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Ofatumumab as part of reduced intensity conditioning in high risk B-cell lymphoma patients: final long-term analysis from a prospective multicenter Phase-II Trial
Cabrero, M., López-Corral, L., Jarque, I., de la Cruz-Vicente, F., Pérez-López, E., Valcárcel, D., Sanz, J., Espigado, I., Ortí, G., Martín-Calvo, C., et al
Bone marrow transplantation. 2024
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Editor's Choice
Abstract
Curative potential of allogeneic transplantation (AlloSCT) in high-risk non-Hodgkin lymphoma (NHL) could be enhanced by the integration of Ofatumumab (OFA), a 2nd generation anti-CD20 moAb, due to an antitumor effect and a role over graft-versus-host disease (GVHD). In this phase II trial (NCT01613300), we investigated safety and effectiveness of OFA-based reduced intensity conditioning (RIC). High-risk B-cell NHL patients with chemorrefractory disease or post-autologous SCT relapse were eligible. OFA was added to a standard RIC regimen. Primary endpoint was grade 3-4 aGVHD rate, while secondary endpoints included CR and survival rates. Thirty-three patients were included (median age 51; diffuse large B-cell:68%, HLA-identical donor: 74%). No grade >2 OFA toxicity was observed. Acute GVHD affected 77% of patients (16% grade 3-4). Remarkably, GVHD achieved CR in 75% of patients after first-line treatment. Chronic GVHD, primarily mild or moderate, occurred in 54% of patients. NHL CR rate at day +100 was 81%. Relapses occurred in 7 patients after a median of 3 months. Causes of death were lymphoma progression (5), infections (10), and GVHD (2). At 24 months, progression-free and overall survival rates were 50.1 and 51.6% respectively. OFA-RIC regimen is safe and effective, though acute GVHD remains a significant complication. However, data suggest that OFA could mitigate its severity.
PICO Summary
Population
Adults with high-risk B-cell non-Hodgkin lymphoma with either chemorrefractory disease or who relapsed post-autologous transplant, from centres in Spain (n=33)
Intervention
Ofatumumab (OFA), a 2nd generation anti-CD20 moAb, added to a reduced intensity conditioning (RIC) regime
Comparison
None
Outcome
Acute GVHD affected 77% of patients (16% grade 3-4). Remarkably, GVHD achieved CR in 75% of patients after first-line treatment. Chronic GVHD, primarily mild or moderate, occurred in 54% of patients. NHL CR rate at day +100 was 81%. Relapses occurred in 7 patients after a median of 3 months. Causes of death were lymphoma progression (5), infections (10), and GVHD (2). At 24 months, progression-free and overall survival rates were 50.1 and 51.6% respectively.
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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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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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Fludarabine melphalan versus fludarabine treosulfan for reduced intensity conditioning regimen in allogeneic hematopoietic stem cell transplantation: a retrospective analysis
Chichra, A., Nayak, L., Kothari, R., Kalantri, S., Bonda, A., Gokarn, A., Punatar, S., Mirgh, S., Jindal, N., Bagal, B., et al
International journal of hematology. 2023
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Editor's Choice
Abstract
Various reduced-intensity conditioning (RIC) regimens are used to decrease toxicity while providing comparable outcomes to myeloablative regimens. We compared toxicity and outcomes between two RIC regimens, fludarabine with melphalan (Flu-Mel) and fludarabine with treosulfan (Flu-Treo), retrospectively over a 10-year period in two donor groups, matched related donor (MRD)/matched unrelated donor (MUD) and haploidentical (Haplo) transplants. The study included 138 patients, of which 105 received MRD/MUD (Flu-Mel: 94, Flu-Treo: 11) and 33 Haplo (Flu-Mel: 17, Flu-Treo: 16) transplants. In the MRD/MUD group, 44 (47%) of patients who received Flu-Mel had grade 3/4 oral mucositis compared to 1 (9%) who received Flu-Treo (P = 0.02). Corresponding numbers in the Haplo group were 7 (41%) and 1 (6%). Grade 3/4 diarrhoea was more frequent with Flu-Mel than Flu-Treo in the Haplo group (41% vs 6%; P = 0.039), but not the MRD/MUD group. Median follow-up time for all patients was 4.8 years. Five-year OS in the MRD/MUD group was 62% with Flu-Mel versus 53% with Flu-Treo (P = 0.0694). Similarly, 5-year OS was 41% with Flu-Mel and 28% with Flu-Treo (P = 0.770) in the Haplo group. Severe mucositis and diarrhoea were significantly less frequent with Flu-Treo than Flu-Mel. Flu-Treo provided comparable outcomes to Flu-Mel in all donor transplants.
