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Reports of the Midterm Focus Meeting on Non-Malignant Diseases 8-10 July 2020

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Paediatric Diseases Working Party - Wednesday, 8 July 2020

Summary by Selim Corbacioglu, Chair of the Paediatric Diseases Working Party 

The format in all sessions of the Midterm Meeting were similar so that speakers summarized briefly their presentations for the subsequent (virtual) discussions.

In summary the talks were of very high relevance and top of the art, giving the audience an excellent overview of their respective topics.  

Keynote Lecture on Iron Metabolism

Prof. John Porter elaborated elegantly the current status of knowledge on iron metabolism, a field that is usually not in the focus of transplant physicians but that in many ways is affecting our daily work, in particular with patients suffering from hemoglobinopathies.

The mechanism of iron mediated toxicity leading to cell death and fibrosis is the baseline for all thalassemia related clinical consequences. Underlining the urgent need for early curative intervention. In particular the direct correlation between cardiac iron content and consecutive heart failure and the reduction in mortality with stringent iron depletion over the last decades in the UK is impressive.

Remarkable is also the difference between thalassemia and sickle cell disease with regard to iron overload and related complications where Vichinsky et al showed that endocrine and cardiac insufficiency is present exclusively in thalassemia patients.    

Thalassemia

The presentations on thalassemia by Profs. Marktel, Locatelli and Piga covered all aspects from novel disease modifying drugs (Luspatercept) to the different transplant modalities and gene editing/therapy, demonstrating that standard of care in 2020 is highly efficient and safe and that Luspatercept as an erythroid maturation inducer can modulate pivotal aspects of the disease in order to reduce transfusion frequency and consecutively iron overload. All current trials in clinical phase I/II evaluation using gene addition and editing strategies demonstrate efficacy and safety with regard to transfusion requirement, persistence of editied cells and treatment safety so that further expansion of these trials to younger age will enlarge the pool of evidence. Albeit longterm follow-up is still scarce, gene manipulation will be an increasingly relevant therapeutic modality in near future.

Sickle Cell Disease

This topic was brilliantly covered in depth by Profs. Zecca, Dela Fuente and Walters elaborating on the different alternative curative approaches besides MSD HSCT. Prof Zecca summarized the outcome of MUD HSCT for sickle cell disease pointing at the various aspects of donor availability, the risk of GvHD in relation to age and the particular problems related to the systemic vasculopathy of this disease. Prof. De la Fuente covered the topic on haploidentical HSCT nicely summarizing the results from the different approaches, post-transplant cyclophosphamide and aß/CD19 depleted haploidentical HSCT, clearly showing that both treatment options are feasible and increasingly comparable to MSD HSCT. With regard to donor availability in particular in LMIC these results are very encouraging. Prof. Walters presented the most recent results of the ongoing phase I/II trials where in summary the outcomes with regard to cessation of sickle related crises and associated hemolytic parameters are extremely encouraging. Above all treatment related adverse events were not reported in any of the ongoing trials, assuming that gene editing/addition strategies remain a safe and highly effective curative option for the future.

To conclude this session Dr. Armstrong elucidated the various pivotal psychological aspects surrounding the care of patients with sickle cell disease.

Inborn Errors Working Party - Thursday, 9 July 2020

Summary by Dagmar Berghuis, Pediatrician - infectious diseases/immunology, Dept. of pediatric immunology and stem cell transplantation Willem Alexander Children’s Hospital Leiden University Medical Center, The Netherlands

In all sessions of the Inborn Errors Working Party, speakers provided a short summary of their pre-recorded presentations and participated in the subsequent (virtual) discussion with the audience.

