Donor Lymphocyte Infusions After Allogeneic Stem Cell Transplantation in Acute Leukemia: A Survey From the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

Sperotto, Alessandra; Lorentino, Francesca; Oldani, Elena; Mammoliti, Sonia; Isola, Miriam; Picardi, Alessandra; Arcese, William; Saporiti, Giorgia; Sorasio, Roberto; Mordini, Nicola; Cavattoni, Irene; Musso, Maurizio; Borghero, Carlo; Micò, Caterina; Fanin, R; Bruno, Benedetto; Ciceri, Fabio; Bonifazi, Francesca

doi:10.3389/fonc.2020.572918

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…Traditional approaches for the treatment of post-HCT relapse include the use of donor lymphocyte infusions (DLIs) or additional chemotherapy followed by a second HCT ( 1 ). While DLI is associated with remission rates of 10% to 25%, it is also associated with a high risk of moderate to severe graft-versus-host disease (GvHD), and long-term survival with this approach remains poor ( 4 ). With the recent increase in haploidentical HCT (haplo-HCT), whereby it is less clear whether the risk of GvHD due to DLI is outweighed by its efficacy ( 5 – 8 ), the treatment of posttransplant relapse must be improved.…”

Section: Introductionmentioning

confidence: 99%

Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse

Shapiro¹,

Birch²,

Hu³

et al. 2022

Journal of Clinical Investigation

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Background Responses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell–based therapy is a promising modality to treat post-HCT relapse. Methods We initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion. Results In the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires. Conclusion Given their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies. Trial Registration ClinicalTrials.gov NCT04024761. Funding Dunkin’ Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.

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Section: Introductionmentioning

confidence: 99%

Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse

Shapiro¹,

Birch²,

Hu³

et al. 2022

Journal of Clinical Investigation

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“…More recently, the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has published the results of a survey on the use of DLIs among 34 centers in Italy between 2010 and 2015 [ 67 ].…”

Section: Treatment Of Aml Relapsed After Hsctmentioning

confidence: 99%

“…Of note, the rate of CR and stable disease after DLIs from haploidentical donors was inferior to that with DLIs from unrelated donors (33% vs. 78%; p = 0.03). The response rates to DLIs from HLA-matched-related and haploidentical donors were not different [ 67 ].…”

Section: Treatment Of Aml Relapsed After Hsctmentioning

confidence: 99%

Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives

Leotta

Condorelli

Sciortino

et al. 2022

JCM

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Allogeneic hematopoietic stem cell transplantation (HSCT) for high-risk acute myeloid leukemia (AML) represents the only curative option. Progress has been made in the last two decades in the pre-transplant induction therapies, supportive care, selection of donors and conditioning regimens that allowed to extend the HSCT to a larger number of patients, including those aged over 65 years and/or lacking an HLA-identical donor. Furthermore, improvements in the prophylaxis of the graft-versus-host disease and of infection have dramatically reduced transplant-related mortality. The relapse of AML remains the major reason for transplant failure affecting almost 40–50% of the patients. From 10 to 15 years ago to date, treatment options for AML relapsing after HSCT were limited to conventional cytotoxic chemotherapy and donor leukocyte infusions (DLI). Nowadays, novel agents and targeted therapies have enriched the therapeutic landscape. Moreover, very recently, the therapeutic landscape has been enriched by manipulated cellular products (CAR-T, CAR-CIK, CAR-NK). In light of these new perspectives, careful monitoring of minimal-residual disease (MRD) and prompt application of pre-emptive strategies in the post-transplant setting have become imperative. Herein, we review the current state of the art on monitoring, prevention and treatment of relapse of AML after HSCT with particular attention on novel agents and future directions.

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“…/kg, according donor type, mainly if given before 6 months after HCT. 31 Some authors suggest that is safe and more effective to administer G-CSF-primed DLIs early after transplant, and this kind of manipulation can provide GVL effect without significant GVHD. [32][33][34] Yan and cols.…”

Section: Prophylactic Donor Lymphocyte Infusionmentioning

confidence: 99%

Prevention and Management of Relapse of Acute Leukemia and Myelodysplastic Syndrome After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients

Tavares

Pelegrina²

2021

jbmtct

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The best way to manage acute leukemia relapse after HCT is to prevent it, buying time for GVL with immunomodulation and, if no GVHD between days +60 and + 90, prophylactic DLI can be indicate for very high or high risk patients. Short-term low dose of cyclosporine or methotrexate can add safety to pro-DLI, particularly after mismatched or unrelated transplantation. Maintenance with imatinib or dastinib, recommended for Ph-positive ALL, with sorafenib, for FLT3-ITD AML, or azacitidine, for myelodysplastic syndrome patients, can be effective in reducing relapse rates. However, target agent maintenance can add toxicity, depends on patient adherence and demands physician experience to know when is safe to start, how adjust the dose according individual tolerance after transplant and to detect undesirable drug interactions. The second step to avoid hematological relapse is preemptive approach guided by measurable residual disease or mixed chimerism. In patients off immunosuppression, chemotherapy followed by DLI is a useful strategy, and if no response, interferon alpha can be associated to enhance GVL. Target-specific agents can be start at this point either. After relapse, antigen-directed therapy with blinatumumab for CD19 ALL, inotuzumab for CD22 ALL are excellent options to induce MRD negativity and facilitate HCT. Disadvantages of new immunotherapies are: high incidence of VOD with inotuzumab and gemtuzumab; lower response in patients with high leukemia burden or concurrent extramedullary relapse; necessity of consolidation with HCT after a bridging therapy with BiTE and probably with CAR-T cell therapy also. It is important to realize that if remission after chemotherapy is associated with the development of GVHD, then there may be limited benefit (and possibly harm) in consolidating with any kind of cellular therapy. However, for patients who achieved remission without GVHD, either DLI or second transplant can be recommend. Further studies are necessary to determine at which point each strategy might yield the best results.

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Donor Lymphocyte Infusions After Allogeneic Stem Cell Transplantation in Acute Leukemia: A Survey From the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

Cited by 12 publications

References 28 publications

Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse

Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse

Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives

Prevention and Management of Relapse of Acute Leukemia and Myelodysplastic Syndrome After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients

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