PICO Summary
Population
Adults undergoing transplantation using either a matched related, matched unrelated donor (MRD/MUD, n=105) or haploidentical donor (n=33) from a single centre in India (n=138)
Intervention
Fludarabine with melphalan conditioning (Flu-Mel, n=94 in the MRD/MUD group, n=17 in haplo group)
Comparison
Fludarabine with treosulfan conditioning (Flu-Treo, n=11 in /MUD group, n=16 in haplo group)
Outcome
In the MRD/MUD group, 44 (47%) of patients who received Flu-Mel had grade 3/4 oral mucositis compared to 1 (9%) who received Flu-Treo. Corresponding numbers in the Haplo group were 7 (41%) and 1 (6%). Grade 3/4 diarrhoea was more frequent with Flu-Mel than Flu-Treo in the Haplo group (41% vs 6%), but not the MRD/MUD group. Median follow-up time for all patients was 4.8 years. Five-year OS in the MRD/MUD group was 62% with Flu-Mel versus 5. 3% with Flu-Treo. Similarly, 5-year OS was 41% with Flu-Mel and 28% with Flu-Treo (P = 0.770) in the Haplo group. Severe mucositis and diarrhoea were significantly less frequent with Flu-Treo than Flu-Mel. Flu-Treo provided comparable outcomes to Flu-Mel in all donor transplants.
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Reduced Intensity Compared to Non-myeloablative Conditioning in Patients with Non-Hodgkin Lymphoma undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Nath, K., Peterson, K., Brown, S., Devlin, S., Rodriguez, N., Barker, J., Giralt, S., Gyurkocza, B., Jakubowski, A., Papadopoulos, E., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
BACKGROUND . Reduced intensity (RIC) and non-myeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) receiving allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens within RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. OBJECTIVES AND STUDY DESIGN . We performed a retrospective single-center analysis to determine outcomes of adult patients with B- and T-cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 - December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4Gy-total body irradiation (Flu-Cy-4Gy-TBI) and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen included fludarabine-cyclophosphamide-2Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival. Secondary outcomes included progression-free survival, non-relapse mortality and the incidence of acute and chronic graft-vs-host-disease (GvHD). RESULTS . Of 279 transplanted patients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up from allo-HCT, there was no significant difference in overall survival between the NMA and RIC groups (median not reached [NR] vs 103 months, respectively. P = 0.1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky performance status, HCT-CI, disease histology), the regression analysis showed no significant difference in progression-free survival with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% CI 0.92 - 2.09, P = 0.24). On univariable analysis, there was no significant difference in non-relapse mortality between RIC and NMA conditioning (100-day estimates: 10.0% vs. 1.8%, respectively, P = 0.5). After adjustment for age, ethnicity, Karnofsky performance score, HCT-CI, GvHD prophylaxis and donor source, RIC conditioning was associated with a significantly higher incidence of non-relapse mortality compared to NMA conditioning (HR 2.61, 95% CI 1.04 - 6.52, P = 0.039). On multivariable analysis, compared with the Flu-Cy-2Gy-TBI regimen, the RIC cohort had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 - 3.86; P = 0.002) and grade III-IV acute GvHD (HR, 5.62; 95% CI, 2.03 - 15.6; P < 0.001). CONCLUSION . The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.
PICO Summary
Population
Adults with B- or T-cell non-Hodgkin lymphoma who underwent allogeneic stem cell transplant (allo-HSCT) at a single centre in USA (n=279)
Intervention
Reduced intensity conditioning (RIC) with or without total body irradiation (n=110)
Comparison
Non-myeloablative (NMA) conditioning (n=169)
Outcome
With a median of 64 months of follow-up from allo-HCT, there was no significant difference in overall survival between the NMA and RIC groups (median not reached [NR] vs 103 months, respectively), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky performance status, HCT-CI, disease histology), the regression analysis showed no significant difference in progression-free survival with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% CI 0.92 - 2.09). On univariable analysis, there was no significant difference in non-relapse mortality between RIC and NMA conditioning (100-day estimates: 10.0% vs. 1.8%, respectively). After adjustment for age, ethnicity, Karnofsky performance score, HCT-CI, GvHD prophylaxis and donor source, RIC conditioning was associated with a significantly higher incidence of non-relapse mortality compared to NMA conditioning (HR 2.61, 95% CI 1.04 - 6.52). On multivariable analysis, compared with the Flu-Cy-2Gy-TBI regimen, the RIC cohort had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 - 3.86) and grade III-IV acute GvHD (HR, 5.62; 95% CI, 2.03 - 15.6).
