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1.
Haploidentical bone marrow transplantation for AML in remission following TBF conditioning: a long-term follow up
Raiola, A. M., Di Grazia, C., Dominietto, A., Bregante, S., Giammarco, S., Varaldo, R., Sorà, F., Metafuni, E. Md, Limongiello, M. A., Laudisi, A., et al
Blood advances. 2024
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2.
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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3.
Addition of venetoclax to myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in high-risk AML
Cao, X. Y., Chen, J. Q., Wang, H., Ma, W., Liu, W. W., Zhang, F. F., Xue, S., Dong, L., Liu, T., Zhao, X. Z., et al
Annals of medicine. 2023;55(1):388-400
Abstract
BACKGROUND Venetoclax monotherapy is an effective option for patients with acute myeloid leukemia (AML). Venetoclax has also been used in non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk AML with a tolerable toxicity profile. However, the efficacy and safety of a venetoclax-containing myeloablative conditioning (MAC) allo-HSCT regimen for high-risk AML have not been evaluated. OBJECTIVE To evaluate the safety and efficacy of a MAC regimen containing venetoclax for high-risk AML. STUDY DESIGN From 25 February 2021 to 4 September 2022, a total of 31 patients with high-risk AML who underwent allo-HSCT and a MAC regimen with venetoclax were analyzed. RESULTS At the time of transplantation, 21 patients were in first complete remission (CR1), 4 were in a second complete remission (CR2), and 6 in non-remission (NR). Twenty-four patients (77.4%) were minimal residual disease (MRD)-positive before transplant. The FLT3-ITD gene mutation was present in 51.6% of patients. NUP98 rearrangement, MLL rearrangement or MLL-PTD and DEK::CAN fusion genes were found in 5 (16.1%), 7(22.6%) and 2 (6.5%) patients, respectively. Twenty-nine (93.6%) patients underwent haploidentical allo-HSCT. The median follow-up time was 278 days (range: 52-632 days). The 100-day cumulative incidence of grade 3 to 4 acute graft-versus-host disease (aGVHD) was 16.1% (95%CI, 7.2-36.0%). The 180-day cumulative incidence of moderate to severe chronic graft-versus-host disease (cGVHD) was 7.1% (95%CI, 1.9-26.9%). Cumulative incidence of 100-day cytomegalovirus (CMV) viraemia and 100-day Epstein-Barr virus (EBV) viraemia was 61.6% (95%CI, 46.5-81.4%) and 3.2% (95%CI, 0.4-22.2%), respectively. The 600-day overall survival (OS) and leukemia-free survival (LFS) were 80.9% (95%CI, 63.5-93.6%) and 81.3% (95%CI, 64.2-93.7%), respectively. The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8-26.3%) and 11.7% (95%CI, 3.9-35.0%). CONCLUSION Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.
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4.
Survival advantage of treosulfan plus fludarabine (FT14) compared to busulfan plus fludarabine (FB4) in active acute myeloid leukemia post allogeneic transplantation: an analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP)
Gavriilaki, E., Sakellari, I., Labopin, M., Bornhäuser, M., Hamladji, R. M., Casper, J., Edinger, M., Zák, P., Yakoub-Agha, I., Ciceri, F., et al
Bone marrow transplantation. 2023
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Full text
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Editor's Choice
Abstract
We compared FT14 (fludarabine 150-160 mg/m(2), treosulfan 42 g/m(2)) versus FB4 (fludarabine 150-160 mg/m(2), 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.
PICO Summary
Population
Adults identified from the EBMT registry, meeting the following criteria: diagnosed with AML, recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated/sibling donor (2010-2020), and with primary refractory/relapsed disease, (n=346)
Intervention
Fludarabine 150-160 mg/m(2), treosulfan 42 g/m(2) conditioning (FT14, n=113)
Comparison
Fludarabine 150-160 mg/m(2), busulfan 12.8 mg/kg) conditioning (FB4, n=233)
Outcome
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.
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5.
Determinants of refined GvHD-free, relapse-free survival after reduced-intensity allogeneic hematopoietic cell transplantation in older patients with myeloid malignancies
Jindra, P., Karas, M., Lysák, D., Šrámek, J., Steinerová, K., Hrabětová, M., Jungová, A.
