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1.
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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2.
Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT
Geerlinks, A. V., Scull, B., Krupski, C., Fleischmann, R., Pulsipher, M. A., Eapen, M., Connelly, J. A., Bollard, C. M., Pai, S. Y., Duncan, C. N., et al
Blood advances. 2023;7(14):3725-3734
Abstract
Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 μg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 μg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.
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3.
[Second allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning and donor changes in relapsed hematological malignancies after the first allogeneic transplant]
Zhao, Y. Q., Song, Y. Z., Li, Z. H., Yang, F., Xu, T., Li, F. F., Yang, D. F., Wu, T.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2023;44(6):465-471
Abstract
Objective: The purpose of this study was to assess the safety and efficacy of a second allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reduced-intensity conditioning (RIC) in patients with hematological malignancies who had relapsed after the first allo-HSCT. Methods: Between April 2018 and June 2021, 44 patients with hematological malignancies (B-ALL 23, T-ALL/T-LBL 4, AML15, and MDS 2) were enrolled and retrospectively examined. Unrelated donors (n=12) or haploidentical donors (n=32) were used. Donors were replaced in all patients for the second allo-HSCT. Hematological and immunological germline predisposition genes and hematopoietic and immune function tests were used to select the best-related donor. Total body irradiation (TBI) /fludarabine (FLU) -based (n=38), busulfan (BU) /FLU-based (n=4), total marrow irradiation (TMI) /FLU-based (n=1), and BU/cladribine-based (n=1) were the RIC regimens used. For graft versus host disease (GVHD) prevention, cyclosporine, mycophenolate mofetil, short-term methotrexate, and ATG were used. Eighteen (40.9%) of 44 patients with gene variations for which targeted medications are available underwent post-transplant maintenance therapy. Results: The median age was 25 years old (range: 7-55). The median interval between the first and second HSCT was 19.5 months (range: 6-77). Before the second allo-HSCT, 33 (75%) of the patients were in complete remission (CR), whereas 11 (25%) were not. All patients had long-term engraftment. The grade Ⅱ-Ⅳ GVHD and severe acute GVHD rates were 20.5% and 9.1%, respectively. Chronic GVHD was found in 20.5% of limited patterns and 22.7% of severe patterns. CMV and EBV reactivation rates were 29.5% and 6.8%, respectively. Hemorrhage cystitis occurred in 15.9% of cases, grade Ⅰ or Ⅱ. The 1-yr disease-free survival (DFS), overall survival (OS), and cumulative recurrence incidence (RI) rates of all patients were 72.5% (95% CI, 54.5%-84.3%), 80.6% (95% CI, 63.4%-90.3%), and 25.1% (95% CI, 13.7%-43.2%), respectively, with a median follow-up of 14 (2-39) months. There were eight deaths (seven relapses and one infection). The rate of non-relapse mortality (NRM) was only 2.3%. The CR patients' 1-yr RI rate was significantly lower than the NR patients (16.8% vs 48.1%, P=0.026). The DFS rate in CR patients was greater than in NR patients, although there was no statistical difference (79.9% vs 51.9%, P=0.072). Univariate analysis revealed that CR before the second allo-HSCT was an important prognostic factor. Conclusion: With our RIC regimens, donor change, and post-transplant maintenance therapy, the second allo-HSCT in relapsed hematological malignancies after the first allo-HSCT is a safe and effective treatment with high OS and DFS and low NRM and relapse rate. The most important factor influencing the prognosis of the second allo-HSCT is the patient's illness condition before the transplant.
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4.
Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation
Kamijo, K., Shimomura, Y., Shinohara, A., Mizuno, S., Kanaya, M., Usui, Y., Kim, S. W., Ara, T., Mizuno, I., Kuriyama, T., et al
Annals of hematology. 2023
Abstract
Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%-60.8%) and 32.2% (95% CI, 22.4-42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30-3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.
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5.
Is Treosulfan-Based Conditioning Attractive as a Reduced-Intensity Conditioning Regimen in Korea?
Kim, S. H., Ji, Y. S., Yun, J., Choi, S. H., Lim, S. H., Kim, C. K., Park, S. K.