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Unique reduced intensity conditioning haploidentical peripheral blood stem cell transplantation protocol for patients with hematological malignancy
Xu, J., Miao, W., Yuan, H., Liu, Y., Chen, G., Wang, H., Aizezi, G., Qu, J., Duan, X., Yang, R., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
Reduced-intensity conditioning haploid hematopoietic stem cell transplantation (RIC-haplo-HSCT) requires more hematopoietic progenitor and stem cells (HPSCs) to promote engraftment and immune reconstitution and needs stronger graft versus leukemia (GVL) effect. Peripheral blood stem cells (PBSCs) offer more advantages compared to bone marrow (BM). However, higher dose non-T cell depleted (non-TCD) in vitro PBSCs may increase the occurrence of severe graft versus host disease (GVHD). This prospective, single-arm clinical research was performed to investigate high-dose non-TCD in vitro PBSCs as graft, Flu/Ara-C/Bu (FAB) as conditioning regimen, adopting rATG to remove T cells in vivo, and enhancing GVHD prophylaxis with IL-2 receptor antagonist in RIC-haplo-HSCT in patients with hematological malignancies aged 50 to 70 years or < 50 years with comorbidities (HCT-CI scores ≥2) classified as intermediate to higher risk. The primary endpoint was day-100 acute GVHD (aGVHD). A total of 47 patients were enrolled; the median age was 52 years (range: 30-68 years), the median follow-up time was 34 months (range: 2-99), and the medium-infused doses of MNC, CD34+ cells, and CD3+ cells were 15.93 × 10(8)/kg, 8.68 × 10(6)/kg and 5.57 × 10(8)/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day-100 was 30.3% (95% CI: 15.9-44.8), while that of grade III-IV aGVHD was 10.2% (95% CI: 0.6-19.8). The two-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI: 19.0-50.8). The two-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI: 11.80-40.40) and 8.7% (95% CI: 3.26-20.65), respectively. The two-year cumulative incidence of relapse was 17.3% (95% CI: 5.1-29.5). The two-year overall survival and disease-free survival rates were 71.2% (95% CI: 57.9-84.5) and 66.2% (95% CI: 52.1-80.3), respectively. The outcomes showed that the incidence of aGVHD was not high, and the overall efficacy was good. This study demonstrated that this unique RIC-haplo-PBSCT protocol was effective in treating hematological malignancies. Nonetheless, larger prospective multi-center clinical trials and experimental studies should be performed to further confirm our findings.
PICO Summary
Population
Adults with haematological malignancies aged 50 to 70 years or less than 50 years but with intermediate or higher risk comorbidities (HCT-CI scores ≥2), from a single centre in China (n=47)
Intervention
Reduced intensity conditioning haploidentical HSCT: high-dose non-T-cell depleted in vitro peripheral blood stem cells as graft, Flu/Ara-C/Bu (FAB) as conditioning regimen, rabbit antithymocyte globulin (rATG) to remove T cells in vivo, and enhanced GVHD prophylaxis with IL-2 receptor antagonist.
Comparison
None
Outcome
The median age was 52 years (range: 30-68 years), the median follow-up time was 34 months (range: 2-99), and the medium-infused doses of MNC, CD34+ cells, and CD3+ cells were 15.93 × 10(8)/kg, 8.68 × 10(6)/kg and 5.57 × 10(8)/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day-100 was 30.3% (95% CI: 15.9-44.8), while that of grade III-IV aGVHD was 10.2% (95% CI: 0.6-19.8). The two-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI: 19.0-50.8). The two-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI: 11.80-40.40) and 8.7% (95% CI: 3.26-20.65), respectively. The two-year cumulative incidence of relapse was 17.3% (95% CI: 5.1-29.5). The two-year overall survival and disease-free survival rates were 71.2% (95% CI: 57.9-84.5) and 66.2% (95% CI: 52.1-80.3), respectively.
