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.

Abdominal aortic calcification in patients newly diagnosed with essential thrombocythemia.

Background: Although atherosclerosis is likely to be involved in the development of arterial thrombotic events in patients with essential thrombocythemia (ET), abdominal aortic calcification (AAC) has rarely been investigated. We evaluated the prevalence and clinical relevance of AAC at the time of ET diagnosis. Methods: This retrospective study included patients newly diagnosed with ET who underwent abdominal computed tomography (CT) at the time of diagnosis between January 2002 and December 2021 at Chungnam National University Hospital, Daejeon, Korea. CT images were reviewed and an aortic calcification score was assigned. Results: Of the 94 patients (median age, 62 yr; range, 18‒90 yr), AAC was detected in 62 (66.0%). AAC was most commonly mild (33.0%), followed by moderate (22.7%) and severe (5.3%). Old age [odds ratio (OR), 34.37; 95% confidence interval (CI), 12.32‒95.91; P＜0.001] was an independent risk factor for AAC. The patients with AAC had a higher WBC count (11.8±4.7 vs. 9.7±2.9×109/L, P=0.017), higher neutrophil-to-lymphocyte ratio (4.3±2.7 vs. 3.1±1.5, P=0.039), and higher JAK2V617F positivity (81.5% vs. 58.8%, P=0.020) compared to those without AAC. AAC was an independent risk factor for arterial thrombotic vascular events that occurred before or at diagnosis of ET (OR, 4.12; 95% CI, 1.11‒15.85; P=0.034). Conclusion: AAC is common in patients with ET and is associated with arterial thrombotic events.

Autoimmune Limbic Encephalitis in Patients with Hematologic Malignancies after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide.

Autoimmune limbic encephalitis (LE) is a rare, but devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). There is currently limited evidence describing the risk factors, laboratory features, and underlying mechanisms of this neurologic adverse event. We retrospectively reviewed available clinical, imaging, and laboratory data from adult patients with hematological malignancies who underwent haploidentical HSCT with post-transplant cyclophosphamide (PTCy) at Chungnam National University Hospital from June 2016 to May 2020. Patients who developed LE were compared to those who did not based on clinical assessment, serum inflammatory biomarkers, and reconstitution of various T cell populations. Of 35 patients, 4 developed LE. There were no differences in patient demographics, donor demographics, or treatment conditions between patients that did and did not develop LE. Overall, patients with LE had worse clinical outcomes and overall survival than those without. In addition, they tended to have higher markers of systemic inflammation in the early post-transplant period, including fever, C-reactive protein (CRP), and cytokines. Remarkably, baseline interleukin-6 levels before HSCT were found to be higher in patients who developed LE than those who did not. In addition, analysis of T cell subsets showed impaired expansion of CD25+FOXP3+ regulatory T (Treg) cells in LE compared to non-LE patients despite appropriate reconstitution of the total CD4+ T cell population. Patients that developed LE within the first 30 days of HSCT were likely to have high serum IL-6 among other inflammatory cytokines coupled with suppression of regulatory T cell differentiation. Further work is needed on the mechanisms underlying impaired Treg expansion following HSCT and potential therapies.

Maintenance therapy with Fluoropyrimidine and cetuximab or bevacizumab after first line FOLFOX-chemotherapy in metastatic colorectal cancer according to RAS or BRAFV600E mutation status.

