Efficacy, safety and cost of emicizumab prophylaxis in haemophilia A patients with inhibitors: A nationwide observational study in Taiwan.

INTRODUCTION: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. METHODS: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. RESULTS AND DISCUSSION: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5-578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p < .01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p < .01). Twenty-seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p < .01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug-related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. CONCLUSIONS: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed.

Case report: Endovascular treatment of acute limb ischemia in an adolescent with newly diagnosed lupus.

We report a 14-year-old adolescent who presented with acute limb ischemia caused by systemic lupus erythematosus-related antiphospholipid syndrome (APS). In the pediatric population, acute limb ischemia is rare. This case is unique in that after the initial medical treatment failed, interventional devices for acute stroke intervention were utilized to salvage the limb in our patient with a small tibial artery vessel to achieve procedural success. To provide limb salvage, operators may combine peripheral and neuro-intervention devices to maximize procedure success.

Pediatric Extracranial Germ Cell Tumors: Review of Clinics and Perspectives in Application of Autologous Stem Cell Transplantation.

Pediatric extracranial germ cell tumors (GCTs) are rare, accounting for approximately 3.5% of childhood cancers. Since the introduction of platinum-based chemotherapy, the survival rate of patients has improved to more than 80%. However, poor-risk subtypes of pediatric extracranial GCTs do not respond well to chemotherapy, leading to refractory or relapsed (R/R) diseases. For example, long-term survival rates of mediastinal GCTs or choriocarcinoma are less than 50%. According to reports in recent years for adult patients with R/R GCTs, the use of high-dose chemotherapy (HDCT) combined with autologous stem cell transplantation (ASCT) has clinical advantages; however, HDCT combined with ASCT has rarely been reported in pediatric GCTs. The R/R and poor-risk groups of pediatric GCTs could benefit from HDCT and ASCT.

Surgical treatment confers prognostic significance in pediatric malignant mediastinal germ cell tumors.

BACKGROUND: Primary malignant mediastinal germ cell tumors (GCTs) are rare pediatric tumors that have a poorer prognosis compared to GCTs occurring elsewhere in the body. The current study aimed to assess the prognostic factors and treatment outcomes of children with primary malignant mediastinal GCT in Taiwan. METHODS: The authors retrospectively reviewed children 0-18 years old who were newly diagnosed with primary malignant mediastinal GCT between January 1, 2005 and December 31, 2019 and were registered in the Taiwan Pediatric Oncology Group patient registry. The impact of presenting characteristics, including sex, age, tumor stage, histology subtype, surgical treatment, and chemotherapy regimens of the patients were analyzed. RESULTS: This study enrolled 52 children with malignant mediastinal GCT who had a median age of 16.0 (range, 6.0-17.9) years at diagnosis. The most common histological subtypes were mixed GCTs (n = 20) and yolk sac tumors (n = 15). Advanced disease stage and choriocarcinoma histology subtype were associated inferior outcomes. Children who received surgical treatment exhibited better outcomes compared to those who did not (5-year overall survival, 78% vs. 7%, p < .001). After comparing patients who received first-line cisplatin- and carboplatin-based chemotherapy, no difference in treatment outcomes was observed. Multivariate analysis showed that surgical management was the only independent predictor for superior OS. CONCLUSIONS: Surgical treatment is recommended for mediastinal GCT. Cisplatin-based chemotherapy was not superior to carboplatin-based chemotherapy as first-line treatment and may be avoided due to toxicity concerns.

Effectiveness and antimicrobial susceptibility profiles during primary antimicrobial prophylaxis for pediatric acute myeloid leukemia.

Limited data are available on antimicrobials exposure and microbiology evolution in pediatric acute myeloid leukemia (AML) patients underwent antimicrobials prophylaxis. To assess the effectiveness of antimicrobials prophylaxis, antibiotic susceptibilities of bacteria, and exposure of antimicrobials during intensive chemotherapy for AML patients, 90 consecutive de novo AML patients aged 0-18 years between January 1, 1997 and March 31, 2018 were enrolled. Vancomycin, ciprofloxacin and voriconazole prophylaxis was administered from January 1, 2010. During the preprophylaxis period, January 1997 to December 2009, 62 patients experienced a total of 87 episodes of bloodstream infection (BSI) and 17 episodes of invasive fungal infection (IFI) among 502 courses of chemotherapy. In contrast, 16 episodes of BSI occurred and no IFIs were reported to occur in 28 patients who received 247 courses of chemotherapy in the prophylaxis period. Patients who received antimicrobial prophylaxis had a significant reduction of BSI, IFI, and febrile neutropenia in comparison with patients without prophylaxis. Exposure to amikacin, carbapenem, amphotericin B was reduced in the prophylaxis period. Imipenem susceptibility of Enterobacter cloacae as well as vancomycin susceptibility of Enterococcus species were reduced in the prophylaxis period. At the time of the last follow up, patients with prophylaxis had a better subsequent 5-year overall survival rate than those without prophylaxis. Prophylactic antimicrobials administration in children with AML who undergo chemotherapy can significantly reduce the rates of life-threatening infection, exposure to antimicrobials, and might result in a better outcome.

