Outcome of Hematopoietic Stem Cell Transplantation in 813 Pediatric Patients with Fanconi Anemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative option for Fanconi anemia (FA) associated bone marrow failure (BMF)/aplastic anemia (AA) and hematological malignancy. We performed a retrospective multicenter study on 813 FA children undergoing first HSCT between 2010 and 2018. Median duration of follow-up was 3.7 years (interquartile range, 3.4-4.0). Median age at transplant was 8.8 years (6.5-18.1). Overall survival (OS), event-free survival (EFS) and GvHD-free, relapse-free survival (GRFS) at 5 years were 83% (80-86%), 78% (75-81%) and 70% (67-74%) respectively. OS was comparable between matched family donor (MFD, n=441, 88%) and matched unrelated donor (MUD, n=162, 86%) and was superior to that of mismatched family or unrelated donor (MMFD/MMUD, n=144, 72%) and haploidentical donor (HID) (n=66, 70%, p<0.001). In multivariable analysis, a transplant indication of acute myeloid leukaemia/myelodysplastic syndrome compared to AA/BMF, use of MMFD/MMUD and HID compared to MFD, Fludarabine-Cyclophosphamide (FluCy) + other conditioning compared to FluCy independently predicted inferior OS, while alemtuzumab compared to ATG was associated with better OS. Age  10 years was associated with worse EFS and GRFS. Cumulative incidences (CIN) of primary and secondary graft failure were 2% (1-3%) and 3% (2-4%) respectively. CIN of grade II-IV acute GvHD, grade III-IV acute GvHD and chronic GvHD were 23% (20-26%), 12% (10-15%) and 8% (6-10%) respectively. The 5-year CIN of secondary malignancy was 2% (1-3%). These data suggest that HSCT should be offered to Fanconi Anemia patients with AA/BMF at a younger age in the presence of a well-matched donor.

Comparable relapse incidence after unrelated allogeneic stem cell transplantation with post-transplant cyclophosphamide versus conventional anti-graft versus host disease prophylaxis in patients with acute myeloid leukemia: A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

We compared relapse incidence (RI) post-unrelated transplantation with post-transplant cyclophosphamide (PTCy) versus no PTCy graft-versus-host disease (GVHD) prophylaxis, in 7049 acute myeloid leukemia (AML) patients in remission, 707 with PTCy, and 6342 without (No PTCy). The patients in the PTCy group were younger, 52.7 versus 56.6 years (p < .001). There were more 9/10 donors in the PTCy group, 33.8% versus 16.4% (p < .001), and more received myeloablative conditioning, 61.7% versus 50.2% (p < .001). In the No PTCy group, 87.7% of patients received in vivo T-cell depletion. Neutrophil and platelet engraftment were lower in the PTCy versus No PTCy group, 93.8% and 80.9% versus 97.6% and 92.6% (p < .001). RI was not significantly different in the PTCy versus the No PTCy group, hazard ratio (HR) of 1.11 (95% confidence interval [CI] 0.9-1.37) (p = .31). Acute GVHD grades II-IV and III-IV, were significantly lower in the PTCy versus the No PTCy group, HR of 0.74 (95% CI 0.59-0.92, p = .007) and HR = 0.56 (95% CI 0.38-0.83, p = .004), as were total and extensive chronic GVHD, HRs of 0.5 (95% CI 0.41-0.62, p < .001) and HR = 0.31 (95% CI 0.22-0.42, p < .001). Non-relapse mortality (NRM) was significantly lower with PTCy versus the No PTCy group, HR of 0.67 (95% CI 0.5-0.91, p = .007). GVHD-free, relapse-free survival (GRFS) was higher in the PTCy versus the No PTCy group, HR of 0.69 (95% CI 0.59-0.81, p = .001). Leukemia-free survival (LFS) and overall survival (OS) did not differ between the groups. In summary, we observed comparable RI, OS, and LFS, significantly lower incidences of GVHD and NRM, and significantly higher GRFS in AML patients undergoing unrelated donor-hematopoietic stem cell transplantation with PTCy versus No PTCy GVHD prophylaxis.

PTCy versus CNI-based GVHD prophylaxis in HLA-matched transplants for Hodgkin Lymphoma: a study of the LWP of the EBMT.

