Double Transplantation Research Articles

Stratification risk computation of primary graft gysfunction in heart transplant recipients on a smartphone application

Abstract Introduction There are no standardized guidelines for helping graft allocation in heart transplant (HTx) and accepting transplants from marginal donors and donors after circulatory arrest make decision making even more complex and time consuming than ever. The organ allocation process should include a risk analysis for primary graft dysfunction (PGD) that represents the most dreadful complication of HTx. There are 3 score systems validated to predict PGD but none has clear superior predictive capability compared to the others and the complexity of score computation potentially discourage their clinical use. A score integrating all the variables presented in a user-friendly format should improve efficacy and safeness of the organ allocation process. Methods Severe PGD defined as need for temporary mechanical circulatory support (ECMO) in the first 24 hours following HTx was considered the end-point for risk stratification computation. As a derivation cohort we used meta-analytic approach for identifying variables that are independently associated to severe PGD. The overall prevalence of each variable was determined to define the absolute risk increase value in presence of each factor. We then created a scoring system applying multivariate logistic regression model. As a validation cohort we studied the performance of the score in a retospective series of HTx performed at our institution from 2013 to 2022. We used C statistic equivalent to the area under a receiver-operating characteristic curve for dichotomous outcomes. Values above 0.7 were considered acceptable. We eventually developed an application for smartphone for risk computation. Results On 64 papers screened, 5 studies were considered eligible for the derivation cohort definition. Cumulative number of patients considered was 10’175 with an incidence of severe PGD of 7.1% (CI 5.3 - 10.4) and a 30-day mortality of 41%. 13 variables were identified (table 1). The ROC curve predicted the use of ECMO with the specificity and the sensitivity of 0,81 and 0,92 respectively. We have included in the validation cohort 128 out of 150 transplanted patients, excluding pediatric and double organs transplants. The mean donor age was 45 +/- 12,4 years, 72 (54%) were men. The mean recipient age was 57 +/- 9,3; 92 were men; 32 recipients (25%) needed ECMO support within 24 hours post-transplant; 75% of the donors in the ECMO group were > 40 y.o.; 30 days mortality was 3.1% and 6,2% in the non-ECMO and ECMO group respectively. We validated the model on our cohort defying a binary outcome (ECMO yes/no). Conclusion Clinicians fill donor, recipient and surgical parameters in user-friendly smartphone application identifying patients that are most likely to need ECMO support post HTx. The decision-making process during organ allocation evolves from what was once little more than personal experience and intuition to a reliable evidence-based method based on personalized risk prediction.Table 1

Analysis of different outcome parameters and quality of life after different techniques of free vascularized lymph node transfer

ObjectiveVascularized lymph node transfer (VLNT) has become an important surgical technique in the treatment of lymphedema. Considering the different available regions available for flap harvest, we aimed to analyze different donor sites for VLNT with respect to donor site morbidity, impact on limb volume, and patient-reported outcome measurements (PROMs). MethodsA single-center prospective study of all patients undergoing VLNT at the Department of Plastic Surgery and Hand Surgery of the University Hospital Zurich between September 2016 and 2023 was conducted. Lymph nodes were harvested either from the omentum (gastroepiploic [GE]-VLNT), the lateral thoracic wall (LTW), or the superficial inguinal region (SI-VLNT). Volume measurements and PROMs were assessed preoperatively and at different postoperative intervals. ResultsOverall, 70 patients with upper limb lymphedema (21%) or lower limb lymphedema (79%) with different lymphedema stages were included. There were 49 patients who underwent GE-VLNT, followed by LTW-VLNT (n = 16) and SI-VLNT (n = 5). Lymph node harvest from the SI was associated with a significantly higher frequency of seroma development. The average percentage volume loss related in comparison to the preoperative volume of the affected limb was 9% after GE-VLNT, 10% after LTW-VLNT, and 5% after SI-VLNT without a significant difference between the groups. PROMs revealed significant improvements for physical functioning, symptoms and psychological well-being, with no differences between the VLNT techniques. ConclusionsVLNT leads to a significant improvement of quality of life and can decrease limb volume effectively, regardless of the selection of donor site. GE-VLNT has become our flap of choice owing to its low donor site morbidity and its properties that allow a double transplantation while avoiding a second donor site.

Clinical Observation on Haploid Hematopoietic Stem Cells Combined with Umbilical Cord Blood Double Transplantation for Aplastic Anaemia in Children

To explore the efficacy and safety of haploidentical hematopoietic stem cell transplantation combined with umbilical cord blood infusion for the treatment of aplastic anaemia in children. Nine cases of children with aplastic anaemia treated with umbilical cord blood combined with haploidentical hematopoietic stem cell transplantation at the People's Hospital of Henan University of Chinese Medicine from January 1, 2021 to September 15, 2023 with a median age of 11(2-13) years and a median follow up of 18(7.5-21) months were included, and the clinical data were retrospectively analyzed. Hematopoiesis reconstitution, the incidence of graft-versus-host disease(GVHD), infections and survival of the patients were analyzed. All 9 children were successfully implanted. The median time to neutrophil and platelet implantation was 11.11±1.27 d and 12.44±3.36 d, respectively. One case developed acute gastrointestinal GVHD of degree I, which was improved after treatment, and the patient developed superficial gastritis and chronic gastrointestinal GVHD at a later stage, which is currently under clinical follow-up. Acute GVHD of II-IV degree was 0%. Hemorrhagic cystitis in 3 cases, CMV infection in 5 cases and bacterial and fungal infections in 5 cases improved with symptomatic treatment.All 9 children demonstrated complete donor chimerism within 1 month after transplantation, at two years of follow-up, all nine children survived without recurrence or development of grade II-IV GVHD, and there were no children with transplant-related deaths. Haploidentical hematopoietic stem cell transplantation combined with umbilical cord blood transfusion for aplastic anaemia in children has a low incidence and mild degree of GVHD, with significant efficacy, and can be used as a therapeutic option for children without an HLA full donor chimeric match.

