-
1.
Myeloablative Haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide and antithymoglobulin
Fakih, R. E., Nassani, M., Rasheed, W., Hanbali, A., Almohareb, F., Chaudhri, N., Alsharif, F., Alfraih, F., Shaheen, M., Alhayli, S., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Haplo-HSCT with PTCy is now performed on a large scale worldwide. Our patient's outcomes did not completely reflect the results published by other groups. We herein present the results of 60 patients with hematologic malignancies treated homogeneously on a modified version of the standard protocol by adding ATG as an additional GvHD-prophylaxis measure. METHODS Retrospective analysis of 60 haplo-transplanted patients using myeloablative regimen with ATG and PTCy for GvHD prophylaxis. RESULTS At 5-years the OS was 59.2%, the RFS was 48.6% and the CRFS was 40%. The median time to ANC and platelets engraftment was 16 and 28.5 days respectively. The grade II-IV aGvHD and extensive cGvHD were 46.7% and 23.3%. The cumulative incidence of relapse (CIR) was 30%, the NRM was 21.6% and the TRM was 11%. Higher DRI and 50% HLA-match were associated with lower RFS. Female to male donation and higher donor age were associated with higher cGvHD. CONCLUSION The use of PTCy may not yield the same results in different populations. Many remaining questions need to be addressed in randomized trials (optimal graft source and donor, date of CNI initiation, personalized or targeted dose of PTCy, immune reconstitution, etc.).
-
2.
Survival Benefit of Myeloablative Therapy with Autologous Stem Cell Transplantation in High-Risk Neuroblastoma: A Systematic Literature Review
Żebrowska, U., Balwierz, W., Wechowski, J., Wieczorek, A.
Targeted oncology. 2024
Abstract
BACKGROUND Multimodal treatment of newly diagnosed high-risk neuroblastoma (HRNB) includes induction chemotherapy, consolidation with myeloablative therapy (MAT) and autologous stem cell transplantation (ASCT), followed by anti-disialoganglioside 2 (GD2) immunotherapy, as recommended by the Children's Oncology Group (COG) and the Society of Paediatric Oncology European Neuroblastoma (SIOPEN). Some centres proposed an alternative approach with induction chemotherapy followed by anti-GD2 immunotherapy, without MAT+ASCT. OBJECTIVE The aim of this systematic literature review was to compare survival outcomes in patients with HRNB treated with or without MAT+ASCT and with or without subsequent anti-GD2 immunotherapy. PATIENTS AND METHODS The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE via PubMed and EMBASE databases were systematically searched for randomised controlled trials (RCT) and observational comparative studies in patients with HRNB using search terms for 'neuroblastoma' and ('myeloablative therapy' OR 'stem cell transplantation'). Reporting of at least one survival outcome [event-free survival (EFS), progression-free survival, relapse-free survival and/or overall survival (OS)] was required for inclusion. Outcomes from RCTs were synthesized in meta-analysis, while meta-analysis of non-RCTs was not planned owing to expected heterogeneity. RESULTS Literature searches produced 2587 results with 41 publications reporting 34 comparative studies included in the review. Of these, 7 publications reported 4 RCTs, and 34 publications reported 30 non-RCT studies. Studies differed with respect to included populations, induction regimen, response to induction, additional treatments and transplantation procedures. Subsequent treatments of relapse were rarely reported and could not be compared. In the meta-analysis, EFS was in favour of MAT+ASCT over conventional chemotherapy or no further treatment [hazard ratio (HR) = 0.78, 95% confidence interval (CI) 0.67-0.91, p = 0.001] with a trend favouring MAT+ASCT for OS (HR = 0.86, 95% CI 0.73-1.00, p = 0.05). Tandem MAT+ASCT was found to improve EFS compared with the single procedure, with improvement in both EFS and OS in patients treated with anti-GD2 therapy. Non-RCT comparative studies were broadly consistent with evidence from the RCTs; however, not all reported survival benefits of MAT+ASCT (single or tandem). Limited comparative evidence on treatment without MAT+ASCT in patients treated with anti-GD2 immunotherapy suggests an increased risk of relapse. In relapsed patients, MAT+ASCT appears to improve OS, but evidence remains scarce. CONCLUSIONS Survival benefits in patients treated with MAT+ASCT confirm that the procedure should remain an integral part of multimodal therapy. In patients treated with anti-GD2 immunotherapy, limited evidence suggests that omitting MAT+ASCT is associated with an increased risk of relapse, and therefore, a change in clinical practice can currently not be recommended. Evidence suggests the use of tandem MAT+ASCT compared with the single procedure, with greater benefits observed in patients treated with anti-GD2 immunotherapy. Limited evidence also suggests improved survival following MAT+ASCT in relapsed patients, which needs to be viewed in light of emerging chemoimmunotherapy in this setting.
-
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.
-
4.
