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Prophylactic donor lymphocyte infusion after haploidentical hematopoietic cell transplantation and post-transplant cyclophosphamide for treatment of high-risk myeloid neoplasms in children: A retrospective study
Qi, S. S., Chen, Z., Du, Y., Sun, M., Wang, Z., Long, F., Luo, L., Xiong, H.
Pediatric blood & cancer. 2023;:e30659
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Editor's Choice
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCy) has been recommended for prevention of graft-versus-host disease (GvHD) following haploidentical hematopoietic cell transplantation (haplo-HCT) for treatment of malignant blood diseases, but disease relapse remains a problem. Although donor lymphocyte infusion (DLI) is reported to be effective for treating post-transplantation relapse, the efficacy and safety of prophylactic-DLI (pro-DLI) post haplo-HCT, and PTCy in pediatric patients with hematological malignancies is unknown. METHODS We retrospectively analyzed the outcomes of 54 pediatric patients with high-risk myeloid neoplasms who received a PTCy regimen for GvHD prophylaxis and pro-DLI after haploidentical peripheral blood stem cell transplantation. The high-risk myeloid neoplasms in this cohort included acute myeloid leukemia (n = 46) and myelodysplastic syndromes (n = 8). RESULTS Median follow-up was for 19.7 (range: 3.4-46.6) months. The cumulative incidences of grade II-IV and III-IV acute GvHD were 37.0% (95% CI: 22.7%-48.7%) and 16.7% (95% CI: 6.1%-26.0%), respectively. There were no graft-failure events, and the 2-year rate of moderate/severe chronic GvHD was 8.1% (95% CI: 0%-16.7%). The 2-year non-relapse mortality, relapse, disease-free survival, GvHD-free relapse-free survival, and overall survival rates were 5.1% (95% CI: 0%-11.7%), 16.6% (95% CI: 5.3%-26.6%), 78.9% (95% CI: 68.0%-91.6%), 62.2% (95% CI: 49.4%-78.3%), and 87.3% (95% CI: 78.3%-97.4%), respectively. CONCLUSIONS Prophylactic donor lymphocyte infusion in the setting of haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide appears to be effective and safe in pediatric patients with high-risk myeloid neoplasms.
PICO Summary
Population
Children with high-risk myeloid neoplasms undergoing haploidentical peripheral blood transplant at a single centre in China (n=54)
Intervention
Post-transplant cyclophosphamide (PTCy) regimen for GvHD prophylaxis and prophylactic donor lymphocyte infusion (pro-DLI)
Comparison
None
Outcome
Median follow-up was for 19.7 (range: 3.4-46.6) months. The cumulative incidences of grade II-IV and III-IV acute GvHD were 37.0% (95% CI: 22.7%-48.7%) and 16.7% (95% CI: 6.1%-26.0%), respectively. There were no graft-failure events, and the 2-year rate of moderate/severe chronic GvHD was 8.1% (95% CI: 0%-16.7%). The 2-year non-relapse mortality, relapse, disease-free survival, GvHD-free relapse-free survival, and overall survival rates were 5.1% (95% CI: 0%-11.7%), 16.6% (95% CI: 5.3%-26.6%), 78.9% (95% CI: 68.0%-91.6%), 62.2% (95% CI: 49.4%-78.3%), and 87.3% (95% CI: 78.3%-97.4%), respectively.
