed. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, patients with a DDX41 mutation were more frequently male, older, had a normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the four ICUS patients with germline DDX41 mutations progressed to MDS. The incidence of DDX41 mutations in Korean patients was high and there was a distinct mutation pattern, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating patients with myeloid malignancies.

Healthcare resource utilization trends in patients with acute myeloid leukemia ineligible for intensive chemotherapy receiving first-line systemic treatment or best supportive care: A multicenter international study.

OBJECTIVES: This retrospective chart review examined real-world healthcare resource utilization (HRU) in patients with AML ineligible for intensive therapy who received first-line systemic therapy or best supportive care (BSC). METHODS: Data were collected anonymously on patients with AML who initiated first-line hypomethylating agents (HMA), low-dose cytarabine (LDAC), other systemic therapy, or BSC. HRU endpoints included hospitalizations, outpatient consultations, transfusions, and supportive care. RESULTS: Of 1762 patients included, 46% received HMA, 11% received LDAC, 17% received other systemic therapy, 26% received BSC; median treatment durations were 118, 35, 33, and 57 days, respectively. Most patients were hospitalized, most commonly for treatment administration, transfusion, or infection (HMA 82%, LDAC 93%, other systemic therapy 83%, BSC 83%). A median number of hospitalizations were 2-6 across systemic groups and two for BSC, with median durations of 8-18 days. Transfusion rates and outpatient consultations were highest for HMA (80% and 79%) versus LDAC (57% and 53%), other systemic therapy (57% and 63%), and BSC (71% and 66%). Antivirals/antibiotics and antifungals were used more frequently than growth factors (72-92%, 34-63%, and 7-27%, respectively). CONCLUSION: Patients with AML ineligible for intensive therapy have high HRU; novel therapies are needed to alleviate this burden.

Busulfan, etoposide, cytarabine, and melphalan as a high-dose regimen for autologous stem cell transplantation in peripheral T-cell lymphomas.

Given the unsatisfactory survival in patients who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for peripheral T-cell lymphomas (PTCLs), we conducted a prospective trial of busulfan (Bu), etoposide (E), cytarabine (A), and melphalan (M) (BuEAM), including IV Bu instead of carmustine (BCNU) as in standard BEAM, as a high-dose regimen in such patients. This study evaluated the efficacy and toxicity of BuEAM as a high-dose regimen for ASCT in patients with T-cell lymphomas. The high-dose chemotherapy at seven centers in Korea included Bu (3.2 mg/kg IV qd from day 6 to day 5), E (200 mg/m2 IV bid on day 4 and day 3), A (1 g/m2 IV qd on day 4 and day 3), and M (140 mg/m2 IV qd on day 2). Eighty-one patients were enrolled in this study. The main subtypes were peripheral T-cell lymphoma, not other specified (n = 32, 39.5%), NK/T-cell lymphoma (n = 22, 27.5%), and angioimmunoblastic T-cell lymphoma (n = 12, 14.8%). Upfront and salvage ASCTs were performed in 65 (80.2%) and 16 (19.8%) patients, respectively. The disease status of the patients before ASCT was 54 patients (66.7%) with complete response and 27 patients (33.3%) with partial response. The common grade-III toxicities were anorexia (8.6%), diarrhea (7.4%), and stomatitis (4.9%). No veno-occlusive disorder was noted. Fifty-six (69.1%) and seven (8.6%) patients achieved complete and partial response, respectively, after ASCT, although 17 patients (21.0%) showed progressive disease. At a median follow-up duration of 49.3 months, the estimated 3-year progression-free survival and overall survival were 55.2% and 68.2% in all patients. The BuEAM high-dose regimen for ASCT was well tolerated and seemed to be effective in patients with T-cell lymphomas.

Clinical characteristics and prognostic factors of acquired haemophilia A in Korea.

INTRODUCTION: Acquired haemophilia A (AHA) treatment involves the haemostatic treatment for acute haemorrhage and immunosuppressive therapy (IST) to eradicate FVIII inhibitory antibodies. AIM: We assessed the clinical features of AHA and analysed treatment outcomes in Korea. We further identified prognostic factors affecting treatment outcomes. METHODS: Medical records of 55 patients with AHA from 18 institutions were reviewed retrospectively. Logistic and Cox regression analyses were performed to elucidate clinical factors affecting the achievement of complete remission (CR). The primary endpoint was time to CR after IST, and secondary endpoints were time to haemostasis, the achievement of CR, and overall survival (OS). RESULTS: Among the 55 patients, 50 (91%) had bleeding symptoms. Bleeding was severe in 74% of patients. Thirty-six (72%) patients received haemostatic therapy. Of the 42 patients who received IST, 23 (52%) received steroid alone, with a 52% response rate, and 10 (25%) received a combination of steroid and cyclophosphamide, with an 83% response rate. Five (16%) patients relapsed after a median duration of 220 days. There were eight deaths. In the Cox regression analysis, the FVIII inhibitor titre ≥ 20 BU/mL was the only significant prognostic factor affecting time to CR and haemostasis. No significant difference was observed in OS based on the inhibitor titre. CONCLUSION: The present study demonstrated the demographic data of AHA in Korea and showed that FVIII inhibitory antibody titre was a predictor of time to achieve CR after IST.

