-
1.
Mocravimod, a selective S1PR modulator in allogeneic hematopoietic stem cell transplantation for malignancy
Dertschnig, S., Gergely, P., Finke, J., Schanz, U., Holler, E., Holtick, U., Socié, G., Medinger, M., Passweg, J., Teshima, T., et al
Transplantation and cellular therapy. 2022
-
-
-
Free full text
-
Editor's Choice
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for patients with acute myelogenous leukemia (AML). Outcomes are limited by leukemia relapse, graft-versus-host disease (GvHD) and abnormal immune reconstitution. Mocravimod (KRP203) is an oral sphingosine-1-phosphate receptor (S1PR) modulator that blocks the signal required by T cells to egress from lymph nodes and other lymphoid organs. Mocravimod retains T cell effector function, a main differentiator to immunosuppressants. In preclinical models, mocravimod improves survival by maintaining graft-versus-leukemia (GvL) activity while reducing GvHD. In patients undergoing allo-HSCT for hematological malignancies, mocravimod is postulated to prevent GvHD by redistributing allogeneic donor T cells to lymphoid tissues while allowing sufficient GvL in the lymphoid where malignant cell usually reside. OBJECTIVES Primary objective of the study was to assess the safety and tolerability of mocravimod in subjects undergoing allo-HSCT for hematological malignancies. Secondary objectives were to determine the pharmacokinetic profile of mocravimod and its active metabolite mocravimod-phosphate in this patient group as well as to assess GvHD-free, relapse free survival at 6 months after last treatment. STUDY DESIGN In this two-part, single- and two-arm randomized, open-label trial we evaluated the safety, tolerability, and pharmacokinetics of mocravimod in allo-HSCT recipients (clinicaltrials.gov; NCT01830010). Subjects received either 1 mg or 3 mg mocravimod/day on top of standard of care GvHD prophylaxis with either cyclosporine A/methotrexate or tacrolimus/methotrexate. RESULTS We found that the S1PR modulator mocravimod can safely be added to standard treatment regimens in patients with hematological malignancies requiring allo-HSCT. Mocravimod resulted in a significant reduction of circulating lymphocyte numbers and had no negative impact on engraftment and transplant outcomes. CONCLUSIONS Mocravimod is safe and the here presented results support a larger study to investigate efficacy in a homogeneous AML patient population undergoing allo-HSCT.
PICO Summary
Population
Adults undergoing allo-HSCT for haematological malignancies (n=23)
Intervention
3 mg mocravimod/day on top of standard of care GvHD prophylaxis: either cyclosporine A/methotrexate or tacrolimus/methotrexate (Mo3CsA, n=10) or mocravimod plus tacrolimus/MTX (Mo3Tac, n=7).
Comparison
1 mg/day mocravimod on top of standard of care GvHD prophylaxis, cyclosporine A/methotrexate (Mo1CsA, n=6)
Outcome
Mocravimod resulted in a significant reduction of circulating lymphocyte numbers and had no negative impact on engraftment and transplant outcomes.
-
2.
Allogeneic hematopoietic cell transplantation in patients with CML chronic phase in the era of third generation tyrosine kinase inhibitors: a retrospective study by the Chronic Malignancies Working Party of the EBMT
Chalandon, Y., Sbianchi, G., Gras, L., Koster, L., Apperley, J., Byrne, J., Salmenniemi, U., Sengeloev, H., Aljurf, M., Helbig, G., et al
American journal of hematology. 2022
-
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic haematopoietic cell transplantation (allo-HCT) for chronic phase (CP) CML has dramatically decreased. Imatinib was the 1(st) TKI introduced to the clinical arena, predominantly utilised in the 1(st) line setting. In cases of insufficient response, resistance or intolerance, CML patients can subsequently be treated with either a 2(nd) or 3(rd) generation TKI. Between 2006 and 2016, we analyzed the impact of the use of 1, 2 or 3 TKI prior to allo-HCT for CP CML in 904 patients. A total of 323-, 371- and 210 patients had 1, 2 or 3 TKI prior to transplant respectively; imatinib (n=778), dasatinib (n=508), nilotinib (n=353), bosutinib (n=12) and ponatinib (n=44). The majority had imatinib as first TKI (n=747, 96%). Transplants were performed in CP1, n=549, CP2, n=306, and CP3, n=49. With a median follow-up of 52 months, 5-year OS for the entire population was 64.4% (95% CI 60.9-67.9 %), PFS 50% (95% CI 46.3-53.7%), RI 28.7% (95% CI 25.4-32.0%) and NRM 21.3% (95% CI 18.3-24.2%). No difference in OS, PFS, RI or NRM was evident related to the number of TKI prior to allo-HCT or to the type of TKI (p=ns). Significant factors influencing OS and PFS were >CP1 vs CP1 and Karnofsky performance (KPS) score > 80 vs ≤80, highlighting CP1 patients undergoing allo-HCT have improved survival compared to >CP1 and the importance of careful allo-HCT candidate selection. This article is protected by copyright. All rights reserved.