Studies comparing the efficacy of post-transplant cyclophosphamide (PTCy) to conventional calcineurin inhibitor (CNI)-based GVHD prophylaxis regimens in Hodgkin lymphoma (HL) patients are scarce. This study aimed to compare the outcomes of HL patients undergoing hematopoietic stem cell transplantation from HLA-matched donors who received GVHD prophylaxis with either PTCy or conventional CNI-based regimens, using data reported to the EBMT database between January 2015 and December 2022. Among the cohort, 270 recipients received conventional CNI-based prophylaxis and 176 received PTCy prophylaxis. Notably, PTCy prophylaxis was associated with delayed hematopoietic recovery, but also with a lower risk of chronic (25% versus 43%, p<0.001) and extensive chronic GVHD (13% versus 28% p=0.003) compared to the CNI-based cohort. The 2-year cumulative incidence of non-relapse mortality and relapse were 11% versus 17% (p=0.12), and 17% versus 30% (p=0.007) for PTCy and CNI-based, respectively. Moreover, the 2-year overall survival, progression-free survival and GVHD-free, relapse-free survival were all significantly better in the PTCy group compared with the CNI-based group: 85% versus 72% (p=0.005), 72% versus 53% (p<0.001), and 59% versus 31% (p<0.001), respectively. In multivariable analysis, PTCy was associated with a lower risk of chronic and extensive chronic GVHD, reduced relapse, and better OS, PFS, and GRFS compared to the CNI-based platform. Our findings suggest that PTCy as GVHD prophylaxis offers more favorable outcomes compared to conventional CNI-based prophylaxis in adult patients with HL undergoing HSCT from HLA-matched donors.

Donor/recipient Rh-mismatched allogeneic hematopoietic stem cell transplantation: transfusion strategy and allo-immunization to red blood cell antigens.

In the case of donor/recipient rhesus (Rh)-incompatibility after allogeneic hematopoietic stem cell transplantation (alloHSCT), the transfusion policy in France is to transfuse red blood cells (RBC) in the donor's Rh phenotype from the day of transplantation, leading to a risk of allo-immunization, either of donor or recipient origin. In this single-center retrospective study, the incidence of donor/recipient Rh incompatibility was 7.1% over an 8-year period including 1012 alloHSCT. Six of 58 evaluable patients (10.3%) developed alloantibodies to RBC antigens within one year of alloHSCT. None of these allo-immunizations were directed against the donor-mismatched Rh antigens and none could have been prevented by the transfusion of recipient and donor Rh-compatible RBC units. None of these allo-immunizations led to immune-mediated hemolytic anemia. We observed a statistically significant higher incidence of chronic GVHD among patients with anti-RBC allo-immunization. In the context of donor/recipient Rh incompatibility, the transfusion of packed RBC units in the donor's Rh phenotype from the day of alloHSCT is feasible and not associated with a high risk of allo-immunization. The generalization of this strategy could be discussed even when donor and recipient Rh phenotypes could be respected, to allow the preservation of units of infrequent phenotypes for other indications.

Outcomes of allogeneic haematopoietic cell transplantation for myelofibrosis in children and adolescents: the retrospective study of the EBMT Paediatric Diseases WP.

This retrospective study evaluated 35 children (median age 5.2 years; range 0.4-18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II-IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3-41.1) vs 58.8% (31-78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1-32.8), relapse incidence was 15.9% (5.6-30.9), progression-free survival (PFS) was 66.1% (47-79.7), GvHD-free relapse-free survival was 50% (30.6-66.7), and overall survival (OS) was 71.1% (51.4-84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3-96.1) vs 50.8% (26.3-71), p = 0.03, and 90.9% (50.8-98.7) vs 54% (28.1-74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3-53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies.

Hemolysis events in the phase 3 PEGASUS study of pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria.

ABSTRACT: Patients with paroxysmal nocturnal hemoglobinuria (PNH) experience complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Pegcetacoplan, a C3 inhibitor, demonstrated sustained improvements in hematologic and clinical parameters in the phase 3 PEGASUS trial in patients with PNH who remained anemic despite C5 inhibitor therapy. The present post hoc analysis describes 26 hemolysis adverse events (AEs) experienced in 19 patients during pegcetacoplan therapy in PEGASUS and baseline patient characteristics potentially associated with increased hemolysis risk. Lactate dehydrogenase (LDH) ≥2× the upper limit of normal (ULN) was observed in 19 events, including 2 with LDH ≥10× ULN. All patients experienced decreased hemoglobin during hemolysis (mean decrease, 3.0 g/dL). In 16 events (62%), a potential complement-amplifying condition underlying the event could be identified. Hemolysis AEs led to study discontinuation in 5 patients. However, of 26 hemolysis AEs, 17 (65%) were manageable without pegcetacoplan discontinuation. A greater proportion of patients with hemolysis AEs (n = 19) had key characteristics of higher disease activity at baseline compared to patients without hemolysis AEs (n = 61), namely higher-than-label eculizumab dose (53% vs 23%), detectable CH50 (total complement function; 74% vs 54%), and ≥4 transfusions in the previous 12 months (68% vs 51%). These characteristics may be useful predictors of potential future hemolysis events. This trial was registered at www.ClinicalTrials.gov as #NCT03500549.