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Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis
Murthy, G. S. G., Kim, S., Estrada-Merly, N., Abid, M. B., Aljurf, M., Assal, A., Badar, T., Badawy, S. M., Ballen, K., Beitinjaneh, A., et al
Haematologica. 2023
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Editor's Choice
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (Fludarabine/busulfan=166, Fludarabine/melphalan=327) and 379 using MAC (Fludarabine/busulfan=247, Busulfan/cyclophosphamide=132). In multivariable analysis with RIC, Fludarabine/melphalan was associated with inferior overall survival (HR 1.80, 95% CI 1.15-2.81, p=0.009), higher early non-relapse mortality (HR 1.81, 95% CI 1.12-2.91, p=0.01) and higher acute graft versus host disease (GVHD) (grade II-IV- HR 1.45, 95% CI 1.03-2.03, p=0.03; grade III-IV HR 2.21, 95%CI 1.28-3.83, p=0.004) compared to Fludarabine/busulfan. In the MAC setting, Busulfan/cyclophosphamide was associated with a higher acute GVHD (grade II-IV HR 2.33, 95% CI 1.67-3.25, p<0.001; grade III-IV HR 2.31, 95% CI 1.52-3.52, p<0.001) and inferior GVHD-free relapse-free survival (GRFS) (HR 1.94, 95% CI 1.49-2.53, p<0.001) as compared to Fludarabine/busulfan. Hence, our study suggests that Fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GVHD) and MAC (lower acute GVHD and better GRFS) in myelofibrosis.
PICO Summary
Population
Adults with myelofibrosis undergoing allogeneic HSCT between 2008-2019 and reported to the CIBMTR database (n=872)
Intervention
Reduced intensity conditioning (RIC) regimens (n=493): fludarabine/busulfan (n=166) or fludarabine/melphalan (n=327)
Comparison
Myeloablative conditioning (MAC) regimens (n=379): fludarabine/busulfan (n=247) or busulfan/cyclophosphamide (n=132).
Outcome
In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (HR 1.80, 95% CI 1.15-2.81), higher early non-relapse mortality (HR 1.81, 95% CI 1.12-2.91,) and higher acute graft versus host disease (GVHD) (grade II-IV- HR 1.45, 95% CI 1.03-2.03; grade III-IV HR 2.21, 95%CI 1.28-3.83) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GVHD (grade II-IV HR 2.33, 95% CI 1.67-3.25; grade III-IV HR 2.31, 95% CI 1.52-3.52) and inferior GVHD-free relapse-free survival (GRFS) (HR 1.94, 95% CI 1.49-2.53) as compared to fludarabine/busulfan.
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Influence of conditioning regimen intensity on outcomes post-allogeneic hematopoietic cell transplantation for acute myeloid leukemia in complete morphological remission
Alfaro Moya, T., Mattsson, J., Remberger, M., Lipton, J. H., Kim, D. D., Viswabandya, A., Kumar, R., Lam, W., Law, A. D., Gerbitz, A., et al
European journal of haematology. 2023
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Editor's Choice
Abstract
INTRODUCTION The literature comparing outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) for acute myeloid leukemia (AML) is conflicting. METHODS We retrospectively analyzed 451 patients who underwent allogenic hematopoietic cell transplantation (alloHCT) for AML in complete remission (CR) with either RIC (n = 331) or MAC (n = 120) with the use of dual T-cell depletion as graft-versus-host disease (GVHD) prophylaxis. RESULTS Univariate analysis demonstrated nonrelapse mortality (NRM) at 2 years was 19.1% for MAC and 22.5% for RIC (p = .44). Two-year cumulative incidence of relapse (CIR) was 19.8% for MAC and 24.5% for RIC (p = .15). Two-year overall survival (OS) was 61% and 53% for MAC and RIC, respectively (p = .02). Two-year graft-versus-host disease relapse-free survival (GRFS) was 40.8% for MAC and 33.7% for RIC (p = .30). A propensity score-matched analysis was done matching patients for age, HLA match, in vivo T-cell depletion, and Disease Risk Index (DRI). Two-year OS was 67% for MAC, 66% for RIC (p = .95). A subgroup analysis identified that matched related donor transplants benefit from MAC with OS at 2 years 82.6% versus 57.3% for RIC (p = .006). CONCLUSIONS In the matched-related donor setting, MAC regimens may offer superior survival. Overall, for our cohort of predominantly in vivo T-cell depleted patients the outcomes of MAC and RIC were similar.
