Summary report by Ivan Moiseev, RM Gorbacheva Research Institute, Pavlov University, Saint-Petersburg, Russian Federation, and Lars Klingen Gjærde, MD, Department of Hematology, Rigshospitalet, University Hospital Copenhagen, Copenhagen, Denmark, and Cristobal Frutos, Instituo de Previsión Social, Department of Hematology, Asunción, Paraguay, and Sophie Van Lancker, Department of Pediatric Hemato-Oncology and Stem Cells Transplant, Ghent University Hospital, Ghent, Belgium.
This was the first Transplant Complications Working Party Educational Meeting since 2019, and the first virtual one. The event was attended by more than 70 physicians, nurses, data managers and medical students from 25 countries around the world. The meeting focused on novel agents in the transplant field and their complications, like CAR-T cells, checkpoint inhibitors, immunoconjugates. Another focus of the meeting was on novel technologies in the prevention, diagnosis and treatment of transplant complications, including telemedicine, artificial intelligence implications and digital tools for clinic-patient interaction. An important step this year was the participation of patients’ advocates as part of the EBMT patient engagement task force.
The meeting started with the introduction by Zinaida Perić covering the main goals and activities of the working party, including main research focus of the Early Complications, GVHD, Survivorship and Artificial Intelligence sub-committees.
Early complications and Regimen-related toxicities session chaired by Christian Koenecke & Ivan Moiseev.
Secondary HLH after HSCT and CAR-T - Robert Sandler
The session was started with Robert Sandler covering the underrecognized problem of secondary haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome after HSCT and CAR-T. Robert Sandler gave overview of existing criteria of diagnosis as well as the practical view on screening and identifying this complication, timing of development and key clinical features. Existing therapy approaches, including anti-cytokine therapies, ruxolitinib, corticosteroids and etoposide were discussed.
Neurotoxicity after HSCT and CAR-T - Christian Koenecke
The second topic of the session was presented by Christian Koenecke, Early Complications sub-committee chair, and covered important aspects of neurotoxicity of conditioning regimens and CAR-T cells. Christian Koenecke presented the EBMT registry data on the incidence of neurologic complications following fludarabine-based conditioning. Furthermore, his presentation covered existing evidence on immune effector cell-associated neurotoxicity syndrome, including clinical presentation, diagnostic workout and treatment approaches.
VOD after HSCT and immunoconjugates - Ivan Moiseev
Ivan Moiseev presented the existing evidence regarding veno-occlusive disease (VOD) after inotuzumab ozogamicin and gemtuzumab ozogamicin, covered the main aspects of pathogenetic link between these novel agents and VOD, existing evidence on modifiable and non-modifiable risk factors of VOD after these bridging therapies. His talk also summarized possible approaches to reduce the risk of VOD by prolonging the time to transplant, limiting the number of courses, avoiding conditioning regimens with dual alkylating agents and modifying GVHD prophylaxis.
Toxicities after HSCT and checkpoint inhibitors - Alberto Mussetti
Alberto Mussetti then presented the data on the potential risks of transplantation after administration of checkpoint inhibitors to Hodgkin lymphoma patients. Increased risk of acute and chronic GVHD was discussed, including potential of posttransplantation cyclophosphamide to alleviate this risk. Optimal timing of allogeneic HSCT after checkpoint blockade is still to be determined.
Graft-versus-host disease session chaired by Olaf Penack and Grzegorz Basak.
