Acute myeloid leukemia (AML) is the most common indication for allogeneic hematopoietic cell transplantation (alloHCT), yet graft-versus-host disease (GVHD) remains a major post-transplant complication. Conditioning regimens, particularly reduced-intensity approaches, are critical in optimizing outcomes. This subgroup analysis of the phase 3 MC-FludT.14/L trial compared treosulfan-fludarabine with reduced-intensity busulfan-fludarabine in 352 AML patients (aged 31–70) undergoing alloHCT. The primary endpoint was 24-month event-free survival (EFS); secondary endpoints included overall survival (OS), GVHD incidence, relapse/progression, and non-relapse mortality (NRM). Treosulfan compared to busulfan demonstrated superiority: 24-month EFS was 65% vs. 53% (p = 0.01), and OS was 73% vs. 65%. EFS benefits were consistent across AML risk categories and notably higher in patients with hematopoietic cell transplantation comorbidity index >2 (62% vs. 42%, p = 0.02). Treosulfan also showed lower NRM and relapse rates. GVHD outcomes favored treosulfan, with a significantly lower incidence of extensive chronic GVHD at 24 months (15.1% vs. 28.1%, p = 0.01). GVHD-free and relapse-free survival was also improved (53% vs. 40%, p = 0.02). The safety profile was more favorable with treosulfan. These findings support treosulfan-fludarabine as a more effective and safer conditioning regimen than busulfan-fludarabine for AML patients undergoing alloHCT, particularly those at higher risk.

Primary refractory acute myeloid leukemia (prAML) is a poor prognosis disease, with allogeneic hematopoietic stem cell transplantation (allo-HSCT) being the only potentially curative option. We retrospectively evaluated outcomes in 1574 adult prAML patients who underwent allo-HSCT from matched sibling donors (MSD), 10/10 or 9/10 unrelated donors (UD), or haploidentical donors between 2015 and 2020. Median follow-up was 24, 30, 38, and 24 months for MSD, UD 10/10, UD 9/10, and haploidentical transplants, respectively. MSD recipients were younger (median age 53 vs. 58–59 years in other groups, p < 0.001), had better performance status, and proceeded to transplant more quickly (3.8 months vs. >4 months in other groups, p = 0.004). In multivariate analysis, haploidentical HSCT was associated with inferior leukemia-free survival (LFS) and overall survival (OS) compared to other donor types. Additional negative predictors included adverse cytogenetics and longer time from diagnosis to transplant. Conversely, reduced-intensity conditioning and good performance status of the patient were associated with improved LFS. Disease progression remained the leading cause of transplant failure, underscoring the urgent need for more effective early post-transplant strategies.

357 Background: Data for cabozantinib after IO-combinations in metastatic renal cell carcinoma (mRCC) remain scarce. We therefore evaluated safety and effectiveness of cabozantinib after failure of IO-based therapies. Methods: Data from patients (pts) with mRCC and cabozantinib treatment after IO-based therapy was retrospectively collected from medical records. Primary endpoint was the incidence of serious adverse events (SAEs). Response rate was assessed clinically (CRR) and/or according to RECIST 1.1. Overall Survival (OS) and Progression Free Survival (PFS) were assessed from start of therapy and data were compared for pts with starting dose of 60 mg (cohort A) vs < 60 mg (cohort B) in a post-hoc analysis. Descriptive statistics and KM-plots were utilized, where appropriate. Results: This final analysis (cut off 08-Oct-21) assessed 56 eligible pts (71.4% male) with median age of 66 yrs. 87.5% (n = 49) had previous nephrectomy. 66.1% (n = 37) had clear cell RCC. 89.3% (n = 50) had ≥2 previous lines. ECOG ≤1 was 33.9% (n = 19). IMDC factors were 0 in 2 (3.6%), ≥1 in 21 (37.5%), missing in 31 pts (55.4%). 62.5% (n = 35) started at reduced dose. 55.4% (n = 31) required dose reductions and 1.8% (n = 1) discontinuation. Median treatment duration was 6.1 months (m). PR was 10.7% (n = 6), SD 19.6% (n = 11), PD 12.5% (n = 7) and missing in 57.1% (n = 32). Median OS and PFS were 15.34 m (95% CI 8.94, 20.93) and 6.34 m (95% CI 5.29, 8.25) in the ITT, 10.48 m (95% CI 6.01, 34.14) and 6.51 m (95% CI 2.99, 10.87) in cohort A and 16.46 m (95% CI 9.56, 23.33) and 6.34 m (95% CI 4.86, 8.71) in cohort B, respectively. All grade AEs and grade 3-5 AEs were 87.5% (n = 49) and 44.6% (n = 25) in the ITT, 95.0% (n = 19) and 55.0% (n = 11) in cohort A and 85.7% (n = 30) and 40.0% (n = 14) in cohort B. SAEs were reported in 21.4% (n = 12) of pts, which were 30.0% (n = 6) of cohort A and 17.1% (n = 6) of cohort B. Treatment related SAEs were reported in 10.7% (n = 6) of pts, which were 15.0% (n = 3) in cohort A and 8.6% (n = 3) in cohort B. Conclusions: Cabozantinib directly after IO therapy was safe and feasible. No new safety signals were reported. A reduced starting dose was frequently utilized and was not associated with adverse outcomes. Our data supports the use of cabozantinib after IO-failure. Major limitation was the retrospective nature of our study.[Table: see text]

