Emicizumab in children: bleeding episodes and outcome before and after transition to Emicizumab

doi:10.21203/rs.3.rs-1520829/v2

Download PDF

Research Article

Emicizumab in children: bleeding episodes and outcome before and after transition to Emicizumab

https://doi.org/10.21203/rs.3.rs-1520829/v2

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Purpose

Real-world data and study data regarding therapy with Emicizumab in pediatric cohorts with haemophilia A is scarce. Especially, data on previously untreated pediatric patients (PUPs) and minimally treated patients (MTPs) are missing.

Methods

14 pediatric patients with haemophilia A and treatment with Emicizumab were retrospectively evaluated for Annual Bleeding Rates (ABR) pre-and post-Emicizumab treatment. Safety data and data on management of minor surgery as well as laboratory results were collected. Additionally, we describe the clinical features of two PUPs and one MTP that are included in our cohort.

Results

Median age at initiation of Emicizumab was 5.9 (0.26–21.34) years, three patients were younger than one year at initiation of treatment with Emicizumab. Median follow-up time on Emicizumab was 24 (0.7–40) months. Total ABR (p = 0.006) as well as spontaneous (p = 0.018), traumatic (p = 0.012), and joint (p = 0.018) ABR reduced significantly post-Emicizumab transition. Safety profile was favourable as only one local site reaction occurred; no cessation of treatment was necessary. Surgery was successfully performed in three patients receiving rFVlla pre- and post-surgery. Emicizumab trough levels showed a median of 43.4 µg/ml (23.9–72.1) after three doses of 3 mg/kg and 53.9 µg/ml (30.4–75) at first follow-up with 1.5 mg/kg.

Conclusion

Emicizumab is safe and efficient in pediatric patients with and without inhibitors. More data on larger multicenter cohorts and especially on PUPs/MTPs are still needed.

Emicizumab

Hemlibra

Children

Annual Bleeding Rate

What is known:

Emicizumab significantly reduces Annual Bleeding Rate in adults and children and has a favourable safety profile in study setting. Data on young children, especially primary untreated patients is scarce.

What is new:

We add real-world data of young children, including primary untreated and minimally treated patients and confirm reduction of Annual Bleeding rate as well as a favourable safety profile in this younger cohort.

Haemophilia A is a severe bleeding disorder caused by deficiency or complete lack of coagulation factor Vlll (FVlll). Due to its X-linked mode of inheritance, male patients are affected by severe bleeding episodes not only causing acute life-threatening conditions but also haemophilic arthropathy subjects patients to a chronic severe health burden [1]. Lifelong prophylactic intravenous substitution of FVlll used to be the treatment of choice since the 1980s. In addition, patients may developed FVIII antibodies, which requires frequent FVIII substitution via a central venous line in the course of immune tolerance induction (ITI) [2].

In 2017, Emicizumab (Hemlibra→, Roche), a humanized bi-specific antibody was approved by the Food and Drug Administration (USA) for prophylactic treatment in patients with inhibitors. HAVEN 3 study demonstrated safety in haemophilia patients without inhibitors [3]. Emicizumab mimics the co-factor function of FVlll, bridging activated FlX and FX [4]. A big advantage of Emicizumab is its subcutaneous application, (i.e. once weekly) and therefore, the advantage especially in pediatric patients remains undisputed. Annual bleeding rates (ABR) of patients, formerly treated with prophylactic FVlll, reduced when treated with Emicizumab and the safety profile revealed no serious side effects under exclusive treatment with Emicizumab [4]. Several phase lll studies (HAVEN 1–4) further investigated different age cohorts, while only HAVEN 2 investigated pediatric patients (n = 85 aged < 12 years). All studies confirmed safety and efficacy of Emicizumab [3], [5]–[7]. Only single other studies have since investigated pediatric patients under prophylaxis with Emicizumab [8]–[12], especially data on previously untreated patients (PUPs) and minimally treated patients (MTPs) [13], [14] are limited.

