Safety of FEIBA and emicizumab (SAFE): Dose escalation study evaluating the safety of in vivo administration of activated prothrombin complex concentrate in haemophilia A patients on emicizumab.

INTRODUCTION: Emicizumab is a humanized bispecific monoclonal antibody licensed for patients with severe haemophilia A. Breakthrough bleeding still occurs in patients on emicizumab and can be managed with recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC). Thrombotic events were reported when patients on emicizumab received concomitant aPCC at relatively high doses. We studied the effect of infusing various doses of aPCC to patients on emicizumab. MATERIAL AND METHODS: Nine patients with severe haemophilia A with inhibitors who are on emicizumab were recruited to participate. Patients were infused with varying doses of aPCC in vivo. Samples were tested with thrombin generation (TG) assay. RESULTS: In the current in vivo arm of the study four out of nine patients reached the highest dose, 75 U/kg of aPCC and six out of nine patients were actually eligible for the highest dose. In the previous in vitro arm of the study seven out of eight patients reached the normal plasma with spiking aPCC at a very low concentration equivalent to 5 U/kg. CONCLUSION: The in vitro portion of the study demonstrated that clinically relevant concentrations of aPCC resulted in excessive TG, however, in vivo administration of aPCC to the same patients demonstrated that most of the patients had normal TG at the approved doses of aPCC. In the management of breakthrough bleeding clinicians should heed the boxed warning for concomitant use of emicizumab and aPCC, however, should also be aware that low doses of aPCC may not result in sufficient TG.

Effects of PK-guided prophylaxis on clinical outcomes and FVIII consumption for patients with moderate to severe Haemophilia A.

INTRODUCTION: In recent years, there has been increased focus on individualizing treatment for persons with hemophilia including pharmacokinetic-guided (PK) dosing. AIMS: In this retrospective study clinical outcomes before and after PK-guided prophylaxis were examined. MATERIALS AND METHODS: Eight Haemophilia Treatment Centres from the United States participated in the study and included 132 patients classified into two cohorts: those undergoing a PK-assessment for product switch (switchers) or to optimize treatment (non-switchers). Subset analyses for the two most common products and patients with dosing per prescription label were included for annual bleeding rates (ABR), mean weekly consumption outcomes, and annualized cost of prophylaxis. RESULTS: The most common products before and after index date were octocog alfa, rurioctocog alfa pegol, and efmoroctocog alfa. Seventy-four (56%) patients were identified as switchers and 58 (44%) patients were classified as non-switchers. The majority of patients (78.0%) experienced either a decrease in ABR post-index or maintained 0 ABR during pre- and post-index time periods, with similar proportions identified in both switchers (77.0%) and non-switchers (79.3%) populations. Non-switchers were identified as having no significant change in cost of therapy, while switchers experienced increased cost of therapy driven by higher price of extended half-life products. Within subset analyses, patients receiving rurioctocog alfa pegol and efmoroctocog alfa had mean ABR under 1 after index date. CONCLUSION: PK-guided prophylaxis has the potential to improve clinical outcomes without increase in cost of therapy for patients maintaining product and can aid in maintaining effective protection against bleeds in those switching product.

Markers of hypercoagulability in children with newly diagnosed acute lymphoblastic leukemia.

BACKGROUND: Venous thromboembolism (VTE) is a known complication for children with acute lymphoblastic leukemia (ALL). The aim of this study was to identify laboratory biomarkers that predict which children with ALL are at risk for VTE during induction chemotherapy. MATERIALS AND METHODS: Newly diagnosed ALL patients admitted to Children's Hospital Los Angeles with a central venous catheter (CVC) were eligible to participate. Participants' blood samples (complete blood count [CBC], quantitative D-dimer, prothrombin fragment 1.2 [PTF 1.2], and thrombin-antithrombin complexes [TAT]) were collected at day 0 (baseline/prior to induction), day 7 (±2 days), day 14 (±2 days), day 21 (±2 days), and day 28 (±2 days) of induction chemotherapy or until participants presented with a symptomatic VTE. RESULTS: Seventy-five participants aged 1-21 years were enrolled and included in the final analysis. Twenty-six (35%) of the 75 participants were diagnosed with a CVC-associated VTE (22 asymptomatic and four symptomatic). There was a statistically significant difference between VTE and non-VTE participants for D-dimer (odds ratio [OR] 1.61, 95% confidence interval [CI]: 1.59-1.64), TAT (OR 1.34, 95% CI: 1.32-1.38), and PTF 1.2 (OR 1.31, 95% CI: 1.25-1.37) at all time points. Participants >10 years had a significantly higher risk of developing a VTE compared to participants <4 years (p = .007). CONCLUSION: Older children with ALL as well as those with an elevated TAT, PTF 1.2, or D-dimer showed an increased risk of VTE, which may hold potential for predicting VTE in future studies.