PURPOSE: Fluoropyrimidine (FP) with oxaliplatin-based chemotherapy is the standard first-line treatment for metastatic colorectal cancer (mCRC); however, oxaliplatin-induced neuropathy critically affects the quality of life of patients. Maintenance strategies with FP plus bevacizumab have been well-established; nonetheless, the real-world outcomes of maintenance therapy with FP and cetuximab are unclear. We investigated the clinical outcomes of patients who underwent maintenance therapy with cetuximab. METHODS: We retrospectively identified and analyzed patients with mCRC who were treated between 2012 and 2021 with first-line oxaliplatin-based induction chemotherapy (IC) plus biologic agents (either cetuximab or bevacizumab), and underwent maintenance therapy (IC regimen without oxaliplatin) after IC. RESULTS: In total, 19 patients who were treated with mFOLFOX6 (FP/leucovorin/oxaliplatin) with cetuximab, and 26 patients who were treated with mFOLFOX6 with bevacizumab were included. In the cetuximab group, all patients were KRAS-, NRAS-, and BRAF-wild type, whereas most patients in the bevacizumab group harbored KRAS or BRAFV600E or NRAS mutants. During the maintenance treatment, seven patients (four [21%] in the cetuximab group and three [11%] in the bevacizumab group) achieved partial response after achieving nadir during induction chemotherapy. The disease control rates of maintenance therapy were 79% and 74% in the cetuximab and bevacizumab groups, respectively. The median progression-free survival of maintenance therapy and overall survival was 5.98 months and 32.4 months in the cetuximab group, and 4.83 months and 25.6 months in the bevacizumab group, respectively. CONCLUSIONS: Maintenance therapy with FP plus biologic agents (either bevacizumab or cetuximab) is a feasible strategy for appropriate mCRC patients according to their RAS/BRAF status. Further large-scale randomized studies are needed to validate the efficacy of anti-epidermal growth factor receptor-based maintenance therapy.

Efficacy of cisplatin combined with vinorelbine as second- or higher-line palliative chemotherapy in patients with advanced ovarian cancer.

The aim of this study was to assess the therapeutic efficacy of a cisplatin and vinorelbine combination as second- or higher-line palliative chemotherapy in patients with advanced ovarian cancer. We retrospectively reviewed the medical records of patients with advanced ovarian cancer who were treated with cisplatin (60 mg/m2 on day 1) and vinorelbine (25 mg/m2 on days 1 and 8) every 3 weeks between January 2004 and March 2021. Treatment responses, progression-free survival (PFS), and overall survival (OS) were assessed; laboratory data were reviewed to determine toxicity. Thirty-two patients with advanced ovarian cancer were treated with a combination of vinorelbine and cisplatin. The objective response rate (ORR) was 18.8% and the disease control rate was 75.1%. The median PFS was 4.13 months (95% confidence interval [CI], 2.4-5.8 months). The median OS was 56.9 months (95% CI, 50.5-63.7 months). The ORR (42.9% vs 9.1%; P = .035) was higher in the platinum-sensitive group than in the platinum-resistant group. The median PFS tended to be longer in the platinum-sensitive group (5.3 vs 3.8 months; P = .339) and the median OS was significantly longer in the platinum-sensitive group than in the platinum-resistant group (69.6 vs 24 months; P < .001). All patients developed hematological toxicities, with 56% experiencing grade 3 to 4 neutropenia. Two (6.2%) patients developed febrile neutropenia, but no treatment-related death occurred. This combination therapy may be effective in patients with heavily treated advanced ovarian cancer, particularly in platinum-sensitive patients.

Acquired von willebrand syndrome in patients with philadelphia-negative myeloproliferative neoplasm.

Background: Acquired von Willebrand syndrome (AVWS) has not been investigated in Korean patients with Philadelphia chromosome-negative myeloproliferative neoplasm. Methods: This study analyzed the prevalence at diagnosis and clinical features of AVWS in patients with essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic/early primary myelofibrosis (pre-PMF), or overt PMF (PMF) diagnosed between January 2019 and December 2021 at Chungam National University Hospital, Daejeon, Korea. AVWS was defined as below the lower reference limit (56%) of ristocetin cofactor activity (VWF:RCo). Results: Sixty-four consecutive patients (36 with ET, 17 with PV, 6 with pre-PMF, and 5 with PMF; 30 men and 34 women) with a median age of 67 years (range, 18‒87 yr) were followed for a median of 25.1 months (range, 2.6‒46.4 mo). AVWS was detected in 20 (31.3%) patients at diagnosis and was most frequent in ET patients (41.4%), followed by patients with pre-PMF (33.3%) and PV (17.6%) patients. VWF:RCo was negatively correlated with the platelet count (r=0.937; P=0.002). Only one episode of minor bleeding occurred in a patient with ET and AVWS. Younger age (<50 yr) [odds ratio (OR), 7.08; 95% confidence interval (CI), 1.27‒39.48; P=0.026] and thrombocytosis (>600×109/L) (OR, 13.70; 95% CI, 1.35‒138.17; P=0.026) were independent risk factors for developing AVWS. Conclusion: AVWS based on VWF:RCo was common in patients with ET and pre-PMF, but less common in patients with PV in the Korean population. Clinically significant bleeding is rare in these patients.