Fontan-Associated Liver Disease and the Double Organ Transplant: Addressing the Heart of the Argument

Fontan-Associated Liver Disease and the Double Organ Transplant: Addressing the Heart of the Argument

Primary hyperoxaluria in adults and children: a nationwide cohort highlights a persistent diagnostic delay.

Primary hyperoxalurias (PH) are extremely rare genetic disorders characterized by clinical heterogeneity. Delay in diagnosing these conditions can have detrimental effects on patient outcomes. The primary objective of this study is to assess the current diagnostic delay for PH. This nationwide, observational and retrospective study included patients who received a genetic diagnosis of PH types 1, 2 and 3 between 1 January 2015 and 31 December 2019. Diagnostic delay was defined as the duration between the onset of symptoms and the time of genetic diagnosis. A total of 52 patients (34 children and 18 adults) were included in the study, with 40 PH1 (77%), 3 PH2 (6%) and 9 PH3 (17%). At the time of diagnosis, 12 patients (23%) required dialysis. Among the PH1 patients, the predominant symptom at onset in adults was renal colic (79% of cases), whereas symptoms in children were more diverse (renal colic in 17% of cases). The diagnostic delay was significantly shorter in children compared with adults [median (interquartile range)]: 1.2 (0.1-3.0) versus 30 (17-36) years, respectively (P<.0001). RNA interference was utilized in 23 patients (58%). Five individuals (13%) underwent double liver-kidney transplantation, and five (13%) received isolated kidney transplantation, with lumasiran therapy in four patients. For PH2 and PH3 patients, the diagnostic delay ranges from 0 to 3 years, with renal colic as first symptom in 33% of cases. This extensive and recent cohort of PH underscores the considerable delay in diagnosing PH, particularly in adults, even in a country with a dedicated organization for enhancing the overall management of rare diseases. These findings reinforce the imperative for increased awareness among relevant specialties regarding the evaluation of urolithiasis.

Obtaining M Protein Immune Reconstitution As Soon As Possible after Tandem Autologous Hematopoietic Stem Cell Transplantation Improves the Prognosis of Patients with Newly Diagnosis Multiple Myeloma

Objective: In the era of new drug therapy, autologous hematopoietic stem cell transplantation after induction therapy is the standard of care for patients with multiple myeloma, and Tandem autologous hematopoietic stem cell transplantation is a treatment option to improve the prognosis of patients with high-risk cytogenetics, and obtaining M protein immune reconstitution as soon as possible after double transplantation can further improve the survival of such patients. METHODS: A total of 12 patients with newly diagnosed multiple myeloma diagnosed from June 1, 2019 to April 30, 2021 at the First Affiliated Hospital of Sun Yat-sen University were included, and all patients underwent tandem autologous hematopoietic stem cell transplantation after induction therapy containing bortezomib, and the prognostic survival of patients who obtained M-protein reconstitution after transplantation was analyzed Results: 58.3% (7/12) of patients obtained M protein immune reconstitution after Tandem transplantation, the most common type of M protein was IgG-type M protein, the median time to obtain M protein immune reconstitution was 3 months (2-9 months) after Tandem transplantation, the median duration of reconstitution was 3 months (3-6 months), and all patients were R-ISS stage II-III, 83.3% (10/12) of patients had high-risk cytogenetics, all patients achieved at least VGPR efficacy after transplantation, with a higher CR rate in the M protein immune reconstitution group (71.4% vs 60.0%, P=0.679), although not statistically significant, and a median survival time of 2 years in the immune reconstitution group CONCLUSION: Tandem transplantation is a treatment option to improve prognosis in patients with high-risk cytogenetic multiple myeloma, and patients who received M protein immune reconstitution after Tandem transplantation significantly improved survival time.

Mismatched Unrelated Donor Transplantation with Ptcy-Based Gvhd Prophylaxis Is Associated with Better Survival Than Double Unit Umbilical Cord Blood Transplantation in Patients with AML in First CR: A Study from the ALWP of the EBMT

Background: The best donor option for acute myeloid leukemia (AML) patients lacking an HLA-matched donor has remained unknown. The recently reported BNT CTN 1101 trial observed higher non-relapse mortality (NRM) and lower overall survival (OS) in patients randomized to double-unit unrelated umbilical cord blood transplantation (dCBT) in comparison to those randomized to HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis 1. In addition, recent registry studies observed at least as good transplantation outcomes in AML patients given grafts from 9/10 HLA-matched unrelated donor (UD 9/10) with PTCy-based GVHD prophylaxis as those given grafts from HLA-haploidentical donors 2,3. These observations prompted us to perform a retrospective registry study comparing hematopoietic cell transplantation (HCT) outcomes between UD 9/10 and dCBT. Methods: Inclusion criteria consisted of adult patient, AML in CR1 at transplantation, either peripheral blood stem cells (PBSC) from UD 9/10 with PTCy as GVHD prophylaxis or dCBT, transplantation between 2013 and 2021, and no in vivo T-cell depletion. Results: A total of 208 dCBT patients and 270 UD 9/10 allo-HCT were included. The 180-day cumulative incidence of grade II-IV acute GVHD was 29% in UD 9/10 versus 44% in dCBT recipients (P=0.001). The 2-year cumulative incidences of relapse and of NRM were 23.5% and 12.5%, respectively, in UD 9/10 recipients versus 27% (P=0.39) and 18% (P=0.07), respectively in dCBT recipients. Two-year OS and LFS were 70% and 64%, respectively, in UD 9/10 recipients versus 60% (P=0.016) and 55% (P=0.028), respectively in dCBT recipients. In multivariate analyses, in comparison with UD 9/10 recipients, dCBT patients had a higher non-relapse mortality (HR=2.35, 95% CI: 1.23-4.48; P=0.01), comparable relapse incidence (HR=1.12, 95% CI: 0.67-1.86; P=0.66), lower leukemia-free survival (HR=1.5, 95% CI: 1.01-2.23; P=0.047), and lower overall survival (HR=1.66, 95% CI: 1.08-2.55; P=0.02). Conclusions: In summary, our results suggest that transplantation outcomes are better with UD 9/10 with PTCy-based GVHD prophylaxis than with dCBT for AML patients in CR1. These data might support the use of UD 9/10 with PTCy-based GVHD prophylaxis in AML patients lacking an HLA-matched donor. References Fuchs, E. J. et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood 137, 420-428 (2021).Baron, F. et al. Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia. Bone Marrow Transplant. 57, 1657-1663 (2022).Battipaglia, G. et al. Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 57, 562-571 (2022).