Second allogeneic hematopoietic stem cell transplantation in patients with acute leukemia relapsed after allogeneic hematopoietic stem cell transplantation.

The prognosis of patients with acute leukemia relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) is dismal. We aimed to evaluate the outcomes and prognostic factors of the second HSCT (HSCT2) in acute leukemia patients relapsed after the first HSCT (HSCT1). We analyzed 80 patients who received HSCT2 for relapsed acute leukemia in two Korean institutes. All but four patients received HSCT2 from a donor other than matched sibling donor: an unrelated donor (URD) in 30 and a familial haploidentical donor (FHD) in 46. Forty-four patients (55.0%) were in complete remission (CR) or CR with incomplete count recovery (CRi) at HSCT2, and the median time from HSCT1 to relapse was 9 months. The 2-year overall survival (OS) and event-free survival (EFS) were 21.0% and 17.5%, respectively. The outcomes were similar between URD and FHD. Multivariate analysis demonstrated that disease status (active disease vs. CR/CRi) at HSCT2 and remission duration after HSCT1 were independent prognostic factors for OS and EFS after HSCT2. HSCT2 from URD or FHD was feasible in patients with acute leukemia relapsed after allogeneic HSCT. Also, our study confirmed two critical prognostic factors; disease status at HSCT2 and remission duration after HSCT1.

Diagnostic yield of a bronchoalveolar lavage fluid galactomannan assay in patients with negative serum galactomannan results suspected to have invasive pulmonary aspergillosis.

BACKGROUND AND OBJECTIVES: There are limited data in real clinical practice on the diagnostic value of a bronchoalveolar lavage (BAL) fluid galactomannan (GM) assay in patients with suspected invasive pulmonary aspergillosis (IPA) who had negative serum GM results. Thus, we investigated the diagnostic performance of a BAL GM assay in patients with negative serum GM assay results who were suspected to have IPA. METHODS: This retrospective study was performed between May 2008 and April 2019 at a tertiary-care hospital in Seoul, South Korea. All patients with suspected IPA whose serum GM assays revealed negative results who sequentially underwent BAL were enrolled in this study. RESULTS: A total of 341 patients with suspected IPA including four cases of proven IPA, 38 cases of probable IPA, 107 cases of possible IPA and 192 patients without IPA were enrolled. Of these 341 patients, 107 (31%) with possible IPA were excluded from the final analysis. Of 42 patients with proven and probable IPA who had initial negative serum GM results, 24 (57%) had positive BAL GM results (n = 24) or BAL fungal culture results (n = 8). In addition, BAL revealed evidence of other opportunistic infections including Pneumocystis jirovecii pneumonia (14% [26/190]), cytomegalovirus (CMV) pneumonia (5% [9/188]) and respiratory viral pneumonia (6% [12/193]). CONCLUSION: Sequential BAL in patients with suspected IPA who had initial negative serum GM results provided additional diagnostic yield in approximately half of patients with evidence of another co-infection.

A Case Report of Immune Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.

Immune thrombocytopenia (ITP) is an autoimmune condition characterized by platelet destruction through antibody-mediated mechanism. ITP is one of the manifestations of a coronavirus disease, as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several cases of ITP have been described after vaccination with two mRNA-based vaccines-BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-against SARS-CoV-2. Herein, we report a case of ITP occurring after vaccination with ChAdOx1 adenovirus vector nCoV-19 (AstraZeneca) vaccine in Korea. A 66-year-old woman presented with multiple ecchymoses on both upper and lower extremities and gingival bleeding, appearing 3 days after receiving the first dose of ChAdOx1 nCoV-19. Her laboratory results showed isolated severe thrombocytopenia without evidence of combined coagulopathy. She was diagnosed with ITP and successfully treated with high-dose dexamethasone and intravenous immunoglobulin. Clinical suspicion to identify vaccine-related ITP is important to promptly initiate appropriate treatment.

