Research Studies

The hemophilia and thrombosis centers in Tucson and Phoenix would like to join efforts to make a meaningful contribution to our understanding of the mental health profile of our pediatric population. This knowledge could contribute to a more tailored approach when designing clinics and programming, and, by identifying mental health issues, inform the development of targeted interventions. We hope to look at the prevalence of depression and anxiety in children with bleeding disorders including hemophilia, von Willebrand disease, and other congenital coagulopathies. We expect that the existence of a chronic health condition could affect a child's psychological development. We're also aware of the critical impact of family culture so our survey will include data on the mental health of the participants’ primary caretakers as well as other significant socioeconomic markers.

Background:

Recombinant adeno-associated viruses (rAAV) are replication-deficient, non-integrating viruses commonly used as vectors for gene therapies currently in clinical development. Systemic administration of gene therapy raises the possibility of vertical germline transmission of the vector DNA.

Aim:

Here, we investigated the possibility of germline transmission following IV administration of an AAV serotype 5 vector designed for the liver-directed expression of human Factor IX which is being studied in clinical trials for hemophilia B.

Methods:

Since hemophilia B predominantly occurs in male patients, paternal germline transmission was investigated in mice in a GLP compliant study, according to current gene therapy guidelines (EMEA/273974/2005). Male C57Bl/6 mice (n=15) each received a single intravenous infusion of 2x1014 gc/kg AAV5-hFIX and were mated 6 days later with untreated female mice (n=30). On day 20 post-treatment, males were sacrificed and the seminal vesicle, epididymis, testes and a sperm sample were collected. Successfully mated females were necropsied on day 17 of gestation and the uterus, placenta and fetuses collected for each female. Each fetus was examined for viability and externally visible abnormalities. All samples were analyzed for vector DNA by QPCR.

Results:

No effect of treatment was observed on male mating performance, fertility indices, maternal body weight, food consumption, pregnancy performance, external fetal abnormalities, or fetal weights. Vector DNA levels of up to 2x106 gc/μg gDNA were detected in male reproductive tissues (epididymis, seminal vesicle, sperm, and testes), but not in female uterus, placenta and offspring. Although vector DNA was detected in the reproductive tissues of males, there was no evidence of transmission of vector DNA to female reproductive tissues or to the fetuses.

Conclusion:

The risk of paternal germline transmission following AAV5-based vector administration is therefore considered to be low.

Objective:

To investigate how bleeding disorder characteristics influence patient perceived challenges and management strategies.

Methods:

This is a mixed-method, retrospective, cross-sectional continuation of a pilot study identifying themes of self-perceived challenges and management strategies for persons with bleeding disorders. Sixty-one participants with a bleeding disorder (BD), either hemophilia (PWH) or Von Willebrand disease (PWVWD), were asked what their most significant challenge was in managing their BD and how they managed that challenge. Data were collected from March, 2017 through December, 2018, coded for themes and uploaded to NVivo. Similar themes were grouped for analysis. Subject-level data was extracted from the electronic medical record including demographics, disease type, severity and presence of joint disease (JD).  Pain interference was determined from participant response to the Brief Pain Inventory (BPI). 

Results:

• The mean age of the cohort was 31.4 years, with a median of 25 years, and range of 7 to 75 years. 87% were PWH, 13% PWvWD.
• There were 26% mild, 25% moderate, and 49% severe PWH.
• 54% had JD.
• Identified challenges included: participation restriction (24%), acute bleeding (22%), infusion (19%), bleeding sequelae (10%), other’s unfamiliarity with bleeding disorder (other’s unfamiliarity) (10%), no challenges (10%), and other (6%). Management strategies reported were: acceptance (37%), learning through experience (25%), education/advocacy (11%), seeking help (9%), other (9%), and no challenges (9%).
• Severe PWH greatest reported challenges were participation restriction (27%) and infusion (27%).  Management strategies were acceptance (41%) and experiential learning (31%).
• Mild-moderate PWH greatest reported challenges were acute bleeding (35%), infusion and no challenge (17% each). Management strategies were acceptance (30%) and seeks help (26%).
• Seek help was not identified as a strategy among severe PWH.
• Reports of no challenges was higher among those <18 years than those ≥ 18 years.
• Mean pain interference was 13.2 out of 70 based on the composite score of BPI measures.
• As age increased, the likelihood of JD and interference increased.
• Regardless of challenge, people with JD reported interference averaging 18% (range 0-27%).

Conclusions:

Gaining insight to patient-perceived challenges and management strategies is important to be able to tailor an effective treatment approach that is individualized and meets the changing needs of PWBD across circumstance and life-course.