Autologous Hematopoietic Stem Cell Transplantation Combined with High-Dose Chemotherapy As First-Line Treatment for HIV-Associated Lymphoma: A Retrospective Analysis

BACKRGOUND At present, lymphoma is one of the three most common malignant tumors in AIDS patients. With the popularization of cART treatment, the incidence of AIDS-associated lymphoma has decreased, but it is still higher than that in the general population with poor prognosis. The Central and Western China AIDS Lymphoma League (CALL) is committed to investigate the efficacy and related factors of autologous hematopoietic stem cell transplantation (auto-HSCT) as consolidation therapy for newly diagnosed HIV-associated lymphoma. METHODS From 2018 to 2023, 11 newly diagnosed patients with AIDS-associated lymphoma in our center were collected, including 10 males and 1 female, 2 of whom received double ASCT, with a median age of 38 years (range 25-64 years). One case (11.1%) had bone marrow involvement, 3 cases (27.3%) had low/low-intermediate risk according to IPI, and 2 cases (63.6%) had high/intermediate risk according to IPI. Ten patients (90.9%) achieved complete remission (CR) and 1 patient (9.1%) achieved partial remission (PR) before transplantation. RESULTS Among the 11 patients, 2 patients (1 with high-risk diffuse large B cell lymphoma and 1 with plasmablastic lymphoma) received double transplantation within 6 months, and the remaining patients received single transplantation. The median CD34 collection before transplantation was 4.67 (2.5-12.52) *10^6/kg. 3 patients received BeEAC regimen, 7 patients received BeEAM regimen, and 1 patient received IAC regimen for the second transplantation. Five patients (45%) developed various degrees of infection during transplantation, which was improved after anti-infection treatment. All patients achieved hematopoietic reconstitution. The median time of neutrophil and platelet engraftment was 11.9 ± 2.23 days and 12.1 ± 2.96 days, respectively. At a median follow-up of 12 (3-14) months after transplantation, 1 patient died within 100 days after transplantation, 1 patient died of Covid-19 virus infection, 1patient achieved PR, other 8 patients remained CR.. Patient no. 1 died from bacteremia 1 months after ASCT. Patient no. 8 relapsed 6 months after ASCT and died from Covid-19 virus infection when 5 months after ASCT. Patient no. 9 relapsed 6 months after ASCT, but is still alive in second CR and is receiving lenalidomide maintenance therapy. Other 8 patients in CR post-ASCT are receiving lenalidomide/Interferon/rituximab maintenance therapies. Therefore, overall survival for the 11 transplanted patients is 81% at 12 months, with a median follow-up of 12 months (range 5-60 months). Furthermore, eight patients remained in CR, for an progression-free survival of 72% at 12 months, with a median follow-up of 19 months (range 9-60 months).It is worth mentioning that active HIV replication was not monitored with the continuous use of cART agents during lymphoma chemotherapy and ASCT; cART administration did not affect the number of harvested stem cells or the time to engraftment after transplantation.

A fatal case of tick-borne encephalitis in an immunocompromised patient: case report from Northeastern Poland and review of literature

Tick-borne encephalitis (TBE) is an infectious illness of the central nervous system caused by the TBE virus, which is commonly transmitted through a tick-bite. TBE is endemic in Europe and mid-Asia. In this study, we report a case of a 36-year-old woman, living in Northeastern Poland, with a history of double corneal transplantation and post-transplant immunosuppressive therapy who was admitted to hospital because of progressive weakness, acute headache, nausea, vertigo, vomiting, and fever. The patient was diagnosed with TBE. However, the diagnosis was challenging as the initial serological tests for antibodies against the TBE virus were negative. We want to raise the awareness among the clinicians that the course of TBE is often unpredictable and that it tends to be more severe in immunocompromised individuals.. Delayed production of antibodies against TBE virus, which might inhibit the diagnosis of the disease, is observed in some immunocompromised patients.

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone Induction and Consolidation with Tandem Transplant in High-Risk Newly Diagnosed Myeloma Patients: Final Results of the Phase 2 Study IFM 2018-04

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) evaluated an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Treatment strategy included Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance for 2 years. The primary endpoint was the feasibility of this intensive strategy. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers. Median age was 57 (range 38 -65). Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10, 20%). Four (8%) patients had extramedullary disease. At data cut-off, the study met the primary endpoint with 36 (72%) patients completing second transplant. Twenty-one patients (42%) discontinued the study, due to stem-cell collection failure (n=8), disease progression (n=8), adverse event (n=4), consent withdrawal (n=1). Grade 3-4 Dara-KRD induction/consolidation related adverse event (&amp;gt;5% of patients) were neutropenia (44%), anemia (22%), thrombocytopenia (24%) and infection (14%). Four patients discontinued treatment due to severe adverse event (COVID-19 infection, drug-induced hepatitis, JC virus related encephalopathy, intracerebral hemorrhage). Seven patients died, 5 due to disease progression and 2 due to infection. Responses deepened over time with an overall response rate before maintenance of 100%, including 81 % complete response. Among evaluable patients (33/36), pre maintenance Minimal Residual Disease negativity rate (NGS, 10 -6) was 94%. After a median follow up of 32 months, the 24-months PFS is 87% (78-87%) and the 24-months OS is 94% (87-100%). Conclusions: Dara-KRD induction/consolidation with tandem transplant was feasible in TE NDMM patients with high-risk cytogenetic profile, and resulted in high MRD negativity rate and high progression free survival.

