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Donor Lymphocyte Infusion and Molecular Monitoring for Relapsed Myelofibrosis After Hematopoietic Cell Transplantation
Gagelmann, N., Wolschke, C., Badbaran, A., Janson, D., Berger, C., Klyuchnikov, E., Ayuk, F., Fehse, B., Kröger, N.
HemaSphere. 2023;7(7):e921
Abstract
Hematopoietic cell transplantation (HCT) is a curative approach for myelofibrosis patients, but relapse is a major cause of treatment failure. We investigated the effect of donor lymphocyte infusion (DLI) in 37 patients with molecular (n = 17) or hematological relapse (n = 20) after HCT. Patients received median of 2 (range, 1-5) cumulative DLI (total of 91 infusions). Median starting dose was 1 × 10(6) cells/kg, escalated by half-log ≥6 weeks if no response nor graft-versus-host disease (GvHD) occurred. Median time to first DLI was 40 weeks for molecular relapse versus 145 weeks for hematological relapse. Overall molecular complete response (mCR) at any time was 73% (n = 27) and was significantly higher for initial molecular relapse (88%) versus hematological relapse (60%; P = 0.05). The 6-year overall survival was 77% versus 32% (P = 0.03). Acute GvHD 2-4 occurred in 22% and half of the patients achieved mCR without any GvHD. All patients who relapsed from mCR achieved after first DLI could be salvaged with subsequent DLI, showing long-term survival. No second HCT was needed for molecular relapse versus 6 for hematological relapse. This comprehensive and largest study to date suggests molecular monitoring together with DLI as standard of care and a crucial approach to achieve excellent outcomes in relapsed myelofibrosis.
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Differential effects of donor lymphocyte infusion upon treatment response and GVHD according to relapse level and donor sources in patients with myelodysplastic syndrome
Park, S., Kim, T. Y., Lee, J. H., Lee, J. Y., Min, G. J., Park, S. S., Yahng, S. A., Shin, S. H., Yoon, J. H., Lee, S. E., et al
Therapeutic advances in hematology. 2021;12:20406207211043748
Abstract
INTRODUCTION Donor lymphocyte infusion (DLI) is one of the effective options for post-transplant disease control of myelodysplastic syndrome (MDS). Its success or failure depends on the induction of antitumor immune reactions, durability of clinical responses, and severity of unwanted toxicities mainly from graft-versus-host disease (GVHD). METHODS By analyzing 61 patients receiving DLI for post-transplant MDS relapse, we assessed treatment outcomes and affecting factors, especially focusing on the level of relapse (hematological, molecular, and imminent relapse). RESULTS The response rate (42.1%, 36.4%, 72.7%), and overall survival (OS) at 2?years (27.8%, 45.5%, 70.1%) were different for each relapse level with imminent relapse group showing the most promising results. For OS, response to DLI or pre-DLI chemotherapy, and time to relapse were independent prognostic factors. Meanwhile, post-DLI GVHD and time to relapse were independently predictive for DLI response; post-DLI GVHD was predictive for DLI response, but not for OS, suggesting a potential detrimental impact of GVHD on survival. The incidence of GVHD and GVHD-related deaths were 37.7% and 10.0%, respectively, and CD3(+) cell doses triggering GVHD tended to be lower in cases with haploidentical donor or imminent relapse. CONCLUSION Despite being limited by small number of cases and its retrospective nature, this study again demonstrated the therapeutic effects of DLI in relapsed MDS, and that earlier detection and intervention at lower level relapse might possibly be associated with better results. Furthermore, we propose that tailored cell dosing schedule based on relapse level and donor source may be helpful in minimizing fatal GVHD.
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Donor-derived CIK Cell Infusion as Consolidation after Non-myeloablative Allogeneic Transplant for Myeloid Neoplasms
Narayan, R., Benjamin, J. E., Shah, O., Tian, L., Tate, K., Armstrong, R., Xie, B., Lowsky, R., Laport, G., Negrin, R. S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Non-myeloablative conditioning, such as with total lymphoid irradiation and anti-thymocyte globulin (TLI-ATG), has allowed hematopoietic allotransplantation with curative potential for older patients and those with comorbid medical conditions with myeloid neoplasms. However, early achievement of full donor chimerism (FDC) and relapse remain challenges. Cytokine induced killer (CIK) cells have been shown to have anti-tumor cytotoxicity. Infusion of donor-derived CIK cells has been studied for hematologic malignancies relapsed after allotransplant but has not been evaluated as post-transplant consolidation. In this phase II study, we prospectively studied whether a one-time infusion of 1x10(8)/kg CD3(+) donor-derived CIK cells administered between Days +21-35 after TLI-ATG conditioning, could improve FDC achievement by Day +90 and 2-year clinical outcomes in patients with myeloid neoplasms. CIK cells were infused in 31 of 44 patients treated on study and contained predominantly CD3(+)CD8(+)NKG2D(+) cells along with significantly expanded CD3(+)CD56(+) cells. Outcomes were compared to a retrospective historical cohort of 100 patients. We found that this one-time CIK infusion did not increase the rate of FDC by Day +90. On an intention-to-treat analysis, 2-year non-relapse mortality (6.8%, 95%CI: 0-14.5%), event-free survival (27.3%, 95%CI: 16.8-44.2%), and overall survival (50.6%, 95%CI: 37.5-68.2%) were similar to our historical cohort. Cumulative incidence of grade II-IV acute graft versus host disease at 1-year was 25.1% (95%CI: 12-38.2%). On univariate analysis, the presence of monosomal or complex karyotype was adversely associated with relapse-free and overall survival. Given the favorable safety profile of CIK cell infusion, strategies such as repeat dosing or genetic modification are worth exploration. This trial was registered at clinicaltrials.gov (NCT01392989).
