Safety and efficacy of the low-dose memory (CD45RA-depleted) donor lymphocyte infusion in recipients of αβ T cell-depleted haploidentical grafts: results of a prospective randomized trial in high-risk childhood leukemia

Дунайкина, М. А.; Zhekhovtsova, Zhanna; Shelikhova, Larisa; Glushkova, Svetlana; Nikolaev, Ruslan; Blagov, Sergey; Khismatullina, Rimma; Balashov, Dmitriy; Kurnikova, Elena; Pershin, Dmitriy; Muzalevskii, Yakov; Kazachenok, Alexei; Osipova, E. Yu.; Miakova, Natalia; Литвинов, Д. В.; Novichkova, Galina; Maschan, Alexei; Maschan, Michael

doi:10.1038/s41409-021-01232-x

Cited by 26 publications

(16 citation statements)

References 37 publications

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“… 41 Regarding the latter strategy, a recent randomized trial testing the efficacy of repeated infusions of naïve -depleted (CD45RA-depleted) donor lymphocyte infusion (DLI) after TCRαβ + /CD19 + -depleted haploHSCT failed to demonstrate a clinical effect in the study population. 42 On the contrary, Roy and colleagues demonstrated a reduction of TRM in T-cell depleted haploHSCT setting with the use of allo-depleted DLI as compared with TCD-HSCT alone. 43 We recently tested the use of genetically modified donor lymphocytes (transduced with the safety switch inducible Caspase-9, which can be activated in case of uncontrolled GVHD), showing feasibility and encouraging results in terms of survival, 44 although specific analyses on viral infections are ongoing.…”

Section: Discussionmentioning

confidence: 97%

TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

et al. 2022

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Several non-malignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected by primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood cell disorders or metabolic diseases, lacking a fully-matched donor or requiring urgent transplantation, underwent TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative as part of a prospective study (#NCT01810120). Median age at transplant was 3.5 years (range 0.3-16.1); median time from diagnosis to transplant was 10.5 months (2.7 for SCID patients). Primary engraftment was obtained in 51 patients, while 19 and 2 patients experienced either primary or secondary graft failure (GF), the overall incidence of this complication being 30.4%. Most GFs were observed in children with disease at risk for this complication (e.g., aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/recent infections at time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade I-II acute GvHD was 14.4% (no patient developed grade III-IV acute GVHD). Only one patient at risk developed mild chronic GvHD. With a median follow-up of 3.5 years, the 5-year probability of overall and disease-free survival was 91.4% and 86.8%, respectively. In conclusion, TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially matched relative is confirmed to be an effective treatment for children with NMDs. Prompt donor availability, low incidence of GvHD and TRM make this strategy an attractive option in NMDs patients.

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Section: Discussionmentioning

confidence: 97%

TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

et al. 2022

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“…Our previous results also demonstrated that OC-TBI appears to be a promising technique for the treatment of pediatric patients (43,44). Applying a standardization approach allowed us to homogeneously implement pediatric OC-TBI in routine clinical practice.…”

Section: Conclusion and Future Directionmentioning

confidence: 81%

Optimized Conformal Total Body Irradiation methods with Helical TomoTherapy and Elekta VMAT: Implementation, Imaging, Planning and Dose Delivery for Pediatric Patients

