Summary reports by the EBMT Trainee Committee
Physicians Session 1: Summary by Cristobal Frutos
Alejandro Madrigal: HLA Principles and donor selection (including DSA)
The most important factor that influences outcome after HSCT is HLA matching. HLA: Human Leukocyte Antigen. Function is to present peptides to T cells allowing elimination of foreign particles and recognition of self, in transplant this needs to be modulated.
HLA is located in chromosome 6. The classical class 1 HLA are A, B, and C; and class 2 are DR, DQ and DP. Due to the structure of the HLA molecule single amino acid changes may result in significant differences in peptide/antigen interactions. As of 2021 there are over 20000 described alleles of HLA class 1 and over 7000 for class 2.
Concept: Linkage Disequilibrium & Haplotypes: LD are alleles that occur together with a higher frequency than would be expected by chance e.g. B*08:01 and Cw*07:01. Haplotypes refer to a group of genes inherited together e.g. A*01:01, B*08:01, Cw07:01, DRB1*03:01, DQB1*02:01.
Donor age also has a strong impact in post-transplant survivor with best results when donor is around 30 years of age. Sex has some degree of impact specially with female donors to male recipients. CMV status (+ to + and - to -) as well.
Donor Specific Antibodies: Against HLA of donor. May be unique to a specific allele or an epitope that is shared by more than one HLA molecule resulting in cross-reactivity. It can be as low as 5% in males or as high as 86% in female recipients. Options to reduce graft failure include plasmapheresis, immune-adsorption, antibody neutralization using platelets among others if titers are high.
Christian Chabannon: Basic principles of cell procurement and cell processing
Definitions: Hematopoietic graft: Non-substantial modifications of the collected cell products. Will not affect functional properties.
Somatic cellular therapy medicinal product or gene therapy medicinal product: substantial modifications through cell engineering of collected cells. Will affect functional properties.
Cell Collection: May be Hematopoietic or Immune Cells. HSC may be collected from peripheral blood (apheresis), bone marrow (aspiration), cord blood (after delivery).
Apheresis: automated techniques based on the physical separation of blood components in an extracorporeal medical device. Cells can be separated by size by centrifugation for instance. Circulating CD34+ cell numbers are predictive of collected cells by formula CD34 cells per liter of processed blood = (peripheral blood CD34/L) x 30% / body weight. Stem cell content is measured using flow cytometry to provide CD34+, CD45+ and viability. In stem cell products most cells are “contaminants”, CD34+ cells account to 0,1 to a few percent of the total collected cells.
Physical characteristics and cellular composition of collected cell products depend on the choice of stem cell source. Bear in mind peripheral blood grafts have 10x the amount of CD3+ cells than that of bone marrow and cord blood has about 10x less.
For Immune effector cells CD3+, CD4+ and CD8+ cells are measured by flow cytometry to calculate donor lymphocyte infusion.
Cell Processing: Minimally manipulated examples: plasma removal for volume reduction or minor ABO incompatibility, red blood cell depletion to prevent intravascular hemolysis in ABO incompatible donors, T-cell depletion total (also removes NK and B cells) or selective (alpha-beta depletion).
HSC cryopreservation: for autologous HSCT, for cord blood preservation.
Rafael Duarte: HSCT Mobilization Techniques and Options
There are currently 3 commonest mobilisation regimens: A. Steady state mobilisation: Only GSCF. B. Disease specific chemotherapy + GSCF (predominantly lymphomas). C. Disease specific Chemotherapy + Mobilisation chemotherapy (at a later time) + GSCF.
Multiple Myeloma: Steady State (a) or Chemotherapy based mobilisation (c). Chemotherapy based mobilisation using cyclophosphamide 1.5g-4.0g/m2 or etoposide yields a higher CD34+ count but adds toxicity of chemotherapy vs GSCF alone.
Lymphomas: Disease specific (b) or Steady state (a). Disease specific approaches are suggested to avoid the burden of additional chemotherapy cycles. Steady state may be an option for selected patients: in CR +/- ineligible for chemo mobilisation.
Goals of Stem Cell collection are to maximize CD34+ cells per kilo of recipient weight with the least number of apheresis to achieve HSCT.
Chemotherapy based mobilisation associates with febrile neutropenia and hospitalization ranging from 20% to 48%.
Poor Mobilisers: Peak CD34+ circulating count less than 20/µL on days 4-6 after GCSF alone, on days 18-20 after Chemo + GSCF or less than 2 x 10*6 cells per kilo collected after 3 apheresis. Known risk factors: Age 60+, previous Qtx and Rtx, multiple cycles, previous melphalan, carmustine or fludarabine, lenalidomide.
Plerixafor: if CD34+ count prior to apheresis below 10/µL give pre-emptively. If above 20/µL no intervention needed. If between 10-20 dynamic approach. If plerixafor is available there is no benefit to adding chemotherapy to the mobilisation regimen.
Physicians Session 2: Summary by Yasmina Serroukh
Alvaro Urbano-Ispizua: T-cell engineering and CAR T cell manufacturing: where do we stand?
CAR-T cell production is now available in several European centres. A chimeric antigen receptor (CAR) is a genetic construct introduced to the T cell nucleus via a viral vector. CAR include an antigen-specific extracellular domain linked to an intracellular stimulatory and co-stimulatory domains.
A CAR-T clinical program must follow different steps: leukapheresis, T-cell enrichment and activation, viral transduction, CAR-T cells expansion and infusion to patients.
The biggest challenge faced by academic structures is to obtain a clinical scale quantity of viral particles. Viral production happens in clean room facilities according to GMP. Before clinical use, viral transduction has to be tested for efficacy and specificity using tumoral cell lines or murine models. Humanized CAR-T cells offer an advanced disease model for selection of the more active and less toxic construct before clinical translation. Expansion of CAR-T cells is then achieved in a bioreactor, which is a semi-automatic closed device. After a median of 8,5 days, the amount of CAR-T cells obtained are much superior to what is needed for infusion. This will allow shortening of expansion time. In order to validate the process, two centres handle the half of the leukapheresis product in parallel. Finally, the manufactured CAR-T cell product has to be tested inside a clinical trial and implemented in multiple centres. Therefore, support and approval of the regulatory agencies are mandatory. Despite financial and logistic challenges CAR-T manufacturing is highly feasible in Europe and various collaborative initiatives exist to support and increase accessibility.