Non-SCID primary immunodeficiencies

Prof. Emma Morris kicked off by presenting flow charts on ‘who, when and how’ to transplant adolescents and adults with primary immunodeficiencies. Several key issues, concerns and challenges were discussed including the current poor prognosis of these patients with conservative treatment, difficulties associated with phenotypic heterogeneity in defining transplantation indications for specific genetic diseases, presence of significant comorbidity with impact on transplantation outcome and the availability and promising role of alternative therapies including targeted therapies and gene therapy. Prof. Tayfun Güngör continued by presenting current knowledge and challenges in transplantation for CGD, with a specific focus on the relevance of conditioning and (mis)matched donors in prevention of graft failure and the importance of early transplantation to improve patient outcome. Use of X-CGD carriers as donor and identification of patients for gene therapy were discussed in plenary. Prof. Despina Moshous provided a comprehensive overview of available data on antibody-based treatment in HLH as a bridge to transplantation. First line alemtuzumab treatment was compared to first/second line ATG and emapalumab treatment and demonstrated highly efficacious in remission-induction of HLH activity pre-transplantation which, in turn, impacts on post-transplantation survival. Prof. Andy Gennery finished the session by summarizing available knowledge on transplantation for DNA double strand breakage repair disorders and emphasizing the importance of both a genetic diagnosis before start of transplantation and the use of reduced-intensity conditioning in reducing transplant-related mortality and late effects. Non-genotoxic monoclonal antibody-based conditioning may become a preferable regime in this patient category.

Immune dysregulation

In her pre-recorded presentation, prof. Sophie Hambleton highlighted immune dysregulation as a common manifestation of inborn errors of immunity with, currently, 45 immune dysregulation genes being published. Several red flags that may point to a monogenic disorder underlying auto-immune manifestations were highlighted, including early onset, multisystem involvement, positive family history, developmental delay and infections and/or lymphoproliferation. Prof. Eleonora Gambineri started the live session with an overview of the so-called ‘T-regopathies’, IPEX being the prototype of this category of primary immune regulatory disorders (PIRD). A special focus was put on management of PIRD, including use of immune suppressive and -modulatory treatment regimens and the curative potential of transplantation. The importance of early diagnosis and treatment to improve patients’ clinical condition before transplant was emphasized. Dr. Jennifer Leiding continued the session by presenting recent insights into ‘precision medicine’ for PIRD: modulation of aberrant immune responses responsible for disease manifestations using targeted therapies based on molecular and mechanistic characteristics of these diseases. Again, although lots of questions remain, the importance of disease activity before transplant was highlighted. Precision medicine ‘as a bridge to transplant’ may significantly impact on the outcome after transplant and will be increasingly used for this purpose. Dr. Isabelle André finished this session with an overview of the current pre-clinical activities and results concerning development of gene therapy for IPEX. A promising approach with encouraging pre-clinical (murine) results. Translation to the human setting may follow shortly.

Inherited metabolic diseases (IEM)

Prof. Robert Wynn discussed principles of cell therapy for lysosomal storage disease. ‘Cross correction’ of enzyme deficient cells after enzyme delivery by donor hematopoietic cells, including their potential to cross the blood-brain barrier and provide long term enzyme delivery to the CNS, was highlighted. Since transplant is considered more effective in preventing disease progression rather than reversion of established manifestations, early treatment seems important. Dr. Jaap-Jan Boelens emphasized the significance of early transplant and the benefits of newborn screening: leukodystrophy patients with good pre-transplant performance scores have better outcomes. Moreover, use of myeloablative conditioning and cord blood (stem cell source) results in highest donor chimerism rates/enzyme levels and better outcome. Dr. Jörn-Sven Kühl further underlined the importance of early transplant: post-transplant outcome of adult patients with IEM seems more dependent on patient selection (pre-transplant condition) than transplant conditions. All speakers highlighted the promise of gene therapy reaching supra-normal enzyme levels, which was supported by Dr. Maria Ester Bernardo demonstrating results of a phase I/II clinical trial for gene therapy in Hurler disease: supra-normal enzyme levels in peripheral blood and depletion of GAGs in urine and CSF were reached, with (preliminary) evidence for clinical efficacy in two patients. Dr. Arunabha Ghosh finished the session with an overview of different treatment modalities for several IEM. He provided evidence for and considerations about current standards of care, (dis)advantages of competing and/or complementary therapies, new or promising future treatment modalities and discussed the challenges for treatment of individual patients and design of clinical trials.