Central Nervous System Fungal Infections in Children With Leukemia and Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Central nervous system fungal infections (CNSFI) are seen in patients with hematologic malignancies and have high morbidity and mortality. Because of their rarity, there is limited data on CNSFI in children with no established treatment protocols or guidelines. MATERIALS AND METHODS: In this multicenter retrospective study, 51 pediatric patients with leukemia, 6 of whom had undergone bone marrow transplantation, with proven or probable CNSFI were evaluated. Fungal infections were defined as proven or probable based on European Organisation for Research and Treatment of Cancer criteria. Proven CNSFI was diagnosed by appropriate central nervous system (CNS) imaging or tissue sample findings in combination with positive microbiological results of cerebrospinal fluid. A positive culture, microscopic evidence of hyphae, a positive result of the galactomannan assays are defined as positive microbiological evidence. Probable CNSFI was defined as appropriate CNS imaging findings together with proven or probable invasive fungal infections at another focus without CNS when there is no other explanatory condition. Data was collected by using the questionnaire form (Supplemental Digital Content 1, http://links.lww.com/JPHO/A541 ). RESULTS: Seventeen patients had proven, 34 patients had probable CNSFI. Headaches and seizures were the most common clinical findings. The median time between the onset of fever and diagnosis was 5 days. The most common fungal agent identified was Aspergillus . Sixteen patients received single-agent, 35 received combination antifungal therapy. Surgery was performed in 23 patients. Twenty-two patients (43%) died, 29 of the CNSFI episodes recovered with a 20% neurological sequelae. CONCLUSION: CNSFIs should be considered in the differential diagnosis in patients with leukemia and refractory/recurrent fever, headache, neurologicalocular symptoms, and a radiologic-serological evaluation should be performed immediately. Early diagnosis and prompt management, both medical and surgical, are essential for improving clinical outcomes.

Determining the approximate factor VIII level of patients with severe haemophilia A on emicizumab using in vivo global haemostasis assays.

INTRODUCTION: Emicizumab is a recombinant, humanized bispecific monoclonal antibody that mimics the function of factor VIII (FVIII) which results in a significant reduction in the annualized bleeding rate in patients with haemophilia A (HA), however, the degree with which emicizumab corrects the coagulation defect remains unclear. The objective of this study was to predict the approximate FVIII level in severe haemophilia A patients with inhibitors on emicizumab using global haemostasis assays. MATERIALS AND METHODS: Patients with moderate and mild HA in the non-bleeding state and healthy controls had FVIII levels and thrombin generation assessed. Linear regression was utilized to model the FVIII levels as a function of the thrombin generation assay parameters and to make a calibration curve of FVIII levels versus peak thrombin and endogenous thrombin potential. Patients with severe haemophilia A with inhibitors on emicizumab had thrombin generation performed in the same manner and their peak thrombin and endogenous thrombin potential results were placed on the calibration curve to calculate their FVIII Equivalency of Emicizumab by Thrombin Generation (F8EmT). RESULTS: All patients with severe HA with inhibitors on emicizumab had F8EmT >10%, suggesting they had been converted to a mild haemophilia phenotype. The patient's weight was inversely correlated to their F8EmT. CONCLUSION: The results from this study suggest that the F8EmT in patients with severe HA on emicizumab falls within the range of mild haemophilia which is consistent with the data noted in the emicizumab clinical trials and in vivo studies in animals.

Comparison of bypassing agents in patients on emicizumab using global hemostasis assays.