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A Multicenter Phase 2 Clinical Trial of 10-Day Decitabine, Dose-Escalated Donor Lymphocyte Infusion, and Ruxolitinib for Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Cell Transplantation
Rashidi, A., Huselton, E. J., Stefanski, H. E., DeFor, T. E., Shanley, R., Choi, J., DiPersio, J. F., Juckett, M., Miller, J. S., Weisdorf, D. J., et al
Transplantation and cellular therapy. 2023;29(5):328.e1-328.e6
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Editor's Choice
Abstract
Post-transplantation relapse of acute myeloid leukemia and myelodysplastic syndromes has a poor prognosis. Donor lymphocyte infusion (DLI) is one treatment approach. However, efficacy is limited, and toxicity, mostly in the form of acute graft-versus-host disease (GVHD), is frequent. We tested a novel approach using 10-day decitabine, dose-escalated DLI, and ruxolitinib in a multicenter phase 2 trial aimed at increasing the efficacy of DLI and reducing its toxicity. Up to four 28-day cycles were administered. The primary endpoint was 6-month overall survival (OS). Of the 14 patients who started cycle 1, 13 received 1 DLI, 6 received 2 DLIs, and 1 received 3 4 DLIs. A preplanned interim analysis after enrolling 14 patients suggested futility, and the trial was closed to accrual. The final analysis showed a 6-month OS of 36% (95% confidence interval [CI], 18 to 72), a 1-year progression-free survival of 7% (95% CI, 1% to 47%), a 6-month cumulative incidence of grade II-IV acute GVHD of 57% (95% CI, 26% to 80%), and a 1-year nonrelapse mortality of 14% (95% CI, 2% to 38%). The combined modality treatment studied in this trial was ineffective and did not reduce DLI toxicity.
PICO Summary
Population
Patients with aged 12 years or over with relapsed acute myeloid leukaemia or myelodysplastic syndromes after allogeneic transplant, from three centres in USA (n=14)
Intervention
10-day decitabine, dose-escalated donor lymphocyte infusion (DLI), and ruxolitinib, for up to four 28-day cycles (n=13)
Comparison
None
Outcome
The trial was stopped for futility after interim analysis. The final analysis showed a 6-month OS of 36% (95% confidence interval [CI], 18 to 72), a 1-year progression-free survival of 7% (95% CI, 1% to 47%), a 6-month cumulative incidence of grade II-IV acute GVHD of 57% (95% CI, 26% to 80%), and a 1-year nonrelapse mortality of 14% (95% CI, 2% to 38%).
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The infusion of ex vivo, interleukin-15 and -21-activated donor NK cells after haploidentical HCT in high-risk AML and MDS patients-a randomized trial
Lee, K. H., Yoon, S. R., Gong, J. R., Choi, E. J., Kim, H. S., Park, C. J., Yun, S. C., Park, S. Y., Jung, S. J., Kim, H., et al
Leukemia. 2023
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Editor's Choice
Abstract
Clinical effect of donor-derived natural killer cell infusion (DNKI) after HLA-haploidentical hematopoietic cell transplantation (HCT) was evaluated in high-risk myeloid malignancy in phase 2, randomized trial. Seventy-six evaluable patients (aged 21-70 years) were randomized to receive DNKI (N = 40) or not (N = 36) after haploidentical HCT. For the HCT conditioning, busulfan, fludarabine, and anti-thymocyte globulin were administered. DNKI was given twice 13 and 20 days after HCT. Four patients in the DNKI group failed to receive DNKI. In the remaining 36 patients, median DNKI doses were 1.0 × 10(8)/kg and 1.4 × 10(8)/kg on days 13 and 20, respectively. Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%, P = 0.040; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8(+) effector-memory T cells. In high-risk myeloid malignancy, DNKI after haploidentical HCT reduced disease progression. This enhanced graft-vs-leukemia effect may be related to the DNKI-induced, post-HCT expansion of NK and T cells. Clinical trial number: NCT02477787.
PICO Summary
Population
Adults 21-70 years undergoing haploidentical transplant for high-risk myeloid malignancy from a single centre in Korea (n=76)
Intervention
Two doses of donor-derived natural killer cell infusion (DNKI) on day 13 and day 20 (n=40)
Comparison
No NK cell infusion (n=36)
Outcome
Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8(+) effector-memory T cells.