A retrospective study of clinical features and outcome in patients with refractory or recurrent hepatoblastoma: A single institution experience.

BACKGROUND: Hepatoblastoma (HB) is the most common childhood primary hepatic malignancy. The overall survival rate in patients with HB has reached more than 80% over the past decades. The poor prognostic and high-risk HB have been defined, but the treatment and cure of refractory or relapsed HB is still an arduous task. METHODS: The complete records of HB in patients under the age of 18 at the MacKay Memorial Hospital between 1990 and 2019 were examined. RESULTS: The treatment results for 11 patients with refractory or relapsed HB are presented. The multi-modality treatment records were reviewed and the clinical characteristics associated with poor outcome included multifocal lesions, low α-fetoprotein, great vessel invasion and metastases. Delayed liver tumor surgery was carried out in eight cases. The median duration of follow-up for the 11 patients was 48.6 months (range 1.9 to 316.8 months). The 5-year and 10-year overall survival rate were 62.3% ± 15% (SE) and 49.9% ± 16.4% (SE), respectively. Most treatment-related toxicities were tolerable. The major concern during long term follow-up was irreversible high-frequency hearing loss. CONCLUSION: Patients with refractory/relapsed HB are still a thorny issue and more research is needed to improve the outcome.

Treatment outcomes of pediatric acute myeloid leukemia: a retrospective analysis from 1996 to 2019 in Taiwan.

Improvement in outcomes of children with acute myeloid leukemia (AML) is attributed to several refinements in clinical management. We evaluated treatment outcomes of Taiwanese pediatric AML patients in the past 20 years. Overall, 860 de novo AML patients aged 0-18 years and registered in the Childhood Cancer Foundation of R.O.C during January 1996-December 2019 were included. Survival analysis was performed to identify factors that improved treatment outcomes. Regardless of treatment modalities used, patients during 2008-2019 had better 5-year event-free survival (EFS) and overall survival (OS) rates than patients during 1996-2007. For patients received the TPOG-AML-97A treatment, only 5-year OS rates were significantly different between patients diagnosed before and after 2008. Patients with RUNX1-RUNX1T1 had similar relapse-free survival rates, but 5-year OS rates were better during 2008-2019. However, the survival of patients who received hematopoietic stem-cell transplantations (HSCT) did not differ significantly before and after 2008. For patients without relapse, the 5-year OS improved during 2008-2019. Non-relapse mortality decreased annually, and cumulative relapse rates were similar. In conclusion, 5-year EFS and OS rates improved during 2008-2019, though intensities of chemotherapy treatments were similar before and after 2008. Non-relapse mortality decreased gradually. Further treatment strategies including more intensive chemotherapy, novel agents' use, identification of high-risk patients using genotyping and minimal residual disease, early intervention of HSCT, and antibiotic prophylaxis can be considered for future clinical protocol designs in Taiwan.

Efficacy and safety of denosumab therapy for low bone mineral density in childhood cancer survivors: A report of preliminary experience.

BACKGROUND: In childhood cancer survivors, low bone mineral density (BMD) is a bone-related consequence. Efficacy of denosumab, an effective therapy for adult patients with osteoporosis, remains unclear in children. This study aimed to investigate denosumab therapy efficacy for low BMD in childhood cancer survivors. PROCEDURE: Between January 2014 and January 2018, we monitored lumbar BMD of children with cancer using dual-energy X-ray absorptiometry after completing chemotherapy with a 6-month interval. For patients with low BMD, defined as height-adjusted Z-scores of BMD < -1.5 in this study, calcium carbonate and vitamin D supplements were initially administered. When low BMD continued for at least 6 months, denosumab therapy was introduced. Calcium and vitamin D supplementation were continued in patients on denosumab. We investigated BMD change and adverse effects during denosumab therapy. RESULTS: During the study period, 20 patients received denosumab treatment. Mean height-adjusted Z-score of BMD before denosumab treatment was -2.68 but increased to -2, -1.96, and -1.33 at 0.5, 1, and 1.5 years after denosumab treatment, respectively (P = .012). In addition, hypocalcemia occurred in 40% (8/20) of patients; three patients had hypocalcemic symptoms with numbness in all four limbs. All hypocalcemic patients, except one patient who died due to relapsed leukemia, recovered well after continuous calcium supplementation. CONCLUSIONS: Denosumab is an effective treatment for low BMD in childhood cancer survivors. However, the complication of hypocalcemia might develop posttreatment.

Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG-ALL-2002 study.

BACKGROUND: To eliminate cranial irradiation (CrRT)-related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)-directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL). METHODS: This study compared the treatment outcomes of patients overall and patients with a non-CNS-1 status (CNS-2, CNS-3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG-ALL-2002 protocol by the introduction of the modification (era 1 [2002-2008] with CrRT and era 2 [2009-2012] with delayed first TIT and no CrRT). RESULTS: There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5-year event-free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non-CNS-1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5-year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2. CONCLUSIONS: The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non-CNS-1 status.

