Effectiveness and safety of interferon α-2a combined with phototherapy for patients with early-stage mycosis fungoides - a single-arm prospective study in 13 patients.

Background: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma.Objectives: This study was conducted to evaluate efficacy and safety of interferon (IFN) α-2a combined with phototherapy for early-stage MF.Methods: Thirteen patients with early-stage MF received subcutaneous injections of IFN α-2a at 3 million IU combined with phototherapy three times per week for 6 months. Treatment efficacy was measured by changes in body surface area (BSA) score and modified severity-weighted assessment tool (mSWAT) score at 1, 3, and 6 months after treatment. Histopathologic examinations of skin lesions were performed before and after treatment.Results: After 3 months of treatment, all 13 patients achieved a partial response, and BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001). After 6 months, BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001) and after 3 months (p < 0.05). Eleven patients achieved complete remission and two patients achieved a partial response (overall response rate, 100%). Histopathologic examination showed a significant decrease in the number of atypical lymphocytes in both epidermis and dermis. No severe adverse effects occurred.Conclusion: IFN α-2a in combination with phototherapy may be an effective and safe alternative modality for early-stage MF.

Aortitis after switching short-acting granulocyte colony-stimulating factors in a lymphoma patient with HLA-B52.

Aortitis is a rare adverse event of granulocyte colony-stimulating factor (G-CSF) treatment. Several previous studies have described recurrent aortitis caused by re-administration of the same G-CSF. However, no previous studies have examined the safety of switching between short-acting G-CSFs in patients who develop aortitis. We report the case of a 55-year-old man with refractory diffuse large B-cell lymphoma, who developed G-CSF-associated aortitis. The aortitis was triggered by filgrastim and recurred after treatment with lenograstim. The patient possessed human leukocyte antigen B52, which has been implicated in Takayasu arteritis. In addition, a drug-induced lymphocyte stimulation test for lenograstim performed upon detection of recurrent G-CSF-associated aortitis produced a positive result. Our case suggests that switching from one short-acting G-CSF to another does not prevent recurrence of G-CSF-associated aortitis. Although the etiology of G-CSF-associated aortitis has not been fully elucidated, our case also suggests that some patients may be genetically predisposed to aortitis.

Safety and Effectiveness of a Biosimilar Recombinant Human Growth Hormone in Children Requiring Growth Hormone Treatment: Analysis of Final Data from PATRO Children, an International, Post-Marketing Surveillance Study.

Purpose: Omnitrope® (somatropin) was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. Here, we report final data from the PAtients TReated with Omnitrope® (PATRO) Children study, a post-marketing surveillance study designed to monitor the long-term safety and effectiveness of this treatment in pediatric patients. Methods: The study population included all pediatric patients treated with Omnitrope® (biosimilar rhGH), administered via daily injection, in routine clinical practice. The primary objective was to assess long-term safety, with effectiveness assessed as a secondary objective. Results: In total, 7359 patients were enrolled and treated in the PATRO Children study; 86.0% were treatment-naïve at baseline. Growth hormone deficiency was the most frequent indication (57.9%), followed by patients born small for gestational age (SGA; 26.6%). The mean (SD) duration of exposure to biosimilar rhGH was 3.66 years (2.39). A total of 16,628 adverse events (AEs) were reported in 3981 (54.1%) patients, most of which were mild/moderate. AEs suspected to be treatment related occurred in 8.3% of patients, most frequently headache (1.6%), injection-site pain (1.1%), or injection-site hematoma (1.1%). The incidence rate (IR) of type 2 diabetes mellitus was 0.11 per 1000 person-years (PY) across all patients, and 0.13 per 1000 PY in patients born SGA. The IR of newly diagnosed primary malignancies was 0.22 per 1000 PY across all patients. In the 6589 patients included in the effectiveness population, a sustained catch-up growth was observed across all indications. After 5 years of treatment, height SDS increased from baseline by a median (range) of +1.79 (-3.7 to 6.2) in treatment-naïve patients and +0.73 (-1.4 to 3.7) in pretreated patients. Conclusion: This final analysis of the PATRO Children study indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice. These data are consistent with the well-characterized safety profile of rhGH treatment in pediatric patients.