Severe Aplastic Anaemia Working Party - Friday, 10 July 2020

Summary by Pedro Henrique de Lima Prata, Physician associate at the Bone Marrow Transplant Unit at Saint Louis Hospital, Paris, France

Aplastic anemia diagnosis algorithm and Diamond Blackfan anemia

Dr. Régis Peffault de Latour reviewed germline mutation screening in aplastic anemia: it is indicated to patients presenting with a combination of chronic progressive cytopenias, early age, positive physical findings, family history of blood diseases, lung fibrosis or liver cirrhosis, elevations in fetal hemoglobin / α-fetoprotein or absence of PNH clone. Dr. de Latour recommended that all children and adolescents undergo, in a stepwise fashion, chromosome breakage test, telomere studies, and those younger than ten years, a dedicated genetic panel.

Dr. Thierry Leblanc discussed non-transplant treatments for Diamond Blackfan anemia (DBA). Transfusion support with appropriate iron chelation should aim for quality of life. Steroids are the mainstay treatment and should be tested in every patient and kept at the lowest effective dose – with systematic prevention against toxicity. Steroids' associations with other drugs are not effective. Patients who remain transfusion-dependent are candidates for transplantation. Dr. Leblanc concluded presenting a preclinical gene therapy study with promising results.

Dr. Jean-Hugues Dalle noted that transplantation from a healthy matched sibling or unrelated donor is a reliable treatment for DBA – scarce data with haploidentical donors. A normal hemoglobin level is insufficient to rule out DBA in siblings, and genetic studies are necessary. Dr. Dalle concluded recommending that patients undergo aggressive iron chelation and transplantation before ten years of age, with a myeloablative busulfan or treosulfan conditioning regimen without TBI.

Current and future treatments in Fanconi Anemia

Dr. Carlo Dufour reviewed HLA-matched transplantation for Fanconi anemia: it is the only consistent option to restore hematopoiesis and is indicated to patients with severe cytopenias, poor-risk cytogenetics, or excess of blasts. Patients with secondary MDS/AML need debulking before transplantation. The best moment for transplantation is the shift from moderate to severe cytopenias, and a fludarabine-based regimen yields better results. Chronic GvHD increases the risk of solid cancers, and close surveillance is crucial for long-term survival.

Dr. Camem Bonfim emphasized that haploidentical transplantation for Fanconi patients is continually improving. T cell-depleted grafts provided good engraftment and low risk of GvHD but are expensive and not widely available. T cell-replete grafts with an adapted dose of PTCy, cyclosporin, mycophenolate, and lymphodepletion with ATG or alemtuzumab decreased GvHD risk and improved survival.

Dr. Juan Bueren explained that gene therapy mimics the natural somatic mosaicism seen in Fanconi patients who present a milder, revertant hematologic phenotype. He underlined that cell collection in Fanconi patients is challenging. Contrary to other disorders treatable with gene therapy, the defect is in stem cells. Then, he presented his team’s experience: stem cells were mobilized, harvested, purified for CD34+, transduced with a lentivirus carrying the gene, and re-infused into the same patients without any conditioning regimen. The infusion of sufficient corrected CD34+ cells resulted in progressive hematopoietic reconstitution. Dr. Bueren concluded presenting a phase 2 trial to treat patients in an earlier stage of marrow failure to collect, transduce, and infuse a higher number of corrected cells.