BACKGROUND:Secondary malignancies are potential complications after high-dose therapy and autologous stem cell transplantation (ASCT). Information on the detailed course of such events is scarce, yet may be essential to minimize the impact of these sequelae. PATIENTS AND METHODS:We regularly monitored 877 patients for up to 31 years after ASCT in our outpatient department. RESULTS:Four-hundred and five patients with malignant lymphoma and 472 patients with multiple myeloma were analysed with a median follow-up from the initial malignant diagnosis of 7.0 years (0.5-35.5), from ASCT of 4.8 years (range 0.2-31.3). Eighty-nine of these patients suffered from 94 invasive secondary malignancies (30 haematologic malignancies, 64 solid tumours). In 29 patients a non-melanoma skin cancer was observed. 31/64 (48%) patients with solid tumours were diagnosed in an early stage of the disease (UICC 0-2) and had a chance of cure. 5% of the patients developed an invasive malignancy within 5 years, 12% within 10 years, 21% within 20 years. Risk factors were advanced age, the diagnosis lymphoma and in lymphoma patients additionally male sex. CONCLUSIONS:Secondary malignancies after ASCT are relatively frequent complications. Our findings suggest that systematic life-long cancer screening after ASCT is essential to improve the prognosis of these adverse events.

MICA polymorphisms have been associated with increased incidence of acute GvHD and adverse outcome in allogeneic haematopoietic stem cell transplantation (HSCT). MICB is another expressed member of MHC class I-related chain genes and its impact on HSCT outcome is yet to be fully defined. We typed a large cohort of patients and donors for MICB polymorphisms and investigated the impact of MICB matching on outcome after unrelated HSCT. 69.2% of the patients were 10/10 human leukocyte antigen (HLA) matched and 30.8% were 9/10 HLA matched. MICB typing was performed using a short amplicon-based NGS typing assay on the Illumina MiSeq platform. Differences in proteins were considered as mismatches. MICA polymorphisms were identified as possible confounder and were therefore included as parameter in the multivariate analyses. Due to the strong linkage disequilibrium with the classical HLA-genes, sub-stratification for HLA matching status was necessary, and no effect of MICB mismatches was seen in the 10/10 HLA matched group when compared to the MICB matched cases. However, in the 9/10 HLA matched group, MICB mismatched cases showed significantly worse disease free survival (DFS), GvHD and relapse free survival (GRFS) compared to the MICB matched cases (DFS: HR 1.24, p = 0.011; GRFS: HR 1.26, p = 0.002). MICA mismatches had no impact on any outcome parameter. According to our findings, effects previously attributed to MICA differences may have been confounded by MICB polymorphisms. We show that MICB differences contribute a small but relevant effect in 9/10 HLA-matched transplantations, which in turn highlights the possible usefulness of MICB typing in donor selection among similarly suitable 9/10 matched donors, especially when HLA-B mismatches have to be accepted.

Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80 www.clinicaltrials.gov as NCT03676504.