Andexanet Alfa: What We Have Learned from Clinical Trials and Real-World Data.

Andexanet alfa is a specific reversal agent for factor Xa inhibitors with immediate reversal of their anticoagulant effect. Andexanet alfa is currently approved for use in patients treated with rivaroxaban and apixaban who have life-threatening or uncontrolled bleeding. New data from both controlled clinical trials and real-world experience are continuously being published, providing greater insight into the clinical characteristics of the drug, such as efficacy and safety. It is worth considering that andexanet alfa could be of benefit in a variety of different clinical scenarios where patients receiving treatment with apixaban and rivaroxaban (and endoxaban) have life-threatening conditions. These different clinical scenarios, which range from pre-treatment of urgent surgery, especially neurosurgical interventions, and concomitant use of andexanet alfa and prothrombin complex concentrate to onset of bleeding more than 6 h prior to admission, should be clarified as well as the issue of "low/high" dose of andexanet alfa and the need for baseline anti-Xa inhibitor levels measured by point-of-care testing. Finally, management of patients at high risk of thrombosis or recent arterial/venous thrombotic events needs to be further explored. In this current opinion, we address these urgent questions in the light of recent literature and clinical trial data.

Subcutaneous panniculitic-like T-cell lymphoma localized to a site of peginterferon alfa-2a administration.

T cell dyscrasias that demonstrate a proclivity for the subcutaneous fat include atypical lymphocytic lobular panniculitis, lupus profundus, and primary subcutaneous T cell lymphoma, including subcutaneous panniculitis-like T cell lymphoma (SPTCL). We encountered two patients who developed fever and indurated abdominal erythema at their peginterferon alfa-2a injection sites. Biopsies showed an atypical CD8 positive, granzyme positive, CD5 negative, MXA negative lymphocytic lobular panniculitis, diagnostic of SPTCL. Peginterferon alfa-2a was held in both patients. One patient received chemotherapy with an excellent response, while the other continued to have progressive disease. Peginterferon alfa-2a is known to significantly elevate serum MXA, which may induce high levels of MXA expression at the injection site, creating a microenvironment for the development of lupus profundus, which may eventuate into SPTCL. In summation, a potential risk of peginterferon alfa-2a injections is the development of SPTCL potentially arising in a background of an exogenous interferon triggered lymphocytic panniculitis.

A post hoc analysis of previously untreated patients with severe hemophilia A who developed inhibitors in the PUPs A-LONG trial.

ABSTRACT: Inhibitor development is a major therapeutic complication for people with hemophilia. The phase 3 PUPs A-LONG study evaluated the safety and efficacy of efmoroctocog alfa (a recombinant factor VIII Fc fusion protein, herein referred to as rFVIIIFc) in previously untreated patients (PUPs) with severe hemophilia A. Male PUPs <6 years old were enrolled and received rFVIIIFc; inhibitor development was the primary end point. Post hoc analyses, including patient treatment regimen patterns and timing of inhibitor development, descriptive and Kaplan-Meier analyses of time to first inhibitor-positive test by treatment regimen and by titer, and consumption, were performed to describe patients who developed inhibitors during PUPs A-LONG. We investigated patient characteristics (eg, demographics and genotype) and nongenetic risk factors (eg, intense factor exposure and central venous access device [CVAD] placement) that may predict inhibitor development and characteristics of inhibitor development (low-titer vs high-titer inhibitor). Baseline characteristics were similarly distributed for age, race, and ethnicity across both patients who were inhibitor-positive and those who were inhibitor-negative (all P > .05). High-risk F8 variants were associated with development of high-titer inhibitors (P = .028). High-titer inhibitor development was often preceded by the presence of a low-titer inhibitor. Patients whose low-titer inhibitor progressed to a high-titer inhibitor received a higher mean dose per infusion (98.4 IU/kg, n = 5) compared with those whose low-titer inhibitor resolved spontaneously (59.2 IU/kg, n = 7; P = .033) or persisted (45.0 IU/kg, n = 5; P = .047). There was no association between CVAD placement surgery and inhibitor development. Post hoc analyses suggest that F8 genotype and dose of factor are as important as inhibitor risk factors and require further investigation. This study was registered at ClinicalTrials.gov as #NCT02234323.