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Prophylactic versus Preemptive modified donor lymphocyte infusion for high-risk acute leukemia after allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study
Yang, L., Lai, X., Yang, T., Lu, Y., Liu, L., Shi, J., Zhao, Y., Wu, Y., Chen, Y., Yu, J., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
Donor lymphocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely used in preventing post-transplant relapse. We conducted this study to compare the superiority of prophylactic modified DLI (pro-DLI) and preemptive modified DLI (pre-DLI) in patients with high-risk relapse features acute leukemia. Pro-DLI was performed in 95 patients, whereas the pre-DLI cohort included 176 patients. In the pre-DLI cohort, 42 patients relapsed without chance for pre-DLI while 95 patients remained CR without detectable minimal residual disease (MRD). Thirty-nine patients in the pre-DLI cohort became minimal MRD positive/mixed chimerism and received pre-DLI. Pro-DLI cohort had higher 3-year progression-free-survival (PFS) (63.4%vs.53.0%, P = 0.026) and overall survival (OS) (65.2% vs. 57.0%, P = 0.14) compared to the pre-DLI cohort. The 3-year cumulative incidence of relapse (CIR) was 25.3% in the pro-DLI cohort which was significantly lower than 36.7% in the pre-DLI cohort (P = 0.02). The cumulative incidence of grade III-IV aGVHD, cGVHD and non-relapse mortality were comparable between cohorts. Multivariable analysis demonstrated strong protective effect of pro-DLI on OS (hazard ratio (HR) = 0.63, P = 0.04), PFS (HR = 0.54, P = 0.005) and CIR (HR = 0.50, P = 0.005). In high-risk patients with acute leukemia, early scheduled pro-DLI rather than pre-DLI after detectable MRD would reduce post-transplant relapse and improve long-term survival.
PICO Summary
Population
Patients with high-risk acute leukaemia undergoing allogeneic transplant with myeloablative conditioning, in continuous complete remission without GvHD, from six centres in China (n=280)
Intervention
Prophylactic modified donor lymphocyte infusion (pro-DLI, n=95)
Comparison
Preemptive modified donor lymphocyte infusion (pre-DLI, n=186)
Outcome
In the pre-DLI cohort, 42 patients relapsed without chance for pre-DLI while 95 patients remained in complete remission (CR) without detectable minimal residual disease (MRD). Thirty-nine patients in the pre-DLI cohort became minimal MRD positive/mixed chimerism and received pre-DLI. Pro-DLI cohort had higher 3-year progression-free-survival (PFS) (63.4%vs.53.0%) and overall survival (OS) (65.2% vs. 57.0%) compared to the pre-DLI cohort. The 3-year cumulative incidence of relapse (CIR) was 25.3% in the pro-DLI cohort which was significantly lower than 36.7% in the pre-DLI cohort (P = 0.02). The cumulative incidence of grade III-IV aGVHD, cGVHD and non-relapse mortality were comparable between cohorts. Multivariable analysis demonstrated strong protective effect of pro-DLI on OS (hazard ratio (HR) = 0.63), PFS (HR = 0.54) and CIR (HR = 0.50). In high-risk patients with acute leukemia, early scheduled pro-DLI rather than pre-DLI after detectable MRD would reduce post-transplant relapse and improve long-term survival.
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5.