INTRODUCTION: Emicizumab is a humanized bispecific monoclonal antibody licensed for patients with severe haemophilia A with and without inhibitors. Management of breakthrough bleeding in patients with inhibitors on emicizumab involves episodic treatment with bypassing agents (BPA), activated prothrombin complex concentrate (aPCC) or recombinant activated factor VII (rFVIIa). Thrombotic events and thrombotic microangiopathy were reported when patients on emicizumab received concomitant aPCC at relatively high doses yet such events were not reported with rFVIIa. We studied the effect of spiking various concentrations of BPA on plasma taken from patients on emicizumab. MATERIAL AND METHODS: Eleven patients with severe haemophilia A with inhibitors who are on emicizumab were recruited to participate. Blood samples drawn from patients were spiked in vitro with varying concentrations of aPCC and rFVIIa. All samples were tested utilizing global haemostasis assays, thromboelastography and thrombin generation assay. RESULTS: Thrombin generation increased with higher concentrations of spiked BPA with a normalized endogenous thrombin potential at a concentration of 0.05 IU/ml and 4 mcg/ml for aPCC and rFVIIa, respectively. Concentrations of aPCC in the range of licensed dosing led to excessive thrombin generation. Thromboelastography was not sufficiently sensitive. CONCLUSION: Due to the known thrombotic complications when emicizumab is used in conjunction with aPCC, there has been a large-scale abandonment of the use of aPCC in patients on emicizumab. However, it is possible that aPCC can be used safely with emicizumab albeit with lower doses than are typically prescribed. It would be important to test this hypothesis in a clinical study.

Emerging drugs for hemophilia A: insights into phase II and III clinical trials.

INTRODUCTION: Hemophilia is a lifelong, genetic-bleeding disorder, which inadequately treated results in permanent joint damage. It is characterized by spontaneous and trauma-related bleeding episodes. In the last 50 years, treatment has seen dramatic improvements which have improved the quality of life of persons with hemophilia. AREAS COVERED: This review will provide a summary of current pharmacological approaches for hemophilia A as well as discuss novel agents which are either approved recently or in phase II-III clinical trials, plasma-derived and recombinant factor VIII (FVIII) products, extended half-life FVIII products, bypassing agents and non-replacement therapies. EXPERT OPINION: Novel therapies are already changing the way that hemophilia A is managed, and as more new therapies get approved, there will be a revolution in the management of this serious condition. Clinicians will have both the opportunities as well as the challenges of incorporating such new technologies into clinical practice.

Hepatosplenic Fungal Infections in Children With Leukemia-Risk Factors and Outcome: A Multicentric Study.

BACKGROUND: Invasive fungal infections, including hepatosplenic fungal infections (HSFI), cause significant morbidity and mortality in children with leukemia. There are not enough data to support for the best approach to diagnosis of HSFI in children, nor for the best treatment. PROCEDURE: In this multicentric study, we assessed the demographic data, clinical and radiologic features, treatment, and outcome of 40 children with leukemia and HSFI from 12 centers. RESULTS: All cases were radiologically diagnosed with abdominal ultrasound, which was performed at a median of 7 days, of the febrile neutropenic episode. Mucor was identified by histopathology in 1, and Candida was identified in blood cultures in 8 patients. Twenty-two had fungal infection in additional sites, mostly lungs. Nine patients died. Four received a single agent, and 36 a combination of antifungals. CONCLUSIONS: Early diagnosis of HSFI is challenging because signs and symptoms are usually nonspecific. In neutropenic children, persistent fever, back pain extending to the shoulder, widespread muscle pain, and increased serum galactomannan levels should alert clinicians. Abdominal imaging, particularly an abdominal ultrasound, which is easy to perform and available even in most resource-limited countries, should be recommended in children with prolonged neutropenic fever, even in the absence of localizing signs and symptoms.

Diagnosis and treatment of hemophilia.

Hemophilia A and B are inherited bleeding disorders characterized by deficiency or dysfunction of coagulation protein factors VIII and IX, respectively. Recurrent joint and muscle bleeds are the major clinical manifestations. Replacement therapy with clotting factors, either at the time of bleeding or as part of a prophylactic regimen, is adapted to individual patient needs. The major complication of therapy is the development of neutralizing antibodies. In response, researchers have developed novel agents to both reduce the treatment burden and prevent bleeding regardless of the presence of inhibitors. Another new development, gene therapy, has the potential for a definitive cure. This review summarizes the pathophysiology, clinical presentation, diagnosis, and treatment of hemophilia, as well as information regarding neutralizing antibodies, immune tolerance induction, novel agents, and gene therapy.