PICO Summary
Population
Adults who underwent allogenic HSCT for AML in complete remission, from a single centre in Canada (n=451)
Intervention
Myeloablative conditioning regimen with dual T-cell depletion as GvHD prophylaxis (MAC, n=120)
Comparison
Reduced intensity conditioning regimen with dual T-cell depletion (n=331)
Outcome
Univariate analysis demonstrated nonrelapse mortality (NRM) at 2 years was 19.1% for MAC and 22.5% for RIC. Two-year cumulative incidence of relapse (CIR) was 19.8% for MAC and 24.5% for RIC. Two-year overall survival (OS) was 61% and 53% for MAC and RIC, respectively. Two-year graft-versus-host disease relapse-free survival (GRFS) was 40.8% for MAC and 33.7% for RIC. A propensity score-matched analysis was done matching patients for age, HLA match, in vivo T-cell depletion, and Disease Risk Index (DRI). Two-year OS was 67% for MAC, 66% for RIC. A subgroup analysis identified that matched related donor transplants benefit from MAC with OS at 2 years 82.6% versus 57.3% for RIC.
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Reduced intensity hematopoietic stem cell transplantation for myelofibrosis in accelerated-phase
Gagelmann, N., Wolschke, C., Salit, R. B., Schroeder, T., Ditschkowski, M., Panagiota, V., Cassinat, B., Thol, F., Badbaran, A., Robin, M., et al
Blood advances. 2022
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Editor's Choice
Abstract
Accelerated-phase (AP) myelofibrosis, currently defined by circulating blasts 10-19%, usually confers very high risk for progression and poor outcome. The outcome of hematopoietic stem cell transplantation for AP myelofibrosis has not been evaluated yet. We analyzed the outcome of 349 clinically and genetically annotated patients with primary or secondary myelofibrosis undergoing reduced intensity transplantation, of whom 35 had AP myelofibrosis. In comparison with chronic-phase (CP, <10% blasts), median leukocyte counts were higher, more patients had constitutional symptoms, and RAS mutations were detected more frequently in the AP group. After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% (95% confidence interval, 49-81%) versus 64% (95% confidence interval, 59-69%) for the CP group (P=0.91), and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the AP group was 49% (95% confidence interval, 32-67%) versus 55% (95% confidence interval, 50-61%) for the CP group (P=0.65). Estimated 5-year non-relapse mortality was 20% (95% CI, 8-33%) for the AP group versus 30% (95% confidence interval, 24-35%; P=0.25) for the CP group. In terms of relapse, 5-year incidence was 30% (95% confidence interval, 14-46%) for the AP group versus 15% (95% confidence interval, 11-19%) for the CP group (P=0.02). Results were confirmed in multivariable analysis and propensity score matching. Increase in circulating blasts was associated with increased risk for relapse, showing strongest increase in risk for ≥10% blasts. In conclusion, reduced intensity transplantation showed excellent survival but higher relapse for AP myelofibrosis.
PICO Summary
Population
People with primary or secondary myelofibrosis in four centres in France, Germany and USA (n=349)
Intervention
Reduced intensity conditioning and allogeneic transplantation in accelerated phase (AP, n=35)
Comparison
Reduced intensity conditioning and allogeneic transplantation in chronic phase (CP, n=314)
Outcome
After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% in the AP group (95% confidence interval, 49-81%) versus 64% (95% CI, 59-69%) for the CP group, and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the AP group was 49% (95% CI, 32-67%) versus 55% (95% CI, 50-61%) for the CP group. Estimated 5-year non-relapse mortality was 20% (95% CI, 8-33%) for the AP group versus 30% (95% CI, 24-35%) for the CP group. In terms of relapse, 5-year incidence was 30% (95% CI, 14-46%) for the AP group versus 15% (95% CI, 11-19%) for the CP group. Results were confirmed in multivariable analysis and propensity score matching. Increase in circulating blasts was associated with increased risk for relapse, showing strongest increase in risk for ≥10% blasts.
