Venetoclax and donor lymphocyte infusion for early relapsed acute myeloid leukemia after allogeneic hematopoietic cell transplantation. A retrospective multicenter trial

Amit, Odelia; On, Yael Bar; Perez, Galit; Shargian, Liat; Yeshurun, Moshe; Ram, Ron

doi:10.1007/s00277-021-04398-y

Cited by 23 publications

(15 citation statements)

References 25 publications

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“…The three treatments in our study, venetoclax, azacitidine, and DLI, are reported to be tolerable in relapsed AML patients, both in combination with other therapies or using alone. A previous study reports that in AML patients who relapse after allo-HSCT and then treated with venetoclax plus DLI, most of the patients can tolerate the post-treatment adverse events without admissions to the hospital [22]. In addition, a phase I/II study reveals that using azacitidine and gemtuzumab ozogamicin (GO) for relapsed AML patients, post treatment, there does not exist any dose-limiting toxicities (75 mg/m 2 daily for 6 consecutive days, followed by GO 6 mg/m 2 on days 7 and 21) or hepatic sinusoidal obstructive syndrome [23].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the enrolled patients were from year 2018–2019; at that time, the clinical experience of venetoclax administration was very limited in China; therefore, we increased venetoclax dose every week (at a dose of 100 mg once a day (qd) in the first week, 200 mg qd in the second week, 300 mg qd in the third week, and a final dose at 400 mg/day as maintenance dose) to explore the experience instead of every 2 days or every 3–5 days [ 22 , 33 ]. Meanwhile, the delayed recovery of hemogram was another reason we increased the venetoclax dose slowly.…”

Section: Discussionmentioning

confidence: 99%

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Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Zhao

et al. 2021

Ann Hematol

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This study aimed to evaluate the efficacy and safety of venetoclax plus azacitidine and donor lymphocyte infusion (DLI) in treating patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-six AML patients who relapsed after allo-HSCT were enrolled and treated with venetoclax plus azacitidine and DLI. Complete remission with incomplete recovery (CRi), partial remission (PR), and objective remission rate (ORR) were assessed, and then event-free survival (EFS) and overall survival (OS) were evaluated. Besides, adverse events were documented. Additionally, whole exome sequencing was performed in bone marrow samples. The CRi, PR, and ORR rates were 26.9%, 34.6%, and 61.5%, respectively. The median time of EFS and OS was 120 (95% CI: 71–610) days and 284.5 (95% CI: 81–610) days, respectively. The most common adverse events were hematologic system adverse events including agranulocytosis, anemia, and thrombocytopenia, while the adverse events of other systems were relatively less and milder. In addition, no serious adverse events existed. Of note, there were 6 (23.1%) patients who developed GVHD. As for gene mutation, 49 mutated genes were found, which were categorized as first-, second-, and third-class mutations, and then further analysis revealed that the first-class mutations were not correlated with EFS or OS. Additionally, the most frequent mutated genes were FLT3, CEBPA, DNMT3A, KIT, KRAS, and NRAS. Venetoclax plus azacitidine and DLI is efficient and tolerant in treating patients with relapsed AML after allo-HSCT, implying this combined therapy as a potential treatment option in the studied patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Zhao

et al. 2021

Ann Hematol

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“…Grade III/IV neutropenia and thrombocytopenia occurred during 65 and 63% of treatment cycles in a prospective single-arm multicenter phase II trial, conducted by Schroeder et al, testing azacytidine plus therapeutic cDLI for AML/MDS relapse after allo-HCT (91). Similarly, venetoclax plus therapeutic mDLI led to anemia, neutropenia, and thrombocytopenia in 55, 73, and 64% of patients with relapsed AML after allo-HCT, respectively (92). However, it is important to clarify the reason for cytopenia since it could be due to other reasons than DLI itself, including primary disease, infection, GVHD, etc.…”

Section: Feasibility and Side Effects Of DLImentioning

confidence: 99%

“…Amit et al summarized 22 AML patients with post-transplant relapse who received the venetoclax/DLI combination; a total of 11 patients (50%) responded, and CR/CRi was achieved in 5 patients (23%). Meanwhile, microbiology-documented infections occurred in 8 patients (36%) and aGVHD in 4 patients (18%) (92).…”

Section: Bcl-2 Inhibitorsmentioning

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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“…These results were not confirmed by another European study, showing that relapsing patients who responded to AZA had better OS, with or without DLI [57]. More recently, the addition of Venetoclax to DLI has shown to be feasible in a small retrospective trial [58], with ORR of 50%. Regarding AZA + Venetoclax combinations, a study of the German Cooperative group concludes that toxicity remains high, and responses might be better in molecular relapse and as first salvage therapy [59].…”

Section: Post-transplant Relapsementioning

confidence: 86%

Allogeneic Stem Cell Transplantation for MDS

Villar

Robin

2021

Hemato

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Myelodysplastic syndromes are clonal disorders with morphological dysplasia, a variable degree of cytopenia and a risk of transformation to acute myeloid leukemia. Prognosis is very variable and is defined by blast count, cytopenia, cytogenetics and more recently by somatic mutations, with IPSS or revised IPSS score being the most widely used to assess disease risk. HSCT remains the only curative treatment to date, with high-risk patients obtaining the biggest benefit. However, NRM should be carefully assessed before indicating the transplant in this usually old population, where organ toxicity and comorbid conditions are to be considered. Multi-domain assessment tools, such as CGA (comprehensive geriatric assessment) and EBMT score, are useful in this context and might guide physician decisions regarding the transplant. Indeed, with the development of reduced intensity conditioning regimens, the number of patient candidates for an HSCT has increased. Regarding pre-transplant treatment, patients with a blast excess > 10% might be treated with HMAs or chemotherapy, although there are no randomized trials confirming the benefit of this approach, even when achieving a complete response. Concerning donor choice, matched sibling donors continue to be the first option, although matched unrelated donors, and more recently haploidentical donors, have proven to be valid options and should be offered in the absence of a related donor. Relapse remains the main cause of transplantation failure. MRD assessment and pre-emptive or prophylactic use of HMA or other targeted inhibitors with or without DLI are accepted strategies to reduce relapse risk, but the prognosis in this context remains dismal, and is the subject for several ongoing clinical protocols.

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Venetoclax and donor lymphocyte infusion for early relapsed acute myeloid leukemia after allogeneic hematopoietic cell transplantation. A retrospective multicenter trial

Cited by 23 publications

References 25 publications

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

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

Allogeneic Stem Cell Transplantation for MDS

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