Cardiopulmonary Exercise Test With Comorbidity Index Before Allogeneic Hematopoietic Stem Cell Transplantation.

PURPOSE: To evaluate the role of the cardiopulmonary exercise test (CPET) with comorbidity index as a predictor of overall survival (OS) and non-relapse mortality (NRM) in patients with hematological malignancies who undergo allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We retrospectively analyzed consecutive adult patients with hematological malignancies who underwent HLA-matched donor-HSCT at Chungnam National University Hospital (Daejeon, South Korea) between January 2014 and December 2020. Maximal oxygen consumption (VO2max) was classified using the recommendations of the Mayo Clinic database. RESULTS: Of 72 patients, 38 (52.8%) had VO2max values lower than the 25th percentile (VO2max ≤ 25th) of an age- and sex-matched normal population. Patients with VO2max ≤ 25th had no significant differences both OS and NRM (30 month OS 29.8% vs 41%, P = .328; and 30 month NRM 16% vs 3.3%, P = .222), compared with other patients. VO2max ≤ 25th was assigned a weight of 1 when added to the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) to form a composite comorbidity/CPET index (HCT-CI/CPET). Patients with HCT-CI/CPET scores of 0 to 1 demonstrated significantly better OS and NRM than did patients with HCT-CI/CPET scores ≥2 [median OS not reached vs 6 months, P < .001 and 30 month NRM 7.4% vs 33.3%, P = .006]. An HCT-CI/CPET score ≥2 was the only adverse risk factor for NRM on multivariate analysis [hazard ratio (HR) of NRM 10.36 (95% CI 1.486-2.25, P = .018)]. CONCLUSION: The composite HCT-CI/CPET score can predict the survival and mortality of patients with hematological malignancies who undergo allogeneic HSCT.

Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia.

BACKGROUND/AIMS: We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. RESULTS: The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. CONCLUSION: Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Early diagnosis of Gaucher disease in Korean patients with unexplained splenomegaly: a multicenter observational study.

Background: Gaucher disease (GD) is an autosomal recessive disorder characterized by excessive accumulation of glucosylceramide in multiple organs. This study was performed to determine the detection rate of GD in a selected patient population with unexplained splenomegaly in Korea. Methods: This was a multicenter, observational study conducted at 18 sites in Korea between December 2016 and February 2020. Adult patients with unexplained splenomegaly were enrolled and tested for ß-glucosidase enzyme activity on dried blood spots (DBS) and in peripheral blood leukocytes. Mutation analysis was performed if the test was positive or indeterminate for the enzyme assay. The primary endpoint was the percentage of patients with GD in patients with unexplained splenomegaly. Results: A total of 352 patients were enrolled in this study (male patients, 199; mean age, 48.42 yr). Amongst them, 14.77% of patients had concomitant hepatomegaly. The most common sign related to GD was splenomegaly (100%), followed by thrombocytopenia (44.32%) and, anemia (40.91%). The ß-glucosidase activity assay on DBS and peripheral leukocytes showed abnormal results in sixteen and six patients, respectively. Eight patients were tested for the mutation, seven of whom were negative and one patient showed a positive mutation analysis result. One female patient who presented with splenomegaly and thrombocytopenia was diagnosed with type 1 GD. The detection rate of GD was 0.2841% (exact 95% CI, 0.0072‒1.5726). Conclusion: The detection rate of GD in probable high-risk patients in Korea was lower than expected. However, the role of hemato-oncologists is still important in the diagnosis of GD.

Safety and efficacy of nilotinib in adult patients with chronic myeloid leukemia: a post-marketing surveillance study in Korea.