Leukemia research. 2023;127:107052
Abstract
BACKGROUND Older patients with AML/MDS have a poor prognosis with alloHCT as the only curative option. However alloHCT is challenging given its high TRM. Recently, a composite endpoint of GRFS was proposed to define transplant success. A single centre retrospective analysis was performed to determine the main variables influencing GRFS. PATIENTS AND METHODSMETHODS 91 consecutive patients≥ 60 years (median 64 years, range 60-74) with AML/MDS who received reduced-intensity alloHCT during 2001-2017 analysed. Disease risk index (DRI) at HCT was low/intermediate in 47pts (52%) and high in 44 pts (48%). RESULTS After median follow-up for survivors of 56 months (range 7-144), 37 (40.6%) patients were alive. The OS, LFS and GRFS were 61.4%, 58.1%, 49.1% at 1 year and 35.5%, 32.3% and 23.1% at 5 years, respectively. The 1-year and 5-year incidences of NRM and relapse were 26.9%, 21.3% and 47.9% and 35.4%, respectively. In univariate analysis, high DRI was the strongest factor for worse OS (HR 2.121; p = 0.049), LFS (HR 1.924; p = 0.0123) and GRFS (HR 2.319; p = 0.0005). The donor age ≥ 62 years had a negative impact on OS (HR 2.110; p = 0.0345) and GRFS (HR 2.014; p = 0.0341). High DRI (HR 2.652; p = 0.0003) and donor age (HR 2.304; p = 0.0257) retained its significance in multivariate analysis for GRFS. CONCLUSION A significant portion of older patients with myeloid malignancies survive alloHCT without experiencing GRFS event with DRI as the main determinant of outcome. Negative impact of donor age≥ 62 years suggests preference of a young donor, regardless of being related or unrelated.
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Analysis of long-term mortality after total body irradiation-based and melphalan-based chemotherapy conditioning for acute myeloid leukemia
Gruber, I., Koelbl, O., Treutwein, M., Zeman, F., Herr, W., Holler, E., Edinger, M., Wolff, D.
Annals of hematology. 2023
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for selected patients with acute myeloid leukemia. Yet, the influence of total body irradiation (TBI)-based conditioning as compared to non-TBI-based conditioning on long-term mortality is unclear. We retrospectively evaluated outcomes after TBI-based (n = 91) and non-TBI-based conditioning (melphalan-based, n = 248) for 1st allo-HSCT patients transplanted at the University Hospital Regensburg between 1999 and 2020. TBI was performed with an average dose rate of 4 cGy/min. Median follow-up was 8.3 years (interquartile range, 4.8-12.9 years). Cumulative incidence rates of 5-year non-relapse mortality (NRM) were 17% (95% confidence interval, CI, 10-25) and 33% (95% CI, 27-40) after TBI- and non-TBI-based conditioning (P < 0.001). Five-year cumulative incidences of relapse (CIR) were 42% (95% CI, 32-52) and 29% (95% CI, 23-35) after TBI- and non-TBI-based conditioning (P = 0.030). The 5-year OS was 54% (95% CI, 43-64) and 55% (95% CI, 48-62) after TBI- and non-TBI-based conditioning. Both groups had similar 100-day acute graft-versus-host disease (aGVHD, 43% vs. 40%) and 5-year chronic GVHD (34% vs. 36%). The multivariable regression models found no associations of TBI with the outcomes NRM, CIR, PFS, OS, aGVHD, and cGVHD. TBI was no risk factor for NRM, even including mortality caused by secondary malignancies. NRM was influenced by patient age, advanced disease status, and the use of female donors for male recipients. TBI- and non-TBI-based conditioning appear to be equally effective and tolerable for AML patients eligible for 1st allo-HSCT.
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7.
DNTT activation, TdT-aided gene length mutation, and better prognosis in ATG-based regimen allo-HSCT in AML
Zhou, X., Nie, D., Zhang, Y., Liu, Z., Zhao, Y., Zhang, J., Wang, F., Fang, J., Cao, P., Chen, X., et al
Molecular carcinogenesis. 2023
Abstract
This study aimed to investigate the relationship between anomalous DNA nucleotidylexotransferase (DNTT) activation and the mutagenesis of gene length mutations (LMs) in acute myeloid leukemia (AML), and the relevance of their prognosis in antithymocyte globulin (ATG)-based regimen allogeneic hematopoietic stem cell transplantation (allo-HSCT). A cohort of 578 AML cases was enrolled. Next-generation sequencing was performed to screen mutations of 86 leukemia driver genes. RNA-seq was used to analyze gene expression. Prognostic analysis was investigated in 239 AML cases who underwent ATG-based regimen allo-HSCT. We report a refined subtyping algorithm of LMs (type I-IV) based on sequence anatomy considering the TdT-aided mutagenesis mechanism. GC content adjacent to LM junctions, inserted nontemplate nucleotide bases, and DNTT expression analysis supported the DNTT activation and TdT-aided mutagenesis in type II/III LMs in the total AML cohort. Both single-variate and multivariate analyses showed a better overall survival of FLT3 type III compared to type I in a subset of ATG-based regimen allo-HSCT cases. The novel LM subtyping algorithm not only deciphers the etiology of the mutagenesis of LMs but also helps to fine-tune prognosis differentiation in AML. The possible prognostic versatility of this novel LM subtyping algorithm in terms of chemotherapy, targeted therapy, and allo-HSCT merits further investigation.