Christian Chabannon: Centre Qualification for CAR T cells
Centre qualification for CAR-T cells is needed due to the peculiar nature of CAR-T cells that are medicinal products, manufactured from human primary immune cells. They are produced on demand for one single administration per patient. CAR-T cells qualify as advance therapy medicinal product, gene therapy medicinal product and genetically modified organisms. They persist in vivo after administration which requires sustained monitoring of long-term effects. The centre qualification process is dependent on different actors who cover different aspects such as supply chain mastering and optimization of clinical care in terms of efficacy and safety. Every actor has by nature a different hierarchy of priorities. Pharmaceutical companies (pharmas) may act as commercial manufacturers or as clinical trial sponsors. Pharmas provide the starting material and check that the supply chain meets their quality standard. They also implement a risk mitigation plan in the clinical practice and audit the whole process on a regular basis. Health authorities act at the regional, national and European levels and rather focus on global organization established in the hospital and partners. Their priority is the management of patient’s trajectory from referral, selection and early outcome to long term effects. Actors such as the EBMT play a role in this management by holding a systematic registry that includes more than 2000 patients as from June 2021. Finally, JACIE accreditation warrants conformity to international standards for cellular therapy and is required at various levels in the centre qualification process.
Physicians Session 3: Summary by Lars Klingen Gjærde
This session, chaired by Dr. Florent Malard, consisted of an introduction to the principles of conditioning followed by several presentations on the topic of graft-versus-host disease. Finally, Dr. Lars Klingen Gjærde presented a clinical case on behalf of the EBMT Trainee Committee.
Mohamad Mohty: Principles of Conditioning
- Three “traditional” principles for the ideal preparative regimen: 1) be capable of eradicating malignancy, 2) tolerable morbidity without mortality, and 3) have sufficient immunosuppressive effect to avoid graft rejection.
- Initial concept of conditioning: myeloablation was mandatory to promote engraftment (creating host immunosuppression and marrow space).
- Up until mid-1980’s this was done using high-dose total body irradiation (TBI); after then, chemotherapy-based conditioning was introduced.
- TBI was used because of several important properties: immunosuppressive, anti-neoplastic activity and ability to penetrate sanctuary sites (CNS).
- Chemotherapy-based conditioning was developed to achieve better disease-specific regimens, to avoid detrimental side effects of TBI (growth/CNS development, late effects) and prior dose-limiting irradiation.
- Cyclophosphamide emerged as a good option: an alkylating agent with both antineoplastic and immunosuppressive effects (NB! cardiotoxicity).
- The developments happened in parallel: irradiation was improved by fractionated TBI, chemotherapy-based conditioning was improved by introduction of busulfan.
- Two main traditional regimens: BuCy (especially after introducing IV BU with less pharmacokinetic variability) and CyTBI.
- From late 1990’s: Reduced intensity conditioning. Founding principle from the 1950’s: that the success of allogeneic transplant is mainly due to the graft-versus-tumor/graft-versus-leukemia effect. RIC shifts the burden of tumor eradication from chemo-radiotherapy to the donor immune cells.
- Dr. Rainer Storb from Seattle pioneered the use of RIC and especially the Fludarabine (Flu)-TBI 2 Gy regimen with cyclosporine + mycophenolate mofetil as GvHD prophylaxis. Different regimens were used globally, but most used fludarabine as the backbone, e.g. FluBu.
- BuCy vs. FluBu (Rambaldi et al., Lancet Oncol, 2015): Similar relapse rate but less non-relapse mortality after FluBu.
- However, choice of conditioning is not black and white, cannot be completely disentangled from the choice of donor, use of immunosuppression and many other aspects of HCT.
Ernst Holler: Pathophysiology of Graft versus Host Disease
- Pathophysiology of GvHD divided into three phases: 1) activation of APCs secondary to damage from the conditioning, 2) donor T-cell activation, 3) activation of numerous cellular and inflammatory effectors.
- Minor antigen-specific T-cell activation is important in the development of GvHD.
- Different organ targets in acute (mainly skin, gut, liver) and chronic (mainly skin, mouth, liver, eyes, joints, urogenital tract, lung, gut) GvHD. Main target organs are those with exposure to the environment and to the microbiota.
- Loss of microbiota diversity early after transplantation has been associated with lower overall survival.
- Enterococcal dominance of gut microbiota is often observed after HCT and is associated with poorer outcome.
- Early initiation of IV broad-spectrum antibiotics causes intestinal microbiota disruption.
- Bacterial metabolites (indoles, butyrate, short-chain fatty acids) are important mediators of how microbiota modulates GvHD. Might also be strain-specific effects.
- Natural T-regs suppress T-cell activation and GvHD but maintain GvL effect.
- GvHD development can also be understood through the concept of tissue tolerance interacting with immune tolerance to mediate immunopathology.
- Prior acute GvHD is a major risk factor for later chronic GvHD due its damage of important immunological niches; higher age also a risk factor due to more thymic damage.
- Three phases of chronic GvHD: 1) acute inflammation and tissue injury, 2) chronic inflammation and dysregulated immunity, 3) aberrant tissue repair and fibrosis.
- WNT pathway recently found to be a major contributor to fibrosis, possible beneficial role of WNT inhibitors.
- MAGIC consort biomarkers (ST2 and Reg3α) can, at the time of onset of acute GvHD, predict mortality.
- There are multiple biomarker candidates for chronic GvHD, but prospective multicenter studies are lacking.
- Conclusions: There is a pathophysiological continuum between acute and chronic GvHD. Both tissue and immunological tolerance needed to avoid immunopathology. Biomarkers might pave the way for earlier intervention.
Florent Malard: Acute GVHD Prophylaxis and Therapy
- Effective prevention and treatment of acute GvHD comes with an increased risk of relapse and infections.
- Historical gold standard was calcineurin inhibitor (CNI) + methotrexate (MTX). No benefit in adding prednisolone. CNI can also be combined with mycophenolate mofetil (MMF).
- Anti-thymocyte globulin (ATG) added to the conditioning regimen reduces the incidence of severe acute GvHD.