Donor lymphocyte infusions after haploidentical stem cell transplantation with PTCY: A study on behalf of the EBMT cellular therapy & immunobiology working party
Santoro, N., Mooyaart, J. E., Devillier, R., Koc, Y., Vydra, J., Castagna, L., Gülbas, Z., Martin, J. D., Araujo, M. C., Kulagin, A., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Donor lymphocyte infusion (DLI) is a treatment option to prevent or treat relapse after allogeneic hematopoietic cell transplantation (HCT). We here report data for 173 patients who received one or multiple DLIs after haploidentical-HCT with post-transplant cyclophosphamide (PTCY) at 47 EBMT centers from 2009 to 2018. Indication for DLI was: prophylactic for 59(34.3%), preemptive for 20(11.6%), and therapeutic for 93(54.1%). For the prophylactic group, the median number of DLIs was 1 (IQR:1-2.5) with a median first dose of 0.1 × 10(6) CD3+ T cell/kg, for the preemptive 2 (IQR:1-3) with 0.5 × 10(6) CD3+ T cell/kg, for the therapeutic 1 (IQR:1-3) with 1 × 10(6)CD3+ Tcell/kg, respectively. OS after first DLI was 61% (46-75%) for prophylactic, 40% (19-61%) for preemptive, and 22% (13-31%) for therapeutic. CI of II-IV aGVHD and cGVHD was 17%(7-27%) and 53% (40-67%) for the prophylactic, 20% (2-38%) and 21% (3-39%) for the preemptive, 17% (9-24%) and 24% (15-33%) for the therapeutic group, respectively. Our data show great variability in the indications and modalities of DLI across responding EBMT centers. Survival rates remain relatively low in patients with active disease. While the cumulative incidence of aGVHD appears acceptable, we showed a high incidence proportion of cGVHD in the prophylactic group, compared with preemptive and therapeutic DLI. These data should be investigated further in prospective clinical trials.
PICO Summary
Population
Adults drawn from 47 EBMT centres receiving donor lymphocyte infusions (DLIs) after haploidentical transplant with post-transplant cyclophosphamide (n=173)
Intervention
DLIs for a prophylactic indication (n=59)
Comparison
DLIs for a pre-emptive indication (n=20), or a therapeutic indication (n=93)
Outcome
For the prophylactic group, the median number of DLIs was 1 (IQR:1-2.5) with a median first dose of 0.1 × 10(6) CD3+ T cell/kg, for the pre-emptive 2 (IQR:1-3) with 0.5 × 10(6) CD3+ T cell/kg, for the therapeutic 1 (IQR:1-3) with 1 × 10(6)CD3+ Tcell/kg, respectively. Overall survival after first DLI was 61% (46-75%) for prophylactic, 40% (19-61%) for pre-emptive, and 22% (13-31%) for therapeutic. Cumulative incidence of II-IV acute GVHD and chronic GVHD was 17%(7-27%) and 53% (40-67%) for the prophylactic, 20% (2-38%) and 21% (3-39%) for the pre-emptive, 17% (9-24%) and 24% (15-33%) for the therapeutic group, respectively.
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Outcomes following DLI in patients with haematological malignancies: Donor characteristics matter
Ros-Soto, J., Snowden, J. A., Szydlo, R., Nicholson, E., Madrigal, A., Easdale, S., Potter, M., Ethell, M., Anthias, C.
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
In the context of T-cell depletion, failing to achieve full donor chimerism (FDC) entails higher risk of graft loss and disease relapse. Donor lymphocyte infusion (DLI) is an adoptive immunotherapy for mixed chimerism (MC) and/or relapsed disease following reduced intensity conditioning (RIC) allogeneic haematopoietic stem cell transplantation (HSCT). Nevertheless, little is known of factors associated with attaining FDC or disease remission. We carried out a retrospective study with 100 adult patients to identify patient and donor factors that can predict achievement of FDC and disease remission and describe complications following DLI. Indications for DLI were T-cell mixed chimerism (MC) in 61 patients and relapsed disease in 39 patients. Forty patients (65.6%) with MC attained T-Full Donor Chimerism (T-FDC), with higher responses seen in patients whose donors were female (81.5% vs 52.9%, p=0.004) and cytomegalovirus (CMV) negative (76.5% vs 52%, p=0.004). However, only patients with younger donors (<30 years old) compared to older donors (94.4% vs 53.5%, p=0.013) and those attaining unfractionated whole blood (UWB) FDC post-DLI (76.6% vs 28.6%, p<0.001) had a survival benefit, and subsequently a better GvHD-free/relapse-free survival (GRFS). Nineteen out of 39 patients (48.7%) with relapsed disease achieved remission after DLI. In this cohort, attaining T-FDC impacted favourably in disease control (76.7% vs 12.5%, p=0.012) and improved survival (45.5% vs 12.5%, p=0.007). In the whole population, the cumulative incidence of acute graft-versus-host disease (aGvHD) at day +100 post-DLI was 23%, and chronic GvHD (cGvHD) at 1-year post-DLI was 22%. In the whole population, donor age was also a determining factor for aGvHD, as patients with younger donors had a lower incidence of aGvHD (8% vs 36%, p=0.021). cGvHD was more likely to occur in patients who converted to T-FDC (34% vs 10.3%, p=0.025). Donor characteristics are increasingly considered when deciding approaches for HSCT. Donor age should be considered when planning HSCT, as well as doses and scheduling of DLI. As per our experience, this should be done alongside T/UWB chimerism to achieve the maximal clinical benefit with fewer toxicity associated. Selection of younger male donors from stem cell registries can minimise the risk of GvHD and improve survival.
PICO Summary
Population
Patients with haematological malignancies from a single UK centre undergoing allogeneic HSCT with reduced intensity conditioning (whole cohort n=584)
Intervention
Pre-emptive or therapeutic donor lymphocyte infusion (n=100)
Comparison
None
Outcome
Forty patients (65.6%) with mixed attained T-Full Donor Chimerism (T-FDC), with higher responses seen in patients whose donors were female (81.5% vs 52.9%) and cytomegalovirus (CMV) negative (76.5% vs 52%). However, only patients with younger donors (<30 years old) compared to older donors (94.4% vs 53.5%) and those attaining unfractionated whole blood (UWB) FDC post-DLI (76.6% vs 28.6%) had a survival benefit, and subsequently a better GvHD-free/relapse-free survival (GRFS). Nineteen out of 39 patients (48.7%) with relapsed disease achieved remission after DLI. In this cohort, attaining T-FDC impacted favourably in disease control (76.7% vs 12.5%) and improved survival (45.5% vs 12.5%). In the whole population, the cumulative incidence of acute graft-versus-host disease (aGvHD) at day +100 post-DLI was 23%, and chronic GvHD (cGvHD) at 1-year post-DLI was 22%. In the whole population, donor age was also a determining factor for aGvHD, as patients with younger donors had a lower incidence of aGvHD (8% vs 36%). cGvHD was more likely to occur in patients who converted to T-FDC (34% vs 10.3%).
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Safety and efficacy of the low-dose memory (CD45RA-depleted) donor lymphocyte infusion in recipients of aß T cell-depleted haploidentical grafts: results of a prospective randomized trial in high-risk childhood leukemia
Dunaikina, M., Zhekhovtsova, Z., Shelikhova, L., Glushkova, S., Nikolaev, R., Blagov, S., Khismatullina, R., Balashov, D., Kurnikova, E., Pershin, D., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
Depletion of aß T cells from the graft prevents graft-vs.-host disease (GVHD) and improves outcome of HSCT from haploidentical donors. In a randomized trial, we aimed to evaluate the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with aß T-cell depletion. A cohort of 149 children was enrolled, 76 were randomized to receive scheduled mDLI and 73 received standard care. Conditioning was based on either 12?Gy total body irradiation or treosulfan. Rabbit antithymocyte globulin was replaced by tocilizumab and abatacept. Primary end points were the incidence of acute GVHD grades II-IV and the incidence of cytomegalovirus (CMV) viremia. The incidence of grades II-IV aGVHD was 14% in the experimental arm and 12% in the control arm, p-0.8. The incidence of CMV viremia was 45% in the experimental arm and 55% in the control arm, p-0.4. Overall, in the total cohort 2-year NRM was 2%, cumulative incidence of relapse was 25%, event-free survival 71%, and overall survival 80%, without difference between the study arms. Memory DLI was associated with improved recovery of CMV-specific T-cell responses in a subcohort of CMV IgG seropositive recipients.
PICO Summary
Population
Children with high-risk leukaemia undergoing of aß T cell-depleted haploidentical transplantation (n=149)
Intervention
Scheduled mDLI: low-dose memory (CD45RA-depleted) donor lymphocytes (Experimental arm, n=76)
Comparison
Standard care (Control arm, n=73)
Outcome
The incidence of grades II-IV aGVHD was 14% in the experimental arm and 12% in the control arm. The incidence of CMV viremia was 45% in the experimental arm and 55% in the control arm. Overall, in the total cohort 2-year NRM was 2%, cumulative incidence of relapse was 25%, event-free survival 71%, and overall survival 80%, without difference between the study arms. Memory DLI was associated with improved recovery of CMV-specific T-cell responses in a subcohort of CMV IgG seropositive recipients.
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8.
Comparison of Outcomes After Second Allogeneic Hematopoietic Cell Transplantation Versus Donor Lymphocyte Infusion in Allogeneic Hematopoietic Cell Transplant Patients
Al-Shaibani, E., Bautista, R., Lipton, J. H., Kim, D. D., Viswabandya, A., Kumar, R., Lam, W., Law, A. D., Al-Shaibani, Z., Gerbitz, A., et al
Clinical lymphoma, myeloma & leukemia. 2021
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Editor's Choice
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for hematological disease however can be complicated by relapse or graft failure (GF), for which second-HCT and donor lymphocyte infusions (DLI) are performed. This study aimed to compare outcomes following the two interventions. METHODS We retrospectively investigated 89 patients with relapse or GF after first-HCT, 50 (56%) underwent second HCT and 39 (44%) received (DLI), from June 2011 to September 2020. RESULTS Median age at intervention was 55 years (19-72). Second-HCT was performed for relapse in 19 patients and for GF in 31 patients (primary GF in 11 and secondary in 20 patients), same donor was used in 25 (50%) patients. DLI was performed for relapse in 20 and for secondary GF in 19 patients. Median number of DLI administered was 2 (range 1-11). Univariate analysis demonstrated 2 year overall survival (OS) for second-HCT was superior when performed for relapse (65%) compared to GF (44%) (P = .03). For DLI patients, 2 year OS was 49% for GF and 45% for relapse patients (P = .49). For relapse as an indication, second-HCT demonstrated borderline superiority compared to DLI (P = .07). Multivariable analysis demonstrated for OS for the entire cohort demonstrated donor mismatch (HR 0.50, 95% CI 0.26%-0.94%, P = .03), KPS at time of intervention (HR 2.10, 95% CI 1.14%-3.85%, P = .02) and time from first-HCT to intervention (HR 0.51, 95% CI 0.28%-0.93%, P = .03) as significant variables. CONCLUSION Second-HCT may improve outcomes when performed for relapse post-transplant if patients achieve remission again, while DLI may be reserved for patients with active disease.
PICO Summary
Population
Patients with relapse or graft failure after first HSCT, retrospectively identified from a single centre in Canada (n=89)
Intervention
Second allogeneic transplant (second-HCT, n=50)
Comparison
Donor lymphocyte infusion (DLI, n=39)
Outcome
Median age at intervention was 55 years (19-72). Second-HCT was performed for relapse in 19 patients and for GF in 31 patients (primary GF in 11 and secondary in 20 patients), same donor was used in 25 (50%) patients. DLI was performed for relapse in 20 and for secondary GF in 19 patients. Median number of DLI administered was 2 (range 1-11). Univariate analysis demonstrated 2 year overall survival (OS) for second-HCT was superior when performed for relapse (65%) compared to GF (44%). For DLI patients, 2 year OS was 49% for GF and 45% for relapse patients. For relapse as an indication, second-HCT demonstrated borderline superiority compared to DLI. Multivariable analysis demonstrated for OS for the entire cohort demonstrated donor mismatch (HR 0.50, 95% CI 0.26%-0.94%), KPS at time of intervention (HR 2.10, 95% CI 1.14%-3.85%) and time from first-HCT to intervention (HR 0.51, 95% CI 0.28%-0.93%) as significant variables.
