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Report of the Transplant Complications Working Party Educational Meeting - 29 September - 1 October 2022 – Berlin

Transplant Complications Working Party (TCWP)

Summary report written by Ivan Moiseev, TCWP Secretary, RM Gorbacheva Research Institute, Pavlov University, Saint-Petersburg, Russian Federation.

This year Transplant Complications Working Party Educational Meeting was conducting an offline “hands-on” meeting focusing on practical aspects of transplant complications. Experts among physicians, nurses and patient advocates shared their experience in the field of transplant and CAR-T complications in the form of interactive case-based discussions where practical aspects of decision-making were closely interlinked with theory behind them. Vast majority if topics regarding complications were covered, including risk assessment at different stages of transplant, graft-versus host disease (GVHD), veno-occlusive disease (VOD), transplant-associated microangiopathy (TMA), late events, survivorship after stem cell transplantation, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) after CAR-T therapy. The meeting program was enriched by discussion of “difficult patient” cases from young physicians, Sheila Torrado Gonzalez, Mustafa Güven and Marta Castelli, which were chosen from a number of cases submitted and awarded with travel grant.  

The meeting started by Zinaida Perić introducing TCWP team members and covering the main goals and activities of the working party. Ivan Moiseev gave a short overview of the program and Olaf Penack welcomed everyone in Berlin. This year the meeting had more than 70 participants registered.  

Patient journey through allogeneic transplant complications by Ivan Moiseev, Michelle Kenyon, Sheila Torrado Gonzalez.

The interactive session started with discussion of two educational cases to demonstrate the available instruments for risk assessment. The first one described acute lymphoblastic leukemia patient in CR3 after monoclonal antibodies re-induction with high risk of vascular complications and none-relapse mortality. The second case involved Hodgkin’s lymphoma patient with complications after previous treatment undergoing allogeneic HSCT in the fifth line. Different tools for pre-transplant assessment were discussed, like EBMT risk score, Sorror score, novel machine learning-based scores like R. Shouval et al. etc. The necessary clinical, laboratory and instrumental workout necessary to calculate these indexes were discussed. The practical hints in identifying high-risk patients were given by Michelle Kenyon. The first case was representing the utility of available indexes, while the second was demonstrating that for some malignancies the existing indexes have low predictive value, because they were not trained on these populations of patients. The second part of the session was dedicated to a key events that occur in the early post-transplant period that redefine the prognosis, like VOD, severe poor graft function and GVHD. Assessment of late events risk was discussed for each clinical situation with the focus on frequency of clinical visits interaction with patients and their relatives, defining the goals of a follow up and therapy.

Sheila Torrado Gonzalez presented a case of pediatric acute myeloid leukemia patient after intensified induction and conditioning with multiple infectious, vascular and hemorrhagic complications. Clinical decisions on keeping the balance between co-existing complications were discussed.  

Patient journey through GVHD by Hildegard Greinix, Daniel Wolf, Mustafa Güven

The session was started by Hildegard Greinix and Daniel Wolf. It involved discussion of three educational cases, two with acute and one with chronic GVHD with interactive voting on key difficulties in staging and treatment process. All cases described steroid-refractory situations to cover the majority of situations. Latest aspects of EBMT—NIH—CIBMTR Task Force consensus for diagnosis of acute GVHD were covered in the interactive manner. The utility of biopsy in different manifestations was discussed. Key aspects of response, time points for assessment of response were covered. The session incorporated data on emerging therapies for second-line treatment like ruxolitinib, ibrutinib, ECP, belumosudil, fecal transplantation and their place in the course of GVHD treatment.

The session was concluded by presentation of selected case by young physician Mustafa Güven. It described severe steroid-refractory gastrointestinal (GI) GVHD that was treated with ruxolitinib, mesenchymal stem cells and alpha-1 antitrypsin. Emerging infectious complications during the course of immunosuppressive therapy were discussed. Possible slow pace of recovery in GI GVHD was highlighted.

Patient journey through early complications after alloSCT by Sophie Van Lancker, Igor Blau, Tapani Ruutu, Marta Castelli

Tapani Ruutu started the session by presenting the data on EBMT retrospective study on VOD with the spectrum of severity and outcomes. He continued with a case of severe VOD with theoretical bases for diagnosis and therapy like EBMT consensus by M. Mohty et al., ultrasound findings, pace of response to defibrotide, potential aspects of rebound disease after stopping of therapy. Sophie Van Lancker commented with practical tips for nurses on early diagnosis of this complication in children. She highlighted that fluid retention and restless state of young children post-transplant are very important when monitoring patient condition for early VOD signs.

Igor Blau continued the session with a lecture focusing on pathogenesis, clinical diagnosis, utility of biomarker and instrumental findings, as well as necessity of early treatment. He embraced the necessity to follow international diagnostic recommendations and early therapy strategies that were demonstrated by P. Richardson to improve the prognosis.

The session was concluded by Marta Castelli who presented the case of TMA in a 67-y.o. women with MDS. The case described a classical presentation of TMA within several days after onset of acute GVHD. She was treated with tapering cyclosporine dose and narsoplimab with complete recovery. Live discussion of the case covered major existing problems in TMA: lack of severity criteria, lack of clear indications for complement inhibition, potential heterogeneity of pathogenesis with potentially complement-independent cases, lack of comparative studies of different modalities.