- The use of post-transplant cyclophosphamide (PT-Cy) as GvHD prophylaxis was pioneered by the Baltimore group for patients receiving a transplant from a haploidentical donor. Easy to use, cheap and associated with a good outcome. Similar outcomes of PT-Cy vs. ATG.
- Gold standard for treating (grade 2-4) acute GvHD: corticosteroids 2 mg/kg/day. Higher doses of steroids do not improve the response rate. Lower doses (1 mg/kg/day) did not yield poorer overall survival but was associated with an increased risk of needing 2nd line immunosuppressive therapy for treating grade 2b-4 acute GvHD.
- Addition of MMF to corticosteroids did not improve clinical outcome over steroids alone.
- In practice: Stage 1-2 skin GvHD (grade I): topic steroids, if no improvement corticosteroids 1 mg/kg/day. Grade 2 acute GvHD: corticosteroids 1-2 mg/kg/day. Grade 3-4 acute GvHD: corticosteroids 2 mg/kg/day. Effective supportive care is critical. Evaluate efficacy after (3-) 7 days. Complete response rate approx. 50%.
- Steroid-refractory acute GvHD: progression after 3 days, no change after 7 days or incomplete response after 14 days.
- New standard 2nd line treatment is ruxolitinib. Still, around 40% are also ruxolitinib-refractory, so there is a need for further therapy in these patients: Fecal microbiota transplantation might be an option, this is under investigation.
Olaf Penack: Chronic GVHD management
- Chronic GvHD should be scored according to the NIH 2014 criteria.
- Steroid-refractoriness/-resistance in chronic GvHD: progression of GvHD while on prednisone ≥1 mg/kg/day for 1-2 weeks or stable GvHD while on ≥0.5 mg/kg/day of prednisolone for 1-2 months.
- Steroid-dependence in chronic GvHD: inability to control GvHD symptoms while tapering prednisolone below 0.25 mg/kg/day in at least two individual attempts, separated by at least 8 weeks.
- Main indication for systemic 1st line treatment is moderate or severe chronic GvHD.
- Standard 1st line treatment is steroids (prednisone 1 mg/kg/day), however, in severe chronic GvHD, the primary addition of another immunosuppressant in order to spare steroids is a valuable option.
- The time needed to preliminary assess the efficacy of 1st line treatment is at least one month.
- Bronchiolitis obliterans syndrome should be treated with FAM (fluticasone, azithromycin and montelukast) regimen in combination with systemic steroids (NB! No use of FAM for prophylaxis).
- There is no standard 2nd line treatment for chronic GvHD; many different immunosuppressants can be considered. Enroll patients in trials as far as possible. Novel substances with encouraging potential: ruxolitinib, ibrutinib, belumosudil. Also, for prophylaxis, panobinostat could be an option in the future.
Lars Klingen Gjærde: Case Presentation: 51-year old woman with jaundice
Lars Klingen Gjærde from the EBMT Trainee Committee presented a clinical case about a 51-year woman presenting with jaundice 9 months after a matched unrelated donor transplant for MDS. The case illustrated the diagnostic workup of jaundice after transplant and the differential diagnoses, including infection, late-onset sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD), drug-mediated hepatotoxicity, gallbladder/biliary disease, and hepatic GvHD.
Physicians Session 4: summary by Nico Gagelmann
Enric Carreras: Early and Rare Complications after HSCT
Enric Carreras depicted the delicate landscape of diagnosis and treating veno-occlusive disease and transplant-associated thrombotic microangiopathy, still a devastating complication. Current consensus defines a 3-hit hypothesis for TA-TMA with 1) inherent risk factors such as female sex, CMV seropositivity, genetic disposition; 2) transplant associated risk factors, such as endothelial injury and a procoagulant endothelium; and 3) post-transplant risk factors such as calcineurin inhibitors and m-TOR inhibitors, acute GVHD, and other infections. Main diagnosis features include proteinuria, sC5b-9 level and ADAMTS13. New treatments coming up such as narsoplimab may eventually improve outcome but evidence is still immature.
Zinaida Perić: Late Complications after HSCT
Zina Perić, current chair of the Transplant Complication Working Party, covered the complex minefield of late complications and survivorship. Althoug new tools such as electronic follow-up etc can help, there is still plenty space for understanding the long-term evolution of complications.
Per Ljungman: How I Manage viral Infections after HSCT?
Per Ljungman showed (lack of) evidence on handling viral infectious complications. Every center has to have algorithms, letermovir with significant benefit in CMV seropositive patients but with blips when it comes to monitoring and treatment initiation for CMV reactivation during letermovir therapy, COVID-19, while parainfluenza and RSV present with severe disease and mortality.
Thomas Lehrnbecher: How I Manage fungal Infections after HSCT?
Thomas Lehrnbecher presented the diagnostic and treatment spectrum of fungal infections, incl differences in adult and pediatric care. Invasive candidiasis and aspergillosis still the main challenges.
Lidia Gil: How I Manage bacterial Infections after HSCT?
Lidia Gil had no other topic to present than bacterial infections and especially points to frequent species and risk factors at different time points. Resistance keeps being a major issue, which is why identifying risk factors is so important.
Nico Gagelmann: Case Presentation
Nico Gagelmann from the Trainee Committee presented a case of a patient with COVID-19 prior to transplant. The discussion afterwards even suggested no urgent need to vaccinate after transplant for infected patients, while evidence for this still needs to accumulate. The role of antibody testing and boosters needs to be determined, and no specific recommendations can be made at the moment.
Physicians Session 5: summary by Yuliya Rogacheva
Alice Polomeni: HCT: Psychological and quality of life issues
Alice Polomeni talk addressed the problem of quality of life in patients before and after HSCT. The study of Mosher C.E. et al. demonstrated, that only 50% of distressed HSCT survivors receive mental health services and it is stay a big problem.