PICO Summary
Population
Adults, identified from the EBMT registry who had chronic myeloid leukaemia and received tyrosine kinase inhibitor (TKI) therapy prior to first allogeneic transplant (n=904)
Intervention
1 TKI prior to transplant (n=323)
Comparison
2 TKI prior to transplant (n=371); 3 TKI prior to transplant (n=210)
Outcome
With a median follow-up of 52 months, 5-year overall survival (OS) for the entire population was 64.4% (95% CI 60.9-67.9 %), Progression free survival (PFS) 50% (95% CI 46.3-53.7%), relapse incidence (RI) 28.7% (95% CI 25.4-32.0%) and non-relapse mortality (NRM) 21.3% (95% CI 18.3-24.2%). No difference in OS, PFS, RI or NRM was evident related to the number of TKI prior to allo-HCT or to the type of TKI. Significant factors influencing OS and PFS were chronic phase (CP) >1 vs CP1 and Karnofsky performance score > 80 vs </=80.
-
3.
The added value of multi-state modelling in a randomized controlled trial: The HOVON 102 study re-analyzed
Bakunina, K., Putter, H., Versluis, J., Koster, E. A. S., van der Holt, B., Manz, M. G., Breems, D. A., Gjertsen, B. T., Cloos, J., Valk, P. J. M., et al
Cancer Medicine. 2022;11(3):630-640
Abstract
Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events.
-
4.
Conditioning intensity before allogeneic haematopoietic stem cell transplantation: a quality control audit
Gratwohl, A., Passweg, J., Baldomero, H., Orchard, K., Kröger, N., Snowden, J. A.
British journal of haematology. 2021
-
5.
Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myeloid Leukemia and Myelodysplastic Syndromes with Low/Intermediate, but not High Disease Risk Index: A CIBMTR Study: Superior DFS with MAC compared to RIC HCT in AML/MDS with low/intermediate risk DRI
Bejanyan, N., Zhang, M., Bo-Subait, K., Brunstein, C., Wang, H., Warlick, E. D., Giralt, S., Nishihori, T., Martino, R., Passweg, J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
-
-
-
Free full text
-
Editor's Choice
Abstract
Myeloablative (MAC) as compared to reduced-intensity conditioning (RIC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, disease specific risk factors in AML/MDS can further inform when MAC vs. RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the disease risk index (DRI) in 4387 adults (age 40-65 years) to identify the impact of conditioning intensity. In the low/intermediate risk DRI cohort, RIC was associated with lower non-relapse mortality (NRM) (HR=0.74, 95% CI 0.62-0.88; p<0.001), but significantly higher relapse risk (HR=1.54, 95% CI 1.35-1.76; p<0.001) and thus inferior disease-free survival (DFS) (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM (HR=0.83, 95% CI 0.68-1.00; p=0.051), and significantly higher relapse risk (HR=1.23, 95% CI 1.08-1.41; p=0.002) leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for AML/MDS with low/intermediate risk DRI, but similar benefit to RIC in high/very high risk DRI. Novel MAC regimens with less toxicity could benefit all, but more potent anti-neoplastic approaches are needed for the high/very high risk DRI group.