Journal of Korean medical science. 2023;38(36):e281
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (HSCT) was not actively performed in elderly acute myeloid leukemia (AML) or myelodysplastic syndrome patients who are at a high-risk based on hematopoietic cell transplantation-specific comorbidity index (HCT-CI). The advent of reduced-intensity conditioning (RIC) regimens has made HSCT applicable in this population. However, the selection of appropriate conditioning is a major concern for the attending physician. The benefits of combination of treosulfan and fludarabine (Treo/Flu) have been confirmed through many clinical studies. Korean data on treosulfan-based conditioning regimen are scarce. METHODS A retrospective study was conducted to compare the clinical outcomes of allogeneic HSCT using RIC between 13 patients receiving Treo/Flu and 39 receiving busulfan/fludarabine (Bu/Flu). RESULTS In terms of conditioning-related complications, the frequency of ≥ grade 2 nausea or vomiting was significantly lower and the duration of symptoms was shorter in the Treo/Flu group than in the Bu/Flu group. The incidence of ≥ grade 2 mucositis tended to be lower in the Treo/Flu group. In the analysis of transplant outcomes, all events of acute graft versus host disease (GVHD) and ≥ grade 2 acute GVHD occurred more frequently in the Treo/Flu group. The frequency of Epstein-Barr virus reactivation was significantly higher in the Treo/Flu group (53.8% vs. 23.1%, P = 0.037). Non-relapse mortality (NRM) at 12 months was higher in the Treo/Flu group (30.8% vs. 7.7%, P = 0.035). Significant prognostic factors included disease type, especially secondary AML, disease status and high-risk based on HCT-CI, ≥ grade 2 acute GVHD, and cases requiring ≥ 2 immunosuppressive drugs for treating acute GVHD. In the comparison of survival outcomes according to conditioning regimen, the Bu/Flu group seemed to show better results than the Treo/Flu group (60% vs. 46.2%, P = 0.092 for overall survival; 56.4% vs. 38.5%, P = 0.193 for relapse-free survival). In additional analysis for only HCT-CI high-risk groups, there was no difference in transplant outcomes except that the Treo/Flu group tended to have a higher NRM within one year after transplantation. Survival outcomes of both groups were similar. CONCLUSION This study suggests that Treo/Flu conditioning may be an alternative to Bu/Flu regimen in elderly patients with high-risk who are not suitable for standard conditioning.
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6.
Excellent outcome of stem cell transplantation for sickle cell disease
Vallée, T., Schmid, I., Gloning, L., Bacova, M., Ahrens, J., Feuchtinger, T., Klein, C., Gaertner, V. D., Albert, M. H.
Annals of hematology. 2023
Abstract
Many sickle cell disease (SCD) patients lack matched family donors (MFD) or matched unrelated donors (MUD), implying haploidentical donors (MMFD) as a logical donor choice. We used a reduced toxicity protocol for all donor types. We included 31 patients (2-22 years) with MFD (n = 15), MMFD (10), or MUD (6) HSCT and conditioning with alemtuzumab/ATG, thiotepa, fludarabine and treosulfan, and post-transplant cyclophosphamide for MMFD. After the initial six patients, treosulfan was replaced by targeted busulfan (AUC 65-75 ng*h/ml). After a median follow-up of 26 months (6-123), all patients are alive and off immunosuppression. Two MMFD patients experienced secondary graft failure with recurrence of SCD, both after treosulfan conditioning. Neither acute GVHD ≥ °III nor moderate/severe chronic GVHD was observed. The disease-free, severe GVHD-free survival was 100%, 100%, and 80% in the MFD, MUD, and MMFD groups, respectively (p = 0.106). There was a higher rate of virus reactivation in MMFD (100%) and MUD (83%) compared to MFD (40%; p = 0.005), but not of viral disease (20% vs 33% vs 13%; p = 0.576). Six patients had treosulfan-based conditioning, two of whom experienced graft failure (33%), compared to 0/25 (0%) after busulfan-based conditioning (p = 0.032). Donor chimerism was ≥ 80% in 28/31 patients (90%) at last follow-up. Reduced toxicity myeloablative conditioning resulted in excellent overall survival, negligible GVHD, and low toxicity among all donor groups in pediatric and young adult patients with SCD.