For all non-factor replacement therapies like Emicizumab there is a potential risk of thrombosis. But an increased risk of thrombosis in patients under sole Emicizumab prophylaxis or in combination with rFVII has not yet been described in clinical trials. Severe adverse events (death due to TMA) occured under combination therapy with FEIBA. Therefore, activated prothrombin complex concentrate is prohibited under Emicizumab therapy [5]. Other risks are antidrug antibodies that were described in two pediatric patients (one with loss of efficacy of Emicizumab) [6] or breakthrough bleeding, mainly associated with trauma [8].

There is no standard procedure for surgery for patients with haemophilia and Emicizumab treatment in place. It is recommended to add FVlll according to the extent of the surgery in non-inhibitor patients and rFVlla in patients with inhibitors [15].

Conventional monitoring of therapy in haemophilia patients consists of FVlll activity analysis using one stage clotting assays. Emicizumab interferes with this laboratory testing and therefore, chromogenic FVlll activity analysis is necessary. The same applies for FVIII inhibitor testing. Monitoring of Emicizumab therapy is not generally recommended, but mean steady state concentrations for different dosing intervals in clinical trials were if administered once weekly: 51,1 µg/mL [3], [5], every two weeks: 46,7 µg/mL [3] and every four weeks: 38,3 µg/mL [7]. An exposure–response model showed that ABR decrease rapidly with an increasing Emicizumab plasma concentration. Concentrations above 30 µg/mL were predicted to provide clinically meaningful control of bleeding (mean ABR < 1.83) [16]. aPTT values generally normalize under treatment with low doses of Emicizumab. However, this does not reflect normalization of hemostasis [17].

As real-world data regarding pediatric patients and especially PUPs and MTPs on Emicizumab is still scarce, we investigated efficacy and safety of a cohort of 14 pediatric patients treated with Emicizumab in our outpatient clinic, focusing on the intrapersonal ABR before and after initiation of treatment. We also describe the clinical characteristics of two PUPs and one MTP of this cohort.

Patients

Retrospective data analyses of 14 consecutive pediatric patients with haemophilia A (13 severe, 1 moderate) and treatment with Emicizumab was performed at our section of pediatric hemostaseology. Two out of fourteen patients were PUPs, the youngest being 3 months old at the time of treatment initiation with Emicizumab and 3 patients were minimally treated patients with less than 20 exposure days to FVlll.

Study inclusion criteria were: (1) Diagnosis of haemophilia A, objectively confirmed by FVlll activity of < 1% for severe and 1–5% for moderate haemophilia A and molecular genetic analysis, (2) treatment with Emicizumab, (3) regular follow-up examination and laboratory parameters at our department of pediatric hemostaseology, (4) informed consent to use data for evaluation and publication.

Indication to transition to Emicizumab

Presence of inhibitors (high and low responder)
Difficulties in venous access
Preference of parents/patient due to easier form of application and/or hope for better compliance

Emicizumab was applied once weekly according to the manufacturer´s recommendation. The first dose of Emicizumab (3 mg/kg) was applied in our hospital to observe safety and side effects. The next two weekly loading doses of 3 mg/kg were administered by the children’s pediatrician. Emicizumab levels were screened before the fourth loading dose at our outpatient clinic. The following weekly dose consisted of 1,5 mg/kg Emicizumab.

FVlll substitution remained the treatment of choice for patients without inhibitors in case of breakthrough bleeds while on Emicizumab. For patients with inhibitors rFVlla was employed in case of trauma or surgery. No other bypassing agent was used for any patient on Emicizumab.

Data collection

The retrospective systematic collection of clinically derived data included: patient demographics, previous FVlll therapy (prophylactic, ITI, PUP/MTP), treated bleeds in ABR before/after transition to Emicizumab subdivided into a) total ABR, b) spontaneous ABR, c) traumatic ABR, d) joint ABR, treatment duration before/after Emicizumab, reasons for transition to Emicizumab, comorbidities, motor activity level, side effects and treatment during surgery.

Of note, ABRs were calculated to account for different lengths of therapy with prophylactic FVlll and Emicizumab and only treated bleeds were considered for analysis.