Nurses Group - Wednesday, 8 July 2020

Summary by Miranda v Harmelen, Nurse stem cell transplant Willem-Alexander Children's Hospital (WAKZ), Leiden University Medical Center, The Netherlands

Care for the donor

Being a pediatric donor for your sibling

Daphna Hutt gives us a presentation about the meaning of being a pediatric donor for your sibling. Although bone marrow and peripheral blood collection in minors is generally safe, we have to keep in mind the both positive and negative emotional and psychological consequences of the donation. Parents in general do have concerns for both children, but tend to look at the more good effects of the donation. It seems parents have a difficulty to contain the complexity of the situation and the dilemma’s there are involved. She spoke about the 5 conditions of the American Academy of pediatrics (2010) under which a minor may participate as HSC donor. Like the FACT-JACIE international standard 7th edition, they recommend the role of a donor advocate. Recent studies showed however that increased adherence to the recommendations is needed. In addition, long term follow-up of the donor is required, although it is not yet clear how long this follow-up should be.

Being an adult donor for your sibling

Annika Kisch speaks about some important and difficult aspects in adult sibling donation care. Sibling donors are in a vulnerable situation, with a mix of both positive and negative experiences. She illustrates the ethical complexity of stem cell donation and transplantation with some vivid examples from her study. Both recipient and potential donor/ donor has to be respected and treated as an autonomous person with autonomous choices. In order to be able to make a well considered choice, the potential donor needs honest and correct information. We have to keep the care and information to recipient and donor separated. Annika also highlights the need of long term follow-up of donors, based on individual needs which may change over time.

The information roadmap during HSCT

Information session pre-HSCT

Simon Slade discusses the importance of pre-transplant information for patients preparing to undergo HSCT. He advocates that the transplant work-up should consist of a medical work-up (clinician-led), but also a practical and pastoral work-up (nurse-led) paying attention to emotional and psychological welfare, information giving and forward planning. He give’s an insight in how these pre-transplant sessions are delivered at King’s College Hospital. He urges to collect feedback at different time-points post transplant about wether patients think they were well informed pre-transplant for future service development. 

Using E-heath

Sabine Valenta starts her presentation emphasizing the high need of people in general for digital tools and technology like internet and mobile phones. She explains e-health is an umbrella term covering a wide variety of ICT applications for health. It creates many opportunities for innovation in health and can foster progress in healthcare. However, to maximize their use and effectiveness the applications should be developed by a User Centered-Design in which the needs, wants and limitations of the end user are given attention at each step of the design process. She finishes her presentation by giving us a brief insight in the SMILe study and the development of an e-health app for patients post HSCT. 

Nurses Group - Thursday, 9 July 2020

Summary by Teija Schroder, Nurse, New Children’s Hospital, Helsinki, Finland 

Emotional and physical preparation for HSCT - Chair: Simon Slade

Emotional preparation for HSCT: Renee Gregson, Pedagogical Specialist, Leiden, NL

Renee Gregson explained why it is important to prepare children for Hematopoietic stem cell transplantation. Children have the right to be informed, they should understand what is happening, gain control over what is happening and learn how to best cope with minimizing distress and trauma. Knowing the individual needs of the child and family is important. The pedagogical specialists have meeting with families to gain information. It is also important to build a trusting relationship. Using language with positive suggestions and words instead of negative ones is vital.

Empowerment of the child is important so that children have more control over their situation. That is why they teach different coping strategies (such as distraction and medical hypnosis). Empowerment of the parents is important as they play a key role in their child’s life. The team makes a plan together with the parents outlining how to best support the child. Video interaction guidance is a good way to support the parents so they can reflect on their own interactions with their child.

Renee discussed the specific aspects of HSCT. In general, it means a long stay in isolation and coping with bad days. They encourage the children to bring important things from home to make the room feel like their own and they find things to do in the room. They also prepare for the bad days. It is ok to not feel like talking sometimes etc.

HSCT is a treatment with serious risks and the older the child is, the more they understand. It is important to prepare before returning home and families need support the whole time. As Renee ended her presentation, she said that the most important option is to prepare children personally and individually to meet their needs.