Triple intrathecal therapy alone with omission of cranial radiation in children with acute lymphoblastic leukemia.

PURPOSE: To eliminate the toxicities and sequelae of cranial irradiation (CrRT) and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, a prospective study of a modified CNS-directed therapy was conducted in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Since June 1999, children with newly diagnosed ALL have been treated with triple intrathecal therapy (TIT) alone without CrRT. The first TIT was delayed until the disappearance of blasts from peripheral blood (PB) for up to 10 days of multidrug induction, and CrRT was omitted in all patients. If PB blasts persisted on treatment day 10 (d10), the TIT was then performed. RESULTS: Of a total of 156 patients, 152 were eligible. Seventeen patients did not have PB blasts at diagnosis. Three fourths of the remaining patients achieved complete clearance of PB blasts by d10. Only hyperleukocytosis at diagnosis showed a significantly lower clearance rate. Six standard-risk patients were upgraded to high risk because of detectable PB blasts on d10. TLPs were encountered in four patients (2.6%), but none were contaminated with lymphoblasts. Neither CNS-2 (less than 5 WBCs/µL with blasts in a nontraumatic sample) nor CNS-3 (≥5 WBCs/µL with blasts in a nontraumatic sample or the presence of cranial nerve palsy) was present. The 5-year event-free survival and overall survival rates±SE were 84.2%±3.0% and 90.6%±2.4%, respectively. No isolated CNS relapse occurred, but two patients experienced combined CNS relapses. The 7-year cumulative risk of any CNS relapse was 1.4%±1.0%. CONCLUSION: Delaying first TIT until circulating blasts have cleared may improve CNS control in children with newly diagnosed ALL and preclude the need for CrRT.

Minimally early morbidity in children with acute myeloid leukemia and hyperleukocytosis treated with prompt chemotherapy without leukapheresis.

BACKGROUND/PURPOSE: Patients with acute myeloid leukemia (AML) and hyperleukocytosis, defined as an initial white blood cell (WBC) count of ≥ 100 × 10(9)/L, are often treated with leukapheresis. In this study, we have reported our experience of treating AML without leukapheresis. METHODS: From November 1, 1995, to May 31, 2012, there were 74 children (≤18 years old) with de novo AML other than acute promyelocytic leukemia. Seventeen patients had an initial WBC count ≥ 100 × 10(9)/L. Prompt chemotherapy was started within hours whereas leukapheresis was not performed. RESULTS: The median age of the 17 patients with hyperleukocytosis was 7.4 years (range: 0-16 years), and the median initial WBC count was 177 × 10(9)/L (range: 117-635 × 10(9)/L). The median time between admission and initiation of chemotherapy was 4.5 hours (range: 2-72 hours) in patients with hyperleukocytosis, whereas it was 13 hours (range: 2-120 hours) in those without hyperleukocytosis. Seven patients (7/17, 41%) had one or more early complications before or during the first 2 weeks of chemotherapy. Fifteen of the 16 patients who received prompt chemotherapy achieved complete remission (93.8%), comparable with those without hyperleukocytosis (98.2%; p = 0.33). CONCLUSION: Children with AML and hyperleukocytosis, treated with prompt chemotherapy without leukapheresis, had minimal early morbidities.

Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis.

BACKGROUND: The purpose of the current study was to prevent bloodstream infection and invasive fungal infection (IFI) by administering prophylactic antibiotic and antifungal agents during intensive chemotherapy in patients being treated for acute leukemia. METHODS: Prophylaxis treatment was administered during intensive chemotherapy in children with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) from January 1, 2010 to December 31, 2012. Oral ciprofloxacin (at a dose of 300 mg/m(2) /12 hours) was administered after chemotherapy when a patient with AML or ALL became neutropenic and > 7 days of neutropenia was expected. Voriconazole (at a dose of 4 mg/kg/12 hours) was initiated at the onset of neutropenia in patients with AML and after 7 days of neutropenia in patients with ALL. Micafungin (at a dose of 2 mg/kg/day) was substituted for voriconazole when patients with ALL received vincristine. Prophylaxis treatment was discontinued when the absolute neutrophil count recovered to > 100/µL. All episodes of bloodstream infection, IFI, febrile neutropenia, and intensive care unit stays related to severe infection occurring between January 1, 2005 and December 31, 2012 were recorded. RESULTS: During the preprophylaxis period, 62 children with ALL and 24 children with AML experienced a total of 44 episodes of bloodstream infection and 22 episodes of IFI. Seven patients died of severe infection. In contrast, in the prophylaxis period, 10 episodes of bloodstream infection occurred and no IFIs were reported to occur in 51 patients with ALL and 14 patients with AML. Moreover, no patient died of severe infection. Episodes of febrile neutropenia and intensive care unit stay were significantly reduced during the prophylaxis period. CONCLUSIONS: Prophylaxis with ciprofloxacin and voriconazole or micafungin was found to reduce the rates of bloodstream infection and IFI in children with acute leukemia undergoing intensive chemotherapy.