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Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes
Naik, S., Nicholas, S. K., Martinez, C. A., Leen, A. M., Hanley, P. J., Gottschalk, S. M., Rooney, C. M., Hanson, I. C., Krance, R. A., Shpall, E. J., et al
Journal of Allergy & Clinical Immunology. 2016;137(5):1498-1505.e1
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Abstract
BACKGROUND Viral infections are a leading fatal complication for patients with primary immunodeficiencies (PIDs) who require hematopoietic stem cell transplantation (HSCT). Use of virus-specific T lymphocytes (VSTs) has been successful for the treatment and prevention of viral infections after HSCT for malignant and nonmalignant conditions. Here we describe the clinical use of VSTs in patients with PIDs at 4 centers. OBJECTIVE We sought to evaluate the safety and efficacy of VSTs for treatment of viral infections in patients with PIDs. METHODS Patients with PIDs who have received VST therapy on previous or current protocols were reviewed in aggregate. Clinical information, including transplantation details, viral infections, and use of antiviral and immunosuppressive pharmacotherapy, were evaluated. Data regarding VST production, infusions, and adverse reactions were compared. RESULTS Thirty-six patients with 12 classes of PID diagnoses received 37 VST products before or after HSCT. Twenty-six (72%) patients had received a diagnosis of infection with cytomegalovirus, EBV, adenovirus, BK virus, and/or human herpesvirus 6. Two patients were treated before HSCT because of EBV-associated lymphoproliferative disease. Partial or complete responses against targeted viruses occurred in 81% of patients overall. Time to response varied from 2 weeks to 3 months (median, 28 days). Overall survival at 6 months after therapy was 80%. Four patients had graft-versus-host disease in the 45 days after VST infusion, which in most cases was therapy responsive. CONCLUSION VSTs derived from either stem cell donors or third-party donors are likely safe and effective for the treatment of viral infections in patients with PIDs. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Management of Myelodysplastic Syndrome Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation: A Study by the French Society of Bone Marrow Transplantation and Cell Therapies
Guieze, R., Damaj, G., Pereira, B., Robin, M., Chevallier, P., Michallet, M., Vigouroux, S., Beguin, Y., Blaise, D., El Cheikh, J., et al
Biology of Blood & Marrow Transplantation. 2016;22(2):240-7
Abstract
To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively (P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P = .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P = .007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively (P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Comparison of second transplantation and donor lymphocyte infusion for donor mixed chimerism after allogeneic stem cell transplantation for nonmalignant diseases
Umeda, K., Adachi, S., Tanaka, S., Miki, M., Okada, K., Hashii, Y., Inoue, M., Cho, Y., Koh, K., Goto, H., et al
Pediatric Blood & Cancer. 2016;63(12):2221-2229
Abstract
BACKGROUND Donor mixed chimerism (MC) is an increasing problem after hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. PROCEDURE In this study, a self-administered questionnaire was used to retrospectively compare efficacy and safety in 49 patients undergoing second HSCT (n = 13) or donor lymphocyte infusion (DLI; n = 36) as treatment for MC. RESULTS The response rate to DLI of patients with secondary graft failure (GF) (25.0%) was significantly lower than that of patients without secondary GF (81.3%; P = 0.041). Among patients undergoing DLI, the rates of successful response were significantly higher in patients having at least 30% donor chimerism (94.1%) than in patients having less than 30% donor chimerism (61.1%; P = 0.041). Furthermore, the rates of successful response were significantly higher in patients receiving larger first or maximum doses of DLI. Sixteen (50.0%) of 32 patients without secondary GF attained complete chimerism after DLI. The cumulative incidence of grade II-IV acute graft-versus-host disease and cytopenia was 37.6 and 26.1%, respectively. CONCLUSIONS DLI yields promising response rates in most patients with higher donor chimerism levels, whereas second HSCT is more likely to benefit patients with lower donor chimerism levels. Copyright © 2016 Wiley Periodicals, Inc.