Background: Nilotinib is a tyrosine kinase inhibitor approved by the Ministry of Food and Drug Safety for frontline and 2nd line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). This study aimed to confirm the safety and efficacy of nilotinib in routine clinical practice within South Korea. Methods: An open-label, multicenter, single-arm, 12-week observational post-marketing surveillance (PMS) study was conducted on 669 Korean adult patients with Ph+ CML from December 24, 2010, to December 23, 2016. The patients received nilotinib treatment in routine clinical practice settings. Safety was evaluated by all types of adverse events (AEs) during the study period, and efficacy was evaluated by the complete hematological response (CHR) and cytogenetic response. Results: During the study period, AEs occurred in 61.3% (410 patients, 973 events), adverse drug reactions (ADRs) in 40.5% (271/669 patients, 559 events), serious AEs in 4.5% (30 patients, 37 events), and serious ADRs in 0.7% (5 patients, 8 events). Furthermore, unexpected AEs occurred at a rate of 6.9% (46 patients, 55 events) and unexpected ADRs at 1.2% (8 patients, 8 events). As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was achieved in 85.8% (139/162 patients). Conclusion: This PMS study shows consistent results in terms of safety and efficacy compared with previous studies. Nilotinib was well tolerated and efficacious in adult Korean patients with Ph+ CML in routine clinical practice settings.

Splenic Infarction in Patients with Philadelphia-negative Myeloproliferative Neoplasms.

Objective We retrospectively analyzed the prevalence and clinical features of splenic infarctions in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph- MPNs). Patients Patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic/early primary myelofibrosis (pre-PMF), or PMF from January 1996 to October 2020 in Chungnam National University Hospital, Daejeon, Korea, were reviewed. Results A total of 347 patients (143 ET, 129 PV, 44 pre-PMF, and 31 PMF patients; 201 men and 146 women) with a median age of 64 (range 15-91) years old were followed up for a median of 4.7 (range 0.1-26.5) years. Fifteen (4.3%) patients exhibited splenic infarctions at the diagnosis. These were most common in PMF patients (12.9%), followed by pre-PMF (9.1%) and PV (5.4%) patients. Multifocal infarcts (60.0%) were most common, followed by solitary (33.3%) and extensive infarcts (6.7%). The cumulative incidence of thrombosis in patients with splenic infarctions tended to be higher than in those lacking infarctions (10-year incidence 46.7% vs. 21.0% in PV; p=0.215; 33.3% vs. 17.9% in pre-PMF; p=0.473) patients, but statistical significance was lacking. Palpable splenomegaly (hazard ratio 14.89; 95% confidence interval 4.00-55.35; p<0.001) was the only independent risk factor for splenic infarction. During follow-up, 5 (1.4%) patients developed splenic infarctions. Conservative treatment adequately controlled the symptoms; no serious complications were noted in any patient. Conclusion Splenic infarctions occurred most frequently in patients with PMF; it was rare in patients with ET. The clinical courses were generally mild.

Myelofibrotic and leukemic transformation in 2016 WHO-defined Philadelphia-negative myeloproliferative neoplasm.

Background: Information on myelofibrotic and leukemic transformations in Korean Philadelphia chromosome- negative myeloproliferative neoplasms (Ph‒ MPNs) is limited. Methods: This study retrospectively analyzed transformations in patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV) prefibrotic/early primary myelofibrosis (pre-PMF), or overt primary myelofibrosis (PMF) based on the 2016 World Health Organization criteria between January 1996 and December 2020 at Chungam National University Hospital, Daejeon, Korea. Results: A total of 351 patients (144 with ET, 131 with PV, 45 with pre-PMF, and 31 with PMF; 204 men and 147 women) with a median age of 64 years (range, 15‒91 years) were followed for a median of 4.6 years (range, 0.2‒24.8 years). The 10-year incidence of overt myelofibrosis was higher in pre-PMF than in ET (31.3% and 13.7%, respectively; P =0.031) and PV (12.2%; P =0.003). The 10-year incidence of leukemic transformation was significantly higher in PMF than in ET (40.0% and 7.9%, respectively; P =0.046), pre-PMF (4.7%; P =0.048), and PV (3.2%; P =0.031). The 5-year incidence of leukemic transformation was higher in patients with secondary myelofibrosis (SMF) than in those with PMF (19.0% and 11.4%, respectively; P =0.040). The 5-year overall survival of patients with SMF was significantly worse than that of patients with pre-PMF (74% and 93%, respectively; P=0.027) but did not differ from that of patients with PMF (57%; P=0.744). Conclusion: The rates and clinical courses of myelofibrotic and leukemic transformations in Korean patients with Ph‒ MPN did not differ from those in Western populations.