Dr. Satish Nandakumar is currently a postdoctoral fellow in the laboratory of Dr. Vijay Sankaran at the Boston Children's Hospital. Previously, he did his graduate work at the St. Jude's Children's Research Hospital in Memphis, Tennessee. In his JGP Fellowship project, Dr. Nandakumar aims to develop a novel gene therapy approach for hemophilia that involves activation of the endogenous factor VIII or IX genes within hematopoietic stem cells by taking advantage of the CRISPR/Cas9 gene activation system. This work has the potential to benefit patients with mild hemophilia mutations.

Objectives:

This study has a primary objective to determine the efficacy of VWF/FVIIII concentrate (Wilate) in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD.

Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication.

Also the study will examine, the efficacy of VWF/FVIIII concentrate in the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the quality of life (QoL) during prophylaxis with VWF/FVIIII concentrate.

Methods:

The study is planned to enrol 28 PTPs aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run in observational study to collect bleeding rate prior to the start of prophylaxis.

From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated.

Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none)
In case patients undergo surgeries, efficacy of VWF/FVIIII concentrate will be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator.

Summary/conclusions:

Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve quality of life in patients. This form of treatment in VWD is not well characterized prospectively as yet. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the quality of life in VWD patients.
 

Objective:

The National Hemophilia Foundation Education team partnered with an evaluator to conduct a needs assessment of the rare bleeding disorder (RBD) community to help inform the development of programming tailored to the community’s unique experiences and needs.

Methods:

A guided discussion with the attendees of a Bleeding Disorder Conference (BDC) session titled, “The Lonely Island: Dealing with Being Rare” in 2018 as well as brief surveys at the end of the session were compiled as part of the needs assessment. Additionally, 12 one on one interviews of those part of the RBD community (either affected themselves or a close relative to someone that is affected) were conducted.

Summary:

Various challenges for this population were identified, including: connecting with others who have the same RBD; healthcare providers’ lack of knowledge/understanding of specific RBDs; accessing knowledgeable hematologists and RBD experts; accessing the latest science specific to their RBD; scarcity of treatment resources; difficulty getting diagnosed. Other secondary challenges were also expressed. While challenges were identified, those that participated in the needs assessment also highlighted the ways in which they see the RBD community can best be served. Common suggestions included: the addition of RBD-specific programming at NHF’s Bleeding Disorder Conference (BDC); continuing to make NHF and Chapters inclusive; creating more opportunities for the RBD community to connect with others with the same RBD (at NHF’s BDC and other events); creating targeted educational materials and opportunities for the RBD community; creating opportunities for members of the RBD community to identify and engage with the medical community.

Conclusions:

By conducting this needs assessment, NHF took an important step in asking the RBD community directly how they can best be supported given their unique experiences and needs. While challenges for the RBD community were identified, several opportunities to support the RBD community were also identified.
 

Helping teens with bleeding disorders prepare to manage their care as they transition to adulthood is a national priority for US Hemophilia Treatment Centers (HTC).  The National HTC Patient Satisfaction Surveys (PSS) reveal high satisfaction with HTC teen transition services. Yet how satisfaction differs comparing HTCs that primarily care for children to HTCs that care for patients throughout the lifespan is unknown.

Objective:

To assess variation in patient satisfaction with US HTC teen transition services by HTC type.

Methods:

The US HTC Network conducted nationally uniform patient satisfaction surveys in 2015 and 2018 on care received, respectively, in 2014 and 2017. A Regional workgroup devised, piloted, and finalized an electronic, two-page survey for self-administration at clinic, or at home, in English or Spanish. Participation was voluntary.  Respondents were anonymous but identified their HTC. Parents completed surveys for children under age 18. The PSS included two teen transition questions for respondents age 12-17 to complete. HTC type was categorized as ‘pediatric’ if >80% of responses were from patients/caregivers of individuals under age 18, and ‘adult’ if >80% were from patients over age 24.  All other HTCs were categorized as ‘lifespan’.  For both years, approximately 26% of HTCs were classified as pediatric, 52% as life-span, and 22% as adult.

Results:

Over 700 teens age 12-17 (or their parents/guardians) from an average of 130 HTCs (94.0%) from all US regions participated in 2015 and 2018. Approximately 96.5% of teens at pediatric HTCs (96.4% - 96.5%) and 96.2% at lifespan HTCs (95.9% - 96.5%) reported being ‘always’ or ‘usually’ (A/U) satisfied with HTC services overall.  On average, 90.4% of teens at pediatric HTCs (90.1% - 90.7%) and 91.0% at lifespan HTCs (90.3%–91.6%) reported being A/U satisfied with how HTC clinic staff talked about how to care for the bleeding disorder as they became an adult. Similarly, 92.5% (92.0%– 92.9%) of teens at pediatric HTCs and 92.5% (92.3%-92.7%) reported being A/U satisfied with how the HTC clinic staff encouraged them to become more independent in managing their bleeding disorder. 