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Health-related quality of life in reduced intensity hematopoietic cell transplantation based on donor availability in patients aged 50-75 with advanced myelodysplastic syndrome: BMT CTN 1102
Cusatis, R., Martens, M. J., Nakamura, R., Cutler, C. S., Saber, W., Lee, S. J., Logan, B. R., Shaw, B. E., Gregory, A., D'Souza, A., et al
American journal of hematology. 2022
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Editor's Choice
Abstract
INTRODUCTION For myelodysplastic syndrome (MDS), allogeneic hematopoietic cell transplantation (alloHCT) is the only available curative therapy. The Blood and Marrow Transplant Clinical Trials Network study 1102 (BMT CTN 1102, NCT02016781) was a multicenter, biologic assignment trial based on matched donor availability in adults aged 50-75 with higher risk de novo MDS who were candidates for reduced-intensity conditioning (RIC) alloHCT. The primary analysis showed that those who received alloHCT had a survival benefit, but whether this is at the cost of worse quality of life (QOL) has not been described in detail. METHODS English and Spanish-speaking trial participants completed the Functional Assessment of Cancer Therapy - General (FACT-G), the SF-36, and the EQ-5D, at enrollment, every 6 months until 24 months, and 36 months. We compared patient-reported outcome (PRO) scores between study arms using an inverse probability weighted - independent estimating equation (IPW-IEE) model. RESULTS Between January 2014 and November 2018, 384 subjects (median age 66.7 years, range: 50.1-75.3) enrolled at 34 centers. PRO completion rates were generally high at 65-78%. The PRO trajectories for both arms were similar, with most decreasing or stable from baseline to 6 months and improving thereafter. Baseline PRO scores were the most consistent independent predictors of subsequent QOL outcomes and survival, even after controlling for clinical and patient-level factors. DISCUSSION For older adults with MDS, the survival advantage associated with Donor availability and alloHCT did not come at the cost of worse QOL. These results should reassure older patients and clinicians who prefer a curative approach to treating MDS. This article is protected by copyright. All rights reserved.
PICO Summary
Population
Adults aged 50-75 with higher risk de novo myelodysplastic syndrome,, who were candidates for reduced-intensity conditioning and allogeneic transplant, identified in 34 centres in the USA (n=384)
Intervention
Patients with an available donor and were transplanted (n=261)
Comparison
Patients with no available donor who did not receive transplantation (n=123)
Outcome
The patient recorded outcome (PRO) trajectories for both arms were similar, with most decreasing or stable from baseline to 6 months and improving thereafter. Baseline PRO scores were the most consistent independent predictors of subsequent QOL outcomes and survival, even after controlling for clinical and patient-level factors.
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Reduced-toxicity myeloablative conditioning regimen using fludarabine and full doses of intravenous busulfan in pediatric patients not eligible for standard myeloablative conditioning regimens: Results of a multicenter prospective phase 2 trial
Rialland, F., Grain, A., Labopin, M., Michel, G., Gandemer, V., Paillard, C., Pochon, C., Clement, L., Brissot, E., Jubert, C., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological malignancies in pediatric patients are limited. This prospective multicenter, phase 2 trial investigated a RTC regimen based on the combination of intravenous busulfan (3.2 mg/kg/d x 4 days), fludarabine (30 mg/m(2)/d x 5 days) and antithymocyte globulin (Thymoglobulin®, Genzyme; 5 mg/kg total dose) with the aim of delivering high dose myeloablation that would allow optimal disease control while minimizing toxicity, in a subgroup of children at very high risk of non-relapse mortality (NRM). The primary endpoint was NRM at 1 year after allo-SCT. A total of 48 high risk patients were included (median age, 13 years; range, 3-24). At 1 year, the cumulative incidence of recurrence/disease progression and NRM were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively. We conclude that the RTC regimen used in this prospective trial is safe, with a < 10% NRM rate noted among high-risk children and adolescents, paving the way for larger phase 3 trials incorporating novel agents pre- and post-allo-SCT.(ClinicalTrials.gov Identifier: NCT01572181).
PICO Summary
Population
Children and adolescents with haematological malignancies, but not eligible for standard myeloablative conditioning regimens, in 16 centres in France (n=48)
Intervention
30 mg/m2/d fludarabine for 5 consecutive days (day -6 to -2), 3.2 mg/kg/day IV Busulfan administered four times daily in a 2 h infusion for 4 consecutive days (day -5, -4, -3, and -2), and 2.5 mg/Kg/d antithymocyte globulin for 2 consecutive days (day -2 and -1).
Comparison
None
Outcome
At 1 year, the cumulative incidence of recurrence/disease progression and non-relapse mortality (NRM) were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively.