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1.
Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis
Gagelmann, N., Hobbs, G. S., Campodonico, E., Helbig, G., Novak, P., Schroeder, T., Schneider, A., Rautenberg, C., Reinhardt, H. C., Bosques, L., et al
American journal of hematology. 2024
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Editor's Choice
Abstract
Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.
PICO Summary
Population
Adults with with primary myelofibrosis, post polycythemia vera, and post-essential thrombocythemia myelofibrosis, identified from centres worldwide (n=171)
Intervention
Splenic irradiation within a median of 2 weeks before transplant (n=59)
Comparison
Matched controls receiving immediate transplant without splenic irradiation (n=56), or who had splenectomy (n=56)
Outcome
Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse, showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy.
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2.
Cost-Effectiveness of Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Older Patients With High-Risk Myelodysplastic Syndrome: Analysis of BMT CTN 1102
Saber, W., Bansal, A., Li, L., Scott, B. L., Sangaralingham, L. R., Thao, V., Roth, J. A., Wright, W., Steuten, L. M. G., Pidala, J. A., et al
JCO oncology practice. 2024;:Op2300413
Abstract
PURPOSE BMT CTN 1102 was a phase III trial comparing reduced-intensity allogeneic hematopoietic cell transplantation (RIC alloHCT) to standard of care for persons with intermediate- or high-risk myelodysplastic syndrome (MDS). We report results of a cost-effectiveness analysis conducted alongside the clinical trial. METHODS Three hundred eighty-four patients received HCT (n = 260) or standard of care (n = 124) according to availability of a human leukocyte antigen-matched donor. Cost-effectiveness was calculated from US commercial and Medicare perspectives over a 20-year time horizon. Health care utilization and costs were estimated using propensity score-matched cohorts of HCT recipients in the OptumLabs Data Warehouse (age 50-64 years) and Medicare (age 65 years and older). EuroQol 5 Dimension (EQ-5D) surveys of trial participants were used to derive health state utilities. RESULTS Extrapolated 20-year overall survival for those age 50-64 years was 29% for HCT (n = 105) versus 13% for usual care (n = 44) and 31% for HCT (n = 155) versus 12% for non-HCT (n = 80) for those age 65 years and older. HCT was more effective (+2.36 quality-adjusted life-years [QALYs] for age 50-64 years and +2.92 QALYs for age 65 years and older) and more costly (+$452,242 in US dollars (USD) for age 50-64 years and +$233,214 USD for age 65 years and older) than usual care, with incremental cost-effectiveness ratios of $191,487 (USD)/QALY and $79,834 (USD)/QALY, respectively. For persons age 50-64 years, there was a 29% chance that HCT was cost-effective using a willingness-to-pay (WTP) threshold of $150K (USD)/QALY and 51% at a $200K (USD)/QALY. For persons age 65 years and older, the probability was 100% at a WTP >$150K (USD)/QALY. CONCLUSION Among patients age 65 years and older with high-risk MDS, RIC HCT is a high-value strategy. For those age 50-64 years, HCT is a lower-value strategy but has similar cost-effectiveness to other therapies commonly used in oncology.
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Long-term complications after allogeneic hematopoietic stem cell transplantation for pediatric patients with acute leukemia or myelodysplastic syndrome given either a Treosulfan- or a Busulfan-based conditioning regimen: results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study
Saglio, F., Pagliara, D., Zecca, M., Balduzzi, A., Cattoni, A., Prete, A., Tambaro, F. P., Faraci, M., Calore, E., Locatelli, F., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Patients given hematopoietic stem cell transplantation (HSCT) during their childhood for hematological malignancies have an increased risk of developing long-term sequelae that are in part attributable to the conditioning regimen. OBJECTIVE The present study aimed to assess the occurrence of long-term toxicities in a population of children undergone to HSCT for hematological malignancies using either Treosulfan or Busulfan in the conditioning regimen. STUDY DESIGN Cumulative Incidence of growth impairment, alteration of gonadal function, alteration of the thyroid function, cataract, incidence of secondary malignant neoplasia and alteration of pulmonary function were retrospectively evaluated by univariable and multivariable analysis in a population of 521 pediatric patients affected by acute leukemias and myelodysplastic syndromes treated in 20 Italian Transplant Centers affiliated to AIEOP (Associazione Italiana Ematologia ed Oncologia Pediatrica) RESULTS The median duration of the follow up of the entire study population was of 7,1 years (range 1 -16 years). Overall, patients given Busulfan developed long-term toxicities in a larger proportion of cases compared to patients treated with Treosulfan (34% versus 20% p=0.01). In univariable analysis, patients having received Treosulfan developed gonadal toxicity in 10% (95%CI: 3-15) of the cases compared with 38% (95%CI: 24-39) of Bu-treated patients (p=0,02) and this finding was confirmed by multivariable analysis (Relative Risk: 0,51 95%CI: 0,34-0,76 p=0.0009). For all the other long-term toxicities our study did not show a statistically significant association between their occurrence and the use of either Busulfan or Treosulfan. CONCLUSIONS This study provides evidence that the use of Treosulfan is correlated with a reduced incidence of gonadal toxicity in children undergoing HSCT for hematological malignancies.
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Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission
Zhao, X., Xu, Z., Li, Z., Zhou, X., Hu, Y., Wang, H.
Cancer medicine. 2024
Abstract
PURPOSE Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. METHODS Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. RESULTS In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. CONCLUSION This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.
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5.
Graft-versus-host disease after an outpatient peripheral blood hematopoietic cell transplant using reduced-intensity conditioning: a single-center LATAM experience
Jaime-Pérez, J. C., Meléndez-Flores, J. D., Valdespino-Valdes, J., Gómez-De León, A., Colunga-Pedraza, P. R., Gutiérrez-Aguirre, C. H., Cantú-Rodríguez, O. G., Gómez-Almaguer, D.
Expert review of hematology. 2024;:1-10
Abstract
BACKGROUND HLA compatibility predicts allogeneic hematopoietic cell transplant (allo-HCT) and graft-versus-host disease (GvHD) outcomes. There is insufficient information regarding GvHD outcomes for outpatient HLA-identical and haploidentical-HCT employing reduced-intensity conditioning (RIC). RESEARCH DESIGN AND METHODS We compare GvHD outcomes between donor types and report risk factors associated with GvHD. Stem cell source was T-cell replete peripheral blood. GvHD prophylaxis was post-transplant cyclophosphamide (PT-CY), mycophenolic acid, and calcineurin inhibitors for haploidentical (n = 107) and oral cyclosporine (CsA) plus methotrexate i.v. for HLA-identical (n = 89) recipients. RESULTS One hundred and ninety-six HCT transplant patients were included. aGvHD and cGvHD frequency were similar between HCT types. aGvHD severity was comparable, but severe cGvHD was less frequent in the haploidentical group (p = .011). One-hundred-day cumulative incidence (CI) of aGvHD for haploidentical and HLA-identical was 31% and 33% (p = .84); 2-year CI of cGvHD was 32% and 38% (p = .6), respectively. Haploidentical recipients had less steroid-refractory cGvHD (p = .043). Patients with cGvHD had less 2-year relapse (p = .003); both aGvHD and cGvHD conferred higher OS (p = .010 and p = .001), respectively. Male sex was protective for steroid-refractory cGvHD (p = .028). CONCLUSIONS Acute and chronic GvHD rates were comparable between HLA-identical and haploidentical transplant groups. cGvHD severity was lower in the haploidentical group.
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6.
Comparison of melphalan dose in patients with myelodysplastic syndrome undergoing allogeneic transplantation with reduced-intensity conditioning
Kurosawa, S., Shimomura, Y., Itonaga, H., Katayama, Y., Onizuka, M., Tanaka, M., Kobayashi, H., Ozawa, Y., Sawa, M., Kanda, J., et al
Transplantation and cellular therapy. 2024
Abstract
The present study compared lower-dose melphalan (80 mg/m(2), FM80) and higher-dose melphalan (140 mg/m(2), FM140) when administering reduced-intensity conditioning with fludarabine in adult patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed nationwide registry data (2006-2019) and compared transplant outcomes between the two groups. Ninety-two patients (median age, 61 [interquartile range, 56-65] years) were assigned to the FM80 and FM140 groups by propensity score matching. The 3-year overall survival (OS) rate in the FM140 group (63.9%; 95% confidence interval [CI], 52.9-73.0%) was significantly higher than that in the FM80 group (54.2%; 95% CI, 37.1-52.1%) (P = 0.038). The FM140 group had a non-significantly (P = 0.095) lower 3-year cumulative incidence of relapse (15.5%; 95% CI, 8.9-23.8% versus 26.0%; 95% CI, 17.3-35.5%). The 3-year cumulative incidences of non-relapse mortality were 22.3% (95% CI, 14.1-31.8%) and 23.7% (95% CI, 15.4-33.2%) in the FM80 and FM140 groups, respectively (P = 0.49). The beneficial effect of FM140 was more evident in patients with a poor cytogenetic risk. Our findings suggest the superiority of FM140 in patients with MDS undergoing allo-HSCT, especially in high-risk patients.
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7.
TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia
Ueki, H., Ogawa, C., Goto, H., Nishi, M., Yamanaka, J., Mochizuki, S., Nishikawa, T., Kumamoto, T., Nishiuchi, R., Kikuta, A., et al
International journal of hematology. 2024
Abstract
BACKGROUND In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. PROCEDURE We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). RESULTS Twenty patients with post-induction MRD ≥ 10(-3) and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. CONCLUSION Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.
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8.
Finding a balance in reduced toxicity hematopoietic stem cell transplantation for thalassemia: role of infused CD3+ cell count and immunosuppression
Meissner, B., Lang, P., Bader, P., Hoenig, M., Müller, I., Meisel, R., Greil, J., Sauer, M. G., Metzler, M., Corbacioglu, S., et al
Bone marrow transplantation. 2024
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Full text
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Editor's Choice
Abstract
We performed a retrospective analysis on 124 patients with transfusion-dependent thalassemia who were registered in the German pediatric registry for stem cell transplantation. All patients underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 2011 and 2020 and belonged mainly to Pesaro risk class 1-2. Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% (P = 0.763) and 96.9% ± 3.1% (P = 0.155) after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3% (P = 0.029); TFS: 79.9% ± 7.4% (P = 0.082)). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 10(7)/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses. Taken together, this information might be used to develop more risk-adapted HSCT regimens for thalassemia patients.