Volumetric Splenomegaly in Patients With Polycythemia Vera.

BACKGROUND: Non-palpable splenomegaly in patients with polycythemia vera (PV) has seldom been addressed. In this retrospective study, we evaluated non-palpable, volumetric splenomegaly defined based on age- and body surface area (BSA)-matched criteria in patients with PV diagnosed according to the 2016 World Health Organization diagnostic criteria. METHODS: Patients with PV who underwent abdominal computed tomography (CT) and who had palpable splenomegaly at diagnosis from January 1991 to December 2020 at Chungnam National University Hospital were enrolled. The spleen volume of each patient was determined by volumetric analysis of abdominal CT and adjusted for the patient's age and BSA. Then the degree of splenomegaly was classified as no splenomegaly, borderline volumetric splenomegaly, overt volumetric splenomegaly, or palpable splenomegaly. RESULTS: Of the 87 PV patients enrolled, 15 (17.2%) had no splenomegaly, whereas 17 (19.5%), 45 (51.7%), and 10 (11.5%) had borderline volumetric, overt volumetric, and palpable splenomegaly, respectively. The degree of splenomegaly did not affect the cumulative incidence of thrombotic vascular events (10-year incidence: 7.7%, 0%, 22.3%, and 50.7%, respectively, P = 0.414). By contrast, splenomegaly tended to adversely affect myelofibrotic transformation (10-year cumulative incidence: 0%, 0%, 7.1%, and 30.3%, respectively, P = 0.062). Moreover, the cumulative incidence of myelofibrotic transformation was significantly higher in patients with overt volumetric or palpable splenomegaly than those with no or borderline volumetric splenomegaly (10-year incidence: 0% vs. 10.3%, respectively; 15-year incidence: 0% vs. 26.3%, respectively, P = 0.020). Overall survival (OS) differed among patients with different degrees of splenomegaly (15-year OS: 100%, 78.6%, 71.7%, and 51.9%, respectively, P = 0.021). CONCLUSION: The degree of splenomegaly, including volumetric splenomegaly, based on age- and BSA-matched reference spleen volumes at diagnosis reflects disease progression in PV patients. Therefore, volumetric splenomegaly should be evaluated at the time of diagnosis and taken into consideration when predicting the prognosis of patients with PV.

Pulmonary hypertension in patients with chronic myeloid leukemia.

ABSTRACT: Dasatinib, a tyrosine kinase inhibitor (TKI), induces pulmonary hypertension (PH) in patients with chronic myeloid leukemia (CML). However, information on other TKIs is limited.We retrospectively analyzed PH prevalence by reviewing transthoracic echocardiography (TTE) findings in a population of Korean CML patients treated with TKI at a single hospital between 2003 and 2020. PH was defined as a high PH probability according to the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines.Of the 189 patients treated with TKI(s) during the study period, 112 (59.3%) underwent TTE. Among the 112 patients treated with a TKI for a median of 40.4 months (range: 1.1-167.2 months), PH was found in 12 (10.7%), most frequently in those treated with dasatinib (ie, in 3 [7.5%] of 40 of those treated with imatinib, 1 [3.1%] of 32 of those treated with nilotinib, and 8 [21.6%] of 37 of those treated with dasatinib). PH resolved in 4 (50.0%) of the 8 dasatinib-treated patients after discontinuation of the agent. One nilotinib-treated and all three imatinib-treated patients recovered from PH. In multivariate analyses, age >60 years, dasatinib treatment, and positive cardiopulmonary symptoms/signs at the time of transthoracic echocardiography were statistically significant risk factors for developing PH.These results show that PH is induced not only by dasatinib, but also by imatinib and nilotinib. Careful screening for PH during any TKI treatment may thus be warranted in patients with CML.

Thrombotic and hemorrhagic events in 2016 World Health Organization-defined Philadelphia-negative myeloproliferative neoplasm.