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Repetitively Administered Low-Dose Donor Lymphocyte Infusion for Prevention of Relapse after Allogeneic Stem Cell Transplantation in Patients with High-Risk Acute Leukemia
Tsirigotis, P., Gkirkas, K., Kitsiou, V., Chondropoulos, S., Athanassiades, T., Thomopoulos, T., Tsirogianni, A., Stamouli, M., Karagiannidi, A., Siafakas, N., et al
Cancers. 2021;13(11)
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Editor's Choice
Abstract
BACKGROUND Patients with high-risk acute leukemia have a high risk of relapse after allogeneic stem cell transplantation (allo-SCT). In an effort to reduce the relapse rate, various therapeutic methods have been implemented into clinical practice. Among them, prophylactic donor lymphocyte infusion (pro-DLI) has shown significant efficacy. However, the widespread application of pro-DLI has been restricted mostly due to concerns regarding the development of graft versus host disease (GVHD). In the present study, we tested the safety and efficacy of a novel method of prophylactic-DLI based by repetitive administration of low lymphocyte doses. METHODS DLI was administered to patients with high-risk acute leukemia at a dose of 2 × 10(6)/kg CD3-positive cells. DLI at the same dose was repeated every two months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first. Forty-four patients with a median age of 53 years (range 20-67) who underwent allo-SCT between 2011 and 2020 were included in our study. Thirty-three patients with high-risk acute myeloid leukemia (AML) and 11 with high-risk acute lymphoblastic leukemia (ALL) after allo-SCT from a matched sibling (MSD, no = 38 pts) or a matched-unrelated donor (MUD, no = 6 pts) received pro-DLI. Twenty-three patients were in CR1, all with unfavorable genetic features; 12 patients were in CR2 or beyond; and 9 patients had refractory disease at the time of transplant. Ten out of 23 patients in CR1 had detectable minimal residual disease (MRD) at the time of allo-SCT. Disease risk index (DRI) was high and intermediate in 21 and 23 patients, respectively. Conditioning was myeloablative (MAC) in 36 and reduced intensity (RIC) in 8 patients, while GVHD prophylaxis consisted of cyclosporine-A in combination with low-dose alemtuzumab in 39 patients or with low-dose MTX in 5 patients, respectively. RESULTS Thirty-five patients completed the scheduled treatment and received a median of 8 DLI doses (range 1-35). Fifteen out of 35 patients received all planned doses, while DLI was discontinued in 20 patients. Reasons for discontinuation included GVHD development in nine, donor unavailability in seven, disease relapse in three, and secondary malignancy in one patient, respectively. Nine patients were still on treatment with DLI, and they received a median of four (range 2-12) doses. Fourteen percent of patients developed transient grade-II acute GVHD while 12% developed chronic GVHD post-DLI administration. Acute GVHD was managed successfully with short course steroids, and four out of five patients with cGVHD were disease-free and off immunosuppression. With a median follow-up of 44 months (range 8-120), relapse-free (RFS) and overall survival (OS) were 74%, (95% CI, 54-87%) and 78%, (95% CI, 58-89%) respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13% (95% CI, 4-28%). The cumulative incidence of relapse in patients with intermediate and high DRI is 7% and 15%, respectively. CONCLUSION Prolonged-up to three years-low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk acute leukemia. The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells. This novel strategy deserves testing in larger cohort of patients with high-risk acute leukemia.
