EBMT 2024 Highlights

Papanicolaou et al - Sr Angela Leather

Abstract A181 – Papanicolaou et al. MULTINATIONAL STUDY ASSESSING TREATMENT PATTERNS, OUTCOMES, AND HEALTHCARE RESOURCE UTILIZATION IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS WITH CYTOMEGALOVIRUS INFECTION AND INTOLERANCE TO ANTICYTOMEGALOVIRUS THERAPIES Poster presentation by Martha Fox at EBMT 50th Annual Meeting 14th to 17th April 2024.

This retrospective multi centre (international) study reviewed patient data from 14 transplant centres in US, and Europe, including France Germany, Italy UK and Spain over a 7-year period between 2014-2021. It highlighted the effects of CMV on HSCT patients, including the need for hospitalisation, mainly because of treatment effects including neutropenia and nephrotoxicity. In 250 patient reviews, 85 were classified as intolerant to treatment. Intolerance was identified as neutropenia, nephrotoxicity, immunosuppression, nausea etc. Patients highlighted as intolerant needed several lines of treatment and had a more resistance to CMV viraemia, with a median time of intolerance to treatment being 57 days post-transplant (35-85) and spending a median of 12 days on treatment, (range 6-21 days), Interestingly the study identified that 64% (n=55) of patients experienced graft versus host disease (GVHD) in some form, with 35 patients being diagnosed after CMV resistance. This leads to question if CMV or its treatment exacerbates GVHD?

Most patients 71% in the study needed more than one line of treatment, and 96% of patients required dose alteration, for a variety of reasons including viraemia clearance or intolerance. There was a variation in days to CMV intolerance which was highlighted with the above toxicities, with the common anti-viral medication being identified as the intolerances including valganciclovir, ganciclovir and foscarnet. Valganciclovir was commonly highlighted as the first ‘intolerant’ treatment option – however is most used treatment as first line.

There was reactivation of viraemia on stopping treatment, which often resulted in increased hospitalisation and effects on both physical and psychological health, and a burden to healthcare systems. 40% patients had more than one recurrence of CMV after their first intolerant episode with 38% requiring hospitalisation with an average length of stay of 17 days.

Letermovir usage started in 2014, and it was recognised that some patients in this therapy group may be less likely to experience early onset viremia. However, most patients experiencing intolerance to previous anti-CMV therapy were D+/R+ or D-/R+ patient, donor groups (45 and 35% respectively). Letermovir is licensed for only positive recipients, therefore a need to identify suitable antiviral treatments are of huge benefit.

Conclusion – My take aways from this were that HSCT recipients have an increased burden and higher risk of mortality and morbidity if intolerance to antiviral treatment is seen, which, alongside the current pressures on healthcare systems highlights the need for treatments with low side effect and greater tolerability, including the importance of being able to take medication whilst remaining an outpatient.

Maertens et al - Dr Bhuvan Kishore

P122- Maertens et al. Real world outcomes and treatment patterns of CMV infections in HSCT recipients who are refractory or intolerant to treatments.

Presented at EBMT 50th Annual Meeting 14th to 17th April 2024.

Real world data from 31 patients across 10 transplant centres spanning 2016-2023 Patients had to be relapsed, with CMV refractory to previous therapy, with or without resistance, or intolerant to at least 1 anti-cmv agent (RRI). Only 3 had letermovir. 83% refractory and 16% intolerant. 35% did not achieve viremia clearance. I think both A181 (Papanicolaou et al) and P122 highlight that we don’t have similar data in the era of latest therapies regarding what effect these have had on the landscape, underscoring them as a priority for real world evidence.

See Bhuvan and Angela discuss these first two presentations in the video below.

Zamora et al - Dr Bhuvan Kishore

OS11-02 Zamora et al Analysis of Pre-transplantation CMV-specific humoral immunity as a predictor for CMV reactivation after HSCT using VIRSCAN serologic profiling and pentameric complex-specific neutralisation.

Presented at EBMT 50th Annual Meeting 14th to 17th April 2024.