BACKGROUND/AIMS: Recent changes in the diagnostic criteria for myeloproliferative neoplasms (MPNs) and increasing patient numbers necessitate updating of the data on vascular events in patients with such disorders. METHODS: In this single-center study, thrombotic and hemorrhagic events were retrospectively analyzed in patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV) prefibrotic/early primary myelofibrosis (pre-PMF), or PMF, based on the 2016 World Health Organization diagnostic criteria. RESULTS: Of a total of 335 consecutive patients (139 ET, 42 pre-PMF, 124 PV, and 30 PMF patients; 192 males and 143 females) of median age 64 years (range, 15 to 91), 112 (33.4%) experienced a total of 126 thrombotic events before diagnosis, at the time of diagnosis, or during follow-up over a median of 4.6 years (range, 0.1 to 26.5). Cerebrovascular thrombosis (18.8%) was the most common initial event, followed by coronary heart disease (10.1%) and splanchnic (1.5%) and peripheral thrombosis (1.5%). Arterial thrombosis was more common than venous thrombosis (31.3% vs. 2.1%, respectively; p = 0.001). Thrombosis was most frequent in PV patients (39.5%), followed by patients with pre-PMF (38.1%), ET (30.9%), and PMF (13.3%). Of the 112 patients who experienced thromboses, 53 (47%) and 39 (33.9%) had thrombotic events before and at the time of MPN diagnosis, respectively. Twenty-seven patients (8.1%) experienced 29 hemorrhagic events, of which gastrointestinal bleeding (n = 20) was the most common. CONCLUSION: Most thrombotic events occurred before or at the time of diagnosis, and the prevalence of arterial thrombosis was markedly higher than that of venous thrombosis in patients with MPN.

Treatment-free remission of chronic myeloid leukemia in real-world practice by the detection limit of MR4.3.

BACKGROUND: Molecular response (MR) 4.0 or 4.3 remains an indicator of treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in countries that accept it as the criterion of undetectable minimal residual disease (UMRD) in clinical practice. We retrospectively analyzed the TFR outcomes to identify the clinical efficacy of MR4.0/4.3 as the UMRD criterion. PATIENTS AND METHODS: CML patients treated with tyrosine kinase inhibitors (TKIs) between March 2001 and May 2015 for >3 years and treatment cessation for over 6 months were included. TFR was analyzed using MR3.0 loss and UMRD loss as criteria. TFR failure-free survival was defined as the time from cessation of TKI therapy to MR loss or restarting TKI, and overall survival as the time from TKI cessation to death. The probability of regaining the MR was evaluated. RESULTS: In the 93 participants, the median duration of follow-up and TKI therapy were 17.3 (3.9-92.0) months and 7.4 (3.1-16.9) years, respectively. TFR at 5 years was 47.9 % and 44.4 %, for MR3.0 loss and UMRD loss, respectively. Among the 42 patients who restarted TKI, 41 regained MR3.0 (97.6 %). In multivariate analysis, the time to UMRD was ≤12 months, and the absence of prior TKI treatment (P = 0.018 and 0.044 in UMRD loss, respectively) was significantly correlated with TFR failure-free survival. CONCLUSION: Clinical outcomes were comparable to those of clinical trials. Our results suggest that the detection limit of MR4.3 can be used in clinical practice for TKI treatment cessation for TFR in CML patients.

Volumetric splenomegaly in patients with essential thrombocythemia and prefibrotic/early primary myelofibrosis.

Non-palpable, volumetric splenomegaly at diagnosis was evaluated using computed tomography in patients with essential thrombocythemia (ET) and prefibrotic/early primary myelofibrosis (pre-PMF) based on 2016 World Health Organization guidelines. Each patient's spleen volume was adjusted for their age and body surface area. The degree of splenomegaly was classified as no, borderline volumetric, overt volumetric, or palpable splenomegaly. Seventy-six patients with ET (median age, 62.5 years) and 19 patients with pre-PMF (median age, 65 years) were followed up for a median of 2.4 years (range 0.1-17.6 years) and 4.2 years (range 0.2-19.6 years), respectively. Spleen volume was significantly greater in pre-PMF patients than in ET patients (377.9 ± 92.2 cm3 vs. 224.9 ± 115.2 cm3, P < 0.001). No, borderline volumetric, overt volumetric, and palpable splenomegaly were found in 42 (55.3%), 24 (31.6%), 10 (13.2%), and 0 (0%) patients with ET, respectively, and in 0 (0%), 8 (42.1%), 19 (52.6%), and 1 (5.2%) patient with pre-PMF, respectively (P < 0.001). Volumetric splenomegaly did not affect thrombosis-free survival in patients with ET or those with pre-PMF. This study indicates that all patients with pre-PMF present with splenomegaly, whereas half of the patients with ET have a normal-sized spleen at diagnosis.