- Fatigue developed in 35-42% patients during 1 year after HSCT. Sociodemographic risk factors: female, younger age. Clinical risk factors: chronic pain, cGVHD, inactivity
- Sleep disturbance developed in 14-51% patients during 1 year after HSCT. Sociodemographic risk factors: older age, female, divorced, unemployed. Clinical risk factors: depression, distress
- 15-40% of patients did not return to previous employment during 1 year after HSCT. Sociodemographic risk factors: lower income, female. Clinical risk factors: cGVHD, physical impairment, more symptoms, more hospitalizations
- Financial burden increased up 73% during 1 year after HSCT. Sociodemographic risk factors: younger age, low income. Clinical risk factors: poorer physical and mental functioning=cGVHD
Addressing physical and psychological symptoms during hospitalization reduces long-term psychological symptoms. Alice Polomeni recommends according to M. Bevans et al psychological interventions for better QoL: psychodynamic psychotherapy, cognitive-behavioral therapy, meaning-centered therapy, mind-body practices (relaxation, guided imaginary). Multicenter trial of an online program for distress patients 2-10 years post HCT: 41% of eligible survivors enrolled.
Helene Schoemans: Patients' reported outcomes in HCT
Helene Schoemans discussed about patient reported outcomes (PRO) in HST. She demonstrated cross-sectional study of Swiss HSCT long-term survivors (n=367) compares to matched controls from the general population. Group of HSCT recipients had overweight BMI and low physical activity compared with general population. This data was confirmed in the Norwegian study from H.S. Bersvendsen et al. Doctor demonstrated important data of E.Basch et al. about integration of PROs into the routine care of patients with metastatic cancer. That was associated with increased survival compared with usual care. Helene Schoemans reported results of a survey from the EBMT: one thousand voices address patient engagement in hematopoietic stem cell transplantation and cell therapy.
Kim Orchard: JACIE and quality markers in HCT
Kim Orchard highlighted the topic of JACIE and quality markers in HSCT and cellular therapy. He discussed about meaning of quality markers in health care. He noted that the quality of a HSCT program is note about outcome; considerations of quality should permeate the entire program. He demonstrated 8th edition of FACT-JACIE Standards and discussed about the Clinical Program, Collection Facility, and Processing Facility must define what key performance data there are going to analyze. Minimally this should include data necessary to complete the quality management activities required in these Standards. He also mentioned that essential elements of quality management program are quality assurance, control assessment, quality improvement activities and discussed about how to achieve the Standards with national and/or international Benchmarking procedures.
Natacha Bolaños: The patient perspective
Natacha Bolaños attempted to clarify the issue of the patient perspective on stem cell transplantation. She discussed that information about transplantation needs to be provided in different formats, and over different intervals and at diverse occasions and communication skills and knowledge have been found to be significant in patient’s preparation, decision-making, and post HSCT Quality of Life. Role of physical therapy and exercise in HSCT is important: exercise during the transplant process was found to help patients recover physically and psychologically. HSCT can impact physical sexual function in a variety of ways, including GVHD affecting the genitals and pelvic floor muscle weakness from sarcopenia and/or steroid use. Physical therapists trained in pelvic floor rehabilitation can play a significant role in improving patient sexual health by educating and instructing patients on exercises aimed at improving pelvic floor strength and reducing symptom burden.
Physicians Session 6: Summary by Alexandra Gomez (presentations 1-4)
Jorge Sierra: Transplant for acute myeloid leukemia (AML)
Dr Sierra provided an overview of transplantation for AML.
- Overall survival (OS) for young patients with AML that undergo an allogeneic hematopoietic transplant has continued to improve over time (Bazarbachi, Clinical Cancer Research 2021).
- Transplant Indications: The 2019 EBMT report on current indications for allogeneic HCT has a good summary of levels of recommendation for AML risks groups including when is recommended as standard of care, clinical option or not recommended (Duarte, BMT 2019). Indications for autologous transplantation in AML has continued to decrease over time.
- Conditioning intensity: Decisions should be individualized (good summary by Gagelmann, Haematologica 2021); the BMT-CTN 0902 prospective RCT, MAvRIC study, clearly showed a benefit for myeloablative (MA) conditioning but the EBMT RICMAC trial did not. There were differences in study population.
- Updates in alternative stem cell donors: Haploidentical transplantation has rapidly expanded in the past years, but cord blood (CB) transplants continue to be a reasonable approach. Beside haplo-cord transplants that significantly reduced the delay in engraftment of a CB unit, there is new data of CB expansion with nicotinamide (Horwitz, JCO 2019).
- Minimal residual disease (MRD) prior to transplant is a strong prognostic factor for outcomes (Zhou, Leukemia 2016).Data from the Fred Hutch suggests that better GVL effect can be achieved by CB transplants, especially for people with MRD pre-HCT (Milano, NEJM 2016).
- GvHD regimens were reviewed and data using ATG (Kroger, NEJM 2016 & Bonifazi, Lancet Haematology 2019) and T-cell depletion was presented (Barba BBMT 2019)
- Transplantation for refractory AML is challenging; the GITMO study suggested better probability of survival for patients with low tumor burden, responses within 2 chemotherapy courses, low blast in PB, younger and favorable/intermediate I Cytogenetics (Todisco, BMT 2017).
- Finally, on discussing novel strategies to prevent relapse after alloHCT, more data on maintenance/preemptive strategies continue to evolve. The Sormain trial for FLT3 positive patients showed a clear benefit for sorafenib (Burchert, JCO 2020). There are novel strategies in the horizon including the novel use of gene therapies (Chapuis, Nat Med 2019).
Charles Craddock: Integrating MRD into AML transplant strategies
Dr Craddock discussed the emergent role of personalization of HCT, particularly on the setting of MRD. He expanded on the discussion of the 3 prospective RCT evaluating the impacting of the conditioning intensity (initially discussed by Dr Sierra; the MAvRIC study, the RICMA study and also included the German AML Cooperative Group). In the discussion, he highlighted several important points on the design and results of the trials that are important to consider when evaluating the results, such as the high Relapsed Risk observed in the RIC arm of the MAvRIC study compared to other historical RIC prospective studies. He also presented the prospective data confirming the impact of pre-transplant MRD on CI of Relapse (Figaro trial, Craddock JCO 2020) that before was only available based on retrospective studies. With the data from Hourigan et al ( JCO 2019) confirming the impact on MRD on the risk of relapse with MA vs RIC conditioning, he emphasizes the need of prospective RCT studies, but also highlights that some patients can have good outcomes when transplanted with a RIC approach , even with pre-transplant MRD positivity. Emerging prognostic indicators are arising in this population, such as the T cell chimerism at day 90 after transplant (Figaro study) and alternative approaches to overcome the relapse risk such as maintenance studies. Prospective examination of novel strategies with the potential to improve transplant outcomes is required, with embedded MRD and genomic studies.