We compared FT14 (fludarabine 150–160 mg/m2, treosulfan 42 g/m2) versus FB4 (fludarabine 150–160 mg/m2, busulfan 12.8 mg/kg) in acute myeloid leukemia (AML) transplanted at primary refractory/relapsed disease. We retrospectively studied: (a) adults diagnosed with AML, (b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated/sibling donor (2010–2020), (c) HSCT with primary refractory/relapsed disease, (d) conditioning regimen with FT14 or FB4. We studied 346 patients, 113 transplanted with FT14, and 233 with FΒ4. FT14 patients were significantly older, more frequently had an unrelated donor and had received a lower dose of fludarabine. Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV and extensive chronic GVHD was similar. With a median follow-up of 28.7 months, 2-year CI of relapse was 43.4% in FT14 versus 53.2% in FB4, while non-relapse mortality (NRM) was respectively 20.8% versus 22.6%. This led to 2-year leukemia-free survival (LFS) of 35.8% for FT14 versus 24.2% in FB4, and overall survival (OS) of 44.4% versus 34%. Adverse cytogenetics and conditioning regimen independently predicted CI of relapse. Furthermore, conditioning regimen was the only independent predictor of LFS, OS, and GVHD-free/relapse-free survival. Therefore, our real-world multicenter study suggests that FT14 is associated with better outcomes in primary refractory/relapsed AML.

Previous studies have illustrated associations between the presence of activating killer cell immunoglobulin-like receptor (KIR) genes and lower susceptibility to hematologic malignancies in humans. In addition, favorable hematopoietic stem cell transplantation (HSCT) outcomes have been reported in patients who received transplants from donors with KIR genotypes dominant for activating KIR receptors. However, the association of activating KIR genes on an allelic level with disease and their impact on HSCT outcome has been little investigated to date. To this end, we genotyped a large transplantation cohort for KIR 2 Ig domains and short cytoplasmic tail 4 (KIR2DS4) polymorphisms and investigated their association with disease. We next investigated the impact of KIR-AA genotype donor KIR2DS4 polymorphisms (AA/KIR2DS4 versus AA/ KIR 1 Ig domain [KIR1D]) on clinical outcomes of HSCT in myeloid versus lymphoid patient subgroups. Among 2810 transplantation donor-recipient pairs, 68.8% (n = 1934) were 10/10 HLA-matched and 31.2% (n = 876) were 9/10 HLA-matched. The distribution of KIR1D was equal in patients and donors (P = .205). Multivariate analysis in 10/10 HLA-matched patients with lymphoid disease showed improved HSCT outcomes when they received grafts from AA/KIR1D donors (overall survival: hazard ratio [HR], .62, P = .002; disease free survival: HR, .70, P = .011; graft-versus-host disease-free and relapse-free survival: HR, .67, P = .002; nonrelapse mortality: HR, .55, P < .001). This effect was not seen in either 9/10 HLAmatched patients with lymphoid disease or patients with myeloid disease. Our study indicates that the presence of KIR1D alleles is not associated with disease in patients, and, interestingly, using grafts from AA/ KIR1D donors translated into beneficial survival outcomes in 10/10 HLA-matched patients with lymphoid disease.

Purpose: The prognosis of patients with peripheral T-cell lymphoma and missing complete remission or relapsing before ASCT is assessed to be unfavourable. The aim of this study is to contribute data to the open question, whether additional radiotherapy improves the outcome. Patients and Methods: Forty-eight patients with peripheral T-cell-lymphoma were treated in our institution with high-dose therapy (usually BEAM protocol) and ASCT (age median 54 years, range 19-77). Twenty-five patients received ASCT in first treatment line, 13 in second line, 10 in third line (all refractory to 2nd-line salvage therapy). Seven of these 48 patients received radiotherapy (36-40 Gy, median 36) after ASCT. Results: Five-year overall survival (OS) and progression-free survival (PFS) after 1st-line ASCT and 2nd-line ASCT were 59% and 50%, respectively, and after 3rd-line ASCT significantly lower with 30% and 30%, respectively. Twenty-one patients achieved a sustained complete remission of 2.7 - 22.7 years (median 5.8). No patient relapsed after radiotherapy. Conclusion: Sustained long-term remissions can be achieved in patients with peripheral T-cell lymphoma following ASCT in first, second or third treatment line. Early irradiation after ASCT can possibly consolidate remission in localized residual or refractory disease.

Herpes zoster (HZ) is a frequent complication after autologous stem cell transplantation (ASCT). The option of zoster prophylaxis with an antiviral drug is described in the literature, but there is no consensus on the drug and the dosage.