Myeloablative dose of busulfan and fludarabine combined with in vivo T-cell depletion is a safe and effective conditioning for acute myeloid leukaemia and myelodysplastic syndrome patients
Avenoso, D., Mehra, V., Slonim, L. B., de Farias, M., Alshehri, H., Bouziana, S., Krishnamurthy, P., Kulasekararaj, A., Dazzi, F., Wood, H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Allogeneic haematopoietic stem cell transplant (HSCT) is a curative strategy for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). The prediction of transplant related mortality (TRM) using the HCT-CI score and an arbitrary upper limit of 55 years for administering myeloablative conditioning (MAC) are common strategies to ensure a safe procedure. Reduced toxicity conditioning regimens are additional methods to deliver safe and effective myeloablation. OBJECTIVES Herein we report the outcome of AML and MDS patients conditioned with fludarabine and a myeloablative dose of busulfan (FB4) stratified by age and HCT-CI score. The primary objective was overall survival (OS) for patients aged ≥55 years. Secondary objectives were total OS, TRM, graft versus-host disease (GVHD) and GVHD-relapse-free survival (GRFS). RESULTS The two years' OS in patients aged < 55 and aged ≥ 55 were 72% and 51%, respectively. In patients aged ≥55 with an HCT-CI <2, the estimated two years' OS was 64%, with median OS not reached. In those with HCT-CI ≥2, the two-year OS was 43%, with median OS of 14 months. The total cumulative incidence of relapse was 30% regardless of age or HCT-CI score. CONCLUSIONS FB4 conditioning regimen offers a high rate of prolonged remission with a relapse rate similar to that reported in previous studies. These positive outcomes suggest that this conditioning platform can be offered to patients aged ≥55 in absence of comorbidities, and that age should not be the sole determinate of conditioning intensity.
-
5.
Characterising the autoantibody repertoire in systemic sclerosis following myeloablative haematopoietic stem cell transplantation
Ayoglu, B., Donato, M., Furst, D. E., Crofford, L. J., Goldmuntz, E., Keyes-Elstein, L., James, J., Macwana, S., Mayes, M. D., McSweeney, P., et al
Annals of the rheumatic diseases. 2023;82(5):670-680
Abstract
OBJECTIVES Results from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes. METHODS We used a bead-based array containing 221 protein antigens to profile serum IgG autoantibodies in participants of the SCOT trial. RESULTS Comparison of autoantibody profiles at month 26 (n=23 HSCT; n=22 CTX) revealed antibodies against two viral antigens and six self-proteins (SSB/La, CX3CL1, glycyl-tRNA synthetase (EJ), parietal cell antigen, bactericidal permeability-increasing protein and epidermal growth factor receptor (EGFR)) that were significantly different between treatment groups. Linear mixed model analysis identified temporal increases in antibody levels for hepatitis B surface antigen, CCL3 and EGFR in HSCT-treated patients. Eight of 32 HSCT-treated participants and one of 31 CTX-treated participants had temporally varying serum antibody profiles for one or more of 14 antigens. Baseline autoantibody levels against 20 unique antigens, including 9 secreted proteins (interleukins, IL-18, IL-22, IL-23 and IL-27), interferon-α2A, stem cell factor, transforming growth factor-β, macrophage colony-stimulating factor and macrophage migration inhibitory factor were significantly higher in patients who survived event-free to month 54. CONCLUSIONS Our results suggest that HSCT favourably alters the autoantibody repertoire, which remains virtually unchanged in CTX-treated patients. Although antibodies recognising secreted proteins are generally thought to be pathogenic, our results suggest a subset could potentially modulate HSCT in scleroderma.
-
6.
Appropriate pre-transplant strategy for patients with myelodysplastic syndromes receiving allogeneic haematopoietic stem cell transplantation after myeloablative conditioning
Wang, H., Wang, Q., Qi, J., Li, X., Chu, T., Qiu, H., Fu, C., Tang, X., Ruan, C., Wu, D., et al
Frontiers in immunology. 2023;14:1146619
Abstract
PURPOSE Appropriate pre-transplant strategies in patients with myelodysplastic syndromes (MDS) remain challenging. We sought to assess the effect of different pre-transplant therapies and transplantation interval times on patient prognosis. METHODS We retrospectively analysed clinical data for 371 consecutive MDS patients after myeloablative transplantation between 2007 and 2019. RESULTS The median age of the patients was 38 years (range, 12-64 years). A total of 114 patients (31%) received supportive care (SC), 108 (29%) hypomethylating agents (HMAs), and 149 (40%) chemotherapy-based therapy before transplantation. In patients who received HMA or SC, there was no significant difference in overall survival (OS; P=0.151) or relapse-free survival (RFS; P=0.330), except that HMA-treated patients had a lower rate of non-relapse mortality (5-year NRM: 18% vs. 32%, P=0.035). However, compared with patients who received HMA, those who received chemotherapy-based therapy had a lower 5-year OS rate (56% vs. 69%, P=0.020) and a slightly higher 5-year NRM rate (28% vs. 18%, P=0.067). Compared to the delayed transplant group (transplant interval ≥6 months), the early transplant group (transplant interval <6 months) had a superior 5-year OS (66% vs. 51%, P=0.001) and a lower 5-year cumulative incidence of NRM (22% vs. 36%, P=0.001). CONCLUSION The findings of the study indicate that receiving an appropriate pre-transplant strategy (SC/HMA + <6 months) significantly improves OS and decreases NRM in MDS patients after myeloablative transplantation.