Treatment of plasminogen deficiency patients with fresh frozen plasma.

Congenital plasminogen (Plg) deficiency leads to the development of ligneous membranes on mucosal surfaces. Here, we report our experience with local and intravenous fresh frozen plasma (FFP). We retrospectively reviewed medical files of 17 patients and their eight first-degree relatives. Conjunctivitis was the main complaint. Thirteen patients were treated both with intravenous and conjunctival FFP. Venous thrombosis did not develop in any. Genetic evaluation revealed heterogeneous mutations as well as polymorphisms. Diagnosis and treatment of Plg deficiency is challenging; topical and intravenous FFP may be an alternative treatment.

Homozygous protein C deficiency presenting as neonatal purpura fulminans: management with fresh frozen plasma, low molecular weight heparin and protein C concentrate.

Purpura fulminans in neonates is a rapidly progressive thrombotic disorder manifesting as hemorrhagic skin infarction and disseminated intravascular coagulation. Being inherited in an autosomal dominant manner, it is a medical emergency. Clinical presentations of patients may vary depending on the genetic mutations. Retinal and intracranial hemorrhages are the worst clinical scenarios with persistent morbidity. During acute phase, fresh frozen plasma, protein C concentrates and anticoagulant therapy should be administered rapidly. Here we report a patient with homozygous protein C deficiency.

Sinusoidal Obstruction Syndrome During Chemotherapy of Pediatric Cancers and its Successful Management With Defibrotide.

Sinusoidal obstruction syndrome (SOS) is a life-threatening complication generally occurring after hematopoietic stem cell transplantation. SOS after standard dose chemotherapy in malignancies is rare. Between the year 1995 and 2016, 414 patients were diagnosed with acute lymphoblastic leukemia and 113 patients were diagnosed with Wilms tumor in our institution. Among these patients, 4 patients with acute lymphoblastic leukemia (0.96%) and 2 patients with Wilms tumor (1.7%) developed SOS during treatment. SOS behaves like a local disseminated intravascular coagulation. Defibrotide has proved to be effective in SOS. In this article, we report our experience with defibrotide in SOS.

Osteosarcoma After Hematopoietic Stem Cell Transplantation in Children and Adolescents: Case Report and Review of the Literature.

Osteosarcoma as a secondary malignancy after hematopoietic stem cell transplantation (HSCT) is very rare. We present a case and review of 18 other cases reported to date. Our patient underwent HSCT for myelodysplastic syndrome at the age of 4 years. She developed osteosarcoma 13 years later. She underwent surgery after three courses of neoadjuvant chemotherapy followed by chemotherapy and mifamurtide. She has no evidence of disease 28 months after termination of chemotherapy. In 18 other cases of secondary osteosarcoma in the literature, 15 had received total body irradiation, eight had received alkylating agents, and six had received etoposide. The median interval from HSCT to the onset of osteosarcoma was 6.5 years (range 2.5-15.3), which confirms that children undergoing HSCT should be followed up for many years. In conclusion, osteosarcoma must be included in the differential diagnosis among solid tumors that may develop following HSCT.

Neutralizing antidrug antibody to emicizumab in patients with severe hemophilia A: Case report of a first noninhibitor patient and review of the literature.

Background: Hemophilia A (HA) is a genetic bleeding disorder characterized by the deficiency of the coagulation protein factor (F) VIII (FVIII). The development of neutralizing antidrug antibodies (ADAs) to factor concentrates (inhibitors) created an unmet need for novel therapies. The first agent to address this need is emicizumab. Key Clinical Question: Can emicizumab ADA occur in patients with HA without FVIII inhibitors? Clinical Approach: A new case (the first in a noninhibitor patient) presented with unexpected and excessive bleeding and a prolonged activated partial thromboplastin time. The patient was evaluated by assessing FVIII levels, and the previously published modified version of the Bethesda assay was used to determine the level of ADA to emicizumab. Conclusion: Although emicizumab is very effective and has minimal immunogenicity, ADAs, albeit rare, can still occur. There have been 4 previously published anti-emicizumab ADA cases with severe HA with inhibitors, and herein, we describe 1 new case with severe HA without inhibitors.