A systematic review and meta-analysis of recombinant human soluble thrombomodulin for the treatment of DIC associated with hematological malignancies.

BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) is commonly used in Japan to treat disseminated intravascular coagulation (DIC), but its efficacy compared with other anticoagulants is unclear. We conducted a systematic review and meta-analysis to investigate this issue in DIC patients with hematological malignancies. METHODS: We searched PubMed, Cochrane, and Scopus for prospective and retrospective studies evaluating the efficacy and safety of rhTM in DIC patients with hematological malignancies between April 2008 and April 2023. We performed a systematic review and meta-analysis evaluating recovery from DIC, hemorrhagic adverse events (AEs), and overall survival (OS). RESULTS: We analyzed one prospective (64 patients) and seven retrospective studies (209 patients). Use of rhTM was associated with a higher rate of recovery from DIC (OR: 2.25 [1.09-4.63] and 1.98 [1.12-3.50] in prospective and retrospective studies, respectively; same order below) and fewer hemorrhagic AEs (OR: 0.83 [0.30-2.30] and 0.21 [0.08-0.57]). rhTM did not improve OS (OR: 1.06 [0.42-2.66] and 1.72 [0.87-3.39]), although the incidence of hemorrhagic death was lower in the rhTM group (0 of 94 patients). CONCLUSION: Use of rhTM in patients with hematological malignancy-associated DIC is strongly expected to be effective and safe.

Four-factor prothrombin complex concentrate versus andexanet alfa for direct oral anticoagulant reversal.

BACKGROUND: Optimal reversal agent for direct oral anticoagulant (DOAC)-associated major bleeding has not been described. Before the approval of andexanet alfa (AA) in 2018, 4-factor prothrombin complex concentrate (4F-PCC) was recommended by major guidelines. Currently, AA is recommended as the first-line agent by most guidelines. With a paucity of literature comparing the 2 agents, there is clinical value in assessing hemostatic efficacy and safety of the 2 agents. OBJECTIVE: This study aimed to evaluate hemostatic efficacy and safety of AA and 4F-PCC in all DOAC-associated major bleedings. METHODS: A multicenter, retrospective chart review was performed of adult subjects who were admitted for a DOAC-associated major bleeding and received 4F-PCC from February 2018 to May 2019 or AA from May 2019 to September 2021. Some of the exclusion criteria included not receiving a DOAC, receiving multiple reversal agents during the same hospitalization, receiving reversal for any nonmajor bleeding indication, and not receiving the full dose of a reversal agent. The primary outcome was hemostatic efficacy 24 hours after the end of the reversal agent administration. Secondary outcomes included time to administration, hospital mortality, length of stay, need for surgery, and need for additional blood product. Safety outcome was incidence of thrombotic events. RESULTS: There were 99 subjects included in the 4F-PCC group and 84 subjects in the AA group. Hemostatic efficacy was achieved in 69 subjects (69.7%) in the 4F-PCC group and 63 subjects (75%) in the AA group (P = 0.927). In-hospital mortality was seen in 20 subjects (20.2%) in the 4F-PCC group and 10 subjects (11.9%) in the AA group. Thrombotic events were seen in 7 subjects (7.1%) in the 4F-PCC group and 6 subjects (7.1%) in the AA group. CONCLUSIONS: There were no significant differences in hemostatic efficacy, in-hospital mortality, and number of thrombotic events between 4F-PCC and AA.

Meta-Analysis on Efficacy and Complications of Bone Morphogenetic Protein-2 for Posterior Fusion of Cervical Spine.