Iberdomide Maintenance after Autologous Stem-Cell Transplantation in Newly Diagnosed MM: First Results of the Phase 2 EMN26 Study

Background. Iberdomide is a novel oral cereblon E3 ligase modulator (CELMoD TM) with enhanced direct antitumor effects and immune stimulatory effects, compared to lenalidomide or pomalidomide. In the ongoing phase 1/2 CC-220-MM-001 study, iberdomide plus dexamethasone had a favorable safety profile and demonstrated clinically meaningful activity in triple-class refractory multiple myeloma (MM) patients, including those refractory to lenalidomide and pomalidomide (IMiDs ®). Based on these data, we aimed to evaluate the safety and clinical activity of 3 different doses of iberdomide as a novel maintenance treatment post-transplant in newly diagnosed MM patients. Here we report results from the first interim analysis for patients who have been treated with at least 6 treatment cycles, or discontinued treatment earlier. Methods. The EMN26 study is a multicohort, phase 2 study conducted in 4 European countries. Patients aged 18 years or older with MM, who had achieved at least a partial response (PR) after induction therapy containing a proteasome inhibitor (PI) plus IMiD followed by single or double autologous stem-cell transplantation (ASCT) +/- consolidation, were enrolled into one of 3 different cohorts (iberdomide 0.75, 1.0, or 1.3 mg on days 1-21 of each 28-day cycle; treatment continued until progression or unacceptable toxicity; 40 patients in each cohort). The primary outcome is improvement in response, and secondary outcomes include safety and progression-free survival (PFS). Response was evaluated at screening and after every cycle (bone marrow analysis was done at screening, at 6 and 12 months after treatment initiation, and to confirm (s)CR). This trial is ongoing and is registered with ClinicalTrials.gov (NCT04564703). Results. At data cut-off (May 31, 2023) 31 patients were enrolled in the 0.75 mg cohort, and 40 patients each in the 1.0 and 1.3 mg cohorts (total of 111). A total of 69 patients had received ≥6 cycles of iberdomide treatment or discontinued earlier (n=34 in 1.0 mg cohort; n=35 in 1.3 mg cohort; n=0 in 0.75 mg cohort [this cohort was added later]). Median age of these 69 patients was 59 years, and 57% were male. At diagnosis, 37% of patients presented with International Staging System (ISS) stage 1 disease, 35% with ISS stage 2, and 28% with stage 3. High-risk disease (del(17p), t(4;14), and/or t(14;16)) was present in 14% of patients. All patients received a PI/IMiD-containing induction regimen which also included daratumumab in 41% of patients. Double ASCT was administered to 19% and post-ASCT consolidation to 7%. Best response at the time of enrollment in the study was PR in 15%, very good (VG)PR in 59%, complete response (CR) in 12%, stringent (s)CR in 15% [≥CR: 26%] in the 1.0 mg cohort, and PR in 3%, VGPR in 69%, CR in 11%, sCR in 17% [≥CR: 29%] in the 1.3 mg cohort. After 6 treatment cycles, there was comparable deepening of response in both cohorts (1.0 mg cohort: PR 6%, VGPR 44%, CR 3%, sCR 47% [≥CR: 50%]; 1.3 mg cohort: PR 3%, VGPR 37%, CR 9%, sCR 51% [≥CR: 60%]). Improvement of response was reported in 48% (90% CI 32-65%) of patients treated with 1.0 mg iberdomide and 45% (90% CI 29-62%) in the 1.3 mg iberdomide cohort ( Figure), which are significantly higher than the null hypothesis of ≤20% response improvement within 6 months. The most common grade 3 or worse adverse events (AEs) during cycles 1-6 were neutropenia (21% in 1.0 mg cohort and 46% in 1.3 mg cohort), infections (3% and 14%), fatigue/asthenia (12% and 14%). There were no events of ≥grade 3 thrombocytopenia, anemia, diarrhea, VTE, or neuropathy. Dose reductions were used to manage AEs in 18% of patients in the 1.0 mg cohort and 31% in the 1.3 mg cohort. Treatment discontinuation occurred in 3 patients in 1.0 mg cohort (1 due to AE, 2 PD), and 4 patients in 1.3 mg cohort (2 due to AE, 1 PD, and 1 death [unknown cause]). PFS at 6 months was 97% and 94% in the 1.0 and 1.3 mg cohorts. With longer follow-up, results from the 0.75 mg cohort and MRD conversion data will be presented at the meeting. Conclusions. Iberdomide represents a novel effective post-ASCT maintenance strategy with a favorable safety profile and superior response improvement at 6 months than what has been observed with lenalidomide maintenance (26% at 6 months in the EMN02 study). Additional follow-up is needed to define the recommended maintenance dose that will be used in the randomized phase 3 EXCALIBER maintenance study, which will evaluate iberdomide vs. lenalidomide maintenance post-ASCT.