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Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT Acute Leukemia Working Party
Duque-Afonso, J., Finke, J., Ngoya, M., Galimard, J. E., Craddock, C., Raj, K., Bloor, A., Nicholson, E., Eder, M., Kim, O., et al
Bone marrow transplantation. 2023
Abstract
Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m(2) (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m(2). We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.
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9.
A uniform conditioning regimen of busulfan, fludarabine, and antithymocyte globulin for allogeneic haematopoietic cell transplantation from haploidentical family, matched sibling, or unrelated donors-A single-centre, prospective, explorative study
Choi, Y., Choi, E. J., Park, H. S., Lee, J. H., Lee, J. H., Lee, Y. S., Kang, Y. A., Jeon, M., Woo, J. M., Kang, H., et al
British journal of haematology. 2023;200(5):608-621
Abstract
In a prospective, explorative study, the donor-source difference of haploidentical family (HF), matched sibling (MS), and unrelated donors (UD) was evaluated for the outcome of haematopoietic cell transplantations (HCT) in 101 patients with acute myeloid leukaemia (AML) in complete remission (CR). To eliminate compounding effects, a uniform conditioning regimen containing antithymocyte globulin (ATG) was used. After transplantation, there was a significantly higher cumulative incidence of acute graft-versus-host disease (GVHD) in HF-HCT patients (49%, 7%, and 16% for HF-, MS- and UD-HCT respectively; p < 0.001). A quarter of acute GVHD cases observed in HF-HCT patients occurred within three days of engraftment and were characterized by diffuse skin rash, fever, weight gain, and hypoalbuminaemia. This peri-engraftment acute GVHD was not observed in MS-HCT or UD-HCT patients. Additionally, a significantly higher proportion of HF-HCT patients achieved complete donor chimaerism in the peripheral mononuclear cells at one month (88%, 46%, and 69% for HF-, MS- and UD-HCT respectively; p = 0.001). There was no significant difference in engraftment, chronic GVHD, leukaemia recurrence, non-relapse mortality, and patient survival. In patients with AML in CR who received HCT using ATG-containing conditioning, stronger donor-patient alloreactivity was observed in HF-HCT, in terms of increased acute GVHD and higher likelihood of complete donor chimaerism.
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10.
Impact of Type of Induction Therapy on Outcomes in Older Adults with AML after Allogeneic Stem Cell Transplantation
Short, N. J., Ong, F., Ravandi, F., Nogueras Gonzalez, G. M., Kadia, T. M., Daver, N. G., DiNardo, C. D., Konopleva, M. Y., Borthakur, G., Oran, B., et al
Blood advances. 2023
Abstract
Although venetoclax-based lower-intensity regimens have greatly improved outcomes for older adults with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy, the optimal induction for older patients with newly diagnosed AML who are suitable candidates for hematopoietic stem cell transplant (HSCT) is controversial. We retrospectively analyzed post-HSCT outcomes of 127 patients ≥60 years of age who received induction therapy at our institution with intensive chemotherapy (IC, n=44), lower-intensity therapy (LIT) without venetoclax (n=29) or LIT with venetoclax (n=54) and who underwent allogeneic HSCT in first remission. The 2-year relapse-free survival with LIT with venetoclax was 60%, versus 54% with IC and 41% with LIT without venetoclax, and 2-year overall survival for LIT with venetoclax was 72%, versus 58% with IC and 41% with LIT without venetoclax. The benefit to LIT with venetoclax induction was greatest in patients with adverse-risk AML (2-year OS 74%, 46%, and 29%, respectively). Induction with LIT, with or without venetoclax, was associated with the lowest rate of non-relapse mortality (NRM) (2-year NRM 17% versus 27% with IC; P=0.04). By multivariate analysis, type of induction therapy did not significantly impact any of the post-HSCT outcomes evaluated; hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was the only factor that independently predicted for RFS and OS. LIT plus venetoclax followed by HSCT is feasible treatment strategy in older, fit, and HSCT-eligible patients with newly diagnosed AML and may be particularly beneficial in those with adverse-risk disease.