Novel drugs for steroid-refractory GVHD - Olaf Penack
First-line treatment of grade II-IV acute GvHD is still methylprednisolone 2 mg/kg/day. There is no evidence of benefit in treating grade I acute GvHD. Grade II acute GVHD with isolated skin or upper GI involvement, one can use a lower dose of 1 mg/kg/day. First-line treatment of newly diagnosed chronic GvHD is steroids 1 mg/kg/day orally; there is no evidence of benefit in adding concomitant therapy in first line. The Chronic GVHD NIH 2014 criteria should be used for grading the severity of the disease, and the EBMT-NIH-CIBMTR task force guidelines should be used to define steroid refractoriness. FAM regimen (fluticasone, azithromycin, montelukast) in combination with systemic steroid recommended by the EBMT for treating chronic lung GvHD (it is not beneficial as prophylaxis). Ruxolitinib is now the primary choice in steroid refractory acute GvHD. The REACH1 phase 2-study showed high response rates, and the REACH2 randomized phase 3-trial showed an improved overall response at day 28 (62% vs. 39% when using best available therapy) and improved failure-free survival. Ruxolitinib and many other drugs being used to treat GvHD are immunosuppressive and this might compromise the graft-versus-leukemia immunotherapeutic effect of HCT. Blocking of integrins (the mechanism of action of e.g. vedolizumab and natalizumab), leading to less intestinal homing of T-cells, is an alternative approach in treating (steroid refractory) GvHD. Results from trials are awaited. The use of ruxolitinib in steroid refractory chronic GvHD was superior to best available therapy in the REACH3 randomized phase III-trial with an improved overall response in week 24 (50% vs. 25%) and improved failure-free survival. Ibrutinib is another FDA approved alternative for 2nd line treatment of chronic GvHD.
Fecal microbiota transplantation for GVHD - Jaroslaw Bilinski
Jaroslaw Bilinski talked about fecal microbiota transplantation as a treatment strategy for GVHD. The main points covered were: GVHD is microbiota dependent; microbiota-depleted mice do not develop GVHD; microbiome diversity decrease early after transplant, followed by a slow and variable recovery; fecal microbiota transplantation (FMT) might be a therapy to improve the recovery of microbiota diversity which may give a beneficial immunomodulatory effect; gut colonization of antibiotic-resistant bacteria has been associated with decreased survival, and lower pre-transplantation microbiota diversity has been associated with higher transplant-related mortality. FMT acts anti-infective in transplant-patients even if the antibiotic-resistant bacteria were not decolonized. In a prospective, multicenter study of patients with acute and chronic GvHD, the overall response rate after FMT was 57%. In a collection of FMT studies the overall response rate was ~70% in total. There might be a potential in combining FMT with ruxolitinib (double immunomodulation).
Telemonitoring for lung GVHD - home spirometry - Guang-Shing Cheng
Dr. Guang-Shing Cheng introduced us to the use of home spirometry telemonitoring for lung GVHD. The diagnosis for bronchiolitis obliterans syndrome (BOS) relies on spirometric criteria (airflow obstruction and airflow decline) per NIH 2014 consensus guidelines. Early detection of BOS is important; having more severe lung symptoms at diagnosis is associated with higher mortality. At diagnosis of BOS, the FEV1 is on average approximately 50% of normal, hence, the pathological process has been underway for some time prior to diagnosis. The key to making an early diagnosis of BOS is routine interval spirometry looking for patterns of FEV1 over time, rather than diagnosing at a specific cutoff. BOS should be screened for in high-risk patients, i.e. patients with chronic GvHD (in whom BOS occurs in approximately 14%, usually withing 6 months of diagnosis of chronic GvHD) and patients with a history of respiratory viral infection or with evidence of spirometric decline at day 80-100 post-transplant. Measurements using handheld spirometry correlated well with laboratory spirometry; however, adherence can be poor. An enhanced implementation is through an app that gives feedback and sends data directly to the treating physician as well as sends reminders to the patient to do new tests. Further work needs to be done to improve adherence, reliability, and implementation and to address whether the use of home spirometry it improves outcomes after HCT.
Machine learning in GVHD - Amin Turki
Dr. Amin Turki gave a walkthrough of the use of machine learning methods in GVHD research. Several HCT risk scores exist that use traditional statistical methods on baseline variables and prognostic biomarkers. Machine learning may improve the prediction and classification of outcomes after HCT. Basis for machine learning is big data, obtained from registries, large collaborative groups, and new initiatives, e.g., the HARMONY big data platform (~45.000 patients with malignant hematologic disease). A study using machine learning methods (alternating decision tree) to develop a prediction model of day +100 mortality after HCT (Shouval et al., JCO, 2015) showed an improved discrimination compared with the traditional EBMT risk score (AUC 0.70 vs. 0.65). Arai et al. (Blood Advances, 2019) also used an alternating decision tree model to prediction grade II-IV acute GVHD with an AUC of 0.62. Tang et al. (JCO Clin Cancer Inform, 2020) predicted acute GVHD from longitudinal vital sign data from electronic health records which improved discrimination compared with only using baseline data. Gandelmann et al. (Haematologica, 2019) used machine learning methods to identify different phenotypes of chronic GvHD with different risks of mortality. Future predictive models should address dynamic, individual predictions over the course of transplant.