PICO Summary
Population
Adult patients aged 40-65 years with acute myeloid leukaemia or myelodysplastic syndrome (AML/MDS) (n=4387)
Intervention
Reduced intensity conditioning (RIC) and low/intermediate risk (n=999), RIC and high/very high risk (n=728)
Comparison
Myeloablative conditioning (MAC) and low/intermediate risk (n=1539), MAC and high/very high risk (n=1121)
Outcome
In the low/intermediate risk disease risk index (DRI) cohort, RIC was associated with lower non-relapse mortality (NRM) , but significantly higher relapse risk and thus inferior disease-free survival (DFS). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM, and significantly higher relapse risk leading to similar DFS using either RIC or MAC.
-
6.
Idelalisib exposure before allogeneic stem cell transplantation in patients with follicular lymphoma: an EBMT survey
Sellner, L., Schetelig, J., Koster, L., Choi, G., Blaise, D., Beelen, D., Schianca, F. C., Passweg, J., Schanz, U., Gyan, E., et al
Bone marrow transplantation. 2020
-
7.
Conditioning-based outcomes after allogeneic transplantation for myeloma following a prior autologous transplant (1991-2012) on behalf of EBMT CMWP
Hayden, P. J., Iacobelli, S., Perez-Simon, J. A., van Biezen, A., Minnema, M., Niittyvuopio, R., Schonland, S., Meijer, E., Blaise, D., Milpied, N., et al
European journal of haematology. 2019
Abstract
OBJECTIVES The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma - Reduced Intensity Conditioning (RIC), Non-myeloablative, Myeloablative Conditioning (MAC), or Auto-Allo SCT - on outcomes in patients who had had a prior autologous transplant. METHODS A retrospective analysis of the EBMT database (1991-2012) was performed. RESULTS A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto-Allo transplants. At a median follow-up of 54 months, the probabilities of overall survival (OS) at five years were 39% (95%CI 31-47%), 45% (95%CI 32-57%), 19% (95%CI 6-32%), and 34% (95%CI 17-51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P=0.004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR=4.1, p<0.001) but not after 2002 (HR=1.2, p=0.276). CONCLUSION From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.
-
8.
Thiotepa, busulfan and fludarabine compared to busulfan and cyclophosphamide as conditioning regimen for allogeneic stem cell transplant from matched siblings and unrelated donors for acute myeloid leukemia
Saraceni, F., Beohou, E., Labopin, M., Arcese, W., Bonifazi, F., Stepensky, P., Aljurf, M., Bruno, B., Pioltelli, P., Passweg, J., et al
American journal of hematology. 2018
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
Busulfan plus cyclophosphamide (BuCy) is the traditional conditioning regimen for allogeneic stem cell transplant (allo-SCT) for young, fit patients with acute myeloid leukemia (AML). The Thiotepa-busulfan-fludarabine (TBF) protocol has recently demonstrated promising outcome in cord blood and haploidentical SCT; however, there is limited evidence about this regimen in transplant from matched siblings (MSD) and unrelated donors (UD). We retrospectively compared outcomes of 2523 patients aged 18-50 with AML in remission, undergoing transplant from MSD or UD prepared with either TBF or BuCy conditioning. A 1:3 pair-matched analysis was performed: 146 patients receiving TBF were compared to 438 patients receiving BuCy. Relapse risk was significantly lower in the TBF compared to BuCy group (HR 0.6,p=0.02), while NRM did not differ. No significant difference was observed in LFS and OS between the two regimens. TBF was associated with a trend towards higher risk of grade III-IV aGVHD (HR 1.8,p=0.06) and inferior cGVHD (HR 0.7,p=0.04) as compared to BuCy. In patients undergoing transplant in first remission, the advantage for TBF in terms of relapse was more evident (HR 0.4, p=0.02), leading to a trend for better LFS in favor of TBF (HR 0.7,p=0.10), while OS did not differ between the two cohorts. In conclusion, TBF represents a valid myeloablative conditioning regimen providing significantly lower relapse and similar survival as compared to BuCy. Patients in first remission appear to gain the most from this protocol, as in this subgroup a tendency for better LFS was observed when compared to BuCy. This article is protected by copyright. All rights reserved.