OBJECTIVE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is effective for promoting robust fusion for long-level cervical deformity and revision surgeries. However, only a few studies have reported its efficacy and complications in posterior cervical fusion (PCF). METHODS: Therefore we evaluated the efficacy and complications of rhBMP-2 application in PCF surgery by searching 3 electronic databases (PubMed, Cochrane Database, and EMBASE) for studies that evaluated the use of rhBMP-2 in PCF. Five studies (1 prospective and 4 retrospective) were included in the meta-analysis. RESULTS: The quality of each study was assessed, and data on pseudarthrosis, wound infection, neurologic, and immediate medical complications were extracted and analyzed. We found that the use of rhBMP-2 in PCF showed significant benefits in terms of pseudarthrosis and no significant increases in the risk for neurologic and immediate medical complications regardless of the dose. However, high-dose (>2.1 mg/level) rhBMP-2 was a risk factor for wound infection after PCF. CONCLUSIONS: Our meta-analysis of the currently available literature suggests that patients with PCF may benefit from BMP-2 usage without increasing the risk of complications. However, dose control and containment are important to ensure a low risk of complications.

Efficacy and Safety of Single-dose Pegfilgrastim for CD34 + Cell Mobilization in Healthy Volunteers: A Phase 2 Study.

BACKGROUND: Pegfilgrastim, a long-acting form of granulocyte-colony stimulating factor, with a convenient single-injection dosage, is being investigated for peripheral blood stem cell (PBSC) mobilization in healthy volunteers. However, data on the adequate dose of pegfilgrastim for PBSC mobilization are limited. This phase 2, single-arm study evaluated the efficacy and safety of pegfilgrastim for PBSC mobilization in healthy volunteers. METHODS: The study comprised 2 phases: pilot (steps 1-3, dose escalation, a single subcutaneous dose of 3.6, 7.2, and 10.8 mg pegfilgrastim, respectively) and evaluation (step 4, efficacy and safety assessments). The primary endpoint was the proportion of subjects who achieved mobilization of ≥20 × 10 6 /L cluster of differentiation 34 positive (CD34 + ) cells. RESULTS: Thirty-five subjects (6 each in steps 1 and 2 and 23 in step 4) were included. In the pilot phase, step 3 with a 10.8 mg dose was not conducted due to favorable outcomes in step 2 (desired CD34 + cell count), at 7.2 mg pegfilgrastim, which was identified as the optimal dose for the evaluation phase. In the evaluation phase, successful CD34 + mobilization was achieved in all 23 subjects. The mean peripheral blood CD34 + cells count peaked on day 5. Back pain, thrombocytopenia, transient elevations of alkaline phosphatase, and lactate dehydrogenase were the most common adverse events. All adverse events were mild, and none led to study discontinuation. CONCLUSIONS: A single-dose pegfilgrastim successfully mobilized an optimal number of CD34 + cells and was well tolerated. Pegfilgrastim could be an alternative option for PBSC mobilization in healthy volunteers. The trial was registered at www.clinicaltrials.gov (NCT03993639).

Intraoperative Bivalirudin Use in Patient Undergoing Femoral Endarterectomy with Heparin-Induced Thrombocytopenia: Case Report and Review of the Literature.