Ibrahim Yakoub-Agha: allo-HCT in higher-risk MDS
Dr Yakoub-Agha summarized his approach for evaluating a patient with MDS in need of a transplant. 1st is the patient fit for allogeneic transplant? There is an Optimized EBMT-transplant specific risk score (Gagelmann Haematologica 2019) to help prognosticate outcomes. For example, the very high-risk group can have up to 50% risk of NRM which is unacceptable. 2nd What is the disease risk score by r-ISS? For patients who are high or very high rISS, transplant should be offer without delay with the caveat that for very high-risk pts, transplantation may not overcome the risk of relapse (Gauthier, Transplantation 2016). For intermediate r_IPSS, if there are additional risk factors such as profound cytopenias, severe fibrosis, poor CG or blasts>5%, he considers them as high-risk. If low risk or intermediate without risk factors, pts can receive non -transplant approaches and evaluate for POD. 3rd: Does the patient need pre-HCT therapy? Retrospective studies failed to show a difference is survival with possible increased toxicities (Damaj, JCO2012). You can use a decision-making algorithm to help decide which patients would benefit the most (Yakoub-Agha, BBMT 2014), but we need prospective RCT to answer this question.
Nicolaus Kroger Transplant for MPN
There is evidence of a graft versus malignancy effect of transplant for patients with MF that is evidence by the improved fibrosis after transplant. Luckily, over the last few years, the use of Allogeneic HCT has expanded for older adults with MF. Dr Kroger summarized how the field has evolved in evaluating patients with MF for transplant. The 2015 EBMT /ELN recommendations regarding patient selection recommend considering pts with INT-2 or high-risk according to IPSS, DIPSS or DIPSS-plus. For Int-1 patients, they should be considered if they present with transfusion-dependent anemia, PB blast>2% or adverse cytogenetics. For lower risk pts the consortium recommended to evaluate for transplant upon disease progression. (Kroger, Leukemia 2015). The field has now evolved to include molecular mutations into prognostics scores that include the MIPSS70 and the MYSEC_PM for post ET-PV MF. Specifically, for transplant outcomes, the novel transplant-related risk scores (MTSS) using novel predictors can be used for decision making.
Physicians Session 6: Summary by Vera Radici (presentations 5-6)
Eolia Brissot: CAR T cells for ALL
Although CD-19 CAR T-cell therapy achieves high rates of MRD negative response in 80% patients, relapses are common and the duration of response remain limited in adults: the median duration of response was 8-19 months with important variations in the proportion of patients receiving consolidative HSCT in CR treatment (35-75%).
Several studies have looked for factors associated with the duration of response to therapy: LDH, higher platelet count, incorporation of fludarabine into the lymphodepletion regimen and HCT after CAR-T cell therapy were associate with better EFS. Lymphodepletion drugs also play an important role, where Flu-Cy showed greater car expansion in vivo and higher response rates.
In clinical practice CAR T-cell therapy is also impacted by prior blinatumomab therapy, associated with a significantly higher rate of failure to achieve MRD remission and CD19 MRD relapse.
With regard to the concept of resistance, several coexisting mechanisms have been described: lack of expansion, lack of persistence and exhaustion. Factors related to the tumor itself include: loss of target antigen, like CD19, resistance to immune killing and the impact of the tumor microenvironment.
Shah has shown that CD19 CAR-T cells followed by a consolidative alloHCT can provide long-term durable disease control. In patients who relapse of CD19-positive B-ALL post-HCT, on the other hand, there is the possibility of infusing donor-derived CD19 CAR-T cell therapy or combination of CD19 and CD22 CAR-T cells therapy.
Current strategies to improve CAR-T cell efficacy focus on improved CAR-T cells in vivo, multispecific CAR-T cells to overcome immune escape and news CAR designs. Access to CAR-T cells therapy remains a major challenge considering the manufacturing process and the cost.
Arnon Nagler: Transplant indication for Acute Lymphoblastic Leukemia
In ALL relapse remains the main cause of treatment failure and the most important prognostic factor in adult ALL therapy is eradication of MRD as early as possible. AlloHCT is the best strategy for preventing relapse but his role is an area of active investigation, especially in relation to the increasing availability of salvage options after relapse, mainly immunotherapy-based. It is currently recommended for eligible patients with high-risk features: poor-risk genetic markers and an inadequate MRD clearance at critical time-points.
In recent years, in addition to an increased use of MUD and haploidentical transplants (with overlapping results in terms of LFS and OS compared to MSD transplants), there has been an improvement outcomes (> LFS).
MRD status prior to alloHCT (MRD<10-3) is a powerful predictor for post-transplant outcome, but alternative therapies are especially needed for patients with poor MRD clearance.
Immunotherapy is assuming an important role in the treatment paradigm thanks to monoclonal antibodies (Blinatumomab, Inotuzumab) and they will be incorporated into first line therapy for both Ph-negative and Ph-positive adult ALL.
In addition, developments of sophisticated technologies with cellular therapies (CAR and TCR engineering) are highly promising. The hot question is if there is a role for alloHCT consolidation post CAR T-cells therapy: currently there are paucity of long-term data and lack of randomized trial, alloHCT is most probably more important in patients with rapid loss of CAR T-cells persistency and in patients who have not been transplanted before.
Overall, we may expect less allogeneic transplants for adult ALL (for example chemotherapy free induction for Ph+ ALL). Positioning of CAR and alloHCT in the treatment paradigm for adult ALL is a key future question.
Physicians Session 7: Summary by Claire Horgan
Regis Peffault de Latour: Transplant indications for SAA and constitutional marrow failure syndromes
Regis Peffault de Latour began the session discussing transplant indications for severe aplastic anaemia and constitutional marrow failure syndromes. Patients under 40 with severe aplastic anaemia and a matched sibling donor should undergo transplant as soon as possible. MUD may be considered upfront as an emerging strategy, particularly in younger patients where the transplant toxicity is lower. Further experimental strategies evaluating the role of cord and haplo (post Cy) BMT in refractory and young patients are showing promising results. When considering transplant for constitutional bone marrow failure syndromes, it is essential to ensure that the donor is unaffected if using a family donor, timing is important, and it’s essential to use reduced intensity regimens to minimise TRM. Long term follow-up is mandatory in view of the high risk of 2nd malignancy.
Benedicte Neven: HCT in immune disorders/immune deficiencies
Benedicte Neven then discussed transplant for immune deficiencies. Indication for transplant depends on severity of the condition and the goal is immune reconstitution. Full chimerism is not always mandatory and important to consider clinical status of the recipient as they may be severely compromised by infection and inflammation. Conditioning regimens and serotherapy should be tailored towards the disease and clinical status/age of the patient. Gene therapy early phase studies ongoing.
Selim Corbacioglu: Curative approaches for hemoglobinopathies
Selim Corbacioglu concluded the session discussing curative approaches in haemoglobinopathies. In thalasaaemia, MSD is the standard of care, although MUD is equivalent to MSD. Haplo is curative, available for almost everybody, and comparable to MUD. Post-Cy is cost-efficient and affordable in low- and middle-income countries, hence the classical hierarchy can be challenged. In sickle cell disease, MSD is the standard of care although >80% no sibling available and outcomes are only excellent in infants and small children. Haplo BMT is an option and best done between age 3-18 if no MSD available. Gene editing/therapy offer further curative approaches, particularly in older patients who have a higher TRM.
Physicians Session 8: Summary by Razan Mohty
Ali Bazarbachi: Transplant for non-Hodgkin lymphomas
The most frequent indication for autologous stem cell transplantation (ASCT) to date is diffuse large B cell lymphoma (DLBCL) where ASCT is the standard of care for relapsed patients with chemo-sensitive disease in second complete remission (CR) or more and allogeneic stem cell transplantation (allo-SCT) is recommended for chemo-sensitive relapse after ASCT failure. In the French Gela group study, 15 to 25% of patients with DLBCL are refractory to any chemotherapy and 20 to 30% will relapse. ASCT was assessed in the first-line setting in a meta-analysis published in 2007 showing that overall, there is no benefit using ASCT in the first line even in high-risk groups. He discussed the findings of the GAINED trial where ASCT was used in a PET-adapted strategy where PET positive patients only received consolidation ASCT. This study showed that those patients had similar outcomes as PET negative patients.
He discussed the results of the old PARMA study showing the benefit of the use of ASCT as consolidation after salvage chemoimmunotherapy in primary refractory disease and till now remain the standard of care even in the rituximab era. The CORAL study showed that both R-CHOP and R-DHAP as salvage therapy offer a similar outcome and that post-transplant maintenance rituximab did not offer any benefit.
For patients failing ASCT, allogeneic stem cell transplant can offer long-term disease control, and this is based on a large EBMT study on more than 100 patients.
Moving to follicular lymphoma, the EBMT indications for ASCT are CR2 or beyond and for allo-SCT being after failure of ASCT. Indeed, multiple studies explored the benefit of ASCT in the first-line setting showing improvement in PFS but no effect on overall survival. Conversely, in the relapse setting, high dose chemotherapy and ASCT as compared to chemotherapy alone improves PFS and OS offering a very good long-term disease control even beyond 10 years. Maintenance rituximab for 2 years is the standard of care in follicular lymphoma based on the results of the EBMT randomized trial with a significant effect on PFS but not on OS. Allogeneic stem cell transplant can be used in patients relapsing after ASCT.
Moving to mantle cell lymphoma, indications for ASCT as the standard of care in first CR and relapsed patients if they did not receive ASCT in the first line and allo-SCT is standard for failure after ASCT. The European mantle cell lymphoma network established high dose cytarabine as a standard induction before ASCT. The LYMA trial showed PFS benefit with maintenance rituximab.
For peripheral T-cell lymphoma (PTCL), the Reimer study in 2009 and the NORDIC study in 2012 established the use of ASCT. Also, the COMPLETE registry which is the largest prospective database for PTCL in the US showed significant benefit from ASCT for patients with advanced-stage and age-adjusted IPI of four or more. For allogeneic transplants in PTCL, the combined analysis from the French LYSA and German lymphoma study group there was a clear disadvantage for allo-SCT mostly because of an unexpectedly high non-relapse mortality. However, the SFGM French group reported very encouraging results using allo-SCT in relapsed refractory PTCL with five-year PFS and OS about 50%.
Peter Dreger: CAR T cells for non-Hodgkin Lymphoma
The 4 CAR T cell constructs approved in lymphoma are lisocabtagene ciloleucel, tisagenlecleucel, and axicabtagene ciloleucel and brexucabtagene autoleucel.
He discussed the factors affecting response following CAR T cell therapy. The GERMAN LYMPHOMA alliance concluded that patients with poor performance status, patients with prognosis limited cancer, patients with HIV, and critically ill patients have a poorer outcome. In real-world studies, disease status plays an important impact on outcome whether in the GERMAN or FRENCH studies.
The ZUMA-1 post-hoc analysis, tumor burden, inflammation, and product attribute the outcome after axicabtagene ciloleucel.
Based on non-comparative studies of CIBMTR, ZUMA-1, and LYSA studies, Axi-cel could be more effective than Tisa-cel. However, Tisa-cel has less toxicity, less non-relapse mortality at least in the GERMAN study.
How to sequence CAR T cell and allo-SCT is a relevant clinic question nowadays. Allo-SCT can be preferred in refractory cytopenia.
In mantle cell lymphoma, the KTE-X19 trial including Bruton tyrosine kinase inhibitors refractory patients showed high responses even in a patient with TP53 mutation.
Finally, in the ZUMA-7 study press release, Axi-cel could be used in the second line in DLBCL with an improved PFS.
Anna Sureda: Transplant for Hodgkin Lymphoma
Despite all advances, we still have a proportion of patients that are primary refractory to first-line therapy, and eventually 30% of patients relapse after achieving a first complete remission.