Emicizumab levels were monitored after 3 doses of the loading dose of 3 mg/kg and at every follow-up appointment under therapy with 1,5 mg/kg. In addition, aPTT before and after transition to Emicizumab was analysed and FVIII inhibitor (Bethesda assay) was measured regularly. FVlll activity using chromogenic assay was also monitored. Transaminases, electrolytes and creatinine were regularly assessed.

Statistical methods

Median values and ranges were reported, and nonparametric statistics were used to test for differences in continuous variables in terms of Inhibitor-status (Mann-Whitney-U-Test). Spearman's rank correlation was performed to measure the degree of association between the two continuously measured variables (age and ABR variables). The paired samples Wilcoxon rank test was used to compare paired data (ABR before – after treatment).

All p-values were 2-sided and values less than 0.05 were considered statistically significant. P values greater than 0.1 were reported as non-significant, whereas those between 0.05 and 0.1 were reported in detail. SPSS for Windows 28.0.1 (IBM Corp) was used for the statistical analysis of data.

Patient Demographics

Fourteen patients were included in the study. Thirteen patients had severe haemophilia A, whereas one patient had FVlll-activities between < 1–2%. All patients received molecular genetic testing, confirming pathogenic mutations in the FVlll-gene in all patients. Their demographics and pre-Emicizumab treatment as well as description of reasons for initiating treatment with Emicizumab are presented in Table 1.

The median age at initiation of Emicizumab treatment was 5.9 (0.26–21.34) years. Three patients were younger than one year at initiation of treatment with Emicizumab. The oldest patient was 20 years old. This patient suffered from developmental delay after brain injury occurring prior to any FVlll treatment and was therefore still seen at the pediatric outpatient clinic. Four out of fourteen (29%) patients were high-responding inhibitor patients, the other 10/14 (71%) patients did not have inhibitors.

Prior treatment consisted of prophylactic FVlll-substitution: for 8/14 (57%) patients (25–35 IE/kg thrice weekly), of whom in one patient (patient 11) Emicizumab plus ITI was started immediately after diagnosis of an FVIII-inhibitor. Two out of fourteen (14%) patients were on ITI when being switched to Emicizumab. ITI had failed in one patient (7%), and FEIBA (factor eight bypassing agent) had been used for prophylaxis before starting Emicizumab. Two (14%) patients were PUPs and 3 (21%) were MTPs.

Median treatment time before transition to Emicizumab was 59.5 (0-228) months and median follow-up time on Emicizumab was 24 (0.7–40) months.

Efficacy

Median total ABR pre-Emicizumab was 0.25 (0–4) compared to 0 (0-0.5) post-Emicizumab (p = 0.006), (Table 2).

In addition, median spontaneous ABR (p = 0.018), traumatic ABR (p = 0.012), and median joint ABR (p = 0.018) were significantly reduced after transition to Emicizumab.

Thirteen (93%) of the patients experienced no bleeds after transition to Emicizumab. There was traumatic bleed on Emicizumab in one patient.

If patients aged > 6 years were compared to patients < 6 years, the only significant difference occurred in spontaneous ABR, which was significantly reduced post-Emicizumab (p = 0.035).

There was no correlation between age and ABR. There was a tendency towards higher spontaneous ABR before Emicizumab in patients with inhibitors compared to non-inhibitor patients (p = 0.082), however it did not reach significance level.

One patient presented with a target joint before transition to Emicizumab (patient 14).

Surgery

Three inhibitor-patients received minor surgery, all regarding removal of their central venous lines, while one patient additionally underwent keloid scar removal. All of them received one pre-operative dose of rFVlla (∼100µg/kg bw). Two patients received two additional post-operative FVIIa substitutions after surgery and on the first postoperative day. The patient with keloid scar removal received a total of 6 postoperative doses rFVlla until 3 days post-surgery. No peri- or postsurgical bleeding occurred.