Conclusions:

HTC patients age 12-17 years consistently report very high levels of satisfaction with HTC teen transition services, regardless if the HTC primarily cares for patients up to age 17, or throughout the life-span.  This suggests teens receive support and tools to successfully transition to adult care across the US HTC Network.  A national uniform HTC Patient Satisfaction Survey provides vital information, is feasible to conduct using a regional structure, and well received nationwide.
 

Objective:

The ongoing pediatric phase 3 paradigm 5 trial is assessing N9-GP (nonacog beta pegol, REBINYN^®) use for routine prophylaxis and treatment of breakthrough bleeds in previously treated children with hemophilia B (FIX ≤2%). This analysis presents 5-year safety and efficacy data in a group of children treated with weekly prophylaxis to a higher mean FIX trough (≥15%).

Methods:

paradigm 5 is a multinational, single-arm study evaluating safety, efficacy, and pharmacokinetics. Children (aged ≤12 years at enrollment) were administered weekly prophylaxis (N9-GP 40 IU/kg) through a 52-week main phase followed by an ongoing extension study. Mild/moderate bleeds were treated with 40 IU/kg. Prophylaxis, bleed treatments, and hemostatic efficacy were captured in electronic diaries. Current analysis extends from May 2012 through October 2018.

Summary:

Of the 25 children enrolled in the main phase (12 ages 0-6, 13 ages 7-12), 24 completed the main phase and 22 entered the extension (11 per age group). At the time of this analysis, 17 remain in the trial. No patients withdrew due to adverse events. Ten participants remaining in the trial have become adolescents (mean 2.6 adolescent-years of exposure).

The cumulative exposure in the study was 116 patient-years (6,194 exposure days). The median (range) time in study was 5.2 (0.2-6.1) years representing 290 (10-325) N9-GP doses per patient. The median/mean prophylactic dose was 43.1 IU/kg/wk.

A total of 573 adverse events were reported, including 4 serious adverse events, all of which were considered unlikely related by the investigator. No patients developed anti-FIX inhibitory antibodies (primary endpoint). There were 7 medical events of interest, including 6 allergic reactions (no anaphylaxis).

Age-related increase in trough FIX levels was seen; the mean FIX trough levels were 0.179 IU/mL (overall), 0.166 IU/mL (younger), and 0.192 IU/mL (older). Mean PEG plasma concentration reached steady state after ~6 months.

Overall, 20 patients (80.0%) experienced 115 bleeds, the majority of which were traumatic (64%) or spontaneous (33%) and in joints (43%). Most (93%) were treated with 1-2 doses with 89% rated as excellent/good. Median individual ABRs are shown in the TABLE; 64% of patients were spontaneous-bleed-free throughout the study.

Conclusion:

These data support the safety and efficacy of N9-GP 40 IU/kg weekly over a median of 5 years in a controlled phase 3 trial setting in children. N9-GP prophylaxis with a trough of ~18% was effective in preventing bleeds with low reported ABR and with 64% of patients reporting no spontaneous bleeds during the entire study period. No unexpected safety issues were identified.

Objective:

While a new generation of therapies for patients with Hemophilia A are available, it is unclear what patient characteristics, perceptions, and barriers are associated with the decision to switch FVIII replacement therapies. This study assessed patient characteristics, health history, and reasons for switching from a FVIII product with more frequent dosing (³3x infusions/week) to a product with less frequent dosing (≤2x infusions/week) from patient/caregiver and physician perspectives.

Methods:

Data collection was a mix of qualitative and quantitative procedures. The qualitative portion consisted of two online discussion forums: patients (n=17) and caregivers of patients (n=11) receiving a FVIII product dosed ³3x/week, and patients (n=22) and caregivers of patients (n=5) who switched to a product dosed ≤2x/week. The quantitative portion was a retrospective medical chart review (n=207) which captured variables (e.g., bleed rate, treatment history) 6 months pre- and 6 months post-switching to a product with less frequent dosing.

Summary:

Prominent drivers among patients for starting a FVIII product with less frequent dosing included: 1) experiencing diminished effectiveness while on a product dosed ³3x/week resulting in increased breakthrough bleeding, 2) experiencing vein access issues, and 3) beginning prophylaxis as opposed to on-demand infusions after a bleed.

Key barriers to changing included: 1) fears regarding the process of switching being complicated, time consuming, and costly, 2) perceived risks associated with switching, and, 3) possible lack of healthcare provider support.

Physicians were most likely to report that patients switched products because they sought a newer product with twice weekly dosing or less per FDA-approved dosing recommendations (35.3%), followed by patient requested the switch (30.4%), and patient sought a reduction in infusion frequency to improve adherence (27.5%).

