Haploidentical versus HLA-matched sibling transplantation for refractory acute leukemia undergoing sequential intensified conditioning followed by DLI: an analysis from two prospective data
Journal of hematology & oncology. 2020;13(1):18
BACKGROUND Compared with HLA-matched sibling donor (MSD) transplant, the outcomes of haploidentical donor (HID) transplant for refractory acute leukemia need to be further explored. In this study, we compared the outcomes of HID with MSD for refractory acute leukemia. PATIENTS AND METHODS This study population came from two prospective multicenter trials (NCT01883180, NCT02673008). Two hundred and seventy-eight patients with refractory acute leukemia were enrolled in this study, including 119 in HID group and 132 in MSD group. Sequential intensified conditioning was employed in all patients, and donor lymphocyte infusion (DLI) was administered in patients in the absence of active GVHD and according to minimal residual disease (MRD) from day + 60 post-transplantation for preventing relapse. RESULTS The complete remission of leukemia by day + 30 post-transplant were 94% and 93%, respectively, in HID and MSD groups (p = .802). The 1-year incidence of grades II-IV acute GVHD was 62% and 54% (p = .025), and 3-year incidence of chronic GVHD was 55% and 55% (p = .789), respectively, in two groups. HID transplant had lower incidence of first episode of MRD positivity and relapse than MSD transplant (28% vs 45%, p = .006; 26% vs 38%, p = .034). There was higher infection-related mortality in HID than MSD (8% vs 2%, p = .049) within the first 100 days' post-transplant. The 5-year overall survival was 46% and 42% (p = .832), respectively; the 5-year disease-free survival was 43% and 39% (p = .665), in HID and MSD groups, respectively. CONCLUSIONS HID transplant has lower relapse, but higher infection-related mortality and similar survival rates in refractory acute leukemia by the strategy of sequential intensified conditioning followed by DLI compared with MSD transplant.
Impact of prophylactic/preemptive donor lymphocyte infusion and intensified conditioning for relapsed/refractory leukemia: a real-world study
Science China. Life sciences. 2020
Prophylactic/preemptive donor lymphocyte infusion (p/pDLI) and intensified conditioning have shown promising results in experimental studies of refractory/relapsed acute leukemia (RRAL), but real-world data remain scarce. We conducted a multicenter, population-based analysis of 932 consecutive patients. The three-year leukemia-free survival (LFS) rates were 56% for patients receiving both p/pDLI and intensified myeloablative conditioning (MAC) (intenseMAC) and 30% for those who received neither therapy per landmark analysis. Multivariable analyses were run separately for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and p/pDLI treatment was linked to significantly higher LFS than non-DLI for both AML and ALL patients without increasing the nonrelapse mortality. IntenseMAC was associated with significantly lower relapse and higher LFS than nonintensified MAC despite higher nonrelapse mortality rates in ALL, while there was no impact of intenseMAC observed in AML. p/pDLI achieved superior outcomes in both matched-sibling donor (MSD) and haploidentical donor transplantation, while intenseMAC only influenced MSD outcomes. Data suggest that RRAL patients receiving "total therapy" by way of p/pDLI and intensified conditioning treatment have an improved chance for LFS, with p/pDLI being safer with a more extensive impact relative to intenseMAC. Patients with RRAL can tolerate both interventions and achieve a reasonable outcome.
Panobinostat and decitabine prior to donor lymphocyte infusion in allogeneic stem cell transplantation
Blood advances. 2020;4(18):4430-4437
Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score =1.5. A total of 140 poor-risk patients with AML aged 18 to 70 years were registered, and 110 proceeded to allo-HSCT. Three dose levels were evaluated for dose-limiting toxicities, including panobinostat monotherapy 20 mg at days 1, 4, 8, and 11 of a 4-week cycle (PNB mono group) and panobinostat combined with either decitabine 20 mg/m2 (PNB/DAC20 group) or decitabine 10 mg/m2 (PNB/DAC10 group) at days 1 to 3 of every 4-week cycle. After phase 1, the study continued as phase 2, focusing on completion of protocol treatment and treatment outcome. PNB mono and PNB/DAC10 were feasible, whereas PNB/DAC20 was not related to prolonged cytopenia. Sixty of 110 patients who underwent transplantation were eligible to receive their first DLI within 115 days after allo-HSCT. Grade 3 and 4 adverse events related to panobinostat and decitabine were observed in 23 (26%) of the 87 patients, and they received epigenetic therapy. Cumulative incidence of relapse was 35% (standard error [SE] 5), and overall survival and progression-free survival at 24 months were 50% (SE 5) and 49% (SE 5). Post-allo-HSCT epigenetic therapy with panobinostat alone or in combination with low-dose decitabine is feasible and is associated with a relatively low relapse rate. The trial was registered at the European Clinical Trial Registry, https://www.clinicaltrialsregister.eu, as ECT2012-003344-74.