PICO Summary
Population
Children and young adults with transfusion-dependent thalassemia who underwent first allogeneic transplant between 2011 and 2020 and were registered in the German pediatric registry for stem cell transplantation. (n=124)
Intervention
Treosulfan-fludarabine-thiotepa based conditioning (n=92)
Comparison
Busulfan-fludarabine-based conditioning (n=32)
Outcome
Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% and 96.9% ± 3.1% after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3%; TFS: 79.9% ± 7.4%). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 10(7)/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses.
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Smart Conditioning with Venetoclax-Enhanced Sequential FLAMSA + RIC in Patients with High-Risk Myeloid Malignancies
Schulz, F., Jäger, P., Tischer, J., Fraccaroli, A., Bug, G., Hausmann, A., Baermann, B. N., Tressin, P., Hoelscher, A., Kasprzak, A., et al
Cancers. 2024;16(3)
Abstract
Up to 50% of patients with high-risk myeloid malignancies die of relapse after allogeneic stem cell transplantation. Current sequential conditioning regimens like the FLAMSA protocol combine intensive induction therapy with TBI or alkylators. Venetoclax has synergistic effects to chemotherapy. In a retrospective survey among German transplant centers, we identified 61 patients with myeloid malignancies that had received FLAMSA-based sequential conditioning with venetoclax between 2018 and 2022 as an individualized treatment approach. Sixty patients (98%) had active disease at transplant and 74% had genetic high-risk features. Patients received allografts from matched unrelated, matched related, or mismatched donors. Tumor lysis syndrome occurred in two patients but no significant non-hematologic toxicity related to venetoclax was observed. On day +30, 55 patients (90%) were in complete remission. Acute GvHD II°-IV° occurred in 17 (28%) and moderate/severe chronic GvHD in 7 patients (12%). Event-free survival and overall survival were 64% and 80% at 1 year as well as 57% and 75% at 2 years, respectively. The off-label combination of sequential FLAMSA-RIC with venetoclax appears to be safe and highly effective. To further validate these insights and enhance the idea of smart conditioning, a controlled prospective clinical trial was initiated in July 2023.
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Treosulfan-based conditioning regimen in pediatric hematopoietic stem cell transplantation: A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC)
Galán, V., Beléndez, C., Echecopar, C., Estival, P., Sissini, L., Olivas, R., Bueno, D., Molina, B., Fuentes, C., Regueiro, A., et al
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION Data on treosulfan-based conditioning regimens are little by little increasing, and the benefits of this approach are consistent, particularly regarding acute toxicity. This study aims to describe the results of treosulfan-based conditioning regimens in children, focusing on toxicity and outcomes when used to treat both malignant and non-malignant diseases. METHODS Retrospective observational study on pediatric patients treated in Spain with treosulfan-based conditioning regimens before hematopoietic stem cell transplantation (HSCT), based on data collection from electronic clinical records. RESULTS One hundred and sixty treosulfan-based conditioning HSCTs to treat non-malignant diseases (n=117) or malignant diseases (n=43) in 158 children and adolescents are reported. Median age at HSCT was 5.1 years (IQR: 2-10). The most frequent diagnoses were primary immunodeficiency (n=42; 36%) and sickle cell disease (n=42; 36%) in the non-malignant cohort and acute lymphoblastic leukemia (n=15; 35%) in the malignant cohort. Engraftment occurred in 97% of the patients. There was a longer median time to neutrophil engraftment (17 vs. 14 days; p=0.008) and platelet engraftment (20 vs. 15 days; p=0.002) in the non-malignant cohort. The 1-year cumulative incidence of VOD was 7.98 (95%CI [4.6-13.6]), with no significant differences between cohorts. The 1-year cumulative incidence of grade III-IV aGvHD was higher in the malignant cohort (18% vs. 3.2%; p=0.011). Overall, cGvHD was more frequently observed in the malignant cohort for both total incidence (9 vs. 3%; p<0.001) and 2-year cumulative incidence of total cGvHD (16 vs. 1.9%; p<0.001). The 2-year cumulative TRM was 15%, with no differences between cohorts. 5-year Overall Survival was 80% (95%CI [72-86]) and was higher in the non-malignant cohort (87 vs. 61%; p=0.01). The 2-year cumulative incidence of relapse in the malignant cohort was 25%. 5-year cumulative GRFS rate was 60% (95%CI [51-70]) and was higher in the non-malignant cohort (72 vs. 22%; p<0.001). CONCLUSIONS The treosulfan-based radiation-free conditioning regimen is feasible, achieving a high engraftment rate and 5-year overall survival. A treosulfan-based conditioning regimen is an emerging option for the first HSCT in non-malignant diseases.