Survivoship. Chairs: Helene Schoemans & Zinaida Peric
Male-specific late effects after HCT – Andre Tichelli
No standard screening for male survivors and late effects are often neglected as opposed to female patients. Genital cGVHD is underreported. The incidence is 5-20%, frequent with other GVHD manifestations. Pain, itching, erectile dysfunction, non-infectious inflammation and histopathological findings are compatible with cGVHD. The treatment includes topical, systemic treatment and surgery if phimosis develops (circumcision). Hypogonadism is associated with low testosterone and the major risk factors are TBI, age, cGVHD, excessive weight, diabetes, and iron overload. Mayor manifestations are reduced libido, erectile dysfunction, depression, decreased muscle mass, osteoporosis, gynecomastia. Endocrinologist consult is mandatory in this complication. The same guidelines should be applied as for regular population. 27% of patients remain sexually inactive after HCT (when compared to 8% of general population). Survivors with high sexual knowledge are more sexually active. Male infertility is frequent, and sperm preservation should occur as early as possible. Mayor risk factors of infertility are TBI, cGVDH, age, short follow up after HCT. The incidence of prostate or testicular cancer is not increased after HSCT, however penile cancers do occur in patients with cGVHD. Screening programs for secondary cancers should be implicated after HSCT. A multidisciplinary approach including urologist, dermatologist, sexual health specialist and endocrinologist with appropriate is needed.
Pregnancy after HCT – Nina Salooja
BMT survivors are 36x less likely to report conception than their siblings. Relevant factors: age, radiation, chemotherapy agents, assisted conception. Total dose of radiation & age: time needed for recovery of fertility. Sterility may be permanent. Busulfan is more toxic for female fertility with 0% getting pregnant after BuCy. BEAM conditioning is less toxic for women but some men are left sterile. Preservation of fertility should include cryopreservation of sperm for males. embryo and oocyte cryopreservation, donor eggs, ovarian tissue cryopreservation (less time consuming) for females. The problem with ovarian tissue is ovarian metastasis from main tumors (11% for leukemias). During pregnancy one should consider risk for cardiac, respiratory, and renal disease in the early trimesters. After radiotherapy & chemotherapy the following adverse outcomes of pregnancies were reported: smaller uterus, lower pregnancy rates, low birth weight. Follow up of HCT patients for thalassemia resulted in normal pregnancies for partners of male patients and 13/22 pregnancies with complications while in females 22/27 pregnancies resulted in low weight at birth. No congenital abnormalities ere documented for both genders.
Telehealth model of long-term follow-up clinic – Catherine Lee & Denae Davis
Telemedicine practitioners have a license to practice in the residence area of the patient or partnered with local oncology practices. This model was more extensively used due to COVID-19 pandemic in the US. Patients were required to stay near the transplant center for 60 days and then return home. For allogeneic HCT after day 90 if requirements are met a monthly in person or virtual visit is scheduled to assess for GVHD and other early complications. At 1-year formal transition to Survivorship program was done virtually or in person. Vaccines were given locally. Late follow-up by telemedicine began at Fred Hutchinson in the 1980s via telephone. This approach served to guide patients and respond to queries. Research nurses address 60-70 queries per week, about half are responded by nursing stuff and half are discussed with attending physicians before providing an answer. The benefits for a patient include no travel requirements, cost-effectiveness, better communication with local provider. Current challenges are the need of a proper equipment and technical support, reimbursement is not uniform, limitations of physical assessment, limited number of evidence-based studies.