PICO Summary
Population
Patients with high-risk acute leukemia who underwent allo-SCT between 2011 and 2020 (n=44)
Intervention
Donor lymphocyte infusion at a dose of 2 × 10(6)/kg CD3-positive cells, every two months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first.
Comparison
None
Outcome
35 patients completed the scheduled treatment and received a median of 8 DLI doses (range 1-35). 15 out of 35 patients received all planned doses, while DLI was discontinued in 20 patients. Reasons for discontinuation included GVHD development in 9, donor unavailability in 7, disease relapse in 3, and secondary malignancy in one patient, respectively. 9 patients were still on treatment with DLI, and they received a median of 4 doses. 14% of patients developed transient grade-II acute GVHD while 12% developed chronic GVHD post-DLI administration. Acute GVHD was managed successfully with short course steroids, and 4 out of 5 patients with cGVHD were disease-free and off immunosuppression. With a median follow-up of 44 months (range 8-120), relapse-free (RFS) and overall survival (OS) were 74%, and 78%, respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13%. The cumulative incidence of relapse in patients with intermediate and high DRI is 7% and 15%, respectively.
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10.
Feasibility and Efficacy of CD45RA+ Depleted Donor Lymphocytes Infusion After Haploidentical Transplantation With Post-Transplantation Cyclophosphamide in Patients With Hematological Malignancies
Castagna, L., Valli, V., Timofeeva, I., Capizzuto, R., Bramanti, S., Mariotti, J., De Philippis, C., Sarina, B., Mannina, D., Giordano, L., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
Allogeneic stem cell transplantation from haploidentical donor using post-transplantation cyclophosphamide has been used to cure hematological diseases. Because of slow immunological reconstitution, there is an increased incidence of viral infection. The aim of our study was to prospectively evaluate the efficacy and the feasibility of a CD45RA+ depleted donor lymphocytes infusion (DLI) in terms of reduction of viral infection early after haploidentical transplantation. This a prospective single-center study. We enrolled 23 patients, of whom 19 were evaluable. Graft-versus-host disease (GVHD) prophylaxis was the same for all patients. The primary endpoint was 100-day cumulative incidence of viral infections. The primary endpoint was met, because the 100-day cumulative incidence of viral infection was 32%. The median time from transplantation to first CD45RA+ depleted DLI was 55 days (range, 46-63). 28% of patients had cytomegalovirus reactivation, no patients reactivated human herpesvirus-6; 1 patient developed BK virus related hemorrhagic cystitis. Most of the patients received the planned 3 infusions. Only 1 patient had development of grade 2 acute GVHD, and 2 patients had moderate chronic GVHD. All evaluable patients were off immunosuppressive therapy at last follow-up. The median follow-up was 12 months (range, 3-23), the 1-year overall survival and progression-free survival were 79% and 75%, respectively; the 100-day and 1-year NRM were 5% and 12%, respectively. CD45RA+ depleted DLI are feasible in patients treated with haploidentical transplantation. The toxic profile is good with a low risk for development of both acute and chronic GVHD.
PICO Summary
Population
Patients with haematological malignancies (n=23)
Intervention
Haploidentical stem cell transplantation with CD45RA+ depleted donor lymphocytes infusion (DLI)
Comparison
None
Outcome
The 100-day cumulative incidence of viral infection was 32%. The median time from transplantation to first CD45RA+ depleted DLI was 55 days (range, 46-63). 28% of patients had cytomegalovirus reactivation, no patients reactivated human herpesvirus-6; 1 patient developed BK virus related hemorrhagic cystitis. Most of the patients received the planned 3 infusions. Only 1 patient had development of grade 2 acute GVHD, and 2 patients had moderate chronic GVHD. All evaluable patients were off immunosuppressive therapy at last follow-up. The median follow-up was 12 months (range, 3-23), the 1-year overall survival and progression-free survival were 79% and 75%, respectively; the 100-day and 1-year NRM were 5% and 12%, respectively.