PUPs/MTPs

The two PUPs of our cohort and one of the MTPs are presented in detail:

Patient 1 (PUP)

A 9-month-old boy was referred to our outpatient department because of recurrent hematoma. A diagnosis of severe haemophilia A was made based on a reduced FVlll activity (< 1%). No other bleeding event had occurred. The parents received comprehensive and repeated education and opted for Emicizumab as primary prophylaxis, since i.v. injections were very challenging in this patient. After head trauma, the patient once received plasmatic FVlll in addition to his Emicizumab prophylaxis and did not develop any bleeding. Molecular genetic testing revealed a hemizygous variant of the FVlll-gene (c.[5188A > G];[0] p.(Met1730Val)). Follow-up examinations (12 months) did not show any signs of inhibitors against FVlll and no bleeding had occurred.

Patient 2 (PUP)

A 3.5-year-old boy was diagnosed with haemophilia A after a traumatic joint bleed of the ankle. Medical history only revealed one extended mucocutaneous bleeding at the age of 1.5 years. FVlll activity was < 1% and 2%, respectively. Molecular genetic analysis revealed a hemizygous FVlll-gene variant (c.[5339C > T];[0] p.(Pro1780Leu)). Because of the increased bleeding symptoms, a prophylaxis using Emicizumab was initiated based on parental preference.

Follow-up examinations (2 months) did not show any FVIII-inhibitors and no bleeding occurred. No FVlll was administered until inclusion to the study.

Patient 3 (MTP)

At the time of diagnosis, a 3-month-old boy had already suffered from postnatal cephalic hematoma that required transfusion of red blood cells, but no further diagnostics were initiated. After persistent bleeding following frenectomy, coagulation studies were initiated, and severe haemophilia A was diagnosed. The initial treatment of the acute bleeding consisted of 5 substitutions with plasmatic FVlll (30 IE/kg bw). Because venous access was very difficult, the parents asked for prophylactic treatment with Emicizumab, which was initiated shortly after. In addition, the boy received prophylactical FVlll-substitution once weekly (30 IE/kg bw). Molecular genetic testing revealed a missense mutation of the FVlll-gene (c.[1043G > A];[0] p.(Cys348Tyr)).

Follow-up examination after 3 months did not show any signs of inhibitors against FVlll and no other bleeding episodes occurred so far.

Emicizumab levels

Emicizumab trough levels after three doses of 3mg/kg (= before 4th dose) showed a median of 43.4 µg/ml (23.9–72.1) and at first follow-up (with 1.5mg/kg) increased to 53.9 µg/ml (30.4–75). Median follow-up Emicizumab testing was performed after 68 days (42–163), (Table 2).

aPTT levels

aPTT decreased inversely to Emicizumab levels from median 118 sec. (71->140) to 27 sec. (23–40).

Safety

Two patients presented with local skin reaction at the injection site after the first Emicizumab dose. One of the two patients recurrently showed urticaria at injection site after every injection (Fig. 1). We performed skin prick test to exclude allergic reaction to Emicizumab or other contents of the medication. No skin reaction occurred during prick test. Deeper subcutaneous injection improved the clinical symptoms remarkably. No patient developed thrombosis, thrombotic microangiopathy, renal failure, liver function impairment or blood count abnormalities. No cessation of treatment was necessary in any patient due to side effects.

Data on efficacy and safety of Emicizumab in children, especially in young children < 3 years and PUPs is still scarce. Between 2019–2021 several publications have reported the use of Emicizumab in children, including about 40 children under the age of 3 years [8], [9], [11]–[13]. All studies showed similar results regarding reduction of ABR, safety and laboratory results as adult cohorts. But especially PUPs demand special attention, because avoiding FVlll exposure might impose a higher risk of inhibitor development on these patients in case of breakthrough bleeding or surgery [18] .

This current study provides additional evidence on efficacy and safety of Emicizumab in 5 children < the age of 3 years, 2 PUPs and 3 MTPs. Our data show that the ABR significantly reduced under Emicizumab, regardless of age and inhibitor status. There were no spontaneous breakthrough bleeds during the long follow up-time of 24 months in our study. Other studies presented data of up to 50% breakthrough bleeds on Emicizumab [8].

Regarding PUPs, there is still no standardized recommendation regarding primary prophylaxis with Emicizumab in very young children. In 2020, the Society for Thrombosis und Hemostasis (GTH) published a guidance regarding the use of Emicizumab that stated a 92% agreement rate to the statement that “The decision to use Emicizumab in small children, especially PUPs, has to be made on an individual base” [15]. Published studies of pediatric patients on Emicizumab included three PUPs and one minimally treated patient in a total cohort of 52 individuals [14] and one PUP in the HOHOEMI study [13]. Both studies reported no other safety profiles or differences in efficacy compared to the other pediatric studies.

Therefore, our study adds to the data that, although haemostasis may still be developing in young children and FlX -activities may be low during the first months of life, efficacy in terms of reduction of ABR of Emicizumab is nevertheless comparable to adults. In addition, the same dosing can reach stable levels of Emicizumab. We were able to confirm this finding in children under the age of 3 years. We also report on two PUPs and three MTPs that experienced no complications while being treated with Emicizumab. This was independent of whether Emicizumab was the initial treatment, initiated upon occurrence of inhibitors or administered in combination with FVlll.

Although this current study provides crucial information about treatment of PUPs, future studies, e.g. the FREE-study, on PUPs, will provide more extensive data on this particular group and add valuable insight.

Currently, there is still an ongoing debate on eradication of inhibitors in the era of Emicizumab. Most experts argue that inhibitor eradication by ITI should be initiated to be able to use FVlll products in case of breakthrough bleeds or surgery. Others argue that Emicizumab is efficient to prevent bleeding and therefore, ITI is not mandatory [19]–[21]. The German expert panel of the GTH recommended that one treatment trial with ITI should be offered to patients on Emicizumab [22]. Our cohort consisted of four high-titre inhibitor patients of whom three had already received several years of ITI long before transition to Emicizumab. One patient was transitioned to Emicizumab and additional ITI according to the Atlanta-Protocol (3 x 100/IE/kg bw weekly) immediately after diagnosis of high-titre inhibitors. Due to very difficult venous access and parental decision, ITI was terminated in this patient after a total of 2,5 years on ITI. Overall, none of our patients had a breakthrough bleed and according to patients and parents perspective, quality of life improved significantly.

In our cohort injection site reactions including minor skin reddening resembled previous reports [6]. We used a skin prick test to exclude acute allergic reaction to Emicizumab. Deeper deposition of the Emicizumab (still on the subcutaneous level) led to no more local side reaction in this patient. No other safety issues occurred during the study period.

We show that minor surgery in patients receiving Emicizumab prophylaxis is safe and that no bleeding or thrombosis occurred, even if few doses of rFVlla were administered additionally [5]. Nevertheless, treatment strategies in case of major trauma or other major surgery should still be investigated in further studies.

Lastly, we demonstrate that efficient Emicizumab levels were reached already after 3 doses of 3 mg/kg bw and were stable at follow-ups in most patients. This went along with the already well documented effect of shortening the aPTT [8], [17].

This study has some limitations, especially due to its retrospective design and limited number of patients. This makes statistical analysis vulnerable for outliers and generalization of results must be considered carefully. One example is patient no 1, who experienced two bleeds in 6 months and therefore has an ABR of 4, which is very high compared to our cohort in total.

In conclusion, we report longitudinal data on a small pediatric cohort including two PUPs and three MTPs that were treated safely and efficiently with Emicizumab. The debate on ITI and treatment decision making on PUPs/MTPs in the era of Emicizumab must be validated by larger cohorts.

ABR Annual bleeding rate

aPTT activated partial thromboplastine time

FVlll Factor eight

GTH Gesellschaft für Thrombose und Hämostase (Society for Thrombosis und Hemostasis)

ITI Immune tolerance induction

MTP Minimally treated patient

PUP Primary untreated patient

rFVlla recombinant Factor FVll a

Ethics approval and consent to participate

Ethics approval by the Ethics Committee of the University of Freiburg was obtained prior to inclusion of patients into the retrospective analysis. All methods were carried out in accordance with relevant guidelines and regulations. Parents gave written informed consent to participate in this study.

Consent for publication

Written informed consent was obtained from the parents for publication.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing Interests

All authors have no competing interests to declare pertaining to this manuscript.

Funding

No funding was received for this study.

Generally, Dr. Barbara Zieger has received funding from Takeda, CSL Behring, Biotest and fully forwarded it to the University Medical Center, Freiburg.

Authors` Contributions

HG performed regular clinical assessment of patients, collected the data, performed the data analysis and drafted the manuscript. FA performed regular clinical assessment of patients and substantially revised the manuscript. FK and SM revised the manuscript. MB performed the laboratory testing and revised the manuscript.

BZ provided data and study oversight, contributed to data interpretation as well as manuscript drafting.

All authors critically reviewed the manuscript and agreed to the contents.

Acknowledgments

We thank Peter Nöllke for supporting the analysis of data with statistical expertise.

R. Gualtierotti, L. P. Solimeno, und F. Peyvandi, „Hemophilic arthropathy: Current knowledge and future perspectives.“, J. Thromb. Haemost. JTH, Bd. 19, Nr. 9, S. 2112–2121, Sep. 2021, doi: 10.1111/jth.15444.
H.-H. Brackmann, G. C. 2nd White, E. Berntorp, T. Andersen, und C. Escuriola-Ettingshausen, „Immune tolerance induction: What have we learned over time?“, Haemoph. Off. J. World Fed. Hemoph., Bd. 24 Suppl 3, S. 3–14, Apr. 2018, doi: 10.1111/hae.13445.
J. Mahlangu u. a., „Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors.“, N. Engl. J. Med., Bd. 379, Nr. 9, S. 811–822, Aug. 2018, doi: 10.1056/NEJMoa1803550.
M. Shima u. a., „Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A.“, N. Engl. J. Med., Bd. 374, Nr. 21, S. 2044–2053, Mai 2016, doi: 10.1056/NEJMoa1511769.
J. Oldenburg u. a., „Emicizumab Prophylaxis in Hemophilia A with Inhibitors.“, N. Engl. J. Med., Bd. 377, Nr. 9, S. 809–818, Aug. 2017, doi: 10.1056/NEJMoa1703068.
G. Young u. a., „A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.“, Blood, Bd. 134, Nr. 24, S. 2127–2138, Dez. 2019, doi: 10.1182/blood.2019001869.
S. W. Pipe u. a., „Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study.“, Lancet Haematol., Bd. 6, Nr. 6, S. e295–e305, Juni 2019, doi: 10.1016/S2352-3026(19)30054-7.
A. A. Barg u. a., „Emicizumab treatment and monitoring in a paediatric cohort: real-world data.“, Br. J. Haematol., Bd. 191, Nr. 2, S. 282–290, Okt. 2020, doi: 10.1111/bjh.16964.
A. A. Barg u. a., „Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort.“, Pediatr. Blood Cancer, Bd. 66, Nr. 11, S. e27886, Nov. 2019, doi: 10.1002/pbc.27886.
S. Le Quellec, „Clinical Evidence and Safety Profile of Emicizumab for the Management of Children with Hemophilia A.“, Drug Des. Devel. Ther., Bd. 14, S. 469–481, 2020, doi: 10.2147/DDDT.S167731.
I. McCary u. a., „Real-world use of emicizumab in patients with haemophilia A: Bleeding outcomes and surgical procedures.“, Haemoph. Off. J. World Fed. Hemoph., Bd. 26, Nr. 4, S. 631–636, Juli 2020, doi: 10.1111/hae.14005.
J. Garcia und A. Zia, „Real-world case series and summary of current literature of infants and toddlers with severe hemophilia A with inhibitor on prophylaxis with emicizumab.“, Pediatr. Blood Cancer, Bd. 68, Nr. 5, S. e28942, Mai 2021, doi: 10.1002/pbc.28942.
M. Shima u. a., „A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors.“, Haemoph. Off. J. World Fed. Hemoph., Bd. 25, Nr. 6, S. 979–987, Nov. 2019, doi: 10.1111/hae.13848.
E. Hassan, L. Jonathan, und M. Jayashree, „Real-world experience on the tolerability and safety of emicizumab prophylaxis in paediatric patients with severe haemophilia A with and without FVIII inhibitors.“, Haemoph. Off. J. World Fed. Hemoph., Bd. 27, Nr. 6, S. e698–e703, Nov. 2021, doi: 10.1111/hae.14432.
K. Holstein u. a., „Practical Guidance of the GTH Haemophilia Board on the Use of Emicizumab in Patients with Haemophilia A.“, Hamostaseologie, Bd. 40, Nr. 5, S. 561–571, Dez. 2020, doi: 10.1055/a-1127-6476.
F. Jonsson, C. Schmitt, C. Petry, F. Mercier, N. Frey, und S. Retout, „Exposure-Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII.“, Clin. Pharmacokinet., Bd. 60, Nr. 7, S. 931–941, Juli 2021, doi: 10.1007/s40262-021-01006-0.
J. Müller, I. Pekrul, B. Pötzsch, B. Berning, J. Oldenburg, und M. Spannagl, „Laboratory Monitoring in Emicizumab-Treated Persons with Hemophilia A.“, Thromb. Haemost., Bd. 119, Nr. 9, S. 1384–1393, Sep. 2019, doi: 10.1055/s-0039-1692427.
K. Kurnik, C. Bidlingmaier, und M. Olivieri, „How Do I Counsel Parents of a Newly Diagnosed Boy with Haemophilia A?“, Hamostaseologie, Bd. 40, Nr. 1, S. 88–96, Feb. 2020, doi: 10.1055/s-0039-3402805.
G. Young, „Implementing emicizumab in hemophilia inhibitor management: emicizumab should be prescribed after tolerance.“, Blood Adv., Bd. 2, Nr. 20, S. 2780–2782, Okt. 2018, doi: 10.1182/bloodadvances.2018015842.
S. Le Quellec und C. Negrier, „Emicizumab should be prescribed independent of immune tolerance induction.“, Blood Adv., Bd. 2, Nr. 20, S. 2783–2786, Okt. 2018, doi: 10.1182/bloodadvances.2018015859.
M. Carcao, M. E. Mancuso, G. Young, und V. Jiménez-Yuste, „Key questions in the new hemophilia era: update on concomitant use of FVIII and emicizumab in hemophilia A patients with inhibitors.“, Expert Rev. Hematol., Bd. 14, Nr. 2, S. 143–148, Feb. 2021, doi: 10.1080/17474086.2021.1875817.
C. Escuriola-Ettingshausen u. a., „Optimizing the management of patients with haemophilia A and inhibitors in the era of emicizumab: Recommendations from a German expert panel.“, Haemoph. Off. J. World Fed. Hemoph., Bd. 27, Nr. 3, S. e305–e313, Mai 2021, doi: 10.1111/hae.14010.