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7.
Thiotepa-based regimens are a valid alternative to total body irradiation-based reduced-intensity conditioning regimens in patients with acute lymphoblastic leukemia: a retrospective study on behalf of the Acute Leukemia Working Party of the EBMT
Battipaglia, G., Labopin, M., Mielke, S., Ruggeri, A., Nur Ozkurt, Z., Henri Bourhis, J., Rabitsch, W., Yakoub-Agha, I., Grillo, G., Sanz, J., et al
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, in elderly and unfit patients, where reduced-intensity conditioning (RIC) regimens are preferred, whether a TBI- or chemotherapy-based approach is better, is unexplored. Thiotepa can be used as part of ALL conditioning regimens. The aim of the current study is to compare transplant outcomes after RIC with TBI- or thiotepa-based regimens in ALL. METHODS Included were patients aged ≥40 years undergoing allo-HSCT for ALL in first complete remission between 2000-2020, receiving a RIC regimen containing either TBI- (4-6 Gray, Gy) or thiotepa. RESULTS We identified a total of 265 patients, including 117 receiving TBI- and 148 receiving a thiotepa-based RIC regimen. In univariate analysis, no differences were observed in transplant outcomes (for TBI versus thiotepa: relapse, 23% versus 28%, p=0.24; non-relapse mortality, 20% versus 26%, p=0.61; leukemia-free survival, 57% versus 46%, p=0.12; overall survival, 67% versus 56%, p=0.18; graft-versus-host disease [GVHD]/relapse-free survival, 45% versus 38%, p=0.21; grade II-IV acute GVHD, 30% in both groups, p=0.84; grade III-IV acute GVHD, 9% versus 10%, p=0.89) except for chronic GVHD which was higher for TBI-based regimens (43% versus 29%, p=0.03). However, on multivariate analysis no differences in transplant outcomes were observed. CONCLUSION In patients ≥40 years receiving a RIC regimen, use of a thiotepa-based regimen may represent a valid alternative to TBI-based regimens as no differences were observed in the main transplant outcomes.
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8.
Comorbidities in recipients of low transplant conditioning intensity regimens for acute myeloid leukemia: an ALWP EBMT study
Fein, J. A., Shouval, R., Galimard, J. E., Labopin, M., Socié, G., Finke, J., Cornelissen, J. J., Malladi, R., Itälä-Remes, M., Chevallier, P., et al
Blood advances. 2023
Abstract
Older age and high burden of comorbidities often drive selection of low-intensity conditioning regimens in allogeneic-hematopoietic stem cell transplantation (HSCT) recipients. However, the impact of comorbidities in the low-intensity conditioning setting is unclear. We sought to determine the contribution of individual comorbidities and their cumulative burden on the risk of non-relapse mortality (NRM) in patients receiving low-intensity regimens. In a retrospective analysis of adults (≥ 18 years) transplanted for acute myeloid leukemia (AML) in first complete remission (CR) between 2008-2018, we studied recipients of low-intensity regimens as defined by the Transplantation Conditioning Intensity (TCI) scale. Multivariable Cox models were constructed to study associations of comorbidities with NRM. Comorbidities identified as putative risk factors in the low-TCI setting were included in combined multivariable regression models assessed for overall survival, NRM, and relapse. A total of 1,663 patients with a median age of 61 years received low-TCI regimens. Cardiac comorbidity (including arrhythmia/valvular disease) and psychiatric disease were associated with increased NRM risk (hazard ratio [HR] 1.54 [95% CI 1.13, 2.09] and 1.69 [1.02, 2.82], respectively). Moderate pulmonary dysfunction, though prevalent, was not associated with increased NRM. In a combined model, cardiac, psychiatric, renal, and inflammatory bowel disease were independently associated with adverse transplantation outcomes. These findings may inform patient and regimen selection and reinforce the need for further investigation of cardioprotective transplantation approaches.
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9.