Salvage conventional treatments and consolidation with ASCT is the standard of care in that setting. Two important prospective clinical trials that were published indicated that consolidation with ASCT can significantly improve PFS but around 50% of the patients fail ASCT. The use of PET-directed therapy and the use of metabolic tumor volume can identify patients who might benefit from ASCT.
To improve the outcome of these patients, PD-1 and PD-L1 inhibitors and anti-CD30 antibodies have been used. Brentuximab vedotin (BV) in addition to chemotherapy or chemo-free strategies are being used as salvage therapy before ASCT with high complete metabolic remission rates. Furthermore, checkpoint inhibitors can chemo-sensitize patients before ASCT based on a retrospective analysis by Merryman et al.
Do we still need to consolidate with ASCT in 2021? Several trials are ongoing and will be able to answer this question.
In patients who relapse after ASCT, novel BV with Nivolumab as consolidation after ASCT showed 19 months PFS was 90%. Allo-SCT can be used in that category of patients with an OS for those patients being allograft in between 1990 and 1994 was around 20% and it has been improved up to 75 or 70% for those patients being allographic between 2010 and 2014. However, the number of allo-SCT has significantly decreased over the year in the era of monoclonal antibodies.
Several refractory studies showed that haploidentical transplant could lead to better PFS that could be due to the haplotype mismatch. Post-transplant cyclophosphamide could be the game player in that setting.
The best sequence of all these patients is not yet established.
Maria-Victoria Mateos: Transplant for multiple myeloma
ASCT was established by the IFM study in the 90s and it remains the standard of care 20 years later allowing deep responses as shown in studies conducted by the Spanish and the French groups.
The biological age is the actual cut-off for transplant and not the chronological age.
The GIMEMA and PETHEMA trials established VTD as the standard of care induction regimen. However, nowadays, other induction regimens replaced VTD including VRD with better efficacy and lower side effects including peripheral neuropathy.
The monoclonal antibodies are being incorporated with induction triplet regimens including the DARA-VTD combination studied in the CASSIOPEA trial.
The European Leukemia Network prospective trial assessed the use of tandem transplants showing benefit in high-risk groups. These results were confirmed in the STAMINA trial.
The FORTE study assessed the use of carfilzomib induction regimen with patients who receive ASCT had better PFS and high MRD negativity rate.
The CARDMON study comparing KCD with or without ASCT with no significant difference in terms of survival. However, ASCT leads to higher MRD negativity. Longer follow-up is needed to know if this MRD negativity translates into an OS benefit.
Patients with high-risk myeloma achieving MRD negativity have similar outcomes as patients with low-risk disease as shown in the IFM DFCI 2009 study.
The novel cell therapy using BCMA as a target and bispecific antibodies are being studied and might be moving earlier in lines of treatment.
MRD negativity and sustainability will be introduced in the clinical algorithm for the treatment of patients with myeloma and it might allow choosing patients who can omit ASCT in the first-line setting.
Raffaella Greco: Transplant for auto-immune diseases
ASCT is capable to achieve major clinical response in patients with auto-immune disease otherwise resistant to other treatment and allows sustained freedom from immunosuppressive/disease-modifying treatment.
ASCT works in auto-immune diseases through the debulking of inflammation with cytotoxic therapy and resetting the immune system. Allo-SCT works through immune replacement through graft versus immunity effect.
The activity of transplant in auto-immune disease is increasing over the last years.
In multiple sclerosis, ASCT and allo-SCT have been used. The conditioning regimen most widely used in allo-SCT is cyclophosphamide and ATG conditioning as shown in the MIST trial with prolonged survival.
Other disorders including neuromyelitis optica and chronic inflammatory polyradiculoneuropathy can also be treated with ASCT.
In systemic sclerosis, the SCOT trial showed improvement in event-free survival with the use of ASCT, and mortality was reduced to 6%. Appropriate cardiopulmonary assessment should precede any transplant.
In lupus and Crohn's disease based on the ASTIC trial leading to complete mucosal healing), insulin-dependent diabetes, immune cytopenia are other indications for ASCT>
Allo-SCT is indicated in pediatric autoimmune diseases with a strong genetic component with a PFS of 60% and OS of 70% at 5-years.
Further studies about the best conditioning regimen are warranted.
Harry Dolstra: Combining cellular therapy and HCT
T cell or NK engineered cell can be used.
Allo NK cell therapy against AML and MDS mainly from haploidentical donors have been used showing 15-20% complete remission rate in refractory patients and can be used as bridge to allo-SCT.
NK cells can be expanded from stem cells through a GMP-compliant stem cell expansion which allows 1000-fold expansion with high purity of NK cells.
CAR T cell therapy and allo-SCT can be combined where patients who achieved CR after autologous CAR T cells receive allo-SCT consolidation. CAR T cells also can be part of the conditioning regimen.
Still many patients relapse, DLI, dendritic cells, gamma delta T cell, antigen-specific alpha beta T cells, and genetically engineered T cell inducing GVL without GVH can all be used in that setting.
Donor NK cells enhance alloreactivity and are involved in eliminating residual donor cells.
Razan Mohty: Case Presentation
Finally, I have presented a case of a patient with primary refractory primary mediastinal large B-cell lymphoma, and we have discussed the use of CAR T cell therapy versus ASCT in this patient.
Physicians Session 9: Summary by Claire Horgan
The final session of the ITC focussed on paediatrics.
Adriana Balduzzi: State of the Art Transplantation of Childhood Leukemia and MDS
Adriana Balduzzi began by discussing Start of the Art Transplantation for Childhood Leukaemia and MDS. Only very high risk paediatric ALL should be transplanted in CR1, and this is mainly MRD-based. It’s essential to have MRD negative or low upon HSCT and there is increasing evidence for the utility of immunotherapy to achieve this. She then went on to review the latest transplant data for paediatric AML, MDS and CML.
Maura Faraci: Late effects in children after HCT
Maura Faraci delivered the next presentation on the important issue of late effects in children after HSCT and its vast and varied implications. She highlighted the significant risks of metabolic and cardiovascular complications in stem cell transplant recipients, even in the paediatric setting, and the importance of screening for these and addressing risk factors where possible. She underlined pre-transplant and HSCT-related risk factors for a range of systems-based complications, as well as some therapeutic strategies for the prevention and treatment. She also stressed the importance of screening for second malignancies and the significant impact this can have on survivors of paediatric BMT.