PURPOSE: To describe the intraoperative use of bivalirudin during lower extremity revascularization in the setting of heparin-induced thrombocytopenia (HIT). CASE SUMMARY: A 65 year-old man presented with left common iliac, external iliac, and femoral artery occlusion necessitating revascularization with left femoral endarterectomy and common and external iliac stent angioplasty. Three months before the femoral endarterectomy, the patient was hospitalized for a coronary artery bypass procedure. During this admission, the patient tested positive for the presence of heparin-PF4 antibody complexes. With the patient's recent history of HIT, bivalirudin was selected as the optimal agent for intraoperative anticoagulation. Bivalirudin was administered as a 50 mg bolus, followed by a continuous infusion initiated at 1.75 mg/kg/hr. Repeated bivalirudin boluses were necessary to maintain an activated clotting time (ACT) necessary for the revascularization procedures and recurrent subacute thrombi despite appropriate ACT values. DISCUSSION: Bivalirudin has been utilized for cardiopulmonary bypass and carotid endarterectomy (CEA), but data for dosing in lower extremity revascularization are lacking. As the risk for thrombosis with HIT continues for months after diagnosis, it is important to elucidate optimal dosing of non-heparin anticoagulant options, such as the direct thrombin inhibitor, bivalirudin. The absence of validated dosing strategies for bivalirudin can result in prolonged operative times, increased risk of bleeding, and inadequate anticoagulation. CONCLUSION: Bivalirudin is an appropriate agent for intraoperative anticoagulation in lower extremity revascularization. However, further investigation into the optimal intraoperative bivalirudin dosing regimen is necessary.

Recombinant erythropoietin in autoimmune hemolytic anemia with inadequate bone marrow response: a prospective analysis.

ABSTRACT: Up to 30% of patients with autoimmune hemolytic anemia (AIHA) show inadequate bone marrow (BM) compensatory response with inappropriately low levels of reticulocytes and endogenous erythropoietin. Ineffective BM compensation is associated with more severe anemia, transfusion need, and hospital admission, and treatment with recombinant erythropoietin (rEPO) may be beneficial. Here, we prospectively analyzed the efficacy and safety of rEPO in a single-center cohort of 47 patients with AIHA with inadequate reticulocytosis and endogenous erythropoietin at baseline. Epoetin alpha 40 000 international units per week were administered subcutaneously until hemoglobin (Hb) >11 g/dL and then tapered off. Overall response was 55% at 15 days, 74% at 1 month, 74% at 3 months, 80% at 6 months, and 91% at 12 months. Consistently, Hb values significantly increased from baseline to each subsequent time point (P<.001) with a median increase of +1.4, +2.4, +3.4, +3.8, and +4.4 g/dL, respectively. Transfusion needs reduced from 30% to <10% at 15 days and thereafter (P < .001). Concomitant medications included prednisone or methylprednisolone (N = 40, stable since >2 weeks from enrollment), mycophenolate mofetil (N = 1, ongoing since >3 months from enrollment), and rituximab (N = 7 patients with cold agglutinin disease from day 8). No association between concomitant medications and response to rEPO was found. Treatment was generally safe without rEPO-related severe adverse events. The comparison with an AIHA population not treated with rEPO showed a significant benefit of rEPO at 15 days and 1 month on response and Hb increase. These data support the use of rEPO as an add on to standard immunosuppression in AIHA with inadequate BM compensation. This trial was registered at www.clinicaltrials.gov as #NCT05931718.

High- vs regular-dose recombinant human thrombopoietin plus cyclosporine A in patients with newly diagnosed non-severe aplastic anemia: a retrospective cohort study.

BACKGROUND: Cyclosporine A (CsA) and regular doses of recombinant human thrombopoietin (rhTPO) can accelerate platelet recovery in patients with non-severe aplastic anemia (NSAA). However, it is unclear whether CsA plus rhTPO at a higher dose can further increase the efficacy. METHODS: Data from patients with newly diagnosed NSAA, who had been treated with CsA in combination with different doses of rhTPO between February 2021 and August 2021 at Peking Union Medical College Hospital, were reviewed. All the enrolled patients had been treated with CsA at 3-5 mg/(kg/d), and patients were further classified into high-dose (with rhTPO 30000U qd × 14 days for 2 months) group or regular-dose (with rhTPO 15000U qd × 7days for 3 months) group. The treatment response and therapy-related adverse events were compared. RESULTS: 36 patients including 16 (44.4%) in the high-dose and 20 (55.6%) in the regular-dose group were enrolled. The baseline characteristics were compatible between the two groups. The platelet counts were significantly higher at 1/3/6 months in the high-dose group (p = 0.028, 0.0063 and p = 0.040, respectively). The high-dose group had a significantly shorter time to platelet transfusion independence ([1 (0.5-6) months vs 2.5 (1-12) months, p = 0.040]). There was no significant difference in overall response and complete response rate between the two groups at 1/3/6/12 months (p > 0.05). Treatment-related morbidities were similar between the two groups (p > 0.05). CONCLUSIONS: Adding a higher dose of rhTPO can further accelerate platelet recovery and platelet transfusion independence in patients with newly diagnosed NSAA.