Patient journey through late effects and practical guide to implementing patient reported outcomes & Case Presentation by Helene Schoemans, Zinaida Peric, Elke Stienissen

The session involved patient advocate and gave a unique perspective on late complications both from the point of view of physicians and patients. With an interactive case the session gave an overview of quality of life, secondary malignancies and their screening, fertility and social rehabilitation. This interactive session covered usually underestimated and underdiagnosed problems like fatigue, chronic anxiety due to frequent clinical visits, genital chronic GVHD, sexual inactivity and lack of libido, problems with social contacts and maintaining family relationships. These aspects were described in the context of survivorship clinic workflow. Mandatory laboratory and instrumental screenings were discussed as well as tests that could be omitted without significant impact on QoL and outcomes. Aspects of return to work were also covered. Live discussions on the necessity of pre-transplant assessment of baseline goals not to demand to much from rehabilitation program complemented the session.

Combination regimens with extracorporeal photopheresis, an industry symposium by Therakos completed the first day of the meeting. Olaf Penack presented current EBMT recommendations for management of acute and chronic GVHD, gave an overview steroid-refractory GVHD management and novel therapies. Zinaida Peric covered the emerging combination regimens with ECP both for chronic and acute GVHD. The existing clinical data defines 30-40% as refractory even to novel targeted therapies. For these patients there are no standards of care. Most common combination regimen reported is the combination of ruxolitinib and ECP, while several smaller studies were published describing ECP combinations with other targeted therapies.    

HSCT: Real-World-Evidence in CMV-Prophylaxis & Immunreconstitution, an industry symposium by MDS, opened the second day of the educational meeting. Georg-Nikolaus Franke covered the mechanism of action of letermovir in cytomegalovirus (CMV) reactivation prophylaxis. The existing evidence on significance of pp65 expression on cells for graft-versus-leukemia was demonstrated. Published studies highlight lower risk of relapse in patients with malignant diseases who had CMV reactivation. Letermovir retains expression of pp65 protein without competent virus replication. Clinical data on letermovir prophylaxis efficacy was presented. Elisa Sala presented the data on immunological aspects of anti-CMV immunity and time to competent immune response to CMV after different GVHD prophylaxis regimens.

Patient journey through CAR T-cell therapy by Leo Hansmann and Christian Schultze-Florey

The focuse of the session was placed on CAR T-cell therapy associated complications apart from CRS, ICANS and cytopenias. In an interactive case-based approach, Christian Schultze-Florey from Hannover Medical School discussed the role of bridging therapy and indications for dose adjustments of lymphodepleting chemotherapy. Moreover, tumor lysis syndrome induced acute kidney failure was covered including renal replacement therapy as possibility to proceed with lymphodepletion in such settings. Leo Hansmann from Charité - Universitaetsmedizin Berlin then focused on infections post CAR T-cell therapy. After providing an overview about the incidences of bacterial, viral and fungal infections following CAR T-cell therapy, strategies for prophylaxis were presented, including vaccination schedules. Of note, no guidelines have been published to this end yet and the audience discussed different approaches applied in the transplant centers.” Current guidelines for prophylaxis and management of infections after CAR-T were described in detail.

 Practical guide to manage CAR-T complications by Olaf Penack, Christian Könecke, Nora Möhn

The session consisted of two interactive cases describing classical manifestation of CRS after CAR-T therapy, but unusual further clinical course. Olaf Penack presented a case of NHL patient treated with CAR-T in the second line, but developed grade II CRS early after infusion she was treated with steroids and tocilizumab. Aspects of early steroid administration in CRS were discussed. The existing studies demonstrate that there is limited impact of short-course immunosuppressive therapy on long-term anti-tumor outcomes. However the patient developed cytopenia lasting beyong 100 days. The results of the resent TCWP study on the incidence and outcomes of cytopenia after CAR-T therapy were described. New TCWP survey on the strategies to manage cytopenia was advertised.

Second case was presented by Christian Koenecke with Nora Möhn. It described refractory NHL patient who developed both CRS and ICANS after CAR-T infusion. ASTCT guidelines for diagnosis of ICANS and monitoring strategies for neurotoxicity were described. The potential risk of exacerbation of ICANS with anti-IL-6 therapies was discussed. After response to dexamethasone the patient developed macrophage activation syndrome (MAS) with multiorgan failure and was treated with anakinra. Existing evidence on dosage regimens was covered. The patient was diagnosed sepsis several days thereafter. The difficulties of differential diagnosis between sepsis and MAS and response in the cases presenting with both were discussed.

Impact of novel tools on complication management: artificial intelligence and more by Jaroslaw Bilinski and Amin Turki

Amin Turki presented an overview of existing studies using complex models and neural networks in the field of stem cell transplantation to define prognosis. The first implementation of these models was done by Rony Shouval who used decision tree models to predict mortality in acute leukemia patients undergoing matched related and unrelated allogeneic stem cell transplantation. Subsequent studies involved re-staging of graft-versus-disease with machine learning tools, additional modeling to predict non-relapse mortality. The major disadvantage of these models is lack of input information and relatively low predictive value. The recurrent neural networks on the contrary use additional time-dependent data, like laboratory results that increase the predictive values dramatically and can be use to assist physicians in decision making. The future looks more promising with practical application of the latter type of neural networks.

Jaroslaw Bilinski presented another break-through direction in the field of stem cell transplantation: gut microbiome studies and correction of microbiota with fecal microbiota transplantation (FMT). The results of ongoing EBMT multicenter study was presented that incorporated data from almost all centers applying academic-developed FMT. The group of patients mostly involved patients failing second-line immunosuppressive therapy of acute GVHD, yet the response rate was high, exceeding 60%. The other part of the lecture described the use of FMT for decolonization of a GI tract from multidrug-resistant bacteria that are associated with high mortality in case of bacteremia. The efficacy of the procedure was also high, but the mechanisms behind of FMT and tools to predict response are still to be elucidated.