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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
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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.
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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.
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Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial
Löwenberg, B., Pabst, T., Maertens, J., Gradowska, P., Biemond, B. J., Spertini, O., Vellenga, E., Griskevicius, L., Tick, L. W., Jongen-Lavrencic, M., et al
Blood advances. 2021;5(4):1110-1121
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Abstract
Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.
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Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML
Lowenberg, B., Pabst, T., Maertens, J., van Norden, Y., Biemond, B. J., Schouten, H. C., Spertini, O., Vellenga, E., Graux, C., Havelange, V., et al
Blood. 2017;129(12):1636-1645
Abstract
Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS, 35% +/- 3 [standard error] at 4 years) and clofarabine treatments (38% +/- 3) but a markedly reduced relapse rate (44% +/- 3 vs 35% +/- 3) in favor of clofarabine and an increased death probability in remission (15% +/- 2 vs 22% +/- 3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic risk AML (EFS, 26% +/- 4 vs 40% +/- 5 at 4 years; Cox P = .002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% +/- 5 vs 40% +/- 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187. Copyright © 2017 by The American Society of Hematology.