-
9.
Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC
Malard, F., Labopin, M., Cho, C., Blaise, D., Papadopoulos, E. B., Passweg, J., O'Reilly, R., Forcade, E., Maloy, M., Volin, L., et al
Journal of hematology & oncology. 2018;11(1):127
Abstract
BACKGROUND Graft-versus-host disease (GVHD) is one of the leading causes of non-relapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HCT). METHODS We evaluated the outcomes of two well-established strategies used for GVHD prevention: in vivo T cell depletion using antithymocyte globulin (ATG) and ex vivo T cell depletion using a CD34-selected (CD34+) graft. A total of 525 adult patients (363 ATG, 162 CD34+) with intermediate or high-risk cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1) were included. Patients underwent myeloablative allo-HCT using matched related or unrelated donors. RESULTS Two-year overall survival estimate was 69.9% (95% CI, 58.5-69.4) in the ATG group and 67.6% (95% CI, 60.3-74.9) in the CD34+ group (p = 0.31). The cumulative incidence of grade II-IV acute GVHD and chronic GVHD was higher in the ATG cohort [HR 2.0 (95% CI 1.1-3.7), p = 0.02; HR 15.1 (95% CI 5.3-42.2), p < 0.0001]. Parameters associated with a lower GVHD-free relapse-free survival (GRFS) were ATG [HR 1.6 (95% CI 1.1-2.2), p = 0.006], adverse cytogenetic [HR 1.7 (95% CI 1.3-2.2), p = 0.0004], and the use of an unrelated donor [HR 1.4 (95% CI 1.0-1.9), p = 0.02]. There were no statistical differences between ATG and CD34+ in terms of relapse [HR 1.52 (95% CI 0.96-2.42), p = 0.07], non-relapse mortality [HR 0.96 (95% CI 0.54-1.74), p = 0.90], overall survival [HR 1.43 (95% CI 0.97-2.11), p = 0.07], and leukemia-free survival [HR 1.25 (95% CI 0.88-1.78), p = 0.21]. Significantly, more deaths related to infection occurred in the CD34+ group (16/52 vs. 19/112, p = 0.04). CONCLUSIONS These data suggest that both ex vivo CD34-selected and in vivo ATG T cell depletion are associated with a rather high OS and should be compared in a prospective randomized trial.
-
10.
Cyclophosphamide versus etoposide in combination with total body irradiation as conditioning regimen for adult patients with Ph-negative acute lymphoblastic leukemia undergoing allogeneic stem cell transplant: On behalf of the ALWP of the European Society for Blood and Marrow Transplantation
Czyz, A., Labopin, M., Giebel, S., Socie, G., Apperley, J., Volin, L., Remenyi, P., Yakoub-Agha, I., Orchard, K., Michallet, M., et al
American journal of hematology. 2018
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) with myeloablative conditioning based on total body irradiation (TBI) is widely used for the treatment of adults with acute lymphoblastic leukemia (ALL). TBI is most frequently administered in combination with either cyclophosphamide (Cy/TBI) or etoposide (Vp/TBI). The goal of this study was to retrospectively compare these two regimens. Adult patients with Ph-negative ALL treated with alloHCT in first or second complete remission who received Cy/TBI (n = 1346) or Vp/TBI (n = 152) conditioning were included in the analysis. In a univariate analysis, as compared to Cy/TBI, the use of Vp/TBI was associated with reduced incidence of relapse (17% vs. 30% at 5 years, P = .007), increased rate of leukemia-free survival (60% vs. 50%, P = .04), and improved "graft versus host disease (GVHD) and relapse-free survival" (GRFS, 43% vs. 33%, P = .04). No significant effect could be observed in terms of the incidence of nonrelapse mortality or acute or chronic GVHD. In a multivariate model, the use of Vp/TBI was associated with reduced risk of relapse (HR = 0.62, P = .04) while the effect on other study end-points was not significant. In conclusion, conditioning regimen based on Vp combined with TBI appears more effective for disease control than the combination of Cy with TBI for adult patients with Ph-negative ALL treated with alloHCT.