INTRODUCTION:Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is highly influenced by the degree of HLA matching between recipient and donor. The HLA-class Ib molecule HLA-G has been shown to promote tolerogenicity through its interaction with inhibitory receptors found on several immunocompetent cells. We hypothesized that in an allo-HSCT setting, HLA-G mismatches may negatively impact the HLA-G-mediated tolerogenicity either due to inefficient interaction with the inhibitory receptors of the transplanted immune cells or due to direct allorecognition of mismatched HLA-G on host cells by the immune cells of the donor. METHODS:In order to explore this hypothesis, we investigated the impact of HLA-G mismatching in 2.083 10/10 matched high resolution HLA-typed allo-HSCT transplants. RESULTS:We found that the risk of chronic GvHD was significantly higher in HLA-G-mismatched transplant cases as compared with the HLA-G-matched control group (HR: 1.46, 95%CI = 1.11-1.91, p = 0.006). Sub-analysis of the mismatch vector revealed that this effect was only detectable in the GvH (HR: 1.89, 95%CI 1.39-2.57, p < 0.001) but not the HvG direction (HR: 1.01, 95%CI = 0.63-1.63, p = 0.967). In addition, the negative impact of HLA-G mismatching on chronic GvHD was only significant in younger patients (<30y HR: 3.02, 95%CI = 1.25-7.28, p = 0.014; >29y HR: 1.28, 95%CI = 0.94-1.72, p = 0.113). DISCUSSION:Our results indicate that HLA-G mismatches may contribute to the onset of chronic GvHD, especially in younger patients and should therefore be avoided when possible.

A common genetic variant within the T cell receptor alpha (TCRA)-T cell receptor delta (TCRD) locus (rs2204985) has been recently found to associate with thymic function. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient's outcome after unrelated hematopoietic stem cell transplantation (uHSCT). 2016 adult patients were retrospectively analyzed. rs2204985 genotyping was performed by next generation sequencing, p < 0.05 was considered significant and donor rs2204985 GG/AG genotypes were set as reference vs. the AA genotype. Multivariate analysis of the combined cohort regarding the impact of donor's rs2204985 genotype indicated different risk estimates in 10/10 and 9/10 HLA matched transplantations. A subanalysis on account of HLA incompatibility revealed that donor AA genotype in single HLA mismatched cases (n = 624) associated with significantly inferior overall- (HR: 1.48, p = 0.003) and disease-free survival (HR: 1.50, p = 0.001). This effect was driven by a combined higher risk of relapse incidence (HR: 1.40, p = 0.026) and non-relapse mortality (HR: 1.38, p = 0.042). This is the first study to explore the role of rs2204985 in a clinical uHSCT setting. Our data suggest that donor rs2204985 AA genotype in combination with single HLA mismatches may adversely impact post-HSCT outcome and should thus be avoided.

The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m2 IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.

The prognosis of an early relapse of diffuse large B-cell lymphoma (DLBCL) appears to be poor following autologous stem cell transplantation (ASCT). The aim of this study is to contribute data to the open question on whether additional radiotherapy can improve the outcome. Forty-eight patients with an early relapse (median 4 months after the end of initial immunochemotherapy, range 1–11) of DLBCL have been treated in our institution with high-dose therapy (usually the BEAM protocol) and ASCT since 2008 (median age 61 years, range 28–73). Twenty-three patients received ASCT in a second treatment line, 25 in a third line (19 refractory to second-line salvage therapy, 5 after second relapse). Fifteen of these 48 patients received radiotherapy (36–50 Gy, median 40) of residual masses after ASCT. Three-year overall survival (OS) and progression-free survival (PFS) after second-line ASCT were 61 and 57%, after third-line ASCT 47 and 44%, respectively, without significant differences. A prognostic factor was the International Prognostic Index (IPI) at the start of salvage therapy. Three-year OS and PFS in low-risk patients were 69 and 69%, in low-intermediate-risk 63 and 53%, and in high-intermediate-risk 23 and 23%, respectively (p = 0.033). Twenty-three patients achieved a sustained complete remission (13–146 months, median 62). Sustained long-term remissions can be achieved in patients with early relapse of DLBCL following ASCT in a second or third treatment line, particularly in patients with low- and low-intermediate-risk IPI, following radiotherapy of residual disease after ASCT. Further investigations are required to clarify which patients need an alternative therapy (potentially CAR T‑cells or allogeneic transplantation).