Chemotherapy plus DLI for relapse after haploidentical HSCT: the biological characteristics of relapse influences clinical outcomes of acute leukemia patients

Sun, Wei; Mo, Xiao‐Dong; Zhang, Xiao-Hui; Xu, Lei; Wang, Yu; Yan, Chen‐Hua; Chen, Huan; Chen, Yuhong; Wang, Han; Wang, Feng-Rong; Wang, Jing‐Zhi; Liu, Kai-Yan; Huang, Xiao‐Jun

doi:10.1038/s41409-018-0406-z

Cited by 14 publications

(7 citation statements)

References 28 publications

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“…The therapeutic use of DLI is limited to T cell-replete allo-HCT protocols. Regarding the claim that DLI alone may not be sufficient to control overt relapse and that high tumor burden prior to DLI is associated with poor therapeutic response (4,5,(18)(19)(20), cytoreduction with chemotherapy prior to therapeutic DLI (chemo+DLI) is frequently used, which may improve the efficacy and exert potential immunomodulatory effects (21,22). Consistently, chemotherapy plus DLI has been found to be superior to DLI (23) or chemotherapy alone (13) in inducing disease remission after post-HCT AML hematological relapse.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Yang

Yuan

et al. 2022

Front. Oncol.

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Donor lymphocyte infusion (DLI) is a key strategy for the treatment of AML relapse after allogeneic hematopoietic cell transplantation (allo-HCT) and has been used for either prophylactic, pre-emptive, or therapeutic purposes. However, the prognosis of these patients remains dismal even after DLI infusion (2-year overall survival, ~25%), and the efficacy is achieved at the cost of toxicities such as graft-versus-host (GVH) disease. Attempts to optimize DLI efficacy and safety, such as dose/timing modification and the use of cytoreduction, before DLI have been performed previously. Recently, a great number of novel targeted and immunomodulatory agents have emerged. Some of them, such as hypomethylating agents, FLT3 and Bcl-2 inhibitors, have been used in combination with DLI, aiming to enhance the graft-versus-leukemia effect. Moreover, manipulation of the DLI graft through cell selection (e.g., donor NK cells) or cell engineering (donor CAR-T cells) has shown potentially superior anti-tumor effects but less GVH effect than conventional DLI in clinical trials. This review summarizes the recent advances on the use of DLI for the prophylaxis/treatment of AML relapse and discusses future strategies which may further improve the treatment efficacy.

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Section: Introductionmentioning

confidence: 99%

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Yang

Yuan

et al. 2022

Front. Oncol.

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“…DLI has been widely used for the prevention and treatment of leukemia relapse post-transplant, but it is associated with a high incidence and mortality of GVHD [29][30][31][32]. The efficacy of DLI alone in relapsed acute leukemia is reported to be very poor, and chemotherapy plus DLI could improve the outcomes compared with chemotherapy or DLI alone [33,34]. Recent studies suggested that immunotherapy treatment such as DLI should preferably be started in leukemia patients with relatively low tumor burden [34,35].…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of DLI alone in relapsed acute leukemia is reported to be very poor, and chemotherapy plus DLI could improve the outcomes compared with chemotherapy or DLI alone [33,34]. Recent studies suggested that immunotherapy treatment such as DLI should preferably be started in leukemia patients with relatively low tumor burden [34,35]. Meanwhile, given that the prognosis of these relapsed patients was dismal, DLI was administered at the following day of chemotherapy end for patients without severe GVHD at relapse in all eligible patients.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib Therapy Is Associated with Improved Outcomes for FMS-like Tyrosine Kinase 3 Internal Tandem Duplication Acute Myeloid Leukemia Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation

Xuan

Wang

Chen

et al. 2019

Biology of Blood and Marrow Transplantation

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The optimal therapy for patients with acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) who relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. In this study we retrospectively evaluated the efficacy of sorafenib combined with other therapeutic strategies as salvage therapy for these patients. Eighty-three AML patients with FLT3-ITD relapsing after allo-HSCT were enrolled in this study. Fifty-three patients received salvage therapy containing sorafenib and 30 patients did not. Salvage therapy containing sorafenib was superior to that without sorafenib with respect to complete remission rates, overall survival (OS), and progression-free survival (PFS) (66.0% versus 30.0%, 46.8% versus 20.0%, and 44.9% versus 16.7%, respectively; P = .002, P = .003, and P = .001). Further subgroup analysis revealed that the OS and PFS of patients who received sorafenib combined with chemotherapy followed by donor lymphocyte infusion (DLI) were superior to those receiving other therapeutic regimens, including sorafenib combined with chemotherapy, chemotherapy followed by DLI, and monochemotherapy (P = .003, P < .001). Multivariate analysis revealed that salvage therapy including sorafenib was the only protective factor for longer OS (P = .035; hazard ratio [HR], .526); salvage therapy including sorafenib and DLI were the protective factors for longer PFS (P = .011, HR, .423; P = .019, HR, .508). Our data suggest that sorafenib therapy is associated with improved outcomes for FLT3-ITD AML relapsing after allo-HSCT, and whether sorafenib combined with chemotherapy followed by DLI reveals an optimal efficacy merits further study.

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“…Of 86 patients, 20 developed Grade III-IV aGVHD and 41 developed cGHVD. NRM was 10.3%, and 62% of patients achieved a CR after chemo-DLI of which 50% experienced re-relapse at a median duration of 92 days (212). A modified GIAC backbone was also utilized to assess preemptive DLI at a median of 77 days post haplo-HCT in high risk patients to prevent relapse.…”

Section: Haploidentical Donor Lymphocyte Infusionsmentioning

confidence: 99%

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

et al. 2020

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Hematopoietic stem cell transplantation from a haploidentical donor is increasingly used and has become a standard donor option for patients lacking an appropriately matched sibling or unrelated donor. Historically, prohibitive immunological barriers resulting from the high degree of HLA-mismatch included graft-vs.-host disease (GVHD) and graft failure. These were overcome with increasingly sophisticated strategies to manipulate the sensitive balance between donor and recipient immune cells. Three different approaches are currently in clinical use: (a) ex vivo T-cell depletion resulting in grafts with defined immune cell content (b) extensive immunosuppression with a T-cell replete graft consisting of G-CSF primed bone marrow and PBSC (GIAC) (c) T-cell replete grafts with post-transplant cyclophosphamide (PTCy). Intriguing studies have recently elucidated the immunologic mechanisms by which PTCy prevents GVHD. Each approach uniquely affects post-transplant immune reconstitution which is critical for the control of post-transplant infections and relapse. NK-cells play a key role in haplo-HCT since they do not mediate GVHD but can successfully mediate a graft-vs.-leukemia effect. This effect is in part regulated by KIR receptors that inhibit NK cell cytotoxic function when binding to the appropriate HLA-class I ligands. In the context of an HLA-class I mismatch in haplo-HCT, lack of inhibition can contribute to NK-cell alloreactivity leading to enhanced anti-leukemic effect. Emerging work reveals immune evasion phenomena such as copy-neutral loss of heterozygosity of the incompatible HLA alleles as one of the major mechanisms of relapse. Relapse and infectious complications remain the leading causes impacting overall survival and are central to scientific advances seeking to improve haplo-HCT. Given that haploidentical donors can typically be readily approached to collect additional stem-or immune cells for the recipient, haplo-HCT represents a unique platform for cell-and immune-based therapies aimed at further reducing relapse and infections. The rapid advancements in our understanding of the immunobiology of haplo-HCT are therefore poised to lead to iterative innovations resulting in further improvement of outcomes with this compelling transplant modality.

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Chemotherapy plus DLI for relapse after haploidentical HSCT: the biological characteristics of relapse influences clinical outcomes of acute leukemia patients

Cited by 14 publications

References 28 publications

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Sorafenib Therapy Is Associated with Improved Outcomes for FMS-like Tyrosine Kinase 3 Internal Tandem Duplication Acute Myeloid Leukemia Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

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