Table 1: Patient characteristics

Patient number	Age (years)	Ethnicity	Inhibitors	Prior regimen	treatment duration Pre-Emicizumab	treatment duration Post-Emicizumab	Reason to transition to Emicizumab	Comorbidities	Motor activity level
1	0.4	Caucasian	none	MTP¹	0	0.7 mo	difficult venous access, parental decision	none	normal
2	2	Caucasian	none	PUP²	0	12 mo	difficult venous access, parental decision	none	normal
3	2	Caucasian	none	PUP²	0	0.9 mo	parental decision	none	normal
4	3	Caucasian	none	MTP¹	4 mo	25 mo	difficult venous access, parental decision	none	normal
5	6	Caucasian	none	proph. FVlll³	4 y, 6 mo	12 mo	increasing problems with FVlll administration	autism	normal
6	9	Caucasian	none	proph. FVlll³	8 y, 1 mo	3 mo	parental decision, wish for more protection from bleeding	linguistic development delay	normal, very careful parents
7	12	African	none	proph. FVlll³	10 y, 4 mo	24 mo	parental decision	Juvenile idiopathic arthritis, asthma	normal
8	15	Caucasian	none	proph. FVlll³	12 y, 7 mo	3 mo	parental decision, reduced compliance due to puberty	hyperreactive bronchitis	normal
9	20	Caucasian	none	proph. FVlll³	16 y, 5 mo	28 mo	change of FVlll required due to availability	none	reduced
10	23	Caucasian	none	proph. FVlll³	19 y	29 mo	paravasation plus hematoma after FVlll infusion	developmental delay (SDH⁶)	normal
11	3	Caucasian	high-titre	MTP¹	2 mo	29 mo	inhibitors	none	normal
12	6	Caucasian	high-titre	ITI⁴, FEIBA	3 y, 2 mo	24 mo	inhibitors	ADHD⁷	high
13	9	Caucasian	high-titre	ITI⁴, FEIBA	5 y, 5 mo	33 mo	inhibitors	none	normal
14	15	Caucasian	high-titre	failed ITI⁴, FEIBA⁵	11 y	40 mo	inhibitors	none	normal