Donor Lymphocyte Infusions After Allogeneic Transplantation: A Single-Center Experience
Clinical lymphoma, myeloma & leukemia. 2020
Allogeneic hematopoietic cell transplantation (AHCT) represents the only curative therapy for many hematological malignancies. The graft versus leukemia effect, driven by donor T cells, plays a major role in its curative potential. This effect is sometimes very evident when patients with acute myeloid leukemia and myelodysplasia relapse after AHCT and are treated with donor lymphocyte infusions (DLIs). We retrospectively reviewed the charts of 64 patients who received DLI between 2012 and 2017 in our center. The mean age of the patients was 59 years (range, 34-79). Fifty percent were male (n = 32). The mean follow-up time after AHCT was 50.17 months (range, 8-174). The indication for DLI were disease progression, mixed chimerism, minimal residual disease, and other etiologies in 43.8%, 40.7%, 14%, and 1.5% of patients, respectively. The most common diagnosis was acute leukemia, followed by multiple myeloma. Of all patients, 59.4% received a transplant from a related donor, 39% received a transplant from an unrelated donor, and 1.6% received a transplant from a haploidentical donor. Reduced-intensity conditioning AHCT was the most frequent regimen used (53%). DLI was given alone in 79.7% of patients. Prophylactic DLI was given at 30 days after transplantation in patients who received human leukocyte antigen (HLA)-matched related human stem cell transplantation (HSCT) or 45 to 60 days post-transplant in patients receiving haploidentical HSCT or HLA-matched unrelated HSCT. Patients were treated without graft versus host disease (GVHD) prophylaxis. The use of DLI after transplantation remains a feasible procedure with rates of response >60%. Moreover, DLIs are well tolerated with a GVHD rate <10% in our series. We can hypothesize that in our experience the efficacy of this strategy does not rely on the induction of GVHD.
Dose escalation prophylactic donor lymphocyte infusion after T-cell depleted matched related donor allogeneic hematopoietic cell transplantation is feasible and results in higher donor chimerism, faster immune re-constitution, and prolonged progression-free survival
Bone marrow transplantation. 2020
Prophylactic donor lymphocyte infusion (pDLI) is a potential intervention to prolong remission for patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT), however, the optimal timing and dose are unknown. We conducted a prospective trial exploring the feasibility of early withdrawal of immunosuppression (WOI) at day 60 followed by dose escalation of pDLI after alemtuzumab-based, T-cell depleted conditioning for patients with high-risk hematologic malignancies. pDLI were administered at day 75 to day 90 and again in 4-8 week intervals with receipt of up to 5 pDLI infusions. Fourty-six patients with matched-related donors (MRD) and 29 patients with matched-unrelated donors (MUD) were considered. Twenty-eight MRD patients were able to undergo WOI, 26 patients (93%) received at least 1 DLI, 16 patients (57%) received 3+, and 7 patients (25%) received 5 pDLI. Only 7 MUD patients were able to undergo WOI, 4 (57%) received at least 1 pDLI, 1 patient (14%) received 3 DLI, and no patients received all 5. Median PFS for patients on the study was 366 days. The estimated 2-year PFS and OS rates for all patients were 41% (95% CI, 32-54%) and 51% (95% CI, 41-63%) compared with 57% (95% CI, 41-77%) and 67% (95% CI, 52-86%) for patients who received at least one pDLI. In addition, MRD patients receiving pDLI had faster immune re-constitution and improved donor chimerism. Our trial proposes a novel dosage and treatment schedule for pDLI that is tolerable for patients who have received MRD allo-SCT and leads to improved outcomes.
A Retrospective Comparison of DLI and gDLI for Post-Transplant Treatment
Journal of clinical medicine. 2020;9(7)
Donor lymphocyte infusion (DLI) is used to prevent or treat haematological malignancies relapse after allogeneic stem cell transplantation (allo-SCT). Recombinant human granulocyte colony-stimulated factor primed DLI (gDLI) is derived from frozen aliquots of the peripheral blood stem cell collection. We compared the efficacy and safety of gDLI and classical DLI after allo-SCT. We excluded haploidentical allo-SCT. Initial diseases were acute myeloblastic leukaemia (n = 45), myeloma (n = 38), acute lymphoblastic leukaemia (n = 20), non-Hodgkin lymphoma (n = 10), myelodysplasia (n = 8), Hodgkin lymphoma (n = 8), chronic lymphocytic leukaemia (n = 7), chronic myeloid leukaemia (n = 2) and osteomyelofibrosis (n = 1). Indications for DLI were relapse (n = 96) or pre-emptive treatment (n = 43). Sixty-eight patients had classical DLI and 71 had gDLI. The response rate was 38.2%, the 5-year progression-free survival (PFS) rate was 38% (29-48) and the 5-year overall survival (OS) rate was 37% (29-47). Graft versus host disease rate was 46.7% and 10.1% of patients died from toxicity. There were no differences between classical DLI and gDLI in terms of response (p = 0.28), 5-year PFS (p = 0.90), 5-year OS (p. 0.50), GvHD (p = 0.86), treated GvHD (p = 0.81) and cause of mortality (p. 0.14). In conclusion, this study points out no major effectiveness or toxicity of gDLI compared to classical DLI.