I was really keen to understand this technology that was presented, and this attracted me to this presentation. Despite low B cells there is some immunoglobulin that persist and may be due to resistant plasma cells. The team chose D-R+ patients so one could study the pre-transplant humoral immunity. They used neutralising antibody to CMV pentamer and VIRSCAN. VIRSCAN technology based on detecting antibodies against a pre-defined phage library. 4000 CMV sequences and 16 public epitopes. You add patient serum and then lyse and detect the immune profile. The team hypothesised that high titres pre transplant would result in less CMV reactivation. The results were quite the opposite. This was similar with neutralising antibodies and VIRSCAN. This suggests that higher antibodies pre HSCT may represent a latent burden of CMV going into HSCT. My thoughts on this: - Can these tests be used to diagnose a reservoir of infection and identify a cohort of patients at a high risk of CMV reactivation. - What about GVHD? This was never tested in letermovir era and other novel anti-CMV drugs - Can this technology be used for other viral disorders in the setting of HSCT. Also what about immune reconstitution analysis post HSCT?

Duplessix et al - Dr Bhuvan Kishore

OS11-07 Duplessix et al CMV specific T-Cell activity determines the risk of clinically significant CMV reactivation following letermovir prophylaxis after allogeneic-HSCT.

Presented at EBMT 50th Annual Meeting 14th to 17th April 2024.

• Letermovir prophylaxis introduced in 2017 has reduced CMV reactivations but we do not know data on late reactivations.
• Primary objective – Identify patients at risk of CMV reactivations post HSCT in spite of letermovir prophylaxis.
  
• Secondary objective – Duration of reconstitution of CMV-specific T cells post transplantation with CMV+ and CMV- donors, and to determine the threshold value of sufficient T cell activity that would prevent CMV reactivation.
  
• Methodology – 49 allogeneic-HSCT patients. All had CMV prophylaxis with letermovir and were cmv + or donor was pos. Monitored for 200 days. Complex- timed serum samples Day100/200 and at CMV reactivation and 1 and 3 months- CMV Elispot assay. Clinically significant CMV infection (CS-CMVi) was treated with Valgan and a non CS-CMVi was an isolated positive PCR. Definitions IE spot count <10, pp65<100 on day 100.
• N=49 – 18 recativated during prophylaxis 21 post prophylaxis, CS-CMVi 11% on prophylaxis vs 38% post prophylaxis.
• 80% had CMV reactivation in study period. I had not expected this value to be this high.
  
• Patients with lower spot values on Day 100 had higher risk of reactivation.
  
• Very few patients needed treatment or developed clinical significant CMV reactivation while on letermovir (2 out of 18) but this rate increased post stoppage( 8 out of 21). The patients that did develop CMV reactivation while on letermovir registered higher immune response signal- the CMV Elispot. Those that had a low Elispot activity had a higher risk of reactivation post stopping.

See Bhuvan and Angela discuss the Zamora and Duplessix presentations in the video below.

Maiers, M et al - Sr Angela Leather

OS2-08 Maiers, M et al AN AI MODEL TO OPTIMIZE DONOR SELECTION USING A CONTEMPORARY DATASET Oral presentation.

Presented at EBMT 50th Annual Meeting 14th to 17th April 2024.

This presentation looked at a data model to identify if it was possible to predict transplant outcomes through a computer algorithm. The data was collected and reviewed by the CIBMTR, reviewing the 8.7 million donors on the US registry to see if the algorithm could predict if a better outcome could be achieved with variances on finding a better donor to the one that was used.

These reviews were undertaken in patients having received a transplant in the USA, the large cohort of over 31000, received a transplant between 2016-2019 and had received a matched or mismatched 9/10 related or unrelated donor. The results of patient outcomes were reviewed of the potential donors on the registry to see if a better donor could have been identified through the data programme, 4 years of donor data looking at 4 end points at 1 year post transplant included overall survival, disease relapse, graft rejection and chronic Graft versus host disease, and the ultimate end point of event free survival, and looking at the predictable impacts including donor age, sex, donor type, matching and the use of PT CY. Most of the results suggested HLA matched transplants were better, but in some situations a mismatched transplant was predicted as better, particularly in the increased use of post-transplant cyclophosphamide. The thoughts have been that matched related donors have a lower chance of GVHD and mortality, but this model identified in some cases that unrelated donors surpassed this in some circumstances, particularly in older sibling groups. Unrelated donors also surpassed siblings in the event of graft rejection, as previous data highlights being male and young gives a better outcome. Mismatched related donors (often haploidentical transplants) had a poorer outcome over a matched unrelated donor, however in practice the biggest number of patients receiving a haplo transplant are unable to find that suitable unrelated donor in the first instance.