Safety and Efficacy of Pegcetacoplan in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria over 48 Weeks: 307 Open-Label Extension Study.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first targeted complement component 3 (C3) PNH therapy, was safe and efficacious in treatment-naive and pre-treated patients with PNH in five clinical trials. METHODS: The 307 open-label extension (OLE) study (NCT03531255) is a non-randomized, multicenter extension study of long-term safety and efficacy of pegcetacoplan in adult patients with PNH who completed a pegcetacoplan parent study. All patients received pegcetacoplan. Outcomes at the 48-week data cutoff (week 48 of 307-OLE or August 27, 2021, whichever was earlier) are reported. Hemoglobin concentrations, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and transfusion avoidance were measured. Hemoglobin > 12 g/dL and sex-specific hemoglobin normalization (i.e., male, ≥ 13.6 g/dL; female, ≥ 12 g/dL) were assessed as percentage of patients with data available and no transfusions 60 days before data cutoff. Treatment-emergent adverse events, including hemolysis, were reported. RESULTS: Data from 137 patients with at least one pegcetacoplan dose at data cutoff were analyzed. Mean (standard deviation [SD]) hemoglobin increased from 8.9 (1.22) g/dL at parent study baseline to 11.6 (2.17) g/dL at 307-OLE entry and 11.6 (1.94) g/dL at data cutoff. At parent study baseline, mean (SD) FACIT-Fatigue score of 34.1 (11.08) was below the general population norm of 43.6; scores improved to 42.8 (8.79) at 307-OLE entry and 42.4 (9.84) at data cutoff. In evaluable patients, hemoglobin > 12 g/dL occurred in 40.2% (43 of 107) and sex-specific hemoglobin normalization occurred in 31.8% (34 of 107) at data cutoff. Transfusion was not required for 114 of 137 patients (83.2%). Hemolysis was reported in 23 patients (16.8%). No thrombotic events or meningococcal infections occurred. CONCLUSION: Pegcetacoplan sustained long-term improvements in hemoglobin concentrations, fatigue reduction, and transfusion burden. Long-term safety findings corroborate the favorable profile established for pegcetacoplan. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03531255.

Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT.

Selecting the most suitable alternative donor becomes challenging in severe aplastic anemia (SAA) when a matched sibling donor (MSD) is unavailable. We compared outcomes in SAA patients undergoing SCT from matched unrelated donors (MUD, n=1106), mismatched unrelated donors (MMUD, n=340), and haploidentical donors (Haplo, n=206) registered in the EBMT database (2012-2021). For Haplo-SCT, only those receiving post-transplant cyclophosphamide (PT-Cy) for graft-versus-host disease (GVHD) prophylaxis were included. Median age was 20 years, and the median time from diagnosis to transplantation 8.7 months. Compared to MUD, MMUD (HR, 2.93; 95% CI, 1.52-5.6) and Haplo (HR, 5.15; 95% CI, 2.5-10.58) showed significantly higher risks of primary graft failure. MUD had lower rates of acute GVHD compared to MMUD and Haplo, grade II-IV (13%, 22%, and 19%, respectively, p<0.001) and III-IV (5%, 9%, and 7%, respectively, p=0.028). The 3-year non-relapse mortality was 14% for MUD, 19% for MMUD, and 27% for Haplo (p<0.001), while overall survival (OS) and GVHD and relapse-free survival (GRFS) were 81% and 73% for MUD, 74% and 65% for MMUD, and 63% and 54% for Haplo, respectively (p<0.001). In addition to donor type, multivariable analysis identified other factors like patient age, performance status, and interval between diagnosis and transplant associated with GRFS. For SAA patients lacking an MSD, our findings support MUD transplantation as the preferable alternative donor. However, selecting between a MMUD or Haplo donor remains uncertain and requires further exploration.

Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

ATG or post-transplant cyclophosphamide to prevent GVHD in matched unrelated stem cell transplantation?