Incidence, Management, and Prognosis of Graft Failure and Autologous Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: This study presents outcomes of management in graft failure (GF) after allogeneic hematopoietic stem cell transplantation (HCT) and provides prognostic information including rare cases of autologous reconstitution (AR). METHODS: We analyzed risk factors and outcomes of primary and secondary GF, and occurrence of AR in 1,630 HCT recipients transplanted over period of 18 years (January 2000-September 2017) at our center. RESULTS: Primary and secondary GF occurred in 13 (0.80%), and 69 patients (10-year cumulative incidence, 4.5%) respectively. No peri-transplant variables predicted primary GF, whereas reduced intensity conditioning (RIC) regimen (relative risk [RR], 0.97-28.0, P < 0.001) and lower CD34⁺ cell dose (RR, 2.44-2.84, P = 0.002) were associated with higher risk of secondary GF in multivariate analysis. Primary GF demonstrated 100% mortality, in the secondary GF group, the 5-year Kaplan-Meier survival rate was 28.8%, relapse ensued in 18.8%, and AR was observed in 11.6% (n = 8). In survival analysis, diagnosis of aplastic anemia (AA), chronic myeloid leukemia and use of RIC had a positive impact. There were 8 patients who experienced AR, which was rarely reported after transplantation for acute leukemia. Patient shared common characteristics such as young age (median 25 years), use of RIC regimen, absence of profound neutropenia, and had advantageous survival rate of 100% during follow period without relapse. CONCLUSION: Primary GF exhibited high mortality rate. Secondary GF had 4.5% 10-year cumulative incidence, median onset of 3 months after HCT, and showed 5-year Kaplan-Meier survival of 28.8%. Diagnosis of severe AA and use of RIC was both associated with higher incidence and better survival rate in secondary GF group. AR occurred in 11.6% in secondary GF, exhibited excellent prognosis.

Treatment of Latent Tuberculosis Infection Based on the Interferon-γ Release Assay in Allogeneic Stem Cell Transplant Recipients.

In hematopoietic stem cell transplant recipients, the incidence of tuberculosis in positive interferon-γ release assay (IGRA) without isoniazid prophylaxis (3.58/100 person-years) was higher than in negative or indeterminate IGRA (1.15/100 person-years; P = .01) and in positive IGRA with isoniazid prophylaxis (0/100 person-years; P = .09). The number needed to treat was 22 (95% confidence interval, 12-99) with positive IGRA results.

Differences in PD-1 expression on CD8+ T-cells in chronic myeloid leukemia patients according to disease phase and TKI medication.

Malignant cells can increase in number using immune escape mechanisms such as immune checkpoints. In this study, we evaluated the expression of an immune checkpoint programmed death 1 (PD-1) on T-cell subsets in chronic myeloid leukemia (CML). We obtained bone marrow aspirate samples from CML patients and from individuals without evidence of hematologic malignancies (controls). PD-1 expression on T-cell subsets was measured using flow cytometric analysis. PD-1 expression levels on CD8+ T-cells were significantly lower in complete hematologic response (CHR) than in controls, chronic phase, and blast phase (BP). In CML patients receiving imatinib and dasatinib, PD-1 expression levels on CD8+ T-cells were lower than that at diagnosis. PD-1 expression levels on CD8+ T-cells were positively correlated with quantitative levels of the BCR/ABL fusion gene. PD-1 expression levels on CD4+ T-cells were higher in BP than in CHR. PD-1 expression levels on CD4+ T-cells did not differ significantly according to different medications or quantitative BCR/ABL1 fusion gene levels. Low PD-1 expression on CD8+ T-cells might play a role in maintaining CHR in CML patients. Immune monitoring of PD-1 expression on CD8+ T-cells may predict the disease course. In cases of refractory disease or resistance to imatinib or dasatinib, the use of PD-1 inhibitors would be helpful.

Immunodeficiency risk score for prediction of mortality by parainfluenza virus infection in patients with hematologic malignancy.

Parainfluenza virus (PIV) infection is a significant cause of morbidity and mortality, especially in hematologic malignancy patients including hematopoietic stem cell transplantation (HCT) recipients. However, limited information is available for risk stratification in PIV-infected patients with hematologic malignancy with or without HCT. Patients with hematologic malignancy diagnosed with PIV from January 2009 to December 2018 were retrospectively included in a tertiary care hospital in Seoul, South Korea. Upper respiratory tract infection (URTI) was defined as the detection of PIV in a nasopharyngeal sample with URTI symptoms without new pulmonary infiltrates. Lower respiratory tract infection (LRTI) was defined as detection of PIV in either upper or lower respiratory tract samples with new pulmonary infiltrates, with or without hypoxia. PIV-associated mortality was defined as death with respiratory failure and persistent LRTI within 90 days after diagnosis. The study included 143 adult patients. Of these, 55 (38%) progressed to or initially presented with LRTI. Among these, 22 (40%) died from PIV-associated mortality. An immunodeficiency risk score was developed from associated risk factors using a multivariable Cox regression model. Patients were stratified into low (0-2), moderate (3-5), and high risk (6-8) groups with PIV-associated mortalities of 0%, 9%, and 67%, respectively (p < 0.005, Harrell's C-index = 0.84). PIV infection can result in substantial mortality in patients with hematologic malignancy if it progresses to LRTI. The immunodeficiency risk score presented here may be useful for distinguishing moderate and high risk groups that might benefit from antiviral therapy.