¹MTP: minimally treated patient, ²PUP: previously untreated patient, proph. ³FVlll: prophylactic treatment with FVlll, ⁴ITI: Immune tolerance induction, ⁵FEIBA: Factor eight bypassing agent, ⁶SDH: subdural hemorrhage, ⁷ADHD: Attention Deficit Hyperactivity Disorder

Table 2: Annual Bleeding Rate and laboratory results before and after transition to Emicizumab

Patient number	ABR¹ total Pre-Emicizumab	ABR¹ total Post-Emicizumab	ABR¹ spont.² Pre-Emicizumab	ABR¹ spont.² Post-Emicizumab	ABR¹ traumatic Pre-Emicizumab	ABR¹ traumatic Post-Emicizumab	ABR¹ joint Pre-Emicizumab	ABR¹ joint Post-Emicizumab	Emicizumab (mg/ml) level after 3 doses (3mg/kg)	Emicizumab level at first follow-up (1.5mg/kg)
1	4	0	0	0	4	0	0	0	56.8	56.8
2	0	0	0	0	0	0	0	0	34.4	68.4
3	1	0	0	0	1	0	0.5	0	51.9	51.9
4	0	0	0	0	0	0	0	0	49.9	75
5	0.16	0	0	0	0	0	0	0	37.4	66.3
6	1.5	0	0.25	0	1.13	0	0.5	0	43.2	51.6
7	0.08	0	0.1	0	0	0	0	0	41.4	49.9
8	0.53	0	0.16	0	0.24	0	0.16	0	48.4	51.8
9	0.4	0.5	0.18	0	0.24	0.06	0.18	0	43.7	63.5
10	0.17	0	0	0	0.21	0	0.11	0	72.1	73.6
11	0	0	0	0	0	0	0	0	35.1	56.1
12	0.33	0	0.33	0	0.33	0	0.33	0	23.9	30.4
13	0.11	0	0.18	0	0	0	0	0	39.6	38.1
14	1.55	0	1	0	0.27	0	0.63	0	52.1	41.7
Median (Min-Max)	0.25 (0-4)	0 (0-0.5)*	0.05 (0-1)	0 (0-0)*	0.23 (0-4)	0 (0-0.06)*	0.06 (0-0.63)	0 (0-0)*	43.4 (23.9-72.1)	53.9 (30.4-75)

ABR: Annual bleeding rate, ²spont.: spontaneous

*p <0.05

No competing interests reported.

Download PDF

Editorial decision: Major revision
10 Jun, 2022
Reviews received at journal
30 May, 2022
Reviewers agreed at journal
24 May, 2022
Reviewers agreed at journal
09 May, 2022
Reviewers agreed at journal
09 May, 2022
Reviewers invited by journal
07 May, 2022
Editor assigned by journal
01 May, 2022
Editor invited by journal
28 Apr, 2022
Submission checks completed at journal
28 Apr, 2022
First submitted to journal
25 Apr, 2022

You are reading this latest preprint version

Emicizumab in children: bleeding episodes and outcome before and after transition to Emicizumab

Status:

Version 2

Abstract

Purpose

Methods

Results

Conclusion

Figures

What Is Known-what Is New?

Introduction

Methods

Patients

Indication to transition to Emicizumab

Data collection

Statistical methods

Results

Patient Demographics

Efficacy

Surgery

PUPs/MTPs

Emicizumab levels

aPTT levels

Safety

Discussion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 2