Switching to a product with less frequent dosing was associated with improvements in patient-reported bleeding-related outcomes. Patients were more likely to self-administer the treatment post-switch (63.8%) compared with pre-switch (48.8%; p<0.001) and had fewer infusions per week post-switch (2.8 vs. 3.3; p<0.001). Patients’ annualized bleed rate was lower (5.9) post-switch compared with pre-switch (7.7; p<0.001).

Both the number of spontaneous joint bleeds and joint bleeds after trauma or injury were lower (3.2 and 2.7) post-switch (3.6 and 4.3; p=0.044 and p<0.001). The bleeding event was less likely to be classified as moderate or severe (34.5% and 5.9%) post-switch compared with pre-switch (55.0% and 10.0%; p<0.001 and p=0.049). Fewer infusions were required to resolve the bleeding event post-switch (2.6 vs. 3.2; p<0.001).

Conclusion:

A prominent reason why patients switch treatment is to improve bleeding-related outcomes. Indeed, we found that switching to a FVIII product with less frequent dosing was associated with improved patient-reported bleeding-related outcomes. These findings are critical for improving patient outcomes and support the FDA mandate to incorporate patient perspectives in the regulatory process.

Background:

There are no reported cases of acute lymphoblastic leukemia (ALL) in patients with hemophilia B. There is one case report of a young adult with hemophilia B and acute myeloid leukemia (1). Currently, there is no best practice recommendation for the management of patients with hemophilia B and ALL.

Objectives:

To report our experience in managing a pediatric patient with congenital hemophilia B and ALL, which presents a rare and unique clinical challenge.

Design/Method:

Retrospective chart review

Results:

This is a 2y/o male with hemophilia B diagnosed at birth from a cord blood sample showing a factor IX level <1%. Mother is a known carrier and maternal grandfather has severe hemophilia B. Patient started prophylaxis with a standard half-life product through central venous access around 8months of age, following a spontaneous wrist bleed. The schedule was 35 units/kg twice a week. He had no spontaneous joint or soft tissue bleed on this regimen. 3mo ago he presented with pain and swelling of the right wrist. He fell on an outstretched hand the day before and received 100% factor infusion. X-ray showed metaphyseal lucencies with overlying soft tissue swelling. No evidence of fracture. Due to this finding, additional labs were done. WBC 4.8K, hemoglobin 7.1 g/dL, platelets 18K and 31% blasts. Flow cytometry confirmed the diagnosis of preB-ALL. On exam, he had pallor, scattered petechiae and cervical lymphadenopathy.

Based on recovery studies and thrombocytopenia, the prophylaxis was changed to 50 units/kg every third day. The platelets are kept above 30K at baseline. For lumbar punctures, he has been corrected to 100% factor level and platelets kept above 50K. However, due to the risk of port infection with frequent accessing, he was switched to long-acting albumin fusion factor IX product on day 22 of induction. The current prophylaxis regimen is 75units/kg weekly and the schedule is adjusted to coincide with lumbar puncture days whenever needed. He has tolerated all his procedures well without increased bleeding, including end of induction bone marrow aspiration, biopsy and lumbar puncture with intrathecal chemotherapy. He is currently in remission and is in interim maintenance phase of treatment per COG protocol AALL0932.

Conclusion:

Long-acting factor IX products could potentially decrease the number of infusions and need for frequent central venous access in immunocompromised patients with hemophilia B. In addition, a higher trough level with a weekly schedule could provide better bleed control in patients with severe thrombocytopenia due to underlying malignancy. A baseline platelet count of at least 30K is recommended during treatment. More treatment guidelines need to be established.

(1) Clark C et al, Pediatric Blood and Cancer Jan 2011

Hemophilia causes repetitive bleeding episodes throughout the musculoskeletal system, primarily into joints, such as knees and ankles. This leads to significant joint damage resulting in increased pain reproduction, decreased functional abilities, such as walking, and negatively impacts quality of life. Traditionally the extend of joint damage has been examined via clinical assessments, such as the Hemophilia Joint Health Scores, x-rays, MRIs, and more recently musculoskeletal ultrasound (MSKUS). However, these modalities fail to establish the global impact of joint damage on the entire body of a person with hemophilia and their functional abilities. Analyzing joint motion and forces acting upon the joint during walking has been a widely established technique to gain understanding of abnormal three-dimensional movements and is a key factor in clinical decision making-processes. With the overall goal of establishing better treatment approaches for persons with hemophilia it is vital to understand the underlying functional joint limitations. Therefore, the purpose of this study is to investigate characteristics of damaged joints, joint motion and control as well as forces acting upon the joint during walking in persons with hemophilia.