Successful outcome of mucormycosis in a child with acute lymphoblastic leukemia.

Invasive fungal infections may cause morbidity and mortality in pediatric patients with hematologic and oncologic malignancies treated with intensive protocols. We present a case of mucormycosis in an 8-year-old boy with acute lymphoblastic leukemia. In our patient, the suspicion for an oculoorbital and paranasal infection only due to mild pain in the orbital area without any abnormal pathologic findings in the ophthalmologic and otolaryngologic examination, led us to an early diagnosis. Despite the use of antifungal therapy, the lesion persisted and fever subsided after surgical drainage of the periorbital abscess. Antifungal treatment continued during chemotherapy. He has been in remission for four years. Mucormycosis should be in the differential diagnosis in infections in children with cancer, especially leukemia, according to clinical and radiologic findings. A high degree of suspicion and prompt systemic empirical antifungal therapy, as well as surgical debridement, are crucial for the survival of patients. Beside antifungals, early surgery plays an important role in patients with mucormycosis.

Neutralizing antidrug antibody to emicizumab in a patient with severe hemophilia A with inhibitors: New case with detailed laboratory evaluation.

Hemophilia A is an inherited bleeding disorder characterized by deficiency of the coagulation protein factor VIII. Development of clotting factor concentrates has resulted in an excellent prognosis for this historically fatal disease. However, neutralizing antidrug antibodies to factor concentrates can develop, complicating management and worsening the prognosis, and thus creating an unmet need for novel therapies. One such agent is emicizumab, a bispecific monoclonal antibody which mimics the function of factor VIII. Collectively across the HAVEN clinical trial program, the rate of antidrug antibodies with neutralizing potential was 0.75%. Since its licensure, there have been no further reports of such antibodies, despite its use in thousands of patients. In this report, we describe a patient with severe hemophilia A with inhibitors who developed a neutralizing antidrug antibody to emicizumab, for whom we performed extensive testing in the special coagulation laboratory.

Late Effects of Therapy in Childhood Acute Lymphoblastic Leukemia Survivors

Over the last 50 years, the survival rates in children with acute lymphoblastic leukemia (ALL) have increased remarkably. The optimal use of antileukemic agents in cooperative group protocols, central nervous system-directed treatment, improvements in supportive care, and recognition of biological, clinical, and treatment response characteristics that predict patients with a higher or a lower risk of treatment failure have improved 5-year event-free survival rates, reaching more than 85%, and 5-year overall survival rates, reaching more than 90%. Consequently, it has become increasingly important to characterize the occurrence of long-term late effects. ALL treatments have been associated with increased risks for adverse outcomes such as late mortality, secondary malignancies, and neurological, cardiac, endocrine, and social/psychological disorders. In recent decades, cooperative groups in Europe and in the United States have provided essential information about the long-term effects of ALL therapy, giving recommendations for screening as well as facilitating new approaches for reducing late-term morbidity and mortality. Current frontline protocols continue to examine ways to lower the intensity and amount of therapy to reduce late effects, whereas survivorship studies attempt to predict such adverse effects precisely and develop targeted prevention and treatment strategies.

Seroprevalence of Hepatitis B, Hepatitis C, and HIV in children with cancer at diagnosis and following therapy in Turkey: progress within the last 25 years.