Psychological preparation for transplants-Holistic Pre-transplant psychological assessments: Surabhi Chaturvedi, Psychotherapist,London, UK

HSCT is a common treatment, but remains gruelling and demanding with late effects and accompanying psychological distress. There are three levels of preparation ahead HSCT (medical, practical, psychological). The goal of assessment is to paint a holistic picture, identify risk factors and offer support early in the pathway and to identify anything that suggests a transplant should be delayed because further exploration is needed.

Assessment can be a single event or an ongoing process that occurs over time within the doctor–patient–nurse relationship. Surabhi Chaturvedi explained the practice at Kings College Hospital and they have routine assessments with all HSCT patients. Patients are referred by transplant clinical nurse specialists. And where there is known distress, patients might be referred for psychological input quite early even when HSCT is tentative.

Patients see the assessments as evidence of a caring attitude from the department and express their appreciation for such a holistic approach. It helps to build trust and confidence in the transplant team. The purpose of the assessment is to form a picture of each patient through collaborative discussion and talk about how they might cope with transplant anticipated hurdles and how to adapt the care.

In Surabhi’s concluding comments, she wanted to point out two important things we all can do: Don’t make assumptions about how patients might be feeling. Be open to asking them instead. Be prepared to validate/understand/normalise what they are feeling. The other thing is, remember that there is no right or wrong way of coping with HSCT;-people’s coping strategies in dealing with uncertainty and threats are very different. Holistic care can start with a small step such as integrating a psychological mindset into the routine care you are already providing.

How to survive isolation during HSCT - Chair D. Hutt

Patient experiences: P. Van Leewen
Surviving physically: M. Bakker & M. Van Der Holst

The first speaker in this session, Pepijn van Leeuwen, was unfortunately not able to join the live session due to school exams. Pepijn is a 21-year-old student and a former patient of the LUMC hospital. He shared his experiences with us in a very interesting recorded talk. Included in this interview, a nurse asked him by mail what nurses can do to support patients in (re)defining goals. Pepijn answered as follows and he agreed in sharing this with all of you: “I think working with patient goals works best in three steps. These are (1) identifying, (2) facilitating and (3) evaluating.” In the first step a goal for the patient must found. When no long-term goal can be found for a patient, a "small" and achievable goal per day can always be made up. Pepijn sees key role for nurses, pedagogical specialists and the teachers. The second step is to facilitate working towards the goal. Nurses play a key role here as well, because they are the first contacts for the patient and they also know best what is feasible for a patient or not. The final step is to evaluate the patient's goals. Pepijn wrote that nurses, pedagogical specialists and teachers should again be involved. Probably they can meet to discuss patient, so that the patient's goals are clear for everyone.

Charlotte Bakker and Menno van der Holst, both paediatric physiotherapists at the LUMC in Leiden explained us very clearly the goals of physiotherapy during HSC per age stage. These goals are to stimulate motor development (especially in the youngest age group), to maintain physical fitness, muscle strength, range of motion, motor activities and to promote daily activities and/or sports. These activities need to be included in the very intensive period of HSCT and around 5% of the total time of day focusing on active time should be the goal. Charlotte and Menno explained several facilitators to keep children active during HSC, such as an active lifestyle before hospitalization, an active family, a positive look on being active from caretakers, normal day completion, the possibility to go outside, an attractive and challenging environment and a multidisciplinary team promoting activity. Again, a huge role for nurses, since they are involved in a lot of the mentioned aspects. Include being active during daily care and make being active attractive where possible.


Nurses Group - Friday, 10 July 2020

Looking back on HSCT - Chair: Hilda Mekelenkamp

Long term follow-up after HSCT with non–malignant indication: Tony Neuman van Eijk, nurse practioner, Leiden, NL & Joell Bense, PhD student, Leiden, NL

Tony and Joëll presented their experience on (long term) follow-up after HSCT and value-based health care in paediatric HSCT.

Tony Neuman discussed the impact of HSCT and explained her experience with children where she works in a late effects outpatient clinic. They have long term evaluation of complications after HSCT, for malignant indications and non-malignant indications. The focus is on clinical outcomes and patients’ experiences. They want to put the patient in the middle and their greatest necessity is to change the standard psychosocial follow-up.