Conclusion – I took from this that additional learning and the use of PT Cy benefits patient outcomes in some circumstances, I guess this raises the question of whether transplant teams should use a mismatched donor over an elderly sibling in the era of post-transplant cyclophosphamide?

Descamps et al - Sr Angela Leather

Abstract NG20-04 - Descamps et al PATIENTS' PERSPECTIVES ON PSYCHOSOCIAL SUPPORT IN ALLOGENEIC STEM CELL TRANSPLANTATION WITH A RELATED DONOR Oral presentation by Lotte Kinds (Finalist for research abstract - Nurse group).

Presented at EBMT 50th Annual Meeting 14th to 17th April 2024.

This presentation was based on the results of a masters thesis and was a pneumological monocentric study looking at the psychological support received and the impact of having a related donor from a patient perspective. The study was undertaken using 27 patients who had received an allogeneic transplant in the past 5 years, the donors mostly being siblings – Brother 13, sister 9 and child in 5 cases, with the average age of 52 years (range 24- 72) and an even split between male and female participants.

The findings were categorised into 4 themes,

Ambivalence of having a related donor - it was found that patients were interested in the results and to see who the suitable match for them was, but also a little anxious about the process and whether a donor will be found or if they are available at the right time, alongside the relief when the donor was found. The results identified that the patients felt happier when they knew who their donor was and where the cells would be coming from. There were some anxieties regarding the impact that the donation would have on the donor and if there was a need for additional cells there was an added anxiety/guilt.

Gratitude was recognised in that the patient felt proud and incredibly grateful for the family member's donation, and some gave a gift of thanks, celebrating anniversaries of the time of donation/transplant, overall, the study identified a special bond between patient and donor.

The impact of the patient / donor relationship was important in this study and in some cases the bond between them increased and in others it went back to the same relationship as previously.

The psychological impact from care givers was also identified during the process, and from other family members too. Not every patient has access to professional psychological support, but may have found support from outside of the hospital. Their findings and conclusions suggested a need for personalised tailored information, and a referral for psychological services, the results were retrospective, and it was acknowledged that the findings may differ dependent upon the length from transplant admission. I think that these are important and useful findings – I am not sure if the psychological impact would differ if the patient had an unrelated transplant, I suspect the anxiety at the early part would be greater if a family member was not found, equally during the conference there was more emphasis on the donor welfare and I feel that this is an important factor in this huge ethical area.

See Bhuvan and Angela discuss the Maiers & Descamps presentations in the video below.

Gagelmann et al - Dr Bhuvan Kishore

OS15-01 - Gagelmann et al Daratumumab for PRCA after HSCT: A study from the transplant complications working party of EBMT

Presented at EBMT 50th Annual Meeting 14th to 17th April 2024.

• Pure red cell aplasia occurs in major and bidirectional ABO mismatch transplant at a prevalence of 7-30%.
• Variable, highly heterogeneous treatment algorithms exist.
• Daratumumab (dara) was reported to have worked in a single case in 2018, then again in a 2020 NEJM case series by reducing isoagglutinin.
• The team wished to leverage the EBMT database to retrospectively collect data with inclusion criteria including Dara use post diagnosis of PRCA post allogeneic transplant.
• Primary outcome was 12 weeks of transfusion independence post daratumumab use in cases with PRCA, secondary outcomes Hb and reticulocyte levels.
• There were 45 patients with the largest group of patients being those with mostly myeloid disorders.
• Daratumumab was first line in1/3rd of patients- this drug is not licensed for this. In my view this may suggest a selection bias. Others mostly received rituximab before. Median duration of Daratumumab was 21 days.
• Median follow up 17 months- this is good in my opinion.
• Transfusion independence at 6 months was 70%; and 80% at 12 months.
• Hb recovery 56% at 6 months and 64% at 12 months.
• Retic recovery 77% at 6 months and 83% at 12 months.
• OS 81% at 12 months.
• Most deaths were GVHD related.

Conclusions - The largest collection of this group of patients to be studied to date, but still numbers are small. What is quite interesting is the upfront use. In discussions the frequency of use of dara came up and some patients got twice a week. Some data suggests PRCA can resolve spontaneously, how does one allocate dara benefit? This study leaves more questions than answers for me. We don’t learn about the optimum approach but there is a signal of quick and rapid responses in some patients. I felt that this is a small niche area where an IIS/IIT may answer the questions regarding dosing and the use of this technology.

See Bhuvan and Angela discuss the Gagelmann et al presentation in the video below.