Impact of extramedullary disease in AML patients undergoing sequential RIC for HLA-matched transplantation: occurrence, risk factors, relapse patterns, and outcome
Fraccaroli, A., Vogt, D., Rothmayer, M., Spiekermann, K., Pastore, F., Tischer, J.
Annals of hematology. 2023
Abstract
We sought to evaluate the role of extramedullary disease (EMD) in sequential RIC retrospectively analyzing data of 144 high-risk AML patients undergoing HLA-matched transplantation. Median long-term follow-up was 11.6 years. Eighteen percent of patients (n = 26/144) presented with extramedullary AML (EM AML) or a history of EMD at time of transplantation. Overall relapse rate was 25% (n = 36/144) with 15% (n = 21/144) of all patients developing isolated BM relapse and 10% (n = 15/144) developing EM AML relapse with or without concomitant BM relapse (EM ± BM). Manifestation of EM relapse after transplantation occurred frequently at multiple sites and presented mostly as solid tumor mass. Only 3/15 patients with EM ± BM relapse showed a prior EMD manifestation. EMD prior to allogeneic transplantation had no impact on post-transplant OS when compared to non-EMD (median post-transplant OS 3.8 years versus 4.8 years; ns). Risk factors (p = < 0.1) for EM ± BM relapse included younger age and a higher number of prior intensive chemotherapies, whereas the presence of chronic GVHD was a protective factor. Median post-transplant OS (15.5 months vs. 15.5 months), RFS (9.6 months vs 7.3 months), and post-relapse OS (6.7 months vs. 6.3 months) were not significantly different between patients with isolated BM vs. EM ± BM relapse. Taken together, occurrence of EMD prior to as well as of EM ± BM AML relapse after transplantation was moderate, presenting mostly as solid tumor mass after transplantation. However, diagnosis of those does not seem to influence outcomes after sequential RIC. A higher number of chemotherapy cycles prior to transplantation was identified as recent risk factor for EM ± BM relapse.
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10.
Fludarabine-Melphalan-Campath, Followed by Unmanipulated Peripheral-Blood Haematopoietic Stem Cells, Can Still Cure Lymphoma
Avenoso, D., Alabdulwahab, A., Kenyon, M., Mehra, V., Krishnamurthy, P., Dazzi, F., Leung, Y. T., Anteh, S., Shah, M. N., Kuhnl, A., et al
Mediterranean journal of hematology and infectious diseases. 2023;15(1):e2023041
Abstract
BACKGROUND The second decade of this millennium was characterized by a widespread availability of chimeric antigen receptor T-cell (CAR-T) therapies to treat relapsed and refractory lymphomas. As expected, the role and indication of allogeneic haematopoietic stem cell transplant (allo-HSCT) in the management of lymphoma changed. Currently, a non-neglectable proportion of patients will be considered candidate for an allo-HSCT, and the debate of which transplant platform should be offered is still active. OBJECTIVES to report the outcome of patients affected with relapsed/refractory lymphoma and transplanted following reduced intensity conditioning at King's College Hospital, London, between January 2009 and April 2021. METHODS Conditioning was with 150mg/m2 of fludarabine and melphalan of 140mg/m2. The graft was unmanipulated G-CSF mobilized peripheral blood haematopoietic stem cells (PBSC). Graft-versus-host disease (GVHD) prophylaxis consisted of pre-transplant Campath at the total dose of 60 mg in unrelated donors and 30 mg in fully matched sibling donors and ciclosporin. RESULTS One-year and five years OS were 87% and 79.9%, respectively, and median OS was not reached. The cumulative incidence of relapse was 16%. The incidence of acute GVHD was 48% (only grade I/II); no cases of grade III/IV were diagnosed. Chronic GVHD occurred in 39% of patients. TRM was 12%, with no cases developed within day 100 and 18 months after the procedure. CONCLUSIONS The outcomes of heavily pretreated lymphoma patients are favorable, with median OS and survival not reached after a median of 49 months. In conclusion, even if some lymphoma subgroups cannot be treated (yet) with advanced cellular therapies, this study confirms the role of allo-HSCT as a safe and curative strategy.