Retrospective Comparison of Recombinant Activated Factor VII Versus 4-Factor Prothrombin Complex Concentrate in Cardiac Surgical Patients.

OBJECTIVES: To compare the incidences of postoperative thrombotic complications, transfusion of blood products, and chest tube output in congenital cardiac surgical patients who received either recombinant activated factor VII (rFVIIa) or 4-factor prothrombin complex concentrate (4F-PCC). DESIGN: We performed a retrospective study. SETTING: Patients who underwent surgery at a tertiary academic hospital. PARTICIPANTS: Pediatric patients who underwent cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were obtained from the Society of Thoracic Surgeons and the Pediatric Cardiac Critical Care Consortium databases, as well as from manual chart review. Adjusted p values were obtained from multivariate regression using age (days), surgeon (number), cardiopulmonary bypass time (minutes), and need for deep hypothermic circulatory arrest (yes/no). A total of 55 patients were included in the 4F-PCC group, and 89 in the rFVIIa group. The median dose of rFVIIa was 77 mcg/kg (46-88), and the median dose of 4F-PCC was 31 IU/kg (24-43). The incidences of thrombotic complications were 8% in the 4F-PCC group and 30% in the rFVIIa group (adjusted p = 0.023). No difference was reported between the groups regarding chest tube output on days 1 and 2 or transfusion of blood products. Using a sensitivity analysis with propensity matching, the incidence of thrombosis was 10% in the 4F-PCC group (n = 38), and 31% in the rFVIIa group (n = 39) (p = 0.036). No difference was reported in terms of bleeding or transfusion. CONCLUSIONS: This retrospective study suggested that the administration of rFVIIa was associated with a higher risk of thrombotic complications when compared to 4F-PCC, without benefits in terms of bleeding and transfusions.

Impact of Recombinant Granulocyte Colony-Stimulating Factor During Neoadjuvant Therapy on Outcomes of Resected Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. The granulocyte colony-stimulating factor (G-CSF)-neutrophil axis promotes oncogenesis and progression of PDAC. Despite frequent use of recombinant G-CSF in the management and prevention of chemotherapy-induced neutropenia, its impact on oncologic outcomes of patients with resected PDAC is unclear. PATIENTS AND METHODS: This cohort study assessing the impact of G-CSF administration was conducted on 351 patients with PDAC treated with neoadjuvant therapy (NAT) and pancreatic resection at a high-volume tertiary care academic center from 2014 to 2019. Participants were identified from a prospectively maintained database and had a median follow-up of 45.8 months. RESULTS: Patients receiving G-CSF (n=138; 39.3%) were younger (64.0 vs 66.7 years; P=.008), had lower body mass index (26.5 vs 27.9; P=.021), and were more likely to receive 5-FU-based chemotherapy (42.0% vs 28.2%; P<.0001). No differences were observed in baseline or clinical tumor staging. Patients receiving G-CSF were more likely to have an elevated (>5.53) post-NAT neutrophil-to-lymphocyte ratio (45.0% vs 29.6%; P=.004). G-CSF recipients also demonstrated higher circulating levels of neutrophil extracellular traps (+709 vs -619 pg/mL; P=.006). On multivariate analysis, G-CSF treatment was associated with perineural invasion (hazard ratio [HR], 2.65; 95% CI, 1.16-6.03; P=.021) and margin-positive resection (HR, 1.67; 95% CI, 1.01-2.77; P=.046). Patients receiving G-CSF had decreased overall survival (OS) compared with nonrecipients (median OS, 29.2 vs 38.7 months; P=.001). G-CSF administration was a negative independent predictor of OS (HR, 2.02; 95% CI, 1.45-2.79; P<.0001). In the inverse probability weighted analysis of 301 matched patients, neoadjuvant G-CSF administration was associated with reduced OS. CONCLUSIONS: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration may be associated with worse oncologic outcomes and should be further evaluated.