Claire Horgan: Case Presentation
The session concluded with Claire Horgan delivering a case-based presentation of a child with relapsed refractory MDS undergoing a T-replete mismatched cord transplant. This generated several interesting discussion points including the use T-replete cord blood transplant to enhance the GVL effect in refractory and high-risk myeloid malignancies, and the use of different therapeutic strategies for acute GVHD in the paediatric setting.
Summary reports by the Nurses Group
The International Training course is an opportunity to offer a comprehensive programme of sessions each with a set of four 15-minute presentations covering 4 key areas of JACIE standards for nursing care.
Nurses session 1: Supportive care
This opening session, chaired by Michelle Kenyon, included a great range of talks each focused on a different element of supportive care.
Alice Polomeni: Psychosocial care – practical tips
Alice shared great insights for nurses working in our challenging environment beginning with some underpinning principles and working through to summarise with some excellent practical tips for understanding psychological issues.
Steve Bass: Palliative Care – symptom support and parallel planning
Key to offering best supportive care is understanding what matters to our patients as early in the pathway as possible and revisiting this at regular intervals.
Sophie van Lancker: Early complications
Sophie’s talk gave a very clear and comprehensive overview of some of the most common early post-transplant complications and the role of the nurse in supporting our patients fully at this time.
Julia Ruiz: Late complications
Complementing Sophie’s talk brilliantly, Julia spoke about complications at the other side of the transplant journey. Offering programmes of care that include treatment consequences, psychosocial support and health and well-being interventions is important.
Nurses session 2: Cell collection, conditioning and infusion consideration
This session of talks gave a great overview of the steps necessary to the transplant process.
Dirk Berckmans: cell collection – what to consider in 2021
Bringing us right up to date, Dirk described the key elements of cell collection as well as current considerations for patient care in light of the pandemic.
Sandra Schoenfeld: preparative conditioning regimes and transplant options
Understanding which conditioning therapy for which transplant is one of the fundamentals of transplant nursing care. Sandra gave a great tour of regimes as well as a clear overview of the different types of transplant.
Marijke Quaghebeur: how to safely perform HCT infusions and CVC access solutions
Moving us on from conditioning to infusion, Marijkes talk answered many of the frequently asked questions about stem cells and infusion pumps and venous access devices.
Sarah Hutton: Patient experience
Finally, we were privileged to hear Sarah Hutton share her experiences of her transplant. Sarah’s story gave an honest and frank account of her concerns and worries as well as the things that really mattered to her and made a difference.
Nurses session 3: Post infusion care
Michelle Kenyon: Rare complications
The focus of the rare complications talk by Michelle, was Veno-occlusive Disease (VOD) and the important role of the nurse. This complex problem was unpicked to produce strong messages critical to the understanding VOD and patient care. By improving nurse understanding of VOD risk factors, early warning signs and symptoms, we can improve patient outcomes.
Sandra Schoenfeld: Central venous catheters, how to keep them working and how to know when they are not
In Sandra’s second talk, she spoke about essential care for central venous catheters. This highly relevant session offered valuable guidance on routine maintenance procedures to minimise infection and thrombus, main complications and when to escalate concern.
Iris Agrieter: Neutropenic fever – getting it right first time, every time
Iris presented pathophysiology and clinical development of neutropenic sepsis. Guidelines are well established but prompt sepsis care is not always instituted with fatal consequences. Iris’s talk outlined very clearly the important steps that need to be taken to ‘get it right first time, every time’.
Marta Canesi: viral illnesses and keeping our patients safe
Finally, and very topically, Marta’s session covered viral illnesses. Improving nurse knowledge on viral illness is even more relevant now than ever. Of course, over the last 18 months our healthcare staff and extremely vulnerable patients have been dealing with biggest viral threat of our lifetime, but the dangers of our old viral friends still exist. This great final talk summarised the main viral threats and how to keep our patients safe and protected.
Nurses session 4: Essential update
Genevieve French: CAR T – new developments and training the nursing workforce
Where better to start with our essential update that CAR T. Working as a CAR T CNS, Genevieve is working right at the heart of all things CAR T. This rapidly expanding area demands a flexible and dynamic workforce to enable safe treatment delivery and guidelines based care.
Annika Kisch: Donor work-up – important and difficult aspects
We are lucky to have Annika speak once again on the topic of donor care. Here Annika reminds us of the importance of thoughtful and considered donor care to ensure their interests remain at the forefront.
Daphna Hutt: Paediatric update
For nurses working with our youngest transplant recipients, Daphna offered a great overview of new developments and current considerations. This overview complemented our other sessions brilliantly.
Tuula Rintala: JACIE – what’s new for nurses
Finally, Tuula presented a download of the latest JACIE version 8 standards with a particular focus on the nursing related areas. For those unable to join the session, check out the EBMT website: https://www.ebmt.org/8th-edition-fact-jacie-standards.
Authors’ affiliations (by alphabetical order)
- Cristobal Frutos, Hospital Central Del Instituto De Prevision Social, Asuncion, Paraguay.
- Nico Gagelmann, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Lars Klingen Gjærde, MD, Department of Hematology, Rigshospitalet, University Hospital Copenhagen, Copenhagen, Denmark.
- Alexandra Gomez-Arteaga, MD, Assistant Professor of Medicine. Bone Marrow Transplant & Cell Therapy Program. Weill Cornell Medicine/New York-Presbyterian Hospital. New York, NY.
- Claire Horgan, Clinical Fellow in Paediatric BMT, CAR-T and Stem Cell Gene Therapy, Royal Manchester Children’s Hospital, UK.
- Razan Mohty, Bone marrow transplantation and CAR T cell fellow at Mayo Clinic in Florida, USA.
- Vera Radici, Clinical Hematology and Bone Marrow Transplant Centre, S. Maria della Misericordia University Hospital, Italy / Department of Clinical Hematology and Cellular Therapy, Saint Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
- Yuliya Rogacheva, I. P. Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia.
- Yasmina Serroukh, MD PhD, Erasmus Medical center Cancer Institute, University Medical Center Rotterdam, Department of Hematology, Rotterdam, Netherlands.