Impact of pre-transplant use of antibiotics on the graft-versus-host disease in adult patients with hematological malignancies.

OBJECTIVES: Changes in fecal microbiota affect the incidence and extent of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Most patients with hematological malignancies receive antibiotics for the treatment of febrile neutropenia prior to allogeneic HSCT, and pre-transplant use of antibiotics may influence the fecal microbiota and GVHD. METHODS: We retrospectively analysed consecutive adult patients with hematological malignancies who received allogeneic HSCT at Chungnam National University Hospital between 2007 and 2018. Pre-transplant use of antibiotics was defined as the use of antibiotics before conditioning chemotherapy. RESULTS: This study included 131 patients with a median age of 46 (range, 18-71) years: 76 (58%) patients were AML, 28 (21.4%) with ALL, 23 (17.6%) with MDS, and 4 (3.1%) with CML. All patients received calcineurin inhibitors with short-course methotrexate for GVHD prophylaxis. A total of 31 (23.7%) patients received anti-thymocyte globulin. All patients received antibiotics prior to HSCT: 70 (53.4%) patients received glycopeptide, 114 (87.0%) received cefepime, 87 (66.4%) received piperacillin/tazobactam, and 51 (38.9%) received carbapenem. Patients who received glycopeptide had more frequently extensive chronic GVHD (cGVHD) than those who did not (51.1% vs. 28.1% at 5 years) and had more frequently cGVHD of the lung (34.8% vs. 15.8% at 5 years). Pre-transplant use of glycopeptide did not affect the overall survival (OS) or GVHD- and relapse-free survival (GRFS) (median OS; 49 months in glycopeptide group vs. not reached in non-glycopeptide group, p=0.475; median GRFS; 9 months in glycopeptide group vs. 16 months in non-glycopeptide group, p=0.092). CONCLUSION: Pre-transplant use of glycopeptide tends to increase the incidence of extensive cGVHD.

Clinical features and outcomes of hypocellular acute myeloid leukemia in adults: A Korean AML registry data.

ABSTRACT: The hypocellular variant of acute myeloid leukemia (AML) is defined as bone marrow cellularity of <20% in a biopsy specimen at presentation. We performed a retrospective analysis of the clinical features and survival outcomes of hypocellular AML in a Korean population. We reviewed the medical records of all patients diagnosed with AML at nine hospitals participating in the Korean AML registry from 2006 to 2012. Overall survival (OS) and event-free survival (EFS) rates were calculated from the time of diagnosis until death or an event, respectively. In total, 2110 patients were enrolled and 102 (4.8%) were identified as having hypocellular AML. Patients with hypocellular AML were older than those with non-hypocellular AML (median age: 59 vs 49 years; P < .001) and presented with leukopenia more frequently (mean white blood cell count: 5810/µL vs 40549/µL; P < .001). There was no difference between patients with and without hypocellular AML in terms of the presence of antecedent hematologic disorders (5.9% vs 5.3%; P  = .809). FLT3-ITD and NPM1 mutations were less common in hypocellular than non-hypocellular AML (FLT3-ITD mutations: 1.2% vs 14.3%, P < .001; NPM1 mutations: 0% vs 9.5%, P = .019). No differences were seen between the hypocellular and non-hypocellular AML groups in the complete remission rate (53.9% vs 61.3%, P = .139) or early death rate (defined as any death before 8 weeks; 14.7% vs 13.0%, P = .629). The OS and EFS did not differ between the hypocellular and non-hypocellular AML groups (median OS: 16 vs 23 months, P = .169; median EFS: 6 vs 9 months, P = .215). Hypocellular AML is more frequently observed in older-aged patients and have fewer FLT3-ITD and NPM1 mutation, but the clinical outcomes of hypocellular AML do not differ from those of non-hypocellular AML.