Efbemalenograstim alfa, an Fc fusion protein, long-acting granulocyte-colony stimulating factor for reducing the risk of febrile neutropenia following chemotherapy: results of a phase III trial.

PURPOSE: Evaluate the safety and efficacy of efbemalenograstim alfa for reducing the risk of febrile neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy. METHODS: A phase III, randomized, double-blind, placebo-controlled study was conducted. A total of 122 subjects received up to 4 cycles of TA chemotherapy (75 mg/m2 docetaxel + 60 mg/m2 doxorubicin). Patients were randomized in a 2:1 ratio to subcutaneously inject a single 20 mg of efbemalenograstim alfa or placebo on day 2 of cycle 1, and all subjects received efbemalenograstim alfa on day 2 of cycles 2, 3, and 4. Duration of severe (grade 4) neutropenia (DSN), depth of neutrophil nadir, incidence of febrile neutropenia (FN), time to neutrophil recovery, and safety information were recorded. RESULTS: For the primary endpoint, the mean DSN in cycle 1 was 1.3 days and 3.9 days for efbemalenograstim alfa and placebo respectively (95% CI, 2.3, 3.4). As the lower bound of the 95% CI was > 0, superiority of efbemalenograstim alfa over placebo can be declared. In addition, the incidence of FN in Cycle 1 was lower in efbemalenograstim alfa group than in placebo group (4.8% vs. 25.6%; p = 0.0016). Patients in the efbemalenograstim alfa group required less intravenous antibiotics (3.6% vs. 17.9%; p = 0.0119). Most adverse events were consistent with those expected for breast cancer patient receiving TA chemotherapy. CONCLUSION: Efbemalenograstim alfa is effective and safe for significantly decreasing the duration of severe neutropenia and the incidence of febrile neutropenia in breast cancer patients who are receiving TA chemotherapy. TRIAL REGISTRATION: NCT02872103, August 19, 2016.

Safety of long-term use of daily and long-acting growth hormone in growth hormone-deficient adults on cancer risk.

Daily injections of recombinant human growth hormone (rhGH) have been used in clinical practice for almost four decades as a replacement therapy in adult patients with GH deficiency (GHD). Long-term adherence to daily injections of rhGH is a clinical concern that may result in reduced therapeutic efficacy, and long-acting GH (LAGH) formulations have been developed in an attempt of overcoming this problem. Long-term safety issues of rhGH are the other side of the coin that has been carefully monitored over the years, particularly related to the proliferative actions of GH that could increase the risk of tumor recurrence or induce the development of new benign and malignant tumors. In this review, we present what is currently known about the cancer risk in GHD adults treated with daily rhGH injections and we discuss the major concerns and responses needed from future surveillance studies regarding the safety of LAGH preparations.

Long-term safety and efficacy of pegunigalsidase alfa: A multicenter 6-year study in adult patients with Fabry disease.

PURPOSE: Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD. METHODS: In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks. RESULTS: Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed. CONCLUSION: In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD.

Efficacy and safety of PEG-rhG-CSF versus rhG-CSF in preventing chemotherapy-induced-neutropenia in early-stage breast cancer patients.