Digital Methods for Survivorship Care: The INSPIRE Project – Karen Syrjala & Jean Yi
HSCT survivors have a lower life expectancy than general population for several reasons, among them are new cancers and cardiovascular diseases. 44% of patients are not adherent to health care guidelines. Factors associated with non-adherence: avoidance, lack of knowledge, provider barriers. Digital methods can alleviate these problems by reaching a growing number of HSCT survivors with programmed personalized recommendations regardless of distance. Several survivorship studies were performed. Inspire 1 included 755 patients who were randomized to participate in the Internet survivorship program. Distress and fatigue were the major endpoints. The study comprised 3 arms: Inspire website, inspire website + phone calls, control resources website with delayed inspire access. No effect on fatigue was observed, but improvement of distress was observed compared to the control group. In the Inspire 2 study 936 patients were randomized to website with social media or control, resources with delayed INSPIRE access. The major endpoints were distress and health care adherence. 2 arms: No significant impact on distress was documented. Only 40% viewed the Inspire web pages. The main lesson of the study was that digital survivorship care reduced distress in people who use the materials. Inspire 3 study is underway. Distress and poor health care adherence to cardiometabolic or subsequent malignancy surveillance is the main focus of the study. This study is using web based application where the response adapts to patients.
Patient, Nurses and Physicians Joint Session. Chairs: Jaleel Mohammed & Sophie Van Lancker
EBMT patient engagement Task force - Helene Schoemans
This topic is related to the engagement of the patients in het EBMT. As health care workers we have to see the patient as an individual experiencing a disease with whom we partner to achieve optimal care. By engaging patients and caregivers we can increase the relevance, the uptake and the real-life use of the research topic. The place of the patients and the caregivers can be introduced in the whole research cycle. It is very important to provide feedback to the participants and reach out to broader groups. The key word is co-creation. The EBMT aims to be the connection between patients, scientific community and other stakeholders to anticipate. The EBMT patient advocacy committee and the EBMT transplant complication working party started a taskforce the patient Engagement. The mission is to promote active, collaborative participation of patients, donors and caregivers and health care professionals as partners.
What matters from a patient’s view? - Chris Lewis
Chris is a survivor of various forms of graft versus host disease several years after transplant. This changed his life. From his perspective he wants some organised support, peer support because of the uniqueness of the GvHD illness. Also support in the work environment and financial support are big issues for a patient with GvHD. It is different from the diagnosis of cancer, this is a disease that is difficult to treat and is associated with recurrence. There is less money and less interest in this topic. All this makes life of a GVHD difficult.
Patient-oriented physical rehabilitation - Jaleel Mohammed
QoL in patients after HSCT is different from the point of a clinician and a patient. For patients it can be a very practical thing, like to be able to sit on the floor, are to be able to walk properly etc. These are things that you have to do to go further with your life as before. There is a variable range of expectations. In the assessment it is important to do a whole body assessment and not only focus on the area that causes pain. Exercises are not always appropriate to the patients’ problems. But exercises have multiple benefits if they are adjusted to a patient. The prescript exercises must have a rationale behind. You have to measure improvement. There is the guideline for physical therapy for managing HSCT patients at all stages of treatment. Rehab starts before the HSCT. One size don’t fit all. It is recommend that each transplant centres have a dedicated HSCT case manager who will be responsible for overseeing the patient’s journey from pre SCT up to three years after.
Promoting health and well-being through mobile app - Sung Won Choi
The last years there is a growth in mobile connectivity, computing power and data science. Also data security and privacy are very important issues. Development of mHealth technology to promote health at the right persons at the right time gives a reduced cost in healthcare. In march 2020 with the pandemic this way of reaching patients was developing fast. The BMT roadmap (mobile app) for inpatients to give advice 24/7 and it was very patient-specific in real time. Family caregivers and patients (adult, AYA, paediatric pt) were involved in the design and testing. Outpatient tool provides further guidelines and help to discharged patients. The roadmap 2.0 was born. Now there are a chat forum, a page about resilience building activities, mood and sleep issues.