The Role of Donor Lymphocyte Infusion (DLI) in Post Hematopoietic Cell Transplant (HCT) Relapse for Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) includes tyrosine kinase inhibitors (TKI) with or without donor lymphocyte infusions (DLI), however the most effective treatment strategy is unknown. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We retrospectively reviewed all patients reported to the CIBMTR registry from 2002-2014 who underwent HCT for CML and were alive 30 days post relapse. A total of 215 HCT recipients relapsed and were analyzed in the following groups 1) TKI alone n=128, 2) TKI with DLI n=48, and 3) DLI without TKI n=39. In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). Patients that received a DLI alone compared to a TKI with DLI had inferior survival HR 2.28 (95% CI 1.23-4.24; p=0.009). Those who received TKI alone had similar survival compared to those who received TKI with DLI (p=0.81). These data supports that despite use of TKI pre-transplantation, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. These data does not suggest that adding a DLI to TKI adds an improvement in OS.
Maintenance sorafenib is superior to prophylactic donor lymphocyte infusion at improving the prognosis of acute myeloid leukemia with FMS-like tyrosine kinase 3 internal tandem duplication after allogeneic hematopoietic stem cell transplantation
Bone marrow transplantation. 2020
Prophylactic donor lymphocyte infusion for relapse prevention: a meta-analysis
Japanese journal of clinical oncology. 2020
OBJECTIVE Primary disease relapse (PDR) of malignant hematologic conditions after standard hematopoietic stem cell transplant (HSCT) is one of the most challenging diseases; therefore ongoing researches are aiming at relapse prevention and minimizing the transplant-related side effects. Prophylactic donor lymphocytes (pDLI) had been proposed as a valuable strategy for PDR prevention, but early studies had been discouraging due to the limited benefit and possible association with acute graft-versus-host disease (aGVHD). Therefore, we conducted a meta-analysis to evaluate the association between pDLI use, PDR, aGVHD and OS. METHOD We performed a comprehensive literature search in MEDLINE, Cochrane library and Embase database from inception to May 2019 for studies that evaluated the association between pDLI and PDR. We conducted a random effect meta-analysis of 9 studies involving a total of 748 participants (pDLI = 398, non-pDLI = 350) and reported the pooled odd ratio (OR) for association of pDLI use, PDR, aGVHD and OS. RESULT We found a significant decreased odd of PDR in the pDLI group (pooled OR = 0.42, 95% CI 0.30-0.58, I2 = 0%), but there was no significant increased odd of aGVHD (pooled OR of 0.98, 95% CI 0.56-1.72, I2 = 0.8%). We also found that there was an increased odd of overall survival (OS) (pooled OR 3.17, 95% CI 1.85-5.45, I2 = 50.2%). CONCLUSION There are significantly decreased odd of PDR and increased odd of OS in the pDLI group compared to the control group, but there is no statistically significant increased odd of aGVHD as suggested by previous studies. We concluded that pDLI is a potentially valuable method for post-transplant PDR prevention.
CTLA4Ig Primed Donor Lymphocyte Infusion: A Novel Approach To Immunotherapy Following Haploidentical Transplantation for Advanced Leukemia
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
CTLA4Ig attenuates T cell activation by costimulation blockade, but natural killer (NK) cells are not only resistant to CTLA4Ig, they might demonstrate better anti-leukemia effect in presence of CTLA4Ig. To explore this phenomenon, we employed sequential CTLA4Ig primed donor lymphocyte infusion (DLI) following post-transplant cyclophosphamide (PTCy) based haploidentical transplantation. Thirty patients (CTLA4Ig-DLI group) with advanced leukemia received CTLA4Ig on day-1, and subsequently on days +7, +21 and +35, followed 12 hours later by DLI of 1-10x10(6) CD3(+) T cells/kg containing 0.1-3.27x10(6)/kg CD56(+) NK cells, with low dose cyclosporine for 60 days. The incidences of acute GVHD, chronic GVHD and non-relapse mortality (NRM) were 6.7%, 21% and 4.5 %, with disease progression (DP) of 23.3 % and overall survival of 79 % at 18 months. Patients without DP had significant early surge in CD56(dim)CD16(+)NK cells with lower NKG2A expression. CTLA4Ig primed DLI was associated with an upregulation of CD86 in the mature NK cells which was not witnessed with CTLA4Ig administration alone. Thus, CTLA4Ig primed DLI resulted in early proliferation of mature NK cells with cytotoxic potential enabling early institution of adoptive immunotherapy to mitigate the risk of relapse in advanced leukemia with reduced GVHD and NRM.