et al. 2022

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Optimized conformal total body irradiation (OC-TBI) is a highly conformal image guided method for irradiating the whole human body while sparing the selected organs at risk (OARs) (lungs, kidneys, lens). This study investigated the safety and feasibility of pediatric OC-TBI with the helical TomoTherapy (TomoTherapy) and volumetric modulated arc (VMAT) modalities and their implementation in routine clinical practice. This is the first study comparing the TomoTherapy and VMAT modalities in terms of treatment planning, dose delivery accuracy, and toxicity for OC-TBI in a single-center setting. The OC-TBI method with standardized dosimetric criteria was developed and implemented with TomoTherapy. The same OC-TBI approach was applied for VMAT. Standardized treatment steps, namely, positioning and immobilization, contouring, treatment planning strategy, plan evaluation, quality assurance, visualization and treatment delivery procedure were implemented for 157 patients treated with TomoTherapy and 52 patients treated with VMAT. Both modalities showed acceptable quality of the planned target volume dose coverage with simultaneous OARs sparing. The homogeneity of target irradiation was superior for TomoTherapy. Overall assessment of the OC-TBI dose delivery was performed for 30 patients treated with VMAT and 30 patients treated with TomoTherapy. The planned and delivered (sum of doses for all fractions) doses were compared for the two modalities in groups of patients with different heights. The near maximum dose values of the lungs and kidneys showed the most significant variation between the planned and delivered doses for both modalities. Differences in the patient size did not result in statistically significant differences for most of the investigated parameters in either the TomoTherapy or VMAT modality. TomoTherapy-based OC-TBI showed lower variations between planned and delivered doses, was less time-consuming and was easier to implement in routine practice than VMAT. We did not observe significant differences in acute and subacute toxicity between TomoTherapy and VMAT groups. The late toxicity from kidneys and lungs was not found during the 2.3 years follow up period. The study demonstrates that both modalities are feasible, safe and show acceptable toxicity. The standardized approaches allowed us to implement pediatric OC-TBI in routine clinical practice.

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“…Memory DLI was associated with improved CMVspecific T-cell reconstitution in a subcohort of CMV IgG seropositive recipients. Analysis of a subcohort of CMV seropositive recipients indicated remarkably better CMVspecific T-cell reconstitution on day 30 in the experimental arm (104). Compared to that of the historical cohort, restoration of CMV-specific immunity at day 30 was significantly enhanced in the prospective cohort (40% versus 25%) (105).…”

Section: Prophylactic DLImentioning

confidence: 97%

“…Prophylactic and therapeutic DLI are administered to improve posttransplant immune restoration to reduce both infectious complications and disease relapse. Michael Maschan et al investigated low-dose memory (CD45RA-depleted) donor lymphocyte infusion (mDLI) after ab T-cell depleted HSCT (103)(104)(105). The incidence of CMV reactivation was 45-50% in the experimental mDLI arm and 54-55% in the control arm.…”

Section: Prophylactic DLImentioning

confidence: 99%

CMV Infection and CMV-Specific Immune Reconstitution Following Haploidentical Stem Cell Transplantation: An Update

et al. 2021

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Haploidentical stem cell transplantation (haploSCT) has advanced to a common procedure for treating patients with hematological malignancies and immunodeficiency diseases. However, cure is seriously hampered by cytomegalovirus (CMV) infections and delayed immune reconstitution for the majority of haploidentical transplant recipients compared to HLA-matched stem cell transplantation. Three major approaches, including in vivo T-cell depletion (TCD) using antithymocyte globulin for haploSCT (in vivo TCD-haploSCT), ex vivo TCD using CD34 + positive selection for haploSCT (ex vivo TCD-haploSCT), and T-cell replete haploSCT using posttransplant cyclophosphamide (PTCy-haploSCT), are currently used worldwide. We provide an update on CMV infection and CMV-specific immune recovery in this fast-evolving field. The progress made in cellular immunotherapy of CMV infection after haploSCT is also addressed. Groundwork has been prepared for the creation of personalized avenues to enhance immune reconstitution and decrease the incidence of CMV infection after haploSCT.

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Safety and efficacy of the low-dose memory (CD45RA-depleted) donor lymphocyte infusion in recipients of αβ T cell-depleted haploidentical grafts: results of a prospective randomized trial in high-risk childhood leukemia

Cited by 26 publications

References 37 publications

TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

Optimized Conformal Total Body Irradiation methods with Helical TomoTherapy and Elekta VMAT: Implementation, Imaging, Planning and Dose Delivery for Pediatric Patients

CMV Infection and CMV-Specific Immune Reconstitution Following Haploidentical Stem Cell Transplantation: An Update

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