Outcomes of Haplo-Cord and Dual-Cord Transplants: A Single-Center Retrospective Analysis

Background: Despite the concurrent use of tandem haploidentical-umbilical cord (haplo-cord) and dual-umbilical cord (dual-cord) allogeneic hematopoietic stem cell transplant (HSCT) approaches for over a decade, there have been few comparisons of their outcomes (van Besien et al. Hematologica, 2016). No previous studies have evaluated differences following identical conditioning regimens. We report a retrospective analysis comparing patients treated with haplo-cord or dual-cord HSCTs at our institution following the same conditioning regimen. Methods: Between 10/2012-10/2022, 70 haplo-cord and 133 dual-cord transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m 2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. Cyclosporine and mycophenolate mofetil were used for graft versus host disease (GVHD) prophylaxis. Patient selection, infectious disease prophylaxis, and donor selection were per institutional standards. Patient characteristics between groups were compared using Fisher's exact test. Kaplan-Meier estimates were used to evaluate OS and RFS. Cumulative incidence estimates were used to compare relapse, aGVHD, cGVHD, and neutrophil and platelet engraftment. Two-tailed t-test was used to compare average in-hospital stays for transplant admissions. Results: There were no significant differences between median age at transplant (51.6 vs 50.3), female representation (41.4% vs 45.1%), or disease types (47.1% vs 51.1% acute myeloid leukemia (AML), 25.75% vs 17.3% acute lymphoblastic leukemia (ALL), 17.2% vs 15.1% myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), 10% vs 16.5% other; p=0.373). With a median follow-up of over 2 years, there was no difference in or OS (p=0.96) or RFS (Figure 1, p=1) for all patients, or for the MDS/MPN and AML subset (OS p=0.47, RFS p=0.43). There was a significant increase in grade 3-4 acute GVHD (aGVHD) in haplo-cord recipients (Figure 2, p=0.007), but no difference in grade 2-4 aGVHD (p=0.11), all chronic GVHD (p=0.8), and moderate-severe cGVHD (p=0.3). Time to neutrophil recovery was faster in haplo-cord recipients (p=0.021), but there was no difference in platelet recovery to 20,000/uL (p=0.12). Average days admitted for haplo-cord HSCTs was 20.61 days compared to 27.56 days for dual-cord HSCTs (p&amp;lt;0.0001). Conclusion: In our experience, there were no differences in survival, relapse, or cGVHD between haplo-cord and dual cord HSCT. Haplo-cord HSCTs were associated with faster neutrophil engraftment and shorter hospital stays compared to dual-cord HSCTs; however, haplo-cord SCTs had significantly higher grade 3-4 aGVHD. When both are options, the choice of haplo-cord versus dual-cord HSCTs should consider these opposing factors. Reference: 1. Koen van Besien, Parameswaran Hari, Mei-Jie Zhang, Hong-Tao Liu, Wendy Stock, Lucy Godley, Olatoyosi Odenike, Richard Larson, Michael Bishop, Amittha Wickrema, Usama Gergis, Sebastian Mayer, Tsiporah Shore, Stephanie Tsai, Joanna Rhodes, Melissa M. Cushing, Sandra Korman, Andrew Artz. Reduced intensity haplo plus single cord transplant compared to double cord transplant: improved engraftment and graft-versus-host disease-free, relapse-free survival. Haematologica 2016;101(5):634-643; https://doi.org/10.3324/haematol.2015.138594.

Impact of Graft Source [Cord Blood Supported By CD34+ Selected Cells (Haplo-Cord) Vs. Matched Donor] on Transplant Outcomes in Myelofibrosis

Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for patients with myelofibrosis (MF). Here, we evaluated the impact of donor type [cord blood transplant supported by CD34+ cells (haplo-cord) vs adult matched donor] on outcomes in MF. Methods: All adult patients with primary or secondary (post-ET or post-PV) MF, including those progressing to acute leukemia (AML) who underwent their first allo-HCT at NewYork-Presbyterian Hospital/Weill Cornell Medicine between 01/2015 and 06/2022 were included. Results: 40 patients were transplanted. Median age was 63 years (range 21-77). 23% had a Karnofsky performance scale (KPS) of &amp;lt;80. Two had undergone splenectomy prior to HCT. The median spleen size was 18cm (10-28). Median number of pre-HCT molecular mutations was 2 (range 0-7). 16 (40%) had MF-3 (Table 1). 24 (60%) underwent a matched sibling donor (MSD) (n=9) or unrelated donor (MUD) (n=15) HCT, and 16 (40%) underwent a cord-based (CB) HCT. 39 received Fludarabine/Melphalan +/- low dose total body irradiation (TBI), one underwent myeloablative conditioning with TBI/etoposide based on extensive extramedullary disease. The median time to neutrophil engraftment in the MSD/MUD group was 14 days (IQR 14-18) vs 30 days in the CB group (IQR 15-36) and (p=0.1). The median time to platelet engraftment was 22 days (IQR 17-38) in MSD/MUD vs 49 days (IQR 26-60) in the CB group (P=0.07). The CI of absolute neutrophil count (ANC) and platelet engraftment by day 60 for MSD/MUD vs CB was 92% (95% CI 65-98%) vs 80% (95% CI 45-94%) (p=0.09) and 75% (95% CI 51%- 88%) vs 59% (95% CI 27-81%) (p=0.36), respectively. One patient in the MSD/MUD died without neutrophil engraftment compared to 3 in CB group. 5 patients in each group died without platelet engraftment. Median follow-up for all alive patients was 53 months. Overall survival (OS) for the cohort was 62% at 1 year (95% CI 49-79) and 34% at 3 years (95% CI 21-55). OS at 3 years was similar between MSD/MUD group and CB (32% vs 37%, P=0.9) (figure 1). Graft versus host disease relapse free survival (GRFS) at 3 years was not significantly different in MSD/MUD group, compared to CB group (15% vs 33%, P=0.64). Cumulative incidence of relapse at 3 years in MSD/MUD group was 28% (95% CI 10-49), and 12% (95% CI 1.8-34) in CB group (p=0.356). Non-relapse mortality (NRM) at 1 year was 33% (95% CI 15-52) in MSD/MUD group and 38% (95% CI 15-61) in CB group. NRM at 3 years was 54% (95% CI 29-73) in MSD/MUD group and 48% (95% CI 19-72) on CB group (P=0.95). Discussion: In our small cohort, we showed that OS after haplo-cord transplant was comparable to adult matched donors' grafts (MSD or MUD). While the haplo-cord platforms have been shown to decrease the time to engraftment (11 days for neutrophils and 22 days for platelets) compared with double cord transplants or haploidentical transplants (van Besien K et al . Haematologica 2016, van Besien K et al. Blood Adv 2019), in patients with MF, we saw a trend towards delayed engraftment compared to patients transplanted with adult matched donors' grafts (MSD or MUD). This suggests that the CD34 selected cells may not be able to provide an adequate myeloid bridge and overcome the low cellular content in the CB for adult patients with extensive marrow fibrosis. Larger studies are needed to compare best alternative graft (CB-based versus haploidentical or mismatched unrelated donors) for patients with MF that lack a matched donor.

Real-World Outcomes of Newly Diagnosed Multiple Myeloma (NDMM) Patients Treated before the Anti-CD38 Antibodies Era in France, the Emmy Cohort 2017 to 2020

Background In randomized clinical trials (RCTs), patients (pts) with comorbidities or a very aggressive presentation of myeloma may be excluded. The results of RCTs may not be generalizable to pts in the real-world setting. Therefore, RCT data need to be backed up by results from real-world studies. Methods EMMY is a non-interventional, prospective study conducted in 73 IFM (Intergroupe Francophone du Myélome) sponsor sites in France. Any patient initiating treatment for multiple myeloma (MM) over a 3-month (mo) period, from October to December, is included, since 2017. It is a dynamic cohort with 900 pts on average, enrolled each year. Here, we present the results of NDMM pts for the first 4 years of inclusion (2017 to 2020). Pts with NDMM who receive front-line therapy with an autologous stem cell transplant (ASCT group) are described separately from non-transplant eligible pts (NTE group). Results 1597 pts with NDMM were included in EMMY over the 2017-2020 period. Of these, 1036 were in the NTE group (64.9%) and 561 in the ASCT group (35.1%). Data are presented with a median follow-up of 23.7 mo (IQR 12.3 - 39.0). ASCT group These pts had a median age of 60.6 years (range 23.4 - 78.5). 5.2 % were older than 70 years at ASCT. In routine practice, cytogenetic tests were carried out for 75.7% of pts, 19.6% of them harboured high-risk (HR) anomalies of t(4;14) or del(17p). The period 2017-2020 was marked by a shift in induction treatment from Velcade Thalidomide dexamethasone (VTd) (n = 163, 29.1% of pts who received ASCT) to Velcade Revlimid dexamethasone (VRd) (n = 309, 55.1%). Fifty-three (9.5%) pts received a double transplantation which was stable over time. 22.8 % of pts with HR anomalies received a double transplant. NTE group The 1036 NTE pts had a median age of 74.9 years (range 33.8 - 97.8), and more than 30.4% (n = 315) were aged ≥ 80 years. Among these pts, 65.9% were considered frail, with 33.6% having an Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≥ 2 and almost half (47.1%) had comorbidities. Significant renal impairment (glomerular filtration rate [GFR] &amp;lt; 30 mL/min) was observed in 118 (13%) pts at treatment initiation. A subgroup of 126 younger pts (age &amp;lt; 65 years) was considered ineligible for transplantation. Regarding cytogenetics 56.4% of the pts were tested in regular practice (mean age 73.3 years). NTE pts mostly received three main combinations: VRd (28.4% of pts, n = 294), Velcade Melphalan prednisone (VMp) (21.9% of pts, n = 21.9%) and Revlimid dexamethansone (Rd) (21.1%, n = 219). During the study period, VMp use decreased from 36.9% to 6.5% of pts, VRd use increased from 10.6% to 48.5% and Rd use remained constant, at around 20%. Other bortezomib-based regimens, including Velcade dexamethasone (Vd) and Velcade Cyclophosphamide dexamethasone (VCd), were used steadily, in approximately 12% and 7% of pts, respectively, over the period. Survival data Median progression-free survival (mPFS) was 25.8 mo (95% CI: 23.5-29.1) in the overall NDMM population, 46.5 mo (95% CI: 37.8-50.6) in pts who received ASCT and 18.7 mo (95% CI: 16.3-20.8) in NTE pts ( P &amp;lt; 0.0001). (Figure 1). The median PFS2 (mPFS2) was estimated at 50.6 mo (95% CI: 47.6-NA) in all pts with NDMM. mPFS2 was 36.4 mo (95% CI: 34.7-39.9) in NTE pts; it was not reached in the ASCT group. The median overall survival (OS) had not yet been reached. The estimated OS rate was 72.9% (95% CI: 69.8-75.9) at 48 mo for the total NDMM population. (Figure 2). AE leading to discontinuation. 139 pts experienced an adverse event (AE) leading to treatment discontinuation (6.8 % of ASCT pts and 14.5% in the NTE group). This occurred at a median of 4.3 mo after treatment initiation and was mainly reported with the most used agents (lenalidomide, bortezomib or melphalan). The most frequently reported AEs were neuropathy (n = 14; 10.1%), digestive disorders (n = 13; 9.4%), rash (n = 12; 8.6%), deterioration of general condition (n = 12; 8.6%), cardiovascular AEs (n = 10; 7.2%) and acute renal failure (n = 10; 7.2%). Conclusion The 2017-2020 period for pts with NDMM in France was marked by the expansion of the use of lenalidomide in first line for the majority of pts. A major difference in PFS and OS is still observed between ASCT and NTE pts. A shorter PFS than in IFM2009 trial (PFS 50 mo) was observed in EMMY ASCT pts.

Impact of the Addition of Daratumumab to the Standard Bortezomib-Thalidomide-Dexamethasone Regimen on Hematopoietic Stem Cell Mobilization and Collection, Post-Transplant Engraftment and Infectious Complications: A Case-Control Multicentre Real-Life Analysis

Background The pivotal clinical trial CASSIOPEIA established the quadruplet Daratumumab-Bortezomib-Thalidomide-Dexamethasone (Dara-VTD) as superior with regards to the standard Bortezomib-Thalidomide-Dexamethasone (VTD) regimen as induction therapy in newly diagnosed transplant-eligible (NDTE) multiple myeloma (MM) patients. As a matter of facts, Dara-VTD is currently the approved induction scheme in NDTE MM patients in Italy. Previous reports showed that adding Daratumumab in induction therapy patients yielded to a higher number of poor mobilizers, with a lower median number of collected hematopoietic stem cells (HSC). However, these reports included different types of induction therapies, merging patients on and off clinical trials, and real-life data focusing exclusively on Dara-VTD is lacking. We report our experience on the impact of Dara-VTD on HSC mobilization and collection, with a retrospective comparison with a cohort of patients treated with VTD and we also provided data concerning post-transplant engraftment and infectious complications. Methods From January 2022 to June 2023, 109 NDTE MM patients from 5 Haematology Institutions received Dara-VTD treatment induction according to the approved doses and schedule. The control group consisted of 116 age-matched patients treated with VTD in the years 2015-2016. Mobilizing therapy consisted of cyclophosphamide 1-3 gr/sqm followed by granulocyte colony-stimulating factor (G-CSF) 10 mcg/kg starting the 5th day thereafter, with HSC harvest planned on the 11th day. Patients received only G-CSF 10 mcg/kg if they were older than 70 years or had renal impairment (i.e., eGFR &amp;lt; 50 ml/min). Poor mobilizer was defined as having less than 20 CD34+/µL in peripheral blood on the 11th day after cyclophosphamide and G-CSF or on the 4th day of G-CSF alone administration. In that case, plerixafor was added at the standard dose of 0.24 mg/kg. Results In the Dara-VTD group, 96/109 patients received cyclophosphamide and G-CSF; among them, 3 patients had failed a previous G-CSF mobilizing therapy, even with the addition of plerixafor. Thirteen patients received G-CSF only. In the VTD group, all patients had received cyclophosphamide and G-CSF. Pre-harvest median number of CD34+/mL in the Dara-VTD group was 26 (range 0.8-279) vs 76 (range 20-294) in the VTD group and the incidence of poor mobilizing patients was 41.7% vs 5.9%, respectively (OR 0.3, 95% CI 0.16-0.54, P &amp;lt; 0.0001). Baseline disease characteristic did not have an impact on poor mobilizing events. On the contrary, patients who developed hematologic toxicity during induction turned out to be poor mobilizers (OR 3.5, 95% IC 1.36-9.59, p= 0.011). Plerixafor was used in 54/109 patients in the Dara-VTD group and in 16/116 patients of the VTD group. Two patients failed HSC mobilization both with G-CSF and cyclophosphamide and G-CSF. All patients that received G-CSF only resulted in poor mobilizers and required plerixafor before HSC harvest; therefore, cyclophosphamide showed to be superior with regards to G-CSF as mobilizing therapy (p= 0.011). The median number of collected HSC was significantly lower in the Dara-VTD group vs VTD group: 5.17 x 10^6/Kg (IQR 3.9-5.47) vs 8.7 x 10^6/kg (IQR 6.35-11.15), respectively (p &amp;lt; 0.0001). 33% of patients in Dara-VTD group collected at least 6 x 10^6 CD34+/Kg). Median time to neutrophils and platelets engraftment were different between the two groups (13 and 11 days, respectively, P &amp;lt; 0.0001), but we did not observe any difference in terms of infection incidence. Notably, post-transplant infections incidence in Dara-VTD group was 43%. Although the second transplant was planned for 36 patients treated with Dara-VTD, it was performed in 10 patients only, mainly because of insufficient HSC harvest. Conclusions Our experience with Dara-VTD confirms an increased number of poor mobilizers, a higher need for the use of plerixafor and a lower number of collected HSC. We observed a slightly lower engraftment in Dara-VTD group, probably because of a lower number of infused HSC. The lower number of collected HSC hampers the possibility of a double transplant.

312.2: Combined double thymus transplantation and mixed xenogeneic chimerism for the induction of optimal tolerance and enhancement of immune function

312.2: Combined double thymus transplantation and mixed xenogeneic chimerism for the induction of optimal tolerance and enhancement of immune function

Effect of once versus twice intracoronary injection of allogeneic-derived mesenchymal stromal cells after acute myocardial infarction: BOOSTER-TAHA7 randomized clinical trial

BackgroundMesenchymal stromal cell (MSC) transplantation can improve the left ventricular ejection fraction (LVEF) after an acute myocardial infarction (AMI). Transplanted MSCs exert a paracrine effect, which might be augmented if repeated doses are administered. This study aimed to compare the effects of single versus double transplantation of Wharton’s jelly MSCs (WJ-MSCs) on LVEF post-AMI.MethodsWe conducted a single-blind, randomized, multicenter trial. After 3–7 days of an AMI treated successfully by primary PCI, 70 patients younger than 65 with LVEF < 40% on baseline echocardiography were randomized to receive conventional care, a single intracoronary infusion of WJ-MSCs, or a repeated infusion 10 days later. The primary endpoint was the 6-month LVEF improvement as per cardiac magnetic resonance (CMR) imaging.ResultsThe mean baseline EF measured by CMR was similar (~ 40%) in all three groups. By the end of the trial, while all patients experienced a rise in EF, the most significant change was seen in the repeated intervention group. Compared to the control group (n = 25), single MSC transplantation (n = 20) improved the EF by 4.54 ± 2%, and repeated intervention (n = 20) did so by 7.45 ± 2% when measured by CMR imaging (P < 0.001); when evaluated by echocardiography, these values were 6.71 ± 2.4 and 10.71 ± 2.5%, respectively (P < 0.001).ConclusionsIntracoronary transplantation of WJ-MSCs 3–7 days after AMI in selected patients significantly improves LVEF, with the infusion of a booster dose 10 days later augmenting this effect.Trial registration: Trial registration: Iranian Registry of Clinical Trials, IRCT20201116049408N1. Retrospectively Registered 20 Nov. 2020, https://en.irct.ir/trial/52357

Outcomes of lung transplantation for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease is a progressive airway disease that can progress to the terminal stage requiring oxygen supply. In this period, lung volume reduction therapies and/or lung transplantation may be considered. Morbidity and mortality risks due to transplant surgery and posttransplant immunosuppressive therapy show the importance of selecting the best candidates who will benefit from transplantation. In this context, BODE index criteria serve as important markers. This study aimed to analyze the outcomes of lung transplantation in patients with chronic obstructive pulmonary disease and to identify variables that may affect post-transplant clinical outcomes. Lung transplants diagnosed with chronic obstructive pulmonary disease performed in our center between March 2013 and January 2023 were included in the study. Demographic information and both pre-op and post-op clinical data of the transplant patients were collected. The effect of BODE index criteria and other pre-transplant clinical data on short- and long-term outcomes after transplantation were investigated. During the study period, 34 lung transplants were performed for chronic obstructive pulmonary disease. One patient died during the operation, three patients received single transplants, and 30 received double transplants. Post-operative primary graft dysfunction was more common in single transplant recipients. The results were comparable between single and double transplants in terms of post-transplant pulmonary function and the development of chronic lung allograft dysfunction. BODE index criteria had no effect on early and late post-operative clinical data, however intra-operative use of extracorporeal membrane oxygenation, primary graft dysfunction, and prolonged extubation were significantly higher in recipients younger than 60 years. Our study suggests that prelisting demographic and clinical data of chronic obstructive pulmonary disease patients had no significant effect on post-operative outcomes, however, intra-operative ECMO use, prolonged extubation, primary graft dysfunction (p< 0.05 for each) and chronic rejection (p> 0.05) were more common in patients who are <60 years of age. These data need to be confirmed by larger studies.

Treatment of primary plasma cell leukaemia with carfilzomib and lenalidomide-based therapy (EMN12/HOVON-129): final analysis of a non-randomised, multicentre, phase 2 study

Primary plasma cell leukaemia is a rare and aggressive plasma cell disorder with a poor prognosis. The aim of the EMN12/HOVON-129 study was to improve the outcomes of patients with primary plasma cell leukaemia by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance therapy. The EMN12/HOVON-129 study is a non-randomised, phase 2, multicentre study conducted at 19 academic centres and hospitals in seven European countries (Belgium, Czech Republic, Denmark, Italy, Norway, The Netherlands, and the UK) for previously untreated patients with primary plasma cell leukaemia aged 18 years or older. Inclusion criteria were newly diagnosed primary plasma cell leukaemia (defined as >2 ×109 cells per L circulating monoclonal plasma cells or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Patients aged 18-65 years (younger patients) and 66 years or older (older patients) were treated in age-specific cohorts and were analysed separately. Younger patients were treated with four 28-day cycles of carfilzomib (36 mg/m2 intravenously on days 1, 2, 8, 9, 15, and 16), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 8, 9, 15, 16, 22, and 23). Carfilzomib-lenalidomide-dexamethasone (KRd) induction was followed by double autologous haematopoietic stem-cell transplantation (HSCT), four cycles of KRd consolidation, and then maintenance with carfilzomib (27 mg/m2 intravenously on days 1, 2, 15, and 16 for the first 12 28-day cycles, and then 56 mg/m2 on days 1 and 15 in all subsequent cycles) and lenalidomide (10 mg orally on days 1-21) until progression. Patients who were eligible for allogeneic HSCT, could also receive a single autologous HSCT followed by reduced-intensity conditioning allogeneic HSCT and then carfilzomib-lenalidomide maintenance. Older patients received eight cycles of KRd induction followed by maintenance therapy with carfilzomib and lenalidomide until progression. The primary endpoint was progression-free survival. The primary analysis population was the intention-to-treat population, irrespective of the actual treatment received. Data from all participants who received any study drug were included in the safety analyses. The trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR5350; recruitment is complete and this is the final analysis. Between Oct 23, 2015, and Aug 5, 2021, 61 patients were enrolled and received KRd induction treatment (36 patients aged 18-65 years [20 (56%) were male and 16 (44%) female], and 25 aged ≥66 years [12 (48%) were male and 13 (52%) female]). With a median follow-up of 43·5 months (IQR 27·7-67·8), the median progression-free survival was 15·5 months (95% CI 9·4-38·4) for younger patients. For older patients, median follow-up was 32·0 months (IQR 24·7-34·6), and median progression-free survival was 13·8 months (95% CI 9·2-35·5). Adverse events were most frequently observed directly after treatment initiation, with infections (two of 36 (6%) younger patients and eight of 25 (32%) older patients) and respiratory events (two of 36 [6%] younger patients and four of 25 [16%] older patients) being the most common grade 3 or greater events during the first four KRd cycles. Treatment-related serious adverse events were reported in 26 (72%) of 36 younger patients and in 19 (76%) of 25 older patients, with infections being the most common. Treatment-related deaths were reported in none of the younger patients and three (12%) of the older patients (two infections and one unknown cause of death). Carfilzomib and lenalidomide-based therapy provides improved progression-free survival compared with previously published data. However, results remain inferior in primary plasma cell leukaemia compared with multiple myeloma, highlighting the need for new studies incorporating novel immunotherapies. Dutch Cancer Society, Celgene (a BMS company), and AMGEN.

Meniscus Allograft Transplantation With Bone Plugs Using Knotless All-Suture Anchors and Cortical Button Suspensory Fixation

Meniscus allograft transplantation can be successful for treatment of meniscal deficiency using a number of transplant techniques. In this Technical Note, we describe a double bone plug medial meniscus allograft transplantation technique that uses knotless all-suture anchors with cortical-button suspensory fixation. This technique maintains the reported advantages for bone-plug fixation while mitigating the risk for meniscal root damage, facilitating easier bone plug insertion and seating, expanding tensioning capabilities, and preventing soft-tissue irritation from suture knot stacks.