There is a high risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) from unrelated donors. Prophylaxis with rabbit anti-thymocyte globulin (rATG) is standard in Europe but post-transplantation Cyclophosphamide (PTCy) is an emerging alternative. We analyzed outcomes of rATG (n = 7725) vs. PTCy (n = 1039) prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen-matched unrelated donors (MUD) between January 2018 and June 2021 in the EBMT database. The provided P-values and hazard ratios (HR) are derived from multivariate analysis. Two years after alloSCT, NRM in the PTCy group was 12.1% vs. 16.4% in the rATG group; p = 0.016; HR 0.72. Relapse was less frequent after PTCy vs. rATG (22.8% vs. 26.6%; p = 0.046; HR 0.87). Overall survival after PTCy was higher (73.1% vs. 65.9%; p = 0.001, HR 0.82). Progression free survival was better after PTCy vs. rATG (64.9% vs. 57.2%; p < 0.001, HR 0.83). The incidence of chronic GVHD was lower after PTCy (28.4% vs. rATG 31.4%; p = 0.012; HR 0.77), whereas the incidence and severity of acute GVHD were not significantly different. GVHD-free relapse-free survival was significantly higher in the PTCy arm compared to the rATG arm (2 y incidence: 51% vs. 45%; HR: 0.86 [95% CI 0.75-0.99], p = 0.035). In the absence of evidence from randomized controlled trials, our findings support a preference for the use of PTCy in adult recipients of peripheral blood alloSCTs from MUD.

Management of acute breakthrough hemolysis with intensive pegcetacoplan dosing in patients with PNH.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Breakthrough hemolysis (BTH) was first described in patients with PNH treated with terminal complement C5 inhibitors when intravascular hemolysis reoccurred despite treatment. Pegcetacoplan, the first proximal complement C3 inhibitor, offers broad hemolysis control in patients with PNH. While experience of managing BTH on C5 inhibitors is documented, very limited guidance exists for proximal complement inhibitors. This interim analysis assessed the effect of intensive treatment with pegcetacoplan following an acute BTH event in a subset of patients enrolled in the ongoing open-label extension study of pegcetacoplan in PNH. Thirteen patients with acute BTH included in the analysis received either a single IV dose of 1080 mg (n = 4) or 1080 mg subcutaneous (SC) dosing on 3 consecutive days (n = 9). A potential, clinically-relevant complement-amplifying condition, such as infection or vaccination, was reported in approximately half of the patients experiencing an acute BTH. Lactate dehydrogenase (LDH) levels decreased between day 1 and day 2 in 8 of 12 evaluable patients and in all 13 patients at day 7 to 12. Nine of 13 patients (69%) achieved LDH <2× the upper limit of normal by day 14 to 19. All adverse events associated with the acute BTH event were considered resolved by the investigators. Overall, intensive treatment with pegcetacoplan was safe and well tolerated. These novel data support effective management of acute BTH events in patients on pegcetacoplan with intensive IV or SC pegcetacoplan dosing. This trial was registered at www.clinicaltrials.gov as #NCT03531255.

Impact of comorbidities and body mass index on the outcomes of allogeneic hematopoietic cell transplantation in myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of EBMT.

Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT.

Real-world experience of pegcetacoplan in paroxysmal nocturnal hemoglobinuria.

Pegcetacoplan significantly improves outcomes for patients with paroxysmal nocturnal hemoglobinuria (PNH) experiencing extravascular hemolysis (EVH) on eculizumab, leading to approval in 2021/2022 (USA/Europe). We report the first collaborative real-world evidence on pegcetacoplan use in UK and France. A total of 48 patients were either currently receiving or previously received pegcetacoplan (2019-2023). A total of 12 patients had participated in the PEGASUS clinical trial, continuing treatment after trial completion. Five patients were on combination treatment of C5 inhibition and pegcetacoplan. Mean pegcetacoplan duration was 20.2 months. Indication for pegcetacoplan was EVH on C5 inhibitors (Eculizumab, n = 29, Ravulizumab n = 16, others n = 3) with 35/48 patients requiring blood transfusion within the previous 12 months. Mean hemoglobin and reticulocyte count at pegcetacoplan commencement and after 3 months: 91 g/L and 205 × 109/L and 115.8 g/L and 107 × 109/L, respectively, resulting in mean Hb change of 22.3 g/L. Mean LDH pre- and post-pegcetacoplan was unchanged. Six patients have stopped pegcetacoplan. A total of 32 breakthrough hemolysis (BTH) events occurred in 13/48 patients. A total of 14 events were within clinical trials (reported separately). Six patients experienced 18 acute BTH events outside clinical trials, 7/18 associated with complement activating conditions. Successful clinical management included daily pegcetacoplan subcutaneously for 3 days or single eculizumab doses; these events are manageable with prompt intervention. Pegcetacoplan is effective for patients with PNH experiencing EVH. In this large patient cohort, treatment was well tolerated with improved hemoglobin and reticulocytes and maintained LDH control. Although BTH occurs, this is manageable by acute dose modification, with the majority of patients being maintained on pegcetacoplan.