-
7.
Myeloablative conditioning regimens in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission: a systematic review and network meta-analysis
Luo, C., Wu, G., Huang, X., Ding, Y., Huang, Y., Song, Q., Hou, Y., Chen, J., Li, X., Xu, S.
Bone Marrow Transplantation. 2023;58(2):175-185
Abstract
The optimal myeloablative conditioning (MAC) regimens in adult patients with acute myeloid leukemia (AML) undergoing allogeneic hemopoietic stem cell transplantation (allo-HSCT) in complete remission (CR) remain unclear. We performed a systematic review and network meta-analysis to compare the effects of different MAC regimens. Bayesian network meta-analysis was performed using WinBUGS version 1.4.3. The commonly used MAC regimen Bu/Cy (4-day busulfan for toal 16 mg/kg orally or 12.8 mg/kg intravenously, plus 2-day cyclophosphamide for toal 120 mg/kg intravenously) is chosen as the common comparator. Pooled hazard ratios (HRs) with the associated 95% credibility interval (95% CrI) are obtained for all comparisons. We included 19 eligible studies, involving 8104 AML patients and 9 MAC regimens. Compared with Bu/Cy, 3-day busulfan plus fludarabine and thiotepa (Bu3/Flu/TT) is associated with significantly better overall survival (HR, 0.70; 95% CrI, 0.51 to 0.96) and lower risk of relapse (HR, 0.59; 95% CrI, 0.35 to 0.98). Bu3/Flu/TT is also associated with superior overall survival than Cy/TBI (cyclophosphamide plus total body irradiation), and lower risk of relapse than Bu4/Flu (4-day busulfan plus fludarabine). These results suggest that thiotepa-based new MAC regimen Bu3/Flu/TT is associated with improved outcomes in AML patients undergoing allo-HSCT in CR and worth further investigation.
-
8.
Improved myeloablative conditioning regimen for allogeneic stem cell transplantation in adult patients with chronic myelomonocytic leukaemia
Zhang, T., Liu, X., Fei, H., Zhang, L., Ma, R., Shen, Y., Pang, A., Yang, D., Chen, X., Zhang, R., et al
British journal of haematology. 2023;200(2):256-260
-
9.
Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation
Bognàr, T., Bartelink, I. H., Egberts, T. C. G., Rademaker, C. M. A., Versluys, A. B., Slatter, M. A., Kletzel, M., Nath, C. E., Cuvelier, G. D. E., Savic, R. M., et al
Transplantation and cellular therapy. 2022;28(4):196-202
Abstract
Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.
-
10.
Myeloablative Conditioning Regimen in Haploidentical Stem Cell Transplantation With Posttransplant Cyclophosphamide in Children With High-risk Hematologic Malignancies
Dufort, Y. Alvarez G.
Journal of pediatric hematology/oncology. 2022
Abstract
Limited information is available on outcomes of haploidentical stem cell transplantation (haploSCT) with posttransplant cyclophosphamide using myeloablative conditioning regimens in children and adolescents. We report the results of a single-institution retrospective study of myeloablative haploSCT in 36 children and adolescents (median age, 8 y; range, 9 mo to 22 y) with high-risk hematologic malignancies. Donor engraftment occurred in 31 of 33 evaluable patients (94%). Recovery of neutrophils and platelets occurred at a median of 15 and 20 days. Cumulative incidence of acute graft-versus-host-disease (GVHD) grades II to IV and grades III to IV at 100 days was 36±8.7% and 10±5.4% and of chronic GVHD at 1 year was 55±9.2%, with 31±8.6% moderate to severe. Nonrelapse mortality was 16±6.1% and 22±6.9% at 100 days and 1 year. The cumulative incidence of relapse at 4 years was 32±8.8%. With a median follow-up of 57 months (range, 8 to 89 mo), the overall survival and event-free survival at 4 years was 55.6±8.7% and 44.8±8.5%. Myeloablative conditioning T-replete haploSCT with posttransplant cyclophosphamide is a viable alternative to matched unrelated transplantation for children and adolescents with high-risk hematologic malignancies. The high rates of nonrelapse mortality and chronic GVHD is a concern and deserves careful consideration.