Joëll Bense continued explaining about the paediatric HSCT center LUMC Leiden in the Netherlands. This hospital is an expertise centre specialised in paediatric HSCT and late effect follow-up for non-malignant haematological, immunological diseases and bone marrow failures.

She explained the outpatient clinic organisation, where they have late effect follow-up from 2 years post HSCT and the transition to adult care where a lifelong follow-up is present.

They are moving forward to value-based healthcare: value is expressed in clinical outcomes, patients reported outcomes and patient reported experiences which is put against cost and efforts of both patients and the healthcare personnel.

The team is improving continuously their quality of care by doing research with health care provider and patient (research together) and creating patient value by a collective effort to improve quality of care in collaboration with patients, their families, doctors and their teams.

Surviving Cognitively: Angela Scherwath, Psychologist, Hamburg, DE  

In her presentation Angela Scherwath explained the terminology and gave some examples of cognitive side –effects of cancer and cancer therapies.

The so-called “chemo-brain” where common examples given by patients are problems like keeping track while reading a book, forgetting important appointments or dates, being easily distracted and unable to multi-task, difficulties learning new information, forgetting words during conversations. Patients use the term “chemo-brain” to describe concentration and memory problems during or after cancer treatment. It is not only chemotherapy that can cause cognitive impairment. Multifactorial genesis (cancer, cancer therapies, associated symptoms) is scientifically termed as “cancer or cancer-therapy associated cognitive change”.

Potential causes to cancer or cancer therapy associated cognitive change are: Cancer, cancer therapies (chemotherapy, radiotherapy, antihormonal therapy, immunotherapy, HSCT, other treatments), psychological and biological factors (fatigue, anxiety, depression, sleep problems, pain, age, cognitive reserve and other factors). For patients it has an impact on nearly all the important parts of life. It can mean problems with their return to work, work performance, family, relationships, social life, pursuing hobbies, self-confidence, psychological well-being, etc. It is important to realise that cognitive problems exist and patients need support.

What can we do to help: Support and validate patients who experience cognitive problems. We can be proactive: educate patients about cognitive problems as potential treatment side-effects, provide informational materials and give patients the opportunity to ask questions, ask patients regularly about memory and concentration problems. We can keep ourselves updated on the topic to provide the best support possible. We can get support from other team members. We should encourage patients to talk with their doctor regarding their cognitive problems.

Supportive Care - Chair: Simon Slade

"To BMT or not to BMT” Transplant and PNH: Joanna Large, Clinical Nurse Specialist for PNH, London UK

Joanna Large started with explaining what PNH is, what the hallmarks of PNH, complications of PNH, signs and symptoms and the standard treatment of PNH are. Prior to Eculizumab (pre 2003) blood transfusions, steroids, anticoagulation, Epo/danazol and bone marrow transplantation was standard treatment.

Joanna pointed out that BMT for PNH is not performed anymore.

Understanding the needs of AYA`s (during HSCT): David Wright, Teenage Cancer Trust Lead Nurse for Teenagers and young Adults, Manchester, UK

David Wright’s presentation started with a definition of AYA (TYA) and he explained that the age range of AYA is not the same in all countries. Why should this group be given special consideration? The AYA/TYA of 13-24-year-olds are a time of great turbulence alongside great development. Life, in this stage, is challenging as young people move from childhood to adulthood. They are in the middle of social, cognitive, psychological and physiological development.

The important support for transplant patients comes from cancer peers, healthcare professional and environment. It is important to make the environment suitable for the young patients and create a room which works and is nice for them. It is also important to have something to keep them occupied. Wi-Fi and food are important for the young. We as professionals, need to be flexible. Also, complimentary therapies might be supportive.

Issues with isolation (impact on inpatients, face to face support and digital offer) need to be attended to. Increased engagement through digital platforms will probably be alive long after COVID. Collaboration is important and professionals need to work together to recognising the specialities in patient care.