AIM: Children with cancer receiving intensive chemotherapy require multiple transfusions and are at increased risk for blood transmittable diseases such as hepatitis B virus (HBV), hepatitis C virus (HBC), and HIV infections. The aim of this study was to investigate the seroprevalence of HBV, HCV, and HIV in children with cancer and to compare the results with findings in our previous cancer studies conducted before the national free HBV vaccination and the HCV screening program in blood banks were established. MATERIAL AND METHODS: Sera from 100 children (51 females, 49 males) with cancer treated between January 2010 and January 2012 who received multiple transfusions were investigated for hepatitis B surface antigen (HBsAg), anti-HBs, anti-HCV, anti-HIV at diagnosis and at the end of treatment. Patients were born after 1998 when the national free hepatitis B vaccination program began. RESULTS: HBsAg, anti-HCV, and anti-HIV seropositivities were 0% at diagnosis and at the end of treatment. Anti-HBs seropositivity was 58% at diagnosis and 42% at the end of treatment. HBsAg seropositivity, which was 0% at the end of treatment, was lower than 10% during 1994-95, and 40% from 1986 to 1989. Anti-HCV was 0% in contrast to 14% between 1994 and 1995. Seventeen patients with anti-HBs seropositivity at diagnosis were found to be seronegative after intensive chemotherapy. CONCLUSION: The nil seroprevalence of anti-HBsAg, anti-HCV, and anti-HIV in this cohort of children with cancer is encouraging. This progress is due to advances in donor screening techniques in blood banks, good hygenic practices, and the national free hepatitis B vaccination program in Turkey.

AMAÇ: Çocukluk çagi kanserlerinde yogun kemoterapi sonrasi kan transfüzyonu gerekliligi artmakta ve buna bagli olarak hepatit B, hepatit C ve HIV gibi enfektif hastaliklarin bulasma olasiligi olusmaktadir. Bu çalismanin amaci çocukluk çagi kanserlerinde hepatit B, hepatit C ve HIV seroprevalansini incelemek ve bu sonuçlari ulusal Hepatit B asilamasi baslamadan önceki ve kan bankalarinda rutin hepatit C virüs (HCV) tarama programlari olmadigi dönemki çalismalarla karsilastirmaktir. GEREÇ VE YÖNTEMLER: Ocak 2010­Ocak 2012 arasi kanser tedavisi gören ve çoklu kereler kan transfüzyonu alan 100 olguda (51 kiz, 49 erkek) tanida ve tedavi sonrasi HBsAg, anti-HBs, anti-HCV ve anti-HIV çalisildi. Hastalarimiz 1998 ve sonrasi dogumlu olup, ayni yil baslatilan ulusal hepatit B asi programina dahil idiler. BULGULAR: HBsAg, anti-HCV ve anti-HIV seropozitifitesi tanida ve tedavi sonu %0 saptandi. Anti-HbS seropozitivitesi tani aninda %58 iken, tedavi sonunda %42 idi. HBsAg seropozitifitesi tedavi sonunda 1986­89'da %40, 1994­95'te %10 iken son çalismamizda %0 olarak bulunarak anlamli fark gösterdi. Anti-HCV ise 1994­95'te saptanan %14'e oranla %0 bulundu. Tanida Anti-HBs'si pozitif olan 17 hastanin kemoterapi sonrasi Anti-HBs'leri negatiflesmesine ragmen hiçbirinde HBV enfeksiyonu gelismedi. ÇIKARIMLAR: Bu sonucun elde edilmesinde en önemli etkenler kan bankalarindaki donör tarama tekniklerinde gelisme, hijyen kosullarinin iyilesmesi ve ulusal ücretsiz hepatit B asi programi olarak düsünülebilir. Bu sonuç, gelismekte olan ülkeler için yol gösterici olacaktir.

Management of perioperative hemostasis in a severe hemophilia A patient with inhibitors on emicizumab using global hemostasis assays.

BACKGROUND: Patients with severe hemophilia A and inhibitors are at risk of bleeding during invasive procedures. The standard of care for preventing perioperative bleeding has been replacement therapy with FVIII concentrates or for patients with high-titer inhibitors, bypassing agents. However, there is no consensus on the appropriate management of surgery in patients receiving the novel agent emicizumab. The aim of this study was to demonstrate a case of a patient on emicizumab undergoing major surgery with bypassing agents with preoperative use of the thrombin generation assay (TGA) and thromboelastography (TEG). METHODS: We report a patient with hemophilia A with inhibitors who had undergone a total knee replacement while on emicizumab combined with a bypassing agent. We utilized TEG and TGA to determine which bypassing agent to choose as well as to inform about the ideal dose. RESULTS: We elected to use recombinant FVIIa as a bypassing agent for the surgery based upon the TGA results. CONCLUSION: The TGA can be utilized to support decision-making in patients on emicizumab undergoing major surgery to both predict efficacy and potentially minimize the risk of thrombotic events.