BACKGROUND: To compare the clinical value of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and pegylated rhG-CSF(PEG-rhG-CSF) in early-stage breast cancer (EBC) patients receiving adjuvant chemotherapy, compare the efficacy of PEG-rhG-CSF with different dose and explore the timing of rhG-CSF rescue treatment. METHODS: Patients in two PEG-rhG-CSF subgroups were given 3 mg or 6 mg PEG-rhG-CSF within 24 ~ 48 h after chemotherapy for preventing myelosuppression, while patients in the rhG-CSF group were given rhG-CSF. Observation indicators include the incidence of febrile neutropenia (FN) and grade 3/4 chemotherapy-induced-neutropenia (CIN), the overall levels and nadir values of white blood cells (WBC) and absolute neutrophil count (ANC), comparison of WBC and ANC curves over time, the incidence of CIN-related complications, the incidence of adverse events in each group and the timing of rescue treatment for rhG-CSF. RESULTS: There was no significant difference in the incidence of FN in the first cycle among the groups (P = 0.203). But the incidence of ≥ 3 grade CIN in two PEG-rhG-CSF subgroups was significantly lower than that in the rhG-CSF group (P < 0.001). The overall WBC and ANC levels in the PEG-rhG-CSF group were significantly higher than those in the rhG-CSF group (P < 0.001). In terms of CIN-related complications, less chemotherapy delay rate (1.1 vs. 7.5%, P = 0.092), less dose reduction rate (6.9 vs. 7.5%, P = 1.000), less antibiotic use rate (3.4 vs. 17.5%, P = 0.011) and less proportion of rhG-CSF rescue therapy (24.1 vs. 85.0%, P < 0.001) in the PEG-rhG-CSF group, and there were no significant differences between PEG-rhG-CSF subgroups. In the incidence of adverse events among the groups, there were no statistical differences. All patients undergoing rhG-CSF rescue treatment were mainly 4 grade (63.6%) and 3 grade (25.5%) CIN, and 10.9% of patients with 1 ~ 2 grade CIN who had high infection risk or had been infected. CONCLUSION: PEG-rhG-CSF has better efficacy and equal tolerance compared with rhG-CSF in preventing CIN in EBC patients receiving EC regimen. Moreover, a half-dose 3 mg PEG-rhG-CSF also had good efficacy. Last, patients with ≥ 3 grade CIN and others who have been assessed to be at high risk of infection or have co-infection should consider rhG-CSF or even antibiotic rescue treatment.

Safety and efficacy of zinpentraxin alfa as monotherapy or in combination with ruxolitinib in myelofibrosis: stage I of a phase II trial.

Pentraxin 2 (PTX-2; serum amyloid P component), a circulating endogenous regulator of the inflammatory response to tissue injury and fibrosis, is reduced in patients with myelofibrosis (MF). Zinpentraxin alfa (RO7490677, PRM-151) is a recombinant form of PTX-2 that has shown preclinical antifibrotic activity and no dose-limiting toxicities in phase I trials. We report results from stage 1 of a phase II trial of zinpentraxin alfa in patients with intermediate-1/2 or high-risk MF. Patients (n=27) received intravenous zinpentraxin α weekly (QW) or every 4 weeks (Q4W), as monotherapy or an additional therapy for patients on stable-dose ruxolitinib. The primary endpoint was overall response rate (ORR; investigatorassessed) adapted from International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria. Secondary endpoints included modified Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) change, bone marrow (BM) MF grade reduction, pharmacokinetics, and safety. ORR at week 24 was 33% (n=9/27) and varied across individual cohorts (QW: 38% [3/8]; Q4W: 14% [1/7]; QW+ruxolitinib: 33% [2/6]; Q4W+ruxolitinib: 50% [3/6]). Five of 18 evaluable patients (28%) experienced a ≥50% reduction in MPN-SAF TSS, and six of 17 evaluable patients (35%) had a ≥1 grade improvement from baseline in BM fibrosis at week 24. Most treatment-emergent adverse events (AE) were grade 1-2, most commonly fatigue. Among others, anemia and thrombocytopenia were infrequent (n=3 and n=1, respectively). Treatment-related serious AE occurred in four patients (15%). Overall, zinpentraxin alfa showed evidence of clinical activity and tolerable safety as monotherapy and in combination with ruxolitinib in this open-label, non-randomized trial (clinicaltrials gov. Identifier: NCT01981850).